Modulators of cystic fibrosis transmembrane conductance regulator

Abstract

This disclosure provides modulators of cystic fibrosis transmembrane conduction regulators (CFTRs) having a core structure: a pharmaceutical composition containing at least one such modulator; a method of treating CFTR-mediated diseases involving cystic fibrosis using such modulators and pharmaceutical compositions; combination pharmaceutical compositions and combination therapies; and methods and intermediates for preparing such modulators.

Description

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 088,935, 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 and pharmaceutical compositions; 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 be actively transported, its transepithelial flow depends on the small transepithelial osmotic gradient generated by the large flow of sodium and chloride ions.

[0009] Several CFTR-regulating 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 and VI, compounds 1-508, 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% mixed aromatic compounds;

[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] W2 Choose from N and CH, provided that W is selected. 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 and

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

[0030] The ring C is selected from C6-C groups optionally substituted by 1 to 3 independently selected groups from the following. 10 Aryl:

[0031] ■ Halogen,

[0032] ■C1-C6 alkyl groups, and

[0033] ■N(R N )2;

[0034] Each R 3 Selected independently from:

[0035] ■ Halogen,

[0036] ■C1-C6 alkyl groups,

[0037] ■C1-C6 alkoxy groups,

[0038] ■C3-C 10 cycloalkyl,

[0039] ■ C6-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 Aryl, and

[0040] ■3 to 10-membered heterocyclic groups;

[0041] R 4 Selected from hydrogen and C1-C6 alkyl groups;

[0042] Each R 5 Selected independently from:

[0043] ■ Hydrogen,

[0044] ■ Halogen,

[0045] ■Hydroxy

[0046] ■N(R N )2,

[0047] ■-SO-Me,

[0048] ■-CH=C(R LC )2, where two R LC Together they form C3-C 10 cycloalkyl,

[0049] ■ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0050] ○Hydroxy group,

[0051] ○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,

[0052] ○C3-C 10 cycloalkyl,

[0053] ○Optionally substituted with 1-3 groups independently selected from C1-C6 alkyl and C1-C6 alkoxy groups -(O) 0-1 -(C6-C 10 Aryl),

[0054] ○3 to 10-membered heterocyclic groups, and

[0055] ○N(R N )2,

[0056] ■ C1-C6 alkoxy groups optionally substituted with 1-3 independently selected groups from the following:

[0057] ○ Halogen,

[0058] ○C6-C 10 Aryl, and

[0059] ○ C3-C substituted with 1-3 independently selected C1-C6 fluoroalkyl groups 10 cycloalkyl,

[0060] ■C1-C6 fluoroalkyl groups,

[0061] ■C3-C 10 cycloalkyl,

[0062] ■C6-C 10 Aryl, and

[0063] ■3 to 10-membered heterocyclic groups;

[0064] R YN Selected from:

[0065] ■ C3-C, optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[0066] ○Hydroxy group,

[0067] ○Oxygenation,

[0068] ○ Halogen,

[0069] ○Cyano

[0070] ○N(R N )2,

[0071] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0072] ◆Hydroxy group,

[0073] ◆Oxygenation,

[0074] ◆N(R N )2,

[0075] ◆C1-C6 alkoxy groups, and

[0076] ◆C6-C 10 Aryl,

[0077] ○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,

[0078] ○ Halogen,

[0079] ○C3-C 10 cycloalkyl,

[0080] ○Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, and

[0081] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0082] ◆Hydroxy group,

[0083] ◆Cyano

[0084] ◆Oxygenation,

[0085] ◆Halogen,

[0086] ◆N(R N )2,

[0087] ◆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,

[0088] ◆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,

[0089] ◆C1-C6 fluoroalkyl groups,

[0090] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[0091] ◆C6-C 10 Aryl, and

[0092] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, 3- to 10-membered heterocyclic groups,

[0093] ■C6-C 10 Aryl,

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

[0095] ○Oxygenation,

[0096] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0097] ◆Oxygenation,

[0098] ◆Hydroxy group,

[0099] ◆N(R N )2, and

[0100] ◆Optionally selected by 1-3 independent elements chosen from halogens and C6-C 10 The C1-C6 alkoxy group substituted with an aryl group, and -(O) 0-1 -(C3-C 10 cycloalkyl),

[0101] ○C1-C6 fluoroalkyl,

[0102] ○ C3-C groups optionally substituted with 1-3 independently selected halogen groups 10 cycloalkyl groups, and

[0103] ○3 to 10-membered heterocyclic groups, and

[0104] ■ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0105] ○ Halogen,

[0106] ○Optionally selected by 1-3 independently chosen from oxo, C1-C6 alkoxy and N(R) N C1-C6 alkyl groups substituted with )2, and

[0107] ○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;

[0108] R ZN Selected from:

[0109] ■ Hydrogen,

[0110] ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0111] ○Hydroxy group,

[0112] ○Oxygenation,

[0113] ○Cyano

[0114] ○ C1-C6 alkoxy groups optionally substituted with 1-3 independently selected halogen and C1-C6 alkoxy groups,

[0115] ○N(R N )2,

[0116] ○SO2Me,

[0117] ○ C3-C cells optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[0118] ◆Hydroxy group,

[0119] ◆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,

[0120] ◆C1-C6 fluoroalkyl groups,

[0121] ◆C1-C6 alkoxy groups,

[0122] ◆COOH,

[0123] ◆N(R N )2,

[0124] ◆C6-C 10 Aryl, and

[0125] ◆Optionally substituted with 1-3 independently selected oxo and C1-C6 alkyl groups, 3- to 10-membered heterocyclic groups,

[0126] ○ C6-C cells optionally substituted with 1-3 independently selected groups from the following 10 Aryl:

[0127] ◆Halogen,

[0128] ◆Hydroxy group,

[0129] ◆Cyano

[0130] ◆SiMe3,

[0131] ◆SO2Me,

[0132] ◆SF5,

[0133] ◆N(R N )2,

[0134] ◆P(O)Me2,

[0135] ◆Optionally substituted with 1-3 independently selected C1-C6 fluoroalkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[0136] ◆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,

[0137] ◆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,

[0138] ◆C1-C6 fluoroalkyl groups,

[0139] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, 3- to 10-membered heterocyclic groups,

[0140] ◆-(O) 0-1 -(C6-C 10 Aryl), and

[0141] ◆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),

[0142] ○Optionally substituted with 1 to 4 independently selected groups from the following 3- to 10-membered heterocyclic groups:

[0143] ◆Hydroxy group,

[0144] ◆Oxygenation,

[0145] ◆N(R N )2,

[0146] ◆C1-C6 alkyl groups optionally substituted with 1-3 independently selected oxo and C1-C6 alkoxy groups,

[0147] ◆C1-C6 alkoxy groups,

[0148] ◆C1-C6 fluoroalkyl groups,

[0149] ◆C6-C cells optionally substituted with 1-3 independently selected halogen groups 10 Aryl, and

[0150] ◆5 to 10 aryl compounds, and

[0151] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0152] ◆Hydroxy group,

[0153] ◆Cyano

[0154] ◆Oxygenation,

[0155] ◆Halogen,

[0156] ◆B(OH)2,

[0157] ◆N(R N )2,

[0158] ◆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,

[0159] ◆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,

[0160] ◆C1-C6 fluoroalkyl groups,

[0161] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups -(O)0-1 -(C3-C 10 cycloalkyl),

[0162] ◆-(O) 0-1 -(C6-C 10 Aryl),

[0163] ◆Optionally selected by 1-4 independently chosen from hydroxyl, oxo, halogen, cyano, N(R) N 2. C1-C6 alkyl groups (optionally separated by 1-3 independently selected from hydroxyl, oxo, N(R) groups) N -(O) groups are substituted with C1-C6 alkoxy groups, C1-C6 alkoxy groups, C1-C6 fluoroalkyl groups, and 3 to 10-membered heterocyclic groups (optionally substituted with 1 to 3 groups independently selected from C1-C6 fluoroalkyl groups). 0-1 -(3 to 10-membered heterocyclic groups), and

[0164] ◆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,

[0165] ■C1-C6 fluoroalkyl groups,

[0166] ■ C3-C, optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[0167] ○Hydroxy group,

[0168] ○Oxygenation,

[0169] ○ Halogen,

[0170] ○Cyano

[0171] ○N(R N )2,

[0172] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0173] ◆Hydroxy group,

[0174] ◆Oxygenation,

[0175] ◆N(R N )2,

[0176] ◆C1-C6 alkoxy groups, and

[0177] ◆C6-C 10 Aryl,

[0178] ○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,

[0179] ○ Halogen,

[0180] ○C3-C 10 cycloalkyl,

[0181] ○Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, and

[0182] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0183] ◆Hydroxy group,

[0184] ◆Cyano

[0185] ◆Oxygenation,

[0186] ◆Halogen,

[0187] ◆N(R N )2,

[0188] ◆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,

[0189] ◆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,

[0190] ◆C1-C6 fluoroalkyl groups,

[0191] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[0192] ◆C6-C 10 Aryl, and

[0193] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, 3- to 10-membered heterocyclic groups,

[0194] ■C6-C 10 Aryl,

[0195] ■Optionally substituted with 1 to 3 independently selected groups from the following: 3- to 10-membered heterocyclic groups

[0196] ○Oxygenation,

[0197] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0198] ◆Oxygenation,

[0199] ◆Hydroxy group,

[0200] ◆N(R N )2,

[0201] ◆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

[0202] ◆-(O) 0-1 -(C3-C 10 cycloalkyl),

[0203] ○C1-C6 fluoroalkyl,

[0204] ○ C3-C groups optionally substituted with 1-3 independently selected halogen groups 10 cycloalkyl groups, and

[0205] ○3 to 10-membered heterocyclic groups,

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

[0207] ○ Halogen,

[0208] ○Optionally selected by 1-3 independently chosen from oxo, C1-C6 alkoxy and N(R) N C1-C6 alkyl groups substituted with )2, and

[0209] ○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

[0210] ■R F ;

[0211] Each R ZC Selected independently from:

[0212] ■ Hydrogen,

[0213] ■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),

[0214] ■ C6-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10Aryl, and

[0215] ■R F ;

[0216] Or two Rs ZC Together they form an oxo group;

[0217] Each R L1 Selected independently from:

[0218] ■ Hydrogen,

[0219] ■N(R N )2, the condition is two N(R) N )2 does not combine with the same carbon atom.

[0220] ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0221] ○ Halogen,

[0222] ○Hydroxy group,

[0223] ○Oxygenation,

[0224] ○N(R N )2,

[0225] ○Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[0226] ○ C3-C substituted with 1-3 independently selected groups selected from halogens and C1-C6 fluoroalkyl groups 10 cycloalkyl,

[0227] ○ C6-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 Aryl, and

[0228] ○ 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),

[0229] ■C3-C 10 cycloalkyl,

[0230] ■ C6-C cells optionally substituted with 1-4 independently selected groups from the following 10 Aryl:

[0231] ○ Halogen,

[0232] ○Cyano

[0233] ○SiMe3,

[0234] ○POMe2,

[0235] ○ C1-C7 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0236] ◆Hydroxy group,

[0237] ◆Oxygenation,

[0238] ◆Cyano

[0239] ◆SiMe3,

[0240] ◆N(R N )2, and

[0241] ◆C3-C substituted with 1-3 independently selected C1-C6 fluoroalkyl groups 10 cycloalkyl,

[0242] ○ C1-C6 alkoxy groups optionally substituted with 1-3 independently selected groups from the following:

[0243] ◆C3-C substituted with 1-3 independently selected C1-C6 fluoroalkyl groups 10 cycloalkyl groups, and

[0244] ◆C1-C6 alkoxy groups,

[0245] ○C1-C6 fluoroalkyl,

[0246] ○ C3-C2 groups optionally substituted with 1-3 groups independently selected from C1-C6 alkyl and C1-C6 fluoroalkyl groups 10 cycloalkyl,

[0247] ○C6-C 10 Aryl,

[0248] ○Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, and

[0249] ○5 to 10 yuan of mixed aromatic compounds,

[0250] ■Optionally substituted with 1 to 3 independently selected groups from the following: 3- to 10-membered heterocyclic groups

[0251] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0252] ◆Oxygenation, and

[0253] ◆C1-C6 alkoxy groups,

[0254] ■ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0255] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0256] ◆C3-C substituted with 1-3 independently selected C1-C6 fluoroalkyl groups 10 cycloalkyl groups, and

[0257] ○ C6-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 Aryl, and

[0258] ■R F ;

[0259] Or two R atoms on the same carbon atom L1 Together they form an oxo group;

[0260] Each R L2 Independently selected from hydrogen and R F ;

[0261] Or two R atoms on the same carbon atom L2 Together they form an oxo group;

[0262] Each R N Selected independently from:

[0263] ■ Hydrogen,

[0264] ■ C1-C8 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0265] ○Oxygenation,

[0266] ○ Halogen,

[0267] ○Hydroxy group,

[0268] ○NH2,

[0269] ○NHMe,

[0270] ○NMe2,

[0271] ○NHCOMe,

[0272] ○Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[0273] ○-(O) 0-1 -(C3-C 10 cycloalkyl),

[0274] ○ C6-C alkyl groups optionally substituted with 1-3 independently selected groups selected from halogens and C1-C6 alkyl groups 10 Aryl,

[0275] ○Optionally substituted with 1-4 independently selected oxo and C1-C6 alkyl groups, and

[0276] ○ 5- to 14-membered heteroaryl groups optionally substituted by 1 to 4 independently selected oxo and C1-C6 alkyl groups,

[0277] ■ C3-C, optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[0278] ○Hydroxy group,

[0279] ○NH2,

[0280] ○NHMe, and

[0281] ○ C1-C6 alkyl groups optionally substituted with 1-3 independently selected groups selected from hydroxyl groups, and

[0282] ■C6-C 10 Aryl, and

[0283] ■3 to 10-membered heterocyclic groups;

[0284] 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:

[0285] ■Hydroxy

[0286] ■Oxytochemicals

[0287] ■Cyano

[0288] ■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,

[0289] ■C1-C6 alkoxy groups, and

[0290] ■C1-C6 fluoroalkyl groups;

[0291] Or an R 4 And an R L1 Together they form C6-C8 alkylene groups;

[0292] When R F When they exist, two R F Together with the atoms they are bonded to, they form groups selected from the following:

[0293] ■ C3-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 cycloalkyl,

[0294] ■ C6-C, optionally substituted by 1-3 independently selected groups from the following 10 Aryl:

[0295] ○ Halogen,

[0296] ○C1-C6 alkyl,

[0297] ○N(R N )2, and

[0298] ○ A 3- to 10-membered heterocyclic group optionally substituted by 1 to 3 independently selected groups chosen from hydroxyl groups.

[0299] ■ 3- to 11-membered heterocyclic groups optionally substituted by 1 to 3 independently selected groups from the following:

[0300] ○Oxygenation,

[0301] ○N(R N )2,

[0302] ○ C1-C9 alkyl groups optionally substituted by 1-4 independently selected groups from the following:

[0303] ◆Oxygenation,

[0304] ◆Halogen,

[0305] ◆Hydroxy group,

[0306] ◆N(R N )2,

[0307] ◆-SO2-(C1-C6 alkyl),

[0308] ◆Optionally selected by 1-3 independent elements chosen from halogens, C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[0309] ◆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,

[0310] ◆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),

[0311] ◆Optionally composed of 1-3 independently selected oxo, C1-C6 alkyl groups (optionally 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, etc. 10 cycloalkyl and R N substituted 3- to 10-membered heterocyclic groups,

[0312] ◆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

[0313] ◆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,

[0314] ○ 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,

[0315] ○C6-C 10 Aryl,

[0316] ○3 to 10-membered heterocyclic groups, and

[0317] ○Optionally substituted with 1-3 groups independently selected from C1-C6 alkoxy and C1-C6 fluoroalkyl groups, and

[0318] ■ 5 to 12 heteroaryl groups optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl and C1-C6 fluoroalkyl groups;

[0319] The condition is that the compound is not selected from:

[0320] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[0321] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,2-tetradeuterium)spiro[2.3]hex-5-yl]-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[0322] (11R)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-12-(4,4,5,6,6-pentadeuterspiro[2.3]hex-5-yl)-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one,

[0323] (11R)-12-(5-deuteronitro[2.3]hex-5-yl)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one, and

[0324] (11R)-6-[2,6-bis(trideuterium)methylphenyl]-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione.

[0325] Formula I also includes compounds of Formula Ia:

[0326]

[0327] 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 YN As defined in Formula I, the condition is that the compound is not selected from:

[0328] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[0329] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,2-tetradeuterium)spiro[2.3]hex-5-yl]-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[0330] (11R)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-12-(4,4,5,6,6-pentadeuterspiro[2.3]hex-5-yl)-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one,

[0331] (11R)-12-(5-deuteronitro[2.3]hex-5-yl)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one, and

[0332] (11R)-6-[2,6-bis(trideuterium)methylphenyl]-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6-Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione.

[0333] Formula I also includes compounds of Formula IIa:

[0334]

[0335] 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 YN As defined in Formula I, the condition is that the compound is not selected from:

[0336] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[0337] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,2-tetradeuterium)spiro[2.3]hex-5-yl]-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[0338] (11R)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-12-(4,4,5,6,6-pentadeuterspiro[2.3]hex-5-yl)-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one,

[0339] (11R)-12-(5-deuteronitro[2.3]hex-5-yl)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-9-oxa-2λ6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one, and

[0340] (11R)-6-[2,6-bis(trideuterium)methylphenyl]-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione.

[0341] Formula I also includes compounds of Formula IIb:

[0342]

[0343] 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 YN As defined in Formula I, the condition is that the compound is not selected from:

[0344] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[0345] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,2-tetradeuterium)spiro[2.3]hex-5-yl]-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[0346] (11R)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-12-(4,4,5,6,6-pentadeuterspiro[2.3]hex-5-yl)-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one,

[0347] (11R)-12-(5-deuteronitro[2.3]hex-5-yl)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one, and

[0348] (11R)-6-[2,6-bis(trideuterium)methylphenyl]-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione.

[0349] Formula I also includes compounds of Formula III:

[0350]

[0351] 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 YN As defined in Formula I, the condition is that the compound is not selected from:

[0352] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[0353] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,2-tetradeuterium)spiro[2.3]hex-5-yl]-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[0354] (11R)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-12-(4,4,5,6,6-pentadeuterspiro[2.3]hex-5-yl)-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one,

[0355] (11R)-12-(5-deuteronitro[2.3]hex-5-yl)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one, and

[0356] (11R)-6-[2,6-bis(trideuterium)methylphenyl]-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione.

[0357] Formula I also includes compounds of Formula IV:

[0358]

[0359] 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 1 R 4 R 5 and R YN As defined in Formula I, the condition is that the compound is not selected from:

[0360] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[0361] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,2-tetradeuterium)spiro[2.3]hex-5-yl]-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[0362] (11R)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-12-(4,4,5,6,6-pentadeuterspiro[2.3]hex-5-yl)-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one,

[0363] (11R)-12-(5-deuteronitro[2.3]hex-5-yl)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one, and

[0364] (11R)-6-[2,6-bis(trideuterium)methylphenyl]-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione.

[0365] Formula I also includes compounds of Formula V:

[0366]

[0367] 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 YN As defined in Formula I, the condition is that the compound is not selected from:

[0368] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[0369] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,2-tetradeuterium)spiro[2.3]hex-5-yl]-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[0370] (11R)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-12-(4,4,5,6,6-pentadeuterspiro[2.3]hex-5-yl)-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one,

[0371] (11R)-12-(5-deuteronitro[2.3]hex-5-yl)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one, and

[0372] (11R)-6-[2,6-bis(trideuterium)methylphenyl]-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6-Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione.

[0373] Formula I also includes compounds of Formula VI:

[0374]

[0375] 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 YN As defined in Formula I, the condition is that the compound is not selected from:

[0376] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[0377] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,2-tetradeuterium)spiro[2.3]hex-5-yl]-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[0378] (11R)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-12-(4,4,5,6,6-pentadeuterspiro[2.3]hex-5-yl)-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one,

[0379] (11R)-12-(5-deuteronitro[2.3]hex-5-yl)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-9-oxa-2λ 6-Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one, and

[0380] (11R)-6-[2,6-bis(trideuterium)methylphenyl]-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione.

[0381] 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 a pharmaceutically acceptable salt of any of the foregoing, and at least one pharmaceutically acceptable carrier. These compositions may further comprise at least one additional active pharmaceutical ingredient. In some embodiments of the pharmaceutical compositions disclosed herein, 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 and CFTR modulators.

[0382] Therefore, another aspect of this disclosure provides a method for treating CFTR-mediated cystic fibrosis, the method comprising administering at least one of a compound selected from the novel compounds disclosed herein, a pharmaceutically acceptable salt thereof, a deuterated derivative of any of the foregoing, and at least one pharmaceutically acceptable carrier. In some embodiments, the method comprises administering a pharmaceutical composition disclosed herein, wherein the pharmaceutical composition comprises at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active ingredient is at least one other CFTR modulator. In some embodiments, the at least one other CFTR modulator is selected from CFTR synergists and CFTR modulators.

[0383] In some embodiments, the pharmaceutical compositions of this disclosure comprise at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy) (b) At least one compound selected from N-[2,4-bis(1,1-dimethylethyl)cyclopropaneformamide (tezacaftor), 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxane-5-yl)cyclopropaneformamide)-3-methylpyridin-2-yl)benzoic acid (lumacaftor), and deuterated derivatives of tezacaftor and lumacaftor, as well as pharmaceutically acceptable salts; and / or (b) selected from N-[2,4-bis(1,1-dimethylethyl)]cyclopropaneformamide (tezacaftor), 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxaneformamide)-3-methylpyridin-2-yl)benzoic acid (lumacaftor), and deuterated derivatives of tezacaftor and lumacaftor, as well as pharmaceutically acceptable salts thereof; and / or (b) selected from N-[2,4-bis(1,1-dimethylethyl)]cyclopropaneformamide (tezacaftor), 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxaneformamide)-3-methylpyridin-2-yl)cyclopropaneformamide (lumacaftor ... [-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (ivacaftor), 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 (deutivacaftor), (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3 At least one compound of ,4,18-triazatricyclic[12.3.1.12,5]nonadecan-1(18),2,4,14,16-penten-6-ol, ivacator, deuterated derivatives of deuteric acid, and (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-penten-6-ol, and a pharmaceutically acceptable salt of any of the foregoing.

