Regulators of the cystic fibrosis transmembrane conductance regulator

Abstract

The present disclosure provides modulators of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), pharmaceutical compositions comprising at least one such modulator, methods of treating cystic fibrosis using such modulators and pharmaceutical compositions, and processes for making such modulators.

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 307,954, filed February 8, 2022, the contents of which are incorporated herein by reference in their entirety.

[0002] The present invention relates to modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), pharmaceutical compositions comprising the modulators, methods of treating cystic fibrosis and CFTR-mediated disorders using such modulators and pharmaceutical compositions, and processes for making such modulators. [Background technology]

[0003] Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 83,000 children and adults worldwide. Despite advances in CF treatment, there is no cure.

[0004] In patients with CF, mutations in endogenously expressed CFTR in respiratory epithelia result in reduced apical anion secretion, leading to an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to increased mucus accumulation in the lungs, accompanied by microbial infections that ultimately lead to death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal disorders and pancreatic insufficiency, which can be fatal if left untreated. Additionally, the majority of men with cystic fibrosis are infertile, and fertility is reduced in women 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 2,000 CF gene mutations have been identified, and the CFTR2 database currently contains information on at least 322 of these identified mutations, with sufficient evidence to define at least 281 mutations as disease-causing. The most common disease-causing mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, commonly referred to as the F508del mutation. This mutation occurs in many cases of cystic fibrosis and is associated with severe disease.

[0006] CFTR is a cAMP / ATP-mediated anion channel expressed in various cell types, including absorptive and secretory epithelial cells, where it controls anion flux across the membrane and also regulates the activity of other ion channels and proteins. In epithelial cells, normal CFTR function is essential for maintaining electrolyte transport throughout the body, including respiratory and digestive tissues. CFTR consists of 1,480 amino acids that encode a protein composed of tandem repeats of transmembrane domains, each containing six transmembrane helices and a nucleotide-binding domain. The two transmembrane domains are linked via large, polar regulatory (R) domains to multiple phosphorylation sites that control channel activity and cellular trafficking.

[0007] Chloride transport is mediated by the coordinated activity of ENaC (epithelial sodium channel) and CFTR present on the apical membrane, and Na + -K + -ATPase pump and Cl -Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which is then transported through the Cl - It can passively leave the cell through channels, resulting in vectorial transport. + / 2Cl - / K + Na symporter on the basolateral surface + -K + -ATPase pump and basolateral membrane K + The channel, as well as the positioning of CFTR on the luminal side, regulates chloride secretion: presumably because water itself is not actively transported, its flow across the epithelium depends on a small transepithelial osmotic gradient generated by the bulk flow of sodium and chloride. Recently, several CFTR modulators have been identified. These modulators are considered, for example, potentiators, correctors, potentiators / co-potentiators, amplifiers, read-through agents, and nucleic acid therapies. CFTR modulators that increase the channel gating activity of mutant and wild-type CFTR at the epithelial cell surface are known as potentiators. Correctors improve defective protein processing, resulting in transport to the epithelial surface. Ghelani and Schneider-Futschik (2020) ACS Pharmacol. Transl. Sci. 3:4-10. Three CFTR correctors are approved by the US Food and Drug Administration for the treatment of cystic fibrosis. However, monotherapy with some CFTR correctors has proven ineffective, and as a result, combination therapy with potentiators is often required to enhance CFTR activity. Currently, only one CFTR potentiator is approved for the treatment of cystic fibrosis. Thus, although the treatment of cystic fibrosis has been transformed by these new small molecule CFTR modulators, new and better modulators are needed to prevent disease progression, reduce the severity of cystic fibrosis and other CFTR-mediated diseases, and treat more severe forms of these diseases. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Cutting, GRet al. (1990) Nature 346:366-369 [Non-patent document 2] Dean, M. et al. (1990) Cell 61:863:870 [Non-patent document 3] Kerem, BS. et al. (1989) Science 245:1073-1080 [Non-patent document 4] Kerem, BS et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451 [Non-Patent Document 5] Ghelani and Schneider-Futschik(2020)ACS Pharmacol.Transl.Sci.3:4-10 Summary of the Invention [Means for solving the problem]

[0009] One aspect of the present invention provides novel compounds, including compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing. DETAILED DESCRIPTION OF THE INVENTION

[0010] For example, a compound of formula I can be represented as follows: [ka] including deuterated derivatives and pharmaceutically acceptable salts thereof, wherein: X is -C(R X1 )2-, -CO-, [ka] -Si(RZ3 )2-, and [ka] is selected from Ring A is a cyclic group selected from phenyl and 5- to 6-membered heteroaryl, which cyclic group is optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl; Each R X1 H, C1-C6 alkyl (oxo, -OR X2 , and -N(R X2 ) optionally substituted with 1 to 3 groups independently selected from 2), C3-C8 cycloalkyl, halogen, cyano, -OR X2 and C1-C6 fluoroalkyl; Each R X2 are independently selected from H and C1-C6 alkyl; Each Y is -C(R Y )2-, -O-, -CO-, -NR YN - and [ka] are independently selected from Each R Y is hydrogen, hydroxy, halogen, C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from hydroxy, C1-C6 alkoxy, and Q), C3-C8 cycloalkyl, C6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from halogen), 5 to 10 membered heteroaryl, -OR Y1 , -CO2R Y1 , -COR Y1 , -CON(R Y1 )2, and -N(R Y1 )2 are independently selected from or two R, one on one atom and the other on an adjacent atom Y together to form a pi bond, Each R Y1are independently selected from hydrogen and C1-C6 alkyl, or two R Y1 together form a 3- to 6-membered heterocyclyl, Each R YN but, ■H and ■ C1-C6 alkyl, o-oxo, C3-C8 cycloalkyl (optionally substituted with 1 to 5 groups independently selected from halogen and C1-C6 alkyl); oC6-C 10 aryl, ◆Halogen, ◆Cyano, C1-C6 alkyl (optionally substituted with 1 to 3 hydroxy); ◆C1-C6 fluoroalkyl, C1-C6 alkoxy (optionally substituted with C3-C8 cycloalkyl optionally substituted with C1-C6 fluoroalkyl), ◆C1-C6 fluoroalkoxy, C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogen, C1-C6 alkyl, and C1-C6 fluoroalkyl), and phenyl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, and halogen); C6-C optionally substituted with 1 to 3 groups independently selected from 10 aryl, o 5-10 membered heteroaryl, ◆Halogen, ◆C1-C6 alkyl, ◆C1-C6 fluoroalkyl, ◆C1-C6 fluoroalkoxy, ◆-O (0-1) (C3-C8 cycloalkyl)(optionally substituted with C1-C6 fluoroalkyl), and ◆ 3- to 12-membered heterocyclyl; o 3- to 12-membered heterocyclyl optionally substituted with 1-3 groups selected from halogen and C1-C6 alkyl; and ■ C1-C6 fluoroalkyl, ■C6-C 10 aryl and ■ C3-C8 cycloalkyl, oHalogen, o cyano, o- N(R YN1 ) C1-C4 alkyl optionally substituted with 1 to 3 groups selected from 2; o C1-C6 fluoroalkyl, o C1-C6 alkoxy, C3-C8 cycloalkyl, and o phenyl (optionally substituted with 1 to 3 groups independently selected from C-C alkyl); ■ 3- to 12-membered heterocyclyl optionally substituted with 1 to 3 groups selected from oxo and C1-C4 alkyl (optionally substituted with 1 to 2 groups selected from oxo and C3-C8 cycloalkyl); ■ 5-6 membered heteroaryl (optionally substituted with 1 to 3 groups selected from C1-C6 alkyl), ■CO2R YN1 and are selected independently from Each R YN1 is independently selected from H, C1-C4 alkyl (optionally substituted with oxo), and C3-C6 cycloalkyl; Ring B is ■C6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy); ■ C3-C8 cycloalkyl, ■ 5- to 10-membered heteroaryl, and ■ 3- to 6-membered heterocyclyl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl), Each Q is ■ C1-C6 alkyl, oHalogen, o-oxo, oC6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from halogen and —OCF3), and C1-C6 alkyl optionally substituted with 1 to 3 groups independently selected from: C3-C8 cycloalkyl; ■ C3-C8 cycloalkyl, oHalogen, oCN, C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogen, -NH2, and -NHCOMe); o C1-C6 alkoxy, oC6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl), and o C3-C8 cycloalkyl, optionally substituted with 1 to 3 groups independently selected from: C3-C8 cycloalkyl; ■C6-C 10 aryl, oHalogen, oCN, o C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogen and hydroxy); o C1-C6 alkoxy, ◆Halogen, C1-C6 alkoxy optionally substituted with 1 to 4 groups independently selected from C3-C8 cycloalkyl (optionally substituted with CF3); oC3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogen, CF3, OCF3, and C1-C6 alkyl), and oC6-C 10 C-C optionally substituted with 1 to 3 groups independently selected from aryl, 10 aryl, ■ 5- to 10-membered heteroaryl, oHalogen, o C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogen); C3-C8 cycloalkyl (optionally substituted with 1 to 3 CF3 groups), and o 3- to 10-membered heterocyclyl; and ■ 3- to 10-membered heterocyclyl, o C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from oxo and C3-C8 cycloalkyl), and oxo; and 3- to 10-membered heterocyclyl optionally substituted with 1 to 3 groups independently selected from Each R 1 However, halogen, C1-C6 fluoroalkyl, C1-C6 alkyl (hydroxy, C6-C 10 aryl, and 5- to 6-membered heteroaryl), -OR 2 , -N(R 2 )2, -CO2R 2 , -CO-N(R 2 )2, -CN, C3-C8 cycloalkyl, C6-C 10 aryl, 5- to 6-membered heteroaryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl), 3- to 6-membered heterocyclyl, -B(OR 2 )2, -SO2R 2 , -SR 2 , -SOR 2 , -PO(OR 2 )2, and -PO(R2 )2 are independently selected from Each R 2 is selected from hydrogen, C1-C6 alkyl (optionally substituted with 1 to 6 groups independently selected from halogen), C1-C6 fluoroalkyl, and C6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 fluoroalkyl and C1-C6 fluoroalkoxy); Z, [ka] is selected from In the formula, ring C is C6-C 10 selected from aryl and 5- to 10-membered heteroaryl; R Z1 is hydrogen, —CN, C1-C6 alkyl (optionally substituted with 1 to 3 hydroxy), C1-C6 fluoroalkyl, 3- to 6-membered heterocyclyl, C3-C6 cycloalkyl, C6-C 10 aryl, and 5- to 6-membered heteroaryl; R Z2 is hydrogen, halogen, hydroxy, NH2, NH(CO)(C1-C6 alkyl), and C1-C6 alkoxy (C3-C 10 optionally substituted with 1 to 3 groups independently selected from cycloalkyl; or R Z1 and R Z2 together form a group selected from oxo and =N-OH, Each R Z3 is hydroxy, C1-C6 alkoxy, C1-C6 alkyl, and C6-C 10 aryl, or two R Z3 together form a 3- to 6-membered heterocyclyl, n is selected from 4, 5, 6, 7, and 8; m is selected from 0, 1, 2, and 3.

[0011] In some embodiments of Formula I, X is —C(RX1 )2-. In some embodiments of Formula I, -C(R X1 )2- is, -CH2-, [ka] is a group selected from

[0012] In some embodiments of Formula I, X is —CO—.

[0013] In some embodiments of Formula I, X is [ka] In some embodiments of Formula I, X is [ka] is a group selected from

[0014] In some embodiments of Formula I, X is [ka] In some embodiments of Formula I, Ring A is a cyclic group selected from phenyl, pyrazole, and oxadiazole.

[0015] In some embodiments of Formula I, X is -CO-, -CH2-, [ka] is selected from.

[0016] In some embodiments of Formula I, each R X1 is H, C1-C6 alkyl, halogen, cyano, -OR X2 and C1-C6 fluoroalkyl. In some embodiments of Formula I, each R X2 is independently selected from H and C1-C4 alkyl. In some embodiments of Formula I, each RX1 are independently selected from H, F, —CF 3 , —CH 3 , —OH, —OCH 3 , and CN.

[0017] In some embodiments of Formula I, each Y is —C(R Y )2-, -CO-, -NR YN - and [ka] are independently selected from

[0018] In some embodiments of Formula I, each R Y is independently selected from hydrogen, hydroxy, halogen, and C1-C6 alkyl. In some embodiments of Formula I, each R Y are independently selected from H, —OH, —F, and —CH 3 .

[0019] In some embodiments of Formula I, each R YN teeth, ■H and ■-CH2CF3 and ■ C1-C6 alkyl, o-oxo, o-cyclopropyl, o cyclobutyl optionally substituted with 1 to 2 fluoro groups; o cyclohexyl optionally substituted with 1 to 2 fluoro groups; o spiro[2.2]pentane, o-bicyclo[4.1.0]heptane, o-dispiro[2.0.24.13]heptane, oF, Cl, Br, CN, methyl, propyl (optionally substituted with one hydroxy), tert-butyl, neopentyl, -CHF2, -CF3, -C(CH3)2CF3, -OCH3, -O(2-propyl), -OCHF2, -OCF3, -OCF2CHF2, -OCH2CF3, cyclopropyl (optionally substituted with one CF3), cyclobutyl (optionally substituted with 1 to 2 groups selected from fluoro and methyl), spiro[2.2]pentane, bicyclo[1.1.1]pentane, bicyclo[4.1.0]heptane, dispiro[2.0.24.13]heptane, phenyl, naphthyl, and [ka] phenyl optionally substituted with 1 to 3 groups independently selected from o-naphthyl, o 2,2-dimethyl-2,3-dihydrobenzofuran, o2,2-difluorobenzo[d][1,3]dioxole, o tetrahydro-2H-pyran, pyrazole optionally substituted with one group selected from methyl and propyl; pyridine optionally substituted with one group selected from o-methyl, tert-butyl, CF3, -O(cyclobutyl), -OCHF2, cyclopropyl optionally substituted with one CF3, and piperidine; and pyrimidine optionally substituted with one group selected from methyl and tert-butyl; Cyclopropyl optionally substituted with 1 to 2 groups selected from methyl, tert-butyl, cyclopropyl, and phenyl (optionally substituted with one tert-butyl group); Cyclobutyl optionally substituted with 1 to 3 groups selected from fluoro, methyl, and phenyl; Cyclopentyl and Cyclohexyl optionally substituted with 1 to 2 groups selected from fluoro, methyl, tert-butyl, cyano, -CF3, -CH2NH2, and -CH2NHAc; bicyclo[1.1.1]pentane optionally substituted with one group selected from fluoro, methyl, and tert-butyl; a bicyclo[2.2.1]heptane optionally substituted with one -OCH3 group; Bicyclo[2.2.2]octane, ■ spiro[3.3]heptane optionally substituted with 1 to 2 fluoro groups; ■Phenyl and Tetrahydro-2H-pyran, 2-azaspiro[3.3]heptane optionally substituted with one group selected from -COMe and -CO(cyclopropyl); ■ Thietane 1,1-dioxide, ■ Tetrahydro-2H-thiopyran 1,1-dioxide, a pyrazole optionally substituted with one methyl group; ■ pyridine, and

[0020] In some embodiments of Formula I, each R YN teeth, H, -CH3, [ka] [ka] [ka] [ka] [ka] are independently selected from

[0021] In some embodiments of Formula I, ring B is ■C6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from halogen); C3-C8 cycloalkyl, and ■ 3- to 6-membered heterocyclyl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl).

[0022] In some embodiments of Formula I, ring B is [ka] is selected from.

[0023] In some embodiments of Formula I, each R 2 is H.

[0024] In some embodiments of Formula I, each R 1 is C1-C6 fluoroalkyl, -N(R 2 In some embodiments of Formula I, each R 1 are independently selected from —CF 3 , —NH 2 , and —CN.

[0025] In some embodiments of Formula I, Z is [ka] In some embodiments of Formula I, Z is selected from: [ka] is selected from.

[0026] In some embodiments of Formula I, Z is [ka] wherein ring C is C6-C 10 In some embodiments of Formula I, the group: [ka] teeth, [ka] is selected from.

[0027] In some embodiments of Formula I, the group: [ka] teeth, [ka] is.

[0028] In some embodiments of Formula I, Z is [ka] In some embodiments of Formula I, Z is [ka] In some embodiments of Formula I, Z is [ka] In some embodiments of Formula I, Z is [ka] wherein (R) refers to the stereochemical designation of the central carbon atom according to the Cahn-Ingold-Prelog convention. In some embodiments of Formula I, Z is [ka] where (S) refers to the stereochemical designation of the central carbon atom according to the Cahn-Ingold-Prelog convention.

[0029] In some embodiments of Formula I, R Z1 is selected from C1-C6 fluoroalkyl.

[0030] In some embodiments of Formula I, R Z2 is selected from halogen and hydroxy.

[0031] In some embodiments of Formula I, n is selected from 5, 6, and 7.

[0032] In some embodiments of Formula I, m is selected from 1 and 2.

[0033] In some embodiments, the compound of formula I can be represented as formula I': [ka] including deuterated derivatives and pharmaceutically acceptable salts thereof, wherein: X is -C(R X1 )2-, -CO-, [ka] -Si(R Z3 )2-, and [ka] is selected from Ring A is a cyclic group selected from phenyl and 5- to 6-membered heteroaryl, which cyclic group is optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl; Each R X1 H, C1-C6 alkyl (oxo, -OR X2 , and -N(R X2 ) optionally substituted with 1 to 3 groups independently selected from 2), C3-C8 cycloalkyl, halogen, cyano, -OR X2 and C1-C6 fluoroalkyl; Each R X2 are independently selected from H and C1-C6 alkyl; Each Y is -C(R Y )2-, -O-, -CO-, -NR YN - and [ka] are independently selected from Each R Y is hydrogen, hydroxy, halogen, C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from hydroxy, C1-C6 alkoxy, and Q), C3-C8 cycloalkyl, C6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from halogen), 5 to 10 membered heteroaryl, -OR Y1 , -CO2R Y1 , -COR Y1 , -CON(R Y1 )2, and -N(R Y1 )2 are independently selected from or two R, one on one atom and the other on an adjacent atom Y together to form a pi bond, Each R Y1 are independently selected from hydrogen and C1-C6 alkyl, or two R Y1 together form a 3- to 6-membered heterocyclyl, Each R YN but, ■H and ■ C1-C6 alkyl, o-oxo, C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogen and C1-C6 alkyl); oC6-C 10 aryl, ◆Halogen, ◆Cyano, C1-C6 alkyl (optionally substituted with 1 to 3 hydroxy); ◆C1-C6 fluoroalkyl, C1-C6 alkoxy (optionally substituted with C3-C8 cycloalkyl optionally substituted with C1-C6 fluoroalkyl), ◆C1-C6 fluoroalkoxy, C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogen, C1-C6 alkyl, and C1-C6 fluoroalkyl), and phenyl (optionally substituted with C1-C6 alkyl), C6-C 10 aryl, o 5-10 membered heteroaryl, ◆Halogen, ◆C1-C6 alkyl, ◆C1-C6 fluoroalkyl, ◆C1-C6 fluoroalkoxy, ◆-O (0-1) (C3-C8 cycloalkyl)(optionally substituted with C1-C6 fluoroalkyl), and ◆ 3- to 12-membered heterocyclyl; o 3- to 12-membered heterocyclyl optionally substituted with 1-3 groups selected from halogen and C1-C6 alkyl; and ■ C1-C6 fluoroalkyl, ■C6-C 10 aryl and ■ C3-C8 cycloalkyl, oHalogen, o cyano, o- N(R YN1 ) C1-C4 alkyl optionally substituted with 1 to 3 groups selected from 2; o C1-C6 fluoroalkyl, o C1-C6 alkoxy, C3-C8 cycloalkyl, and o phenyl (optionally substituted with 1 to 3 groups independently selected from C-C alkyl); ■ 3- to 12-membered heterocyclyl optionally substituted with 1 to 3 groups selected from oxo and C1-C4 alkyl (optionally substituted with 1 to 2 groups selected from oxo and C3-C8 cycloalkyl); ■ 5-6 membered heteroaryl (optionally substituted with 1 to 3 groups selected from C1-C6 alkyl), ■CO2R YN1 and are selected independently from Each R YN1 is independently selected from H, C1-C4 alkyl (optionally substituted with oxo), and C3-C6 cycloalkyl; Ring B is ■C6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy); ■ C3-C8 cycloalkyl, ■ 5- to 10-membered heteroaryl, and ■ 3- to 6-membered heterocyclyl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl), Each Q is ■ C1-C6 alkyl, oHalogen, o-oxo, oC6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from halogen and —OCF3), and o C3-C8 cycloalkyl; and C1-C6 alkyl optionally substituted with 1 to 3 groups independently selected from: ■ C3-C8 cycloalkyl, oHalogen, oCN, C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogen, -NH2, and -NHCOMe); o C1-C6 alkoxy, oC6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl), and o C3-C8 cycloalkyl, optionally substituted with 1 to 3 groups independently selected from: C3-C8 cycloalkyl; ■C6-C 10aryl, oHalogen, oCN, o C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogen and hydroxy); o C1-C6 alkoxy, ◆Halogen, C1-C6 alkoxy optionally substituted with 1 to 4 groups independently selected from C3-C8 cycloalkyl (optionally substituted with CF3); oC3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogen, CF3, OCF3, and C1-C6 alkyl), and oC6-C 10 C-C optionally substituted with 1 to 3 groups independently selected from aryl, 10 aryl and ■ 5- to 10-membered heteroaryl, oHalogen, o C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogen); C3-C8 cycloalkyl (optionally substituted with 1 to 3 CF3 groups), and o 3- to 10-membered heterocyclyl; and ■ 3- to 10-membered heterocyclyl, o C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from oxo and C3-C8 cycloalkyl), and oxo; and 3- to 10-membered heterocyclyl optionally substituted with 1 to 3 groups independently selected from Each R 1 However, halogen, C1-C6 fluoroalkyl, C1-C6 alkyl (hydroxy, C6-C 10 aryl, and 5- to 6-membered heteroaryl), -OR 2 , -N(R 2 )2, -CO2R2 , -CO-N(R 2 )2, -CN, C3-C8 cycloalkyl, C6-C 10 aryl, 5- to 6-membered heteroaryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl), 3- to 6-membered heterocyclyl, -B(OR 2 )2, -SO2R 2 , -SR 2 , -SOR 2 , -PO(OR 2 )2, and -PO(R 2 )2 are independently selected from Each R 2 is selected from hydrogen, C1-C6 alkyl (optionally substituted with 1 to 6 groups independently selected from halogen), C1-C6 fluoroalkyl, and C6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 fluoroalkyl and C1-C6 fluoroalkoxy); Z, [ka] is selected from In the formula, ring C is C6-C 10 selected from aryl and 5- to 10-membered heteroaryl; R Z1 is hydrogen, —CN, C1-C6 alkyl (optionally substituted with 1 to 3 hydroxy), C1-C6 fluoroalkyl, 3- to 6-membered heterocyclyl, C3-C6 cycloalkyl, C6-C 10 aryl, and 5- to 6-membered heteroaryl; R Z2 is hydrogen, halogen, hydroxy, NH2, NH(CO)(C1-C6 alkyl), and C1-C6 alkoxy (C3-C 10 optionally substituted with 1 to 3 groups independently selected from cycloalkyl; or R Z1 and R Z2 together form a group selected from oxo and =N-OH, Each R Z3 is hydroxy, C1-C6 alkoxy, C1-C6 alkyl, and C6-C 10 aryl, or two R Z3 together form a 3- to 6-membered heterocyclyl, n is selected from 4, 5, 6, 7, and 8; m is selected from 0, 1, 2, and 3.

[0034] In some embodiments of Formula I', X is -C(R X1 In some embodiments of Formula I', -C(R X1 )2- is, -CH2-, [ka] is a group selected from

[0035] In some embodiments of Formula I', X is -CO-.

[0036] In some embodiments of Formula I', X is [ka] In some embodiments of Formula I', X is [ka] is a group selected from

[0037] In some embodiments of Formula I', X is [ka] In some embodiments of Formula I', Ring A is a cyclic group selected from phenyl, pyrazole, and oxadiazole.

[0038] In some embodiments of Formula I', X is -CO-, -CH2-, [ka] is selected from.

[0039] In some embodiments of Formula I′, each R X1 is H, C1-C6 alkyl, halogen, cyano, -OR X2 and C1-C6 fluoroalkyl. In some embodiments of Formula I', each R X2 is independently selected from H and C1-C4 alkyl. In some embodiments of Formula I', each R X1 are independently selected from H, F, —CF 3 , —CH 3 , —OH, —OCH 3 , and CN.

[0040] In some embodiments of Formula I', each Y is -C(R Y )2-, -CO-, -NR YN - and [ka] are independently selected from

[0041] In some embodiments of Formula I′, each R Y is independently selected from hydrogen, hydroxy, halogen, and C1-C6 alkyl. In some embodiments of Formula I', each R Y are independently selected from H, —OH, —F, and —CH 3 .

[0042] In some embodiments of Formula I′, each R YN teeth, ■H and ■-CH2CF3 and ■ C1-C6 alkyl, o-oxo, o-cyclopropyl, o cyclobutyl optionally substituted with 1 to 2 fluoro groups; o cyclohexyl optionally substituted with 1 to 2 fluoro groups; o spiro[2.2]pentane, o-bicyclo[4.1.0]heptane, o-dispiro[2.0.24.13]heptane, oF, Cl, Br, CN, methyl, propyl (optionally substituted with one hydroxy), tert-butyl, neopentyl, -CHF2, -CF3, -C(CH3)2CF3, -OCH3, -O(2-propyl), -OCHF2, -OCF3, -OCF2CHF2, -OCH2CF3, cyclopropyl (optionally substituted with one CF3), cyclobutyl (optionally substituted with 1 to 2 groups selected from fluoro and methyl), spiro[2.2]pentane, bicyclo[1.1.1]pentane, bicyclo[4.1.0]heptane, dispiro[2.0.24.13]heptane, phenyl, naphthyl, and [ka] phenyl optionally substituted with 1 to 3 groups independently selected from o-naphthyl, o 2,2-dimethyl-2,3-dihydrobenzofuran, o2,2-difluorobenzo[d][1,3]dioxole, o tetrahydro-2H-pyran, pyrazole optionally substituted with one group selected from methyl and propyl; pyridine optionally substituted with one group selected from o-methyl, tert-butyl, CF3, -O(cyclobutyl), -OCHF2, cyclopropyl optionally substituted with one CF3, and piperidine; and pyrimidine optionally substituted with one group selected from methyl and tert-butyl; Cyclopropyl optionally substituted with 1 to 2 groups selected from methyl, tert-butyl, cyclopropyl, and phenyl (optionally substituted with one tert-butyl group); Cyclobutyl optionally substituted with 1 to 3 groups selected from fluoro, methyl, and phenyl; Cyclopentyl and Cyclohexyl optionally substituted with 1 to 2 groups selected from fluoro, methyl, tert-butyl, cyano, -CF3, -CH2NH2, and -CH2NHAc; bicyclo[1.1.1]pentane optionally substituted with one group selected from fluoro, methyl, and tert-butyl; a bicyclo[2.2.1]heptane optionally substituted with one -OCH3 group; Bicyclo[2.2.2]octane, ■ spiro[3.3]heptane optionally substituted with 1 to 2 fluoro groups; ■Phenyl and Tetrahydro-2H-pyran, 2-azaspiro[3.3]heptane optionally substituted with one group selected from -COMe and -CO(cyclopropyl); ■ Thietane 1,1-dioxide, ■ Tetrahydro-2H-thiopyran 1,1-dioxide, a pyrazole optionally substituted with one methyl group; ■ pyridine, and

[0043] In some embodiments of Formula I′, each R YN teeth, H, -CH3, [ka] [ka] [ka] [ka] [ka] are independently selected from

[0044] In some embodiments of Formula I', ring B is ■C6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from halogen); C3-C8 cycloalkyl, and ■ 3- to 6-membered heterocyclyl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl).

[0045] In some embodiments of Formula I', ring B is [ka] is selected from.

[0046] In some embodiments of Formula I′, each R 2 is H.

[0047] In some embodiments of Formula I′, each R 1 is C1-C6 fluoroalkyl, -N(R 2 In some embodiments of Formula I', each R 1 are independently selected from CF3, -NH2, and -CN.

[0048] In some embodiments of Formula I', Z is [ka] In some embodiments of Formula I', Z is selected from: [ka] is selected from.

[0049] In some embodiments of Formula I', Z is [ka] wherein ring C is C6-C 10In some embodiments of Formula I', the group: [ka] teeth, [ka] is selected from.

[0050] In some embodiments of Formula I', the group: [ka] teeth, [ka] is.

[0051] In some embodiments of Formula I', Z is [ka] In some embodiments of Formula I', Z is [ka] In some embodiments of Formula I', Z is [ka] In some embodiments of Formula I', Z is [ka] wherein (R) refers to the stereochemical designation of the central carbon atom according to the Cahn-Ingold-Prelog convention. In some embodiments of Formula I', Z is [ka] where (S) refers to the stereochemical designation of the central carbon atom according to the Cahn-Ingold-Prelog convention.

[0052] In some embodiments of Formula I', R Z1 is selected from C1-C6 fluoroalkyl.

[0053] In some embodiments of Formula I', R Z2 is selected from halogen and hydroxy.

[0054] In some embodiments of Formula I', n is selected from 5, 6, and 7.

[0055] In some embodiments of Formula I', m is selected from 1 and 2.

[0056] The compounds of the present invention also include compounds of formula Ia and Ib: [ka] and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein all variables are as defined for Formula I.

[0057] In some embodiments of Formulas Ia and Ib, [ka] The portion of the compound represented by [ka] wherein (R) refers to the stereochemical designation of the central carbon atom according to the Cahn-Ingold-Prelog convention. [ka] The portion of the compound represented by [ka] where (S) refers to the stereochemical designation of the central carbon atom according to the Cahn-Ingold-Prelog convention.

[0058] The compounds of the present invention also include compounds of formula Ia' and Ib': [ka] and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein all variables are as defined for Formula I.

[0059] In some embodiments of Formulas Ia' and Ib', [ka] The portion of the compound represented by [ka] wherein (R) refers to the stereochemical designation of the central carbon atom according to the Cahn-Ingold-Prelog convention. [ka] The portion of the compound represented by [ka] where (S) refers to the stereochemical designation of the central carbon atom according to the Cahn-Ingold-Prelog convention.

[0060] The compounds of the present invention also include compounds of formula IIa, IIb, IIc, IId, IIe, and IIf: [ka] and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein all variables are as defined for Formula I.

[0061] In some embodiments of Formulas IIa, IIb, IIc, IId, IIe, and IIf, [ka] The portion of the compound represented by [ka] wherein (R) refers to the stereochemical designation of the central carbon atom according to the Cahn-Ingold-Prelog convention. In some embodiments of Formula I″, [ka] The portion of the compound represented by [ka] where (S) refers to the stereochemical designation of the central carbon atom according to the Cahn-Ingold-Prelog convention.

[0062] Another aspect of the present invention provides pharmaceutical compositions comprising at least one compound selected from the compounds of Formulas I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing, and at least one pharmaceutically acceptable carrier, which may further comprise at least one additional active pharmaceutical ingredient. Accordingly, another aspect of the present invention provides methods of treating the CFTR-mediated disease cystic fibrosis, the method comprising administering to a subject in need thereof at least one compound selected from the compounds of Formulas I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing, and at least one pharmaceutically acceptable carrier, optionally including at least one additional component as part of a pharmaceutical composition.

[0063] In certain embodiments, pharmaceutical compositions of the present invention comprise at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, compositions comprising at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing may optionally further comprise at least one compound selected from Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing.

[0064] Another aspect of the present invention is a method of treating the 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 administering to a patient in need thereof (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methyl) ... 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-dihydroquinol-3-one (compound II), N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (compound III), or 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-dihydroquinol-3-one (compound III). Compound III-d), 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound IV), N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl] N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (compound VI), (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6-Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound VII), (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hexan-5-yl}-9-oxa-2λ 6 and optionally further administering one or more additional CFTR modulators selected from -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione (Compound VIII), N-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound IX), and N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound X).

[0065] Another aspect of the invention is a method of treating the CFTR-mediated disease cystic fibrosis, comprising administering to a patient in need thereof at least one compound selected from the compounds of Formulas I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing; [ka] (ASP-11) (disclosed in Journal of Cystic Fibrosis (2018), 17(5), 595-606), and [ka] (nesolicaftor or PTI-428) (disclosed in WO 2016 / 105485). In one embodiment, the additional CFTR modulating agent is ASP-11. In one embodiment, the additional CFTR modulating agent comprises PTI-428.

[0066] Another aspect of the invention is a method of treating the CFTR-mediated disease cystic fibrosis, comprising administering to a patient in need thereof at least one compound selected from the compounds of Formulas I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing; [ka] (galicaftor or ABBV-2222) (disclosed in U.S. Patent Application Publication No. 2016-0120841), [ka] (ABBV-3221) (disclosed in WO2018 / 065921), [ka] and optionally further administering one or more additional CFTR modulators selected from (posenacaftor or PTI-801) (disclosed in WO2017 / 062581), ABBV-2851 (disclosed in WO2017 / 009804), GLPG2737 (disclosed in U.S. Patent Application Publication No. 2017-0101405), ABBV-3748, ABBV-3903, and ABBV-119.

[0067] definition As used herein, "Compound II" refers to (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, which can be represented by the following structure: [ka] Compound II can be in the form of a pharmaceutically acceptable salt. Compound II and methods of making and using Compound II are disclosed in WO2010 / 053471, WO2011 / 119984, WO2011 / 133751, WO2011 / 133951, and WO2015 / 160787, each of which is incorporated herein by reference.

[0068] As used throughout this disclosure, "Compound III" refers to N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (also known as N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide), which is represented by the following structure: [ka] Compound III may also be in the form of a pharmaceutically acceptable salt. Compound III and methods of making and using Compound III are disclosed in WO2006 / 002421, WO2007 / 079139, WO2010 / 108162, and WO2010 / 019239, each of which is incorporated herein by reference.

[0069] In some embodiments, a deuterated derivative of Compound III (Compound III-d) is used in the compositions and methods disclosed herein. Compound III-d has the chemical name N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d)propan-2-yl-1,1,1,3,3,3-d)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide and is represented by the following structure: [ka] Compound III-d can be in the form of a pharmaceutically acceptable salt. Compound III-d and methods for making and using compound III-d are disclosed in WO2012 / 158885, WO2014 / 078842, WO2019 / 109021, and U.S. Patent No. 8,865,902, which are incorporated herein by reference.

[0070] As used herein, "Compound IV" refers to 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, which is represented by the following chemical structure: [ka] Compound IV can be in the form of a pharmaceutically acceptable salt. Compound IV and methods of making and using Compound IV are disclosed in WO2007 / 056341, WO2009 / 073757, and WO2009 / 076142, which are incorporated herein by reference.

[0071] As used herein, "Compound V" refers to N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, which is represented by the following chemical structure: [ka] Compound V can be in the form of a pharmaceutically acceptable salt. Compound V and methods of making and using Compound V are disclosed in WO2018 / 107100 and WO2019 / 113476, which are incorporated herein by reference.

[0072] As used herein, "Compound VI" refers to N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, which is represented by the following chemical structure: [ka] Compound VI can be in the form of a pharmaceutically acceptable salt. Compound VI and methods of making and using Compound VI are disclosed in WO2018 / 064632 and WO2019 / 113476, which are incorporated herein by reference.

[0073] As used herein, "Compound VII" refers to (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione, which is represented by the following chemical structure: [ka] Compound VII may be in the form of a pharmaceutically acceptable salt. Compound VII and methods of making and using Compound VII are described in WO2019 / 161078, which are incorporated herein by reference. WO2020 / 102346, and PCT Application No. PCT / US2020 / 046116.

[0074] As used herein, "Compound VIII" refers to (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hexan-5-yl}-9-oxa-2λ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione, which has the following chemical structure: [ka] Compound VIII can be in the form of a pharmaceutically acceptable salt. Compound VIII and methods for making and using Compound VIII are disclosed in WO2020 / 206080, which is incorporated herein by reference.

[0075] As used herein, "compound IX" refers to N-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, which is represented by the following chemical structure: [ka] Compound IX can be in the form of a pharmaceutically acceptable salt. Compound IX and methods of making and using Compound IX are disclosed in WO2016 / 057572, which is incorporated herein by reference.

[0076] As used herein, "Compound X" refers to N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, which is represented by the following chemical structure: [ka] Compound X may be in the form of a pharmaceutically acceptable salt. Compound X and methods of making and using Compound X are disclosed in WO2016 / 057572, which is incorporated herein by reference.

[0077] As used herein, the term "alkyl" refers to a saturated branched or unbranched aliphatic hydrocarbon having 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, etc.). An alkyl group can be substituted or unsubstituted.

[0078] As used herein, the term "pi bond" refers to a covalent bond formed by the p orbitals of adjacent atoms. A pi bond exists when there is a multiple bond, i.e., a double or triple bond, between two atoms. For example, a carbon-carbon double bond consists of one pi bond, and a carbon-carbon triple bond consists of two pi bonds.

