Cystic fibrosis transmembrane conductance regulator modulators

Abstract

The present disclosure provides modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), pharmaceutical compositions comprising at least one such modulator, methods of using such modulators and pharmaceutical compositions to treat CFTR-mediated diseases, including cystic fibrosis, combination pharmaceutical compositions and combination therapies using the modulators, and processes and intermediates for making such modulators. One aspect of the disclosure provides novel compounds, including compounds of formula I, including any of the compounds of formula Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, and If(i), tautomers thereof, deuterated derivatives of the compounds and tautomers thereof, and pharmaceutically acceptable salts of any of the foregoing.

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Application No. 63 / 328,097, filed April 6, 2022, and U.S. Application No. 63 / 393,405, filed July 29, 2022, the disclosures of which are incorporated herein by reference in their entireties.

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

[0003] Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 70,000 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 mutations have been identified in the CFTR gene. The CFTR2 database currently contains information on only 432 of these identified mutations, leaving 352 mutations with sufficient evidence to define them 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] The deletion of residue 508 in CFTR prevents the nascent protein from folding correctly. This prevents the mutant protein from exiting the endoplasmic reticulum (ER) and entering the plasma membrane. As a result, the number of CFTR channels for anion transport present in the membrane is much lower than that observed in cells expressing wild-type CFTR, i.e., CFTR without the mutation. In addition to impaired transport, this mutation also results in defective channel gating. The reduced number of channels in the membrane combined with the gating defect leads to reduced anion and fluid transport across epithelia. (Quinton, PM (1990), FASEB J. 4:2709-2727). Channels defective due to the F508del mutation are less functional than wild-type CFTR channels, but are still functional. (Dalemans et al. (1991), Nature London. 354:526-528; Pasyk and Foskett (1995), J. Cell. Biochem. 270:12347-50.) In addition to F508del, other disease-causing mutations in CFTR that result in defects in transport, synthesis, and / or channel gating alter anion secretion and can be modulated to modify disease progression and / or severity.

[0007] CFTR is a cAMP / ATP-mediated anion channel expressed in various cell types, including absorptive and secretory epithelial cells, 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 is a 1,480-amino acid protein that encodes a tandem repeat 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.

[0008] Chloride transport is mediated by ENaC and CFTR, which are present on the apical membrane, and Na(+) receptors, which are expressed on the basolateral surface of the cell. + -K + -Pump and Cl - This occurs through the coordinated activity of the channels. Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, followed by 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, and the positioning of luminal CFTR, regulates luminal CFTR-mediated chloride secretion: presumably because water itself is not actively transported, its flow across the epithelium depends on the small transepithelial osmotic gradient generated by the bulk flow of sodium and chloride. Recently, several CFTR-modulating compounds have been identified. However, there remains a need for compounds that can treat or reduce the severity of cystic fibrosis and other CFTR-mediated diseases, particularly the more severe forms of these diseases. [Prior art documents] [Non-patent literature]

[0009] [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] Quinton, PM (1990), FASEB J.4:2709-2727 [Non-patent document 6] Dalemans et al. (1991), Nature Lond.354:526-528 [Non-Patent Document 7] Pasyk and Foskett (1995), J.Cell.Biochem.270:12347-50 Summary of the Invention [Means for solving the problem]

[0010] One aspect of the present disclosure provides novel compounds, including compounds of Formula I, including compounds of any of Formulae Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, and If(i), their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. Another aspect of the disclosure provides compounds of Formulas II, III, and IV, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. Further aspects of the disclosure provide compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. Formula I includes compounds that include the following structure: [ka] including tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein: Ring A is [ka] and Q is selected from -C- and -N-; W is selected from -CH-, -C(F)-, -C(CF3)-, and -N-; X 1 , X 2 , and X 3 are each independently selected from —CH— and —N—; Y is -N-, -N(R y )-, -C(R y )-, and -O-; R y is selected from hydrogen, halogen, C1-C8 haloalkyl, cyano, —NH2, C3-C6 cycloalkyl, C1-C8 alkyl (which may be optionally substituted with a group selected from —OH and C1-C8 alkoxy), —NHC(O)OC1-C8 alkyl (which may be optionally substituted with a group selected from —OH and halogen); Z is -CH-, -O-, -S-, -S(O)-, -S(O)2-, -N-, or -NR z is selected from R z is selected from hydrogen and C1-C8 alkyl; R 1 is selected from C3-C6 cycloalkyl, C1-C8 alkoxy, and C1-C8 alkyl (which can be optionally substituted with a group selected from C4-C6 cycloalkyl, C5-C6 aryl, 4- to 6-membered heterocyclyl, and 4- to 6-membered heteroaryl); R 2 is selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 alkoxy; R 3a and R 3bare independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), C1-C8 alkoxy (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), or together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl); R 4 but, C3-C6 cycloalkyl, which may be optionally substituted with 1 to 3 groups independently selected from halogen, C1-C8 haloalkyl, and C1-C8 alkyl, and C1-C9 alkyl, C3-C8 cycloalkyl (optionally substituted with 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), C1-C8 haloalkyl, O-C-C cycloalkyl (optionally substituted with 1 to 2 groups selected from C-C alkyl, C-C alkoxy, halogen, and C-C haloalkyl), phenyl (optionally substituted with a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), C1-C8 alkoxy (optionally substituted with a group selected from C3-C6 cycloalkyl and halogen), 4- to 6-membered heterocyclyl (optionally substituted with 1 to 2 groups independently selected from halogen, C1-C8 haloalkyl, C1-C8 alkyl, and C1-C8 alkoxy), and silicon (which may be optionally substituted with 1 to 3 groups independently selected from C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 haloalkyl); R 5a and R 5b are independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), C1-C8 alkoxy (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), or together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl); R 6 is selected from halogen, 4-6 membered heterocyclyl, C3-C8 cycloalkyl (which may be optionally substituted with groups selected from C1-C8 alkyl, C1-C8 haloalkyl, and halogen), and C1-C8 alkyl (which may be optionally substituted with 1-2 groups independently selected from C1-C8 alkoxy, halogen, oxo, -OH, -NH2, and -SO2CH3); R 7 is selected from O and NR; R is selected from hydrogen and C1-C8 alkyl.

[0011] Formula I also includes the following compounds: [ka] [ka] [ka] including tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein all variables are as defined for Formula I. DETAILED DESCRIPTION OF THE INVENTION

[0012] In some embodiments, the compound of Formula (I) is selected from compounds I-1 through I-265, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0013] Formula II includes compounds that include the following structure: [ka] and tautomers thereof, or deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein: Ring B is ·halogen 4-10 membered heterocyclyl (optionally substituted with 1-3 groups independently selected from halogen, oxo, and C1-C4 alkyl) ·N(R x )2, (R x are independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl (which may be optionally substituted with a group selected from halogen, C1-C4 haloalkyl, and C1-C4 alkyl). a 6-membered heteroaryl optionally substituted by 1 to 2 groups independently selected from C1-C4 alkyl (optionally substituted with C3-C6 cycloalkyl (which may further be optionally substituted with a group selected from halogen and OH)); R 1 is selected from C3-C6 cycloalkyl, C1-C6 alkoxy, and C1-C6 alkyl (which can be optionally substituted with a group selected from C4-C6 cycloalkyl, C4-C6 aryl, 4- to 6-membered heterocyclyl, and 4- to 6-membered heteroaryl); R 2 is selected from hydrogen, halogen, C1-C8 alkyl, C1-C4 haloalkyl, and C1-C8 alkoxy; R 3a and R 3b are independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), C1-C8 alkoxy (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), or together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl); R 4 but, C3-C6 cycloalkyl, which may be optionally substituted with 1 to 3 groups independently selected from halogen, C1-C8 haloalkyl, and C1-C8 alkyl, and C1-C9 alkyl, C3-C8 cycloalkyl (optionally substituted with 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), C1-C8 haloalkyl, phenyl (optionally substituted with a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), C1-C8 alkoxy (optionally substituted with a group selected from C3-C6 cycloalkyl and halogen), 4- to 6-membered heterocyclyl (optionally substituted with 1 to 2 groups independently selected from halogen, C1-C8 haloalkyl, C1-C8 alkyl, and C1-C8 alkoxy), and silicon (which may be optionally substituted with 1 to 3 groups independently selected from C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 haloalkyl); R 5a and R 5b are independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6-membered heterocyclyl), C1-C8 alkoxy (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6-membered heterocyclyl), or may be joined together to form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6-membered heterocyclyl).

[0014] In some embodiments, ring B in the compound, tautomer, deuterated derivative, or salt of formula II is [ka] is selected from.

[0015] In some embodiments, the compound of formula II is selected from compounds II-1 through II-38, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0016] Formula III is a compound that includes the following structure: [ka] or tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein: Ring C is [ka] is selected from Each R c are independently selected from hydrogen, halogen, cyano, amino, C1-C4 alkyl (which may be optionally substituted with a group selected from —OH, halogen, and oxo), and C3-C6 alkeny; R 1 is selected from C3-C6 cycloalkyl, C1-C6 alkoxy, and C1-C6 alkyl (which can be optionally substituted with a group selected from C4-C6 cycloalkyl, C4-C6 aryl, 4- to 6-membered heterocyclyl, and 4- to 6-membered heteroaryl); R 2 is selected from hydrogen, halogen, C1-C8 alkyl, C1-C4 haloalkyl, and C1-C8 alkoxy; R 3a and R 3b are independently hydrogen, halogen, C 1~ C alkyl (which may be optionally substituted with 1 to 2 groups selected from halogen, hydroxyl, oxo, C-C cycloalkyl, C-C aryl, and 3- to 6-membered heterocyclyl), C-C alkoxy (which may be optionally substituted with 1 to 2 groups selected from halogen, hydroxyl, oxo, C-C cycloalkyl, C-C aryl, and 3- to 6-membered heterocyclyl), or together form C-C cycloalkyl (which may be optionally substituted with 1 to 2 groups selected from halogen, hydroxyl, oxo, C-C alkyl, C-C haloalkyl, C-C cycloalkyl, C-C aryl, and 3- to 6-membered heterocyclyl); R 4 but, C3-C6 cycloalkyl, which may be optionally substituted with 1 to 3 groups independently selected from halogen, C1-C8 haloalkyl, and C1-C8 alkyl, and C1-C9 alkyl, C3-C8 cycloalkyl (optionally substituted with 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), C1-C8 haloalkyl, phenyl (optionally substituted with a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), C1-C8 alkoxy (optionally substituted with a group selected from C3-C6 cycloalkyl and halogen), 4- to 6-membered heterocyclyl (optionally substituted with 1 to 2 groups independently selected from halogen, C1-C8 haloalkyl, C1-C8 alkyl, and C1-C8 alkoxy), and silicon (which may be optionally substituted with 1 to 3 groups independently selected from C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 haloalkyl); R 5a and R 5b are independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6-membered heterocyclyl), C1-C8 alkoxy (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6-membered heterocyclyl), or may be joined together to form C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6-membered heterocyclyl).

[0017] In some embodiments, the compound of formula III is selected from compounds III-1 through III-25, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0018] Formula IV represents compounds that fall within the structure: [ka] or tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein: Ring D is [ka] and Q is selected from -C- and -N-; W is selected from -CH-, -C(F)-, -C(CF3)-, and -N-; X 1 , X 2 , and X 3 are each independently selected from —CH— and —N—; X 4 is selected from C and N; Y is -N-, -N(R y )-, -C(R y )-, and -O-; R y is selected from hydrogen, halogen, C1-C8 haloalkyl, cyano, —NH2, C3-C6 cycloalkyl, C1-C8 alkyl (which may be optionally substituted with a group selected from —OH and C1-C8 alkoxy), —NHC(O)OC1-C8 alkyl (which may be optionally substituted with a group selected from —OH and halogen); Z is -CR z -, -O-, -S-, -S(O)-, -S(O)2-, -N-, and -NR z is selected from R z is selected from hydrogen, halogen, and C1-C8 alkyl (which may be optionally substituted with C1-C8 alkoxy); R 0 is selected from C1-C2 alkyl; R 1 is selected from C3-C6 cycloalkyl, C1-C8 alkoxy, and C1-C8 alkyl (which can be optionally substituted with a group selected from C1-C8 alkoxy, C4-C6 cycloalkyl, C5-C6 aryl, 4- to 6-membered heterocyclyl, and 4- to 6-membered heteroaryl); R 2 is selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 alkoxy; R 3a and R 3b are independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), C1-C8 alkoxy (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), or together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl); R 4 but, C3-C8 cycloalkyl, which may be optionally substituted with 1 to 3 groups independently selected from halogen, C1-C8 haloalkyl, and C1-C8 alkyl, and C1-C9 alkyl, -OH C3-C8 cycloalkyl (optionally substituted with 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), C1-C8 haloalkyl, -OC3-C7 cycloalkyl (optionally substituted with 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), phenyl (optionally substituted with a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), C1-C8 alkoxy (which may be optionally substituted with a group selected from C3-C6 cycloalkyl and phenyl or may be optionally substituted with 1 to 3 halogen atoms), 4- to 6-membered heterocyclyl (optionally substituted with 1 to 2 groups independently selected from halogen, C1-C8 haloalkyl, C1-C8 alkyl, and C1-C8 alkoxy), and silicon (which may be optionally substituted with 1 to 3 groups independently selected from C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 haloalkyl); R 5a and R 5b are independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), C1-C8 alkoxy (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), or together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl); R 6is selected from hydrogen, cyano, halogen, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl (which may be optionally substituted with 1-2 groups selected from C1-C8 alkyl), C3-C8 cycloalkyl (which may be optionally substituted with groups selected from C1-C8 alkyl, C1-C8 haloalkyl, and halogen), phenyl, and C1-C8 alkyl (which may be optionally substituted with 1-2 groups independently selected from C1-C8 alkoxy, C1-C8 haloalkyl, halogen, oxo, —OH, —NH2, and —SO2CH3); R 7 is selected from O and NR; R is selected from hydrogen and C1-C8 alkyl.

[0019] In some embodiments, the compound of formula IV is selected from compounds IV-1 through IV-106, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0020] Another aspect of the present disclosure provides pharmaceutical compositions comprising at least one compound selected from the novel compounds disclosed herein, tautomers thereof, deuterated derivatives of those compounds and tautomers, 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. In some embodiments of the pharmaceutical compositions disclosed herein, the at least one additional active pharmaceutical ingredient is at least one other CFTR modulator. In some embodiments, the at least one other CFTR modulator is selected from a CFTR potentiator and a CFTR modulator.

[0021]

[0010] Accordingly, another aspect of the present disclosure provides methods of treating the CFTR-mediated disease cystic fibrosis, comprising administering to a subject in need thereof at least one compound selected from the novel compounds disclosed herein, their tautomers, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and optionally at least one pharmaceutically acceptable carrier as part of a pharmaceutical composition comprising at least one additional ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient in the methods of treatment disclosed herein is at least one other CFTR modulator. In some embodiments, the at least one other CFTR modulator is selected from a CFTR potentiator and a CFTR corrector.

[0022] In certain embodiments, the pharmaceutical compositions of the present disclosure comprise at least one compound selected from compounds of Formula I, including any of Formulas Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, and If(i), including tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In certain embodiments, the pharmaceutical compositions of the present disclosure comprise at least one compound selected from Compound II, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In certain embodiments, the pharmaceutical compositions of the present disclosure comprise at least one compound selected from Compound III, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In certain embodiments, the pharmaceutical compositions of the present disclosure comprise at least one compound selected from Compound IV, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In certain embodiments, the pharmaceutical compositions of the present disclosure comprise at least one compound selected from Compounds I-1 to I-265, Compounds II-1 to II-38, Compounds III-1 to III-25, and Compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0023] In some embodiments, a composition comprising at least one compound selected from compounds of Formula I, including compounds comprising any of Formulas Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, optionally comprises (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 (tezacaftor), 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (lumacaftor), deuterated derivatives of tezacaftor and lumacaftor and pharmaceutically acceptable salts of any of the foregoing, and / or (b) at least one compound (i.e., one or more) selected from N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (ivacaftor), N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydro Quinoline-3-carboxamide (deutoivacaftor), (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol; ivacaftor, deutoivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and (6R)-1 The composition may comprise at least one compound (i.e., one or more compounds) selected from the group consisting of a deuterated derivative of 7-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and a pharmaceutically acceptable salt of any of the foregoing.

[0024] In some embodiments, a composition comprising at least one compound selected from Compounds I-1 to I-265, Compounds II-1 to II-38, Compounds III-1 to III-25, Compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, optionally comprises (a)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropyl)-2-methylpropional. at least one (i.e., one or more) compounds selected from N-[2,4-bis(1,1-dimethylethyl)-5-(2,4-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (tezacaftor), 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (lumacaftor), deuterated derivatives of tezacaftor and lumacaftor, and pharmaceutically acceptable salts of any of the foregoing; and / or (b) N-[2,4-bis(1,1-dimethylethyl)-5-(2,4-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (tezacaftor), 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (lumacaftor), Hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (ivacaftor), N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (deuterivaftor), (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1 (18),2,4,14,16-pentaen-6-ol, and (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, the deuterated derivative of ivacaftor, deutoivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18).12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and pharmaceutically acceptable salts of any of the foregoing.

[0025] Another aspect of the present disclosure provides methods 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 optionally further administering one or more additional CFTR modulators selected from tezacaftor, ivacaftor, and lumacaftor.

[0026] In further aspects, compounds of the disclosure (e.g., compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 through I-265, compounds II-1 through II-38, compounds III-1 through III-25, compounds IV-1 through IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing), and pharmaceutical compositions comprising these compounds and optionally further one or more CFTR modulating agents, are used in therapy or for the manufacture of a medicament. In some embodiments, the one or more additional CFTR modulating agents are selected from CFTR potentiators. In some embodiments, the one or more additional CFTR modulating agents are selected from CFTR correctors. In some embodiments, the one or more additional CFTR modulating agents are selected from tezacaftor, lumacaftor, ivacaftor, deutoivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.

[0027] A further aspect of the present disclosure provides intermediates and methods for making the compounds and compositions disclosed herein.

[0028] definition As used herein, "tezacaftor" 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, and can be represented by the following structure: [ka] Tezacaftor can be in the form of a deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative. Tezacaftor and methods of making and using tezacaftor are disclosed in WO2010 / 053471, WO2011 / 119984, WO2011 / 133751, WO2011 / 133951, WO2015 / 160787, and US2009 / 0131492, each of which is incorporated herein by reference.

[0029] As used throughout this disclosure, "ivacaftor" refers to N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide and is represented by the following structure: [ka] Ivacaftor may also be in the form of a deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative. Ivacaftor and methods of making and using ivacaftor are disclosed in WO2006 / 002421, WO2007 / 079139, WO2010 / 108162, and WO2010 / 019239, each of which is incorporated herein by reference.

[0030] In some embodiments, the deuterated derivative of ivacaftor (deuterivative ivacaftor) is used in the compositions and methods disclosed herein. The chemical name for deuterivative ivacaftor is N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide and is represented by the following structure: [ka] Deutoivacaftor may also be in the form of a deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative. Deutoivacaftor and methods of making and using deutoivacaftor are disclosed in WO2012 / 158885, WO2014 / 078842, and U.S. Patent No. 8,865,902, each of which is incorporated herein by reference.

[0031] "Lumacaftor," as used herein, refers to 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, represented by the following chemical structure: [ka] Lumacaftor may be in the form of a deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative. Lumacaftor and methods of making and using lumacaftor are disclosed in WO2007 / 056341, WO2009 / 073757, and WO2009 / 076142, each of which is incorporated herein by reference.

[0032] (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, as well as deuterated derivatives and pharmaceutically acceptable salts, are described in WO2022 / 032068, which is incorporated herein by reference.

[0033] (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives and pharmaceutically acceptable salts are described in PCT / US2021 / 072475, which is incorporated herein by reference.

[0034] As used herein, the term "alkyl" refers to a saturated or partially saturated, branched or unbranched aliphatic hydrocarbon containing carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms, etc.), which may contain a double (alkenyl) or triple (alkynyl) bond between one or more pairs of adjacent carbon atoms. An alkyl group may be substituted or unsubstituted.

[0035] The terms "aliphatic" or "aliphatic group," as used herein, refer to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation; or a monocyclic or bicyclic hydrocarbon (also referred to herein as an "alicyclic," "carbocyclic," or "cycloalkyl") that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-20 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-10 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-8 aliphatic carbon atoms. In yet other embodiments, an aliphatic group contains 1-6 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C ring that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the rest of the molecule. 3~8 Hydrocarbon or bicyclic or tricyclic C 8~14 " refers to a hydrocarbon, where any individual ring within the bicyclic ring system has 3 to 7 members. Suitable aliphatic groups include, but are not limited to, straight-chain or branched-chain, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrid groups thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, and (cycloalkyl)alkenyl. Suitable alicyclic groups include cycloalkyl, bicyclic cycloalkyl (e.g., decalin), bridged bicycloalkyl, such as norbornyl or [2.2.2]bicyclo-octyl, and bridged tricyclic, such as adamantyl.