[0384] Another aspect of this disclosure provides a method for treating CFTR-mediated cystic fibrosis, the method comprising administering to a patient in need at least one compound selected from the novel compounds disclosed herein, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing, and optionally further administering one or more additional CFTR modulators selected from tezacotto, 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 rumacotto.

[0385] In another aspect, the compounds of this disclosure (e.g., compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V, and VI, compounds 1-508, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing) and pharmaceutical compositions comprising these compounds, and optionally further comprising one or more CFTR modulators, are used for treatment or pharmaceutical manufacturing. In some embodiments, the 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.

[0386] Further aspects of this disclosure provide intermediates and methods for preparing the compounds and compositions disclosed herein.

[0387] definition

[0388] 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:

[0389]

[0390] Tizacalo may be in the form of a deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative. Tizacalo and methods for its preparation and use are disclosed in WO 2010 / 053471, WO 2011 / 119984, WO 2011 / 133751, WO 2011 / 133951, WO2015 / 160787, and US 2009 / 0131492, each of which is incorporated herein by reference.

[0391] As used throughout this disclosure, “evaccato” is N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, which is described by the following structure:

[0392]

[0393] 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, each of which is incorporated herein by reference.

[0394] In some embodiments, a 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:

[0395]

[0396] Deutericare can be in the form of other deuterated derivatives, pharmaceutically acceptable salts, or pharmaceutically acceptable salts of 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, each of which is incorporated herein by reference.

[0397] 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:

[0398]

[0399] 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, each of which is incorporated herein by reference.

[0400] 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 double bonds (alkenyl) or triple bonds (alkynyl). Alkyl groups may be substituted or unsubstituted.

[0401] 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.

[0402] 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.

[0403] As used herein, the term "haloalkoxy" refers to an alkoxy group that is substituted with one or more halogen atoms.

[0404] As used herein, “cycloalkyl” refers to 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 groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, dispiro[2.0.2.1]heptane, and spiro[2,3]hexane. Cycloalkyl groups may be substituted or unsubstituted.

[0405] 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.

[0406] 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.

[0407] 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.

[0408] 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.

[0409] Non-limiting examples of nitrogen protecting groups include, for example, tert-butyl carbamate (Boc), benzyl (Bn), p-methoxybenzyl (PMB), tetrahydropyranyl (THP), methyl 9-fluorenylcarbamate (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, benzylamine, 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.

[0410] 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.

[0411] When referring to one or more specific compounds, the phrase "and deuterated derivatives and pharmaceutically acceptable salts thereof" may be used interchangeably with "and deuterated derivatives and pharmaceutically acceptable salts thereof." As used herein, these terms are intended to include deuterated derivatives of the one or more specific compounds and pharmaceutically acceptable salts of the one or more specific compounds, as well as pharmaceutically acceptable salts of deuterated derivatives of the one or more specific compounds.

[0412] As used in this article, "CFTR" refers to the transmembrane conduction regulator of cystic fibrosis.

[0413] As used herein, the term "CFTR modulator" refers to a compound that increases CFTR activity. Increased activity caused by CFTR modulators includes, but is not limited to, compounds that correct, enhance, stabilize, and / or amplify CFTR.

[0414] As used interchangeably herein, the term "CFTR corrector" or "corrector" refers to a compound that promotes the processing and transport of CFTR to increase the amount of CFTR on the cell surface. The novel compounds disclosed herein are CFTR correctors. Tezacotto, rumacotto, and deuterated derivatives and their pharmaceutically acceptable salts, as mentioned herein, are also CFTR correctors.

[0415] As used interchangeably in this document, the terms “CFTR enhancer” and “enhancer” refer to compounds that increase the channel activity of CFTR proteins located on the cell surface, thereby enhancing ion transport. Ivacaptor, deutericatator, (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, are CFTR enhancers. It should be understood that when describing a combination of compounds selected from formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, the combination will generally, but not necessarily, contain a CFTR synergist, such as ivacatho, deuteric acid catarrh, (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 pharmaceutically acceptable salt of any of the foregoing. Furthermore, the combination will generally, but not necessarily, contain only a single synergist, but may contain more than a single corrector. Therefore, 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 1-508, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing will comprise an synergist 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, and may also comprise another CFTR corrector, such as a corrector compound selected from tizacato, rumamacato, and deuterated derivatives and their pharmaceutically acceptable salts.

[0416] As used herein, the term “selected from at least one compound” means one or more compounds selected from a particular group.

[0417] In this disclosure, reference to “compounds 1-508” is intended to indicate a separate reference to each of compounds 1 to 508 or to a group of compounds, such as compounds 1-474, compounds 475-506, and compounds 507 and 508.

[0418] As used herein, the terms “active pharmaceutical ingredient” or “therapeutic agent” (“API”) refer to bioactive compounds.

[0419] The terms “patient” and “subject” are used interchangeably and refer to animals including humans.

[0420] 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).

[0421] As used herein, the terms "treatment" or "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, the following: increased growth in the subject, increased weight gain, reduced pulmonary mucus, improved pancreatic and / or liver function, reduced chest infection, and / or reduced cough or shortness of breath. Improvement in any of these symptoms or reduction in their severity can be readily assessed using standard methods and techniques known in the art.

[0422] 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.

[0423] It should be understood that the therapeutic methods mentioned herein, 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 and VI, compounds 1-508, 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) (e.g., methods for treating CFTR-mediated diseases or methods for treating cystic fibrosis), should also be interpreted as references:

[0424] - A method of treating, for example, cystic fibrosis using one or more compounds (e.g., compounds selected from formula I, any one of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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

[0425] Use of one or more compounds (e.g., compounds selected from formula I, any one of formula Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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.

[0426] It should also be understood that the methods of treatment using pharmaceutical compositions of this disclosure (e.g., pharmaceutical compositions comprising compounds selected from compounds of formula I, compounds of any one of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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) mentioned herein should also be interpreted as references:

[0427] - A pharmaceutical composition (e.g., a pharmaceutical composition comprising at least one compound selected from compounds of formula I, any one of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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

[0428] Use of a pharmaceutical composition (e.g., a pharmaceutical composition comprising at least one compound selected from compounds of formula I, any one of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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.

[0429] 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.

[0430] As used herein, the term "solvent" means any liquid that can at least partially dissolve the product (product solubility > 1 g / L).

[0431] As used in this article, the terms “room temperature” or “ambient temperature” refer to 15°C to 30°C.

[0432] 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.

[0433] 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:

[0434]

[0435] 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.

[0436] 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.

[0437] 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 thereof." 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.

[0438] 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.

[0439] 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:

[0440] Table 1:

[0441]

[0442]

[0443] 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 1-4Alkyl)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.

[0444] The terms “selected from” and “chosen from” are used interchangeably in this document.

[0445] Treatment

[0446] Any novel compound disclosed herein, such as compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V, and VI, compounds 1-508, 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.

[0447] Therefore, in some embodiments, this disclosure provides a method of 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 formulas Ia, IIa, IIb, III, IV, V, and VI, compounds 1-508, 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 selected from ivacato, deutericcato, rumacotto, and tezacotto. In some embodiments, the patient has an F508del / minimum function (MF) genotype, an F508del / F508del genotype (for F508del mutations to be homozygous), an F508del / gated genotype, or an F508del / residual function (RF) genotype. In some embodiments, the patient is heterozygous and has an F508del mutation. In some embodiments, the patient is isotype-binding to the N1303K mutation.

[0448] In some embodiments, 5 mg to 500 mg of the compounds disclosed herein, their tautomers, deuterated derivatives of said compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing may be administered daily.

[0449] In some embodiments, the patient 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:

[0450] Table 2: CFTR mutations

[0451]

[0452]

[0453]

[0454] 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.

[0455] 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 ( 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.

[0456] In some embodiments, the isotope-labeled compound and salt are deuterium ( 2 Compounds and salts labeled with deuterium (H). In some embodiments, the isotope-labeled compounds and salts are labeled with deuterium (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".

[0457] 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).

[0458] Combination therapy

[0459] 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, Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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.

[0460] In some embodiments, at least one additional active pharmaceutical ingredient is selected from mucolytics, bronchodilators, antibiotics, anti-infectives, and anti-inflammatory agents.

[0461] 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.

[0462] In some embodiments, the additional agent is a mucus dissolving agent. Exemplary mucus dissolving agents that may be used herein include...

[0463] In some embodiments, the additional agent is a bronchodilator. Exemplary bronchodilators include albuterol, metaprotenerol sulfate, pirbuterolacetate, salmeterol, or tetrabuline sulfate.

[0464] 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.

[0465] 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 some embodiments, an additional nutrient is pancreatic lipase.

[0466] In some embodiments, at least one additional active pharmaceutical ingredient is selected from CFTR modifiers. In some embodiments, the at least one additional active pharmaceutical ingredient is selected from CFTR synergists. In some embodiments, the synergist is selected from ivacato, deuteric acid catalyst, (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 preceding embodiments. In some embodiments, the at least one additional active pharmaceutical ingredient is selected from CFTR correctors. In some embodiments, the corrector is selected from rumacato, tizacato, and deuterated derivatives and pharmaceutically acceptable salts of any of the preceding embodiments.

[0467] In some embodiments, the at least one additional active pharmaceutical ingredient is selected from: (a) compounds of tizacaloto, rumacator and deuterated derivatives thereof and pharmaceutically acceptable salts thereof; and / or (b) 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 thereof and pharmaceutically acceptable salts thereof.

[0468] Therefore, in some embodiments, the combination therapies provided herein include: (a) compounds selected from formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; and (b) at least one compound selected from tezacotto, rumacotto, and deuterated derivatives and their pharmaceutically acceptable salts; or (c) at least one compound selected from ivacatho, deuteric acid tezacotto, and deuterated derivatives and their pharmaceutically acceptable salts. In other embodiments, the combination therapies provided herein include: (a) at least one compound selected from compounds of formula I, Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 their pharmaceutically acceptable salts; and (c) at least one compound selected from ivacatho, deuteric acid tezacotto, and deuterated derivatives and their pharmaceutically acceptable salts. In other embodiments, the combination therapies provided herein include: (a) at least one compound selected from compounds of formula I, Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 their pharmaceutically acceptable salts; 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 and their pharmaceutically acceptable salts.

[0469] In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 pharmaceutically acceptable salts. In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 its pharmaceutically acceptable salts. In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 pharmaceutically acceptable salts thereof. In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 deutericata and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 its pharmaceutically acceptable salts.

[0470] In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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.

[0471] In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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.

[0472] Each of the compounds of formula I, the compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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.

[0473] In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered once daily. In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered twice daily.

[0474] In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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.

[0475] In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 rumacata and deuterated derivatives and pharmaceutically acceptable salts of the foregoing, is administered once daily. In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 rumacata and deuterated derivatives and pharmaceutically acceptable salts of the foregoing, is administered twice daily.

[0476] In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 ivacarto, deuteric acid, and deuterated derivatives and pharmaceutically acceptable salts of the foregoing, is administered once daily. In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 ivacarto, deuteric acid, and deuterated derivatives and pharmaceutically acceptable salts of the foregoing, is administered twice daily.

[0477] In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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.

[0478] In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 pharmaceutically acceptable salts thereof, and at least one compound selected from ivacato, deuteric acid thiocarb, 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 formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 pharmaceutically acceptable salts thereof, and at least one compound selected from ivacato, deuteric acid thiocarb, and its deuterated derivatives and pharmaceutically acceptable salts thereof, is administered twice daily.

[0479] The compounds of Formula I, compounds of Formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 and its deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one compound selected from rumacator and its deuterated derivatives and pharmaceutically acceptable salts thereof, are administered once daily. In some embodiments, the compounds of Formula I, compounds of Formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 ivacatho, deuteric acid and its deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one compound selected from rumacator and its deuterated derivatives and pharmaceutically acceptable salts thereof, are administered twice daily.

[0480] In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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, rumacotto, 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 are administered once daily. In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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, rumacotto, 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 are administered twice daily.

[0481] In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 pharmaceutically acceptable salts, and at least one compound selected from ivacatho and its pharmaceutically acceptable salts, are administered once daily, and at least one compound selected from ivacatho and its pharmaceutically acceptable salts, are administered twice daily. In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 pharmaceutically acceptable salts, and at least one compound selected from ivacatho and its pharmaceutically acceptable salts, are administered once daily, and at least one compound selected from ivacatho and its pharmaceutically acceptable salts, are administered twice daily.

[0482] Compounds of Formula I, compounds of Formulas Ia, IIa, IIb, III, IV, V, and VI, compounds 1-508, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, tezacotto, ivacatho, and deuterictotho, and their pharmaceutically acceptable salts and deuterated derivatives, may be administered in a single pharmaceutical composition or in a separate pharmaceutical composition. Such pharmaceutical compositions may be administered once daily or multiple times daily, such as twice 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 thereof or a pharmaceutically acceptable salt thereof) administered once or twice daily or daily administration means that the given amount is administered once or twice daily for each dose.

[0483] In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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.

[0484] In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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.

[0485] In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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.

[0486] In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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, rumacotto, and 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 deuterated derivatives and their pharmaceutically acceptable salts are administered in a third pharmaceutical composition.

[0487] In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V, and VI, compounds 1-508, 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 tizacaloto and deuterated derivatives and their pharmaceutically acceptable salts, and at least one compound selected from ivacaloto, deuteric acid tizacaloto and 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 ivacaloto, and the other half of the daily dose of ivacaloto is administered in a third pharmaceutical composition.

[0488] In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V, and VI, compounds 1-508, 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 rumacarbose and deuterated derivatives and their pharmaceutically acceptable salts, and at least one compound selected from ivacarbose, deuteric acid carboxylate and 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 ivacarbose, and the other half dose of ivacarbose is administered in a third pharmaceutical composition.

[0489] In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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, rumacotto, and deuterated compounds 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 compounds and their pharmaceutically acceptable salts are administered in a second pharmaceutical composition.

[0490] In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 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 the first pharmaceutical composition. In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; at least one compound selected from rumacotto 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 the first pharmaceutical composition. In some embodiments, at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V, and VI, compounds 1-508, 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, rumacotto, 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 their 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 when the first pharmaceutical composition includes ivacato, the second composition including only ivacato is administered once daily.

[0491] Any suitable pharmaceutical composition may be used for compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. Some exemplary pharmaceutical compositions for tezacotto and its pharmaceutically acceptable salts can be found in WO 2011 / 119984 and WO 2014 / 014841, which are incorporated herein by reference. Exemplary pharmaceutical compositions for ivacator and its pharmaceutically acceptable salts can be found in WO 2007 / 134279, WO 2010 / 019239, WO2011 / 019413, WO 2012 / 027731 and WO 2013 / 130669, and exemplary pharmaceutical compositions for deutericatar and its pharmaceutically acceptable salts can be found in US 8,865,902, US 9,181,192, US 9,512,079, WO2017 / 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, which are incorporated herein by reference.

[0492] Pharmaceutical Composition

[0493] Another aspect of this disclosure provides a pharmaceutical composition comprising at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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.

[0494] In some embodiments, this disclosure provides a pharmaceutical composition comprising at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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.

[0495] In some embodiments, this disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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.

[0496] In some embodiments, this disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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, and deuterated derivatives of the foregoing, and pharmaceutically acceptable salts thereof; and (c) at least one pharmaceutically acceptable carrier.

[0497] In some embodiments, this disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 deuterated derivatives and their pharmaceutically acceptable salts; and (c) at least one pharmaceutically acceptable carrier.

[0498] In some embodiments, this disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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.

[0499] In some embodiments, this disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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.

[0500] In some embodiments, this disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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.

[0501] In some embodiments, this disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 thereof, and pharmaceutically acceptable salts thereof; (c) at least one compound selected from rumacato and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof; and (d) at least one pharmaceutically acceptable carrier.

[0502] In some embodiments, this disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from compounds of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V and VI, compounds 1-508, 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 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 deuterated derivatives and their pharmaceutically acceptable salts; and (d) at least one pharmaceutically acceptable carrier.

[0503] 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.

[0504] The pharmaceutical compositions described herein may be used to treat cystic fibrosis and other CFTR-mediated diseases.

[0505] As described above, the pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier. 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 (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, lanolin, and sugars (such as lactose, glucose, and sucrose). Starch (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and 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, flavorings, aromas, preservatives and antioxidants.

[0506] Exemplary embodiments

[0507] The following is a non-limiting list of exemplary embodiments:

[0508] 1. A compound of formula I:

[0509]

[0510] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0511] Ring A is selected from:

[0512] ■C6-C 10 Aryl,

[0513] ■C3-C 10 cycloalkyl,

[0514] ■3 to 10-membered heterocyclic groups, and

[0515] ■5 to 10-membered heteroaryl groups;

[0516] Ring B is selected from:

[0517] ■C6-C 10 Aryl,

[0518] ■C3-C 10 cycloalkyl,

[0519] ■3 to 10-membered heterocyclic groups, and

[0520] ■5 to 10-membered heteroaryl groups;

[0521] V is selected from O and NH;

[0522] W 1 Selected from N and CH;

[0523] W 2 Choose from N and CH, provided that W is selected. 1 and W 2 At least one of them is N;

[0524] 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;

[0525] Each L 1 Independently selected from C(R) L1 )2 and

[0526] Each L 2 Independently selected from C(R) L2 )2;

[0527] The ring C is selected from C6-C groups optionally substituted by 1 to 3 independently selected groups from the following. 10 Aryl:

[0528] ■ Halogen,

[0529] ■C1-C6 alkyl groups, and

[0530] ■N(R N )2;

[0531] Each R 3 Selected independently from:

[0532] ■ Halogen,

[0533] ■C1-C6 alkyl groups,

[0534] ■C1-C6 alkoxy groups,

[0535] ■C3-C 10 cycloalkyl,

[0536] ■ C6-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 Aryl, and

[0537] ■3 to 10-membered heterocyclic groups;

[0538] R 4 Selected from hydrogen and C1-C6 alkyl groups;

[0539] Each R 5 Selected independently from:

[0540] ■ Hydrogen,

[0541] ■ Halogen,

[0542] ■Hydroxy

[0543] ■N(R N )2,

[0544] ■-SO-Me,

[0545] ■-CH=C(R LC )2, where two R LC Together they form C3-C 10 cycloalkyl,

[0546] ■ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0547] ○Hydroxy group,

[0548] ○Optionally selected by 1-3 independently chosen C1-C6 alkoxy groups and C6-C10 The C1-C6 alkoxy group substituted by the aryl group,

[0549] ○C3-C 10 cycloalkyl,

[0550] ○Optionally substituted with 1-3 groups independently selected from C1-C6 alkyl and C1-C6 alkoxy groups -(O) 0-1 -(C6-C 10 Aryl),

[0551] ○3 to 10-membered heterocyclic groups, and

[0552] ○N(R N )2,

[0553] ■ C1-C6 alkoxy groups optionally substituted with 1-3 independently selected groups from the following:

[0554] ○ Halogen,

[0555] ○C6-C 10 Aryl, and

[0556] ○ C3-C substituted with 1-3 independently selected C1-C6 fluoroalkyl groups 10 cycloalkyl,

[0557] ■C1-C6 fluoroalkyl groups,

[0558] ■C3-C 10 cycloalkyl,

[0559] ■C6-C 10 Aryl, and

[0560] ■3 to 10-membered heterocyclic groups;

[0561] R YN Selected from:

[0562] ■ C3-C, optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[0563] ○Hydroxy group,

[0564] ○Oxygenation,

[0565] ○ Halogen,

[0566] ○Cyano

[0567] ○N(R N )2,

[0568] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0569] ◆Hydroxy group,

[0570] ◆Oxygenation,

[0571] ◆N(R N )2,

[0572] ◆C1-C6 alkoxy groups, and

[0573] ◆C6-C 10 Aryl,

[0574] ○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,

[0575] ○ Halogen,

[0576] ○C3-C 10 cycloalkyl,

[0577] ○Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, and

[0578] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0579] ◆Hydroxy group,

[0580] ◆Cyano

[0581] ◆Oxygenation,

[0582] ◆Halogen,

[0583] ◆N(R N )2,

[0584] ◆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,

[0585] ◆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,

[0586] ◆C1-C6 fluoroalkyl groups,

[0587] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[0588] ◆C6-C 10 Aryl, and

[0589] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, 3- to 10-membered heterocyclic groups,

[0590] ■C6-C 10 Aryl,

[0591] ■Optionally substituted with 1 to 3 independently selected groups from the following: 3- to 10-membered heterocyclic groups

[0592] ○Oxygenation,

[0593] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0594] ◆Oxygenation,

[0595] ◆Hydroxy group,

[0596] ◆N(R N )2,

[0597] ◆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

[0598] ◆-(O) 0-1 -(C3-C 10 cycloalkyl),

[0599] ○C1-C6 fluoroalkyl,

[0600] ○ C3-C groups optionally substituted with 1-3 independently selected halogen groups 10 cycloalkyl groups, and

[0601] ○3 to 10-membered heterocyclic groups, and

[0602] ■ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0603] ○ Halogen,

[0604] ○Optionally selected by 1-3 independently chosen from oxo, C1-C6 alkoxy and N(R) N C1-C6 alkyl groups substituted with )2, and

[0605] ○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;

[0606] R ZN Selected from:

[0607] ■ Hydrogen,

[0608] ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0609] ○Hydroxy group,

[0610] ○Oxygenation,

[0611] ○Cyano

[0612] ○ C1-C6 alkoxy groups optionally substituted with 1-3 independently selected halogen and C1-C6 alkoxy groups,

[0613] ○N(R N )2,

[0614] ○SO2Me,

[0615] ○ C3-C cells optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[0616] ◆Hydroxy group,

[0617] ◆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,

[0618] ◆C1-C6 fluoroalkyl groups,

[0619] ◆C1-C6 alkoxy groups,

[0620] ◆COOH,

[0621] ◆N(R N )2,

[0622] ◆C6-C 10 Aryl, and

[0623] ◆Optionally substituted with 1-3 independently selected oxo and C1-C6 alkyl groups, 3- to 10-membered heterocyclic groups,

[0624] ○ C6-C cells optionally substituted with 1-3 independently selected groups from the following 10 Aryl:

[0625] ◆Halogen,

[0626] ◆Hydroxy group,

[0627] ◆Cyano

[0628] ◆SiMe3,

[0629] ◆SO2Me,

[0630] ◆SF5,

[0631] ◆N(R N )2,

[0632] ◆P(O)Me2,

[0633] ◆Optionally substituted with 1-3 independently selected C1-C6 fluoroalkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[0634] ◆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,

