Modulators of cystic fibrosis transmembrane conductance regulator

Abstract

The present disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) having core structure (I); pharmaceutical compositions containing at least one such modulator; methods of using such modulators and pharmaceutical compositions to treat CFTR-mediated diseases, including cystic fibrosis; combination pharmaceutical compositions and combination therapies; and processes and intermediates for making such modulators.

Description

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

[0002] This disclosure relates to modulators of cystic fibrosis transmembrane conduction regulators (CFTR); pharmaceutical compositions containing said modulators; methods of treating CFTR-mediated diseases involving cystic fibrosis using such modulators; combination therapies and combination pharmaceutical compositions using such modulators; and methods and intermediates for preparing such modulators.

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

[0004] In patients with cystic fibrosis (CF), endogenously expressed CFTR mutations in the respiratory epithelium lead to reduced apical anion secretion, resulting in an imbalance of ion and fluid transport. This reduced anion transport causes increased mucus accumulation in the lungs, accompanied by microbial infections, ultimately leading to death in CF patients. In addition to respiratory problems, CF patients often suffer from gastrointestinal issues and pancreatic insufficiency, which can also be fatal if left untreated. Furthermore, most men with cystic fibrosis are infertile, and women with cystic fibrosis experience reduced fertility.

[0005] Sequence analysis of the CFTR gene has revealed a variety of disease-causing mutations (Cutting, GR 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 in the CF gene have been identified; currently, the CFTR2 database contains information on only 432 of these identified mutations, with sufficient evidence to define 352 mutations as pathogenic. The most common pathogenic 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 results in the mutant protein being unable to leave the endoplasmic reticulum (ER) and be transported to the plasma membrane. Consequently, the number of CFTR channels present in the membrane for anion transport is significantly lower than that observed in cells expressing wild-type CFTR, i.e., those without the mutant CFTR. In addition to impaired transport, the mutation results in defective channel gating. The reduced number of channels in the membrane, along with the defective gating, leads to reduced anion and fluid transport across the epithelium (Quinton, PM (1990), FASEB J.4:2709-2727). Channels defective due to the F508del mutation remain functional, although less so than wild-type CFTR channels (Dalemans et al. (1991), Nature Lond. 354:526-528; Pasyk and Foskett (1995), J. Cell. Biochem. 270:12347-50). Besides F508del, other pathogenic mutations in CFTR that lead to defective transport, synthesis, and / or channel gating can be upregulated or downregulated to alter anion secretion and change 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, where it regulates transmembrane anion flux and the activity of other ion channels and proteins. In epithelial cells, normal CFTR function is crucial for maintaining electrolyte transport throughout the body, including respiratory and digestive tissues. CFTR consists of a 1480-amino acid protein encoding a tandem repeat sequence of transmembrane domains, each containing six transmembrane helices and a nucleotide-binding domain. Two transmembrane domains are linked to multiple phosphorylation sites via a large polarity regulation (R) domain, thereby regulating channel activity and cellular transport.

[0008] Chloride ion transport is facilitated by ENaC and CFTR present on the apical membrane and Na+ expressed on the outer surface of the cell basolateral surface. + -K + The coordinated activity of ATPase pumps and Cl- channels is involved. Secondary active transport of chloride ions from the luminal side leads to intracellular chloride ion accumulation, which can then be transported via Cl- channels. - The channel passively leaves the cell, thus leading to the transport of mediators. Na + / 2Cl - / K + Cotransporter protein, Na + -K + -ATPase pump and basolateral membrane on the basolateral surface K +The channels and the arrangement of CFTRs on the luminal side coordinate chloride ion secretion via the CFTRs on the luminal side. Since water itself may not be able to actively transport, its transepithelial flow depends on the small transepithelial osmotic gradient generated by the large flow of sodium and chloride ions.

[0009] Several CFTR-modulating compounds have recently been identified. However, there remains a need for compounds that can treat or alleviate cystic fibrosis and other CFTR-mediated diseases, especially the more severe forms of these diseases.

[0010] One aspect of this disclosure provides novel compounds comprising at least one compound of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0011] Formula I covers compounds within the following structural ranges:

[0012]

[0013] And includes tautomers of those compounds, deuterated derivatives of any of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein:

[0014] Ring A is selected from:

[0015] ■C6-C 10 Aryl,

[0016] ■C3-C 10 cycloalkyl,

[0017] ■3 to 10-membered heterocyclic groups, and

[0018] ■5 to 10-membered heteroaryl groups;

[0019] Ring B is selected from:

[0020] ■C6-C 10 Aryl,

[0021] ■C3-C 10 cycloalkyl,

[0022] ■3 to 10-membered heterocyclic groups, and

[0023] ■5 to 10-membered heteroaryl groups;

[0024] V is selected from O and NH;

[0025] W 1 Selected from N and CH;

[0026] W 2 Selected from N and CH; condition is W 1 and W 2 At least one of them is N;

[0027] Z is selected from O and NR. ZN and C(R) ZC )2, the condition is when L 2 When Z does not exist, Z is C(R) ZC )2;

[0028] Each L 1 Independently selected from C(R) L1 )2;

[0029] Each L 2 Independently selected from C(R) L2 )2;

[0030] Each R 3 Selected independently from:

[0031] ■ Halogen,

[0032] ■C1-C6 alkyl groups,

[0033] ■C1-C6 alkoxy groups,

[0034] ■C3-C 10 cycloalkyl,

[0035] ■ C6-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 Aryl, and

[0036] ■3 to 10-membered heterocyclic groups;

[0037] R 4 Selected from hydrogen and C1-C6 alkyl groups;

[0038] Each R 5 Selected independently from:

[0039] ■ Hydrogen,

[0040] ■ Halogen,

[0041] ■Hydroxy

[0042] ■N(R N )2,

[0043] ■-SO-Me,

[0044] ■-CH=C(R LC )2, where two R LC Together they form C3-C 10 cycloalkyl,

[0045] ■ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0046] ○Hydroxy group,

[0047] ○Optionally selected by 1-3 independently chosen C1-C6 alkoxy groups and C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[0048] ○C3-C 10 cycloalkyl,

[0049] ○Optionally substituted with 1-3 groups independently selected from C1-C6 alkyl and C1-C6 alkoxy groups -(O) 0-1 -(C6-C 10 Aryl),

[0050] ○3 to 10-membered heterocyclic groups, and

[0051] ○N(R N )2,

[0052] ■ C1-C6 alkoxy groups optionally substituted with 1-3 independently selected groups from the following:

[0053] ○ Halogen,

[0054] ○C6-C 10 Aryl, and

[0055] ○ C3-C substituted with 1-3 independently selected C1-C6 fluoroalkyl groups 10 cycloalkyl,

[0056] ■C1-C6 fluoroalkyl groups,

[0057] ■C3-C 10 cycloalkyl,

[0058] ■C6-C 10 Aryl, and

[0059] ■3 to 10-membered heterocyclic groups;

[0060] R ZN Selected from:

[0061] ■ Hydrogen,

[0062] ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0063] ○Hydroxy group,

[0064] ○Oxygenation,

[0065] ○Cyano

[0066] ○ C1-C6 alkoxy groups optionally substituted with 1-3 independently selected halogen and C1-C6 alkoxy groups,

[0067] ○N(R N )2,

[0068] ○SO2Me,

[0069] ○ C3-C cells optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[0070] ◆Hydroxy group,

[0071] ◆Optionally composed of 1-3 independently selected hydroxyl, oxo, C1-C6 alkoxy, C6-C 10 Aryl and N(R) N C1-C6 alkyl groups substituted with 2 groups,

[0072] ◆C1-C6 fluoroalkyl groups,

[0073] ◆C1-C6 alkoxy groups, and

[0074] ◆COOH,

[0075] ◆N(R N )2,

[0076] ◆C6-C 10 Aryl, and

[0077] ◆Optionally substituted with 1-3 independently selected oxo and C1-C6 alkyl groups, 3- to 10-membered heterocyclic groups,

[0078] ○ C6-C cells optionally substituted with 1-3 independently selected groups from the following 10 Aryl:

[0079] ◆Halogen,

[0080] ◆Hydroxy group,

[0081] ◆Cyano

[0082] ◆SiMe3,

[0083] ◆SO2Me,

[0084] ◆SF5,

[0085] ◆N(R N )2,

[0086] ◆P(O)Me2,

[0087] ◆Optionally substituted with 1-3 independently selected C1-C6 fluoroalkyl groups -(O) 0-1-(C3-C 10 cycloalkyl),

[0088] ◆Optionally composed of 1-3 independently selected hydroxyl, oxo, C1-C6 alkoxy, 5- to 10-membered heteroaryl, SO2Me and N(R) N C1-C6 alkyl groups substituted with 2 groups,

[0089] ◆Optionally selected by 1-3 independently chosen from hydroxyl, oxo, N(R) N )2 and C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[0090] ◆C1-C6 fluoroalkyl groups,

[0091] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, 3- to 10-membered heterocyclic groups,

[0092] ◆-(O) 0-1 -(C6-C 10 Aryl), and

[0093] ◆Optionally coated with hydroxyl, oxidized, N(R) N 2. C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl and C3-C 10 Cycloalkyl-substituted -(O) 0-1 -(5 to 10 heteroaryl),

[0094] ○Optionally substituted with 1 to 4 independently selected groups from the following 3- to 10-membered heterocyclic groups:

[0095] ◆Hydroxy group,

[0096] ◆Oxygenation,

[0097] ◆N(R N )2,

[0098] ◆C1-C6 alkyl groups (optionally substituted with 1-3 independently selected oxo and C1-C6 alkoxy groups),

[0099] ◆C1-C6 alkoxy groups,

[0100] ◆C1-C6 fluoroalkyl groups,

[0101] ◆C6-C cells optionally substituted with 1-3 independently selected halogen groups 10 Aryl, and

[0102] ◆5 to 10 aryl compounds, and

[0103] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0104] ◆Hydroxy group,

[0105] ◆Cyano

[0106] ◆Oxygenation,

[0107] ◆Halogen,

[0108] ◆B(OH)2,

[0109] ◆N(R N )2,

[0110] ◆Optionally substituted with 1-3 independently selected hydroxyl, oxo, C1-C6 alkoxy (optionally substituted with 1-3 -SiMe3) and N(R) N C1-C6 alkyl groups substituted with 2 groups,

[0111] ◆Optionally composed of 1-3 independently selected from hydroxyl, oxo, C1-C6 alkoxy, N(R) N )2 and C3-C 10 C1-C6 alkoxy groups substituted with cycloalkyl groups,

[0112] ◆C1-C6 fluoroalkyl groups,

[0113] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[0114] ◆-(O) 0-1 -(C6-C 10 Aryl),

[0115] ◆Optionally selected by 1-4 independently chosen from hydroxyl, oxo, halogen, cyano, N(R) N 2. C1-C6 alkyl groups (optionally surrounded by 1-3 independently selected from hydroxyl, oxo, N(R) groups) N -(O) groups substituted with C1-C6 alkoxy groups, C1-C6 alkoxy groups, C1-C6 fluoroalkyl groups, or 3- to 10-membered heterocyclic groups (optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl groups). 0-1 -(3 to 10-membered heterocyclic groups), and

[0116] ◆Optionally composed of 1-4 independently selected C1-C6 alkyl groups and C3-C 10 Cycloalkyl groups substituted with 5 to 10-membered heteroaryl groups,

[0117] ■C1-C6 fluoroalkyl groups,

[0118] ■ C3-C, optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[0119] ○Hydroxy group,

[0120] ○Oxygenation,

[0121] ○ Halogen,

[0122] ○Cyano

[0123] ○N(R N )2,

[0124] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0125] ◆Hydroxy group,

[0126] ◆Oxygenation,

[0127] ◆N(R N )2,

[0128] ◆C1-C6 alkoxy groups, and

[0129] ◆C6-C 10 Aryl,

[0130] ○Optionally selected by 1-3 independent elements chosen from halogen, oxidative, C6-C 10 Aryl and N(R) N The C1-C6 alkoxy group substituted with )2,

[0131] ○ Halogen,

[0132] ○C3-C 10 cycloalkyl,

[0133] ○Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, and

[0134] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0135] ◆Hydroxy group,

[0136] ◆Cyano

[0137] ◆Oxygenation,

[0138] ◆Halogen,

[0139] ◆N(R N )2,

[0140] ◆Optionally composed of 1-3 independently selected hydroxyl, oxo, C1-C6 alkoxy, and N(R) groups. NC1-C6 alkyl groups substituted with 2 groups,

[0141] ◆Optionally composed of 1-3 independently selected hydroxyl, C1-C6 alkoxy, N(R) N )2 and C3-C 10 C1-C6 alkoxy groups substituted with cycloalkyl groups,

[0142] ◆C1-C6 fluoroalkyl groups,

[0143] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[0144] ◆C6-C 10 Aryl, and

[0145] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, 3- to 10-membered heterocyclic groups,

[0146] ■C6-C 10 Aryl,

[0147] ■Optionally substituted with 1 to 3 independently selected groups from the following: 3- to 10-membered heterocyclic groups

[0148] ○Oxygenation,

[0149] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0150] ◆Oxygenation,

[0151] ◆Hydroxy group,

[0152] ◆N(R N )2,

[0153] ◆Optionally selected by 1-3 independent elements chosen from halogens and C6-C 10 The C1-C6 alkoxy group substituted with the aryl group, and

[0154] ◆-(O) 0-1 -(C3-C 10 cycloalkyl),

[0155] ○C1-C6 fluoroalkyl,

[0156] ○ C3-C groups optionally substituted with 1-3 independently selected halogen groups 10 cycloalkyl groups, and

[0157] ○3 to 10-membered heterocyclic groups,

[0158] ■ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0159] ○ Halogen,

[0160] ○Optionally selected by 1-3 independently chosen from oxo, C1-C6 alkoxy and N(R) N C1-C6 alkyl groups substituted with )2, and

[0161] ○Optionally composed of 1-3 independently selected C1-C6 alkyl groups (optionally composed of 1-3 selected oxo, C1-C6 alkoxy, and C6-C... 10 3 to 10-membered heterocyclic groups substituted with aryl groups

[0162] ■R F ;

[0163] Each R ZC Selected independently from:

[0164] ■ Hydrogen,

[0165] ■Optionally selected from 1-3 independent choices of C6-C 10 C1-C6 alkyl groups substituted with aryl groups (optionally replaced by 1-3 independently selected C1-C6 alkyl groups),

[0166] ■ C6-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 Aryl, and

[0167] ■R F ;

[0168] Or two Rs ZC Together they form an oxo group;

[0169] Each R L1 Selected independently from:

[0170] ■ Hydrogen,

[0171] ■N(R N )2, the condition is two N(R) N )2 does not combine with the same carbon atom.

[0172] ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0173] ○ Halogen,

[0174] ○Hydroxy group,

[0175] ○Oxygenation,

[0176] ○N(R N )2,

[0177] ○Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[0178] ○ C3-C substituted with 1-3 groups independently selected from halogens and C1-C6 fluoroalkyl groups 10 cycloalkyl,

[0179] ○ C6-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 Aryl, and

[0180] ○ A 3- to 10-membered heterocyclic group optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl groups (optionally substituted with 1 to 3 groups independently selected from hydroxyl and oxo groups),

[0181] ■C3-C 10 cycloalkyl,

[0182] ■ C6-C cells optionally substituted with 1-4 independently selected groups from the following 10 Aryl:

[0183] ○ Halogen,

[0184] ○Cyano

[0185] ○SiMe3,

[0186] ○POMe2,

[0187] ○ C1-C7 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0188] ◆Hydroxy group,

[0189] ◆Oxygenation,

[0190] ◆Cyano

[0191] ◆SiMe3,

[0192] ◆N(R N )2, and

[0193] ◆C3-C2 substituted with 1-3 independently selected C1-C6 fluoroalkyl groups 10 cycloalkyl,

[0194] ○ C1-C6 alkoxy groups optionally substituted with 1-3 independently selected groups from the following:

[0195] ◆C3-C2 substituted with 1-3 independently selected C1-C6 fluoroalkyl groups 10 cycloalkyl groups, and

[0196] ◆C1-C6 alkoxy groups,

[0197] ○C1-C6 fluoroalkyl,

[0198] ○ C3-C2 groups optionally substituted with 1-3 groups independently selected from C1-C6 alkyl and C1-C6 fluoroalkyl groups 10 cycloalkyl,

[0199] ○C6-C 10 Aryl,

[0200] ○Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, and

[0201] ○5 to 10 yuan of mixed aromatic compounds,

[0202] ■Optionally substituted with 1 to 3 independently selected groups from the following: 3- to 10-membered heterocyclic groups

[0203] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0204] ◆Oxygenation, and

[0205] ◆C1-C6 alkoxy groups,

[0206] ■ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0207] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0208] ◆C3-C2 substituted with 1-3 independently selected C1-C6 fluoroalkyl groups 10 cycloalkyl groups, and

[0209] ○ C6-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 Aryl, and

[0210] ■R F ;

[0211] Or two R atoms on the same carbon atom L1 Together they form an oxo group;

[0212] Each R L2 Independently selected from hydrogen and R F Or two R atoms on the same carbon atom L2 Together they form an oxo group; provided that at least one R L1 Or R L2 It is R F ;

[0213] Each R N Selected independently from:

[0214] ■ Hydrogen,

[0215] ■ C1-C8 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0216] ○Oxygenation,

[0217] ○ Halogen,

[0218] ○Hydroxy group,

[0219] ○NH2,

[0220] ○NHMe,

[0221] ○NMe2,

[0222] ○Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[0223] ○-(O) 0-1 -(C3-C 10 cycloalkyl),

[0224] ○ C6-C alkyl groups optionally substituted with 1-3 independently selected groups selected from halogens and C1-C6 alkyl groups 10 Aryl, and

[0225] ○Optionally substituted with 1-4 independently selected oxo and C1-C6 alkyl groups, and

[0226] ○ 5- to 14-membered heteroaryl groups optionally substituted by 1 to 4 independently selected oxo and C1-C6 alkyl groups,

[0227] ■ C3-C, optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[0228] ○Hydroxy group,

[0229] ○NH2, and

[0230] ○NHMe, and

[0231] ○ C1-C6 alkyl groups optionally substituted with 1-3 independently selected groups selected from hydroxyl groups,

[0232] ■C6-C 10 Aryl, and

[0233] ■3 to 10-membered heterocyclic groups;

[0234] Or two R atoms on the same nitrogen atomN Together with the nitrogen it binds to, it forms a 3- to 10-membered heterocyclic group, optionally substituted with 1 to 3 groups selected from the following:

[0235] ■Hydroxy

[0236] ■Oxytochemicals

[0237] ■Cyano

[0238] ■Optionally selected by 1-3 independently chosen from oxo, hydroxyl, C1-C6 alkoxy and N(R) N2 )2 substituted C1-C6 alkyl groups, wherein each R N2 Independently selected from hydrogen and C1-C6 alkyl groups,

[0239] ■C1-C6 alkoxy groups, and

[0240] ■C1-C6 fluoroalkyl groups;

[0241] Or an R 4 And an R L1 Together they form C6-C8 alkylene groups;

[0242] Two Rs F Together with the atoms they are bonded to, they form groups selected from the following:

[0243] ■ C3-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 cycloalkyl,

[0244] ■ C6-C, optionally substituted by 1-3 independently selected groups from the following 10 Aryl:

[0245] ○ Halogen,

[0246] ○C1-C6 alkyl,

[0247] ○N(R N )2, and

[0248] ○ A 3- to 10-membered heterocyclic group optionally substituted by 1 to 3 independently selected groups chosen from hydroxyl groups.

[0249] ■ 3- to 11-membered heterocyclic groups optionally substituted by 1 to 3 independently selected groups from the following:

[0250] ○Oxygenation,

[0251] ○N(R N )2,

[0252] ○ C1-C9 alkyl groups optionally substituted by 1-4 independently selected groups from the following:

[0253] ◆Oxygenation,

[0254] ◆Halogen,

[0255] ◆Hydroxy group,

[0256] ◆N(R N )2,

[0257] ◆-SO2-(C1-C6 alkyl),

[0258] ◆Optionally selected by 1-3 independent elements chosen from halogens, C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[0259] ◆Optionally substituted with 1-3 groups independently selected from hydroxyl, halogen, cyano, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C1-C6 alkoxy), C1-C6 alkoxy (optionally substituted with 1-3 groups independently selected from C6-C6). 10 Aryl group substitution), -(O) 0-1 -(C1-C6 fluoroalkyl) and C6-C 10 The C6-C group substituted with an aryl group (optionally replaced by 1-3 groups independently selected from C1-C6 alkoxy groups). 10 Aryl,

[0260] ◆Optionally selected by 1-4 independently chosen from hydroxyl, halogen, N(R) N 2. C1-C6 alkyl groups (optionally substituted with 1-3 groups independently selected from oxo, hydroxyl, and C1-C6 alkoxy groups), C1-C6 fluoroalkyl groups, and C6-C6 alkyl groups. 10 The -(O) group substituted by the aryl group 0-1 -(C3-C 10 cycloalkyl),

[0261] ◆Optionally, it is composed of 1-3 independently selected oxo, C1-C6 alkyl groups (optionally, it is composed of 1-3 independently selected C6-C6 alkyl groups). 10 Aryl groups (optionally substituted with 1-3 independently selected halogen groups), C1-C6 alkoxy groups, C3-C6 alkoxy groups, C4-C6 alkoxy groups, C5-C6 alkoxy groups, C6-C6 alkoxy groups, C6-C6 alkoxy groups, C7 ... 10 cycloalkyl and R N substituted 3- to 10-membered heterocyclic groups,

[0262] ◆Optionally selected from 1-3 independent selections from C6-C 10 -O- (5 to 12-membered heteroaryl groups) substituted with aryl groups (optionally substituted with 1 to 3 independently selected halogen groups) and C1-C6 alkyl groups, and

[0263] ◆Optionally selected by 1-3 independently chosen from hydroxyl, oxo, N(R) N2. 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 10 Cycloalkyl groups substituted with 5 to 10-membered heteroaryl groups,

[0264] ○ C3-C alkyl groups optionally substituted with 1-4 independently selected groups chosen from halogens, C1-C6 alkyl groups, and C1-C6 fluoroalkyl groups 12 cycloalkyl,

[0265] ○C6-C 10 Aryl,

[0266] ○3 to 10-membered heterocyclic groups, and

[0267] ○Optionally composed of 1-3 independently selected C1-C6 alkoxy, C1-C6 fluoroalkyl and N(R) N )2 substituted with 5 to 10 heteroaryl groups, and

[0268] ■ 5 to 12 heteroaryl groups optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl and C1-C6 fluoroalkyl groups.

[0269] In some cases of Equation I, when two R F When forming a 3- to 11-membered heterocyclic group, wherein the 3- to 11-membered heterocyclic group is optionally substituted with a 5- to 10-membered heteroaryl group, and wherein the 5- to 10-membered heteroaryl group is optionally substituted with a C1-C6 alkoxy group, wherein the C1-C6 alkoxy group may optionally be substituted with a C6-C6 alkoxy group. 10 Aryl substitution.

[0270] Formula I also includes compounds of Formula Ia:

[0271]

[0272] Tautomers of those compounds, deuterated derivatives of the compounds and any of the tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein ring A, ring B, and ring W 1 W 2 Z, L 1 L 2 R 3 R 4 R 5 and R F As defined in Equation I.

[0273] Formula I also includes compounds of Formula IIa:

[0274]

[0275] Tautomers of those compounds, deuterated derivatives of the compounds and any of the tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein rings B and W 1 W 2 Z, L 1 L 2 R 3 R 4 R 5 and R F As defined in Equation I.

[0276] Formula I also includes compounds of Formula IIb:

[0277]

[0278] Tautomers of those compounds, deuterated derivatives of the compounds and any of the tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein rings A and W 1 W 2 Z, L 1 L 2 R 3 R 4 R 5 and R F As defined in Equation I.

[0279] Formula I also includes compounds of Formula III:

[0280]

[0281] Tautomers of those compounds, deuterated derivatives of the compounds and any of the tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein W 1 W 2 Z, L 1 L 2 R 4 R 5 and R F As defined in Equation I.

[0282] Formula I also includes compounds of Formula IV:

[0283]

[0284] Tautomers of those compounds, deuterated derivatives of the compounds and any of the tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein Z, L 1 L 2 R 4 R 5 and R FAs defined in Equation I.

[0285] Formula I also includes compounds of Formula V:

[0286]

[0287] Tautomers of those compounds, deuterated derivatives of the compounds and any of the tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein Z, L 1 L 2 R 4 R 5 and R F As defined in Equation I.

[0288] Formula I also includes compounds of formula Va and formula Vb:

[0289]

[0290] Tautomers of those compounds, deuterated derivatives of the compounds and any of the tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein Z, L 1 L 2 R 4 R 5 and R F As defined in Equation I.

[0291] Formula I also includes compounds of Formula VI:

[0292]

[0293] Tautomers of those compounds, deuterated derivatives of the compounds and any of the tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein L 1 R 4 R 5 and R F As defined in Equation I.

[0294] Another aspect of this disclosure provides pharmaceutical compositions comprising at least one compound selected from the novel compounds disclosed herein, its tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one pharmaceutically acceptable carrier, the composition possibly further 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 modulator. In some embodiments, the at least one other CFTR modulator is selected from CFTR synergists. 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 both a synergist and a corrector. In some embodiments, the at least one other CFTR modifier is selected from tezacaftor, lumacaftor, ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadecan-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives of any of the foregoing and pharmaceutically acceptable salts.

[0295] Therefore, another aspect of this disclosure provides a method for treating CFTR-mediated cystic fibrosis, the method comprising administering to a subject in need at least one compound selected from novel compounds disclosed herein, its tautomers, deuterated derivatives of these compounds and tautomers, and a pharmaceutically acceptable salt of any of the foregoing, and at least one pharmaceutically acceptable carrier, optionally as part of a pharmaceutical composition 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 modulator. In some embodiments, the at least one other CFTR modulator is selected from CFTR potentiators. 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 both a potentiator and a corrector. In some embodiments, the at least one other CFTR modifier is selected from tizacator, rumacator, ivacator, deuteric acid, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadecan-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives of any of the foregoing and pharmaceutically acceptable salts.

[0296] In some embodiments, the pharmaceutical compositions of this disclosure comprise at least one (i.e., one or more) of a compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, a composition comprising at least one (i.e., one or more) of a compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing may optionally further comprise: (a) a compound selected from (R)-1-(2,2-difluoro) Benzo[d][1,3]dioxacyclopenten-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropane-2-yl)-1H-indol-5-yl)cyclopropaneformamide (tizacator), 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)cyclopropaneformamido)-3-methylpyridin-2-yl)benzoic acid (Lumacator), and tizacator and At least one (i.e., one or more) compounds of deuterated derivatives of rumacator and pharmaceutically acceptable salts; and / or (b) selected from N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (evaccator), N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propane-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo At least one (i.e., one or more) of the following compounds: 1,4-dihydroquinoline-3-carboxamide (deuteric acid), (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclic[12.3.1.12,5]nonadecan-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives of any of the foregoing, and pharmaceutically acceptable salts thereof.

[0297] Another aspect of this disclosure provides a method for treating CFTR-mediated disease, cystic fibrosis, the method comprising administering to a patient in need at least one compound selected from novel compounds disclosed herein, their deuterated derivatives, and pharmaceutically acceptable salts of any of the foregoing, and optionally further administering one or more additional CFTR modulators. Another aspect of this disclosure provides pharmaceutical compositions comprising at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and optionally one or more CFTR modulators for therapeutic or pharmaceutical purposes. In some embodiments, the optional one or more additional CFTR modulators are selected from CFTR enhancers. In some embodiments, the one or more additional CFTR modulators are selected from CFTR correctors. In some embodiments, the one or more additional CFTR modifiers are selected from tizacator, rumacator, ivacator, deuteric acid, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadecan-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives of any of the foregoing and pharmaceutically acceptable salts.

[0298] Further aspects of this disclosure provide intermediates and methods for preparing the compounds and pharmaceutical compositions disclosed herein.

[0299] definition

[0300] As used in this article, "tizacato" refers to (R)-1-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropane-2-yl)-1H-indol-5-yl)cyclopropaneformamide, which can be described by the following structure:

[0301]

[0302] Tizacalo may be in the form of a deuterated derivative or a pharmaceutically acceptable salt or a pharmaceutically acceptable salt of a deuterated derivative. Tizacalo and methods for preparing and using tizacalo are disclosed in WO 2010 / 053471, WO 2011 / 119984, WO 2011 / 133751, WO 2011 / 133951, WO2015 / 160787 and US 2009 / 0131492, which are incorporated herein by reference.

[0303] As used throughout this disclosure, “evaccato” refers to N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, which is characterized by the following structure:

[0304]

[0305] Ivacarto may also be in the form of a deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative. Ivacarto, as well as methods for preparing and using it, are disclosed in WO 2006 / 002421, WO 2007 / 079139, WO 2010 / 108162 and WO 2010 / 019239, which are incorporated herein by reference.

[0306] In some embodiments, a specific deuterated derivative of ivacatho (deuteric acid cataphor) is used in the compositions and methods disclosed herein. The chemical name of deuteric acid cataphor is N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propane-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide, as depicted in the following structure:

[0307]

[0308] Deutericare can be in the form of other deuterated derivatives, pharmaceutically acceptable salts, or pharmaceutically acceptable salts of other deuterated derivatives. Deutericare and methods for preparing and using deutericare are disclosed in WO 2012 / 158885, WO 2014 / 078842, and U.S. Patent No. 8,865,902, which are incorporated herein by reference.

[0309] As used in this article, "rumacato" refers to 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)cyclopropanecarbamate)-3-methylpyridin-2-yl)benzoic acid, whose chemical structure is described below:

[0310]

[0311] Rumacaprot can be in the form of a deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative. Rumacaprot and methods for its preparation and use are disclosed in WO 2007 / 056341, WO 2009 / 073757, and WO 2009 / 076142, which are incorporated herein by reference.

[0312] As used herein, the term "alkyl" refers to a saturated or partially saturated, branched or unbranched aliphatic hydrocarbon 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), wherein one or more bonds between adjacent carbon atoms may be di(alkenyl) or tri(ynyl). Alkyl groups may be substituted or unsubstituted.

[0313] As used herein, the term "halogenated alkyl" refers to an alkyl group substituted with one or more halogen atoms, such as fluoroalkyl, which refers to an alkyl group substituted with one or more fluorine atoms.

[0314] As used herein, the term "alkoxy" refers to an alkyl or cycloalkyl group covalently bonded to an oxygen atom. Alkoxy groups may be substituted or unsubstituted.

[0315] As used herein, the term "haloalkoxy" refers to an alkoxy group that has been substituted with one or more halogen atoms.