[0036] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0037] As used herein, the term "π bond" refers to a covalent bond formed by p orbitals of adjacent atoms. A π 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 π bond, and a carbon-carbon triple bond consists of two π bonds.

[0038] As used herein, the term "haloalkyl group" refers to an alkyl group substituted with one or more halogen atoms, e.g., fluoroalkyl, which refers to an alkyl group substituted with one or more fluorine atoms. In some embodiments, one carbon atom of the alkyl group is substituted with one or more halogen atoms. In some embodiments, each carbon atom of the alkyl group is substituted with one or more halogen atoms. In some embodiments, one or more carbon atoms of the alkyl group are perhalocarbon atoms (i.e., all hydrogen atoms of the alkyl group are replaced with halogen atoms). In some embodiments, each carbon atom of the alkyl group is a perhalocarbon atom. Non-limiting examples of fluoroalkyl include -CHF, -CHF, -CF, -CF-, and perhaloalkyl, e.g., -CFCF.

[0039] As used herein, the term "halogen" or "halo" means F, Cl, Br, or I.

[0040] As used herein, the terms "oxo" and "=O" refer to a substituent oxygen atom that is attached by a double bond to another atom.

[0041] The term "alkoxy" as used herein refers to an alkyl or cycloalkyl covalently linked to an oxygen atom. An alkoxy group can be substituted or unsubstituted.

[0042] 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) and may contain one or more unsaturated bonds. "Cycloalkyl" groups encompass monocyclic, bicyclic, tricyclic, bridged, fused, and spirocyclic rings, including monospirocyclic and dispirocyclic rings. Non-limiting examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, dispiro[2.0.2.1]heptane, bicyclo[1.1.1]pentane, and spiro[2,3]hexane. Cycloalkyl groups can be substituted or unsubstituted.

[0043] 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. Aryl groups can be optionally substituted with one or more substituents. Non-limiting examples of aryl groups include phenyl, naphthyl, and 1,2,3,4-tetrahydronaphthalenyl.

[0044] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocycle, such as N (such as 3,4-dihydro-2H-pyrrolyl), NH (such as pyrrolidinyl), or NR + (including a substitutable nitrogen of a heterocyclic ring, such as N-substituted pyrrolidinyl)

[0045] The term "heteroaliphatic," as used herein, refers to an aliphatic group in which one or two carbon atoms are independently replaced with one or more heteroatoms, such as oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroaliphatic groups can be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include "heterocycle," "heterocyclyl," "heterocycloaliphatic," and "heterocyclic" groups.

[0046] As used herein, the term "heteroaryl ring" refers to an aromatic ring containing at least one ring atom that is a heteroatom, such as O, N, or S. Heteroaryl groups encompass monocyclic rings having a total of 5 to 14 ring members, 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, at least one ring in the system contains one or more heteroatoms, and each ring in the system contains 3 to 7 ring members. Non-limiting examples of heteroaryl rings include pyridine, quinoline, indole, and indoline. Heteroaryl groups can be optionally substituted with one or more substituents. In certain embodiments, the term "heteroaryl ring" encompasses heteroaryl rings in various oxidation states, such as heteroaryl rings containing N-oxides and sulfoxides. Non-limiting examples of such heteroaryl rings include pyrimidine N-oxide, quinoline N-oxide, thiophene S-oxide, and pyrimidine N-oxide.

[0047] As used herein, the term "heterocyclyl ring" refers to a non-aromatic hydrocarbon containing 3 to 12 atoms (e.g., 3 to 10 atoms) in the ring, including at least one ring atom that is a heteroatom such as O, N, or S, and may contain one or more unsaturated bonds. "Heterocyclyl" rings encompass monocyclic, bicyclic, tricyclic, polycyclic, bridged, fused, and spiro rings, including monospiro and dispiro rings.

[0048] Combined display [ka] is intended to reflect the presence of an aromatic (i.e., conjugated) ring system. It will be understood that ring A of formula I includes a 6-membered aryl or heteroaryl ring fused to a 5-membered aryl or heteroaryl ring.

[0049] It is to be understood that certain compounds of the present disclosure 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 E / Z stereochemistry as drawn. As used in the chemical structures disclosed herein, [ka] (a "wavy" line perpendicular to a "straight" bond to group "A") indicates that group "A" is a substituent whose point of attachment is at the terminus of the bond that terminates in the "wavy" line. As used herein, stereoatoms designated (R) or (S) indicate the stereochemical designation of the stereoatom by the Cahn-Ingold-Prelog convention.

[0050] Certain compounds may exist as atropisomers. It is understood that certain compounds of the present disclosure may exist as isolated atropisomers and / or mixtures of these atropisomers, i.e., subclasses of stereoisomers resulting from restricted rotation about a single bond or axis of chirality and that can be isolated as distinct chemical species. As used herein, the designations (P) or (M) for stereogenic units refer to the stereochemical designation of the stereogenic unit based on the Cahn-Ingold-Prelog convention (basic terminology of stereochemistry, IUPAC Recommendations 1996, Pure & Appl. Chem., Vol. 68, No. 12, pp. 2193-2222, 1996).

[0051] Certain compounds disclosed herein can exist as tautomers, and both tautomeric forms are intended, even though only a single tautomeric structure is depicted. For example, a description of compound X is understood to include its tautomeric compound Y, and vice versa, as well as mixtures thereof. [ka] Unless otherwise specified, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0052] "Tert" and "t-" are used interchangeably and mean tertiary.

[0053] The compounds described herein can be optionally substituted with one or more substituents, as generally indicated above or as exemplified by the specific classes, subclasses, and species of the present disclosure. It will be understood that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." "Substituted," whether preceded by the term "optionally," or not, 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 substitutable position of the group, and when multiple positions in any given structure may be substituted with multiple substituents selected from a specified group, the substituents may be the same or different at each position. Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds.

[0054] The term "stable," as used herein, refers to compounds that do not substantially change when subjected to conditions that allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.

[0055] As used herein, the term "stable compound" refers to a compound that is sufficiently stable to permit its manufacture and maintains its integrity for a period of time sufficient to be useful for the purposes detailed herein (e.g., as a therapeutic agent, an intermediate for use in the manufacture of a therapeutic compound, formulation into an intermediate that can be isolated or stored, and / or treatment of a disease or condition that responds to a therapeutic agent).

[0056] In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at its natural abundance isotopic composition.

[0057] As used herein, the term "derivative" refers to a collection of molecules that have the same chemical structure as a compound of the present disclosure, except that one or more atoms of the molecule may be replaced with another atom. Additionally, unless otherwise specified, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the substitution of carbon at C, are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools, probes in biological assays, or compounds with improved therapeutic profiles.

[0058] As used herein, a "deuterated derivative" refers to a compound having the same chemical structure as a reference compound, in which one or more hydrogen atoms have been replaced with deuterium atoms. In some embodiments, the one or more hydrogen atoms replaced with deuterium are part of an alkyl group. In some embodiments, the one or more hydrogen atoms replaced with deuterium are part of a methyl group. In the chemical structure, deuterium may be represented by "D."

[0059] As used herein, "CFTR" means cystic fibrosis transmembrane conductance regulator.

[0060] As used herein, the term "modulator" refers to a compound that increases the activity of a biological compound or molecule, such as a protein.

[0061] As used herein, the term "CFTR modulator" refers to a compound that increases the activity of CFTR. The increased activity provided by a CFTR modulator includes, but is not limited to, compounds that correct, enhance, stabilize, and / or amplify CFTR.

[0062] As used herein, the terms "corrector" and "CFTR corrector" are used interchangeably and refer to compounds that promote CFTR processing and trafficking, increasing the amount of CFTR at the cell surface. The novel compounds disclosed herein are CFTR correctors. Tezacaftor and lumacaftor, and their deuterated derivatives and pharmaceutically acceptable salts, referred to herein, are correctors.

[0063] As used herein, the terms "potentiator" and "CFTR potentiator" are used interchangeably and refer to compounds that increase the channel activity of the CFTR protein located on the cell surface, thereby enhancing ion transport. Ivacaftor, deutoivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol are CFTR potentiators as referred to herein.Descriptions of combinations of compounds that include compounds of the present disclosure (e.g., compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, Compounds I-1 through I-265, Compounds II-1 through II-38, Compounds III-1 through III-25, Compounds IV-1 through IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing) typically include, for example, ivacaftor, deutoivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca

[00134] It is understood that the term "CFTR potentiators" includes, but does not necessarily include, CFTR potentiators such as (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, or a deuterated derivative or pharmaceutically acceptable salt of any of the foregoing. In addition, the combination typically includes only one potentiating agent, but not necessarily, may include more than one correcting agent.Thus, in some embodiments, the combination of at least one compound of the present disclosure (e.g., compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 through I-265, compounds II-1 through II-38, compounds III-1 through III-25, compounds IV-1 through IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing) includes ivacaftor, deuterioivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19- The combination may include a potentiator selected from dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, or a deuterated derivative or pharmaceutically acceptable salt thereof, and may also include another CFTR corrector, such as a corrector compound selected from tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof. In some embodiments, such a combination may also include a CFTR potentiator enhancer.

[0064] As used herein, the terms "CFTR potentiator potentiator," "CFTR potentiator," and "CFTR co-potentiator" are used interchangeably and refer to compounds that increase CFTR potentiation.

[0065] The term "compound," when referring to a compound of the present disclosure, refers to a collection of molecules having identical chemical structure except that isotopic variations may exist among the constituent atoms of the molecule.

[0066] The phrase "novel compounds of the present disclosure" refers to compounds selected from any one of Formulas I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, and If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. Specifically excluded from the phrase "novel compounds of the present disclosure" is any compound disclosed in PCT / US2021 / 053858 (incorporated herein by reference).

[0067] As used herein, the term "at least one compound selected from" refers to a selection of one or more compounds from a particular group. "Selected" and "chosen" are used interchangeably herein.

[0068] Reference herein to "compounds I-1 through I-265" is intended to refer to each of compounds 1 through 264 encompassed by Formula I, individually or as a group. Similarly, reference to "compounds II-1 through II-38" refers to compounds 1 through 38 encompassed by Formula II, either as a group or individually as each compound. Reference to "compounds III-1 through III-24" refers to compounds 1 through 24 encompassed by Formula III, either as a group or individually as each compound. Reference to "compounds IV-1 through IV-106" refers to compounds 1 through 106 encompassed by Formula IV, either as a group or individually as each compound. Reference to "compounds I-1 through I-265, compounds II-1 through II-38, compounds III-1 through III-25, and compounds IV-1 through IV-106" is intended to refer to the compounds encompassed by each of Formulas I, II, III, and IV individually, or to the compounds encompassed by the three distinct groups of compounds.

[0069] As used herein, the term "active pharmaceutical ingredient" or "therapeutic agent" ("API") refers to a biologically active compound.

[0070] The terms "patient" and "subject" are used interchangeably and refer to animals, including humans.

[0071] 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).

[0072] 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 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.

[0073]

[0023] Reference herein to a method of treatment (e.g., a method of treating a CFTR-mediated disease or a method of treating cystic fibrosis) using one or more disclosed compounds, optionally in combination with one or more additional CFTR-modulating agents (e.g., a compound selected from the compounds of Formulas I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 through I-265, compounds II-1 through II-38, compounds III-1 through III-25, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, optionally in combination with one or more additional CFTR-modulating agents) also refers to one or more compounds of the present disclosure (e.g., a compound selected from compounds of formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, and If(i), compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, optionally in combination with one or more additional CFTR modulators, for use in a method for treating cystic fibrosis; and / or and tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, optionally in combination with one or more additional CFTR modulators) of the present disclosure, for example, in the manufacture of a medicament for treating cystic fibrosis.

[0074] Also herein, references to methods of treatment (e.g., methods of treating a CFTR-mediated disease or methods of treating cystic fibrosis) using pharmaceutical compositions of the present disclosure (e.g., pharmaceutical compositions comprising at least one compound selected from a compound of any of Formulas I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 through I-265, compounds II-1 through II-38, compounds III-1 through III-25, compounds IV-1 through IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and optionally further comprising one or more additional CFTR modulators) are intended to mean a pharmaceutical composition (e.g., a pharmaceutical composition comprising at least one compound selected from a compound of any of Formulas I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and optionally further comprising one or more additional CFTR modulators, for example, for use in a method for treating cystic fibrosis; and / or It should also be understood that this reference should also be construed as a reference to the use of a pharmaceutical composition (e.g., a pharmaceutical composition comprising at least one compound selected from a compound of any of Formulas I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 through I-265, compounds II-1 through II-38, compounds III-1 through III-25, compounds IV-1 through IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and optionally further comprising one or more additional CFTR modulators), for example, in the manufacture of a medicament for treating cystic fibrosis.

[0075] 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.

[0076] As used herein, the terms "about" and "approximately," when used in connection with amounts, volumes, reaction times, reaction temperatures, and the like, refer to an acceptable error for a particular value as determined by one of ordinary skill in the art and will depend, in part, on how the value is measured or determined. In some embodiments, the terms "about" and "approximately" mean within 1, 2, 3, or 4 standard deviations. In certain embodiments, the terms "about" and "approximately" mean within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range. As used herein, the symbol "~" appearing immediately before a numerical value has the same meaning as the terms "about" and "approximately."

[0077] The term "at least one" refers to one or more.

[0078] As used herein, the term "solvent" refers to any liquid in which the product is at least partially soluble (product solubility >1 g / L).

[0079] Non-limiting examples of suitable solvents that can be used in the present disclosure include, for example, water (HO), methanol (MeOH), methylene chloride or dichloromethane (DCM; CHCl), acetonitrile (MeCN; CHCN), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (EtO), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0080] As used herein, the term "ambient conditions" refers to room temperature, open air conditions, and uncontrolled humidity conditions. As used herein, the term "room temperature" or "ambient temperature" refers to 15°C to 30°C.

[0081] As used herein, "mutation" can refer to a mutation in the CFTR gene or CFTR protein. A "CFTR gene mutation" refers to a mutation in the CFTR gene, and a "CFTR protein mutation" refers to a mutation in the CFTR protein. Generally, a genetic defect or mutation, or a nucleotide change in a gene, results in a mutation or frameshift in the CFTR protein translated from that gene.

[0082] 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 CFTR synthesis (or minimal CFTR synthesis), and mutations associated with a severe defect in channel conductance.

[0083] As used herein, the term "F508del" refers to a mutant CFTR protein lacking the amino acid phenylalanine at position 508, or a mutant CFTR gene encoding a CFTR protein lacking the amino acid phenylalanine at position 508.

[0084] The present disclosure also provides a process for preparing salts of the disclosed compounds. Salts of the disclosed compounds are formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group. In some embodiments, the salt is a pharmaceutically acceptable salt.

[0085] As used herein, the term "pharmaceutically acceptable" refers to a material that is suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and the like, and that is consistent with sound medical judgment and commensurate with a reasonable benefit / risk ratio.

[0086] As used herein, the term "pharmaceutically acceptable salt" refers to any non-toxic salt that is capable of providing a compound of the present disclosure, either directly or indirectly, upon administration to a recipient. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. A "pharmaceutically acceptable counterion" is an ionic portion of the salt that is not toxic when released from the salt upon administration to a recipient. One of ordinary skill in the art will recognize that when an amount of "a compound or a pharmaceutically acceptable salt thereof" is disclosed, the amount of the pharmaceutically acceptable salt form of the compound is the amount corresponding to the concentration of the free base of the compound.

[0087] The "free base" form of a compound does not include ion-bonded salts. Please note that the disclosed amounts of compounds or their pharmaceutically acceptable salts herein are based on their free base form. For example, "10 mg of at least one compound selected from Compound I and its pharmaceutically acceptable salts" includes 10 mg of Compound I and the concentration of the pharmaceutically acceptable salt of Compound I that corresponds to 10 mg of Compound I.

[0088] 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 article provides the following pharmaceutically acceptable salts: [Table 1]

[0089] 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-hydroxybenzoate, benzoates, benzoates, benzoates, benzoates, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxybenzoates, ... Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and valerate salts. + (C 1-4(Alkyl) 4 salts are also included. The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable, non-limiting examples of alkali metal and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0090] CFTR Modulator Compounds In some embodiments, the present disclosure provides a compound of formula I: [ka] Tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are provided, wherein: Ring A is [ka] and Q is selected from -C- and -N-; W is selected from -CH-, -C(F)-, -C(CF3)-, and -N-; X 1 , X 2 , and X 3 are each independently selected from —CH— and —N—; Y is -N-, -N(R y )-, -C(R y )-, and -O-; R yis selected from hydrogen, halogen, C1-C8 haloalkyl, cyano, —NH2, C3-C6 cycloalkyl, C1-C8 alkyl (which may be optionally substituted with a group selected from —OH and C1-C8 alkoxy), —NHC(O)OC1-C8 alkyl (which may be optionally substituted with a group selected from —OH and halogen); Z is -CH-, -O-, -S-, -S(O)-, -S(O)2-, -N-, or -NR z is selected from R z is selected from hydrogen and C1-C8 alkyl; R 1 is selected from C3-C6 cycloalkyl, C1-C8 alkoxy, and C1-C8 alkyl (which can be optionally substituted with a group selected from C4-C6 cycloalkyl, C5-C6 aryl, 4- to 6-membered heterocyclyl, and 4- to 6-membered heteroaryl); R 2 is selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 alkoxy; R 3a and R 3b are independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), C1-C8 alkoxy (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), or together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl); R 4 but, C3-C6 cycloalkyl, which may be optionally substituted with 1 to 3 groups independently selected from halogen, C1-C8 haloalkyl, and C1-C8 alkyl, and C1-C9 alkyl, C3-C8 cycloalkyl (optionally substituted with 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), C1-C8 haloalkyl, O-C-C cycloalkyl (optionally substituted with 1 to 2 groups selected from C-C alkyl, C-C alkoxy, halogen, and C-C haloalkyl), phenyl (optionally substituted with a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), C1-C8 alkoxy (optionally substituted with a group selected from C3-C6 cycloalkyl and halogen), 4- to 6-membered heterocyclyl (optionally substituted with 1 to 2 groups independently selected from halogen, C1-C8 haloalkyl, C1-C8 alkyl, and C1-C8 alkoxy), and silicon (which may be optionally substituted with 1 to 3 groups independently selected from C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 haloalkyl); R 5a and R 5bare independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), C1-C8 alkoxy (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), or together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl); R 6 is selected from halogen, 4-6 membered heterocyclyl, C3-C8 cycloalkyl (which may be optionally substituted with groups selected from C1-C8 alkyl, C1-C8 haloalkyl, and halogen), and C1-C8 alkyl (which may be optionally substituted with 1-2 groups independently selected from C1-C8 alkoxy, halogen, oxo, -OH, -NH2, and -SO2CH3); R 7 is selected from O and NR; R is selected from hydrogen and C1-C8 alkyl; provided that the compound of formula I is [Table 8-1] [Table 8-2] and tautomers, deuterated derivatives, and pharmaceutically acceptable salts thereof.

[0091] In some embodiments, ring A of the compound of formula I is selected from: [ka] In the formula, R 6 , W, X 2 , X3 , Y, R y and Z are as defined above. In some embodiments, ring A of the compound of formula I is [ka] wherein R y and R 6 is as defined above.

[0092] In some embodiments, the compound of formula I is compound Ia: [ka] or formula Ia(i): [ka] and tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0093] In some embodiments, the compound of formula I is compound Ib: [ka] and formula Ib(i): [ka] and tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0094] In some embodiments, the compound of formula I is compound Ic: [ka] and formula Ic(i): [ka] and tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0095] In some embodiments, the compound of formula I is compound Id: [ka] and Formula Id(i): [ka] and tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0096] In some embodiments, the compound of formula I is compound Ie: [ka] and formula Ie(i): [ka] and tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0097] In some embodiments, the compound of formula I is Expression If: [ka] and the formula If(i): [ka] and tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0098] In some embodiments, R in a compound of any of formulas I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, and If(i) 4 is selected from C1-C6 alkyl optionally substituted with a group selected from halogen, haloalkyl, and C1-C4 alkoxy. In some embodiments, R in a compound of any of Formulas I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, and If(i) is 4 is selected from C1-C6 alkyl substituted with 1-2 groups independently selected from C3-C5 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, haloalkyl, and C1-C4 alkyl). In some embodiments, R in a compound of any of Formulas I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, and If(i) is 4 is selected from C1-C6 alkyl optionally substituted with phenyl (which may be optionally substituted with a group selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, and haloalkyl). In some embodiments, R in a compound of any of Formulas I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, and If(i) is 4 is selected from C1-C6 alkyl substituted with 4-6 membered heterocyclyl (which may be optionally substituted with 1-2 groups independently selected from halogen, haloalkyl, and C1-C4 alkyl).

[0099] In some embodiments, R in a compound of any of formulas I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, and If(i) 4 is selected from the following: [ka]

[0100] In some embodiments of Formula I, R y is selected from bromine, chlorine, hydrogen, cyano, NH, butyl, cyclopropyl, CH, and CF. In some embodiments, R in the compound of Formula I y is selected from hydrogen, chlorine, amino, methyl, and butyl groups.