[0635] ◆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,

[0636] ◆C1-C6 fluoroalkyl groups,

[0637] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, 3- to 10-membered heterocyclic groups,

[0638] ◆-(O) 0-1 -(C6-C 10 Aryl), and

[0639] ◆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),

[0640] ○Optionally substituted with 1 to 4 independently selected groups from the following 3- to 10-membered heterocyclic groups:

[0641] ◆Hydroxy group,

[0642] ◆Oxygenation,

[0643] ◆N(R N )2,

[0644] ◆C1-C6 alkyl groups optionally substituted with 1-3 independently selected oxo and C1-C6 alkoxy groups,

[0645] ◆C1-C6 alkoxy groups,

[0646] ◆C1-C6 fluoroalkyl groups,

[0647] ◆C6-C cells optionally substituted with 1-3 independently selected halogen groups 10 Aryl, and

[0648] ◆5 to 10 aryl compounds, and

[0649] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0650] ◆Hydroxy group,

[0651] ◆Cyano

[0652] ◆Oxygenation,

[0653] ◆Halogen,

[0654] ◆B(OH)2,

[0655] ◆N(R N )2,

[0656] ◆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,

[0657] ◆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,

[0658] ◆C1-C6 fluoroalkyl groups,

[0659] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[0660] ◆-(O) 0-1 -(C6-C 10 Aryl),

[0661] ◆Optionally selected by 1-4 independently chosen from hydroxyl, oxo, halogen, cyano, N(R) N 2. C1-C6 alkyl groups (optionally separated by 1-3 independently selected from hydroxyl, oxo, N(R) groups) N -(O) groups are substituted with C1-C6 alkoxy groups, C1-C6 alkoxy groups, C1-C6 fluoroalkyl groups, and 3 to 10-membered heterocyclic groups (optionally substituted with 1 to 3 groups independently selected from C1-C6 fluoroalkyl groups). 0-1 -(3 to 10-membered heterocyclic groups), and

[0662] ◆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,

[0663] ■C1-C6 fluoroalkyl groups,

[0664] ■ C3-C, optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[0665] ○Hydroxy group,

[0666] ○Oxygenation,

[0667] ○ Halogen,

[0668] ○Cyano

[0669] ○N(R N )2,

[0670] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0671] ◆Hydroxy group,

[0672] ◆Oxygenation,

[0673] ◆N(R N )2,

[0674] ◆C1-C6 alkoxy groups, and

[0675] ◆C6-C 10 Aryl,

[0676] ○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,

[0677] ○ Halogen,

[0678] ○C3-C 10 cycloalkyl,

[0679] ○Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, and

[0680] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0681] ◆Hydroxy group,

[0682] ◆Cyano

[0683] ◆Oxygenation,

[0684] ◆Halogen,

[0685] ◆N(R N )2,

[0686] ◆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,

[0687] ◆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,

[0688] ◆C1-C6 fluoroalkyl groups,

[0689] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[0690] ◆C6-C 10 Aryl, and

[0691] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, 3- to 10-membered heterocyclic groups,

[0692] ■C6-C 10 Aryl,

[0693] ■Optionally substituted with 1 to 3 independently selected groups from the following: 3- to 10-membered heterocyclic groups

[0694] ○Oxygenation,

[0695] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0696] ◆Oxygenation,

[0697] ◆Hydroxy group,

[0698] ◆N(R N )2,

[0699] ◆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

[0700] ◆-(O) 0-1 -(C3-C 10 cycloalkyl),

[0701] ○C1-C6 fluoroalkyl,

[0702] ○ C3-C groups optionally substituted with 1-3 independently selected halogen groups 10 cycloalkyl groups, and

[0703] ○3 to 10-membered heterocyclic groups,

[0704] ■ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0705] ○ Halogen,

[0706] ○Optionally selected by 1-3 independently chosen from oxo, C1-C6 alkoxy and N(R) N C1-C6 alkyl groups substituted with )2, and

[0707] ○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

[0708] ■R F ;

[0709] Each R ZC Selected independently from:

[0710] ■ Hydrogen,

[0711] ■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),

[0712] ■ C6-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 Aryl, and

[0713] ■R F ;

[0714] Or two Rs ZC Together they form an oxo group;

[0715] Each R L1 Selected independently from:

[0716] ■ Hydrogen,

[0717] ■N(R N )2, the condition is two N(R) N )2 does not combine with the same carbon atom.

[0718] ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0719] ○ Halogen,

[0720] ○Hydroxy group,

[0721] ○Oxygenation,

[0722] ○N(R N )2,

[0723] ○Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[0724] ○ C3-C substituted with 1-3 independently selected groups selected from halogens and C1-C6 fluoroalkyl groups 10 cycloalkyl,

[0725] ○ C6-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 Aryl, and

[0726] ○ 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),

[0727] ■C3-C 10 cycloalkyl,

[0728] ■ C6-C cells optionally substituted with 1-4 independently selected groups from the following 10 Aryl:

[0729] ○ Halogen,

[0730] ○Cyano

[0731] ○SiMe3,

[0732] ○POMe2,

[0733] ○ C1-C7 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0734] ◆Hydroxy group,

[0735] ◆Oxygenation,

[0736] ◆Cyano

[0737] ◆SiMe3,

[0738] ◆N(R N )2, and

[0739] ◆C3-C substituted with 1-3 independently selected C1-C6 fluoroalkyl groups 10 cycloalkyl,

[0740] ○ C1-C6 alkoxy groups optionally substituted with 1-3 independently selected groups from the following:

[0741] ◆C3-C substituted with 1-3 independently selected C1-C6 fluoroalkyl groups 10 cycloalkyl groups, and

[0742] ◆C1-C6 alkoxy groups,

[0743] ○C1-C6 fluoroalkyl,

[0744] ○ C3-C2 groups optionally substituted with 1-3 groups independently selected from C1-C6 alkyl and C1-C6 fluoroalkyl groups 10 cycloalkyl,

[0745] ○C6-C 10 Aryl,

[0746] ○Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, and

[0747] ○5 to 10 yuan of mixed aromatic compounds,

[0748] ■Optionally substituted with 1 to 3 independently selected groups from the following: 3- to 10-membered heterocyclic groups

[0749] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0750] ◆Oxygenation, and

[0751] ◆C1-C6 alkoxy groups,

[0752] ■ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0753] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0754] ◆C3-C substituted with 1-3 independently selected C1-C6 fluoroalkyl groups 10 cycloalkyl groups, and

[0755] ○ C6-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 Aryl, and

[0756] ■R F ;

[0757] Or two R atoms on the same carbon atom L1 Together they form an oxo group;

[0758] Each R L2Independently selected from hydrogen and R F ;

[0759] Or two R atoms on the same carbon atom L2 Together they form an oxo group;

[0760] Each R N Selected independently from:

[0761] ■ Hydrogen,

[0762] ■ C1-C8 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0763] ○Oxygenation,

[0764] ○ Halogen,

[0765] ○Hydroxy group,

[0766] ○NH2,

[0767] ○NHMe,

[0768] ○NMe2,

[0769] ○NHCOMe,

[0770] ○Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[0771] ○-(O) 0-1 -(C3-C 10 cycloalkyl),

[0772] ○ C6-C alkyl groups optionally substituted with 1-3 independently selected groups selected from halogens and C1-C6 alkyl groups 10 Aryl,

[0773] ○Optionally substituted with 1-4 independently selected oxo and C1-C6 alkyl groups, and

[0774] ○ 5- to 14-membered heteroaryl groups optionally substituted by 1 to 4 independently selected oxo and C1-C6 alkyl groups,

[0775] ■ C3-C, optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[0776] ○Hydroxy group,

[0777] ○NH2,

[0778] ○NHMe, and

[0779] ○ C1-C6 alkyl groups optionally substituted with 1-3 independently selected groups selected from hydroxyl groups,

[0780] ■C6-C 10 Aryl, and

[0781] ■3 to 10-membered heterocyclic groups;

[0782] 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:

[0783] ■Hydroxy

[0784] ■Oxytochemicals

[0785] ■Cyano

[0786] ■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,

[0787] ■C1-C6 alkoxy groups, and

[0788] ■C1-C6 fluoroalkyl groups;

[0789] Or an R 4 And an R L1 Together they form C6-C8 alkylene groups;

[0790] When R F When they exist, two R F Together with the atoms they are bonded to, they form groups selected from the following:

[0791] ■ C3-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 cycloalkyl,

[0792] ■ C6-C, optionally substituted by 1-3 independently selected groups from the following 10 Aryl:

[0793] ○ Halogen,

[0794] ○C1-C6 alkyl,

[0795] ○N(R N )2, and

[0796] ○ A 3- to 10-membered heterocyclic group optionally substituted by 1 to 3 independently selected groups chosen from hydroxyl groups.

[0797] ■ 3- to 11-membered heterocyclic groups optionally substituted by 1 to 3 independently selected groups from the following:

[0798] ○Oxygenation,

[0799] ○N(R N )2,

[0800] ○ C1-C9 alkyl groups optionally substituted by 1-4 independently selected groups from the following:

[0801] ◆Oxygenation,

[0802] ◆Halogen,

[0803] ◆Hydroxy group,

[0804] ◆N(R N )2,

[0805] ◆-SO2-(C1-C6 alkyl),

[0806] ◆Optionally selected by 1-3 independent elements chosen from halogens and C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[0807] ◆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,

[0808] ◆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),

[0809] ◆Optionally composed of 1-3 independently selected oxo, C1-C6 alkyl groups (optionally 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, etc. 10 cycloalkyl and R Nsubstituted 3- to 10-membered heterocyclic groups,

[0810] ◆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

[0811] ◆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,

[0812] ○ 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,

[0813] ○C6-C 10 Aryl,

[0814] ○3 to 10-membered heterocyclic groups, and

[0815] ○Optionally substituted with 1-3 groups independently selected from C1-C6 alkoxy and C1-C6 fluoroalkyl groups, and

[0816] ■ 5 to 12 heteroaryl groups optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl and C1-C6 fluoroalkyl groups;

[0817] The condition is that the compound is not selected from:

[0818] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[0819] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,2-tetradeuterium)spiro[2.3]hex-5-yl]-9-oxa-2λ 6-Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[0820] (11R)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-12-(4,4,5,6,6-pentadeuterspiro[2.3]hex-5-yl)-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one,

[0821] (11R)-12-(5-deuteronitro[2.3]hex-5-yl)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one, and

[0822] (11R)-6-[2,6-bis(trideuterium)methylphenyl]-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione.

[0823] 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Example 1, wherein ring A is selected from C6-C6. 10 Aryl and 5 to 10 heteroaryl compounds.

[0824] 3. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Example 1 or 2, wherein ring A is selected from phenyl, pyridyl, pyrazinyl, and pyrazolyl.

[0825] 4. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of Examples 1 to 3, wherein ring A is phenyl.

[0826] 5. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 1 to 4, wherein ring B is selected from C6-C6. 10 Aryl and C3-C 10 Cycloalkyl.

[0827] 6. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 1 to 5, wherein ring B is selected from phenyl and cyclohexyl.

[0828] 7. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 1 to 6, wherein ring B is phenyl.

[0829] 8. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of Examples 1 to 7, wherein V is O.

[0830] 9. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 1 to 8, wherein W 1 It is N and W 2 It is N.

[0831] 10. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 1 to 8, wherein W 1 It is CH and W 2 It is N.

[0832] 11. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 1 to 10, wherein Z is C(R ZC )2.

[0833] 12. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 1 to 11, wherein two R... ZC Together they form an oxo group.

[0834] 13. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 1 to 12, wherein each R 3 It is independently selected from C1-C6 alkyl groups.

[0835] 14. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 1 to 13, wherein each R 3 It is a methyl group.

[0836] 15. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 1 to 12, wherein R 3 It does not exist.

[0837] 16. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 1 to 15, wherein R 4 Selected from hydrogen and methyl.

[0838] 17. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 1 to 16, wherein R 4 It is a methyl group.

[0839] 18. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 1 to 17, wherein each R 5 Independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl and C6-C 10 Aryl.

[0840] 19. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 1 to 18, wherein R YN Selected from:

[0841] ■ C3-C, optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[0842] ○Hydroxy group,

[0843] ○Cyano

[0844] ○N(R N )2,

[0845] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0846] ◆Hydroxy group,

[0847] ◆Oxygenation,

[0848] ◆N(R N )2, and

[0849] ◆C6-C 10 Aryl,

[0850] ○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,

[0851] ○C3-C 10 cycloalkyl groups, and

[0852] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0853] ◆Hydroxy group,

[0854] ◆Oxygenation,

[0855] ◆N(R N )2,

[0856] ◆C1-C6 alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkoxy groups, and

[0857] ◆Optionally selected from 1-3 independent choices C3-C 10 C1-C6 alkoxy groups substituted with cycloalkyl groups,

[0858] ■Optionally substituted with 1 to 3 independently selected groups from the following: 3- to 10-membered heterocyclic groups

[0859] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0860] ◆Oxygenation,

[0861] ◆Hydroxy group,

[0862] ◆N(R N )2,

[0863] ◆Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted with the aryl group, and

[0864] ◆-(O) 0-1 -(C3-C 10 cycloalkyl),

[0865] ○C1-C6 fluoroalkyl,

[0866] ○ C3-C groups optionally substituted with 1-3 independently selected halogen groups 10 cycloalkyl groups, and

[0867] ○3 to 10-membered heterocyclic groups, and

[0868] ■ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0869] ○ Halogen,

[0870] ○Optionally selected by 1-3 independently chosen from oxo, C1-C6 alkoxy and N(R) N C1-C6 alkyl groups substituted with )2, and

[0871] ○Optionally substituted with 1-3 groups independently selected from C1-C6 alkyl groups (optionally substituted with 1-3 groups selected from oxo, C1-C6 alkoxy and C6-C... 10 (Aromatic groups substituted) 3 to 10-membered heterocyclic groups.

[0872] 20. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 1 to 19, wherein each R L1 Selected independently from:

[0873] ■ Hydrogen,

[0874] ■N(R N )2, the condition is two N(R) N )2 does not combine with the same carbon atom.

[0875] ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0876] ○ Halogen,

[0877] ○hydroxyl group, and

[0878] ○ C3-C substituted with 1-3 independently selected groups selected from halogens and C1-C6 fluoroalkyl groups 10 cycloalkyl groups, and

[0879] ■C3-C 10 Cycloalkyl.

[0880] 21. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 1 to 20, wherein each R N Selected independently from:

[0881] ■ Hydrogen,

[0882] ■ C1-C8 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0883] ○NH2,

[0884] ○NHCOMe,

[0885] ○C1-C6 alkoxy groups,

[0886] ○-(O) 0-1 -(C3-C 10 cycloalkyl),

[0887] ○C6-C 10 Aryl, and

[0888] ○Optionally substituted with 1-4 independently selected C1-C6 alkyl groups, and

[0889] ■C6-C 10 Aryl, and

[0890] Or two R atoms on the same nitrogen atom NTogether 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:

[0891] ■Cyano

[0892] ■C1-C6 alkyl groups, and

[0893] ■C1-C6 alkoxy groups.

[0894] 22. A compound of formula Ia:

[0895]

[0896] 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 YN As defined according to Example 1, provided that the compound is not selected from:

[0897] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[0898] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,2-tetradeuterium)spiro[2.3]hex-5-yl]-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[0899] (11R)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-12-(4,4,5,6,6-pentadeuterspiro[2.3]hex-5-yl)-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one,

[0900] (11R)-12-(5-deuteronitro[2.3]hex-5-yl)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one, and

[0901] (11R)-6-[2,6-bis(trideuterium)methylphenyl]-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione.

[0902] 23. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Example 22, wherein ring A is selected from C6-C6. 10 Aryl and 5 to 10 heteroaryl compounds.

[0903] 24. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Example 22 or 23, wherein ring A is selected from phenyl, pyridyl, pyrazinyl, and pyrazolyl.

[0904] 25. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of Examples 22 to 24, wherein ring A is phenyl.

[0905] 26. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 22 to 25, wherein ring B is selected from C6-C. 10 Aryl and C3-C 10 Cycloalkyl.

[0906] 27. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 22 to 26, wherein ring B is selected from phenyl and cyclohexyl.

[0907] 28. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of Examples 22 to 27, wherein ring B is phenyl.

[0908] 29. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 22 to 28, wherein W 1 It is N and W 2 It is N.

[0909] 30. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 22 to 29, wherein W 1 It is CH and W 2 It is N.

[0910] 31. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 22 to 30, wherein Z is C(R ZC )2.

[0911] 32. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 22 to 31, wherein two R ZC Together they form an oxo group.

[0912] 33. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 22 to 32, wherein each R 3 It is independently selected from C1-C6 alkyl groups.

[0913] 34. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 22 to 33, wherein each R 3 It is a methyl group.

[0914] 35. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 22 to 32, wherein R 3 It does not exist.

[0915] 36. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 22 to 35, wherein R 4 Selected from hydrogen and methyl.

[0916] 37. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 22 to 36, wherein R 4 It is a methyl group.

[0917] 38. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 22 to 37, wherein each R 5 Independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl and C6-C 10 Aryl.

[0918] 39. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 22 to 38, wherein R YN Selected from:

[0919] ■ C3-C, optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[0920] ○Hydroxy group,

[0921] ○Cyano

[0922] ○N(R N )2,

[0923] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0924] ◆Hydroxy group,

[0925] ◆Oxygenation,

[0926] ◆N(R N )2, and

[0927] ◆C6-C 10 Aryl,

[0928] ○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,

[0929] ○C3-C 10 cycloalkyl groups, and

[0930] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0931] ◆Hydroxy group,

[0932] ◆Oxygenation,

[0933] ◆N(R N )2,

[0934] ◆C1-C6 alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkoxy groups, and

[0935] ◆Optionally selected from 1-3 independent choices C3-C 10 C1-C6 alkoxy groups substituted with cycloalkyl groups,

[0936] ■Optionally substituted with 1 to 3 independently selected groups from the following: 3- to 10-membered heterocyclic groups

[0937] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0938] ◆Oxygenation,

[0939] ◆Hydroxy group,

[0940] ◆N(R N )2,

[0941] ◆Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted with the aryl group, and

[0942] ◆-(O) 0-1 -(C3-C 10 cycloalkyl),

[0943] ○C1-C6 fluoroalkyl,

[0944] ○ C3-C groups optionally substituted with 1-3 independently selected halogen groups 10 cycloalkyl groups, and

[0945] ○3 to 10-membered heterocyclic groups, and

[0946] ■ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0947] ○ Halogen,

[0948] ○Optionally selected by 1-3 independently chosen from oxo, C1-C6 alkoxy and N(R) N C1-C6 alkyl groups substituted with )2, and

[0949] ○Optionally substituted with 1-3 groups independently selected from C1-C6 alkyl groups (optionally substituted with 1-3 groups selected from oxo, C1-C6 alkoxy and C6-C... 10 (Aromatic groups substituted) 3 to 10-membered heterocyclic groups.

[0950] 40. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 22 to 39, wherein each R L1 Selected independently from:

[0951] ■ Hydrogen,

[0952] ■N(R N )2, the condition is two N(R) N )2 does not combine with the same carbon atom.

[0953] ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0954] ○ Halogen,

[0955] ○hydroxyl group, and

[0956] ○ C3-C substituted with 1-3 independently selected groups selected from halogens and C1-C6 fluoroalkyl groups 10cycloalkyl groups, and

[0957] ■C3-C 10 Cycloalkyl.

[0958] 41. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 22 to 40, wherein each R N Selected independently from:

[0959] ■ Hydrogen,

[0960] ■ C1-C8 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0961] ○NH2,

[0962] ○NHCOMe,

[0963] ○C1-C6 alkoxy groups,

[0964] ○-(O) 0-1 -(C3-C 10 cycloalkyl),

[0965] ○C6-C 10 Aryl, and

[0966] ○Optionally substituted with 1-4 independently selected C1-C6 alkyl groups, and

[0967] ■C6-C 10 Aryl, and

[0968] 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:

[0969] ■Cyano

[0970] ■C1-C6 alkyl groups, and

[0971] ■C1-C6 alkoxy groups.

[0972] 42. A compound of formula IIa:

[0973]

[0974] 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 4R 5 and R YN As defined according to Example 1, provided that the compound is not selected from:

[0975] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[0976] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,2-tetradeuterium)spiro[2.3]hex-5-yl]-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[0977] (11R)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-12-(4,4,5,6,6-pentadeuterspiro[2.3]hex-5-yl)-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one,

[0978] (11R)-12-(5-deuteronitro[2.3]hex-5-yl)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one, and

[0979] (11R)-6-[2,6-bis(trideuterium)methylphenyl]-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione.

[0980] 43. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Example 42, wherein ring B is selected from C6-C6. 10 Aryl and C3-C 10 Cycloalkyl.

[0981] 44. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Example 42 or 43, wherein ring B is selected from phenyl and cyclohexyl.

[0982] 45. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 42 to 44, wherein ring B is phenyl.

[0983] 46. ​​The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 42 to 45, wherein W 1 It is N and W 2 It is N.

[0984] 47. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 42 to 46, wherein W 1 It is CH and W 2 It is N.

[0985] 48. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 42 to 47, wherein Z is C(R ZC )2.

[0986] 49. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 42 to 48, wherein two R ZC Together they form an oxo group.

[0987] 50. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 42 to 49, wherein each R 3 It is independently selected from C1-C6 alkyl groups.

[0988] 51. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 42 to 50, wherein each R 3 It is a methyl group.

[0989] 52. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 42 to 49, wherein R 3 It does not exist.

[0990] 53. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 42 to 52, wherein R 4 Selected from hydrogen and methyl.

[0991] 54. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 42 to 53, wherein R 4 It is a methyl group.

[0992] 55. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 42 to 54, wherein each R 5 Independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl and C6-C 10 Aryl.

