Modulators of cystic fibrosis transmembrane conductance regulator

Abstract

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

Description

[0001] This application claims the benefit of priority of U.S. Provisional Application No. 63 / 088,686, filed October 7, 2020, the contents of which are incorporated by reference in their entirety.

[0002] The present disclosure relates to modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), pharmaceutical compositions containing the modulators, methods of using such modulators to treat CFTR-mediated diseases, including cystic fibrosis, using such modulators, combination therapies and combination pharmaceutical compositions, and processes and intermediates for making such modulators.

[0003] Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 70,000 children and adults worldwide. Despite some advances in the treatment of CF, it remains incurable.

[0004] In CF patients, mutations in endogenously expressed CFTR in the respiratory epithelium result in decreased apical anion secretion, causing an imbalance in ion and fluid transport. The resulting decrease in anion transport leads to increased mucus accumulation in the lungs, accompanied by microbial infection, ultimately leading to death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency, which, if left untreated, can lead to death. Additionally, most males with cystic fibrosis are infertile, and fertility is reduced in females with cystic fibrosis.

[0005] Sequence analysis of the CFTR gene has revealed a variety of disease-causing mutations (Cutting, G.R. et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem, B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S. et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, over 2000 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 prevalent pathogenic mutation is the deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is commonly referred to as the F508del mutation. This mutation occurs in many cystic fibrosis cases and is associated with severe disease.

[0006] Deletion of residue 508 in CFTR prevents the nascent protein from folding correctly. This results in the mutant protein failing to leave the endoplasmic reticulum (ER) and traffic to the plasma membrane. Thus, the number of CFTR channels for anion transport present in the membrane is much lower than observed in cells expressing wild-type CFTR, i.e., CFTR not containing the mutation. In addition to impaired trafficking, the mutation results in defective channel gating. The reduction in the number of channels in the membrane, together with defective gating, results in reduced anion and fluid transport across the epithelium. (Quinton, P. M. (1990), FASEB J. 4:2709-2727). The defective channels present due to the F508del mutation are still functional, although their function is less than that of wild-type CFTR channels. (Dalemans et al. (1991), Nature Lond. 354:526-528; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). In addition to F508del, other disease-causing mutations in CFTR that result in defective trafficking, synthesis, and / or channel gating can be up- or down-regulated to alter anion secretion and alter 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 the transmembrane flux of anions as well as the activity of other ion channels and proteins. In epithelial cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport across the airway surface liquid layer in the lung and across the secretory surface in the pancreas. CFTR is composed of 1480 amino acids encoding a protein that is made up of tandem repeats of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. Two transmembrane domains are connected by a large, polar regulatory (R) domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking.

[0008] Chloride ion transport occurs through ENaC and CFTR present on the apical membrane and Na + -K + -ATPase pumps and Cl- channels. Secondary active transport of chloride from the luminal side results in intracellular chloride accumulation, which can then passively leave the cell via Cl - channels, resulting in vectorial transport. Na + / 2Cl - / K + co-transporters, Na + -K + -ATPase pumps and basolateral membrane K +The arrangement of the channels and CFTR on the luminal side coordinates chloride secretion via CFTR on the luminal side. Since water cannot be actively transported per se, its flow across the epithelium depends on the small transepithelial osmotic gradient generated by the bulk flow of sodium and chloride ions.

[0009] A variety of CFTR modulating compounds have been identified recently. However, there remains a need for compounds that are capable of treating or alleviating cystic fibrosis and other CFTR-mediated diseases, and in particular more severe forms of these diseases.

[0010] One aspect of the present disclosure provides novel compounds comprising a compound of Formula I, a compound of any of Formulas la, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0011] Formula I encompasses compounds within the following structural range:

[0012]

[0013] and tautomers thereof, deuterated derivatives 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 heterocyclyl, and

[0018] ■5 to 10 membered heteroaryl;

[0019] Ring B is selected from:

[0020] ■C6-C 10 aryl,

[0021] ■C3-C 10 cycloalkyl,

[0022] ■3 to 10 membered heterocyclyl, and

[0023] ■5 to 10 membered heteroaryl;

[0024] V is selected from O and NH;

[0025] W 1 selected from N and CH;

[0026] W2 is selected from N and CH, provided that W 1 and W 2 is N;

[0027] Z is selected from O, NR ZN and C(R ZC )2, provided that when L 2 is absent, Z is C(R ZC )2;

[0028] each L 1 is independently selected from C(R L1 )2and

[0029] each L 2 is independently selected from C(R L2 )2;

[0030] Ring C is selected from C6-C 10 aryl optionally substituted with 1-3 groups independently selected from:

[0031] ■halo,

[0032] ■C1-C6alkyl, and

[0033] ■N(R N )2;

[0034] each R 3 is independently selected from:

[0035] ■halo,

[0036] ■C1-C6alkyl,

[0037] ■C1-C6alkoxy,

[0038] ■C3-C 10 cycloalkyl,

[0039] ■C6-C 10 aryl optionally substituted with 1-3 groups independently selected from C1-C6alkyl, and

[0040] ■3- to 10-membered heterocyclyl;

[0041] R 4 is selected from hydrogen and C1-C6alkyl;

[0042] each R 5 is independently selected from:

[0043] ■hydrogen,

[0044] ■halo,

[0045] ■hydroxyl,

[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] ■hydrogen,

[0066] ■C1-C9 alkyl optionally substituted with 1-3 groups independently selected from:

[0067] o hydroxy,

[0068] o oxo,

[0069] o cyano,

[0070] o C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from halogen and C1-C6 alkoxy,

[0071] o N(R N )2,

[0072] o SO2Me,

[0073] o C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from:

[0074] ♦ hydroxy,

[0075] ♦ C1-C6 alkyl optionally substituted with 1-3 groups independently selected from hydroxy, oxo, C1-C6 alkoxy, C6-C 10 aryl and N(R N )2,

[0076] ♦ C1-C6 fluoroalkyl,

[0077] ♦ C1-C6 alkoxy,

[0078] ♦ COOH,

[0079] ♦ N(R N )2,

[0080] ♦ C6-C 10 aryl, and

[0081] ♦ 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from oxo and C1-C6 alkyl,

[0082] o C6-C 10 aryl optionally substituted with 1-3 groups independently selected from:

[0083] ♦ halogen,

[0084] ♦ hydroxy,

[0085] ♦ cyano,

[0086] ♦ SiMe3,

[0087] ♦ SO2Me,

[0088] ♦ SF5,

[0089] ♦ N(R N )2,

[0090] ♦ P(O)Me2,

[0091] ♦ -(O) 0-1 -(C3-C 10 cycloalkyl),

[0092] ♦ C1-C6 alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6 alkoxy, 5- to 10-membered heteroaryl, SO2Me, and N(R N )2,

[0093] ♦ C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, N(R N )2, and C6-C 10 aryl,

[0094] ♦ C1-C6 fluoroalkyl,

[0095] ♦ 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl,

[0096] ♦ -(O) 0-1 -(C6-C 10 aryl), and

[0097] ♦ -(O) N optionally substituted with hydroxyl, oxo, N(R 10 )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, and C3-C 0-1 cycloalkyl,

[0098] ♦ 3- to 10-membered heterocyclyl optionally substituted with 1-4 groups independently selected from:

[0099] ♦ hydroxyl,

[0100] ♦ oxo,

[0101] ♦ N(R N )2,

[0102] ♦ C1-C6 alkyl optionally substituted with 1-3 groups independently selected from oxo and C1-C6 alkoxy,

[0103] ♦ C1-C6 alkoxy,

[0104] ♦ C1-C6fluoroalkyl,

[0105] ♦ C6-C10aryl optionally substituted with 1-3 groups independently selected from halogen, 10 aryl, and

[0106] ♦ 5- to 10-membered heteroaryl,

[0107] ♦ 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from halogen,

[0108] ♦ hydroxyl,

[0109] ♦ cyano,

[0110] ♦ oxo,

[0111] ♦ halogen,

[0112] ♦ B(OH)2,

[0113] ♦ N(R N )2,

[0114] ♦ C1-C6alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6alkoxy (optionally substituted with 1-3 -SiMe3), 3- to 10-membered heterocyclyl, and N(R N )2,

[0115] ♦ C1-C6alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, halogen, C1-C6alkoxy, N(R N )2, 3- to 10-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C1-C6alkyl), and C3-C 10 cycloalkyl,

[0116] ♦ C1-C6fluoroalkyl,

[0117] ♦ -(O) 0-1 -(C3-C 10 cycloalkyl) optionally substituted with 1-3 groups independently selected from halogen, C1-C6alkyl, and C1-C6alkoxy,

[0118] ♦ -(O) 0-1 -(C6-C 10 aryl) optionally substituted with 1-3 groups independently selected from halogen, C1-C6alkyl, and C1-C6alkoxy,

[0119] ♦ C1-C6alkyl optionally substituted with 1-4 groups independently selected from hydroxyl, oxo, halogen, cyano, N(R N )2, C1-C6alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, N(R N)2, and C1-C6alkoxy, C1-C6fluoroalkyl, C3-C 10 cycloalkyl, 5- to 10-membered heteroaryl (optionally substituted with 1-3 groups independently selected from C1-C6alkyl), and 3- to 10-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C1-C6fluoroalkyl), and 0-1 -(3- to 10-membered heterocyclyl), and

[0120] ♦ 5- to 10-membered heteroaryl optionally substituted with 1-4 groups independently selected from C1-C6alkyl and C3-C 10 cycloalkyl, and

[0121] ■C1-C6fluoroalkyl;

[0122] R ZN selected from:

[0123] ■hydrogen,

[0124] ■C1-C9alkyl optionally substituted with 1-3 groups independently selected from:

[0125] o hydroxy,

[0126] o oxo,

[0127] o cyano,

[0128] o C1-C6alkoxy optionally substituted with 1-3 groups independently selected from halogen and C1-C6alkoxy,

[0129] o N(R N )2,

[0130] o SO2Me,

[0131] o C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from:

[0132] ♦ hydroxy,

[0133] ♦ C1-C6alkyl optionally substituted with 1-3 groups independently selected from hydroxy, oxo, C1-C6alkoxy, C6-C 10 aryl, and N(R N )2,

[0134] ♦ C1-C6fluoroalkyl,

[0135] ♦ C1-C6alkoxy,

[0136] ♦ COOH,

[0137] ♦ N(R N)2,

[0138] ◆C6-C 10 Aryl, and

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

[0140] ○ C6-C cells optionally substituted with 1-3 independently selected groups from the following 10 Aryl:

[0141] ◆Halogen,

[0142] ◆Hydroxy group,

[0143] ◆Cyano

[0144] ◆SiMe3,

[0145] ◆SO2Me,

[0146] ◆SF5,

[0147] ◆N(R N )2,

[0148] ◆P(O)Me2,

[0149] ◆Optionally substituted with 1-3 independently selected C1-C6 fluoroalkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[0150] ◆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,

[0151] ◆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,

[0152] ◆C1-C6 fluoroalkyl groups,

[0153] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, 3- to 10-membered heterocyclic groups,

[0154] ◆-(O) 0-1 -(C6-C 10 Aryl), and

[0155] ◆Optionally coated with hydroxyl, oxidized, N(R) N)2, C1-C6alkyl, C1-C6alkoxy, C1-C6fluoroalkyl, and C3-C 10 cycloalkyl-substituted -(O) 0-1 -(5- to 10-membered heteroaryl),

[0156] o 3- to 10-membered heterocyclyl optionally substituted with 1-4 groups independently selected from:

[0157] ♦ hydroxy,

[0158] ♦ oxo,

[0159] ♦ N(R N )2,

[0160] ♦ C1-C6alkyl optionally substituted with 1-3 groups independently selected from oxo and C1-C6alkoxy,

[0161] ♦ C1-C6alkoxy,

[0162] ♦ C1-C6fluoroalkyl,

[0163] ♦ C6-C10aryl optionally substituted with 1-3 groups independently selected from halogen, 10 and

[0164] ♦ 5- to 10-membered heteroaryl,

[0165] o 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

[0166] ♦ hydroxy,

[0167] ♦ cyano,

[0168] ♦ oxo,

[0169] ♦ halogen,

[0170] ♦ B(OH)2,

[0171] ♦ N(R N )2,

[0172] ♦ C1-C6alkyl optionally substituted with 1-3 groups independently selected from hydroxy, oxo, C1-C6alkoxy (optionally substituted with 1-3 -SiMe3), and N(R N )2,

[0173] ♦ C1-C6alkoxy optionally substituted with 1-3 groups independently selected from hydroxy, oxo, C1-C6alkyl, N(R N )2, and C3-C 10 cycloalkyl,

[0174] ♦ C1-C6fluoroalkyl,

[0175] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[0176] ◆-(O) 0-1 -(C6-C 10 (Aryl),

[0177] ◆Optionally selected by 1-4 independently chosen from hydroxyl, oxo, halogen, cyano, N(R) N 2. C1-C6 alkyl groups (optionally surrounded by 1-3 independently selected from hydroxyl, oxo, N(R) groups) N -(O) groups substituted with C1-C6 alkoxy groups, C1-C6 alkoxy groups, C1-C6 fluoroalkyl groups, or 3- to 10-membered heterocyclic groups (optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl groups). 0-1 -(3 to 10-membered heterocyclic groups), and

[0178] ◆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,

[0179] ■C1-C6 fluoroalkyl groups,

[0180] ■ C3-C, optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[0181] ○Hydroxy group,

[0182] ○Oxygenation,

[0183] ○ Halogen,

[0184] ○Cyano

[0185] ○N(R N )2,

[0186] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0187] ◆Hydroxy group,

[0188] ◆Oxygenation,

[0189] ◆N(R N )2,

[0190] ◆C1-C6 alkoxy groups, and

[0191] ◆C6-C 10 Aryl,

[0192] o C1-C6alkyl optionally substituted with 1-3 groups independently selected from halo, oxo, C6-C10aryl, 3- to 10-membered heterocyclyl, -NR 10 aryl and N(R N )2,

[0193] o halo,

[0194] o C3-C 10 cycloalkyl,

[0195] o 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl,

[0196] o 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

[0197] ♦ hydroxy,

[0198] ♦ cyano,

[0199] ♦ oxo,

[0200] ♦ halo,

[0201] ♦ N(R N )2,

[0202] ♦ C1-C6alkyl optionally substituted with 1-3 groups independently selected from hydroxy, oxo, C1-C6alkoxy, and N(R N )2,

[0203] ♦ C1-C6alkoxy optionally substituted with 1-3 groups independently selected from hydroxy, C1-C6alkoxy, N(R N )2, and C3-C 10 cycloalkyl,

[0204] ♦ C1-C6fluoroalkyl,

[0205] ♦ -(O) 0-1 -(C3-C 10 cycloalkyl),

[0206] ♦ C6-C 10 aryl,

[0207] ♦ 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl,

[0208] ■ C6-C 10 aryl,

[0209] ■ 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from: ■ C6-C 10 aryl,

[0209] ■ 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

[0210] • oxo,

[0211] • C1-C6 alkyl optionally substituted with 1-3 groups independently selected from:

[0212] • oxo,

[0213] • hydroxyl,

[0214] • N(R N )2,

[0215] • C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from halogen and C6-C 10 aryl, and

[0216] • -(O) 0-1 -(C3-C 10 cycloalkyl),

[0217] • C1-C6 fluoroalkyl,

[0218] • C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from halogen, and

[0219] • 3- to 10-membered heterocyclyl,

[0220] • 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

[0221] • halogen,

[0222] • C1-C6 alkyl optionally substituted with 1-3 groups independently selected from oxo, C1-C6 alkoxy, and N(R N )2, and

[0223] • 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl (optionally substituted with 1-3 groups selected from oxo, C1-C6 alkoxy, and C6-C 10 aryl,

[0224] R F ;

[0225] each R ZC is independently selected from:

[0226] • hydrogen,

[0227] • C1-C6 alkyl optionally substituted with 1-3 groups independently selected from C6-C 10 aryl (optionally substituted with 1-3 groups independently selected from C1-C6 alkyl),

[0228] ■ C6-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 Aryl, and

[0229] ■R F ;

[0230] Or two Rs ZC Together they form an oxo group;

[0231] Each R L1 Selected independently from:

[0232] ■ Hydrogen,

[0233] ■N(R N )2, the condition is two N(R) N )2 does not combine with the same carbon atom.

[0234] ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0235] ○ Halogen,

[0236] ○Hydroxy group,

[0237] ○Oxygenation,

[0238] ○N(R N )2,

[0239] ○Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[0240] ○ C3-C alkyl groups optionally substituted with 1-3 independently selected groups chosen from halogens, C1-C6 alkyl groups, and C1-C6 fluoroalkyl groups 10 cycloalkyl,

[0241] ○-O-(C3-C 10 cycloalkyl),

[0242] ○ C6-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 Aryl, and

[0243] ○ 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),

[0244] ■ C3-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 cycloalkyl,

[0245] ■ C6-C cells optionally substituted with 1-4 independently selected groups from the following10 aryl:

[0246] o halogen,

[0247] o cyano,

[0248] o SiMe3,

[0249] o POMe2,

[0250] o C1-C7 alkyl optionally substituted with 1-3 groups independently selected from:

[0251] o hydroxy,

[0252] o oxo,

[0253] o cyano,

[0254] o SiMe3,

[0255] o N(R N )2, and

[0256] o C3-C7 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl, 10 cycloalkyl,

[0257] o C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from:

[0258] o C3-C7 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl, 10 cycloalkyl, and

[0259] o C1-C6 alkoxy,

[0260] o C1-C6 fluoroalkyl,

[0261] o C3-C7 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl and C1-C6 fluoroalkyl, 10 cycloalkyl,

[0262] o C6-C 10 aryl,

[0263] o 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl, and

[0264] o 5- to 10-membered heteroaryl,

[0265] o 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

[0266] o C1-C6 alkyl optionally substituted with 1-3 groups independently selected from:

[0267] ♦ oxo, and

[0268] ♦ C1-C6alkoxy,

[0269] ■5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

[0270] o C1-C6alkyl optionally substituted with 1-3 groups independently selected from:

[0271] ♦ C3-C6cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl, 10 cycloalkyl, and

[0272] o C6-C10aryl optionally substituted with 1-3 groups independently selected from C1-C6alkyl, 10 aryl, and

[0273] ■R F ;

[0274] or two R L1 on the same carbon atom together form an oxo group;

[0275] each R L2 is independently selected from hydrogen and R F ;

[0276] or two R L2 on the same carbon atom together form an oxo group;

[0277] each R N is independently selected from:

[0278] ■ hydrogen,

[0279] ■ C1-C8alkyl optionally substituted with 1-3 groups independently selected from:

[0280] o oxo,

[0281] o halogen,

[0282] o hydroxyl,

[0283] o NH2,

[0284] o NHMe,

[0285] o NMe2,

[0286] o NHCOMe,

[0287] o N(R N3 )2, wherein each R N3independently selected from C1-C6alkyl (optionally substituted with 1-3 groups independently selected from oxo and C1-C6alkoxy),

[0288] o C6-C 10 aryl, oxo, NMe2, and NHMe,

[0289] o -(O) 0-1 -(C3-C 10 cycloalkyl),

[0290] o C6-C 10 aryl,

[0291] o 3- to 14-membered heterocyclyl optionally substituted with 1-4 groups independently selected from oxo and C1-C6alkyl, and

[0292] o 5- to 14-membered heteroaryl optionally substituted with 1-4 groups independently selected from oxo and C1-C6alkyl,

[0293] ■ C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from:

[0294] o hydroxy,

[0295] o halogen,

[0296] o NH 2，

[0297] o NHMe,

[0298] o C1-C6alkoxy, and

[0299] o C1-C6alkyl optionally substituted with 1-3 groups independently selected from hydroxy and C1-C6alkoxy,

[0300] ■ C6-C 10 aryl,

[0301] ■ 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from C1-C6alkyl, and

[0302] ■ 3- to 10-membered heterocyclyl;

[0303] or two R Nwith the nitrogen to which it is bound forms a 3- to 10-membered heterocyclyl group optionally substituted with 1-4 groups selected from:

[0304] ■hydroxy,

[0305] ■halogen,

[0306] ■oxo,

[0307] ■cyano,

[0308] ■C1-C6 alkyl optionally substituted with 1-3 groups independently selected from oxo, hydroxy, C1-C6 alkoxy, and N(R N2 )2, wherein each R N2 is independently selected from hydrogen and C1-C6 alkyl,

[0309] ■C1-C6 alkoxy, and

[0310] ■C1-C6 fluoroalkyl;

[0311] or one R 4 and one R L1 together with the atoms to which they are bound form a C6-C8 alkylene group;

[0312] when R F is present, two R F together with the atom to which they are bound form a group selected from:

[0313] ■C3-C6 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl, 10

[0314] ■C6-C10 aryl optionally substituted with 1-3 groups independently selected from: 10

[0315] o halogen,

[0316] o C1-C6 alkyl,

[0317] o N(R N )2, and

[0318] o 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from hydroxy,

[0319] ■3- to 11-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

[0320] o oxo,

[0321] o N(R N )2,

[0322] ​​o C1-C9alkyl optionally substituted by 1-4 groups independently selected from:

[0323] ♦ oxo,

[0324] ♦ halogen,

[0325] ♦ hydroxyl,

[0326] ♦ N(R N )2,

[0327] ♦ -SO2-(C1-C6alkyl),

[0328] ♦ C1-C6alkoxy optionally substituted by 1-3 groups independently selected from halogen and C6-C 10 aryl,

[0329] ♦ C6-C 10 aryl optionally substituted by 1-3 groups independently selected from hydroxyl, halogen, cyano, C1-C6alkyl optionally substituted by 1-3 groups independently selected from oxo and C1-C6alkoxy, C1-C6alkoxy optionally substituted by 1-3 groups independently selected from C6-C 0-1 aryl optionally substituted by 1-3 groups independently selected from halogen, -(O) 10 -(C1-C6fluoroalkyl) and C6-C 10 aryl optionally substituted by 1-3 groups independently selected from C1-C6alkoxy,

[0330] ♦ -(O) N )2, C1-C6alkyl optionally substituted by 1-3 groups independently selected from oxo, hydroxyl and C1-C6alkoxy, C1-C6fluoroalkyl and C6-C 10 aryl, 0-1 -(C3-C 10 cycloalkyl),

[0331] ♦ 3- to 10-membered heterocyclyl optionally substituted by 1-3 groups independently selected from oxo, C1-C6alkyl optionally substituted by 1-3 groups independently selected from C6-C 10 aryl optionally substituted by 1-3 groups independently selected from halogen, C1-C6alkoxy, C3-C 10 cycloalkyl and R N ,

[0332] ♦ -O-(5- to 12-membered heteroaryl) optionally substituted by 1-3 groups independently selected from C6-C 10 aryl optionally substituted by 1-3 groups independently selected from halogen and C1-C6alkyl, and

[0333] ♦ 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from hydroxy, 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,

[0334] ♦ C3-C 12 cycloalkyl optionally substituted with 1-4 groups independently selected from halogen, C1-C6 alkyl, and C1-C6 fluoroalkyl,

[0335] ♦ C6-C 10 aryl,

[0336] ♦ 3- to 10-membered heterocyclyl, and

[0337] ♦ 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from C1-C6 alkoxy and C1-C6 fluoroalkyl, and

[0338] ♦ 5- to 12-membered heteroaryl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl and C1-C6 fluoroalkyl.

[0339] Formula I encompasses compounds of Formula la within the following structural range:

[0340]

[0341] and including tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein:

[0342] Ring A is selected from:

[0343] ♦ C6-C 10 aryl,

[0344] ♦ C3-C 10 cycloalkyl,

[0345] ♦ 3- to 10-membered heterocyclyl, and

[0346] ♦ 5- to 10-membered heteroaryl;

[0347] Ring B is selected from:

[0348] ♦ C6-C 10 aryl,

[0349] ♦ C3-C 10 cycloalkyl,

[0350] ■3- to 10-membered heterocyclyl, and

[0351] ■5- to 10-membered heteroaryl;

[0352] V is selected from O and NH;

[0353] W 1 is selected from N and CH;

[0354] W 2 is selected from N and CH, provided that at least one of W 1 and W 2 is N;

[0355] Z is selected from O, NR ZN , and C(R ZC )2, provided that when L 2 is absent, Z is C(R ZC )2;

[0356] each L 1 is independently selected from C(R L1 )2and

[0357] each L 2 is independently selected from C(R L2 )2;

[0358] Ring C is selected from C6-C 10 aryl optionally substituted with 1-3 groups independently selected from:

[0359] ■halo,

[0360] ■C1-C6alkyl, and

[0361] ■N(R N )2;

[0362] each R 3 is independently selected from:

[0363] ■halo,

[0364] ■C1-C6alkyl,

[0365] ■C1-C6alkoxy,

[0366] ■C3-C 10 cycloalkyl,

[0367] ■C6-C 10 aryl optionally substituted with 1-3 groups independently selected from C1-C6alkyl, and

[0368] ■3- to 10-membered heterocyclyl;

[0369] R 4 selected from hydrogen and Ci-C6alkyl;

[0370] each R 5 is independently selected from:

[0371] ■ hydrogen,

[0372] ■ halogen,

[0373] ■ hydroxyl,

[0374] ■ N(R N )2,

[0375] ■ -SO-Me,

[0376] ■ -CH=C(R LC )2, wherein both R LC together form a C3-C 10 cycloalkyl,

[0377] ■ Ci-C6alkyl optionally substituted with 1-3 groups independently selected from:

[0378] o hydroxyl,

[0379] o Ci-C6alkoxy optionally substituted with 1-3 groups independently selected from Ci-C6alkyl and C6-C 10 aryl,

[0380] o C3-C 10 cycloalkyl,

[0381] o -(O) 0-1 -(C6-C 10 aryl) optionally substituted with 1-3 groups independently selected from Ci-C6alkyl and Ci-C6alkoxy,

[0382] o 3- to 10-membered heterocyclyl, and

[0383] o N(R N )2,

[0384] ■ Ci-C6alkoxy optionally substituted with 1-3 groups independently selected from:

[0385] o halogen,

[0386] o C6-C 10 aryl, and

[0387] o C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from Ci-C6fluoroalkyl,

[0388] ■ Ci-C6fluoroalkyl,

[0389] ■C3-C 10 cycloalkyl,

[0390] ■C6-C 10 aryl, and

[0391] ■3- to 10-membered heterocyclyl;

[0392] R YN is selected from:

[0393] ■hydrogen,

[0394] ■C1-C9 alkyl optionally substituted with 1-3 groups independently selected from:

[0395] o hydroxy,

[0396] o oxo,

[0397] o cyano,

[0398] o C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from halogen and C1-C6 alkyl,

[0399] o N(R N )2,

[0400] o SO2Me,

[0401] o C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from:

[0402] o hydroxy,

[0403] o C1-C6 alkyl optionally substituted with 1-3 groups independently selected from hydroxy, oxo, C1-C6 alkoxy, C6-C 10 aryl, and N(R N )2,

[0404] o C1-C6 fluoroalkyl,

[0405] o C1-C6 alkoxy,

[0406] o COOH,

[0407] o N(R N )2,

[0408] o C6-C 10 aryl, and

[0409] o 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from oxo and C1-C6 alkyl,

[0410] ○ C6-C cells optionally substituted with 1-3 independently selected groups from the following 10 Aryl:

[0411] ◆Halogen,

[0412] ◆Hydroxy group,

[0413] ◆Cyano

[0414] ◆SiMe3,

[0415] ◆SO2Me,

[0416] ◆SF5,

[0417] ◆N(R N )2,

[0418] ◆P(O)Me2,

[0419] ◆Optionally substituted with 1-3 independently selected C1-C6 fluoroalkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[0420] ◆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,

[0421] ◆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,

[0422] ◆C1-C6 fluoroalkyl groups,

[0423] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, 3- to 10-membered heterocyclic groups,

[0424] ◆-(O) 0-1 -(C6-C 10 Aryl), and

[0425] ◆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),

[0426] ○Optionally substituted with 1 to 4 independently selected groups from the following 3- to 10-membered heterocyclic groups:

[0427] ◆Hydroxy group,

[0428] ♦ oxo,

[0429] ♦ N(R N )2,

[0430] ♦ C1-C6alkyl optionally substituted with 1-3 groups independently selected from oxo and C1-C6alkoxy,

[0431] ♦ C1-C6alkoxy,

[0432] ♦ C1-C6fluoroalkyl,

[0433] ♦ C6-C 10 aryl optionally substituted with 1-3 groups independently selected from halogen, and

[0434] ♦ 5- to 10-membered heteroaryl,

[0435] o 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

[0436] ♦ hydroxy,

[0437] ♦ cyano,

[0438] ♦ oxo,

[0439] ♦ halogen,

[0440] ♦ B(OH)2,

[0441] ♦ N(R N )2,

[0442] ♦ C1-C6alkyl optionally substituted with 1-3 groups independently selected from hydroxy, oxo, C1-C6alkoxy (optionally substituted with 1-3 -SiMe3), and N(R N )2,