[0101] In some embodiments, R in a compound of any of formulas I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, and If(i) 6 is selected from C3-C8 cycloalkyl (which may be optionally substituted with a group selected from C1-C4 alkyl, haloalkyl, and halogen). In some embodiments, R in a compound of any of Formulas I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, and If(i) is 6 is C1-C6 alkyl (C1-C4 alkoxy, halogen, In some embodiments, R in a compound of any of Formulas I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, and If(i) is selected from the group consisting of: -(Ia), -(Ia), -(Ib), -(Ic), -(Ic), -(Ic), -(Id), -(Id), -(Ie), -(Ic ... 6 is selected from the following: [ka]

[0102] In some embodiments of Formula I, the compound is selected from compounds I-1 through I-265 and tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. [Table 3-1] [Table 3-2]

Table 3-3

Table 3-4

Table 3-5

Table 3-6

Table 3-7

Table 3-8

Table 3-9

Table 3-10

Table 3-11

Table 3-12

Table 3-13

Table 3-14

Table 3-15

Table 3-16

Table 3-17

Table 3-18

Table 3-19

[0103] In some embodiments, the present disclosure provides a compound of formula II: [ka] or a tautomer thereof, or a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Ring B is ·halogen 4-10 membered heterocyclyl (optionally substituted with 1-3 groups independently selected from halogen, oxo, and C1-C4 alkyl) ·N(R x )2, (R x are independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl (which may be optionally substituted with a group selected from halogen, C1-C4 haloalkyl, and C1-C4 alkyl). a 6-membered heteroaryl optionally substituted by 1 to 2 groups independently selected from C1-C4 alkyl (optionally substituted with C3-C6 cycloalkyl (which may further be optionally substituted with a group selected from halogen and —OH)); R 1 is selected from C3-C6 cycloalkyl, C1-C6 alkoxy, and C1-C6 alkyl (which can be optionally substituted with a group selected from C4-C6 cycloalkyl, C4-C6 aryl, 4- to 6-membered heterocyclyl, and 4- to 6-membered heteroaryl); R 2 is selected from hydrogen, halogen, C1-C8 alkyl, haloalkyl, and C1-C8 alkoxy; R 3a and R 3b are independently hydrogen, halogen, C 1~ C alkyl (which may be optionally substituted with 1 to 2 groups selected from halogen, hydroxyl, oxo, C-C cycloalkyl, C-C aryl, and 3- to 6-membered heterocyclyl), C-C alkoxy (which may be optionally substituted with 1 to 2 groups selected from halogen, hydroxyl, oxo, C-C cycloalkyl, C-C aryl, and 3- to 6-membered heterocyclyl), or together form C-C cycloalkyl (which may be optionally substituted with 1 to 2 groups selected from halogen, hydroxyl, oxo, C-C alkyl, C-C haloalkyl, C-C cycloalkyl, C-C aryl, and 3- to 6-membered heterocyclyl); R 4 but, C3-C6 cycloalkyl, which may be optionally substituted with 1 to 3 groups independently selected from halogen, C1-C8 haloalkyl, and C1-C8 alkyl, and C1-C9 alkyl, C3-C8 cycloalkyl (optionally substituted with 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), C1-C8 haloalkyl, phenyl (optionally substituted with a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), C1-C8 alkoxy (optionally substituted with a group selected from C3-C6 cycloalkyl and halogen), 4- to 6-membered heterocyclyl (optionally substituted with 1 to 2 groups independently selected from halogen, C1-C8 haloalkyl, C1-C8 alkyl, and C1-C8 alkoxy), and silicon (which may be optionally substituted with 1 to 3 groups independently selected from C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 haloalkyl); R 5a and R 5b are independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6-membered heterocyclyl), C1-C8 alkoxy (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6-membered heterocyclyl), or may be joined together to form C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6-membered heterocyclyl).

[0104] In some embodiments, ring B in the compound, tautomer, deuterated derivative, or salt of formula II is [ka] is a heteroaryl selected from Ring B is ·halogen 4-10 membered heterocyclyl (optionally substituted with 1-3 groups independently selected from halogen, oxo, and C1-C4 alkyl) ·N(R x )2, (R x is selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl (which may be optionally substituted with a group selected from halogen, C1-C4 haloalkyl, and C1-C4 alkyl) Optionally substituted with 1 to 2 groups independently selected from C1-C4 alkyl (optionally substituted with C3-C6 cycloalkyl (which may further be optionally substituted with a group selected from halogen and OH)).

[0105] In some embodiments, ring B in the compound, tautomer, deuterated derivative, or salt of formula II is [ka] is selected from.

[0106] In some embodiments, the compound of formula II is selected from compounds II-1 through II-38, tautomers of those compounds, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4]

[0107] In some embodiments, the present disclosure provides a compound of formula III: [ka] or a tautomer thereof, or a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Ring C is [ka] is selected from: Each R c are independently selected from hydrogen, halogen, cyano, amino, C1-C4 alkyl (which may be optionally substituted with a group selected from —OH, halogen, and oxo), and C3-C6 alkeny; R 1 is selected from C3-C6 cycloalkyl, C1-C6 alkoxy, and C1-C6 alkyl (which can be optionally substituted with a group selected from C4-C6 cycloalkyl, C4-C6 aryl, 4- to 6-membered heterocyclyl, and 4- to 6-membered heteroaryl); R 2 is selected from hydrogen, halogen, C1-C8 alkyl, haloalkyl, and C1-C8 alkoxy; R 3a and R 3b are independently hydrogen, halogen, C 1~ C alkyl (which may be optionally substituted with 1 to 2 groups selected from halogen, hydroxyl, oxo, C-C cycloalkyl, C-C aryl, and 3- to 6-membered heterocyclyl), C-C alkoxy (which may be optionally substituted with 1 to 2 groups selected from halogen, hydroxyl, oxo, C-C cycloalkyl, C-C aryl, and 3- to 6-membered heterocyclyl), or together form C-C cycloalkyl (which may be optionally substituted with 1 to 2 groups selected from halogen, hydroxyl, oxo, C-C alkyl, C-C haloalkyl, C-C cycloalkyl, C-C aryl, and 3- to 6-membered heterocyclyl); R 4 but, C3-C6 cycloalkyl, which may be optionally substituted with 1 to 3 groups independently selected from halogen, C1-C8 haloalkyl, and C1-C8 alkyl, and C1-C9 alkyl, C3-C8 cycloalkyl (optionally substituted with 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), C1-C8 haloalkyl, phenyl (optionally substituted with a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), C1-C8 alkoxy (optionally substituted with a group selected from C3-C6 cycloalkyl and halogen), 4- to 6-membered heterocyclyl (optionally substituted with 1 to 2 groups independently selected from halogen, C1-C8 haloalkyl, C1-C8 alkyl, and C1-C8 alkoxy), and silicon (which may be optionally substituted with 1 to 3 groups independently selected from C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 haloalkyl); R 5a and R 5b are independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6-membered heterocyclyl), C1-C8 alkoxy (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6-membered heterocyclyl), or may be joined together to form C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6-membered heterocyclyl).

[0108] In some embodiments, the compound of formula III is selected from compounds III-1 through III-25, tautomers of those compounds, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. [Table 5-1] [Table 5-2] [Table 5-3]

[0109] In some embodiments, the present disclosure provides a compound of formula IV: [ka] Tautomers thereof, or deuterated derivatives of the compounds or tautomers, as well as pharmaceutically acceptable salts of any of the foregoing, are provided, wherein: Ring D is [ka] and Q is selected from -C- and -N-; W is selected from -CH-, -C(F)-, -C(CF3)-, and -N-; X 1 , X 2 , and X 3 are each independently selected from —CH— and —N—; X 4 is selected from C and N; Y is -N-, -N(R y )-, -C(R y )-, and -O-; R yis selected from hydrogen, halogen, C1-C8 haloalkyl, cyano, —NH2, C3-C6 cycloalkyl, C1-C8 alkyl (which may be optionally substituted with a group selected from —OH and C1-C8 alkoxy), —NHC(O)OC1-C8 alkyl (which may be optionally substituted with a group selected from —OH and halogen); Z is -CR z -, -O-, -S-, -S(O)-, -S(O)2-, -N-, and -NR z is selected from R z is selected from hydrogen, halogen, and C1-C8 alkyl (which may be optionally substituted with C1-C8 alkoxy); R 0 is selected from C1-C2 alkyl; R 1 is selected from C3-C6 cycloalkyl, C1-C8 alkoxy, and C1-C8 alkyl (which can be optionally substituted with a group selected from C1-C8 alkoxy, C4-C6 cycloalkyl, C5-C6 aryl, 4- to 6-membered heterocyclyl, and 4- to 6-membered heteroaryl); R 2 is selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 alkoxy; R 3a and R 3b are independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), C1-C8 alkoxy (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), or together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl); R4 but, C3-C8 cycloalkyl, which may be optionally substituted with 1 to 3 groups independently selected from halogen, C1-C8 haloalkyl, and C1-C8 alkyl, and C1-C9 alkyl, -OH C3-C8 cycloalkyl (optionally substituted with 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), C1-C8 haloalkyl, -OC3-C7 cycloalkyl (optionally substituted with 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), phenyl (optionally substituted with a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), C1-C8 alkoxy (which may be optionally substituted with a group selected from C3-C6 cycloalkyl and phenyl or may be optionally substituted with 1 to 3 halogen atoms), 4- to 6-membered heterocyclyl (optionally substituted with 1 to 2 groups independently selected from halogen, C1-C8 haloalkyl, C1-C8 alkyl, and C1-C8 alkoxy), and silicon (which may be optionally substituted with 1 to 3 groups independently selected from C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 haloalkyl); R 5a and R 5bare independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), C1-C8 alkoxy (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), or together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl); R 6 is selected from hydrogen, cyano, halogen, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl (which may be optionally substituted with 1-2 groups selected from C1-C8 alkyl), C3-C8 cycloalkyl (which may be optionally substituted with groups selected from C1-C8 alkyl, C1-C8 haloalkyl, and halogen), phenyl, and C1-C8 alkyl (which may be optionally substituted with 1-2 groups independently selected from C1-C8 alkoxy, C1-C8 haloalkyl, halogen, oxo, —OH, —NH2, and —SO2CH3); R 7 is selected from O and NR; R is selected from hydrogen and C1-C8 alkyl; provided that the compound of formula IV is [Table 6-1] [Table 6-2] and tautomers, deuterated derivatives, and pharmaceutically acceptable salts thereof.

[0110] In some embodiments, the compound of formula IV is selected from compounds IV-1 through IV-106, tautomers of those compounds, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7] [Table 7-8]

[0111] Treatment method Any of the novel compounds disclosed herein, such as compounds selected from any of Formulas I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, Compounds I-1 through I-265, Compounds II-1 through II-38, Compounds III-1 through III-25, and Compounds IV-1 through IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, can act as CFTR modulators, i.e., regulate 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 present on the cell surface, or can affect CFTR function, i.e., the functional ability of each channel to open and transport ions. Mutations that affect CFTR abundance include those that cause synthesis defects (Class I defects), processing and trafficking defects (Class II defects), reduced synthesis of CFTR (Class V defects), and reduced surface stability of CFTR (Class VI defects). Mutations that affect CFTR function include those that cause gating defects (Class III defects) and 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.

[0112] Accordingly, in some embodiments, the present disclosure provides a method of treating, reducing the severity of, or treating the symptoms of cystic fibrosis in a patient, comprising administering to the patient an effective amount of any of the novel compounds disclosed herein, such as a compound selected from any of the compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 through I-265, compounds II-1 through II-38, compounds III-1 through III-25, compounds IV-1 through IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, alone or in combination with another active ingredient, e.g., one or more CFTR modulators. In some embodiments, the one or more CFTR modulators are selected from ivacaftor, deutoivacaftor, lumacaftor, and tezacaftor. In some embodiments, the patient has an F508del / minimal function (MF) genotype, an F508del / F508del genotype (homozygous for the F508del mutation), an F508del / gating genotype, or an F508del / residual function (RF) genotype. In some embodiments, the patient is heterozygous and has one F508del mutation. In some embodiments, the patient is homozygous for the N1303K mutation.

[0113] In some embodiments, between 5 mg and 500 mg of a compound disclosed herein, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing is administered daily.

[0114] In some embodiments, the patient has at least one F508del mutation in the CFTR gene. In some embodiments, the patient has a CFTR gene mutation that responds to a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the invention based on in vitro data. In some embodiments, the patient is heterozygous and has an F508del mutation in one allele and a mutation selected from Table 2 in the other allele. [Table 2-1] [Table 2-2]

[0115] 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 as described 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.

[0116] Isotopically labeled compounds and salts can be used in several beneficial ways. They may be suitable for various types of assays, such as drug and / or substrate tissue distribution assays. For example, tritium ( 3 H) labeling and / or carbon-14 (14 C) labeled compounds are particularly useful in various types of assays, such as substrate tissue distribution assays, due to their relatively simple preparation and excellent detectability. 2 H) The labeled compound is therapeutically useful and non- 2 H-labeled compounds have potential therapeutic advantages over H-labeled compounds. 2 H) 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.

[0117] In some embodiments, isotopically labeled compounds and salts contain deuterium ( 2 H) labeled compounds and salts. In some particular embodiments, the isotopically labeled compounds and salts are deuterium ( 2 H) labeled in which one or more hydrogen atoms have been replaced by deuterium. In chemical structures, deuterium is represented as "D."

[0118] The concentration of an isotope (e.g., deuterium) incorporated in 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 substituents in compounds of the present disclosure are expressed as 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).

[0119] 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 any compound of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 through I-265, compounds II-1 through II-38, compounds III-1 through III-25, compounds IV-1 through IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, in combination with at least one additional active pharmaceutical ingredient.

[0120] 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 agent.

[0121] 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.

[0122] In some embodiments, the additional agent is a mucolytic agent. Exemplary mucolytic agents useful herein include Pulmozyme®.

[0123] In some embodiments, the additional agent is a bronchodilator. Exemplary bronchodilators include albuterol, metaproterenol sulfate, pirbuterol acetate, salmeterol, or tetrabuline sulfate.

[0124] 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.

[0125] 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 some embodiments, the additional nutritional agent is pancrelipase.

[0126] In some embodiments, the at least one additional active pharmaceutical ingredient is selected from a CFTR modulator. In some embodiments, the at least one additional active pharmaceutical ingredient is selected from a CFTR potentiator. In some embodiments, the potentiator is selected from ivacaftor, deutoivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the at least one additional active pharmaceutical ingredient is selected from a CFTR corrector. In some embodiments, the compensator is selected from lumacaftor, tezacaftor, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.

[0127] In some embodiments, the at least one or more additional active pharmaceutical ingredients are (a) tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof, and / or (b) ivacaftor, deutoivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5 ]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.

[0128] Thus, in some embodiments, the combination therapy provided herein comprises (a) a compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; and (b) at least one compound selected from tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof; or (c) and at least one compound selected from ivacaftor, deutoivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing. In other embodiments, the combination therapies provided herein include: (a) at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 through I-265, compounds II-1 through II-38, compounds III-1 through III-25, and compounds IV-1 through IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from tezacaftor and pharmaceutically acceptable salts thereof; and (c) at least one compound selected from ivacaftor, deutoivacaftor, and pharmaceutically acceptable salts thereof.In still other embodiments, the combination therapy provided herein comprises (a) at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; and (b) at least one compound selected from tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof. and / or (c) at least one compound selected from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof.

[0129] In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound selected from tezacaftor and a pharmaceutically acceptable salt thereof. In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 through I-265, compounds II-1 through II-38, compounds III-1 through III-25, compounds IV-1 through IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound selected from lumacaftor and a pharmaceutically acceptable salt thereof. In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 through I-265, compounds II-1 through II-38, compounds III-1 through III-25, compounds IV-1 through IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound selected from ivacaftor and pharmaceutically acceptable salts thereof.In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound selected from deutoivacaftor and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is (6R,12R)-17-amino-12-methyl-6,15-bis(trimethylsilyl)-1,15-dihydro-2,2-dihydro-1,2 ... and (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof.

[0130] In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 through I-265, compounds II-1 through II-38, compounds III-1 through III-25, compounds IV-1 through IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound selected from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one compound selected from ivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound selected from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one compound selected from deuterated derivatives and pharmaceutically acceptable salts of deutoivacaftor.In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is at least one compound selected from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, and (6R,12 and (6R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof.

[0131] In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 through I-265, compounds II-1 through II-38, compounds III-1 through III-25, compounds IV-1 through IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound selected from lumacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one compound selected from ivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 through I-265, compounds II-1 through II-38, compounds III-1 through III-25, compounds IV-1 through IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound selected from lumacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one compound selected from deutoivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof.In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is at least one compound selected from lumacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, and (6R,12 and (6R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof.

[0132] Each of the compounds of the disclosure (e.g., compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 through I-265, compounds II-1 through II-38, compounds III-1 through III-25, compounds IV-1 through IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing) can independently be administered once daily, twice daily, or three times daily. In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 through I-265, compounds II-1 through II-38, compounds III-1 through III-25, compounds IV-1 through IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered once daily. In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 through I-265, compounds II-1 through II-38, compounds III-1 through III-25, compounds IV-1 through IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered twice daily.

[0133] In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound selected from tezacaftor 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, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound selected from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, is administered twice daily.

[0134] In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, as well as ivacaftor, deutoivacaftor, (6R,12R)-17-amino-12-methyl-6, At least one compound selected from 15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing, is administered once daily.In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, as well as ivacaftor, deuteriovacaftor, (6R,12R)-17-amino-12-methyl- and (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof, are administered twice daily.

[0135] In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, at least one compound selected from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, and ivacaftor, deutoivacaf At least one compound selected from tolyl, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, 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, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, at least one compound selected from tezacaftor and pharmaceutically acceptable salts, and ivacaftor, deutoivacaftor, (6 At least one compound selected from (R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof is administered twice daily.

[0136] In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, ivacaftor, deutoivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dihydro-2,3-dihydro-1,3 ... At least one compound selected from oxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one compound selected from lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof, are administered once daily.In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, ivacaftor, deutoivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dihydro-2,3-dihydro-1,3 ... At least one compound selected from oxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one compound selected from lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof, are administered twice daily.

[0137] In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound selected from tezacaftor and its deuterated derivatives and pharmaceutically acceptable salts are administered once daily, and at least one compound selected from ivacaftor and its deuterated derivatives and pharmaceutically acceptable salts are administered twice daily. In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 through I-265, compounds II-1 through II-38, compounds III-1 through III-25, compounds IV-1 through IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound selected from lumacaftor and a pharmaceutically acceptable salt thereof is administered once daily, and at least one compound selected from ivacaftor and a pharmaceutically acceptable salt thereof is administered twice daily.

[0138] In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, at least one compound selected from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof is administered once daily, and (6R ,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof are administered twice daily.In some embodiments, the composition comprises at least one compound selected from compounds of formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id(i), Ie, Ie(i), if (i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound selected from lumacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof. , administered once daily, and (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof, administered once or twice daily.

[0139] Compounds of the present disclosure (e.g., compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 through I-265, compounds II-1 through II-38, compounds III-1 through III-25, compounds IV-1 through IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing), as well as additional CFTR modulator compounds, such as tezacaftor, lumacaftor, ivacaftor, deutoivacaftor, (6R,12R)-17-amivir amide, tetracycline, thiazolinone ... No-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and the like, as well as their deuterated derivatives and pharmaceutically acceptable salts, can be administered in a single pharmaceutical composition or in separate pharmaceutical compositions. Such pharmaceutical compositions can be administered once a day or multiple times a day, for example, twice a day. As used herein, a given amount of an API (e.g., tezacaftor, lumacaftor, ivacaftor, deutoivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12, The phrase 12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]-nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof, administered once daily or twice daily or every other day means that the given amount is administered once daily or twice daily per dose.

[0140] In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, and compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in a first pharmaceutical composition; at least one compound selected from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition; and at least one compound selected from ivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.

[0141] In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, and compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in a first pharmaceutical composition; at least one compound selected from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition; and at least one compound selected from deuterivivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.

[0142] In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in a first pharmaceutical composition, and at least one compound selected from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition. and at least one compound selected from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof, is administered in a third pharmaceutical composition.

[0143] In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in a first pharmaceutical composition, At least one compound selected from oxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition, and at least one compound selected from lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.

[0144] In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in a first pharmaceutical composition, and at least one compound selected from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, and ivacaftor, jute At least one compound selected from ivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof are administered in a second pharmaceutical composition. In some embodiments, the second pharmaceutical composition comprises half of the daily dose of the at least one compound selected from ivacaftor and its deuterated derivatives and pharmaceutically acceptable salts, and the other half of the daily dose of the at least one compound selected from ivacaftor and its deuterated derivatives and pharmaceutically acceptable salts is administered in a third pharmaceutical composition.

[0145] In some embodiments, at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, at least one compound selected from tezacaftor and pharmaceutically acceptable salts thereof, and at least one compound selected from ivacaftor, deutoivacaftor, and pharmaceutically acceptable salts thereof, is administered in a first pharmaceutical composition. In some embodiments, the first pharmaceutical composition is administered to the patient twice daily. In some embodiments, the first pharmaceutical composition is administered once daily. In some embodiments, when a first pharmaceutical composition is administered once daily and the first pharmaceutical composition comprises ivacaftor, a second composition comprising only ivacaftor is administered once daily.