[0993] 56. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 42 to 55, wherein R YN Selected from:

[0994] ■ C3-C, optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[0995] ○Hydroxy group,

[0996] ○Cyano

[0997] ○N(R N )2,

[0998] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0999] ◆Hydroxy group,

[1000] ◆Oxygenation,

[1001] ◆N(R N )2, and

[1002] ◆C6-C 10 Aryl,

[1003] ○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,

[1004] ○C3-C 10 cycloalkyl groups, and

[1005] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[1006] ◆Hydroxy group,

[1007] ◆Oxygenation,

[1008] ◆N(R N )2,

[1009] ◆C1-C6 alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkoxy groups, and

[1010] ◆Optionally selected from 1-3 independent choices C3-C 10 C1-C6 alkoxy groups substituted with cycloalkyl groups,

[1011] ■Optionally substituted with 1 to 3 independently selected groups from the following: 3- to 10-membered heterocyclic groups

[1012] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1013] ◆Oxygenation,

[1014] ◆Hydroxy group,

[1015] ◆N(R N )2,

[1016] ◆Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted with the aryl group, and

[1017] ◆-(O) 0-1 -(C3-C 10 cycloalkyl),

[1018] ○C1-C6 fluoroalkyl,

[1019] ○ C3-C groups optionally substituted with 1-3 independently selected halogen groups 10 cycloalkyl groups, and

[1020] ○3 to 10-membered heterocyclic groups, and

[1021] ■ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[1022] ○ Halogen,

[1023] ○Optionally selected by 1-3 independently chosen from oxo, C1-C6 alkoxy and N(R) N C1-C6 alkyl groups substituted with )2, and

[1024] ○Optionally substituted with 1-3 groups independently selected from C1-C6 alkyl groups (optionally substituted with 1-3 groups selected from oxo, C1-C6 alkoxy and C6-C... 10(Aromatic groups substituted) 3 to 10-membered heterocyclic groups.

[1025] 57. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 42 to 56, wherein each R L1 Selected independently from:

[1026] ■ Hydrogen,

[1027] ■N(R N )2, the condition is two N(R) N )2 does not combine with the same carbon atom.

[1028] ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1029] ○ Halogen,

[1030] ○hydroxyl group, and

[1031] ○ C3-C substituted with 1-3 independently selected groups selected from halogens and C1-C6 fluoroalkyl groups 10 cycloalkyl groups, and

[1032] ■C3-C 10 Cycloalkyl.

[1033] 58. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 42 to 57, wherein each R N Selected independently from:

[1034] ■ Hydrogen,

[1035] ■ C1-C8 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1036] ○NH2,

[1037] ○NHCOMe,

[1038] ○C1-C6 alkoxy groups,

[1039] ○-(O) 0-1 -(C3-C 10 cycloalkyl),

[1040] ○C6-C 10 Aryl, and

[1041] ○Optionally substituted with 1-4 independently selected C1-C6 alkyl groups, and

[1042] ■C6-C 10 Aryl,

[1043] 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:

[1044] ■Cyano

[1045] ■C1-C6 alkyl groups, and

[1046] ■C1-C6 alkoxy groups.

[1047] 59. A compound of formula IIb:

[1048]

[1049] 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 YN As defined according to Example 1, provided that the compound is not selected from:

[1050] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[1051] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,2-tetradeuterium)spiro[2.3]hex-5-yl]-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[1052] (11R)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-12-(4,4,5,6,6-pentadeuterspiro[2.3]hex-5-yl)-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one,

[1053] (11R)-12-(5-deuteronitro[2.3]hex-5-yl)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one, and

[1054] (11R)-6-[2,6-bis(trideuterium)methylphenyl]-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione.

[1055] 60. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Example 59, wherein ring A is selected from C6-C6. 10 Aryl and 5 to 10 heteroaryl compounds.

[1056] 61. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Example 59 or 60, wherein ring A is selected from phenyl, pyridyl, pyrazinyl, and pyrazolyl.

[1057] 62. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of Examples 59 to 61, wherein ring A is phenyl.

[1058] 63. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 59 to 62, wherein W 1 It is N and W 2 It is N.

[1059] 64. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 59 to 63, wherein W 1 It is CH and W 2 It is N.

[1060] 65. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 59 to 64, wherein Z is C(R ZC )2.

[1061] 66. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 59 to 65, wherein two RZC Together they form an oxo group.

[1062] 67. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 59 to 66, wherein each R 3 It is independently selected from C1-C6 alkyl groups.

[1063] 68. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 59 to 67, wherein each R 3 It is a methyl group.

[1064] 69. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 59 to 66, wherein R 3 It does not exist.

[1065] 70. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 59 to 69, wherein R 4 Selected from hydrogen and methyl.

[1066] 71. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 59 to 70, wherein R 4 It is a methyl group.

[1067] 72. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 59 to 71, wherein each R 5 Independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl and C6-C 10 Aryl.

[1068] 73. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 59 to 72, wherein R YN Selected from:

[1069] ■ C3-C, optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[1070] ○Hydroxy group,

[1071] ○Cyano

[1072] ○N(R N )2,

[1073] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1074] ◆Hydroxy group,

[1075] ◆Oxygenation,

[1076] ◆N(R N )2, and

[1077] ◆C6-C 10 Aryl,

[1078] ○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,

[1079] ○C3-C 10 cycloalkyl groups, and

[1080] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[1081] ◆Hydroxy group,

[1082] ◆Oxygenation,

[1083] ◆N(R N )2,

[1084] ◆C1-C6 alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkoxy groups, and

[1085] ◆Optionally selected from 1-3 independent choices C3-C 10 C1-C6 alkoxy groups substituted with cycloalkyl groups,

[1086] ■Optionally substituted with 1 to 3 independently selected groups from the following: 3- to 10-membered heterocyclic groups

[1087] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1088] ◆Oxygenation,

[1089] ◆Hydroxy group,

[1090] ◆N(R N )2,

[1091] ◆Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted with the aryl group, and

[1092] ◆-(O) 0-1 -(C3-C 10 cycloalkyl),

[1093] ○C1-C6 fluoroalkyl,

[1094] ○ C3-C groups optionally substituted with 1-3 independently selected halogen groups 10 cycloalkyl groups, and

[1095] ○3 to 10-membered heterocyclic groups, and

[1096] ■ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[1097] ○ Halogen,

[1098] ○Optionally selected by 1-3 independently chosen from oxo, C1-C6 alkoxy and N(R) N C1-C6 alkyl groups substituted with )2, and

[1099] ○Optionally substituted with 1-3 groups independently selected from C1-C6 alkyl groups (optionally substituted with 1-3 groups selected from oxo, C1-C6 alkoxy and C6-C... 10 (Aromatic groups substituted) 3 to 10-membered heterocyclic groups.

[1100] 74. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 59 to 73, wherein each R L1 Selected independently from:

[1101] ■ Hydrogen,

[1102] ■N(R N )2, the condition is two N(R) N )2 does not combine with the same carbon atom.

[1103] ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1104] ○ Halogen,

[1105] ○hydroxyl group, and

[1106] ○ C3-C substituted with 1-3 independently selected groups selected from halogens and C1-C6 fluoroalkyl groups 10 cycloalkyl groups, and

[1107] ■C3-C 10 Cycloalkyl.

[1108] 75. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 59 to 74, wherein each R N Selected independently from:

[1109] ■ Hydrogen,

[1110] ■ C1-C8 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1111] ○NH2,

[1112] ○NHCOMe,

[1113] ○C1-C6 alkoxy groups,

[1114] ○-(O) 0-1 -(C3-C 10 cycloalkyl),

[1115] ○C6-C 10 Aryl, and

[1116] ○Optionally substituted with 1 to 4 independently selected C1-C6 alkyl groups, 3 to 14 membered heterocyclic groups,

[1117] ■C6-C 10 Aryl, and

[1118] 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:

[1119] ■Cyano

[1120] ■C1-C6 alkyl groups, and

[1121] ■C1-C6 alkoxy groups.

[1122] 76. A compound of formula III:

[1123]

[1124] 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 YN As defined according to Example 1, provided that the compound is not selected from:

[1125] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[1126] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,2-tetradeuterium)spiro[2.3]hex-5-yl]-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[1127] (11R)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-12-(4,4,5,6,6-pentadeuterspiro[2.3]hex-5-yl)-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one,

[1128] (11R)-12-(5-deuteronitro[2.3]hex-5-yl)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one, and

[1129] (11R)-6-[2,6-bis(trideuterium)methylphenyl]-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione.

[1130] 77. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Example 76, wherein W 1 It is N and W 2 It is N.

[1131] 78. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Example 76 or 77, wherein W 1 It is CH and W 2 It is N.

[1132] 79. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 76 to 78, wherein Z is C(R ZC )2.

[1133] 80. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 76 to 79, wherein two R ZC Together they form an oxo group.

[1134] 81. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 76 to 80, wherein R 4 Selected from hydrogen and methyl.

[1135] 82. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 76 to 81, wherein R 4 It is a methyl group.

[1136] 83. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 76 to 82, wherein each R 5 Independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl and C6-C 10 Aryl.

[1137] 84. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 76 to 83, wherein R YN Selected from:

[1138] ■ C3-C, optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[1139] ○Hydroxy group,

[1140] ○Cyano

[1141] ○N(R N )2,

[1142] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1143] ◆Hydroxy group,

[1144] ◆Oxygenation,

[1145] ◆N(R N )2, and

[1146] ◆C6-C 10 Aryl,

[1147] ○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,

[1148] ○C3-C10 cycloalkyl groups, and

[1149] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[1150] ◆Hydroxy group,

[1151] ◆Oxygenation,

[1152] ◆N(R N )2,

[1153] ◆C1-C6 alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkoxy groups, and

[1154] ◆Optionally selected from 1-3 independent choices C3-C 10 C1-C6 alkoxy groups substituted with cycloalkyl groups,

[1155] ■Optionally substituted with 1 to 3 independently selected groups from the following: 3- to 10-membered heterocyclic groups

[1156] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1157] ◆Oxygenation,

[1158] ◆Hydroxy group,

[1159] ◆N(R N )2,

[1160] ◆Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted with the aryl group, and

[1161] ◆-(O) 0-1 -(C3-C 10 cycloalkyl),

[1162] ○C1-C6 fluoroalkyl,

[1163] ○ C3-C groups optionally substituted with 1-3 independently selected halogen groups 10 cycloalkyl groups, and

[1164] ○3 to 10-membered heterocyclic groups, and

[1165] ■ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[1166] ○ Halogen,

[1167] ○Optionally selected by 1-3 independently chosen from oxo, C1-C6 alkoxy and N(R) N C1-C6 alkyl groups substituted with )2, and

[1168] ○Optionally substituted with 1-3 groups independently selected from C1-C6 alkyl groups (optionally substituted with 1-3 groups selected from oxo, C1-C6 alkoxy and C6-C... 10 (Aromatic groups substituted) 3 to 10-membered heterocyclic groups.

[1169] 85. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 76 to 84, wherein each R L1 Selected independently from:

[1170] ■ Hydrogen,

[1171] ■N(R N )2, the condition is two N(R) N )2 does not combine with the same carbon atom.

[1172] ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1173] ○ Halogen,

[1174] ○hydroxyl group, and

[1175] ○ C3-C substituted with 1-3 independently selected groups selected from halogens and C1-C6 fluoroalkyl groups 10 cycloalkyl groups, and

[1176] ■C3-C 10 Cycloalkyl.

[1177] 86. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 76 to 85, wherein each R N Selected independently from:

[1178] ■ Hydrogen,

[1179] ■ C1-C8 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1180] ○NH2,

[1181] ○NHCOMe,

[1182] ○C1-C6 alkoxy groups,

[1183] ○-(O) 0-1 -(C3-C 10 cycloalkyl),

[1184] ○C6-C 10 Aryl, and

[1185] ○Optionally substituted with 1-4 independently selected C1-C6 alkyl groups, and

[1186] ■C6-C 10 Aryl, and

[1187] 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:

[1188] ■Cyano

[1189] ■C1-C6 alkyl groups, and

[1190] ■C1-C6 alkoxy groups.

[1191] 87. A compound of formula IV:

[1192]

[1193] 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 YN As defined according to Example 1, provided that the compound is not selected from:

[1194] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[1195] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,2-tetradeuterium)spiro[2.3]hex-5-yl]-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[1196] (11R)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-12-(4,4,5,6,6-pentadeuterspiro[2.3]hex-5-yl)-9-oxa-2λ 6-Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one,

[1197] (11R)-12-(5-deuteronitro[2.3]hex-5-yl)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one, and

[1198] (11R)-6-[2,6-bis(trideuterium)methylphenyl]-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione.

[1199] 88. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Example 87, wherein Z is C(R ZC )2.

[1200] 89. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Example 87 or 88, wherein two R ZC Together they form an oxo group.

[1201] 90. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 87 to 89, wherein R 4 Selected from hydrogen and methyl.

[1202] 91. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 87 to 90, wherein R 4 It is a methyl group.

[1203] 92. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 87 to 91, wherein each R 5 Independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl and C6-C 10 Aryl.

[1204] 93. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 87 to 92, wherein R YN Selected from:

[1205] ■ C3-C, optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[1206] ○Hydroxy group,

[1207] ○Cyano

[1208] ○N(R N )2,

[1209] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1210] ◆Hydroxy group,

[1211] ◆Oxygenation,

[1212] ◆N(R N )2, and

[1213] ◆C6-C 10 Aryl,

[1214] ○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,

[1215] ○C3-C 10 cycloalkyl groups, and

[1216] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[1217] ◆Hydroxy group,

[1218] ◆Oxygenation,

[1219] ◆N(R N )2,

[1220] ◆C1-C6 alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkoxy groups, and

[1221] ◆Optionally selected from 1-3 independent choices C3-C 10 C1-C6 alkoxy groups substituted with cycloalkyl groups,

[1222] ■Optionally substituted with 1 to 3 independently selected groups from the following: 3- to 10-membered heterocyclic groups

[1223] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1224] ◆Oxygenation,

[1225] ◆Hydroxy group,

[1226] ◆N(R N )2,

[1227] ◆Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted with the aryl group, and

[1228] ◆-(O) 0-1 -(C3-C 10 cycloalkyl),

[1229] ○C1-C6 fluoroalkyl,

[1230] ○ C3-C groups optionally substituted with 1-3 independently selected halogen groups 10 cycloalkyl groups, and

[1231] ○3 to 10-membered heterocyclic groups, and

[1232] ■ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[1233] ○ Halogen,

[1234] ○Optionally selected by 1-3 independently chosen from oxo, C1-C6 alkoxy and N(R) N C1-C6 alkyl groups substituted with )2, and

[1235] ○Optionally substituted with 1-3 groups independently selected from C1-C6 alkyl groups (optionally substituted with 1-3 groups selected from oxo, C1-C6 alkoxy and C6-C... 10 (Aromatic groups substituted) 3 to 10-membered heterocyclic groups.

[1236] 94. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 87 to 93, wherein each R L1 Selected independently from:

[1237] ■ Hydrogen,

[1238] ■N(R N )2, the condition is two N(R) N )2 does not combine with the same carbon atom.

[1239] ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1240] ○ Halogen,

[1241] ○hydroxyl group, and

[1242] ○ C3-C substituted with 1-3 independently selected groups selected from halogens and C1-C6 fluoroalkyl groups 10 cycloalkyl groups, and

[1243] ■C3-C 10 Cycloalkyl.

[1244] 95. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 87 to 94, wherein each R N Selected independently from:

[1245] ■ Hydrogen,

[1246] ■ C1-C8 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1247] ○NH2,

[1248] ○NHCOMe,

[1249] ○C1-C6 alkoxy groups,

[1250] ○-(O) 0-1 -(C3-C 10 cycloalkyl),

[1251] ○C6-C 10 Aryl, and

[1252] ○Optionally substituted with 1 to 4 independently selected C1-C6 alkyl groups, 3 to 14 membered heterocyclic groups,

[1253] ■C6-C 10 Aryl, and

[1254] 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:

[1255] ■Cyano

[1256] ■C1-C6 alkyl groups, and

[1257] ■C1-C6 alkoxy groups.

[1258] 96. A compound of formula V:

[1259]

[1260] 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 R5 and R YN As defined according to Example 1, provided that the compound is not selected from:

[1261] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[1262] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,2-tetradeuterium)spiro[2.3]hex-5-yl]-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[1263] (11R)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-12-(4,4,5,6,6-pentadeuterspiro[2.3]hex-5-yl)-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one,

[1264] (11R)-12-(5-deuteronitro[2.3]hex-5-yl)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one, and

[1265] (11R)-6-[2,6-bis(trideuterium)methylphenyl]-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione.

[1266] 97. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Example 96, wherein Z is C(RZC )2.

[1267] 98. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Example 96 or 97, wherein two R... ZC Together they form an oxo group.

[1268] 99. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 96 to 98, wherein R 4 Selected from hydrogen and methyl.

[1269] 100. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 96 to 99, wherein R 4 It is a methyl group.

[1270] 101. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 96 to 100, wherein each R 5 Independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl and C6-C 10 Aryl.

[1271] 102. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 96 to 101, wherein R YN Selected from:

[1272] ■ C3-C, optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[1273] ○Hydroxy group,

[1274] ○Cyano

[1275] ○N(R N )2,

[1276] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1277] ◆Hydroxy group,

[1278] ◆Oxygenation,

[1279] ◆N(R N )2, and

[1280] ◆C6-C 10 Aryl,

[1281] ○Optionally selected by 1-3 independent elements chosen from halogen, oxidative, C6-C 10 Aryl and N(R) NThe C1-C6 alkoxy group substituted with )2,

[1282] ○C3-C 10 cycloalkyl,

[1283] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[1284] ◆Hydroxy group,

[1285] ◆Oxygenation,

[1286] ◆N(R N )2,

[1287] ◆C1-C6 alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkoxy groups, and

[1288] ◆Optionally selected from 1-3 independent choices C3-C 10 C1-C6 alkoxy groups substituted with cycloalkyl groups,

[1289] ■Optionally substituted with 1 to 3 independently selected groups from the following: 3- to 10-membered heterocyclic groups

[1290] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1291] ◆Oxygenation,

[1292] ◆Hydroxy group,

[1293] ◆N(R N )2,

[1294] ◆Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted with the aryl group, and

[1295] ◆-(O) 0-1 -(C3-C 10 cycloalkyl),

[1296] ○C1-C6 fluoroalkyl,

[1297] ○ C3-C groups optionally substituted with 1-3 independently selected halogen groups 10 cycloalkyl groups, and

[1298] ○3 to 10-membered heterocyclic groups, and

[1299] ■ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[1300] ○ Halogen,

[1301] ○Optionally selected by 1-3 independently chosen from oxo, C1-C6 alkoxy and N(R) N C1-C6 alkyl groups substituted with )2, and

[1302] ○Optionally substituted with 1-3 groups independently selected from C1-C6 alkyl groups (optionally substituted with 1-3 groups selected from oxo, C1-C6 alkoxy and C6-C... 10 (Aromatic groups substituted) 3 to 10-membered heterocyclic groups.

[1303] 103. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 96 to 102, wherein each R L1 Selected independently from:

[1304] ■ Hydrogen,

[1305] ■N(R N )2, the condition is two N(R) N )2 does not combine with the same carbon atom.

[1306] ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1307] ○ Halogen,

[1308] ○hydroxyl group, and

[1309] ○ C3-C substituted with 1-3 independently selected groups selected from halogens and C1-C6 fluoroalkyl groups 10 cycloalkyl groups, and

[1310] ■C3-C 10 Cycloalkyl.

[1311] 104. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 96 to 103, wherein each R N Selected independently from:

[1312] ■ Hydrogen,

[1313] ■ C1-C8 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1314] ○NH2,

[1315] ○NHCOMe,

[1316] ○C1-C6 alkoxy groups,

[1317] ○-(O) 0-1 -(C3-C 10 cycloalkyl),

[1318] ○C6-C 10 Aryl, and

[1319] ○Optionally substituted with 1-4 independently selected C1-C6 alkyl groups, and

[1320] ■C6-C 10 Aryl,

[1321] 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:

[1322] ■Cyano

[1323] ■C1-C6 alkyl groups, and

[1324] ■C1-C6 alkoxy groups.

[1325] 105. A compound of formula VI:

[1326]

[1327] 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 YN As defined according to Example 1, provided that the compound is not selected from:

[1328] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[1329] (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,2-tetradeuterium)spiro[2.3]hex-5-yl]-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione,

[1330] (11R)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-12-(4,4,5,6,6-pentadeuterspiro[2.3]hex-5-yl)-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one,

[1331] (11R)-12-(5-deuteronitro[2.3]hex-5-yl)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(18),4,6,8(19),14,16-hexane-13-one, and

[1332] (11R)-6-[2,6-bis(trideuterium)methylphenyl]-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclic[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione.

[1333] 106. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Example 105, wherein R 4 Selected from hydrogen and methyl.

[1334] 107. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Example 105 or 106, wherein R 4 It is a methyl group.

[1335] 108. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 105 to 107, wherein each R 5 Independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl and C6-C 10 Aryl.

[1336] 109. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 105 to 108, wherein R YN Selected from:

[1337] ■ C3-C, optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[1338] ○Hydroxy group,

[1339] ○Cyano

[1340] ○N(R N )2,

[1341] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1342] ◆Hydroxy group,

[1343] ◆Oxygenation,

[1344] ◆N(R N )2, and

[1345] ◆C6-C 10 Aryl,

[1346] ○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,

[1347] ○C3-C 10 cycloalkyl,

[1348] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[1349] ◆Hydroxy group,

[1350] ◆Oxygenation,

[1351] ◆N(R N )2,

[1352] ◆C1-C6 alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkoxy groups, and

[1353] ◆Optionally selected from 1-3 independent choices C3-C 10 C1-C6 alkoxy groups substituted with cycloalkyl groups,

[1354] ■Optionally substituted with 1 to 3 independently selected groups from the following: 3- to 10-membered heterocyclic groups

[1355] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1356] ◆Oxygenation,

[1357] ◆Hydroxy group,

[1358] ◆N(R N )2,

[1359] ◆Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted with the aryl group, and

[1360] ◆-(O) 0-1 -(C3-C 10 cycloalkyl),

[1361] ○C1-C6 fluoroalkyl,

[1362] ○ C3-C groups optionally substituted with 1-3 independently selected halogen groups 10 cycloalkyl groups, and

[1363] ○3 to 10-membered heterocyclic groups, and

[1364] ■ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[1365] ○ Halogen,

[1366] ○Optionally selected by 1-3 independently chosen from oxo, C1-C6 alkoxy and N(R) N C1-C6 alkyl groups substituted with )2, and

[1367] ○Optionally substituted with 1-3 groups independently selected from C1-C6 alkyl groups (optionally substituted with 1-3 groups selected from oxo, C1-C6 alkoxy and C6-C... 10 (Aromatic groups substituted) 3 to 10-membered heterocyclic groups.

[1368] 110. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 105 to 109, wherein each R L1 Selected independently from:

[1369] ■ Hydrogen,

[1370] ■N(R N )2, the condition is two N(R) N )2 does not combine with the same carbon atom.

[1371] ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1372] ○ Halogen,

[1373] ○hydroxyl group, and

[1374] ○ C3-C substituted with 1-3 independently selected groups selected from halogens and C1-C6 fluoroalkyl groups 10 cycloalkyl groups, and

[1375] ■C3-C 10 Cycloalkyl.