[0316] As used herein, “cycloalkyl” means a cyclic, bicyclic, tricyclic, or polycyclic non-aromatic hydrocarbon group having 3 to 12 carbons (e.g., 3-10 carbons) and may contain one or more unsaturated bonds. “Cycloalkyl” encompasses monocyclic, bicyclic, tricyclic, bridged, fused, and spirocyclic rings, including monospirocyclic and dispirocyclic rings. Non-limiting examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, and dispiro[2.0.2.1]heptane. Cycloalkyl groups may be substituted or unsubstituted.

[0317] As used herein, the term "aryl" is a functional group or substituent derived from an aromatic ring and encompasses monocyclic aromatic rings and bicyclic, tricyclic, and fused ring systems, wherein at least one ring in said system is aromatic. Non-limiting examples of aryl groups include phenyl, naphthyl, and 1,2,3,4-tetrahydronaphthyl.

[0318] As used herein, the term "heteroaryl ring" refers to an aromatic ring comprising at least one ring atom, which is a heteroatom such as O, N, or S. Heteroaryl rings encompass monocyclic and bicyclic, tricyclic, bridged, fused, and spirocyclic systems (including monospirocyclic and bispirocyclic rings), wherein at least one ring in such systems is aromatic. Non-limiting examples of heteroaryl rings include pyridine, quinoline, indole, and dihydroindole.

[0319] As used herein, the term "heterocyclic ring" refers to a non-aromatic hydrocarbon containing 3 to 12 atoms (e.g., 3-10 atoms) in a ring, said ring comprising at least one ring atom, said ring atom being a heteroatom such as O, N, or S, and may contain one or more unsaturated bonds. "Heterocyclic" rings encompass monocyclic, bicyclic, tricyclic, polycyclic, bridged, fused, and spirocyclic rings, including monospirocyclic and bispirocyclic rings.

[0320] The term “substituted”, whether or not preceded by the term “optionally”, indicates that at least one hydrogen atom in the “substituted” group is replaced by a substituent. Unless otherwise indicated, the “optionally substituted” group may have suitable substituents at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure can be substituted by more than one substituent selected from the specified group.

[0321] Examples of nitrogen-protecting groups include, for example, tert-butyl carbamate (Boc), benzyl (Bn), p-methoxybenzyl (PMB), tetrahydropyranyl (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, benzyleneamine, and p-toluenesulfonamide. A complete 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.

[0322] As used in this article, the terms “selected from” and “chosen from” are used interchangeably.

[0323] As used herein, "one or more deuterated derivatives" refers to a compound having the same chemical structure as the reference compound and in which one or more hydrogen atoms are replaced by deuterium atoms. In some embodiments, the one or more hydrogen atoms replaced by deuterium are part of an alkyl group. In some embodiments, the one or more hydrogen atoms replaced by deuterium are part of a methyl group.

[0324] As used in this article, "CFTR" refers to the transmembrane conduction regulator of cystic fibrosis.

[0325] The terms "CFTR modulator" and "CFTR regulator" are used interchangeably herein and refer to compounds that increase the activity of CFTR. The increase in activity caused by CFTR modulators includes, but is not limited to, compounds that correct, enhance, stabilize, and / or amplify CFTR.

[0326] The terms "corrector" or "CFTR corrector," used interchangeably herein, refer to compounds that promote the processing and transport of CFTR to increase the amount of CFTR on the cell surface. The novel compounds disclosed herein are CFTR correctors. Other correctors may be used in combination therapies with the novel compounds disclosed herein to treat CFTR-mediated diseases, such as cystic fibrosis. Such other correctors include, for example, tezacotto, rumacotto, and their deuterated derivatives and pharmaceutically acceptable salts.

[0327] The terms “synergist” and “CFTR synergist” used interchangeably herein refer to compounds that enhance ion transport by increasing the channel activity of CFTR proteins located on the cell surface. Ivacapor and deuteric acid troponin disclosed herein are CFTR synergists. Synergists can be used in combination with the novel compounds disclosed herein to treat CFTR-mediated diseases such as cystic fibrosis. Such synergists comprise, for example, ivacapor, deuteric acid troponin, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadecan-1(18),2,4,14,16-pentaen-6-ol and their deuterated derivatives, as well as pharmaceutically acceptable salts.

[0328] It should be understood that when describing a combination of compounds selected from Formula I, any one of Formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and other specific CFTR modifiers provided herein, the combination or treatment regimen will typically, but not necessarily, include at least one potentiator, for example, a potentiator selected from ivacato, deuteric acid, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadecan-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives and their pharmaceutically acceptable salts. It should be understood that a single potentiator is typically, but not necessarily, used in combination drug compositions or therapies. In some embodiments, a combination of at least one compound selected from compounds of formula I, any one of formulas Ia, IIa, IIb, III, IV, V, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and other specific CFTR modifiers, will include CFTR synergists, such as ivacato, deuteric acid, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadecan-1(18),2,4,14,16-pentaen-6-ol and their deuterated derivatives and pharmaceutically acceptable salts, and another CFTR corrector, such as corrector compounds selected from tizacato, rumacotto, and their deuterated derivatives and pharmaceutically acceptable salts.

[0329] As used herein, the term “selected from at least one compound” means one or more compounds selected from a particular group.

[0330] In this disclosure, references to “compounds 1-426” are intended to indicate a separate reference to each of compounds 1 to 426 or to a group of compounds, such as compounds 1-371, compounds 372-385 and compounds 386-426.

[0331] As used herein, the terms “active pharmaceutical ingredient” or “therapeutic agent” (“API”) refer to bioactive compounds.

[0332] The terms “patient” and “subject” are used interchangeably and refer to animals including humans.

[0333] The terms “effective dose” and “effective amount” are used interchangeably herein and refer to the amount of compound that produces the desired effect of administration (e.g., improvement of symptoms of CF or CF, or reduction of the severity of symptoms of CF or CF). The exact amount of effective dose will depend on the therapeutic purpose and will be determined by a person skilled in the art using known techniques (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0334] As used herein, the terms "treatment" and "treating" generally refer to improving one or more symptoms of CF in a subject, or reducing the severity of CF or one or more symptoms of CF. As used herein, "treatment" includes, but is not limited to, increased growth in a subject, increased weight gain, reduced pulmonary mucus, improved pancreatic and / or liver function, reduced chest infection and / or reduced cough or shortness of breath. Any improvement in these symptoms or reduction in severity can be readily assessed using standard methods and techniques known in the art. It should be understood that the methods of treatment (e.g., methods of treating CFTR-mediated diseases or methods of treating cystic fibrosis) using one or more compounds of this disclosure optionally in combination with one or more additional CFTR modulators (e.g., compounds selected from Formula I, compounds of any one of Formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers and pharmaceutically acceptable salts of any of the foregoing, optionally in combination with one or more additional CFTR modulators) mentioned herein should also be interpreted as references.

[0335] - A method of treating, for example, cystic fibrosis using one or more compounds (e.g., compounds selected from formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, optionally in combination with one or more additional CFTR modulators); and / or

[0336] Use of one or more compounds (e.g., compounds selected from any one of formula I, Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers and pharmaceutically acceptable salts of any of the foregoing, optionally in combination with one or more additional CFTR modulators) in the preparation of a medicament for treating, for example, cystic fibrosis.

[0337] It should also be understood that the methods of treatment using pharmaceutical compositions of this disclosure (e.g., pharmaceutical compositions comprising at least one compound selected from compounds of formula I, compounds of formula Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers and pharmaceutically acceptable salts of any of the foregoing, and optionally further comprising one or more additional CFTR modulators) (e.g., methods of treating CFTR-mediated diseases or methods of treating cystic fibrosis) should also be interpreted as references:

[0338] - A pharmaceutical composition (e.g., a pharmaceutical composition comprising at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and optionally further comprising one or more additional CFTR modulators) for the treatment of, for example, cystic fibrosis; and / or

[0339] - Use of a pharmaceutical composition (e.g., a composition comprising at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers and pharmaceutically acceptable salts of any of the foregoing, and optionally further comprising one or more additional CFTR modulators) in the preparation of a medicament for treating, for example, cystic fibrosis.

[0340] As used herein, when referring to two or more compounds, agents or other active pharmaceutical ingredients, the term “in combination with” means administering two or more compounds, agents or active pharmaceutical ingredients to a patient before, at the same time as or after each other.

[0341] The terms “about” and “approximately” can refer to an acceptable error in a particular value as determined by a person skilled in the art, depending in part on how the 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.

[0342] As used herein, the term "solvent" refers to any liquid that can at least partially dissolve the product (product solubility > 1 g / L).

[0343] As used in this article, the terms “room temperature” or “ambient temperature” refer to 15°C to 30°C.

[0344] It should be understood that certain compounds of this disclosure may exist as individual stereoisomers or enantiomers and / or mixtures of such stereoisomers or enantiomers.

[0345] Some compounds disclosed herein may exist in tautomer forms, and both tautomer forms are expected, even if only a single tautomer structure is described. For example, the description of compound X should be understood to include its tautomer compound Y and vice versa, as well as mixtures thereof:

[0346]

[0347] As used herein, “minimum function (MF) mutation” refers to a CFTR gene mutation (extremely low to non-functional CFTR protein) associated with minimum CFTR function, and includes, for example, mutations associated with a severe deficiency in the ability of CFTR channels to open and close, referred to as defective channel gating or “gating mutations”; mutations associated with a severe deficiency in CFTR cellular processing and its delivery to the cell surface; mutations associated with no (or minimal) CFTR synthesis; and mutations associated with a severe deficiency in channel transduction.

[0348] As used herein, the term "pharmaceutically acceptable salt" refers to the salt form of the compounds of this disclosure, wherein the salt is non-toxic. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. For example, the "free base" form of the compounds contains salts without ionic bonds.

[0349] When referring to one or more compounds or formulas of this disclosure, the phrase "and deuterated derivatives and pharmaceutically acceptable salts thereof" may be used interchangeably with "and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing". These phrases are intended to cover pharmaceutically acceptable salts of any of the mentioned compounds, deuterated derivatives of any of the mentioned compounds, and pharmaceutically acceptable salts of those deuterated derivatives.

[0350] Those skilled in the art will recognize that when the amount of "a compound or a pharmaceutically acceptable salt thereof" is disclosed, the amount of the pharmaceutically acceptable salt form of the compound is equal to the concentration of the free base of the compound. It should be noted that the amounts of the compound or its pharmaceutically acceptable salts disclosed herein are in their free base form.

[0351] Suitable pharmaceutically acceptable salts are those disclosed, for example, in SMBerge et al., J. Pharmaceutical Sciences, 1977, 66, 1-19. Table 1 of that article provides the following pharmaceutically acceptable salts:

[0352] Table 1:

[0353] Acetate iodide Benzathine benzenesulfonate Hydroxyethyl sulfonate Chloroprocaine Benzoate lactate choline bicarbonate Lacturonate diethanolamine Tartrate malate ethylenediamine bromide Maleate meglumine calcium edetate Mandelates Procaine Camphor sulfonate Methanesulfonates aluminum carbonate rocks Methyl bromide calcium chloride Methyl nitrate lithium citrate Methyl sulfate magnesium dihydrochloride mucinate Potassium edetate Naphthalenesulfonate sodium ethanedisulfonate nitrates Zinc Estolate Dihydroxynaphthyl salt (Embonate) ethanesulfonate pantothenate Fumarate Phosphate / Diphosphate gluconate Polygalacturonate gluconate Salicylate glutamate Stearates p-hydroxyacetaminophenylarsine Basic acetate Hexylresorcinol salt Succinate Hydrabamine sulfates hydrobromide Tannins hydrochloride Tartrate Hydroxynaphthyl carbamate Theophylline salt Triethyl iodide

[0354] 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 adipate, alginate, ascorbic acid, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, gluconate, glyceryl phosphate, gluconate, hemisulfate, heptaate, hexanoate, hydroiodate, 2-hydroxyethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, p-valerate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate. Pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl)4 salts. This disclosure also contemplates quaternization of any basic nitrogen-containing group in the compounds disclosed herein. Suitable non-limiting examples of alkali metal and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Other non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, low-carbon alkyl sulfonate, and aryl sulfonate. Other suitable non-limiting examples of pharmaceutically acceptable salts include benzenesulfonates and glucosamine salts.

[0355] This article also discloses compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0356] Treatment

[0357] Any novel compound disclosed herein, such as compounds of formula I, compounds of any of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, can act as a CFTR regulator, i.e., regulate CFTR activity in vivo. Individuals with mutations in the gene encoding CFTR can benefit from receiving CFTR regulators. CFTR mutations may affect the number of CFTRs, i.e., the number of CFTR channels on the cell surface, or they may affect CFTR function, i.e., the function of each channel in opening and transporting ions. Mutations affecting the number of CFTRs include mutations leading to synthetic defects (class I defects), mutations leading to processing and transport defects (class II defects), mutations leading to reduced CFTR synthesis (class V defects), and mutations reducing the surface stability of CFTRs (class VI defects). Mutations affecting CFTR function include mutations leading to gating defects (class III defects) and mutations leading to conduction defects (class IV defects). Some CFTR mutations exhibit characteristics of multiple classes. Certain mutations in the CFTR gene lead to cystic fibrosis.

[0358] Therefore, in some embodiments, this disclosure provides a method for treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient, the method comprising administering to the patient an effective amount of any novel compound disclosed herein, such as compounds of formula I, compounds of any of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, alone or in combination with another active ingredient such as one or more CFTR modulators. In some embodiments, the one (or more) CFTR modulators are corrective agents. In some embodiments, the one (or more) CFTR modulators are synergists. In some embodiments, the CFTR modulator comprises both a corrective agent and a synergist. In some embodiments, the one or more CFTR modifiers are selected from synergists: ivacato, deuteric acid, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadecan-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing; and correctors: rumacotto, tizacato and deuterated derivatives and pharmaceutically acceptable salts thereof.

[0359] In some embodiments, the patient to be treated has an F508del / minimum function (MF) genotype, an F508del / F508del genotype (isotype-binding against the F508del mutation), an F508del / gated genotype, or an F508del / residual function (RF) genotype. In some embodiments, the patient is allotype-binding against the N1303K mutation.

[0360] In some embodiments, 5 mg to 500 mg of the compounds disclosed herein, their tautomers, deuterated derivatives of the compounds and tautomers, or pharmaceutically acceptable salts of any of the foregoing may be administered daily.

[0361] In some embodiments, the patient to be treated has at least one F508del mutation in the CFTR gene. In some embodiments, based on in vitro data, the patient has a CFTR gene mutation that responds to compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure. In some embodiments, the patient is heterozygous and has an F508del mutation in one allele selected from Table 2 and a mutation in the other allele:

[0362] Table 2: CFTR mutations

[0363]

[0364]

[0365] a Also known as 2183delAA→G.

[0366] CFTR: a regulator of transmembrane conduction in cystic fibrosis;

[0367] IVA: Ivacato.

[0368] SwCl: Chloride in sweat.

[0369] TEZ: Tezacató

[0370] Source: CFTR2.org [Internet]. Baltimore (MD): Clinical and Functional Translation of CFTR. Clinical and Functional Translation of CFTR (CFTR2), Cystic Fibrosis Foundation, Johns Hopkins University, Sick Children's Hospital. Available at http: / / www.cftr2.org / . Accessed May 15, 2018.

[0371] Note: %PI: Percentage of F508del-CFTR heterozygous patients with pancreatic insufficiency in the CFTR2 patient registry; SwCl: Mean sweat chloride in F508del-CFTR heterozygous patients in the CFTR2 patient registry.

[0372] In some embodiments, this disclosure also relates to treatment methods using isotopically labeled compounds or pharmaceutically acceptable salts of the aforementioned compounds, wherein the chemical formulas and variables of such compounds and salts are each independently as described above or in any other of the above embodiments, provided that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those of naturally occurring atoms (isotopically labeled). Examples of commercially available isotopes suitable for use in this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, respectively, 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.

[0373] Isotope-labeled compounds and salts can be used in a variety of beneficial ways. They are applicable to pharmaceutical and / or various types of assays, such as substrate tissue distribution assays. For example, tritium ( 3 H) and / or carbon-14 (H) and / or carbon-14 14 C)-labeled compounds are particularly suitable for various types of assays, such as substrate tissue distribution assays, due to their relatively simple preparation and excellent detectability. For example, deuterium ( 2 H)-labeled compounds are therapeutically available and, compared to non-H)-labeled compounds, are more effective. 2 H-labeled compounds have potential therapeutic advantages. Generally, compared to non-isotope-labeled compounds and salts, deuterium (… 2 H)-labeled compounds and salts can exhibit higher metabolic stability due to the kinetic isotope effect described below. Higher metabolic stability directly translates to an increased in vivo half-life or a lower dose, which is desirable. Isotope-labeled compounds and salts can generally be prepared by substituting a non-isotope-labeled reactant with an readily available isotope-labeled reactant, following the procedures disclosed in the synthetic schemes and related descriptions, examples, and preparation sections herein.

[0374] In some embodiments, the isotope-labeled compound and salt are deuterium ( 2 Compounds and salts labeled with deuterium (H). In some specific embodiments, the isotope-labeled compounds and salts are deuterated (H). 2 The symbol (H) indicates that one or more hydrogen atoms have been replaced by deuterium. In chemical structures, deuterium is represented by "D".

[0375] The concentration of isotopes (e.g., deuterium) in isotopically labeled compounds and salts incorporated into this disclosure can be defined by an isotope enrichment factor. As used herein, the term "isotope enrichment factor" refers to the ratio between the isotopic abundance of a specified isotope and its natural abundance. In some embodiments, if the substituent in the compounds of this disclosure is deuterium, such compounds have an isotopic enrichment factor for each specified deuterium atom of at least 3500 (52.5% deuterium inclusion at each specified deuterium atom), at least 4000 (60% deuterium inclusion), at least 4500 (67.5% deuterium inclusion), at least 5000 (75% deuterium inclusion), at least 5500 (82.5% deuterium inclusion), at least 6000 (90% deuterium inclusion), at least 6333.3 (95% deuterium inclusion), at least 6466.7 (97% deuterium inclusion), at least 6600 (99% deuterium inclusion), or at least 6633.3 (99.5% deuterium inclusion).

[0376] Combination therapy

[0377] One aspect disclosed herein provides a method for treating cystic fibrosis and other CFTR-mediated diseases by combining any novel compound disclosed herein, such as compounds of formula I, compounds of any of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, with at least one additional active pharmaceutical ingredient.

[0378] In some embodiments, at least one additional active pharmaceutical ingredient is selected from mucolytics, bronchodilators, antibiotics, anti-infectives, and anti-inflammatory agents.

[0379] In some embodiments, the additional therapeutic agent is an antibiotic. Exemplary antibiotics that may be used herein include tobramycin, including tobramycin inhalation powder (TIP); azithromycin; aztreonam, including an aerosolized form of aztreonam; amikacin, including its liposomal formulation; ciprofloxacin, including its formulation suitable for inhalation administration; levofloxacin, including its aerosolized formulation; and combinations of two antibiotics, such as fosfomycin and tobramycin.

[0380] In some embodiments, the additional agent is a mucus dissolving agent. Exemplary mucus dissolving agents that may be used herein include...

[0381] In some embodiments, the additional agent is a bronchodilator. Exemplary bronchodilators include albuterol, metaprotenerol sulfate, pirbuterolacetate, salmeterol, or tetrabuline sulfate.

[0382] In some embodiments, the additional agent is an anti-inflammatory agent, i.e., an agent that can reduce inflammation in the lungs. Exemplary such agents that may be used herein include ibuprofen, docosahexaenoic acid (DHA), sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine, or simvastatin.

[0383] In some embodiments, the additional agent is a nutrient. An exemplary nutrient contains pancreatic lipase (a pancreatic enzyme substitute), comprising... or (previous) ), Alternatively, glutathione can be inhaled. In one embodiment, an additional nutrient is pancreatic lipase.

[0384] 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 enhancer is selected from ivacato, deuteric acid, and (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadecan-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives of any of the foregoing and pharmaceutically acceptable salts. In some embodiments, the additional active pharmaceutical ingredient is selected from CFTR correctors. In some embodiments, the corrector is selected from rumacotto, tezacotto, rumacotto and deuterated derivatives of tezacotto and deuterated derivatives of any of the foregoing and pharmaceutically acceptable salts. In some embodiments, the additional active pharmaceutical ingredient comprises both a CFTR enhancer and a CFTR corrector.

[0385] In some embodiments, the at least one additional active pharmaceutical ingredient is selected from: (a) compounds of tizacato, rumacotto, and deuterated derivatives thereof and pharmaceutically acceptable salts thereof; and (b) ivacato, deutericto, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadecan-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives thereof and pharmaceutically acceptable salts thereof. Therefore, in some embodiments, the combination therapies provided herein include: (a) compounds selected from any of the formula I, Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from tezacotto, rumacotto and deuterated derivatives and pharmaceutically acceptable salts of the foregoing; or (c) at least one compound selected from ivacato, deutericto, deuterated derivatives of any of the foregoing and pharmaceutically acceptable salts of the foregoing. In some embodiments, the combination therapies provided herein include: (a) at least one compound selected from compounds of formula I, any of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from tezacotto, rumacotto and deuterated derivatives and pharmaceutically acceptable salts of the foregoing; and (c) at least one compound selected from ivacato, deutericto, and deuterated derivatives of any of the foregoing and pharmaceutically acceptable salts of the foregoing. In some embodiments, the combination therapies provided herein comprise: (a) at least one compound selected from compounds of formula I, any of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from tezacotto, rumacotto and deuterated derivatives and pharmaceutically acceptable salts of the foregoing; and / or (c) 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]nonadecan-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives of any of the foregoing and pharmaceutically acceptable salts of the foregoing.

[0386] In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are combined with at least one compound selected from tezacotto and deuterated derivatives and pharmaceutically acceptable salts of the foregoing. In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are combined with at least one compound selected from rumacotto and deuterated derivatives and pharmaceutically acceptable salts of the foregoing. In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are combined with at least one compound selected from ivacator and deuterated derivatives and pharmaceutically acceptable salts of the foregoing. In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are combined with at least one compound selected from deuteric acid and deuterated derivatives and pharmaceutically acceptable salts of the foregoing. In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are combined 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]nonadecan-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives and their pharmaceutically acceptable salts.

[0387] In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are combined with at least one compound selected from tezacotto and its deuterated derivatives and pharmaceutically acceptable salts, and at least one compound selected from ivacato and its deuterated derivatives and pharmaceutically acceptable salts. In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are combined with at least one compound selected from tezacotto and its deuterated derivatives and pharmaceutically acceptable salts, and at least one compound selected from deutericto and its deuterated derivatives and pharmaceutically acceptable salts. In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers and pharmaceutically acceptable salts of any of the foregoing are combined with at least one compound selected from tezacotto and its deuterated derivatives and their 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]nonadecan-1(18),2,4,14,16-pentaen-6-ol and its deuterated derivatives and their pharmaceutically acceptable salts.

[0388] In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are combined with at least one compound selected from rumacator and deuterated derivatives and pharmaceutically acceptable salts of the foregoing, and at least one compound selected from ivacato and deuterated derivatives and pharmaceutically acceptable salts of the foregoing. In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are combined with at least one compound selected from rumacator and deuterated derivatives and pharmaceutically acceptable salts of the foregoing, and at least one compound selected from deutericto and deuterated derivatives and pharmaceutically acceptable salts of the foregoing are combined with at least one compound selected from deutericto and deuterated derivatives and pharmaceutically acceptable salts of the foregoing. In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers and pharmaceutically acceptable salts of any of the foregoing are combined with at least one compound selected from rumacator and deuterated derivatives and their 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]nonadecan-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives and their pharmaceutically acceptable salts.

[0389] Each of the compounds 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 these compounds and tautomers, and 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 Formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing may be administered once daily. 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 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing may be administered twice daily.

[0390] In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound selected from tezacotto and its deuterated derivatives and pharmaceutically acceptable salts thereof, is administered once daily. In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound selected from tezacotto and its deuterated derivatives and pharmaceutically acceptable salts thereof, is administered twice daily.

[0391] In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-371, compounds 372-385, compounds 386-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound selected from ivacato, deuteric acid thiocarb, and their deuterated derivatives and pharmaceutically acceptable salts thereof, is administered once daily. In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound selected from ivacato, deuteric acid thiocarb, and their deuterated derivatives and pharmaceutically acceptable salts thereof, is administered twice daily.

[0392] In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers and pharmaceutically acceptable salts of any of the foregoing, 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]nonadecan-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives and their pharmaceutically acceptable salts are administered once daily. In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers and pharmaceutically acceptable salts of any of the foregoing, 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]nonadecan-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives and their pharmaceutically acceptable salts are administered twice daily.

[0393] In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers and pharmaceutically acceptable salts of any of the foregoing, at least one compound selected from tezacotto and its deuterated derivatives and their pharmaceutically acceptable salts, and at least one compound selected from ivacato, deuteric acid tezacotto and its deuterated derivatives and their pharmaceutically acceptable salts are administered once daily. In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers and pharmaceutically acceptable salts of any of the foregoing, at least one compound selected from tezacotto and its deuterated derivatives and their pharmaceutically acceptable salts, and at least one compound selected from ivacato, deuteric acid tezacotto and its deuterated derivatives and their pharmaceutically acceptable salts are administered twice daily.

[0394] In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers and pharmaceutically acceptable salts of any of the foregoing, at least one compound selected from tezacotto and its deuterated derivatives and their 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]nonadecan-1(18),2,4,14,16-pentaen-6-ol and its deuterated derivatives and their pharmaceutically acceptable salts are administered once daily. In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers and pharmaceutically acceptable salts of any of the foregoing, at least one compound selected from tizacator and its deuterated derivatives and their 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]nonadecan-1(18),2,4,14,16-pentaen-6-ol and its deuterated derivatives and their pharmaceutically acceptable salts are administered twice daily.

[0395] In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, at least one compound selected from ivacatho, deuteric acid sorbitol, and their deuterated derivatives, and pharmaceutically acceptable salts of the foregoing, and at least one compound selected from rumacator and its pharmaceutically acceptable salts, is administered once daily. In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, at least one compound selected from ivacatho, deuteric acid sorbitol, and their deuterated derivatives, and pharmaceutically acceptable salts of the foregoing, and at least one compound selected from rumacator and its pharmaceutically acceptable salts, is administered twice daily.

[0396] In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers and pharmaceutically acceptable salts of any of the foregoing, 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]nonadecan-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives and their pharmaceutically acceptable salts, and at least one compound selected from rumacator and its pharmaceutically acceptable salts are administered once daily. In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers and pharmaceutically acceptable salts of any of the foregoing, 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]nonadecan-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives and their pharmaceutically acceptable salts, and at least one compound selected from rumacator and its pharmaceutically acceptable salts are administered twice daily.

[0397] In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound selected from tezacotto and its deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one compound selected from ivacathotoxin and its deuterated derivatives and pharmaceutically acceptable salts thereof, are administered once daily, and at least one compound selected from ivacathotoxin and its deuterated derivatives and pharmaceutically acceptable salts thereof, are administered twice daily. In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound selected from rumacotto and its deuterated derivatives and pharmaceutically acceptable salts thereof, are administered once daily, and at least one compound selected from ivacathotoxin and its deuterated derivatives and pharmaceutically acceptable salts thereof, are administered twice daily.

[0398] At least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound selected from tezacotto, rumacotto, ivacato, deuteric acid tezacotto, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadecan-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives of any of the foregoing, and pharmaceutically acceptable salts of any of the foregoing, may be administered in a single pharmaceutical composition or in a single pharmaceutical composition. Such pharmaceutical compositions may be administered once daily or multiple times daily, such as twice daily or three times daily. As used herein, a phrase indicating a given amount of API (e.g., tezacotto, rumacotto, ivacato, deuteric acid, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadecan-1(18),2,4,14,16-pentaen-6-ol or a deuterated derivative or a pharmaceutically acceptable salt of any of the foregoing) administered once or twice daily, or daily administration means that the given amount is administered once or twice daily for each dose.

[0399] In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered in a first pharmaceutical composition; at least one compound selected from tezacotto and its deuterated derivatives and their pharmaceutically acceptable salts are administered in a second pharmaceutical composition; and at least one compound selected from ivacathotoxin and its deuterated derivatives and their pharmaceutically acceptable salts are administered in a third pharmaceutical composition.

[0400] In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered in a first pharmaceutical composition; at least one compound selected from tezacotto and its deuterated derivatives and their pharmaceutically acceptable salts are administered in a second pharmaceutical composition; and at least one compound selected from deuteric acid tezacotto and its deuterated derivatives and their pharmaceutically acceptable salts are administered in a third pharmaceutical composition.

[0401] In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered in a first pharmaceutical composition; at least one compound selected from tezacotto and its deuterated derivatives and their pharmaceutically acceptable salts are administered 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]nonadecan-1(18),2,4,14,16-pentaen-6-ol and its deuterated derivatives and their pharmaceutically acceptable salts are administered in a third pharmaceutical composition.

[0402] In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered in a first pharmaceutical composition; at least one compound selected from ivacato, deuteric acid, and deuterated derivatives and their pharmaceutically acceptable salts are administered in a second pharmaceutical composition; and at least one compound selected from rumacato, deuterated derivatives and their pharmaceutically acceptable salts are administered in a third pharmaceutical composition.

[0403] In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are 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]nonadecan-1(18),2,4,14,16-pentaen-6-ol and their deuterated derivatives and pharmaceutically acceptable salts are administered in a second pharmaceutical composition; and at least one compound selected from rumacator and their deuterated derivatives and pharmaceutically acceptable salts are administered in a third pharmaceutical composition.

[0404] In some embodiments, at least one compound selected from compounds 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 these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered in a first pharmaceutical composition; and at least one compound selected from tezacotto and its pharmaceutically acceptable salts and at least one compound selected from ivacato, deuteric acid tezacotto, and its deuterated derivatives and their pharmaceutically acceptable salts are administered in a second pharmaceutical composition. In some embodiments, the second pharmaceutical composition comprises half a daily dose of ivacato or its pharmaceutically acceptable salt, and the other half a daily dose of ivacato or its pharmaceutically acceptable salt is administered in a third pharmaceutical composition.

[0405] In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered in a first pharmaceutical composition; and at least one compound selected from tezacotto and its 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]nonadecan-1(18),2,4,14,16-pentaen-6-ol and its deuterated derivatives and their pharmaceutically acceptable salts are administered in a second pharmaceutical composition.

[0406] In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered in the first pharmaceutical composition; at least one compound selected from tizacator and its pharmaceutically acceptable salts; and at least one compound selected from ivacator, deuteric acid tizacator, and its deuterated derivatives and their pharmaceutically acceptable salts are administered in the first pharmaceutical composition. 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 ivacator is administered once daily.