[0079] As used herein, the term "haloalkyl" refers to an alkyl or alkyl group substituted with one or more halogen atoms.

[0080] As used herein, the term "fluoroalkyl" refers to an alkyl group substituted with one or more fluorine atoms. In some embodiments, the fluoroalkyl group is substituted with 1 to 6 fluorine atoms. In some embodiments, the fluoroalkyl group is perfluorinated.

[0081] The term "alkoxy," as used herein, refers to an alkyl or cycloalkyl covalently linked to an oxygen atom. An alkoxy group may be substituted or unsubstituted.

[0082] As used herein, the term "haloalkoxy group" refers to an alkoxy group substituted with one or more halogen atoms.

[0083] As used herein, the term "fluoroalkoxy" refers to an alkoxy group substituted with one or more fluorine atoms. In some embodiments, the fluoroalkoxy group is substituted with 1 to 6 fluorine atoms. In some embodiments, the fluoroalkoxy group is perfluorinated.

[0084] As used herein, "cycloalkyl" refers to a cyclic, bicyclic, tricyclic, or polycyclic non-aromatic hydrocarbon group having 3 to 12 carbons (e.g., 3 to 10 carbons, etc.). "Cycloalkyl" groups encompass monocyclic, bicyclic, tricyclic, bridged, fused, and spirocyclic groups, including monospiro and dispiro rings. Non-limiting examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, and dispiro[2.0.2.1]heptane. Cycloalkyl groups can be substituted or unsubstituted.

[0085] As used herein, the term "aryl" refers to a functional group or substituent derived from an aromatic ring and includes monocyclic aromatic rings, as well as 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-tetrahydronaphthalenyl.

[0086] As used herein, the terms "heteroaryl ring" and "heteroaryl" refer to an aromatic ring containing at least one ring atom that is a heteroatom, such as O, N, or S. Heteroaryl groups include monocyclic rings, as well as bicyclic, tricyclic, bridged, fused, and spiro ring systems (including monospiro and dispiro rings), in which at least one ring in the system is aromatic. Non-limiting examples of heteroaryl rings include pyridine, quinoline, indole, and indoline.

[0087] As used herein, the terms "heterocyclyl ring" and "heterocyclyl" refer to a non-aromatic hydrocarbon containing 3 to 12 atoms (e.g., 3 to 10 atoms) in the ring, including at least one ring atom that is a heteroatom such as O, N, S, or Si and that may contain one or more unsaturated bonds. "Heterocyclyl" rings encompass monocyclic, bicyclic, tricyclic, polycyclic, bridged, fused, and spiro rings, including monospiro and dispiro rings.

[0088] "Substituted" indicates that at least one hydrogen of the "substituted" group is replaced by a substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each of the substitutable positions of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be the same or different at each position.

[0089] Examples of nitrogen protecting groups include, for example, t-butyl carbamate (Boc), benzyl (Bn), para-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 comprehensive list of nitrogen protecting groups can be found in Wuts, PGM, "Greene's Protective Groups in Organic Synthesis: Fifth Edition," 2014, John Wiley and Sons.

[0090] As used herein, "deuterated derivative" means the same chemical structure in which one or more hydrogen atoms have been replaced by deuterium atoms.

[0091] As used herein, "CFTR" means cystic fibrosis transmembrane conductance regulator.

[0092] As used herein, the terms "CFTR modulator," "CFTR-modulating compound," and "CFTR-modulating agent" refer interchangeably to compounds that directly or indirectly increase the activity of CFTR. Increased activity provided by a CFTR modulator includes, but is not limited to, compounds that correct, enhance, stabilize, and / or amplify CFTR.

[0093] As used herein, the term "CFTR corrector" refers to a compound that promotes CFTR processing and trafficking, increasing the amount of CFTR at the cell surface. Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, and Compound X disclosed herein are CFTR correctors.

[0094] As used herein, the term "CFTR potentiator" refers to a compound that increases the channel activity of the CFTR protein located on the cell surface, resulting in enhanced ion transport. The novel compounds disclosed herein are CFTR potentiators. Compound III and Compound III-d disclosed herein are CFTR potentiators.

[0095] As used herein, the terms "CFTR potentiator," "CFTR potentiator," and "CFTR co-potentiator" are used interchangeably and refer to compounds that potentiate CFTR potentiation.

[0096] As used herein, the term "active pharmaceutical ingredient" ("API") or "therapeutic agent" refers to a biologically active compound.

[0097] The terms "patient" and "subject" are used interchangeably and refer to animals, including humans.

[0098] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to the amount of a compound that, when administered, produces a desired effect (e.g., improvement in CF or symptoms of CF, or a reduction in the severity of CF or symptoms of CF). The exact amount of an effective dose will vary depending on the purpose of the treatment, and will be ascertainable by one of ordinary skill in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0099] As used herein, the terms "treatment," "treating," and the like generally refer to an improvement in one or more symptoms of CF or a reduction in the severity of CF or one or more symptoms of CF in a subject. As used herein, "treatment" includes, but is not limited to, an increase in growth, an increase in weight gain, a reduction in mucus in the lungs, an improvement in pancreatic and / or liver function, a reduction in lung infections, and / or a reduction in cough or shortness of breath in a subject. Improvement in or a reduction in the severity of any of these symptoms can be readily assessed according to standard methods and techniques known in the art.

[0100] As used herein, the term "in combination with," when referring to two or more compounds, agents, or additional active pharmaceutical ingredients, means that the two or more compounds, agents, or active pharmaceutical ingredients are administered to a patient before, simultaneously with, or after each other.

[0101] The terms "about" and "approximately," when used in reference to a dose, amount, or weight percent of a component of a composition or dosage form, include a particular dose, amount, or weight percent value, or a range of doses, amounts, or weight percents, that would be recognized by one of ordinary skill in the art as providing an equivalent pharmacological effect to that obtained from the particular dose, amount, or weight percent. The terms "about" and "approximately" may refer to an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In some embodiments, the terms "about" and "approximately" mean within 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range.

[0102] As used herein, the term "room temperature" or "ambient temperature" means 15°C to 30°C.

[0103] It is to be understood that certain compounds of the present invention may exist as separate stereoisomers or enantiomers and / or as mixtures of those stereoisomers or enantiomers. As used in the chemical structures disclosed herein, a "wedge" to a stereoatom [ka] or "hash" [ka] The bond denotes a chiral center of known absolute stereochemistry (i.e., one stereoisomer). As used in the chemical structures disclosed herein, a "wavy" bond to a stereoatom [ka] indicates a chiral center of unknown absolute stereochemistry (i.e., one stereoisomer). As used in the chemical structures disclosed herein, a "wavy" bond to a double bond carbon [ka] indicates a mixture of E / Z isomers. When used in the chemical structures disclosed herein, [ka] A ("straight") bond indicates that a mixture (e.g., a racemate or concentrate) is present. As used herein, two bonds to a double bond carbon [ka] A ("straight") bond indicates that the double bond has the E / Z stereochemistry depicted. As used in the chemical structures disclosed herein, [ka] (i.e., a "wavy" line perpendicular to the "straight" bond to group "A") indicates that group "A" is a substituent, the point of attachment of which is the terminus of the bond that terminates at the "wavy" line.

[0104] Certain compounds disclosed herein may exist as tautomers, and both tautomeric forms are intended, even if only a single tautomeric structure is represented. For example, a description of compound A is understood to include its tautomeric compound B, and vice versa, as well as mixtures thereof. [ka]

[0105] As used herein, "minimal function (MF) mutation" refers to a CFTR gene mutation associated with minimal CFTR function (a CFTR protein with little or no function), including, for example, mutations associated with a severe defect in the ability of the CFTR channel to open and close, known as a channel gating defect or "gating mutation," mutations associated with a severe defect in the cellular processing of CFTR 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.

[0106] As used herein, the term "pharmaceutically acceptable salt" refers to a salt form of a compound of the present disclosure, wherein the salt is non-toxic. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. The "free base" form of a compound does not include, for example, ionically bonded salts.

[0107] The phrase "a deuterated derivative or a pharmaceutically acceptable salt thereof" is used interchangeably with "a deuterated derivative thereof or a pharmaceutically acceptable salt of any of the foregoing" in reference to one or more compounds or formulas of the present invention. The phrase "a pharmaceutically acceptable salt and a deuterated derivative thereof" is used interchangeably with "a pharmaceutically acceptable salt and a deuterated derivative of any of the foregoing" in reference to one or more compounds or formulas of the present invention.

[0108] Those skilled in the art will recognize that when an amount of "a compound or a pharmaceutically acceptable salt thereof" is disclosed, the amount of the pharmaceutically acceptable salt form of that compound is the amount equivalent to the concentration of the free base of that compound. Note that the disclosed amounts of compounds or their pharmaceutically acceptable salts herein are based on their free base forms.

[0109] Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, 1-19. For example, Table 1 of that paper provides the following pharmaceutically acceptable salts: [Table 1]

[0110] Non-limiting examples of pharmaceutically acceptable acid addition salts include salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid, salts formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, and salts formed using other methods used 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, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and valerate salts. + (C 1-4

[0033] Suitable non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0111] Detailed Description of the Embodiments In addition to compounds of Formula I, pharmaceutically acceptable salts thereof, and deuterated derivatives of those compounds and salts, the present invention provides compounds of Formula I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing.

[0112] For example, in some embodiments, the compound of Formula I is a compound of either Formula Ia or Ib: [ka] and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein all variables are as defined for Formula I.

[0113] For example, in some embodiments, the compound of Formula I is a compound of either one of Formulas Ia' and Ib': [ka] and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein all variables are as defined for Formula I.

[0114] For example, in some embodiments, the compound of Formula I is a compound of any one of Formulas IIa, IIb, IIc, IId, IIe, and IIf: [ka] and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein all variables are as defined for Formula I.

[0115] Also disclosed herein are compounds having a formula selected from any one of the formulas represented in Table 7, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of these compounds and deuterated derivatives.

[0116] Treatment method Any of the novel compounds disclosed herein, such as compounds of Formulas I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, their deuterated derivatives, and pharmaceutically acceptable salts of any of the foregoing, can act as CFTR modulators, i.e., modulate CFTR activity in the body. Individuals suffering from mutations in the gene encoding CFTR may benefit from receiving a CFTR modulator. CFTR mutations can affect CFTR abundance, i.e., the number of CFTR channels on the cell surface, or CFTR function, i.e., the functional ability of each channel to open and transport ions. Mutations that affect CFTR abundance include mutations that cause synthesis defects (Class I defects), mutations that cause processing and trafficking defects (Class II defects), mutations that cause 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 those that cause gating defects (class III defects) and those that cause conductance defects (class IV defects). Some CFTR mutations exhibit characteristics of more than one class. Certain mutations in the CFTR gene result in cystic fibrosis.

[0117] Thus, in some embodiments, the present invention provides methods of treating, alleviating, or symptomatically treating cystic fibrosis in a patient, the methods comprising administering to the patient an effective amount of any of the novel compounds disclosed herein, such as compounds of Formulas I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing, alone or in combination with another active ingredient, e.g., another CFTR modulator. In some embodiments, the patient has the F508del / minimal function (MF) genotype, the F508del / F508del genotype (homozygous for the F508del mutation), the F508del / gating genotype, or the F508del / residual function (RF) genotype. In some embodiments, the patient is heterozygous and has one F508del mutation. In some embodiments, the patient is homozygous for the F508del mutation. In some embodiments, the patient is homozygous for the N1303K mutation. In some embodiments, the patient has a G551D mutation.

[0118] In some embodiments, between 1 mg and 1000 mg of a compound disclosed herein, a deuterated derivative thereof, or a pharmaceutically acceptable salt of the compound or deuterated derivative is administered daily.

[0119] In some embodiments, the patient is heterozygous and carries the F508del mutation in one allele and a mutation selected from Table 2 in the other allele. [Table 2-1] [Table 2-2]

[0120] In some embodiments, the present disclosure is also directed to methods of treatment using isotopically labeled compounds of the foregoing compounds or pharmaceutically acceptable salts thereof, wherein the formulas and variables of such compounds and salts are each independently as described above or in any other embodiment above, except that one or more atoms therein are replaced (isotopically labeled) by an atom having an atomic mass or mass number different from the atomic mass or mass number of the atom normally occurring in nature. Examples of isotopes that are commercially available and suitable for the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, 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 Examples include Cl.

[0121] Isotopically labeled compounds and salts can be used in a number of beneficial ways. They may be suitable for various types of assays, such as drug and / or substrate tissue distribution assays. For example, tritium ( 3 H) labeling and / or carbon-14 ( 14 C) labeled compounds are particularly useful in various types of assays, such as substrate tissue distribution assays, due to their relatively simple preparation and excellent detectability. 2 H) The labeled compound is therapeutically useful and non- 2 H-labeled compounds have potential therapeutic advantages over H-labeled compounds. 2H) Labeled compounds and salts can have higher metabolic stability than non-isotopically labeled compounds due to the kinetic isotope effect described below. Higher metabolic stability directly translates into desired increased in vivo half-life or lower dosage. Isotopically labeled compounds and salts can generally be prepared by following the procedures disclosed in the synthetic schemes and related descriptions, examples, and preparations herein, substituting readily available isotopically labeled reactants for non-isotopically labeled reactants.

[0122] In some embodiments, isotopically labeled compounds and salts contain deuterium ( 2 In some specific embodiments, isotopically labeled compounds and salts are deuterium (H) labeled compounds and salts in which one or more hydrogen atoms have been replaced by deuterium. 2 H) labeled. In the chemical structure, deuterium is 2 It is represented by "H" or "D".

[0123] In discovering and developing therapeutic agents, those skilled in the art attempt to optimize pharmacokinetic parameters while retaining desirable in vitro properties, and it may be reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism.

[0124] deuterium( 2 H) labeled compounds and salts can modulate the oxidative metabolism of compounds through the primary kinetic isotope effect. The primary kinetic isotope effect is a change in the rate of a chemical reaction resulting from the exchange of an isotope nucleus, which in turn is caused by a change in the ground state energy required for covalent bond formation after this isotope exchange. The exchange of a heavier isotope usually results in a lowering of the ground state energy of the chemical bond, and therefore a decrease in rate-limiting bond cleavage. If bond cleavage occurs within or near a saddle point region along the configuration of a multi-product reaction, the product distribution ratio can change significantly. For illustrative purposes, when deuterium is attached to a carbon atom in a non-exchangeable position, k M / k DA rate difference of 2 to 7 is typical. For further discussion, see S.L. Harbeson and R.D. Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417, which is incorporated herein by reference in its entirety.

[0125] The concentration of an isotope (e.g., deuterium) incorporated into the isotopically labeled compounds and salts of the present disclosure can be defined by the isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specified isotope. In some embodiments, when a substituent of a compound of the present disclosure is represented by deuterium, such compounds have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0126] Combination therapy One aspect disclosed herein provides methods of treating cystic fibrosis and other CFTR-mediated diseases using any of the novel compounds disclosed herein, such as compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing, in combination with at least one additional active pharmaceutical ingredient.

[0127] Thus, in some embodiments, the present invention provides methods of treating, alleviating, or symptomatically treating cystic fibrosis in a patient, the methods comprising administering to the patient an effective amount of any of the novel compounds disclosed herein, such as compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of these compounds and deuterated derivatives, alone or in combination with at least one additional active pharmaceutical ingredient, such as a CFTR modulator.

[0128] In some embodiments, the at least one additional active pharmaceutical ingredient is selected from a mucolytic agent, a bronchodilator, an antibiotic, an anti-infective, and an anti-inflammatory.

[0129] In some embodiments, the additional therapeutic agent is an antibiotic. Exemplary antibiotics useful herein include tobramycin, including tobramycin inhalation powder (TIP), azithromycin, aztreonam, including an aerosolized form of aztreonam, amikacin, including a liposomal formulation of amikacin, ciprofloxacin, including a formulation of ciprofloxacin suitable for administration by inhalation, levofloxacin, including an aerosolized formulation of levofloxacin, and a combination of two antibiotics, such as fosfomycin and tobramycin.

[0130] In some embodiments, the additional agent is a mucolytic agent. Exemplary mucolytic agents useful herein include Pulmozyme®.

[0131] In some embodiments, the additional agent is a bronchodilator. Exemplary bronchodilators include albuterol, metaproterenol sulfate, pirbuterol acetate, salmeterol, or tetrabuline sulfate.

[0132] In some embodiments, the additional agent is an anti-inflammatory agent, i.e., an agent that can reduce inflammation in the lungs. Examples of such agents useful herein include ibuprofen, docosahexaenoic acid (DHA), sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine, or simavastatin.

[0133] In some embodiments, the additional agent is a nutritional agent. Exemplary nutritional agents include pancrelipase (pancreatic enzyme replacement), including Pancrease®, Pancreacarb®, Ultrase®, or Creon®, Liprotomase® (formerly Trizytek®), Aquadeks®, or glutathione inhalation. In one embodiment, the additional nutritional agent is pancrelipase.

[0134] In some embodiments, the at least one additional active pharmaceutical ingredient is selected from a CFTR modulator. In some embodiments, the CFTR modulator is a CFTR corrector. In some embodiments, the CFTR modulator is a CFTR potentiator / co-potentiator (e.g., ASP-11). In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR amplifier. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR readthrough agent. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR nucleic acid therapy.

[0135] In some embodiments, at least one additional active pharmaceutical ingredient is an ENaC inhibitor. In some embodiments, at least one additional active pharmaceutical ingredient is a TMEM16A modulator. In some embodiments, at least one additional active pharmaceutical ingredient is a GPR39 agonist.

[0136] In some embodiments, the at least one additional active pharmaceutical ingredient is selected from (a) Compound II and its deuterated derivatives and pharmaceutically acceptable salts, (b) Compound IV and its deuterated derivatives and pharmaceutically acceptable salts, (c) Compound V and its deuterated derivatives and pharmaceutically acceptable salts, (d) Compound VI and its deuterated derivatives and pharmaceutically acceptable salts, (e) Compound VII and its deuterated derivatives and pharmaceutically acceptable salts, and (f) Compound VIII and its deuterated derivatives and pharmaceutically acceptable salts. Thus, in some embodiments, the combination therapies provided herein include a compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, deuterated derivatives of these compounds, and pharmaceutically acceptable salts of any of the foregoing compounds and deuterated derivatives, and at least one compound selected from Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives and pharmaceutically acceptable salts thereof. In some embodiments, the combination therapy provided herein includes: (a) at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, deuterated derivatives of these compounds, and pharmaceutically acceptable salts of any of the foregoing compounds and deuterated derivatives; (b) at least one compound selected from Compound II, Compound IV, and pharmaceutically acceptable salts and deuterated derivatives thereof; and (c) at least one compound selected from Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives and pharmaceutically acceptable salts thereof.In some embodiments, the combination therapy provided herein includes: (a) at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, deuterated derivatives of these compounds, and pharmaceutically acceptable salts of any of the foregoing compounds and deuterated derivatives; (b) at least one compound selected from compound II and pharmaceutically acceptable salts and deuterated derivatives thereof; and (c) at least one compound selected from compound VII and deuterated derivatives and pharmaceutically acceptable salts thereof.

[0137] In some embodiments, the combination therapy provided herein comprises (a) a compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, Compounds 1-271, deuterated derivatives of these compounds, and pharmaceutically acceptable salts of any of the foregoing compounds and deuterated derivatives; (b) at least one compound selected from Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives and pharmaceutically acceptable salts thereof; and (c) a compound described in WO2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO2017 / 062581, Phuan, P.-W. et al. al.J.Cyst.Fibros.2018,17(5),595-606, Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640, Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32, Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,EJet al.PLoS One 2019, 14(12), e0223954; Smith, NJ, Solovay, CF, Pharm. Pat. Anal. 2017, 6(4), 179-188; Kunzelmann, K. et al., Front. Pharmacol. 2019, 10, 3; or Son, J.-H. et al., Eur. J. of Med. Chem. 2020, 112888.

[0138] In some embodiments, the combination therapy provided herein comprises (a) a compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, Compounds 1-271, deuterated derivatives of these compounds, and pharmaceutically acceptable salts of any of the foregoing compounds and deuterated derivatives; (b) at least one compound selected from Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives and pharmaceutically acceptable salts thereof; and (c) at least one compound selected from PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, FDL-169, ARN5562, ARN 21586, ARN22081, ARN22652, ARN23765, ARN23766, PTI-801, FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2 451 / ABBV-2451, QBW251(Icenticaftor), GLPG3067 / ABBV-3067(Navocaftor), ABBV-191, ELX-02, MRT5005 , Lunar-CF, RCT223, amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI1265162, ARO-ENaC1001, ETD002, and at least one compound selected from DS-1039.

[0139] In some embodiments, the combination therapy provided herein comprises (a) a compound selected from the group consisting of compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, deuterated derivatives of these compounds, and pharmaceutically acceptable salts of any of the foregoing compounds and deuterated derivatives; and (b) a compound selected from the group consisting of compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, deuterated derivatives of these compounds, and pharmaceutically acceptable salts of any of the foregoing compounds and deuterated derivatives, and compounds of Formula I, I', Ia, Ib ... , WO2015 / 160787, WO2007 / 056341, WO2009 / 073757, WO2009 / 076142, WO2018 / 107 100, WO2019 / 113476, WO2018 / 064632, WO2019 / 152940, WO2016 / 057572, WO2021 / 0 30554, WO2020 / 206080, WO2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO2017 / 062581, Phuan, P.-W. et al.J.Cyst.Fibros.2018,17(5),595-606, Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640, Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32, Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,EJet al.PLoS One 2019, 14(12), e0223954; Smith, NJ, Solovay, CF, Pharm. Pat. Anal. 2017, 6(4), 179-188; Kunzelmann, K. et al., Front. Pharmacol. 2019, 10, 3; or Son, J.-H. et al., Eur. J. of Med. Chem. 2020, 112888.

[0140] In some embodiments, the combination therapy provided herein comprises (a) a compound selected from the group consisting of compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, Compounds 1-271, deuterated derivatives of these compounds, and pharmaceutically acceptable salts of any of the foregoing compounds and deuterated derivatives; and (b) a compound selected from the group consisting of Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, ARN 23766, PTI-801, FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW251(Icenticaftor ), GLPG3067 / ABBV-3067(Navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, Amiloride, ETD001, and at least two compounds selected from CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI1265162, ARO-ENaC1001, ETD002, and DS-1039, and deuterated derivatives and pharmaceutically acceptable salts thereof.

[0141] In some embodiments, at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, deuterated derivatives of these compounds, and pharmaceutically acceptable salts of any of the foregoing compounds and deuterated derivatives, is administered in combination with at least one compound selected from Compound II and its deuterated derivatives and pharmaceutically acceptable salts. In some embodiments, at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, deuterated derivatives of these compounds, and pharmaceutically acceptable salts of these compounds and deuterated derivatives, is administered in combination with at least one compound selected from Compound IV and its deuterated derivatives and pharmaceutically acceptable salts. In some embodiments, at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, deuterated derivatives of these compounds, and pharmaceutically acceptable salts of these compounds and deuterated derivatives, is administered in combination with at least one compound selected from Compound V and deuterated derivatives and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, deuterated derivatives of these compounds, and pharmaceutically acceptable salts of any of these compounds and deuterated derivatives, is administered in combination with at least one compound selected from Compound VI and deuterated derivatives and pharmaceutically acceptable salts thereof.In some embodiments, at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, deuterated derivatives of these compounds, and pharmaceutically acceptable salts of any of the foregoing compounds and deuterated derivatives, is administered in combination with at least one compound selected from Compound VII and deuterated derivatives and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, deuterated derivatives of these compounds, and pharmaceutically acceptable salts of any of the foregoing compounds and deuterated derivatives, is administered in combination with at least one compound selected from Compound VIII and deuterated derivatives and pharmaceutically acceptable salts thereof.

[0142] Each of the compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, Compounds 1-271, Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, and Compound X, and deuterated derivatives and pharmaceutically acceptable salts thereof, can be independently administered once daily, twice daily, or three times daily. In some embodiments, at least one compound selected from the compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, Compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof, is administered once daily. In some embodiments, at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof, is administered twice daily. In some embodiments, at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one compound selected from compound II and a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one compound selected from Compound II and pharmaceutically acceptable salts thereof, are administered twice daily. In some embodiments, at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one compound selected from Compound IV and pharmaceutically acceptable salts thereof, are administered once daily.In some embodiments, at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one compound selected from Compound IV and pharmaceutically acceptable salts thereof, are administered twice daily. In some embodiments, at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one compound selected from Compound V and pharmaceutically acceptable salts thereof, are administered once daily. In some embodiments, at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one compound selected from Compound V and pharmaceutically acceptable salts thereof, are administered twice daily. In some embodiments, at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one compound selected from Compound VI and pharmaceutically acceptable salts thereof, are administered once daily. In some embodiments, at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one compound selected from Compound VI and pharmaceutically acceptable salts thereof, are administered twice daily. In some embodiments, at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one compound selected from Compound VII and pharmaceutically acceptable salts thereof, are administered once daily.In some embodiments, at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one compound selected from Compound VII and pharmaceutically acceptable salts thereof, are administered twice daily. In some embodiments, at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one compound selected from Compound VIII and pharmaceutically acceptable salts thereof, are administered once daily. In some embodiments, at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one compound selected from compound VIII and pharmaceutically acceptable salts thereof, are administered twice daily.

[0143] In some embodiments, at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, Compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof, at least one compound selected from Compound II, Compound IV, and pharmaceutically acceptable salts thereof, and at least one compound selected from Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts thereof are administered once daily. In some embodiments, at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, Compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof, at least one compound selected from Compound II, Compound IV, and pharmaceutically acceptable salts thereof, and at least one compound selected from Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts thereof are administered twice daily. In some embodiments, at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof, at least one compound selected from Compound II and pharmaceutically acceptable salts thereof, and at least one compound selected from Compound VII and pharmaceutically acceptable salts thereof are administered once daily. In some embodiments, at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof, at least one compound selected from Compound II and pharmaceutically acceptable salts thereof, and at least one compound selected from Compound VII and pharmaceutically acceptable salts thereof are administered twice daily.

[0144] The compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, Compounds 1-271, Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and their deuterated derivatives 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 daily or multiple times daily, for example, twice daily. As used herein, the phrase "a given amount of API (e.g., Compound II, Compound VII, or a pharmaceutically acceptable salt thereof) administered daily or once or twice per day" means that the given amount is administered per dose, and that this dose can occur once or twice daily.

[0145] In some embodiments, at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof, is administered in a first pharmaceutical composition, and at least one compound selected from compound VII and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition.

[0146] In some embodiments, at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof, is administered in a first pharmaceutical composition, at least one compound selected from compound II and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition, and at least one compound selected from compound VII and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.

[0147] Any suitable pharmaceutical composition known in the art can be used for compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, Compounds 1-271, Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives and pharmaceutically acceptable salts thereof. Some exemplary pharmaceutical compositions of Compound II and its pharmaceutically acceptable salts can be found in WO2011 / 119984 and WO2014 / 014841, which are incorporated herein by reference. Some exemplary pharmaceutical compositions of Compound III and its pharmaceutically acceptable salts can be found in WO2007 / 134279, WO2010 / 019239, WO2011 / 019413, WO2012 / 027731, and WO2013 / 130669, and some exemplary pharmaceutical compositions of Compound III-d and its pharmaceutically acceptable salts can be found in US8,865,902, US9,181,192, US9,512,079, WO2017 / 053455, and WO2018 / 080591, all of which are incorporated herein by reference. Some exemplary pharmaceutical compositions of Compound IV and its pharmaceutically acceptable salts can be found in WO2010 / 037066, WO2011 / 127421, and WO2014 / 071122, which are incorporated herein by reference. Some exemplary pharmaceutical compositions of Compound V and its pharmaceutically acceptable salts can be found in WO2019 / 152940, which are incorporated herein by reference. Some exemplary pharmaceutical compositions of Compound VI and its pharmaceutically acceptable salts can be found in WO2019 / 079760, which are incorporated herein by reference.

[0148] Pharmaceutical Composition Another aspect of the present invention provides a pharmaceutical composition comprising at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.

[0149] In some embodiments, the present invention provides pharmaceutical compositions comprising at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof, 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 at least one additional active pharmaceutical ingredient is a compound that enhances CFTR potentiation, i.e., a CFTR potentiator / co-potentiator. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR amplifier. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR readthrough agent. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR nucleic acid therapy. In some embodiments, at least one additional active pharmaceutical ingredient is an ENaC inhibitor. In some embodiments, at least one additional active pharmaceutical ingredient is a TMEM16A modulator. In some embodiments, at least one additional active pharmaceutical ingredient is a GPR39 agonist. In some embodiments, the pharmaceutical composition comprises at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least two additional active pharmaceutical ingredients, each of which is a CFTR corrector. In some embodiments, the pharmaceutical composition comprises at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least two additional active pharmaceutical ingredients, one of which is a CFTR corrector and one of which is a CFTR potentiator.

[0150] In some embodiments, the present invention provides pharmaceutical compositions comprising: (a) at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof; (b) at least one compound selected from Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts thereof; and (c) at least one pharmaceutically acceptable carrier.

[0151] In some embodiments, the present invention provides pharmaceutical compositions comprising: (a) at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof; (b) at least one compound selected from compound II and pharmaceutically acceptable salts thereof; and (c) at least one pharmaceutically acceptable carrier.

[0152] In some embodiments, the present invention provides pharmaceutical compositions comprising: (a) at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof; (b) at least one compound selected from compound VII and pharmaceutically acceptable salts thereof; and (c) at least one pharmaceutically acceptable carrier.

[0153] In some embodiments, the present disclosure provides pharmaceutical compositions comprising: (a) at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof; (b) at least one compound selected from Compound II, Compound IV, and pharmaceutically acceptable salts thereof; (c) at least one compound selected from Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts thereof; and (d) at least one pharmaceutically acceptable carrier.

[0154] In some embodiments, the present disclosure provides pharmaceutical compositions comprising: (a) at least one compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof; (b) at least one compound selected from compound II and pharmaceutically acceptable salts thereof; (c) at least one compound selected from compound VII and pharmaceutically acceptable salts thereof; and (d) at least one pharmaceutically acceptable carrier.

[0155] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) a compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, Compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof; (b) at least one compound selected from Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof; and (c) a compound selected from compounds described in WO2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO2017 / 062581, Phuan, P.-W. et al. al.J.Cyst.Fibros.2018,17(5),595-606, Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640, Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32, Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,EJet al.PLoS One 2019, 14(12), e0223954; Smith, NJ, Solovay, CF, Pharm.Pat.Anal. 2017, 6(4), 179-188; Kunzelmann, K. et al., Front.Pharmacol. 2019, 10, 3; or Son, J.-H. et al., Eur.J.of Med.Chem. 2020, 112888; and (d) at least one pharmaceutically acceptable carrier.

[0156] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) a compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, Compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof; (b) at least one compound selected from Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof; and (c) PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, AR16061, AR16061, AR16062, AR16063, AR16064, AR16065, AR16066, AR16067, AR16068, AR16069 ... N23765, ARN23766, PTI-801, FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW251(Icen ticaftor), GLPG3067 / ABBV-3067(Navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, Amiloride, E at least one compound selected from TD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI1265162, ARO-ENaC1001, ETD002, and DS-1039; and (d) at least one pharmaceutically acceptable carrier.

[0157] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) a compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof; and (b) a compound selected from compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof, and compounds 1-271, as described in WO2019 / 195739, WO2019 / 200246, WO2021 / 030555, WO2021 / 030556, WO2010 / 053471, WO2011 / 119984, WO2011 / 133751, WO2011 / 133951, WO2015 / 160787 , WO2007 / 056341, WO2009 / 073757, WO2009 / 076142, WO2018 / 107100, WO2019 / 113476, WO2018 / 064632, WO2019 / 152940, WO2016 / 057572, WO2021 / 030554, WO2020 / 206080, WO2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO2017 / 062581, Phuan, P.-W. et al.J.Cyst.Fibros.2018,17(5),595-606, Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640, Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32, Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,EJet al.PLoS One 2019, 14(12), e0223954; Smith, NJ, Solovay, CF, Pharm. Pat. Anal. 2017, 6(4), 179-188; Kunzelmann, K. et al., Front. Pharmacol. 2019, 10, 3; or Son, J.-H. et al., Eur. J. of Med. Chem. 2020, 112888; and (c) at least one pharmaceutically acceptable carrier.

[0158] In some embodiments, the pharmaceutical compositions provided herein comprise a compound selected from the group consisting of: (a) compounds of Formula I, I', Ia, Ib, Ia', Ib', IIa, IIb, IIc, IId, IIe, and IIf, Compounds 1-271, and deuterated derivatives and pharmaceutically acceptable salts thereof; and (b) Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV -119, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, ARN23766, PTI-801, FDL-176, PTI- 808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW251(Icenticaftor), GLPG3067 / ABBV-3067(Navoc aftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, Amiloride, ETD001, CF552, GS-9411, GS-5737, P-1 037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI1265162, ARO-ENaC1001, ETD002, and DS-1039, and pharmaceutically acceptable salts and deuterated derivatives thereof; and (c) at least one pharmaceutically acceptable carrier.

[0159] Any pharmaceutical composition disclosed herein may include at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable vehicle and a pharmaceutically acceptable adjuvant. In some embodiments, the at least one pharmaceutically acceptable is selected from a pharmaceutically acceptable filler, disintegrant, surfactant, binder, or lubricant.

[0160] The pharmaceutical compositions described herein are useful for the treatment of cystic fibrosis and other CFTR-mediated diseases.

[0161] As mentioned above, the pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be selected from adjuvants and vehicles. As used herein, at least one pharmaceutically acceptable carrier includes any solvent, diluent, other liquid vehicle, dispersion aid, suspension aid, surfactant, isotonicity agent, thickener, emulsifier, preservative, solid binder, and lubricant suitable for the desired specific dosage form. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C.B. Boylan, 1988-1999, Marcel Dekker, New York, disclose various carriers used in formulating pharmaceutical compositions and known techniques for their preparation. Except insofar as any conventional carrier is incompatible with the compounds of the present disclosure, for example, by imparting any undesirable biological effect or otherwise interacting in a deleterious manner with any other component of the pharmaceutical composition, its use is contemplated within the scope of the present disclosure.Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., carboxymethylcellulose), and the like. Examples of suitable additives include, but are not limited to, cellulose acetate, cellulose acetate, maltose, ethylcellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository waxes), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (e.g., propylene glycol and polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solution, non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweetening agents, flavoring agents, fragrances, preservatives, and antioxidants.