[0146] Any suitable pharmaceutical composition can be used for the compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, tezacaftor, ivacaftor, deutoivacaftor, lumacaftor and tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. Some exemplary pharmaceutical compositions of tezacaftor and its pharmaceutically acceptable salts can be found in WO2011 / 119984 and WO2014 / 014841, all of which are incorporated herein by reference. Some exemplary pharmaceutical compositions of ivacaftor 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 deutoivacaftor 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 lumacaftor and its pharmaceutically acceptable salts can be found in WO2010 / 037066, WO2011 / 127421, and WO2014 / 071122, all of which are incorporated herein by reference.

[0147] Pharmaceutical Composition Another aspect of the present disclosure provides pharmaceutical compositions comprising at least one novel compound of the present disclosure (e.g., compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 through I-265, compounds II-1 through II-38, compounds III-1 through III-25, compounds IV-1 through IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing), and at least one pharmaceutically acceptable carrier.

[0148] In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 through I-265, compounds II-1 through II-38, compounds III-1 through III-25, and compounds IV-1 through IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, in combination with at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR modulator. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR corrector. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR potentiator. In some embodiments, the pharmaceutical composition comprises at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 through I-265, compounds II-1 through II-38, compounds III-1 through III-25, compounds IV-1 through IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least two additional active pharmaceutical ingredients, one of which is a CFTR corrector and the other of which is a CFTR potentiator.

[0149] In some embodiments, the disclosure provides pharmaceutical compositions comprising: (a) at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from tezacaftor and pharmaceutically acceptable salts thereof; and (c) at least one pharmaceutically acceptable carrier.

[0150] In some embodiments, the disclosure provides a method for treating atopic dermatitis, comprising: (a) at least one compound selected from compounds of formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; and (b) ivacaftor, deutoivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-1,2-dihydro-2,3-dihydro-2,4-dihydro-1,2,4 ... and (c) at least one pharmaceutically acceptable carrier.

[0151] In some embodiments, the present disclosure provides pharmaceutical compositions comprising: (a) at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, and compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof; (c) at least one compound selected from ivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof; and (d) at least one pharmaceutically acceptable carrier.

[0152] In some embodiments, the present disclosure provides pharmaceutical compositions comprising: (a) at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, and compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof; (c) at least one compound selected from deutoivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof; and (d) at least one pharmaceutically acceptable carrier.

[0153] In some embodiments, the disclosure provides a method for treating atopic dermatitis, comprising administering to a subject a disease or condition where the disease or condition is one of the following: (a) at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof; and (c) (6R,12R)-17-azathioprine. and (d) at least one pharmaceutically acceptable carrier; and (e) at least one compound selected from the group consisting of (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof.

[0154] In some embodiments, the disclosure provides a method for producing a pharmaceutical composition comprising: (a) at least one compound selected from compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; and (b) ivacaftor, deutoivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-trimethyl-14- ... Provided is a pharmaceutical composition comprising: (a) at least one compound selected from riazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing; (c) at least one compound selected from lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof; and (d) at least one pharmaceutically acceptable carrier.

[0155] Any pharmaceutical composition disclosed herein may comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from 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, and lubricant.

[0156] The pharmaceutical compositions described herein are useful for the treatment of cystic fibrosis and other CFTR-mediated diseases.

[0157] As described above, the pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be selected from adjuvants and vehicles. As used herein, the term "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. 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, such as by producing any undesired biological effects or otherwise interacting in a deleterious manner with any other components 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. List of Exemplary Embodiments 1. A compound of formula I, [ka] selected from tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein: Ring A is [ka] and Q is selected from -C- and -N-; W is selected from -CH-, -C(F)-, -C(CF3)-, and -N-; X 1 , X 2 , and X 3 are each independently selected from —CH— and —N—; Y is -N-, -N(R y )-, -C(R y )-, and -O-; R y is selected from hydrogen, halogen, C1-C8 haloalkyl, cyano, —NH2, C3-C6 cycloalkyl, C1-C8 alkyl (which may be optionally substituted with a group selected from —OH and C1-C8 alkoxy), —NHC(O)OC1-C8 alkyl (which may be optionally substituted with a group selected from —OH and halogen); Z is -CH-, -O-, -S-, -S(O)-, -S(O)2-, -N-, or -NR z is selected from R z is selected from hydrogen and C1-C8 alkyl; R 1 is selected from C3-C6 cycloalkyl, C1-C8 alkoxy, and C1-C8 alkyl (which can be optionally substituted with a group selected from C4-C6 cycloalkyl, C5-C6 aryl, 4- to 6-membered heterocyclyl, and 4- to 6-membered heteroaryl); R 2 is selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 alkoxy; R 3a and R 3bare independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), C1-C8 alkoxy (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), or together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl); R 4 but, C3-C6 cycloalkyl, which may be optionally substituted with 1 to 3 groups independently selected from halogen, C1-C8 haloalkyl, and C1-C8 alkyl, and C1-C9 alkyl, C3-C8 cycloalkyl (optionally substituted with 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), C1-C8 haloalkyl, O-C-C cycloalkyl (optionally substituted with 1 to 2 groups selected from C-C alkyl, C-C alkoxy, halogen, and C-C haloalkyl), phenyl (optionally substituted with a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), C1-C8 alkoxy (optionally substituted with a group selected from C3-C6 cycloalkyl and halogen), 4- to 6-membered heterocyclyl (optionally substituted with 1 to 2 groups independently selected from halogen, C1-C8 haloalkyl, C1-C8 alkyl, and C1-C8 alkoxy), and silicon (which may be optionally substituted with 1 to 3 groups independently selected from C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 haloalkyl); R 5a and R 5b are independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), C1-C8 alkoxy (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), or together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl); R 6 is selected from halogen, 4-6 membered heterocyclyl, C3-C8 cycloalkyl (which may be optionally substituted with groups selected from C1-C8 alkyl, C1-C8 haloalkyl, and halogen), and C1-C8 alkyl (which may be optionally substituted with 1-2 groups independently selected from C1-C8 alkoxy, halogen, oxo, -OH, -NH2, and -SO2CH3); R 7 is selected from O and NR; R is selected from hydrogen and C1-C8 alkyl; provided that the compound of formula I is [Table 9-1] [Table 9-2] and tautomers, deuterated derivatives, and pharmaceutically acceptable salts thereof, of the compounds of Formula I, their tautomers, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 2. The compound, tautomer, deuterated derivative, or salt of embodiment 1, wherein R1 is selected from C1-C4 alkyl. 3. The compound, tautomer, deuterated derivative, or salt of embodiment 1, wherein R1 is CH3. 4.R 2 The compound, tautomer, deuterated derivative, or salt of any one of embodiments 1-3, wherein is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy. 5.R 2 The compound, tautomer, deuterated derivative, or salt of any one of embodiments 1-4, wherein is selected from hydrogen and C1-C4 alkyl. 6.R 2 The compound, tautomer, deuterated derivative, or salt of any one of embodiments 1-5, wherein is selected from hydrogen and methyl. 7.R 3a and R 3b The compound, tautomer, deuterated derivative, or salt of embodiment 1, wherein is independently selected from hydrogen, halogen, C1-C4 alkyl, and C3-C7 cycloalkyl. 8.R 3a and R 3b The compound, tautomer, deuterated derivative, or salt of embodiment 1, wherein is hydrogen. 9.R 4 is selected from C1-C6 alkyl optionally substituted with a group selected from halogen, haloalkyl, and C1-C4 alkoxy. 10.R 4 The compound, tautomer, deuterated derivative, or salt of any one of embodiments 1-8, wherein is selected from C1-C4 alkyl substituted with C3-C5 cycloalkyl. 11.R 4is selected from C1-C4 alkyl substituted with 1-2 groups independently selected from C3-C5 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, haloalkyl, and C1-C4 alkyl). 12.R 4 is selected from C1-C6 alkyl optionally substituted with phenyl (which may be optionally substituted with a group selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, and haloalkyl). 13.R 4 is selected from C1-C6 alkyl substituted with 4-6 membered heterocyclyl (which may be optionally substituted with 1-2 groups independently selected from halogen, haloalkyl, and C1-C4 alkyl). 14.R 4 The compound, tautomer, deuterated derivative, or salt of any one of embodiments 1-8, wherein is selected from: [ka] 15.R 5a and R 5b The compound, tautomer, deuterated derivative, or salt of any one of embodiments 1-14, wherein is independently selected from hydrogen, halogen, C1-C4 alkyl, and C3-C7 cycloalkyl. 16.R 5a and R 5b The compound, tautomer, deuterated derivative, or salt of any one of embodiments 1-15, wherein is hydrogen. 17.R 6 is selected from C3-C8 cycloalkyl (which may be optionally substituted with a group selected from C1-C4 alkyl, haloalkyl, and halogen). 18.R 6is selected from C3-C6 cycloalkyl (which may be optionally substituted with a group selected from C1-C4 alkyl). 19.R 6 is selected from C1-C6 alkyl (optionally substituted with a group selected from C1-C4 alkoxy, halogen, —OH, oxo, —NH2, and —SO2CH3). 20.R 6 The compound, tautomer, deuterated derivative, or salt of any one of embodiments 1-16, wherein is selected from C1-C6 alkyl and C3-C6 cycloalkyl. 21.R 6 is selected from C1-C4 alkyl (optionally substituted with —OH) and C4 cycloalkyl (optionally substituted with a group selected from C1-C4 alkyl). 22.R 6 is selected from C alkyl and C cycloalkyl (which may be optionally substituted with a group selected from C-C alkyl). 23.R 6 The compound, tautomer, deuterated derivative, or salt of any one of embodiments 1-16, wherein is selected from C3-C4 cycloalkyl optionally substituted with methyl. 24.R 6 17. The compound, tautomer, deuterated derivative, or salt of any one of embodiments 1-16, wherein is selected from: [ka] 25.R 7 The compound, tautomer, deuterated derivative, or salt of any one of embodiments 1-24, wherein is O. 26.X 1The compound, tautomer, deuterated derivative, or salt of any one of embodiments 1-24, wherein is C. 26. The compound, tautomer, deuterated derivative, or salt according to any one of embodiments 1-24, wherein Q is C. 27. Compound of Formula Ia: [ka] and tautomers thereof, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; 4 and R 6 is as defined in embodiment 1. 28. Compound of Formula Ia(i): [ka] and tautomers thereof, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; 4 and R 6 is as defined in embodiment 1. 29. Compound of Formula Ib: [ka] and tautomers thereof, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; 4 and R 6 is as defined in embodiment 1. 30. Compound of Formula Ib(i): [ka] and tautomers thereof, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing;4 and R 6 is as defined in embodiment 1. 31. Compound of Formula Ic: [ka] and tautomers thereof, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; 4 and R 6 is as defined in embodiment 1. 32. Compound of Formula Ic(i): [ka] and tautomers thereof, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; 4 and R 6 is as defined in embodiment 1. 33. Compound of formula Id: [ka] and tautomers thereof, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; 4 and R 6 is as defined in embodiment 1. 34. Compound of Formula Id(i): [ka] and tautomers thereof, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; 4 and R 6is as defined in embodiment 1. 35. Compound of Formula Ie: [ka] and tautomers thereof, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; 4 and R 6 is as defined in embodiment 1. 36. Compound of formula Ie(i): [ka] and tautomers thereof, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; 4 and R 6 is as defined in embodiment 1. 37. A compound of formula If: [ka] and tautomers thereof, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; 4 and R 6 is as defined in embodiment 1. 38. A compound of formula If(i): [ka] and tautomers thereof, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; 4 and R 6is as defined in embodiment 1. 39. Ring A is selected from: [ka] In the formula, R 6 , W, X 2 , X 3 , Y, R y and Z is as defined in embodiment 1. 40. Ring A is [ka] wherein R y and R 6 is as defined in embodiment 1. 41.R y 41. The compound, tautomer, deuterated derivative, or salt of embodiment 1, 39, or 40, wherein is selected from: [ka] 42. Ring A is [ka] wherein R 6 is as defined in embodiment 1; R 4 is selected from C1-C6 alkyl substituted with C3-C6 cycloalkyl (optionally substituted with methyl). 43.R 4 The compound, tautomer, deuterated derivative, or salt of any one of embodiments 27-41, wherein is selected from C1-C6 alkyl optionally substituted with 1-3 halogens. 44.R 4The compound, tautomer, deuterated derivative, or salt of any one of embodiments 27-41, wherein is selected from C1-C6 alkyl substituted with C1-C4 alkoxy. 45.R 4 is selected from C1-C6 alkyl substituted with C3-C6 cycloalkyl (optionally substituted with methyl). 46.R 4 The compound, tautomer, deuterated derivative, or salt of any one of embodiments 27-41, wherein is selected from C1-C6 alkyl substituted with 5-6 membered heterocyclyl. 47.R 4 The compound, tautomer, deuterated derivative, or salt of any one of embodiments 27-41, wherein is selected from C1-C6 alkyl substituted with O-C3-C6 cycloalkyl. 48. A compound selected from compounds I-1 to I-265, tautomers thereof, deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 49.Compound I-4: [ka] and tautomers thereof, deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 50.Compound I-23: [ka] and tautomers thereof, deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 51.Compound I-34: [ka] and tautomers thereof, deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 52.Compound I-35: [ka] and tautomers thereof, deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 53.Compound I-40: [ka] and tautomers thereof, deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 54.Compound I-49: [ka] and tautomers thereof, deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 55.Compound I-52: [ka] and tautomers thereof, deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 56.Compound I-88: [ka] and tautomers thereof, deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 57.Compound I-96: [ka] and tautomers thereof, deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 58.Compound I-97: [ka] and tautomers thereof, deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 59.Compound I-98: [ka] and tautomers thereof, deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 60.Compound I-99: [ka] and tautomers thereof, deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 61.Compound I-139: [ka] and tautomers thereof, deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 62. Compound I-158: [ka] and tautomers thereof, deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 63.Compound I-188: [ka] and tautomers thereof, deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 64.Compound I-206: [ka] and tautomers thereof, deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 65.Compound I-255: [ka] and tautomers thereof, deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 66.Compound I-256: [ka] and tautomers thereof, deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 67. A compound of formula II, [ka] During the ceremony, Ring B is ·halogen 4-10 membered heterocyclyl (optionally substituted with 1-3 groups independently selected from halogen, oxo, and C1-C4 alkyl) ·N(R x )2, (R x are independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl (which may be optionally substituted with a group selected from halogen, C1-C4 haloalkyl, and C1-C4 alkyl). a 6-membered heteroaryl optionally substituted by 1 to 2 groups independently selected from C1-C4 alkyl (optionally substituted with C3-C6 cycloalkyl (which may further be optionally substituted with a group selected from halogen and OH)); R 1 is selected from C3-C6 cycloalkyl, C1-C6 alkoxy, and C1-C6 alkyl (optionally substituted with C4-C6 cycloalkyl); R 2 is selected from hydrogen, halogen, C1-C2 alkyl, C1-C4 haloalkyl, and C1-C2 alkoxy; R 3a and R 3b are independently hydrogen, halogen, C 1~ C alkyl (which may be optionally substituted with 1 to 2 groups selected from halogen, hydroxyl, oxo, C-C cycloalkyl, C-C aryl, and 3- to 6-membered heterocyclyl), C-C alkoxy (which may be optionally substituted with 1 to 2 groups selected from halogen, hydroxyl, oxo, C-C cycloalkyl, C-C aryl, and 3- to 6-membered heterocyclyl), or together form C-C cycloalkyl (which may be optionally substituted with 1 to 2 groups selected from halogen, hydroxyl, oxo, C-C alkyl, C-C haloalkyl, C-C cycloalkyl, C-C aryl, and 3- to 6-membered heterocyclyl); R 4 but, C3-C6 cycloalkyl, which may be optionally substituted with 1 to 3 groups independently selected from halogen, C1-C8 haloalkyl, and C1-C8 alkyl, and C1-C9 alkyl, C3-C8 cycloalkyl (optionally substituted with 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), C1-C8 haloalkyl, phenyl (optionally substituted with a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), C1-C8 alkoxy (optionally substituted with a group selected from C3-C6 cycloalkyl and halogen), 4- to 6-membered heterocyclyl (optionally substituted with 1 to 2 groups independently selected from halogen, C1-C8 haloalkyl, C1-C8 alkyl, and C1-C8 alkoxy), and silicon (which may be optionally substituted with 1 to 3 groups independently selected from C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 haloalkyl); R 5a and R 5b are independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), C1-C8 alkoxy (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), or together form C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl); The compound of formula II is selected from compounds II-1 to II-38, and tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 68. A compound of formula III, [ka] During the ceremony, Ring C is [ka] is selected from: Each R c are independently selected from hydrogen, halogen, cyano, amino, C1-C4 alkyl (which may be optionally substituted with a group selected from —OH, halogen, and oxo), and C3-C6 alkeny; R 1 is selected from C3-C6 cycloalkyl, C1-C6 alkoxy, and C1-C6 alkyl (optionally substituted with C4-C6 cycloalkyl); R 2 is selected from hydrogen, halogen, C1-C2 alkyl, C1-C4 haloalkyl, and C1-C2 alkoxy; R 3a and R 3b are independently hydrogen, halogen, C 1~ C alkyl (which may be optionally substituted with 1 to 2 groups selected from halogen, hydroxyl, oxo, C-C cycloalkyl, C-C aryl, and 3- to 6-membered heterocyclyl), C-C alkoxy (which may be optionally substituted with 1 to 2 groups selected from halogen, hydroxyl, oxo, C-C cycloalkyl, C-C aryl, and 3- to 6-membered heterocyclyl), or together form C-C cycloalkyl (which may be optionally substituted with 1 to 2 groups selected from halogen, hydroxyl, oxo, C-C alkyl, C-C haloalkyl, C-C cycloalkyl, C-C aryl, and 3- to 6-membered heterocyclyl); R 4 but, C3-C6 cycloalkyl, which may be optionally substituted with 1 to 3 groups independently selected from halogen, C1-C8 haloalkyl, and C1-C8 alkyl, and C1-C9 alkyl, C3-C8 cycloalkyl (optionally substituted with 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), C1-C8 haloalkyl, phenyl (optionally substituted with a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), C1-C8 alkoxy (optionally substituted with a group selected from C3-C6 cycloalkyl and halogen), 4- to 6-membered heterocyclyl (optionally substituted with 1 to 2 groups independently selected from halogen, C1-C8 haloalkyl, C1-C8 alkyl, and C1-C8 alkoxy), and silicon (which may be optionally substituted with 1 to 3 groups independently selected from C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 haloalkyl); R 5a and R 5b are independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), C1-C8 alkoxy (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), or together form C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl); The compound of formula III is selected from compounds III-1 to III-25, and tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 69. A compound of formula IV, [ka] During the ceremony, Ring D is [ka] and Q is selected from -C- and -N-; W is selected from -CH-, -C(F)-, -C(CF3)-, and -N-; X 1 , X 2 , and X 3 are each independently selected from —CH— and —N—; X 4 is selected from C and N; Y is -N-, -N(R y )-, -C(R y )-, and -O-; R y is selected from hydrogen, halogen, C1-C8 haloalkyl, cyano, —NH2, C3-C6 cycloalkyl, C1-C8 alkyl (which may be optionally substituted with a group selected from —OH and C1-C8 alkoxy), —NHC(O)OC1-C8 alkyl (which may be optionally substituted with a group selected from —OH and halogen); Z is -CR z -, -O-, -S-, -S(O)-, -S(O)2-, -N-, and -NR z is selected from R z is selected from hydrogen, halogen, and C1-C8 alkyl (which may be optionally substituted with C1-C8 alkoxy); R 0is selected from C1-C2 alkyl; R 1 is selected from C3-C6 cycloalkyl, C1-C8 alkoxy, and C1-C8 alkyl (which can be optionally substituted with a group selected from C1-C8 alkoxy, C4-C6 cycloalkyl, C5-C6 aryl, 4- to 6-membered heterocyclyl, and 4- to 6-membered heteroaryl); R 2 is selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 alkoxy; R 3a and R 3b are independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), C1-C8 alkoxy (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), or together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl); R 4 but, C3-C8 cycloalkyl, which may be optionally substituted with 1 to 3 groups independently selected from halogen, C1-C8 haloalkyl, and C1-C8 alkyl, and C1-C9 alkyl, -OH C3-C8 cycloalkyl (optionally substituted with 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), C1-C8 haloalkyl, -OC3-C7 cycloalkyl (optionally substituted with 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), phenyl (optionally substituted with a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, and C1-C8 haloalkyl), C1-C8 alkoxy (which may be optionally substituted with a group selected from C3-C6 cycloalkyl and phenyl or may be optionally substituted with 1 to 3 halogen atoms), 4- to 6-membered heterocyclyl (optionally substituted with 1 to 2 groups independently selected from halogen, C1-C8 haloalkyl, C1-C8 alkyl, and C1-C8 alkoxy), and silicon (which may be optionally substituted with 1 to 3 groups independently selected from C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 haloalkyl); R 5a and R 5b are independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), C1-C8 alkoxy (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl), or together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxyl, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl, and 3-6 membered heterocyclyl); R 6is selected from hydrogen, cyano, halogen, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl (which may be optionally substituted with 1-2 groups selected from C1-C8 alkyl), C3-C8 cycloalkyl (which may be optionally substituted with groups selected from C1-C8 alkyl, C1-C8 haloalkyl, and halogen), phenyl, and C1-C8 alkyl (which may be optionally substituted with 1-2 groups independently selected from C1-C8 alkoxy, C1-C8 haloalkyl, halogen, oxo, —OH, —NH2, and —SO2CH3); R 7 is selected from O and NR; R is selected from hydrogen and C1-C8 alkyl provided that the compound of formula IV is [Table 10-1] [Table 10-2] and a compound of Formula IV, or a tautomer thereof, or a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, that is not selected from tautomers, deuterated derivatives, and pharmaceutically acceptable salts thereof: 70. A compound selected from compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 71. A method of treating cystic fibrosis, comprising administering a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-70. 72. The method of embodiment 71, wherein the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 to 70 is administered in combination with at least one additional active pharmaceutical ingredient. 73. The method of embodiment 72, wherein the at least one additional active pharmaceutical ingredient is selected from mucolytics, bronchodilators, antibiotics, anti-infectives, and anti-inflammatory agents. 74. The method of embodiment 72, wherein the at least one additional active pharmaceutical ingredient is selected from CFTR potentiators. 75. The method of embodiment 74, wherein the CFTR enhancer is selected from ivacaftor, deutoivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing. 76. The method of embodiment 72, wherein the at least one additional active pharmaceutical ingredient is selected from CFTR correctors. 77. The method of embodiment 76, wherein the compensator is selected from lumacaftor, tezacaftor, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing. 78. A method for treating cystic fibrosis, comprising: (a) a compound selected from compounds of formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof, and / or (c) administering a combination therapy comprising at least one compound selected from ivacaftor, deutoivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing. 79. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1-70, for use in treating cystic fibrosis. 80. A compound selected from compounds of formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, (a) at least one compound selected from tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof, and / or (b) A compound for use in treating cystic fibrosis in combination with at least one compound selected from ivacaftor, deutoivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing. 81. Use of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1-70 in the manufacture of a medicament for treating cystic fibrosis. 82. A compound selected from compounds of formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, (a) at least one compound selected from tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof, and / or (b) Use of a compound in the manufacture of a medicament for treating cystic fibrosis in combination with at least one compound selected from ivacaftor, deutoivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing. 83. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1-70, and a pharmaceutical carrier. 84. A pharmaceutical composition comprising: (a) a compound selected from compounds of formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), II, III, and IV, compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof, and / or (c) A pharmaceutical composition comprising at least one compound selected from ivacaftor, deutoivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing. [Example]