[0407] In some embodiments, at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; at least one compound selected from tizacator and its 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]nonadecan-1(18),2,4,14,16-pentaen-6-ol and its deuterated derivatives and their pharmaceutically acceptable salts are administered in the first pharmaceutical composition. 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 the 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]nonadecan-1(18),2,4,14,16-pentaen-6-ol (or a deuterated derivative thereof or a pharmaceutically acceptable salt thereof) is administered once daily.

[0408] Any suitable pharmaceutical composition may be used for compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, tezacotto, rumacotto, ivacato, deuteric acid, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadecan-1(18),2,4,14,16-pentaen-6-ol and their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. Exemplary pharmaceutical compositions for tezaccato and its pharmaceutically acceptable salts can be found in WO 2011 / 119984 and WO 2014 / 014841, each of which is incorporated herein by reference. Exemplary pharmaceutical compositions for ivacalto and its pharmaceutically acceptable salts can be found in WO 2007 / 134279, WO 2010 / 019239, WO 2011 / 019413, WO 2012 / 027731 and WO2013 / 130669, and exemplary pharmaceutical compositions for deutericata and its pharmaceutically acceptable salts can be found in US 8,865,902, US 9,181,192, US 9,512,079, WO 2017 / 053455 and WO 2018 / 080591, all of which are incorporated herein by reference. Exemplary pharmaceutical compositions for rumacata and its pharmaceutically acceptable salts are found in WO 2010 / 037066, WO 2011 / 127421 and WO 2014 / 071122, each of which is incorporated herein by reference.

[0409] Pharmaceutical Composition

[0410] Another aspect of this disclosure provides a pharmaceutical composition comprising at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers and pharmaceutically acceptable salts of any of the foregoing, and at least one pharmaceutically acceptable carrier.

[0411] In some embodiments, this disclosure provides a pharmaceutical composition comprising at least one compound selected from compounds 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 these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, combined with at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR modifier. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR corrector. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR enhancer. In some embodiments, the pharmaceutical composition comprises at least one compound selected from compounds 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 these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least two additional active pharmaceutical ingredients, one of which is a CFTR corrector and the other of which is a CFTR enhancer.

[0412] In some embodiments, this disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from tezacotto and its deuterated derivatives and their pharmaceutically acceptable salts; and (c) at least one pharmaceutically acceptable carrier. In some embodiments, this disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from rumacator and its deuterated derivatives and pharmaceutically acceptable salts thereof; and (c) at least one pharmaceutically acceptable carrier.

[0413] In some embodiments, this disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from ivacato, deuteric acid sorbitol and deuterated derivatives of the foregoing and their pharmaceutically acceptable salts; and (c) at least one pharmaceutically acceptable carrier.

[0414] In some embodiments, this disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (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]nonadecan-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives thereof; and (c) at least one pharmaceutically acceptable carrier.

[0415] In some embodiments, this disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from tezacotto and its deuterated derivatives and their pharmaceutically acceptable salts; (c) at least one compound selected from ivacathotoxin and its deuterated derivatives and their pharmaceutically acceptable salts; and (d) at least one pharmaceutically acceptable carrier.

[0416] In some embodiments, this disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from tezacotto and its deuterated derivatives and their pharmaceutically acceptable salts; (c) at least one compound selected from deuteric acid tezacotto and its deuterated derivatives and their pharmaceutically acceptable salts; and (d) at least one pharmaceutically acceptable carrier.

[0417] In some embodiments, this disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from ivacato, deuteric acid catarrh and deuterated derivatives of the foregoing, and pharmaceutically acceptable salts thereof; (c) at least one compound selected from rumacapto and pharmaceutically acceptable salts thereof; and (d) at least one pharmaceutically acceptable carrier.

[0418] In some embodiments, this disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from tezacotto and its deuterated derivatives and their pharmaceutically acceptable salts; (c) 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]nonadecan-1(18),2,4,14,16-pentaen-6-ol and its deuterated derivatives and their pharmaceutically acceptable salts; and (d) at least one pharmaceutically acceptable carrier. In some embodiments, this disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb and VI, compounds 1-426, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from rumacator and its deuterated derivatives and their pharmaceutically acceptable salts; (c) 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]nonadecan-1(18),2,4,14,16-pentaen-6-ol and its deuterated derivatives and their pharmaceutically acceptable salts; and (d) at least one pharmaceutically acceptable carrier.

[0419] 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 mediators and pharmaceutically acceptable adjuvants. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants.

[0420] The pharmaceutical compositions described herein may be used to treat cystic fibrosis and other CFTR-mediated diseases.

[0421] As described above, the pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be selected from adjuvants and mediators. As used herein, at least one pharmaceutically acceptable carrier includes any and all solvents, diluents, other liquid mediators, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders, and lubricants suitable for the desired particular dosage form. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, edited by DBTroy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J.C. Boylan, 1988–1999, Marcel Dekker, New York discloses various carriers for formulating pharmaceutical compositions and known techniques for their preparation. Unless any conventional carrier is incompatible with the compounds of this disclosure, such as by producing any undesirable biological effects or otherwise interacting in a harmful manner with any other component of the pharmaceutical composition, its use is contemplated within the scope of this disclosure. Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffering substances (e.g., phosphates, glycine, sorbic acid, and potassium sorbate), mixtures of saturated vegetable fatty acid metaglycerides, water, salts, and electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., sodium carboxymethyl cellulose, ethyl cellulose, etc.). The ingredients include: cellulose (including cellulose acetate), powdered tragacanth gum, malt, gelatin, talc, excipients (such as cocoa butter and suppository wax), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, phosphate buffer, non-toxic and compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweeteners, flavoring agents, aroma agents, preservatives, and antioxidants.

[0422] Exemplary embodiments

[0423] The following is a non-limiting list of embodiments:

[0424] 1. A compound of formula I:

[0425]

[0426] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0427] Ring A is selected from:

[0428] ■C6-C 10 Aryl,

[0429] ■C3-C 10 cycloalkyl,

[0430] ■3 to 10-membered heterocyclic groups, and

[0431] ■5 to 10-membered heteroaryl groups;

[0432] Ring B is selected from:

[0433] ■C6-C 10 Aryl,

[0434] ■C3-C 10 cycloalkyl,

[0435] ■3 to 10-membered heterocyclic groups, and

[0436] ■5 to 10-membered heteroaryl groups;

[0437] V is selected from O and NH;

[0438] W 1 Selected from N and CH;

[0439] W 2 Selected from N and CH; condition is W 1 and W 2 At least one of them is N;

[0440] Z is selected from O and NR. ZN and C(R) ZC )2, the condition is when L 2 When Z does not exist, Z is C(R) ZC )2;

[0441] Each L 1 Independently selected from C(R) L1 )2;

[0442] Each L 2 Independently selected from C(R) L2 )2;

[0443] Each R 3 Selected independently from:

[0444] ■ Halogen,

[0445] ■C1-C6 alkyl groups,

[0446] ■C1-C6 alkoxy groups,

[0447] ■C3-C 10 cycloalkyl,

[0448] ■ C6-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 Aryl, and

[0449] ■3 to 10-membered heterocyclic groups;

[0450] R 4 Selected from hydrogen and C1-C6 alkyl groups;

[0451] Each R 5 Selected independently from:

[0452] ■ Hydrogen,

[0453] ■ Halogen,

[0454] ■Hydroxy

[0455] ■N(R N )2,

[0456] ■-SO-Me,

[0457] ■-CH=C(R LC )2, where two R LC Together they form C3-C 10 cycloalkyl,

[0458] ■ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0459] ○Hydroxy group,

[0460] ○Optionally selected by 1-3 independently chosen C1-C6 alkoxy groups and C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[0461] ○C3-C 10 cycloalkyl,

[0462] ○Optionally substituted with 1-3 groups independently selected from C1-C6 alkyl and C1-C6 alkoxy groups -(O) 0-1 -(C6-C 10 Aryl),

[0463] ○3 to 10-membered heterocyclic groups, and

[0464] ○N(R N )2,

[0465] ■ C1-C6 alkoxy groups optionally substituted with 1-3 independently selected groups from the following:

[0466] ○ Halogen,

[0467] ○C6-C 10 Aryl, and

[0468] ○ C3-C substituted with 1-3 independently selected C1-C6 fluoroalkyl groups 10 cycloalkyl,

[0469] ■C1-C6 fluoroalkyl groups,

[0470] ■C3-C 10 cycloalkyl,

[0471] ■C6-C 10 Aryl, and

[0472] ■3 to 10-membered heterocyclic groups;

[0473] R ZN Selected from:

[0474] ■ Hydrogen,

[0475] ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0476] ○Hydroxy group,

[0477] ○Oxygenation,

[0478] ○Cyano

[0479] ○ C1-C6 alkoxy groups optionally substituted with 1-3 independently selected halogen and C1-C6 alkoxy groups,

[0480] ○N(R N )2,

[0481] ○SO2Me,

[0482] ○ C3-C cells optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[0483] ◆Hydroxy group,

[0484] ◆Optionally composed of 1-3 independently selected hydroxyl, oxo, C1-C6 alkoxy, C6-C 10 Aryl and N(R) N C1-C6 alkyl groups substituted with 2 groups,

[0485] ◆C1-C6 fluoroalkyl groups,

[0486] ◆C1-C6 alkoxy groups, and

[0487] ◆COOH,

[0488] ◆N(R N )2,

[0489] ◆C6-C 10 Aryl, and

[0490] ◆Optionally substituted with 1-3 independently selected oxo and C1-C6 alkyl groups, 3- to 10-membered heterocyclic groups,

[0491] ○ C6-C cells optionally substituted with 1-3 independently selected groups from the following 10 Aryl:

[0492] ◆Halogen,

[0493] ◆Hydroxy group,

[0494] ◆Cyano

[0495] ◆SiMe3,

[0496] ◆SO2Me,

[0497] ◆SF5,

[0498] ◆N(R N )2,

[0499] ◆P(O)Me2,

[0500] ◆Optionally substituted with 1-3 independently selected C1-C6 fluoroalkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[0501] ◆Optionally composed of 1-3 independently selected hydroxyl, oxo, C1-C6 alkoxy, 5- to 10-membered heteroaryl, SO2Me and N(R) N C1-C6 alkyl groups substituted with 2 groups,

[0502] ◆Optionally selected by 1-3 independently chosen from hydroxyl, oxo, N(R) N )2 and C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[0503] ◆C1-C6 fluoroalkyl groups,

[0504] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, 3- to 10-membered heterocyclic groups,

[0505] ◆-(O) 0-1 -(C6-C 10 Aryl), and

[0506] ◆Optionally coated with hydroxyl, oxidized, N(R) N 2. C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl and C3-C 10 Cycloalkyl-substituted -(O) 0-1 -(5 to 10 heteroaryl),

[0507] ○Optionally substituted with 1 to 4 independently selected groups from the following 3- to 10-membered heterocyclic groups:

[0508] ◆Hydroxy group,

[0509] ◆Oxygenation,

[0510] ◆N(R N )2,

[0511] ◆C1-C6 alkyl groups (optionally substituted with 1-3 independently selected oxo and C1-C6 alkoxy groups),

[0512] ◆C1-C6 alkoxy groups,

[0513] ◆C1-C6 fluoroalkyl groups,

[0514] ◆C6-C cells optionally substituted with 1-3 independently selected halogen groups 10 Aryl, and

[0515] ◆5 to 10 aryl compounds, and

[0516] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0517] ◆Hydroxy group,

[0518] ◆Cyano

[0519] ◆Oxygenation,

[0520] ◆Halogen,

[0521] ◆B(OH)2,

[0522] ◆N(R N )2,

[0523] ◆Optionally substituted with 1-3 independently selected hydroxyl, oxo, C1-C6 alkoxy (optionally substituted with 1-3 -SiMe3) and N(R) N C1-C6 alkyl groups substituted with 2 groups,

[0524] ◆Optionally composed of 1-3 independently selected from hydroxyl, oxo, C1-C6 alkoxy, N(R) N )2 and C3-C 10 C1-C6 alkoxy groups substituted with cycloalkyl groups,

[0525] ◆C1-C6 fluoroalkyl groups,

[0526] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[0527] ◆-(O) 0-1 -(C6-C 10 Aryl),

[0528] ◆Optionally selected by 1-4 independently chosen from hydroxyl, oxo, halogen, cyano, N(R) N 2. C1-C6 alkyl groups (optionally surrounded by 1-3 independently selected from hydroxyl, oxo, N(R) groups) N -(O) groups substituted with C1-C6 alkoxy groups, C1-C6 alkoxy groups, C1-C6 fluoroalkyl groups, or 3- to 10-membered heterocyclic groups (optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl groups). 0-1 -(3 to 10-membered heterocyclic groups), and

[0529] ◆Optionally composed of 1-4 independently selected C1-C6 alkyl groups and C3-C 10 Cycloalkyl groups substituted with 5 to 10-membered heteroaryl groups,

[0530] ■C1-C6 fluoroalkyl groups,

[0531] ■ C3-C, optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[0532] ○Hydroxy group,

[0533] ○Oxygenation,

[0534] ○ Halogen,

[0535] ○Cyano

[0536] ○N(R N )2,

[0537] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0538] ◆Hydroxy group,

[0539] ◆Oxygenation,

[0540] ◆N(R N )2,

[0541] ◆C1-C6 alkoxy groups, and

[0542] ◆C6-C 10 Aryl,

[0543] ○Optionally selected by 1-3 independent elements chosen from halogen, oxidative, C6-C 10 Aryl and N(R) N The C1-C6 alkoxy group substituted with )2,

[0544] ○ Halogen,

[0545] ○C3-C 10 cycloalkyl,

[0546] ○Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, and

[0547] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0548] ◆Hydroxy group,

[0549] ◆Cyano

[0550] ◆Oxygenation,

[0551] ◆Halogen,

[0552] ◆N(R N )2,

[0553] ◆Optionally composed of 1-3 independently selected hydroxyl, oxo, C1-C6 alkoxy, and N(R) groups. N C1-C6 alkyl groups substituted with 2 groups,

[0554] ◆Optionally composed of 1-3 independently selected hydroxyl, C1-C6 alkoxy, N(R) N )2 and C3-C 10 C1-C6 alkoxy groups substituted with cycloalkyl groups,

[0555] ◆C1-C6 fluoroalkyl groups,

[0556] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[0557] ◆C6-C 10 Aryl, and

[0558] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, 3- to 10-membered heterocyclic groups,

[0559] ■C6-C 10 Aryl,

[0560] ■Optionally substituted with 1 to 3 independently selected groups from the following: 3- to 10-membered heterocyclic groups

[0561] ○Oxygenation,

[0562] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0563] ◆Oxygenation,

[0564] ◆Hydroxy group,

[0565] ◆N(R N )2,

[0566] ◆Optionally selected by 1-3 independent elements chosen from halogens and C6-C 10 The C1-C6 alkoxy group substituted with the aryl group, and

[0567] ◆-(O) 0-1 -(C3-C 10 cycloalkyl),

[0568] ○C1-C6 fluoroalkyl,

[0569] ○ C3-C groups optionally substituted with 1-3 independently selected halogen groups 10 cycloalkyl groups, and

[0570] ○3 to 10-membered heterocyclic groups,

[0571] ■ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0572] ○ Halogen,

[0573] ○Optionally selected by 1-3 independently chosen from oxo, C1-C6 alkoxy and N(R) N C1-C6 alkyl groups substituted with )2, and

[0574] ○Optionally composed of 1-3 independently selected C1-C6 alkyl groups (optionally composed of 1-3 selected oxo, C1-C6 alkoxy, and C6-C... 10 3 to 10-membered heterocyclic groups substituted with aryl groups, and

[0575] ■R F ;

[0576] Each R ZC Selected independently from:

[0577] ■ Hydrogen,

[0578] ■Optionally selected from 1-3 independent choices of C6-C 10 C1-C6 alkyl groups substituted with aryl groups (optionally replaced by 1-3 independently selected C1-C6 alkyl groups),

[0579] ■ C6-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 Aryl, and

[0580] ■R F ;

[0581] Or two Rs ZC Together they form an oxo group;

[0582] Each R L1 Selected independently from:

[0583] ■ Hydrogen,

[0584] ■N(R N )2, the condition is two N(R) N )2 does not combine with the same carbon atom.

[0585] ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0586] ○ Halogen,

[0587] ○Hydroxy group,

[0588] ○Oxygenation,

[0589] ○N(R N )2,

[0590] ○Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[0591] ○ C3-C substituted with 1-3 groups independently selected from halogens and C1-C6 fluoroalkyl groups 10 cycloalkyl,

[0592] ○ C6-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 Aryl, and

[0593] ○ A 3- to 10-membered heterocyclic group optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl groups (optionally substituted with 1 to 3 groups independently selected from hydroxyl and oxo groups),

[0594] ■C3-C 10cycloalkyl,

[0595] ■ C6-C cells optionally substituted with 1-4 independently selected groups from the following 10 Aryl:

[0596] ○ Halogen,

[0597] ○Cyano

[0598] ○SiMe3,

[0599] ○POMe2,

[0600] ○ C1-C7 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0601] ◆Hydroxy group,

[0602] ◆Oxygenation,

[0603] ◆Cyano

[0604] ◆SiMe3,

[0605] ◆N(R N )2, and

[0606] ◆C3-C2 substituted with 1-3 independently selected C1-C6 fluoroalkyl groups 10 cycloalkyl,

[0607] ○ C1-C6 alkoxy groups optionally substituted with 1-3 independently selected groups from the following:

[0608] ◆C3-C2 substituted with 1-3 independently selected C1-C6 fluoroalkyl groups 10 cycloalkyl groups, and

[0609] ◆C1-C6 alkoxy groups,

[0610] ○C1-C6 fluoroalkyl,

[0611] ○ C3-C2 groups optionally substituted with 1-3 groups independently selected from C1-C6 alkyl and C1-C6 fluoroalkyl groups 10 cycloalkyl,

[0612] ○C6-C 10 Aryl,

[0613] ○Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, and

[0614] ○5 to 10 yuan of mixed aromatic compounds,

[0615] ■Optionally substituted with 1 to 3 independently selected groups from the following: 3- to 10-membered heterocyclic groups

[0616] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0617] ◆Oxygenation, and

[0618] ◆C1-C6 alkoxy groups,

[0619] ■ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0620] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0621] ◆C3-C2 substituted with 1-3 independently selected C1-C6 fluoroalkyl groups 10 cycloalkyl groups, and

[0622] ○ C6-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 Aryl, and

[0623] ■R F ;

[0624] Or two R atoms on the same carbon atom L1 Together they form an oxo group;

[0625] Each R L2 Independently selected from hydrogen and R F Or two R atoms on the same carbon atom L2 Together they form an oxo group; provided that at least one R L1 Or R L2 It is R F ;

[0626] Each R N Selected independently from:

[0627] ■ Hydrogen,

[0628] ■ C1-C8 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0629] ○Oxygenation,

[0630] ○ Halogen,

[0631] ○Hydroxy group,

[0632] ○NH2,

[0633] ○NHMe,

[0634] ○NMe2,

[0635] ○Optionally selected from 1-3 independent selections from C6-C10 The C1-C6 alkoxy group substituted by the aryl group,

[0636] ○-(O) 0-1 -(C3-C 10 cycloalkyl),

[0637] ○ C6-C alkyl groups optionally substituted with 1-3 independently selected groups selected from halogens and C1-C6 alkyl groups 10 Aryl,

[0638] ○Optionally substituted with 1-4 independently selected oxo and C1-C6 alkyl groups, and

[0639] ○ 5- to 14-membered heteroaryl groups optionally substituted by 1 to 4 independently selected oxo and C1-C6 alkyl groups,

[0640] ■ C3-C, optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[0641] ○Hydroxy group,

[0642] ○NH2, and

[0643] ○NHMe, and

[0644] ○ C1-C6 alkyl groups optionally substituted with 1-3 independently selected groups selected from hydroxyl groups,

[0645] ■C6-C 10 Aryl, and

[0646] ■3 to 10-membered heterocyclic groups;

[0647] Or two R atoms on the same nitrogen atom N Together with the nitrogen it binds to, it forms a 3- to 10-membered heterocyclic group, optionally substituted with 1 to 3 groups selected from the following:

[0648] ■Hydroxy

[0649] ■Oxytochemicals

[0650] ■Cyano

[0651] ■Optionally selected by 1-3 independently chosen from oxo, hydroxyl, C1-C6 alkoxy and N(R) N2 )2 substituted C1-C6 alkyl groups, wherein each R N2 Independently selected from hydrogen and C1-C6 alkyl groups,

[0652] ■C1-C6 alkoxy groups, and

[0653] ■C1-C6 fluoroalkyl groups;

[0654] Or an R 4 And an R L1 Together they form C6-C8 alkylene groups;

[0655] Two Rs F Together with the atoms they are bonded to, they form groups selected from the following:

[0656] ■ C3-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 cycloalkyl,

[0657] ■ C6-C, optionally substituted by 1-3 independently selected groups from the following 10 Aryl:

[0658] ○ Halogen,

[0659] ○C1-C6 alkyl,

[0660] ○N(R N )2, and

[0661] ○ A 3- to 10-membered heterocyclic group optionally substituted by 1 to 3 independently selected groups chosen from hydroxyl groups.

[0662] ■ 3- to 11-membered heterocyclic groups optionally substituted by 1 to 3 independently selected groups from the following:

[0663] ○Oxygenation,

[0664] ○N(R N )2,

[0665] ○ C1-C9 alkyl groups optionally substituted by 1-4 independently selected groups from the following:

[0666] ◆Oxygenation,

[0667] ◆Halogen,

[0668] ◆Hydroxy group,

[0669] ◆N(R N )2,

[0670] ◆-SO2-(C1-C6 alkyl),

[0671] ◆Optionally selected by 1-3 independent elements chosen from halogens, C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[0672] ◆Optionally substituted with 1-3 groups independently selected from hydroxyl, halogen, cyano, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C1-C6 alkoxy), C1-C6 alkoxy (optionally substituted with 1-3 groups independently selected from C6-C6).10 Aryl group substitution), -(O) 0-1 -(C1-C6 fluoroalkyl) and C6-C 10 The C6-C group substituted with an aryl group (optionally replaced by 1-3 groups independently selected from C1-C6 alkoxy groups). 10 Aryl,

[0673] ◆Optionally selected by 1-4 independently chosen from hydroxyl, halogen, N(R) N 2. C1-C6 alkyl groups (optionally substituted with 1-3 groups independently selected from oxo, hydroxyl, and C1-C6 alkoxy groups), C1-C6 fluoroalkyl groups, and C6-C6 alkyl groups. 10 The -(O) group substituted by the aryl group 0-1 -(C3-C 10 cycloalkyl),

[0674] ◆Optionally, it is composed of 1-3 independently selected oxo, C1-C6 alkyl groups (optionally, it is composed of 1-3 independently selected C6-C6 alkyl groups). 10 Aryl groups (optionally substituted with 1-3 independently selected halogen groups), C1-C6 alkoxy groups, C3-C6 alkoxy groups, C4-C6 alkoxy groups, C5-C6 alkoxy groups, C6-C6 alkoxy groups, C6-C6 alkoxy groups, C7 ... 10 cycloalkyl and R N substituted 3- to 10-membered heterocyclic groups,

[0675] ◆Optionally selected from 1-3 independent selections from C6-C 10 -O- (5 to 12-membered heteroaryl groups) substituted with aryl groups (optionally substituted with 1 to 3 independently selected halogen groups) and C1-C6 alkyl groups, and

[0676] ◆Optionally selected by 1-3 independently chosen from 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 10 Cycloalkyl groups substituted with 5 to 10-membered heteroaryl groups,

[0677] ○ C3-C alkyl groups optionally substituted with 1-4 independently selected groups chosen from halogens, C1-C6 alkyl groups, and C1-C6 fluoroalkyl groups 12 cycloalkyl,

[0678] ○C6-C 10 Aryl,

[0679] ○3 to 10-membered heterocyclic groups, and

[0680] ○Optionally composed of 1-3 independently selected C1-C6 alkoxy, C1-C6 fluoroalkyl and N(R) N )2 substituted with 5 to 10 heteroaryl groups, and

[0681] ■ 5 to 12 heteroaryl groups optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl and C1-C6 fluoroalkyl groups.

[0682] 1A. In some cases of Example 1, when two R F When forming a 3- to 11-membered heterocyclic group, wherein the 3- to 11-membered heterocyclic group is optionally substituted with a 5- to 10-membered heteroaryl group, and wherein the 5- to 10-membered heteroaryl group is optionally substituted with a C1-C6 alkoxy group, wherein the C1-C6 alkoxy group may optionally be substituted with a C6-C6 alkoxy group. 10 Aryl substitution.

[0683] 2. The compound, salt, or deuterated derivative according to Example 1, wherein ring A is selected from C6-C. 10 Aryl, 3- to 10-membered heterocyclic and 5- to 10-membered heteroaryl.

[0684] 3. The compound, salt, or deuterated derivative according to Example 1 or 2, wherein ring A is selected from phenyl, pyridyl, pyrazolyl, 1H-pyrroleyl, indololinyl, and piperidinyl.

[0685] 4. The compound, salt or deuterated derivative according to any one of Examples 1 to 3, wherein ring A is phenyl.

[0686] 5. The compound, salt, or deuterated derivative according to any one of Examples 1 to 4, wherein ring B is selected from C6-C. 10 Aryl.

[0687] 6. The compound, salt, or deuterated derivative according to any one of Examples 1 to 5, wherein ring B is phenyl.

[0688] 7. The compound, salt or deuterated derivative according to any one of Examples 1 to 6, wherein V is O.

[0689] 8. The compound, salt or deuterated derivative according to any one of Examples 1 to 6, wherein V is NH.

[0690] 9. The compound, salt, or deuterated derivative according to any one of Examples 1 to 8, wherein W 1 It is N and W 2 It is N.

[0691] 10. The compound, salt, or deuterated derivative according to any one of Examples 1 to 9, wherein Z is selected from NR. ZN and C(R) ZC )2.

[0692] 11. The compound, salt, or deuterated derivative according to any one of Examples 1 to 10, wherein each R 3 It is independently selected from C1-C6 alkyl groups.

[0693] 12. The compound, salt, or deuterated derivative according to any one of Examples 1 to 11, wherein each R 3 It is a methyl group.

[0694] 13. The compound, salt, or deuterated derivative according to any one of Examples 1 to 10, wherein R 3 It does not exist.

[0695] 14. The compound, salt, or deuterated derivative according to any one of Examples 1 to 13, wherein R 4 Selected from hydrogen and methyl.

[0696] 15. The compound, salt, or deuterated derivative according to any one of Examples 1 to 14, wherein R 4 It is a methyl group.

[0697] 16. The compound, salt, or deuterated derivative according to any one of Examples 1 to 14, wherein R 4 It is hydrogen.

[0698] 17. The compound, salt, or deuterated derivative according to any one of Examples 1 to 16, wherein each R 5 It is independently selected from C1-C6 alkyl and C1-C6 alkoxy.

[0699] 18. The compound, salt, or deuterated derivative according to any one of Examples 1 to 17, wherein each R 5 Independently selected from methyl,

[0700] 19. The compound, salt, or deuterated derivative according to any one of Examples 1 to 18, wherein R ZN Selected from hydrogen and R F .

[0701] 20. The compound, salt, or deuterated derivative according to any one of Examples 1 to 19, wherein R ZN It is hydrogen.

[0702] 21. The compound, salt, or deuterated derivative according to any one of Examples 1 to 19, wherein R ZN It is R F .

[0703] 22. The compound, salt, or deuterated derivative according to any one of Examples 1 to 21, wherein R ZCIt's hydrogen, or two Rs. ZC Together they form an oxo group.

[0704] 23. The compound, salt, or deuterated derivative according to any one of Examples 1 to 22, wherein each R L1 Independently selected from hydrogen, optionally selected by 1-3 independently selected from C6-C 10 Aryl groups substituted with C1-C9 alkyl groups and R F .

[0705] 24. The compound, salt, or deuterated derivative according to any one of Examples 1 to 23, wherein each R L2 Independently selected from hydrogen and R F Or two R atoms on the same carbon atom L2 Together they form an oxo group.

[0706] 25. The compound, salt, or deuterated derivative according to any one of Examples 1 to 24, wherein each R N Independently selected from hydrogen and C1-C8 alkyl groups (optionally 1-3 independently selected from oxo, C1-C6 alkoxy, C3-C... 10 cycloalkyl and C6-C 10 (Substitution of aryl groups).

[0707] 26. The compound, salt, or deuterated derivative according to any one of Examples 1 to 25, wherein the two Rs F Together with the atoms they are bonded to, they form groups selected from the following:

[0708] ■C6-C 10 Aryl, and

[0709] ■ 3- to 11-membered heterocyclic groups optionally substituted by 1 to 3 independently selected groups from the following:

[0710] ○Oxygenation,

[0711] ○ C1-C9 alkyl groups optionally substituted by 1-4 independently selected groups from the following:

[0712] ◆Oxygenation,

[0713] ◆Halogen,

[0714] ◆Hydroxy group,

[0715] ◆N(R N )2,

[0716] ◆Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[0717] ◆C6-C groups optionally substituted with 1-3 independently selected groups chosen from hydroxyl, cyano, and C1-C6 alkyl groups 10 Aryl,

[0718] ◆Optionally selected from 1-4 independent factors N(R) N 2. -(O) groups substituted with C1-C6 alkyl groups (optionally substituted with 1-3 groups independently selected from oxo, hydroxyl, and C1-C6 alkoxy groups) and C1-C6 fluoroalkyl groups. 0-1 -(C3-C 10 cycloalkyl),

[0719] ◆Optionally substituted with 1-3 independently selected oxo and C1-C6 alkyl groups, and

[0720] ◆Optionally selected from 1-3 independent selections from N(R) N )2, C1-C6 alkyl groups and -O-(C6-C 10 5-10 membered heteroaryl groups substituted with aryl groups,

[0721] ○ C3-C alkyl groups optionally substituted with 1-4 independently selected groups selected from halogens and C1-C6 alkyl groups 12 cycloalkyl,

[0722] ○C6-C 10 Aryl, and

[0723] ○3 to 10-membered heterocyclic groups.

[0724] 27. A compound of formula Ia:

[0725]

[0726] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A, ring B, and ring W 1 W 2 Z, L 1 L 2 R 3 R 4 R 5 and R F Defined as described in Example 1.

[0727] 28. The compound, salt, or deuterated derivative according to Example 27, wherein ring A is selected from C6-C. 10 Aryl, 3- to 10-membered heterocyclic and 5- to 10-membered heteroaryl.