[0162] Non-limiting exemplary embodiments 1. A compound selected from compounds of formula I: [ka] and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein: X is -C(R X1 )2-, -CO-, [ka] -Si(R Z3 )2-, and [ka] is selected from Ring A is a cyclic group selected from phenyl and 5- to 6-membered heteroaryl, which cyclic group is optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl; Each R X1 H, C1-C6 alkyl (oxo, -OR X2 , and -N(R X2 ) optionally substituted with 1 to 3 groups independently selected from 2), C3-C8 cycloalkyl, halogen, cyano, -OR X2 and C1-C6 fluoroalkyl; Each R X2 are independently selected from H and C1-C6 alkyl; Each Y is -C(R Y )2-, -O-, -CO-, -NR YN - and [ka] are independently selected from Each R Y is hydrogen, hydroxy, halogen, C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from hydroxy, C1-C6 alkoxy, and Q), C3-C8 cycloalkyl, C6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from halogen), 5 to 10 membered heteroaryl, -OR Y1 , -CO2R Y1 , -COR Y1 , -CON(R Y1 )2, and -N(R Y1 )2 are independently selected from or two R, one on one atom and the other on an adjacent atom Y together to form a pi bond, Each R Y1are independently selected from hydrogen and C1-C6 alkyl, or two R Y1 together form a 3- to 6-membered heterocyclyl, Each R YN but, ■H and ■ C1-C6 alkyl, o-oxo, C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogen and C1-C6 alkyl); oC6-C 10 aryl, ◆Halogen, ◆Cyano, C1-C6 alkyl (optionally substituted with 1 to 3 hydroxy); ◆C1-C6 fluoroalkyl, C1-C6 alkoxy (optionally substituted with C3-C8 cycloalkyl optionally substituted with C1-C6 fluoroalkyl), ◆C1-C6 fluoroalkoxy, C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogen, C1-C6 alkyl, and C1-C6 fluoroalkyl), and phenyl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, and halogen); C6-C optionally substituted with 1 to 3 groups independently selected from 10 aryl, o 5-10 membered heteroaryl, ◆Halogen, ◆C1-C6 alkyl, ◆C1-C6 fluoroalkyl, ◆C1-C6 fluoroalkoxy, ◆-O (0-1) (C3-C8 cycloalkyl)(optionally substituted with C1-C6 fluoroalkyl), and ◆ 3- to 12-membered heterocyclyl; o 3- to 12-membered heterocyclyl optionally substituted with 1-3 groups selected from halogen and C1-C6 alkyl; and ■ C1-C6 fluoroalkyl, ■C6-C 10 aryl and ■ C3-C8 cycloalkyl, oHalogen, o cyano, oN(R YN1 ) C1-C4 alkyl optionally substituted with 1 to 3 groups selected from 2; o C1-C6 fluoroalkyl, o C1-C6 alkoxy, C3-C8 cycloalkyl, and o phenyl (optionally substituted with 1 to 3 groups independently selected from C-C alkyl); ■ 3- to 12-membered heterocyclyl optionally substituted with 1 to 3 groups selected from oxo and C1-C4 alkyl (optionally substituted with 1 to 2 groups selected from oxo and C3-C8 cycloalkyl); ■ 5-6 membered heteroaryl (optionally substituted with 1 to 3 groups selected from C1-C6 alkyl), ■CO2R YN1 and are selected independently from Each R YN1 is independently selected from H, C1-C4 alkyl (optionally substituted with oxo), and C3-C6 cycloalkyl; Ring B is ■C6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy); ■ C3-C8 cycloalkyl, ■ 5- to 10-membered heteroaryl, and ■ 3- to 6-membered heterocyclyl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl), Each Q is ■ C1-C6 alkyl, oHalogen, o-oxo, oC6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from halogen and —OCF3), and o C3-C8 cycloalkyl; and C1-C6 alkyl optionally substituted with 1 to 3 groups independently selected from: ■ C3-C8 cycloalkyl, oHalogen, oCN, C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogen, -NH2, and -NHCOMe); o C1-C6 alkoxy, oC6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl), and o C3-C8 cycloalkyl, optionally substituted with 1 to 3 groups independently selected from: C3-C8 cycloalkyl; ■C6-C 10 aryl, oHalogen, oCN, o C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogen and hydroxy); o C1-C6 alkoxy, ◆Halogen, C1-C6 alkoxy optionally substituted with 1 to 4 groups independently selected from C3-C8 cycloalkyl (optionally substituted with CF3); oC3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogen, CF3, OCF3, and C1-C6 alkyl), and oC6-C 10 C-C optionally substituted with 1 to 3 groups independently selected from aryl, 10 aryl and ■ 5- to 10-membered heteroaryl, oHalogen, o C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogen); C3-C8 cycloalkyl (optionally substituted with 1 to 3 CF3 groups), and o 3- to 10-membered heterocyclyl; and ■ 3- to 10-membered heterocyclyl, o C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from oxo and C3-C8 cycloalkyl), and oxo; and 3- to 10-membered heterocyclyl optionally substituted with 1 to 3 groups independently selected from Each R 1 However, halogen, C1-C6 fluoroalkyl, C1-C6 alkyl (hydroxy, C6-C 10 aryl, and 5- to 6-membered heteroaryl), -OR 2 , -N(R 2 )2, -CO2R 2 , -CO-N(R 2 )2, -CN, C3-C8 cycloalkyl, C6-C 10 aryl, 5- to 6-membered heteroaryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl), 3- to 6-membered heterocyclyl, -B(OR 2 )2, -SO2R 2 , -SR 2 , -SOR 2 , -PO(OR 2 )2, and -PO(R2 )2 are independently selected from Each R 2 is selected from hydrogen, C1-C6 alkyl (optionally substituted with 1 to 6 groups independently selected from halogen), C1-C6 fluoroalkyl, and C6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 fluoroalkyl and C1-C6 fluoroalkoxy); Z, [ka] is selected from In the formula, ring C is C6-C 10 selected from aryl and 5- to 10-membered heteroaryl; R Z1 is hydrogen, —CN, C1-C6 alkyl (optionally substituted with 1 to 3 hydroxy), C1-C6 fluoroalkyl, 3- to 6-membered heterocyclyl, C3-C6 cycloalkyl, C6-C 10 aryl, and 5- to 6-membered heteroaryl; R Z2 is hydrogen, halogen, hydroxy, NH2, NH(CO)(C1-C6 alkyl), and C1-C6 alkoxy (C3-C 10 optionally substituted with 1 to 3 groups independently selected from cycloalkyl; or R Z1 and R Z2 together form a group selected from oxo and =N-OH, Each R Z3 is hydroxy, C1-C6 alkoxy, C1-C6 alkyl, and C6-C 10 aryl, or two R Z3 together form a 3- to 6-membered heterocyclyl, n is selected from 4, 5, 6, 7, and 8; Compounds, and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein m is selected from 0, 1, 2, and 3.

[0163] 1a. A compound selected from compounds of formula I': [ka] and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein: X is -C(R X1 )2-, -CO-, [ka] -Si(R Z3 )2-, and [ka] is selected from Ring A is a cyclic group selected from phenyl and 5- to 6-membered heteroaryl, which cyclic group is optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl; Each R X1 H, C1-C6 alkyl (oxo, -OR X2 , and -N(R X2 ) optionally substituted with 1 to 3 groups independently selected from 2), C3-C8 cycloalkyl, halogen, cyano, -OR X2 and C1-C6 fluoroalkyl; Each R X2 are independently selected from H and C1-C6 alkyl; Each Y is -C(R Y )2-, -O-, -CO-, -NR YN - and [ka] are independently selected from Each R Y is hydrogen, hydroxy, halogen, C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from hydroxy, C1-C6 alkoxy, and Q), C3-C8 cycloalkyl, C6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from halogen), 5 to 10 membered heteroaryl, -ORY1 , -CO2R Y1 , -COR Y1 , -CON(R Y1 )2, and -N(R Y1 )2 are independently selected from or two R, one on one atom and the other on an adjacent atom Y together to form a pi bond, Each R Y1 are independently selected from hydrogen and C1-C6 alkyl, or two R Y1 together form a 3- to 6-membered heterocyclyl, Each R YN but, ■H and ■ C1-C6 alkyl, o-oxo, C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogen and C1-C6 alkyl); oC6-C 10 aryl, ◆Halogen, ◆Cyano, C1-C6 alkyl (optionally substituted with 1 to 3 hydroxy); ◆C1-C6 fluoroalkyl, C1-C6 alkoxy (optionally substituted with C3-C8 cycloalkyl optionally substituted with C1-C6 fluoroalkyl), ◆C1-C6 fluoroalkoxy, C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogen, C1-C6 alkyl, and C1-C6 fluoroalkyl), and phenyl (optionally substituted with C1-C6 alkyl), C6-C 10 aryl, o 5-6 membered heteroaryl, ◆Halogen, ◆C1-C6 alkyl, ◆C1-C6 fluoroalkyl, ◆C1-C6 fluoroalkoxy, ◆-O (0-1) (C3-C8 cycloalkyl)(optionally substituted with C1-C6 fluoroalkyl), and ◆ 3- to 12-membered heterocyclyl; o 3- to 12-membered heterocyclyl optionally substituted with 1-3 groups selected from halogen and C1-C6 alkyl; and ■ C1-C6 fluoroalkyl, ■C6-C 10 aryl and ■ C3-C8 cycloalkyl, oHalogen, o cyano, oN(R YN1 ) C1-C4 alkyl optionally substituted with 1 to 3 groups selected from 2; o C1-C6 fluoroalkyl, o C1-C6 alkoxy, C3-C8 cycloalkyl, and o phenyl (optionally substituted with 1 to 3 groups independently selected from C-C alkyl); ■ 3- to 12-membered heterocyclyl optionally substituted with 1 to 3 groups selected from oxo and C1-C4 alkyl (optionally substituted with 1 to 2 groups selected from oxo and C3-C8 cycloalkyl); ■ 5-6 membered heteroaryl (optionally substituted with 1 to 3 groups selected from C1-C6 alkyl), ■CO2R YN1 and are selected independently from Each R YN1 is independently selected from H, C1-C4 alkyl (optionally substituted with oxo), and C3-C6 cycloalkyl; Ring B is ■C6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy); ■ C3-C8 cycloalkyl, ■ 5- to 10-membered heteroaryl, and ■ 3- to 6-membered heterocyclyl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl), Each Q is ■ C1-C6 alkyl, oHalogen, o-oxo, oC6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from halogen and —OCF3), and o C3-C8 cycloalkyl; and C1-C6 alkyl optionally substituted with 1 to 3 groups independently selected from: ■ C3-C8 cycloalkyl, oHalogen, oCN, C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogen, -NH2, and -NHCOMe); o C1-C6 alkoxy, oC6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl), and o C3-C8 cycloalkyl, optionally substituted with 1 to 3 groups independently selected from: C3-C8 cycloalkyl; ■C6-C 10 aryl, oHalogen, oCN, o C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogen and hydroxy); o C1-C6 alkoxy, ◆Halogen, C1-C6 alkoxy optionally substituted with 1 to 4 groups independently selected from C3-C8 cycloalkyl (optionally substituted with CF3); oC3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogen, CF3, OCF3, and C1-C6 alkyl), and oC6-C 10 C-C optionally substituted with 1 to 3 groups independently selected from aryl, 10 aryl and ■ 5- to 10-membered heteroaryl, oHalogen, o C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogen); C3-C8 cycloalkyl (optionally substituted with 1 to 3 CF3 groups), and o 3- to 10-membered heterocyclyl; and ■ 3- to 10-membered heterocyclyl, o C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from oxo and C3-C8 cycloalkyl), and oxo; and 3- to 10-membered heterocyclyl optionally substituted with 1 to 3 groups independently selected from Each R 1 However, halogen, C1-C6 fluoroalkyl, C1-C6 alkyl (hydroxy, C6-C 10 aryl, and 5- to 6-membered heteroaryl), -OR 2 , -N(R 2 )2, -CO2R 2 , -CO-N(R 2 )2, -CN, C3-C8 cycloalkyl, C6-C 10 aryl, 5- to 6-membered heteroaryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl), 3- to 6-membered heterocyclyl, -B(OR 2 )2, -SO2R2 , -SR 2 , -SOR 2 , -PO(OR 2 )2, and -PO(R 2 )2 are independently selected from Each R 2 is selected from hydrogen, C1-C6 alkyl (optionally substituted with 1 to 6 groups independently selected from halogen), C1-C6 fluoroalkyl, and C6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 fluoroalkyl and C1-C6 fluoroalkoxy); Z, [ka] is selected from In the formula, ring C is C6-C 10 selected from aryl and 5- to 10-membered heteroaryl; R Z1 is hydrogen, —CN, C1-C6 alkyl (optionally substituted with 1 to 3 hydroxy), C1-C6 fluoroalkyl, 3- to 6-membered heterocyclyl, C3-C6 cycloalkyl, C6-C 10 aryl, and 5- to 6-membered heteroaryl; R Z2 is hydrogen, halogen, hydroxy, NH2, NH(CO)(C1-C6 alkyl), and C1-C6 alkoxy (C3-C 10 optionally substituted with 1 to 3 groups independently selected from cycloalkyl; or R Z1 and R Z2 together form a group selected from oxo and =N-OH, Each R Z3 is hydroxy, C1-C6 alkoxy, C1-C6 alkyl, and C6-C 10 aryl, or two R Z3 together form a 3- to 6-membered heterocyclyl, n is selected from 4, 5, 6, 7, and 8; Compounds, and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein m is selected from 0, 1, 2, and 3.

[0164] 2. The compound, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1 or embodiment 1a, wherein Ring A is a cyclic group selected from phenyl, pyrazole, and oxadiazole.

[0165] 3.Each R X1 H, C1-C6 alkyl, halogen, cyano, -OR X2 and C1-C6 fluoroalkyl.

[0166] 4.Each R X2 is independently selected from H and C1-C4 alkyl.

[0167] 5.Each R X1 is independently selected from H, F, —CF3, —CH3, —OH, —OCH3, and CN.

[0168] 6.X is -CO-, -CH2-, [ka] 6. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-5, selected from:

[0169] 7. Each Y is -C(R Y )2-, -CO-, -NR YN - and [ka] 7. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-6, independently selected from:

[0170] 8.Each R Y The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-7, wherein is independently selected from hydrogen, hydroxy, halogen, and C1-C6 alkyl.

[0171] 9.Each R Y But, H, The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-8, wherein: -OH, -F, and -CH3 are independently selected from:

[0172] 10.R YN but, ■H and ■-CH2CF3 and ■ C1-C6 alkyl, o-oxo, o-cyclopropyl, o cyclobutyl optionally substituted with 1 to 2 fluoro groups; o cyclohexyl optionally substituted with 1 to 2 fluoro groups; o spiro[2.2]pentane, o-bicyclo[4.1.0]heptane, o-dispiro[2.0.24.13]heptane, oF, Cl, Br, CN, methyl, propyl (optionally substituted with one hydroxy), tert-butyl, neopentyl, -CHF2, -CF3, -C(CH3)2CF3, -OCH3, -O(2-propyl), -OCHF2, -OCF3, -OCF2CHF2, -OCH2CF3, cyclopropyl (optionally substituted with one CF3), cyclobutyl (optionally substituted with 1 to 2 groups selected from fluoro and methyl), spiro[2.2]pentane, bicyclo[1.1.1]pentane, bicyclo[4.1.0]heptane, dispiro[2.0.24.13]heptane, phenyl, naphthyl, and [ka] phenyl optionally substituted with 1 to 3 groups independently selected from o-naphthyl, o 2,2-dimethyl-2,3-dihydrobenzofuran, o2,2-difluorobenzo[d][1,3]dioxole, o tetrahydro-2H-pyran, pyrazole optionally substituted with one group selected from methyl and propyl; pyridine optionally substituted with one group selected from o-methyl, tert-butyl, CF3, -O(cyclobutyl), -OCHF2, cyclopropyl optionally substituted with one CF3, and piperidine; and pyrimidine optionally substituted with one group selected from methyl and tert-butyl; Cyclopropyl optionally substituted with 1 to 2 groups selected from methyl, tert-butyl, cyclopropyl, and phenyl (optionally substituted with one tert-butyl group); Cyclobutyl optionally substituted with 1 to 3 groups selected from fluoro, methyl, and phenyl; Cyclopentyl and Cyclohexyl optionally substituted with 1 to 2 groups selected from fluoro, methyl, tert-butyl, cyano, -CF3, -CH2NH2, and -CH2NHAc; bicyclo[1.1.1]pentane optionally substituted with one group selected from fluoro, methyl, and tert-butyl; a bicyclo[2.2.1]heptane optionally substituted with one -OCH3 group; Bicyclo[2.2.2]octane, ■ spiro[3.3]heptane optionally substituted with 1 to 2 fluoro groups; ■ Phenyl and Tetrahydro-2H-pyran, 2-azaspiro[3.3]heptane optionally substituted with one group selected from -COMe and -CO(cyclopropyl); ■ Thietane 1,1-dioxide, ■ Tetrahydro-2H-thiopyran 1,1-dioxide, a pyrazole optionally substituted with one methyl group; ■ A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 9, independently selected from pyridine and

[0173] 11.Each R YN but, H, -CH3, [ka] [ka] [ka] [ka] [ka] The compound of any one of embodiments 1-10, independently selected from:

[0174] 12. Ring B is ■C6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from halogen); ■C3-C8 cycloalkyl and ■ A compound, deuterated derivative, or pharmaceutically acceptable salt described in any one of embodiments 1 to 11 selected from 3- to 6-membered heterocyclyl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl).

[0175] 13. Ring B is [ka] 13. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-12, selected from:

[0176] 14.Each R 2 The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-13, wherein is H.

[0177] 15.Each R 1 is C1-C6 fluoroalkyl, -N(R 2 15. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-14, wherein:

[0178] 16.Each R 1 But -CF3, 16. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-15, independently selected from: —NH 2 , and —CN.

[0179] 17.R Z1 The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-16, wherein is selected from C1-C6 fluoroalkyl.

[0180] 18.R Z2 The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-17, wherein is selected from halogen and hydroxy.

[0181] 19.Z is, [ka] 19. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-18, selected from:

[0182] 20.Z is, [ka] 20. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-19, selected from:

[0183] 21. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-20, wherein n is selected from 5, 6, and 7.

[0184] twenty two. X is selected from —CH— and —CO—; Each Y is -C(R Y )2-, -NR YN - and [ka] are independently selected from Each R Y are independently selected from hydrogen, halogen, and C1-C6 alkyl; Each R YN but, ■ C1-C4 alkyl, oC6-C 10 aryl, o C1-C6 alkyl, C1-C6 fluoroalkoxy, and C6-C cycloalkyl (optionally substituted with 1 to 3 groups independently selected from C1-C6 fluoroalkyl); 10 C1-C4 alkyl optionally substituted with 1 to 3 groups independently selected from: C3-C8 cycloalkyl optionally substituted with 1 to 3 groups independently selected from halogen; Ring B is selected from C3-C8 cycloalkyl; Each R 1 is independently selected from C1-C6 fluoroalkyl and -NH2; Z, [ka] is selected from R Z1 is selected from C1-C6 fluoroalkyl; R Z2 is hydroxy, n is 6, 22. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-21, wherein m is 2.

[0185] 23.Each-C(R Y )2-, -CH2-, [ka] 23. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-22, independently selected from:

[0186] 24.Each-NR YN -but, [ka] 24. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-23, independently selected from:

[0187] 25. Ring B is [ka] 25. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-24, wherein:

[0188] 26.-(Y) n -but, [ka] 26. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-25, wherein:

[0189] 27. The compound has the formula IA: [ka] and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein: X is selected from —CH— and —CO—; n is selected from 5, 6, and 7; Each Y is -C(R Y )2-, -NR YN - and [ka] are independently selected from Each R Y are independently selected from hydrogen, hydroxy, halogen, and C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from hydroxy and C1-C6 alkoxy); Each R YN but, ■H and ■ C1-C4 alkyl, o-oxo, C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogen and C1-C6 alkyl); oC6-C 10 aryl, ◆Halogen, ◆Cyano, C1-C6 alkyl (optionally substituted with 1 to 3 hydroxy); ◆C1-C6 fluoroalkyl, C1-C6 alkoxy (optionally substituted with C3-C8 cycloalkyl optionally substituted with C1-C6 fluoroalkyl), ◆C1-C6 fluoroalkoxy, C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogen, C1-C6 alkyl, and C1-C6 fluoroalkyl), and phenyl (optionally substituted with C1-C6 alkyl), C6-C 10 aryl, o 5-6 membered heteroaryl, ◆Halogen, ◆C1-C6 alkyl, ◆C1-C6 fluoroalkyl, ◆C1-C6 fluoroalkoxy, ◆-O (0-1) (C3-C8 cycloalkyl)(optionally substituted with C1-C6 fluoroalkyl), and ◆ 3- to 12-membered heterocyclyl; C1-C4 alkyl optionally substituted with 1 to 3 groups independently selected from: o 3- to 12-membered heterocyclyl optionally substituted with 1 to 3 groups selected from halogen and C1-C6 alkyl; ■ C1-C6 fluoroalkyl, ■C6-C 10 aryl and ■ C3-C8 cycloalkyl, oHalogen, o cyano, oN(R YN1 ) C1-C4 alkyl optionally substituted with 1 to 3 groups selected from 2; o C1-C6 fluoroalkyl, o C1-C6 alkoxy, C3-C8 cycloalkyl, and o phenyl (optionally substituted with 1 to 3 groups independently selected from C-C alkyl); ■ 3- to 12-membered heterocyclyl optionally substituted with 1 to 3 groups selected from oxo and C1-C4 alkyl (optionally substituted with 1 to 2 groups selected from oxo and C3-C8 cycloalkyl); ■ 5-6 membered heteroaryl (optionally substituted with 1 to 3 groups selected from C1-C6 alkyl), ■CO2R YN1 and are selected independently from Each R YN1 is independently selected from H and C1-C4 alkyl (optionally substituted with oxo); Ring B is ■C6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy); C3-C8 cycloalkyl, and ■ 3- to 6-membered heterocyclyl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl), Each R 1 is halogen, C1-C6 fluoroalkyl, C1-C6 alkyl, -N(R 2 )2, and -CN; Each R 2 is independently selected from hydrogen, C1-C3 alkyl, and C1-C6 fluoroalkyl.

[0190] 28. The compound has the formula IA': [ka] and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein: X is selected from —CH— and —CO—; n is selected from 5, 6, and 7; Each Y is -C(R Y )2-, -NR YN - and [ka] are independently selected from Each R Yare independently selected from hydrogen, hydroxy, halogen, and C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from hydroxy and C1-C6 alkoxy); Each R YN but, ■H and ■ C1-C4 alkyl, o-oxo, C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogen and C1-C6 alkyl); oC6-C 10 aryl, ◆Halogen, ◆Cyano, C1-C6 alkyl (optionally substituted with 1 to 3 hydroxy); ◆C1-C6 fluoroalkyl, C1-C6 alkoxy (optionally substituted with C3-C8 cycloalkyl optionally substituted with C1-C6 fluoroalkyl), ◆C1-C6 fluoroalkoxy, C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogen, C1-C6 alkyl, and C1-C6 fluoroalkyl), and phenyl (optionally substituted with C1-C6 alkyl), C6-C 10 aryl, o 5-6 membered heteroaryl, ◆Halogen, ◆C1-C6 alkyl, ◆C1-C6 fluoroalkyl, ◆C1-C6 fluoroalkoxy, ◆-O (0-1) (C3-C8 cycloalkyl)(optionally substituted with C1-C6 fluoroalkyl), and ◆ 3- to 12-membered heterocyclyl; C1-C4 alkyl optionally substituted with 1 to 3 groups independently selected from: o 3- to 12-membered heterocyclyl optionally substituted with 1 to 3 groups selected from halogen and C1-C6 alkyl; ■ C1-C6 fluoroalkyl, ■C6-C 10 aryl and ■ C3-C8 cycloalkyl, oHalogen, o cyano, oN(R YN1 ) C1-C4 alkyl optionally substituted with 1 to 3 groups selected from 2; o C1-C6 fluoroalkyl, o C1-C6 alkoxy, C3-C8 cycloalkyl, and o phenyl (optionally substituted with 1 to 3 groups independently selected from C-C alkyl); ■ 3- to 12-membered heterocyclyl optionally substituted with 1 to 3 groups selected from oxo and C1-C4 alkyl (optionally substituted with 1 to 2 groups selected from oxo and C3-C8 cycloalkyl); ■ 5-6 membered heteroaryl (optionally substituted with 1 to 3 groups selected from C1-C6 alkyl), ■CO2R YN1 and are selected independently from Each R YN1 is independently selected from H and C1-C4 alkyl (optionally substituted with oxo); Ring B is ■C6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy); C3-C8 cycloalkyl, and ■ 3- to 6-membered heterocyclyl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl), Each R1 is halogen, C1-C6 fluoroalkyl, C1-C6 alkyl, -N(R 2 )2, and -CN; Each R 2 is independently selected from hydrogen, C1-C3 alkyl, and C1-C6 fluoroalkyl.

[0191] 29. The compound, deuterated derivative, or pharmaceutically acceptable salt of embodiment 27 or embodiment 28, wherein n is 6.

[0192] 30. A compound having formula IB: [ka] and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein: X is selected from —CH— and —CO—; Each Y is -CH2-, -C(CH3)2-, -CH(CH3)-, -CF2-, cyclobutyl, and -NR YN - independently selected from each R YN but, ■ C1-C4 alkyl substituted with phenyl optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl, C1-C6 fluoroalkoxy, and C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from C1-C6 fluoroalkyl), and ■ A compound, deuterated derivative, or pharmaceutically acceptable salt described in embodiment 1, independently selected from the group consisting of C3-C8 cycloalkyl optionally substituted with 1 to 3 groups independently selected from halogen.

[0193] 31. A compound having the formula IB': [ka] and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein: X is selected from —CH— and —CO—; Each Y is -CH2-, -C(CH3)2-, -CH(CH3)-, -CF2-, cyclobutyl, and -NR YN - independently selected from each R YN but, ■ C1-C4 alkyl substituted with phenyl optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl, C1-C6 fluoroalkoxy, and C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from C1-C6 fluoroalkyl), and ■ A compound, deuterated derivative, or pharmaceutically acceptable salt described in embodiment 1, independently selected from the group consisting of C3-C8 cycloalkyl optionally substituted with 1 to 3 groups independently selected from halogen.

[0194] 32. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 27-31, wherein X is -CO-.

[0195] 33. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 27-31, wherein X is -CH2-.

[0196] 34. A compound selected from the compounds of Table 7, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing.

[0197] 35. The compound of any one of embodiments 1-31 or embodiment 34, wherein the compound is selected from: [Table 9-1] [Table 9-2] [Table 9-3]

[0198] 36. A pharmaceutical composition comprising a compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1-35, and a pharmaceutically acceptable carrier.

[0199] 37. The pharmaceutical composition of embodiment 36, further comprising one or more additional therapeutic agents.

[0200] 38. The pharmaceutical composition of embodiment 37, wherein the one or more additional therapeutic agents comprises a compound having CFTR modulating activity, or a salt or deuterated derivative thereof.

[0201] 39. The pharmaceutical composition of embodiment 37 or embodiment 38, wherein the one or more additional therapeutic agents comprises a CFTR corrector.

[0202] 40. The pharmaceutical composition of any one of embodiments 37-39, wherein the one or more additional therapeutic agents comprises (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 (Compound II). [ka]

[0203] 41. The pharmaceutical composition of any one of embodiments 37-40, wherein the one or more additional therapeutic agents comprises 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound IV). [ka]

[0204] 42. The pharmaceutical composition of any one of embodiments 37-41, wherein the one or more additional therapeutic agents comprises N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound V). [ka]

[0205] 43. The pharmaceutical composition of any one of embodiments 37-42, wherein the one or more additional therapeutic agents comprises N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound VI). [ka]

[0206] 44. The one or more additional therapeutic agents are (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 44. The pharmaceutical composition according to any one of embodiments 37 to 43, comprising -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound VII). [ka]

[0207] 45. The one or more additional therapeutic agents are (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hexan-5-yl}-9-oxa-2λ 645. The pharmaceutical composition of any one of embodiments 37 to 44, comprising -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione (compound VIII). [ka]

[0208] 46. ​​The pharmaceutical composition of any one of embodiments 37-45, wherein the one or more additional therapeutic agents comprises at least one compound selected from PTI-428, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, ARN23766, and PTI-801.

[0209] 47. The pharmaceutical composition of any one of embodiments 37-46, wherein the one or more additional therapeutic agents comprises a CFTR potentiator.

[0210] 48. The pharmaceutical composition of any one of embodiments 37-47, wherein the one or more additional therapeutic agents comprises ASP-11.

[0211] 49. The pharmaceutical composition of any one of embodiments 37-48, wherein the one or more additional therapeutic agents comprises a CFTR potentiator.

[0212] 50. The one or more additional therapeutic agents is N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (compound III): [ka] and 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 (compound III-d): [ka] 50. The method of any one of embodiments 37-49, comprising a compound selected from:

[0213] 51. The pharmaceutical composition of any one of embodiments 37-50, wherein the one or more additional therapeutic agents comprises at least one compound selected from FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW251 (Icenticaftor), GLPG3067 / ABBV-3067 (Navocaftor), and ABBV-191.

[0214] 52. The pharmaceutical composition of any one of embodiments 37-51, wherein the one or more additional therapeutic agents comprises a CFTR amplifier.

[0215] 53. The pharmaceutical composition of any one of embodiments 37-52, wherein the one or more additional therapeutic agents comprises PTI-428.

[0216] 54. The pharmaceutical composition of any one of embodiments 37-53, wherein the one or more additional therapeutic agents comprises a CFTR readthrough agent.

[0217] 55. The pharmaceutical composition of any one of embodiments 37-54, wherein the one or more additional therapeutic agents comprises ELX-02.

[0218] 56. The pharmaceutical composition of any one of embodiments 37-55, wherein the one or more additional therapeutic agents comprises a nucleic acid therapy.

[0219] 57. The pharmaceutical composition of any one of embodiments 37-56, wherein the one or more additional therapeutic agents comprises at least one agent selected from MRT5005, Lunar-CF, and RCT223.

[0220] 58. The pharmaceutical composition of any one of embodiments 37-57, wherein the one or more additional therapeutic agents comprises an ENaC inhibitor.

[0221] 59. The pharmaceutical composition of any one of embodiments 37-58, wherein the one or more additional therapeutic agents comprise amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI1265162, and ARO-ENaC1001.

[0222] 60. The pharmaceutical composition of any one of embodiments 37-59, wherein the one or more additional therapeutic agents comprises a TMEM16A modulator.

[0223] 61. The pharmaceutical composition of any one of embodiments 37-60, wherein the one or more additional therapeutic agents comprises ETD002.

[0224] 62. The pharmaceutical composition of any one of embodiments 37-61, wherein the one or more additional therapeutic agents comprises a GPR39 agonist.

[0225] 63. The pharmaceutical composition of any one of embodiments 37-62, wherein the one or more additional therapeutic agents comprises DS-1039.

[0226] 64. A method for treating cystic fibrosis, comprising administering to a patient in need thereof an effective amount of a compound, salt, or deuterated derivative according to any one of embodiments 1-35, or a pharmaceutical composition according to any one of embodiments 36-63.

[0227] 65. The method of embodiment 64, further comprising administering one or more additional therapeutic agents.

[0228] 66. The method of embodiment 65, wherein the one or more additional therapeutic agents comprise a compound having CFTR modulating activity, or a salt or deuterated derivative thereof.

[0229] 67. The method of embodiment 65 or 66, wherein the one or more additional therapeutic agents comprises a CFTR corrector.

[0230] 68. The method of any one of embodiments 65-67, wherein the one or more additional therapeutic agents comprises Compound II.

[0231] 69. The method of any one of embodiments 65-68, wherein the one or more additional therapeutic agents comprises compound IV.

[0232] 70. The method of any one of embodiments 65-69, wherein the one or more additional therapeutic agents comprises compound V.

[0233] 71. The method of any one of embodiments 65-70, wherein the one or more additional therapeutic agents comprises compound VI.

[0234] 72. The method of any one of embodiments 65-71, wherein the one or more additional therapeutic agents comprises compound VII.

[0235] 73. The method of any one of embodiments 65-72, wherein the one or more additional therapeutic agents comprises compound VIII.

[0236] 74. The method of any one of embodiments 65-73, wherein the one or more additional therapeutic agents comprises at least one compound selected from PTI-428, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, ABBV-2851, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, ARN23766, and PTI-801.

[0237] 75. The method of any one of embodiments 65-74, wherein the one or more additional therapeutic agents comprises a CFTR potentiator.

[0238] 76. The method of any one of embodiments 65-75, wherein the one or more additional therapeutic agents comprises ASP-11.

[0239] 77. The method of any one of embodiments 65-76, wherein the one or more additional therapeutic agents comprises a CFTR potentiator.

[0240] 78. The method of any one of embodiments 65-77, wherein the one or more additional therapeutic agents comprises a compound selected from compound III and compound III-d.

[0241] 79. The method of any one of embodiments 65-78, wherein the one or more additional therapeutic agents comprises at least one compound selected from FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW251 (Icenticaftor), GLPG3067 / ABBV-3067 (Navocaftor), and ABBV-191.

[0242] 80. The method of any one of embodiments 65-79, wherein the one or more additional therapeutic agents comprises a CFTR amplifier.

[0243] 81. The method of any one of embodiments 65-80, wherein the one or more additional therapeutic agents comprises PTI-428.

[0244] 82. The method of any one of embodiments 65-81, wherein the one or more additional therapeutic agents comprises a CFTR readthrough agent.

[0245] 83. The method of any one of embodiments 65-82, wherein the one or more additional therapeutic agents comprises ELX-02.

[0246] 84. The method of any one of embodiments 65-83, wherein the one or more additional therapeutic agents comprises a nucleic acid therapy.

[0247] 85. The pharmaceutical composition of any one of embodiments 65-84, wherein the one or more additional therapeutic agents comprises at least one agent selected from MRT5005, Lunar-CF, and RCT223.

[0248] 86. The method of any one of embodiments 65-85, wherein the one or more additional therapeutic agents comprises an ENaC inhibitor.

[0249] 87. The pharmaceutical composition of any one of embodiments 65-86, wherein the one or more additional therapeutic agents comprise amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI1265162, and ARO-ENaC1001.

[0250] 88. The method of any one of embodiments 65-87, wherein the one or more additional therapeutic agents comprises a TMEM16A modulator.

[0251] 89. The method of any one of embodiments 65-88, wherein the one or more additional therapeutic agents comprises ETD002.

[0252] 90. The method of any one of embodiments 65-89, wherein the one or more additional therapeutic agents comprises a GPR39 agonist.

[0253] 91. The method of any one of embodiments 65-90, wherein the one or more additional therapeutic agents comprises DS-1039.

[0254] 92. A compound, salt, or deuterated derivative according to any one of embodiments 1-35, or a pharmaceutical composition according to any one of embodiments 36-63, for use in the treatment of cystic fibrosis.

[0255] 93. Use of a compound, salt, or deuterated derivative according to any one of embodiments 1 to 35, or a pharmaceutical composition according to any one of embodiments 36 to 63, in the manufacture of a medicament for the treatment of cystic fibrosis. [Example]

[0256] General experimental procedure Abbreviation AcOH: acetic acid Boc anhydride ((Boc)2O): Di-tert-butyl dicarbonate Boc: butoxycarbonyl BOP: benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate t-BuOH: tert-butanol CDCl3: chloroform-d CDI: 1,1′-carbonyldiimidazole CD3OD:methyl-d 4ア Alcohol-d CH2Cl2: Dichloromethane CH3CN:Acetonitrile CO2: Carbon dioxide Cs2CO3: Cesium carbonate CuI: Copper(I) iodide DCE: 1,2-dichloroethane DCM: dichloromethane DIEA: (DIPEA; N,N-diisopropylethylamine) DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide DMP: Dess-Martin periodinane DMSO: dimethyl sulfoxide DMSO-d6: dimethyl sulfoxide-d6 EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ESI-MS: Electrospray ionization mass spectrometry Et2O: Diethyl ether Et3N or TEA: Triethylamine EtOAc: ethyl acetate EtOH: ethanol Et2O: Diethyl ether ESI-MS: Electrospray ionization mass spectrometry Second Generation Grubbs Catalyst: [1,3-Bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-[(2-isopropoxyphenyl)methylene]ruthenium H2: Hydrogen HATU: N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide HCl: Hydrochloric acid HOBT: Hydroxybenzotriazole HPLC: High-performance liquid chromatography H2: Hydrogen H2O2: Hydrogen peroxide KHSO4: Potassium sulfite KOH: Potassium hydroxide K2CO3: Potassium carbonate KMnO4: Potassium permanganate KHCO3: Potassium bicarbonate LC: liquid chromatography LiAlH4: Lithium aluminum hydride LiOH: Lithium hydroxide MeMgCl: methylmagnesium chloride MeTHF or 2-MeTHF or 2-Me-THF: 2-methyltetrahydrofuran MeOH: Methanol MTBE: Methyl tert-butyl ether MgSO4: Magnesium sulfate MS: Mass spectrometry n-Bu4NF·H2O: Tetra-n-butylammonium fluoride monohydrate Na: Sodium NaH: sodium hydride NaHCO3: Sodium bicarbonate NaOAc: sodium acetate NaOH: Sodium hydroxide Na2SO4: Sodium sulfate NBS: N-bromosuccinimide NH3: Ammonia NH4Cl: Ammonium chloride NH4HCO3: Ammonium bicarbonate NMP: N-methyl-2-pyrrolidone NMR: nuclear magnetic resonance N2: Nitrogen Pd / C: Palladium on carbon Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2: 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride Pd(OAc)2: Palladium(II) acetate PhI(OAc)2: (diacetoxyiodo)benzene POCl3: Phosphoryl chloride PtO2: platinum oxide RT or rt: room temperature SFC: Supercritical Fluid Chromatography Silica Cat Pd: Palladium silica SiO2: Silica gel TBAF: Tetra-n-butylammonium fluoride TBAI: Tetrabutylammonium iodide TBDPS-Cl or TBDPSCl: tert-butyldiphenylchlorosilane TEA: Triethylamine TEMPO: 2,2,6,6-tetramethylpiperidinyloxy TFA: Trifluoroacetic acid THF: tetrahydrofuran Ti(OEt)4: Titanium(IV) ethoxide TMEDA: Tetramethylethylenediamine TMSCF3: Trifluoromethyltrimethylsilane p-TsCl or tosyl chloride: p-toluenesulfonyl chloride or 4-toluenesulfonyl chloride T3P: 1-propanephosphonic anhydride UPLC: Ultra-high performance liquid chromatography Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Zhan Catalyst-1B: Dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][[5-[(dimethylamino)sulfonyl]-2-(1-methylethoxy-O)phenyl]methylene-C]ruthenium(II)

[0257] Common UPLC-MS / HPLC-MS / GC analysis methods: LC Method A: Waters Acquity UPLC-MS BEH C 18 Analytical reversed-phase UPLC-MS was performed using a column (50 x 2.1 mm, 1.7 μm particle size) (product number: 186002350) and a dual gradient run of 1% to 99% mobile phase B over 3.0 min. Mobile phase A = water (+0.05% trifluoroacetic acid). Mobile phase B = acetonitrile (+0.035% trifluoroacetic acid). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, column temperature = 60 °C.