[0443] ♦ C1-C6alkoxy optionally substituted with 1-3 groups independently selected from hydroxy, oxo, halogen, C1-C6alkyl, N(R N )2, and C3-C 10 cycloalkyl,

[0444] ♦ C1-C6fluoroalkyl,

[0445] ♦ -(O) 0-1 -(C3-C 10 cycloalkyl) optionally substituted with 1-3 groups independently selected from halogen, C1-C6alkyl, and C1-C6alkoxy,

[0446] ♦ -(O) 0-1 -(C6-C 10 aryl),

[0447] ♦ -(O)0-2-(C3-C6cycloalkyl), and N N ♦ -(O)0-2-(3- to 10-membered heterocyclyl), and 0-1 ♦ -(O)0-2-(5- to 10-membered heteroaryl), and

[0448] ♦ -(O)0-2-(5- to 10-membered heteroaryl), and 10 ♦ -(O)0-2-(5- to 10-membered heteroaryl), and

[0449] ♦ -(O)0-2-(5- to 10-membered heteroaryl), and

[0450] ♦ -(O)0-2-(5- to 10-membered heteroaryl), and ZN ♦ -(O)0-2-(5- to 10-membered heteroaryl), and

[0451] ♦ -(O)0-2-(5- to 10-membered heteroaryl), and

[0452] ♦ -(O)0-2-(5- to 10-membered heteroaryl), and

[0453] ♦ -(O)0-2-(5- to 10-membered heteroaryl), and

[0454] ♦ -(O)0-2-(5- to 10-membered heteroaryl), and

[0455] ♦ -(O)0-2-(5- to 10-membered heteroaryl), and

[0456] ♦ -(O)0-2-(5- to 10-membered heteroaryl), and

[0457] ♦ -(O)0-2-(5- to 10-membered heteroaryl), and N ♦ -(O)0-2-(5- to 10-membered heteroaryl), and

[0458] ♦ -(O)0-2-(5- to 10-membered heteroaryl), and

[0459] ♦ -(O)0-2-(5- to 10-membered heteroaryl), and 10 ♦ -(O)0-2-(5- to 10-membered heteroaryl), and

[0460] ♦ -(O)0-2-(5- to 10-membered heteroaryl), and

[0461] ♦ -(O)0-2-(5- to 10-membered heteroaryl), and 10 ♦ -(O)0-2-(5- to 10-membered heteroaryl), and N ♦ -(O)0-2-(5- to 10-membered heteroaryl), and

[0462] ♦ -(O)0-2-(5- to 10-membered heteroaryl), and

[0463] ♦ -(O)0-2-(5- to 10-membered heteroaryl), and ♦ -(O)0-2-(5- to 10-membered heteroaryl), and

[0464] ♦ COOH,

[0465] ♦ N(R N )2,

[0466] ♦ C6-C 10 aryl, and

[0467] ♦ 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from oxo and C1-C6 alkyl,

[0468] o C6-C 10 aryl optionally substituted with 1-3 groups independently selected from:

[0469] ♦ halogen,

[0470] ♦ hydroxyl,

[0471] ♦ cyano,

[0472] ♦ SiMe3,

[0473] ♦ SO2Me,

[0474] ♦ SF5,

[0475] ♦ N(R N )2,

[0476] ♦ P(O)Me2,

[0477] ♦ -(O) 0-1 -(C3-C 10 cycloalkyl) optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl,

[0478] ♦ C1-C6 alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6 alkoxy, 5- to 10-membered heteroaryl, SO2Me, and N(R N )2,

[0479] ♦ C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, N(R N )2, and C6-C 10 aryl,

[0480] ♦ C1-C6 fluoroalkyl,

[0481] ♦ 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl,

[0482] ♦ -(O) 0-1 -(C6-C 10 aryl), and

[0483] ◆ C1-C6 alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6 alkoxy, 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-membered heteroaryl),

[0484] o 3- to 10-membered heterocyclyl optionally substituted with 1-4 groups independently selected from:

[0485] ◆ hydroxyl,

[0486] ◆ oxo,

[0487] ◆ N(R N )2,

[0488] ◆ C1-C6 alkyl optionally substituted with 1-3 groups independently selected from oxo and C1-C6 alkoxy,

[0489] ◆ C1-C6 alkoxy,

[0490] ◆ C1-C6 fluoroalkyl,

[0491] ◆ C6-C10 aryl optionally substituted with 1-3 groups independently selected from halogen, 10 and

[0492] ◆ 5- to 10-membered heteroaryl,

[0493] o 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

[0494] ◆ hydroxyl,

[0495] ◆ cyano,

[0496] ◆ oxo,

[0497] ◆ halogen,

[0498] ◆ B(OH)2,

[0499] ◆ N(R N )2,

[0500] ◆ C1-C6 alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6 alkoxy (optionally substituted with 1-3 -SiMe3), and N(R N )2,

[0501] ◆ C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6 alkoxy, N(R N )2, and C3-C 10 cycloalkyl,

[0502] ♦ C1-C6fluoroalkyl,

[0503] ♦ -(O) 0-1 -(C3-C 10 cycloalkyl),

[0504] ♦ -(O) 0-1 -(C6-C 10 aryl),

[0505] ♦ -(O) N )2, C1-C6alkyl (optionally substituted with 1-3 groups independently selected from the group consisting of hydroxyl, oxo, N(R N )2, and C1-C6alkoxy), C1-C6alkoxy, C1-C6fluoroalkyl, 3- to 10-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C1-C6fluoroalkyl), 0-1 -(3- to 10-membered heterocyclyl), and

[0506] ♦ 5- to 10-membered heteroaryl optionally substituted with 1-4 groups independently selected from C1-C6alkyl and C3-C 10 cycloalkyl,

[0507] ♦ C1-C6fluoroalkyl,

[0508] ♦ C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from the group consisting of:

[0509] o hydroxyl,

[0510] o oxo,

[0511] o halogen,

[0512] o cyano,

[0513] o N(R N )2,

[0514] o C1-C6alkyl optionally substituted with 1-3 groups independently selected from the group consisting of:

[0515] ♦ hydroxyl,

[0516] ♦ oxo,

[0517] ♦ N(R N )2,

[0518] ♦ C1-C6alkoxy, and

[0519] ♦ C6-C 10aryl,

[0520] o C1-C6 alkyl optionally substituted with 1-3 groups independently selected from halo, oxo, C6-C10 aryl, 3- to 10-membered heterocyclyl, -N(R 10 aryl, and N(R N )2,

[0521] o halo,

[0522] o C3-C6 cycloalkyl, 10 o C3-C6 cycloalkyl,

[0523] o 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl,

[0524] o 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

[0525] • hydroxyl,

[0526] • cyano,

[0527] • oxo,

[0528] • halo,

[0529] • N(R N )2,

[0530] • C1-C6 alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6 alkoxy, and N(R N )2,

[0531] • C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from hydroxyl, C1-C6 alkoxy, N(R N )2, and C3-C6 cycloalkyl, 10 • C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from hydroxyl, C1-C6 alkoxy, N(R 0-1 )2, and C3-C6 cycloalkyl,

[0532] • C1-C6 fluoroalkyl,

[0533] • -(O) 10 -(C3-C6 cycloalkyl) optionally substituted with 1-3 groups independently selected from C1-C6 alkyl,

[0534] • C6-C10 aryl, 10 • C6-C10 aryl,

[0535] • 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl,

[0536] • C6-C10 aryl, 10 • C6-C10 aryl,

[0537] • 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

[0538] ○Oxygenation,

[0539] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[0540] ◆Oxygenation,

[0541] ◆Hydroxy group,

[0542] ◆N(R N )2,

[0543] ◆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

[0544] ◆-(O) 0-1 -(C3-C 10 cycloalkyl),

[0545] ○C1-C6 fluoroalkyl,

[0546] ○ C3-C groups optionally substituted with 1-3 independently selected halogen groups 10 cycloalkyl groups, and

[0547] ○3 to 10-membered heterocyclic groups,

[0548] ■ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0549] ○ Halogen,

[0550] ○Optionally selected by 1-3 independently chosen from oxo, C1-C6 alkoxy and N(R) N C1-C6 alkyl groups substituted with )2, and

[0551] ○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

[0552] ■R F ;

[0553] Each R ZC Selected independently from:

[0554] ■ Hydrogen,

[0555] ■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),

[0556] ■C6-C10aryl optionally substituted with 1-3 groups independently selected from C1-C6alkyl, 10 aryl, and

[0557] ■R F ;

[0558] or two R ZC groups together form an oxo group;

[0559] each R L1 is independently selected from:

[0560] ■hydrogen,

[0561] ■N(R N )2, provided that both N(R N )2groups are not bound to the same carbon,

[0562] ■C1-C9alkyl optionally substituted with 1-3 groups independently selected from:

[0563] o halogen,

[0564] o hydroxyl,

[0565] o oxo,

[0566] o N(R N )2,

[0567] o C1-C6alkoxy optionally substituted with 1-3 groups independently selected from C6-C 10 aryl,

[0568] o C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from halogen and C1-C6fluoroalkyl,

[0569] o C6-C 10 aryl optionally substituted with 1-3 groups independently selected from C1-C6alkyl,

[0570] o 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and oxo),

[0571] ■C3-C 10 cycloalkyl,

[0572] ■C6-C 10 aryl optionally substituted with 1-4 groups independently selected from:

[0573] o halogen,

[0574] o cyano,

[0575] o SiMe3,

[0576] o POMe2,

[0577] o C1-C7 alkyl optionally substituted with 1-3 groups independently selected from:

[0578] ♦ hydroxy,

[0579] ♦ oxo,

[0580] ♦ cyano,

[0581] ♦ SiMe3,

[0582] ♦ N(R N )2, and

[0583] ♦ C3-C7 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl, 10 ♦ C3-C7 cycloalkyl,

[0584] o C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from:

[0585] ♦ C3-C7 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl, 10 ♦ C3-C7 cycloalkyl, and

[0586] ♦ C1-C6 alkoxy,

[0587] o C1-C6 fluoroalkyl,

[0588] o C3-C7 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl and C1-C6 fluoroalkyl, 10 ♦ C3-C7 cycloalkyl,

[0589] o C6-C 10 aryl,

[0590] o 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl, and

[0591] o 5- to 10-membered heteroaryl,

[0592] ■ 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

[0593] o C1-C6 alkyl optionally substituted with 1-3 groups independently selected from:

[0594] ♦ oxo, and

[0595] ♦ C1-C6 alkoxy,

[0596] ■5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

[0597] ○C1-C6alkyl optionally substituted with 1-3 groups independently selected from:

[0598] ◆C3-C6cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6fluoroalkyl, 10 cycloalkyl, and

[0599] ○C6-C10aryl optionally substituted with 1-3 groups independently selected from C1-C6alkyl, 10 aryl, and

[0600] ■R F ;

[0601] or two R L1 on the same carbon atom together form an oxo group;

[0602] each R L2 is independently selected from hydrogen and R F ;

[0603] or two R L2 on the same carbon atom together form an oxo group;

[0604] each R N is independently selected from:

[0605] ■hydrogen,

[0606] ■C1-C8alkyl optionally substituted with 1-3 groups independently selected from:

[0607] ○oxo,

[0608] ○halo,

[0609] ○hydroxy,

[0610] ○NH2,

[0611] ○NHMe,

[0612] ○NMe2,

[0613] ○NHCOMe,

[0614] ○C1-C6alkoxy optionally substituted with 1-3 groups independently selected from C6-C10aryl, 10

[0615] ○-(O) 0-1 -(C3-C 10 cycloalkyl),

[0616] ​• C6-C10aryl optionally substituted with 1-3 groups independently selected from halogen and C1-C6alkyl, 10 • C6-C10aryl,

[0617] • 3- to 14-membered heterocyclyl optionally substituted with 1-4 groups independently selected from oxo and C1-C6alkyl, and

[0618] • 5- to 14-membered heteroaryl optionally substituted with 1-4 groups independently selected from oxo and C1-C6alkyl,

[0619] • C3-C6cycloalkyl optionally substituted with 1-3 groups independently selected from halogen and C1-C6alkyl, 10 • C3-C6cycloalkyl:

[0620] • hydroxyl,

[0621] • NH 2，

[0622] • NHMe, and

[0623] • C1-C6alkyl optionally substituted with 1-3 groups independently selected from hydroxyl,

[0624] • C6-C10aryl, and 10 • C6-C10aryl, and

[0625] • 3- to 10-membered heterocyclyl;

[0626] • two R N groups on the same nitrogen atom, together with the nitrogen to which they are bound, form a 3- to 10-membered heterocyclyl optionally substituted with 1-4 groups selected from:

[0627] • hydroxyl,

[0628] • halogen,

[0629] • oxo,

[0630] • cyano,

[0631] • C1-C6alkyl optionally substituted with 1-3 groups independently selected from oxo, hydroxyl, C1-C6alkoxy and N(R N2 )2, wherein each R N2 is independently selected from hydrogen and C1-C6alkyl,

[0632] • C1-C6alkoxy, and

[0633] • C1-C6fluoroalkyl;

[0634] • one R 4 and one R L1 together form a C6-C8alkylene;

[0635] R F R F together with the atom to which they are attached form a group selected from:

[0636] ■C3-C 10 cycloalkyl,

[0637] ■C6-C 10 aryl optionally substituted with 1-3 groups independently selected from:

[0638] o halogen,

[0639] o C1-C6alkyl,

[0640] o N(R N )2, and

[0641] o 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from hydroxyl,

[0642] ■3- to 11-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

[0643] o oxo,

[0644] o N(R N )2,

[0645] o C1-C9alkyl optionally substituted with 1-4 groups independently selected from:

[0646] ♦ oxo,

[0647] ♦ halogen,

[0648] ♦ hydroxyl,

[0649] ♦ N(R N )2,

[0650] ♦ -SO2-(C1-C6alkyl),

[0651] ♦ C1-C6alkoxy optionally substituted with 1-3 groups independently selected from halogen and C6-C 10 aryl,

[0652] ♦ C6-C 10 aryl optionally substituted with 1-3 groups independently selected from hydroxyl, halogen, cyano, C1-C6alkyl (optionally substituted with 1-3 groups independently selected from oxo and C1-C6alkoxy), C1-C6alkoxy (optionally substituted with 1-3 groups independently selected from C6-C 0-1 aryl, -(O) 10 -(C1-C6fluoroalkyl), and C6-CThe C6-C group substituted with an aryl group (optionally replaced by 1-3 groups independently selected from C1-C6 alkoxy groups). 10 Aryl,

[0653] ◆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),

[0654] ◆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,

[0655] ◆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

[0656] ◆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,

[0657] ○ 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,

[0658] ○C6-C 10 Aryl,

[0659] ○3 to 10-membered heterocyclic groups, and

[0660] ○Optionally substituted with 1-3 groups independently selected from C1-C6 alkoxy and C1-C6 fluoroalkyl groups, and

[0661] ■5- to 12-membered heteroaryl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl and C1-C6 fluoroalkyl.

[0662] Formula I also includes compounds of Formula Ib:

[0663]

[0664] tautomers of those compounds, deuterated derivatives of any of the described compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein all variables are as defined in Formula la.

[0665] Formula I also includes compounds of Formula Ila:

[0666]

[0667] tautomers of those compounds, deuterated derivatives of any of the described compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein all variables are as defined in Formula la.

[0668] Formula I also includes compounds of Formula lib:

[0669]

[0670] tautomers of those compounds, deuterated derivatives of any of the described compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein all variables are as defined in Formula la.

[0671] Formula I also includes compounds of Formula III:

[0672]

[0673] tautomers of those compounds, deuterated derivatives of any of the described compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein all variables are as defined in Formula la.

[0674] Formula I also includes compounds of Formula IV:

[0675]

[0676] tautomers of those compounds, deuterated derivatives of any of the described compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein all variables are as defined in Formula la.

[0677] Formula I also includes compounds of Formula V:

[0678]

[0679] tautomers of those compounds, deuterated derivatives of the compounds and any of the tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein all variables are as defined in Formula Ia.

[0680] Formula I also includes compounds of Formula VI:

[0681]

[0682] tautomers of those compounds, deuterated derivatives of the compounds and any of the tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein all variables are as defined in Formula Ia.

[0683] Another aspect of the present disclosure provides pharmaceutical compositions comprising at least one compound selected from the novel compounds disclosed herein, tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one pharmaceutically acceptable carrier, which compositions can 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 potentiators and CFTR correctors.

[0684] Accordingly, another aspect of the present disclosure provides methods of treating CFTR-mediated disease cystic fibrosis, comprising administering to a subject in need thereof at least one compound selected from the novel compounds disclosed herein, tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one pharmaceutically acceptable carrier, optionally as part of a pharmaceutical composition comprising at least one additional component. In some embodiments, the at least one additional active pharmaceutical ingredient in the methods of treatment disclosed herein is at least one other CFTR modulator. In some embodiments, the at least one other CFTR modulator is selected from CFTR potentiators and CFTR correctors.

[0685] In certain embodiments, the pharmaceutical compositions of the present disclosure include at least one compound selected from the group consisting of a compound of Formula I, a compound of Formulas la, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the compositions including at least one compound selected from the group consisting of a compound of Formula I, a compound of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing can optionally further include: (a) at least one (i.e., one or more) compound selected from the group consisting of (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1- hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (tezacaftor), 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3- methylpyridin-2-yl)benzoic acid (lumacaftor), deuterated derivatives of tezacaftor and lumacaftor, and pharmaceutically acceptable salts of any of the foregoing; and / or (b) at least one (i.e., one or more) compound selected from the group consisting of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3- carboxamide (ivacaftor), N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (deutivacaftor), (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, ivacaftor, deutivacaftor, deuterated derivatives of ivacaftor and deutivacaftor, and pharmaceutically acceptable salts of any of the foregoing.

[0686] Another aspect of the present disclosure provides methods of treating CFTR-mediated disease cystic fibrosis, comprising administering to a patient in need thereof 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 tezacaftor, efruxaftor, and lumacaftor.

[0687] In further aspects, the compounds of the present disclosure (e.g., compounds of Formula I, compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and compositions, 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 in therapy or drug manufacture. In some embodiments, the one or more additional CFTR modulators are selected from CFTR potentiators. In some embodiments, the one or more additional CFTR modulators are selected from CFTR correctors. In some embodiments, the one or more additional CFTR modulators are selected from tezacaftor, lumacaftor, efruxaftor, deutetrcaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.

[0688] Further aspects of the present disclosure provide intermediates and methods for making the compounds and compositions disclosed herein.

[0689] Definitions

[0690] As used herein, “tezacaftor” means (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3- dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, which can be depicted by the following structural:

[0691]

[0692] Tizacatol can be in the form of a deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative. Tizacatol and methods of making and using tizacatol are disclosed in WO 2010 / 053471, WO 2011 / 119984, WO 2011 / 133751, WO 2011 / 133951, WO 2015 / 160787, and US 2009 / 0131492, each of which is incorporated herein by reference.

[0693] “Efavacatol” as used throughout this disclosure is N-[2,4-bis(l,l-dimethylethyl)-5- hydroxyphenyl]-l,4-dihydro-4-oxoquinoline-3-carboxamide, which is depicted by the following structure:

[0694]

[0695] Efavacatol can also be in the form of a deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative. Efavacatol and methods of making and using efavacatol are disclosed in WO 2006 / 002421, WO 2007 / 079139, WO 2010 / 108162, and WO 2010 / 019239, which are incorporated herein by reference.

[0696] In some embodiments, a deuterated derivative of efavacatol (deutetracatol) is used in the compositions and methods disclosed herein. The chemical name of deutetracatol is N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-l, l, l,3,3,3-d6)phenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide, depicted by the following structure:

[0697]

[0698] Deutetracatol can be in the form of a further deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative. Deutetracatol and methods of making and using deutetracatol are disclosed in WO 2012 / 158885, WO 2014 / 078842, and U.S. Patent No. 8,865,902, which are incorporated herein by reference.

[0699] As used herein, “rumacatol” refers to 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5- yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, which is depicted by the following chemical structure:

[0700]

[0701] Rumacirat can be in the form of a deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative. Rumacirat and methods of making and using rumacirat are disclosed in WO 2007 / 056341, WO 2009 / 073757, and WO 2009 / 076142, which are incorporated herein by reference.

[0702] 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 adjacent carbon atoms are interrupted by a double (alkenyl) or triple (alkynyl) bond. Alkyl groups can be substituted or unsubstituted.

[0703] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms, e.g., fluoroalkyl, refers to an alkyl group substituted with one or more fluorine atoms.

[0704] As used herein, the term "alkoxy" refers to an alkyl or cycloalkyl group covalently bonded to an oxygen atom. Alkoxy groups can be substituted or unsubstituted.

[0705] As used herein, the term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms.

[0706] As used herein, "cycloalkyl" refers to cyclic, bicyclic, tricyclic, or polycyclic non-aromatic hydrocarbon groups having 3 to 12 carbons (e.g., 3-10 carbons) and can contain one or more unsaturated bonds. "Cycloalkyl" encompasses monocyclic, bicyclic, tricyclic, bridged cyclic, fused cyclic, and spirocyclic, including monospirocyclic and dispirocyclic. 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 can be substituted or unsubstituted.

[0707] The term "aryl" as used herein is a functional group or substituent derived from an aromatic ring and encompasses monocyclic aromatic rings and bicyclic, tricyclic, and fused ring systems in which at least one ring in the system is aromatic. Non-limiting examples of aryl groups include phenyl, naphthyl, and 1,2,3,4-tetrahydronaphthyl.

[0708] The term "heteroaryl ring" as used herein refers to an aromatic ring that includes at least one ring atom that is a heteroatom such as O, N, or S. Heteroaryl encompasses monocyclic and bicyclic, tricyclic, bridged, fused, and spiro systems (including mono- and bi- spiro), where at least one ring of the system is aromatic. Non-limiting examples of heteroaryl rings include pyridine, quinoline, indole, and indoline. In certain embodiments, the term "heteroaryl ring" encompasses heteroaryl rings having various oxidation states, such as heteroaryl rings containing N-oxides and sulfoxides. Non-limiting examples of such heteroaryl rings include pyrimidine N-oxide, quinoline N-oxide, thiophene S-oxide, and pyrimidine N-oxide.

[0709] As used herein, the term "heterocyclyl ring" refers to a non-aromatic hydrocarbon containing 3 to 12 atoms (e.g., 3-10 atoms) in the ring, the ring including at least one ring atom that is a heteroatom such as O, N, or S and can include one or more unsaturated bonds. "Heterocyclyl" rings encompass monocyclic, bicyclic, tricyclic, polycyclic, bridged, fused, and spiro rings, including mono- and bi- spiro rings.

[0710] "Substituted," whether preceded by the term "optionally" or not, indicates that at least one hydrogen present in the "substituted" group is replaced with a substituent. Unless otherwise indicated, a "substituted" group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent, each position is independently substituted with a suitable substituent.

[0711] Non-limiting examples of protecting groups for nitrogen include, for example, tert- butyl carbamate (Boc), benzyl (Bn), p-methoxybenzyl (PMB), tetrahydropyranyl (THP), 9-fluorenylmethyl carbamate (Fmoc), benzyl carbamate (Cbz), methyl carbamate, ethyl carbamate, 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), allyl carbamate (Aloc or Alloc), formamide, acetamide, benzamide, allylamine, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide. A complete list of nitrogen protecting groups can be found in Wuts, P.G.M. "Greene's Protective Groups in Organic Synthesis: Fifth Edition," 2014, John Wiley and Sons.

[0712] As used herein, "one or more deuterated derivatives" refers to a compound having the same chemical structure as a reference compound and one or more hydrogen atoms replaced with a deuterium atom. In some embodiments, the one or more hydrogens replaced with deuterium are part of an alkyl group. In some embodiments, the one or more hydrogens replaced with deuterium are part of a methyl group.

[0713] The phrase "and deuterated derivatives and pharmaceutically acceptable salts thereof" can be used interchangeably with "and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing" when referring to one or more particular compounds. As used herein, these terms are intended to encompass deuterated derivatives of the one or more particular compounds and pharmaceutically acceptable salts of the one or more particular compounds, as well as pharmaceutically acceptable salts of deuterated derivatives of the one or more particular compounds.

[0714] As used herein, "CFTR" refers to Cystic Fibrosis Transmembrane Conductance Regulator.

[0715] As used herein, the term "CFTR modulator" refers to a compound that increases CFTR activity. Increases in activity caused by CFTR modulators include, but are not limited to, compounds that correct, enhance, stabilize, and / or augment CFTR.

[0716] As used herein, the terms "corrective agent" and "CFTR corrective agent" are applied interchangeably and refer to a compound that facilitates the processing and trafficking of CFTR to increase the amount of CFTR at the cell surface. The novel compounds disclosed herein are CFTR corrective agents. Tizacat and Lumacat and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof, as referred to herein are corrective agents.

[0717] As used herein, the terms “potentiator” and “CFTR potentiator” refer to a compound that increases the channel activity of CFTR protein located at the cell surface, thereby enhancing ion transport. Ivacaftor, deutivacaftor, and (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa- 3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol are CFTR potentiators as referred to herein. It will be understood that when describing combinations of compounds selected from Formula I, compounds of any of Formulas I, Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, the combinations will typically, but not necessarily, include a CFTR potentiator, such as ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa- 3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, or a deuterated derivative or pharmaceutically acceptable salt of any of the foregoing. Additionally, the combinations will typically, but not necessarily, include only a single potentiator, but can include more than one corrector. Thus, in some embodiments, combinations of at least one compound selected from Formula I, compounds of any of Formulas Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing will include a potentiator selected from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa- 3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, or a deuterated derivative or pharmaceutically acceptable salt thereof, and can also include another CFTR corrector, such as a corrector compound selected from tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof.

[0718] As used herein, the term “at least one compound selected from” means one or more compounds selected from a particular group.

[0719] References herein to "Compounds 1-1924" are intended to mean either individual reference to each of Compounds 1 through 1294 or reference to groups of compounds, such as Compounds 1-1193, Compounds 1194-1294, and Compounds 1295-1972.

[0720] As used herein, the term "active pharmaceutical ingredient" or "therapeutic agent" ("API") refers to a biologically active compound.

[0721] The terms "patient" and "subject" are used interchangeably and refer to an animal, including a human.

[0722] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to the amount of a compound that produces a desired effect (e.g., improvement in CF or symptoms of CF, or reduction in severity of CF or symptoms of CF) of the administered compound. The exact amount of an effective dose will depend on the therapeutic purpose, and will be determined by one of skill in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0723] As used herein, the terms "treatment," "treating," and the like, generally mean improvement in one or more symptoms of CF in a subject, or reduction in severity of CF or one or more symptoms of CF. As used herein, "treatment" includes, but is not limited to, the following: increased growth, increased gain in weight, decreased lung mucus, improved pancreatic and / or liver function, decreased chest infections, and / or decreased coughing or shortness of breath in a subject. Improvement in any of these symptoms or reduction in severity thereof can be readily assessed according to standard methods and techniques known in the art.

[0724] It should be understood that references herein to methods of treatment (e.g., methods of treating a CFTR-mediated disease or methods of treating cystic fibrosis) using one or more compounds of the disclosure, optionally in combination with one or more additional CFTR modulators (e.g., a compound selected from the group consisting of compounds of Formula I, compounds of any one of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, 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) should also be interpreted as references to methods of treatment (e.g., methods of treating a CFTR-mediated disease or methods of treating cystic fibrosis) using one or more compounds of the disclosure, optionally in combination with one or more additional CFTR modulators (e.g., a compound selected from the group consisting of compounds of Formula I, compounds of any one of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, 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).

[0725] - one or more compounds (e.g., a compound selected from the group consisting of a compound of Formula I, a compound of any one of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, 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) for use in a method of treatment, e.g., a method of treating cystic fibrosis, optionally in combination with one or more additional CFTR modulators; and / or

[0726] - one or more compounds (e.g., a compound selected from the group consisting of a compound of Formula I, a compound of any one of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, 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) for use in a method of treatment, e.g., a method of treating cystic fibrosis, optionally in combination with one or more additional CFTR modulators; and / or

[0727] It will also be understood that reference herein to a method of treatment (e.g., a method of treating a CFTR-mediated disease or a method of treating cystic fibrosis) using a pharmaceutical composition of the present disclosure (e.g., a pharmaceutical composition comprising at least one compound selected from the group consisting of a compound of Formula I, a compound of any one of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, 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) should also be interpreted to refer to:

[0728] - a pharmaceutical composition (e.g., comprising at least one compound selected from the group consisting of a compound of Formula I, a compound of any one of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, 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 use in a method of treatment, e.g., a method of treating cystic fibrosis; and / or

[0729] - use of a pharmaceutical composition (e.g., a pharmaceutical composition comprising at least one compound selected from a compound of Formula I, a compound of any one of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, 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 manufacture of a medicament for treating, for example, cystic fibrosis.