[1376] 111. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 105 to 110, wherein each R N Selected independently from:

[1377] ■ Hydrogen,

[1378] ■ C1-C8 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1379] ○NH2,

[1380] ○NHCOMe,

[1381] ○C1-C6 alkoxy groups,

[1382] ○-(O) 0-1 -(C3-C 10 cycloalkyl),

[1383] ○C6-C 10 Aryl, and

[1384] ○Optionally substituted with 1-4 independently selected C1-C6 alkyl groups, and

[1385] ■C6-C 10 Aryl,

[1386] 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:

[1387] ■Cyano

[1388] ■C1-C6 alkyl groups, and

[1389] ■C1-C6 alkoxy groups.

[1390] 112. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Examples 1 to 111, selected from compounds of formulas I, Ia, IIa, IIb, III, IV, V and VI, their tautomers, deuterated derivatives of these compounds and tautomers and pharmaceutically acceptable salts of any of the foregoing.

[1391] 113. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Examples 1 to 112, selected from compounds 1-474 (Tables 8, 9, 10, 11), compounds 475-506 (Table 7), compounds 507 and 508 (Table 12), their tautomers, deuterated derivatives of these compounds and tautomers and pharmaceutically acceptable salts of any of the foregoing.

[1392] 114. 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 113.

[1393] 115. The pharmaceutical composition according to Example 114, further comprising one or more additional therapeutic agents.

[1394] 116. The pharmaceutical composition according to Example 115, wherein one or more additional therapeutic agents are selected from mucolytics, bronchodilators, antibiotics, anti-infectives, and anti-inflammatory agents.

[1395] 117. The pharmaceutical composition according to Example 115, 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.

[1396] 118. The pharmaceutical composition according to Example 115, wherein the one or more additional therapeutic agents are one or more CFTR modulators.

[1397] 119. The pharmaceutical composition according to Example 118, wherein the one or more CFTR modifiers are selected from CFTR enhancers.

[1398] 120. The pharmaceutical composition according to Example 118, wherein the one or more CFTR modifiers are selected from CFTR correctors.

[1399] 121. The pharmaceutical composition according to Example 118, wherein the one or more CFTR modulators comprise at least one CFTR enhancer and at least one CFTR corrector.

[1400] 122. The pharmaceutical composition according to any one of Examples 118 to 121, wherein the one or more CFTR modifiers are selected from: (a) tezacotto, rumacotto and deuterated derivatives thereof and pharmaceutically acceptable salts thereof; and (b) ivacato, deuteric acid, and deuterated derivatives thereof and pharmaceutically acceptable salts thereof.

[1401] 123. The pharmaceutical composition according to any one of Examples 118 to 121, wherein the one or more CFTR modifiers are selected from: (a) tizacator, rumacator and deuterated derivatives thereof and pharmaceutically acceptable salts thereof; or (b) (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.

[1402] 124. The pharmaceutical composition according to any one of Examples 118 to 121, wherein the composition comprises tezacotto and ivacato.

[1403] 125. The pharmaceutical composition according to any one of Examples 118 to 121, wherein the composition comprises tezacotto and deuteric acid tezacotto.

[1404] 126. The pharmaceutical composition according to any one of Examples 118 to 121, wherein the composition comprises tezacotto 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.

[1405] 127. The pharmaceutical composition according to any one of Examples 118 to 121, wherein the composition comprises rumacalto and ivacalto.

[1406] 128. The pharmaceutical composition according to any one of Examples 118 to 121, wherein the composition comprises rumacator and deuteric acid.

[1407] 129. The pharmaceutical composition according to any one of Examples 118 to 121, wherein the composition comprises rumacator 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.

[1408] 130. 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 113, or a pharmaceutical composition according to any one of Examples 114 to 129.

[1409] 131. The method according to Example 130, further comprising 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 113 or the pharmaceutical composition according to Example 114.

[1410] 132. The method according to Example 131, wherein the one or more additional therapeutic agents are selected from CFTR modulators.

[1411] 133. The method according to Example 132, wherein the one or more CFTR modifiers are selected from CFTR synergists.

[1412] 134. The method according to Example 132, wherein the one or more CFTR modifiers are selected from CFTR correctors.

[1413] 135. The method according to Example 132, wherein the one or more CFTR modifiers comprises both a CFTR enhancer and an additional CFTR corrector.

[1414] 136. The method according to Examples 133 and 135, 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.

[1415] 137. The method according to Example 134 or Example 135, wherein the CFTR corrector is selected from tezacotto, rumacotto, and deuterated derivatives and their pharmaceutically acceptable salts.

[1416] 138. The method according to Example 131, wherein the one or more additional therapeutic agents are compounds selected from tezacotto, ivacato, deuteric acid, rumacotto, and pharmaceutically acceptable salts thereof.

[1417] 139. The method according to Example 131, wherein the one or more additional therapeutic agents are compounds 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 pharmaceutically acceptable salts thereof.

[1418] 140. The method according to Example 131, wherein the one or more additional therapeutic agents are tezacator and ivacator.

[1419] 141. The method according to Example 131, wherein the one or more additional therapeutic agents are tezaccato and deuteric acid.

[1420] 142. The method according to Example 131, wherein one or more additional therapeutic agents are tezacotto 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.

[1421] 143. The method according to Example 131, wherein the one or more additional therapeutic agents are rumacapto and ivacapto.

[1422] 144. The method according to Example 131, wherein the one or more additional therapeutic agents are rumacapto and deuteric acid.

[1423] 145. The method according to Example 131, wherein one or more additional therapeutic agents are rumacator 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.

[1424] 146. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Examples 1 to 113, or the pharmaceutical composition of any one of Examples 114 to 129, for the treatment of cystic fibrosis.

[1425] 147. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Examples 1 to 113, or the pharmaceutical composition of any one of Examples 114 to 129, used to manufacture a medicament for treating cystic fibrosis.

[1426] 148. A compound selected from compounds 1-508, its tautomers, deuterated derivatives of these compounds and tautomers, and a pharmaceutically acceptable salt of any of the foregoing.

[1427] 149. A deuterated derivative of a compound selected from compounds 1-508.

[1428] 150. A pharmaceutically acceptable salt of a compound selected from compounds 1-508.

[1429] 151. A compound selected from compounds 1-508.

[1430] 152. A pharmaceutical composition comprising a compound selected from compounds 1-508, its tautomers, deuterated derivatives of these compounds and tautomers, a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier.

[1431] 153. A pharmaceutical composition comprising a deuterated derivative of a compound selected from compounds 1-508 and a pharmaceutically acceptable carrier.

[1432] 154. A pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound selected from compounds 1-508 and a pharmaceutically acceptable carrier.

[1433] 155. A pharmaceutical composition comprising a compound selected from compounds 1-508 and a pharmaceutically acceptable carrier.

[1434] 156. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-508, 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.

[1435] 157. A pharmaceutical composition comprising: (a) a deuterated derivative of a compound selected from compounds 1-508; (b) a CFTR enhancer; and (c) a pharmaceutically acceptable carrier.

[1436] 158. A medicament comprising: (a) a pharmaceutically acceptable salt of a compound selected from compounds 1-508; (b) a CFTR enhancer; and (c) a pharmaceutically acceptable carrier.

[1437] 159. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-508; (b) a CFTR enhancer; and (c) a pharmaceutically acceptable carrier.

[1438] 160. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-508, 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.

[1439] 161. A pharmaceutical composition comprising: (a) a deuterated derivative of a compound selected from compounds 1-508; (b) a further CFTR corrector; and (c) a pharmaceutically acceptable carrier.

[1440] 162. A pharmaceutical composition comprising: (a) a pharmaceutically acceptable salt of a compound selected from compounds 1-508; (b) a further CFTR corrector; and (c) a pharmaceutically acceptable carrier.

[1441] 163. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-508; (b) a further CFTR corrector; and (c) a pharmaceutically acceptable carrier.

[1442] 164. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-508, 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.

[1443] 165. A pharmaceutical composition comprising: (a) a deuterated derivative of a compound selected from compounds 1-508; (b) a further CFTR corrector; (c) a CRTR enhancer; and (d) a pharmaceutically acceptable carrier.

[1444] 166. A pharmaceutical composition comprising: (a) a pharmaceutically acceptable salt of a compound selected from compounds 1-508; (b) a further CFTR corrector; (c) a CRTR enhancer; and (d) a pharmaceutically acceptable carrier.

[1445] 167. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-508; (b) a further CFTR corrector; (c) a CRTR enhancer; and (d) a pharmaceutically acceptable carrier.

[1446] 168. A method for treating cystic fibrosis using a compound selected from compounds 1-508, its tautomers, deuterated derivatives of these compounds and tautomers, and a pharmaceutically acceptable salt of any of the foregoing.

[1447] 169. A method for treating cystic fibrosis using a deuterated derivative of a compound selected from compounds 1-508.

[1448] 170. A method for treating cystic fibrosis with a pharmaceutically acceptable salt of a compound selected from compounds 1-508.

[1449] 171. A method for treating cystic fibrosis with a compound selected from compounds 1-508.

[1450] 172. A method for treating cystic fibrosis using a pharmaceutical composition comprising a compound selected from compounds 1-508, its tautomers, deuterated derivatives of these compounds and tautomers, a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier.

[1451] 173. A method for treating cystic fibrosis using a pharmaceutical composition comprising a deuterated derivative of a compound selected from compounds 1-508 and a pharmaceutically acceptable carrier.

[1452] 174. A method for treating cystic fibrosis using a pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound selected from compounds 1-508 and a pharmaceutically acceptable carrier.

[1453] 175. A method for treating cystic fibrosis using a pharmaceutical composition comprising a compound selected from compounds 1-508 and a pharmaceutically acceptable carrier.

[1454] 176. A method for treating cystic fibrosis with a pharmaceutical composition comprising: (a) a compound selected from compounds 1-508, 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.

[1455] 177. A method for treating cystic fibrosis with a medicament comprising: (a) a deuterated derivative of a compound selected from compounds 1-508; (b) a CFTR enhancer; and (c) a pharmaceutically acceptable carrier.

[1456] 178. A method for treating cystic fibrosis with a pharmaceutical composition comprising: (a) a pharmaceutically acceptable salt of a compound selected from compounds 1-508; (b) a CFTR enhancer; and (c) a pharmaceutically acceptable carrier.

[1457] 179. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-508; (b) a CFTR enhancer; and (c) a pharmaceutically acceptable carrier.

[1458] 180. A method of treating cystic fibrosis with a pharmaceutical composition comprising: (a) a compound selected from compounds 1-508, 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.

[1459] 181. A method for treating cystic fibrosis with a pharmaceutical composition comprising: (a) a deuterated derivative of a compound selected from compounds 1-508; (b) a further CFTR corrector; and (c) a pharmaceutically acceptable carrier.

[1460] 182. A method of treating cystic fibrosis with a pharmaceutical composition comprising: (a) a pharmaceutically acceptable salt of a compound selected from compounds 1-508; (b) a further CFTR corrector; and (c) a pharmaceutically acceptable carrier.

[1461] 183. A method of treating cystic fibrosis with a pharmaceutical composition comprising: (a) a compound selected from compounds 1-508; (b) a further CFTR corrector; and (c) a pharmaceutically acceptable carrier.

[1462] 184. A method of treating cystic fibrosis with a pharmaceutical composition comprising: (a) a compound selected from compounds 1-508, 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.

[1463] 185. A method of treating cystic fibrosis with a pharmaceutical composition comprising: (a) a deuterated derivative of a compound selected from compounds 1-508; (b) a further CFTR corrector; (c) a CRTR enhancer; and (d) a pharmaceutically acceptable carrier.

[1464] 186. A method of treating cystic fibrosis with a pharmaceutical composition comprising: (a) a pharmaceutically acceptable salt of a compound selected from compounds 1-508; (b) a further CFTR corrector; (c) a CRTR enhancer; and (d) a pharmaceutically acceptable carrier.

[1465] 187. A method of treating cystic fibrosis with a pharmaceutical composition comprising: (a) a compound selected from compounds 1-508; (b) a further CFTR corrector; (c) a CRTR enhancer; and (d) a pharmaceutically acceptable carrier.

[1466] Example

[1467] I. List of Abbreviations

[1468] ACN: Acetonitrile

[1469] Boc anhydride ((Boc)₂O): ditert-butyl dicarbonate

[1470] CDCl3: Chloroform-d

[1471] CDI: Carbodiimidazole

[1472] CDMT: 2-Chloro-4,6-dimethoxy-1,3,5-triazine

[1473] CH2Cl2: Dichloromethane

[1474] CH3CN: Acetonitrile

[1475] COMU: (1-Cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholino-carbomony hexafluorophosphate

[1476] Cmpd: compound

[1477] DABCO: 1,4-diazabicyclo[2.2.2]octane

[1478] DBU: 1,8-diazabicyclo(5.4.0)undec-7-ene

[1479] DCE: 1,2-Dichloroethane

[1480] DCM: Dichloromethane

[1481] DI: Deionized

[1482] DIAD: Diisopropyl azodicarbonate

[1483] DIEA (DIPEA, DiPEA): N,N-diisopropylethylamine

[1484] DMA: N,N-dimethylacetamide

[1485] DMAP: 4-Dimethylaminopyridine

[1486] DMF: N,N-dimethylformamide

[1487] DMSO: Dimethyl sulfoxide

[1488] DMP: Des Martin periodine

[1489] EA: Ethyl acetate

[1490] EDC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[1491] ELSD: Evaporative Light Scattering Detector

[1492] Diethyl ether: Diethyl ether

[1493] ESI-MS: Electrospray ionization mass spectrometry

[1494] EtOAc: Ethyl acetate

[1495] EtOH: Ethanol

[1496] GC: Gas Chromatography

[1497] Grubbs' first-generation catalyst: Dichloro(benzyl)bis(tricyclohexylphosphine)ruthenium(II)

[1498] Grubbs' second-generation catalyst: [1,3-bis(2,4,6-trimethylphenyl)imidazolidine-2-ylidene]-dichloro-[(2-isopropoxyphenyl)methylene]ruthenium

[1499] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-3-hexafluorophosphate oxide

[1500] HPLC: High Performance Liquid Chromatography

[1501] 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-imidazolylylene](2-isopropoxyphenylmethylene)ruthenium(II)

[1502] IPA: Isopropyl alcohol

[1503] KHSO4: Potassium hydrogen sulfate

[1504] LC: Liquid Chromatography

[1505] LCMS: Liquid Chromatography-Mass Spectrometry

[1506] LCMS Met.: LCMS Methodology

[1507] LCMS Rt: LCMS retention time

[1508] LDA: Lithium diisopropylamino

[1509] LiOH: Lithium hydroxide

[1510] MeCN: Acetonitrile

[1511] MeOH: Methanol

[1512] MTBE: Methyl tert-butyl ether

[1513] MeTHF or 2-MeTHF: 2-methyltetrahydrofuran

[1514] MgSO4: Magnesium sulfate

[1515] NaHCO3: Sodium bicarbonate

[1516] NaOH: Sodium hydroxide

[1517] NMP: N-methyl-2-pyrrolidone

[1518] NMM: N-methylmorpholine

[1519] Pd2(dba)3:tris(dibenzylacetone)dipalladium(0)

[1520] Pd / C: Palladium / Carbon

[1521] Pd(dppf)Cl2:[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloro

[1522] Pd(OAc)2: Palladium(II) acetate

[1523] PTFE: Polytetrafluoroethylene

[1524] rt, RT: room temperature

[1525] RuPhos: 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl

[1526] SFC: Supercritical Fluid Chromatography

[1527] TBAI: Tetrabutylammonium iodide

[1528] TEA: Triethylamine

[1529] TFA: Trifluoroacetic acid

[1530] THF: Tetrahydrofuran

[1531] TLC: Thin-layer chromatography

[1532] TMS: Trimethylsilyl

[1533] TMSCl: Trimethylchlorosilane

[1534] T3P: Propanephosphonic anhydride

[1535] UPLC: Ultra-high performance liquid chromatography

[1536] XANTPHOS: 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene

[1537] XPhos: 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

[1538] II. General Method

[1539] Unless otherwise stated, reagents and starting materials should be obtained from commercial sources and used without purification.

[1540] 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.

[1541] 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.

[1542] 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.

[1543] 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 256 k 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 128 k acquisition points. The FID was zero-filled to 256 k points, and a 0.3 Hz line broadening was applied before the Fourier transform.

[1544] 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).

[1545] 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.

[1546] III. General UPLC / HPLC analytical methods

[1547] 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.

[1548] LC Method D: Acquity UPLC BEH C manufactured by Waters 18 The 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.

[1549] 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.

[1550] 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.

[1551] LC method K: Kinetex Polar C 18 3.0×50mm 2.6μm, 3 minutes, 5%-95% ACN / H2O (0.1% formic acid) 1.2 mL / min.

[1552] LC Method Q: 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 30% to 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.

[1553] 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).

[1554] 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).

[1555] 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.

[1556] LC Method V: Acquity UPLC BEH C manufactured by Waters 18 The column (50 × 2.1 mm, 1.7 μm particles) (pn: 186002350) and a dual gradient were used, running from 1% to 30% mobile phase B over 2.9 minutes. Mobile phase A = H₂O (0.05% CF₃CO₂H). Mobile phase B = CH₃CN (0.035% CF₃CO₂H). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, and column temperature = 60 °C.

[1557] 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 in 100% B for 0.5 min, equilibrate to 5% B over 1.5 min.

[1558] LC Method X: UPLC Luna C 18 (2) 50×3mm 3μm. Run: 2.5 min. Mobile phase: Initial 95% H2O 0.1% FA / 5% MeCN 0.1% FA, linear gradient to 95% MeCN 0.1% FA within 1.3 min, hold for 1.2 min at 95% CH3CN 0.1% FA, T: 45°C, flow rate: 1.5 mL / min

[1559] LC method Y: UPLC SunFire C 18 75×4.6mm 3.5μm, run time: 6 minutes. Mobile phase conditions: initial 95% H₂O + 0.1% FA / 5% CH₃CN + 0.1% FA, linear gradient to 95% CH₃CN for 4 minutes, hold at 95% CH₃CN for 2 minutes. T: 45℃, flow rate: 1.5 mL / min

[1560] LC Method 1A: A Waters-manufactured Viridis BEH 2-ethylpyridine column (150 × 2.1 mm, 3.5 μm particles) (pn: 186006655) was used with a dual-gradient reversed-phase UPC2 column, running from 5% to 80% mobile phase B over 4.5 min. Mobile phase A = CO2. Mobile phase B = MeOH (20 mM NH3). Variable flow rate = 1.30–0.40 mL / min to maintain constant pressure, injection volume = 2.0 μL, and column temperature = 55 °C.

[1561] IV. Synthesis of Common Intermediates

[1562] Example A: Preparation of 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid

[1563]

[1564] Step 1: N-tert-Butoxycarbonyl-N-(4,6-dichloropyrimidin-2-yl)carbamate tert-butyl ester

[1565]

[1566] 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-butoxycarbonyl-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).

[1567] Step 2: N-tert-butoxycarbonyl-N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]carbamate tert-butyl ester.

[1568]

[1569] 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), (2,6-dimethylphenyl)boronic acid (approx. 36.24 g, 241.6 mmol), and Cs₂CO₃ (approx. 196.8 g, 604.0 mmol) in DME (704 mL) and water (176 mL), Pd(dppf)Cl₂ (approx. 8.839 g, 12.08 mmol) was added, and the mixture was vigorously stirred under nitrogen at 80 °C (reflux) for 1 hour (no SM remaining). 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).

[1570] Step 3: 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (hydrochloride)

[1571]

[1572] 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 value 233.072, experimental value 234.1 (M+1). + Retention time: 2.1 minutes (LC method C).

[1573] Step 4: 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine

[1574]

[1575] 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).

[1576] Step 5: 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid

[1577]

[1578] 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).

[1579] Example B: Preparation of 3-[[4-[(2R)-2-(tert-butoxycarbonylamino)-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid

[1580]

[1581] Step 1: 3-[[4-[(2R)-2-(tert-Butoxycarbonylamino)-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid

[1582]

[1583] Sodium tert-butoxide (15.276 g, 158.95 mmol) was added to a stirred solution of (2R)-2-amino-4-methyl-pentane-1-ol (12.419 g, 105.97 mmol) in anhydrous THF (200 mL) at room temperature and under nitrogen atmosphere. The reaction mixture was stirred for 10 min, and 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (22.14 g, 52.983 mmol) was added. The reaction mixture was placed in a water bath preheated to 60 °C and stirred for 20 min. After cooling to room temperature, di-tert-butyl dicarbonate (69.381 g, 317.90 mmol) was added, and the reaction mixture was stirred for 3 h. The reaction was quenched with a saturated aqueous solution of ammonium chloride (150 mL). Volatile substances were removed under vacuum, and the aqueous layer was acidified with a 10% aqueous solution of citric acid to a pH of approximately 3. The product was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, and concentrated to a residual volume of approximately 250 mL. The product was precipitated in excess hexane (750 mL) and collected by vacuum filtration. The resulting white solid was further purified by silica gel chromatography using a gradient of hexane (0.15% acetate buffer) to 0–40% acetone (0.15% acetate buffer) to give 3-[[4-[(2R)-2-(tert-butoxycarbonylamino)-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (20.73 g, 61%) as a white solid. ESI-MS calculated m / z 598.2461, experimental 599.4 (M+1). + Retention time: 5.85 minutes (LC method S).

[1584] Step 2: 3-[[4-[(2R)-2-amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (hydrochloride).

[1585]

[1586] HCl (4M solution in 87 mL of 1,4-dioxane, 346.24 mmol) was added to a stirred solution of 3-[[4-[(2R)-2-(tert-butoxycarbonylamino)-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (20.73 g, 34.624 mmol) in DCM (200 mL) at room temperature. The reaction mixture was stirred for 2 hours. The volatiles were removed under vacuum and the resulting solid was ground with diethyl ether (150 mL). After the volatiles were removed, the product was dried under vacuum to give 3-[[4-[(2R)-2-amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (hydrochloride) (19.68 g, 100%) as a white solid. 1 ¹H NMR (250MHz, DMSO-d⁶) δ 8.56–8.27 (m, 4H), 8.14 (t, J = 6.8 Hz, 2H), 7.70 (t, J = 7.8 Hz, 1H), 7.34–7.18 (m, 1H), 7.17–7.02 (m, 2H), 6.31 (s, 1H), 4.42–4.23 (m, 1H), 4.23–4.06 (m, 1H), 3.5–3.4 (m, 1H, overlapping with water), 2.01 (s, 6H), 1.82–1.31 (m, 3H), 1.02–0.78 (m, 6H). ESI-MS m / z calculated value 498.1937, experimental value 499.3 (M+1). + Retention time: 1.63 minutes (LC method T).