[0258] LC method B: Kinetex C 18 Analytical reverse-phase HPLC-MS was performed using a column (4.6 × 50 mm, 2.6 μm particle size) with a temperature of 45°C, a flow rate of 2.0 mL / min, a run time of 3 min, and a mobile phase consisting of an initial linear gradient of 95% water (+0.1% formic acid) and 5% acetonitrile (+0.1% formic acid) to 95% acetonitrile (+0.1% formic acid) in 2.0 min, followed by a 1.0 min hold at 95% acetonitrile (+0.1% formic acid).

[0259] LC method C: Kinetex Polar C 18 Analytical reverse-phase HPLC-MS using a column (3.0 × 50 mm, 2.6 μm particle size), temperature: 45°C, flow rate: 1.2 mL / min, run time: 6 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) in 4.0 min, then hold at 95% acetonitrile (+0.1% formic acid) for 2.0 min.

[0260] LC Method D: Waters Acquity UPLC-MS BEH C 18 Analytical reversed-phase UPLC-MS was performed using a column (50 x 2.1 mm, 1.7 μm particle size) (product number: 186002350) and a dual gradient run of 1% to 99% mobile phase B over 5.0 min. Mobile phase A = water (+0.05% trifluoroacetic acid). Mobile phase B = acetonitrile (+0.035% trifluoroacetic acid). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, column temperature = 60 °C.

[0261] LC method E: Kinetex Polar C 18 Analytical reverse-phase HPLC-MS using a column (3.0 × 50 mm, 2.6 μm particle size), temperature: 45°C, flow rate: 1.2 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) in 2.0 min, then hold at 95% acetonitrile (+0.1% formic acid) for 1.0 min.

[0262] LC method F:Kinetex C 18 Analytical reverse-phase HPLC-MS using a column (4.6 × 50 mm, 2.6 μm particle size), temperature: 45°C, flow rate: 2.0 mL / min, run time: 6 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) in 4.0 min, then hold at 95% acetonitrile (+0.1% formic acid) for 2.0 min.

[0263] LC method G: Merckmillipore Chromolith SpeedROD C 18 Analytical reversed-phase HPLC-MS was performed using a column (50 × 4.6 mm) and a double gradient run of 5% to 100% mobile phase B over 6 min. Mobile phase A = water (+0.1% trifluoroacetic acid). Mobile phase B = acetonitrile (+0.1% trifluoroacetic acid).

[0264] LC Method H: Waters Cortex C18 Analytical reverse-phase HPLC-MS was performed using a 3.0 x 50 mm, 2.7 μm particle size column (product number 186007370). Temperature: 55 °C, flow rate: 1.2 mL / min, mobile phase A: water (+0.1% trifluoroacetic acid). Mobile phase B: acetonitrile (+0.1% trifluoroacetic acid). Gradient: 5% to 100% B over 4 min, equilibration at 100% B for 0.5 min, equilibration to 5% B over 1.5 min.

[0265] LC method I: Kinetex Polar C 18 Analytical reverse-phase HPLC-MS using a column (3.0 × 50 mm, 2.6 μm particle size), temperature: 45°C, flow rate: 1.0 mL / min, run time: 6 min, mobile phase: initial 98% water (+0.1% formic acid) and 2% acetonitrile (+0.1% formic acid) held for 0.5 min, then a linear gradient to 95% acetonitrile (+0.1% formic acid) for 3.0 min, then a 2.5 min hold at 95% acetonitrile (+0.1% formic acid).

[0266] LC Method J: Waters Acquity UPLC-MS BEH C 18 Analytical reversed-phase UPLC-MS was performed using a column (50 x 2.1 mm, 1.7 μm particle size) (product number: 186002350) and a dual gradient run of 30% to 99% mobile phase B over 3.0 min. Mobile phase A = water (+0.05% trifluoroacetic acid). Mobile phase B = acetonitrile (+0.035% trifluoroacetic acid). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, column temperature = 60 °C.

[0267] LC method K:Kinetex EVO C 18 Analytical reverse-phase HPLC-MS using a column (4.6 × 50 mm, 2.6 μm particle size), temperature: 45°C, flow rate: 2.0 mL / min, run time: 4 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) in 2.0 min, then hold at 95% acetonitrile (+0.1% formic acid) for 2.0 min.

[0268] LC method L:X-Terra MS C 18Analytical reverse-phase HPLC-MS using a column (4.6 × 150 mm, 5 μm particle size), temperature: 40°C, flow rate: 1.5 mL / min, run time: 10 min, mobile phase: initial 95% water (+10 mM ammonium bicarbonate) and linear gradient from 5% acetonitrile to 95% acetonitrile in 6.5 min, then hold at 95% acetonitrile for 3.5 min.

[0269] LC Method M: Waters Acquity UPLC-MS BEH C 18 Analytical reversed-phase UPLC-MS was performed using a column (50 x 2.1 mm, 1.7 μm particle size) (product number: 186002350) and a dual gradient run of 50% to 99% mobile phase B over 3.0 min. Mobile phase A = water (+0.05% trifluoroacetic acid). Mobile phase B = acetonitrile (+0.035% trifluoroacetic acid). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, column temperature = 60 °C.

[0270] LC Method N: Waters Acquity UPLC-MS BEH C 18 Analytical reversed-phase UPLC-MS was performed using a column (30 x 2.1 mm, 1.7 μm particle size) (product number: 186002349) and a dual gradient run of 1% to 99% mobile phase B over 2.9 min. Mobile phase A = water (+ 5 mM ammonium hydroxide). Mobile phase B = acetonitrile. Flow rate = 1.5 mL / min, injection volume = 1.5 μL, column temperature = 60 °C.

[0271] LC method O:Kinetex Polar C 18 Analytical reverse-phase HPLC-MS using a column (3.0 × 50 mm, 2.6 μm particle size), temperature: 45°C, flow rate: 1.2 mL / min, run time: 4 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) in 3.0 min, then hold at 95% acetonitrile (+0.1% formic acid) for 1.0 min.

[0272] LC method P: Waters Acquity UPLC-MS BEH C 18Analytical reversed-phase UPLC-MS was performed using a column (100 x 2.1 mm, 1.7 μm particle size) (product number: 186002352) and a dual gradient run of 1% to 99% mobile phase B over 13.5 min. Mobile phase A = water (+0.05% trifluoroacetic acid). Mobile phase B = acetonitrile (+0.035% trifluoroacetic acid). Flow rate = 0.8 mL / min, injection volume = 1.5 μL, column temperature = 60 °C.

[0273] LC Method Q: Onyx Monolithic C sold by Phenomenex 18 Analytical reversed-phase HPLC-MS was performed using a column (50 x 4.6 mm) (product number: CH0-7644) and a double gradient run of 1% to 99% mobile phase B over 2.9 min. Mobile phase A = water (+0.05% trifluoroacetic acid). Mobile phase B = acetonitrile (+0.035% trifluoroacetic acid). Flow rate = 12 mL / min, injection volume = 50 μL, and column temperature = 25 °C.

[0274] LC method R: Waters Acquity UPLC-MS BEH C 18 Analytical reversed-phase UPLC-MS was performed using a column (30 x 2.1 mm, 1.7 μm particle size) (product number: 186002349) and a dual gradient run of 30% to 99% mobile phase B over 1.0 min. Mobile phase A = water (+0.05% trifluoroacetic acid). Mobile phase B = acetonitrile (+0.035% trifluoroacetic acid). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, column temperature = 60 °C.

[0275] LC method: Waters Acquity UPLC-MS BEH C 18 Analytical reversed-phase UPLC-MS was performed using a column (30 x 2.1 mm, 1.7 μm particle size) (product number: 186002349) and a dual gradient run of 1% to 99% mobile phase B over 1.0 min. Mobile phase A = water (+0.05% trifluoroacetic acid). Mobile phase B = acetonitrile (+0.035% trifluoroacetic acid). Flow rate = 1.5 mL / min, injection volume = 1.5 μL, column temperature = 60 °C.

[0276] LC method: Waters Acquity UPLC-MS BEH C18 Analytical reversed-phase UPLC-MS was performed using a column (30 x 2.1 mm, 1.7 μm particle size) (product number: 186002349) and a dual gradient run of 50% to 99% mobile phase B over 1.0 min. Mobile phase A = water (+0.05% trifluoroacetic acid). Mobile phase B = acetonitrile (+0.035% trifluoroacetic acid). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, column temperature = 60 °C.

[0277] LC method: Waters Acquity UPLC-MS BEH C 18 Analytical reversed-phase UPLC-MS was performed using a column (30 x 2.1 mm, 1.7 μm particle size) (product number: 186002349) and a dual gradient run of 75% to 99% mobile phase B over 1.0 min. Mobile phase A = water (+0.05% trifluoroacetic acid). Mobile phase B = acetonitrile (+0.035% trifluoroacetic acid). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, column temperature = 60 °C.

[0278] LC method V:Kinetex EVO C 18 Analytical reverse-phase HPLC-MS was used with a column (2.1 × 50 mm, 2.6 μm particle size), temperature: 45°C, flow rate: 1.0 mL / min, run time: 1.5 min, mobile phase: initial 98% mobile phase A (10 mM ammonium formate in water:acetonitrile, 95:5, pH 9) and 2% mobile phase B (acetonitrile) in 1.15 min, linear gradient to 98% acetonitrile, then hold at 98% acetonitrile for 0.2 min, then return to 98% water and 10 mM ammonium formate for 0.05 min, and hold for 0.1 min.

[0279] LC method W:XBridge C 18 Analytical reverse-phase HPLC-MS using a column (3.0 × 30 mm, 5 μm particle size), flow rate: 2.0 mL / min, run time: 3 min, mobile phase: initial 95% water (+10 mM ammonium bicarbonate) and 5% acetonitrile over 2 min to 5% water (+10 mM ammonium bicarbonate) and 95% acetonitrile, then hold at 95% acetonitrile and 5% water (+10 mM ammonium bicarbonate) for 1 min.

[0280] LC method X: Kinetex Polar C 18 Analytical reverse-phase HPLC-MS using a column (3.0 × 50 mm, 2.6 μm particle size), temperature: 45°C, flow rate: 1.2 mL / min, run time: 5 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) in 4.0 min, then hold at 95% acetonitrile (+0.1% formic acid) for 1.0 min.

[0281] LC Method Y: Luna C 18 Analytical reverse-phase HPLC-MS using a column (3.0 × 50 mm, 3 μm particle size), temperature: 45°C, flow rate: 1.5 mL / min, run time: 3.5 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) in 1.3 min, then hold at 95% acetonitrile (+0.1% formic acid) for 2.2 min.

[0282] LC Method Z: Luna C 18 Analytical reverse-phase HPLC-MS using a column (3.0 × 50 mm, 3 μm particle size), temperature: 45°C, flow rate: 1.5 mL / min, run time: 2.5 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) in 1.3 min, then hold at 95% acetonitrile (+0.1% formic acid) for 1.2 min.

[0283] LC method AA: SunFire C 18 Analytical reverse-phase HPLC-MS using a column (4.6 × 75 mm, 3.5 μm particle size), temperature: 45°C, flow rate: 1.5 mL / min, run time: 6 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) in 4.0 min, then hold at 95% acetonitrile (+0.1% formic acid) for 2.0 min.

[0284] LC Method BB:XBridge C 18Analytical reverse-phase HPLC-MS using a column (4.6 × 75 mm, 5 μm particle size), flow rate: 1.5 mL / min, run time: 6 min, mobile phase: initial 95% water (+10 mM ammonium bicarbonate) and 5% acetonitrile over 3 min to 5% water (+10 mM ammonium bicarbonate) and 95% acetonitrile, then hold at 95% acetonitrile and 5% water (+10 mM ammonium bicarbonate) for 3 min.

[0285] LC Method CC: Analytical GC using a Phenomenex ZB-1MS column (0.25 x 30 mm, 0.25 μm particle size), starting temperature 50°C, ramping to 300°C at 20°C / min and holding for 5 min.

[0286] LC method DD: Merckmillipore Chromolith SpeedROD C 18 Analytical reversed-phase HPLC-MS was performed using a column (50 × 4.6 mm) and a double gradient run of 5% to 100% mobile phase B over 12 min. Mobile phase A = water (+0.1% trifluoroacetic acid). Mobile phase B = acetonitrile (+0.1% trifluoroacetic acid).

[0287] LC method EE: Kinetex EVO C 18 Analytical reverse-phase HPLC-MS was performed using a column (4.6 × 50 mm, 2.6 μm particle size), temperature: 45° C., flow rate: 2.0 ml / min, run time: 3 min. Mobile phase conditions: initial 95% water (+0.1% formic acid) and 5% acetonitrile (+0.1% formic acid) linear gradient to 95% acetonitrile (+0.1% formic acid) in 2.0 min, followed by a 1.0 min hold at 95% acetonitrile (+0.1% formic acid).

[0288] LC method FF: Waters Acquity UPLC-MS BEH C 18 Analytical reversed-phase UPLC using a column (50 × 2.1 mm, 1.7 μm particle size) (product number: 186002350) and a dual gradient of 1% to 99% mobile phase B over 4.5 min (mobile phase A = water (+0.05% CF3CO2H), mobile phase B = acetonitrile (0.035% CF3CO2H), flow rate = 1.2 mL / min, injection volume = 1.5 μL, and column temperature = 60 °C).

[0289] LC Method GG: Waters Acquity UPLC-MS BEH C 18 Analytical reversed-phase UPLC-MS was performed using a column (30 x 2.1 mm, 1.7 μm particle size) (product number: 186002349) and a dual gradient run of 50% to 99% mobile phase B over 1.0 min. Mobile phase A = water (+0.05% formic acid). Mobile phase B = acetonitrile (+0.035% formic acid). Flow rate = 1.5 mL / min, injection volume = 1.5 μL, column temperature = 60 °C.

[0290] LC method HH: Waters Acquity UPLC-MS BEH C 18 Analytical reversed-phase UPLC-MS was performed using a column (30 x 2.1 mm, 1.7 μm particle size) (product number: 186002349) and a dual gradient run of 1% to 99% mobile phase B over 1.0 min. Mobile phase A = water (+0.05% formic acid). Mobile phase B = acetonitrile (+0.035% formic acid). Flow rate = 1.5 mL / min, injection volume = 1.5 μL, column temperature = 60 °C.

[0291] LC Method II: Waters Acquity UPLC-MS BEH C 18 Analytical reversed-phase UPLC-MS was performed using a column (50 x 2.1 mm, 1.7 μm particle size) (product number: 186002350) and a dual gradient run of 30% to 99% mobile phase B over 2.9 min. Mobile phase A = water (+0.05% formic acid). Mobile phase B = acetonitrile (+0.035% formic acid). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, column temperature = 60 °C.

[0292] LC method JJ: Waters Acquity UPLC-MS BEH C 18 Analytical reversed-phase UPLC-MS was performed using a column (50 x 2.1 mm, 1.7 μm particle size) (product number: 186002350) and a dual gradient run of 1% to 99% mobile phase B over 2.9 min. Mobile phase A = water (+0.05% formic acid). Mobile phase B = acetonitrile (+0.035% formic acid). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, column temperature = 60 °C.

[0293] Preparation of general intermediates Intermediate 1: Preparation of methyl 3-[bis(tert-butoxycarbonyl)amino]-6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate [ka]

[0294] Step 1: Methyl 3-(benzhydrylideneamino)-5-(trifluoromethyl)pyridine-2-carboxylate [ka] A mixture of methyl 3-chloro-5-(trifluoromethyl)pyridine-2-carboxylate (47.3 g, 197.43 mmol), diphenylmethanimine (47 g, 259.33 mmol), Xantphos (9.07 g, 15.675 mmol), and cesium carbonate (131 g, 402.06 mmol) in dioxane (800 mL) was degassed by bubbling nitrogen through for 30 minutes. Pd(OAc)2 (3.52 g, 15.679 mmol) was added, and the system was purged with nitrogen three times. The reaction mixture was heated at 100 °C for 18 hours. The reaction was cooled to room temperature and filtered through a pad of Celite. The cake was washed with ethyl acetate, and the solvent was evaporated under reduced pressure to give methyl 3-(benzhydrylideneamino)-5-(trifluoromethyl)pyridine-2-carboxylate (90 g, 84%) as a yellow solid. ESI-MS m / z calculated 384.10855, observed 385.1 (M+1) + ; Retention time: 2.24 minutes (LC method B).

[0295] Step 2: Methyl 3-amino-5-(trifluoromethyl)pyridine-2-carboxylate [ka] To a suspension of methyl 3-(benzhydrylideneamino)-5-(trifluoromethyl)pyridine-2-carboxylate (65 g, 124.30 mmol) in methanol (200 mL) was added HCl (3 M in methanol) (146 mL of 3 M, 438 mmol). The mixture was stirred at room temperature for 1.5 hours, and then the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (2 L) and dichloromethane (500 mL). The organic phase was washed with 5% aqueous sodium bicarbonate (3 × 500 mL) and brine (2 × 500 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was triturated with heptane (2 × 50 mL), and the mother liquor was discarded. The resulting solid was triturated with a mixture of dichloromethane and heptane (1:1, 40 mL) and filtered to give methyl 3-amino-5-(trifluoromethyl)pyridine-2-carboxylate (25.25 g, 91%) as a yellow solid. 1 H NMR(300MHz,CDCl3)δ 8.24(s,1H),7.28(s,1H),5.98(br.s,2H),4.00(s,3H). 19 F NMR (282 MHz, CDCl3) δ -63.23 (s, 3F) ppm. ESI-MS m / z calculated 220.046, found 221.1 (M+1). + ; Retention time: 1.62 minutes (LC method E).

[0296] Step 3: Methyl 3-amino-6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate [ka] To a solution of methyl 3-amino-5-(trifluoromethyl)pyridine-2-carboxylate (18.75 g, 80.91 mmol) in acetonitrile (300 mL) was added N-bromosuccinimide (18.7 g, 105.3 mmol) in small portions at 0 °C. The mixture was stirred overnight at 25 °C. Ethyl acetate (1000 mL) was added. The organic layer was washed with 10% sodium thiosulfate solution (3 × 200 mL), which was back-extracted with ethyl acetate (2 × 200 mL). The combined organic extracts were washed with saturated sodium bicarbonate solution (3 × 200 mL), brine (200 mL), dried over sodium sulfate, and concentrated in vacuo to give methyl 3-amino-6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate (25.46 g, 98%). 1 H NMR(300MHz,CDCl3)ppm 7.37(s,1H),6.01(br.s.,2H),3.93-4.03(m,3H)ppm. 19 F NMR (282 MHz, CDCl3) ppm -64.2 (s, 3F) ppm. ESI-MS m / z calculated 297.9565, found 299.0 (M+1). + ; Retention time: 2.55 minutes (LC method F).

[0297] Step 4: Methyl 3-[bis(tert-butoxycarbonyl)amino]-6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate [ka] A mixture of methyl 3-amino-6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate (5 g, 15.549 mmol), (Boc)O (11 g, 11.579 mL, 50.402 mmol), DMAP (310 mg, 2.5375 mmol), and CHCl (150 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (0-15% ethyl acetate / heptane) to give methyl 3-[bis(tert-butoxycarbonyl)amino]-6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate (6.73 g, 87%) as a pale yellow solid. 1H NMR(300MHz,CDCl3)ppm 7.85(s,1H),3.96(s,3H),1.42(s,18H)ppm. 19 F NMR(282MHz,CDCl3)ppm-63.9(s,3F)ppm.ESI-MS m / z calculated value 498.06134, retention time: 2.34 minutes (LC method B).

[0298] Intermediate 2: Preparation of 6-bromo-3-(tert-butoxycarbonylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid [ka] To a mixture of methyl 3-[bis(tert-butoxycarbonyl)amino]-6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate (247 g, 494.7 mmol) in THF (1.0 L) was added a solution of LiOH (47.2 g, 1.971 mol) in water (500 mL). The mixture was stirred at ambient temperature for 18 hours, resulting in a yellow slurry. The mixture was cooled in an ice bath and slowly acidified with HCl (1000 mL 2 M, 2 mol), maintaining the reaction temperature below 15 °C. The mixture was diluted with heptane (1.5 L), mixed, and the organic phase separated. The aqueous phase was extracted with heptane (500 mL). The combined organic phase was washed with brine, dried over MgSO4, filtered, and concentrated. The crude oil was dissolved in heptane (600 mL), seeded, and stirred at ambient temperature for 18 hours to give a thick slurry. The slurry was diluted with cold heptane (500 mL) and the precipitate was collected using a medium frit. The filter cake was washed with cold heptane, air-dried for 1 hour, and then dried in vacuo at 45° C. for 48 hours to give 6-bromo-3-(tert-butoxycarbonylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid (158.3 g, 83%). 1 H NMR(400MHz,DMSO-d6)δ 10.38(s,1H),9.01(s,1H),1.50(s,9H)ppm.ESI-MS m / z calculated value 383.99326, measured value 330.9(M+1)+; Retention time: 2.55 minutes (LC method FF).

[0299] Intermediate 3: Preparation of 2-benzyloxy-2-(trifluoromethyl)hex-5-enehydrazide (hydrochloride) [ka]

[0300] Step 1: Ethyl 2-hydroxy-2-(trifluoromethyl)hex-5-enoate [ka] To a solution of ethyl 3,3,3-trifluoro-2-oxopropanoate (25.15 g, 147.87 mmol) in EtO (270 mL) at −78°C, a solution of bromo(but-3-enyl)magnesium in THF (190 mL, 0.817 M, 155.23 mmol) was added dropwise over 1.5 h (internal temperature −72 to −76°C). The mixture was stirred at −78°C for 20 min. The dry ice-acetone bath was removed. The mixture was slowly warmed to 5°C over 1 h and added to a mixture of 1 N aqueous HCl (170 mL) and crushed ice (150 g) (pH = 4). The two layers were separated. The organic layer was concentrated, and the residue was combined with the aqueous phase and extracted with ethyl acetate (2 × 150 mL). The combined organic phase was washed with 5% aqueous NaHCO (50 mL) and brine (20 mL) and dried over NaSO. The mixture was filtered, concentrated, and co-evaporated with THF (2 x 40 mL) to give ethyl 2-hydroxy-2-(trifluoromethyl)hex-5-enoate (37.44 g, 96%) as a colorless oil. 1 H NMR(300MHz,CDCl3)δ 5.77(m,1H),5.15-4.93(m,2H),4.49-4.28(m,2H),3.88(s,1H),2.35-2.19(m,1H),2.17-1.89(m,3H),1.34(t,J=7.0Hz,3H)ppm. 19 F NMR(282MHz,CDCl3)δ -78.74(s,3F)ppm.

[0301] Step 2: Ethyl 2-benzyloxy-2-(trifluoromethyl)hex-5-enoate [ka] To a solution of ethyl 2-hydroxy-2-(trifluoromethyl)hex-5-enoate (24.29 g, 87.6% purity, 94.070 mmol) in DMF (120 mL) was added NaH (60% in mineral oil, 5.64 g, 141.01 mmol) in small portions at 0 °C. The mixture was stirred at 0 °C for 10 min. Benzyl bromide (24.13 g, 141.08 mmol) and tetrabutylammonium iodide (8.68 g, 23.500 mmol) were added. The mixture was stirred at room temperature overnight. NHCl (3 g, 0.6 equiv.) was added. The mixture was stirred for 10 min. 30 mL of ethyl acetate was added, followed by ice water (400 g). The mixture was extracted with CHCl, and the combined organic layers were concentrated. Purification by silica gel chromatography (0-20% CH2Cl2 in heptane) gave ethyl 2-benzyloxy-2-(trifluoromethyl)hex-5-enoate (26.05 g, 88%) as a pink oil. 1 H NMR(300MHz,CDCl3)δ 1.34(t,J=7.2Hz,3H),2.00-2.19(m,3H),2.22-2.38(m,1H),4.33(q,J=7.2Hz,2H),4.64(d,J =10.6Hz,1H),4.84(d,J=10.9Hz,1H),4.91-5.11(m,2H),5.62-5.90(m,1H),7.36(s,5H)ppm. 19 F NMR (282 MHz, CDCl3) δ -70.5 (s, 3F) ppm. ESI-MS m / z calculated 316.12863, found 317.1 (M+1). + ; Retention time: 2.47 minutes (LC method B).

[0302] Step 3: 2-Benzyloxy-2-(trifluoromethyl)hex-5-enoic acid [ka] A solution of sodium hydroxide (7.86 g, 196.51 mmol) in water (60 mL) was added to a solution of ethyl 2-benzyloxy-2-(trifluoromethyl)hex-5-enoate (24.86 g, 78.593 mmol) in methanol (210 mL). The reaction was heated at 50° C. overnight. The reaction was concentrated to remove methanol, diluted with water (150 mL), and the carboxylic acid sodium salt was washed with heptane (1×100 mL). The aqueous solution was acidified to pH=2 with a 3N solution of HCl. The carboxylic acid was extracted with dichloromethane (3×100 mL) and dried over sodium sulfate. The solution was filtered and concentrated to give 2-benzyloxy-2-(trifluoromethyl)hex-5-enoic acid (22.57 g, 97%) as a pale yellow oil. 1 H NMR(300MHz,DMSO-d6)δ 14.31(br.s.,1H),7.55-7.20(m,5H),5.93-5.70(m,1H),5.17-4.91(m,2H),4.85-4.68(m,1H),4.67-4.55(m,1H),2.32-1.94(m,4H)ppm. 19 F NMR(282MHz,DMSO-d6)δ -70.29(s,3F)ppm.ESI-MS m / z calculated value 288.09732, actual value 287.1(M-1); Retention time: 3.1 min (LC method C).

[0303] Step 4: tert-Butyl N-[[2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]amino]carbamate [ka] To a solution of 2-benzyloxy-2-(trifluoromethyl)hex-5-enoic acid (21.92 g, 92.4% purity, 70.263 mmol) in DMF (130 mL) was added HATU (37.2 g, 97.836 mmol) and EtN (15 g, 148.24 mmol). The mixture was stirred for 10 minutes, and then tert-butyl N-aminocarbamate (12.2 g, 92.312 mmol) was added. The mixture was stirred at 25 °C overnight and then at 40 °C for 1 hour. The mixture was diluted with ice water (500 g) and extracted with CHCl. ​​The organic layer was dried over anhydrous sodium sulfate and concentrated. Purification by silica gel chromatography (0-30% ethyl acetate in heptane) gave tert-butyl N-[[2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]amino]carbamate (26.08 g, 92%) as a white solid. 1 H NMR(300MHz,CDCl3)δ 1.46(s,9H),2.10-2.31(m,3H),2.34-2.51(m,1H),4.60-4.72(m,1H),4.73-4.86(m,1H),4. 95-5.19(m,2H),5.83(m,1H),6.28(br.s.,1H),7.30-7.51(m,5H),8.34(d,J=2.6Hz,1H)ppm. 19 F NMR(282MHz,CDCl3)δ -73.6(s,3F)ppm.

[0304] Step 5: 2-Benzyloxy-2-(trifluoromethyl)hex-5-enehydrazide (hydrochloride) [ka] To a solution of tert-butyl N-[[2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]amino]carbamate (43.12 g, 107.2 mmol) in CHCl (200 mL) was added HCl (100 mL of 4 M, 400.0 mmol), and the mixture was stirred at ambient temperature for 7 h. The solvent was removed in vacuo, the residue was stripped twice from heptane, and the resulting solid was dried under high vacuum for 20 h to give 2-benzyloxy-2-(trifluoromethyl)hex-5-enehydrazide (hydrochloride salt) (35 g, 96%). 1 H NMR(400MHz,chloroform-d)δ 9.92(s,2H),7.41-7.31(m,2H),7.30-7.24(m,2H),7.24-7.16(m,1H),5.72-5.57(m,1H),5.02-4.8 7(m,2H),4.71(d,J=10.9Hz,1H),4.62(d,J=11.0Hz,1H),3.70(s,2H),2.34-1.85(m,4H)ppm.ESI-MS m / z calculated value 302.1242, actual value 303.2(M+1) + ; Retention time: 1.5 minutes (LC method A).

[0305] Intermediate 4: Preparation of tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate [ka]

[0306] Step 1: tert-butyl N-[2-[[[2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate [ka] To a mixture of 6-bromo-3-(tert-butoxycarbonylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid (239.2 g, 621.1 mmol) and 2-benzyloxy-2-(trifluoromethyl)hex-5-enehydrazide (hydrochloride) (230.1 g, 761.2 mmol) in ethyl acetate (2.2 L) was added pyridine (200 mL, 2.473 mol) at ambient temperature to give a precipitate. 1-Propanephosphonic anhydride (500 g, 50% w / w, 785.7 mmol) was added, and the reaction mixture was stirred at ambient temperature for 12 hours. The reaction was quenched by the slow addition of a solution of NaOH (149 g, 50% w / w, 1.863 mol) in water (2 L), and the mixture was stirred for 15 minutes. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (1 L). The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. After removing half of the solvent, the organic phase was washed twice with aqueous HCl (1000 mL of 1 M, 1 mol). The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was slurried in warm heptane (2.5 L) and MTBE (0.25 L), and the mixture was stirred at ambient temperature for 12 hours to give a pale yellow slurry. The slurry was filtered and the resulting filter cake was washed twice with 10% MTBE / heptane (1 L). The off-white solid was air-dried for 2 hours and then vacuum-dried at 40° C. for 20 hours to give tert-butyl N-[2-[[[2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (379.9 g, 91%). 1 H NMR(400MHz,DMSO-d6)δ 11.09(s,1H),10.92(s,1H),10.35(s,1H),9.15(s,1H),7.50(d,J=7.4Hz,2H),7.36(m,3H),5.87(m,1H),5.09 (d,J=16.9Hz,1H),5.02(d,J=10.1Hz,1H),4.84(q,J=11.4Hz,2H),2.35-2.12(m,4H),1.49(s,9H)ppm.ESI-MS m / z calculated value 668.1069, actual value 670.9(M+1) + ; Retention time: 3.5 minutes (LC method D).

[0307] Step 2: tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate [ka] tert-Butyl N-[2-[[[2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (102 g, 150.8 mmol) was dissolved in anhydrous acetonitrile (1000 mL) and DIEA (92 mL, 528.2 mmol) was added. The resulting orange solution was heated to 70 °C (internal temperature) to give a clear yellow solution. p-Toluenesulfonyl chloride (37.4 g, 196.2 mmol) was then added in three equal portions (12.47 g) at 10 minute intervals, and the reaction was heated for an additional 30 minutes. The reaction was cooled to room temperature, and the acetonitrile was concentrated under reduced pressure. MTBE (1000 mL) was added to the mixture, followed by 800 mL of water. The mixture was stirred and the layers were separated. The organic layer was washed with a solution of citric acid (36.3 g, 188.9 mmol) in 700 mL of water, then 400 mL of saturated NaHCO3, then 300 mL of brine. The organic layer was then dried over anhydrous MgSO4 and concentrated under reduced pressure. This material was purified by silica gel chromatography using a 15% to 50% gradient of 8% ethyl acetate in hexanes to afford tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (91.7 g, 93%). 1H NMR(400MHz,chloroform-d)δ 10.18(s,1H),9.35(s,1H),7.55-7.47(m,2H),7.45-7.37(m,2H),7.36-7.28(m,1H),5.83-5.68(m,1H),5. 10-4.93(m,2H),4.82(d,J=10.5Hz,1H),4.69(d,J=10.5Hz,1H),2.59-2.13(m,4H),1.56(s,9H)ppm.ESI-MS m / z calculated value 650.0963, actual value 651.0(M+1) + ; Retention time: 3.81 minutes (LC method D).

[0308] Intermediate 5: Preparation of (2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoic acid [ka]

[0309] Step 1: (2R)-2-Benzyloxy-2-(trifluoromethyl)hex-5-enoic acid; (R)-4-quinolyl-[(2S,4S)-5-vinylquinuclidin-2-yl]methanol [ka] Isopropyl acetate (IPAC, 100 L, 0.173 M, 20 vol) was added to an N2-purged, jacketed reactor set at 20 °C, followed by pre-melted 2-benzyloxy-2-(trifluoromethyl)hex-5-enoic acid (5.00 kg, 17.345 mol) and cinchonidine (2.553 kg, 8.67 mol) to create a slurry containing a small amount of reaction solvent. The reactor was set to increase to an internal temperature of 80 °C over 1 h. After heating to the set temperature, the solids went into solution, and the solution was held at that temperature for at least 10 min. It was then cooled to 70 °C, held, and seeded with the chiral salt (50 g, 1.0 wt%). The mixture was stirred for 10 min, then increased to an internal temperature of 20 °C over 4 h and then held at 20 °C overnight. The mixture was filtered, and the cake was washed with isopropyl acetate (10.0 L, 2.0 vol) and dried under vacuum. The cake was then vacuum dried (50°C, vacuum) to yield 4.7 kg of salt. The resulting solid salt was slurried back into the reactor with a portion of the isopropyl acetate (94 L, 20 volumes based on the current salt weight), pumped into the reactor, and stirred. The mixture was then heated to an internal temperature of 80°C, and the hot slurry was stirred for at least 10 minutes, then allowed to rise to 20°C over 4-6 hours and then stirred at 20°C overnight. The material was then filtered, and the cake was washed with isopropyl acetate (9.4 L, 2.0 volumes), removed dry, and skimmed and vacuum dried (50°C, vacuum) to yield 3.1 kg of solid. The solids (3.1 kg) and isopropyl acetate (62 L, 20 volumes based on the salt solids weight) were slurried, added to a reactor, purged with N, stirred, heated to 80°C, held at that temperature for at least 10 minutes, then allowed to rise to 20°C over 4-6 hours and stirred overnight. The mixture was filtered, the cake washed with isopropyl acetate (6.2 L, 2 volumes), removed dry, skimmed, and vacuum dried (50°C, vacuum) to yield 2.25 kg of solid salt. The solids (2.25 kg) and isopropyl acetate (45 L, 20 volumes based on the salt solids weight) were slurried, added to a reactor, purged with N, stirred, heated to 80°C, held at that temperature for at least 10 minutes, then allowed to rise to 20°C over 4-6 hours and stirred overnight.The mixture was filtered, and the cake was washed with isopropyl acetate (4.5 L, 2 volumes), drained dry, skimmed, and dried under vacuum (50° C.) to give (2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoic acid; (R)-4-quinolyl-[(2S,4S)-5-vinylquinuclidin-2-yl]methanol (1.886 kg, >98.0% enantiomeric excess) as an off-white to tan solid. Chiral purity was determined by an Agilent 1200 HPLC instrument using a Phenomenex Lux i-Amylose-3 column (3 μm, 150 × 4.6 mm) and a double isocratic gradient run of 30% to 70% mobile phase B over 20 min (mobile phase A = HO (0.1% CFCOH), mobile phase B = MeOH (0.1% CFCOH), flow rate = 1.0 mL / min, injection volume = 2 μL, and column temperature = 30 °C, sample concentration: 1 mg / mL in 60% acetonitrile / 40% water).

[0310] Step 2: (2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoic acid [ka] A suspension of (2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoic acid; (R)-4-quinolyl-[(2S,4S)-5-vinylquinuclidin-2-yl]methanol (50 g, 87.931 mmol) in ethyl acetate (500 mL) was treated with aqueous hydrochloric acid (200 mL of 1 M, 200 mmol). After stirring at room temperature for 15 minutes, the two phases were separated. The aqueous phase was extracted twice with ethyl acetate (200 mL). The combined organic layers were washed with 1 N HCl (100 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated. This material was dried overnight under high vacuum to give (2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoic acid (26.18 g, 96%) as a light brown oil. 1H NMR(400MHz,CDCl3)δ 7.46-7.31(m,5H),5.88-5.73(m,1H),5.15-4.99(m,2H),4.88(d,J=10.3Hz,1H),4.70(d,J=10.3Hz,1H),2.37-2.12(m,4H)ppm. 19 F NMR (377 MHz, CDCl3) δ -71.63 (br s, 3F) ppm. ESI-MS m / z calculated 288.0973, found 287.0 (M-1). - ; Retention time: 2.15 minutes (LC method B).

[0311] Intermediate 6: Preparation of (2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enehydrazide [ka]

[0312] Step 1: tert-butyl N-[[(2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]amino]carbamate [ka] To a solution of (2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoic acid (365 g, 1.266 mol) in DMF (2 L) was added HATU (612 g, 1.610 mol) and DIEA (450 mL, 2.584 mol), and the mixture was stirred at ambient temperature for 10 minutes. tert-Butyl N-aminocarbamate (200 g, 1.513 mol) was added (slight exotherm upon addition) and the mixture was stirred at ambient temperature for 16 hours. The reaction was poured into ice-water (5 L). The resulting precipitate was collected by filtration and washed with water. The solid was dissolved in ethyl acetate (2 L) and washed with brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The oil was diluted with ethyl acetate (500 mL), followed by heptane (3 L), and stirred at ambient temperature for several hours to give a thick slurry. The slurry was diluted with additional heptane and filtered to give a fluffy white solid (343 g). The filtrate was concentrated and purified by silica gel chromatography (0-40% ethyl acetate / hexanes) to give tert-butyl N-[[(2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]amino]carbamate (464 g, 91%, combined with product from crystallization). ESI-MS m / z calculated 402.17664, found 303.0 (M+1-Boc). + ; Retention time: 2.68 minutes (LC method D).