[0730] As used herein, the term “in combination with” when referring to two or more compounds, agents, or additional pharmaceutically active ingredients means that the two or more compounds, agents, or pharmaceutically active ingredients are administered to a patient before, simultaneously with, or after each other.

[0731] The terms “about” and “approximately” can refer to an acceptable error for the particular value as determined by one of ordinary skill in the art, which is dependent upon 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.

[0732] As used herein, the term “solvent” refers to any liquid that can at least partially dissolve a product (product solubility > 1 g / L).

[0733] As used herein, the terms “room temperature” or “ambient temperature” mean 15 °C to 30 °C.

[0734] It should be understood that certain compounds of the disclosure can exist as separate stereoisomers or enantiomers and / or mixtures of these stereoisomers or enantiomers.

[0735] Certain compounds disclosed herein can exist in tautomeric forms, and both tautomeric forms are contemplated, even if only a single tautomeric structure is depicted. For example, a description of a compound X is understood to include its tautomeric compound Y and vice versa, as well as mixtures thereof:

[0736]

[0737] As used herein, a“minimal function (MF) mutation” refers to a CFTR gene mutation associated with minimal CFTR function (very low to no functional CFTR protein) and includes, for example, mutations associated with a severe lack of CFTR channel opening and closing ability, referred to as defective channel gating or“gating mutations”; mutations associated with a severe lack of CFTR cell processing and its delivery to the cell surface; mutations associated with no (or minimal) CFTR synthesis; and mutations associated with a severe defect in channel conductance.

[0738] As used herein, the term“pharmaceutically acceptable salt” refers to a salt form of a compound of the disclosure, wherein the salt is non-toxic. Pharmaceutically acceptable salts of the compounds of the disclosure include those derived from suitable inorganic and organic acids and bases. For example, the“free base” form of a compound contains no ionically bound salt.

[0739] One of ordinary skill in the art will recognize that when an amount of a“compound or a pharmaceutically acceptable salt thereof” is disclosed, the amount of the pharmaceutically acceptable salt form of the compound is equivalent to the amount of the free base of the compound. It is noted that the amounts of a compound or a pharmaceutically acceptable salt thereof disclosed herein are in terms of the free base form thereof.

[0740] Suitable pharmaceutically acceptable salts are those disclosed in, for example, S. M. Berge et al. J. Pharmaceutical Sciences, 1977, 66, 1-19. For example, Table 1 of this article provides the following pharmaceutically acceptable salts:

[0741] Table 1:

[0742] Acetate Iodide Benzathine Benzenesulfonate Benzyl alcohol Chloroprocaine Benzoate Lactate Choline Bicarbonate Lactobionate Diethanolamine Bitartrate Malate Ethylenediamine Bromide Maleate Meglumine Calcium edetate Mandelate Procaine Camphorsulfonate Methanesulfonate Aluminum Carbonate Methyl bromide Calcium Chloride Methylnitrate Lithium Citrate Methyl sulfate Magnesium Dihydrochloride Mucate Potassium Edetate Napsylate Sodium Edisylate Nitrate Zinc Estolate Embonate Esylate Pantothenate Fumarate Phosphate / diphosphate Gluceptate Polygalacturonate Glycolate Salicylate Glutamate Stearate Para-aminomethyl benzoate Subacetate Hexylresorcinolate Succinate Hydrabamine Sulfate Hydrobromide Tannate Hydrochloride Tartrate Oxynate Chlortheophyllinate Triethiodide

[0743] 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; with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid; and by using other methods known in the art such as ion exchange. Non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 Quaternary ammonium salts of the foregoing. The present disclosure also contemplates quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. Further suitable non-limiting examples of pharmaceutically acceptable salts include benzenesulfonate and glucosamine salts.

[0744] “Selected from” and “chosen from” are used interchangeably herein.

[0745] Therapeutic methods

[0746] Any novel compound disclosed herein, e.g., a compound of Formula I, a compound of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing, can act as a CFTR modulator, i.e., it modulates CFTR activity in vivo. Individuals in whom mutations occur in the gene encoding CFTR can benefit from receiving a CFTR modulator. CFTR mutations can affect the number of CFTR, i.e., the number of CFTR channels at the cell surface, or they can affect CFTR function, i.e., the function of each channel to open and transport ions. Mutations that affect the number of CFTR include mutations that result in synthesis defects (Class I defects), mutations that result in processing and trafficking defects (Class II defects), mutations that result in reduced synthesis of CFTR (Class V defects), and mutations that reduce the surface stability of CFTR (Class VI defects). Mutations that affect CFTR function include mutations that result in gating defects (Class III defects) and mutations that result in conductance defects (Class IV defects). Some CFTR mutations exhibit features of multiple classes. Certain mutations in the CFTR gene result in cystic fibrosis.

[0747] Thus, in some embodiments, the present disclosure provides methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering to the patient an effective amount of any novel compound disclosed herein, e.g., a compound of Formula I, a compound of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, alone or in combination with another active ingredient, e.g., one or more CFTR modulators. In some embodiments, the one or more CFTR modulators is selected from the group consisting of ivacaftor, deuterium substituted ivacaftor, lumacaftor, and tezacaftor. In some embodiments, the patient has a F508del / minimal function (MF) genotype, a F508del / F508del genotype (homozygous for the F508del mutation), a F508del / gating genotype, or a F508del / residual function (RF) genotype. In some embodiments, the patient is heterozygous and has one F508del mutation. In some embodiments, the patient is homozygous for the N1303K mutation.

[0748] In some embodiments, 5 mg to 500 mg of a compound disclosed herein, a tautomer thereof, a deuterated derivative of said compound and tautomer, or a pharmaceutically acceptable salt of any of the foregoing, is administered daily.

[0749] In some embodiments, the patient has at least one F508del mutation in the CFTR gene. In some embodiments, the patient has a CFTR gene mutation that is responsive to the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the application based on in vitro data. In some embodiments, the patient is heterozygous and has the F508del mutation on one allele selected from Table 2 and a mutation on the other allele:

[0750] Table 2: CFTR mutations

[0751]

[0752]

[0753] a Also known as 2183delAA→G.

[0754] CFTR: Cystic Fibrosis Transmembrane Conductance Regulator;

[0755] IVA: Ivacaftor.

[0756] SwCl: Sweat chloride.

[0757] TEZ: Tezacaftor.

[0758] Source: CFTR2.org [Internet]. Baltimore (MD): Clinical and Functional Translation of CFTR. Clinical and Functional Translation of CFTR, Cystic Fibrosis Foundation, Johns Hopkins University, Children’s Hospital. Available from http: / / www.cftr2.org / . Accessed May 15, 2018.

[0759] Note: % PI: Percentage of F508del-CFTR heterozygous patients with pancreatic insufficiency in the CFTR2 Patient Registry; SwCl: Mean sweat chloride of F508del-CFTR heterozygous patients in the CFTR2 Patient Registry.

[0760] In some embodiments, the present disclosure also relates to methods of treatment using isotopically-labeled compounds of the foregoing compounds or pharmaceutically acceptable salts thereof, wherein the formula and variables of such compounds and salts are each independently as described above or any other embodiment described above, provided that one or more atoms are replaced (labeled by an isotope) with atoms having an atomic mass or mass number different from the atomic mass or mass number usually present in nature. Examples of isotopes that are commercially available and suitable for use in the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, e.g., 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.

[0761] Isotopically-labeled compounds and salts can be useful in a variety of ways. They can be useful in medicine and / or in 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 useful in various types of assays, such as substrate tissue distribution assays, because of the relative ease of preparation and excellent detectability. For example, deuterium ( 2 H) labeled compounds are therapeutically useful and have potential therapeutic advantages over non- 2 H) labeled compounds. In general, deuterium ( 2 H) labeled compounds and salts can have higher metabolic stability due to the kinetic isotope effect as described below, compared to non-isotopically labeled compounds and salts. Higher metabolic stability translates directly into increased in vivo half-life or lower dosing, which can be desirable. Isotopically-labeled compounds and salts generally can be prepared by substituting a readily available isotopically-labeled reagent for a non-isotopically labeled reagent in a synthetic scheme and associated descriptions herein, in the Examples section, and in the Preparation section.

[0762] In some embodiments, isotopically-labeled compounds and salts are deuterium ( 2 H) labeled compounds and salts. In some particular embodiments, isotopically-labeled compounds and salts are deuterium ( 2 H) labeled, wherein one or more hydrogen atoms have been replaced by deuterium. In chemical structures, deuterium is denoted as “D”.

[0763] The concentration of isotopes (e.g., deuterium) incorporated into the isotopically labeled compounds and salts of the disclosure can be defined by an isotopic enrichment factor. As used herein, the term “isotopic enrichment factor” means the ratio between the isotopic abundance of a specified isotope and the natural abundance. In some embodiments, if a substituent in a compound of the disclosure is represented as deuterium, such compound has an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation at each specified deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) for each specified deuterium atom.

[0764] Combination therapy

[0765] One aspect disclosed herein provides methods of treating cystic fibrosis and other CFTR-mediated diseases using any of the novel compounds disclosed herein, e.g., a compound of Formula I, a compound of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, in combination with at least one additional active pharmaceutical ingredient.

[0766] In some embodiments, the at least one additional active pharmaceutical ingredient is selected from mucolytics, bronchodilators, antibiotics, anti-infectives, and anti-inflammatories.

[0767] In some embodiments, the additional therapeutic agent is an antibiotic. Exemplary antibiotics useful herein include tobramycin, including tobramycin inhalation powder (TIP); azithromycin; aztreonam, including aerosolized forms of aztreonam; amikacin, including liposomal formulations thereof; ciprofloxacin, including formulations thereof suitable for administration by inhalation; levoflaxacin, including aerosolized formulations thereof; and combinations of two antibiotics, such as fosfomycin and tobramycin.

[0768] In some embodiments, the additional agent is a mucolytic. Exemplary mucolytics useful herein include

[0769] In some embodiments, the additional agent is a bronchodilator. Exemplary bronchodilators include albuterol, metaprotenerol sulfate, pirbuterol acetate, salmeterol, or tetrabuline sulfate.

[0770] 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 useful herein include ibuprofen, docosahexaenoic acid (DHA), sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine, or simavastatin.

[0771] In some embodiments, the additional agent is a nutritional agent. Exemplary nutritional agents include pancrelipase (pancreatic enzyme replacement), including Creon®, Zenpep®, and Ultresa®. (Previous ), or glutathione inhalation. In some embodiments, the additional nutritional agent is pancrelipase.

[0772] In some embodiments, the at least one additional active pharmaceutical ingredient is selected from a CFTR modulator. In some embodiments, the at least one additional active pharmaceutical ingredient is selected from a CFTR potentiator. In some embodiments, the potentiator is selected from ivacaftor, deuterated ivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18- triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the at least one additional active pharmaceutical ingredient is selected from a CFTR corrector. In some embodiments, the corrector is selected from lumacaftor, tezacaftor, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.

[0773] In some embodiments, the at least one additional active pharmaceutical ingredient is selected from: (a) compounds of tizacotat, lumacaftor, and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof; and / or (b) compounds of elvucatat, deutetacat, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa- 3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.

[0774] Accordingly, in some embodiments, the combination therapies provided herein include: (a) a compound selected from a compound of Formula I, a compound of any one of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; and (b) at least one compound selected from tazemetostat, epigenetide, and deuterated derivatives and pharmaceutically acceptable salts thereof; or (c) at least one compound selected from iniparib, deuterated iniparib, (6R, 12R)-17-amino-12-methyl-6, 15-bis(trifluoromethyl)-13, 19-dioxa-3, 4, 18-triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4, 14, 16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing. In other embodiments, the combination therapies provided herein include: (a) at least one compound selected from a compound of Formula I, a compound of any one of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from tazemetostat and pharmaceutically acceptable salts thereof; and (c) at least one compound selected from iniparib, deuterated iniparib, and pharmaceutically acceptable salts thereof. In still other embodiments, the combination therapies provided herein include: (a) at least one compound selected from a compound of Formula I, a compound of any one of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from tazemetostat, epigenetide, and deuterated derivatives and pharmaceutically acceptable salts thereof; 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]nonadeca-l(18),2,4, 14, 16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof.

[0775] In some embodiments, at least one compound chosen from compounds of Formula I, compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered in combination with at least one compound chosen from tazemetostat and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound chosen from compounds of Formula I, compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered in combination with at least one compound chosen from rumacatostat and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound chosen from compounds of Formula I, compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered in combination with at least one compound chosen from inafatostat and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound chosen from compounds of Formula I, compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing is administered in combination with at least one compound chosen from deuterated tazemetostat and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound chosen from compounds of Formula I, compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered in combination with at least one compound chosen from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4,14,16-pentaen-6-ol and pharmaceutically acceptable salts thereof.

[0776] In some embodiments, at least one compound chosen from compounds of Formula I, compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered in combination with at least one compound chosen from tazemetostat and deuterated derivatives thereof and pharmaceutically acceptable salts thereof and at least one compound chosen from inafatamab and deuterated derivatives thereof and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound chosen from compounds of Formula I, compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered in combination with at least one compound chosen from tazemetostat and deuterated derivatives thereof and pharmaceutically acceptable salts thereof and at least one compound chosen from inafatamab and deuterated derivatives thereof and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound chosen from compounds of Formula I, compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered in combination with at least one compound chosen from tazemetostat and deuterated derivatives thereof and pharmaceutically acceptable salts thereof and at least one compound chosen from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18- triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4,14,16-pentaen-6-ol and deuterated derivatives thereof and pharmaceutically acceptable salts thereof.

[0777] In some embodiments, at least one compound chosen from compounds of Formula I, compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from lumacaftor and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof, and at least one compound chosen from elacrtor and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound chosen from compounds of Formula I, compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from lumacaftor and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof, and at least one compound chosen from deucalctor and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound chosen from compounds of Formula I, compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from lumacaftor and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof, and at least one compound chosen from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18- triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4,14,16-pentaen-6-ol and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof.

[0778] Each of the compounds of Formula I, the compounds of any of Formulae la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, can be administered independently once per day, twice per day, or three times per day. In some embodiments, at least one compound selected from the compounds of Formula I, the compounds of any of Formulae la, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered once per day. In some embodiments, at least one compound selected from the compounds of Formula I, the compounds of any of Formulae la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered twice per day.

[0779] In some embodiments, at least one compound selected from the compounds of Formula I, the compounds of any of Formulae la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing and at least one compound selected from tazemetostat and deuterated derivatives thereof and pharmaceutically acceptable salts thereof is administered once per day. In some embodiments, at least one compound selected from the compounds of Formula I, the compounds of any of Formulae la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing and at least one compound selected from tazemetostat and deuterated derivatives thereof and pharmaceutically acceptable salts thereof is administered twice per day.

[0780] In some embodiments, at least one compound chosen from compounds of Formula I, compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound chosen from evacetoricoxib, deutetoricoxib, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa- 3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing, are administered once a day. In some embodiments, at least one compound chosen from compounds of Formula I, compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound chosen from evacetoricoxib, deutetoricoxib, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa- 3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing, are administered twice a day.

[0781] In some embodiments, at least one compound chosen from compounds of Formula I, compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, at least one compound chosen from tazemetostat and deuterated derivatives thereof and pharmaceutically acceptable salts thereof, and at least one compound chosen from inafatmstat, deutetazemetostat, (6R, 12R)-17-amino-12-methyl-6, 15-bis(trifluoromethyl)- 13, 19-dioxa-3, 4, 18-triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4, 14, 16-pentaen-6-ol and deuterated derivatives thereof and pharmaceutically acceptable salts thereof are administered once a day. In some embodiments, at least one compound chosen from compounds of Formula I, compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, at least one compound chosen from tazemetostat and deuterated derivatives thereof and pharmaceutically acceptable salts thereof, and at least one compound chosen from inafatmstat, deutetazemetostat, (6R, 12R)-17-amino-12-methyl-6, 15-bis(trifluoromethyl)- 13, 19-dioxa-3, 4, 18-triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4, 14, 16-pentaen-6-ol and deuterated derivatives thereof and pharmaceutically acceptable salts thereof are administered twice a day.

[0782] In some embodiments, at least one compound chosen from compounds of Formula I, compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, at least one compound chosen from evacetoricoi, deutetoricoi, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)- 13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof, and at least one compound chosen from rumacatoi and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof, is administered once a day. In some embodiments, at least one compound chosen from compounds of Formula I, compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, at least one compound chosen from evacetoricoi, deutetoricoi, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)- 13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof, and at least one compound chosen from rumacatoi and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof, is administered twice a day.

[0783] In some embodiments, at least one compound chosen from compounds of Formula I, compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound chosen from tazemetostat and deuterated derivatives thereof, and pharmaceutically acceptable salts of the foregoing, is administered once per day and at least one compound chosen from inebilizumab and deuterated derivatives thereof, and pharmaceutically acceptable salts of the foregoing, is administered twice per day. In some embodiments, at least one compound chosen from compounds of Formula I, compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound chosen from lumacaftor and pharmaceutically acceptable salts thereof, is administered once per day and at least one compound chosen from inebilizumab and pharmaceutically acceptable salts thereof, is administered twice per day.

[0784] In some embodiments, at least one compound chosen from compounds of Formula I, compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound chosen from tazemetostat and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof, is administered once a day, and at least one compound chosen from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)- 13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4,14,16-pentaen-6-ol and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof, is administered once or twice a day. In some embodiments, at least one compound chosen from compounds of Formula I, compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound chosen from rumacatostat and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof, is administered once a day, and at least one compound chosen from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)- 13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4,14,16-pentaen-6-ol and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof, is administered once or twice a day.

[0785] The compounds of Formula I, the compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and the pharmaceutically acceptable salts of any of the foregoing, tazemetostat, rumacirat, inavolisib, deutetracetostat, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa- 3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof, can be administered in a single pharmaceutical composition or in separate pharmaceutical compositions. Such pharmaceutical compositions can be administered once a day or multiple times a day, such as twice a day. As used herein, the phrase a given amount of API (e.g., tazemetostat, rumacirat, inavolisib, deutetracetostat, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa- 3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof) is administered once or twice a day or every day means that the given amount is administered once or twice a day for each dosing.

[0786] In some embodiments, at least one compound selected from the compounds of Formula I, the compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and the pharmaceutically acceptable salts of any of the foregoing, is administered in a first pharmaceutical composition; at least one compound selected from tazemetostat and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof, is administered in a second pharmaceutical composition; and at least one compound selected from inavolisib and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof, is administered in a third pharmaceutical composition.

[0787] In some embodiments, at least one compound chosen from compounds of Formula I, compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered in a first pharmaceutical composition; at least one compound chosen from tazacatol and deuterated derivatives thereof and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition; at least one compound chosen from deuterotazacatol and deuterated derivatives thereof and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.

[0788] In some embodiments, at least one compound chosen from compounds of Formula I, compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered in a first pharmaceutical composition; at least one compound chosen from tazacatol and deuterated derivatives thereof and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition; at least one compound chosen from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4,14,16-pentaen-6-ol and deuterated derivatives thereof and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.

[0789] In some embodiments, at least one compound chosen from compounds of Formula I, compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered in a first pharmaceutical composition; at least one compound chosen from evacatol, deuterotazacatol, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4,14,16-pentaen-6-ol and deuterated derivatives thereof and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition; at least one compound chosen from rumacatol and deuterated derivatives thereof and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.

[0790] In some embodiments, at least one compound selected from compounds of formula I, any of formulas Ia, Ib, IIa, IIb, III, IV, V, and VI, compounds 1-1193, compounds 1194-1294, compounds 1295-1972, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered in the first pharmaceutical composition; and at least one compound selected from tezacotto and its deuterated derivatives and their pharmaceutically acceptable salts, and at least one compound selected from 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 its deuterated derivatives and their pharmaceutically acceptable salts are administered in the second pharmaceutical composition. In some embodiments, the second pharmaceutical composition comprises half of the daily dose of at least one compound selected from ivacato and its deuterated derivatives and pharmaceutically acceptable salts, and the other half of the daily dose of at least one compound selected from ivacato and its deuterated derivatives and pharmaceutically acceptable salts is administered in a third pharmaceutical composition.

[0791] In some embodiments, at least one compound selected from compounds of formula I, any one of formulas Ia, Ib, IIa, IIb, III, IV, V, and VI, compounds 1-1193, compounds 1194-1294, compounds 1295-1972, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, at least one compound selected from tizacaloto and its pharmaceutically acceptable salts, and at least one compound selected from ivacaloto, deutericolato, and its 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 composition includes ivacaloto, a second composition including only ivacaloto is administered once daily.

[0792] Any suitable pharmaceutical composition can be used for the compounds of Formula I, the compounds of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, the compounds 1-1193, the compounds 1194-1294, the compounds 1295-1972, the tautomers thereof, the deuterated derivatives of these compounds and tautomers, and the pharmaceutically acceptable salts of any of the foregoing, tazemetostat, inavolisib, deutetracetostat, rumacacetate, and the tautomers thereof, the deuterated derivatives of these compounds and tautomers, and the pharmaceutically acceptable salts of any of the foregoing. Some exemplary pharmaceutical compositions for tazemetostat and pharmaceutically acceptable salts thereof can be found in WO 2011 / 119984 and WO 2014 / 014841, all of which are incorporated herein by reference. Some exemplary pharmaceutical compositions for inavolisib and pharmaceutically acceptable salts thereof can be found in WO 2007 / 134279, WO 2010 / 019239, WO 2011 / 019413, WO 2012 / 027731, and WO 2013 / 130669, and some exemplary pharmaceutical compositions for deutetracetostat and pharmaceutically acceptable salts thereof can be found in US 8,865,902, US 9,181,192, US 9,512,079, WO 2017 / 053455, and WO 2018 / 080591, all of which are incorporated herein by reference. Some exemplary pharmaceutical compositions for rumacacetate and pharmaceutically acceptable salts thereof can be found in WO 2010 / 037066, WO 2011 / 127421, and WO 2014 / 071122, each of which is incorporated herein by reference.

[0793] Pharmaceutical compositions

[0794] Another aspect of the present disclosure provides a pharmaceutical composition comprising at least one compound selected from the group consisting of a compound of Formula I, a compound of any of Formulas la, lb, Ila, lib, III, IV, V, and VI, the compounds 1-1193, the compounds 1194-1294, the compounds 1295-1972, the tautomers thereof, the deuterated derivatives of these compounds and tautomers, and the pharmaceutically acceptable salts of any of the foregoing, and at least one pharmaceutically acceptable carrier.

[0795] In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from the group consisting of a compound of Formula I, a compound of any one of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, in combination with at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR modulator. 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 potentiator. In some embodiments, the pharmaceutical composition comprises at least one compound selected from the group consisting of a compound of Formula I, a compound of any one of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least two additional active pharmaceutical ingredients, wherein one is a CFTR corrector and wherein the other is a CFTR potentiator.

[0796] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from the group consisting of a compound of Formula I, a compound of any one of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from the group consisting of tazemetostat and pharmaceutically acceptable salts thereof; and (c) at least one pharmaceutically acceptable carrier.

[0797] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from the group consisting of a compound of Formula I, a compound of any one of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from the group consisting of evacetorico, deutecatorico, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa- 3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing; and (c) at least one pharmaceutically acceptable carrier.

[0798] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from the group consisting of a compound of Formula I, a compound of any one of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from the group consisting of tizacatol and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof; (c) at least one compound selected from the group consisting of evacetol and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof; and (d) at least one pharmaceutically acceptable carrier.

[0799] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from the group consisting of a compound of Formula I, a compound of any one of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from the group consisting of tizacatol and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof; (c) at least one compound selected from the group consisting of deutecatol and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof; and (d) at least one pharmaceutically acceptable carrier.

[0800] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from the group consisting of a compound of Formula I, a compound of any one of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from the group consisting of tizacatol and deuterated derivatives thereof and pharmaceutically acceptable salts thereof; (c) at least one compound selected from the group consisting of (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18- triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4,14,16-pentaen-6-ol and deuterated derivatives thereof and pharmaceutically acceptable salts thereof; and (d) at least one pharmaceutically acceptable carrier.

[0801] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from the group consisting of a compound of Formula I, a compound of any one of Formulas la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from the group consisting of ivacaatol, deuterated ivacaatol, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18- triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4,14,16-pentaen-6-ol and deuterated derivatives thereof and pharmaceutically acceptable salts of any of the foregoing; (c) at least one compound selected from the group consisting of rumacatol and deuterated derivatives thereof and pharmaceutically acceptable salts thereof; and (d) at least one pharmaceutically acceptable carrier.

[0802] Any of the pharmaceutical compositions disclosed herein can include at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from the group consisting of pharmaceutically acceptable vehicles and pharmaceutically acceptable adjuvants. In some embodiments, the at least one pharmaceutically acceptable is selected from the group consisting of pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants.

[0803] The pharmaceutical compositions described herein can be used to treat cystic fibrosis and other CFTR-mediated diseases.

[0804] As described above, the pharmaceutical compositions disclosed herein can optionally further comprise at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier can be selected from adjuvants and vehicles. As used herein, the at least one pharmaceutically acceptable carrier includes any and all solvents, diluents, other liquid vehicles, diluent adjuvants, suspending adjuvants, surface active agents, isotonifying agents, thickening agents, emulsifying agents, preservatives, solid binders, and lubricants as suited to the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 21st ed., 2005, D.B. Troy, editor, Lippincott Williams & Wilkins, Philadelphia and Encyclopedia of Pharmaceutical Technology, J. Swarbrick and J.C. Boylan, editors, 1988-1999, Marcel Dekker, New York disclose various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier is incompatible with a compound of the disclosure, such as by producing an undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, the use thereof is contemplated to be within the scope of the disclosure. Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar-agar, buffering agents (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives, and antioxidants.