[1587] Example C: Preparation of 3-[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid

[1588]

[1589] Step 1: (2R)-2-amino-4,4-dimethyl-pentan-1-ol

[1590]

[1591] Borane-THF (1M, 260.0 mmol) was added dropwise to a solution of (2R)-2-amino-4,4-dimethyl-valeric acid (15 g, 103.3 mmol) in THF (150 mL) at 0 °C, maintaining the reaction temperature <10 °C. The addition time was approximately 30 minutes. The mixture was warmed to ambient temperature and stirred for 22 hours. The reaction was quenched by the slow addition of methanol (80 mL, 1.975 mol) and the solvent was removed under vacuum. The residue was co-evaporated three times with methanol (200 mL, 4.937 mol). The crude residue was diluted with HCl (1M, 200 mL, 200.0 mmol) and washed with 200 mL of MTBE. The aqueous phase was evaporated to remove residual organic solvent. The water was further removed under vacuum to give an off-white solid. The solid was further dried using an acetonitrile azeotrope. The solid was slurried in 200 mL of ACN and the precipitate was collected using M glass frit. The solid was air-dried for 1 hour and then dried in a vacuum at 45°C for 20 hours to obtain (2R)-2-amino-4,4-dimethyl-pentane-1-ol (hydrochloride) (14.73 g, 85%). 1 ¹H NMR (400MHz, DMSO-d⁶) δ 7.80 (s, 3H), 5.36 (t, J = 5.1Hz, 1H), 3.59 (dt, J = 11.7, 4.1Hz, 1H), 3.42–3.34 (m, 1H), 3.10 (dq, J = 7.7, 3.8Hz, 1H), 1.46 (dd, J = 14.5, 7.1Hz, 1H), 1.33 (dd, J = 14.5, 3.5Hz, 1H), 0.91 (s, 9H). ESI-MS m / z calculated value 131.13101, experimental value 132.1 (M+1). + Retention time: 0.51 minutes (LC method A).

[1592] Step 2: 3-[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid

[1593]

[1594] 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (20 g, 47.862 mmol) was suspended in a mixture of 2-methyltetrahydrofuran (80 mL) and DMF (20 mL), and the solution was cooled to -5 °C. Sodium tert-butoxide (23 g, 239.33 mmol) was then dissolved in 2-methyltetrahydrofuran (100 mL), cooled to 5 °C, and added over 10 minutes, followed by (2R)-2-amino-4,4-dimethyl-pentane-1-ol (hydrochloride) (8.02 g, 47.830 mmol). The reaction was then heated to 10 °C and stirred for 4 hours. The reaction was then cooled to 0 °C and quenched by adding aqueous hydrochloric acid (2 M, 200 mL) over 10 minutes. The phases were separated, and the aqueous phase was extracted with 2-methyltetrahydrofuran (200 mL). The organic phases were combined and washed with an aqueous sodium chloride solution (15% w / w, 2 × 200 mL), dried over sodium sulfate (60 g), filtered, and evaporated to dryness. The solid was then ground with ethyl acetate (200 mL) for 16 hours, filtered, washed with ethyl acetate, and dried in a vacuum oven at 50 °C for 20 hours to give 3-[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (hydrochloride) (22.29 g, 80%). 1 H NMR (400MHz, DMSO-d6) δ13.26(br.s.,2H),8.45(t,J=1.6Hz,1H),8.28-8.06(m,5H),7.69(t,J=7.8Hz,1H),7.31-7.21(m,1H),7.13(d,J=7.6Hz,2H) ,6.29(br.s.,1H),4.30(dd,J=11.7,2.7Hz,1H),4.10(dd,J=11.5,7.1Hz, 1H),3.56(br.s.,1H),2.13-1.90(s,6H),1.62-1.47(m,2H),0.94(s,9H). ESI-MS calculated m / z value: 512.20935; experimental value: 513.0 (M+1) + Retention time: 2.334 minutes; LC method U.

[1595] Example D: Preparation of 3-[[4-[(2R)-2-amino-5,5,5-trifluoro-4,4-dimethyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid

[1596]

[1597] Step 1: 4,4,4-Trifluoro-3,3-dimethyl-butanal

[1598]

[1599] To a 1 L three-necked flask, add 4,4,4-trifluoro-3,3-dimethyl-butane-1-ol (8.987 g, 57.555 mmol), DCM (63 mL), water (63 mL), NaBr (544 mg, 5.2870 mmol), sodium bicarbonate (12.32 g, 146.66 mmol), and TEMPO (92 mg, 0.5888 mmol). Cool the mixture in an ice-water bath. At 2.5–4.4 °C, add dropwise NaOCl aqueous solution (47 mL, 1.31 M, 61.570 mmol) over 2 hours. After addition, stir the mixture for 10 minutes. Separate the two layers. Extract the aqueous phase with DCM (2 × 15 mL). Dry the combined organic layers with sodium sulfate and filter to give 113.7 g (approximately 80 mL) of crude product in DCM, which was used directly in the next step. 1 H NMR (300MHz, CDCl3) δ9.82-9.78 (m, 1H), 2.54 (d, J = 2.6Hz, 2H), 1.28 (s, 6H). 19 F NMR (282MHz, CDCl3) δ-79.11 (s, 3F).

[1600] Step 2: (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]valerate and (2S)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]valerate

[1601]

[1602] MeOH (110 mL) was added to a DCM (80 mL) solution of 4,4,4-trifluoro-3,3-dimethyl-butanal (113.7 g, 57.540 mmol) (approximately 7.8% purity). The mixture was cooled in an ice-water bath. (1R)-1-phenylethylamine (8.46 g, 69.814 mmol) was added, followed by acetic acid (4.41 g, 73.436 mmol). The mixture was stirred at 0 °C for 10 minutes, followed by the addition of NaCN (3.56 g, 72.642 mmol). The mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was cooled to 0 °C and a solution of potassium carbonate (4 g) in water (20 mL) was added dropwise, followed by brine (40 mL). The mixture was extracted with DCM (2 × 100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by rapid chromatography (120 g silica gel, heptane / EtOAc 0-30%) to give a 4:1 mixture (14.87 g, 91%) of (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]valerate and (2S)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]valerate as a colorless oil. ESI-MS calculated m / z: 284.15002, experimental: 285.2 (M+1). + Retention time: 3.38 minutes; LC method U.

[1603] Step 3: (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanamide and (2S)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanamide

[1604]

[1605] Sulfuric acid (56.3 g, 551.06 mmol) was added to a 4:1 mixture of (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]valerate and (2S)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]valerate (14.87 g, 52.300 mmol) in DCM (105 mL). The mixture was stirred overnight at room temperature, poured into crude ice (200 g), and neutralized to pH 9 with 28% NH3 in water (100 mL). The mixture was extracted with DCM (500 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by rapid chromatography (330 g silica gel, heptane / EtOAc 20-50%) to give (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanamide (10.77 g, 68%) as a white solid. 1 H NMR (300MHz, CDCl3) δ7.39-7.22(m,5H),6.35(br.s.,1H),5.55(br.s.,1H),3.65(q,J=6.5Hz,1H),2.93(dd,J=7 .6,3.8Hz,1H),1.87(dd,J=15.0,3.8Hz,1H),1.65-1.56(m,2H),1.35(d,J=6.5Hz,3H),1.04(s,3H),1.00(s,3H). 19 F NMR (282MHz, CDCl3) δ -78.77 (s, 3F). Measured by 19F NMR: 99.4% de.

[1606] Step 4: (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]valeric acid

[1607]

[1608] Concentrated HCl (65 mL, 11.8 M, 767.00 mmol) was added to a solution of (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanamide (11.35 g, 37.541 mmol) in HOAc (50 mL), followed by water (50 mL). A white precipitate formed. The mixture was heated at 100 °C for 66 hours. More concentrated HCl (40 mL, 11.8 M, 472.00 mmol) and HOAc (10 mL) were added. The mixture was stirred at 100 °C overnight. More aqueous HCl (20 mL, 6 M, 120.00 mmol) was added. After 7 hours at 100 °C, more aqueous HCl (20 mL, 6 M, 120.00 mmol) was added. The mixture was stirred at 100 °C overnight. The mixture became a clear solution. Add more HCl aqueous solution (20 mL, 6 M, 120.00 mmol). Stir the mixture at 100 °C for 7 hours, then add more HCl aqueous solution (20 mL, 6 M, 120.00 mmol). Stir the mixture at 100 °C overnight. Concentrate the mixture and co-evaporate with water (50 mL). Mix the residue (17 g) with water (25 mL) at 50 °C for 20 minutes, cool in an ice-water bath for 20 minutes, and filter. Mix the crude product with 1,4-dioxane (60 mL). Concentrate the mixture and vacuum dry overnight to give (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]valerate (hydrochloride) (13.04 g, 97%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ10.09(br.s.,1H),7.54-7.31(m,5H),7.29-7.05(m,1H),4.07(q,J=5.9 Hz, 1H), 3.16-2.98 (m, 1H), 2.08-1.83 (m, 2H), 1.49 (d, J = 6.5Hz, 3H), 0.99 (s, 3H), 0.92 (s, 3H). 19 F NMR (282MHz, DMSO-d6) δ -78.28 (s, 3F). ESI-MS m / z calculated value 303.14462, experimental value 304.2 (M+1). + Retention time: 1.98 minutes; LC method U.

[1609] Step 5: (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentane-1-ol

[1610]

[1611] At 35°C, LAH (1M 100mL, 100.00mmol) in THF was added dropwise to a suspension of (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]valeric acid (hydrochloride) (13.04 g, 36.267 mmol) in THF (200 mL). The mixture was stirred at 40°C for 2 hours, cooled to 10°C in an ice-water bath, and diluted with THF (200 mL). A mixture of water (3.8 g) and THF (50 mL) was added dropwise, followed by 25% NaOH aqueous solution (3.8 g) and water (10 g). The resulting mixture was stirred at room temperature for 30 minutes and at 50°C for 1 hour, filtered, and washed with warm THF. The filtrate was concentrated to give 12.02 g of the product (free amine) as a colorless oil. 1 H NMR (300MHz, CDCl3) δ7.37-7.24(m,5H),3.82(q,J=6.5Hz,1H),3.72-3.67(m,1H),3.21(dd,J=10.6,4.7Hz,1H),2.67( quin,J=4.6Hz,1H),1.66(dd,J=14.7,5.9Hz,1H),1.54-1.45(m,1H),1.36(d,J=6.5Hz,3H),1.03(s,3H),0.97(s,3H). 19 F NMR (282 MHz, CDCl3) δ -78.83 (s, 3F). The crude product (12.02 g) was dissolved in diethyl ether (20 mL) and diluted with heptane (80 mL) and cooled in an ice-water bath. HCl (10.5 mL, 4 M, 42.000 mmol) in 1,4-dioxane was added dropwise. The mixture was stirred at room temperature for 30 minutes and filtered to give (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentane-1-ol (hydrochloride) (11.56 g, 98%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ9.57(br.s.,1H),9.25(t,J=9.8Hz,1H),7.80-7.59(m,2H),7.53-7.32(m,3H),5.63(br.s.,1H),4.58(t,J=6.3Hz,1H), 3.81-3.65(m,1H),3.64-3.51(m,1H),2.91-2.74(m,1H),1.98-1.85(m, 1H), 1.85-1.74 (m, 1H), 1.63 (d, J = 6.8Hz, 3H), 0.91 (s, 3H), 0.88 (s, 3H). 19F NMR (282MHz, DMSO-d6) δ -77.71 (s, 3F). ESI-MS m / z calculated value 289.16534, experimental value 290.2 (M+1). + Retention time: 2.08 minutes; LC method U.

[1612] Step 6: (2R)-2-amino-5,5,5-trifluoro-4,4-dimethyl-pentane-1-ol

[1613]

[1614] Add 10% palladium / carbon, 50% wet (5 g, 2.3492 mmol), to a solution of (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentane-1-ol (hydrochloride) (11.56 g, 35.482 mmol) in EtOH (200 mL). Hydrogenate the mixture at room temperature for 9 hours at 40 psi using a Parr shaker. Add more 10% palladium / carbon, 50% wet (1 g, 0.4698 mmol). Shake the mixture at 40 psi for 7 hours. Filter the mixture through diatomaceous earth and wash with EtOH. Concentrate the filtrate. Grind the residue (7.9 g) with a mixture of 2-methyltetrahydrofuran (28 mL) and heptane (200 mL) and stir overnight. The mixture was filtered and the white solid was dried under vacuum to give (2R)-2-amino-5,5,5-trifluoro-4,4-dimethyl-pentane-1-ol (hydrochloride) (7.66 g, 93%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ8.08(br.s.,3H),5.46(t,J=5.0Hz,1H),3.67-3.52(m,1H),3.43(dt,J=11 .7,5.8Hz,1H),3.29-3.16(m,1H),1.88-1.73(m,1H),1.72-1.58(m,1H),1.15(s,3H),1.10(s,3H). 19 F NMR (282MHz, DMSO-d6) δ -78.07 (s, 3F). ESI-MS m / z calculated value 185.10275, experimental value 186.2 (M+1). + Retention time: 0.64 minutes; LC method U.

[1615] Step 7: 3-[[4-[(2R)-2-amino-5,5,5-trifluoro-4,4-dimethyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid

[1616]

[1617] 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (6.12 g, 14.65 mmol) and (2R)-2-amino-5,5,5-trifluoro-4,4-dimethyl-pentan-1-ol (hydrochloride) (3.27 g, 14.75 mmol) were combined in THF (30 mL), and the resulting suspension was cooled in a water-ice bath. Sodium tert-butoxide (5.63 g, 58.58 mmol) was added, inducing rapid partial dissolution of the solid. After 5 minutes, the cooling bath was removed, and the reaction was stirred at room temperature for 1 hour (90% conversion). More (2R)-2-amino-5,5,5-trifluoro-4,4-dimethyl-pentan-1-ol (hydrochloride) (363 mg, 1.638 mmol) was added, and the mixture was stirred for one hour (no change). Add more sodium tert-butoxide (744 mg, 7.742 mmol) and stir the mixture for 40 minutes (96% conversion). Add ethyl acetate (100 mL), HCl (90 mL, 1 M, 90.00 mmol), and brine (50 mL) and separate the resulting two phases. Wash the organic phase with brine (50 mL), dry over sodium sulfate, and concentrate. Grind the residue in EtOAc / MeOH / hexane and evaporate the solvent to give 3-[[4-[(2R)-2-amino-5,5,5-trifluoro-4,4-dimethyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (hydrochloride) (8.88 g, 93%) as creamy solids. 1 H NMR(400MHz,DMSO-d6)δ13.15(very broad s,1H),8.61-8.30(m,4H),8.14(dd,J=7.9,1.9Hz,2H),7.69(t,J=7.8Hz,1H),7.31-7.20(m,1H),7.12(d,J=7.6Hz,2H),6.33(s,1H ), 4.43 (dd, J = 11.9, 3.3Hz, 1H), 4.29-4.15 (m, 1H), 3.74 (s, 1H), 2.06-1.94 (width m, 6H), 1.94-1.85 (m, 2H), 1.22 (s, 3H), 1.16 (s, 3H). ESI-MS calculated m / z value: 566.1811; experimental value: 567.62 (M+1) + Retention time: 1.13 minutes (LC method A).

[1618] Example E: Preparation of 3-[[4-[(2R)-2-amino-3-[1-(trifluoromethyl)cyclopropyl]propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid

[1619]

[1620] Step 1: 2-[1-(trifluoromethyl)cyclopropyl]ethanol

[1621]

[1622] LAH (49.868 g, 1.3139 mol) was added to THF (1700 mL) under nitrogen atmosphere and the mixture was stirred for 30 minutes, then cooled to 0 °C. 2-[1-(trifluoromethyl)cyclopropyl]acetic acid (190.91 g, 1.0107 mol) was added dropwise to THF (500 mL) while maintaining the temperature <5 °C. The mixture was warmed to room temperature and stirred for 24 hours. The resulting suspension was cooled to 0 °C, and water (50 mL) was added very slowly, followed by 15% w / w sodium hydroxide (50 mL) and water (150 mL). The mixture was stirred at 0 °C for 30 minutes and filtered through a diatomaceous earth mat. The filter cake was washed with THF (2 × 500 mL). The combined filtrates were evaporated under vacuum to give 160.27 g (98%) of 2-[1-(trifluoromethyl)cyclopropyl]ethanol containing about 5% w / w THF as an amber oil (by NMR). 1 H NMR (250MHz, DMSO-d6) δ4.57 (t, J = 5.2 Hz, 1H), 3.55-3.39 (m, 2H), 1.74 (t, J = 7.3 Hz, 2H), 1.00-0.58 (m, 4H).

[1623] Step 2: 2-[1-(trifluoromethyl)cyclopropyl]acetaldehyde

[1624]

[1625] A solution of 2-[1-(trifluoromethyl)cyclopropyl]ethanol (80 g, 467.1 mmol) in dichloromethane (1.1 L) was stirred at room temperature and treated fractionally with Dysmartin periodide (250 g, 589.4 mmol) (exothermic! cooled in an ice bath and kept T < 15 °C). Water (12 mL, 666.1 mmol) was added to the mixture slowly over 0.5 hours (exothermic to 33 °C during addition, maintained between 20 and 33 °C by cooling with cold water) to obtain a thick suspension. After addition, the pale yellow fine suspension was stirred at room temperature for 18 hours. The yellow suspension was diluted with ether (500 mL) and stirred for 30 minutes. The slurry was filtered through diatomaceous earth and the precipitate was washed with 100 mL of ether. The organic phase was carefully treated with a saturated aqueous sodium carbonate solution (500 mL, strong gas release, final pH approximately 10). The three-phase mixture was stirred at room temperature for 1 hour, and the solids were removed by filtration (large glass frit). The phases (yellow turbid ether phase, colorless aqueous phase) were separated, and the organic phase was washed once with a saturated aqueous solution of sodium carbonate (250 mL), once with 1 M sodium thiosulfate (250 mL), and once with brine (250 mL). The aqueous phase was back-extracted once with ether (150 mL), and the combined organic phases were dried, filtered, and evaporated to give 2-[1-(trifluoromethyl)cyclopropyl]acetaldehyde (40 g, 56%) as a yellow liquid.

[1626] Step 3: 2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propionitrile

[1627]

[1628] 2-[1-(trifluoromethyl)cyclopropyl]acetaldehyde (102 g, 670.5 mmol) in MeOH (700 mL) was treated with (1R)-1-phenylethylamine (86 mL, 667.1 mmol) and cooled in an ice bath. The solution was treated with acetic acid (38 mL, 668.2 mmol) and stirred in an ice bath for 20 min, then solid NaCN (note, 33 g, 673.4 mmol) was added in a single addition, and the suspension was stirred in a molten ice bath for 14 h. The solution was concentrated under reduced pressure (note, HCN!, exhaust gas from the pump passed through a bleach trap), and the residue was extracted with MTBE (1000 mL) and saturated sodium carbonate / water 1:1 (1000 mL) and washed with brine (350 mL). The aqueous phase was back-extracted once with MTBE (250 mL), and the combined organic phases were dried, filtered, and evaporated to give a 3:1 mixture of diastereomers of 2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propionitrile (180.8 g, 96%). ESI-MS m / z calculated value 282.13437, experimental value 283.0 (M+1). + Retention times: 1.69 minutes (major isomer) and 1.62 minutes (minor isomer), LC method A.

[1629] Step 4: (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]acrylamide

[1630]

[1631] In a 2L flask equipped with a mechanical stirrer and temperature probe, sulfuric acid (285 mL, 5.130 mol, 18M) was added and cooled in an ice bath. At an internal temperature of 5°C, a solution of 2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propionitrile (180.8 g, 640.4 mmol, a 3:1 mixture of diastereomers) was added dropwise to a solution in DCM (900 mL) over 20 minutes. The ice bath was removed, and the deep orange emulsion was stirred at room temperature for 18 hours and then at 30–40°C for 2 hours. The deep orange emulsion was carefully added to a mixture of ice and water (2.2 L) with mechanical stirring to give a yellow three-phase mixture, which was alkalized under ice cooling by the slow addition of ammonium hydroxide (1.33 L, 10.25 mol, 30% w / w) (very exothermic, the internal temperature was maintained between 10 and 25°C by adding ice). The yellow emulsion was stirred at room temperature (pH approximately 10) for 10 minutes, diluted with DCM (500 mL), and the phases were separated. The aqueous phase was washed at least twice with DCM (400 and 200 mL), and the combined organic phase was washed once with water / salt water at a 1:1 ratio (500 mL). The DCM phase was dried, filtered, and evaporated to give crude 2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propionamide (189.5 g, 99%) as a yellow-orange oil. ESI-MS m / z calculated value 300.14496, experimental value 301.0 (M+1). + Retention times: 1.40 min (major isomer) and 1.50 min (minor isomer) (3:1 mixture of diastereomers). The product was dissolved in ethanol (1.5 L) and rapidly treated with HCl (240 mL, 960.0 mmol, 4 M) (4 M in dioxane) and the resulting thick suspension was mechanically stirred overnight at room temperature. The solid was collected by filtration, washed with cold ethanol and dried under vacuum with nitrogen at 40–45 °C to give (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propionamide (hydrochloride) (147 g, 68%). 1¹H NMR (499MHz, DMSO-d⁶) δ 9.74 (d, J = 67.9Hz, 2H), 8.16–7.94 (m, 1H), 7.86 (s, 1H), 7.64–7.51 (m, 2H), 7.51–7.34 (m, 3H), 4.22 (s, 1H), 3.46–3.37 (m, 1H), 2.45 (d, J = 15.9Hz, 1H), 1.85 (dd, J = 15.1, 10.4Hz, 1H), 1.58 (d, J = 6.7Hz, 3H), 0.89 (pd, J = 9.6, 9.2, 4.3Hz, 2H), 0.84–0.66 (m, 2H). ESI-MS m / z calculated value 300.14496, experimental value 301.0 (M+1). + Retention time: 1.40 min (major isomer) and 1.40 min (minor isomer), 97:3 mixture of diastereomers (LC method V).