[0313] Step 2: (2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enehydrazide [ka] To a solution of tert-butyl N-[[(2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]amino]carbamate (464 g, 1.153 mol) in dichloromethane (1.25 L) was added HCl (925 mL of 4 M, 3.700 mol), and the mixture was stirred at ambient temperature for 20 h. The mixture was concentrated in vacuo to remove most of the DCM. The mixture was diluted with isopropyl acetate (1 L) and basified to pH = 6 with NaOH (140 g of 50% w / w, 1.750 mol) in 1 L of ice water. The organic phase was separated and washed with 1 L of brine, and the combined aqueous phases were extracted with isopropyl acetate (1 L). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo to give a dark yellow oil. (2R)-2-Benzyloxy-2-(trifluoromethyl)hex-5-enehydrazide (358 g, quantitative) 1 H NMR(400MHz,CDCl3)δ 8.02(s,1H),7.44-7.29(m,5H),5.81(m,J=16.8,10.1,6.4Hz,1H),5.13-4.93(m,2H),4.75(dd,J=10.5,1.5H z,1H),4.61(d,J=10.5Hz,1H),3.78(s,2H),2.43(m,J=14.3,11.0,5.9Hz,1H),2.26-1.95(m,3H)ppm.ESI-MS m / z calculated value 302.1242, actual value 303.0(M+1) + ; Retention time: 2.0 minutes (LC method D).

[0314] Intermediate 7: Preparation of tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate [ka]

[0315] Step 1: tert-butyl N-[2-[[[(2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate [ka] To a mixture of 6-bromo-3-(tert-butoxycarbonylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid (304 g, 789.3 mmol) and (2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enehydrazide (270 g, 893.2 mmol) in ethyl acetate (2.25 L) was added DIEA (425 mL, 2.440 mol) at ambient temperature. Using an ice-water bath to keep the temperature below 35°C, T3P (622 g of 50% w / w, 977.4 mmol) was slowly added (the temperature rose to 34°C), and the reaction mixture was stirred at ambient temperature for 18 hours. Additional DIEA (100 mL, 574.1 mmol) and T3P (95 g, 298.6 mmol) were added, and the mixture was stirred at ambient temperature for 2 days. Since starting material was still observed, additional T3P (252 g, 792 mmol) was added and stirred for 5 days. Water (2.5 L) was slowly added to quench the reaction, and the mixture was stirred for 30 minutes. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (2 L). The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was dissolved in MTBE (300 mL), diluted with heptane (3 L), and the mixture was stirred at ambient temperature for 12 hours to give a pale yellow slurry. The slurry was filtered, and the resulting solid was air-dried for 2 hours, then vacuum-dried at 40 °C for 48 hours. The filtrate was concentrated in vacuo, purified by silica gel chromatography (0–20% ethyl acetate / hexanes), and combined with the material obtained from the crystallization to give tert-butyl N-[2-[[[(2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (433 g, 82%). 1H NMR(400MHz,DMSO)δ 11.07(s,1H),10.91(s,1H),10.32(s,1H),9.15(s,1H),7.53-7.45(m,2H),7.45-7.28(m,3H),5.87(m,J=17.0,10.2,5.1Hz,1H ),5.09(m,J=17.1,1.3Hz,1H),5.02(dd,J=10.3,1.9Hz,1H),4.84(q,J=11.3Hz,2H),2.37-2.13(m,4H),1.49(s,9H)ppm.ESI-MS m / z calculated value 668.1069, actual value 669.0(M+1) + ; Retention time: 3.55 minutes (LC method FF).

[0316] Step 2: tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate [ka] To a solution of tert-butyl N-[2-[[[(2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (240 g, 358.5 mmol) in anhydrous acetonitrile (1.5 L) was added DIEA (230 mL, 1.320 mol) under nitrogen, and the orange solution was heated to 70°C. To the mixture was added p-toluenesulfonyl chloride (80.5 g, 422.2 mmol) in three equal portions over 1 hour. The mixture was stirred at 70°C for 9 hours, after which additional p-toluenesulfonyl chloride (6.5 g, 34.09 mmol) was added. The mixture was stirred for a total of 24 hours and then allowed to cool to ambient temperature. The acetonitrile was removed in vacuo to give a thick orange oil, which was diluted with ethyl acetate (1.5 L) and water (1.5 L). The organic phase was separated, washed with 500 mL of 1 M HCl, 500 mL of brine, dried over MgSO, filtered, and concentrated in vacuo. Purification by silica gel chromatography (0–20% ethyl acetate / hexanes) gave tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (200 g, 86%). 1 H NMR(400MHz,DMSO)δ 10.11(s,1H),9.10(s,1H),7.55-7.48(m,2H),7.47-7.28(m,3H),5.87 (m,J=16.7,10.2,6.4Hz,1H),5.11(m,J=17.2,1.7Hz,1H),5.01(m,J=1 0.2,1.5Hz,1H),4.74(d,J=10.6Hz,1H),4.65(d,J=10.6Hz,1H),2.55-2.42(m,2H),2.30(m,J=11.3,10.3,6.9Hz,2H),1.52(s,9H)ppm.ESI-MS m / z Calculated value 650.0963, measured value 650.0 (M+1) + ; Retention time: 3.78 minutes (LC method FF).

[0317] Intermediate 8: Preparation of methyl 3-[bis(tert-butoxycarbonyl)amino]-6-pent-4-enoyl-5-(trifluoromethyl)pyridine-2-carboxylate [ka]

[0318] Step 1: Methyl 3-[bis(tert-butoxycarbonyl)amino]-6-(1-ethoxyvinyl)-5-(trifluoromethyl)pyridine-2-carboxylate [ka] To an oven-dried three-neck flask (1 L) equipped with a magnetic stir bar was added methyl 3-[bis(tert-butoxycarbonyl)amino]-6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate (10 g, 20.03 mmol) and PdCl2(PPh3)2 (1.4 g, 1.995 mmol). The flask was evacuated and filled with nitrogen gas three times. Tributyl(1-ethoxyvinyl)stannane (7.6 g, 21.04 mmol) in dioxane (200 mL) was injected through a septum under an inert atmosphere. The mixture was stirred at 75 °C for 14 h. The mixture was cooled to room temperature, filtered through a Celite pad, washed with ethyl acetate, and concentrated. Purification by silica gel chromatography (15:85 ethyl acetate:hexanes) gave methyl 3-[bis(tert-butoxycarbonyl)amino]-6-(1ethoxyvinyl)-5-(trifluoromethyl)pyridine-2-carboxylate (8.6 g, 88%). 1 H NMR (400 MHz, chloroform-d) δ 7.89 (s, 1H), 4.78 (d, J = 2.7 Hz, 1H), 4.52 (d, J = 2.8 Hz, 1H), 3.97-3.92 (m, 5H), 1.42-1.36 (m, 21H) ppm. ESI-MS m / z calculated 490.1927, found 491.2 (M+1). + ; Retention time: 1.52 minutes (LC method J).

[0319] Step 2: Methyl 3-[bis(tert-butoxycarbonyl)amino]-6-(2-bromoacetyl)-5-(trifluoromethyl)pyridine-2-carboxylate [ka] 1-Bromopyrrolidine-2,5-dione (3.4 g, 19.10 mmol) was added to a solution of methyl 3-[bis(tert-butoxycarbonyl)amino]-6-(1-ethoxyvinyl)-5-(trifluoromethyl)pyridine-2-carboxylate (8.5 g, 17.33 mmol) in 100 mL of THF and 20 mL of water. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with a solution of NaHCO3, extracted with dichloromethane (3 × 100 mL), washed with brine, and the organic layers were combined, dried over sodium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (15:85 ethyl acetate:hexanes) gave methyl 3-[bis(tert-butoxycarbonyl)amino]-6-(2-bromoacetyl)-5-(trifluoromethyl)pyridine-2-carboxylate (8.0 g, 85%). 1 H NMR (400 MHz, chloroform-d) δ 8.04 (s, 1H), 4.74 (s, 2H), 3.99 (s, 3H), 1.43 (s, 18H) ppm. ESI-MS m / z calculated 540.0719, found 542.0 (M+1). + ; Retention time: 0.7 minutes (LC method M).

[0320] Step 3: Methyl 3-[bis(tert-butoxycarbonyl)amino]-6-pent-4-enoyl-5-(trifluoromethyl)pyridine-2-carboxylate [ka] To an oven-dried 250 mL flask were added methyl 3-[bis(tert-butoxycarbonyl)amino]-6-(2-bromoacetyl)-5-(trifluoromethyl)pyridine-2-carboxylate (8 g, 14.78 mmol) and allyl(tributyl)stannane (5.2 g, 15.70 mmol) along with benzene (100 mL). 2-[(E)-(1-cyano-1-methyl-ethyl)azo]-2-methyl-propanenitrile (2.5 g, 15.22 mmol) was then added, and the flask was evacuated and backfilled with nitrogen three times. The mixture was stirred at 70 °C for 15 h. The reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure. Purification by silica gel chromatography (0-15% ethyl acetate in hexanes) gave methyl 3-[bis(tert-butoxycarbonyl)amino]-6-pent-4-enoyl-5-(trifluoromethyl)pyridine-2-carboxylate (5.7 g, 77%). 1 H NMR(400MHz,chloroform-d)δ 7.98(s,1H),5.89(m,1H),5.10(m,J=17.1,1.6Hz,1H),5.02(m,J=10.2,1.4Hz,1H ),3.98(s,3H),3.26(t,J=7.4Hz,2H),2.60-2.44(m,2H),1.43(s,18H)ppm.ESI-MS m / z calculated value 502.1927, actual value 503.2(M+1) + ; Retention time: 1.58 minutes (LC method J).

[0321] Intermediate 9: Preparation of 3-(tert-butoxycarbonylamino)-6-pent-4-enoyl-5-(trifluoromethyl)pyridine-2-carboxylic acid [ka] To a solution of methyl 3-[bis(tert-butoxycarbonyl)amino]-6-pent-4-enoyl-5-(trifluoromethyl)pyridine-2-carboxylate (4.1 g, 8.160 mmol) in 50 mL of THF was added MeOH (40 mL) and water (30 mL). LiOH (587 mg, 24.51 mmol) was added in three portions (approximately 196 mg each at 5-minute intervals) to the mixture. The mixture was stirred at 60 °C for 1 hour. After removing the THF and methanol under reduced pressure, 22 mL of HCl (10%, approximately 25 mmol) was added, and the organic compound was extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0% to 50% ethyl acetate in hexanes) gave 3-(tert-butoxycarbonylamino)-6-pent-4-enoyl-5-(trifluoromethyl)pyridine-2-carboxylic acid (2.4 g, 76%). 1 H NMR(400MHz,chloroform-d)δ 10.86(bs,1H),10.40(s,1H),9.46(s,1H),6.32-5.67(m,1H),5.34-4.77 (m,2H),3.16(t,J=7.3Hz,2H),2.83-2.29(m,2H),1.56(s,9H)ppm.ESI-MS m / z calculated value 388.1246, actual value 389.0(M+1) + ; Retention time: 1.45 minutes (LC method J).

[0322] Intermediate 10: Preparation of methyl 3-(tert-butoxycarbonylamino)-6-pent-4-enoyl-5-(trifluoromethyl)pyridine-2-carboxylate [ka] Methyl 3-[bis(tert-butoxycarbonyl)amino]-6-pent-4-enoyl-5-(trifluoromethyl)pyridine-2-carboxylate (2.21 g, 4.3982 mmol) was dissolved in ethyl acetate (55 mL) and treated with silica gel (18.5 g, 307.90 mmol). The reaction was stirred at 80° C. overnight. The reaction was filtered and concentrated to give methyl 3-(tert-butoxycarbonylamino)-6-pent-4-enoyl-5-(trifluoromethyl)pyridine-2-carboxylate (1.98 g, quantitative) as a yellow solid. ESI-MS m / z calculated 402.1403, found 403.2 (M+1). + ; Retention time: 2.42 minutes (LC method B).

[0323] Preparation of Intermediate 11: 6-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylic acid [ka]

[0324] Step 1: Methyl 6-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate [ka] To a solution of tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (5.18 g, 7.9522 mmol) in MeOH (200 mL) was added TEA (2.5410 g, 3.5 mL, 25.111 mmol). After purging the reaction with nitrogen for 5 minutes, Pd(dppf)Cl (604.1 mg, 0.8091 mmol) was added to the reaction mixture. The reaction was then stirred at 80 °C under 50 psi of carbon monoxide for 6 hours. After cooling the reaction to room temperature, the MeOH was removed in vacuo. The residue was diluted with ethyl acetate (100 mL) and water (100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with saturated aqueous NaCl (100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (0–20% ethyl acetate / hexanes) afforded methyl 6-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate (3.10 g, 62%) as a pale yellow semisolid. ESI-MS m / z calculated 630.1913, found 631.5 (M+1); retention time: 3.94 min (LC Method G).

[0325] Step 2: 6-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylic acid [ka] To a solution of methyl 6-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate (3.10 g, 4.9165 mmol) in a solvent mixture of THF (38 mL) and DI water (12 mL) was added LiOH (water (1)) (1.06 g, 25.260 mmol). The reaction mixture turned yellow. The reaction was stirred at room temperature for 24 hours. The reaction mixture was acidified to pH 5 using 1 M aqueous HCl and diluted with water (100 mL) and ethyl acetate (100 mL). The two layers were separated, and the ethyl acetate layer was washed with DI H2O (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (0% to 5% methanol in dichloromethane buffered with 0.3% acetic acid) afforded 6-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylic acid (1.22 g, 36%) as a white foamy solid. 1 H NMR(500MHz,DMSO-d6)δ 10.27(s,1H),9.12(s,1H),7.57-7.48(m,2H),7.43-7.36(m,2H),7.37-7.31(m,1H),5.95-5.81(m,1H),5.18-5.07(m,1H) ),5.07-4.95(m,1H),4.74-4.59(m,2H),2.58-2.50(m,2H),2.48-2.40(m,1H),2.38-2.22(m,2H),1.53(s,9H)ppm.ESI-MS m / z calculated value 616.17566, actual value 617.2(M+1) + ; Retention time: 3.49 minutes (LC method G).

[0326] Preparation of Intermediate 12: 6-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylic acid [ka] To tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (3.08 g, 4.728 mmol) in ether (45 mL) at −78° C. was added n-BuLi (4.2 mL of 2.5 M, 10.5 mmol) as a hexane solution, and the mixture was stirred at −78° C. for 15 minutes, then warmed to 0° C. for 5 seconds, and a small piece of solid CO was added. The mixture was stirred at 0° C. for 15 minutes. The mixture was diluted with citric acid (15 mL of 1 M, 15 mmol) to pH 4, and ethyl acetate was added. The organic layer was separated, washed with water, brine, dried (MgSO), and evaporated. Purification by silica gel chromatography (5–50% solution (10% MeOH in ethyl acetate) to hexanes) afforded 6-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylic acid (1.67 g, 53%). 1 H NMR (400 MHz, chloroform-d) δ 10.45 (s, 1H), 9.61 (s, 1H), 7.48-7.28 (m, 5H), 5.78 (m, J = 16.7, 10.2, 6.4 Hz, 1H), 5.07 (m, J = 17.1, 1.6 Hz, 1H), 5.00 (d, J = 1.5 Hz, 1H), 4.84 (d, J = 11.0 Hz, 1H), 4.69 (d, J = 11.0 Hz, 1H), 2.65-2.44 (m, 2H), 2.43-2.33 (m, 1H), 2.32-2.14 (m, 1H), 1.59 (s, 9H) ppm; 19 F NMR (376 MHz, chloroform-d) δ -61.10, -72.83 ppm. ESI-MS m / z calculated 616.17566, found 617.2 (M+1). + ; Retention time: 0.42 minutes (LC method T).

[0327] Intermediate 13: Preparation of 2-benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (hydrochloride) [ka]

[0328] Step 1: Ethyl 2-hydroxy-2-(trifluoromethyl)pent-4-enoate [ka] To a solution of ethyl 3,3,3-trifluoro-2-oxopropanoate (30 g, 176.38 mmol) in diethyl ether (300 mL) was added allyl(bromo)magnesium (185 mL 1 M, 185 mmol) dropwise over 3 h at −78 °C (internal temperature: −74 °C to −76 °C). The mixture was stirred at −78 °C for 45 min. The dry ice-acetone bath was removed. The mixture was allowed to warm to approximately 10 °C over a 1 h period and added to a mixture of 1 N aqueous HCl (210 mL) and crushed ice (400 g) (pH 4). The mixture was extracted with ethyl acetate, washed with 5% aqueous NaHCO₃, brine, and dried over anhydrous Na₂SO₄. The mixture was filtered, concentrated, and coevaporated with hexane to give ethyl 2-hydroxy-2-(trifluoromethyl)pent-4-enoate (42.2 g, 90%) as a pale yellow oil. 1 H NMR(300MHz,CDCl3)δ 1.33(t,J=7.1Hz,3H),2.60-2.79(m,2H),3.84(br.s.,1H),4.24-4.48(m,2H),5.09-5.33(m,2H),5.59-5.82(m,1H)ppm. 19 F NMR(282MHz,CDCl3)δ -78.5(s,3F)ppm.

[0329] Step 2: Ethyl 2-benzyloxy-2-(trifluoromethyl)pent-4-enoate [ka] To a solution of ethyl 2-hydroxy-2-(trifluoromethyl)pent-4-enoate (18.56 g, 83.105 mmol) in DMF (100 mL) was added NaH (5.3 g, 60% w / w, 132.51 mmol) at 0° C. The reaction was stirred for 15 minutes, and then benzyl bromide (21.14 g, 15 mL, 121.12 mol) and tetrabutylammonium iodide (8.5 g, 23.012 mmol) were added. The mixture was stirred overnight at room temperature. The reaction was quenched with water (300 mL) and extracted with ethyl acetate (3×300 mL), then washed with brine (500 mL), and dried over sodium sulfate. Purification by silica gel chromatography (20% to 60% dichloromethane in hexanes) gave ethyl 2-benzyloxy-2-(trifluoromethyl)pent-4-enoate (22.01 g, 70%) as a colorless oil. 1 H NMR(250MHz,CDCl3)δ 7.55-7.25(m,5H),6.00-5.80(m,1H),5.30-5.10(m,2H),4.86(d,J=10.5Hz,1H),4.68(d,J= 10.5Hz,1H),4.33(q,J=7.0Hz,2H),2.81(d,J=7.0Hz,2H),1.34(t,J=7.1Hz,3H)ppm.ESI-MS m / z calculated value 302.113, actual value 303.5(M+1)+; retention time: 4.14 minutes (LC method G).

[0330] Step 3: 2-Benzyloxy-2-(trifluoromethyl)pent-4-enoic acid [ka] To a solution of ethyl 2-benzyloxy-2-(trifluoromethyl)pent-4-enoate (28.99 g, 95.902 mmol) in methanol (150 mL) was added a solution of NaOH (7.6714 g, 191.80 mmol) in water (50 mL). The reaction mixture was stirred at 40 °C for 3 hours. The reaction mixture was concentrated in vacuo, and the residue was diluted with water (200 mL) and washed with diethyl ether (200 mL). The aqueous layer was acidified to pH 1 with concentrated HCl and extracted with diethyl ether (3 × 200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 2-benzyloxy-2-(trifluoromethyl)pent-4-enoic acid (28.04 g, 99%) as a pale yellow liquid. 1 H NMR(250MHz,CDCl3)δ 7.55-7.28(m,5H),5.97-5.69(m,1H),5.33-5.17(m,2H),4.95-4.66(m,2H),2.91(d,J=7.1Hz,2H)ppm.

[0331] Step 4: tert-Butyl N-[[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamate [ka] To a solution of 2-benzyloxy-2-(trifluoromethyl)pent-4-enoic acid (300 g, 1.094 mol) in DMF (2 L) were added HATU (530 g, 1.394 mol) and DIEA (400 mL, 2.296 mol), and the mixture was stirred at ambient temperature for 10 minutes. To the mixture was added tert-butyl N-aminocarbamate (152 g, 1.150 mol), and the mixture was stirred at ambient temperature for 36 hours. The reaction was quenched with cold water (4 L), and the mixture was extracted twice with ethyl acetate (2 L). The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (0-40% ethyl acetate / hexanes) gave tert-butyl N-[[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamate (386.49 g, 91%) as an oil, which slowly crystallized to give an off-white solid.1 H NMR(400MHz,DMSO)δ 10.00(d,J=37.9Hz,1H),8.93(s,1H),7.46-7.39(m,2H),7.38-7.29(m,3H),6.01-5.64(m,1H),5.32( d,J=17.1Hz,1H),5.17(d,J=10.1Hz,1H),4.77(s,2H),2.96(m,2H),1.39(d,J=17.3Hz,9H)ppm.ESI-MS m / z calculated value 388.16098, actual value 389.0(M+1)+; retention time: 2.51 minutes (LC method D).

[0332] Step 5: 2-Benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (hydrochloride) [ka] To a solution of tert-butyl N-[[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamate (98.5 g, 240.94 mmol) in dichloromethane (400 mL) was added HCl in dioxane (200 mL of 4 M, 800 mmol). The mixture was stirred at room temperature for 2 hours, concentrated, and coevaporated with dichloromethane and hexane to give 2-benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (hydrochloride salt) (81.15 g, 97%) as an off-white solid. 1 H NMR(500MHz,DMSO-d6)δ 11.07(s,1H),7.70-7.16(m,5H),5.87-5.61(m,1H),5.45-5.09(m,2H),4.7 9(s,2H),3.6-3.4(m,2H),3.23-3.07(m,1H),3.04-2.87(m,1H)ppm.ESI-MS m / z calculated value 288.10855, actual value 289.2(M+1) + ; Retention time: 2.0 minutes (LC method H).

[0333] Intermediate 14: Preparation of tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate [ka]

[0334] Step 1: tert-butyl N-[2-[[[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate [ka] To a mixture of 6-bromo-3-(tert-butoxycarbonylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid (53 g, 137.6 mmol) and 2-benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (hydrochloride) (55 g, 169.4 mmol) in ethyl acetate (500 mL) was added pyridine (44 mL, 544 mmol). T3P (111 g, 50% w / w, 174.4 mmol) was added, and the reaction mixture was stirred at ambient temperature for 12 hours. The reaction was quenched by the slow addition of a solution of NaOH (35 g, 50% w / w, 437.5 mmol) in water (500 mL), and the mixture was stirred for 15 minutes. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (500 mL). The combined organic phases were washed with HCl (250 mL of 1 M, 250 mmol), brine, dried over MgSO, filtered, and concentrated in vacuo. Purification by silica gel chromatography (0–20% ethyl acetate / hexanes in hexanes) afforded tert-butyl N-[2-[[[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (66 g, 73%) as a pale pink solid. 1H NMR(400MHz,DMSO)δ 11.11(s,1H),10.91(s,1H),10.40(s,1H),9.16(s,1H),7.47(d,J=6.9Hz,2H),7.42-7.29(m,3H),5.91(m,J=17.1,10.6,7.1Hz,1 H),5.37(dd,J=17.2,1.9Hz,1H),5.22(dd,J=10.4,1.8Hz,1H),4.85(d,J=2.1Hz,2H),3.20-2.91(m,2H),1.50(s,9H)ppm.ESI-MS m / z calculated value 654.09125, actual value 657.0(M+1) + ; Retention time: 3.49 minutes (LC method FF).

[0335] Step 2: tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate [ka] A solution of tert-butyl N-[2-[[[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (2.15 g, 3.2641 mmol) and DIEA (1.12 g, 1.5 mL, 8.6117 mmol) in acetonitrile (43 mL) was heated at 50 °C, and then p-toluenesulfonyl chloride (765 mg, 4.0127 mmol) was added in portions at 50 °C. The resulting mixture was stirred at 70 °C for 2 hours. The reaction mixture was cooled, basified with a saturated solution of sodium bicarbonate (100 mL), and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (0% to 10% ethyl acetate in heptane) afforded tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (1.7 g, 80%) as a yellow viscous oil. 1 H NMR(300MHz,CDCl3)δ 10.18(br.s,1H),9.33(br.s,1H),7.53-7.27(m,5H),6.00-5.83(m,1H),5.32-5.1 3(m,2H),4.86-4.76(m,1H),4.73-4.64(m,1H),3.27-3.11(m,2H),1.55(s,9H)ppm. 19 F NMR(282MHz,CDCl3)δ -63.78(s,3F),-72.93(s,3F)ppm.Retention time: 2.7 minutes (LC method O).

[0336] Intermediate 15: Preparation of tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate [ka]

[0337] Step 1: tert-butyl N-[2-[[[(2S)-2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate and tert-butyl N-[2-[[[(2R)-2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate [ka] Racemic tert-butyl N-[2-[[[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (24.5 g, 37.38 mmol) was purified by preparative chiral SFC by injection of 500 μL of a 32 mg / mL solution onto a ChiralPak IC (250 × 21.2 mm) 5 μm column eluted with 8% MeOH (20 mM NH) and 92% CO at 40 °C and 70 mL / min. Enantiomer 1 eluted first (peak 1 at 4.17 min at room temperature) to give tert-butyl N-[2-[[[(2S)-2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (11.73 g, 96%). 1 H NMR(400MHz,chloroform-d)δ 10.59(s,1H),9.83(s,1H),9.28(s,1H),9.02(d,J=29.6Hz,1H),7.48-7.33(m,5H),5.96-5.77(m,1H),5.41(d,J=1.6 Hz,1H),5.36-5.29(m,1H),4.86(s,2H),3.19(dd,J=15.5,5.9Hz,1H),3.03(dd,J=15.5,7.8Hz,1H),1.53(s,9H)ppm; 19F NMR (376 MHz, chloroform-d) δ -63.89, -73.76 ppm. ESI-MS m / z calculated 654.09125, found 655.3 (M+1). + ; Retention time: 0.53 minutes (LC method T). The later eluting enantiomer 2 (peak 2 at 6.63 min at room temperature) gave tert-butyl N-[2-[[[(2R)-2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (11.62 g, 95%). 1 H NMR(400MHz,chloroform-d)δ 10.59(s,1H),9.74(s,1H),9.28(s,1H),9.06(s,1H),7.39(d,J=4.4Hz,5H),6.02-5.79(m,1H),5.44-5.36(m,1H),5.34 (dd,J=10.3,1.3Hz,1H),4.91-4.81(m,2H),3.19(dd,J=15.4,5.8Hz,1H),3.03(dd,J=15.5,7.8Hz,1H),1.53(s,9H)ppm; 19 F NMR (376 MHz, chloroform-d) δ -63.89, -73.76 ppm. ESI-MS m / z calculated 654.09125, found 657.2 (M+1). + ; Retention time: 0.53 minutes (LC method T).

[0338] Step 2: tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate [ka] tert-Butyl N-[2-[[[(2R)-2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (enantiomer 2; 24.97 g, 38.10 mmol) was dissolved in anhydrous acetonitrile (200 mL) under nitrogen to produce a clear yellow solution. DIEA (19.91 mL, 114.3 mmol) was added, causing the solution to turn orange. The solution was heated to 70 °C, and then p-TsCl (7.99 g, 41.91 mmol) was added in three portions at 30 min intervals. The mixture was heated for approximately 3 h. The reaction mixture was cooled to room temperature, and most of the MeCN was evaporated by rotary evaporation at 45 °C. 145 mL of MTBE, followed by a solution of citric acid (11.0 g, 57.25 mmol) in 250 mL of water, was added and stirred, followed by 73 mL of hexane. The layers were separated, and the aqueous layer was extracted with MTBE. The combined organic layers were dried over MgSO4 and concentrated on a rotary evaporator at 45 °C. Purification by silica gel chromatography (15% to 80% 10% ethyl acetate / hexane in hexane) gave tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (20.47 g, 84%). 1 H NMR(400MHz,chloroform-d)δ 10.18(s,1H),9.34(s,1H),7.48(d,J=7.1Hz,2H),7.39(t,J=7.5Hz,2H),7.31(t,J=7.3Hz,1H),6.00-5.81(m,1H),5.25(d,J=17.1, ESI-MS m / z calculated value 636.0807, actual value 637.3(M+1) + ; Retention time: 3.81 minutes (LC method FF).

[0339] Preparation of Intermediate 16: 6-[5-[1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylic acid [ka] A solution of tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (570 mg, 0.8943 mmol) in ether (12 mL) was added with n-BuLi (830 μL of 2.5 M, 2.075 mmol) and stirred at −78° C. for 15 min. The mixture was then warmed to 0° C. in 5 s and a small piece of solid CO was added. The mixture was stirred at 0° C. for 15 min. The mixture was diluted with ethyl acetate, and 2.8 mL of 1 M citric acid was added to change the pH to 4 by paper. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried (MgSO), and evaporated. Purification by silica gel chromatography (10–20% ethyl acetate in hexanes) afforded 6-[5-[1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylic acid (326 mg, 54%). 1 H NMR (400 MHz, chloroform-d) δ 10.38 (s, 1H), 9.55 (s, 1H), 7.33 (s, 5H), 5.90 (s, 1H), 5.31-5.11 (m, 2H), 4.88-4.76 (m, 1H), 4.68 (s, 1H), 3.21 (d, J = 7.6 Hz, 2H), 1.58 (s, 9H) ppm; 19 F NMR (376 MHz, chloroform-d) δ -61.04, -73.19 ppm. ESI-MS m / z calculated 602.16003, found 603.1 (M+1). + ; Retention time: 0.8 minutes (LC method S).

[0340] Preparation of Intermediate 17: 6-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylic acid [ka] To tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (4.7 g, 7.005 mmol) in ether (89 mL) at −78° C. was added n-BuLi (6.2 mL of 2.5 M, 15.50 mmol), and the mixture was stirred at −78° C. for 20 min, then warmed to 0° C. in 5 s, and a small piece of solid CO was added. The mixture was stirred at 0° C. for 15 min. The mixture was diluted with aqueous citric acid (22 mL of 1 M, 22 mmol), the pH was changed to 4 by paper, and ethyl acetate was added. The organic layer was separated, washed with water, brine, dried (MgSO), and evaporated. Purification by silica gel chromatography (5% to 50% of 10% MeOH in ethyl acetate and hexanes) afforded 6-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylic acid (2.1 g, 50%). 1 H NMR(400MHz,chloroform-d)δ 10.43(s,1H),9.61(s,1H),7.42-7.31(m,4H),7.30-7.26(m,1H),5.94(m,J=17.1,7.2Hz,1H),5.33-5. 20(m,2H),4.84(d,J=11.0Hz,1H),4.71(d,J=11.0Hz,1H),3.24(m,J=15.2,7.0Hz,2H),1.59(s,9H)ppm; 19F NMR (376 MHz, chloroform-d) δ -61.10, -73.16 ppm. ESI-MS m / z calculated 602.16003, found 603.2 (M+1). + ; Retention time: 0.4 minutes (LC method T).

[0341] Intermediate 18: Preparation of 2-benzyloxy-6-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)hexanehydrazide [ka]

[0342] Step 1: Ethyl 6-(1,3-dioxolan-2-yl)-2-hydroxy-2-(trifluoromethyl)hexanoate [ka] A dry 250 mL three-neck flask equipped with a reflux condenser under nitrogen was charged with magnesium (2.2 g, 83.584 mmol) and iodine (5 mg, 0.0197 mmol) was added. The mixture was heated neat with stirring to 55°C. A solution of 2-(4-bromobutyl)-1,3-dioxolane (14.35 g, 68.634 mmol) in THF (115 mL) was added dropwise over 20 minutes, ensuring the reaction mixture continued to boil. After the addition, the dark reaction mixture was heated at 78°C for 1 hour and then cooled to room temperature. The resulting bromo-[4-(1,3-dioxolan-2-yl)butyl]magnesium in THF (115 mL of 0.6 M, 69 mmol) was slowly added dropwise over 20 minutes to a solution of ethyl 3,3,3-trifluoro-2-oxopropanoate (11.547 g, 9 mL, 67.889 mmol) in diethyl ether (120 mL) at −78° C. The mixture was stirred at −78° C. for 20 minutes. The dry ice-acetone bath was removed. The reaction mixture was slowly warmed to 10° C. over 20 minutes and added to a mixture of 1N aqueous hydrochloric acid (100 mL) and crushed ice (60 g). The two layers were separated. The organic layer was concentrated, and the residue was combined with the aqueous phase and extracted with ethyl acetate (3×100 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL) and dried over sodium sulfate. The mixture was filtered and concentrated to give ethyl 6-(1,3-dioxolan-2-yl)-2-hydroxy-2-(trifluoromethyl)hexanoate (21.52 g, 93%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 4.87-4.81(m,1H),4.57(br s,1H),4.43-4.29(m,2H),3.99-3.93(m,2H),3.88-3.82(m,2H),2.03-1.95(m,1H),1.92-1.8 2(m,1H),1.71-1.62(m,2H),1.61-1.52(m,1H),1.51-1.37(m,3H),1.34(t,J=7.1Hz,3H)ppm. 19 F NMR (377 MHz, CDCl3) δ -78.66 (s, 3F) ppm. ESI-MS m / z calculated 300.11847, found 323.2 (M+23). +; Retention time: 1.71 minutes (LC method Z).

[0343] Step 2: Ethyl 2-benzyloxy-6-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)hexanoate [ka] To a solution of ethyl 6-(1,3-dioxolan-2-yl)-2-hydroxy-2-(trifluoromethyl)hexanoate (21.5 g, 63.010 mmol) in DMF (90 mL) at 0° C., NaH (4.6 g, 115.01 mmol) was added portionwise. The mixture was stirred at 0° C. for 30 minutes. Bromomethylbenzene (21.139 g, 14.7 mL, 123.60 mmol) was added dropwise, followed by tetrabutylammonium iodide (4.2 g, 11.371 mmol). The mixture was allowed to warm slowly to room temperature and stirred overnight at room temperature. Ammonium chloride (2.9 g, 54.215 mmol) was added. The mixture was stirred at room temperature for 10 minutes. Water (500 mL) was added, followed by a mixture of MTBE and heptane 2:1 (200 mL). The two layers were separated, and the aqueous phase was extracted with a mixture of MTBE and heptane (2:1, 2 × 200 mL). The combined organic layers were washed with water (200 mL) and brine (200 mL) and then dried over sodium sulfate. The mixture was filtered and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0% to 30% ethyl acetate in heptane gave ethyl 2-benzyloxy-6-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)hexanoate (18.4 g, 58%) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ 7.46-7.29(m,5H),4.87-4.77(m,2H),4.69-4.60(m,1H),4.33(m,2H),3.98-3.91(m,2H),3.87- 3.79(m,2H),2.05-1.96(m,2H),1.71-1.54(m,3H),1.50-1.37(m,3H),1.34(t,J=7.2Hz,3H)ppm. 19F NMR (377 MHz, CDCl3) δ -70.53 (s, 3F) ppm. ESI-MS m / z calculated 390.1654, found 413.2 (M+23). + ; Retention time: 2.02 minutes (LC method Z).

[0344] Step 3: 2-Benzyloxy-6-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)hexanoic acid [ka] To a solution of sodium hydroxide (7.5 g, 187.51 mmol) in water (75 mL) was added a solution of ethyl 2-benzyloxy-6-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)hexanoate (28.9 g, 74.028 mmol) in methanol (230 mL). The reaction was heated at 50° C. for 6 hours. The reaction was concentrated to remove methanol. The crude material was diluted with water (300 mL), and the carboxylic acid sodium salt was washed with heptane (100 mL) and MTBE (100 mL). The aqueous solution was acidified to pH=2 with an aqueous solution of 3N HCl. The carboxylic acid was extracted with dichloromethane (4×200 mL) and dried over sodium sulfate. The solution was filtered and concentrated to give 2-benzyloxy-6-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)hexanoic acid (27.75 g, 96%) as a clear oil that solidified on standing. 1 H NMR(400MHz,CDCl3)δ 8.64(br s,1H),7.45-7.30(m,5H),4.91-4.80(m,2H),4.77-4.64(m,1H),4.02-3.92(m,2H),3.90-3 .79(m,2H),2.22-2.01(m,2H),1.74-1.65(m,2H),1.64-1.55(m,1H),1.54-1.34(m,3H)ppm. 19 F NMR (377 MHz, CDCl3) δ -71.58 (s, 3F) ppm. ESI-MS m / z calculated 362.1341, found 361.1 (M-1). + ; Retention time: 4.29 minutes (LC method AA).