[0158] I. List of Abbreviations ACN: acetonitrile Boc2O Di-tert-butyl dicarbonate CDMT: 2-chloro-4,6-dimethoxy-1,3,5-triazine Cmpd: Compound DBU: 1,8-diazabicyclo(5.4.0)undec-7-ene DCM: dichloromethane DI: Deionized DIEA: (DIPEA, DiPEA): N,N-diisopropylethylamine DMA: N,N-dimethylacetamide DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide EA: Ethyl acetate diethylether: diethyl ether EtOAc: ethyl acetate EtOH: ethanol GC: Gas chromatography GCMS: Gas chromatography mass spectrometry HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC: High-performance liquid chromatography IPA: Isopropanol LAH: Lithium aluminum hydride LC: liquid chromatography LCMS: Liquid Chromatography Mass Spectrometry LCMS Rt:LCMS retention time MeCN: acetonitrile MeOH: Methanol MTBE: Methyl tert-butyl ether MeTHF or 2-MeTHF: 2-methyltetrahydrofuran NMP: N-methyl-2-pyrrolidone NMM: N-methylmorpholine Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) RBF: Round-bottom flask rt, RT: room temperature SFC: Supercritical Fluid Chromatography TEA: Triethylamine TFA: Trifluoroacetic acid THF: tetrahydrofuran TLC: Thin Layer Chromatography TMS: trimethylsilyl T3P: Propanephosphonic anhydride UPLC: Ultra-high performance liquid chromatography Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene II. General Methods Reagents and starting materials were obtained from commercial sources and used without purification unless otherwise noted.

[0159] Proton and carbon NMR spectra were measured at 400 MHz and 100 MHz, respectively. 1 H resonance frequency and 13Spectra were acquired on either a Bruker Biospin DRX 400 MHz FTNMR spectrometer operating at the C resonance frequency or a 300 MHz NMR spectrometer. One-dimensional proton and carbon spectra were acquired using a broadband observation (BBFO) probe with 20 Hz sample rotation at digital resolutions of 0.1834 Hz / Pt and 0.9083 Hz / Pt, respectively. All proton and carbon spectra were acquired with temperature control at 30 °C using standard, previously published pulse sequences and routine processing parameters.

[0160] NMR (1D and 2D) spectra were also recorded on a Bruker AVNEO 400 MHz spectrometer equipped with a 5 mm multinuclear Iprobe operating at 400 MHz and 100 MHz, respectively.

[0161] NMR spectra were acquired using a pulse angle of 45 degrees, a spectral width of 4800 Hz, and 28860 acquisition points. 1 NMR spectra were also recorded on a 300 MHz Varian Mercury NMR instrument for H. The FID was zero-filled to 32 k points and 0.3 Hz line broadening was applied before Fourier transformation. 19F NMR spectra were recorded at 282 MHz using a 30 degree pulse angle, 100 kHz spectral width, and acquired 59,202 points. The FID was zero-filled to 64 k points and 0.5 Hz line broadening was applied before Fourier transformation.

[0162] NMR spectra were acquired using a pulse angle of 30 degrees, a spectral width of 8000 Hz, and 128k acquisition points. 1 Spectra were also recorded on a 400 MHz Bruker Avance III HD NMR instrument for H. The FID was zero-filled to 256 k points and 0.3 Hz line broadening was applied before Fourier transformation. 19F NMR spectra were recorded at 377 MHz using a 30 degree pulse angle, a spectral width of 89286 Hz, and 128 k acquisition points. The FID was zero-filled to 256 k points and 0.3 Hz line broadening was applied before Fourier transformation.

[0163] NMR spectra were also recorded on a Bruker AC 250 MHz instrument equipped with a 5 mm QNP (H1 / C13 / F19 / P31) probe (type: 250-SB, s#23055 / 0020) or a Varian 500 MHz instrument equipped with a 5 mm ID PFG 50-202 / 500 MHz probe (model / part number 99337300).

[0164] III. Common UPLC / HPLC analysis methods LC Method A: Waters Acquity UPLC BEH C 18 Analytical reversed-phase UPLC using a column (50 x 2.1 mm, 1.7 μm particle size) (product number: 186002350) and a double gradient run of 1% to 99% mobile phase B over 3.0 min. Mobile phase A = H2O (0.05% CF3CO2H). Mobile phase B = CH3CN (0.035% CF3CO2H). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, and column temperature = 60 °C.

[0165] LC Method B: Waters Acquity UPLC BEH C 18 Column (30 x 2.1 mm, 1.7 μm particle size) (product number: 186002349) and a double gradient run of 1% to 99% mobile phase B over 1.0 min. Mobile phase A = H2O (0.05% CF3CO2H). Mobile phase B = CH3CN (0.035% CF3CO2H). Flow rate = 1.5 mL / min, injection volume = 1.5 μL, and column temperature = 60 °C.

[0166] LC method C: Waters Acquity UPLC BEH C 18 Reversed-phase UPLC 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 = HO (0.05% CF3CO2H). Mobile phase B = CH3CN (0.035% CF3CO2H). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, and column temperature = 60 °C.

[0167] LC method D: Merckmillipore Chromolith SpeedROD C 18Column (50 x 4.6 mm) and a double gradient run of 5% to 100% mobile phase B over 12 min. Mobile phase A = water (0.1% CF3CO2H). Mobile phase B = acetonitrile (0.1% CF3CO2H).

[0168] LC method E: Merckmillipore Chromolith SpeedROD C 18 Column (50 x 4.6 mm) and a double gradient run of 5% to 100% mobile phase B over 6 min. Mobile phase A = water (0.1% CF3CO2H). Mobile phase B = acetonitrile (0.1% CF3CO2H).

[0169] LC method F: Kinetex Polar C 18 3.0 x 50 mm 2.6 μm, 6 min, 5-95% ACN / HO (0.1% formic acid) 1.2 mL / min.

[0170] LC Method G: Waters Acquity UPLC BEH C 18 Column (50 x 2.1 mm, 1.7 μm particle size) (product number: 186002350) and a double gradient run of 1% to 30% mobile phase B over 2.9 min. Mobile phase A = H2O (0.05% CF3CO2H). Mobile phase B = CH3CN (0.035% CF3CO2H). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, and column temperature = 60 °C.

[0171] LC method H:water Cortex 2.7μ C 18 (3.0 mm × 50 mm), temperature: 55 °C, flow rate: 1.2 mL / min, mobile phase: 100% water + 0.1% trifluoroacetic acid (TFA), then 100% acetonitrile + 0.1% TFA acid, gradient: 5% to 100% B over 4 min, hold at 100% B for 0.5 min, equilibrate to 5% B over 1.5 min.

[0172] LC Method I: UPLC Luna C 18(2) 50 × 3 mm 3 μm, Run time: 2.5 min. Mobile phase: Initial 95% H2O (0.1% FA) / 5% MeCN (0.1% FA), linear gradient to 95% MeCN (0.1% FA) over 1.3 min, hold at 95% CH3CN (0.1% FA) for 1.2 min. Temperature: 45°C, Flow rate: 1.5 mL / min

[0173] LC method J:UPLC SunFire C 18 75 x 4.6 mm 3.5 μm, Run: 6 min. Mobile phase conditions: Initial 95% H2O + 0.1% FA / 5% CH3CN + 0.1% FA, linear gradient to 95% CH3CN in 4 min, hold at 95% CH3CN for 2 min. Temperature: 45 °C, Flow rate: 1.5 mL / min.

[0174] LC method K:XBridge C 18 4.6 x 75 mm, 5 μm, 6 min run with an initial gradient of 95% NH4HCO3 / 5% MeCN, 1 min equilibration, 0–3 min gradient to 95% MeCN, 3 min hold. Flow rate 1.5 mL / min.

[0175] LC method L: Luna C 18 3.0 x 50 mm 3.0 μM, temperature: 45 °C, flow rate: 2.0 mL / min, run time: 3 min. Mobile phase: initial 95% H2O (0.1% formic acid) and 5% CH3CN (0.1% FA), linear gradient to 95% CH3CN (0.1% FA) over 2.0 min, then hold at 95% CH3CN (0.1% FA) for 1.0 min.

[0176] 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 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, and column temperature = 60 °C.

[0177] IV. Synthesis of common intermediates Example 1: Preparation of 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [ka] Step 1: tert-butyl N-tert-butoxycarbonyl-N-(4,6-dichloropyrimidin-2-yl)carbamate [ka] To a solution of 4,6-dichloropyrimidin-2-amine (300 g, 1.829 mol) in DCM (2.1 L) was added (BOC)2O (838 g, 3.840 mol), followed by DMAP (5.6 g, 45.84 mmol). The mixture was stirred at ambient temperature for 6 h. Additional DMAP (5.6 g, 45.84 mmol) was added, and the reaction was continued to stir at ambient temperature for 24 h. The mixture was diluted with water (2.1 L), and the organic phase was separated. The organic phase was washed with water (2.1 L), brine (2.1 L), dried over magnesium sulfate, filtered through Celite, and concentrated in vacuo to give a pale orange oil with silt in the slurry. The mixture was diluted with heptane (approximately 500 mL) and filtered using an M filter. The precipitate (SM) was washed with heptane (250 mL). The filtrate was concentrated in vacuo to give a thick orange oil, which was seeded with the solid from the previous experiment and crystallized on standing to give a pale orange, hard solid: tert-butyl N-tert-butoxycarbonyl-N-(4,6-dichloropyrimidin-2-yl)carbamate (645 g, 97%). 1 H NMR (400 MHz, DMSO-d) δ 8.07 (s, 1H), 1.44 (s, 18H). ESI-MS m / z calculated 363.07526, found 364.1 (M+1). + ; Retention time: 2.12 minutes (LC method A).

[0178] Step 2: tert-Butyl N-tert-butoxycarbonyl-N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]carbamate [ka] All solvents were degassed before use. To a slurry of tert-butyl N-tert-butoxycarbonyl-N-(4,6-dichloropyrimidin-2-yl)carbamate (88 g, 241.6 mmol) was added a solution of (2,6-dimethylphenyl)boronic acid (approximately 36.24 g, 241.6 mmol) and Cs2CO3 (approximately 196.8 g, 604.0 mmol) in DME (704 mL) and water (176 mL). Pd(dppf)Cl2 (approximately 8.839 g, 12.08 mmol) was added, and the mixture was vigorously stirred under nitrogen at 80 °C (reflux) for 1 h (no residual SM). The reaction was cooled to ambient temperature and diluted with water (704 mL). The aqueous phase was separated and extracted with EtOAc (704 mL). The organic phase was washed with 700 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was chromatographed on a 1500 g silica gel column eluting with 0-30% EtOAc / hexanes. The product fractions (eluted with 15% EtOAc) were combined and concentrated in vacuo to give the product as a clear oil that crystallized on standing. tert-Butyl N-tert-butoxycarbonyl-N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]carbamate (81.3 g, 78%). 1 H NMR (400 MHz, DMSO-d6)δ 7.88(s, 1H), 7.30(dd, J=8.2, 7.0 Hz, 1H), 7.21-7.16(m, 2H), 2.03(s, 6H), 1.38(s, 18H).ESI-MS m / z Calculated value 433.17682, actual value 434.1 (M+1) + ; Retention time: 2.32 minutes (LC method A).

[0179] Step 3: 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (hydrochloride salt) [ka] tert-Butyl N-tert-butoxycarbonyl-N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]carbamate (514.8 g, 915.9 mmol) was dissolved in dichloromethane (4 L). A solution of hydrogen chloride in p-dioxane (1 L, 4 mol) was added, and the mixture was stirred at room temperature overnight. The resulting precipitate was collected by vacuum filtration and dried in vacuo to give 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine hydrochloride (213.5 g, 64%) as a white solid (213.5 g, 82%). 1 H NMR (250 MHz, DMSO-d6)δ 7.45-6.91(m, 3H), 6.73(s, 1H), 2.08(s, 6H).ESI-MS m / z calculated value 233.072, measured value 234.1(M+1) + ; Retention time: 2.1 minutes (LC method C).

[0180] Step 4: 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine [ka] 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (hydrochloride) (166 g, 614.5 mmol) and 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (hydrochloride) (30 g, 111.0 mmol) were suspended in DCM (2.5 L), treated with NaOH (725 mL 1 M, 725.0 mmol), and stirred at room temperature for 1 hour. The mixture was transferred to a separatory funnel and allowed to stand overnight. The DCM phase was separated, and the aqueous phase containing insoluble material was extracted twice more with DCM (2 × 500 mL). The combined brown DCM phases were stirred with magnesium sulfate and charcoal for 1 hour, filtered, and the yellow solution was concentrated to a volume of approximately 500 mL. The solution was diluted with heptane (750 mL), and the DCM was removed under reduced pressure at 60 °C to give a cream-colored suspension. This was stirred at room temperature for 1 hour, filtered, washed with cold heptane and dried to give 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (157 g, 91%) as a cream solid. 1H NMR (400 MHz, DMSO-d6)δ 7.28-7.14(m, 3H), 7.10(d, J=7.5 Hz, 2H), 6.63(s, 1H), 2.06(s, 6H).ESI-MS m / z calculated value 233.07198, measured value 234.0(M+1) + ; Retention time: 1.45 minutes (LC method A).

[0181] Step 5: 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [ka] 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (235 g, 985.5 mmol) was dissolved in MeTHF (2.3 L) and cooled in an ice bath with stirring under nitrogen. Methyl 3-chlorosulfonylbenzoate (347 g, 1.479 mol) was added in one portion to the cooled solution (appearing slightly endothermic). To the cooled, pale yellow solution was added 2-methylbutan-2-ol (lithium salt) (875 mL, 3.1 M, 2.712 mol) in heptane dropwise over 1.25 h (exothermic, internal temperature 0–10 °C). The ice bath was removed, and the greenish solution was stirred at room temperature for 4 h. To the greenish solution was added cold HCl (2 L, 1.5 M, 3.000 mol), the phases were separated, and the organic phase was washed once with water (1 L) and once with brine (500 mL). The aqueous phase was back-extracted once with MeTHF (350 mL), and the organic phases were combined. This yellow solution of methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoate in MeTHF (ESI-MS m / z calculated 431.07065, found 432.0 (M+1)) was purified by HPLC. +The resulting yellow, sticky suspension was stirred overnight at room temperature to give a creamy, crispy suspension. The solid was collected by filtration, washed with copious amounts of water, and suction dried for 3 hours. The solid was dried under reduced pressure with a nitrogen leak at 45-50°C for 120 hours to isolate 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (395 g, 96%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6)δ 13.44(s, 1H), 12.46(s, 1H), 8.48-8.39(m, 1H), 8.25-8.15(m, 1H), 8.15-8.08(m, 1H), 7.68(t, J=7.8 Hz, 1H), 7.31(s, 1H), 7.28-7.18(m, 1H), 7.10(d, J=7.6 Hz, 2H), 1.84(s, 6H).ESI-MS m / z calculated value 417.055, measured value 418.0(M+1) + ;Retention time: 1.56 minutes. (LC method A).

[0182] Example 2: Preparation of -[[4-[(2R)-2-(tert-butoxycarbonylamino)-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [ka] Step 1: 3-[[4-[(2R)-2-(tert-butoxycarbonylamino)-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [ka] To a stirred solution of (2R)-2-amino-4-methyl-pentan-1-ol (12.419 g, 105.97 mmol) in anhydrous THF (200 mL) was added sodium tert-butoxide (15.276 g, 158.95 mmol) at room temperature under nitrogen. The reaction mixture was stirred for 10 minutes, and 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (22.14 g, 52.983 mmol) was added. The reaction mixture was placed in a preheated water bath at 60 °C and stirred for 20 minutes. After cooling to room temperature, di-tert-butyl dicarbonate (69.381 g, 317.90 mmol) was added, and the reaction mixture was stirred for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride (150 mL). The volatiles were removed in vacuo, and the aqueous layer was acidified to pH ∼3 with 10% aqueous citric acid. The product was extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, and concentrated to a residual volume of ∼250 mL. The product was precipitated in excess hexane (750 mL) and collected by vacuum filtration. The resulting white solid was repurified by silica gel chromatography using a 0–40% acetone (0.15% acetate buffer) / hexane (0.15% acetate buffer) gradient to afford 3-[[4-[(2R)-2-(tert-butoxycarbonylamino)-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (20.73 g, 61%) as a white solid. ESI-MS m / z calculated 598.2461, observed 599.4 (M+1) + ; Retention time: 5.85 minutes (LC method D).

[0183] Step 2: 3-[[4-[(2R)-2-amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride) [ka] To a stirred solution of 3-[[4-[(2R)-2-(tert-butoxycarbonylamino)-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (20.73 g, 34.624 mmol) in DCM (200 mL) was added HCl (87 mL 4 M solution in 1,4-dioxane, 346.24 mmol) at room temperature. The reaction mixture was stirred for 2 hours. The volatiles were removed in vacuo, and the resulting solid was triturated with diethyl ether (150 mL). After removal of the volatiles, the product was dried in vacuo to give 3-[[4-[(2R)-2-amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) (19.68 g, 100%) as a white solid. 1 H NMR(250MHz,DMSO-d6)δ8.56-8.27(m,4H),8.14(t,J=6.8Hz,2H),7.70(t,J=7.8Hz,1H),7.34-7.18(m,1H),7.17-7.02(m,2H),6. 31(s,1H),4.42-4.23(m,1H),4.23-4.06(m,1H),3.5-3.4(m,1H,overlapping with water),2.01(s,6H),1.82-1.31(m,3H),1.02-0.78(m,6H).ESI-MS m / z calculated value 498.1937, actual value 499.3(M+1) + ; Retention time: 1.63 minutes (LC method E).