[0728] 29. The compound, salt, or deuterated derivative according to Example 27 or 28, wherein ring A is selected from phenyl, pyridyl, pyrazolyl, 1H-pyrroleyl, indololinyl, and piperidinyl.

[0729] 30. The compound, salt or deuterated derivative according to any one of Examples 27 to 29, wherein ring A is phenyl.

[0730] 31. The compound, salt, or deuterated derivative according to any one of Examples 27 to 30, wherein ring B is selected from C6-C. 10 Aryl.

[0731] 32. The compound, salt or deuterated derivative according to any one of Examples 27 to 31, wherein ring B is phenyl.

[0732] 33. The compound, salt, or deuterated derivative according to any one of Examples 27 to 32, wherein W 1 It is N and W 2 It is N.

[0733] 34. The compound, salt, or deuterated derivative according to any one of Examples 27 to 33, wherein Z is selected from NR. ZN and C(R) ZC )2.

[0734] 35. The compound, salt, or deuterated derivative according to any one of Examples 27 to 34, wherein each R 3 It is independently selected from C1-C6 alkyl groups.

[0735] 36. The compound, salt, or deuterated derivative according to any one of Examples 27 to 35, wherein each R 3 It is a methyl group.

[0736] 37. The compound, salt, or deuterated derivative according to any one of Examples 27 to 34, wherein R 3 It does not exist.

[0737] 38. The compound, salt, or deuterated derivative according to any one of Examples 27 to 37, wherein R 4 Selected from hydrogen and methyl.

[0738] 39. The compound, salt, or deuterated derivative according to any one of Examples 27 to 38, wherein R 4 It is a methyl group.

[0739] 40. The compound, salt, or deuterated derivative according to any one of Examples 27 to 38, wherein R 4 It is hydrogen.

[0740] 41. The compound, salt, or deuterated derivative according to any one of Examples 27 to 40, wherein each R 5 It is independently selected from C1-C6 alkyl and C1-C6 alkoxy.

[0741] 42. The compound, salt, or deuterated derivative according to any one of Examples 27 to 41, wherein each R 5 Independently selected from methyl,

[0742] 43. The compound, salt, or deuterated derivative according to any one of Examples 27 to 42, wherein R ZN Selected from hydrogen and R F .

[0743] 44. The compound, salt, or deuterated derivative according to any one of Examples 27 to 43, wherein R ZN It is hydrogen.

[0744] 45. The compound, salt, or deuterated derivative according to any one of Examples 27 to 44, wherein R ZN It is R F .

[0745] 46. ​​The compound, salt, or deuterated derivative according to any one of Examples 27 to 45, wherein R ZC It's hydrogen, or two Rs. ZC Together they form an oxo group.

[0746] 47. The compound, salt, or deuterated derivative according to any one of Examples 27 to 46, wherein each R L1 Independently selected from hydrogen, optionally selected by 1-3 independently selected from C6-C 10 Aryl groups substituted with C1-C9 alkyl groups and R F .

[0747] 48. The compound, salt, or deuterated derivative according to any one of Examples 27 to 47, wherein each R L2 Independently selected from hydrogen and R F Or two R atoms on the same carbon atom L2 Together they form an oxo group.

[0748] 49. The compound, salt, or deuterated derivative according to any one of Examples 27 to 48, wherein each R N Independently selected from hydrogen and C1-C8 alkyl groups (optionally 1-3 independently selected from oxo, C1-C6 alkoxy, C3-C... 10 cycloalkyl and C6-C 10 (Substitution of aryl groups).

[0749] 50. The compound, salt, or deuterated derivative according to any one of Examples 27 to 49, wherein the two Rs F Together with the atoms they are bonded to, they form groups selected from the following:

[0750] ■C6-C 10 Aryl, and

[0751] ■ 3- to 11-membered heterocyclic groups optionally substituted by 1 to 3 independently selected groups from the following:

[0752] ○Oxygenation,

[0753] ○ C1-C9 alkyl groups optionally substituted by 1-4 independently selected groups from the following:

[0754] ◆Oxygenation,

[0755] ◆Halogen,

[0756] ◆Hydroxy group,

[0757] ◆N(R N )2,

[0758] ◆Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[0759] ◆C6-C groups optionally substituted with 1-3 independently selected groups chosen from hydroxyl, cyano, and C1-C6 alkyl groups 10 Aryl,

[0760] ◆Optionally selected from 1-4 independent factors N(R) N 2. -(O) groups substituted with C1-C6 alkyl groups (optionally substituted with 1-3 groups independently selected from oxo, hydroxyl, and C1-C6 alkoxy groups) and C1-C6 fluoroalkyl groups. 0-1 -(C3-C 10 cycloalkyl),

[0761] ◆Optionally substituted with 1-3 independently selected oxo and C1-C6 alkyl groups, and

[0762] ◆Optionally selected from 1-3 independent selections from N(R) N )2, C1-C6 alkyl groups and -O-(C6-C 10 5-10 membered heteroaryl groups substituted with aryl groups,

[0763] ○ C3-C alkyl groups optionally substituted with 1-4 independently selected groups selected from halogens and C1-C6 alkyl groups 12 cycloalkyl,

[0764] ○C6-C 10Aryl, and

[0765] ○3 to 10-membered heterocyclic groups.

[0766] 51. A compound of formula IIa:

[0767]

[0768] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein rings B and W 1 W 2 Z, L 1 L 2 R 3 R 4 R 5 and R F Defined as described in Example 1.

[0769] 52. The compound, salt, or deuterated derivative according to Example 51, wherein ring B is selected from C6-C. 10 Aryl.

[0770] 53. The compound, salt, or deuterated derivative according to Example 51 or 52, wherein ring B is phenyl.

[0771] 54. The compound, salt, or deuterated derivative according to any one of Examples 51 to 53, wherein W 1 It is N and W 2 It is N.

[0772] 55. The compound, salt, or deuterated derivative according to any one of Examples 51 to 54, wherein Z is selected from NR. ZN and C(R) ZC )2.

[0773] 56. The compound, salt, or deuterated derivative according to any one of Examples 51 to 55, wherein each R 3 It is independently selected from C1-C6 alkyl groups.

[0774] 57. The compound, salt, or deuterated derivative according to any one of Examples 51 to 56, wherein each R 3 It is a methyl group.

[0775] 58. The compound, salt, or deuterated derivative according to any one of Examples 51 to 55, wherein R 3 It does not exist.

[0776] 59. The compound, salt, or deuterated derivative according to any one of Examples 51 to 58, wherein R 4 Selected from hydrogen and methyl.

[0777] 60. The compound, salt, or deuterated derivative according to any one of Examples 51 to 59, wherein R 4 It is a methyl group.

[0778] 61. The compound, salt, or deuterated derivative according to any one of Examples 51 to 59, wherein R 4 It is hydrogen.

[0779] 62. The compound, salt, or deuterated derivative according to any one of Examples 51 to 61, wherein each R 5 It is independently selected from C1-C6 alkyl and C1-C6 alkoxy.

[0780] 63. The compound, salt, or deuterated derivative according to any one of Examples 51 to 62, wherein each R 5 Independently selected from methyl,

[0781] 64. The compound, salt, or deuterated derivative according to any one of Examples 51 to 63, wherein R ZN Selected from hydrogen and R F .

[0782] 65. The compound, salt, or deuterated derivative according to any one of Examples 51 to 64, wherein R ZN It is hydrogen.

[0783] 66. The compound, salt, or deuterated derivative according to any one of Examples 51 to 64, wherein R ZN It is R F .

[0784] 67. The compound, salt, or deuterated derivative according to any one of Examples 51 to 66, wherein R ZC It's hydrogen, or two Rs. ZC Together they form an oxo group.

[0785] 68. The compound, salt, or deuterated derivative according to any one of Examples 51 to 67, wherein each R L1 Independently selected from hydrogen, optionally selected by 1-3 independently selected from C6-C 10 Aryl groups substituted with C1-C9 alkyl groups and R F .

[0786] 69. The compound, salt, or deuterated derivative according to any one of Examples 51 to 68, wherein each R L2 Independently selected from hydrogen and R F Or two R atoms on the same carbon atom L2 Together they form an oxo group.

[0787] 70. The compound, salt, or deuterated derivative according to any one of Examples 51 to 69, wherein each R N Independently selected from hydrogen and C1-C8 alkyl groups (optionally 1-3 independently selected from oxo, C1-C6 alkoxy, C3-C... 10 cycloalkyl and C6-C 10 (Substitution of aryl groups).

[0788] 71. The compound, salt, or deuterated derivative according to any one of Examples 51 to 70, wherein the two Rs F Together with the atoms they are bonded to, they form groups selected from the following:

[0789] ■C6-C 10 Aryl, and

[0790] ■ 3- to 11-membered heterocyclic groups optionally substituted by 1 to 3 independently selected groups from the following:

[0791] ○Oxygenation,

[0792] ○ C1-C9 alkyl groups optionally substituted by 1-4 independently selected groups from the following:

[0793] ◆Oxygenation,

[0794] ◆Halogen,

[0795] ◆Hydroxy group,

[0796] ◆N(R N )2,

[0797] ◆Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[0798] ◆C6-C groups optionally substituted with 1-3 independently selected groups chosen from hydroxyl, cyano, and C1-C6 alkyl groups 10 Aryl,

[0799] ◆Optionally selected from 1-4 independent factors N(R) N 2. -(O) groups substituted with C1-C6 alkyl groups (optionally substituted with 1-3 groups independently selected from oxo, hydroxyl, and C1-C6 alkoxy groups) and C1-C6 fluoroalkyl groups. 0-1 -(C3-C 10 cycloalkyl),

[0800] ◆Optionally substituted with 1-3 independently selected oxo and C1-C6 alkyl groups, and

[0801] ◆Optionally selected from 1-3 independent selections from N(R) N)2, C1-C6 alkyl groups and -O-(C6-C 10 5-10 membered heteroaryl groups substituted with aryl groups,

[0802] ○ C3-C alkyl groups optionally substituted with 1-4 independently selected groups selected from halogens and C1-C6 alkyl groups 12 cycloalkyl,

[0803] ○C6-C 10 Aryl, and

[0804] ○3 to 10-membered heterocyclic groups.

[0805] 72. A compound of formula IIb:

[0806]

[0807] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein rings A and W 1 W 2 Z, L 1 L 2 R 3 R 4 R 5 and R F Defined as described in Example 1.

[0808] 73. The compound, salt, or deuterated derivative according to Example 72, wherein ring A is selected from C6-C. 10 Aryl, 3- to 10-membered heterocyclic and 5- to 10-membered heteroaryl.

[0809] 74. The compound, salt, or deuterated derivative according to Example 72 or 73, wherein ring A is selected from phenyl, pyridyl, pyrazolyl, 1H-pyrroleyl, indololinyl, and piperidinyl.

[0810] 75. The compound, salt, or deuterated derivative according to any one of Examples 72 to 74, wherein ring A is phenyl.

[0811] 76. The compound, salt, or deuterated derivative according to any one of Examples 72 to 75, wherein W 1 It is N and W 2 It is N.

[0812] 77. The compound, salt, or deuterated derivative according to any one of Examples 72 to 76, wherein Z is selected from NR. ZN and C(R) ZC )2.

[0813] 78. The compound, salt, or deuterated derivative according to any one of Examples 2 to 77, wherein each R 3 It is independently selected from C1-C6 alkyl groups.

[0814] 79. The compound, salt, or deuterated derivative according to any one of Examples 72 to 78, wherein each R 3 It is a methyl group.

[0815] 80. The compound, salt, or deuterated derivative according to any one of Examples 72 to 77, wherein R 3 It does not exist.

[0816] 81. The compound, salt, or deuterated derivative according to any one of Examples 72 to 80, wherein R 4 Selected from hydrogen and methyl.

[0817] 82. The compound, salt, or deuterated derivative according to any one of Examples 72 to 81, wherein R 4 It is a methyl group.

[0818] 83. The compound, salt, or deuterated derivative according to any one of Examples 72 to 81, wherein R 4 It is hydrogen.

[0819] 84. The compound, salt, or deuterated derivative according to any one of Examples 72 to 83, wherein each R 5 It is independently selected from C1-C6 alkyl and C1-C6 alkoxy.

[0820] 85. The compound, salt, or deuterated derivative according to any one of Examples 72 to 84, wherein each R 5 Independently selected from methyl,

[0821] 86. The compound, salt, or deuterated derivative according to any one of Examples 72 to 85, wherein R ZN Selected from hydrogen and R F .

[0822] 87. The compound, salt, or deuterated derivative according to any one of Examples 72 to 86, wherein R ZN It is hydrogen.

[0823] 88. The compound, salt, or deuterated derivative according to any one of Examples 72 to 86, wherein R ZN It is R F .

[0824] 89. The compound, salt, or deuterated derivative according to any one of Examples 72 to 88, wherein R ZC It's hydrogen, or two Rs.ZC Together they form an oxo group.

[0825] 90. The compound, salt, or deuterated derivative according to any one of Examples 72 to 89, wherein each R L1 Independently selected from hydrogen, optionally selected by 1-3 independently selected from C6-C 10 Aryl groups substituted with C1-C9 alkyl groups and R F .

[0826] 91. The compound, salt, or deuterated derivative according to any one of Examples 72 to 90, wherein each R L2 Independently selected from hydrogen and R F Or two R atoms on the same carbon atom L2 Together they form an oxo group.

[0827] 92. The compound, salt, or deuterated derivative according to any one of Examples 72 to 91, wherein each R N Independently selected from hydrogen and C1-C8 alkyl groups (optionally 1-3 independently selected from oxo, C1-C6 alkoxy, C3-C... 10 cycloalkyl and C6-C 10 (Substitution of aryl groups).

[0828] 93. The compound, salt, or deuterated derivative according to any one of Examples 72 to 92, wherein the two Rs F Together with the atoms they are bonded to, they form groups selected from the following:

[0829] ■C6-C 10 Aryl, and

[0830] ■ 3- to 11-membered heterocyclic groups optionally substituted by 1 to 3 independently selected groups from the following:

[0831] ○Oxygenation,

[0832] ○ C1-C9 alkyl groups optionally substituted by 1-4 independently selected groups from the following:

[0833] ◆Oxygenation,

[0834] ◆Halogen,

[0835] ◆Hydroxy group,

[0836] ◆N(R N )2,

[0837] ◆Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[0838] ◆C6-C groups optionally substituted with 1-3 independently selected groups chosen from hydroxyl, cyano, and C1-C6 alkyl groups 10 Aryl,

[0839] ◆Optionally selected from 1-4 independent factors N(R) N 2. -(O) groups substituted with C1-C6 alkyl groups (optionally substituted with 1-3 groups independently selected from oxo, hydroxyl, and C1-C6 alkoxy groups) and C1-C6 fluoroalkyl groups. 0-1 -(C3-C 10 cycloalkyl),

[0840] ◆Optionally substituted with 1-3 independently selected oxo and C1-C6 alkyl groups, and

[0841] ◆Optionally selected from 1-3 independent selections from N(R) N )2, C1-C6 alkyl groups and -O-(C6-C 10 5-10 membered heteroaryl groups substituted with aryl groups,

[0842] ○ C3-C alkyl groups optionally substituted with 1-4 independently selected groups selected from halogens and C1-C6 alkyl groups 12 cycloalkyl,

[0843] ○C6-C 10 Aryl, and

[0844] ○3 to 10-membered heterocyclic groups.

[0845] 94. A compound of formula III:

[0846]

[0847] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein W 1 W 2 Z, L 1 L 2 R 4 R 5 and R F Defined as described in Example 1.

[0848] 95. The compound, salt, or deuterated derivative according to Example 94, wherein W 1 It is N and W 2 It is N.

[0849] 96. The compound, salt, or deuterated derivative according to Example 94 or 95, wherein Z is selected from NR. ZN and C(R) ZC )2.

[0850] 97. The compound, salt, or deuterated derivative according to any one of Examples 94 to 96, wherein R 4 Selected from hydrogen and methyl.

[0851] 98. The compound, salt, or deuterated derivative according to any one of Examples 94 to 97, wherein R 4 It is a methyl group.

[0852] 99. The compound, salt, or deuterated derivative according to any one of Examples 94 to 97, wherein R 4 It is hydrogen.

[0853] 100. The compound, salt, or deuterated derivative according to any one of Examples 94 to 99, wherein each R 5 It is independently selected from C1-C6 alkyl and C1-C6 alkoxy.

[0854] 101. The compound, salt, or deuterated derivative according to any one of Examples 94 to 100, wherein each R 5 Independently selected from methyl,

[0855] 102. The compound, salt, or deuterated derivative according to any one of Examples 94 to 101, wherein R ZN Selected from hydrogen and R F .

[0856] 103. The compound, salt, or deuterated derivative according to any one of Examples 94 to 102, wherein R ZN It is hydrogen.

[0857] 104. The compound, salt, or deuterated derivative according to any one of Examples 94 to 102, wherein R ZN It is R F .

[0858] 105. The compound, salt, or deuterated derivative according to any one of Examples 94 to 104, wherein R ZC It's hydrogen, or two Rs. ZC Together they form an oxo group.

[0859] 106. The compound, salt, or deuterated derivative according to any one of Examples 94 to 105, wherein each R L1 Independently selected from hydrogen, optionally selected by 1-3 independently selected from C6-C 10 Aryl groups substituted with C1-C9 alkyl groups and R F .

[0860] 107. The compound, salt, or deuterated derivative according to any one of Examples 94 to 106, wherein each R L2 Independently selected from hydrogen and R F Or two R atoms on the same carbon atom L2 Together they form an oxo group.

[0861] 108. The compound, salt, or deuterated derivative according to any one of Examples 94 to 107, wherein each R N Independently selected from hydrogen and C1-C8 alkyl groups (optionally 1-3 independently selected from oxo, C1-C6 alkoxy, C3-C... 10 cycloalkyl and C6-C 10 (Substitution of aryl groups).

[0862] 109. The compound, salt, or deuterated derivative according to any one of Examples 94 to 108, wherein the two Rs F Together with the atoms they are bonded to, they form groups selected from the following:

[0863] ■C6-C 10 Aryl, and

[0864] ■ 3- to 11-membered heterocyclic groups optionally substituted by 1 to 3 independently selected groups from the following:

[0865] ○Oxygenation,

[0866] ○ C1-C9 alkyl groups optionally substituted by 1-4 independently selected groups from the following:

[0867] ◆Oxygenation,

[0868] ◆Halogen,

[0869] ◆Hydroxy group,

[0870] ◆N(R N )2,

[0871] ◆Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[0872] ◆C6-C groups optionally substituted with 1-3 independently selected groups chosen from hydroxyl, cyano, and C1-C6 alkyl groups 10 Aryl,

[0873] ◆Optionally selected from 1-4 independent factors N(R) N 2. -(O) groups substituted with C1-C6 alkyl groups (optionally substituted with 1-3 groups independently selected from oxo, hydroxyl, and C1-C6 alkoxy groups) and C1-C6 fluoroalkyl groups. 0-1 -(C3-C 10cycloalkyl),

[0874] ◆Optionally substituted with 1-3 independently selected oxo and C1-C6 alkyl groups, and

[0875] ◆Optionally selected from 1-3 independent selections from N(R) N )2, C1-C6 alkyl groups and -O-(C6-C 10 5-10 membered heteroaryl groups substituted with aryl groups,

[0876] ○ C3-C alkyl groups optionally substituted with 1-4 independently selected groups selected from halogens and C1-C6 alkyl groups 12 cycloalkyl,

[0877] ○C6-C 10 Aryl, and

[0878] ○3 to 10-membered heterocyclic groups.

[0879] 110. A compound of formula IV:

[0880]

[0881] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein Z, L 1 L 2 R 4 R 5 and R F Defined as described in Example 1.

[0882] 111. The compound, salt, or deuterated derivative according to Example 110, wherein Z is selected from NR. ZN and C(R) ZC )2.

[0883] 112. The compound, salt, or deuterated derivative according to Example 110 or 111, wherein R 4 Selected from hydrogen and methyl.

[0884] 113. The compound, salt, or deuterated derivative according to any one of Examples 110 to 112, wherein R 4 It is a methyl group.

[0885] 114. The compound, salt, or deuterated derivative according to any one of Examples 110 to 112, wherein R 4 It is hydrogen.

[0886] 115. The compound, salt, or deuterated derivative according to any one of Examples 110 to 114, wherein each R 5It is independently selected from C1-C6 alkyl and C1-C6 alkoxy.

[0887] 116. The compound, salt, or deuterated derivative according to any one of Examples 110 to 115, wherein each R 5 Independently selected from methyl,

[0888] 117. The compound, salt, or deuterated derivative according to any one of Examples 110 to 116, wherein R ZN Selected from hydrogen and R F .

[0889] 118. The compound, salt, or deuterated derivative according to any one of Examples 110 to 117, wherein R ZN It is hydrogen.

[0890] 119. The compound, salt, or deuterated derivative according to any one of Examples 110 to 117, wherein R ZN It is R F .

[0891] 120. The compound, salt, or deuterated derivative according to any one of Examples 110 to 119, wherein R ZC It's hydrogen, or two Rs. ZC Together they form an oxo group.

[0892] 121. The compound, salt, or deuterated derivative according to any one of Examples 110 to 120, wherein each R L1 Independently selected from hydrogen, optionally selected by 1-3 independently selected from C6-C 10 Aryl groups substituted with C1-C9 alkyl groups and R F .

[0893] 122. The compound, salt, or deuterated derivative according to any one of Examples 110 to 121, wherein each R L2 Independently selected from hydrogen and R F Or two R atoms on the same carbon atom L2 Together they form an oxo group.

[0894] 123. The compound, salt, or deuterated derivative according to any one of Examples 110 to 122, wherein each R N Independently selected from hydrogen and C1-C8 alkyl groups (optionally 1-3 independently selected from oxo, C1-C6 alkoxy, C3-C... 10 cycloalkyl and C6-C 10 (Substitution of aryl groups).

[0895] 124. The compound, salt, or deuterated derivative according to any one of Examples 110 to 123, wherein the two Rs F Together with the atoms they are bonded to, they form groups selected from the following:

[0896] ■C6-C 10 Aryl, and

[0897] ■ 3- to 11-membered heterocyclic groups optionally substituted by 1 to 3 independently selected groups from the following:

[0898] ○Oxygenation,

[0899] ○ C1-C9 alkyl groups optionally substituted by 1-4 independently selected groups from the following:

[0900] ◆Oxygenation,

[0901] ◆Halogen,

[0902] ◆Hydroxy group,

[0903] ◆N(R N )2,

[0904] ◆Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[0905] ◆C6-C groups optionally substituted with 1-3 independently selected groups chosen from hydroxyl, cyano, and C1-C6 alkyl groups 10 Aryl,

[0906] ◆Optionally selected from 1-4 independent factors N(R) N 2. -(O) groups substituted with C1-C6 alkyl groups (optionally substituted with 1-3 groups independently selected from oxo, hydroxyl, and C1-C6 alkoxy groups) and C1-C6 fluoroalkyl groups. 0-1 -(C3-C 10 cycloalkyl),

[0907] ◆Optionally substituted with 1-3 independently selected oxo and C1-C6 alkyl groups, and

[0908] ◆Optionally selected from 1-3 independent selections from N(R) N )2, C1-C6 alkyl groups and -O-(C6-C 10 5-10 membered heteroaryl groups substituted with aryl groups,

[0909] ○ C3-C alkyl groups optionally substituted with 1-4 independently selected groups selected from halogens and C1-C6 alkyl groups 12 cycloalkyl,

[0910] ○C6-C10 Aryl, and

[0911] ○3 to 10-membered heterocyclic groups.

[0912] 125. A compound of formula V:

[0913]

[0914] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein Z, L 1 L 2 R 4 R 5 and R F Defined as described in Example 1.

[0915] 126. The compound, salt, or deuterated derivative according to Example 125, wherein Z is selected from NR. ZN and C(R) ZC )2.

[0916] 127. The compound, salt, or deuterated derivative according to Example 125 or 126, wherein R 4 Selected from hydrogen and methyl.

[0917] 128. The compound, salt, or deuterated derivative according to any one of Examples 125 to 127, wherein R 4 It is a methyl group.

[0918] 129. The compound, salt, or deuterated derivative according to any one of Examples 125 to 127, wherein R 4 It is hydrogen.

[0919] 130. The compound, salt, or deuterated derivative according to any one of Examples 125 to 129, wherein each R 5 It is independently selected from C1-C6 alkyl and C1-C6 alkoxy.

[0920] 131. The compound, salt, or deuterated derivative according to any one of Examples 125 to 131, wherein each R 5 Independently selected from methyl,

[0921] 132. The compound, salt, or deuterated derivative according to any one of Examples 125 to 131, wherein R ZN Selected from hydrogen and R F .

[0922] 133. The compound, salt, or deuterated derivative according to any one of Examples 125 to 132, wherein R ZNIt is hydrogen.

[0923] 134. The compound, salt, or deuterated derivative according to any one of Examples 125 to 132, wherein R ZN It is R F .

[0924] 135. The compound, salt, or deuterated derivative according to any one of Examples 125 to 134, wherein R ZC It's hydrogen, or two Rs. ZC Together they form an oxo group.

[0925] 136. The compound, salt, or deuterated derivative according to any one of Examples 125 to 135, wherein each R L1 Independently selected from hydrogen, optionally selected by 1-3 independently selected from C6-C 10 Aryl groups substituted with C1-C9 alkyl groups and R F .

[0926] 137. The compound, salt, or deuterated derivative according to any one of Examples 125 to 136, wherein each R L2 Independently selected from hydrogen and R F Or two R atoms on the same carbon atom L2 Together they form an oxo group.

[0927] 138. The compound, salt, or deuterated derivative according to any one of Examples 125 to 137, wherein each R N Independently selected from hydrogen and C1-C8 alkyl groups (optionally 1-3 independently selected from oxo, C1-C6 alkoxy, C3-C... 10 cycloalkyl and C6-C 10 (Substitution of aryl groups).

[0928] 139. The compound, salt, or deuterated derivative according to any one of Examples 125 to 138, wherein the two Rs F Together with the atoms they are bonded to, they form groups selected from the following:

[0929] ■C6-C 10 Aryl, and

[0930] ■ 3- to 11-membered heterocyclic groups optionally substituted by 1 to 3 independently selected groups from the following:

[0931] ○Oxygenation,

[0932] ○ C1-C9 alkyl groups optionally substituted by 1-4 independently selected groups from the following:

[0933] ◆Oxygenation,

[0934] ◆Halogen,

[0935] ◆Hydroxy group,

[0936] ◆N(R N )2,

[0937] ◆Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[0938] ◆C6-C groups optionally substituted with 1-3 independently selected groups chosen from hydroxyl, cyano, and C1-C6 alkyl groups 10 Aryl,

[0939] ◆Optionally selected from 1-4 independent factors N(R) N 2. -(O) groups substituted with C1-C6 alkyl groups (optionally substituted with 1-3 groups independently selected from oxo, hydroxyl, and C1-C6 alkoxy groups) and C1-C6 fluoroalkyl groups. 0-1 -(C3-C 10 cycloalkyl),

[0940] ◆Optionally substituted with 1-3 independently selected oxo and C1-C6 alkyl groups, and

[0941] ◆Optionally selected from 1-3 independent selections from N(R) N )2, C1-C6 alkyl groups and -O-(C6-C 10 5-10 membered heteroaryl groups substituted with aryl groups,

[0942] ○ C3-C alkyl groups optionally substituted with 1-4 independently selected groups selected from halogens and C1-C6 alkyl groups 12 cycloalkyl,

[0943] ○C6-C 10 Aryl, and

[0944] ○3 to 10-membered heterocyclic groups.

[0945] 140. A compound of formula VI:

[0946]

[0947] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein L 1 R 4 R 5 and R F Defined as described in Example 1.

[0948] 141. The compound, salt, or deuterated derivative according to Example 140, wherein R4 Selected from hydrogen and methyl.

[0949] 142. The compound, salt, or deuterated derivative according to Example 140 or 141, wherein R 4 It is a methyl group.

[0950] 143. The compound, salt, or deuterated derivative according to Example 140 or 141, wherein R 4 It is hydrogen.

[0951] 144. The compound, salt, or deuterated derivative according to any one of Examples 140 to 143, wherein each R 5 It is independently selected from C1-C6 alkyl and C1-C6 alkoxy.

[0952] 145. The compound, salt, or deuterated derivative according to any one of Examples 140 to 144, wherein each R 5 Independently selected from methyl,

[0953] 146. The compound, salt, or deuterated derivative according to any one of Examples 140 to 145, wherein each R L1 Independently selected from hydrogen, optionally selected by 1-3 independently selected from C6-C 10 Aryl groups substituted with C1-C9 alkyl groups and R F .

[0954] 147. The compound, salt, or deuterated derivative according to any one of Examples 140 to 146, wherein each R N Independently selected from hydrogen and C1-C8 alkyl groups (optionally 1-3 independently selected from oxo, C1-C6 alkoxy, C3-C... 10 cycloalkyl and C6-C 10 (Substitution of aryl groups).

[0955] 148. The compound, salt, or deuterated derivative according to any one of Examples 140 to 147, wherein the two Rs F Together with the atoms they are bonded to, they form groups selected from the following:

[0956] ■C6-C 10 Aryl, and

[0957] ■ 3- to 11-membered heterocyclic groups optionally substituted by 1 to 3 independently selected groups from the following:

[0958] ○Oxygenation,

[0959] ○ C1-C9 alkyl groups optionally substituted by 1-4 independently selected groups from the following:

[0960] ◆Oxygenation,

[0961] ◆Halogen,

[0962] ◆Hydroxy group,

[0963] ◆N(R N )2,

[0964] ◆Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[0965] ◆C6-C groups optionally substituted with 1-3 independently selected groups chosen from hydroxyl, cyano, and C1-C6 alkyl groups 10 Aryl,

[0966] ◆Optionally selected from 1-4 independent factors N(R) N 2. -(O) groups substituted with C1-C6 alkyl groups (optionally substituted with 1-3 groups independently selected from oxo, hydroxyl, and C1-C6 alkoxy groups) and C1-C6 fluoroalkyl groups. 0-1 -(C3-C 10 cycloalkyl),

[0967] ◆Optionally substituted with 1-3 independently selected oxo and C1-C6 alkyl groups, and

[0968] ◆Optionally selected from 1-3 independent selections from N(R) N )2, C1-C6 alkyl groups and -O-(C6-C 10 5-10 membered heteroaryl groups substituted with aryl groups,

[0969] ○ C3-C alkyl groups optionally substituted with 1-4 independently selected groups selected from halogens and C1-C6 alkyl groups 12 cycloalkyl,

[0970] ○C6-C 10 Aryl, and

[0971] ○3 to 10-membered heterocyclic groups.