[1632] Step 5: (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propionic acid

[1633]

[1634] In a 5 L flask equipped with a mechanical stirrer, (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propionamide (hydrochloride) (147 g, 436.5 mmol) was added to acetic acid (735 mL) with stirring, and the thick, colorless suspension was treated with HCl (1.3 L, 15.60 mol, 12 M). The colorless suspension was carefully heated to 60–65 °C (vigorous bubbling, acetic acid (145 mL)) and stirred at 60–65 °C for 16 hours. The suspension was then slowly heated to 100 °C (vigorous bubbling over 4 hours) and the resulting solution was stirred at 100 °C for another 20 hours. The pale yellow solution was concentrated to a semi-solid state under reduced pressure at 65 °C and treated with water (1.5 L). The thick suspension was heated to 70–80 °C and cooled to room temperature with stirring for 2 hours. The solid was collected by filtration, washed with water, and blotted dry overnight. The wet solid was further dried under reduced pressure at 50–60 °C for 4 hours to give (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propionic acid (hydrochloride) (135 g, 92%) as a white solid. ESI-MS calculated m / z 301.12897, experimental 302.0 (M+1) + Retention time: 1.82 minutes; (LC method V).

[1635] Step 6: (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propane-1-ol

[1636]

[1637] In a 5L flask equipped with a mechanical stirrer, under a dry nitrogen atmosphere, (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propionic acid (hydrochloride) (135 g, 399.7 mmol) was suspended in 2L THF (a dense suspension). The mixture was heated to 35–40 °C, and LAH (47.3 g, 1.214 mol) (granules) was slowly added over 1 hour while maintaining the internal temperature between 30 and 40 °C through external cooling. The mixture was stirred at 30–40 °C for 1 hour (with almost no further hydrogen release, a gray suspension, and most of the starting material in solution) and heated at 50–55 °C for 1 hour. The gray suspension was stirred overnight in a cooling heating hood. The gray suspension was cooled in an ice bath and quenched by carefully adding water (44 mL, 2.442 mol), NaOH (41 mL, 6 M, 246.0 mmol), and water (44 mL, 2.442 mol) (the first addition of water was exothermic, and the temperature was maintained between 5°C and 30°C by cooling). The gray suspension was heated to 50–55°C for 1 hour, at which point a colorless suspension was obtained. The warm suspension was filtered through a diatomaceous earth mat covered with magnesium sulfate. The solid was washed with hot THF and evaporated to give crude (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propane-1-ol (121 g, 105%) as an oil. The crude product was dissolved in diethyl ether (1 L, clear solution) and treated slowly with HCl (101 mL, 404.0 mmol, 4 M) (4 M in dioxane) under cooling. The resulting dense suspension was stirred at room temperature for 1 hour. The solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure with nitrogen at 40-45°C to obtain (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propane-1-ol (hydrochloride) (126.6 g, 98%) as an off-white solid. 1¹H NMR (500MHz, DMSO-d⁶) δ 9.34 (s, 2H), 7.66 (d, J = 7.4Hz, 2H), 7.43 (dt, J = 25.1, 7.4Hz, 3H), 5.59 (s, 1H), 4.58 (q, J = 6.6Hz, 1H), 3.83 (d, J = 12.6Hz, 1H), 3.62–3.54 (m, 1H), 2.89 (s, 1H), 2.33–2.24 (m, 1H), 1.67–1.51 (m, 4H), 0.97–0.81 (m, 3H), 0.71 (s, 1H). ESI-MS m / z calculated value 287.1497, experimental value 288.0 (M+1). + Retention time: 0.99 minutes (LC method A).

[1638] Step 7: (2R)-2-amino-3-[1-(trifluoromethyl)cyclopropyl]propane-1-ol

[1639]

[1640] In a 1 L hydrogenation reactor, (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propane-1-ol (hydrochloride) (63.3 g, 195.5 mmol) was dissolved in EtOH (630 mL) (at warm temperature) and treated with Pd / C (6.3 g, 5.920 mmol, 10% w / w) (12.5 g, 50% water-wetted). The reaction was stirred at 40 °C for 24 h at 2 bar of hydrogen. The reaction mixture was filtered through diatomaceous earth. The filtrate was washed with ethanol and the colorless filtrate was evaporated to a solid. The solid was ground with diethyl ether. The suspension was stirred at room temperature for 1 h. The solid was filtered, washed with a large amount of diethyl ether and dried to give (2R)-2-amino-3-[1-(trifluoromethyl)cyclopropyl]propane-1-ol (hydrochloride) (41.8 g, 97%) as an off-white solid. 1 ¹H NMR (500MHz, DMSO-d⁶) δ 8.18 (s, 3H), 5.45 (t, J = 4.9Hz, 1H), 3.71 (dt, J = 11.6, 3.9Hz, 1H), 3.55 (dt, J = 11.2, 5.4Hz, 1H), 3.24 (h, J = 4.7Hz, 1H), 2.08 (dd, J = 15.1, 5.4Hz, 1H), 1.69 (dd, J = 15.1, 9.4Hz, 1H), 0.97 (h, J = 6.5, 5.9Hz, 2H), 0.86 (s, 2H). ESI-MS m / z calculated value 183.0871, experimental value 184.0 (M+1). + Retention time: 0.65 minutes; LC method A.

[1641] Step 8: 3-[[4-[(2R)-2-amino-3-[1-(trifluoromethyl)cyclopropyl]propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid

[1642]

[1643] 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (19.09 g, 45.68 mmol) and (2R)-2-amino-3-[1-(trifluoromethyl)cyclopropyl]propane-1-ol (hydrochloride) (10.18 g, 46.35 mmol) were dissolved in THF (100 mL) and cooled in an ice-water bath. Sodium tert-butoxide (18.14 g, 188.8 mmol) was added and the reaction was warmed to room temperature. The reaction was stirred for 1 hour and then partitioned between ethyl acetate (500 mL) and aqueous HCl solution (275 mL, 1 M, 275.0 mmol). The organic matter was separated, washed with brine, dried over sodium sulfate, and evaporated to give 3-[[4-[(2R)-2-amino-3-[1-(trifluoromethyl)cyclopropyl]propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (hydrochloride) (26.74 g, 94%). ESI-MS m / z calculated value 564.1654, experimental value 565.1 (M+1). + Retention time: 0.48 minutes; LC method D.

[1644] Example F: Preparation of (2R)-4-methyl-2-(spiro[2.3]hex-5-ylamino)pentan-1-ol

[1645] Step 1: (2R)-4-methyl-2-(spiro[2.3]hex-5-ylamino)pentan-1-ol

[1646]

[1647] A mixture of spiro[2.3]hexane-5-one (100 g, 1.040 mol) and (2R)-2-amino-4-methyl-pentane-1-ol (123.5 g, 1.054 mol) in a DCE (1.5 L) was stirred at ambient temperature for 1 hour. Sodium triacetoxyborohydride (228 g, 1.076 mol) was added to the mixture in portions. The mixture was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with HCl (1.1 L, 2.200 mol, 2 M) until the pH was approximately 1. The aqueous phase was separated and the organic phase was extracted with HCl (600 mL, 1.200 mol, 2 M). The organic phase (DCE) was separated and the aqueous layer was alkalized with NaOH (550 g, 6.875 mol, 50% w / w) to give a solution with a pH of approximately 12. The mixture was extracted twice with EtOAc (1 L), and the combined organic phases were washed with brine (150 mL), dried over MgSO4, filtered, and concentrated under vacuum to obtain a clear oil. No further purification was required for use. (2R)-4-methyl-2-(spiro[2.3]hex-5-ylamino)pentan-1-ol (160.7 g, 78%). ESI-MS m / z calculated value 197.17796, experimental value 198.2 (M+1). + Retention time: 0.54 minutes (LC method A)

[1648] Step 2: (2R)-4-methyl-2-(spiro[2.3]hex-5-ylamino)pentan-1-ol (hydrochloride)

[1649]

[1650] Over 20 minutes, 1.416 mol of HCl (4 M in dioxane, 354 mL) was added to a stirred (mechanical) solution of (2R)-4-methyl-2-(spiro[2.3]hex-5-ylamino)pentan-1-ol (254 g, 1.287 mol) in 2.286 L of diethyl ether in an ice / ice-water bath, maintaining the internal temperature between 10 °C and 22 °C. After the addition was complete, the solution was stirred at room temperature for 1.5 hours. The product was filtered off and washed with 2000 mL of diethyl ether. The exact same process was repeated again on the exact same scale (totaling 508 g of amino alcohol SM). The product was dried under vacuum overnight at 35 °C to give 562.3 g of (2R)-4-methyl-2-(spiro[2.3]hex-5-ylamino)pentan-1-ol (hydrochloride) (562.3 g, 93%). 1HNMR(500MHz,DMSO-d6)δ9.17-8.84(m,2H),5.38(s,1H),3.99(p,J=7.2Hz,1H),3.70-3.60(m,1H),3.55-3.45(m,1H),3.03-2.91(m,1H),2.63-2 .54(m,2H),2.20-2.05(m,2H),1.73-1.60(m,1H),1.60-1.48(m,1H),1.4 3-1.30(m,1H),0.93-0.83(m,6H),0.55-0.45(m,2H),0.45-0.36(m,2H).

[1651] Example G: Preparation of 3-[1-(trifluoromethyl)cyclopropyl]propane-1-ol

[1652] Step 1: Ethyl 2-[1-(trifluoromethyl)cyclopropyl]methanesulfonate

[1653]

[1654] 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).

[1655] Step 2: 3-[1-(trifluoromethyl)cyclopropyl]propionitrile

[1656]

[1657] 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).

[1658] Step 3: 3-[1-(trifluoromethyl)cyclopropyl]propionic acid

[1659]

[1660] 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 clarified 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).

[1661] Step 4: 3-[1-(trifluoromethyl)cyclopropyl]propane-1-ol

[1662]

[1663] A 1000 mL three-necked round-bottom flask was equipped with a mechanical stirrer, a cooling bath, a feeding funnel, a J-Kem temperature probe, and a 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 gray-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).

[1664] Example H: Preparation of 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]pyridine-2-carboxylic acid

[1665] Step 1: Methyl 6-benzylthiopyridine-2-carboxylate

[1666]

[1667] 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) at 0 °C. 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. 1 ¹H 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 = 7.8Hz, 2H), 7.28 (t, J = 7.2, 7.2Hz, 2H), 7.24–7.18 (m, 1H), 4.44 (s, 2H), 3.90 (d, J = 1.2Hz, 3H). ESI-MS m / z calculated value 259.0667, experimental value 260.1 (M+1). + Retention time: 3.2 minutes; LC method T.

[1668] Step 2: Methyl 6-chlorosulfonylpyridine-2-carboxylic acid

[1669]

[1670] 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.

[1671] Step 3: Methyl 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]pyridine-2-carboxylic acid

[1672]

[1673] 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, bis(trimethylsilyl)aminolithium (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.

[1674] Step 4: 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]pyridine-2-carboxylic acid

[1675]

[1676] 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%). 1 ¹H 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.

[1677] Example I: Preparation of 3-[[4-[(2R)-2-amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)-2-pyridyl]aminosulfonyl]benzoic acid

[1678] Step 1: 4-Chloro-6-(2,6-dimethylphenyl)pyridine-2-amine

[1679]

[1680] A solution of sodium carbonate (115 mL, 2M, 230.00 mmol) was added to a stirred solution of (2,6-dimethylphenyl)boric acid (11.515 g, 76.775 mmol) and 4,6-dichloropyridin-2-amine (12.513 g, 76.765 mmol) in toluene (425 mL) and EtOH (213 mL), and the reaction mixture was degassed under nitrogen for 45 min. Pd(dppf)Cl2 (6.271 g, 7.6791 mmol) was then added, and degassed for another 15 min. The reaction flask was then sealed, and the mixture was heated to 100 °C and stirred at that temperature for 24 h. After this, the volatiles were removed under reduced pressure, and the residue was extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-25% EtOAc / hexane) and ground with hexane to give 4-chloro-6-(2,6-dimethylphenyl)pyridine-2-amine (6.469 g, 34%) as a white solid. ESI-MS calculated m / z value: 232.07672; experimental value: 233.1 (M+1). + Retention time: 2.31 minutes; (LC method T).

[1681] Step 2: Methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)-2-pyridyl]aminosulfonyl]benzoate

[1682]

[1683] Under nitrogen atmosphere, bis(trimethylsilyl)aminolithium (45 mL, 1 M, 45.000 mmol) was added dropwise to a solution of 4-chloro-6-(2,6-dimethylphenyl)pyridine-2-amine (4.9 g, 20.635 mmol) and methyl 3-chlorosulfonylbenzoate (4.9 g, 20.046 mmol) in 200 mL of THF. The reaction mixture was stirred at -78 °C for 30 min; then warmed to 0 °C and stirred at 0 °C for 2 h. The reaction was quenched with cold 1.0 M hydrochloric acid (50 mL) and diluted with water (200 mL). The mixture was extracted with ethyl acetate (2 × 400 mL). The organic layers were combined, washed with brine (500 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography using 0–20% ethyl acetate / hexane to give methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)-2-pyridyl]aminosulfonyl]benzoate (6.2 g, 68%) as a white solid. ESI-MS calculated m / z: 430.0754, experimental: 431.5 (M+1). + Retention time: 3.65 minutes; (LC method T).

[1684] Step 3: 3-[[4-chloro-6-(2,6-dimethylphenyl)-2-pyridyl]aminosulfonyl]benzoic acid

[1685]

[1686] At room temperature, lithium hydroxide monohydrate (1.55 g, 36.9 mmol) was added to a stirred solution of methyl 3-[4-chloro-6-(2,6-dimethyl-phenyl)-pyridin-2-ylaminosulfonyl]benzoate (5.3 g, 12.3 mmol) in a mixture of tetrahydrofuran (80 mL) and water (80 mL), and the reaction mixture was stirred at 45°C for 2 hours. The tetrahydrofuran was removed under vacuum, and the residue was diluted with water (100 mL). The aqueous layer was washed with diethyl ether (2 × 50 mL), hexane (50 mL), and acidified to pH 2–3 with 1.0 M hydrochloric acid. The precipitated product was collected by filtration and dried to constant weight in a vacuum oven at 75°C to give 3-[4-chloro-6-(2,6-dimethyl-phenyl)-pyridin-2-ylaminosulfonyl]benzoic acid (4.8 g, 93%) as a white solid. 1¹H NMR (250MHz, DMSO-d⁶) δ (ppm): 8.32 (d, J = 1.9Hz, 1H), 8.14 (d, J = 7.7Hz, 1H), 8.03 (d, J = 8.0Hz, 1H), 7.63 (t, J = 7.8Hz, 1H), 7.28–6.96 (m, 5H), 1.77 (s, 6H). ESI-MS m / z calculated value 416.8, experimental value 417.0 (M1). Retention time: 5.11 minutes.

[1687] Step 4: 3-[[4-[(2R)-2-amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)-2-pyridyl]aminosulfonyl]benzoic acid

[1688]

[1689] Add 3-[[4-chloro-6-(2,6-dimethylphenyl)-2-pyridyl]aminosulfonyl]benzoic acid (300 mg, 0.7196 mmol), (2R)-2-amino-4-methyl-pentan-1-ol (110 mg, 0.9387 mmol), and anhydrous tetrahydrofuran (12 mL) to a 20 mL vial in this order. Then purge the vial with nitrogen for 30 seconds and cap it under nitrogen, adding solid potassium tert-butoxide (350 mg, 3.119 mmol). After stirring at 105 °C for 14 hours (overnight), allow the reaction to cool to ambient temperature. Then add glacial acetic acid (200 μL, 3.517 mmol) and remove volatiles under reduced pressure. Add DMSO (5 mL) to the residue and microfilter. Analyze by reversed-phase chromatography (C10). 18 The solution was purified by column chromatography (1-99% acetonitrile / water) over 15 minutes to give 3-[[4-[(2R)-2-amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)-2-pyridyl]aminosulfonyl]benzoic acid (hydrochloride) (278 mg, 72%) as a pale yellow solid. ESI-MS calculated m / z: 497.19846, experimental: 498.2 (M+1). + Retention time: 0.43 minutes (LC method D).

[1690] Example J: Preparation of methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]-(methoxymethyl)aminosulfonyl]benzoate]

[1691] Step 1: Methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]-(methoxymethyl)aminosulfonyl]benzoate

[1692]

[1693] Potassium carbonate (16.8 g, 121.56 mmol) was added to a solution of methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoate (35.04 g, 81.131 mmol) in acetonitrile (525 mL) and 1,2-dichloroethane (525 mL), followed by the addition of chloromethyl methyl ether (7.5260 g, 7.1 mL, 93.475 mmol). The reaction mixture was stirred overnight at room temperature. The solvent was evaporated, and the resulting mixture was partitioned between water (300 mL) and EtOAc (300 mL). The aqueous layer was extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with water (300 mL) and brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel chromatography using 0 to 40% EtOAc / hexane to give methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]-(methoxymethyl)aminosulfonyl]benzoate (30.95 g, 80%) as a clear gel. ESI-MS calculated m / z 475.0969, experimental 476.3 (M+1). + Retention time: 3.96 minutes, LC method T.

[1694] Example K: Preparation of 3-[[4-(2-amino-4,4,4-trifluoro-butoxy)-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid

[1695] Step 1: 3-[[4-[2-(tert-butoxycarbonylamino)-4,4,4-trifluoro-butoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid

[1696]

[1697] A solution of 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (0.63 g, 1.508 mmol), 2-amino-4,4,4-trifluoro-butane-1-ol (hydrochloride) (0.54 g, 3.007 mmol), and sodium tert-butoxide (0.73 g, 7.596 mmol) in THF (8 mL) was stirred for five minutes until it turned bright yellow. The reaction was placed in a preheated 60 °C bath and stirred for 25 minutes. UPLCMS showed complete conversion to the amino intermediate. After cooling to room temperature, di-tert-butyl dicarbonate (0.67 g, 3.070 mmol) was added, and the reaction was stirred for 17 hours. The reaction was quenched with 1 M hydrochloric acid, diluted with water, and extracted with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, and evaporated under vacuum. The residues were purified by silica gel column chromatography with 0–10% methanol / dichloromethane to give a mixture containing the product. The mixture was further purified by silica gel column chromatography with 0-9% methanol / dichloromethane to give 3-[[4-[2-(tert-butoxycarbonylamino)-4,4,4-trifluoro-butoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (0.54 g, 57%). ESI-MS m / z calculated value 624.1866, experimental value 625.3 (M+1). + Retention time: 0.67 minutes, colorless solid, LC method D.

[1698] Step 2: 3-[[4-(2-amino-4,4,4-trifluoro-butoxy)-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid

[1699]

[1700] A solution of 3-[[4-[2-(tert-butoxycarbonylamino)-4,4,4-trifluoro-butoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (83 mg, 0.1329 mmol) and HCl (4 M, 4 mL, 16.00 mmol) (in dioxane) was stirred for one hour. The solvent was removed under vacuum, and the solid was ground with diethyl ether to give 3-[[4-(2-amino-4,4,4-trifluoro-butoxy)-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (hydrochloride) (81 mg, 109%). ESI-MS m / z calculated value 524.13416, experimental value 525.2 (M+1). + Retention time: 0.39 minutes, colorless solid, LC method D.

[1701] Example L: Preparation of 3-[[4-[(2R)-2-aminopropoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid

[1702] Step 1: 3-[[4-[(2R)-2-(tert-Butoxycarbonylamino)propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid

[1703]

[1704] A solution of 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (75 mg, 0.1795 mmol) in THF (0.7 mL) was added to N-[(1R)-2-hydroxy-1-methyl-ethyl]carbamate tert-butyl ester (approximately 47.17 mg, 0.2692 mmol). Then, sodium tert-butoxide (approximately 86.25 mg, 0.8975 mmol) was added. The reaction mixture was stirred at room temperature. Acetic acid (approximately 64.68 mg, 61.25 μL, 1.077 mmol) was added. The reaction mixture was diluted with DCM and washed with HCl (1 M, 1 × 7 mL) and brine (2 × 75 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was analyzed by chromatography on a 12 g silica gel column with an EtOAc / hexane gradient elution. 3-[[4-[(2R)-2-(tert-Butoxycarbonylamino)propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (1.65 g, 2.964 mmol) (65 mg, 65%) was obtained. ESI-MS calculated m / z 556.19916, experimental 557.3 (M+1). + Retention time: 1.63 minutes; LC method A.

[1705] Step 2: 3-[[4-[(2R)-2-aminopropoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid

[1706]

[1707] A solution of 3-[[4-[(2R)-2-(tert-butoxycarbonylamino)propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (1.65 g, 2.964 mmol) in HCl (8 mL, 32.00 mmol, 4 M) (in dioxane) was stirred for two hours, and the solvent was removed under vacuum. The solid was ground with diethyl ether and dried under vacuum to give 3-[[4-[(2R)-2-aminopropoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (hydrochloride) (1.55 g, 106%) as a colorless solid. ESI-MS m / z calculated value 456.14673, experimental value 457.2 (M+1) + Retention time: 0.37 minutes, LC method D.

[1708] Example M: ​​Preparation of 3-[[4-[(2R)-2-amino-5-hydroxy-5-methyl-hexyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid

[1709] Step 1: (4R)-4-(tert-Butoxycarbonylamino)-5-hydroxy-pentanoic acid benzyl ester

[1710]

[1711] (2R)-5-benzyloxy-2-(tert-butoxycarbonylamino)-5-oxo-pentanoic acid (10 g, 29.641 mmol) was dissolved in dimethoxyethane (30 mL) and the solution was cooled to -15 °C. N-methylmorpholine (3.0360 g, 3.3 mL, 30.016 mmol) was added, followed by the slow addition of isobutyl chloroformate (4.1067 g, 3.9 mL, 30.069 mmol), maintaining the reaction temperature below -10 °C. The mixture was stirred for 30 minutes. The solid was rapidly filtered and washed with dimethoxyethane (30 mL). The filtrate was cooled to -40 °C and a solution of sodium borohydride (1.45 g, 38.327 mmol) in water (15 mL) was slowly added, maintaining the reaction temperature between -30 °C and -15 °C. The mixture was stirred for 15 minutes. Water (180 mL) was then added dropwise at -15 °C while the temperature was slowly raised to 5 °C, with gas release controlled. The suspension was filtered and washed with water (300 mL). The solid was dissolved in dichloromethane (100 mL) and transferred to a separatory funnel. The phases were separated, and the organic phase was dried over sodium sulfate, filtered, and evaporated to dryness to give (4R)-4-(tert-butoxycarbonylamino)-5-hydroxypentanoate benzyl ester (7.98 g, 83%) as a white solid. 1H NMR (400MHz, CDCl3) δ 7.42–7.30 (m, 5H), 5.13 (s, 2H), 4.81 (br.s., 1H), 3.65 (br.s., 2H), 3.60–3.51 (m, 1H), 2.57–2.36 (m, 3H), 1.98–1.87 (m, 1H), 1.86–1.73 (m, 1H), 1.44 (s, 9H). ESI-MS m / z calculated value 323.1733, experimental value 224.4 (M⁻⁹)⁺; retention time: 1.696 min, LC method X.