[0345] Step 4: 2-benzyloxy-6-(1,3-dioxolan-2-yl)-2-(trifluoromethylhexanehydrazide [ka] To a solution of 2-benzyloxy-6-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)hexanoic acid (16.7 g, 46.089 mmol) in DMF (175 mL) were added triethylamine (20.546 g, 28.3 mL, 203.04 mmol) and HATU (53.4 g, 140.44 mmol). The mixture was stirred for 10 minutes. Then, hydrazine (aqueous (1)) (92.880 g, 90 mL, 1.8554 mol) was added. The mixture was stirred at room temperature overnight. The mixture was diluted with water (1 L) and extracted with ethyl acetate (3 × 300 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (300 mL), water (300 mL), and brine (300 mL). The organic layer was concentrated by evaporation under reduced pressure. Purification by silica gel chromatography using a gradient of 20% to 80% ethyl acetate in heptane gave 2-benzyloxy-6-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)hexanehydrazide (9.3 g, 48%) as an orange oil. 1 H NMR(400MHz,CDCl3)δ 7.97(br s,1H),7.45-7.30(m,5H),4.85(t,J=4.6Hz,1H),4.75(d,J=10.1Hz,1H),4.61(d,J=10.4Hz,1H),4.02-3.92(m,2H),3 .91-3.77(m,4H),2.40-2.26(m,1H),2.19-2.06(m,1H),1.75-1.64(m,2H),1.61-1.40(m,3H),1.38-1.30(m,1H)ppm. 19 F NMR (377 MHz, CDCl3) δ -73.87 (s, 3F) ppm. ESI-MS m / z calculated 376.16098, found 377.2 (M+1). + ; Retention time: 1.68 minutes (LC method Z).

[0346] Preparation of Intermediate 19: Methyl 6-[5-[1-benzyloxy-6-oxo-1-(trifluoromethyl)hexyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate [ka]

[0347] Step 1: tert-butyl N-[2-[[[2-benzyloxy-6-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)hexanoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate [ka] To a mixture of 6-bromo-3-(tert-butoxycarbonylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid (11.2 g, 29.08 mmol) and 2-benzyloxy-6-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)hexanehydrazide (12.0 g, 31.88 mmol) in ethyl acetate (140 mL) was added pyridine (9.5 mL, 117.5 mmol). To this solution was added T3P (24 mL of 50% w / v, 37.71 mmol), and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction was quenched by the slow addition of NaOH (50% in water) (7.3 mL of 50% w / v, 91.26 mmol) in water (120 mL), and the mixture was stirred in an ice bath for 5 minutes, then at room temperature for 1 hour. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic phases were washed with HCl (50 mL of 1 M), brine, dried (MgSO), filtered, and evaporated. Purification by silica gel chromatography using a gradient of 0% to 25% ethyl acetate in hexanes gave tert-butyl N-[2-[[[2-benzyloxy-6-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)hexanoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (16.4 g, 76%). ESI-MS m / z calculated 742.1437, found 645.2 (M+1). + ; Retention time: 0.43 minutes (LC method T).

[0348] Step 2: tert-butyl N-[2-[5-[1-benzyloxy-5-(1,3-dioxolan-2-yl)-1-(trifluoromethyl)pentyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate [ka] To a solution of tert-butyl N-[2-[[[2-benzyloxy-6-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)hexanoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (2.298 g, 3.0908 mmol) and DIEA (1.2020 g, 1.62 mL, 9.3003 mmol) in acetonitrile (37 mL) was added tosyl chloride (707 mg, 3.7084 mmol) at 50° C. The reaction was stirred at 70° C. for 2 hours. After the reaction was cooled to room temperature, it was diluted with ethyl acetate (150 mL). The organic solution was washed with saturated ammonium chloride (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 0% to 30% ethyl acetate in hexanes to give tert-butyl N-[2-[5-[1-benzyloxy-5-(1,3-dioxolan-2-yl)-1-(trifluoromethyl)pentyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (2.026 g, 87%) as a yellow foam. ESI-MS m / z calculated 724.1331, found 725.3 (M+1). + ; Retention time: 4.33 minutes (LC method G).

[0349] Step 3: Methyl 6-[5-[1-benzyloxy-5-(1,3-dioxolan-2-yl)-1-(trifluoromethyl)pentyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate [ka] To a solution of tert-butyl N-[2-[5-[1-benzyloxy-5-(1,3-dioxolan-2-yl)-1-(trifluoromethyl)pentyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (1.925 g, 2.5473 mmol) in methanol (50 mL) was added TEA (798.60 mg, 1.1 mL, 7.8921 mmol). The reaction was purged with argon for 2 minutes. Pd(dppf)Cl2 (186 mg, 0.2542 mmol) was added to the reaction mixture. The reaction was then stirred at 80 °C under 50 psi of carbon monoxide for 6 hours. After cooling the reaction to room temperature, the methanol was removed in vacuo. The residue was diluted with ethyl acetate (50 mL) and water (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 0% to 40% ethyl acetate in hexanes to give methyl 6-[5-[1-benzyloxy-5-(1,3-dioxolan-2-yl)-1-(trifluoromethyl)pentyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate (1.678 g, 93%) as a white foam. ESI-MS m / z calculated 704.2281, found 705.5 (M+1). + ; Retention time: 4.13 minutes (LC method G).

[0350] Step 4: Methyl 6-[5-[1-benzyloxy-6-oxo-1-(trifluoromethyl)hexyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate [ka] A round-bottom flask was charged with methyl 6-[5-[1-benzyloxy-5-(1,3-dioxolan-2-yl)-1-(trifluoromethyl)pentyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate (1.661 g, 2.2041 mmol) in acetic acid (40 mL). Water (10 mL) was added to the reaction mixture. The reaction was stirred at 60° C. for 3 hours. The reaction was cooled to room temperature. The acetic acid was removed in vacuo. The residue was diluted with ethyl acetate (150 mL). The organic solution was washed with saturated sodium bicarbonate (2×50 mL) and brine (50 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 0% to 30% acetone in hexanes to give methyl 6-[5-[1-benzyloxy-6-oxo-1-(trifluoromethyl)hexyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate (1.382 g, 89%) as a white foam. 1 H NMR(500MHz,DMSO-d6)δ 10.34(s,1H),9.66(t,J=1.4,1.4Hz,1H),9.16(s,1H),7.53-7.43(m,2H),7.43-7.27(m,3H),4.71(d,J=10.6Hz ,1H),4.62(d,J=10.6Hz,1H),3.97(s,3H),2.48-2.32(m,2H),1.68-1.59(m,2H),1.57-1.45(m,13H)ppm.ESI-MS m / z calculated value 660.20184, actual value 661.3(M+1) + ; Retention time: 3.62 minutes (LC method H).

[0351] Preparation of Intermediate 20: Methyl 6-[5-[(1R)-1-benzyloxy-6-oxo-1-(trifluoromethyl)hexyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate [ka]

[0352] Step 1: tert-butyl N-[2-[[[(2R)-2-benzyloxy-6-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)hexanoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate [ka] Racemic tert-butyl N-[2-[[[2-benzyloxy-6-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)hexanoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (16.4 g, 22 mmol) was purified by preparative chiral SFC using a ChiralPak IC column (250 × 21.2 mm; 5 μm) at 40 °C. The mobile phase was 11% MeOH (containing 20 mM NH), 89% CO at a flow rate of 70 mL / min. The sample concentration was 40 mg / mL in methanol (no modifier) ​​with an injection volume of 400 μL at an outlet pressure of 122 bar, yielding the first eluted enantiomer 1, tert-butyl N-[2-[[[(2S)-2-benzyloxy-6-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)hexanoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (6.77 g, 82%). 1 H NMR(400MHz,chloroform-d)δ 10.61(s,1H),9.84(s,1H),9.28(s,1H),9.01(s,1H),7.50-7.30(m,5H),4.93-4.81(m,2H),4.72(d,J=10.5Hz,1H),4.03- 3.90(m,2H),3.90-3.63(m,2H),2.49-2.29(m,1H),2.26-2.10(m,1H),1.71(p,J=5.7,4.7Hz,2H),1.63-1.47(m,13H)ppm. 19F NMR (376 MHz, chloroform-d) δ -63.88, -73.71 ppm. ESI-MS m / z calculated 742.1437, found 645.2 (M+1). + ; Retention time: 0.44 minutes (LC method T).

[0353] Continued elution gave the second eluting enantiomer 2, tert-butyl N-[2-[[[(2R)-2-benzyloxy-6-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)hexanoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (6.83 g, 83%). ESI-MS m / z calculated 742.1437, found 645.2 (M+1). + ; Retention time: 0.44 minutes (LC method T).

[0354] Step 2: tert-butyl N-[2-[5-[(1R)-1-benzyloxy-5-(1,3-dioxolan-2-yl)-1-(trifluoromethyl)pentyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate [ka] To a solution of tert-butyl N-[2-[[[(2R)-2-benzyloxy-6-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)hexanoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (enantiomer 2) (2.97 g, 3.995 mmol) in acetonitrile (50 mL) was added p-toluenesulfonyl chloride (936 mg, 4.910 mmol) and DIEA (2 mL, 11.48 mmol). The resulting mixture was heated at 70 °C for 80 min, then diluted with ether (300 mL), washed with water (500 mL), 1 M NaHCO (2 × 250 mL), dried (MgSO), and evaporated. Purification by silica gel chromatography using a gradient of 0% to 20% ethyl acetate in hexanes gave tert-butyl N-[2-[5-[(1R)-1-benzyloxy-5-(1,3-dioxolan-2-yl)-1-(trifluoromethyl)pentyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (2.56 g, 88%). 1 H NMR(400MHz,chloroform-d)δ 10.19(s,1H),9.34(s,1H),7.49(d,J=7.5Hz,2H),7.39(t,J=7.5Hz,2H),7.31(t,J=7.3Hz,1H),4.86-4.75(m,2H),4.67(d,J=10.6Hz,1H), 4.00-3.90(m,2H),3.84-3.74(m,2H),2.52-2.28(m,2H),1.67(m,J=7.6,7.1,4.7Hz,3H),1.56(s,9H),1.49(m,J=7.6,5.8,3.1Hz,3H)ppm. 19 F NMR (376 MHz, chloroform-d) δ -63.74, -72.67 ppm. ESI-MS m / z calculated 724.1331, found 725.2 (M+1). + ; Retention time: 0.67 minutes (LC method T).

[0355] Step 3: Methyl 6-[5-[(1R)-1-benzyloxy-5-(1,3-dioxolan-2-yl)-1-(trifluoromethyl)pentyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate [ka] A mixture of tert-butyl N-[2-[5-[(1R)-1-benzyloxy-5-(1,3-dioxolan-2-yl)-1-(trifluoromethyl)pentyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (2.47 g, 3.405 mmol), triethylamine (1.42 mL, 10.19 mmol), and Pd(dppf)Cl (249 mg, 0.3403 mmol) in methanol (25 mL) was degassed by bubbling N for 1 minute in a stainless steel Parr reaction vessel. The vessel was sealed, placed under 100 psi of CO, and stirred at 80 °C for 80 minutes. The mixture was then cooled to room temperature, filtered, diluted with ethyl acetate, washed with water, brine, dried (MgSO), and evaporated. Purification by silica gel chromatography using a gradient of 5% to 30% ethyl acetate in hexanes gave methyl 6-[5-[(1R)-1-benzyloxy-5-(1,3-dioxolan-2-yl)-1-(trifluoromethyl)pentyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate (2.03 g, 85%). 1H NMR(400MHz,chloroform-d)δ 10.40(s,1H),9.40(s,1H),7.46(d,J=7.1Hz,2H),7.40-7.34(m,2H),7.33-7.28(m,1H),4.92-4.76(m,2H),4.68(d,J=10.6Hz,1H),4.0 2(s,3H),3.96-3.90(m,2H),3.85-3.76(m,2H),2.53-2.30(m,2H),1.67(m,J=7.7,7.0,4.8Hz,3H),1.57(s,9H),1.53-1.41(m,3H)ppm. 19 F NMR (376 MHz, chloroform-d) δ -60.75, -72.62 ppm. ESI-MS m / z calculated 704.2281, found 705.2 (M+1). + ; Retention time: 0.58 minutes (LC method T).

[0356] Step 4: Methyl 6-[5-[(1R)-1-benzyloxy-6-oxo-1-(trifluoromethyl)hexyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate [ka] A mixture of methyl 6-[5-[(1R)-1-benzyloxy-5-(1,3-dioxolan-2-yl)-1-(trifluoromethyl)pentyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate (2.03 g, 2.881 mmol), acetic acid (40 mL), and water (10 mL) was stirred at 70° C. for 2 hours, then cooled to room temperature and diluted with 200 mL of ether. The organic solution was washed with water (2×200 mL), 1 M NaHCO (2×150 mL), then dried (MgSO), and evaporated. Purification by silica gel chromatography using a gradient of 5% to 40% ethyl acetate in hexanes gave methyl 6-[5-[(1R)-1-benzyloxy-6-oxo-1-(trifluoromethyl)hexyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate (1.644 g, 78%). 1 H NMR(400MHz,chloroform-d)δ 10.38(s,1H),9.74(d,J=1.3Hz,1H),9.41(s,1H),7.45(d,J=7.5Hz,2H),7.42-7.28(m,3H),4.81(d,J=10.6Hz,1H ),4.69(d,J=10.6Hz,1H),4.02(s,3H),2.50-2.30(m,4H),1.77-1.61(m,2H),1.58(s,9H),1.52-1.40(m,2H)ppm. 19 F NMR(376MHz,chloroform-d)δ -60.77,-72.56ppm.ESI-MS m / z calculated value 660.20184, measured value 661.2(M+1)+; retention time: 0.43 min (LC method T).

[0357] Preparation of Intermediate 21: Methyl 6-[5-[1-benzyloxy-5-oxo-1-(trifluoromethyl)pentyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate [ka]

[0358] Step 1: Ethyl 5-(1,3-dioxolan-2-yl)-2-hydroxy-2-(trifluoromethyl)pentanoate [ka] To a solution of ethyl 3,3,3-trifluoro-2-oxopropanoate (7.6980 g, 6 mL, 45.259 mmol) in diethyl ether (75 mL) at −78° C., chloro-[3-(1,3-dioxolan-2-yl)propyl]magnesium (52 ​​mL of 0.92 M, 47.84 mmol) was added dropwise over a 20-minute period. The mixture was stirred at −78° C. for 20 minutes. The dry ice-acetone bath was removed. The reaction mixture was slowly warmed to 10° C. for 20 minutes and then added to a mixture of 1N aqueous hydrochloric acid (200 mL) and crushed ice (50 g). The two layers were separated, and the residual aqueous phase was extracted with ethyl acetate (3×100 mL). The organic layers were combined, washed with saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL), and dried over sodium sulfate. The mixture was filtered and concentrated to give ethyl 5-(1,3-dioxolan-2-yl)-2-hydroxy-2-(trifluoromethyl)pentanoate (13.9 g, 97%) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ 4.90-4.82(m,1H),4.46-4.30(m,2H),4.01-3.92(m,2H),3.90-3.80(m,3H),2.12-2.02 (m,1H),1.99-1.86(m,1H),1.77-1.58(m,3H),1.39-1.32(m,3H),1.31-1.23(m,1H)ppm. 19 F NMR(377MHz,CDCl3)δ -78.65(s,3F)ppm.

[0359] Step 2: Ethyl 2-benzyloxy-5-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)pentanoate [ka] To a solution of ethyl 5-(1,3-dioxolan-2-yl)-2-hydroxy-2-(trifluoromethyl)pentanoate (1.7 g, 4.9293 mmol) in DMF (7 mL) at 0° C., NaH (352 mg, 8.8008 mmol) was added portionwise. The mixture was stirred at 0° C. for 30 minutes. Bromomethylbenzene (1.5818 g, 1.1 mL, 9.2485 mmol) was added dropwise, followed by tetrabutylammonium iodide (318 mg, 0.8609 mmol). The mixture was allowed to warm slowly to room temperature and stirred overnight at room temperature. Ammonium chloride (218 mg, 4.0754 mmol) was added. The mixture was stirred at room temperature for 10 minutes. Water (200 mL) was added, followed by a mixture of MTBE and heptane (2:1, 100 mL). The two layers were separated, and the aqueous phase was extracted with a mixture of MTBE and heptane (2:1, 2 × 100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL) and then dried over sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0% to 30% ethyl acetate in heptane to give ethyl 2-benzyloxy-5-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)pentanoate (1.6 g, 78%) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ 7.48-7.30(m,5H),4.89-4.79(m,2H),4.72-4.61(m,1H),4.42-4.29(m,2H),4.01-3.93(m,2H),3.8 9-3.80(m,2H),2.15-1.99(m,2H),1.77-1.63(m,3H),1.56-1.46(m,1H),1.36(t,J=7.2Hz,3H)ppm. 19 F NMR (377 MHz, CDCl3) δ -70.46 (s, 3F) ppm. ESI-MS m / z calculated 376.1498, found 399.2 (M+23). + ; Retention time: 1.98 minutes (LC method Z).

[0360] Step 3: 2-Benzyloxy-5-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)pentanoic acid [ka] A solution of sodium hydroxide (12.2 g, 305.02 mmol) in water (120 mL) was added to a solution of ethyl 2-benzyloxy-5-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)pentanoate (45.2 g, 120.10 mmol) in methanol (360 mL). The reaction was heated at 50° C. overnight. The reaction was concentrated to remove methanol. The crude material was diluted with water (500 mL), and the carboxylic acid sodium salt was washed with heptane (200 mL) and MTBE (200 mL). The aqueous solution was acidified with 3N aqueous hydrochloric acid to pH = 2. The carboxylic acid was extracted with dichloromethane (4 × 200 mL) and dried over sodium sulfate. The solution was filtered and concentrated to give 2-benzyloxy-5-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)pentanoic acid (43.2 g, quantitative) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 8.94(br s,1H),7.51-7.29(m,5H),4.94-4.80(m,2H),4.70(d,J=10.4Hz,1H),4.04-3.92(m, 2H),3.90-3.77(m,2H),2.29-2.08(m,2H),1.80-1.64(m,3H),1.62-1.46(m,1H)ppm. 19 F NMR (377 MHz, CDCl3) δ -71.58 (s, 3F) ppm. ESI-MS m / z calculated 348.1185, found 347.2 (M-1). - ; Retention time: 4.19 minutes (LC method AA).

[0361] Step 4: 2-benzyloxy-5-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)pentane hydrazide [ka] To a solution of 2-benzyloxy-5-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)pentanoic acid (6.004 g, 16.375 mmol) in DMF (60 mL) was added HATU (8.735 g, 22.973 mmol) and triethylamine (3.6300 g, 5 mL, 35.873 mmol). The mixture was stirred for 10 minutes. Hydrazine hydrate (16.512 g, 16 mL, 329.84 mmol) was added to the reaction mixture. The reaction was stirred at room temperature for 1.5 hours. The reaction was diluted with water (200 mL) and ethyl acetate (200 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 0% to 10% methanol in DCM to give 2-benzyloxy-5-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)pentanehydrazide (6.075 g, 97%) as an orange oil. ESI-MS m / z calculated 362.1453, found 363.3 (M+1). + ; Retention time: 2.33 minutes (LC method G).

[0362] Step 5: tert-butyl N-[2-[[[2-benzyloxy-5-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)pentanoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate [ka] To a mixture of 6-bromo-3-(tert-butoxycarbonylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid (9.62 g, 24.98 mmol) and 2-benzyloxy-5-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)pentanehydrazide (10 g, 27.60 mmol) in ethyl acetate (100 mL) at ambient temperature, pyridine (8.2 mL, 101.4 mmol) was added, resulting in a precipitate. To the mixture was added T3P (20.6 mL of 50% w / v, 32.37 mmol), and the reaction mixture was stirred at ambient temperature for 5 hours. The reaction was quenched by the slow addition of NaOH (50% in water) (6.3 mL of 50% w / v, 78.76 mmol) in water (100 mL), and the mixture was stirred for 1 hour. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic phases were washed with HCl (40 mL of 1 M), brine, dried (MgSO), filtered, and evaporated. The residue was purified by silica gel chromatography using 5% to 30% ethyl acetate in hexanes over 20 minutes to give tert-butyl N-[2-[[[2-benzyloxy-5-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)pentanoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (10.92 g, 60%). 1 H NMR(400MHz,chloroform-d)δ 10.60(s,1H),9.84(s,1H),9.28(s,1H),8.99(s,1H),7.47-7.33(m,5H) ,4.90(t,J=4.5Hz,1H),4.84(d,J=10.4Hz,1H),4.75(d,J=10.5Hz,1H), 4.04-3.92(m,2H),3.88-3.79(m,2H),2.39(m,J=16.6,11.2,5.7Hz,1H) ,2.28(m,J=14.9,11.2,4.9Hz,1H),1.91-1.58(m,4H),1.52(s,9H)ppm. 19 F NMR (376 MHz, chloroform-d) δ -63.88, -73.65 ppm. ESI-MS m / z calculated 728.12805, found 631.0 (M+1). + ; Retention time: 0.41 min (LC method T).

[0363] Step 6: tert-butyl N-[2-[5-[1-benzyloxy-4-(1,3-dioxolan-2-yl)-1-(trifluoromethyl)butyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate [ka] To a solution of tert-butyl N-[2-[[[2-benzyloxy-5-(1,3-dioxolan-2-yl)-2-(trifluoromethyl)pentanoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (10.92 g, 14.97 mmol) in acetonitrile (200 mL) was added p-toluenesulfonyl chloride (3.5 g, 18.36 mmol) and DIEA (7.5 mL, 43.06 mmol). The resulting mixture was heated at 70 °C for 80 min, then diluted with ether (300 mL), washed with water (500 mL), 1 M NaHCO (2 × 300 mL), dried (MgSO), and evaporated. The residue was purified by silica gel chromatography using 0% to 20% ethyl acetate in hexanes over 15 minutes to give tert-butyl N-[2-[5-[1-benzyloxy-4-(1,3-dioxolan-2-yl)-1-(trifluoromethyl)butyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (9.67 g, 91%). 1 H NMR(400MHz,chloroform-d)δ 10.19(s,1H),9.34(s,1H),7.49(d,J=7.5Hz,2H),7.39(t,J=7.5Hz,2H),7.31(t,J=7.4Hz,1H),4.86(t,J=4.1Hz,1H),4.80(d, J=10.6Hz,1H),4.68(d,J=10.6Hz,1H),3.99-3.89(m,2H),3.87-3.73(m,2H),2.71-2.34(m,2H),1.73(m,4H),1.56(s,9H)ppm. 19F NMR (376 MHz, chloroform-d) δ -63.74, -72.61 ppm. ESI-MS m / z calculated 710.1175, found 713.2 (M+1). + ; Retention time: 0.52 minutes (LC method T).

[0364] Step 7: Methyl 6-[5-[1-benzyloxy-4-(1,3-dioxolan-2-yl)-1-(trifluoromethyl)butyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate [ka] A mixture of tert-butyl N-[2-[5-[1-benzyloxy-4-(1,3-dioxolan-2-yl)-1-(trifluoromethyl)butyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (9.67 g, 13.59 mmol), triethylamine (6 mL, 43.05 mmol), and PdCl(dppf) (500 mg, 0.6833 mmol) in methanol (70 mL) and ethyl acetate (30 mL) was degassed by bubbling N for 1 minute in a 450 mL stainless steel Parr reaction vessel. The vessel was sealed, placed under 100 psi of CO, and then stirred at 80 °C for 1 hour. The mixture was cooled to room temperature, PdCl(dppf) (500 mg, 0.6833 mmol) was added, and the mixture was placed under 100 psi of CO and stirred at 80 °C for 3 hours. The mixture was then cooled to room temperature, filtered, diluted with ethyl acetate, washed with water, brine, dried (MgSO), and evaporated. The residue was purified by silica gel chromatography using 5% to 30% ethyl acetate in hexanes over 15 minutes to give methyl 6-[5-[1-benzyloxy-4-(1,3-dioxolan-2-yl)-1-(trifluoromethyl)butyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate (8.26 g, 88%). 1H NMR(400MHz,chloroform-d)δ 10.40(s,1H),9.40(s,1H),7.50-7.43(m,2H),7.41-7.34(m,2H),7.31(d,J=7.3Hz,1H),4.85(t,J=4.2Hz,1H),4.82(d,J=10.6Hz,1H) ),4.68(d,J=10.6Hz,1H),4.01(s,3H),3.98-3.88(m,2H),3.87-3.76(m,2H),2.56-2.39(m,2H),1.83-1.68(m,4H),1.57(s,9H)ppm. 19 F NMR (376 MHz, chloroform-d) δ -60.76, -72.56 ppm. ESI-MS m / z calculated 690.21246, found 691.3 (M+1). + ; Retention time: 0.44 minutes (LC method T).

[0365] Step 8: Methyl 6-[5-[1-benzyloxy-5-oxo-1-(trifluoromethyl)pentyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate [ka] A round-bottom flask was charged with methyl 6-[5-[1-benzyloxy-4-(1,3-dioxolan-2-yl)-1-(trifluoromethyl)butyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate (2.308 g, 3.3421 mmol) in acetic acid (55 mL). Water (14 mL) was added to the reaction mixture. The reaction was stirred at 60° C. for 3 hours. The reaction was cooled to room temperature. The acetic acid was removed in vacuo. The residue was extracted with ethyl acetate (100 mL). The organic solution was washed with saturated sodium bicarbonate (2×20 mL) and brine (20 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 0% to 20% ethyl acetate in hexanes to give methyl 6-[5-[1-benzyloxy-5-oxo-1-(trifluoromethyl)pentyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate (1.564 g, 72%) as a white foam. ESI-MS m / z calculated 646.1862, found 647.4 (M+1). + ; Retention time: 3.94 minutes (LC method G).

[0366] Preparation of Intermediate 22: Methyl 5-(tert-butoxycarbonylamino)-6-[5-[2,2,2-trifluoro-1-[2-fluoro-5-(3-oxopropyl)phenyl]-1-hydroxy-ethyl]-1,3,4-oxadiazol-2-yl]-3-(trifluoromethyl)pyridine-2-carboxylate [ka]

[0367] Step 1: 3-(3-bromo-4-fluoro-phenyl)propanoic acid [ka] Triethylamine (16.6 mL) was placed in a round-bottom flask and briefly cooled in an ice-water bath. Formic acid (11.2 mL) was added portionwise. The mixture was stirred at room temperature for 25 minutes, and DMF (75 mL) was added. 3-Bromo-4-fluorobenzaldehyde (20 g, 98.518 mmol) was added, followed by 2,2-dimethyl-1,3-dioxane-4,6-dione (14.2 g, 98.526 mmol). The mixture was heated at 100 °C for 16 hours. It was then cooled to room temperature and poured into ice water (500 mL). The mixture was extracted with dichloromethane (2 × 300 mL). The combined organic layers were extracted with 10% aqueous NaOH (2 × 200 mL). The combined basic aqueous solution was acidified to pH = 2 with concentrated HCl. The resulting mixture was then extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 3-(3-bromo-4-fluoro-phenyl)propanoic acid (23.2 g, 86%) as a white solid. ESI-MS m / z calculated 245.9692, found 247.3 (M+1). + ; Retention time: 3.09 minutes (LC method G).

[0368] Step 2: 3-(3-bromo-4-fluoro-phenyl)propan-1-ol [ka] 3-(3-Bromo-4-fluoro-phenyl)propanoic acid (23.2 g, 84.514 mmol) was dissolved in THF (150 mL) and the solution was cooled in an ice-water bath. Borane dimethyl sulfide complex (28 mL of 10 M, 280 mmol) was added dropwise. The mixture was heated to reflux for 20 hours. It was cooled to room temperature and placed in an ice-water bath. MeOH was added dropwise to quench any unreacted borane and concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL), washed with aqueous HCl (80 mL, 3N), aqueous NaOH (80 mL, 3N), brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 3-(3-bromo-4-fluoro-phenyl)propan-1-ol (21.3 g, 97%) as a colorless oil.1 H NMR(500MHz,chloroform-d)δ 7.39(dd,J=6.6,2.3Hz,1H),7.15-7.06(m,1H),7.06-6.96(m,1H),3.66(t, J=6.6Hz,2H),2.73-2.60(m,2H),1.91-1.80(m,2H),1.32(s,1H)ppm.ESI-MS m / z calculated value 231.9899, ​​actual value 233.2(M+1) + ; Retention time: 3.16 minutes (LC method G).

[0369] Step 3: 3-(3-bromo-4-fluoro-phenyl)propoxy-tert-butyl-dimethyl-silane [ka] To a solution of 3-(3-bromo-4-fluoro-phenyl)propan-1-ol (10 g, 38.614 mmol) in DMF (100 mL) at room temperature, imidazole (3.2 g, 47.005 mmol) was added, followed by the addition of tert-butyl-chloro-dimethyl-silane (6.8 g, 45.116 mmol) in portions. The mixture was stirred at room temperature for 2 hours and diluted with ethyl acetate (200 mL) and then water (300 mL). The organic layer was separated, washed with water (3 × 100 mL), brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography using 0% to 20% ethyl acetate in hexane to give 3-(3-bromo-4-fluoro-phenyl)propoxy-tert-butyl-dimethyl-silane (12.52 g, 89%) as a white solid. 1 H NMR(500MHz,chloroform-d)δ 7.38(dd,J=6.6,2.2Hz,1H),7.08(m,1H),7.02(t,J=8.4,8.4Hz,1H),3.61(t,J=6.1,6 .1Hz,2H),2.69-2.60(m,2H),1.86-1.73(m,2H),0.91(s,9H),0.05(s,6H)ppm.ESI-MS m / z calculated value 346.0764, actual value 347.3(M+1) + ; Retention time: 5.08 minutes (LC method G).

[0370] Step 4: 1-[5-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-2-fluoro-phenyl]-2,2,2-trifluoro-ethanone [ka] To a cooled (dry ice-acetone bath) solution of 3-(3-bromo-4-fluorophenyl)propoxy-tert-butyl-dimethylsilane (9.4 g, 25.710 mmol) in THF (120 mL), n-BuLi (11.5 mL of 2.5 M, 28.750 mmol) in hexane was added and stirred for 25 minutes under a N balloon. Ethyl 2,2,2-trifluoroacetate (7.1460 g, 6 mL, 50.297 mmol) in THF (10 mL) was then added dropwise over 5 minutes. The mixture was stirred at this temperature for 15 minutes, and the cooling bath was removed. Water (approximately 40 mL) was added and extracted with ethyl acetate (60 mL). The organic layer was washed with brine, dried over anhydrous MgSO, filtered, and concentrated. The residue was purified by silica gel chromatography using 0% to 20% ethyl acetate in hexane to give 1-[5-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-2-fluoro-phenyl]-2,2,2-trifluoro-ethanone (7.6 g, 73%) as a white solid. ESI-MS m / z calculated 364.1482, found 365.5 (M+1). + ; Retention time: 4.96 minutes (LC method G).

[0371] Step 5: tert-butyl N-[6-bromo-2-[5-[1-[5-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-2-fluoro-phenyl]-2,2,2-trifluoro-1-hydroxy-ethyl]-1,3,4-oxadiazol-2-yl]-5-(trifluoromethyl)-3-pyridyl]carbamate [ka] To a solution of 1-[5-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-2-fluorophenyl]-2,2,2-trifluoroethanone (1.38 g, 3.4079 mmol) in DCM (8 mL) at room temperature was added (N-isocyanoimino)triphenylphosphorane (1.03 g, 3.4071 mmol) in DCM (8 mL) dropwise over 10 minutes. The brown solution was stirred at room temperature overnight and concentrated. The residue was purified by silica gel chromatography using 0% to 15% ethyl acetate in hexane to give tert-butyl N-[6-bromo-2-[5-[1-[5-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-2-fluoro-phenyl]-2,2,2-trifluoro-1-hydroxy-ethyl]-1,3,4-oxadiazol-2-yl]-5-(trifluoromethyl)-3-pyridyl]carbamate (870 mg, 47%) as a white solid. ESI-MS m / z calculated 772.1527, found 673.4 (M-100). + ; Retention time: 5.22 minutes (LC method G).

[0372] Step 6: methyl 5-(tert-butoxycarbonylamino)-6-[5-[1-[5-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-2-fluoro-phenyl]-2,2,2-trifluoro-1-hydroxy-ethyl]-1,3,4-oxadiazol-2-yl]-3-(trifluoromethyl)pyridine-2-carboxylate [ka] To a solution of tert-butyl N-[6-bromo-2-[5-[1-[5-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-2-fluoro-phenyl]-2,2,2-trifluoro-1-hydroxy-ethyl]-1,3,4-oxadiazol-2-yl]-5-(trifluoromethyl)-3-pyridyl]carbamate (3.2 g, 3.7228 mmol) in MeOH (50 mL) at room temperature, TEA (1.0890 g, 1.5 mL, 10.762 mmol) was added, followed by Pd(dppf)Cl (150 mg, 0.2050 mmol). The mixture was purged with N for 15 minutes. It was then sealed and subjected to approximately 100 psi of CO at 80 °C for 6 hours. After cooling to room temperature, the mixture was transferred to a flask and concentrated. The residue was purified by silica gel chromatography using 0% to 15% ethyl acetate in hexane to give methyl 5-(tert-butoxycarbonylamino)-6-[5-[1-[5-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-2-fluoro-phenyl]-2,2,2-trifluoro-1-hydroxy-ethyl]-1,3,4-oxadiazol-2-yl]-3-(trifluoromethyl)pyridine-2-carboxylate (1.8 g, 58%) as a white solid. ESI-MS m / z calculated 752.2476, found 753.6 (M+1). + ; Retention time: 5.07 minutes (LC method G).

[0373] Step 7: methyl 5-(tert-butoxycarbonylamino)-6-[5-[2,2,2-trifluoro-1-[2-fluoro-5-(3-hydroxypropyl)phenyl]-1-hydroxy-ethyl]-1,3,4-oxadiazol-2-yl]-3-(trifluoromethyl)pyridine-2-carboxylate [ka] To a solution of methyl 5-(tert-butoxycarbonylamino)-6-[5-[1-[5-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-2-fluoro-phenyl]-2,2,2-trifluoro-1-hydroxy-ethyl]-1,3,4-oxadiazol-2-yl]-3-(trifluoromethyl)pyridine-2-carboxylate (1.8 g, 2.1521 mmol) in THF (10 mL) was added tetrabutylammonium fluoride in THF (20 mL of 1 M, 20 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. Additional tetrabutylammonium fluoride in THF (4 mL of 1 M, 4 mmol) was added, and the mixture was stirred for an additional hour. It was then diluted with ethyl acetate (50 mL) and washed with water (3 × 50 mL). The organic layer was further washed with brine, dried over anhydrous MgSO, filtered, and concentrated to give methyl 5-(tert-butoxycarbonylamino)-6-[5-[2,2,2-trifluoro-1-[2-fluoro-5-(3-hydroxypropyl)phenyl]-1-hydroxy-ethyl]-1,3,4-oxadiazol-2-yl]-3-(trifluoromethyl)pyridine-2-carboxylate (1.4 g, 97%) as a white solid. ESI-MS m / z calculated 638.1611, found 639.6 (M+1). + ; Retention time: 4.04 minutes (LC method G).

[0374] Step 8: Preparation of methyl 5-(tert-butoxycarbonylamino)-6-[5-[2,2,2-trifluoro-1-[2-fluoro-5-(3-oxopropyl)phenyl]-1-hydroxy-ethyl]-1,3,4-oxadiazol-2-yl]-3-(trifluoromethyl)pyridine-2-carboxylate [ka] To a solution of methyl 5-(tert-butoxycarbonylamino)-6-[5-[2,2,2-trifluoro-1-[2-fluoro-5-(3-hydroxypropyl)phenyl]-1-hydroxy-ethyl]-1,3,4-oxadiazol-2-yl]-3-(trifluoromethyl)pyridine-2-carboxylate (300 mg, 0.4464 mmol) in DCM (10 mL) at room temperature was added Dess-Martin periodinane (248 mg, 0.5847 mmol) in one portion. The mixture was stirred at room temperature for 3 h. NaSO (1 g in 10 mL NaHCO) was added. After 10 min, DCM (20 mL) and NaHCO (10 mL) were added, and the organic layer was separated. The organic layer was dried over anhydrous MgSO, filtered, and concentrated. The residue was purified by silica gel chromatography using 0% to 50% ethyl acetate in hexanes to give methyl 5-(tert-butoxycarbonylamino)-6-[5-[2,2,2-trifluoro-1-[2-fluoro-5-(3-oxopropyl)phenyl]-1-hydroxy-ethyl]-1,3,4-oxadiazol-2-yl]-3-(trifluoromethyl)pyridine-2-carboxylate (288 mg, 96%) as a white solid. 1 H NMR(500MHz,chloroform-d)δ 10.52-10.19(m,1H),9.93-9.68(m,1H),9.36(d,J=4.1Hz,1H),7.71(d,J=7.3Hz,1H),7.41-7.12(m,1H),7.08-6 .77(m,1H),6.15(s,1H),4.01-3.70(m,3H),3.07-2.91(m,2H),2.91-2.73(m,2H),1.71-1.36(m,7H)ppm.ESI-MS m / z calculated value 636.1455, actual value 637.4(M+1) + ; Retention time: 4.09 minutes (LC method G).

[0375] Preparation of Intermediate 23: Methyl 6-[5-[1-benzyloxy-2,2,2-trifluoro-1-(3-oxopropoxymethyl)ethyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate [ka]

[0376] Step 1: 2-(trifluoromethyl)prop-2-enoyl chloride [ka] Oxalyl chloride (1.8188 g, 1.25 mL, 14.33 mmol) was added to a stirred solution of 2-(trifluoromethyl)prop-2-enoic acid (2.0 g, 14.279 mmol) and DMF (103.84 mg, 0.11 mL, 1.4206 mmol) in DCM (20 mL) at 0 °C. The yellow solution was stirred at room temperature for 1 h. This gave a stock solution of 2-(trifluoromethyl)prop-2-enoyl chloride (20 mL, 0.7 M) for use in further steps.