[0972] 149. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Examples 1 to 148, wherein the compound is selected from any one of Formula I, Ia, IIa, IIb, III, IV, V, Va, Vb and VI, the tautomer thereof, the deuterated derivatives of such compounds and tautomers and the pharmaceutically acceptable salt of any of the foregoing.

[0973] 150. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Examples 1 to 149, selected from compounds 1-371 (Tables 13, 14 and 15), compounds 372-385 (Table 12), compounds 386-426 (Table 24), their tautomers, deuterated derivatives of these compounds and tautomers and pharmaceutically acceptable salts of any of the foregoing.

[0974] 151. A pharmaceutical composition comprising a compound, a tautomer, a deuterated derivative or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier according to any one of Examples 1 to 150.

[0975] 152. The pharmaceutical composition according to Example 151 further comprises one or more additional therapeutic agents.

[0976] 153. The pharmaceutical composition according to Example 152, wherein one or more additional therapeutic agents are selected from mucolytics, bronchodilators, antibiotics, anti-infectives, and anti-inflammatory agents.

[0977] 154. The pharmaceutical composition according to Example 152, wherein the one or more additional therapeutic agents are antibiotics selected from tobramycin, including tobramycin inhalation powder (TIP), azithromycin, aztreonam, aztreonam in nebulized form, amikacin, liposomal formulations thereof, ciprofloxacin, formulations thereof suitable for inhalation, levofloxacin, nebulized formulations thereof, and combinations of two antibiotics, such as fosfomycin and tobramycin.

[0978] 155. The pharmaceutical composition according to Example 152, wherein one or more additional therapeutic agents are CFTR modulators.

[0979] 156. The pharmaceutical composition according to Example 155, wherein the CFTR modifier is a synergist.

[0980] 157. The pharmaceutical composition according to Example 155, wherein the CFTR modifier is a corrector.

[0981] 158. The pharmaceutical composition according to Example 156 comprises both a CFTR enhancer and a CFTR corrector.

[0982] 159. The pharmaceutical composition according to Example 155 or Example 158, wherein the CFTR synergist is selected from ivacato, deuteric acid catato, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadecan-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives of any of the foregoing and pharmaceutically acceptable salts.

[0983] 160. The pharmaceutical composition according to Example 157 or Example 158, wherein the CFTR corrector is selected from tezacotto and rumacotto.

[0984] 161. The pharmaceutical composition according to Example 152, wherein the composition comprises ivacato and tezacotto.

[0985] 162. The pharmaceutical composition according to Example 152, wherein the composition comprises deuteric acid and tezacotto.

[0986] 163. The pharmaceutical composition according to Example 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]nonadecan-1(18),2,4,14,16-pentaen-6-ol and tezacotto.

[0987] 164. The pharmaceutical composition according to Example 152, wherein the composition comprises ivacato and rumacato.

[0988] 165. The pharmaceutical composition according to Example 152, wherein the composition comprises deuteric acid and rumacapto.

[0989] 166. The pharmaceutical composition according to Example 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]nonadecan-1(18),2,4,14,16-pentaen-6-ol and rumacato.

[0990] 167. A method for treating cystic fibrosis, the method comprising administering to a patient in need a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 1 to 150, or a pharmaceutical composition according to any one of Examples 151 to 166.

[0991] 168. The method according to Example 167 further comprises administering one or more additional therapeutic agents to the patient before, simultaneously with or after administering the compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of Examples 1 to 150 or the pharmaceutical composition according to Example 151.

[0992] 169. The method according to Example 168, wherein the one or more additional therapeutic agents are selected from CFTR modulators.

[0993] 170. The method according to Example 169, wherein the CFTR modifier is a synergist.

[0994] 171. The method according to Example 169, wherein the CFTR modifier is a corrector.

[0995] 172. The method according to Example 169 includes the application of both a CFTR enhancer and a further CFTR corrector.

[0996] 173. The method according to Example 170 or Example 172, wherein the CFTR synergist is selected from ivacarto, deuteric acid carto, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadecan-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives of any of the foregoing and pharmaceutically acceptable salts.

[0997] 174. The method according to Example 171 or Example 172, wherein the CFTR corrector is selected from tezacator and rumacator.

[0998] 175. The method according to Example 169, comprising the administration of ivacato and tezacato.

[0999] 176. The method according to Example 169, comprising administering deuteric acid and tezacotto.

[1000] 177. The method according to Example 169, comprising the application of (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadecan-1(18),2,4,14,16-pentaen-6-ol and tizacatol.

[1001] 178. The method according to Example 169, comprising the application of ivacato and rumacato.

[1002] 179. The method according to Example 169, comprising administering deuteric acid and rumacapto.

[1003] 180. The method according to Example 169, comprising the application of (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadecan-1(18),2,4,14,16-pentaen-6-ol and rumacator.

[1004] 181. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Examples 1 to 150, or the pharmaceutical composition of any one of Examples 151 to 166, for the treatment of cystic fibrosis.

[1005] 182. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Examples 1 to 150, or the pharmaceutical composition of any one of Examples 151 to 166, used to manufacture a medicament for treating cystic fibrosis.

[1006] 183. A compound selected from compounds 1-426, its tautomers, deuterated derivatives of these compounds and tautomers, and a pharmaceutically acceptable salt of any of the foregoing.

[1007] 184. A deuterated derivative of a compound selected from compounds 1-426.

[1008] 185. A pharmaceutically acceptable salt of a compound selected from compounds 1-426.

[1009] 186. A compound selected from compounds 1-426.

[1010] 187. A pharmaceutical composition comprising a compound selected from compounds 1-426, its tautomers, deuterated derivatives of these compounds and tautomers, a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier.

[1011] 188. A pharmaceutical composition comprising a deuterated derivative of a compound selected from compounds 1-426 and a pharmaceutically acceptable carrier.

[1012] 189. A pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound selected from compounds 1-426 and a pharmaceutically acceptable carrier.

[1013] 190. A pharmaceutical composition comprising a compound selected from compounds 1-426 and a pharmaceutically acceptable carrier.

[1014] 191. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-426, its tautomers, deuterated derivatives of these compounds and tautomers, and a pharmaceutically acceptable salt thereof; (b) a CFTR synergist; and (c) a pharmaceutically acceptable carrier.

[1015] 192. A pharmaceutical composition comprising: (a) a deuterated derivative of a compound selected from compounds 1-426; (b) a CFTR synergist; and (c) a pharmaceutically acceptable carrier.

[1016] 193. A medicament comprising: (a) a pharmaceutically acceptable salt of a compound selected from compounds 1-426; (b) a CFTR enhancer; and (c) a pharmaceutically acceptable carrier.

[1017] 194. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-426; (b) a CFTR enhancer; and (c) a pharmaceutically acceptable carrier.

[1018] 195. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-426, its tautomers, deuterated derivatives of these compounds and tautomers, and a pharmaceutically acceptable salt thereof; (b) a further CFTR corrector; and (c) a pharmaceutically acceptable carrier.

[1019] 196. A pharmaceutical composition comprising: (a) a deuterated derivative of a compound selected from compounds 1-426; (b) a further CFTR corrector; and (c) a pharmaceutically acceptable carrier.

[1020] 197. A pharmaceutical composition comprising: (a) a pharmaceutically acceptable salt of a compound selected from compounds 1-426; (b) a further CFTR corrector; and (c) a pharmaceutically acceptable carrier.

[1021] 198. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-426; (b) a further CFTR corrector; and (c) a pharmaceutically acceptable carrier.

[1022] 199. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-426, its tautomers, deuterated derivatives of these compounds and tautomers, and a pharmaceutically acceptable salt thereof; (b) a further CFTR corrector; (c) a CRTR enhancer; and (d) a pharmaceutically acceptable carrier.

[1023] 200. A pharmaceutical composition comprising: (a) a deuterated derivative of a compound selected from compounds 1-426; (b) a further CFTR corrector; (c) a CRTR enhancer; and (d) a pharmaceutically acceptable carrier.

[1024] 201. A pharmaceutical composition comprising: (a) a pharmaceutically acceptable salt of a compound selected from compounds 1-426; (b) a further CFTR corrector; (c) a CRTR enhancer; and (d) a pharmaceutically acceptable carrier.

[1025] 202. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-426; (b) a further CFTR corrector; (c) a CRTR enhancer; and (d) a pharmaceutically acceptable carrier.

[1026] 203. A method for treating cystic fibrosis using a compound selected from compounds 1-426, its tautomers, deuterated derivatives of these compounds and tautomers, and a pharmaceutically acceptable salt of any of the foregoing.

[1027] 204. A method for treating cystic fibrosis using a deuterated derivative of a compound selected from compounds 1-426.

[1028] 205. A method for treating cystic fibrosis with a pharmaceutically acceptable salt of a compound selected from compounds 1-426.

[1029] 206. A method for treating cystic fibrosis with a compound selected from compounds 1-426.

[1030] 207. A method for treating cystic fibrosis using a pharmaceutical composition comprising a compound selected from compounds 1-426, its tautomers, deuterated derivatives of these compounds and tautomers, a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier.

[1031] 208. A method for treating cystic fibrosis using a pharmaceutical composition comprising a deuterated derivative of a compound selected from compounds 1-426 and a pharmaceutically acceptable carrier.

[1032] 209. A method for treating cystic fibrosis using a pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound selected from compounds 1-426 and a pharmaceutically acceptable carrier.

[1033] 210. A method for treating cystic fibrosis using a pharmaceutical composition comprising a compound selected from compounds 1-426 and a pharmaceutically acceptable carrier.

[1034] 211. A method for treating cystic fibrosis with a pharmaceutical composition comprising: (a) a compound selected from compounds 1-426, its tautomers, deuterated derivatives of these compounds and tautomers, and a pharmaceutically acceptable salt thereof; (b) a CFTR enhancer; and (c) a pharmaceutically acceptable carrier.

[1035] 212. A method for treating cystic fibrosis using a medicament comprising: (a) a deuterated derivative of a compound selected from compounds 1-426; (b) a CFTR enhancer; and (c) a pharmaceutically acceptable carrier.

[1036] 213. A method for treating cystic fibrosis with a pharmaceutical composition comprising: (a) a pharmaceutically acceptable salt of a compound selected from compounds 1-426; (b) a CFTR enhancer; and (c) a pharmaceutically acceptable carrier.

[1037] 214. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-426; (b) a CFTR enhancer; and (c) a pharmaceutically acceptable carrier.

[1038] 215. A method for treating cystic fibrosis with a pharmaceutical composition comprising: (a) a compound selected from compounds 1-426, its tautomers, deuterated derivatives of these compounds and tautomers, and a pharmaceutically acceptable salt thereof; (b) a further CFTR corrector; and (c) a pharmaceutically acceptable carrier.

[1039] 216. A method of treating cystic fibrosis with a pharmaceutical composition comprising: (a) a deuterated derivative of a compound selected from compounds 1-426; (b) a further CFTR corrector; and (c) a pharmaceutically acceptable carrier.

[1040] 217. A method of treating cystic fibrosis with a pharmaceutical composition comprising: (a) a pharmaceutically acceptable salt of a compound selected from compounds 1-426; (b) a further CFTR corrector; and (c) a pharmaceutically acceptable carrier.

[1041] 218. A method of treating cystic fibrosis with a pharmaceutical composition comprising: (a) a compound selected from compounds 1-426; (b) a further CFTR corrector; and (c) a pharmaceutically acceptable carrier.

[1042] 219. A method for treating cystic fibrosis with a pharmaceutical composition comprising: (a) a compound selected from compounds 1-426, its tautomers, deuterated derivatives of these compounds and tautomers, and a pharmaceutically acceptable salt thereof; (b) a further CFTR corrector; (c) a CRTR enhancer; and (d) a pharmaceutically acceptable carrier.

[1043] 220. A method of treating cystic fibrosis with a pharmaceutical composition comprising: (a) a deuterated derivative of a compound selected from compounds 1-426; (b) a further CFTR corrector; (c) a CRTR enhancer; and (d) a pharmaceutically acceptable carrier.

[1044] 221. A method of treating cystic fibrosis with a pharmaceutical composition comprising: (a) a pharmaceutically acceptable salt of a compound selected from compounds 1-426; (b) a further CFTR corrector; (c) a CRTR enhancer; and (d) a pharmaceutically acceptable carrier.

[1045] 222. A method of treating cystic fibrosis with a pharmaceutical composition comprising: (a) a compound selected from compounds 1-426; (b) a further CFTR corrector; (c) a CRTR enhancer; and (d) a pharmaceutically acceptable carrier.

[1046] Example

[1047] I. List of Abbreviations

[1048] ACN: Acetonitrile

[1049] Boc anhydride ((Boc)₂O): ditert-butyl dicarbonate

[1050] CDCl3: Chloroform-dCDI: Carbodiimidazole

[1051] CDMT: 2-Chloro-4,6-dimethoxy-1,3,5-triazine

[1052] CH2Cl2: Dichloromethane

[1053] CH3CN: Acetonitrile

[1054] COMU: (1-Cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholino-carbomony hexafluorophosphate

[1055] Cmpd: compound

[1056] DABCO: 1,4-diazabicyclo[2.2.2]octane

[1057] DBU: 1,8-diazabicyclo(5.4.0)undec-7-ene

[1058] DCE: 1,2-Dichloroethane

[1059] DCM: Dichloromethane

[1060] DI: Deionized

[1061] DIAD: Diisopropyl azodicarbonate

[1062] DEIA (DIPEA, DiPEA): N,N-Diisopropylethylamine

[1063] DMA: N,N-dimethylacetamide

[1064] DMAP: 4-Dimethylaminopyridine

[1065] DMF: N,N-Dimethylformamide

[1066] DMSO: Dimethyl sulfoxide

[1067] DMP: Des Martin periodine

[1068] EA: Ethyl acetate

[1069] EDC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[1070] ELSD: Evaporative Light Scattering Detector

[1071] ESI-MS: Electrospray ionization mass spectrometry

[1072] EtOAc: Ethyl acetate

[1073] EtOH: Ethanol

[1074] GC: Gas Chromatography

[1075] Grubbs' first-generation catalyst: Dichloro(benzyl)bis(tricyclohexylphosphine)ruthenium(II)

[1076] Grubbs' second-generation catalyst: [1,3-bis(2,4,6-trimethylphenyl)imidazolidine-2-ylidene]-dichloro-[(2-isopropoxyphenyl)methylene]ruthenium

[1077] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-3-hexafluorophosphate oxide

[1078] HPLC: High Performance Liquid Chromatography

[1079] Hoveyda-Grubbs second-generation catalyst: (1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolylylene)dichloro(o-isopropoxyphenylmethylene)ruthenium, dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolylene](2-isopropoxyphenylmethylene)ruthenium(II)

[1080] IPA: Isopropyl alcohol

[1081] KHSO4: Potassium hydrogen sulfate

[1082] LC: Liquid Chromatography

[1083] LCMS: Liquid Chromatography-Mass Spectrometry

[1084] LCMS Met.: LCMS Methodology

[1085] LCMS Rt: LCMS retention time

[1086] LDA: Lithium diisopropylamino

[1087] LiOH: Lithium hydroxide

[1088] MeCN: Acetonitrile

[1089] MeOH: Methanol

[1090] MgSO4: Magnesium sulfate

[1091] MTBE: Methyl tert-butyl ether

[1092] MeTHF or 2-MeTHF: 2-methyltetrahydrofuran

[1093] NaHCO3: Sodium bicarbonate

[1094] NaOH: Sodium hydroxide

[1095] NMP: N-methyl-2-pyrrolidone

[1096] NMM: N-methylmorpholine

[1097] Pd / C: Palladium / Carbon

[1098] Pd2(dba)3:tris(dibenzylacetone)dipalladium(0)

[1099] Pd(dppf)Cl2:[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloro

[1100] Pd(OAc)2: Palladium(II) acetate

[1101] PTFE: Polytetrafluoroethylene

[1102] rt, RT: room temperature

[1103] RuPhos: 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl

[1104] SFC: Supercritical Fluid Chromatography

[1105] TBAI: Tetrabutylammonium iodide

[1106] TEA: Triethylamine

[1107] TFA: Trifluoroacetic acid

[1108] THF: Tetrahydrofuran

[1109] TLC: Thin-layer chromatography

[1110] TMS: Trimethylsilyl

[1111] TMSCl: Trimethylchlorosilane

[1112] T3P: Propanephosphonic anhydride

[1113] UPLC: Ultra-high performance liquid chromatography

[1114] XANTPHOS: 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene

[1115] XPhos: 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

[1116] II. General Method

[1117] Unless otherwise stated, reagents and starting materials should be obtained from commercial sources and used without purification.

[1118] At 400MHz and 100MHz respectively 1 H and 13 Proton and carbon NMR spectra were obtained on a Bruker Biospin DRX 400MHz FTNMR spectrometer operating at the C resonance frequency or on a 300MHz NMR spectrometer. One-dimensional proton and carbon spectra were acquired at digital resolutions of 0.1834 and 0.9083 Hz / Pt, respectively, using a broadband observation (BBFO) probe with sample rotation at 20 Hz. All proton and carbon spectra were acquired under temperature control at 30 °C using standard, previously published pulse sequences and conventional processing parameters.

[1119] NMR (1D and 2D) spectra were also recorded on a Bruker AVNEO 400MHz spectrometer equipped with a 5mm multi-core Iprobe, operating at 400MHz and 100MHz respectively.

[1120] Also, using a Varian Mercury NMR instrument with a 45-degree pulse angle, a spectral width of 4800 Hz, and 28860 acquisition points, recording at 300 MHz. 1 1H NMR spectra. The FID was zero-filled to 32k points, and a 0.3Hz line broadening was applied before the Fourier transform. Recordings were performed at 282MHz using a 30-degree pulse angle, a 100kHz spectral width, and 59202 acquisition points. 19 F NMR spectra. FID zero-filled to 64k points and 0.5Hz line broadening applied before Fourier transform.

[1121] Also, using a Bruker Avance III HD NMR instrument with a 30-degree pulse angle, an 8000 Hz spectral width, and a 128 k acquisition point, recording was performed at 400 MHz. 1 19F NMR spectra. The FID was zero-filled to 256k points, and a 0.3 Hz line broadening was applied before the Fourier transform. 19F NMR spectra were recorded at 377 MHz using a 30-degree pulse angle, a spectral width of 89286 Hz, and 128k acquisition points. The FID was zero-filled to 256k points, and a 0.3 Hz line broadening was applied before the Fourier transform.

[1122] NMR spectra were also recorded on 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).

[1123] The final purity of the compound was determined by reversed-phase UPLC using Waters-produced Acquity UPLC BEH C. 18 The column (50 × 2.1 mm, 1.7 μm particles) (pn: 186002350) and a dual gradient run from 1% to 99% mobile phase B over 3.0 min were used for determination. 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 areas under the curve (AUC) of the two UV traces (220 nm, 254 nm). Low-resolution mass spectrometry is reported as [M+1] obtained using a single quadrupole mass spectrometer equipped with an electrospray ionization (ESI) source. +The ESI source achieves a mass accuracy of 0.1 Da and a minimum resolution of 1000 (resolution unitless) across the entire detection range. The optical purity of methyl (2S)-2,4-dimethyl-4-nitro-valerate was determined using chiral gas chromatography (GC) on an Agilent 7890A / MSD 5975C instrument with a Restek Rt-βDEXcst (30 m × 0.25 mm × 0.25 μm df) column at a flow rate of 2.0 mL / min (H2 carrier gas) at an injection temperature of 220 °C and an oven temperature of 120 °C for 15 minutes.

[1124] III. General UPLC / HPLC analytical methods

[1125] LC Method A: Using Waters-manufactured Acquity UPLC BEH C 18 A dual-gradient analytical reversed-phase UPLC was used, with a column (50 × 2.1 mm, 1.7 μm particles) (pn: 186002350) and a flow rate of 1-99% mobile phase B over 3.0 min. 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.

[1126] LC Method B: Using Kinetex C 18 A reversed-phase HPLC was performed using a 50 × 3.0 mm column and a dual gradient run from 5% to 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.

[1127] LC method C: Kinetex C 18 4.6 x 50 mm 2.6 μm. Temperature: 45 °C, Flow rate: 2.0 mL / min, Run time: 3 min. Mobile phase: Initially 95% water (0.1% formic acid) and 5% acetonitrile (0.1% formic acid), linear gradient to 95% acetonitrile (0.1% formic acid) for 2.0 min, then held at 95% acetonitrile (0.1% formic acid) for 1.0 min.

[1128] LC Method D: Acquity UPLC BEH C manufactured by Waters 18The column (30 × 2.1 mm, 1.7 μm particles) (pn: 186002349) and a dual gradient were used, running from 1% to 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.

[1129] LC Method G: Symmetry, 4.6 x 75 mm 3.5 μm. Temperature: 45 °C, Flow rate: 2.0 mL / min, Run time: 8 min. Mobile phase: Initially 95% H₂O (0.1% formic acid) and 5% CH₃CN (0.1% FA), linear gradient to 95% CH₃CN (0.1% formic acid) for 6.0 min, then held at 95% CH₃CN (0.1% formic acid) for 2.0 min.

[1130] 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: Initially 95% H₂O (0.1% formic acid) and 5% CH₃CN (0.1% FA), linear gradient to 95% CH₃CN (0.1% FA) for 4.0 min, then held at 95% CH₃CN (0.1% FA) for 2.0 min.

[1131] LC Method I: Acquity UPLC BEH C manufactured by Waters (pn: 186002350) 18 The column (50 × 2.1 mm, 1.7 μm particles) and dual gradients were used, running from 1% to 99% mobile phase B over 5.0 min. 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.

[1132] LC Method J: Using Waters-manufactured Acquity UPLC BEH C 18 A reversed-phase UPLC with a column (50 × 2.1 mm, 1.7 μm particles) (pn: 186002350) and a dual gradient running from 1% to 99% mobile phase B over 2.9 min. 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.

[1133] LC method K: Kinetex Polar C 183.0×50mm 2.6μm, 3 minutes, 5%-95% ACN / H2O (0.1% formic acid) 1.2 mL / min.

[1134] LC Method M: Poroshell 120EC-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) for 4.0 min, then held at 95% CH₃CN (0.1% FA) for 2.0 min.

[1135] 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 to 95% CH3CN (0.1% FA) for 2.0 min, then held at 95% CH3CN (0.1% FA) for 2.0 min.

[1136] 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) to 95% CH3CN (0.1% FA) gradient (2.0 min), then held at 95% CH3CN (0.1% FA) for 1.0 min.

[1137] LC method: Poroshell 120EC-C18 3.0×50mm 2.7μM, temperature 45℃, flow rate: 1.5 mL / min, run time: 3 min. Mobile phase conditions: initial 95% H2O (0.1% formic acid) and 5% CH3CN (0.1% FA), linear gradient to 95% CH3CN (0.1% FA) for 1.5 min, then held at 95% CH3CN (0.1% FA) for 1.5 min.

[1138] LC Method Q: Using Waters-manufactured Acquity UPLC BEH C 18A reversed-phase UPLC with a column (50 × 2.1 mm, 1.7 μm particles) (pn: 186002350) and a dual gradient running from 30-99% mobile phase B over 2.9 min. 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.

[1139] LC Method S: Merckmillipore Chromolith SpeedROD C 18 The column (50 x 4.6 mm) and the dual gradient were run from 5-100% mobile phase B over 12 minutes. Mobile phase A = water (0.1% CF3CO2H). Mobile phase B = acetonitrile (0.1% CF3CO2H).

[1140] LC Method T: Merckmillipore Chromolith SpeedROD C 18 The column (50 x 4.6 mm) and the dual gradient were run from 5-100% mobile phase B over 6 minutes. Mobile phase A = water (0.1% CF3CO2H). Mobile phase B = acetonitrile (0.1% CF3CO2H).

[1141] LC method U: Kinetex Polar C 18 3.0×50mm 2.6μm, 6 minutes, 5%-95% ACN / H2O (0.1% formic acid) 1.2 mL / min.

[1142] LC method W: water cortex 2.7 μC 18 (3.0 mm × 50 mm), temperature: 55 °C; flow rate: 1.2 mL / min; mobile phase: 100% water containing 0.1% trifluoroacetic acid (TFA), then 100% acetonitrile containing 0.1% TFA; gradient: 5% to 100% B over 4 min, residence at 100% B for 0.5 min, equilibrate to 5% B over 1.5 min.

[1143] IV. Synthesis of Common Intermediates

[1144] Example A: Preparation of 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid

[1145]

[1146] Step 1: N-tert-Butoxycarbonyl-N-(4,6-dichloropyrimidin-2-yl)carbamate tert-butyl ester

[1147]

[1148] Add (BOC)₂O (838 g, 3.840 mol) to a solution of 4,6-dichloropyrimidin-2-amine (300 g, 1.829 mol) in DCM (2.1 L), followed by the addition of DMAP (5.6 g, 45.84 mmol). Stir the mixture at ambient temperature for 6 hours. Add additional DMAP (5.6 g, 45.84 mmol), and continue stirring at ambient temperature for 24 hours. Dilute the mixture with water (2.1 L) and separate the organic phase. Wash the organic phase with water (2.1 L) and 2.1 L of brine, dry over magnesium sulfate, filter through diatomaceous earth, and concentrate under vacuum to obtain a light orange oil with sludge in the slurry. Dilute the mixture with approximately 500 mL of heptane and filter using an M filter. Wash the precipitate (SM) with 250 mL of heptane. The filtrate was concentrated under vacuum to obtain a dense orange oil. The dense orange oil was inoculated with the solid from the previous experiment and allowed to crystallize by standing to obtain a light orange hard solid. N-tert-butyloxycarbonyl-N-(4,6-dichloropyrimidin-2-yl)carbamate tert-butyl ester (645 g, 97%). 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.07 (s, 1H), 1.44 (s, 18H). ESI-MS m / z calculated value 363.07526, experimental value 364.1 (M+1). + Retention time: 2.12 minutes (LC method A).

[1149] Step 2: N-tert-Butoxycarbonyl-N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]carbamate tert-butyl ester

[1150]

[1151] All solvents were degassed before use. To a slurry of N-tert-butoxycarbonyl-N-(4,6-dichloropyrimidin-2-yl)carbamate (88 g, 241.6 mmol), DME (704 mL) containing (2,6-dimethylphenyl)boronic acid (approx. 36.24 g, 241.6 mmol) and Cs₂CO₃ (approx. 196.8 g, 604.0 mmol) and water (176 mL) were added. Pd(dppf)Cl₂ (approx. 8.839 g, 12.08 mmol) was added, and the mixture was vigorously stirred at 80 °C (reflux) under nitrogen for 1 hour (without SM residue). The reaction was cooled to ambient temperature and diluted with water (704 mL). The aqueous phase was separated and extracted with EtOAc (704 mL). The organic phase was washed with 700 mL of brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was subjected to chromatographic analysis on a 1500 g silica gel column, eluted with 0-30% EtOAc / hexane. The product fractions (eluted with 15% EtOAc) were combined and concentrated under vacuum to give a clear oil product, which crystallized upon standing. N-tert-butoxycarbonyl-N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]carbamate tert-butyl ester (81.3 g, 78%). 1 ¹H NMR (400MHz, DMSO-d⁶) δ 7.88 (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, experimental value 434.1 (M+1). + Retention time: 2.32 minutes (LC method A).

[1152] Step 3: 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (hydrochloride)

[1153]

[1154] N-tert-butoxycarbonyl-N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]carbamate tert-butyl ester (514.8 g, 915.9 mmol) was dissolved in dichloromethane (4 L). Hydrogen chloride from 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 give 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine hydrochloride (213.5 g, 82%) as a white solid. 1¹H NMR (250MHz, DMSO-d⁶) δ 7.45–6.91 (m, 3H), 6.73 (s, 1H), 2.08 (s, 6H). ESI-MS m / z calculated 233.072, experimental 234.1 (M+1). + Retention time: 2.1 minutes (LC method C).

[1155] Step 4: 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine

[1156]

[1157] 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), treated with NaOH (1 M, 725 mL, 725.0 mmol) and stirred at room temperature for 1 hour. The mixture was transferred to a separatory funnel and left overnight. The DCM phase was separated, and the aqueous phase containing insoluble substances was extracted twice or more with DCM (2 × 500 mL). The combined brown DCM phases were stirred with magnesium sulfate and charcoal for 1 hour, filtered, and the yellow solution was concentrated to approximately 500 mL. The solution was diluted with heptane (750 mL), and the DCM was removed under reduced pressure at 60 °C to give a cream suspension. The cream suspension was stirred at room temperature for 1 hour, filtered, washed with cold heptane and dried to give 4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-amine (157 g, 91%) as cream solids. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 7.28–7.14 (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, experimental value 234.0 (M+1). + Retention time: 1.45 minutes (LC method A).

[1158] Step 5: 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid

[1159]

[1160] 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (235 g, 985.5 mmol) was dissolved in MeTHF (2.3 L) under stirring and nitrogen atmosphere and cooled in an ice bath. Methyl 3-chlorosulfonylbenzoate (347 g, 1.479 mol) (appearing slightly endothermic) was added to the cold solution in a single addition, and a solution of 2-methyl-butane-2-ol (lithium salt) (875 mL, 3.1 M, 2.712 mol) (in heptane) was added dropwise to the cold, pale yellow solution over 1.25 hours (exothermic, internal temperature 0 to 10 °C). The ice bath was removed and the green solution was stirred at room temperature for 4 hours. Cold HCl (2 L, 1.5 M, 3.000 mol) was added to the green solution to separate the phases, and the organic phase was washed once with water (1 L) and once with brine (500 mL). The aqueous phase was back-extracted once with MeTHF (350 mL) and the organic phases were combined. The yellow MeTHF solution of methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoate (ESI-MS m / z calculated value 431.07065, experimental value 432.0 (M+1)) + (Retention time: 1.81 min) The sample was treated with NaOH (2.3 L, 4.600 mol, 2 M) and stirred at room temperature for 1 hour. The phases were separated, and the NaOH phase was washed twice with MeTHF (2 × 500 mL) and the combined organic phases were extracted once with 2 M NaOH (1 × 250 mL). The combined NaOH phases were combined, stirred in an ice bath, and slowly acidified by adding HCl (416 mL, 4.929 mol, 36% w / w) while maintaining the internal temperature between 10 and 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 buttercream suspension. The solids were collected by filtration, washed with plenty of water, and blotted dry for 3 hours. The solids were dried under reduced pressure for 120 hours under nitrogen venting at 45-50 °C. 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (395 g, 96%) was isolated as a white solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 13.44 (s, 1H), 12.46 (s, 1H), 8.48–8.39 (m, 1H), 8.25–8.15 (m, 1H), 8.15–8.08 (m, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.31 (s, 1H), 7.28–7.18 (m, 1H), 7.10 (d, J = 7.6 Hz, 2H), 1.84 (s, 6H). ESI-MS m / z calculated value 417.055, experimental value 418.0 (M+1).+ Retention time: 1.56 minutes. (LC Method A).