[0805] Exemplary embodiments

[0806] A non-limiting list of exemplary embodiments is provided below:

[0807] 1. A compound of Formula I:

[0808]

[0809] and including tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein:

[0810] Ring A is selected from:

[0811] ■C6-C 10 aryl,

[0812] ■C3-C 10 cycloalkyl,

[0813] ■3 to 10 membered heterocyclyl, and

[0814] ■5 to 10 membered heteroaryl;

[0815] Ring B is selected from:

[0816] ■C6-C 10 aryl,

[0817] ■C3-C 10 cycloalkyl,

[0818] ■3 to 10 membered heterocyclyl, and

[0819] ■5 to 10 membered heteroaryl;

[0820] V is selected from O and NH;

[0821] W 1 is selected from N and CH;

[0822] W 2 is selected from N and CH, provided that at least one of W 1 and W 2 is N;

[0823] Z is selected from O, NR ZN , and C(R ZC )2, provided that when L 2 is absent, Z is C(R ZC )2;

[0824] each L 1 is independently selected from C(R L1 )2and

[0825] each L 2 is independently selected from C(R L2)2;

[0826] Ring C is selected from C6-Cio aryl optionally substituted with 1-3 groups independently selected from: 10 aryl:

[0827] halo,

[0828] Ci-C6alkyl, and

[0829] N(R N )2;

[0830] each R 3 is independently selected from:

[0831] halo,

[0832] Ci-C6alkyl,

[0833] Ci-C6alkoxy,

[0834] C3-C 10 cycloalkyl,

[0835] C6-Cio aryl optionally substituted with 1-3 groups independently selected from Ci-C6alkyl; 10 aryl, and

[0836] 3- to 10-membered heterocyclyl;

[0837] R 4 is selected from hydrogen and Ci-C6alkyl;

[0838] each R 5 is independently selected from:

[0839] hydrogen,

[0840] halo,

[0841] hydroxyl,

[0842] N(R N )2,

[0843] -SO-Me,

[0844] -CH=C(R LC )2, wherein the two R LC together form a C3-C 10 cycloalkyl,

[0845] Ci-C6alkyl optionally substituted with 1-3 groups independently selected from:

[0846] hydroxyl,

[0847] Ci-C6alkoxy, and C6-C10 C1-C6alkoxy groups substituted with groups selected from:

[0848] C3-C 10 cycloalkyl groups,

[0849] -(O) 0-1 -(C6-C 10 aryl groups,

[0850] 3- to 10-membered heterocyclyl groups, and

[0851] N(R N )2,

[0852] C1-C6alkoxy groups optionally substituted with 1-3 groups independently selected from:

[0853] halogen,

[0854] C6-C 10 aryl groups, and

[0855] C3-C 10 cycloalkyl groups,

[0856] C1-C6fluoroalkyl groups,

[0857] C3-C 10 cycloalkyl groups,

[0858] C6-C 10 aryl groups, and

[0859] 3- to 10-membered heterocyclyl groups;

[0860] R YN is selected from:

[0861] hydrogen,

[0862] C1-C9alkyl groups optionally substituted with 1-3 groups independently selected from:

[0863] hydroxy,

[0864] oxo,

[0865] cyano,

[0866] C1-C6alkoxy groups optionally substituted with 1-3 groups independently selected from halogen and C1-C6alkoxy,

[0867] N(R N )2,

[0868] o SO2Me,

[0869] o C3-C6cycloalkyl optionally substituted with 1-3 groups independently selected from halo, hydroxyl, oxo, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6alkoxy, C6-C10aryl, 5-10 membered heteroaryl, SO2Me, SF5, N(R 10 Cycloalkyl:

[0870] ♦ hydroxyl,

[0871] ♦ C1-C6alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6alkoxy, C6-C10aryl, and N(R 10 )2, N )2,

[0872] ♦ C1-C6fluoroalkyl,

[0873] ♦ C1-C6alkoxy,

[0874] ♦ COOH,

[0875] ♦ N(R N )2,

[0876] ♦ C6-C 10 aryl, and

[0877] ♦ 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from oxo and C1-C6alkyl,

[0878] o C6-C 10 aryl:

[0879] ♦ halo,

[0880] ♦ hydroxyl,

[0881] ♦ cyano,

[0882] ♦ SiMe3,

[0883] ♦ SO2Me,

[0884] ♦ SF5,

[0885] ♦ N(R N )2,

[0886] ♦ P(O)Me2,

[0887] ♦ -(O) 0-1 -(C3-C 10 cycloalkyl) optionally substituted with 1-3 groups independently selected from C1-C6fluoroalkyl,

[0888] ♦ -(O) N -(C3-C 10 cycloalkyl) optionally substituted with 1-3 groups independently selected from C1-C6fluoroalkyl,C1-C6 alkyl groups substituted with 2 groups,

[0889] ◆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,

[0890] ◆C1-C6 fluoroalkyl groups,

[0891] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, 3- to 10-membered heterocyclic groups,

[0892] ◆-(O) 0-1 -(C6-C 10 Aryl), and

[0893] ◆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),

[0894] ○Optionally substituted with 1 to 4 independently selected groups from the following 3- to 10-membered heterocyclic groups:

[0895] ◆Hydroxy group,

[0896] ◆Oxygenation,

[0897] ◆N(R N )2,

[0898] ◆C1-C6 alkyl groups optionally substituted with 1-3 independently selected oxo and C1-C6 alkoxy groups,

[0899] ◆C1-C6 alkoxy groups,

[0900] ◆C1-C6 fluoroalkyl groups,

[0901] ◆C6-C cells optionally substituted with 1-3 independently selected halogen groups 10 Aryl, and

[0902] ◆5 to 10 aryl compounds,

[0903] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0904] ◆Hydroxy group,

[0905] ◆Cyano

[0906] ◆Oxygenation,

[0907] ◆Halogen,

[0908] ◆B(OH)2,

[0909] ◆N(R N )2,

[0910] ◆Optionally selected from 1-3 independently selected hydroxyl, oxo, C1-C6 alkoxy (optionally substituted with 1-3 -SiMe3), 3- to 10-membered heterocyclic groups and N(R N C1-C6 alkyl groups substituted with 2 groups,

[0911] ◆Optionally composed of 1-3 independently selected from hydroxyl, oxo, halogen, C1-C6 alkoxy, N(R) N )2, 3 to 10-membered heterocyclic groups (optionally substituted by 1 to 3 independently selected C1-C6 alkyl groups) and C3-C 10 C1-C6 alkoxy groups substituted with cycloalkyl groups,

[0912] ◆C1-C6 fluoroalkyl groups,

[0913] ◆Optionally substituted with 1-3 groups independently selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[0914] ◆-(O) 0-1 -(C6-C 10 Aryl),

[0915] ◆Optionally selected by 1-4 independently chosen from hydroxyl, oxo, halogen, cyano, N(R) N 2. C1-C6 alkyl groups (optionally surrounded by 1-3 independently selected from hydroxyl, oxo, N(R) groups) N (2 and C1-C6 alkoxy groups substitution), C1-C6 alkoxy, C1-C6 fluoroalkyl, C3-C 10 -(O) groups substituted with cycloalkyl, 5- to 10-membered heteroaryl groups (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl 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

[0916] ◆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, and

[0917] ■C1-C6 fluoroalkyl groups;

[0918] R ZN Selected from:

[0919] ■hydrogen,

[0920] ■C1-C9 alkyl optionally substituted with 1-3 groups independently selected from:

[0921] ○hydroxy,

[0922] ○oxo,

[0923] ○cyano,

[0924] ○C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from halogen and C1-C6 alkoxy,

[0925] ○N(R N )2,

[0926] ○SO2Me,

[0927] ○C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from:

[0928] ◆hydroxy,

[0929] ◆C1-C6 alkyl optionally substituted with 1-3 groups independently selected from hydroxy, oxo, C1-C6 alkoxy, C6-C 10 aryl and N(R N )2,

[0930] ◆C1-C6 fluoroalkyl,

[0931] ◆C1-C6 alkoxy,

[0932] ◆COOH,

[0933] ◆N(R N )2,

[0934] ◆C6-C 10 aryl, and

[0935] ◆3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from oxo and C1-C6 alkyl,

[0936] ○C6-C 10 aryl optionally substituted with 1-3 groups independently selected from:

[0937] ◆halogen,

[0938] ◆hydroxy,

[0939] ◆cyano,

[0940] ◆SiMe3,

[0941] ◆SO2Me,

[0942] ◆SF5,

[0943] ◆N(R N )2,

[0944] ◆P(O)Me2,

[0945] ◆Optionally substituted with 1-3 independently selected C1-C6 fluoroalkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[0946] ◆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,

[0947] ◆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,

[0948] ◆C1-C6 fluoroalkyl groups,

[0949] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, 3- to 10-membered heterocyclic groups,

[0950] ◆-(O) 0-1 -(C6-C 10 Aryl), and

[0951] ◆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),

[0952] ○Optionally substituted with 1 to 4 independently selected groups from the following 3- to 10-membered heterocyclic groups:

[0953] ◆Hydroxy group,

[0954] ◆Oxygenation,

[0955] ◆N(R N )2,

[0956] ◆Optionally substituted with 1-3 C1-C6 alkyl groups independently selected from oxo and C1-C6 alkoxy groups,

[0957] ◆C1-C6 alkoxy groups,

[0958] ◆C1-C6 fluoroalkyl groups,

[0959] ◆C6-C cells optionally substituted with 1-3 independently selected halogen groups 10 Aryl, and

[0960] ◆5 to 10 aryl compounds,

[0961] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[0962] ◆Hydroxy group,

[0963] ◆Cyano

[0964] ◆Oxygenation,

[0965] ◆Halogen,

[0966] ◆B(OH)2,

[0967] ◆N(R N )2,

[0968] ◆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,

[0969] ◆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,

[0970] ◆C1-C6 fluoroalkyl groups,

[0971] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[0972] ◆-(O) 0-1 -(C6-C 10 Aryl),

[0973] ◆Optionally selected by 1-4 independently chosen from hydroxyl, oxo, halogen, cyano, N(R) N 2. C1-C6 alkyl groups (optionally surrounded by 1-3 independently selected from hydroxyl, oxo, N(R) groups) N -(O) groups substituted with C1-C6 alkoxy groups, C1-C6 alkoxy groups, C1-C6 fluoroalkyl groups, or 3- to 10-membered heterocyclic groups (optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl groups).0-1 - (3- to 10-membered heterocyclyl), and

[0974] ♦ C1-C6alkyl optionally substituted with 1-4 groups independently selected from C1-C6alkyl and C3-C6cycloalkyl, 10 5- to 10-membered heteroaryl optionally substituted with 1-4 groups independently selected from C1-C6alkyl and C3-C6cycloalkyl,

[0975] ■ C1-C6fluoroalkyl,

[0976] ■ C3-C6cycloalkyl optionally substituted with 1-3 groups independently selected from: 10

[0977] o hydroxy,

[0978] o oxo,

[0979] o halogen,

[0980] o cyano,

[0981] o N(R N )2,

[0982] ■ C1-C6alkyl optionally substituted with 1-3 groups independently selected from:

[0983] ♦ hydroxy,

[0984] ♦ oxo,

[0985] ♦ N(R N )2,

[0986] ♦ C1-C6alkoxy, and

[0987] ♦ C6-C 10 aryl,

[0988] o C1-C6alkoxy optionally substituted with 1-3 groups independently selected from halogen, oxo, C6-C 10 aryl and N(R N )2,

[0989] o halogen,

[0990] o C3-C 10 cycloalkyl,

[0991] o 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl,

[0992] o 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

[0993] ♦ hydroxy,

[0994] ♦ cyano, ​

[0995] ♦ oxo,

[0996] ♦ halogen,

[0997] ♦ N(R N )2,

[0998] ♦ C1-C6 alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6 alkoxy, and N(R N )2,

[0999] ♦ C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from hydroxyl, C1-C6 alkyl, N(R N )2, and C3-C 10 cycloalkyl,

[1000] ♦ C1-C6 fluoroalkyl,

[1001] ♦ -(O) 0-1 -(C3-C 10 cycloalkyl) optionally substituted with 1-3 groups independently selected from C1-C6 alkyl,

[1002] ♦ C6-C 10 aryl,

[1003] ♦ 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl,

[1004] ♦ C6-C 10 aryl,

[1005] ♦ 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

[1006] ♦ oxo,

[1007] ♦ C1-C6 alkyl optionally substituted with 1-3 groups independently selected from:

[1008] ♦ oxo,

[1009] ♦ hydroxyl,

[1010] ♦ N(R N )2,

[1011] ♦ C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from halogen and C6-C 10 aryl, and

[1012] ♦ -(O) 0-1 -(C3-C 10 cycloalkyl),

[1013] ○C1-C6 fluoroalkyl,

[1014] ○ C3-C groups optionally substituted with 1-3 independently selected halogen groups 10 cycloalkyl groups, and

[1015] ○3 to 10-membered heterocyclic groups,

[1016] ■ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[1017] ○ Halogen,

[1018] ○Optionally selected by 1-3 independently chosen from oxo, C1-C6 alkoxy and N(R) N C1-C6 alkyl groups substituted with )2, and

[1019] ○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

[1020] ■R F ;

[1021] Each R ZC Selected independently from:

[1022] ■ Hydrogen,

[1023] ■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),

[1024] ■ C6-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 Aryl, and

[1025] ■R F ;

[1026] Or two Rs ZC Together they form an oxo group;

[1027] Each R L1 Selected independently from:

[1028] ■ Hydrogen,

[1029] ■N(R N )2, the condition is two N(R) N )2 does not combine with the same carbon atom.

[1030] ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1031] o halogen,

[1032] o hydroxyl,

[1033] o oxo,

[1034] o N(R N )2,

[1035] o C1-C6alkoxy optionally substituted with 1-3 groups independently selected from C6-C 10 aryl,

[1036] o C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from halogen, C1-C6alkyl, and C1-C6fluoroalkyl,

[1037] o -O-(C3-C 10 cycloalkyl),

[1038] o C6-C 10 aryl optionally substituted with 1-3 groups independently selected from C1-C6alkyl,

[1039] o 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and oxo),

[1040] ■ C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl,

[1041] ■ C6-C 10 aryl optionally substituted with 1-4 groups independently selected from:

[1042] o halogen,

[1043] o cyano,

[1044] o SiMe3,

[1045] o POMe2,

[1046] o C1-C7alkyl optionally substituted with 1-3 groups independently selected from:

[1047] o hydroxyl,

[1048] o oxo,

[1049] o cyano,

[1050] o SiMe3,

[1051] o N(R N)2, and

[1052] ◆ C3-C6cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6fluoroalkyl, 10 cycloalkyl,

[1053] o C1-C6alkoxy optionally substituted with 1-3 groups independently selected from C1-C6alkyl and C1-C6fluoroalkyl,

[1054] ◆ C3-C6cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6fluoroalkyl, 10 cycloalkyl, and

[1055] ◆ C1-C6alkoxy,

[1056] o C1-C6fluoroalkyl,

[1057] o C3-C6cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl and C1-C6fluoroalkyl, 10 cycloalkyl,

[1058] o C6-C10aryl, 10 aryl,

[1059] o 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl,

[1060] o 5- to 10-membered heteroaryl,

[1061] ■ 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

[1062] o C1-C6alkyl optionally substituted with 1-3 groups independently selected from:

[1063] ◆ oxo, and

[1064] ◆ C1-C6alkoxy,

[1065] ■ 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

[1066] o C1-C6alkyl optionally substituted with 1-3 groups independently selected from:

[1067] ◆ C3-C6cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6fluoroalkyl, 10 cycloalkyl, and

[1068] o C6-C10aryl optionally substituted with 1-3 groups independently selected from C1-C6alkyl, 10 aryl, and

[1069] ■ R F;

[1070] or two R on the same carbon atom L1 together form an oxo group;

[1071] each R L2 is independently selected from hydrogen and R F ;

[1072] or two R on the same carbon atom L2 together form an oxo group;

[1073] each R N is independently selected from:

[1074] ■ hydrogen,

[1075] ■ C1-C8 alkyl optionally substituted with 1-3 groups independently selected from:

[1076] ■ oxo,

[1077] ■ halo,

[1078] ■ hydroxyl,

[1079] ■ NH2,

[1080] ■ NHMe,

[1081] ■ NMe2,

[1082] ■ NHCOMe,

[1083] ■ N(R N3 )2, wherein each R N3 is independently selected from C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C1-C6 alkoxy),

[1084] ■ C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from C6-C 10 aryl, oxo, NMe2, and NHMe,

[1085] ■ -(O) 0-1 -(C3-C 10 cycloalkyl) optionally substituted with 1-3 groups independently selected from halo and C1-C6 alkyl,

[1086] ■ C6-C 10 aryl optionally substituted with 1-3 groups independently selected from halo and C1-C6 alkyl,

[1087] ○Optionally substituted with 1-4 independently selected oxo and C1-C6 alkyl groups, and

[1088] ○ 5- to 14-membered heteroaryl groups optionally substituted by 1 to 4 independently selected oxo and C1-C6 alkyl groups,

[1089] ■ C3-C, optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[1090] ○Hydroxy group,

[1091] ○ Halogen,

[1092] ○NH 2，

[1093] ○NHMe,

[1094] ○C1-C6 alkoxy groups, and

[1095] ○ C1-C6 alkyl groups optionally substituted with 1-3 groups independently selected from hydroxyl and C1-C6 alkoxy groups,

[1096] ■C6-C 10 Aryl,

[1097] ■Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, and

[1098] ■3 to 10-membered heterocyclic groups;

[1099] 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 4 groups selected from the following:

[1100] ■Hydroxy

[1101] ■ Halogen,

[1102] ■Oxygenation,

[1103] ■Cyano

[1104] ■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,

[1105] ■C1-C6 alkoxy groups, and

[1106] ■C1-C6 fluoroalkyl groups;

[1107] Or an R4 and one R L1 together form a C6-C8alkylene group;

[1108] when R F is present, two R F together with the atom to which they are bonded form a group selected from:

[1109] ■C3-C6cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl; 10 cycloalkyl,

[1110] ■C6-C10aryl optionally substituted with 1-3 groups independently selected from: 10 C1-C6alkyl,

[1111] o halogen,

[1112] o C1-C6alkyl,

[1113] o N(R N )2, and

[1114] o 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from hydroxyl,

[1115] ■3- to 11-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

[1116] o oxo,

[1117] o N(R N )2,

[1118] o C1-C9alkyl optionally substituted with 1-4 groups independently selected from:

[1119] ♦ oxo,

[1120] ♦ halogen,

[1121] ♦ hydroxyl,

[1122] ♦ N(R N )2,

[1123] ♦ -SO2-(C1-C6alkyl),

[1124] ♦ C1-C6alkoxy optionally substituted with 1-3 groups independently selected from halogen and C6-C 10 aryl,

[1125] ♦ C6-C10aryl optionally substituted with 1-3 groups independently selected from hydroxyl, halogen, cyano, C1-C6alkyl (optionally substituted with 1-3 groups independently selected from oxo and C1-C6alkoxy), C1-C6alkoxy (optionally substituted with 1-3 groups independently selected from C6-C10 aryl (optionally substituted with 1-3 groups independently selected from halo, C1-C6alkyl (optionally substituted with 1-3 groups independently selected from C6-C10aryl and C3-C7cycloalkyl), C1-C6alkoxy, -O-(5- to 10-membered heteroaryl), and C3-C7cycloalkyl), and 0-1 -(C1-C6fluoroalkyl), and C3-C7cycloalkyl, 10 aryl (optionally substituted with 1-3 groups independently selected from C1-C6alkyl (optionally substituted with 1-3 groups independently selected from C6-C10aryl and C3-C7cycloalkyl), C1-C6alkoxy, -O-(5- to 10-membered heteroaryl), and C3-C7cycloalkyl), and 10 aryl,

[1126] ♦ optionally substituted with 1-4 groups independently selected from hydroxy, halo, N(R N )2, C1-C6alkyl (optionally substituted with 1-3 groups independently selected from oxo, hydroxy, and C1-C6alkoxy), C1-C6fluoroalkyl, and C6-C10aryl, 10 aryl (optionally substituted with 1-3 groups independently selected from halo, C1-C6alkyl (optionally substituted with 1-3 groups independently selected from C6-C10aryl and C3-C7cycloalkyl), C1-C6alkoxy, -O-(5- to 10-membered heteroaryl), and C3-C7cycloalkyl), and 0-1 -(C3-C 10 cycloalkyl),

[1127] ♦ optionally substituted with 1-3 groups independently selected from oxo, C1-C6alkyl (optionally substituted with 1-3 groups independently selected from C6-C10aryl (optionally substituted with 1-3 groups independently selected from halo), C1-C6alkoxy, -O-(5- to 10-membered heteroaryl), and C3-C7cycloalkyl), 10 aryl (optionally substituted with 1-3 groups independently selected from halo, C1-C6alkyl (optionally substituted with 1-3 groups independently selected from C6-C10aryl and C3-C7cycloalkyl), C1-C6alkoxy, -O-(5- to 10-membered heteroaryl), and C3-C7cycloalkyl), and 10 cycloalkyl, and R N 3- to 10-membered heterocyclyl substituted with a group selected from C1-C6alkyl (optionally substituted with 1-3 groups independently selected from C6-C10aryl (optionally substituted with 1-3 groups independently selected from halo), C1-C6alkoxy, -O-(5- to 10-membered heteroaryl), and C3-C7cycloalkyl),

[1128] ♦ optionally substituted with 1-3 groups independently selected from C6-C 10 aryl (optionally substituted with 1-3 groups independently selected from halo, C1-C6alkyl (optionally substituted with 1-3 groups independently selected from C6-C10aryl and C3-C7cycloalkyl), C1-C6alkoxy, -O-(5- to 10-membered heteroaryl), and C3-C7cycloalkyl), and

[1129] ♦ optionally substituted with 1-3 groups independently selected from hydroxy, oxo, N(R N )2, C1-C6alkyl (optionally substituted with 1-3 groups independently selected from cyano), C1-C6alkoxy, -(O) 0-1 -(C1-C6fluoroalkyl), -O-(C6-C 10 aryl), and C3-C7cycloalkyl, 10 5- to 10-membered heteroaryl substituted with a group selected from C1-C6alkyl (optionally substituted with 1-3 groups independently selected from C6-C10aryl (optionally substituted with 1-3 groups independently selected from halo), C1-C6alkoxy, -O-(5- to 10-membered heteroaryl), and C3-C7cycloalkyl),

[1130] o C3-C7cycloalkyl optionally substituted with 1-4 groups independently selected from halo, C1-C6alkyl, and C1-C6fluoroalkyl, 12 cycloalkyl,

[1131] o C6-C10aryl, 10 aryl,

[1132] o 3- to 10-membered heterocyclyl, and

[1133] • 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from C1-C6alkoxy and C1-C6fluoroalkyl, and

[1134] • 5- to 12-membered heteroaryl optionally substituted with 1-3 groups independently selected from C1-C6alkyl and C1-C6fluoroalkyl.

[1135] 1a. A compound of Formula la:

[1136]

[1137] a tautomer thereof, deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[1138] Ring A is selected from:

[1139] • C6-C 10 aryl,

[1140] • C3-C 10 cycloalkyl,

[1141] • 3- to 10-membered heterocyclyl, and

[1142] • 5- to 10-membered heteroaryl;

[1143] Ring B is selected from:

[1144] • C6-C 10 aryl,

[1145] • C3-C 10 cycloalkyl,

[1146] • 3- to 10-membered heterocyclyl, and

[1147] • 5- to 10-membered heteroaryl;

[1148] V is selected from O and NH;

[1149] W 1 is selected from N and CH;

[1150] W 2 is selected from N and CH; provided that at least one of W 1 and W 2 is N;

[1151] Z is selected from O, NR ZN , and C(R ZC )2, provided that when L 2 is absent, Z is C(R ZC )2;

[1152] each L 1 is independently selected from C(RL1 )2and

[1153] each L 2 is independently selected from C(R L2 )2;

[1154] ring C is selected from C6-C 10 aryl:

[1155] ■halo,

[1156] ■C1-C6alkyl, and

[1157] ■N(R N )2;

[1158] each R 3 is independently selected from:

[1159] ■halo,

[1160] ■C1-C6alkyl,

[1161] ■C1-C6alkoxy,

[1162] ■C3-C 10 cycloalkyl,

[1163] ■C6-C 10 aryl optionally substituted with 1-3 groups independently selected from C1-C6alkyl, and

[1164] ■3- to 10-membered heterocyclyl;

[1165] R 4 is selected from hydrogen and C1-C6alkyl;

[1166] each R 5 is independently selected from:

[1167] ■hydrogen,

[1168] ■halo,

[1169] ■hydroxyl,

[1170] ■N(R N )2,

[1171] ■-SO-Me,

[1172] ■-CH=C(R LC )2, wherein the two R LC together form a C3-C 10 cycloalkyl,

[1173] ■C1-C6alkyl optionally substituted with 1-3 groups independently selected from:

[1174] o hydroxy,

[1175] o C1-C6alkoxy optionally substituted with 1-3 groups independently selected from C1-C6alkyl and C6-C10aryl, 10 C1-C6alkyl,

[1176] o C3-C6cycloalkyl, 10 C3-C6cycloalkyl,

[1177] o -(O)1-2-(C6-C10aryl) optionally substituted with 1-3 groups independently selected from C1-C6alkyl and C1-C6alkoxy, 0-1 -(C6-C10aryl), 10 -(C6-C10aryl),

[1178] o 3- to 10-membered heterocyclyl, and

[1179] o N(R N )2,

[1180] ■C1-C6alkyl optionally substituted with 1-3 groups independently selected from:

[1181] o halogen,

[1182] o C6-C10aryl, and 10 C6-C10aryl,

[1183] o C3-C6cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6fluoroalkyl, 10 C3-C6cycloalkyl,

[1184] ■C1-C6fluoroalkyl,

[1185] ■C3-C6cycloalkyl, 10 C3-C6cycloalkyl,

[1186] ■C6-C10aryl, and 10 C6-C10aryl,

[1187] ■3- to 10-membered heterocyclyl;

[1188] R YN is selected from:

[1189] ■hydrogen,

[1190] ■C1-C9alkyl optionally substituted with 1-3 groups independently selected from:

[1191] o hydroxy,

[1192] o oxo,

[1193] o cyano,

[1194] • C1-C6alkoxy optionally substituted by 1-3 groups independently selected from halogen and C1-C6alkoxy,

[1195] • N(R N )2,

[1196] • SO2Me,

[1197] • C3-C 10 cycloalkyl optionally substituted by 1-3 groups independently selected from halogen and C1-C6alkoxy,

[1198] • hydroxy,

[1199] • C1-C6alkyl optionally substituted by 1-3 groups independently selected from hydroxy, oxo, C1-C6alkoxy, C6-C 10 aryl and N(R N )2,

[1200] • C1-C6fluoroalkyl,

[1201] • C1-C6alkoxy,

[1202] • COOH,

[1203] • N(R N )2,

[1204] • C6-C 10 aryl, and

[1205] • 3- to 10-membered heterocyclyl optionally substituted by 1-3 groups independently selected from oxo and C1-C6alkyl,

[1206] • C6-C 10 aryl optionally substituted by 1-3 groups independently selected from halogen,

[1207] • halogen,

[1208] • hydroxy,

[1209] • cyano,

[1210] • SiMe3,

[1211] • SO2Me,

[1212] • SF5,

[1213] • N(R N )2,

[1214] • P(O)Me2,

[1215] • -(O) 0-1-(C3-C 10 cycloalkyl),

[1216] ◆ C1-C6 alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6 alkoxy, 5- to 10-membered heteroaryl, SO2Me, and N(R N )2,

[1217] ◆ C1-C6 alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, N(R N )2, and C6-C 10 aryl,

[1218] ◆ C1-C6 fluoroalkyl,

[1219] ◆ 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl,

[1220] ◆ -(O) 0-1 -(C6-C 10 aryl), and

[1221] ◆ -(O) optionally substituted with hydroxyl, oxo, N(R N )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, and C3-C 10 cycloalkyl, 0-1 -(5- to 10-membered heteroaryl),

[1222] o 3- to 10-membered heterocyclyl optionally substituted with 1-4 groups independently selected from:

[1223] ◆ hydroxyl,

[1224] ◆ oxo,

[1225] ◆ N(R N )2,

[1226] ◆ C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C1-C6 alkoxy),

[1227] ◆ C1-C6 alkoxy,

[1228] ◆ C1-C6 fluoroalkyl,

[1229] ◆ C6-C 10 aryl optionally substituted with 1-3 groups independently selected from halogen,

[1230] ◆ 5- to 10-membered heteroaryl, and

[1231] o 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

[1232] • hydroxyl,

[1233] • cyano,

[1234] • oxo,

[1235] • halogen,

[1236] • B(OH)2,

[1237] • N(R N )2,

[1238] • C1-C6 alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6 alkoxy (optionally substituted with 1-3 -SiMe3), and N(R N )2,

[1239] • C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, halogen, C1-C6 alkyl, N(R N )2, and C3-C 10 cycloalkyl,

[1240] • C1-C6 fluoroalkyl,

[1241] • -(O) 0-1 -(C3-C 10 cycloalkyl) optionally substituted with 1-3 groups independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy,

[1242] • -(O) 0-1 -(C6-C 10 aryl),

[1243] • -(O) N -(3- to 10-membered heterocyclyl) optionally substituted with 1-4 groups independently selected from hydroxyl, oxo, halogen, cyano, N(R N )2, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, N(R 0-1 )2, and C1-C6 alkoxy), C1-C6 alkoxy, C1-C6 fluoroalkyl, 3- to 10-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl), and

[1244] • 5- to 10-membered heteroaryl optionally substituted with 1-4 groups independently selected from C1-C6 alkyl and C3-C 10 cycloalkyl, and

[1245] • C1-C6 fluoroalkyl;

[1246] R ZN is selected from:

[1247] ■hydrogen,

[1248] ■C1-C9 alkyl optionally substituted with 1-3 groups independently selected from:

[1249] ○hydroxy,

[1250] ○oxo,

[1251] ○cyano,

[1252] ○C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from halogen and C1-C6 alkoxy,

[1253] ○N(R N )2,

[1254] ○SO2Me,

[1255] ○C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from:

[1256] ◆hydroxy,

[1257] ◆C1-C6 alkyl optionally substituted with 1-3 groups independently selected from hydroxy, oxo, C1-C6 alkoxy, C6-C 10 aryl and N(R N )2,

[1258] ◆C1-C6 fluoroalkyl,

[1259] ◆C1-C6 alkoxy, and

[1260] ◆COOH,

[1261] ◆N(R N )2,

[1262] ◆C6-C 10 aryl, and

[1263] ◆3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from oxo and C1-C6 alkyl,

[1264] ○C6-C 10 aryl optionally substituted with 1-3 groups independently selected from:

[1265] ◆halogen,

[1266] ◆hydroxy,

[1267] ◆cyano,

[1268] ◆SiMe3,

[1269] ♦ SO2Me,

[1270] ♦ SF5,

[1271] ♦ N(R N )2,

[1272] ♦ P(O)Me2,

[1273] ♦ -(O) 0-1 -(C3-C 10 cycloalkyl),

[1274] ♦ C1-C6alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6alkoxy, 5- to 10-membered heteroaryl, SO2Me, and N(R N )2,

[1275] ♦ C1-C6alkoxy optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, N(R N )2, and C6-C 10 aryl,

[1276] ♦ C1-C6fluoroalkyl,

[1277] ♦ 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl,

[1278] ♦ -(O) 0-1 -(C6-C 10 aryl), and

[1279] ♦ -(O) N -(5- to 10-membered heteroaryl) optionally substituted with hydroxyl, oxo, N(R 10 )2, C1-C6alkyl, C1-C6alkoxy, C1-C6fluoroalkyl, and C3-C 0-1 cycloalkyl,

[1280] ♦ 3- to 10-membered heterocyclyl optionally substituted with 1-4 groups independently selected from:

[1281] ♦ hydroxyl,

[1282] ♦ oxo,

[1283] ♦ N(R N )2,

[1284] ♦ C1-C6alkyl (optionally substituted with 1-3 groups independently selected from oxo and C1-C6alkoxy),