[1712] Step 2: Benzyl 3-[(4R)-2-oxooxazolidine-4-yl]propionate

[1713]

[1714] Pyridine (48.900 g, 50 mL, 618.21 mmol) was added to a solution of (4R)-4-(tert-butoxycarbonylamino)-5-hydroxy-valerate benzyl ester (7.98 g, 24.652 mmol) in dichloroethane (80 mL). Then p-toluenesulfonic anhydride (8.65 g, 25.972 mmol) was added, and the mixture was stirred at room temperature for 1 hour and then heated to 90 °C for 2 hours. The mixture was cooled, diluted with dichloromethane (150 mL), and washed with 1N HCl (3 × 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and the solvent was removed under vacuum. The residue was purified by silica gel column chromatography on an 80 g column and eluted with 20% to 80% EtOAc / heptane to give 4.85 g, 77%, of 3-[(4R)-2-oxooxazolidine-4-yl]propionate, which crystallized slowly over time as a light brown oil. 1 ¹H NMR (400MHz, CDCl₃) δ 7.43–7.30 (m, 5H), 6.15 (br.s., 1H), 5.13 (s, 2H), 4.48 (t, J = 8.4 Hz, 1H), 4.02 (dd, J = 8.6, 6.1 Hz, 1H), 3.97–3.88 (m, 1H), 2.45 (t, J = 7.3 Hz, 2H), 2.00–1.85 (m, 2H). ESI-MS m / z calculated value 249.1001, experimental value 250.2 (M+1). + Retention time: 1.511 minutes, LC method X.

[1715] Step 3: (4R)-4-(3-hydroxy-3-methyl-butyl)oxazolidin-2-one

[1716]

[1717] At -20°C, methyl magnesium bromide in diethyl ether (26 mL, 3 M, 78.000 mmol) was added to a mixture of toluene (42 mL) and tetrahydrofuran (42 mL) (methanol + water + dry ice). Then, a warm tetrahydrofuran (22 mL) solution of 3-[(4R)-2-oxooxazolidine-4-yl]propionate (4.85 g, 19.457 mmol) was added dropwise, maintaining the temperature below -10°C. The mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was cooled to 0°C, quenched with a 10% aqueous acetic acid solution (50 mL), and the resulting mixture was stirred at room temperature for 1 hour. The layers were separated. The aqueous layer was extracted with methyl-THF (3 × 100 mL) and then with dichloromethane (2 × 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on 50 g and 120 g columns, eluted with 0 to 15% isopropanol / dichloromethane, to give (4R)-4-(3-hydroxy-3-methyl-butyl)oxazolidin-2-one (1.73 g, 51%) as a white solid. 1 ¹H NMR (400MHz, CDCl₃) δ 6.05 (br.s., 1H), 4.50 (t, J=8.4Hz, 1H), 4.03 (dd, J=8.4, 6.2Hz, 1H), 3.95–3.81 (m, 1H), 1.76–1.64 (m, 2H), 1.59–1.44 (m, 3H), 1.25 (s, 6H). ESI-MS m / z calculated value 173.1052, experimental value 174.2 (M+1). + Retention time: 0.95 minutes, LC method X.

[1718] Step 4: (2R)-2-amino-5-methyl-hexane-1,5-diol

[1719]

[1720] A mixture of (4R)-4-(3-hydroxy-3-methyl-butyl)oxazolidin-2-one (307 mg, 1.7724 mmol), barium hydroxide octahydrate (1.69 g, 5.3572 mmol), ethanol (12 mL), and water (12 mL) was heated under reflux at 95 °C for 2 hours. The reaction mixture was cooled to room temperature, and then dry ice (approximately 1.8 g) was slowly added while the mixture was vigorously stirred for 2 days. The suspension was filtered through a diatomaceous earth mat and washed with ethanol (approximately 15 mL). The filtrate was diluted with toluene, evaporated three times, and concentrated under reduced pressure. Barium salts were observed on the flask walls. A minimal amount of ethanol was added, and the solution was filtered again through a diatomaceous earth mat. The filtrate was concentrated under pressure to give (2R)-2-amino-5-methyl-hexane-1,5-diol (338.4 mg, 130%) as a yellow oil. The crude product was used in the next step without purification. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 3.40–3.28 (m, 1H), 3.25–3.11 (m, 1H), 2.64 (br.s, 1H), 1.81 (s, 2H), 1.51–1.37 (m, 2H), 1.37–1.29 (m, 1H), 1.29–1.18 (m, 1H), 1.06 (d, J = 1.0Hz, 6H). ESI-MS m / z calculated value 147.1259, experimental value 148.4 (M+1). + Retention time: 0.22 minutes, LC method X.

[1721] Step 5: 3-[[4-[(2R)-2-amino-5-hydroxy-5-methyl-hexyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid

[1722]

[1723] Sodium tert-butoxide (375 mg, 3.9020 mmol) was slowly added to a solution of 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (371 mg, 0.8878 mmol) and (2R)-2-amino-5-methyl-hexane-1,5-diol (261 mg, 1.7729 mmol) in THF cooled to 0 °C. After 2 hours, sodium tert-butoxide (76 mg, 0.7908 mmol) was slowly added to the reaction mixture while stirring at room temperature. Two hours after the addition, sodium tert-butoxide (200 μL of 2 M sodium tert-butoxide, 0.4000 mmol) was slowly added to THF, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate (6 mL) and 1N hydrochloric acid (6 mL). The aqueous phase was extracted with ethyl acetate (2 × 6 mL) and 2-methyltetrahydrofuran (3 × 6 mL). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated to dryness. The solid was ground with ethyl acetate (10 mL) and the precipitate was filtered and washed with ethyl acetate (2 × 10 mL) to give 3-[[4-[(2R)-2-amino-5-hydroxy-5-methyl-hexyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (653.4 mg, 139%, the higher mass recovery may be due to salt contamination) as a pale yellow solid. The crude was used in the next step without purification. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 13.24 (br.s, 1H), 8.43 (s, 1H), 8.19–8.06 (m, 3H), 7.70 (t, J = 7.6Hz, 1H), 7.32–7.19 (m, 1H), 7.18–7.05 (m, 2H), 6.30 (s, 1H), 4.46–4.32 (m, 1H), 4.30–4.18 (m, 1H), 3.53 (s, 1H), 1.99 (s, 6H), 1.78–1.61 (m, 2H), 1.57–1.37 (m, 2H), 1.11 (d, J = 7.8Hz, 6H). ESI-MS m / z calculated value 528.2043, experimental value 529.2 (M+1). + Retention time: 1.3 minutes, LC method X.

[1724] Example N: Preparation of 3-[[4-[(2R)-2-amino-4-methyl-pentoxy]-6-[2-(benzyloxymethyl)-6-methyl-phenyl]pyrimidin-2-yl]aminosulfonyl]benzoic acid

[1725] Step 1: (2-bromo-3-methyl-phenyl)methanol

[1726]

[1727] Lithium borohydride (4.9305 g, 215.02 mmol) was added to a solution of methyl 2-bromo-3-methylbenzoate (10.0281 g, 42.902 mmol) in anhydrous THF (100 mL) with stirring at 0 °C. The reaction mixture was then heated to 50 °C and stirred at 50 °C for 4 hours. The reaction mixture was diluted with DI water (30 mL) and extracted with EtOAc (3 × 50 mL). The combined EtOAc layers were washed with a saturated aqueous solution of NaCl (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. A crude product (8.637 g) was given as a pale orange solid. (2-Bromo-3-methylphenyl)methanol (8.637 g, 100%). 1 HNMR(500MHz,DMSO-d6)δ7.37(d,J=7.5Hz,1H),7.28(t,J=7.5,7.5Hz,1H),7.23 (d, J=7.3Hz, 1H), 5.39 (t, J=5.6, 5.6Hz, 1H), 4.51 (d, J=5.7Hz, 2H), 2.35 (s, 3H).

[1728] Step 2: 1-(benzyloxymethyl)-2-bromo-3-methylbenzene

[1729]

[1730] NaH (1.227 g, 30.68 mmol, 60% w / w) was added to (2-bromo-3-methyl-phenyl)methanol (1.87 g, 9.301 mmol) in DMSO (38 mL) cooled to 0 °C in an ice bath, and the reaction was stirred for 15 min. Bromotoluene (1.75 mL, 14.71 mmol) was then added, and the mixture was warmed to room temperature and stirred for 16 h. The mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried (sodium sulfate), filtered, and concentrated to a solid. The solid was purified by silica gel chromatography (80 g column) using a shallow gradient from 100% hexane to 40% EtOAc (the compound was eluted in 18% ethyl acetate) to give 1-(benzyloxymethyl)-2-bromo-3-methyl-benzene (2.69 g, 99%). ESI-MS m / z calculated value 290.03064, experimental value 291.2 (M+1). + Retention time: 2.06 minutes; LC method A.

[1731] Step 3: 2-[2-(benzyloxymethyl)-6-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane

[1732]

[1733] In a 350 mL sealed container, 1-(benzyloxymethyl)-2-bromo-3-methylbenzene (5.4 g, 18.55 mmol) was dissolved in dioxane (55 mL), and KOAc (3.85 g, 39.23 mmol) was added. The mixture was then degassed with nitrogen for several minutes. Bis(pinacol)diboron (7.25 g, 28.55 mmol) was then added, followed by Pd(dppf)Cl2 (1.41 g, 1.932 mmol), and the reaction was again purged with nitrogen. 2吹扫 The mixture was sealed and heated to 100°C for 16 hours. After cooling the reaction to room temperature, saturated ammonium chloride was added, and the reaction was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting brown oil was purified by silica gel column chromatography (220 g column) using a gradient from 100% hexane to 30% ethyl acetate / hexane (the compound eluted in 10% ethyl acetate) to give the desired compound 2-[2-(benzyloxymethyl)-6-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxane-pentaborane (4.63 g, 74%) as a white solid. ESI-MS m / z calculated value 338.20532, experimental value 339.4 (M+1). + Retention time: 2.23 minutes; LC method A. 1 ¹H NMR (499 MHz, chloroform-d) δ 7.37–7.32 (m, 4H), 7.32–7.27 (m, 1H), 7.25–7.20 (m, 1H), 7.10 (dd, J = 23.3, 7.5 Hz, 2H), 4.62 (s, 2H), 4.46 (s, 2H), 2.45 (s, 3H), 1.34 (s, 12H).

[1734] Step 4: N-[4-[2-(benzyloxymethyl)-6-methyl-phenyl]-6-chloro-pyrimidin-2-yl]-N-tert-butoxycarbonyl-carbamate tert-butyl ester

[1735]

[1736] N-tert-butoxycarbonyl-N-(4,6-dichloropyrimidin-2-yl)carbamate tert-butyl ester (1.5 g, 4.118 mmol) and 2-[2-(benzyloxymethyl)-6-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxane-pentaborane (1.4 g, 4.139 mmol) were combined in dimethoxyethane (36 mL) and water (6 mL). [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (315 mg, 0.4305 mmol) and potassium carbonate (1.5 g, 10.85 mmol) were added to the mixture, and nitrogen was bubbled through the suspension for 1 min. The reaction mixture was capped and heated to 80 °C for 2 h. The mixture was cooled to ambient temperature, and saturated ammonium chloride was added and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (80 g column) using a gradient of 100% hexane to 50% ethyl acetate / hexane (the compound eluted in 30% EtOAc) to give N-[4-[2-(benzyloxymethyl)-6-methyl-phenyl]-6-chloro-pyrimidin-2-yl]-N-tert-butoxycarbonyl-carbamate tert-butyl ester (1.73 g, 78%) as a pale yellow oil. ESI-MS calculated m / z 539.2187, experimental 540.2 (M+1). + Retention time: 1.87 minutes; LC method Q. 1 ¹H NMR (499 MHz, chloroform-d) δ 7.39–7.35 (m, 2H), 7.35–7.30 (m, 3H), 7.29–7.23 (m, 4H), 4.40 (s, 2H), 4.30 (s, 2H), 2.13 (s, 3H), 1.44 (s, 18H).

[1737] Step 5: 4-[2-(benzyloxymethyl)-6-methyl-phenyl]-6-chloro-pyrimidine-2-amine

[1738]

[1739] N-[4-[2-(benzyloxymethyl)-6-methyl-phenyl]-6-chloro-pyrimidin-2-yl]-N-tert-butoxycarbonyl-carbamate tert-butyl ester (1.7 g, 3.148 mmol) was dissolved in DCM (35 mL), and HCl (4 M in dioxane) (21 mL of 4 M, 84.00 mmol) was added to the mixture, and the reaction was stirred at room temperature. After 6 hours, the mixture was evaporated to dryness, diluted with diethyl ether (50 mL × 2), then diluted and concentrated with hexane:dichloromethane (1:1 mixture, 50 mL). The substance was then placed on a high vacuum pump for 16 hours to give the product 4-[2-(benzyloxymethyl)-6-methyl-phenyl]-6-chloro-pyrimidin-2-amine (1.07 g, 100%) as a pale yellow gel. ESI-MS m / z calculated value 339.11383, experimental value 340.2 (M+1). + Retention time: 1.67 minutes; LC method A. 1 H NMR (499MHz, DMSO-d6) δ7.35-7.30(m,4H),7.29-7.24(m,2H),7.24-7.15(m,4H),6.65(s,1H),4.37(s,2H),4.33(s,2H),2.10(s,3H).

[1740] Step 6: Methyl 3-[[4-[2-(benzyloxymethyl)-6-methyl-phenyl]-6-chloro-pyrimidin-2-yl]aminosulfonyl]benzoate

[1741]

[1742] 4-[2-(benzyloxymethyl)-6-methyl-phenyl]-6-chloro-pyrimidin-2-amine (2.74 g, 8.063 mmol) was dissolved in THF (50 mL) and cooled to 0 °C in an ice bath. Methyl 3-chlorosulfonylbenzoate (2.85 g, 12.15 mmol) was added in a single addition. Lithium tertiaryol (7.25 mL, 40% w / w, 22.50 mmol) was added dropwise, and the reaction was slowly warmed to room temperature. The reaction was stirred for 6 hours. The mixture was aspirated overnight under high vacuum and then diluted again in THF (25 mL). After cooling in an ice bath, methyl 3-chlorosulfonylbenzoate (1.0 g) was added, followed by lithium tertiaryol (3 mL, 40% w / w), and the reaction was warmed to room temperature for 4 hours. The mixture was acidified by adding 1% HCl. The reaction mixture was extracted with ethyl acetate. The organic matter was washed with brine, dried over sodium sulfate, and evaporated. The crude substance was purified by silica gel column chromatography (120 g column) using a gradient of 100% hexane to 80% ethyl acetate / hexane (the compound was eluted with 50% EtOAc) to give a pale yellow oil, which was solidified under high vacuum to produce methyl 3-[[4-[2-(benzyloxymethyl)-6-methyl-phenyl]-6-chloro-pyrimidin-2-yl]aminosulfonyl]benzoate (2.06 g, 47%). ESI-MS calculated m / z 537.11255, experimental 538.2 (M+1). + Retention time: 1.97 minutes; LC method A.

[1743] Step 7: 3-[[4-[2-(benzyloxymethyl)-6-methyl-phenyl]-6-chloro-pyrimidin-2-yl]aminosulfonyl]benzoic acid

[1744]

[1745] Methyl 3-[[4-[2-(benzyloxymethyl)-6-methyl-phenyl]-6-chloro-pyrimidin-2-yl]aminosulfonyl]benzoate (2.06 g, 3.829 mmol) and NaOH (30 mL, 1 M, 30.00 mmol) were combined in THF (25 mL) and stirred at room temperature for 2 hours. The reaction was acidified by adding 1 M HCl and extracted with ethyl acetate. The organic matter was washed with brine, dried over sodium sulfate, and evaporated. The substance was placed under high vacuum overnight to give 3-[[4-[2-(benzyloxymethyl)-6-methyl-phenyl]-6-chloro-pyrimidin-2-yl]aminosulfonyl]benzoic acid (1.95 g, 97%). ESI-MS m / z calculated value 523.09686, experimental value 524.1 (M+1) + Retention time: 1.72 minutes; LC method A.

[1746] Step 8: 3-[[4-[(2R)-2-amino-4-methyl-pentoxy]-6-[2-(benzyloxymethyl)-6-methyl-phenyl]pyrimidin-2-yl]aminosulfonyl]benzoic acid

[1747]

[1748] In a 500 mL flask, 3-[[4-[2-(benzyloxymethyl)-6-methyl-phenyl]-6-chloro-pyrimidin-2-yl]aminosulfonyl]benzoic acid (2.0 g, 3.817 mmol), (2R)-2-amino-4-methyl-pentane-1-ol (460 mg, 3.925 mmol), and THF (40 mL) were mixed and cooled in an ice bath at 0 °C. KOtBu (2.15 g, 19.16 mmol) was then added. The mixture was stirred for 2 hours. The reaction was acidified by adding HCl (4 M in dioxane) (7 mL of 4 M, 28.00 mmol), stirred for 15 minutes, and then concentrated under vacuum. The substance was dissolved in DCM / ethyl ether and ground, filtered, and dried under high vacuum to give a white solid 3-[[4-[(2R)-2-amino-4-methyl-pentoxy]-6-[2-(benzyloxymethyl)-6-methyl-phenyl]pyrimidin-2-yl]aminosulfonyl]benzoic acid (hydrochloride...

Claims

1. A compound of formula Ia: (It), Its tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Ring A is selected from phenyl, pyridyl, pyrazolyl, and pyrazinyl groups; Cycle B is selected from phenyl and cyclohexyl; W 1 is selected from N and CH; W 2 is N; Z is C(R ZC )2, and both R ZC groups together form an oxo group; each L is independently selected from C(R 1 C(R L1 )2; R 3 is methyl; R 4 Selected from hydrogen and C1-C6 alkyl groups; Each R 5 Selected independently from: ■ Hydrogen, ■ Halogen, ■ C1-C6 alkyl groups optionally substituted with hydroxyl groups: ■ C1-C6 fluoroalkyl groups, and ■ C6-C 10 Aryl; R YN Selected from: ■ C3-C, optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl: ○ Hydroxyl group ○ Oxygenation, ○ Cyano group ○ N(R N )2, ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following: hydroxyl group Oxygenation, N(R N )2, and C6-C 10 Aryl, ○ Optionally selected by 1-3 independently chosen from halogen, oxidative, and C6-C 10 The C1-C6 alkoxy group substituted by the aryl group, ○ C3-C 10 cycloalkyl groups, and ○ Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, 3- to 10-membered heterocyclic groups. ■ C6-C 10 Aryl, ■ Optionally substituted with 1-3 independently selected groups from the following: 3- to 10-membered heterocyclic groups ○ Oxygenation, ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following: Oxygenation, hydroxyl group Optionally selected by 1-3 independently chosen halogens and C6-C 10 The C1-C6 alkoxy group substituted with the aryl group, and -(O) 0-1 -(C3-C 10 cycloalkyl), ○ C1-C6 fluoroalkyl, ○ C3-C groups optionally substituted with 1-3 independently selected halogen groups 10 cycloalkyl groups, and ■ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following: ○ C1-C6 alkyl groups optionally substituted with 1-3 independently selected oxo and C1-C6 alkoxy groups, and ○ Optionally, it is 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; Each R L1 Selected independently from: ■ Hydrogen, ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following: ○ Halogen, ○ Hydroxyl group, and ○ C3-C substituted with 1-3 independently selected C1-C6 fluoroalkyl groups 10 cycloalkyl, ■ C3-C 10 cycloalkyl, Each R N Selected independently from: ■ Hydrogen, ■ C1-C8 alkyl groups optionally substituted by 1-3 independently selected groups from the following: ○ Oxygenation, ○ Halogen, ○ Hydroxyl group, and ○ C1-C6 alkoxy groups, ■ C3-C, optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl: ○ Hydroxyl group, and ○ C1-C6 alkyl groups optionally substituted with 1-3 independently selected groups from hydroxyl groups, ■ C6-C 10 Aryl, and ■ 3- to 10-membered heterocyclic groups; 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: ■ Oxygenation, and ■ C1-C6 alkyl; The condition is that the compound is not selected from: 。 2. The compound according to claim 1, wherein the compound is a compound of formula IIa: (IIa), Its tautomers, or pharmaceutically acceptable salts of any of the foregoing.

3. The compound according to claim 1, wherein the compound is a compound of formula IIb: (IIb), Its tautomers, or pharmaceutically acceptable salts of any of the foregoing.

4. The compound according to claim 1, wherein the compound is a compound of formula III: (III), Its tautomers, or pharmaceutically acceptable salts of any of the foregoing.

5. The compound according to claim 1, wherein the compound is a compound of formula IV: (IV), Its tautomers, or pharmaceutically acceptable salts of any of the foregoing.

6. The compound according to claim 1, wherein the compound is a compound of formula V: （V）， Its tautomers, or pharmaceutically acceptable salts of any of the foregoing.

7. The compound according to claim 1, wherein the compound is a compound of formula VI: (WE), Its tautomers, or pharmaceutically acceptable salts of any of the foregoing.

8. The compound, tautomer, or pharmaceutically acceptable salt according to claim 1, wherein the compound is selected from: And a pharmaceutically acceptable salt of any of the aforementioned.

9. A pharmaceutical composition comprising a compound, a tautomer or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier according to any one of claims 1 to 8.

10. The pharmaceutical composition according to claim 9, further comprising one or more additional therapeutic agents.

11. Use of the compound, tautomer, or pharmaceutically acceptable salt of any one of claims 1 to 8, or the pharmaceutical composition of claim 9 or 10, in the preparation of a medicament for the treatment of cystic fibrosis.

12. The use according to claim 11, wherein the drug is formulated for administration together with one or more other therapeutic agents.

13. The use according to claim 12, wherein the one or more additional therapeutic agents are compounds selected from tezacaftor, ivacaftor, deutivacaftor, lumacaftor, and pharmaceutically acceptable salts thereof.

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