[1161] Example B: Preparation of N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]-3-nitro-benzenesulfonamide Step 1: N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]-3-nitro-benzenesulfonamide

[1162]

[1163] A solution of 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (8.13 g, 0.0348 mol) in anhydrous tetrahydrofuran (30 mL) was added dropwise to a suspension of sodium hydride (60% in mineral oil) (4.87 g, 0.122 mol) in anhydrous tetrahydrofuran (30 mL) at 0 °C. The reaction mixture was stirred at room temperature for 30 min. 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 was stirred at the same temperature for 1 h. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate (100 mL). The reaction solution was extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with water (100 mL), dried over anhydrous sodium sulfate, and then concentrated under vacuum. The residue was purified by silica gel column chromatography using 0 to 10% chloroform-ethyl acetate. The crude product was ground with a solvent mixture of diethyl ether and hexane (1:5) to give N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]-3-nitrobenzenesulfonamide (5.98 g, 41%) as a white solid. ESI-MS m / z calculated value 418.1, experimental 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).

[1164] Example C: Preparation of N-[4-(2,6-dimethylphenyl)-6-methanesulfonyl-pyrimidin-2-yl]-3-nitro-benzenesulfonamide

[1165] Step 1: N-[4-(2,6-dimethylphenyl)-6-methanesulfonyl-pyrimidin-2-yl]-3-nitro-benzenesulfonamide

[1166]

[1167] Stage 1: N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-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. The 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 extracts were washed with water (300 mL), 3% hydrogen peroxide aqueous solution (300 mL), water (300 mL), and saturated sodium chloride aqueous solution (300 mL), dried over sodium sulfate, filtered, and evaporated under vacuum. This yielded an orange foam (16.71 g, 115% crude product yield), which was used for the next step of the reaction.

[1168] Phase 2: DCM (120 mL) was added to a 250 mL round-bottom flask containing the product from Phase 1, followed by the addition of m-CPBA (77% purity, 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 DCM (400 mL) and solid Na₂S₂O₃ (41.15 g, 260.3 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (300 mL) and then washed with water (3 × 400 mL) and a saturated sodium chloride aqueous solution (300 mL). The organic layer was then dried over sodium sulfate, filtered, and evaporated under vacuum. This solid was then partially dissolved in DCM (100 mL) and filtered under vacuum through a Büchner funnel to remove m-chlorobenzoic acid waste (repeated three times). The remaining solution was then purified by silica gel chromatography (330 g silica, 0% to 60% ethyl acetate / hexane gradient) to give N-[4-(2,6-dimethylphenyl)-6-methylsulfonyl-pyrimidin-2-yl]-3-nitro-benzenesulfonamide (5.881 g, 36%). ESI-MS m / z calculated value 462.06677, experimental value 463.1 (M+1). + Retention time: 1.6 minutes; LC method A.

[1169] Example D: Preparation of dispiro[2.0.24.13]heptane-7-carbaldehyde

[1170] Step 1: 1-Cyclopropylcyclopropanol

[1171]

[1172] Titanium isopropoxide (IV) (55.3 mL, 187.4 mmol) was added to a solution of methyl cyclopropanecarbamate (75 g, 749.1 mmol) in diethyl ether (450 mL). Ethyl magnesium bromide (1.6 L, 1.60 mol, 1 M) was slowly added to the mixture over 2 hours. The addition was exothermic and controlled by monitoring the addition rate and using a cooling bath. The reaction temperature was maintained between 21 °C and 26 °C during the addition. After the addition, the mixture was stirred at ambient temperature for another 2 hours. Next, the mixture was cooled to -5 °C using an acetone / dry ice bath and slowly quenched with sulfuric acid (970 g, 990 mmol, 10% w / w). The reaction mixture was cooled in a dry ice / acetone bath to keep the reaction vessel below 0 °C during quenching. As quenching proceeded, a gray / purple solid formed. After the complete addition of the aqueous sulfuric acid solution, the mixture was stirred at 0 °C for 1 hour. The precipitate was filtered through diatomaceous earth using a medium glass frit filter and 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 over magnesium sulfate, filtered through diatomaceous earth, and the solvent was evaporated by rotary evaporation at 100 Torr with the water bath set at 20 °C. The crude product was stored overnight at -23 °C and was ready for use without further purification. The product 1-cyclopropylcyclopropanol (61 g, 83%) was found to contain approximately 50% solvent (tetrahydrofuran and...) i PrOH) and use it as is in the next step. 1 ¹H NMR (400MHz, chloroform-d) δ 1.32 (tt, J = 8.2, 5.1 Hz, 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).

[1173] Step 2: 1-Bromo-1-cyclopropyl-cyclopropane

[1174]

[1175] 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 was stirred at -10 °C for another 15 minutes. The reaction 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 the temperature between -15 °C and -20 °C. After 30 minutes, the addition was complete, and the reaction was gradually warmed to room temperature. The reaction was then stirred overnight at 40 °C. The reaction was then cooled to room temperature and quenched with water (100 mL). The reaction was then stirred for 10 minutes, and the layers were separated. The organic phase was washed sequentially with 1M hydrochloric acid (102 mL), then with saturated sodium bicarbonate (50 mL), dried over sodium sulfate, filtered, and concentrated (30 °C / room vacuum approximately 300 Torr) to remove most of the dichloromethane. The crude reaction mixture was rapidly distilled (40 °C / 20 Torr) to further remove dichloromethane. The solid residue (Ph3PO and product) was reheated and distilled (50–60 °C / 20 Torr) to give 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, 5.0 Hz, 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).

[1176] Step 3: Cyclopropylene

[1177]

[1178] A solution of potassium tert-butoxide (16.7 g, 148.8 mmol) in dimethyl sulfoxide (100 mL) was stirred in a 250 mL round-bottom flask with three necks at room temperature. 1-Bromo-1-cyclopropyl-cyclopropane (20.0 g, 124.2 mmol) was added dropwise, and the reaction immediately turned black and then brown. The reaction was mildly exothermic (the temperature was maintained between 18 °C and 22 °C using an ice-water bath). After 10 minutes, the addition was complete. The ice-water bath was removed, and the reaction was stirred at room temperature. After 90 minutes, the reaction mixture was distilled under vacuum using a bulb-to-bulb distillation. Distillation was carried out between 40 and 100 Torr from 60 °C to 80 °C. The distillate was slowly collected in a receiver to give 18.2 g (7.3 g of product as 42 wt% t-BuOH solution) of a colorless liquid. The distillate was further washed with water (5 × 10 mL). Add dichloromethane (4 g) and dry the mixture with magnesium sulfate, filter (wash with 3 g of dichloromethane from two other portions each) to give 17.30 g of a colorless liquid (6.9 g of product as a 39.6 wt% dichloromethane solution; 69% yield). 1 ¹H NMR (400 MHz, chloroform-d) δ 1.19 (s, 8H). ¹H NMR confirmed the presence of dichloromethane and trace amounts of tert-butanol.

[1179] Step 4: Dispiro[2.0.2.1]heptane-7-carboxylic acid ethyl ester

[1180]

[1181] Rhodium(II) acetate (4.2 g, 9.503 mmol) was added to a solution of cyclohexenepropylcyclopropane (49.5 g, 617.8 mmol) in dichloromethane (110 mL) at 0 °C under a nitrogen atmosphere. Ethyl 2-diazoacetate (106.8 mL, 1.016 mol) was added to the mixture at 0 °C using a syringe pump set at an addition rate of 0.02 mL / min (1.2 mL / h). The addition was continued for 89 hours. The crude reaction mixture was filtered through a silica gel stopper and washed three times each time with 150 mL of dichloromethane. Volatile substances were removed under vacuum to give a crude, dark yellow oil, dispiro[2.0.2.1]heptane-7-carboxylic acid ethyl ester (100 g, 97%, containing about 20% dichloromethane, as contaminants of (E)-but-2-icanoic acid diethyl ester and (Z)-but-2-icanoic acid diethyl ester), which was used directly in the next step. 1¹H NMR (400MHz, chloroform-d) δ 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).

[1182] Step 5: Dispirol [2.0.2.1]hept-7-ylmethanol

[1183]

[1184] Dispiro[2.0.2.1]heptane-7-carboxylic acid ethyl ester (10.77 g, 64.79 mmol) was slowly added to a slurry of lithium aluminum hydride (7.8 g, 200.2 mmol) cooled in an ice-water bath to diethyl ether (300 mL). During the addition, the mixture was warmed to mild reflux and stirred at ambient temperature for 1 hour. The reaction was cooled in an ice-water bath and slowly quenched by adding water (8.0 mL, 440 mmol), followed by adding sodium hydroxide (8.0 mL, 2 M, 16 mmol), and then adding water (24.0 mL, 1.33 mol). The pale yellow slurry was filtered through diatomaceous earth and washed three times with 150 mL of methyl tert-butyl ether. The filtrate was concentrated under vacuum to give 8.87 g of clear oil, dispiro[2.0.2.1]heptane-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).

[1185] Step 6: Dispiro[2.0.24.13]heptane-7-carboxaldehyde

[1186]

[1187] Add {dispiro[2.0.2.1]hept-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) to a 20 mL vial. Stir the reaction mixture at room temperature for 5 hours. Filter the reaction mixture through diatomaceous earth and evaporate (300 Torr, minimal heating in a 40 °C water bath). Dissolve the reaction mixture in diethyl ether, filter through diatomaceous earth, and evaporate at 300 Torr (minimum heating in a 40 °C water bath) to give dispiro[2.0.24.13]heptane-7-carboxaldehyde (433 mg, 58%) as a pale brown oil. The purity is estimated to be about 50%. The crude product can be used in the next step without further purification.

[1188] Example E: Preparation of 2-dispiro[2.0.24.13]hept-7-ylacetaldehyde

[1189] Step 1: 7-(bromomethyl)dispiro[2.0.2.1]heptane

[1190]

[1191] Equip a 1000 mL, 3-necked round-bottom flask with a mechanical stirrer, a cooling bath, a feeding funnel, a J-Kem temperature probe, and a nitrogen inlet / outlet. Under a nitrogen atmosphere, add 102.7 mL of triphenylphosphine (443.2 mmol) and 1 L of dichloromethane to the flask to obtain a clear, colorless solution. Start stirring and add acetone to the cooling bath. Add dry ice in portions to the cooling bath until an autoclave temperature of -15 °C is achieved. Add a solution of bromine (22.82 mL, 443.0 mmol) in dichloromethane (220 mL, 10 mL / g) to the feeding funnel, and then add this solution dropwise over 1 hour. During the addition, add dry ice in portions to the cooling bath to maintain the autoclave temperature at -15 °C. After the bromine addition is complete, continue stirring the pale yellow suspension at -15 °C for 15 minutes, and then cool the suspension to -30 °C at this temperature. A solution of dispiro[2.0.2.1]hept-7-ylmethanol (50 g, 402.6 mmol), pyridine (35.82 mL, 442.9 mmol), and dichloromethane (250 mL, 5 mL / g) was loaded into a feeding funnel. A clear, pale yellow solution was then added dropwise over 1.5 hours, maintaining the reactor temperature at -30°C. The resulting clear, pale yellow reaction mixture was gradually warmed to -5°C and then stirred at -5°C for 1 hour. The reaction mixture was then poured into hexane (2000 mL), resulting in precipitation. The suspension was stirred at room temperature for 30 minutes and then filtered through a glass Buchner funnel with a 20 mm diatomaceous earth layer. The clear filtrate was concentrated under reduced pressure (water bath temperature 20°C) to obtain a yellow oily substance containing some precipitate. The oily substance was diluted with some hexane, allowed to stand at room temperature for 15 minutes, and then filtered through a glass Buchner funnel with a 20 mm diatomaceous earth layer. The clarified filtrate was concentrated under reduced pressure (water bath temperature 20℃) to obtain 7-(bromomethyl)dispiro[2.0.2.1]heptane (70g, 93%), which was a clear yellow oil. 1 ¹H NMR (400MHz, chloroform-d) δ 3.49 (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).

[1192] Step 2: 2-Dispiro[2.0.2.1]hept-7-ylacetonitrile

[1193]

[1194] A 1000 mL, three-necked round-bottom flask was equipped with a mechanical stirrer, a cooling bath for secondary protection, a J-Kem temperature probe, and a nitrogen inlet / outlet. Under a nitrogen atmosphere, 7-(bromomethyl)dispiro[2.0.2.1]heptane (35 g, 187.1 mmol) and dimethyl sulfoxide (245 mL) were added to the flask to obtain a clear amber solution. Stirring was initiated, and the flask temperature was recorded as 19 °C. Then, a single addition of solid sodium cyanide (11.46 g, 233.8 mmol) was added to the flask, resulting in a dark solution that gradually exothermally reached 49 °C over 15 minutes. After a few minutes, the flask temperature began to decrease, and the mixture was stirred overnight at room temperature (approximately 15 hours). The dark reaction mixture was quenched with ice-cold saturated sodium carbonate solution (500 mL) and then transferred to a separatory funnel and partitioned with diethyl ether (500 mL). Organic matter was removed, and residual water was extracted with diethyl ether (2 x 250 mL). The combined organic matter was washed with water (500 mL), dried over sodium sulfate (200 g), and then filtered through a glass Buchner funnel. The clear amber filtrate was concentrated under reduced pressure (water bath temperature 20 °C) to give 2-dispiro[2.0.2.1]hept-7-ylacetonitrile (21 g, 84%) as a clear 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).

[1195] Step 3: 2-Dispiro[2.0.2.1]hept-7-ylacetic acid

[1196]

[1197] Sodium hydroxide (5.12 g, 128.0 mmol) was added to a solution of 2-dispiro[2.0.2.1]hept-7-ylacetonitrile (2.1 g, 14.19 mmol) in EtOH (32 mL), followed by the addition of water (13 mL). 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 (which produced a turbid precipitate) and extracted with diethyl ether (3X). The organic phase was dried (with magnesium sulfate), filtered, and concentrated to give 2-dispiro[2.0.2.1]hept-7-ylacetic acid (2.19 g, 99% yield, 98% purity) as an orange solid, which was used in the next step without further purification. 1H 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,2 H),0.81(dddd,J=8.9,5.2,3.9,0.5Hz,2H),0.69(dddd,J=8.9,5.2,3.9Hz,2H),0.56-0.44(m,2H).

[1198] Step 4: 2-Dispiro[2.0.2.1]hept-7-ylethanol

[1199]

[1200] Over 15 minutes, 7.470 mL of tetrahydrofuran (containing 2-dispiro[2.0.2.1]hept-7-ylacetic acid (2.552 g, 16.77 mmol)) was added dropwise to lithium aluminum hydride (827.4 mg, 902.3 μL, 21.80 mmol) dissolved in tetrahydrofuran (33.71 mL) and kept the reaction temperature <20 °C. The mixture was stirred for a total of 18 hours and gradually heated to ambient temperature. The mixture was cooled in an ice / water bath and quenched by the slow addition of water (838.4 mg, 838.4 μL, 46.54 mmol), followed by the addition of sodium hydroxide (1.006 mL, 5 M, 5.031 mmol), and then by the addition of water (2.493 g, 2.493 mL, 138.4 mmol) to obtain a white granular slurry filtered through diatomaceous earth. The filtered solid was washed with diethyl ether. The filtrate was concentrated under vacuum at approximately 300 mbar and a water bath at 30 °C. The residue was diluted with diethyl ether, dried (magnesium sulfate), filtered, and concentrated under vacuum at approximately 300 mbar and a water bath at 30 °C, followed by vacuum concentration for approximately 30 seconds to give 2-dispiro[2.0.2.1]hept-7-ylethanol (2.318 g, 100%), which was used directly in subsequent steps without further purification. 1 ¹H NMR (400 MHz, chloroform-d) δ 3.64 (s, 2H), 1.68 (d, J = 6.7 Hz, 2H), 1.39 (s, 1H), 1.31 (s, 1H), 0.82 (d, J = 14.0 Hz, 4H), 0.65 (s, 2H), 0.50 (d, J = 3.6 Hz, 2H).

[1201] Step 5: 2-Dispiro[2.0.24.13]hept-7-ylacetaldehyde

[1202]

[1203] Add 2-dispiro[2.0.24.13]hepta-7-ylethanol (506 mg, 2.380 mmol, 65% w / w), dichloromethane (3 mL), potassium bicarbonate (500 mg, 4.994 mmol), and pyridinium chlorochromate (640 mg, 2.969 mmol) (PCC) to a 20 mL vial. Stir the reaction mixture at room temperature for 5 hours. Filter the reaction mixture through diatomaceous earth and evaporate. Dissolve the reaction mixture in diethyl ether, filter through diatomaceous earth, and evaporate at 300 Torr (with minimal heating) to give 2-dispiro[2.0.24.13]hepta-7-ylacetaldehyde (492 mg, 61%).

[1204] Example F: Preparation of 3-[1-(trifluoromethyl)cyclopropyl]propane-1-ol

[1205] Step 1: Ethyl 2-[1-(trifluoromethyl)cyclopropyl]methanesulfonate

[1206]

[1207] A 1000 mL three-necked round-bottom flask was equipped with a mechanical stirrer, a cooling bath, a J-Kem temperature probe, a feeding 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, yielding a clear, colorless solution. Stirring was initiated, and the flask temperature was recorded as 19 °C. Then, pure triethylamine (124.3 mL, 891.8 mmol) was added to the flask in a single addition. Crushed ice / water was then added to the cooling bath, and the flask temperature was lowered to 0 °C. A solution of methanesulfonyl chloride (62.77 mL, 811.0 mmol) in 2-methyltetrahydrofuran (125 mL, 2 mL / g) was added to the feeding funnel, followed by dropwise addition over 90 minutes, yielding a white suspension that was exothermically heated to 1 °C. The mixture was slowly warmed to room temperature and stirred for 1 hour at room temperature. The mixture was then poured into ice-cold water (250 mL) and transferred to a separatory funnel. Organic matter was removed, and the mixture was washed with 20 wt% potassium bicarbonate solution (250 mL), dried over sodium sulfate (200 g), and then filtered through a glass buchner funnel. The clear filtrate was concentrated under reduced pressure to provide 2-[1-(trifluoromethyl)cyclopropyl]propionic acid (185 g, 98%) as a clear, pale yellow oil. 1 ¹H NMR (400MHz, chloroform-d) δ 4.36 (ddt, J = 7.1, 6.4, 0.7Hz, 2H), 3.02 (s, 3H), 2.03 (t, J = 7.1Hz, 2H), 1.11–0.98 (m, 2H), 0.81–0.66 (m, 2H).

[1208] Step 2: 3-[1-(trifluoromethyl)cyclopropyl]propionitrile

[1209]

[1210] A 1000 mL three-necked round-bottom flask was equipped with a mechanical stirrer, a heating hood, a J-Kem temperature probe / controller, a water-cooled reflux condenser, and a nitrogen inlet / outlet. Under a nitrogen atmosphere, ethyl 2-[1-(trifluoromethyl)cyclopropyl]methanesulfonate (50 g, 215.3 mmol) and dimethyl sulfoxide (250 mL) were added to the container, yielding a clear, pale yellow solution. Stirring was initiated, and the reactor temperature was recorded as 19 °C. Sodium cyanide (13.19 g, 269.1 mmol) was added to the container in a single, solid-state addition. The mixture was heated to 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) and then transferred to a separatory funnel and dispensed using methyl tert-butyl ether (500 mL). The organic phase was removed and the remaining aqueous phase 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 buchner funnel. The clarified filtrate was concentrated under reduced pressure to provide 3-[1-(trifluoromethyl)cyclopropyl]propionitrile (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).

[1211] Step 3: 3-[1-(trifluoromethyl)cyclopropyl]propionic acid

[1212]

[1213] A 1000 mL three-necked round-bottom flask was equipped with a mechanical stirrer, a heating hood, a J-Kem temperature probe / controller, a water-cooled reflux condenser, and a nitrogen inlet / outlet. Under a nitrogen atmosphere, 25 g (153.2 mmol) of 3-[1-(trifluoromethyl)cyclopropyl]propionitrile and 375 mL of ethanol were added to the flask to obtain a clear amber solution. Stirring was started and the flask temperature was recorded as 19 °C. Sodium hydroxide (102.1 mL, 612.6 mmol) was then added to the flask in a single addition. The resulting clear amber solution was heated to 70 °C and maintained for 24 hours. After cooling to room temperature, the reaction mixture was concentrated to remove the ethanol. The remaining aqueous solution was diluted with 150 mL of water and then transferred to a separatory funnel and partitioned with methyl tert-butyl ether (50 mL). The aqueous phase was removed and the pH was adjusted to approximately 1 using 6 M hydrochloric acid solution. The resulting aqueous solution was transferred to a separatory funnel and partitioned with methyl tert-butyl ether (250 mL). The organic phase was removed and the remaining aqueous phase was extracted with methyl tert-butyl ether (2 × 150 mL). The combined organic matter was dried over sodium sulfate (150 g) and then filtered through a glass buchner funnel. The clear filtrate was concentrated under reduced pressure to provide 3-[1-(trifluoromethyl)cyclopropyl]propionic acid (26 g, 93%) as a clear amber oil. 1 ¹H NMR (400MHz, 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).

[1214] Step 4: 3-[1-(trifluoromethyl)cyclopropyl]propane-1-ol

[1215]

[1216] Equipped a 1000 mL, 3-necked round-bottom flask with a mechanical stirrer, cooling bath, feeding funnel, J-Kem temperature probe, and nitrogen inlet / outlet. Lithium aluminum hydride granules (6.775 g, 178.5 mmol) were added to the flask under a nitrogen atmosphere. Then, tetrahydrofuran (250 mL) was added to the flask under a nitrogen atmosphere. Stirring was initiated, and the flask temperature was recorded as 20 °C. The mixture was stirred at room temperature for 0.5 hours to dissolve the granules. The temperature of the resulting gray suspension was recorded as 24 °C. Crushed ice / water was then added to the cooling bath, and the flask temperature was lowered to 0 °C. A solution of 3-[1-(trifluoromethyl)cyclopropyl]propionic acid (25 g, 137.3 mmol) in tetrahydrofuran (75 mL, 3 mL / g) was added to the feeding funnel, and a clear, pale yellow solution was added dropwise over 1 hour. After the addition was complete, the temperature of the resulting grayish-brown suspension was recorded as 5 °C. The mixture was slowly warmed to room temperature and stirred for 24 hours at room temperature. The suspension was cooled to 0°C using a crushed ice / water cooling bath and then quenched by very slow dropwise addition of water (6.775 mL), followed by the addition of 15 wt% sodium hydroxide solution (6.775 mL) and finally quenched with water (20.32 mL). The temperature of the resulting white suspension was recorded as 5°C. The suspension was stirred continuously at approximately 5°C for 30 minutes and then filtered through a glass-flush Buchner funnel with a 20 mm diatomaceous earth layer. The filter cake was washed with tetrahydrofuran (2 × 150 mL) and then dried under vacuum for 15 minutes. The filtrate was dried with sodium sulfate (250 g) and then filtered through a glass-flush Buchner funnel. The filtrate was concentrated under reduced pressure to give a clear, light amber oil, the desired product 3-[1-(trifluoromethyl)cyclopropyl]propane-1-ol (21.2 g, 92%). 1 ¹H NMR (400MHz, chloroform-d) δ 3.65 (t, J = 6.0Hz, 2H), 1.78–1.59 (m, 4H), 0.99–0.91 (m, 2H), 0.59 (dp, J = 4.7, 1.7Hz, 2H).

[1217] Example G: Preparation of 2-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]pyridine-4-carboxylic acid

[1218] Step 1: Methyl 2-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]pyridine-4-carboxylic acid

[1219]

[1220] Under nitrogen atmosphere, methyl 2-chlorosulfonylpyridin-4-carboxylate (5 g, 21.218 mmol) and 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (5 g, 21.395 mmol) were dissolved in anhydrous THF (150 mL) and the solution was cooled to -78 °C. A 1 M THF solution of LiHMDS (43 mL, 1 M, 43.000 mmol) was added dropwise, and the mixture was gradually warmed to 0 °C. The reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution (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 give methyl 2-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]pyridin-4-carboxylate (8.3 g, 80.6%) as a white solid. ESI-MS calculated m / z value: 432.06592; experimental value: 432.8 (M+1). + Retention time: 5.5 minutes; LC method S.

[1221] Step 2: 2-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]pyridine-4-carboxylic acid

[1222]

[1223] A 1M NaOH aqueous solution (95 mL, 95.000 mmol) was added to a solution of methyl 2-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]pyridine-4-carboxylic acid (8.1 g, 18.712 mmol) in THF (95 mL), and the mixture was stirred at room temperature for 1 hour. 1M HCl aqueous solution was added to a pH of approximately 8, and the mixture was extracted with 2-MeTHF (2 × 100 mL). The aqueous phase was separated and acidified with 1M HCl aqueous solution to a pH of approximately 2. The formed precipitate was collected by filtration to give 5.17 g, 71%, of 2-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]pyridine-4-carboxylic acid as a white solid. 1 ¹H NMR (250MHz, DMSO(d⁶)) δ 8.87 (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, experimental value 419.3 (M+1). + Retention time: 4.62 minutes; LC method S.

[1224] V. Synthesis of new compounds

[1225] Example 1: Preparation of Compound 1 and Compound 2

[1226] Step 1: N-(2-aminoethyl)-2-nitro-benzenesulfonamide

[1227]

[1228] Under stirring and a nitrogen atmosphere, at 0–5 °C, a solution of 2-nitrobenzenesulfonyl chloride (205 g, 897.26 mmol) in tetrahydrofuran (700 mL) was added dropwise to a solution of ethane-1,2-diamine (600.00 mL, 8.89 mol) in tetrahydrofuran (500 mL). After the addition, the reaction was stirred for another 30 minutes and then warmed to room temperature and concentrated under vacuum. The oily residue was dissolved in DCM (500 mL) and washed with water (500 mL). The organic layers were separated, and the product was extracted from the aqueous layer (pH = 11, 3 × 300 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give an orange gel (161 g, 90% purity). The aqueous layer was treated with 6M HCl to adjust the pH to 8–7, and then extracted with a mixture of chloroform:isopropanol (3:1, v:v, 4 × 300 mL). After evaporation, a further amount of the substance (57.2 g, 98% purity) was separated. The total amount of N-(2-aminoethyl)-2-nitro-benzenesulfonamide was 218.2 g (89%). ESI-MS m / z calculated value 245.04703, experimental value 246.4 (M+1). + Retention time: 1.69 minutes; LC method T.

[1229] Step 2: N-[2-[[(2R)-3-chloro-2-hydroxypropyl]amino]ethyl]-2-nitro-benzenesulfonamide

[1230]

[1231] N-(2-aminoethyl)-2-nitro-benzenesulfonamide (75 g, 275.22 mmol), anhydrous methanol (80 mL), and anhydrous magnesium sulfate (18 g, 149.54 mmol) were added to a 250 mL flask equipped with a magnetic stir bar. Pure (2R)-2-(chloromethyl)ethylene oxide (12 mL, 147.35 mmol) was rapidly added via syringe. The orange suspension was stirred at room temperature under nitrogen for 7 hours. The solid was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (500 mL) and water (200 mL), and the two phases were separated. After drying with sodium sulfate, the solvent was evaporated. The residue was purified by rapid silica gel chromatography (2 × 330 g column) using a methanol / dichloromethane gradient (0 to 10%). The pure fractions were combined and the solvent was removed under vacuum to obtain N-[2-[[(2R)-3-chloro-2-hydroxypropyl]amino]ethyl]-2-nitro-benzenesulfonamide (40.2 g, 78%) as a yellow gel. ESI-MS calculated m / z value: 337.04993; experimental value: 338.4 (M+1). + Retention time: 1.91 minutes; LC method T.

[1232] Step 3: (6R)-1-(2-nitrophenyl)sulfonyl-1,4-diazacyclohepta-6-ol

[1233]

[1234] A suspension of N-[2-[[(2R)-3-chloro-2-hydroxypropyl]amino]ethyl]-2-nitro-benzenesulfonamide (58.3 g, 167.42 mmol) and cesium carbonate (205 g, 629.19 mmol) in anhydrous acetonitrile (1500 mL) was stirred in an oil bath at 65 °C for 2.5 h under nitrogen. After cooling, the solid was filtered off 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 silica gel rapid chromatography (330 g column) using 0 to 15% methanol / dichloromethane. The pure fractions were combined and the solvent was evaporated to give (6R)-1-(2-nitrophenyl)sulfonyl-1,4-diazacyclohepta-6-ol (18.1 g, 34%), which was an orange gel. 1¹H NMR (250MHz, DMSO) δ 8.06–7.93 (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, experimental value 302.1 (M+1). + Retention time: 0.88 minutes; LC method W.

[1235] Step 4: (6R)-6-hydroxy-4-(2-nitrophenyl)sulfonyl-1,4-diazacyclohepta-1-carboxylic acid tert-butyl ester

[1236]

[1237] In a 500 mL flask under nitrogen atmosphere, (6R)-1-(2-nitrophenyl)sulfonyl-1,4-diazacyclohepta-6-ol (12.14 g, 40.29 mmol) was dissolved in anhydrous methanol (130 mL). 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 was concentrated, and the residue was dissolved in DCM (100 mL) and a saturated aqueous solution of sodium bicarbonate (100 mL). Both phases were decanted, and the aqueous phase was further extracted with DCM (25 mL). The combined extracts were dried over sodium sulfate, and the solvent was evaporated to give the residue purified by rapid silica gel chromatography (330 g column) using a gradient of methanol (0 to 10% over 40 minutes) / dichloromethane. The product elutes with approximately 2-3% methanol. The pure fractions are combined and the solvent is evaporated to give (6R)-6-hydroxy-4-(2-nitrophenyl)sulfonyl-1,4-diazacyclohepta-1-carboxylic acid tert-butyl ester (13.93 g, 86%) as a yellow foamy solid. 1 ¹H NMR (400 MHz, chloroform-d) revealed several conformational isomers with δ values ​​of 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), and 1.51–1.42 (m, 9H). ESI-MS m / z calculated value was 401.12567, experimental value was 402.28 (M+1). + Retention time: 1.3 minutes; LC method A.