[1285] ♦ C1-C6alkoxy,

[1286] ◆C1-C6 fluoroalkyl groups,

[1287] ◆C6-C cells optionally substituted with 1-3 independently selected halogen groups 10 Aryl,

[1288] ◆5 to 10 aryl compounds, and

[1289] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[1290] ◆Hydroxy group,

[1291] ◆Cyano

[1292] ◆Oxygenation,

[1293] ◆Halogen,

[1294] ◆B(OH)2,

[1295] ◆N(R N )2,

[1296] ◆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,

[1297] ◆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,

[1298] ◆C1-C6 fluoroalkyl groups,

[1299] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[1300] ◆-(O) 0-1 -(C6-C 10 Aryl),

[1301] ◆Optionally selected by 1-4 independently chosen from hydroxyl, oxo, halogen, cyano, N(R) N 2. C1-C6 alkyl groups (optionally surrounded by 1-3 independently selected from hydroxyl, oxo, N(R) groups) N)2, and C1-C6alkoxy, C1-C6fluoroalkyl, 3- to 10-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C1-C6fluoroalkyl) substituted -(O) 0-1 - (3- to 10-membered heterocyclyl), and

[1302] ♦ 5- to 10-membered heteroaryl optionally substituted with 1-4 groups independently selected from C1-C6alkyl and C3-C 10 cycloalkyl,

[1303] ■C1-C6fluoroalkyl,

[1304] ■C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from:

[1305] o hydroxy,

[1306] o oxo,

[1307] o halogen,

[1308] o cyano,

[1309] o N(R N )2,

[1310] o C1-C6alkyl optionally substituted with 1-3 groups independently selected from:

[1311] ♦ hydroxy,

[1312] ♦ oxo,

[1313] ♦ N(R N )2,

[1314] ♦ C1-C6alkoxy, and

[1315] ♦ C6-C 10 aryl,

[1316] o C1-C6alkoxy optionally substituted with 1-3 groups independently selected from halogen, oxo, C6-C 10 aryl, and N(R N )2,

[1317] o halogen,

[1318] o C3-C 10 cycloalkyl,

[1319] o 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl,

[1320] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[1321] ◆Hydroxy group,

[1322] ◆Cyano

[1323] ◆Oxygenation,

[1324] ◆Halogen,

[1325] ◆N(R N )2,

[1326] ◆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,

[1327] ◆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,

[1328] ◆C1-C6 fluoroalkyl groups,

[1329] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[1330] ◆C6-C 10 Aryl,

[1331] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, 3- to 10-membered heterocyclic groups,

[1332] ■C6-C 10 Aryl,

[1333] ■Optionally substituted with 1 to 3 independently selected groups from the following: 3- to 10-membered heterocyclic groups

[1334] ○Oxygenation,

[1335] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1336] ◆Oxygenation,

[1337] ◆Hydroxy group,

[1338] ◆N(R N )2,

[1339] ◆Optionally selected by 1-3 independent elements chosen from halogens and C6-C 10C6alkyl optionally substituted with 1-3 groups independently selected from C6-C10aryl optionally substituted with 1-3 groups independently selected from C1-C6alkyl,

[1340] ◆-(O) 0-1 -(C3-C 10 cycloalkyl),

[1341] o C1-C6fluoroalkyl,

[1342] o C3-C10cycloalkyl optionally substituted with 1-3 groups independently selected from halogen, 10 cycloalkyl, and

[1343] o 3- to 10-membered heterocyclyl,

[1344] ■ 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

[1345] o halogen,

[1346] o C1-C6alkyl optionally substituted with 1-3 groups independently selected from oxo, C1-C6alkoxy, and N(R N )2, and

[1347] o 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl optionally substituted with 1-3 groups selected from oxo, C1-C6alkoxy, and C6-C10aryl, 10 and

[1348] ■ R F ;

[1349] each R ZC is independently selected from:

[1350] ■ hydrogen,

[1351] ■ C1-C6alkyl optionally substituted with 1-3 groups independently selected from C6-C10aryl optionally substituted with 1-3 groups independently selected from C1-C6alkyl, 10 C6-C10aryl optionally substituted with 1-3 groups independently selected from C1-C6alkyl,

[1352] ■ C6-C10aryl optionally substituted with 1-3 groups independently selected from C1-C6alkyl, 10 and

[1353] ■ R F ;

[1354] or two R ZC together form an oxo group;

[1355] each R L1 is independently selected from:

[1356] ■ hydrogen,

[1357] ■N(R N )2, provided that both N(R N )2 are not bound to the same carbon,

[1358] ■C1-C9 alkyl optionally substituted with 1-3 groups independently selected from:

[1359] ○halo,

[1360] ○hydroxy,

[1361] ○oxo,

[1362] ○N(R N )2,

[1363] ○C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from C6-C 10 aryl,

[1364] ○C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from halo and C1-C6 fluoroalkyl,

[1365] ○C6-C 10 aryl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl,

[1366] ○3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and oxo),

[1367] ■C3-C 10 cycloalkyl,

[1368] ■C6-C 10 aryl optionally substituted with 1-4 groups independently selected from:

[1369] ○halo,

[1370] ○cyano,

[1371] ○SiMe3,

[1372] ○POMe2,

[1373] ○C1-C7 alkyl optionally substituted with 1-3 groups independently selected from:

[1374] ◆hydroxy,

[1375] ◆oxo,

[1376] ◆cyano,

[1377] ◆SiMe3,

[1378] ♦ N(R N )2, and

[1379] ♦ C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl,

[1380] ♦ C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from C1-C6 alkyl and C1-C6 fluoroalkyl,

[1381] ♦ C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl, and

[1382] ♦ C1-C6 alkoxy,

[1383] ♦ C1-C6 fluoroalkyl,

[1384] ♦ C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl and C1-C6 fluoroalkyl,

[1385] ♦ C6-C 10 aryl,

[1386] ♦ 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl, and

[1387] ♦ 5- to 10-membered heteroaryl,

[1388] ♦ 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl,

[1389] ♦ C1-C6 alkyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl,

[1390] ♦ oxo, and

[1391] ♦ C1-C6 alkoxy,

[1392] ♦ 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl,

[1393] ♦ C1-C6 alkyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl,

[1394] ♦ C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl, and

[1395] ♦ C6-C 10 aryl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl, and

[1396] ■R F ;

[1397] or two R L1 on the same carbon atom together form an oxo group;

[1398] each R L2 is independently selected from hydrogen and R F ;

[1399] or two R L2 on the same carbon atom together form an oxo group;

[1400] each R N is independently selected from:

[1401] ■ hydrogen,

[1402] ■ C1-C8alkyl optionally substituted with 1-3 groups independently selected from:

[1403] ■ oxo,

[1404] ■ halo,

[1405] ■ hydroxyl,

[1406] ■ NH2,

[1407] ■ NHMe,

[1408] ■ NMe2,

[1409] ■ NHCOMe,

[1410] ■ C1-C6alkoxy optionally substituted with 1-3 groups independently selected from C6-C 10 aryl,

[1411] ■ -(O) 0-1 -(C3-C 10 cycloalkyl),

[1412] ■ C6-C 10 aryl optionally substituted with 1-3 groups independently selected from halo and C1-C6alkyl, and

[1413] ■ 3- to 14-membered heterocyclyl optionally substituted with 1-4 groups independently selected from oxo and C1-C6alkyl,

[1414] ■ 5- to 14-membered heteroaryl optionally substituted with 1-4 groups independently selected from oxo and C1-C6alkyl,

[1415] ■ C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from:

[1416] • hydroxyl,

[1417] • NH 2， and

[1418] • NHMe,

[1419] • C1-C6alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, and

[1420] • C6-C 10 aryl, and

[1421] • 3- to 10-membered heterocyclyl;

[1422] or two R N on the same nitrogen atom are taken together with the nitrogen to which they are bound to form a 3- to 10-membered heterocyclyl optionally substituted with 1-4 groups selected from:

[1423] • hydroxyl,

[1424] • halo,

[1425] • oxo,

[1426] • cyano,

[1427] • C1-C6alkyl optionally substituted with 1-3 groups independently selected from oxo, hydroxyl, C1-C6alkoxy, and N(R N2 )2, wherein each R N2 is independently selected from hydrogen and C1-C6alkyl,

[1428] • C1-C6alkoxy, and

[1429] • C1-C6fluoroalkyl;

[1430] or one R 4 and one R L1 are taken together to form a C6-C8alkylene;

[1431] when R F is present, two R F together with the atom to which they are bound form a group selected from:

[1432] • C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl,

[1433] • C6-C 10 aryl optionally substituted with 1-3 groups independently selected from:

[1434] • halo,

[1435] ○C1-C6 alkyl groups,

[1436] ○N(R N )2, and

[1437] ○ A 3- to 10-membered heterocyclic group optionally substituted by 1 to 3 independently selected groups chosen from hydroxyl groups.

[1438] ■ 3- to 11-membered heterocyclic groups optionally substituted by 1 to 3 independently selected groups from the following:

[1439] ○Oxygenation,

[1440] ○N(R N )2,

[1441] ○ C1-C9 alkyl groups optionally substituted by 1-4 independently selected groups from the following:

[1442] ◆Oxygenation,

[1443] ◆Halogen,

[1444] ◆Hydroxy group,

[1445] ◆N(R N )2,

[1446] ◆-SO2-(C1-C6 alkyl),

[1447] ◆Optionally selected by 1-3 independent elements chosen from halogens, C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[1448] ◆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,

[1449] ◆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),

[1450] ◆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,

[1451] ◆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

[1452] ◆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,

[1453] ○ 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,

[1454] ○C6-C 10 Aryl,

[1455] ○3 to 10-membered heterocyclic groups, and

[1456] ○Optionally substituted with 1-3 groups independently selected from C1-C6 alkoxy and C1-C6 fluoroalkyl groups, and

[1457] ■ 5 to 12 heteroaryl groups optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl and C1-C6 fluoroalkyl groups.

[1458] 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.

[1459] 3. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Example 1 or 2, wherein ring A is selected from phenyl, pyridyl, and pyrazolyl.

[1460] 4. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 to 3, wherein ring A is phenyl.

[1461] 5. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 to 4, wherein ring B is selected from C6-C 10 aryl.

[1462] 6. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 to 5, wherein ring B is selected from phenyl and naphthyl.

[1463] 7. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 to 6, wherein ring B is phenyl.

[1464] 8. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 to 7, wherein V is O.

[1465] 9. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 to 8, wherein W 1 is N and W 2 is N.

[1466] 10. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 to 9, wherein Z is selected from NR ZN and C(R ZC )2, provided that when L 2 is absent, Z is C(R ZC )2.

[1467] 11. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 to 10, wherein each L 1 is C(R L1 )2.

[1468] 12. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 to 11, wherein L 2 is absent.

[1469] 13. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 to 12, wherein each R 3 is independently selected from C1-C6 alkyl.

[1470] 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.

[1471] 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.

[1472] 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.

[1473] 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.

[1474] 18. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 1 to 17, wherein each R 5 Selected independently from:

[1475] ■ Hydrogen,

[1476] ■Hydroxy

[1477] ■Optionally selected from 1-3 independent choices C3-C 10 C1-C6 alkyl groups substituted with cycloalkyl groups, and

[1478] ■Optionally selected from 1-3 independent choices of C6-C 10 C1-C6 alkoxy groups substituted with aryl groups.

[1479] 19. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 1 to 18, wherein R YN Selected from:

[1480] ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1481] ○Hydroxy group,

[1482] ○Oxygenation,

[1483] ○Cyano

[1484] ○ C1-C6 alkoxy groups optionally substituted with 1-3 independently selected halogen and C1-C6 alkoxy groups,

[1485] ○N(R N )2,

[1486] o SO2Me,

[1487] o C3-C10cycloalkyl optionally substituted with 1-3 groups independently selected from oxo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C6-C10aryl, 5-10 membered heteroaryl, halo, hydroxyl, cyano, N(R 10 cycloalkyl:

[1488] ♦ C1-C6alkyl optionally substituted with 1-3 groups independently selected from oxo, N(R N )2,

[1489] ♦ C1-C6haloalkyl,

[1490] ♦ C1-C6alkoxy, and

[1491] ♦ COOH,

[1492] o C6-C10aryl optionally substituted with 1-3 groups independently selected from oxo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, halo, hydroxyl, cyano, N(R 10 aryl:

[1493] ♦ halo,

[1494] ♦ hydroxyl,

[1495] ♦ cyano,

[1496] ♦ SiMe3,

[1497] ♦ SO2Me,

[1498] ♦ SF5,

[1499] ♦ N(R N )2,

[1500] ♦ P(O)Me2,

[1501] ♦ -(O) 0-1 -(C3-C 10 cycloalkyl) optionally substituted with 1-3 groups independently selected from oxo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, halo, hydroxyl, cyano, N(R N )2,

[1502] ♦ C1-C6alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6alkoxy, 5-10 membered heteroaryl, SO2Me, and N(R N )2,

[1503] ♦ C1-C6alkoxy optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, N(R N )2, and C6-C 10 aryl,

[1504] ♦ C1-C6haloalkyl,

[1505] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, and

[1506] ◆-(O) 0-1 -(C6-C 10 Aryl),

[1507] ○Optionally substituted with 1-4 independently selected oxo and C1-C6 alkoxy groups, and

[1508] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[1509] ◆Hydroxy group,

[1510] ◆Cyano

[1511] ◆Oxygenation,

[1512] ◆Halogen,

[1513] ◆B(OH)2,

[1514] ◆N(R N )2,

[1515] ◆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,

[1516] ◆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,

[1517] ◆C1-C6 fluoroalkyl groups,

[1518] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[1519] ◆-(O) 0-1 -(C6-C 10 Aryl),

[1520] ◆Optionally substituted with 1-4 groups independently selected from C1-C6 alkyl groups (optionally substituted with 1-3 groups independently selected from hydroxyl groups) -(O) 0-1 -(3 to 10-membered heterocyclic groups),

[1521] ◆Optionally substituted with 1 to 4 independently selected C1-C6 alkyl groups, consisting of 5 to 10 heteroaryl groups.

[1522] 20. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-19, wherein each R ZC is hydrogen, or two R ZC are taken together to form an oxo group.

[1523] 21. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-20, wherein each R L1 is independently selected from:

[1524] ■ hydrogen,

[1525] ■ C1-C9 alkyl optionally substituted with 1-3 groups independently selected from:

[1526] ■ halo,

[1527] ■ hydroxyl,

[1528] ■ oxo,

[1529] ■ N(R N )2,

[1530] ■ C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from C6-C 10 aryl,

[1531] ■ C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl, and

[1532] ■ 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and oxo),

[1533] ■ C6-C 10 aryl optionally substituted with 1-4 groups independently selected from:

[1534] ■ halo,

[1535] ■ cyano,

[1536] ■ C1-C7 alkyl optionally substituted with 1-3 groups independently selected from oxo and N(R N )2,

[1537] ■ C3-C 10 cycloalkyl,

[1538] ■ 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl, and

[1539] ○5 to 10 yuan of mixed aromatic compounds,

[1540] ■ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[1541] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1542] ◆C3-C substituted with 1-3 independently selected C1-C6 fluoroalkyl groups 10 cycloalkyl groups, and

[1543] ○ C6-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 Aryl.

[1544] 22. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 1 to 21, wherein each C(R) L2 )2 is CH2 or C=O.

[1545] 23. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 1 to 22, wherein each R N Selected independently from:

[1546] ■ Hydrogen,

[1547] ■ C1-C8 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1548] ○Oxygenation,

[1549] ○Hydroxy group,

[1550] ○C1-C6 alkoxy groups,

[1551] ○-(O) 0-1 -(C3-C 10 cycloalkyl),

[1552] ○C6-C 10 Aryl,

[1553] ○3 to 14-membered heterocyclic groups,

[1554] ○ 5- to 14-membered heteroaryl groups optionally substituted by 1 to 4 independently selected C1-C6 alkyl groups.

[1555] ■ C3-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 cycloalkyl groups, and

[1556] ■3 to 10-membered heterocyclic groups;

[1557] or two R on the same nitrogen atom N with the nitrogen to which it is bound, form a 3- to 10-membered heterocyclyl group optionally substituted with 1-3 groups independently selected from C1-C6alkyl.

[1558] 24. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 23, wherein R F when present, two R F with the atom to which it is bound, form a group selected from 3- to 11-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

[1559] o C1-C9alkyl, and

[1560] o 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from C1-C6alkoxy.

[1561] 25. A compound of Formula lb:

[1562]

[1563] a tautomer thereof, deuterated derivative of said compound or said tautomer, or pharmaceutically acceptable salt of any of the foregoing, wherein ring A, ring B, W 1 , W 2 , Z, L 1 , L 2 , R 3 , R 4 , R 5 and R YN are as defined according to embodiment la.

[1564] 26. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 25, wherein ring A is selected from C6-C 10 aryl and 5- to 10-membered heteroaryl.

[1565] 27. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 25 or 26, wherein ring A is selected from phenyl, pyridyl, and pyrazolyl.

[1566] 28. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 25 to 27, wherein ring A is phenyl.

[1567] 29. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 25 to 28, wherein ring B is selected from C6-C 10 aryl.

[1568] 30. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 25-29, wherein Ring B is selected from phenyl and naphthyl.

[1569] 31. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 25-30, wherein Ring B is phenyl.

[1570] 32. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 25-31, wherein W 1 is N and W 2 is N.

[1571] 33. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 25-32, wherein Z is selected from NR ZN and C(R ZC )2, provided that when L 2 is absent, Z is C(R ZC )2.

[1572] 34. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 25-33, wherein each L 1 is C(R L1 )2.

[1573] 35. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 25-34, wherein L 2 is absent.

[1574] 36. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 25-35, wherein each R 3 is independently selected from C1-C6 alkyl.

[1575] 37. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 25-36, wherein each R 3 is methyl.

[1576] 38. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 25-35, wherein R 3 is absent.

[1577] 39. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 25-38, wherein R 4 is selected from hydrogen and methyl.

[1578] 40. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 25 to 39, wherein R 4 It is a methyl group.

[1579] 41. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 25 to 40, wherein each R 5 Selected independently from:

[1580] ■ Hydrogen,

[1581] ■Hydroxy

[1582] ■Optionally selected from 1-3 independent choices C3-C 10 Cycloalkyl groups substituted with C1-C6 alkyl groups,

[1583] ■Optionally selected from 1-3 independent choices of C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[1584] 42. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 25 to 41, wherein R YN Selected from:

[1585] ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1586] ○Hydroxy group,

[1587] ○Oxygenation,

[1588] ○Cyano

[1589] ○ C1-C6 alkoxy groups optionally substituted with 1-3 independently selected halogen and C1-C6 alkoxy groups,

[1590] ○N(R N )2,

[1591] ○SO2Me,

[1592] ○ C3-C cells optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[1593] ◆Optionally selected by 1-3 independent elements from oxo and N(R) N C1-C6 alkyl groups substituted with 2 groups,

[1594] ◆C1-C6 fluoroalkyl groups,

[1595] ◆C1-C6 alkoxy groups, and

[1596] ♦ COOH,

[1597] ♦ C6-C10aryl optionally substituted with 1-3 groups independently selected from C1-C6alkyl, 10 ♦ C6-C10aryl,

[1598] ♦ halogen,

[1599] ♦ hydroxyl,

[1600] ♦ cyano,

[1601] ♦ SiMe3,

[1602] ♦ SO2Me,

[1603] ♦ SF5,

[1604] ♦ N(R N )2,

[1605] ♦ P(O)Me2,

[1606] ♦ -(O) 0-1 -(C3-C 10 cycloalkyl) optionally substituted with 1-3 groups independently selected from C1-C6alkyl,

[1607] ♦ C1-C6alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6alkoxy, 5- to 10-membered heteroaryl, SO2Me, and N(R N )2,

[1608] ♦ C1-C6alkoxy optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, N(R N )2, and C6-C 10 aryl,

[1609] ♦ C1-C6fluoroalkyl,

[1610] ♦ 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl, and

[1611] ♦ -(O) 0-1 -(C6-C 10 aryl) optionally substituted with 1-3 groups independently selected from C1-C6alkyl,

[1612] ♦ 3- to 10-membered heterocyclyl optionally substituted with 1-4 groups independently selected from oxo and C1-C6alkoxy, and

[1613] ♦ 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

[1614] ♦ hydroxyl,

[1615] ♦ cyano,

[1616] ♦ oxo,

[1617] ♦ halogen,

[1618] ♦ B(OH)2,

[1619] ♦ N(R N )2,

[1620] ♦ C1-C6alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6alkoxy, and N(R N )2,

[1621] ♦ C1-C6alkoxy optionally substituted with 1-3 groups independently selected from hydroxyl, C1-C6alkyl, N(R N )2, and C3-C 10 cycloalkyl,

[1622] ♦ C1-C6fluoroalkyl,

[1623] ♦ -(O) 0-1 -(C3-C 10 cycloalkyl) optionally substituted with 1-3 groups independently selected from C1-C6alkyl,

[1624] ♦ -(O) 0-1 -(C6-C 10 aryl),

[1625] ♦ -(O) 0-1 -(3- to 10-membered heterocyclyl) optionally substituted with 1-4 groups independently selected from C1-C6alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl),

[1626] ♦ 5- to 10-membered heteroaryl optionally substituted with 1-4 groups independently selected from C1-C6alkyl.

[1627] 43. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 25-42, wherein each R ZC is hydrogen, or two R ZC together form an oxo group.

[1628] 44. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 25-43, wherein each R L1 is independently selected from:

[1629] ■ hydrogen,

[1630] ■ C1-C9alkyl optionally substituted with 1-3 groups independently selected from:

[1631] • halo,

[1632] • hydroxyl,

[1633] • oxo,

[1634] • N(R N )2,

[1635] • C1-C6alkoxy optionally substituted with 1-3 groups independently selected from C6-C 10 aryl,

[1636] • C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6fluoroalkyl, and

[1637] • 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and oxo),

[1638] • C6-C 10 aryl optionally substituted with 1-4 groups independently selected from:

[1639] • halo,

[1640] • cyano,

[1641] • C1-C7alkyl optionally substituted with 1-3 groups independently selected from oxo and N(R N )2,

[1642] • C3-C 10 cycloalkyl,

[1643] • 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl,

[1644] • 5- to 10-membered heteroaryl,

[1645] • 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

[1646] • C1-C6alkyl optionally substituted with 1-3 groups independently selected from:

[1647] • C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6fluoroalkyl, and

[1648] • C6-C 10 aryl optionally substituted with 1-3 groups independently selected from C1-C6alkyl.

[1649] 45. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 25-44, wherein each C(R L2 )2 is CH2or C=O.

[1650] 46. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 25-45, wherein each R N is independently selected from:

[1651] ■ hydrogen,

[1652] ■ C1-C8alkyl optionally substituted with 1-3 groups independently selected from:

[1653] o oxo,

[1654] o hydroxy,

[1655] o C1-C6alkoxy,

[1656] o -(O) 0-1 -(C3-C 10 cycloalkyl),

[1657] o C6-C 10 aryl,

[1658] o 3- to 14-membered heterocyclyl,

[1659] o 5- to 14-membered heteroaryl optionally substituted with 1-4 groups independently selected from C1-C6alkyl,

[1660] ■ C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl, and

[1661] ■ 3- to 10-membered heterocyclyl;

[1662] or two R N on the same nitrogen atom, together with the nitrogen to which they are bound, form a 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups selected from C1-C6alkyl.

[1663] 47. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 25-46, wherein when R F is present, two R F together with the atom to which they are bound form a group selected from 3- to 11-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

[1664] o C1-C9alkyl, and

[1665] • C6-C10aryl optionally substituted with 1-3 groups independently selected from C1-C6alkoxy.

[1666] 48. A compound of Formula IIa:

[1667]

[1668] a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring B, W 1 , W 2 , Z, L 1 , L 2 , R 3 , R 4 , R 5 and R YN are as defined according to Embodiment 1a.

[1669] 49. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 48, wherein ring B is selected from C6-C 10 aryl.

[1670] 50. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 48 or 47, wherein ring B is selected from phenyl and naphthyl.

[1671] 51. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 48-50, wherein ring B is phenyl.

[1672] 52. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 48-51, wherein W 1 is N and W 2 is N.

[1673] 53. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 48-52, wherein Z is selected from NR ZN and C(R ZC )2, provided that when L 2 is absent, Z is C(R ZC )2.

[1674] 54. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 48-53, wherein each L 1 is C(R L1 )2.

[1675] 55. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 48-54, wherein L 2 is absent.

[1676] 56. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 48-55, wherein each R 3 is independently selected from C1-C6alkyl.

[1677] 57. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 48-56, wherein each R 3 is methyl.

[1678] 58. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 48-55, wherein R 3 is absent.

[1679] 59. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 48-58, wherein R 4 is selected from hydrogen and methyl.

[1680] 60. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 48-59, wherein R 4 is methyl.

[1681] 61. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 48-60, wherein each R 5 is independently selected from:

[1682] ■ hydrogen,

[1683] ■ hydroxyl,

[1684] ■ C1-C6alkyl optionally substituted with 1-3 groups independently selected from C3-C 10 cycloalkyl,

[1685] ■ C1-C6alkoxy optionally substituted with 1-3 groups independently selected from C6-C 10 aryl,

[1686] 62. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 48-61, wherein R YN is selected from:

[1687] ■ C1-C9alkyl optionally substituted with 1-3 groups independently selected from:

[1688] ○Hydroxy group,

[1689] ○Oxygenation,

[1690] ○Cyano

[1691] ○ C1-C6 alkoxy groups optionally substituted with 1-3 independently selected halogen and C1-C6 alkoxy groups,

[1692] ○N(R N )2,

[1693] ○SO2Me,

[1694] ○ C3-C cells optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[1695] ◆Optionally selected by 1-3 independent elements from oxo and N(R) N C1-C6 alkyl groups substituted with 2 groups,

[1696] ◆C1-C6 fluoroalkyl groups,

[1697] ◆C1-C6 alkoxy groups, and

[1698] ◆COOH,

[1699] ○ C6-C cells optionally substituted with 1-3 independently selected groups from the following 10 Aryl:

[1700] ◆Halogen,

[1701] ◆Hydroxy group,

[1702] ◆Cyano

[1703] ◆SiMe3,

[1704] ◆SO2Me,

[1705] ◆SF5,

[1706] ◆N(R N )2,

[1707] ◆P(O)Me2,

[1708] ◆Optionally substituted with 1-3 independently selected C1-C6 fluoroalkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[1709] ◆Optionally composed of 1-3 independently selected hydroxyl, oxo, C1-C6 alkoxy, 5- to 10-membered heteroaryl, SO2Me and N(R) NC1-C6 alkyl groups substituted with 2 groups,

[1710] ◆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,

[1711] ◆C1-C6 fluoroalkyl groups,

[1712] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, and

[1713] ◆-(O) 0-1 -(C6-C 10 Aryl),

[1714] ○Optionally substituted with 1-4 independently selected oxo and C1-C6 alkoxy groups, and

[1715] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[1716] ◆Hydroxy group,

[1717] ◆Cyano

[1718] ◆Oxygenation,

[1719] ◆Halogen,

[1720] ◆B(OH)2,

[1721] ◆N(R N )2,

[1722] ◆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,

[1723] ◆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,

[1724] ◆C1-C6 fluoroalkyl groups,

[1725] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[1726] ◆-(O) 0-1 -(C6-C 10 Aryl),

[1727] ♦ -(O) optionally substituted with 1-4 groups independently selected from C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl) 0-1 ♦ -(3- to 10-membered heterocyclyl),

[1728] ♦ 5- to 10-membered heteroaryl optionally substituted with 1-4 groups independently selected from C1-C6 alkyl.

[1729] 63. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 48-62, wherein each R ZC is hydrogen, or two R ZC are taken together to form an oxo group.

[1730] 64. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 48-63, wherein each R L1 is independently selected from:

[1731] ■ hydrogen,

[1732] ■ C1-C9 alkyl optionally substituted with 1-3 groups independently selected from:

[1733] o halogen,

[1734] o hydroxyl,

[1735] o oxo,

[1736] o N(R N )2,

[1737] o C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from C6-C 10 aryl,

[1738] o C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl, and

[1739] o 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and oxo),

[1740] ■ C6-C 10 aryl optionally substituted with 1-4 groups independently selected from:

[1741] o halogen,

[1742] o cyano,

[1743] • C1-C7alkyl optionally substituted with 1-3 groups independently selected from oxo and N(R N )2,

[1744] • C3-C 10 cycloalkyl,

[1745] • 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl, and

[1746] • 5- to 10-membered heteroaryl,

[1747] • 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

[1748] • C1-C6alkyl optionally substituted with 1-3 groups independently selected from:

[1749] • C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6fluoroalkyl, and

[1750] • C6-C 10 aryl optionally substituted with 1-3 groups independently selected from C1-C6alkyl.