[0184] Example 3: Preparation of 3-[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [ka] Step 1: (2R)-2-amino-4,4-dimethyl-pentan-1-ol [ka] To a solution of (2R)-2-amino-4,4-dimethyl-pentanoic acid (15 g, 103.3 mmol) in THF (150 mL) was added borane-THF (260 mL 1 M, 260.0 mmol) dropwise at 0 °C, maintaining the reaction temperature below 10 °C. The addition took approximately 30 minutes. The mixture was allowed to warm to ambient temperature and stirred for 22 hours. The reaction was quenched by slow addition of methanol (80 mL, 1.975 mol), and the solvent was removed in vacuo. The residue was coevaporated three times with methanol (200 mL, 4.937 mol). The crude residue was diluted with HCl (200 mL 1 M, 200.0 mmol) and washed with MTBE (200 mL). The aqueous phase was evaporated to remove residual organic solvent. Water was further removed in vacuo to give an off-white solid. The solid was further dried using an acetonitrile azeotrope. The solid was slurried in ACN (200 mL) and the precipitate was collected using an M frit. The solid was air-dried for 1 h and then dried in vacuo at 45° C. for 20 h to give (2R)-2-amino-4,4-dimethyl-pentan-1-ol (hydrochloride salt) (14.73 g, 85%). 1 H NMR (400 MHz, DMSO-d6)δ 7.80(s, 3H), 5.36(t, J=5.1 Hz, 1H), 3.59(dt, J=11.7, 4.1 Hz, 1H), 3.42-3.34(m, 1H), 3.10(dq, J=7.7, 3.8 Hz, 1H), 1.46(dd, J=14.5, 7.1 Hz, 1H), 1.33(dd, J=14.5, 3.5 Hz, 1H), 0.91(s, 9H).ESI-MS m / z Calculated value 131.13101, Actual value 132.1(M+1) + ; Retention time: 0.51 min (LC method A).

[0185] Step 2: 3-[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [ka] 3-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (20 g, 47.862 mmol) was suspended in a mixture of 2-methyltetrahydrofuran (80 mL) and DMF (20 mL), and the solution was cooled to −5° C. Sodium tert-butoxide (23 g, 239.33 mmol) was then dissolved in 2-methyltetrahydrofuran (100 mL) and cooled to 5° C., followed by the addition of (2R)-2-amino-4,4-dimethyl-pentan-1-ol (hydrochloride salt) (8.02 g, 47.830 mmol) over 10 minutes, after which the reaction was warmed to 10° C. and stirred for 4 hours. It was then cooled to 0° C. and quenched by the addition of aqueous hydrochloric acid (2 M, 200 mL) over 10 minutes. The phases were separated and the aqueous phase was extracted with 2-methyltetrahydrofuran (200 mL). The organic phases were combined, washed with aqueous sodium chloride (15% (w / w), 2 × 200 mL), dried over sodium sulfate (60 g), filtered, and evaporated to dryness. The solid was then triturated with ethyl acetate (200 mL) for 16 hours, filtered, washed with ethyl acetate, and dried in a vacuum oven at 50 °C for 20 hours to give 3-[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride) (22.29 g, 80%). 1 H NMR (400 MHz, DMSO-d6)δ 13.26(br.s., 2H), 8.45(t, J=1.6 Hz, 1H), 8.28-8.06(m, 5H), 7.69(t, J=7.8 Hz, 1H), 7.31-7.21(m, 1H), 7.13(d, J=7.6 Hz, 2H), 6.29(br.s., 1H), 4.30(dd, J=11.7, 2.7 Hz, 1H), 4.10(dd, J=11.5, 7.1 Hz, 1H), 3.56(br.s., 1H), 2.13-1.90(s, 6H), 1.62-1.47(m, 2H), 0.94(s, 9H).ESI-MS m / z calculated value 512.20935, observed value 513.0 (M+1) + ; Retention time: 2.334 min; LC method F.

[0186] Example 4: Preparation of 3-[[4-[(2R)-2-amino-5,5,5-trifluoro-4,4-dimethyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [ka] Step 1: 4,4,4-trifluoro-3,3-dimethyl-butanal [ka] A 1 L three-neck flask was charged with 4,4,4-trifluoro-3,3-dimethylbutan-1-ol (8.987 g, 57.555 mmol), DCM (63 mL), water (63 mL), NaBr (544 mg, 5.2870 mmol), sodium bicarbonate (12.32 g, 146.66 mmol), and TEMPO (92 mg, 0.5888 mmol). The mixture was cooled in an ice-water bath. Aqueous NaOCl solution (47 mL, 1.31 M, 61.570 mmol) was added dropwise over 2 h at 2.5–4.4 °C. After the addition, the mixture was stirred for 10 min. The two layers were separated. The aqueous phase was extracted with DCM (2 × 15 mL). The combined organic layers were dried over sodium sulfate and filtered to give 113.7 g (approximately 80 mL) of crude product in DCM, which was used directly in the next step. 1 H NMR (300 MHz, CDCl3)δ 9.82-9.78(m, 1H), 2.54(d, J=2.6 Hz, 2H), 1.28(s, 6H). 19 F NMR (282 MHz, CDCl3) δ-79.11 (s, 3F).

[0187] Step 2: (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanenitrile and (2S)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanenitrile [ka] To a solution of 4,4,4-trifluoro-3,3-dimethyl-butanal (113.7 g, 57.540 mmol) in DCM (80 mL) (purity approximately 7.8%) was added MeOH (110 mL). The mixture was cooled in an ice-water bath. (1R)-1-Phenylethanamine (8.46 g, 69.814 mmol) was added, followed by acetic acid (4.41 g, 73.436 mmol). The mixture was stirred at 0° C. for 10 minutes, after which NaCN (3.56 g, 72.642 mmol) was added. The mixture was allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was cooled to 0° C., and a solution of potassium carbonate (4 g) in water (20 mL) was added dropwise, followed by brine (40 mL). The mixture was extracted with DCM (2×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (120 g silica gel, 0 to 30% heptane / EtOAc) to give a 4:1 mixture of (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanenitrile and (2S)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanenitrile as a colorless oil (14.87 g, 91%). ESI-MS m / z calculated 284.15002, found 285.2 (M+1). + ; Retention time: 3.38 min; LC method F.

[0188] Step 3: (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanamide and (2S)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanamide [ka] To a solution of a 4:1 mixture of (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanenitrile and (2S)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanenitrile (14.87 g, 52.300 mmol) in DCM (105 mL) was added sulfuric acid (56.3 g, 551.06 mmol). The mixture was stirred overnight at room temperature, poured onto crude ice (200 g), and neutralized to pH 9 with 28% aqueous NH3 (100 mL). The mixture was extracted with DCM (500 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (330 g silica gel, heptane / EtOAc 20 to 50%) to give (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanamide (10.77 g, 68%) as a white solid. 1 H NMR (300 MHz, CDCl3)δ 7.39-7.22(m, 5H), 6.35(br.s., 1H), 5.55(br.s., 1H), 3.65(q, J=6.5 Hz, 1H), 2.93(dd, J=7.6, 3.8 Hz, 1H), 1.87(dd, J=15.0, 3.8 Hz, 1H), 1.65-1.56(m, 2H), 1.35(d, J=6.5 Hz, 3H), 1.04(s, 3H), 1.00(s, 3H). 19 F NMR (282 MHz, CDCl3) δ -78.77 (s, 3F). 19F NMR showed a diastereomeric excess of 99.4%.

[0189] Step 4: (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanoic acid [ka] To a solution of (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanamide (11.35 g, 37.541 mmol) in HOAc (50 mL) was added concentrated HCl (65 mL of 11.8 M, 767.00 mmol), followed by water (50 mL). A white precipitate appeared. The mixture was heated at 100° C. for 66 hours. Additional concentrated HCl (40 mL 11.8 M, 472.00 mmol) and HOAc (10 mL) were added. The mixture was stirred at 100° C. overnight. Additional aqueous HCl (20 mL 6 M, 120.00 mmol) was added. After 7 hours at 100° C., additional aqueous HCl (20 mL 6 M, 120.00 mmol) was added. The mixture was stirred at 100° C. overnight. This became a clear solution. Additional aqueous HCl (20 mL 6 M, 120.00 mmol) was added. The mixture was stirred at 100° C. for 7 hours, and additional aqueous HCl (20 mL 6 M, 120.00 mmol) was added. The mixture was stirred at 100° C. overnight. The mixture was concentrated and co-evaporated with water (50 mL). The residue (17 g) was mixed with water (25 mL) at 50° C. for 20 minutes, cooled in an ice-water bath for 20 minutes, and filtered. The crude product was mixed with 1,4-dioxane (60 mL). The mixture was concentrated and dried in vacuo overnight to give (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanoic acid (hydrochloride) (13.04 g, 97%) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6)δ 10.09(br.s., 1H), 7.54-7.31(m, 5H), 7.29-7.05(m, 1H), 4.07(q, J=5.9 Hz, 1H), 3.16-2.98(m, 1H), 2.08-1.83(m, 2H), 1.49(d, J=6.5 Hz, 3H), 0.99(s, 3H), 0.92(s, 3H). 19 F NMR(282 MHz,DMSO-d6)δ-78.28(s,3F).ESI-MS m / z calculated value 303.14462, measured value 304.2(M+1) + ; Retention time: 1.98 min; LC method F.

[0190] Step 5: (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentan-1-ol [ka] A solution of LAH in THF (100 mL of 1 M, 100.00 mmol) was added dropwise to a suspension of (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanoic acid (hydrochloride) (13.04 g, 36.267 mmol) in THF (200 mL) at 35°C. The mixture was stirred at 40°C for 2 hours, cooled to 10°C in an ice-water bath, and diluted with THF (200 mL). A mixture of water (3.8 g) and THF (50 mL) was added dropwise, followed by a mixture of 25% aqueous NaOH (3.8 g) and water (10 g). The resulting mixture was stirred at room temperature for 30 minutes and at 50°C for 1 hour, filtered, and washed with warm THF. The filtrate was concentrated to give 12.02 g of the product (free amine) as a colorless oil. 1 H NMR (300 MHz, CDCl3)δ 7.37-7.24(m, 5H), 3.82(q, J=6.5 Hz, 1H), 3.72-3.67(m, 1H), 3.21(dd, J=10.6, 4.7 Hz, 1H), 2.67(quin, J=4.6 Hz, 1H), 1.66(dd, J=14.7, 5.9 Hz, 1H), 1.54-1.45(m, 1H), 1.36(d, J=6.5 Hz, 3H), 1.03(s, 3H), 0.97(s, 3H). 19 F NMR (282 MHz, CDCl3) δ -78.83 (s, 3F). The above crude product (12.02 g) was dissolved in diethyl ether (20 mL), diluted with heptane (80 mL), and cooled in an ice-water bath. A solution of HCl in 1,4-dioxane (10.5 mL, 4 M, 42.000 mmol) was added dropwise. The mixture was stirred at room temperature for 30 minutes and filtered to give (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentan-1-ol (hydrochloride) (11.56 g, 98%) as a white solid. 1H NMR (300 MHz, DMSO-d6)δ 9.57(br.s., 1H), 9.25(t, J=9.8 Hz, 1H), 7.80-7.59(m, 2H), 7.53-7.32(m, 3H), 5.63(br.s., 1H), 4.58(t, J=6.3 Hz, 1H), 3.81-3.65(m, 1H), 3.64-3.51(m, 1H), 2.91-2.74(m, 1H), 1.98-1.85(m, 1H), 1.85-1.74(m, 1H), 1.63(d, J=6.8 Hz, 3H), 0.91(s, 3H), 0.88(s, 3H). 19 F NMR(282 MHz, DMSO-d6)δ-77.71(s,3F).ESI-MS m / z calculated value 289.16534, measured value 290.2(M+1) + ; Retention time: 2.08 min; LC method F.

[0191] Step 6: (2R)-2-Amino-5,5,5-trifluoro-4,4-dimethyl-pentan-1-ol [ka] To a solution of (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentan-1-ol (hydrochloride) (11.56 g, 35.482 mmol) in EtOH (200 mL) was added 10% palladium on carbon, 50% wet (5 g, 2.3492 mmol). The mixture was hydrogenated in a Parr shaker hydrogenator under 40 psi hydrogen pressure at room temperature for 9 hours. An additional 10% palladium on carbon, 50% wet (1 g, 0.4698 mmol) was added. The mixture was shaken at 40 psi for 7 hours. The mixture was filtered through Celite and washed with EtOH. The filtrate was concentrated. The residue (7.9 g) was triturated with a mixture of 2-methyltetrahydrofuran (28 mL) and heptane (200 mL) and stirred overnight. The mixture was filtered and the white solid was dried in vacuo to give (2R)-2-amino-5,5,5-trifluoro-4,4-dimethyl-pentan-1-ol (hydrochloride salt) (7.66 g, 93%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.08 (br.s., 3H), 5.46 (t, J=5.0 Hz, 1H), 3.67-3.52 (m, 1H), 3.43 (dt, J=11.7, 5.8 Hz, 1H), 3.29-3.16(m, 1H), 1.88-1.73(m, 1H), 1.72-1.58(m, 1H), 1.15(s, 3H), 1.10(s, 3H). 19 F NMR(282MHz,DMSO-d6)δ-78.07(s,3F).ESI-MS m / z calculated value 185.10275, measured value 186.2(M+1) + ; Retention time: 0.64 min; LC method F.

[0192] Step 7: 3-[[4-[(2R)-2-amino-5,5,5-trifluoro-4,4-dimethyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [ka] 3-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (6.12 g, 14.65 mmol) and (2R)-2-amino-5,5,5-trifluoro-4,4-dimethyl-pentan-1-ol (hydrochloride) (3.27 g, 14.75 mmol) were combined in THF (30 mL), and the resulting suspension was cooled in a water-ice bath. Sodium tert-butoxide (5.63 g, 58.58 mmol) was added, inducing rapid partial dissolution of the solid. After 5 min, the cooling bath was removed, and the reaction was stirred at room temperature for 1 h (90% conversion). Additional (2R)-2-amino-5,5,5-trifluoro-4,4-dimethyl-pentan-1-ol (hydrochloride) (363 mg, 1.638 mmol) was added, and the mixture was stirred for 1 h (no change). Additional sodium tert-butoxide (744 mg, 7.742 mmol) was added, and the mixture was stirred for 40 minutes (96% conversion). Ethyl acetate (100 mL), HCl (90 mL of 1 M, 90.00 mmol), and brine (50 mL) were added, and the resulting two phases were separated. The organic phase was washed with brine (50 mL), dried over sodium sulfate, and concentrated. The residue was triturated with EtOAc / MeOH / hexanes, and the solvent was evaporated to give 3-[[4-[(2R)-2-amino-5,5,5-trifluoro-4,4-dimethyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride) (8.88 g, 93%) as a cream solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.15 (very broad s, 1H), 8.61-8.30 (m, 4H), 8.14 (dd, J = 7.9, 1.9 Hz, 2H), 7.69 (t, J = 7.8 Hz, 1H), 7.31-7.20 (m, 1H), 7.12 (d, J = 7.6 Hz, 2H), 6.33 (s, 1H), 4.43 (dd, J = 11.9, 3.3 Hz, 1H), 4.29-4.15 (m, 1H), 3.74 (s, 1H), 2.06-1.94 (broad m, 6H), 1.94-1.85(m, 2H), 1.22(s, 3H), 1.16(s, 3H).ESI-MS m / z calculated value 566.1811, measured value 567.62(M+1) +; Retention time: 1.13 minutes (LC method A).

[0193] Example 5 Preparation of 3-[[4-[(2R)-2-amino-3-[1-(trifluoromethyl)cyclopropyl]propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [ka] Step 1: 2-[1-(trifluoromethyl)cyclopropyl]ethanol [ka] LAH (49.868 g, 1.3139 mol) was added to THF (1700 mL) under nitrogen, and the mixture was stirred for 30 minutes before being cooled to 0° C. A solution of 2-[1-(trifluoromethyl)cyclopropyl]acetic acid (190.91 g, 1.0107 mol) in THF (500 mL) was added dropwise while controlling the temperature at <5° C. The mixture was allowed to warm to room temperature and stirred for 24 hours. The resulting suspension was cooled to 0° C., and water (50 mL) was added very slowly, followed by 15% (w / w) sodium hydroxide (50 mL) and water (150 mL). The mixture was stirred at 0° C. for 30 minutes, filtered through a Celite pad, and the filter cake was washed with THF (2×500 mL). The combined filtrates were evaporated in vacuo to give 2-[1-(trifluoromethyl)cyclopropyl]ethanol (160.27 g, 98%) as an amber oil containing approximately 5% (w / w) THF by NMR. 1 H NMR (250MHz, DMSO-d6) δ 4.57 (t, J = 5.2 Hz, 1H), 3.55-3.39 (m, 2H), 1.74 (t, J = 7.3Hz, 2H), 1.00-0.58 (m, 4H).

[0194] Step 2: 2-[1-(trifluoromethyl)cyclopropyl]acetaldehyde [ka] A solution of 2-[1-(trifluoromethyl)cyclopropyl]ethanol (80 g, 467.1 mmol) in methylene chloride (1.1 L) was stirred at room temperature and treated in small portions with Dess-Martin periodinane (250 g, 589.4 mmol) (exothermic! Cool in an ice bath to maintain the temperature below 15°C). Water (12 mL, 666.1 mmol) was slowly added to the mixture over 0.5 h (exothermic to 33°C during the addition, maintained at 20–33°C with cold water cooling) to give a thick suspension. After the addition, the pale yellow, fine suspension was stirred at room temperature for 18 h. The yellow suspension was diluted with diethyl ether (500 mL) (yellow suspension) and stirred for 30 min. The slurry was filtered through Celite, and the precipitate was washed with 100 mL of diethyl ether. The organic phase was carefully treated with saturated aqueous sodium carbonate (500 mL, strong gas evolution, final pH ≈10). The triphasic mixture was stirred at room temperature for 1 hour, and the solids were removed by filtration (large glass frit). The phases (yellow, cloudy diethyl ether, colorless aqueous) were separated, and the organic phase was washed once more with saturated aqueous sodium carbonate (250 mL), once with 1 M sodium thiosulfate (250 mL), and once with brine (250 mL). The aqueous phase was back-extracted once with diethyl ether (150 mL), and the combined organic phases were dried, filtered, and evaporated to give 2-[1-(trifluoromethyl)cyclopropyl]acetaldehyde (40 g, 56%) as a yellow liquid.

[0195] Step 3: 2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propanenitrile [ka] A solution of 2-[1-(trifluoromethyl)cyclopropyl]acetaldehyde (102 g, 670.5 mmol) in MeOH (700 mL) was treated with (1R)-1-phenylethanamine (86 mL, 667.1 mmol) and cooled in an ice bath. The solution was treated with acetic acid (38 mL, 668.2 mmol) and stirred in the ice bath for 20 min. Solid NaCN (CAUTION, 33 g, 673.4 mmol) was then added in one portion, and the suspension was stirred in a melting ice bath for 14 h. The solution was concentrated under reduced pressure, and the residue was extracted with MTBE (1000 mL) and saturated sodium carbonate / water 1:1 (1000 mL) and washed with brine (350 mL). The aqueous phase was back-extracted once with MTBE (250 mL), and the combined organic phases were dried, filtered, and evaporated to give 2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propanenitrile (180.8 g, 96%) as a 3:1 mixture of diastereomers. ESI-MS m / z calculated 282.13437, found 283.0 (M+1). + Retention times: 1.69 min (major isomer) and 1.62 min (minor isomer), LC Method A.

[0196] Step 4: (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propenamide [ka] A 2 L flask equipped with mechanical stirring and a temperature probe was charged with sulfuric acid (285 mL, 18 M, 5.130 mol) and cooled in an ice bath. At an internal temperature of 5 °C, a solution of 2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propanenitrile (180.8 g, 640.4 mmol, 3:1 mixture of diastereomers) in DCM (900 mL) was added dropwise over 20 min. The ice bath was removed, and the dark orange emulsion was stirred at room temperature for 18 h and at 30–40 °C for 2 h. The dark orange emulsion was carefully added to a mixture of ice and water (2.2 L) under mechanical stirring to give a yellow triphasic mixture, which was basified by the slow addition of ammonium hydroxide (1.33 L, 30% (w / w), 10.25 mol) under ice control (highly exothermic; ice was added to maintain the internal temperature at 10–25 °C). The yellow emulsion was stirred at room temperature for 10 min (pH ∼10), diluted with DCM (500 mL), and the phases were separated. The aqueous phase was washed twice more with DCM (400 and 200 mL), and the combined organic phases were washed once with 1:1 water / brine (500 mL). The DCM phase was dried, filtered, and evaporated to give crude 2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propanamide (189.5 g, 99%) as a yellow-orange oil. ESI-MS m / z calculated 300.14496, found 301.0 (M+1). + Retention times: 1.40 min (major isomer) and 1.50 min (minor isomer) (3:1 mixture of diastereomers). The product was dissolved in ethanol (1.5 L) and rapidly treated with HCl (240 mL 4 M, 960.0 mmol) (4 M in dioxane), and the resulting thick suspension was stirred overnight at room temperature under mechanical stirring. The solid was collected by filtration, washed with cold ethanol, and dried under vacuum at 40-45 °C with a nitrogen bleed to give (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propanamide (hydrochloride salt) (147 g, 68%). 1H NMR (499 MHz, DMSO-d6) δ 9.74 (d, J=67.9 Hz, 2H), 8.16-7.94(m, 1H), 7.86(s, 1H), 7.64-7.51(m, 2H), 7.51-7.34(m, 3H), 4.22(s, 1H), 3.46-3.37(m, 1H), 2.45(d, J=15.9) ESI-MS m / z Calculated value 300.14496, measured value 301.0 (M+1) + Retention times: 1.40 min (major isomer) and 1.40 min (minor isomer), 97:3 mixture of diastereomers (LC Method G).