[1238] Step 5: (6S)-6-hydroxy-1,4-diazacyclohepta-1-carboxylic acid tert-butyl ester

[1239]

[1240] (6R)-6-hydroxy-4-(2-nitrophenyl)sulfonyl-1,4-diazacyclohepta-1-carboxylic acid tert-butyl ester (52 g, 116.58 mmol) was dissolved in acetonitrile (500 mL). 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 in an oil bath at 55 °C under nitrogen 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, 1 N aqueous solution). The layers were separated, and the aqueous layer was washed twice more with DCM (200 mL × 2). The aqueous solution (containing the desired product) was cooled in ice water. NaOH (3 N, aqueous solution) was added to achieve pH 12. DCM was added to extract the free base product. The layers were separated again, and the aqueous phase was further extracted with DCM (200 mL × 2). The combined DCM solutions were washed with brine (3200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give (6S)-6-hydroxy-1,4-diazacyclohepta-1-carboxylic acid tert-butyl ester (15.6 g, 59%). ESI-MS calculated m / z value was 216.1474, and experimental value was 217.4 (M+1). + Retention time: 2.27 minutes. ESI-MS m / z calculated value: 216.1474, experimental value: 217.4 (M+1) + Retention time: 2.27 minutes; LC method T.

[1241] Step 6: (6S)-4-[3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoyl]-6-hydroxy-1,4-diazacyclohepta-1-carboxylic acid tert-butyl ester]

[1242]

[1243] Under nitrogen atmosphere, (6S)-6-hydroxy-1,4-diazacyclohepta-1-carboxylic acid tert-butyl ester (1.195 g, 5.525 mmol), anhydrous DMF (35 mL), and 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (1.828 g, 4.375 mmol) were added to a 100 mL flask. After the reagents were dissolved, 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 min, then quenched by pouring into 150 mL (10% w / v, 78.07 mmol) of citric acid (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 solvent evaporation, the residue (2.76 g) was purified by rapid silica gel chromatography (120 g column) using a gradient of methanol (0 to 10% over 30 minutes) / dichloromethane. The product eluted with approximately 4% methanol. Evaporation of the solvent yielded (6S)-4-[3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoyl]-6-hydroxy-1,4-diazacyclohepta-1-carboxylic acid tert-butyl ester (1.672 g, 62%) as a white, foamy solid. 1 The H NMR (400MHz, DMSO-d6) spectrum of the complex may be due to the presence of rotational isomers, the signal assignment is unclear, and there is an apparent proton surplus. δ 12.40 (s, 1H), 8.05-7.84 (m, 2H), 7.72-7.53 (m, 2H), 7.38-7.30 (m, 1H), 7.24 (t, J = 7.3 Hz, 1H), 7.16-7.01 (m, 2H), 5.27 (d, J = 13.5 Hz, 0.5H), 4.98 (s, 0.5H), 4.13-3.36 (m, 7H), 3.19 (width s, 1H), 3.13-2.95 (m, 2H), 1.90 (d, J = 9.2 Hz, 6H), 1.39 (d, J = 17.4 Hz, 6H), 1.11 (s, 3H). ESI-MS m / z calculated value 615.19183, experimental value 616.41 (M+1). + Retention time: 1.69 minutes; LC method A.

[1244] Step 7: (16S)-12-(2,6-dimethylphenyl)-2,8,8-trioxo-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10,12,14(22)-hexane-18-carboxylic acid tert-butyl ester

[1245]

[1246] (6S)-4-[3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoyl]-6-hydroxy-1,4-diazacyclohepta-1-carboxylic acid tert-butyl ester (1.426 g, 2.314 mmol) and anhydrous DMF (70 mL) were added to a 250 mL flask under nitrogen. The mixture was cooled on ice. NaH (783 mg, 19.58 mmol, 60% w / w) (60% mineral oil dispersion) was added in two portions. The mixture was stirred at 0 °C under nitrogen for 3.5 h. While stirring, the mixture was slowly poured into ice-cold citric acid (300 mL, 156.1 mmol, 10% w / v) (10% aqueous solution). The resulting solid suspension was extracted with EtOAc (4 × 60 mL). After drying with sodium sulfate, solvent evaporation yielded a residue (3.97 g) purified by rapid silica gel chromatography (120 g column) using a methanol / dichloromethane gradient (0 to 10% over 30 minutes). The product eluted with approximately 4-5% methanol. Solvent evaporation gave a colorless, resin-like (16S)-12-(2,6-dimethylphenyl)-2,8,8-trioxo-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarbon-3,5,7(23),10,12,14(22)-hexene-18-carboxylic acid tert-butyl ester (858 mg, 64%). 1 Residual DMF was visible under H NMR (400MHz, DMSO-d6). The two conformational isomers (55:45) were observed to have the following values: δ 12.59 (both broad s, 1H), 8.33 (2s, 1H), 7.95 (s, 2H overlapping with the residual DMF signal), 7.67 (br s, 2H), 7.26 (t, J = 7.6 Hz, 1H), 7.12 (d, J = 7.6 Hz, 2H), 6.34 (br s, 1H), 5.42 (both 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), and 1.44 (both s, 9H). The calculated ESI-MS m / z value was 579.21515, and the experimental value was 580.45 (M+1). + Retention time: 1.51 minutes; LC method A.

[1247] Step 8: (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6-Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarbon-3,5,7(23),10,12,14(22)-hexane-2,8,8-trione (compound 2)

[1248]

[1249] (16S)-12-(2,6-dimethylphenyl)-2,8,8-trioxo-15-oxa-8λ in DCM (200 mL, cooled in an ice-water bath) 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarbamo-3,5,7(23),10,12,14(22)-hexene-18-carboxylic acid tert-butyl ester (21.68 g, 33.661 mmol) was treated with HCl (80 mL of 4 M, 320.00 mmol). The solution was stirred at room temperature for 2 hours. The mixture was concentrated to dryness. The residue was ground with DCM / ethyl 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 give (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ as a white solid. 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarbazo-3,5,7(23),10,12,14(22)-hexane-2,8,8-trione (hydrochloride) (11.88 g, 66%). 1 ¹H NMR (250MHz, DMSO-d⁶) δ 10.36 (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 = 0.9 Hz, 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, experimental value 480.1 (M+1). + Retention time: 1.42 minutes; LC method W.

[1250] Step 9: (16R)-18-(3,3-dimethylbutyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6-Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarb-3,5,7(23),10,12,14(22)-hexane-2,8,8-trione (compound 1)

[1251]

[1252] (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ was stirred. 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10,12,14(22)-hexene-2,8,8-trione (hydrochloride) (4.7 g, 9.108 mmol) was added to DCM (47 mL) and the suspension was treated with 3,3-dimethylbutyraldehyde (4.6 mL, 36.65 mmol), followed by acetic acid (3.1 mL, 54.51 mmol), and the resulting fine gel suspension was stirred at room temperature for 50 min. The suspension was cooled in an ice bath and sodium cyanoborohydride (3.4 g, 54.10 mmol) was slowly added over about 30 seconds, resulting in an exothermic reaction. The suspension was stirred in an ice bath for 15 min, then the ice bath was removed and the suspension was stirred again for 15 min. The reaction mixture was added to a stirred saturated ammonium chloride solution (250 mL) and extracted with ethyl acetate (250 mL). The organic phase was washed once with a saturated ammonium chloride solution (200 mL) and once with brine (100 mL). The aqueous phase was back-extracted with ethyl acetate (200 mL), and the combined organic phases were dried, filtered, and evaporated. The crude product was subjected to reversed-phase chromatography (435 g C). 18 The liquid (containing DMSO and a few drops of 6M HCl) was purified using a linear gradient from 5% acetonitrile to 100% acetonitrile / water containing 5mM HCl. The impure fractions were further purified using the same method. The pure substances were combined to give (16R)-18-(3,3-dimethylbutyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ as a white solid. 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarb-3,5,7(23),10,12,14(22)-hexane-2,8,8-trione (hydrochloride) (3.56 g, 64%). 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 Calculated m / z value: 563.25665; Experimental value: 564.0 (M+1) + Retention time: 4.75 minutes; LC method A, gradient of phase B within 13.5 minutes is 1-99%.

[1253] Example 2: Preparation of Compound 3

[1254] Step 1: (16R)-12-(2,6-dimethylphenyl)-18-{spiro[3.5]nonane-2-yl}-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarbon-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (compound 3)

[1255]

[1256] In a 20 mL vial, add (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ to a stirred solution of spiro[3.5]nonane-2-one (600 mg, 4.341 mmol) in anhydrous dichloromethane (40 mL) in this order. 6-Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10,12,14(22)-hexane-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). The resulting pale yellow solution was stirred at ambient temperature for 25 minutes, and then sodium triacetoxyborohydride (1.743 g, 8.224 mmol) was immediately added and stirring was continued for another hour. Then, a saturated aqueous solution of sodium bicarbonate (5 mL) was added to the reaction and 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 compounds were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by rapid chromatography (80 g silica gel, 0-5% methanol / dichloromethane over 30 minutes). The desired product (16R)-12-(2,6-dimethylphenyl)-18-{spiro[3,5]nonane-2-yl}-15-oxa-8λ was obtained as a white solid. 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarb-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (1.649 g, 70%). 1 H 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,1H ),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), 2.05(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, experimental value 602.5(M+1). + Retention time: 1.29 minutes; LC method A.

[1257] Example 3: Preparation of Compound 4

[1258] Step 1: (16R)-18-(4,4-difluorocyclohexyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarbon-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (compound 4)

[1259]

[1260] Add (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ to the vial 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10,12,14(22)-hexene-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). The reaction was gently heated at 35 °C for 4 hours. The reaction was quenched with methanol, filtered, and purified by reversed-phase HPLC (1%-60% ACN:water and 0.1% HCl modifier) ​​to obtain (16R)-18-(4,4-difluorocyclohexyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ as a solid. 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarb-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (40.1 mg, 53%). 1H 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 0.8Hz, 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, experimental value 598.5(M+1). + Retention time: 1.13 minutes (LC method A).

[1261] Example 4: Preparation of Compound 5

[1262] Step 1: (16R)-18-(4,4-dimethylcyclohexyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarbon-3(23),4,6,10,12,14(22)-hexane-2,8,8-trione (compound 5)

[1263]

[1264] Following this order, under nitrogen atmosphere at ambient temperature, the mixture is directed towards (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ. 6A solution of -thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10,12,14(22)-hexane-2,8,8-trione (hydrochloride) (10 mg, 0.01938 mmol) in anhydrous dichloromethane (0.50 mL) was prepared by adding 4,4-dimethylcyclohexanone (5 mg, 0.03962 mmol), triethylamine (5 μL, 0.03587 mmol), and glacial acetic acid (2 mg, 0.03330 mmol). The pale yellow solution was stirred for 20 minutes, and then sodium triacetoxyborohydride (9 mg, 0.04246 mmol) was added at ambient temperature. After stirring for 12 hours (overnight), an aqueous solution of sodium bicarbonate (1 mL) and dichloromethane (2 mL) were added. The two layers were separated, and the aqueous layer was extracted with dichloromethane (2 × 2 mL). The combined organic extracts were washed successively with water (2 mL) and brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was dissolved in DMSO (0.8 mL), microfiltered, and purified by preparative reversed-phase HPLC, eluting with 0–99% acetonitrile / water for 15 min (HCl as a modifier). The desired product (16R)-18-(4,4-dimethylcyclohexyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ was obtained as a white solid. 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarbon-3(23),4,6,10,12,14(22)-hexane-2,8,8-trione (hydrochloride) (8 mg, 65%). 1 H 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,1H), 3.66 (d, J = 6.0 Hz, 2H), 3.56–3.43 (m, 2H), 3.30 (dd, J = 14.3, 10.8 Hz, 1H), 2.05 (s, 6H), 1.89 (d, J = 12.7 Hz, 2H), 1.74 (two t, J = 12.2 Hz, 2H), 1.52 (d, J = 13.1 Hz, 2H), 1.31 (t, J = 13.4 Hz, 2H), 0.96 (s, 3H), 0.93 (s, 3H). ESI-MS calculated m / z value: 589.2723; experimental value: 590.5 (M+1).+ Retention time: 1.2 minutes; LC method A.

[1265] Example 5: Preparation of Compound 6

[1266] Step 1: (16R)-18-cyclopentyl-12-(2,6-dimethylphenyl)-8,8-dioxo-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10(22),11,13-hexane-2-one (compound 6)

[1267]

[1268] Add (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ to the test tube 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10,12,14(22)-hexane-2,8,8-trione (12 mg, 0.02502 mmol), DCE (0.5 mL), and DIEA (approx. 4.204 mg, 5.666 μL, 0.03253 mmol). After 5 minutes, cyclopentanone (approx. 10.52 mg, 11.06 μL, 0.1251 mmol) and acetic acid (approx. 7.513 mg, 7.115 μL, 0.1251 mmol) were added and the reaction was stirred for 1 hour. Sodium cyanoborohydride (approx. 7.862 mg, 0.1251 mmol) was added and the reaction was stirred at room temperature for 4 hours. The reaction mixture was diluted with DMF (0.5 mL), filtered, and purified by reversed-phase HPLC using a 1%–70% gradient of CAN / water and an HCl modifier. (16R)-18-cyclopentyl-12-(2,6-dimethylphenyl)-8,8-dioxo-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10(22),11,13-hexane-2-one (hydrochloride) was isolated as a solid (5.3 mg, 36.3%). ESI-MS calculated m / z 547.22534, experimental 548.1 (M+1). + Retention time: 0.94 minutes; LC method A.

[1269] Example 6: Preparation of Compound 7

[1270] Step 1: (16R)-18-(3-tert-butylcyclobutyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarbon-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (compound 7)

[1271]

[1272] Add (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ to the vial 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10,12,14(22)-hexene-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). The reaction was heated to 35 °C and stirred overnight. The reaction mixture was diluted with methanol, filtered, and purified by HPLC (1%-60% ACN: water and 0.1% HCl modifier) ​​to give (16R)-18-(3-tert-butylcyclobutyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ as a white solid. 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (hydrochloride) (90.1 mg, 74%). ESI-MS m / z calculated 589.2723, experimental 590.5 (M+1). + Retention time: 1.27 minutes, LC method A.

[1273] Example 7: Preparation of Compound 8

[1274] Step 1: (16R)-12-(2,6-dimethylphenyl)-18-{spiro[3,4]octane-2-yl}-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarbon-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (compound 8)

[1275]

[1276] Add (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ to a 4 mL vial 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10,12,14(22)-hexene-2,8,8-trione (hydrochloride) (55 mg, 0.1066 mmol), spiro[3.4]octane-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 about 10 minutes. Sodium triacetoxyborohydride (66 mg, 0.3114 mmol) was added. The vial was purged with nitrogen, capped, and the reaction was stirred at room temperature for 16 hours. Methanol (100 μL) was added. The DCM was evaporated and the residue was dissolved in DMSO (1 mL). The solution was microfiltered through a PTFE syringe filter and then passed through a reversed-phase preparative HPLC (C1000-C1000 HPLC) system. 18 Purification was performed using a gradient of acetonitrile / water (1 to 99% over 15 minutes) and HCl as a modifier. Evaporation yielded a solid dissolved in DCM / MeOH to be transferred to a vial. Following solvent evaporation, grinding and evaporation in DCM / hexane yielded a white solid of (16R)-12-(2,6-dimethylphenyl)-18-{spiro[3,4]octane-2-yl}-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarb-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (hydrochloride) (44 mg, 65%). 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, possibly 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, experimental value 588.6(M+1). + Retention time: 1.16 minutes; LC method A.

[1277] Example 8: Preparation of Compounds 9 and 10

[1278] Step 1: (16R)-18-(2,2-dimethylcyclobutyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarb-3(23),4,6,10(22),11,13-hexane-2,8,8-trione, diastereomer 1 (compound 9) and (16R)-18-(2,2-dimethylcyclobutyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarb-3(23),4,6,10(22),11,13-hexane-2,8,8-trione, diastereomer 2 (compound 10)

[1279]

[1280] Add (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ to the test tube 6-Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10,12,14(22)-hexene-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). The reaction was stirred overnight at 30 °C. The reaction was quenched with methanol, filtered, and purified by preparative HPLC (1%-50% MeCN, HCl modifier over 30 minutes). The first diastereomer eluted is (16R)-18-(2,2-dimethylcyclobutyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarb-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (hydrochloride) (0.8 mg, 7%) ESI-MS m / z calculated 561.24097, experimental 562.3 (M+1) + Retention time: 1.11 minutes (diastereomer 1). The second diastereomer eluted was (16R)-18-(2,2-dimethylcyclobutyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarb-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (hydrochloride) (0.8 mg, 7%) ESI-MS m / z calculated 561.24097, experimental 562.5 (M+1) + Retention time: 1.14 minutes (diastereomer 2), LC method A.

[1281] Example 9: Preparation of Compound 11

[1282] Step 1: (16R)-12-(2,6-dimethylphenyl)-18-(1-ethylpropyl)-8,8-dioxo-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10,12,14(22)-hexane-2-one (compound 11)

[1283]

[1284] Add (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ to the test tube 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10,12,14(22)-hexane-2,8,8-trione (12 mg, 0.02502 mmol), DIEA (approx. 4.204 mg, 5.666 μL, 0.03253 mmol) and 1,2-dichloroethane (0.5 mL). After stirring for 5 minutes, pentane-3-one (approx. 10.78 mg, 13.26 μL, 0.1251 mmol), acetic acid (approx. 7.513 mg, 7.115 μL, 0.1251 mmol) and sodium triacetoxyborohydride (approx. 26.51 mg, 0.1251 mmol) were added and the reaction was stirred overnight. The reaction was quenched with methanol, filtered, and purified by reversed-phase HPLC to obtain (16R)-12-(2,6-dimethylphenyl)-18-(1-ethylpropyl)-8,8-dioxo-15-oxa-8λ. 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10,12,14(22)-hexane-2-one (hydrochloride) (14.9 mg, 100%). ESI-MS m / z calculated 549.24097, experimental 550.4 (M+1). + Retention time: 1.12 minutes; LC method A.

[1285] Example 10: Characterization of compounds 12-34

[1286] The compounds in the table below were prepared using commercially available reagents and intermediates described herein in a manner similar to that described above.

[1287] Table 3:

[1288]

[1289]

[1290]

[1291]

[1292]

[1293] Table 4:

[1294]

[1295]

[1296] Example 11: Preparation of Compound 35

[1297] Step 1: (16R)-18-(cyclopropylmethyl)-12-(2,6-dimethylphenyl)-8,8-dioxo-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10(22),11,13-hexen-2-one (compound 35)

[1298]

[1299] To contain 12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (hydrochloride) (10.5 mg, 0.02035 mmol) was added to a vial containing dichloroethane (700 μL), cyclopropaneformaldehyde (7.7 μL, 0.1030 mmol), and acetic acid (6 μL, 0.1055 mmol). The reaction was stirred at room temperature for 1 hour. Sodium cyanoborohydride (7 mg, 0.1114 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The reaction was complete as determined by LCMS. The reaction was quenched with methanol, filtered, and purified by preparative HPLC using 1%–99% ACN:water and 0.1% HCl modifier. (16R)-18-(cyclopropylmethyl)-12-(2,6-dimethylphenyl)-8,8-dioxo-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10(22),11,13-hexane-2-one (6.8 mg, 63%) ESI-MS m / z calculated 533.20966, experimental 534.4 (M+1) + Retention time: 0.93 minutes; separated into a white solid. ESI-MS m / z calculated value: 533.20966; experimental value: 534.4 (M+1). + Retention time: 0.93 minutes; LC method A.

[1300] Example 12: Preparation of compounds 36 and 37

[1301] Step 1: (16R)-18-(3,3-dimethylcyclopentyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarb-3,5,7(23),10(22),11,13-hexane-2,8,8-trione (a mixture of diastereomers)

[1302]

[1303] Add (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ to the vial 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10,12,14(22)-hexene-2,8,8-trione (hydrochloride) (20 mg, 0.03876 mmol), 3,3-dimethylcyclopentanone (approx. 21.74 mg, 0.1938 mmol), 5-ethyl-2-methylpyridineborane complex (approx. 15.70 mg, 17.31 μL, 0.1163 mmol), and acetic acid (approx. 46.55 mg, 44.08 μL, 0.7752 mmol). The reaction was heated to 30 °C and stirred overnight. The reaction was quenched with methanol, filtered, and purified by preparative HPLC to give a mixture of diastereomers of (16R)-18-(3,3-dimethylcyclopentyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ. 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarb-3,5,7(23),10(22),11,13-hexane-2,8,8-trione (11.0 mg, 49%).

[1304] Step 2: (16R)-18-(3,3-dimethylcyclopentyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarb-3,5,7(23),10(22),11,13-hexane-2,8,8-trione, diastereomer 1 (compound 36) and (16R)-18-(3,3-dimethylcyclopentyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6-Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10(22),11,13-hexane-2,8,8-trione, diastereomer 2 (compound 37)

[1305]

[1306] (16R)-18-(3,3-dimethylcyclopentyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarbamo-3,5,7(23),10(22),11,13-hexane-2,8,8-trione (11 mg, 0.01911 mmol) was separated by chiral SFC (chiral Cel 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), yielding the first diastereomer eluted, (16R)-18-(3,3-dimethylcyclopentyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10(22),11,13-hexane-2,8,8-trione (hydrochloride) (2.9 mg, 50%). ESI-MS m / z calculated 575.25665, experimental 576.3 (M+1). + Retention time: 1.19 minutes; and the eluted second diastereomer, (16R)-18-(3,3-dimethylcyclopentyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10(22),11,13-hexane-2,8,8-trione (hydrochloride) (3.4 mg, 58%). ESI-MS m / z calculated 575.25665, experimental 576.5 (M+1). + Retention time: 1.2 minutes (LC method A).

[1307] Example 13: Preparation of compounds 38, 39 and 40

[1308] Step 1: (16R)-12-(2,6-dimethylphenyl)-18-(4-fluorocyclohexyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarb-3(23),4,6,10,12,14(22)-hexane-2,8,8-trione, 2:1 diastereomeric mixture (compound 40), (16R)-12-(2,6-dimethylphenyl)-18-(4-fluorocyclohexyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarb-3(23),4,6,10,12,14(22)-hexane-2,8,8-trione, diastereomer 1 (compound 38), and (16R)-12-(2,6-dimethylphenyl)-18-(4-fluorocyclohexyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarb-3(23),4,6,10,12,14(22)-hexane-2,8,8-trione, diastereomer 2 (compound 39)

[1309]

[1310] In a 4 mL vial, add (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ to a stirred solution of 4-fluorocyclohexanone (35 mg, 0.3014 mmol) in anhydrous 1,2-dichloroethane (1.5 mL) in the following order. 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10,12,14(22)-hexane-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). The resulting pale yellow solution was stirred at ambient temperature for 30 minutes, then sodium cyanoborohydride (40 mg, 0.6365 mmol) was added and stirring was continued for 13 hours. The crude material was diluted with DMSO (0.8 mL), microfiltered, and purified by preparative reversed-phase HPLC, eluting with 1-99% acetonitrile / water for 15 minutes (HCl as a modifier). The desired product (16R)-12-(2,6-dimethylphenyl)-18-(4-fluorocyclohexyl)-15-oxa-8λ was obtained as a white solid diastereomeric mixture. 6-Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3(23),4,6,10,12,14(22)-hexane-2,8,8-trione (hydrochloride) (33 mg, 69%). ESI-MS m / z calculated 579.23157, experimental 580.5 (M+1). + Retention time: 1.01 minutes (LC method A).

[1311] Two diastereomers were separated using a preparative SFC (column: chiral Cel OD (250 × 10 mm), 5 μm; 35°C; 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), yielding peak 1, diastereomer 1, (16R)-12-(2,6-dimethylphenyl)-18-(4-fluorocyclohexyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarbon-3(23),4,6,10,12,14(22)-hexane-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),7.14(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, 4.0 Hz, 1H), 3.38 (dd, J = 13.1, 5.2 Hz, 1H), 3.30-3.25 (m, 2H), 3.25-3.18 (m, 1H), 3.00 (dd, J = 13.1, 9.3 Hz, 1H), 2.95 (ddd, J = 13.5, 8.7, 4.6 Hz, 1H), 2.76 (dt, J = 10.9, 6.4 Hz, 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, experimental value: 580.4 (M+1). +Retention time: 0.97 minutes (LC method A); and peak 2, diastereomer 2, (16R)-12-(2,6-dimethylphenyl)-18-(4-fluorocyclohexyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarb-3(23),4,6,10,12,14(22)-hexane-2,8,8-trione (9 mg, 20%) 1 H 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, 4.0 Hz, 1H), 3.35 (dd, J = 13.3, 5.3 Hz, 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 calculated m / z value: 579.23157, experimental value: 580.4 (M+1). + Retention time: 0.98 minutes (LC method A).

[1312] Example 14: Preparation of Compound 41

[1313] Step 1: (16R)-12-(2,6-dimethylphenyl)-18-{2-oxaspiro[3.5]nonane-7-yl}-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarbon-3(23),4,6,10,12,14(22)-hexane-2,8,8-trione (compound 41)

[1314]

[1315] Add (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ to a 4 mL vial 6-Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10,12,14(22)-hexane-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]nonane-7-one (22 mg, 0.1569 mmol), and glacial acetic acid (10 μL, 0.1758 mmol). 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). Add methanol (0.25 mL). Evaporate the volatiles under reduced pressure and dissolve the residue in DMSO (1 mL). Microfilter the solution (0.45 μM) and pass it by reversed-phase preparative HPLC (C6000 HPLC). 18 Purification was performed using an acetonitrile / water gradient (1 to 99% over 15 minutes, with HCl as a modifier) ​​to give a white solid. (16R)-12-(2,6-dimethylphenyl)-18-{2-oxaspiro[3.5]nonane-7-yl}-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarb-3(23),4,6,10,12,14(22)-hexane-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 = 7.7 Hz, 2H), 3.85 (dt, J = 13.4, 6.6 Hz, 1H), 3.75-3.66 (m, 1H), 3.63 (s, 2H), 3.60-3.48 (m, 2H), 3.41 (s, 2H), 3.38-3.32 (m, 1H), 2.11 (s, 6H), 2.03 (d, J = 10.3 Hz, 2H), 1.94-1.73 (m, 4H), 1.37 (t, J = 13.3 Hz, 1H), 1.11 (t, J = 16.7 Hz, 1H). ESI-MS m / z calculated value: 603.2515, experimental value: 604.4 (M+1). + Retention time: 0.92 minutes (LC method A).

[1316] Example 15: Preparation of Compounds 42 and 43

[1317] Step 1: 1,4-Dibenzyl-1,4-diazacyclohepta-6-ol

[1318]

[1319] To a solution of N,N'-dibenzylethane-1,2-diamine (49.97 g, 48.990 mL, 205.83 mmol) in toluene (1.2 L), 1,3-dibromoprop-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 × 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 from 0-100% to give 1,4-dibenzyl-1,4-diazacyclohepta-6-ol (27 g, 42%) as a yellow oil. 1¹H NMR (250MHz, CDCl₃) δ 7.40–7.18 (m, 10H), 3.81 (p, J = 3.7 Hz, 1H), 3.72–3.64 (s, 4H), 2.90–2.66 (m, 6H), 2.47 (tdd, J = 8.1, 6.7, 5.0 Hz, 2H). ESI-MS calculated m / z value 296.18887, experimental value 297.2 (M+1). + Retention time: 1.53 minutes; LC method T.

[1320] Step 2: 6-Hydroxy-1,4-diazacyclohepta-1-carboxylic acid tert-butyl ester

[1321]

[1322] A solution of 1,4-dibenzyl-1,4-diazacyclohepta-6-ol (13.36 g, 45.07 mmol) in methanol (500 mL) was purged under nitrogen. Palladium hydroxide (3.03 g, 20% 20% char, 50% wet, 2.16 mmol) was added, and the reaction mixture was purged under hydrogen and then stirred at one atmosphere of hydrogen for 24 hours. The reaction mixture was purged again under nitrogen, filtered through diatomaceous earth, and washed with methanol (approximately 500 mL). The mixture was concentrated under reduced pressure to give 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 was gradually heated 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 precipitated. The solid was filtered off and the filtrate was adsorbed onto silica gel and purified by silica gel chromatography on a 220 g column, eluting with 0% to 10% methanol / dichloromethane to give tert-butyl 6-hydroxy-1,4-diazacyclohepta-1-carboxylic acid (3.265 g, 32%) as a thick, amber-colored oil. 1 ¹H NMR (300MHz, CDCl₃) δ 1.47 (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 216.1474, experimental 217.2 (M+1). + Retention time: 0.93 minutes (LC method M).

[1323] Step 3: 4-{3-[4-chloro-6-(2,6-dimethyl-phenyl)-pyrimidin-2-ylaminosulfonyl]benzoyl}-6-hydroxy-[1,4]diazacyclohepta-1-carboxylic acid tert-butyl ester

[1324]

[1325] At room temperature, N,N'-diisopropylcarbodiimide (3.68 mL, 23.5 mmol) was added to a solution of 3-[4-chloro-6-(2,6-dimethyl-phenyl)-pyrimidin-2-ylaminosulfonyl]benzoic acid (9.82 g, 23.5 mmol) in dichloromethane (150 mL). The reaction mixture was stirred for 10 minutes. At room temperature, a solution of 6-hydroxy-[1,4]diazacyclohepta-1-carboxylic acid tert-butyl ester (4.53 g, 20.95 mmol) in dichloromethane (75 mL) was added dropwise over 1 hour. The reaction was stirred for another 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 over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography using 0-80% hexane-acetone to give a pink solid of 4-{3-[4-chloro-6-(2,6-dimethyl-phenyl)-pyrimidin-2-ylaminosulfonyl]benzoyl}-6-hydroxy-[1,4]diazacyclohepta-1-carboxylic acid tert-butyl ester (7.62 g, 59%). ESI-MS m / z calculated value 615.19, experimental value 616.0 (M1). Retention time: 5.24 min.

[1326] Step 4: 12-(2,6-dimethylphenyl)-2,8,8-trioxo-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarbon-3(23),4,6,10(22),11,13-hexane-18-carboxylic acid tert-butyl ester (compound 43)

[1327]

[1328] A fractionally added to a solution of 4-{3-[4-chloro-6-(2,6-dimethyl-phenyl)-pyrimidin-2-ylaminosulfonyl]benzoyl}-6-hydroxy-[1,4]diazacyclohepta-1-carboxylic acid tert-butyl ester (7.62 g, 12.37 mmol) in anhydrous dimethylformamide (800 mL) was added to a 60% suspension of 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% citric acid aqueous solution (500 mL). The product was extracted with ethyl acetate (3 × 500 mL) and the combined organic layers were washed with brine (3 × 500 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography using 0-70% hexane-acetone to give 4.404 g (56%) of tert-butyl 6,6-dioxide of 16-(2,6-dimethylphenyl)-4-oxo-2-oxa-6-thia-7-aza-3(6,1)-diazacyclohepta-1(4,2)-pyrimidin-5(1,3)-benzocyclohepta-34-carboxylic acid. ¹H-NMR (250MHz, DMSO-d⁶) δ (ppm): 8.30 (d, J = 15.1Hz, 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 = 10.5Hz, 9H). ESI-MS m / z calculated value 579.21515, experimental value 580.2 (M+1). + Retention time: 4.66 minutes.