[1751] 65. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 48-64, wherein each C(R L2 )2is CH2or C=O.

[1752] 66. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 48-65, wherein each R N is independently selected from:

[1753] • hydrogen,

[1754] • C1-C8alkyl optionally substituted with 1-3 groups independently selected from:

[1755] • oxo,

[1756] • hydroxyl,

[1757] • C1-C6alkoxy,

[1758] • -(O) 0-1 -(C3-C 10 cycloalkyl),

[1759] • C6-C 10 aryl,

[1760] • 3- to 14-membered heterocyclyl,

[1761] o 5- to 14-membered heteroaryl optionally substituted with 1-4 groups independently selected from C1-C6alkyl,

[1762] ■C3-C6cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl, 10 cycloalkyl, and

[1763] ■3- to 10-membered heterocyclyl;

[1764] or two R N groups on the same nitrogen atom, together with the nitrogen to which they are bound, form a 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups selected from C1-C6alkyl.

[1765] 67. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 48-66, wherein R F is present, two R F groups, together with the atom to which they are bound, form a group selected from 3- to 11-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

[1766] o C1-C9alkyl, and

[1767] o 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from C1-C6alkoxy.

[1768] 68. A compound of Formula IIb:

[1769]

[1770] a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A, W 1 , W 2 , Z, L 1 , L 2 , R 3 , R 4 , R 5 and R YN are as defined according to Embodiment 1a.

[1771] 69. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 68, wherein ring A is selected from C6-C 10 aryl and 5- to 10-membered heteroaryl.

[1772] 70. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 68 or 69, wherein ring A is selected from phenyl, pyridyl, and pyrazolyl.

[1773] 71. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 68-70, wherein Ring A is phenyl.

[1774] 72. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 68-71, wherein W 1 is N and W 2 is N.

[1775] 73. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 68-72, wherein Z is selected from NR ZN and C(R ZC )2, provided that when L 2 is absent, Z is C(R ZC )2.

[1776] 74. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 68-73, wherein each L 1 is C(R L1 )2.

[1777] 75. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 68-74, wherein L 2 is absent.

[1778] 76. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 68-75, wherein each R 3 is independently selected from C1-C6 alkyl.

[1779] 77. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 68-76, wherein each R 3 is methyl.

[1780] 78. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 68-75, wherein R 3 is absent.

[1781] 79. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 68-78, wherein R 4 is selected from hydrogen and methyl.

[1782] 80. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 68-79, wherein R 4 is methyl.

[1783] 81. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 68 to 80, wherein each R 5 Selected independently from:

[1784] ■ Hydrogen,

[1785] ■Hydroxy

[1786] ■Optionally selected from 1-3 independent choices C3-C 10 Cycloalkyl groups substituted with C1-C6 alkyl groups,

[1787] ■Optionally selected from 1-3 independent choices of C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[1788] 82. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 68 to 81, wherein R YN Selected from:

[1789] ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1790] ○Hydroxy group,

[1791] ○Oxygenation,

[1792] ○Cyano

[1793] ○ C1-C6 alkoxy groups optionally substituted with 1-3 independently selected halogen and C1-C6 alkoxy groups,

[1794] ○N(R N )2,

[1795] ○SO2Me,

[1796] ○ C3-C cells optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[1797] ◆Optionally selected by 1-3 independent elements from oxo and N(R) N C1-C6 alkyl groups substituted with 2 groups,

[1798] ◆C1-C6 fluoroalkyl groups,

[1799] ◆C1-C6 alkoxy groups, and

[1800] ◆COOH,

[1801] ○ C6-C cells optionally substituted with 1-3 independently selected groups from the following 10 Aryl:

[1802] ♦ halogen,

[1803] ♦ hydroxyl,

[1804] ♦ cyano,

[1805] ♦ SiMe3,

[1806] ♦ SO2Me,

[1807] ♦ SF5,

[1808] ♦ N(R N )2,

[1809] ♦ P(O)Me2,

[1810] ♦ -(O) 0-1 -(C3-C 10 cycloalkyl),

[1811] ♦ C1-C6alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6alkoxy, 5- to 10-membered heteroaryl, SO2Me, and N(R N )2,

[1812] ♦ C1-C6alkoxy optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, N(R N )2, and C6-C 10 aryl,

[1813] ♦ C1-C6fluoroalkyl,

[1814] ♦ 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl, and

[1815] ♦ -(O) 0-1 -(C6-C 10 aryl),

[1816] ♦ 3- to 10-membered heterocyclyl optionally substituted with 1-4 groups independently selected from oxo and C1-C6alkoxy, and

[1817] ♦ 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

[1818] ♦ hydroxyl,

[1819] ♦ cyano,

[1820] ♦ oxo,

[1821] ♦ halogen,

[1822] ◆ B(OH)2,

[1823] ◆ N(R N )2,

[1824] ◆ C1-C6 alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6 alkoxy, and N(R N )2,

[1825] ◆ C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from hydroxyl, C1-C6 alkyl, N(R N )2, and C3-C 10 cycloalkyl,

[1826] ◆ C1-C6 fluoroalkyl,

[1827] ◆ -(O) 0-1 -(C3-C 10 cycloalkyl) optionally substituted with 1-3 groups independently selected from C1-C6 alkyl,

[1828] ◆ -(O) 0-1 -(C6-C 10 aryl),

[1829] ◆ -(O) 0-1 -(3- to 10-membered heterocyclyl) optionally substituted with 1-4 groups independently selected from C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl),

[1830] ◆ 5- to 10-membered heteroaryl optionally substituted with 1-4 groups independently selected from C1-C6 alkyl.

[1831] 83. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof of any one of embodiments 68-82, wherein each R ZC is hydrogen, or two R ZC together form an oxo group.

[1832] 84. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof of any one of embodiments 68-83, wherein each R L1 is independently selected from:

[1833] ■ hydrogen,

[1834] ■ C1-C9 alkyl optionally substituted with 1-3 groups independently selected from:

[1835] o halogen,

[1836] o hydroxyl,

[1837] o oxo,

[1838] ○N(R N )2,

[1839] ○Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[1840] ○ C3-C substituted with 1-3 independently selected C1-C6 fluoroalkyl groups 10 cycloalkyl groups, and

[1841] ○ 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),

[1842] ■ C6-C cells optionally substituted with 1-4 independently selected groups from the following 10 Aryl:

[1843] ○ Halogen,

[1844] ○Cyano

[1845] ○Optionally selected by 1-3 independent elements from oxo and N(R) N C1-C7 alkyl groups substituted with 2 groups,

[1846] ○C3-C 10 cycloalkyl,

[1847] ○Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, and

[1848] ○5 to 10 yuan of mixed aromatic compounds,

[1849] ■ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[1850] ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1851] ◆C3-C substituted with 1-3 independently selected C1-C6 fluoroalkyl groups 10 cycloalkyl groups, and

[1852] ○ C6-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 Aryl.

[1853] 85. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 68 to 84, wherein each C(R) L2 )2 is CH2 or C=O.

[1854] 86. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 68-85, wherein each R N is independently selected from:

[1855] ■ hydrogen,

[1856] ■ C1-C8 alkyl optionally substituted with 1-3 groups independently selected from:

[1857] o oxo,

[1858] o hydroxy,

[1859] o C1-C6 alkoxy,

[1860] o -(O) 0-1 -(C3-C 10 cycloalkyl),

[1861] o C6-C 10 aryl,

[1862] o 3- to 14-membered heterocyclyl,

[1863] o 5- to 14-membered heteroaryl optionally substituted with 1-4 groups independently selected from C1-C6 alkyl,

[1864] ■ C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl, and

[1865] ■ 3- to 10-membered heterocyclyl;

[1866] or two R N on the same nitrogen atom, together with the nitrogen to which they are bound, form a 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups selected from C1-C6 alkyl.

[1867] 87. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 68-86, wherein when R F are present, the two R F together with the atom to which they are bound form a group selected from 3- to 11-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

[1868] o C1-C9 alkyl, and

[1869] o 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from C1-C6 alkoxy.

[1870] 88. A compound of Formula III:

[1871]

[1872] a tautomer thereof, a deuterated derivative of the compound or 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 are as defined according to Embodiment 1a.

[1873] 89. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 88, wherein W 1 is N and W 2 is N.

[1874] 90. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 88 or 89, wherein Z is selected from NR ZN and C(R ZC )2, provided that when L 2 is absent, Z is C(R ZC )2.

[1875] 91. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 88-90, wherein each L 1 is C(R L1 )2.

[1876] 92. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 88-91, wherein L 2 is absent.

[1877] 93. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 88-92, wherein R 4 is selected from hydrogen and methyl.

[1878] 94. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 88-93, wherein R 4 is methyl.

[1879] 95. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 88-94, wherein each R 5 is independently selected from:

[1880] ■ hydrogen,

[1881] ■Hydroxy

[1882] ■Optionally selected from 1-3 independent choices C3-C 10 Cycloalkyl groups substituted with C1-C6 alkyl groups,

[1883] ■Optionally selected from 1-3 independent choices of C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[1884] 96. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 88 to 95, wherein R YN Selected from:

[1885] ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1886] ○Hydroxy group,

[1887] ○Oxygenation,

[1888] ○Cyano

[1889] ○ C1-C6 alkoxy groups optionally substituted with 1-3 independently selected halogen and C1-C6 alkoxy groups,

[1890] ○N(R N )2,

[1891] ○SO2Me,

[1892] ○ C3-C cells optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[1893] ◆Optionally selected by 1-3 independent elements from oxo and N(R) N C1-C6 alkyl groups substituted with 2 groups,

[1894] ◆C1-C6 fluoroalkyl groups,

[1895] ◆C1-C6 alkoxy groups, and

[1896] ◆COOH,

[1897] ○ C6-C cells optionally substituted with 1-3 independently selected groups from the following 10 Aryl:

[1898] ◆Halogen,

[1899] ◆Hydroxy group,

[1900] ◆Cyano

[1901] ◆SiMe3,

[1902] ♦ SO2Me,

[1903] ♦ SF5,

[1904] ♦ N(R N )2,

[1905] ♦ P(O)Me2,

[1906] ♦ -(O) 0-1 -(C3-C 10 cycloalkyl),

[1907] ♦ C1-C6alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6alkoxy, 5- to 10-membered heteroaryl, SO2Me, and N(R N )2,

[1908] ♦ C1-C6alkoxy optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, N(R N )2, and C6-C 10 aryl,

[1909] ♦ C1-C6fluoroalkyl,

[1910] ♦ 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl, and

[1911] ♦ -(O) 0-1 -(C6-C 10 aryl),

[1912] ♦ 3- to 10-membered heterocyclyl optionally substituted with 1-4 groups independently selected from oxo and C1-C6alkoxy, and

[1913] ♦ 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

[1914] ♦ hydroxyl,

[1915] ♦ cyano,

[1916] ♦ oxo,

[1917] ♦ halogen,

[1918] ♦ B(OH)2,

[1919] ♦ N(R N )2,

[1920] ♦ C1-C6alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6alkoxy, and N(R NC6alkyl optionally substituted with 1-3 groups independently selected from hydroxy, C1-C6alkoxy, N(R

[1921] ◆C1-C6alkyl optionally substituted with 1-3 groups independently selected from hydroxy, C1-C6alkoxy, N(R N )2, and C3-C 10 cycloalkyl,

[1922] ◆C1-C6fluoroalkyl,

[1923] ◆-(O) 0-1 -(C3-C 10 cycloalkyl) optionally substituted with 1-3 groups independently selected from hydroxy, C1-C6alkyl, and C1-C6fluoroalkyl,

[1924] ◆-(O) 0-1 -(C6-C 10 aryl) optionally substituted with 1-3 groups independently selected from hydroxy, C1-C6alkyl, and C1-C6fluoroalkyl,

[1925] ◆-(O) 0-1 -(3 to 10 membered heterocyclyl) optionally substituted with 1-4 groups independently selected from C1-C6alkyl optionally substituted with 1-3 groups independently selected from hydroxy,

[1926] ◆5- to 10-membered heteroaryl optionally substituted with 1-4 groups independently selected from C1-C6alkyl.

[1927] 97. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 88-96, wherein each R ZC is hydrogen, or two R ZC are taken together to form an oxo group.

[1928] 98. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 88-97, wherein each R L1 is independently selected from:

[1929] ■hydrogen,

[1930] ■C1-C9alkyl optionally substituted with 1-3 groups independently selected from:

[1931] o halogen,

[1932] o hydroxy,

[1933] o oxo,

[1934] o N(R N )2,

[1935] o C1-C6alkoxy optionally substituted with 1-3 groups independently selected from C6-C 10 aryl,

[1936] o C3-C6cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl, 10 cycloalkyl, and

[1937] o 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl,

[1938] ■ C6-C10aryl optionally substituted with 1-4 groups independently selected from: 10 aryl:

[1939] o halogen,

[1940] o cyano,

[1941] o C1-C7alkyl optionally substituted with 1-3 groups independently selected from oxo and N(R N )2,

[1942] o C3-C6cycloalkyl, 10 cycloalkyl,

[1943] o 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl, and

[1944] o 5- to 10-membered heteroaryl,

[1945] ■ 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

[1946] o C1-C6alkyl optionally substituted with 1-3 groups independently selected from:

[1947] ◆ C3-C6cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6fluoroalkyl, and 10 cycloalkyl,

[1948] o C6-C10aryl optionally substituted with 1-3 groups independently selected from C1-C6alkyl. 10 aryl.

[1949] 99. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 88-98, wherein each C(R L2 )2is CH2or C=O.

[1950] 100. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 88-99, wherein each R N is independently selected from:

[1951] ■ hydrogen,

[1952] ■ C1-C8 alkyl optionally substituted with 1-3 groups independently selected from:

[1953] o oxo,

[1954] o hydroxy,

[1955] o C1-C6 alkoxy,

[1956] o -(O) 0-1 -(C3-C 10 cycloalkyl),

[1957] o C6-C 10 aryl,

[1958] o 3- to 14-membered heterocyclyl,

[1959] o 5- to 14-membered heteroaryl optionally substituted with 1-4 groups independently selected from C1-C6 alkyl,

[1960] ■ C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl, and

[1961] ■ 3- to 10-membered heterocyclyl;

[1962] or two R N on the same nitrogen atom, together with the nitrogen to which they are bound, form a 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups selected from C1-C6 alkyl.

[1963] 101. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 88-100, wherein when R F is present, two R F on the same atom, together with the atom to which they are bound, form a group selected from 3- to 11-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

[1964] o C1-C9 alkyl, and

[1965] o 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from C1-C6 alkoxy.

[1966] 102. A compound of Formula IV:

[1967]

[1968] a tautomer thereof, deuterated derivative of said compound or said tautomer, or pharmaceutically acceptable salt of any of the foregoing, wherein Z, L 1 , L2 , R 4 , R 5 , and R YN are defined as described according to embodiment 1a.

[1969] 103. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 102, wherein Z is selected from NR ZN and C(R ZC )2, provided that when L 2 is absent, Z is C(R ZC )2.

[1970] 104. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 102 or 103, wherein each L 1 is C(R L1 )2.

[1971] 105. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 102 to 104, wherein L 2 is absent.

[1972] 106. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 102 to 105, wherein R 4 is selected from hydrogen and methyl.

[1973] 107. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 102 to 106, wherein R 4 is methyl.

[1974] 108. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 102 to 107, wherein each R 5 is independently selected from:

[1975] ■ hydrogen,

[1976] ■ hydroxyl,

[1977] ■ C1-C6 alkyl optionally substituted with 1-3 groups independently selected from C3-C6 cycloalkyl, 10 ■ C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from C6-C10 aryl,

[1978] ■ C1-C6 alkyl optionally substituted with 1-3 groups independently selected from C3-C6 cycloalkyl, 10 ■ C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from C6-C10 aryl,

[1979] 109. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 102 to 108, wherein RYN Selected from:

[1980] ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[1981] ○Hydroxy group,

[1982] ○Oxygenation,

[1983] ○Cyano

[1984] ○ C1-C6 alkoxy groups optionally substituted with 1-3 independently selected halogen and C1-C6 alkoxy groups,

[1985] ○N(R N )2,

[1986] ○SO2Me,

[1987] ○ C3-C cells optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[1988] ◆Optionally selected by 1-3 independent elements from oxo and N(R) N C1-C6 alkyl groups substituted with 2 groups,

[1989] ◆C1-C6 fluoroalkyl groups,

[1990] ◆C1-C6 alkoxy groups, and

[1991] ◆COOH,

[1992] ○ C6-C cells optionally substituted with 1-3 independently selected groups from the following 10 Aryl:

[1993] ◆Halogen,

[1994] ◆Hydroxy group,

[1995] ◆Cyano

[1996] ◆SiMe3,

[1997] ◆SO2Me,

[1998] ◆SF5,

[1999] ◆N(R N )2,

[2000] ◆P(O)Me2,

[2001] ◆Optionally substituted with 1-3 independently selected C1-C6 fluoroalkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[2002] ◆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,

[2003] ◆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,

[2004] ◆C1-C6 fluoroalkyl groups,

[2005] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, and

[2006] ◆-(O) 0-1 -(C6-C 10 (Aryl),

[2007] ○Optionally substituted with 1-4 independently selected oxo and C1-C6 alkoxy groups, and

[2008] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[2009] ◆Hydroxy group,

[2010] ◆Cyano

[2011] ◆Oxygenation,

[2012] ◆Halogen,

[2013] ◆B(OH)2,

[2014] ◆N(R N )2,

[2015] ◆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,

[2016] ◆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,

[2017] ◆C1-C6 fluoroalkyl groups,

[2018] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[2019] ♦ -(O) 0-1 ♦ -(C6-C 10 aryl),

[2020] ♦ -(O) optionally substituted with 1-4 groups independently selected from C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl) 0-1 ♦ -(3- to 10-membered heterocyclyl),

[2021] ♦ 5- to 10-membered heteroaryl optionally substituted with 1-4 groups independently selected from C1-C6 alkyl.

[2022] 110. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 102-109, wherein each R ZC is hydrogen, or two R ZC are taken together to form an oxo group.

[2023] 111. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 102-110, wherein each R L1 is independently selected from:

[2024] ■ hydrogen,

[2025] ■ C1-C9 alkyl optionally substituted with 1-3 groups independently selected from:

[2026] o halogen,

[2027] o hydroxyl,

[2028] o oxo,

[2029] o N(R N )2,

[2030] o C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from C6-C 10 aryl,

[2031] o C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl, and

[2032] o 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and oxo),

[2033] ■ C6-C 10 aryl optionally substituted with 1-4 groups independently selected from:

[2034] • halo,

[2035] • cyano,

[2036] • C1-C7alkyl optionally substituted with 1-3 groups independently selected from oxo and N(R N )2,

[2037] • C3-C 10 cycloalkyl,

[2038] • 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl, and

[2039] • 5- to 10-membered heteroaryl,

[2040] • 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

[2041] • C1-C6alkyl optionally substituted with 1-3 groups independently selected from:

[2042] • C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6fluoroalkyl, and

[2043] • C6-C 10 aryl optionally substituted with 1-3 groups independently selected from C1-C6alkyl.

[2044] 112. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof of any one of embodiments 102-111, wherein each C(R L2 )2is CH2or C=O.

[2045] 113. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof of any one of embodiments 102-112, wherein each R N is independently selected from:

[2046] • hydrogen,

[2047] • C1-C8alkyl optionally substituted with 1-3 groups independently selected from:

[2048] • oxo,

[2049] • hydroxy,

[2050] • C1-C6alkoxy,

[2051] • -(O) 0-1 -(C3-C 10 cycloalkyl),

[2052] o C6-C 10 aryl,

[2053] o 3- to 14-membered heterocyclyl,

[2054] o 5- to 14-membered heteroaryl, optionally substituted with 1-4 groups independently selected from C1-C6alkyl,

[2055] ■ C3-C 10 cycloalkyl, and

[2056] ■ 3- to 10-membered heterocyclyl;

[2057] or two R N groups on the same nitrogen atom, together with the nitrogen to which they are bound, form a 3- to 10-membered heterocyclyl group, optionally substituted with 1-3 groups selected from C1-C6alkyl.

[2058] 114. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 102-113, wherein R F when present, two R F groups on the same atom, together with the atom to which they are bound, form a group selected from 3- to 11-membered heterocyclyl, optionally substituted with 1-3 groups independently selected from:

[2059] o C1-C9alkyl, and

[2060] o 5- to 10-membered heteroaryl, optionally substituted with 1-3 groups independently selected from C1-C6alkoxy.

[2061] 115. A compound of Formula V:

[2062]

[2063] a tautomer thereof, deuterated derivative of said compound or said tautomer, or pharmaceutically acceptable salt of any of the foregoing, wherein Z, L 1 , L 2 , R 4 , R 5 , and R YN are as defined according to Embodiment 1a.

[2064] 116. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 115, wherein Z is selected from NR ZN and C(R ZC )2, provided that when L 2 is absent, Z is C(R ZC )2.

[2065] 117. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any of embodiments 115 or 116, wherein each L 1 is C(R L1 )2.

[2066] 118. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any of embodiments 115 to 117, wherein L 2 is absent.

[2067] 119. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any of embodiments 115 to 118, wherein R 4 is selected from hydrogen and methyl.

[2068] 120. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any of embodiments 115 to 119, wherein R 4 is methyl.

[2069] 121. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any of embodiments 115 to 120, wherein each R 5 is independently selected from:

[2070] ■ hydrogen,

[2071] ■ hydroxyl,

[2072] ■ C1-C6 alkyl optionally substituted with 1-3 groups independently selected from C3-C 10 cycloalkyl,

[2073] ■ C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from C6-C 10 aryl,

[2074] 122. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any of embodiments 115 to 121, wherein R YN is selected from:

[2075] ■ C1-C9 alkyl optionally substituted with 1-3 groups independently selected from:

[2076] ■ hydroxyl,

[2077] ■ oxo,

[2078] ■ cyano,

[2079] ■ C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from halogen and C1-C6 alkoxy,

[2080] o N(R N )2,

[2081] o SO2Me,

[2082] o C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from oxo and N(R N )2,

[2083] o C1-C6alkyl optionally substituted with 1-3 groups independently selected from oxo and N(R N )2,

[2084] o C1-C6fluoroalkyl,

[2085] o C1-C6alkoxy, and

[2086] o COOH,

[2087] o C6-C 10 aryl optionally substituted with 1-3 groups independently selected from halo, hydroxyl, cyano, oxo, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6alkoxy, SO2Me, SF5, N(R N )2, and P(O)Me2,

[2088] o halo,

[2089] o hydroxyl,

[2090] o cyano,

[2091] o SiMe3,

[2092] o SO2Me,

[2093] o SF5,

[2094] o N(R N )2,

[2095] o P(O)Me2,

[2096] o -(O) 0-1 -(C3-C 10 cycloalkyl) optionally substituted with 1-3 groups independently selected from C1-C6fluoroalkyl,

[2097] o C1-C6alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6alkoxy, 5- to 10-membered heteroaryl, SO2Me, and N(R N )2,

[2098] o C1-C6alkoxy optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, N(R N )2, and C6-C 10 aryl,

[2099] o C1-C6fluoroalkyl,

[2100] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, and

[2101] ◆-(O) 0-1 -(C6-C 10 Aryl),

[2102] ○Optionally substituted with 1-4 independently selected oxo and C1-C6 alkoxy groups, and

[2103] ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following:

[2104] ◆Hydroxy group,

[2105] ◆Cyano

[2106] ◆Oxygenation,

[2107] ◆Halogen,

[2108] ◆B(OH)2,

[2109] ◆N(R N )2,

[2110] ◆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,

[2111] ◆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,

[2112] ◆C1-C6 fluoroalkyl groups,

[2113] ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl),

[2114] ◆-(O) 0-1 -(C6-C 10 Aryl),

[2115] ◆Optionally substituted with 1-4 groups independently selected from C1-C6 alkyl groups (optionally substituted with 1-3 groups independently selected from hydroxyl groups) -(O) 0-1 -(3 to 10-membered heterocyclic groups),

[2116] ◆Optionally substituted with 1 to 4 independently selected C1-C6 alkyl groups, consisting of 5 to 10 heteroaryl groups.

[2117] 123. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any of Embodiments 115 to 122, wherein each R ZC is hydrogen, or two R ZC are taken together to form an oxo group.

[2118] 124. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any of Embodiments 115 to 123, wherein each R L1 is independently selected from:

[2119] ■ hydrogen,

[2120] ■ C1-C9 alkyl optionally substituted with 1-3 groups independently selected from:

[2121] o halogen,

[2122] o hydroxyl,

[2123] o oxo,

[2124] o N(R N )2,

[2125] o C1-C6 alkoxy optionally substituted with 1-3 groups independently selected from C6-C 10 aryl,

[2126] o C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl, and

[2127] o 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and oxo),

[2128] ■ C6-C 10 aryl optionally substituted with 1-4 groups independently selected from:

[2129] o halogen,

[2130] o cyano,

[2131] o C1-C7 alkyl optionally substituted with 1-3 groups independently selected from oxo and N(R N )2,

[2132] o C3-C 10 cycloalkyl,

[2133] o 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl.

[2134] o 5- to 10-membered heteroaryl,

[2135] ■5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

[2136] o C1-C6 alkyl optionally substituted with 1-3 groups independently selected from:

[2137] ♦ C3-C6 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl, 10 cycloalkyl, and

[2138] o C6-C10 aryl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl, 10 aryl.

[2139] 125. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 115 to 124, wherein each C(R L2 )2is CH2or C=O.

[2140] 126. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 115 to 125, wherein each R N is independently selected from:

[2141] ■ hydrogen,

[2142] ■ C1-C8 alkyl optionally substituted with 1-3 groups independently selected from:

[2143] o oxo,

[2144] o hydroxy,

[2145] o C1-C6 alkoxy,

[2146] o -(O) 0-1 -(C3-C 10 cycloalkyl),

[2147] o C6-C 10 aryl,

[2148] o 3- to 14-membered heterocyclyl,

[2149] o 5- to 14-membered heteroaryl optionally substituted with 1-4 groups independently selected from C1-C6 alkyl,

[2150] ■ C3-C6 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl, 10 cycloalkyl, and

[2151] ■3- to 10-membered heterocyclyl;

[2152] or two R N together with the nitrogen to which they are bound form a 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl.

[2153] 127. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 115-126, wherein R F two R F together with the atom to which they are bound form a group selected from 3- to 11-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

[2154] o C1-C9alkyl, and

[2155] o 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from C1-C6alkoxy.

[2156] 128. A compound of Formula VI:

[2157]

[2158] a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein L 1 , R 4 , R 5 , and R YN are as defined according to embodiment 1a.

[2159] 129. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 128, wherein each L 1 is C(R L1 )2.

[2160] 130. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 128 or 129, wherein R 4 is selected from hydrogen and methyl.

[2161] 131. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 128-130, wherein R 4 is methyl.

[2162] 132. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 128-131, wherein each R 5 is independently selected from:

[2163] ■ Hydrogen,

[2164] ■Hydroxy

[2165] ■Optionally selected from 1-3 independent choices C3-C 10 Cycloalkyl groups substituted with C1-C6 alkyl groups,

[2166] ■Optionally selected from 1-3 independent choices of C6-C 10 The C1-C6 alkoxy group substituted by the aryl group,

[2167] 133. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Examples 128 to 132, wherein R YN Selected from:

[2168] ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following:

[2169] ○Hydroxy group,

[2170] ○Oxygenation,

[2171] ○Cyano

[2172] ○ C1-C6 alkoxy groups optionally substituted with 1-3 independently selected halogen and C1-C6 alkoxy groups,

[2173] ○N(R N )2,

[2174] ○SO2Me,

[2175] ○ C3-C cells optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl:

[2176] ◆Optionally selected by 1-3 independent elements from oxo and N(R) N C1-C6 alkyl groups substituted with 2 groups,

[2177] ◆C1-C6 fluoroalkyl groups,

[2178] ◆C1-C6 alkoxy groups, and

[2179] ◆COOH,

[2180] ○ C6-C cells optionally substituted with 1-3 independently selected groups from the following 10 Aryl:

[2181] ◆Halogen,

[2182] ◆Hydroxy group,

[2183] ◆Cyano

[2184] ♦ SiMe3,

[2185] ♦ SO2Me,

[2186] ♦ SF5,

[2187] ♦ N(R N )2,

[2188] ♦ P(O)Me2,

[2189] ♦ -(O) 0-1 -(C3-C 10 cycloalkyl),

[2190] ♦ C1-C6alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6alkoxy, 5- to 10-membered heteroaryl, SO2Me, and N(R N )2,

[2191] ♦ C1-C6alkoxy optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, N(R N )2, and C6-C 10 aryl,

[2192] ♦ C1-C6fluoroalkyl,

[2193] ♦ 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6alkyl, and

[2194] ♦ -(O) 0-1 -(C6-C 10 aryl),

[2195] ♦ 3- to 10-membered heterocyclyl optionally substituted with 1-4 groups independently selected from oxo and C1-C6alkoxy, and

[2196] ♦ 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

[2197] ♦ hydroxyl,

[2198] ♦ cyano,

[2199] ♦ oxo,

[2200] ♦ halogen,

[2201] ♦ B(OH)2,

[2202] ♦ N(R N )2,

[2203] ♦ C1-C6alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, oxo, C1-C6alkoxy, and N(RN C1-C6alkyl substituted by 1-3 groups independently selected from hydroxy, C1-C6alkoxy, N(R

[2204] ◆optionally substituted by 1-3 groups independently selected from hydroxy, C1-C6alkoxy, N(R N C1-C6alkyl substituted by 1-3 groups independently selected from hydroxy, C1-C6alkoxy, N(R 10 C1-C6alkyl substituted by 1-3 groups independently selected from hydroxy, C1-C6alkoxy, N(R

[2205] ◆C1-C6fluoroalkyl,

[2206] ◆optionally substituted by 1-3 groups independently selected from C1-C6alkyl, 0-1 C3-C6cycloalkyl, 10 C3-C6cycloalkyl,

[2207] ◆-(O) 0-1 C6-C10aryl, 10 C6-C10aryl,

[2208] ◆optionally substituted by 1-4 groups independently selected from C1-C6alkyl (optionally substituted by 1-3 groups independently selected from hydroxy), 0-1 3- to 10-membered heterocyclyl,

[2209] ◆5- to 10-membered heteroaryl optionally substituted by 1-4 groups independently selected from C1-C6alkyl.