[0197] Step 5: (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propanoic acid [ka] In a 5 L flask equipped with mechanical stirring, (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propanamide (hydrochloride) (147 g, 436.5 mmol) was added to acetic acid (735 mL) with stirring, and the thick, colorless suspension was treated with HCl (1.3 L of 12 M, 15.60 mol). The colorless suspension was carefully heated to 60-65 °C (strong bubbling, acetic acid (145 mL) was added), and the suspension was stirred at 60-65 °C for 16 h. The suspension was then slowly heated to 100 °C (heating over 4 h, strong bubbling), and the resulting solution was stirred at 100 °C for an additional 20 h. The pale yellow solution was concentrated under reduced pressure at 65 °C to give a semi-solid mass, which was treated with water (1.5 L). The thick suspension was heated to 70-80 °C and allowed to cool to room temperature with stirring for 2 h. The solid was collected by filtration, washed with water, and sucked dry overnight. The wet solid was further dried under reduced pressure at 50-60°C for 4 hours to give (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propanoic acid (hydrochloride) (135 g, 92%) as an off-white solid. ESI-MS m / z calculated 301.12897, found 302.0 (M+1). + ; Retention time: 1.82 minutes; (LC method G).

[0198] Step 6: (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol [ka] In a 5 L flask equipped with mechanical stirring and under a dry nitrogen atmosphere, (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propanoic acid (hydrochloride) (135 g, 399.7 mmol) was suspended in THF (2 L) (thick suspension). This was heated to 35-40 °C, and LAH (47.3 g, 1.214 mol) (pellets) was added slowly over 1 h while maintaining the internal temperature at 30-40 °C with external cooling. The mixture was stirred at 30-40 °C for 1 h (hydrogen evolution had almost ceased, a gray suspension was formed; most of the starting material was in solution), and then heated at 50-55 °C for 1 h. The gray suspension was left stirring overnight in a cooled heating mantle. The gray suspension was cooled in an ice bath and quenched by the careful addition of water (44 mL, 2.442 mol), NaOH (41 mL of 6 M, 246.0 mmol), and water (44 mL, 2.442 mol). (The initial water addition produced a high exotherm and was cooled to 5–30°C.) The gray suspension was heated to 50–55°C for 1 h, yielding a colorless suspension. The warm suspension was filtered through a pad of Celite and covered with magnesium sulfate. The solid was washed with hot THF and evaporated to give crude (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol (121 g, 105%) as an oil. The crude material was dissolved in diethyl ether (1 L, clear solution) and slowly treated with HCl (101 mL 4 M, 404.0 mmol) (4 M in dioxane) with cooling. The resulting thick suspension was stirred at room temperature for 1 h, and the solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure at 40–45° C. with a nitrogen bleed to give (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol (hydrochloride) (126.6 g, 98%) as an off-white solid. 1H NMR (500 MHz, DMSO-d6)δ 9.34(s, 2H), 7.66(d, J=7.4 Hz, 2H), 7.43(dt, J=25.1, 7.4 Hz, 3H), 5.59(s, 1H), 4.58(q, J=6.6 Hz, 1H), 3.83(d, J=12.6 Hz, 1H), 3.62-3.54(m, 1H), 2.89(s, 1H), 2.33-2.24(m, 1H), 1.67-1.51(m, 4H), 0.97-0.81(m, 3H), 0.71(s, 1H).ESI-MS m / z Calculated value 287.1497, actual value 288.0 (M+1) + ; Retention time: 0.99 minutes (LC method A).

[0199] Step 7: (2R)-2-Amino-3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol [ka] In a 1 L hydrogenation reactor, (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol (hydrochloride) (63.3 g, 195.5 mmol) was dissolved (warmed) in EtOH (630 mL) and treated with Pd / C (6.3 g 10% (w / w), 5.920 mmol) (12.5 g, 50% water wet), and the reaction was stirred under 2 bar of hydrogen at 40° C. for 24 h. The reaction mixture was filtered through Celite. The pad was washed with ethanol, and the colorless filtrate was evaporated to give a solid mass, which was triturated with diethyl ether. The suspension was stirred at room temperature for 1 h. The solid was filtered, washed with copious amounts of diethyl ether and dried to give (2R)-2-amino-3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol (hydrochloride salt) (41.8 g, 97%) as an off-white solid. 1H NMR (500 MHz, DMSO-d6)δ 8.18(s, 3H), 5.45(t, J=4.9 Hz, 1H), 3.71(dt, J=11.6, 3.9 Hz, 1H), 3.55(dt, J=11.2, 5.4 Hz, 1H), 3.24(h, J=4.7 ESI-MS m / z Calculated value 183.0871, actual value 184.0 (M+1) + ; Retention time: 0.65 min; LC method A.

[0200] Step 8: 3-[[4-[(2R)-2-amino-3-[1-(trifluoromethyl)cyclopropyl]propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [ka] 3-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (19.09 g, 45.68 mmol) and (2R)-2-amino-3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol (hydrochloride) (10.18 g, 46.35 mmol) were dissolved in THF (100 mL) and cooled in an ice-water bath. Sodium tert-butoxide (18.14 g, 188.8 mmol) was added, and the reaction was allowed to warm to room temperature. The reaction was stirred for 1 hour and then partitioned between ethyl acetate (500 mL) and aqueous HCl (275 mL 1 M, 275.0 mmol). The organics were separated, washed with brine, dried over sodium sulfate, and evaporated to give 3-[[4-[(2R)-2-amino-3-[1-(trifluoromethyl)cyclopropyl]propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride) (26.74 g, 94%). ESI-MS m / z calculated 564.1654, found 565.1 (M+1). + ; Retention time: 0.48 min; LC method B.

[0201] Example 6: Preparation of 3-[[4-[(2R)-2-amino-3-cyclopropyl-propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid Step 1: tert-butyl N-[(1R)-1-(cyclopropylmethyl)-2-hydroxy-ethyl]carbamate [ka] A solution of (2R)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoic acid (0.22 g, 0.9596 mmol) and borane-tetrahydrofuran complex (2.9 mL of 1 M, 2.900 mmol) in THF (5 mL) was stirred for 3 h. The reaction was quenched with 1 M citric acid and extracted with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, and evaporated in vacuo to give tert-butyl N-[(1R)-1-(cyclopropylmethyl)-2-hydroxyethyl]carbamate (89 mg, 43%). ESI-MS m / z calculated 215.15215, found 216.2 (M+1). + ; Retention time: 0.47 min; LC method B.

[0202] Step 2: 3-[[4-[(2R)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [ka] A solution of 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (approximately 172.7 mg, 0.4134 mmol), tert-butyl N-[(1R)-1-(cyclopropylmethyl)-2-hydroxyethyl]carbamate (89 mg, 0.4134 mmol), and sodium t-butoxide (approximately 159.0 mg, 1.654 mmol) in THF (2.067 mL) was stirred for 22 hours. The reaction was quenched with 1 M citric acid, diluted with water, and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography using 0-10% methanol / dichloromethane to give a partially clean product. The impure product was purified using Luna C (Phenomenex) column chromatography. 18( 2) Repurified using a reversed-phase HPLC-MS method using a column (75 x 30 mm, 5 μm particle size) (product number: 00C-4252-U0-AX) and a double gradient run of 1 to 99% mobile phase B over 15.0 min. Mobile phase A = H2O (5 mM HCl). Mobile phase B = CH3CN. Flow rate = 50 mL / min and column temperature = 25 °C. 3-[[4-[(2R)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (45 mg, 18%) was obtained as a colorless solid. ESI-MS m / z calculated 596.23047, found 597.3 (M+1). + ; Retention time: 0.68 min; LC method B.

[0203] Step 3: 3-[[4-[(2R)-2-amino-3-cyclopropyl-propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [ka] A solution of 3-[[4-[(2R)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (45 mg, 0.07542 mmol) in HCl (3 mL 4 M, 12.00 mmol) in dioxane was stirred for 4 h. The solvent was removed in vacuo, and the resulting solid was triturated with diethyl ether and dried in vacuo to give 3-[[4-[(2R)-2-amino-3-cyclopropyl-propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) (53 mg, 132%). ESI-MS m / z calculated 496.17804, found 497.3 (M+1). + ; Retention time: 0.41 min; LC method B.

[0204] Example 7: Preparation of (2R)-2-amino-5,5-dimethyl-hexan-1-ol Step 1: 2-(tert-butoxycarbonylamino)-5,5-dimethyl-hex-2-enoic acid methyl ester [ka] To a stirred solution of methyl 2-(tert-butoxycarbonylamino)-2-dimethoxyphosphorylacetate (16.4 g, 55.174 mmol) and DBU (8.0422 g, 7.9 mL, 52.827 mmol) in DCM (100 mL) was added 3,3-dimethylbutyraldehyde (5.0274 g, 6.3 mL, 50.194 mmol) at 0 °C (ice bath). The reaction mixture was stirred at room temperature for 16 h. Aqueous HCl (1 N) (100 mL) was added and the phases were separated. The aqueous layer was washed with DCM (2 × 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified on a 50 g silica gel pad using a 15% EtOAc / heptane gradient to give methyl 2-(tert-butoxycarbonylamino)-5,5-dimethyl-hex-2-enoate (13.6 g, 95%) as a clear oil that crystallized to a white solid. 1H NMR (400 MHz, CDCl3)δ 6.66(t, J=7.6 Hz, 1H), 5.86(br.s, 1H), 3.79(s, 3H), 2.12(d, J=7.6 Hz, 2H), 1.47(s, 9H), 0.95(s, 9H).

[0205] Step 2: (2R)-2-(tert-butoxycarbonylamino)-5,5-dimethyl-hexanoic acid methyl ester [ka] Nitrogen was bubbled through a solution of methyl 2-(tert-butoxycarbonylamino)-5,5-dimethylhex-2-enoate (13.630 g, 50.230 mmol) in ethanol (184 mL) and 1,4-dioxane (61 mL) for 5 minutes. Then, 1,2-bis[(2R,5R)-2,5-diethylphosphorano]benzene(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (363 mg, 0.5023 mmol) was added, and the mixture was placed in an ultrasonic bath under nitrogen for 5 minutes. The reaction mixture was then purged with nitrogen gas (3 x 30 psi) and then with hydrogen (3 x 50 psi). A hydrogen pressure of 50 psi (3.5 bar) was maintained and the reaction was stirred at room temperature for 16 hours, at which point the volatiles were removed under reduced pressure and the residue was passed through a plug of silica gel (80 g) using an eluent of 15% EtOAc / heptane to give methyl (2R)-2-(tert-butoxycarbonylamino)-5,5-dimethyl-hexanoate (14 g, 97%) as a colorless oil. 1 H NMR (400 MHz, CDCl3)δ 5.00(d, J=7.3 Hz, 1H), 4.27(d, J=5.4 ESI-MS m / z Calculated value 273.194, actual value 296.2 (M+23) + ; Retention time: 4.58 min; LC method J.

[0206] Step 3: tert-butyl N-[(1R)-1-(hydroxymethyl)-4,4-dimethyl-pentyl]carbamate [ka] To a solution of methyl (2R)-2-(tert-butoxycarbonylamino)-5,5-dimethylhexanoate (14 g, 48.652 mmol) in THF (145 mL) was added LiBH (2 M THF solution) (61 mL of 2 M, 122.00 mmol) (no exotherm was observed). The reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was then slowly poured into saturated aqueous NH Cl (50 mL) at 0 °C (strong gas evolution occurred, but no exotherm occurred). The product was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product tert-butyl N-[(1R)-1-(hydroxymethyl)-4,4-dimethyl-pentyl]carbamate (13.23 g, 89%) as a clear oil. ESI-MS m / z calculated 245.1991, observed 268.2 (M+23) + ;Holding time: 1.8 minutes. 1 H NMR (400 MHz, CDCl3)δ 4.62(br.s, 1H), 3.68(d, J=7.1 Hz, 1H), 3.55(d, J=8.1 Hz, 2H), 2.57(br.s, 1H), 1.55-1.29(m, 11H), 1.28-1.19(m, 2H), 0.88(s, 9H); LC method I.

[0207] Step 4: (2R)-2-Amino-5,5-dimethyl-hexan-1-ol [ka] To a solution of tert-butyl N-[(1R)-1-(hydroxymethyl)-4,4-dimethyl-pentyl]carbamate (13.23 g, 43.460 mmol) in 1,4-dioxane (140 mL) was added hydrogen chloride (4N 1,4-dioxane solution) (63 mL of 4 M, 252.00 mmol). The reaction mixture was stirred at room temperature for 16 hours, after which the mixture was evaporated to dryness under reduced pressure. The residue was triturated with THF and then filtered to give (2R)-2-amino-5,5-dimethyl-hexan-1-ol (hydrochloride salt) (8.137 g, 98%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.97(br.s, 3H), 5.28(br.s, 1H), 3.58(dd, J=11.4, 3.5 Hz, 1H), 3.44(dd, J=11.4, 6.2 Hz, 1H), 3.02-2.89(m, 1H), 1.58-1.43(m, 2H), 1.30-1.13(m, 2H), 0.86(s, 9H).ESI-MS m / z calculated value ESI-MS m / z calculated value 145.14667, measured value 146.3(M+1) + ; Retention time: 1.78 min; LC method J.

[0208] Example 8: Preparation of 3-[[4-[(2R)-2-amino-5,5-dimethyl-hexoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid Step 1: 3-[[4-[(2R)-2-amino-5,5-dimethyl-hexoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [ka] A solution of (2R)-2-amino-5,5-dimethyl-hexan-1-ol (hydrochloride) (4.495 g, 23.501 mmol) in anhydrous DMF (23 mL) was added to a solution of 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (13.5 g, 32.384 mmol) in Me-THF (117 mL). The mixture was cooled to 10–15 °C (internal temperature), and then sodium tert-butoxide (17.4 g, 181.05 mmol) was added. The reaction was stirred at 10–15 °C for 2 h, then cooled to 0 °C and quenched by the addition of 1 N aqueous HCl (180 mL) at 0 °C. The biphasic mixture was stirred for 30 min. The layers were then separated, and the aqueous layer was extracted with 2-methyltetrahydrofuran (5 × 500 mL). The combined organic layers were washed with water (3 x 500 mL) and brine (1 x 500 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (75 mL) and precipitated in EtOAc (800 mL). The solid was filtered through a glass frit (porosity 4), and the residue was collected and dissolved using MeOH. The crude mixture was purified by elution with a gradient of 0-80% CHCN / acidic water (0.1% aqueous hydrochloric acid) to give 275 g C 18 Purification by reverse phase chromatography on a cartridge gave, after evaporation, 3-[[4-[(2R)-2-amino-5,5-dimethyl-hexoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride) (10.2 g, 70%) as a white solid. 1H NMR (400 MHz, DMSO-d6)δ 8.45(t, J=1.7 Hz, 1H), 8.38(br.s, 3H), 8.18-8.09(m, 2H), 7.70(t, J=7.8 Hz, 1H), 7.29-7.21(m, 1H), 7.12(d, J=7.8 Hz, 2H), 6.31(s, 1H), 4.43-4.36(m, 1H), 4.35-4.27(m, 1H), 3.45(br.s, 1H), 1.99(s, 6H), 1.70-1.49(m, 2H), 1.31(td, J=12.6, 4.9 Hz, 1H), 1.21-1.11 (m, 1H), 0.83 (s, 9H), 1H unstable loss (from -COOH). ESI-MS m / z calculated 526.225, found 527.2 (M+1). + ; Retention time: 2.58 min; LC method A.

[0209] Example 9: Preparation of (2R)-2-amino-3-(1-methylcyclopropyl)propan-1-ol Step 1: 2-(1-methylcyclopropyl)ethanol [ka] To a solution of diethylzinc (hexane solution) (2 L of 1 M, 2.0000 mol) was added 3-methylbut-3-en-1-ol (135 g, 1.5674 mol) over 30 min at 0–15 °C. The mixture was then warmed to 15 °C and stirred for 20 min, after which a solution of diiodomethane (482.7 g, 1.8022 mol) in DCM (270 mL) was added over 1 h. The reaction was then warmed to 25 °C and stirred for 20 h. After cooling to 5 °C, the reaction mixture was quenched with aqueous HCl (2 M, 1.35 L). The phases were separated, and the aqueous phase was extracted with DCM (2 × 675 mL). The hexane extract was washed with sodium thiosulfate (10% (w / w), 1.35 L) and concentrated in vacuo. The sodium thiosulfate solution was then extracted with two successive DCM extracts. The DCM extract was then combined with the product obtained by concentrating the hexane extract. Water (1.35 L) was then added to the combined organic phase. The mixture was cooled to 2 °C, and aqueous sodium permanganate (83.5 g, 40% (w / w), 235.34 mmol) was added. The mixture was stirred at 2 °C for 15 min, sodium bisulfite (10% (w / w), 1 L) was added, the phases were separated, and the aqueous phase was washed with DCM (2 × 350 mL). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated in vacuo, and distilled (40 °C, 2–5 mbar) to give 2-(1-methylcyclopropyl)ethanol (106.6 g, 66%) as a clear oil. 1 H NMR (400 MHz, CDCl3)δ 3.75(t, J=7.0 Hz, 2H), 1.51(t, J=7.0 Hz, 3H), 1.04(s, 3H), 0.32-0.22(m, 4H).

[0210] Step 2: 2-(1-methylcyclopropyl)acetaldehyde [ka] 2-(1-Methylcyclopropyl)ethanol (106 g, 1.0319 mol) was added to a mixture of water (800 mL) and DCM (800 mL), followed by the sequential addition of sodium bromide (10.6 g, 103.02 mmol), sodium bicarbonate (200 g, 2.3808 mol), and TEMPO (1.6 g, 10.240 mmol). The mixture was cooled to 0 °C, and aqueous NaOCl (1.3 L of 0.8 M, 1.0400 mol) was added over 1 h (temperature = 1.0 °C to 8.2 °C). After 1 h, the mixture was filtered through Celite (0.5 parts), and the phases were separated. The aqueous phase was extracted with DCM (2 × 3.5 volumes). The combined organic phases were dried over sodium sulfate (0.5 parts) and concentrated under reduced pressure (300 mbar, bath: 30° C.) to give a slightly amber solution in DCM (101.27 g, 100%) containing 4.15% (w / w) of 2-(1-methylcyclopropyl)acetaldehyde. 1 H NMR (400 MHz, chloroform-d) δ 9.85-9.79 (m, 1H), 2.26 (d, J = 2.4 Hz, 2H), 1.13 (s, 3H), 0.45 (br d, J = 6.4 Hz, 4H).

[0211] Step 3: 3-(1-methylcyclopropyl)-2-[[(1R)-1-phenylethyl]amino]propanenitrile [ka] To a solution of 2-(1-methylcyclopropyl)acetaldehyde (101.27 g, 1.0319 mol) in MeOH (850 mL) cooled to 0 °C in an ice bath, (1R)-1-phenylethanamine (122.20 g, 130 mL, 1.0084 mol) was added portionwise (temperature increased from 3 °C to 9 °C). Acetic acid (68.640 g, 65 mL, 1.1430 mol) was added dropwise (temperature increased from 3 °C to 5 °C), followed by sodium cyanide (53 g, 1.0815 mol) added portionwise (temperature increased from 1 °C to 5 °C). The mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated under vacuum (rotary evaporator connected to a scrubber containing 6 M aqueous sodium hydroxide). To the residue was added MTBE (5 vol) and aqueous potassium carbonate (10% (w / w), 5 vol). The mixture was stirred for 5 minutes before the phases were separated. The organic layer was washed with brine (15% (w / w), 3 x 5 vol), dried over sodium sulfate (0.5 parts), and concentrated under reduced pressure to give 3-(1-methylcyclopropyl)-2-[[(1R)-1-phenylethyl]amino]propanenitrile (diastereomeric mixture 70:30, 245.86 g, 92%) as a slightly amber oil. ESI-MS m / z calculated 228.16264, found 229.2 (M+1). + ; Retention time: 2.935 min; LC method F.

[0212] Step 4: (2R)-3-(1-methylcyclopropyl)-2-[[(1R)-1-phenylethyl]amino]propanamide [ka] To a combined solution of two batches of 3-(1-methylcyclopropyl)-2-[[(1R)-1-phenylethyl]amino]propanenitrile (diastereomeric mixture 70:30, 245 g, 948.53 mmol, and 19 g, 68.899 mmol) in DMSO (1.2 L) and water (250 mL) stirred at 50 °C was added potassium carbonate (33 g, 238.77 mmol). Aqueous hydrogen peroxide (220 mL 9.8 M, 2.1560 mol) was added dropwise over 1.5 h. The mixture was stirred at 50 °C for 1 h. After the mixture was cooled to room temperature, water (5 L, 20 vol) was added. The aqueous layer was extracted with MTBE (2 × 1.5 L, 2 × 6 vol). The combined organic layers were isolated and extracted with aqueous HCl (2 × 1.5 L 1 M, 2 × 6 vol). The acidic aqueous layers were combined and gently stirred for 2 hours at 5° C. The resulting suspension was filtered and the collected solid was dried under reduced pressure at 50° C. for 2 hours to give (2R)-3-(1-methylcyclopropyl)-2-[[(1R)-1-phenylethyl]amino]propanamide (hydrochloride salt) (151.24 g, 52%) as a white powder. ESI-MS m / z calculated 246.1732, found 274.2 (M+1). + ;Retention time: 1.391 minutes. 1 H NMR (400 MHz, DMSO-d6)δ 10.04-9.89(m, 1H), 9.56-9.37(m, 1H), 8.05(s, 1H), 7.77-7.56(m, 3H), 7.47-7.3 7(m, 3H), 4.28-4.14(m, 1H), 3.45-3.28(m, 1H), 2.20-2.07(m, 1H), 1.59(d, J=6.8 Hz, 3H), 1.44(dd, J=13.4, 10.8 Hz, 1H), 0.92(s, 3H), 0.35-0.11(m, 4H); LC method F.