[0377] Step 2: Benzyl 2-(trifluoromethyl)prop-2-enoate [ka] 2-(Trifluoromethyl)prop-2-enoyl chloride (3 mL of 0.7 M, 2.1 mmol) followed by triethylamine (217.8 mg, 0.3 mL, 2.1524 mmol) were added to a colorless solution of phenylmethanol (209 mg, 0.2 mL, 1.9327 mmol) in DCM (6 mL) at −40° C. The white suspension was stirred at −40° C. for 1 h and then at 0° C. for 1 h. The colorless solution was quenched with saturated aqueous NH4Cl (20 mL) and extracted with DCM (3 × 10 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to give benzyl 2-(trifluoromethyl)prop-2-enoate (429 mg, 96%) as a white solid. 1 H NMR(400MHz,CDCl3)δ 7.44-7.33(m,5H),6.76(q,J=1.6Hz,1H),6.46(d,J=1.2Hz,1H),5.31(s,2H)ppm. 19 F NMR(377MHz,CDCl3)δ -65.58(s,3F)ppm.

[0378] Step 3: Benzyl 2-(trifluoromethyl)oxirane-2-carboxylate [ka] Benzyl 2-(trifluoromethyl)prop-2-enoate (50.45 g, 214.79 mmol) was dissolved in a mixture of dioxane (1000 mL) and water (200 mL). The mixture was cooled in an ice-water bath. With vigorous stirring, NaHCO (91.2 g, 1.0856 mol) was added, followed by the portionwise addition of potassium peroxymonosulfate (135.5 g) over 80 minutes. The mixture was stirred at the same temperature for 120 minutes at room temperature. Water (300 mL) and ethyl acetate (300 mL) were added, and the layers were separated. The organic layer was washed with brine, dried over anhydrous MgSO, filtered, and concentrated. The residue was purified by silica gel chromatography using a gradient of 5% to 50% ethyl acetate in hexane to give benzyl 2-(trifluoromethyl)oxirane-2-carboxylate (57.49 g, 98%) as a colorless oil. 1 H NMR (500 MHz, chloroform-d) δ 7.62-7.28 (m, 5H), 5.33 (d, J = 12.3 Hz, 1H), 5.28 (d, J = 12.2 Hz, 1H), 3.30-3.18 (m, 2H) ppm.

[0379] Step 4: Benzyl 2-[3-[tert-butyl(diphenyl)silyl]oxypropoxymethyl]-3,3,3-trifluoro-2-hydroxy-propanoate [ka] To a solution of benzyl 2-(trifluoromethyl)oxirane-2-carboxylate (3.9 g, 15.842 mmol) in ethyl acetate (16 mL) was added 3-[tert-butyl(diphenyl)silyl]oxypropan-1-ol (11.6 g, 36.885 mmol), followed by magnesium triflate (5.8 g, 17.988 mmol). The reaction mixture was stirred at 90 °C for 16 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and purified by silica gel chromatography using a gradient of 0% to 15% ethyl acetate in hexane to give benzyl 2-[3-[tert-butyl(diphenyl)silyl]oxypropoxymethyl]-3,3,3-trifluoro-2-hydroxypropanoate (5.633 g, 62%). ESI-MS m / z calculated 560.2206, found 561.3 (M+1). + ; Retention time: 4.48 minutes (LC method G).

[0380] Step 5: Benzyl 2-benzyloxy-2-[3-[tert-butyl(diphenyl)silyl]oxypropoxymethyl]-3,3,3-trifluoro-propanoate [ka] To a solution of benzyl 2-[3-[tert-butyl(diphenyl)silyl]oxypropoxymethyl]-3,3,3-trifluoro-2-hydroxypropanoate (5.633 g, 9.5444 mmol) in anhydrous DMF (55 mL) was added a solution of NaH (572.1 mg, 60% w / w, 14.304 mmol) in mineral oil at 0 °C. After stirring the reaction at the same temperature for 20 minutes, bromomethylbenzene (2.2987 g, 1.55 mL, 13.44 mmol) and tetrabutylammonium iodide (352.5 mg, 0.9543 mmol) were added to the reaction mixture. The reaction was allowed to warm slowly to room temperature and stirred overnight. The reaction was quenched with saturated ammonium chloride (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 0% to 20% diethyl ether in hexanes to give benzyl 2-benzyloxy-2-[3-[tert-butyl(diphenyl)silyl]oxypropoxymethyl]-3,3,3-trifluoropropanoate (4.8 g, 77%) as a clear liquid. ESI-MS m / z calculated 650.2675, found 651.6 (M+1). + ; Retention time: 4.75 minutes (LC method G).

[0381] Step 6: 2-benzyloxy-2-[3-[tert-butyl(diphenyl)silyl]oxypropoxymethyl]-3,3,3-trifluoro-propanoic acid [ka] To a solution of benzyl 2-benzyloxy-2-[3-[tert-butyl(diphenyl)silyl]oxypropoxymethyl]-3,3,3-trifluoropropanoate (4.62 g, 6.744 mmol) in 1,4-dioxane (65 mL) was added NaOH (20.3 mL of 2 M, 40.6 mmol) and stirred at ambient temperature overnight. The reaction mixture was acidified with aqueous HCl (1 N) to approximately pH 3. The aqueous solution was extracted with ethyl acetate (3 × 150 mL). The combined ethyl acetate layers were washed with water (2 × 150 mL), brine (200 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 0% to 15% methanol in DCM to give 2-benzyloxy-2-[3-[tert-butyl(diphenyl)silyl]oxypropoxymethyl]-3,3,3-trifluoro-propanoic acid (3.63 g, 96%) as a pale yellow viscous oil. ESI-MS m / z calculated 560.2206, found 561.2 (M+1). + ; Retention time: 4.39 minutes (LC method G).

[0382] Step 7: 2-benzyloxy-2-[3-[tert-butyl(diphenyl)silyl]oxypropoxymethyl]-3,3,3-trifluoro-propanehydrazide [ka] To a solution of 2-benzyloxy-2-[3-[tert-butyl(diphenyl)silyl]oxypropoxymethyl]-3,3,3-trifluoropropanoic acid (3.6 g, 5.1366 mmol) in DMF (50 mL) was added HATU (2.92 g, 7.6796 mmol) and DIEA (2.0034 g, 2.7 mL, 15.501 mmol) at ambient temperature. The reaction was stirred at room temperature for 10 minutes. Hydrazine (3.2672 g, 3.2 mL, 101.96 mmol) was added to the reaction mixture. The reaction was stirred for 4 hours. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction mixture. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 100 mL). The combined ethyl acetate layers were washed with brine (3 × 100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 50% to 80% diethyl ether in hexanes to give 2-benzyloxy-2-[3-[tert-butyl(diphenyl)silyl]oxypropoxymethyl]-3,3,3-trifluoropropanehydrazide (2.71 g, 87%) as a pale pink oil. ESI-MS m / z calculated 574.2475, found 575.4 (M+1). + ; Retention time: 4.19 minutes (LC method G).

[0383] Step 8: tert-butyl N-[2-[[[2-benzyloxy-2-[3-[tert-butyl(diphenyl)silyl]oxypropoxymethyl]-3,3,3-trifluoro-propanoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate [ka] A flask was charged with 2-benzyloxy-2-[3-[tert-butyl(diphenyl)silyl]oxypropoxymethyl]-3,3,3-trifluoropropanehydrazide (2.57 g, 4.4719 mmol) and 6-bromo-3-(tert-butoxycarbonylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid (1.87 g, 4.8555 mmol) in ethyl acetate (50 mL). Pyridine (1.7604 g, 1.8 mL, 22.255 mmol) and T3P (3.5758 g, 6.69 mL of 50% w / w, 5.6191 mmol) in ethyl acetate were then added to the reaction mixture. The reaction was stirred at 50° C. for 2 hours. The reaction was diluted with saturated aqueous ammonium chloride solution (200 mL) and ethyl acetate (150 mL). The aqueous layer was extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 0% to 20% acetone in hexanes to give tert-butyl N-[2-[[[2-benzyloxy-2-[3-[tert-butyl(diphenyl)silyl]oxypropoxymethyl]-3,3,3-trifluoro-propanoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (3.49 g, 83%) as a pale yellow foamy solid. ESI-MS m / z calculated 940.2302, found 941.6 (M+1). + ; Retention time: 4.94 minutes (LC method G).

[0384] Step 9: tert-butyl N-[2-[5-[1-benzyloxy-1-[3-[tert-butyl(diphenyl)silyl]oxypropoxymethyl]-2,2,2-trifluoro-ethyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate [ka] To a solution of tert-butyl N-[2-[[[2-benzyloxy-2-[3-[tert-butyl(diphenyl)silyl]oxypropoxymethyl]-3,3,3-trifluoropropanoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (3.49 g, 3.3350 mmol) and DIEA (1.9663 g, 2.65 mL, 15.214 mmol) in acetonitrile (50 mL) was added TsCl (794.8 mg, 4.1690 mmol). The reaction was stirred at 70° C. for 2 hours. The solvent was removed in vacuo, and the residue was loaded directly onto a column and purified by silica gel chromatography using a gradient of 0% to 20% ethyl acetate in hexanes to give tert-butyl N-[2-[5-[1-benzyloxy-1-[3-[tert-butyl(diphenyl)silyl]oxypropoxymethyl]-2,2,2-trifluoro-ethyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (2.98 g, 95%) as a pale yellow gel. ESI-MS m / z calculated 922.2196, found 923.7 (M+1). + ; Retention time: 5.08 minutes (LC method G).

[0385] Step 10: 6-[5-[1-benzyloxy-1-[3-[tert-butyl(diphenyl)silyl]oxypropoxymethyl]-2,2,2-trifluoro-ethyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate methyl ester [ka] To a solution of tert-butyl N-[2-[5-[1-benzyloxy-1-[3-[tert-butyl(diphenyl)silyl]oxypropoxymethyl]-2,2,2-trifluoro-ethyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (2.93 g, 3.1716 mmol) in methanol (35 mL) was added TEA (3.2670 g, 4.5 mL, 32.286 mmol). The solution was purged with nitrogen for 5 minutes. Pd(dppf)Cl2 (465.2 mg, 0.6358 mmol) was added. The autoclave was sealed and heated at 80 °C under 75 psi of carbon monoxide for 5 hours. Volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a gradient of 0% to 20% ethyl acetate in hexanes to give methyl 6-[5-[1-benzyloxy-1-[3-[tert-butyl(diphenyl)silyl]oxypropoxymethyl]-2,2,2-trifluoro-ethyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate (2.59 g, 90%) as a pale yellow gel. ESI-MS m / z calculated 902.3146, found 903.8 (M+1). + ; Retention time: 4.86 minutes (LC method G).

[0386] Step 11: Methyl 6-[5-[1-benzyloxy-2,2,2-trifluoro-1-(3-hydroxypropoxymethyl)ethyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate [ka] To a solution of methyl 6-[5-[1-benzyloxy-1-[3-[tert-butyl(diphenyl)silyl]oxypropoxymethyl]-2,2,2-trifluoro-ethyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate (2.55 g, 2.8241 mmol) in anhydrous THF (70 mL) was added tetrabutylammonium fluoride in THF (7.1 mL of 1 M, 7.1 mmol) at room temperature. The reaction was stirred overnight at room temperature. The reaction was diluted with water (150 mL) and ethyl acetate (150 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 150 mL). The combined organic layers were washed with brine (250 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 0% to 50% ethyl acetate in hexanes to give methyl 6-[5-[1-benzyloxy-2,2,2-trifluoro-1-(3-hydroxypropoxymethyl)ethyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate (1.783 g, 95%) as a white viscous solid. ESI-MS m / z calculated 664.1968, found 665.1 (M+1). + ; Retention time: 3.91 minutes (LC method G).

[0387] Step 12: Methyl 6-[5-[1-benzyloxy-2,2,2-trifluoro-1-(3-oxopropoxymethyl)ethyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate [ka] To a solution of methyl 6-[5-[1-benzyloxy-2,2,2-trifluoro-1-(3-hydroxypropoxymethyl)ethyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate (1.75 g, 2.6334 mmol) in DCM (65 mL) was added DMP (1.1 g, 2.5935 mmol) at 0 °C. The reaction was stirred at 0 °C for 0.5 h, then allowed to warm to room temperature and stirred overnight. Saturated NaSO (170 mL) and saturated NaHCO (130 mL) were added to the reaction and extracted with DCM (3 × 150 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 0% to 50% ethyl acetate in hexanes to give methyl 6-[5-[1-benzyloxy-2,2,2-trifluoro-1-(3-oxopropoxymethyl)ethyl]-1,3,4-oxadiazol-2-yl]-5-(tert-butoxycarbonylamino)-3-(trifluoromethyl)pyridine-2-carboxylate (1.696 g, 92%) as a viscous off-white solid. 1 H NMR(500MHz,DMSO-d6)δ 10.31(s,1H),9.63(s,1H),9.17(s,1H),7.45(dd,J=8.0,1.7Hz,2H),7.41-7.32(m,3H),4.72(dd,J=17.2,10 .4Hz,2H),4.39(q,J=11.7,11.7,11.7Hz,2H),3.97(s,3H),3.93(m,2H),2.68(m,2H),1.53(s,9H)ppm.ESI-MS m / z calculated value 662.1811, actual value 663.4(M+1) + ; Retention time: 3.42 minutes (LC method H).

[0388] Preparation of Intermediate 24: Methyl 6-chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate [ka]

[0389] Step 1: Methyl 1-oxido-5-(trifluoromethyl)pyridin-1-ium-2-carboxylate [ka] Urea hydrogen peroxide (62.7 g, 646.53 mmol) was added in small portions to a stirred solution of methyl 5-(trifluoromethyl)pyridine-2-carboxylate (40 g, 191.09 mmol) in 1,2-dichloroethane (300 mL) at 0 °C. Trifluoroacetic anhydride (107.70 g, 72 mL, 507.65 mmol) was then added over 30 minutes at −10 °C using a cooling bath (CO₂ / acetone bath). The reaction mixture was then stirred for an additional 30 minutes at 0 °C, followed by stirring at ambient temperature for 1 hour. The reaction mixture was then poured into cooled ice water (600 mL). The mixture was diluted with dichloromethane (300 mL), and the layers were then separated. The aqueous phase was extracted with dichloromethane (2 × 200 mL). The combined organic phases were washed with water (2×300 mL) and brine (1×200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 1-oxido-5-(trifluoromethyl)pyridin-1-ium-2-carboxylate (47.6 g, 90%) as a pale yellow solid. 1 H NMR(300MHz,DMSO-d6)δ 8.89(s,1H),8.02-7.90(m,1H),7.86-7.72(m,1H),3.89(s,3H)ppm. 19 F NMR(282MHz,DMSO-d6)δ -62.00(s,3F)ppm.ESI-MS m / z Calculated value 221.02998, Actual value 222.1(M+1) + ; Retention time: 1.24 minutes (LC method E).

[0390] Step 2: Methyl 6-hydroxy-5-(trifluoromethyl)pyridine-2-carboxylate [ka] Trifluoroacetic anhydride (291.62 g, 193 mL, 1.3885 mol) was added dropwise to a mixture of methyl 1-oxide-5-(trifluoromethyl)pyridin-1-ium-2-carboxylate (51.058 g, 230.66 mmol) in DMF (305 mL) at 0° C. The mixture was then stirred at room temperature overnight. The mixture was concentrated under reduced pressure to remove excess trifluoroacetic acid. The remaining DMF solution was poured dropwise into a stirred water bath (1 L) cooled to 0° C. The precipitated solid was collected by filtration and washed with water (300 mL). The solid was dried under vacuum to give methyl 6-hydroxy-5-(trifluoromethyl)pyridine-2-carboxylate (45.24 g, 86%) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 7.90 (d, J = 7.2 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 4.02 (s, 3H) ppm. Not a single exchangeable proton was observed in NMR. 19 F NMR (282 MHz, CDCl3) δ -66.39 (s, 3F) ppm. ESI-MS m / z calculated 221.03, found 222.1 (M+1). + ; Retention time: 1.43 minutes (LC method E).

[0391] Step 3: Methyl 6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate [ka] To an ice-cold solution of methyl 6-hydroxy-5-(trifluoromethyl)pyridine-2-carboxylate (33.04 g, 149.41 mmol) in sulfuric acid (200 mL of 18.4 M, 3.68 mol) was added nitric acid (13 mL of 15.8 M, 205.4 mmol) dropwise. After 5 minutes, the ice bath was removed, and the reaction mixture was stirred at 38° C. overnight. Since the reaction was not complete, nitric acid (3 mL of 15.8 M, 47.4 mmol) was added dropwise at room temperature, and the reaction was heated at 38° C. for 4.5 hours. The reaction was slowly poured onto ice-cold water (900 mL), and the mixture was cooled to 0° C. for 15 minutes. The resulting solid was then isolated by filtration and washed with water (600 mL). The solid was dried under vacuum overnight to give methyl 6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate (39.49 g, 99%) as a white solid. 1 1 H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 3.95 (s, 3H) ppm. Not a single exchangeable proton was observed in NMR. 19 F NMR(282MHz,DMSO-d6)δ -64.56(s,3F)ppm.ESI-MS m / z Calculated value 266.0151, Actual value 267.1(M+1) + ; Retention time: 1.64 minutes (LC method E).

[0392] Step 4: Methyl 6-chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate [ka] A mixture of methyl 6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate (10 g, 37.575 mmol) and phenyl dichlorophosphate (48.008 g, 34 mL, 227.55 mmol) was heated at 170 °C for 90 min. After cooling to room temperature, the mixture was diluted with ethyl acetate (400 mL) and washed with brine (2 × 200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0% to 15% ethyl acetate in heptane) afforded methyl 6-chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate (5.45 g, 50%) as a yellow solid. 1 H NMR(300MHz,CDCl3)δ 8.75(s,1H),4.07(s,3H)ppm. 19 F NMR (282 MHz, CDCl3) δ -64.12 (s, 3F) ppm. ESI-MS m / z calculated 283.9812, found 285.0 (M+1). + ; Retention time: 1.95 minutes (LC method E).

[0393] Representative preparation of primary amines: Method 1: [5-[1-(trifluoromethyl)cyclopropyl]-2-pyridyl]methanamine (dihydrochloride) [ka]

[0394] Step 1: 5-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carbonitrile [ka] Dicyanozinc (65 mg, 0.55 mmol), Pd(dppf)Cl2 (20 mg, 0.027 mmol), and zinc dust (4 mg, 0.061 mmol) were weighed into a screw-cap vial equipped with a stir bar. The vial was then capped and purged with nitrogen. DMF (2.5 mL) and 2-chloro-5-[1-(trifluoromethyl)cyclopropyl]pyridine (200 mg, 0.90 mmol) were added via syringe, and the reaction was heated to 150 °C for 90 min. The reaction mixture was then cooled to room temperature and partitioned between 30 mL of water and 30 mL of ethyl acetate. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The resulting crude material was purified by silica gel chromatography using a gradient of 0% to 10% methanol in DCM to give 5-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carbonitrile (118 mg, 62%). ESI-MS m / z calculated 212.05614, found 213.1 (M+1). + ; Retention time: 0.55 minutes (LC method S).

[0395] Step 2: tert-Butyl N-[[5-[1-(trifluoromethyl)cyclopropyl]-2-pyridyl]methyl]carbamate [ka] 5-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carbonitrile (118 mg, 0.6 mmol) was dissolved in THF (4 mL) in a nitrogen-flushed round-bottom flask and cooled to 0 °C in an ice bath. LAH in THF (680 μL of 2 M, 1.36 mmol) was added dropwise to the reaction mixture, which was then stirred at 0 °C for 1 h. The reaction mixture was diluted with 5 mL of diethyl ether and quenched by the sequential addition of 0.1 mL of water, 0.1 mL of 15% aqueous NaOH, and 0.3 mL of water. The reaction mixture was then warmed to room temperature and stirred for 30 min. Sodium sulfate was added, and the reaction mixture was filtered. The filtrate was concentrated to give [5-[1-(trifluoromethyl)cyclopropyl]-2-pyridyl]methanamine as a pale yellow solid. ESI-MS m / z calculated 216.08743, found 217.1 (M+1). + ; Retention time: 0.33 minutes (LC method T).

[0396] The residue was dissolved in methanol (3 mL) and di-tert-butyl bicarbonate (140 mg, 0.6415 mmol) and triethylamine (250 μL, 1.794 mmol) were added. The reaction was stirred at room temperature for 30 minutes and then concentrated by rotary evaporation. The residue was purified by silica gel chromatography using a gradient of 0% to 100% ethyl acetate in hexanes to give tert-butyl N-[[5-[1-(trifluoromethyl)cyclopropyl]-2-pyridyl]methyl]carbamate (65 mg, 23%). ESI-MS m / z calculated 316.13986, found 317.3 (M+1). + ; Retention time: 0.53 minutes (LC method T).

[0397] Step 3: [5-[1-(trifluoromethyl)cyclopropyl]-2-pyridyl]methanamine (dihydrochloride) [ka] tert-Butyl N-[[5-[1-(trifluoromethyl)cyclopropyl]-2-pyridyl]methyl]carbamate (65 mg, 0.21 mmol) was combined with HCl (1 mL, 4 M, 4 mmol) as a solution in dioxane and DCM (1 mL) and stirred at room temperature for 1 h. The reaction mixture was then evaporated to dryness. Dichloromethane and hexanes were added, and the reaction was evaporated a second time to give [5-[1-(trifluoromethyl)cyclopropyl]-2-pyridyl]methanamine (dihydrochloride salt) (60 mg, quantitative). ESI-MS m / z calculated 216.08743, found 217.1 (M+1). + ; Retention time: 0.32 minutes (LC method T).

[0398] Method 2: [3-[[1-(trifluoromethyl)cyclopropyl]methoxy]phenyl]methanamine (hydrochloride) [ka]

[0399] Step 1: 3-[[1-(trifluoromethyl)cyclopropyl]methoxy]benzonitrile [ka] 3-Hydroxybenzonitrile (200 mg, 1.68 mmol) was combined with [1-(trifluoromethyl)cyclopropyl]methanol (240 mg, 1.713 mmol) and triphenylphosphine (530 mg, 2.02 mmol) in 11 mL of THF. The reaction mixture was cooled to 0° C. in an ice bath, and diisopropyl azodicarboxylate (450 μL, 470 mg, 2.32 mmol) was added dropwise. After 15 minutes, the reaction was warmed to room temperature and continued to stir at room temperature for 16 hours. The reaction mixture was then warmed to 50° C. for an additional 2 hours. After cooling to room temperature, the solvent was removed by rotary evaporation. The resulting residue was dissolved in 50 mL of ethyl acetate and washed with 1 M aqueous NaOH. The organics were then washed with brine, dried over sodium sulfate, and concentrated. The crude material was purified by silica gel chromatography using a gradient of 0% to 40% ethyl acetate in hexanes to give 3-[[1-(trifluoromethyl)cyclopropyl]methoxy]benzonitrile. ESI-MS m / z calculated 241.0714, found 242.0 (M+1). + ; Retention time: 0.66 minutes (LC method T).

[0400] Step 2: [3-[[1-(trifluoromethyl)cyclopropyl]methoxy]phenyl]methanamine (hydrochloride) [ka] Prepared from 3-[[1-(trifluoromethyl)cyclopropyl]methoxy]benzonitrile as described in Method 1, Step 2. [3-[[1-(trifluoromethyl)cyclopropyl]methoxy]phenyl]methanamine (hydrochloride) was isolated. ESI-MS m / z calculated 245.10275, found 246.2 (M+1). + ; Retention time: 0.4 minutes (LC method T).

[0401] Method 3: [3-(3,3-difluorocyclobutyl)phenyl]methanamine (hydrochloride) [ka]

[0402] Step 1: 1-chloro-3-(3,3-difluorocyclobutyl)benzene [ka] 3-(3-Chlorophenyl)cyclobutanone (500 mg, 2.768 mmol) was dissolved in DCM (25 mL) in a nitrogen-purged round-bottom flask. The reaction flask was placed in a water bath, and diethylaminosulfur trifluoride (1.5 mL, 11.35 mmol) was added dropwise. After stirring at room temperature for 24 h, the reaction was placed in an ice-water bath and quenched with 100 mL of saturated aqueous sodium bicarbonate (dropwise initially). The reaction mixture was extracted with 3 x 50 mL of ethyl acetate. The organics were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting crude material was purified by silica gel chromatography using 1% to 30% ethyl acetate in hexanes to give 1-chloro-3-(3,3-difluorocyclobutyl)benzene (530 mg, 76%) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ 7.28-7.24 (m, 1H), 7.24-7.19 (m, 2H), 7.11 (d, J = 7.4 Hz, 1H), 3.37 (pd, J = 9.2, 2.4 Hz, 1H), 3.01 (tdd, J = 13.8, 8.7, 4.6 Hz, 2H), 2.66 (m, 2H) ppm.

[0403] Step 2: 3-(3,3-difluorocyclobutyl)benzonitrile [ka] Pd[P( t Bu)3]2 (18 mg, 0.03522 mmol) was combined with zinc (8 mg, 0.1223 mmol) and dicyanozinc (42 mg, 0.3576 mmol) and then purged with nitrogen. 1-Chloro-3-(3,3-difluorocyclobutyl)benzene (150 mg, 0.5922 mmol) was added via syringe as a solution in dimethylacetamide (2 mL). The reaction was heated at 90 °C for 4 h. An additional portion of Pd[P( tBu)3]2 (18 mg, 0.03522 mmol) was added, the reaction vial was re-purged with nitrogen, and the reaction temperature was increased to 115 °C for an additional 4 h. The reaction was cooled, filtered through Celite, and the filtrate was diluted with ethyl acetate. The filtrate was washed with 15 mL of water, and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organics were washed with brine, dried over sodium sulfate, and concentrated. The crude material was purified by silica gel chromatography using a gradient of 0% to 40% ethyl acetate in hexanes to give 3-(3,3-difluorocyclobutyl)benzonitrile (50 mg, 44%) as a colorless oil. ESI-MS m / z calculated 193.07031, found 194.1 (M+1). + ; Retention time: 0.59 minutes (LC method T).

[0404] Step 3: [3-(3,3-difluorocyclobutyl)phenyl]methanamine (hydrochloride) [ka] 3-(3,3-Difluorocyclobutyl)benzonitrile (50 mg, 0.2588 mmol) was stirred in THF (3 mL) in a nitrogen-purged round-bottom flask and cooled to 0 °C in an ice bath. LAH in THF (200 μL of 2 M, 0.4 mmol) was added dropwise via syringe. The ice bath was removed, and stirring was continued at room temperature for the indicated time. The reaction mixture was then cooled again to 0 °C in an ice bath, and 0.2 mL of water, followed by 0.2 mL of 15% aqueous NaOH, and finally 0.6 mL of water were slowly added dropwise. The reaction mixture was then warmed to room temperature and stirred for 3 h. Stirring was stopped, and sodium sulfate was added. The reaction mixture was filtered and concentrated, after which the product was suspended in 10 mL of dichloromethane, and HCl in dioxane (250 μL of 4 M, 1 mmol) was added. The mixture was then concentrated by rotary evaporation, followed by the addition of dichloromethane and hexanes, and the product was concentrated a second time to give [3-(3,3-difluorocyclobutyl)phenyl]methanamine (hydrochloride) (54 mg, 89%) as a white solid. ESI-MS m / z calculated 197.10161, found 198.1 (M+1). +; Retention time: 0.34 minutes (LC method T).

[0405] Method 4: (3-Cyclobutylphenyl)methanamine (hydrochloride) [ka]

[0406] Step 1: tert-Butyl N-[(3-cyclobutylphenyl)methyl]carbamate [ka] A mixture of tert-butyl N-[(3-bromophenyl)methyl]carbamate (400 mg, 1.4 mmol), bromo(cyclobutyl)zinc (8 mL of 0.5 M, 4 mmol) as a THF solution, and Pd(PPh3)4 (162 mg, 0.14 mmol) in DMF (8 mL) was bubbled with N2 for 1 min and then heated at 100 °C for 1 h. After that, the mixture was diluted with ether, washed with 1 M HCl, brine, and dried (MgSO4). The yellow solid was filtered. The filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of 0% to 20% ethyl acetate in hexanes to give tert-butyl N-[(3-cyclobutylphenyl)methyl]carbamate (66 mg, 18%). 1 H NMR(400MHz,chloroform-d)δ 7.30-7.21(m,1H),7.16-7.05(m,3H),4.79(s,1H),4.30(d,J=5.9Hz,2H),3.53(p,J=8.7Hz,1H),2.33(m,J=10.3 ESI-MS m / z calculated value 261.17288, actual value 523.3(M+M+1) + ; Retention time: 0.68 minutes (LC method T).

[0407] Step 2: (3-Cyclobutylphenyl)methanamine (hydrochloride) [ka] A solution of tert-butyl N-[(3-cyclobutylphenyl)methyl]carbamate (66 mg, 0.25 mmol) and HCl (500 μL of 4 M, 2 mmol) in dioxane was stirred at room temperature for 30 min, and the solvent was evaporated. The residue was suspended in ethyl acetate and evaporated to give (3-cyclobutylphenyl)methanamine (hydrochloride) (46 mg, 92%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.41(s,3H),7.40(s,1H),7.33(t,J=7.4Hz,1H),7.29(d,J=7.4Hz,1H),7.23(d,J=7.3Hz,1H),3.99(s,2H),3.63-3.46 (m,1H),2.30(qt,J=7.7,2.4Hz,2H),2.11(pd,J=9.5,8.7,1.8Hz,2H),2.04-1.90(m,1H),1.88-1.72(m,1H)ppm.ESI-MS m / z calculated value 161.12045, actual value 162.2(M+1) + ; Retention time: 0.33 minutes (LC method T).

[0408] Method 5: [3-Methoxy-4-(trifluoromethyl)phenyl]methanamine (hydrochloride) [ka] Prepared from 3-methoxy-4-(trifluoromethyl)benzonitrile as described in Method 1, steps 2 and 3. [3-Methoxy-4-(trifluoromethyl)phenyl]methanamine (hydrochloride salt) was isolated. ESI-MS m / z calculated 205.07144, found 206.1 (M+1). + ; Retention time: 0.34 minutes (LC method T).

[0409] Method 6: (3-Cyclopropylphenyl)methanamine (hydrochloride) [ka]

[0410] Step 1: tert-Butyl N-[(3-cyclopropylphenyl)methyl]carbamate [ka] A mixture of tert-butyl N-[(3-bromophenyl)methyl]carbamate (305 mg, 1.07 mmol), cyclopropylboronic acid (128 mg, 1.49 mmol), KPO (792 mg, 3.73 mmol), and tricyclohexylphosphine (57.5 mg, 0.205 mmol) in toluene (6 mL) and water (305 μL) was degassed and then flushed with nitrogen for 10 minutes. After this, palladium(II) acetate (24 mg, 0.11 mmol) was added. The mixture was heated at 100°C for 1 hour and then cooled to room temperature. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (2 × 15 mL). The combined organic extracts were washed with brine (10 mL), dried over NaSO, and evaporated. The residue was purified by silica gel chromatography using a gradient of 0% to 15% ethyl acetate in hexanes to give tert-butyl N-[(3-cyclopropylphenyl)methyl]carbamate (200 mg, 76%) as a yellow oil. 1 H NMR(400MHz,chloroform-d)δ 7.19(t,J=7.6Hz,1H),7.08-6.87(m,3H),4.91(s,1H),4.25(d,J=5.9Hz,2H) ,1.92-1.79(m,1H),1.45(s,9H),0.98-0.88(m,2H),0.67(m,2H)ppm.ESI-MS m / z calculated value 247.15723, retention time: 0.68 min (LC method T).

[0411] Step 2: (3-Cyclopropylphenyl)methanamine (hydrochloride) [ka] To a solution of tert-butyl N-[(3-cyclopropylphenyl)methyl]carbamate (100 mg, 0.3437 mmol) in DCM (500 μL) was added 4 M HCl in 1,4-dioxane (500 μL of 4 M, 2 mmol) and stirred at room temperature for 25 min. Evaporation of the solvent gave (3-cyclopropylphenyl)methanamine (hydrochloride salt) (69 mg, quantitative) as a white solid. ESI-MS m / z calculated 147.1048, found 149.17 (M+1). + ; Retention time: 0.3 minutes (LC method T).

[0412] General Method for the Preparation of Secondary Amines Method 7 [ka] Step 1: A mixture of a primary amine (2 equiv.) and a base such as DIEA, TEA, or Cs2CO3 (1 equiv.) in DMF (20-25 volume equiv.) was stirred at room temperature for 30 min. After that, 4-bromobut-1-ene or 4-iodobut-1-ene (1 equiv.) was added, and the mixture was stirred at room temperature for approximately 24 h. The mixture was then filtered, and the precipitate was washed with ethyl acetate. The filtrate was diluted with ethyl acetate, washed with 1 M NaOH, partitioned, and the organic layer was extracted with ethyl acetate (3x). The combined organic extracts were washed with brine, dried (MgSO4), filtered, and evaporated. Purification by silica gel chromatography or reverse-phase HPLC afforded the desired secondary N-but-3-enylamine as the major product, often accompanied by a small amount of the undesired tertiary amine as a by-product.

[0413] Method 8 [ka] Step 1: A mixture of a primary amine (1 equiv.) and 4-iodobut-1-ene (1 equiv.) in THF (20–25 volume equiv.) was stirred at 80°C for approximately 1–2 hours to give the desired secondary amine along with an undesired tertiary amine by-product. The mixture was cooled to room temperature, and TEA (3 equiv.) and di-tert-butyl bicarbonate (1.2 equiv.) were added. After stirring the mixture at room temperature for approximately 2 hours, it was diluted with ether, washed with 1M NaHCO3, dried (MgSO4), filtered, and evaporated. The residue was purified by silica gel chromatography or reverse-phase HPLC to give the desired N-boc-protected N-but-3-enylamine.

[0414] Step 2: A mixture of Boc-protected primary amine (1 equiv.) and HCl (4 M solution in dioxane, 20 equiv.) was stirred at room temperature for about 16 hours, after which the solvent was evaporated to give the desired secondary N-but-3-enylamine as the hydrochloride salt.

[0415] Method 9 [ka] Step 1: To a mixture of aldehyde (1 equivalent), but-3-en-1-amine (1.2 equivalents), and acetic acid (0.1 equivalents) in 1,2-dichloroethane (approximately 30 volume equivalents) was added dry molecular sieves, and the mixture was stirred at room temperature for approximately 1 hour. A suitable reducing agent, such as sodium triacetoxyborohydride or sodium cyanoborohydride (1.5 equivalents), was added, and the resulting mixture was stirred at room temperature overnight. After completion of the reaction, the reaction was quenched with saturated aqueous NaHCO3, filtered through Celite, and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography or reverse-phase HPLC afforded the desired secondary N-but-3-enylamine.

[0416] Method 10 [ka] Step 1: A stirred suspension of a base such as potassium carbonate, cesium carbonate, cesium fluoride, or cesium acetate (1.2 equivalents) and copper iodide (1 equivalent) in toluene (2 volume equivalents) in a Teflon®-capped vial was degassed by bubbling nitrogen through the mixture for 5 minutes and then sealed. Under a nitrogen atmosphere, a halide (1 equivalent) and but-3-en-1-amine (2 equivalents) were added, followed by degassed DMF (5 volume equivalents), and the resulting mixture was sealed and heated at 90°C overnight. The mixture was cooled to room temperature, diluted with ammonium chloride (ammonium hydroxide was added until a blue color persisted), and then extracted with ethyl acetate. The organic fraction was washed once with brine, dried over MgSO4, filtered, and concentrated to a brown syrup, which was purified by silica gel chromatography or reverse-phase HPLC to give the desired secondary N-but-3-enylamine.

[0417] Method 11 [ka] Step 1: To a mixture of amine (hydrochloride) (1 equiv.) and NEt (3 equiv.) in THF (20 volume equiv.) was added di-tert-butyl dicarbonate (1.1 equiv.) at room temperature. The mixture was stirred at room temperature for approximately 1-2 hours, then diluted with ether, washed with 1M NaHCO, dried (MgSO), filtered, and evaporated. The residue was purified by silica gel chromatography to give the mono-Boc-protected amine.

[0418] Step 2: To a solution of mono-Boc-protected amine (1 equivalent) in DMF (10 volume equivalents) (cooled in an ice bath) was added a base such as [bis(trimethylsilyl)amino]sodium (2 equivalents). After stirring at 0°C for 5 minutes, 3-bromo-1-propene (3 equivalents) was added dropwise. The temperature was allowed to rise to room temperature and stirred at this temperature for approximately 1-2 hours. The mixture was then diluted with 1M NH4Cl and ether, and the aqueous layer was discarded. The organic layer was washed with water and then brine, dried (MgSO4), filtered, and evaporated. The residue was purified by silica gel chromatography or reverse-phase HPLC to afford the Boc-protected allyl amine.