[2210] 134. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof of any one of embodiments 128-133, wherein each R L1 is independently selected from:

[2211] ■hydrogen,

[2212] ■C1-C9alkyl optionally substituted by 1-3 groups independently selected from:

[2213] o halogen,

[2214] o hydroxy,

[2215] o oxo,

[2216] o N(R N )2,

[2217] o C1-C6alkoxy optionally substituted by 1-3 groups independently selected from C6-C10aryl, 10 C3-C6cycloalkyl optionally substituted by 1-3 groups independently selected from C1-C6fluoroalkyl, and

[2218] C3-C6cycloalkyl optionally substituted by 1-3 groups independently selected from C1-C6fluoroalkyl, and 10 C3-C6cycloalkyl optionally substituted by 1-3 groups independently selected from C1-C6fluoroalkyl, and

[2219] ■C6-C10aryl optionally substituted with 1-4 groups independently selected from:

[2220] ■C6-C10aryl optionally substituted with 1-4 groups independently selected from: 10 ■C6-C10aryl optionally substituted with 1-4 groups independently selected from:

[2221] ■halo,

[2222] ■cyano,

[2223] ■C1-C7alkyl optionally substituted with 1-3 groups independently selected from: N

[2224] ■C3-C7cycloalkyl, 10

[2225] ■3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

[2226] ■5- to 10-membered heteroaryl,

[2227] ■5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

[2228] ■C1-C6alkyl optionally substituted with 1-3 groups independently selected from:

[2229] ■C3-C7cycloalkyl optionally substituted with 1-3 groups independently selected from: 10

[2230] ■C6-C10aryl optionally substituted with 1-3 groups independently selected from: 10

[2231] 135. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof of any one of embodiments 128 to 134, wherein each R N is independently selected from:

[2232] ■hydrogen,

[2233] ■C1-C8alkyl optionally substituted with 1-3 groups independently selected from:

[2234] ■oxo,

[2235] ■hydroxyl,

[2236] ■C1-C6alkoxy,

[2237] ■-(O) 0-1 ​​​​-(C3-C 10 cycloalkyl),

[2238] o C6-C 10 aryl,

[2239] o 3- to 14-membered heterocyclyl,

[2240] o 5- to 14-membered heteroaryl optionally substituted with 1-4 groups independently selected from C1-C6 alkyl,

[2241] ■ C3-C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl, and

[2242] ■ 3- to 10-membered heterocyclyl;

[2243] or two R N on the same nitrogen atom, together with the nitrogen to which they are bound, form a 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups selected from C1-C6 alkyl.

[2244] 136. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 128-135, wherein when R F are present, the two R F together with the atom to which they are bound form a group selected from 3- to 11-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

[2245] o C1-C9 alkyl, and

[2246] o 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from C1-C6 alkoxy.

[2247] 137. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1-136, selected from the group consisting of compounds of any one of Formulae I, la, lb, Ila, lib, III, IV, V, and VI, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[2248] 138. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1-137, selected from the group consisting of compounds 1-1193 (Tables 3 and 6-13), compounds 1194-1294 (Table 5), compounds 1295-1972 (Tables 14-16), tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[2249] 139. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1-138 and a pharmaceutically acceptable carrier.

[2250] 140. The pharmaceutical composition of embodiment 139, further comprising one or more additional therapeutic agents.

[2251] 141. The pharmaceutical composition of embodiment 140, wherein the one or more additional therapeutic agents are selected from mucolytics, bronchodilators, antibiotics, anti-infectives, and anti-inflammatory agents.

[2252] 142. The pharmaceutical composition of embodiment 141, wherein the one or more additional therapeutic agents are antibiotics selected from tobramycin, including tobramycin inhalation powder (TIP), azithromycin, amikacin, including liposomal formulations thereof, ciprofloxacin, including formulations thereof suitable for inhaled administration, levofloxacin, including nebulized formulations thereof, and combinations of two antibiotics, such as fosfomycin and tobramycin.

[2253] 143. The pharmaceutical composition of embodiment 140, wherein the one or more additional therapeutic agents are one or more CFTR modulators.

[2254] 144. The pharmaceutical composition of embodiment 143, wherein the one or more CFTR modulators are selected from CFTR potentiators.

[2255] 145. The pharmaceutical composition of embodiment 143, wherein the one or more CFTR modulators are selected from CFTR correctors.

[2256] 146. The pharmaceutical composition of embodiment 143, wherein the one or more CFTR modulators comprise at least one CFTR potentiator and at least one CFTR corrector.

[2257] 147. The pharmaceutical composition of any one of embodiments 143-146, wherein the one or more CFTR modulators are selected from: (a) tezacaftor, lumacaftor, and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof; and (b) ivacaftor, deuterated derivatives of ivacaftor, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.

[2258] 148. The pharmaceutical composition of any one of embodiments 143-146, wherein the one or more CFTR modulators are selected from: (a) tezacaftor, lumacaftor, 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]nonadeca-l(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.

[2259] 149. The pharmaceutical composition of any one of embodiments 143-147, wherein the composition comprises tezacaftor and ivacaftor.

[2260] 150. The pharmaceutical composition of any one of embodiments 143-147, wherein the composition comprises tezacaftor and deutetcaftor.

[2261] 151. The pharmaceutical composition of any one of embodiments 143-147, wherein the composition comprises tezacaftor and (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)- 13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4,14,16-pentaen-6-ol.

[2262] 152. The pharmaceutical composition of any one of embodiments 143-147, wherein the composition comprises lumacaftor and ivacaftor.

[2263] 153. The pharmaceutical composition of any one of embodiments 143-147, wherein the composition comprises lumacaftor and deutetcaftor.

[2264] 154. The pharmaceutical composition of any one of embodiments 143-147, wherein the composition comprises lumacaftor and (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)- 13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4,14,16-pentaen-6-ol.

[2265] 155. A method of treating cystic fibrosis, comprising administering to a patient in need thereof a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-138 or a pharmaceutical composition of any one of embodiments 139-154.

[2266] 156. The method of embodiment 155, further comprising administering to the patient one or more additional therapeutic agents prior to, concurrently with, or following administration of the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof of any one of embodiments 1-138 or the pharmaceutical composition of any one of embodiment 139.

[2267] 157. The method of embodiment 156, wherein the one or more additional therapeutic agents are selected from CFTR modulators.

[2268] 158. The method of embodiment 157, wherein the one or more CFTR modulators are selected from CFTR potentiators.

[2269] 159. The method of embodiment 157, wherein the one or more CFTR modulators are selected from CFTR correctors.

[2270] 160. The method of embodiment 157, wherein the one or more CFTR modulators comprise both a CFTR potentiator and an additional CFTR corrector.

[2271] 161. The method of embodiments 158 and 160, wherein the CFTR potentiator is selected from ivacaftor, deuterated ivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)- 13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.

[2272] 162. The method of embodiment 159 or embodiment 160, wherein the CFTR corrector is selected from tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof.

[2273] 163. The method of embodiment 156, wherein the one or more additional therapeutic agents are compounds selected from tezacaftor, ivacaftor, deuterated ivacaftor, lumacaftor, and pharmaceutically acceptable salts thereof.

[2274] 164. The method of embodiment 163, wherein the one or more additional therapeutic agents are tezacaftor and ivacaftor.

[2275] 165. The method of embodiment 163, wherein the one or more additional therapeutic agents are tezacaftor and deuterated ivacaftor.

[2276] 166. The method of any one of embodiments 163, wherein the one or more additional therapeutic agents is tazemetostat and (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)- 13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4,14,16-pentaen-6-ol.

[2277] 167. The method of any one of embodiments 163, wherein the one or more additional therapeutic agents is lumacaftor and efruxaftor.

[2278] 168. The method of any one of embodiments 163, wherein the one or more additional therapeutic agents is lumacaftor and deucravacitinib.

[2279] 169. The method of any one of embodiments 163, wherein the one or more additional therapeutic agents is lumacaftor and (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)- 13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-l(18),2,4,14,16-pentaen-6-ol.

[2280] 170. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 to 138 or a pharmaceutical composition of any one of embodiments 139 to 154 for use in the treatment of cystic fibrosis.

[2281] 171. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 to 138 or a pharmaceutical composition of any one of embodiments 139 to 154 for use in the manufacture of a medicament for the treatment of cystic fibrosis.

[2282] 172. A compound selected from compounds 1-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[2283] 173. A deuterated derivative of a compound selected from compounds 1-1972.

[2284] 174. A pharmaceutically acceptable salt of a compound selected from compounds 1-1972.

[2285] 175. A compound selected from compounds 1-1972.

[2286] 176. A pharmaceutical composition comprising a compound selected from compounds 1-1972, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and a pharmaceutically acceptable carrier.

[2287] 177. A pharmaceutical composition comprising a deuterated derivative of a compound selected from compounds 1-1972, and a pharmaceutically acceptable carrier.

[2288] 178. A pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound selected from compounds 1-1972, and a pharmaceutically acceptable carrier.

[2289] 179. A pharmaceutical composition comprising a compound selected from compounds 1-1972, and a pharmaceutically acceptable carrier.

[2290] 180. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-1972, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) a CFTR potentiator; and (c) a pharmaceutically acceptable carrier.

[2291] 181. A pharmaceutical composition composition comprising: (a) a deuterated derivative of a compound selected from compounds 1-1972; (b) a CFTR potentiator; and (c) a pharmaceutically acceptable carrier.

[2292] 182. A medicament comprising: (a) a pharmaceutically acceptable salt of a compound selected from compounds 1-1972; (b) a CFTR potentiator; and (c) a pharmaceutically acceptable carrier.

[2293] 183. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-1972; (b) a CFTR potentiator; and (c) a pharmaceutically acceptable carrier.

[2294] 184. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-1972, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) an additional CFTR corrector; and (c) a pharmaceutically acceptable carrier.

[2295] 185. A pharmaceutical composition comprising: (a) a deuterated derivative of a compound selected from compounds 1-1972; (b) an additional CFTR corrector; and (c) a pharmaceutically acceptable carrier.

[2296] 186. A pharmaceutical composition comprising: (a) a pharmaceutically acceptable salt of a compound selected from compounds 1-1972; (b) an additional CFTR corrector; and (c) a pharmaceutically acceptable carrier.

[2297] 187. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-1972; (b) an additional CFTR corrector; and (c) a pharmaceutically acceptable carrier.

[2298] 188. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) an additional CFTR corrector; (c) a CFTR potentiator; and (d) a pharmaceutically acceptable carrier.

[2299] 189. A pharmaceutical composition comprising: (a) a deuterated derivative of a compound selected from compounds 1-1972; (b) an additional CFTR corrector; (c) a CFTR potentiator; and (d) a pharmaceutically acceptable carrier.

[2300] 190. A pharmaceutical composition comprising: (a) a pharmaceutically acceptable salt of a compound selected from compounds 1-1972; (b) an additional CFTR corrector; (c) a CFTR potentiator; and (d) a pharmaceutically acceptable carrier.

[2301] 191. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-1972; (b) an additional CFTR corrector; (c) a CFTR potentiator; and (d) a pharmaceutically acceptable carrier.

[2302] 192. A compound selected from compounds 1-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, for use in a method of treating cystic fibrosis.

[2303] 193. A deuterated derivative of a compound selected from compounds 1-1972, for use in a method of treating cystic fibrosis.

[2304] 194. A pharmaceutically acceptable salt of a compound selected from compounds 1-1972, for use in a method of treating cystic fibrosis.

[2305] 195. A compound selected from compounds 1-1972, for use in a method of treating cystic fibrosis.

[2306] 196. A pharmaceutical composition comprising a compound selected from compounds 1-1972, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and a pharmaceutically acceptable carrier, for use in a method of treating cystic fibrosis.

[2307] 197. A pharmaceutical composition comprising a deuterated derivative of a compound selected from compounds 1-1972, and a pharmaceutically acceptable carrier, for use in a method of treating cystic fibrosis.

[2308] 198. A pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound selected from compounds 1-1972, and a pharmaceutically acceptable carrier, for use in a method of treating cystic fibrosis.

[2309] 199. A pharmaceutical composition comprising a compound selected from compounds 1-1972, and a pharmaceutically acceptable carrier, for use in a method of treating cystic fibrosis.

[2310] 200. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-1972, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) a CFTR potentiator; and (c) a pharmaceutically acceptable carrier, for use in a method of treating cystic fibrosis.

[2311] 201. A pharmaceutical comprising: (a) a deuterated derivative of a compound selected from compounds 1-1972; (b) a CFTR potentiator; and (c) a pharmaceutically acceptable carrier, for use in a method of treating cystic fibrosis.

[2312] 202. A pharmaceutical composition comprising: (a) a pharmaceutically acceptable salt of a compound selected from compounds 1-1972; (b) a CFTR potentiator; and (c) a pharmaceutically acceptable carrier, for use in a method of treating cystic fibrosis.

[2313] 203. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-1972; (b) a CFTR potentiator; and (c) a pharmaceutically acceptable carrier.

[2314] 204. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-1972, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) an additional CFTR corrector; and (c) a pharmaceutically acceptable carrier, for use in a method of treating cystic fibrosis.

[2315] 205. A pharmaceutical composition comprising: (a) a deuterated derivative of a compound selected from compounds 1-1972; (b) an additional CFTR corrector; and (c) a pharmaceutically acceptable carrier, for use in a method of treating cystic fibrosis.

[2316] 206. A pharmaceutical composition comprising: (a) a pharmaceutically acceptable salt of a compound selected from compounds 1-1972; (b) an additional CFTR corrector; and (c) a pharmaceutically acceptable carrier, for use in a method of treating cystic fibrosis.

[2317] 207. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-1972; (b) an additional CFTR corrector; and (c) a pharmaceutically acceptable carrier, for use in a method of treating cystic fibrosis.

[2318] 208. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-1972, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) an additional CFTR corrector; (c) a CFTR potentiator; and (d) a pharmaceutically acceptable carrier, for use in a method of treating cystic fibrosis.

[2319] 209. A pharmaceutical composition comprising: (a) a deuterated derivative of a compound selected from compounds 1-1972; (b) an additional CFTR corrector; (c) a CFTR potentiator; and (d) a pharmaceutically acceptable carrier, for use in a method of treating cystic fibrosis.

[2320] 210. A pharmaceutical composition comprising: (a) a pharmaceutically acceptable salt of a compound selected from compounds 1-1972; (b) an additional CFTR corrector; (c) a CFTR potentiator; and (d) a pharmaceutically acceptable carrier, for use in a method of treating cystic fibrosis.

[2321] 211. A pharmaceutical composition comprising: (a) a compound selected from compounds 1-1972; (b) an additional CFTR corrector; (c) a CFTR potentiator; and (d) a pharmaceutically acceptable carrier, for use in a method of treating cystic fibrosis.

[2322] Examples

[2323] I. List of Abbreviations

[2324] ACN: acetonitrile

[2325] Boc anhydride ((Boc)20): di-tert-butyl dicarbonate

[2326] CDCl3: chloroform-d

[2327] CDI: carbonic diimidazole

[2328] CDMT: 2-chloro-4,6-dimethoxy-1,3,5-triazine

[2329] CH2Cl2: dichloromethane

[2330] CH3CN: acetonitrile

[2331] COMU: (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino- morpholino-carbenium hexafluorophosphate

[2332] Cmpd: compound

[2333] DABCO: 1,4-diazabicyclo[2.2.2]octane

[2334] DBU: 1,8-diazabicyclo(5.4.0)undec-7-ene

[2335] DCE: 1,2-dichloroethane

[2336] DCM: dichloromethane

[2337] DI: deionized

[2338] DIAD: diisopropyl azodicarboxylate

[2339] DEIA: (DIPEA, DiPEA): N,N-diisopropylethylamine

[2340] DMA: N,N-dimethylacetamide

[2341] DMAP: 4-dimethylaminopyridine

[2342] DMF: N,N-dimethylformamide

[2343] DMSO: dimethyl sulfoxide

[2344] DMP: Dess-Martin periodinane

[2345] EA: ethyl acetate

[2346] EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[2347] ELSD: evaporative light scattering detector

[2348] Ethyl ether: diethylether

[2349] ESI-MS: electrospray ionization mass spectrometry

[2350] EtOAc: ethyl acetate

[2351] EtOH: ethanol

[2352] GC: gas chromatography

[2353] Grubbs 1st generation catalyst: dichloro(benzylidene)bis(tricyclohexylphosphine) ruthenium(II)

[2354] Grubbs 2nd generation catalyst: [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]- dichloro-[(2-isopropoxyphenyl)methylene]ruthenium

[2355] HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- hexafluorophosphate

[2356] HPLC: high performance liquid chromatography

[2357] Hoveyda-Grubbs 2nd generation catalyst: (1,3-bis-(2,4,6-trimethylphenyl)-2- imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium, dichloro[1,3- bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II)

[2358] IPA: isopropyl alcohol

[2359] KHSO4: potassium bisulfate

[2360] LC: liquid chromatography

[2361] LCMS: liquid chromatography mass spectrometry

[2362] LCMS Met.: LCMS method

[2363] LCMS Rt: LCMS retention time

[2364] LDA: lithium diisopropylamide

[2365] LiOH: lithium hydroxide

[2366] MeCN: acetonitrile

[2367] MeOH: methanol

[2368] MTBE: methyl tert-butyl ether

[2369] MeTHF or 2-MeTHF: 2-methyltetrahydrofuran

[2370] MgSO 4： magnesium sulfate

[2371] NaHCO3: sodium bicarbonate

[2372] NaOH: sodium hydroxide

[2373] NMP: N-methyl-2-pyrrolidone

[2374] NMM: N-methylmorpholine

[2375] Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0)

[2376] Pd / C: palladium on carbon

[2377] Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[2378] Pd(OAc)2: palladium(II) acetate

[2379] PTFE: polytetrafluoroethylene

[2380] rt, RT: room temperature

[2381] RuPhos: 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl

[2382] SFC: supercritical fluid chromatography

[2383] TBAI: tetrabutylammonium iodide

[2384] TEA: triethylamine

[2385] TFA: trifluoroacetic acid

[2386] THF: tetrahydrofuran

[2387] TLC: thin layer chromatography

[2388] TMS: trimethylsilyl

[2389] TMSCl: trimethylsilyl chloride

[2390] T3P: propane phosphonic anhydride

[2391] UPLC: ultra-performance liquid chromatography

[2392] XANTPHOS: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[2393] XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[2394] II. General methods

[2395] Unless otherwise stated, reagents and starting materials should be obtained from commercial sources and used without purification.

[2396] 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.

[2397] 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.

[2398] Also, using a Varian Mercury NMR instrument with a 45-degree pulse angle, a 4800 Hz spectral width, and 28,860 acquisition points, recording at 300 MHz. 1 19F NMR spectra were recorded at 282 MHz using 30-degree pulse angles, a 100 kHz spectral width, and 59,202 acquisition points. FID was zero-filled to 32 k points, and a 0.3 Hz line broadening was applied before the Fourier transform. FID was zero-filled to 64 k points, and a 0.5 Hz line broadening was applied before the Fourier transform.

[2399] 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 1H NMR spectra. The FID was zero-filled to 256k points, and a 0.3Hz line broadening was applied before the Fourier transform. Recordings were performed at 377MHz using a 30-degree pulse angle, an 89286Hz spectral width, and 128k acquisition points. 19 F NMR spectra. FID was zero-filled to 256k points, and a 0.3Hz spectral line broadening was applied before the Fourier transform.

[2400] 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).

[2401] 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 was capable of achieving 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.

[2402] III. General UPLC / HPLC / GC analytical methods

[2403] 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.

[2404] LC method C: Kinetex C18 4.6 x 50 mm 2.6 pm. Temperature: 45 °C, Flow rate: 2.0 mL / min, Run time: 3 min. Mobile phase: Initial 95% water (0.1% formic acid) and 5% acetonitrile (0.1% formic acid), linear gradient to 95% acetonitrile (0.1% formic acid) over 2.0 min, then 95% acetonitrile (0.1% formic acid) for 1.0 min.

[2405] LC Method D: Acquity UPLC BEH C 18 column (30 x 2.1 mm, 1.7 pm particles) (pn: 186002349) and a dual gradient run from 1-99% mobile phase B over 1.0 min. Mobile phase A = H2O (0.05% CF3CO2H). Mobile phase B = CH3CN (0.035% CF3CO2H). Flow rate = 1.5 mL / min, injection volume = 1.5 pL, and column temperature = 60 °C.

[2406] LC Method G: Symmetry, 4.6 x 75 mm 3.5 pm. Temperature: 45 °C, Flow rate: 2.0 mL / min, Run time: 8 min. Mobile phase: Initial 95% H2O (0.1% formic acid) and 5% CH3CN (0.1% Fa), linear gradient to 95% CH3CN (0.1% formic acid) for 6.0 min, then 95% CH3CN (0.1% formic acid) for 2.0 min.

[2407] LC Method H: Kinetex C 18 4.6 x 50 mm 2.6 um. Temperature: 45 °C, Flow rate: 2.0 mL / min, Run time: 6 min. Mobile phase: Initial 95% H2O (0.1% formic acid) and 5% CH3CN (0.1% FA), linear gradient to 95% CH3CN (0.1% FA) for 4.0 min, then 95% CH3CN (0.1% FA) for 2.0 min.

[2408] LC Method I: Acquity UPLC BEH C 18 column (50 x 2.1 mm, 1.7 pm particles) and a dual gradient run from 1-99% 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 pL, and column temperature = 60 °C

[2409] LC Method J: Acquity UPLC BEH C 18 column (50 x 2.1 mm, 1.7 pm particles) (pn: 186002350) and a dual gradient of 1-99% mobile phase B run in 2.9 minutes. Mobile phase A = H20 (0.05% NH4HCO2). Mobile phase B = CH3CN. Flow rate = 1.2 mL / min, injection volume = 1.5 pL, and column temperature = 60 °C.

[2410] LC Method K: Kinetex Polar C 18 3.0 x 50 mm 2.6 pm, 3 min, 5-95% ACN / H20 (0.1% formic acid) 1.2 mL / min.

[2411] LC Method Q: Acquity UPLC BEH C 18 column (50 x 2.1 mm, 1.7 pm particles) (pn: 186002350) and a dual gradient of 1-99% mobile phase B run in 2.9 minutes. Mobile phase A = H20 (0.05% NH4HCO2). Mobile phase B = CH3CN. Flow rate = 1.2 mL / min, injection volume = 1.5 pL, and column temperature = 60 °C.

[2412] LC Method S: Merckmillipore Chromolith SpeedROD C 18 column (50 x 4.6 mm) and a dual gradient of 5-100% mobile phase B run in 12 minutes. Mobile phase A = water (0.1% CF3CO2H). Mobile phase B = acetonitrile (0.1% CF3CO2H).

[2413] LC Method T: Merckmillipore Chromolith SpeedROD C 18 column (50 x 4.6 mm) and a dual gradient of 5-100% mobile phase B run in 6 minutes. Mobile phase A = water (0.1% CF3CO2H). Mobile phase B = acetonitrile (0.1% CF3CO2H).

[2414] LC Method U: Kinetex Polar C 18 3.0 x 50 mm 2.6 pm, 6 min, 5-95% ACN / H20 (0.1% formic acid) 1.2 mL / min.

[2415] LC Method V: Acquity UPLC BEH C 18 Column (50 x 2.1 mm, 1.7 pm particles) (pn: 186002350) and a dual gradient reverse phase UPLC run from 1-30% mobile phase B in 2.9 minutes. Mobile phase A = H20 (0.05% CF3CO2H). Mobile phase B = CH3CN (0.035% CF3CO2H). Flow rate = 1.2 mL / min, injection volume = 1.5 pL, and column temperature = 60 °C

[2416] LC Method W: Waters Cortecs 2.7 pm C 18 (3.0 mm x 50 mm), temperature: 55 °C; flow rate: 1.2 mL / min; mobile phase: 100% water with 0.1% trifluoroacetic acid (TFA) acid, then 100% acetonitrile with 0.1% TFA acid, gradient: 5% to 100% B in 4 minutes, stay at 100% B for 0.5 minutes, equilibrate to 5% B in 1.5 minutes.

[2417] LC Method X: UPLC Luna C 18 (2) 50 x 3 mm 3 pm. Run: 2.5 minutes. Mobile phase: initial 95% H20 0.1% FA / 5% MeCN 0.1% FA, linear gradient to 95% MeCN 0.1% FA in 1.3 minutes, hold 95% CH3CN 0.1% FA for 1.2 minutes, T: 45 C, flow rate: 1.5 mL / min

[2418] LC Method Y: UPLC SunFire C 18 75 x 4.6 mm 3.5 pm, run: 6 minutes. Mobile phase conditions: initial 95% H20 + 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 °C, flow: 1.5 mL / min

[2419] LC Method 1A: Viridis BEH 2-Ethylpyridine Column (150 x 2.1 mm, 3.5 pm particles) (pn: 186006655) manufactured by Waters and a dual gradient reverse phase UPC2 run from 5-80% mobile phase B in 4.5 minutes. 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 pL, and column temperature = 55 °C

[2420] GC Method IB: Column SPB-1 30m x 0.32mm x 0.25um. Control mode: Head pressure 100 kPa. Separation ratio mode: 10.0. Carrier gas: Hydrogen. Injection temperature: 150 °C. Detector temperature: 250 °C. Oven temperature: Isothermal 40 °C for 1 min, then linear heating at 10 °C / min up to 100 °C, then 20 °C / min up to 220 °C, then isothermal 220 °C for 4 min. Run time 17.0 min. Non-chiral method.

[2421] LC Method 1C: Luna C 18 (2) 3.0 x 50 mm 3 μm, run: 5 min. Mobile phase conditions: initial 95% H20 0.05% TFA 5% CH3CN, linear gradient to 5% H20 0.05% TFA 95% CH3CN for 3.5 min, hold at 95% CH3CN for 1.5 min, T: 45 °C, flow rate: 1.2 mL / min.

[2422] LC Method ID: XBridge C 18 4.6 x 75 mm, 5 μm, initial gradient 95% NH4HCO3 / 5% MeCN, 6 min run, 1 min hold gradient 0 to 3 min, 95% MeCN, hold for 3 min. Flow rate 1.5 mL / min.

[2423] LC Method IE: Acquity UPLC BEH C 18 column (30 x 2.1 mm, 1.7 μm particles) (pn: 186002349) and a dual gradient reverse phase UPLC run from 1-99% mobile phase B in 2.9 min. Mobile phase A = H20 (5 mM NH4OH). Mobile phase B = CH3CN. Flow rate = 1.1 mL / min, injection volume = 1.5 μL, and column temperature = 60 °C.

[2424] IV. Synthesis of common intermediates

[2425] Example A: Preparation of 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid

[2426]

[2427] Step 1: tert-Butyl N-tert-butoxycarbonyl-N-(4,6-dichloropyrimidin-2-yl)carbamate

[2428]

[2429] To a solution of 4,6-dichloropyrimidin-2-amine (300 g, 1.829 mol) in DCM (2.1 L) was added (BOC)20 (838 g, 3.840 mol) followed by DMAP (5.6 g, 45.84 mmol). The mixture was stirred at ambient temperature for 6 hours. Additional DMAP (5.6 g, 45.84 mmol) was added and the reaction continued to stir at ambient temperature for 24 hours. The mixture was diluted with water (2.1 L) and the organic phase separated. The organic phase was washed with water (2.1 L), 2.1 L of brine, dried over magnesium sulfate, filtered through celite and concentrated in vacuo to give a light orange oil with sludge in the slurry. The mixture was diluted with about 500 mL of heptane and filtered using a M filter. The precipitate (SM) was washed with 250 mL of heptane. The filtrate was concentrated in vacuo to give a dense orange oil which was seeded with the solid from a previous experiment and allowed to crystallize to give a light orange hard solid. tert-Butyl N-tert-butoxycarbonyl-N-(4,6-dichloropyrimidin-2-yl)carbamate (645 g, 97%). 1 H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 1.44 (s, 18H). ESI-MS m / z calcd 363.07526, found 364.1 (M + 1) + ; retention time: 2.12 minutes (LC Method A).