[1329] Step 5: 12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarbon-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (compound 42)

[1330]

[1331] TFA (12 mL, 155.8 mmol) was added to 16-(2,6-dimethylphenyl)-2-oxa-6-thia-7-aza-3(6,1)-diazacyclohepta-1(4,2)-pyrimidin-5(1,3)-benzocycloheptan-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 mixture was suspended in DCM / toluene and concentrated under reduced pressure to dryness (this step was repeated 3 times) to give 12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarbon-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (2.3 g, 93%). 1 ¹H NMR (400MHz, DMSO-d⁶) δ 10.42 (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, experimental value 480.0 (M+1). + Retention time: 0.69 minutes; LC method A.

[1332] Example 16: Preparation of Compound 44

[1333] Step 1: 12-(2,6-dimethylphenyl)-18-isobutyl-8,8-dioxo-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10(22),11,13-hexane-2-one (compound 44)

[1334]

[1335] 2-Methylpropionaldehyde (approximately 22.53 mg, 0.3125 mmol) was added to 12-(2,6-dimethylphenyl)-15-oxa-8λ in 0.5 mL of acetic acid in a 3 mL vial. 6-Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (30 mg, 0.06250 mmol) was added, 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 reaction mixture was then cooled to room temperature, filtered, and purified by reversed-phase HPLC to give 12-(2,6-dimethylphenyl)-18-isobutyl-8,8-dioxo-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10(22),11,13-hexane-2-one (4.3 mg, 13%). ESI-MS m / z calculated 535.22534, experimental 536.0 (M+1) + Retention time: 1.0 minute; LC method A.

[1336] Example 17: Characterization of compounds 45-63

[1337] The compounds in the table below were prepared using commercially available reagents and intermediates described herein in a manner similar to that described above.

[1338] Table 5:

[1339]

[1340]

[1341]

[1342]

[1343] Table 6:

[1344]

[1345] Example 18: Preparation of Compound 64

[1346] Step 1: 12-(2,6-dimethylphenyl)-18-[(pyridin-2-yl)methyl]-15-oxa-8λ 6-Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tetrocar-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (compound 64) and 12-(2,6-dimethylphenyl)-18-[(pyridin-4-yl)methyl]-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3(23),4,6,10(22),11,13-hexane-2,8,8-trione

[1347]

[1348] The reaction was run twice in separate vials: 12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3(23),4,6,10(22),11,13-hexane-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 h. The reaction mixture was filtered and purified by reversed-phase HPLC (Waters, HCl, 10-60% ACN-water) to give 12-(2,6-dimethylphenyl)-18-[(pyridin-2-yl)methyl]-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarb-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (8.5 mg, 36%). 1H 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=7.6Hz, 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 Calculated m / z value: 570.2049; Experimental value: 571.0 (M+1) + Retention time: 0.96 minutes (LC method A).

[1349] In the second vial, 12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3(23),4,6,10(22),11,13-hexane-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 h. The reaction mixture was filtered and purified by reversed-phase HPLC (Waters, HCl, 10-60% ACN-water) to give 12-(2,6-dimethylphenyl)-18-[(pyridin-4-yl)methyl]-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarb-3(23),4,6,10(22),11,13-hexane-2,8,8-trione ESI-MS m / z calculated value 570.2049, experimental value 571.0 (M+1) + Retention time: 0.99 minutes (LC method A).

[1350] Example 19: Preparation of Compound 65

[1351] Step 1: 18-(4,4-dimethylpentyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6-Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarbon-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (compound 65)

[1352]

[1353] 12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3(23),4,6,10(22),11,13-hexane-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 h. The reaction mixture was filtered and purified by reversed-phase HPLC (Waters, HCl, 25–75% ACN-water) to give 18-(4,4-dimethylpentyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (2 mg, 6%) ESI-MS m / z calculated 577.2723, experimental 578.0 (M+1) + Retention time: 1.26 minutes (LC method A).

[1354] Example 20: Preparation of Compound 66

[1355] Step 1: (36R)-16-(2,6-dimethylphenyl)-3,4-(pyridin-3-ylmethyl)-2-oxa-6-thia-7-aza-3(6,1)-diazacyclohepta-1(4,2)-pyrimidin-5(1,3)-benzocycloheptan-4-one-6,6-dioxide (compound 66)

[1356]

[1357] 12-(2,6-dimethylphenyl)-15-oxa-8λ 6-Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecane-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (20 mg, 0.04166 mmol), 3-(bromomethyl)pyridine (hydrobromide) (approx. 15.81 mg, 0.06249 mmol), TEA (approx. 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 by reversed-phase HPLC (Waters, HCl, 25–75% ACN-water) to give (36R)-16-(2,6-dimethylphenyl)-34-(pyridin-3-ylmethyl)-2-oxa-6-thia-7-aza-3(6,1)-diazacyclohepta-1(4,2)-pyrimidin-5(1,3)-benzocycloheptan-4-one-6,6-dioxide (2.6 mg, 11%). ESI-MS calculated m / z 570.2049, experimental 571.0 (M+1). + Retention time: 0.97 minutes (LC method A).

[1358] Example 21: Preparation of compounds 67 and 68

[1359] Step 1: (16R)-18-benzyl-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarbon-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (compound 67)

[1360]

[1361] Add (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ to a 4 mL vial 6-Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10,12,14(22)-hexene-2,8,8-trione (hydrochloride) (25 mg, 0.04845 mmol), anhydrous DCM (500 μL), DIEA (15 μL, 0.08612 mmol) (dissolve all solids), benzaldehyde (10 μL, 0.09838 mmol), and acetic acid (10 μL, 0.1758 mmol). Briefly purged the vial with nitrogen, capped, and stirred at room temperature for about 20 minutes. Add sodium triacetoxyborohydride (20 mg, 0.09437 mmol). Purge the vial with nitrogen, capped, and stirred at room temperature for one hour. Add a small amount of methanol. The DCM was evaporated and the residue was dissolved in DMSO (1 mL). The solution was microfiltered and purified by reversed-phase preparative HPLC using a gradient of acetonitrile / water (1 to 99% over 15 minutes) and HCl as a modifier to give (16R)-18-benzyl-12-(2,6-dimethylphenyl)-15-oxa-8λ as a white solid. 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (hydrochloride) (17 mg, 57%). ESI-MS m / z calculated 569.20966, experimental 570.44 (M+1). + Retention time: 1.07 minutes (LC method A). 1 H NMR (400MHz, DMSO-d6+10% D2O (wide 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 (wide 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 (brs, 6H).

[1362] Step 2: (16R)-18-benzyl-12-(2,6-dimethylphenyl)-15-oxa-8λ 6-Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarbon-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (compound 67), and (16S)-18-benzyl-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarbon-3(23),4,6,10,12,14(22)-hexane-2,8,8-trione (compound 68)

[1363]

[1364] 12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (25 mg, 0.05208 mmol) and benzaldehyde (25 μL, 0.2459 mmol) were combined in dichloroethane (0.5 mL) with acetic acid (15 μL, 0.2638 mmol). After 45 minutes, sodium triacetoxyborohydride (45 mg, 0.2123 mmol) was added, and the reaction was stirred at room temperature for 2 hours. At this point, the conversion appeared to have stopped, and additional benzaldehyde (25 μL, 0.2459 mmol) and acetic acid (15 μL, 0.2638 mmol) were added. After stirring the reaction for another hour, sodium cyanoborohydride (16 mg, 0.2546 mmol) was added, and the reaction was stirred at room temperature for another 16 hours. Subsequently, the reaction mixture was diluted with methanol, filtered, and purified by reversed-phase HPLC (1-70% ACN / water, HCl modifier, 15 min run) to give 18-benzyl-12-(2,6-dimethylphenyl)-15-oxa-8λ. 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (hydrochloride) (22 mg, 70%) ESI-MS m / z calculated 569.20966, experimental 570.4 (M+1) + Retention time: 0.48 minutes (LC method D).

[1365] The substance was then separated by chiral SFC (chiral Cel 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) concentration 14 mg / mL, injection volume 70 μL, 100 bar, 220 nm)), yielding each enantiomer as a white solid. The first eluting peak was 1, (16R)-18-benzyl-12-(2,6-dimethylphenyl)-15-oxa-8λ). 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarb-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (4 mg, 13%) ESI-MS m / z calculated 569.20966, experimental 570.5 (M+1) + Retention time: 1.16 minutes (LC method A). And the next eluting peak is 2,(16S)-18-benzyl-12-(2,6-dimethylphenyl)-15-oxa-8λ. 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3(23),4,6,10,12,14(22)-hexane-2,8,8-trione (4.4 mg, 15%). ESI-MS m / z calculated 569.20966, experimental 570.5 (M+1). + Retention time: 1.16 minutes (LC method A).

[1366] Example 22: Preparation of compound 69

[1367] Step 1: 18-Benzyl-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarb-3(23),4,6,10(22),11,13-hexane-2,8,8-trione, enantiomer 1, and 18-benzyl-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarb-3(23),4,6,10(22),11,13-hexane-2,8,8-trione, enantiomer 2

[1368]

[1369] 12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (660 mg, 1.375 mmol) and benzaldehyde (approx. 689.0 mg, 660.0 μL, 6.493 mmol) were combined with acetic acid (approx. 418.2 mg, 396.0 μL, 6.964 mmol) in dichloroethane (13.20 mL). After 45 minutes, sodium cyanoborohydride (approx. 422.4 mg, 6.722 mmol) was added, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was then diluted with methanol, filtered, and purified by preparative HPLC (1-70% ACN / water, HCl modifier, 15 min run) to give 18-benzyl-12-(2,6-dimethylphenyl)-15-oxa-8λ. 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (750 mg, 96%) ESI-MS m / z calculated 569.20966, experimental 570.5 (M+1) + Retention time: 1.14 min (LC method A). The substance was then separated by chiral SFC (chiral Cel 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 of MeCN / MeOH / DMSO (81 / 9 / 10), injection volume 500 μL, 100 bar, 220 nm), yielding 18-benzyl-12-(2,6-dimethylphenyl)-15-oxa-8λ as a white solid, initially eluting as peak 1). 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (121 mg, 31%), ESI-MS m / z calculated 569.20966, experimental 570.5 (M+1) + Retention time: 1.14 minutes; LC method A. Discard the second isomer.

[1370] Step 2: 12-(2,6-dimethylphenyl)-15-oxa-8λ 6-Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3(23),4,6,10(22),11,13-hexane-2,8,8-trione

[1371]

[1372] 18-benzyl-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarbazo-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (121 mg, 0.2124 mmol) (from peak 1 separated in step 1) was dissolved in methanol (22 mL) in a nitrogen-purged flask and briefly sonicated to aid dissolution of the starting material. Dihydroxypalladium (45 mg, 0.06409 mmol) was added, and the reaction mixture was then purged with hydrogen by bubbling into the reaction mixture from a balloon for 15 minutes, followed by stirring under hydrogen for 3 hours. The reaction vessel was then purged with nitrogen, and the reaction mixture was filtered through diatomaceous earth, which was washed with 100 mL of methanol. The filtrate was concentrated to give a white solid 12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (97 mg, 95%) ESI-MS m / z calculated 479.16272, experimental 480.3 (M+1) + Retention time: 0.79 minutes; LC method A.

[1373] Step 3: 12-(2,6-dimethylphenyl)-18-{2-[1-(trifluoromethyl)cyclopropyl]ethyl}-15-oxa-8λ 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricarbon-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (compound 69)

[1374]

[1375] To contain 12-(2,6-dimethylphenyl)-15-oxa-8λ 6A vial containing thiazo-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (28 mg, 0.05839 mmol) was added to dichloroethane (1 mL), 2-[1-(trifluoromethyl)cyclopropyl]acetaldehyde (44 mg, 0.2893 mmol), and acetic acid (17 μL, 0.2989 mmol). The reaction was stirred at room temperature for 1 hour. Sodium cyanoborohydride (19 mg, 0.3023 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The reaction was quenched with methanol, filtered, and purified by preparative HPLC (1%-99% ACN: water and 0.1% HCl modifier) ​​to give 12-(2,6-dimethylphenyl)-18-{2-[1-(trifluoromethyl)cyclopropyl]ethyl}-15-oxa-8λ as a white solid. 6 -Thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tridecano-3(23),4,6,10(22),11,13-hexane-2,8,8-trione (17.4 mg, 48%). ESI-MS m / z calculated 615.2127, experimental 616.3 (M+1). + Retention time: 1.18 minutes; LC method A.

[1376] Example 23: Preparation of Compound 70

[1377] Step 1: Methyl 6-benzylthiopyridine-2-carboxylate

[1378]

[1379] At 0 °C, NaH (11.200 g, 60% w / w, 280.03 mmol) was added fractionally to a solution of phenylmethanethiol (28.408 g, 26.800 mL, 228.72 mmol) in THF (600 mL). The slurry was warmed to room temperature and stirred for 30 minutes, and then methyl 6-bromopyridine-2-carboxylic acid (50 g, 231.45 mmol) was added in a single fraction. After 3 hours, the reaction was diluted with diethyl ether (800 mL) and quenched with water (400 mL) and saturated sodium bicarbonate (50 mL). The layers were separated, and the organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give methyl 6-benzylthiopyridine-2-carboxylate (56.35 g, 89%) as a yellow oil. 1¹H NMR (500MHz, DMSO-d⁶) δ 7.84–7.77 (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, 7.2 Hz, 2H), 7.24–7.18 (m, 1H), 4.44 (s, 2H), 3.90 (d, J = 1.2 Hz, 3H). ESI-MS m / z calculated value 259.0667, experimental value 260.1 (M+1). + Retention time: 3.2 minutes; LC method T.

[1380] Step 2: Methyl 6-chlorosulfonylpyridine-2-carboxylic acid

[1381]

[1382] A solution of methyl 6-benzylthiopyridine-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 sulfonyl chloride (228.14 g, 140 mL, 1.6396 mol) was added dropwise with vigorous stirring while maintaining the temperature below 5 °C. After the addition, the organic phase was separated, washed with DI water (2 × 500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was dissolved in DCM (500 mL). Hexane (1000 mL) was added, and the DCM was slowly evaporated. The white precipitate was filtered through a vacuum filter, 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 DCM (200 mL). Hexane (600 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). After drying, methyl 6-chlorosulfonylpyridine-2-carboxylate (56.898 g, 55%) was isolated. 1 ¹H NMR (500MHz, chloroform-d) δ 8.48 (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, experimental value 236.1 (M+1). + Retention time: 1.74 minutes; LC method T.

[1383] Step 3: Methyl 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]pyridine-2-carboxylic acid

[1384]

[1385] A solution of 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-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. Then, lithium bis(trimethylsilyl)amino (1 M, 143 mL, 143.00 mmol) was added dropwise to the THF solution. The mixture was slowly heated to 0 °C, and then 1 M HCl aqueous solution (146 mL) was added, followed by DI 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 NaCl aqueous solution (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude solution was recrystallized in 10% acetone / hexane (500 mL). The white precipitate was filtered and washed with acetone (2 × 100 mL) to give methyl 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]pyridine-2-carboxylic acid (15.79 g, 50%). ESI-MS calculated m / z: 432.06592; experimental: 433.3 (M+1). + Retention time: 5.5 minutes; LC method S.

[1386] Step 4: 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]pyridine-2-carboxylic acid

[1387]

[1388] A solution of methyl 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]pyridine-2-carboxylic acid (15.79 g, 36.477 mmol) in THF (180 mL) was added to an aqueous solution of sodium hydroxide (182 mL, 1 M, 182.00 mmol). The reaction 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 HCl aqueous solution (250 mL). The precipitate was filtered and the white solid was washed with DI water (2 × 250 mL). The solid was dried under vacuum to give 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]pyridine-2-carboxylic acid (14.3444 g, 93%). 1¹H NMR (250MHz, DMSO-d⁶) δ 8.14–7.99 (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, experimental value 419.1 (M+1). + Retention time: 2.61 minutes; LC method T.

[1389] Step 5: 1,4-Dazacycloheptan-6-ol

[1390]

[1391] Pd(OH)₂ / carbon (6 g, 8.5 mmol, 20 wt%) was added to a solution of 1,4-dibenzyl-1,4-diazacyclohepta-6-ol (54 g, 182 mmol) in MeOH (1400 mL). The mixture was hydrogenated under a hydrogen atmosphere for 16 hours. The reaction was filtered through diatomaceous earth and concentrated to give 1,4-diazacyclohepta-6-ol (20.6 g, 92%) as a colorless oil. ESI-MS calculated m / z: 116.09496, experimental: 117.3 (M+1). + Retention time: 0.78 minutes; LC method T.

[1392] Step 6: 6-Hydroxy-1,4-diazacyclohepta-1-carboxylic acid benzyl ester

[1393]

[1394] At 0°C, ethyl trifluoroacetate (7.2 mL, 59.9 mmol) was slowly added to a solution of 1,4-diazacycloheptan-6-one (7.17 g, 58.6 mmol) in MeOH (100 mL). The solution was stirred at room temperature for 1 hour. Then, the reaction was cooled to 0°C, and TEA (10.0 mL, 69.6 mmol) and benzyl chloroformate (2.7 M, 22 mL, 59.4 mmol) were slowly added. The reaction was stirred at room temperature for 1 hour. Potassium carbonate (13 g, 94.1 mmol) was added to water (5 mL). The reaction 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 MeOH / ethyl acetate gradient of 0-60% to give benzyl 6-hydroxy-1,4-diazacycloheptan-1-carboxylic acid (3.6 g, 23%) as a colorless oil. 1¹H NMR (250MHz, 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, experimental value 251.3 (M+1). + Retention time: 1.81 minutes; LC method T.

[1395] Step 7: 4-(3,3-dimethylbutyl)-6-hydroxy-1,4-diazacyclohepta-1-carboxylic acid benzyl ester

[1396]

[1397] 6-hydroxy-1,4-diazacyclohepta-1-carboxylic acid benzyl ester (608.5 mg, 2.431 mmol) in DCE (5 mL) was combined with 3,3-dimethylbutyraldehyde (460 μL, 3.665 mmol) and acetic acid (500 μL, 8.792 mmol) and stirred at room temperature for 1 hour. Then sodium cyanoborohydride (760 mg, 12.09 mmol) was added, and the reaction was stirred at room temperature for 90 minutes. The mixture was coarsely filtered and subjected to reversed-phase preparative chromatography using C1. 18 Purification was performed using a column and a 15-minute gradient eluent of 1- to 50% acetonitrile / water containing 5 mM hydrochloric acid to give benzyl 4-(3,3-dimethylbutyl)-6-hydroxy-1,4-diazacyclohepta-1-carboxylate (547.6 mg, 67%). ESI-MS calculated m / z: 334.22565; experimental: 335.0 (M+1). + Retention time: 0.98 minutes; LC method A.

[1398] Step 8: 18-(3,3-dimethylbutyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thia-1,9,11,18,22,23-hexaazatetracyclo[14.4.1.13,7.110,14]tricarbon-3,5,7(23),10,12,14(22)-hexaene-2,8,8-trione (compound 70)

[1399]

[1400] Phase 1: 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]pyridine-2-carboxylic acid (170 mg, 0.4059 mmol) and 4-(3,3-dimethylbutyl)-6-hydroxy-1,4-diazacyclohepta-1-carboxylic acid benzyl ester (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 analyzed by reversed-phase preparative chromatography using C1. 18 Purification was performed using a column and a 15-minute gradient eluent of 10–60% acetonitrile / water containing 5 mM hydrochloric acid to give 6-[[4-[[1-benzyloxycarbonyl-4-(3,3-dimethylbutyl)-1,4-diazacyclohepta-6-yl]oxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]pyridine-2-carboxylic acid (29.8 mg, 10%). ESI-MS m / z calculated value 716.2992, experimental value 716.0 (M+1). + Retention time: 1.3 minutes (LC method A), and 6-[[4-[[1-(3,3-dimethylbutyl)-1,4-diazacycloheptyl-6-yl]oxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]pyridine-2-carboxylic acid (45.5 mg, 18%). 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,2 H),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 Calculated m / z value: 582.26245; Experimental value: 583.0 (M+1) + Retention time: 0.92 minutes (LC method A).

[1401] Phase 2: 6-[[4-[[1-(3,3-dimethylbutyl)-1,4-diazacyclohepta-6-yl]oxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]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 mixture was then coarsely filtered and subjected to reversed-phase preparative chromatography using C1... 18 Purification was performed using a column and a 15-minute gradient eluent of 1- to 50% acetonitrile / water containing 5 mM hydrochloric acid to give 18-(3,3-dimethylbutyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ. 6 -Thia-1,9,11,18,22,23-hexaazatetracyclo[14.4.1.13,7.110,14]tridecano-3,5,7(23),10,12,14(22)-hexaen-2,8,8-trione (1.8 mg, 1%). ESI-MS m / z calculated 564.2519, experimental 565.0 (M+1). + Retention time: 1.03 minutes (LC method A).

[1402] Example 24: Preparation of Compound 71

[1403] Step 1: 2-[(2R)-3-(tert-butylamino)-2-hydroxypropyl]isoindoline-1,3-dione

[1404]

[1405] A solution of 2-methylpropane-2-amine (2.16 g, 29.534 mmol) and 2-[[(2S)-epoxyalkyl-2-yl]methyl]isoindoline-1,3-dione (5 g, 24.607 mmol) in isopropanol (160 mL) was added to a pressure vessel. 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 give 2-[(2R)-3-(tert-butylamino)-2-hydroxypropyl]isoindoline-1,3-dione (5.65 g, 78%) as a ...

Claims

1. A compound of formula I: （I）， Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Ring A is selected from: phenyl, pyridyl, 1H-pyrroleyl, pyrazolyl, and indololinyl; Ring B is a phenyl group; V is selected from O and NH; W 1 It is N; W 2 It is N; Z is selected from NR ZN and C(R) ZC )2, the condition is when L 2 When Z does not exist, Z is C(R) ZC )2; Each L 1 Independently selected from C(R) L1 )2; Each L 2 Independently selected from C(R) L2 )2; R 3 It is a C1-C6 alkyl group; R 4 Selected from hydrogen and C1-C6 alkyl groups; Each R 5 Selected independently from: ■ Hydrogen, ■ C1-C6 alkyl groups, and ■ C1-C6 alkoxy groups; R ZN Selected from: ■ Hydrogen, and ■ C1-C9 alkyl groups; Each R ZC Selected independently from: ■ Hydrogen, and ■ C1-C6 alkyl groups; Or two Rs ZC Together they form an oxo group; Each R L1 Selected independently from: ■ Hydrogen, ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following: ○ C6-C 10 Aryl, and ■ R F ； Each R L2 Independently selected from hydrogen and R F Or two R atoms on the same carbon atom L2 Together they form an oxo group; The premise is that there is at least one R L1 Or R L2 It is R F ; Each R N Selected independently from: ■ Hydrogen, ■ C1-C8 alkyl groups optionally substituted by 1-3 independently selected groups from the following: ○ Oxygenation, ○ C1-C6 alkoxy groups, and ○ C6-C 10 Aryl, ■ C3-C 10 cycloalkyl; Or two R atoms on the same nitrogen atom N Together with the nitrogen it binds to, it forms 3 to 10-membered heterocyclic groups; Or an R 4 And an R L1 Together they form C6-C8 alkylene groups; Two Rs F Together with the atoms they are bonded to, they form groups selected from the following: ■ Phenyl ■ Optionally substituted with 1 to 3 independently selected groups from the following: 3 to 11-membered heterocyclic groups ○ Oxygenation, ○ N(R N )2, ○ C1-C9 alkyl groups optionally substituted by 1-4 independently selected groups from the following: Oxygenation, halogen, hydroxyl group N(R N )2, Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted by the aryl group, C6-C cells optionally substituted with 1-3 independently selected groups from the following 10 Aryl groups: hydroxyl, cyano, C1-C6 alkyl. -(O) may optionally be substituted by 1 to 4 groups independently selected from C1-C6 alkyl or C1-C6 fluoroalkyl groups. 0-1 -(C3-C 10 (Cycloalkyl), wherein the C1-C6 alkyl group is optionally substituted with 1-3 groups independently selected from oxo and C1-C6 alkoxy groups, Optionally substituted with 1-3 independently selected oxo and C1-C6 alkyl groups, and Optionally selected by 1-3 independently chosen from oxo, N(R) N )2, C1-C6 alkyl groups and -O-(C6-C 10 5 to 10-membered heteroaryl groups substituted with aryl groups, ○ C3-C alkyl groups optionally substituted with 1-4 independently selected groups chosen from halogens and C1-C6 alkyl groups 12 cycloalkyl, ○ C6-C 10 Aryl, ○ 3- to 10-membered heterocyclic groups, and ○ Optionally composed of 1-3 independently selected C1-C6 alkoxy groups and N(R) N )2 substituted with 5 to 10 heteroaryl groups, and ■ 5- to 12-membered heteroaryl groups optionally substituted with 1 to 3 independently selected C1-C6 alkyl groups; Wherein, a heteroaryl group refers to an aromatic ring comprising at least one ring atom, wherein the ring atom is a heteroatom selected from O, N, or S; and Heterocyclic groups refer to non-aromatic hydrocarbons that include at least one ring atom, which is a heteroatom selected from O, N, or S.

2. The compound of claim 1, its tautomer, deuterated derivative, or pharmaceutically acceptable salt, wherein the compound is a compound of formula Ia: (It).

3. The compound of claim 1, its tautomer, deuterated derivative, or pharmaceutically acceptable salt, wherein the compound is a compound of formula IIa: (IIa)。 4. The compound of claim 1, its tautomer, deuterated derivative, or pharmaceutically acceptable salt, wherein the compound is a compound of formula III: (III)。 5. The compound of claim 1, its tautomer, deuterated derivative, or pharmaceutically acceptable salt, wherein the compound is a compound of formula V: （V）。 6. The compound of claim 1, its tautomer, deuterated derivative, or pharmaceutically acceptable salt, wherein the compound is a compound of formula VI: (WE).

7. A compound, said compound being selected from: These compounds include deuterated derivatives and tautomers, as well as pharmaceutically acceptable salts of any of the foregoing.

8. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier according to any one of claims 1 to 7.

9. The pharmaceutical composition according to claim 8, further comprising one or more additional therapeutic agents.

10. The pharmaceutical composition of claim 9, wherein the one or more additional therapeutic agents are selected from CFTR modulators.

11. The pharmaceutical composition according to claim 10, wherein the CFTR modifier is selected from tezacaftor, lumacaftor, ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadecan-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives of any of the foregoing and pharmaceutically acceptable salts.

12. Use of the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 7, or the pharmaceutical composition of any one of claims 8 to 11, in the manufacture of a medicament for the treatment of cystic fibrosis.

13. The use according to claim 12, wherein the drug is formulated for administration together with one or more other therapeutic agents.

14. The use according to claim 13, wherein the one or more additional therapeutic agents are selected from CFTR modulators.

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

16. A compound of formula I: （I）， Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Ring A is selected from: phenyl, pyridyl, 1H-pyrroleyl, pyrazolyl, and indololinyl; Ring B is a phenyl group; V is selected from O and NH; W 1 It is N; W 2 It is N; Z is selected from NR ZN and C(R) ZC )2, the condition is when L 2 When Z does not exist, Z is C(R) ZC )2; Each L 1 Independently selected from C(R) L1 )2; Each L 2 Independently selected from C(R) L2 )2; R 3 It is a C1-C6 alkyl group; R 4 Selected from hydrogen and C1-C6 alkyl groups; Each R 5 Selected independently from: ■ Hydrogen, ■ C1-C6 alkyl groups, and ■ C1-C6 alkoxy groups; R ZN Selected from: ■ Hydrogen, and ■ C1-C9 alkyl groups; Each R ZC Selected independently from: ■ Hydrogen, and ■ C1-C6 alkyl groups; Or two Rs ZC Together they form an oxo group; Each R L1 Selected independently from: ■ Hydrogen, ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following: ○ C6-C 10 Aryl, and ■ R F ； Each R L2 Independently selected from hydrogen and R F Or two R atoms on the same carbon atom L2 Together they form an oxo group; The premise is that there is at least one R L1 Or R L2 It is R F ; Each R N Selected independently from: ■ Hydrogen, ■ C1-C8 alkyl groups optionally substituted by 1-3 independently selected groups from the following: ○ Oxygenation, ○ C1-C6 alkoxy groups, ○ C6-C 10 Aryl, and ■ C3-C 10 cycloalkyl; Or two R atoms on the same nitrogen atom N Together with the nitrogen it binds to, it forms a 3- to 10-membered heterocyclic group that is optionally substituted with 1-3 oxo groups; Or an R 4 And an R L1 Together they form C6-C8 alkylene groups; Two Rs F Together with the atoms they are bonded to, they form groups selected from the following: ■ Phenyl ■ Optionally substituted with 1 to 3 independently selected groups from the following: 3 to 11-membered heterocyclic groups ○ Oxygenation, ○ N(R N )2, ○ C1-C9 alkyl groups optionally substituted by 1-4 independently selected groups from the following: Oxygenation, halogen, hydroxyl group N(R N )2, Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted by the aryl group, C6-C cells optionally substituted with 1-3 independently selected groups from the following 10 Aryl groups: hydroxyl, cyano, and C1-C6 alkyl. -(O) may optionally be substituted with 1 to 4 groups independently selected from C1-C6 alkyl and C1-C6 fluoroalkyl groups. 0-1 -(C3-C 10 (Cycloalkyl), wherein the C1-C6 alkyl group is optionally substituted with 1-3 groups independently selected from oxo and C1-C6 alkoxy groups, Optionally substituted with 1-3 independently selected oxo and C1-C6 alkyl groups, and Optionally selected by 1-3 independently chosen from hydroxyl, oxo, N(R) N )2, C1-C6 alkyl groups and -O-(C6-C 10 5 to 10-membered heteroaryl groups substituted with aryl groups, ○ C3-C alkyl groups optionally substituted with 1-4 independently selected groups chosen from halogens and C1-C6 alkyl groups 12 cycloalkyl, ○ C6-C 10 Aryl, ○ 3- to 10-membered heterocyclic groups, and ○ Optionally composed of 1-3 independently selected C1-C6 alkoxy groups and N(R) N )2 substituted with 5 to 10 heteroaryl groups, and ■ 5- to 12-membered heteroaryl groups optionally substituted with 1 to 3 independently selected C1-C6 alkyl groups; Wherein, a heteroaryl group refers to an aromatic ring comprising at least one ring atom, wherein the ring atom is a heteroatom selected from O, N, or S; and Heterocyclic groups refer to non-aromatic hydrocarbons that include at least one ring atom, which is a heteroatom selected from O, N, or S.

Images