[0419] Step 3: After stirring a mixture of Boc-protected allylamine (1 equiv.) and HCl (10 equiv., 4 M in dioxane) at room temperature for about 2 h, the solvent was evaporated and the residue was co-evaporated with THF to give the hydrochloride salt of the substituted N-allyl-amine.

[0420] Method 12 [ka] Step 1: To a solution of the acid (1 equiv.) and but-3-en-1-amine (1.1 equiv.) in DMF (12 volume equiv.) was added DIEA (2.5 equiv.) and HATU (1.2 equiv.). The resulting mixture was stirred at room temperature for 2-3 hours. After this time, it was quenched with 1N HCl solution and extracted with ethyl acetate. The combined organic extracts were washed with HO and saturated aqueous NaCl, then dried over NaSO, filtered, and evaporated under vacuum. Purification by silica gel chromatography using ethyl acetate and hexanes afforded the desired amide.

[0421] Step 2: The amide (1 equiv.) was dissolved in diethyl ether (15–20 volume equiv.) and cooled to 0 °C. A solution of LiAlH in THF (1–2 equiv.) was added, and the resulting mixture was stirred at room temperature for approximately 2 h. The mixture was slowly poured into cold water and extracted with ethyl acetate. The combined organic extracts were washed with HO, 1N NaOH solution, HO, and saturated aqueous NaCl, then dried over NaSO, filtered, and evaporated in vacuo. Purification by silica gel chromatography or reverse-phase preparative chromatography afforded the secondary amine as either the free base or salt, depending on the purification method.

[0422] Preparation of final compounds Example 1: 17-amino-6,15-bis(trifluoromethyl)-19-oxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (Compound 1), 17-amino-6,15-bis(trifluoromethyl)-19-oxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (Compound 1) Preparation of 5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (enantiomer 1) (compound 2) and 17-amino-6,15-bis(trifluoromethyl)-19-oxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (enantiomer 2) (compound 3) [ka]

[0423] Step 1: tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-pent-4-enyl-5-(trifluoromethyl)-3-pyridyl]carbamate [ka] An oven-dried screw-cap test tube equipped with a magnetic stir bar and a Teflon® septum was charged with tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (300 mg, 0.534 mmol) and dry THF (2 mL). Bromo(pent-4-enyl)zinc (2.7 mL of 0.5 M, 1.35 mmol) was added, and the vessel was evacuated and backfilled with argon (this process was repeated a total of three times). The solution was cooled to 0 °C in an ice bath, and Pd(OAc) (6 mg, 0.027 mmol) and C-Phos (23.4 mg, 0.054 mmol) were rapidly added. The ice bath was removed, and the reaction was stirred at 25°C overnight. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride and extracted with ethyl acetate (50 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0% to 20% ethyl acetate in heptane to afford tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-pent-4-enyl-5-(trifluoromethyl)-3-pyridyl]carbamate (120 mg, 35%) as a colorless oil. 1 H NMR(300MHz,CDCl3)δ 1.56(s,9H),1.86-1.96(m,2H),2.14-2.29(m,3H),2.30-2.54(m,3H),2.97(t,J=7.6Hz,2H),4.69(d,J=10.6,1H),4.83( d,J=10.6,1H),4.96-5.08(m,4H),5.70-5.89(m,2H),7.30-7.39(m,3H),7.43-7.47(m,2H),9.1(s,1H),10.08(s,1H)ppm. 19 F NMR(282MHz,CDCl3)δ -72.83(s,3F),-61.41(s,3F)ppm.ESI-MS m / z calculated value 640.2484, retention time: 3.13 minutes (LC method K).

[0424] Step 2: tert-butyl N-[6-benzyloxy-6,15-bis(trifluoromethyl)-19-oxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,9,14(18),15-hexaen-17-yl]carbamate (E / Z mixture) [ka] Tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-pent-4-enyl-5-(trifluoromethyl)-3-pyridyl]carbamate (455 mg, 0.7103 mmol) was dissolved in toluene (270 mL). The flask was evacuated and backfilled with nitrogen (3 cycles), then further degassed by purging with nitrogen for 30 minutes. Benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(tricyclohexylphosphine)ruthenium (133 mg, 0.1563 mmol) was added at room temperature, and the mixture was stirred at 100 °C overnight. The black reaction mixture was removed from the hot oil bath and allowed to cool to room temperature. Di(ethylene glycol) vinyl ether (387.20 mg, 0.4 mL, 2.9298 mmol) was added at 0°C, and the mixture was stirred at room temperature for 10 minutes and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0% to 10% ethyl acetate in heptane to give tert-butyl N-[6-benzyloxy-6,15-bis(trifluoromethyl)-19-oxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,9,14(18),15-hexaen-17-yl]carbamate (E / Z mixture) (243 mg, 39%) as a colorless oil. 1H NMR(300MHz,CDCl3)δ 1.55(s,9H),1.80-2.20(m,2H),2.20-2.40(m,2H),2.40-2.70(m,4H),2.90-3.20(m, 2H),4.88(s,2H),5.40-5.60(m,2H),7.20-7.40(m,5H),9.13(s,1H),9.51(s,1H)ppm. 19 F NMR(282MHz,CDCl3)δ -74.62(s,3F),-62.72(s,3F)ppm.

[0425] Step 3: tert-butyl N-[6-hydroxy-6,15-bis(trifluoromethyl)-19-oxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,14(18),15-pentaen-17-yl]carbamate [ka] A mixture of tert-butyl N-[6-benzyloxy-6,15-bis(trifluoromethyl)-19-oxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,9,14(18),15-hexaen-17-yl]carbamate (E / Z mixture) (470 mg, 0.5371 mmol), Silicate Pd (959 mg, 0.24 mmol / g, 0.2302 mmol), and methanol (15 mL) was hydrogenated overnight at room temperature using a hydrogen balloon. The mixture was diluted with ethyl acetate (30 mL) and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0% to 10% ethyl acetate in heptane to give tert-butyl N-[6-hydroxy-6,15-bis(trifluoromethyl)-19-oxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,14(18),15-pentaen-17-yl]carbamate (280 mg, 98%) as a white solid. 1H NMR(300MHz,DMSO-d6)ppm 1.25-1.65(s,16H),1.65-1.90(m,3H),2.05-2.25(m,2H),2.83-3.11(m,2H),7.70(s,1H),8.80(s,1H)ppm. 19 F NMR (282 MHz, DMSO-d6) ppm: -78.2 (s, 3F), -61.4 (s, 3F) ppm. ESI-MS m / z calculated: 524.18585, found: 525.2 (M+1). + ; Retention time: 4.4 minutes (LC method C).

[0426] Step 4: 17-amino-6,15-bis(trifluoromethyl)-19-oxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (compound 1) [ka] TFA (4.44 g, 3 mL, 38.94 mmol) was added to a solution of tert-butyl N-[6-hydroxy-6,15-bis(trifluoromethyl)-19-oxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,14(18),15-pentaen-17-yl]carbamate (270 mg, 0.5148 mmol) in dichloromethane (9 mL) at room temperature. The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (50 mL) and washed with 5% aqueous NaHCO3. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0% to 20% ethyl acetate in heptane to give 17-amino-6,15-bis(trifluoromethyl)-19-oxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (150 mg, 68%) as a white solid. 1H NMR(300MHz,DMSO-d6)ppm 1.25-1.65(m,7H),1.70-1.85(m,3H),2.10-2.20(m,2H),2.67-2.98(m,2H),6.73(s,2H),7.61(s,1H),7.68(s,1H)ppm. 19 F NMR (282 MHz, DMSO-d6) ppm: -78.1 (s, 3F), -61.5 (s, 3F) ppm. ESI-MS m / z calculated: 424.1334, found: 425.1 (M+1). + ; Retention time: 3.72 minutes (LC method C).

[0427] Step 5: 17-amino-6,15-bis(trifluoromethyl)-19-oxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (enantiomer 1) (compound 2) and 17-amino-6,15-bis(trifluoromethyl)-19-oxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (enantiomer 2) (compound 3) [ka] Racemic 17-amino-6,15-bis(trifluoromethyl)-19-oxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (142 mg, 0.3336 mmol) was purified on a Phenomenex LUX-4 column (250 × 10 mm, 5 μm particle size) using a gradient of 14% MeOH (no modifier) ​​and 86% MeOH (no modifier) ​​at a flow rate of 70 mL / min with an injection volume of approximately 23 mg / mL in methanol (no modifier). Purification by chiral SFC using CO gave the first eluting enantiomer 17-amino-6,15-bis(trifluoromethyl)-19-oxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (enantiomer 1) (35 mg, 48%). ESI-MS m / z calculated 424.1334, found 425.1 (M+1).+ Retention time: 2.95 min. The later eluting enantiomer gave 17-amino-6,15-bis(trifluoromethyl)-19-oxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (enantiomer 2) (47 mg, 65%). ESI-MS m / z calculated 424.1334, found 425.1 (M+1). + ; Retention time: 2.95 minutes (LC method FF).

[0428] Example 2 Preparation of 21-amino-6,19-bis(trifluoromethyl)-23-oxa-3,4,22-triazatetracyclo[16.3.1.12,5.012,17]tricosa-1(22),2,4,12,14,16,18,20-octaen-6-ol (enantiomer 1) (compound 4) and 21-amino-6,19-bis(trifluoromethyl)-23-oxa-3,4,22-triazatetracyclo[16.3.1.12,5.012,17]tricosa-1(22),2,4,12,14,16,18,20-octaen-6-ol (enantiomer 2) (compound 5) [ka]

[0429] Step 1: 6-(2-allylphenyl)-3-(tert-butoxycarbonylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid [ka] Part 1: In a 250 mL sealed vial, methyl 3-[bis(tert-butoxycarbonyl)amino]-6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate (1.0 g, 2.003 mmol) and 2-(2-allylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (783 mg, 3.207 mmol) were combined in DMSO (10 mL). To the mix...

Claims

1. A compound selected from the compounds of formula I, 【Chemistry 511】 and deuterated derivatives and pharma- ceutically acceptable salts thereof, wherein: Xが、-C(R Ｘ１ ) ２ -、-CO-、 【Chemistry 512】 -Si(R Ｚ３ ) ２ - and 【Chemistry 513】 is selected from Ring A is a cyclic group selected from phenyl and 5- to 6-membered heteroaryl, said cyclic group being １ -C ６ optionally substituted with 1 to 3 groups independently selected from alkyl; Each R Ｘ１ But, H, C １ -C ６ Alkyl (oxo, -OR Ｘ２ , and -N(R Ｘ２ ) ２ and optionally substituted with 1 to 3 groups independently selected from ３ -C ８ Cycloalkyl, halogen, cyano, -OR Ｘ２ , and C １ -C ６ fluoroalkyl; Each R Ｘ２ But H and C １ -C ６ independently selected from alkyl, Each Y is -C(R Ｙ ) ２ -, -O-, -CO-, -NR ＹＮ - and 【Chemistry 514】 are independently selected from Each R Ｙ is hydrogen, hydroxy, halogen, C １ -C ６ Alkyl (hydroxy, C １ -C ６ Optionally substituted with 1 to 3 groups independently selected from alkoxy, and Q; ３ -C ８ Cycloalkyl, C ６ -C １０ aryl (optionally substituted with 1 to 3 groups independently selected from halogen), 5 to 10 membered heteroaryl, -OR Ｙ１ , -CO ２ R Ｙ１ , -COR Ｙ１ , -CON(R Ｙ１ ) ２ , and -N(R Ｙ１ ) ２ are independently selected from or two R Ｙ together to form a pi bond, Each R Ｙ１ is hydrogen and C １ -C ６ or two R attached to the same nitrogen atom are independently selected from alkyl, Ｙ１ together form a 3- to 6-membered heterocyclyl, Each R ＹＮ but, ■H and ■C １ -C ６ is an alkyl group, o-oxo, oC ３ -C ８ Cycloalkyl (halogen and C １ -C ６ optionally substituted with 1 to 3 groups independently selected from alkyl; oC ６ -C １０ Aryl, ◆Halogen, ◆ Cyano, ◆C １ -C ６ alkyl (optionally substituted with 1 to 3 hydroxy); ◆C １ -C ６ Fluoroalkyl, ◆C １ -C ６ Alkoxy (C １ -C ６ C optionally substituted with fluoroalkyl ３ -C ８ optionally substituted with cycloalkyl; ◆C １ -C ６ Fluoroalkoxy, ◆C ３ -C ８ Cycloalkyl (halogen, C １ -C ６ Alkyl, and C １ -C ６ fluoroalkyl); and ◆ Phenyl (C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Fluoroalkyl, C １ -C ６ Optionally substituted with 1 to 3 groups independently selected from fluoroalkoxy, fluoroalkoxy, and halogen; ６ -C １０ Aryl, o 5-10 membered heteroaryl; ◆Halogen, ◆C １ -C ６ Alkyl, ◆C １ -C ６ Fluoroalkyl, ◆C １ -C ６ Fluoroalkoxy, ◆-O （０－１） (C ３ -C ８ Cycloalkyl) (C １ -C ６ fluoroalkyl), and ◆ 3- to 12-membered heterocyclyl; and o halogen and C １ -C ６ 3- to 12-membered heterocyclyl, optionally substituted with 1 to 5 groups independently selected from alkyl, １ -C ６ Alkyl and ■C １ -C ６ Fluoroalkyl and ■C ６ -C １０ Aryl and ■C ３ -C ８ Cycloalkyl, o-halogens, o Cyano, o-N(R ＹＮ１ ) ２ C optionally substituted with 1 to 3 groups selected from １ -C ４ Alkyl, oC １ -C ６ Fluoroalkyl, oC １ -C ６ Alkoxy, oC ３ -C ８ Cycloalkyl, and o-phenyl (C １ -C ６ optionally substituted with 1 to 3 groups independently selected from alkyl, ３ -C ８ Cycloalkyl and ■ Oxo and C １ -C ４ Alkyl (oxo and C ３ -C ８ cycloalkyl; and ■ 5-6 membered heteroaryl (C １ -C ６ alkyl), ■CO ２ R ＹＮ１ and are selected independently from Each R ＹＮ１ But, H, C １ -C ４ alkyl (optionally substituted with oxo), and C ３ -C ６ cycloalkyl; Ring B is ■C ６ -C １０ Aryl (halogen, C １ -C ６ Alkyl, and C １ -C ６ Optionally substituted with 1 to 3 groups independently selected from alkoxy; ■C ３ -C ８ Cycloalkyl, ■ 5- to 10-membered heteroaryl, and ■ 3-6 membered heterocyclyl (C １ -C ６ optionally substituted with 1 to 3 groups independently selected from alkyl, Each Q is ■C １ -C ６ is an alkyl group, o halogen, o-oxo, oC ６ -C １０ Aryl (halogen and -OCF ３ and oC ３ -C ８ cycloalkyl, optionally substituted with 1 to 3 groups independently selected from １ -C ６ Alkyl and ■C ３ -C ８ Cycloalkyl, o-halogens, oC.N., oC １ -C ６ Alkyl (halogen, -NH ２ and -NHCOMe, oC １ -C ６ Alkoxy, oC ６ -C １０ Aryl (C １ -C ６ optionally substituted with 1 to 3 groups independently selected from alkyl, oC ３ -C ８ cycloalkyl, optionally substituted with 1 to 3 groups independently selected from ３ -C ８ Cycloalkyl and ■C ６ -C １０ Aryl, o halogen, oC.N., oC １ -C ６ alkyl (optionally substituted with 1 to 3 groups independently selected from halogen and hydroxy); oC １ -C ６ Alkoxy, ◆Halogen, ◆C ３ -C ８ Cycloalkyl (CF ３ (optionally substituted with 1 to 4 groups independently selected from １ -C ６ Alkoxy, oC ３ -C ８ Cycloalkyl (halogen, CF ３ , O.C.F. ３ , and C １ -C ６ optionally substituted with 1 to 3 groups independently selected from alkyl, oC ６ -C １０ aryl, optionally substituted with 1 to 3 groups independently selected from ６ -C １０ Aryl and ■ 5- to 10-membered heteroaryl, o halogen, oC １ -C ６ alkyl (optionally substituted with 1 to 3 groups independently selected from halogen); oC ３ -C ８ Cycloalkyl (1 to 3 CF ３ group), and o 3- to 10-membered heterocyclyl; and ■ 3- to 10-membered heterocyclyl, oC １ -C ６ Alkyl (oxo and C ３ -C ８ cycloalkyl), and oxo; and 3- to 10-membered heterocyclyl optionally substituted with 1 to 3 groups independently selected from Each R １ But halogen, C １ -C ６ Fluoroalkyl, C １ -C ６ Alkyl (hydroxy, C ６ -C １０ aryl, and 5- to 6-membered heteroaryl), —OR ２ , -N(R ２ ) ２ , -CO ２ R ２ , —CO—N(R ２ ) ２ , -C.N., C. ３ -C ８ Cycloalkyl, C ６ -C １０ Aryl, 5-6 membered heteroaryl (C １ -C ６ alkyl), 3- to 6-membered heterocyclyl, -B(OR ２ ) ２ , -SO ２ R ２ , -SR ２ , -SOR ２ , -PO(OR ２ ) ２ , and -PO(R ２ ) ２ are independently selected from Each R ２ is hydrogen, C １ -C ６ alkyl (optionally substituted with 1 to 6 groups independently selected from halogen); １ -C ６ Fluoroalkyl, and C ６ -C １０ Aryl (C １ -C ６ Fluoroalkyl and C １ -C ６ fluoroalkoxy; Z, 【Chemistry 515】 is selected from In the formula, ring C is ６ -C １０ aryl and 5-10 membered heteroaryl; R Ｚ１ is hydrogen, -CN, C １ -C ６ alkyl (optionally substituted with 1 to 3 hydroxy), C １ -C ６ Fluoroalkyl, 3- to 6-membered heterocyclyl, C ３ -C ６ Cycloalkyl, C ６ -C １０ aryl, and 5- to 6-membered heteroaryl; R Ｚ２ is hydrogen, halogen, hydroxyl, NH ２ , NH(CO)(C １ -C ６ alkyl), and C １ -C ６ Alkoxy (C ３ -C １０ cycloalkyl; Or R Ｚ１ and R Ｚ２ taken together form a group selected from oxo and =N-OH, Each R Ｚ３ But hydroxy, C １ -C ６ Alkoxy, C １ -C ６ Alkyl, and C ６ -C １０ aryl, or two R Ｚ３ together form a 3- to 6-membered heterocyclyl, n is selected from 4, 5, 6, 7, and 8; Compounds, and deuterated derivatives and pharma- ceutically acceptable salts thereof, wherein m is selected from 0, 1, 2, and 3.

2. 2. The compound, deuterated derivative, or pharma- ceutically acceptable salt of claim 1, wherein Ring A is a cyclic group selected from phenyl, pyrazole, and oxadiazole.

3. Each R Ｘ１ But, H, C １ -C ６ Alkyl, halogen, cyano, -OR Ｘ２ , and C １ -C ６ 3. The compound, deuterated derivative, or pharma- ceutically acceptable salt of claim 1 or 2, independently selected from fluoroalkyl.

4. Each R Ｘ２ But H and C １ -C ４ 4. The compound, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 3, wherein:

5. Each R Ｘ１ H, F, -CF ３ , -CH ３ , -OH, -OCH ３ 5. The compound, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 4, wherein:

6. X, -CO-、-CH ２ -、 【Chemistry 516】 6. The compound, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 5, selected from:

7. Each Y is -C(R Ｙ ) ２ -, -CO-, -NR ＹＮ - and 【Chemistry 517】 7. The compound, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 6, independently selected from:

8. Each R Ｙ is hydrogen, hydroxy, halogen, and C １ -C ６ 8. The compound, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 7, wherein:

9. Each R Ｙ is H, -OH, -F, and -CH ３ 9. The compound, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 8, independently selected from:

10. Each R ＹＮ but, ■H and ■-CH ２ CF ３ and, ■C １ -C ６ is an alkyl group, o-oxo, o-cyclopropyl, o cyclobutyl optionally substituted with 1 to 2 fluoro groups; o cyclohexyl optionally substituted with 1 to 2 fluoro groups; o spiro[2.2]pentane, o-bicyclo[4.1.0]heptane, o-dispiro[2.0.24.13]heptane, oF, Cl, Br, CN, methyl, propyl (optionally substituted with one hydroxy), tert-butyl, neopentyl, -CHF ２ , -CF ３ , -C(CH ３ ) ２ CF ３ , -OCH ３ , —O(2-propyl), —OCHF ２ , -OCF ３ , -OCF ２ CHF ２ , -OCH ２ CF ３ , cyclopropyl (one CF ３ cyclobutyl (optionally substituted with 1 to 2 groups selected from fluoro and methyl), spiro[2.2]pentane, bicyclo[1.1.1]pentane, bicyclo[4.1.0]heptane, dispiro[2.0.24.13]heptane, phenyl, naphthyl, and 【Chemistry 518】 phenyl, optionally substituted with 1 to 3 groups independently selected from o-naphthyl, o 2,2-dimethyl-2,3-dihydrobenzofuran, o 2,2-difluorobenzo[d][1,3]dioxole, o-Tetrahydro-2H-pyran, pyrazole optionally substituted with one group selected from o-methyl and propyl; o-methyl, tert-butyl, CF ３ , —O(cyclobutyl), —OCHF ２ , 1 CF ３ pyridine, optionally substituted with one group selected from cyclopropyl, optionally substituted with pyrimidine optionally substituted with one group selected from o-methyl and tert-butyl; １ -C ６ Alkyl and Cyclopropyl, optionally substituted with 1 to 2 groups selected from methyl, tert-butyl, cyclopropyl, and phenyl (optionally substituted with one tert-butyl group); Cyclobutyl, optionally substituted with 1 to 3 groups selected from fluoro, methyl, and phenyl; Cyclopentyl and ■ Fluoro, methyl, tert-butyl, cyano, -CF ３ , -CH ２ N.H. ２ , and -CH ２ NHAc; and bicyclo[1.1.1]pentane optionally substituted with one group selected from fluoro, methyl, and tert-butyl; ■ 1 piece of -OCH ３ bicyclo[2.2.1]heptane, optionally substituted with a group; Bicyclo[2.2.2]octane, ■ spiro[3.3]heptane, optionally substituted with 1 to 2 fluoro groups; ■ Phenyl and Tetrahydro-2H-pyran, 2-azaspiro[3.3]heptane optionally substituted with one group selected from -COMe and -CO(cyclopropyl); ■ Thietane 1,1-dioxide, ■ Tetrahydro-2H-thiopyran 1,1-dioxide, a pyrazole optionally substituted with one methyl group; ■ Pyridine, and a compound, deuterated derivative, or pharma- ceutically acceptable salt thereof according to any one of claims 1 to 9, independently selected from the group consisting of:

11. Each R ＹＮ but, H、-CH ３ 、 【Hua 519-1】 【Hua 519-2】 【Chemistry 519-3】 【Chemistry 519-4】 【Chemistry 519-5】 The compound according to any one of claims 1 to 10, independently selected from:

12. Ring B is ■C ６ -C １０ aryl (optionally substituted with 1 to 3 groups independently selected from halogen); ■C ３ -C ８ Cycloalkyl, and ■ 3-6 membered heterocyclyl (C １ -C ６ 12. The compound, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 11, wherein the compound is selected from the group consisting of aryl, aryl, aryls, aryls and aryls.

13. Ring B is 【Chemistry 520】 13. The compound, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 12, selected from:

14. Each R ２ The compound, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 13, wherein is H.

15. Each R １ But, C １ -C ６ Fluoroalkyl, -N(R ２ ) ２ 15. The compound, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 14, wherein:

16. Each R １ But -CF ３ , -NH ２ 16. The compound, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 15, independently selected from -CN,

17. R Ｚ１ But, C １ -C ６ 17. The compound, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 16, selected from fluoroalkyl.

18. R Ｚ２ The compound, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 17, wherein is selected from halogen and hydroxy.

19. Z, 【Chemistry 521】 19. The compound, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 18, selected from:

20. Z, 【Chemistry 522】 20. The compound, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 19, selected from:

21. 21. The compound, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 20, wherein n is selected from 5, 6, and 7.

22. X is -CH ２ - and -CO-, Each Y is -C(R Ｙ ) ２ --, --NR ＹＮ - and 【Chemistry 523】 are independently selected from Each R Ｙ is hydrogen, halogen, and C １ -C ６ independently selected from alkyl, Each R ＹＮ but, ■C １ -C ４ is an alkyl group, oC ６ -C １０ Aryl, oC １ -C ６ Alkyl, oC １ -C ６ Fluoroalkoxy, and oC ３ -C ８ Cycloalkyl (C １ -C ６ fluoroalkyl); ６ -C １０ aryl, optionally substituted with 1 to 3 groups independently selected from １ -C ４ Alkyl and ■ C is optionally substituted with 1 to 3 groups independently selected from halogen; ３ -C ８ cycloalkyl; and Ring B is C ３ -C ８ cycloalkyl; Each R １ But, C １ -C ６ Fluoroalkyl and -NH ２ are independently selected from Z, 【Chemistry 524】 is selected from R Ｚ１ But, C １ -C ６ fluoroalkyl; R Ｚ２ is hydroxy, n is 6; 22. The compound, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 21, wherein m is 2.

23. Each -C(R Ｙ ) ２ -but, -CH ２ -、 【Chemistry 525】 23. The compound, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 22, independently selected from:

24. Each -NR ＹＮ -but, 【Chemistry 526】 24. The compound, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 23, independently selected from:

25. Ring B is 【Chemistry 527】 25. The compound, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 24, wherein:

26. - (Y) ｎ -but, 【Chemistry 528】 26. The compound, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 1 to 25, wherein

27. The compound has formula Ia: 【Chemistry 529】 and deuterated derivatives and pharma- ceutically acceptable salts thereof, wherein: X is -CH ２ - and -CO-, n is selected from 5, 6, and 7; Each Y is -C(R Ｙ ) ２ --, --NR ＹＮ - and 【Chemistry 530】 are independently selected from Each R Ｙ is hydrogen, hydroxy, halogen, and C １ -C ６ Alkyl (hydroxy and C １ -C ６ Optionally substituted with 1 to 3 groups independently selected from alkoxy; Each R ＹＮ but, ■H and ■C １ -C ４ is an alkyl group, o-oxo, oC ３ -C ８ Cycloalkyl (halogen and C １ -C ６ optionally substituted with 1 to 3 groups independently selected from alkyl; oC ６ -C １０ Aryl, ◆Halogen, ◆ Cyano, ◆C １ -C ６ alkyl (optionally substituted with 1 to 3 hydroxy); ◆C １ -C ６ Fluoroalkyl, ◆C １ -C ６ Alkoxy (C １ -C ６ C optionally substituted with fluoroalkyl ３ -C ８ optionally substituted with cycloalkyl; ◆C １ -C ６ Fluoroalkoxy, ◆C ３ -C ８ Cycloalkyl (halogen, C １ -C ６ Alkyl, and C １ -C ６ fluoroalkyl); and ◆ Phenyl (C １ -C ６ C is optionally substituted with 1 to 3 groups independently selected from ６ -C １０ Aryl, o 5-6 membered heteroaryl; ◆Halogen, ◆C １ -C ６ Alkyl, ◆C １ -C ６ Fluoroalkyl, ◆C １ -C ６ Fluoroalkoxy, ◆-O （０－１） (C ３ -C ８ Cycloalkyl) (C １ -C ６ fluoroalkyl), and ◆ 3- to 12-membered heterocyclyl; and o halogen and C １ -C ６ 3- to 12-membered heterocyclyl, optionally substituted with 1 to 3 groups independently selected from alkyl; １ -C ４ Alkyl and ■C １ -C ６ Fluoroalkyl and ■C ６ -C １０ Aryl and ■C ３ -C ８ Cycloalkyl, o halogen, o Cyano, o-N(R ＹＮ１ ) ２ C is optionally substituted with 1 to 3 groups selected from １ -C ４ Alkyl, oC １ -C ６ Fluoroalkyl, oC １ -C ６ Alkoxy, oC ３ -C ８ Cycloalkyl, and o-phenyl (C １ -C ６ optionally substituted with 1 to 3 groups independently selected from alkyl, ３ -C ８ Cycloalkyl and ■ Oxo and C １ -C ４ Alkyl (oxo and C ３ -C ８ cycloalkyl; and ■ 5-6 membered heteroaryl (C １ -C ６ alkyl), ■CO ２ R ＹＮ１ and are selected independently from Each R ＹＮ１ But H and C １ -C ４ alkyl (optionally substituted with oxo); Ring B is ■C ６ -C １０ Aryl (halogen, C １ -C ６ Alkyl, and C １ -C ６ Optionally substituted with 1 to 3 groups independently selected from alkoxy; ■C ３ -C ８ Cycloalkyl, and ■ 3-6 membered heterocyclyl (C １ -C ６ optionally substituted with 1 to 3 groups independently selected from alkyl, Each R １ But halogen, C １ -C ６ Fluoroalkyl, C １ -C ６ Alkyl, -N(R ２ ) ２ -CN; Each R ２ is hydrogen, C １ -C ３ Alkyl, and C １ -C ６ 2. The compound of claim 1, a deuterated derivative, or a pharma- ceutically acceptable salt thereof, independently selected from fluoroalkyl.

28. The compound has the formula Ia': 【Chemistry 531】 and deuterated derivatives and pharma- ceutically acceptable salts thereof, wherein: X is -CH ２ - and -CO-, n is selected from 5, 6, and 7; Each Y is -C(R Ｙ ) ２ --, --NR ＹＮ - and 【Chemistry 532】 are independently selected from Each R Ｙ is hydrogen, hydroxy, halogen, and C １ -C ６ Alkyl (hydroxy and C １ -C ６ Optionally substituted with 1 to 3 groups independently selected from alkoxy; Each R ＹＮ but, ■H and ■C １ -C ４ is an alkyl group, o-oxo, oC ３ -C ８ Cycloalkyl (halogen and C １ -C ６ optionally substituted with 1 to 3 groups independently selected from alkyl; oC ６ -C １０ Aryl, ◆Halogen, ◆ Cyano, ◆C １ -C ６ alkyl (optionally substituted with 1 to 3 hydroxy); ◆C １ -C ６ Fluoroalkyl, ◆C １ -C ６ Alkoxy (C １ -C ６ C optionally substituted with fluoroalkyl ３ -C ８ optionally substituted with cycloalkyl; ◆C １ -C ６ Fluoroalkoxy, ◆C ３ -C ８ Cycloalkyl (halogen, C １ -C ６ Alkyl, and C １ -C ６ fluoroalkyl); and ◆ Phenyl (C １ -C ６ C is optionally substituted with 1 to 3 groups independently selected from ６ -C １０ Aryl, o 5-6 membered heteroaryl; ◆Halogen, ◆C １ -C ６ Alkyl, ◆C １ -C ６ Fluoroalkyl, ◆C １ -C ６ Fluoroalkoxy, ◆-O （０－１） (C ３ -C ８ Cycloalkyl) (C １ -C ６ fluoroalkyl), and ◆ 3- to 12-membered heterocyclyl; o halogen and C １ -C ６ alkyl), 3- to 12-membered heterocyclyl; １ -C ４ Alkyl and ■C １ -C ６ Fluoroalkyl and ■C ６ -C １０ Aryl and ■C ３ -C ８ Cycloalkyl, o-halogens, o Cyano, o-N(R ＹＮ１ ) ２ C optionally substituted with 1 to 3 groups selected from １ -C ４ Alkyl, oC １ -C ６ Fluoroalkyl, oC １ -C ６ Alkoxy, oC ３ -C ８ Cycloalkyl, and o-phenyl (C １ -C ６ optionally substituted with 1 to 3 groups independently selected from alkyl, ３ -C ８ Cycloalkyl and ■ Oxo and C １ -C ４ Alkyl (oxo and C ３ -C ８ cycloalkyl; and ■ 5-6 membered heteroaryl (C １ -C ６ alkyl), ■CO ２ R ＹＮ１ and are selected independently from Each R ＹＮ１ But H and C １ -C ４ alkyl (optionally substituted with oxo); Ring B is ■C ６ -C １０ Aryl (halogen, C １ -C ６ Alkyl, and C １ -C ６ Optionally substituted with 1 to 3 groups independently selected from alkoxy; ■C ３ -C ８ Cycloalkyl, and ■ 3-6 membered heterocyclyl (C １ -C ６ alkyl; Each R １ But halogen, C １ -C ６ Fluoroalkyl, C １ -C ６ Alkyl, -N(R ２ ) ２ -CN; Each R ２ is hydrogen, C １ -C ３ Alkyl, and C １ -C ６ 2. The compound of claim 1, a deuterated derivative, or a pharma- ceutically acceptable salt thereof, independently selected from fluoroalkyl.

29. 29. The compound, deuterated derivative, or pharma- ceutically acceptable salt of claim 27 or 28, wherein n is 6.

30. The compound has formula Ib: 【Chemistry 533】 and deuterated derivatives and pharma- ceutically acceptable salts thereof, wherein: X is -CH ２ - and -CO-, Each Y is -CH ２ -, -C(CH ３ ) ２ -, -CH(CH ３ ) -, -CF ２ -, cyclobutyl, and -NR ＹＮ -, each R ＹＮ but, ■C １ -C ６ Alkyl, C １ -C ６ Fluoroalkoxy, and C ３ -C ８ Cycloalkyl (C １ -C ６ phenyl optionally substituted with 1 to 3 groups independently selected from fluoroalkyl; １ -C ４ Alkyl, and C optionally substituted with 1 to 3 groups independently selected from halogen ３ -C ８ cycloalkyl;

31. The compound has the formula Ib': 【Chemical 534】 and deuterated derivatives and pharma- ceutically acceptable salts thereof, wherein: X is -CH ２ - and -CO-, Each Y is -CH ２ -, -C(CH ３ ) ２ -, -CH(CH ３ ) -, -CF ２ -, cyclobutyl, and -NR ＹＮ -, each R ＹＮ but, ■C １ -C ６ Alkyl, C １ -C ６ Fluoroalkoxy, and C ３ -C ８ Cycloalkyl (C １ -C ６ fluoroalkyl) １ -C ４ Alkyl, and C optionally substituted with 1 to 3 groups independently selected from halogen ３ -C ８ cycloalkyl;

32. 32. The compound, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 27 to 31, wherein X is -CO-.

33. X is -CH ２ 32. The compound, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 27 to 31, wherein:

34. A compound selected from the compounds of Table 7, pharma- ceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing.

35. 35. The compound of any one of claims 1 to 31 or claim 34, wherein the compound is selected from: 【Table 8-1】 【Table 8-2】 【Table 8-3】

36. 36. A pharmaceutical composition comprising a compound, deuterated derivative, or pharma- ceutically acceptable salt according to any one of claims 1 to 35, and a pharma- ceutically acceptable carrier.

37. 37. The pharmaceutical composition of claim 36, further comprising one or more additional therapeutic agents.

38. 38. The pharmaceutical composition of claim 37, wherein the one or more additional therapeutic agents comprises a compound having CFTR modulating activity, or a salt or deuterated derivative thereof.

39. 39. The pharmaceutical composition of claim 37 or 38, wherein the one or more additional therapeutic agents comprise one or more compounds selected from the following: (a) (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 (Compound II): 【Chemistry 535】 (b) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound IV): 【Chemistry 536】 (c) N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound V): 【Chemistry 537】 (d) N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound VI). 【Chemistry 538】 (e) (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ ６ -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound VII): 【Chemistry 539】 (f) (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hexan-5-yl}-9-oxa-2λ ６ -Thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexane-2,2,13-trione (Compound VIII): 【Chemistry 540】

40. The pharmaceutical composition of any one of claims 37-39, wherein the one or more additional therapeutic agents comprises a compound selected from the following: N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (Compound III): 【Chemistry 541】 and 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 (compound III-d): 【Chemical 542】

41. A method of treating cystic fibrosis comprising administering to a patient in need thereof an effective amount of a compound, salt, or deuterated derivative of any one of claims 1 to 35, or a pharmaceutical composition of any one of claims 36 to 40.

42. 42. The method of claim 41, further comprising administering one or more additional therapeutic agents.

43. 43. The method of claim 42, wherein the one or more additional therapeutic agents comprises a compound having CFTR modulating activity, or a salt or deuterated derivative thereof.

44. 44. The method of claim 42 or 43, wherein the one or more additional therapeutic agents comprise one or more compounds selected from the following: (a) Compound II, (b) compound IV, (c) compound V, (d) compound VI, (e) Compound VII, and (f) Compound VIII.

45. The method of any one of claims 42-44, wherein the one or more additional therapeutic agents comprises a compound selected from compound III and compound III-d.

46. A compound, salt or deuterated derivative according to any one of claims 1 to 35, or a pharmaceutical composition according to any one of claims 36 to 40, for use in the treatment of cystic fibrosis.

47. 41. Use of a compound, salt or deuterated derivative according to any one of claims 1 to 35, or a pharmaceutical composition according to any one of claims 36 to 40, in the manufacture of a medicament for the treatment of cystic fibrosis.

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