[2430] Step 2: tert-Butyl N-tert-butoxycarbonyl-N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2- yl]carbamate.

[2431]

[2432] All solvents were degassed prior to use. To a slurry of N-tert-butoxycarbonyl-N-(4,6-dichloropyrimidin-2-yl)carbamic acid tert-butyl ester (88 g, 241.6 mmol) was added (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 stirred vigorously at 80 °C (reflux) under nitrogen 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 in vacuo. The crude product was chromatographed on a 1500 g silica gel column eluting with 0-30% EtOAc / hexanes. The product fractions (eluting at 15% EtOAc) were combined and concentrated under vacuum to give the product as a clear oil which crystallized upon standing. N-tert-Butoxycarbonyl-N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2- yl]carbamic acid tert-butyl ester (81.3 g, 78%). 1 H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.30 (dd, J = 8.2, 7.0 Hz, 1H), 7.21-7.16 (m, 2H), 2.03 (s, 6H), 1.38 (s, 18H). ESI-MS m / z calcd 433.17682, found 434.1 (M+1) + ; Retention time: 2.32 minutes (LC Method A).

[2433] Step 3: 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (hydrochloride)

[2434]

[2435] N-tert-Butoxycarbonyl-N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]carbamic acid tert-butyl ester (514.8 g, 915.9 mmol) was dissolved in dichloromethane (4 L). Hydrogen chloride in dioxane (1 L, 4 mol) was added and the mixture was stirred at room temperature overnight. The resulting precipitate was collected by vacuum filtration and dried under vacuum to give 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine hydrochloride as a white solid (213.5 g, 82%). 1H NMR (400 MHz, DMSO-d6) δ 7.28 - 7.14 (m, 3H), 7.10 (d, J = 7.5 Hz, 2H), 6.63 (s, 1H), 2.06 (s, 6H). ESI-MS m / z calcd 233.07198, found 234.0 (M+1) + ; Retention time: 2.1 min (LC Method C).

[2436] Step 4: 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine

[2437]

[2438] Step 4: 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (hydrochloride) (166 g, 614.5 mmol) and 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-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 h. The mixture was transferred to a separatory funnel and allowed to stand overnight. The DCM phase was separated and the aqueous phase containing insoluble material was extracted twice more with DCM (2 x 500 mL). The combined brown DCM phase was stirred over magnesium sulfate and charcoal for 1 h, filtered and the yellow solution concentrated to a volume of approximately 500 mL. The solution was diluted with heptane (750 mL) and the DCM removed under reduced pressure at 60 °C to give a creamy suspension. The suspension was stirred at room temperature for 1 h, filtered, washed with cold heptane and dried to give 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine as a creamy solid (157 g, 91%). 1 H NMR (400 MHz, DMSO-d6) δ 7.28 - 7.14 (m, 3H), 7.10 (d, J = 7.5 Hz, 2H), 6.63 (s, 1H), 2.06 (s, 6H). ESI-MS m / z calcd 233.07198, found 234.0 (M+1) + ; Retention time: 1.45 min (LC Method A).

[2439] Step 5: 3-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[2440]

[2441] 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) (appears slightly endothermic) was added to the cold solution in a single addition, and a solution of 2-methyl-but-2-ol (lithium salt) (875 mL, 3.1 M, 2.712 mol) (in heptane) was added dropwise over 1.25 hours to the cold, pale yellow solution (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 x 500 mL) and the combined organic phases were extracted once with 2 M NaOH (1 x 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 creamy, brittle 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).+ ; Ret Time: 1.56 min. (LC Method A).

[2442] Example B: Preparation of 3-[[4-[(2R)-2-(tert-butoxycarbonylamino)-4-methyl- pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[2443]

[2444] Step 1: 3-[[4-[(2R)-2-(tert-butoxycarbonylamino)-4-methyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[2445]

[2446] To a stirred solution of (2R)-2-amino-4-methyl-pentan-1-ol (12.419 g, 105.97 mmol) in dry THF (200 mL) was added sodium tert-butoxide (15.276 g, 158.95 mmol) at room temperature under nitrogen. The reaction mixture was stirred for 10 minutes and 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (22.14 g, 52.983 mmol) was added. The reaction mixture was placed on a pre-heated water bath to 60 °C and stirred for 20 minutes. 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 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (150 mL). The volatiles were removed in vacuo and the aqueous layer was acidified to pH ~ 3 with 10% aqueous citric acid solution. 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 ~ 250 mL. The product was precipitated into excess hexane (750 mL) and collected by vacuum filtration. The obtained white solid was further purified by silica gel chromatography using 0-40% acetone (0.15% acetic acid buffer) in hexane (0.15% acetic acid buffer) gradient to give 3-[[4-[(2R)-2-(tert-butoxycarbonylamino)-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (20.73 g, 61%) as a white solid. ESI-MS m / z calcd for C32H45N4O8S 598.2461, found 599.4 (M+1) + ; Ret Time: 5.85 min (LC Method S).

[2447] Step 2: 3-[[4-[(2R)-2-amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (hydrochloride).

[2448]

[2449] To a stirred solution of 3-[[4-[(2R)-2-(tert-butoxycarbonylamino)-4-methyl- pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (20.73 g, 34.624 mmol) in DCM (200 mL) was added HC1 (87 mL of 4M solution in 1,4-dioxane, 346.24 mmol) at room temperature. The reaction mixture was stirred for 2 hours. The volatiles were removed under vacuum and the obtained solid was triturated with diethyl ether (150 mL). After removal of volatiles, the product was dried under vacuum to obtain 3-[[4-[(2R)-2-amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (hydrochloride) as a white solid (19.68 g, 100%). 1 HNMR (250 MHz, 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, overlapped with water), 2.01 (s, 6H), 1.82-1.31 (m, 3H), 1.02-0.78 (m, 6H). ESI-MS m / z calcd 498.1937, found 499.3 (M + 1) + ; Retention time: 1.63 minutes (LC Method T).

[2450] Example C: Preparation of N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]-3-nitro- benzenesulfonamide

[2451]

[2452] To a suspension of sodium hydride (60% in mineral oil) (4.87 g, 0.122 mol) in anhydrous tetrahydrofuran (30 mL) was added a solution of 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (8.13 g, 0.0348 mol) in anhydrous tetrahydrofuran (40 mL) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 30 min. A solution of 3-nitrobenzenesulfonyl chloride (11.57 g, 52.2 mmol) in anhydrous tetrahydrofuran (40 mL) was added dropwise to the reaction mixture at 0 °C. The reaction was stirred at the same temperature for 1 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution (100 mL). The reaction solution was extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with water (100 mL), dried over anhydrous sodium sulfate and then concentrated under vacuum. The residue was purified by silica gel column chromatography using 0 to 10% chloroform-ethyl acetate. The crude product was triturated with a solvent mixture of diethyl ether and hexanes (1 :5) to afford N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]-3-nitro- benzenesulfonamide (5.98 g, 41%) as a white solid. ESI-MS m / z calcd 418.1, found 419.0 (M + 1). Retention time: 5.73 min. 1 H NMR (250 MHz, CDC13) δ (ppm): 9.01 (s, 1H); 8.43 (t, J = 10.5 Hz, 2H); 7.682 (t, J = 7.8 Hz, 1H); 7.23 (m, 1H); 7.12 (d, J = 7.5 Hz, 2H); 6.95 (s, 1H); 1.99 (s, 6H).

[2453] Example D: Preparation of N-[4-(2,6-dimethylphenyl)-6-methanesulfonyl-pyrimidin-2-yl]-3-nitro-benzenesulfonamide

[2454] Step 1: N-[4-(2,6-dimethylphenyl)-6-methanesulfonyl-pyrimidin-2-yl]-3-nitro- benzenesulfonamide

[2455]

[2456] Stage 1 : To a 250 mL round bottom flask was added N-[4-chloro-6-(2,6- dimethylphenyl)pyrimidin-2-yl]-3-nitro-benzenesulfonamide (14.14 g, 33.76 mmol), sodium thiomethoxide (5.86 g, 83.61 mmol) and NMP (130 mL). This solution was stirred at 100 °C for 3 hours. The reaction mixture was then cooled to room temperature, quenched with 1 N HC1 (300 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic extracts were washed with water (300 mL), 3% aqueous hydrogen peroxide (300 mL), water (300 mL) and saturated aqueous sodium chloride solution (300 mL) then dried over sodium sulfate, filtered and evaporated in vacuo. This resulted in an orange foam (16.71 g, 115% crude yield) which was used as is for the next reaction.

[2457] Stage 2: To a 250 mL round bottom flask containing the product from Stage 1 was added DCM (120 mL) followed by m-CPBA (77% purity, 27.22 g, 121.5 mmol). This solution was stirred at room temperature for 90 minutes. The reaction mixture was quenched by transfer to a 1 L Erlenmeyer flask containing DCM (400 mL) and solid Na2S2O3(41.15 g, 260.3 mmol). This mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (300 mL) then washed with water (3 x 400 mL) and saturated aqueous sodium chloride solution (300 mL). The organic layer was then dried over sodium sulfate, filtered and evaporated in vacuo. This solid was then partially dissolved in DCM (100 mL) and filtered on a Büchner funnel in vacuo to remove m-chlorobenzoic acid waste (repeated three times). The remaining solution was then purified by silica gel chromatography (330 g silica, 0% to 60% ethyl acetate / hexane gradient) to give N-[4-(2,6-dimethylphenyl)-6-methylsulfonyl-pyrimidin-2-yl]-3-nitro- benzenesulfonamide (5.881 g, 36%). ESI-MS m / z calcd 462.06677, found 463.1 (M+1) + ; Retention time: 1.6 minutes; LC Method A.

[2458] Example E: Preparation of 3-[[4-[(2R)-2-amino-4,4-dimethyl-pent oxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[2459]

[2460] Step 1 : (2R)-2-Amino-4,4-dimethyl-pentan-1-ol

[2461]

[2462] To a solution of (2R)-2-amino-4,4-dimethyl-pentanoic acid (15 g, 103.3 mmol) in THF (150 mL) was added borane-THF (1 M, 260 mL, 260.0 mmol) dropwise at 0 °C, keeping the reaction temperature <10 °C. The addition time was approximately 30 min. The mixture was allowed to warm to ambient temperature and stirred for 22 h. The reaction was quenched by slow addition of methanol (80 mL, 1.975 mol) and the solvent was removed in vacuo. The residue was co-evaporated with methanol (200 mL, 4.937 mol) 3 times. The crude residue was diluted with HC1 (1 M, 200 mL, 200.0 mmol) and washed with 200 mL of MTBE. The aqueous phase was evaporated to remove residual organic solvents. The water was further removed in vacuo to give a white solid. The solid was further dried using acetonitrile azeotrope. The solid was slurried in 200 mL of ACN and the precipitate was collected with a M frit. The solid was air dried for 1 h and then dried in vacuo at 45 °C for 20 h to give (2R)-2-amino-4,4-dimethyl-pentan-1-ol (hydrochloride) (14.73 g, 85%). 1 HNMR (400 MHz, DMSO-d6) δ 7.80 (s, 3H), 5.36 (t, J = 5.1 Hz, 1H), 3.59 (dt, J = 11.7, 4.1 Hz, 1H), 3.42 - 3.34 (m, 1H), 3.10 (dq, J = 7.7, 3.8 Hz, 1H), 1.46 (dd, J = 14.5, 7.1 Hz, 1H), 1.33 (dd, J = 14.5, 3.5 Hz, 1H), 0.91 (s, 9H). ESI-MS m / z calcd 131.13101, found 132.1 (M + 1) + ; Retention time: 0.51 min (LC Method A).

[2463] Step 2: 3-[[4-[(2R)-2-amino-4,4-dimethyl-pentyloxy]-6-(2,6-dimethyl- phenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[2464]

[2465] Dissolve 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (20 g, 47.862 mmol) in a mixture of 2-methyltetrahydrofuran (80 mL) and DMF (20 mL) and cool the solution to -5 °C. Then dissolve sodium tert-butoxide (23 g, 239.33 mmol) in 2-methyltetrahydrofuran (100 mL), cool to 5 °C and add over 10 minutes followed by the addition of (2R)-2-amino-4,4-dimethyl-pentan-1-ol (hydrochloride) (8.02 g, 47.830 mmol). Then warm the reaction to 10 °C and stir for 4 hours. Then cool the reaction to 0 °C and quench by the addition of aqueous hydrochloric acid (2M, 200 mL) over 10 minutes. Separate the phases and extract the aqueous phase with 2-methyltetrahydrofuran (200 mL). Combine the organic phases and wash with aqueous sodium chloride solution (15% w / w, 2 x 200 mL), dry over sodium sulfate (60 g), filter and evaporate to dryness. Then triturate the solid with ethyl acetate (200 mL) for 16 hours, filter, wash with ethyl acetate and dry in a vacuum oven at 50 °C for 20 hours to give 3-[[4-[(2R)-2-amino-4,4-dimethyl-pentyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride) (22.29 g, 80%). 1 H NMR (400 MHz, DMSO-d6) δ 13.26 (br. s., 2 H), 8.45 (t, J=1.6 Hz, 1 H), 8.28 - 8.06 (m, 5 H), 7.69 (t, J=7.8 Hz, 1 H), 7.31 - 7.21 (m, 1 H), 7.13 (d, J=7.6 Hz, 2 H), 6.29 (br. s., 1 H), 4.30 (dd, J=11.7, 2.7 Hz, 1 H), 4.10 (dd, J=11.5, 7.1 Hz, 1 H), 3.56 (br. s., 1 H), 2.13 - 1.90 (s, 6 H), 1.62 - 1.47 (m, 2 H), 0.94 (s, 9 H). ESI-MS m / z calcd 512.20935, found 513.0 (M+1) + ; Retention time: 2.334 minutes; LC Method U.

[2466] Example F: Preparation of 3-[[4-[(2R)2-amino-5,5,5-trifluoro-4,4-dimethyl-pentyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[2467]

[2468] Step 1 : 4,4,4-trifluoro-3,3-dimethyl-butyraldehyde

[2469]

[2470] A 1 L three necked flask was charged with 4,4,4-trifluoro-3,3-dimethyl- butan-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). The mixture was cooled with an ice water bath. NaOCl aqueous solution (1.31 M, 47 mL, 61.570 mmol) was added dropwise over 2 hours at 2.5-4.4 °C. After the addition, the mixture was stirred for 10 minutes. The two layers were separated. The aqueous phase was extracted with DCM (2 x 15 mL). The combined organic layers were dried over sodium sulfate and filtered to give 113.7 g (about 80 mL) of crude product in DCM which was used directly in the next step. 1 H NMR (300 MHz, CDC13) δ 9.82 - 9.78 (m, 1H), 2.54 (d, J = 2.6 Hz, 2H), 1.28 (s, 6H). 19 F NMR (282 MHz, CDC13) δ -79.11 (s, 3F).

[2471] Step 2: (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanenitrile and (2S)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanenitrile

[2472]

[2473] To a solution of 4,4,4-trifluoro-3,3-dimethyl-butyraldehyde (113.7 g, 57.540 mmol) (purity ca. 7.8%) in DCM (80 mL) was added MeOH (110 mL). The mixture was cooled with 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 min, then NaCN (3.56 g, 72.642 mmol) was added. The mixture was allowed to slowly warm 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 x 100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (120 g silica gel, heptane / EtOAc 0-30%) to give a 4:1 mixture of (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanenitrile and (2S)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanenitrile as a colorless oil (14.87 g, 91%). ESI-MS m / z calcd for C15H20F3N2O 284.15002, found 285.2 (M+1) + ; retention time: 3.38 min; LC method U.

[2474] 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

[2475]

[2476] To a solution of a 4:1 mixture of (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1- phenylethyl]amino]pentanenitrile and (2S)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1- phenylethyl]amino]pentanenitrile (14.87 g, 52.300 mmol) in DCM (105 mL) was added sulfuric acid (56.3 g, 551.06 mmol). The mixture was stirred at room temperature overnight, poured into coarse 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 flash chromatography (330 g of silica gel, heptane / EtOAc 20-50%) to give (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1- phenylethyl]amino]pentanamide as a white solid (10.77 g, 68%). 1 H NMR (300 MHz, CDC13) δ 7.39 - 7.22 (m, 5H), 6.35 (br. s., 1H), 5.55 (br. s., 1H), 3.65 (q, J = 6.5 Hz, 1H), 2.93 (dd, J = 7.6, 3.8 Hz, 1H), 1.87 (dd, J = 15.0, 3.8 Hz, 1H), 1.65 - 1.56 (m, 2H), 1.35 (d, J = 6.5 Hz, 3H), 1.04 (s, 3H), 1.00 (s, 3H). 19 F NMR (282 MHz, CDC13) δ -78.77 (s, 3F). 99.4% de by19F NMR.

[2477] Step 4: (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanoic acid

[2478]

[2479] 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) was added concentrated HC1 (65 mL of 11.8 M, 767.00 mmol) followed by water (50 mL). A white precipitate appeared. The mixture was heated at 100 °C for 66 h. More concentrated HC1 (40 mL of 11.8 M, 472.00 mmol) and HOAc (10 mL) were added. The mixture was stirred at 100 °C overnight. More aqueous HC1 (20 mL of 6 M, 120.00 mmol) was added. After 7 h at 100 °C, more aqueous HC1 (20 mL of 6 M, 120.00 mmol) was added. The mixture was stirred at 100 °C overnight. The mixture became a clear solution. More aqueous HC1 (20 mL of 6 M, 120.00 mmol) was added. The mixture was stirred at 100 °C for 7 h, more aqueous HC1 (20 mL of 6 M, 120.00 mmol) was added. The mixture was stirred at 100 °C overnight. The mixture was concentrated and co-evaporated with water (50 mL). The residue (17 g) was mixed with water (25 mL) at 50 °C for 20 min, cooled with an ice water bath for 20 min and filtered. The crude product was mixed with 1,4-dioxane (60 mL). The mixture was concentrated and dried under vacuum overnight to give (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1- phenylethyl]amino]pentanoic acid (hydrochloride) as a off-white solid (13.04 g, 97%). 1 HNMR (300 MHz, DMSO-d6) δ 10.09 (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 = 6.5 Hz, 3H), 0.99 (s, 3H), 0.92 (s, 3H). 19 F NMR (282 MHz, DMSO-d6) δ -78.28 (s, 3F). ESI-MS m / z calcd 303.14462, found 304.2 (M + 1) + ; Retention time: 1.98 min; LC Method U.

[2480] Step 5: (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1- phenylethyl]amino]pentan-1-ol

[2481]

[2482] To a suspension of (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1- phenylethyl]amino]pentanoic acid (hydrochloride) (13.04 g, 36.267 mmol) in THF (200 mL) was added dropwise LAH in THF (1 M of 100 mL, 100.00 mmol) at 35 °C. The mixture was stirred at 40 °C for 2 h, cooled to 10 °C with 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% aqueous NaOH (3.8 g) and water (10 g). The resulting mixture was stirred at room temperature for 30 min and at 50 °C for 1 h, filtered and washed with warm THF. The filtrate was concentrated to give 12.02 g of product (free amine) as a colorless oil. 1 H NMR (300 MHz, DMSO-d6) δ 9.57 (br. s., 1H), 9.25 (t, J = 9.8 Hz, 1H), 7.80 - 7.59 (m, 2H), 7.53 - 7.32 (m, 3H), 5.63 (br. s., 1H), 4.58 (t, J = 6.3 Hz, 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 = 6.8 Hz, 3H), 0.91 (s, 3H), 0.88 (s, 3H). 19 F NMR (282 MHz, CDC13) δ -78.83 (s, 3F). The above 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. HC1 in 1,4-dioxane (4 M of 10.5 mL, 42.000 mmol) was added dropwise. The mixture was stirred at room temperature for 30 min and filtered to give (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1- phenylethyl]amino]pentan-1-ol (hydrochloride) (11.56 g, 98%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 9.57 (br. s., 1H), 9.25 (t, J = 9.8 Hz, 1H), 7.80 - 7.59 (m, 2H), 7.53 - 7.32 (m, 3H), 5.63 (br. s., 1H), 4.58 (t, J = 6.3 Hz, 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 = 6.8 Hz, 3H), 0.91 (s, 3H), 0.88 (s, 3H). 19F NMR (282 MHz, DMSO-d6) δ -77.71 (s, 3F). ESI-MS m / z calcd 289.16534, found 290.2 (M+1) + ; Retention time: 2.08 min; LC Method U.

[2483] Step 6: (2R)-2-Amino-5,5,5-trifluoro-4,4-dimethyl-pentan-1-ol

[2484]

[2485] To a solution of (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1- phenylethyl]amino]pentan-1-ol (hydrochloride) (11.56 g, 35.482 mmol) in EtOH (200 mL) was added 10% palladium on carbon, 50% wet (5 g, 2.3492 mmol). The mixtu...

Claims

1. A compound of formula IIb: Or its pharmaceutically acceptable salt, wherein Ring A is selected from: ■C6-C 10 Aryl, and ■5 to 10% mixed aromatic compounds; W 1 It is N; W 2 It is N; Z is C(R) ZC )2; Two Rs ZC Together they form an oxo group; Each L 1 Independently selected from C(R) L1 )2; Each L 2 Independently selected from C(R) L2 )2; R 3 It is a C1-C6 alkyl group; R 4 Selected from hydrogen and C1-C6 alkyl groups; Each R 5 Selected independently from: ■ Hydrogen, ■ Halogen, ■Hydroxy ■ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following: ○Hydroxy group, ○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, ○C3-C 10 cycloalkyl, ○Optionally substituted with 1-3 groups independently selected from C1-C6 alkyl and C1-C6 alkoxy groups -(O) 0-1 -(C6-C 10 Aryl), and ○3 to 10-membered heterocyclic groups, ■ C1-C6 alkoxy groups optionally substituted with 1-3 independently selected groups from the following: ○ Halogen, ○C6-C 10 Aryl, and ○C3-C 10 cycloalkyl, ■C1-C6 fluoroalkyl groups, and ■C3-C 10 cycloalkyl; R YN Selected from: ■ Hydrogen, ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following: ○Hydroxy group, ○Oxygenation, ○Cyano ○ C1-C6 alkoxy groups optionally substituted with 1-3 independently selected halogen and C1-C6 alkoxy groups, ○N(R N )2, ○SO2Me, ○ C3-C cells optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl: ◆Hydroxy group, ◆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, ◆C1-C6 fluoroalkyl groups, ◆C1-C6 alkoxy groups, ◆COOH, ◆N(R N )2, ◆C6-C 10 Aryl, and ◆Optionally substituted with 1-3 independently selected oxo and C1-C6 alkyl groups, 3- to 10-membered heterocyclic groups, ○ C6-C cells optionally substituted with 1-3 independently selected groups from the following 10 Aryl: ◆Halogen, ◆Hydroxy group, ◆Cyano ◆SiMe3, ◆SO2Me, ◆SF5, ◆N(R N )2, ◆P(O)Me2, ◆Optionally substituted with 1-3 independently selected C1-C6 fluoroalkyl groups -(O) 0-1 -(C3-C 10 cycloalkyl), ◆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, ◆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, ◆C1-C6 fluoroalkyl groups, ◆Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, 3- to 10-membered heterocyclic groups, ◆-(O) 0-1 -(C6-C 10 Aryl), and ◆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), ○Optionally substituted with 1 to 4 independently selected groups from the following 3- to 10-membered heterocyclic groups: ◆Hydroxy group, ◆Oxygenation, ◆N(R N )2, ◆C1-C6 alkyl groups optionally substituted with 1-3 independently selected oxo and C1-C6 alkoxy groups, ◆C1-C6 alkoxy groups, ◆C1-C6 fluoroalkyl groups, ◆C6-C cells optionally substituted with 1-3 independently selected halogen groups 10 Aryl, and ◆5 to 10 aryl compounds, and ○ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following: ◆Hydroxy group, ◆Cyano ◆Oxygenation, ◆Halogen, ◆B(OH)2, ◆N(R N )2, ◆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, ◆Optionally composed of 1-3 independently selected from hydroxyl, oxo, halogen, C1-C6 alkoxy, N(R) N )2 and C3-C 10 C1-C6 alkoxy groups substituted with cycloalkyl groups, ◆C1-C6 fluoroalkyl groups, ◆Optionally substituted with 1-3 groups independently selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups -(O) 0-1 -(C3-C 10 cycloalkyl), ◆-(O) 0-1 -(C6-C 10 Aryl), ◆Optionally selected by 1-4 independently chosen from hydroxyl, oxo, halogen, cyano, N(R) N 2. -(O) groups substituted with C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, and 3 to 10-membered heterocyclic groups. 0-1 -(3 to 10-membered heterocyclic groups), and ◆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, and ■C1-C6 fluoroalkyl groups; Each R L1 Selected independently from: ■ Hydrogen, ■ C1-C9 alkyl groups optionally substituted by 1-3 independently selected groups from the following: ○ Halogen, ○Hydroxy group, ○Oxygenation, ○N(R N )2, ○Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted by the aryl group, ○ C3-C substituted with 1-3 independently selected groups selected from halogens and C1-C6 fluoroalkyl groups 10 cycloalkyl, ○ C6-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 Aryl, and ○Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, 3- to 10-membered heterocyclic groups, ■ C6-C cells optionally substituted with 1-4 independently selected groups from the following 10 Aryl: ○ Halogen, ○Cyano ○ C1-C7 alkyl groups optionally substituted by 1-3 independently selected groups from the following: ◆Hydroxy group, ◆Oxygenation, ◆Cyano ◆N(R N )2, and ◆C3-C substituted with 1-3 independently selected C1-C6 fluoroalkyl groups 10 cycloalkyl, ○ C1-C6 alkoxy groups optionally substituted with 1-3 independently selected groups from the following: ◆C3-C substituted with 1-3 independently selected C1-C6 fluoroalkyl groups 10 cycloalkyl groups, and ◆C1-C6 alkoxy groups, ○C1-C6 fluoroalkyl, ○ C3-C2 groups optionally substituted with 1-3 groups independently selected from C1-C6 alkyl and C1-C6 fluoroalkyl groups 10 cycloalkyl, ○C6-C 10 Aryl, ○Optionally substituted with 1-3 independently selected C1-C6 alkyl groups, and ○5 to 10 yuan of mixed aromatic compounds, ■ 5- to 10-membered heteroaryl groups optionally substituted by 1 to 3 independently selected groups from the following: ○ C1-C6 alkyl groups optionally substituted by 1-3 independently selected groups from the following: ◆C3-C substituted with 1-3 independently selected C1-C6 fluoroalkyl groups 10 cycloalkyl groups, and ○ C6-C alkyl groups optionally substituted with 1-3 independently selected C1-C6 alkyl groups 10 Aryl, and R L2 It is hydrogen; Each R N Selected independently from: ■ Hydrogen, ■ C1-C8 alkyl groups optionally substituted by 1-3 independently selected groups from the following: ○Oxygenation, ○ Halogen, ○Hydroxy group, ○NH2, ○NHMe, ○NMe2, ○NHCOMe, ○Optionally selected from 1-3 independent selections from C6-C 10 The C1-C6 alkoxy group substituted by the aryl group, ○-(O) 0-1 -(C3-C 10 cycloalkyl), ○ C6-C alkyl groups optionally substituted with 1-3 independently selected groups selected from halogens and C1-C6 alkyl groups 10 Aryl, and ○Optionally substituted with 1-4 independently selected oxo and C1-C6 alkyl groups, and ○ 5- to 14-membered heteroaryl groups optionally substituted by 1 to 4 independently selected oxo and C1-C6 alkyl groups, ■ C3-C, optionally substituted by 1-3 independently selected groups from the following 10 Cycloalkyl: ○Hydroxy group, ○NH2, ○NHMe, and ○ C1-C6 alkyl groups optionally substituted with 1-3 independently selected groups selected 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 4 groups selected from the following: ■Hydroxy ■ Halogen, ■Oxygenation, ■Cyano ■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, ■C1-C6 alkoxy groups, and ■C1-C6 fluoroalkyl groups.

2. The compound according to claim 1, wherein the compound is a compound of formula IV: Or its pharmaceutically acceptable salt.

3. The compound according to claim 1, wherein the compound is a compound of formula VI: Or its pharmaceutically acceptable salt.

4. A compound selected from the following:

5. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier according to any one of claims 1 to 4.

6. Use of the compound or pharmaceutically acceptable salt of any one of claims 1 to 4 or the pharmaceutical composition of claim 5 in the preparation of a medicament for the treatment of cystic fibrosis.

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