[0213] Sodium chloride (500 g, 2 parts) was added to the mother liquor, and the aqueous solution was stirred overnight at 5° C. The resulting suspension was filtered, and the collected solid was dried under a stream of air for 2 hours to give the isomeric mixture 3-(1-methylcyclopropyl)-2-[[(1R)-1-phenylethyl]amino]propanamide (hydrochloride salt) (89.42 g, 31%) as a white powder. ESI-MS m / z calculated 246.1732, found 247.2 (M+1)+; retention time: 1.541 min; LC method F.

[0214] Step 5: (2R)-3-(1-methylcyclopropyl)-2-[[(1R)-1-phenylethyl]amino]propanoic acid [ka] To a solution of lithium hydroxide monohydrate (324 g, 7.7210 mol) in water (5 L) was added (2R)-3-(1-methylcyclopropyl)-2-[[(1R)-1-phenylethyl]amino]propanamide (hydrochloride) (228.9 g, 809.38 mmol) at 70° C. The reaction was heated to 97° C. and stirred for 68 hours. The reaction mixture was then cooled to room temperature, neutralized to pH 6 using 3 M aqueous HCl, and the product was collected by filtration. The product was then dissolved in 0.5 M aqueous NaOH (5 L), neutralized to pH 6 using 3 M aqueous HCl, and crystallized four times. The resulting product was then dried in vacuo at 45° C. for 72 hours to yield (2R)-3-(1-methylcyclopropyl)-2-[[(1R)-1-phenylethyl]amino]propanoic acid (161.5 g, 65%) as a white solid. 1H NMR (400 MHz, DMSO-d6)δ 7.62(d, J=6.4 Hz, 2H), 7.45-7.35(m, 3H), 4.31(q, J=6.4 Hz, 1H), 3.25(dd, J=10.9, 3.8 Hz, 1H), 2.34(dd, J=13.6, 3.5 Hz, 1H), 1.61(d, J=6.6 Hz, 3H), 1.33(dd, J=13.3, 11.4 Hz, 1H), 0.82(s, 3H), 0.25-0.11(m, 4H).2H unstable missing. ESI-MS m / z calculated value 247.15723, measured value 248.2(M+1) + ; Retention time: 1.68 min; LC method F.

[0215] Step 6: (2R)-3-(1-methylcyclopropyl)-2-[[(1R)-1-phenylethyl]amino]propan-1-ol [ka] To a solution of (2R)-3-(1-methylcyclopropyl)-2-[[(1R)-1-phenylethyl]ammonio]propanoate (160 g, 523.26 mmol) in THF (3.2 L) was added LiAlH (40 g, 1.0539 mol) over 3 h at 20–25 °C. After stirring for an additional 1 h at room temperature, the reaction mixture was cooled to 10 °C, and water (38.000 g, 38 mL, 2.1093 mol) was added over 150 min. Then, NaOH (35 mL 6 M, 210.00 mmol) and water (38.000 g, 38 mL, 2.1093 mol) were added sequentially. The mixture was stirred overnight at room temperature. The reaction mixture was then filtered through a bed of Celite (top, 80 g) and magnesium sulfate (bottom, 120 g). The filter cake was washed with THF (800 mL). The combined mother liquors were concentrated in vacuo. The resulting yellowish oil was dissolved in diethyl ether (2 L), and HCl / dioxane solution (130 mL 4 M, 520.00 mmol) was added dropwise over 30 minutes to induce precipitation. After stirring at 20° C. for 1 hour, the solid was collected by filtration, washed with diethyl ether (1 L), and dried in vacuo to give (2R)-3-(1-methylcyclopropyl)-2-[[(1R)-1-phenylethyl]amino]propan-1-ol (hydrochloride salt) (126 g, 89%). 1 H NMR(400MHz,DMSO-d6)δ9.30(br.s.,1H),9.11(br.s.,1H),7.69(d,J=7.1Hz,2H),7.4 8-7.35(m,3H),5.43(t,J=5.3Hz,1H),4.56(br.s.,1H),3.79(d,J=12.5Hz,1H),3.65- 3.52(m,1H),2.89(br.s.,1H),1.82(dd,J=13.7,2.2Hz,1H),1.62(d,J=6.6Hz,3H),1. 26(dd,J=13.7,11.2Hz,1H),0.72(s,3H),0.41-0.27(m,1H),0.24-0.06(m,3H).ESI-MS m / z calculated value 233.17796, actual value 234.2(M+1) + ; Retention time: 1.82 min; LC method F.

[0216] Step 7: (2R)-2-Amino-3-(1-methylcyclopropyl)propan-1-ol [ka] A solution of (2R)-3-(1-methylcyclopropyl)-2-[[(1R)-1-phenylethyl]amino]propan-1-ol (hydrochloride) (125 g, 463.29 mmol) in ethanol (1.5 L) was added to palladium on carbon (25 g, 5% (w / w), 11.746 mmol). The reaction vessel was purged with nitrogen and then filled with hydrogen (75 psi), and the reaction was stirred at 50° C. for 24 h. The mixture was filtered through a 0.45 μm Pall filter, washing with EtOH (2×500 mL), and the filtrate was concentrated in vacuo. The resulting white solid was triturated with MTBE (625 mL) for 1 h, then filtered, washed with MTBE (500 mL), and dried in vacuo to give (2R)-2-amino-3-(1-methylcyclopropyl)propan-1-ol (hydrochloride salt) (71.78 g, 93%) as a white solid. 1 H NMR (400 MHz, DMSO-d6)δ 7.98(br.s., 3H), 5.30(t, J=4.9 Hz, 1H), 3.69(dt, J=11.4, 3.6 Hz, 1H), 3.47(dt, J=11.5, 5.7 Hz, 1H), 3.29-3.16(m, 1H), 1.62(dd, J=13.9, 5.9 Hz, 1H), 1.35(dd, J=13.9, 8.6 Hz, 1H), 1.01(s, 3H), 0.41-0.19(m, 4H).ESI-MS m / z Calculated value 129.11537, actual value 130.2 (M+1) + ; Retention time: 0.34 min; LC method F.

[0217] Example 10: Preparation of 3-[[4-[(2R)-2-amino-4-fluoro-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid Step 1: (3R)-3-(tert-butoxycarbonylamino)-4-hydroxy-butanoate benzyl [ka] A stirred solution of (2R)-4-benzyloxy-2-(tert-butoxycarbonylamino)-4-oxobutanoic acid (20 g, 61.854 mmol) was dissolved in tetrahydrofuran (200 mL) and then cooled to −50° C. N-methylmorpholine (7.5440 g, 8.2 mL, 74.585 mmol) was then added, followed by isobutyl chloroformate (10.185 g, 9.7 mL, 74.573 mmol). The reaction was stirred at −50° C. for 2 hours, after which the reaction was filtered and the filtrate was cooled to −10° C. Sodium borohydride (3.50 g, 92.513 mmol) was added, and the reaction was allowed to reach room temperature and stirred at room temperature for 4 hours. The reaction was quenched at 0° C. by the dropwise addition of water (200 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (5 x 150 mL). The combined organic layers were washed with brine (250 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give crude (3R)-3-(tert-butoxycarbonylamino)-4-hydroxy-benzyl butanoate (17.857 g, 49%) as a thick, translucent oil, which was used in the next step without further purification. ESI-MS m / z calculated 309.1576, found 332.2 (M+23); 210.2 (M-99). + ; Retention time: 1.7 min; LC method I.

[0218] Step 2: Benzyl 2-[(4R)-2-oxooxazolidin-4-yl]acetate [ka] To a stirred solution of crude benzyl (3R)-3-(tert-butoxycarbonylamino)-4-hydroxybutanoate (17.9 g, 30.667 mmol) in anhydrous 1,2-dichloroethane (140 mL) under a nitrogen atmosphere, pyridine (23.472 g, 24 mL, 296.74 mmol) and methanetoluenesulfonic anhydride (10 g, 57.407 mmol) were added sequentially at 0 °C under a nitrogen atmosphere. The reaction was stirred at 0 °C for 15 minutes, then at room temperature for 2 hours, and finally at 90 °C overnight. The reaction was then cooled to room temperature, diluted with dichloromethane (140 mL), and quenched by the addition of 1 N aqueous hydrochloric acid (400 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (4 × 100 mL). The combined organic layers were washed with brine (250 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a yellow oil that was purified by flash chromatography on silica gel using a 120 g HP Gold column eluting with an ethyl acetate / heptane gradient (15 to 100% over 15 CV). The desired fractions were concentrated under reduced pressure and dried under vacuum to give benzyl 2-[(4R)-2-oxooxazolidin-4-yl]acetate (5.01 g, 68%) as an off-white powder. 1 H NMR (400 MHz, CDCl3)δ 7.48-7.30(m, 5H), 5.49(br.s, 1H), 5.16(s, 2H), 4.56(t, J=8.6 Hz, 1H), 4.32-4.18(m, 1H), 4.06(dd, J=8.9, 5.7 Hz, 1H), 2.78-2.62(m, 2H).ESI-MS m / z calculated value 235.08446, actual value 236.2(M+1) + ; Retention time: 1.51 min; LC method I.

[0219] Step 3: (4R)-4-(2-hydroxy-2-methyl-propyl)oxazolidin-2-one [ka] The flask was flame-dried, then cooled to room temperature with a stream of nitrogen, and then charged with anhydrous toluene (30 mL) and anhydrous tetrahydrofuran (30 mL). The solvent mixture was then cooled to -50°C. A solution of methylmagnesium bromide in diethyl ether (29 mL of 3 M, 87.000 mmol) was cannulated into the mixture and stirred at -50°C for 30 minutes, after which a solution of 2-[(4R)-2-oxooxazolidin-4-yl]benzyl acetate (5.01 g, 18.678 mmol) in anhydrous tetrahydrofuran (15 mL) was cannulated. The reaction was stirred at -50°C for 30 minutes, then allowed to reach room temperature and stirred overnight at room temperature. The reaction was then cooled to 0°C and quenched by the dropwise addition of a solution of acetic acid (7.9200 g, 7.5 mL, 131.89 mmol) in water (20 mL). The reaction mixture was stirred vigorously at room temperature for 1 hour. Sodium chloride was then added to saturate the aqueous layer. The reaction was then dried over sodium sulfate and filtered through a pad of Celite. The filter cake was washed with dichloromethane (5 × 100 mL), and the filtrate was concentrated under reduced pressure to give a yellow oil, which was purified by flash chromatography on silica gel using a 120 g HP Gold column eluting with an isopropanol / dichloromethane gradient (0-6% over 20 CV). The desired fractions were concentrated under reduced pressure and dried under high vacuum to give (4R)-4-(2-hydroxy-2-methyl-propyl)oxazolidin-2-one (2.02 g, 65%) as a pale yellow crystalline solid. 1 H NMR (400 MHz, DMSO-d6)δ 7.34(br.s, 1H), 4.50-4.26(m, 2H), 4.06-3.88(m, 2H), 1.78-1.48(m, 2H), 1.10(s, 6H).ESI-MS m / z Calculated value 159.08954, actual value 160.2 (M+1) + ; Retention time: 0.74 min; LC method I.

[0220] Step 4: (4R)-4-(2-fluoro-2-methyl-propyl)oxazolidin-2-one [ka] A solution of (4R)-4-(2-hydroxy-2-methyl-propyl)oxazolidin-2-one (4.29 g, 25.603 mmol) in anhydrous dichloromethane (25 mL) was cannulated into a stirred solution of (diethylamino)sulfur trifluoride (4.1480 g, 3.4 mL, 25.734 mmol) in anhydrous dichloromethane (70 mL) at −78° C. The resulting solution was stirred at −78° C. for 15 minutes, then allowed to reach room temperature and stirred at room temperature for 2 hours. The reaction was then slowly added to saturated aqueous sodium bicarbonate (500 mL) at 0° C. The solution was then vigorously stirred at room temperature for 30 minutes. The layers were separated, and the aqueous layer was extracted with dichloromethane (4 × 150 mL). The combined organic layers were washed with water (200 mL), brine (200 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give crude (4R)-4-(2-fluoro-2-methyl-propyl)oxazolidin-2-one (3.51 g, 81%) as brown crystals, which were used directly in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 7.56 (br.s, 1H), 4.44 (td, J=8.2, 1.0 Hz, 1H), 4.06-3.97(m, 1H), 3.95-3.88(m, 1H), 1.93-1.80(m, 2H), 1.35(s, 3H), 1.30(s, 3H).ESI-MS m / z Calculated value 161.0852, Actual value 162.2(M+1) + ; Retention time: 1.28 min; LC method I.

[0221] Step 5: (2R)-2-Amino-4-fluoro-4-methyl-pentan-1-ol [ka] To a solution of potassium hydroxide (2.5 g, 44.559 mmol) in ethanol (15 mL) and water (1.5 mL) was added (4R)-4-(2-fluoro-2-methyl-propyl)oxazolidin-2-one (2.3 g, 13.557 mmol). The reaction mixture was heated at 100° C. for 4 hours. The reaction mixture was then allowed to reach room temperature and concentrated under reduced pressure. The residue was coevaporated with toluene (3×10 mL) to give a pale orange residue, which was filtered through a pad of Celite and washed with dichloromethane (3×20 mL). The filtrate was concentrated under reduced pressure to give (2R)-2-amino-4-fluoro-4-methyl-pentan-1-ol (1.82 g, 94%) as a dark orange oil, which was used directly in the next step without further purification. 1 H NMR(400MHz,CD3OD)δ3.50(dd,J=10.6,4.8Hz,1H),3.35-3.27(m,1H),3.17-3.09(m,1H),1.77-1.59(m,2H),1.42(s,3H),1.37(s,3H).19F NMR(377MHz,CD3OD)δ-139.34(s,1F).ESI-MS m / z calculated value 135.10594, measured value 136.2(M+1) + ; Retention time: 0.23 min; LC method I.

[0222] Step 6: 3-[[4-[(2R)-2-amino-4-fluoro-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [ka] 3-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (1 g, 2.393 mmol) and (2R)-2-amino-4-fluoro-4-methyl-pentan-1-ol (391 mg, 2.892 mmol) were combined in anhydrous THF (9 mL) under nitrogen. To the resulting cloudy solution, sodium tert-butoxide (1.05 g, 10.93 mmol) was added in one portion, resulting in dissolution of the solid and a slightly exothermic reaction. The mixture was stirred at room temperature for 2.5 h. The reaction was diluted with ethyl acetate (20 mL), HCl (20 mL 1 M, 20.00 mmol), and brine (20 mL), and the resulting two phases were separated. The aqueous phase was further extracted with EtOAc (3 × 15 mL). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was triturated with a mixture of EtOAc and hexane (1:3 (v:v)), and the resulting suspension was stirred at room temperature overnight. The solid was filtered and dried to give 3-[[4-[(2R)-2-amino-4-fluoro-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride) (1.238 g, 94%) as a tan solid. ESI-MS m / z calculated 516.18427, found 517.45 (M+1). + ; Retention time: 0.99 min; LC method A.

[0223] Example 11: Preparation of 3-[[4-[(2R)-2-amino-5-methyl-hexoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid Step 1: (2R)-2-amino-5-methyl-hexan-1-ol [ka] Borane tetrahydrofuran complex / THF solution (58 mL 1 M, 58.000 mmol) was slowly added to a suspension of (2R)-2-amino-5-methyl-hexanoic acid (4.05 g, 27.893 mmol) in 2-methyltetrahydrofuran (40 mL). The reaction was stirred at room temperature for 16 hours. Aqueous HCl (28 mL 3 M, 84.00 mmol) was added while maintaining the temperature below 25°C, and the reaction was stirred at room temperature for 45 minutes. MeTHF (100 mL) was added, and excess THF was removed by evaporation. The solution was basified to pH 9 with 25% aqueous NaOH (10 mL). The organic phase was separated. The aqueous layer was extracted with MeTHF (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Aqueous HCl (14 mL 3 M, 42.000 mmol) was added to the residue, and the water was evaporated to dryness, followed by coevaporation with isopropanol (3 × 50 mL). MTBE (100 mL) was added to the residue, and the solvent was evaporated to dryness to give (2R)-2-amino-5-methyl-hexan-1-ol (hydrochloride) (2.231 g, 48%) as a white solid. 1 H NMR (400 MHz, DMSO-d6)δ 7.82(br.s., 3H), 5.26(t, J=4.9 Hz, 1H), 3.58(dt, J=11.2, 4.4 Hz, 1H), 3.42(dt, J=11.3, 5.7 Hz, 1H), 3.00(br.s., 1H), 1.57-1.43(m, 3H), 1.25-1.15(m, 2H), 0.86(d, J=6.1 Hz, 6H).ESI-MS m / z Calculated value 131.131, Actual value 132.2(M+1) +Retention time: 2.022 min. To the aqueous phase, 25% aqueous NaOH (3 mL) was added, and the aqueous layer was extracted with MeTHF (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Aqueous HCl (14 mL 3 M, 42.000 mmol) was added to the residue, and the water was evaporated to dryness, followed by coevaporation with isopropanol (3 × 50 mL). MTBE (100 mL) was added to the residue, and the solvent was evaporated to dryness to give a second batch of (2R)-2-amino-5-methyl-hexan-1-ol (hydrochloride salt) (2.227 g, 45%) as a white solid. 1 H NMR (400 MHz, DMSO-d6)δ 7.94(br.s., 3H), 5.27(t, J=5.0 Hz, 1H), 3.58(dt, J=11.4, 4.3 Hz, 1H), 3.43(dt, J=11.5, 5.7 Hz, 1H), 3.06-2.93(m, 1H), 1.58-1.43(m, 3H), 1.25-1.15(m, 2H), 0.86(d, J=6.4 Hz, 6H).ESI-MS m / z Calculated value 131.131, Actual value 132.2(M+1) + Retention time: 1.994 min. Total weight 4.458 g and overall yield 95%. LC method K.

[0224] Step 2: 3-[[4-[(2R)-2-amino-5-methyl-hexoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [ka] 3-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (1.1 g, 2.632 mmol) and (2R)-2-amino-5-methyl-hexan-1-ol (hydrochloride) (538 mg, 3.209 mmol) were combined in anhydrous THF (10 mL) under nitrogen. To the resulting cloudy solution, sodium tert-butoxide (1.01 g, 10.51 mmol) was added in one portion, resulting in rapid dissolution of the solid and a slightly exothermic reaction. The mixture was stirred at room temperature for 1 hour. Additional (2R)-2-amino-5-methyl-hexan-1-ol (hydrochloride) (86 mg, 0.5129 mmol) and sodium tert-butoxide (sodium salt) (140 mg, 1.457 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. The reaction was diluted with ethyl acetate (20 mL), HCl (20 mL 1M, 20.00 mmol), and brine (20 mL), and the resulting two phases were separated. The aqueous phase was further extracted with EtOAc (3×15 mL). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was triturated with a mixture of EtOAc and hexanes (1:3 (v:v)), and the resulting suspension was stirred at room temperature for 1 h. The solid was filtered and dried to give 3-[[4-[(2R)-2-amino-5-methyl-hexoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) (1.32 g, 82%) as an off-white solid. ESI-MS m / z calculated 512.20935, found 513.59 (M+1). + ; Retention time: 1.1 min; LC method A.

[0225] Example 12: Preparation of 3-[[4-[(2R)-2-amino-4-cyclopropyl-butoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid Step 1: (2R)-2-(benzyloxycarbonylamino)hex-5-enoic acid methyl ester [ka] (2R)-2-Aminohex-5-enoic acid (2 g, 15.485 mmol) was mixed with MeOH (40 mL) and cooled in an acetone-dry ice bath at approximately -10 °C. Thionyl chloride (4.0775 g, 2.5 mL, 34.273 mmol) was added dropwise. The clear mixture was then allowed to warm to room temperature and stirred for 24 h. It was then concentrated. The resulting off-white solid was taken up in DCM (30 mL) and water (15 mL) and cooled in an ice-water bath. Sodium bicarbonate (8.6 g, 102.37 mmol) was added, followed by CbzOSu (4.68 g, 18.779 mmol). The yellowish mixture was stirred efficiently for 15 h (during which time the ice bath temperature reached room temperature). DCM and water (50 mL each) were added. The layers were separated. The DCM solution was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (80 g column) using 5-40% EtOAc / hexanes to give methyl (2R)-2-(benzyloxycarbonylamino)hex-5-enoate (4.23 g, 94%) as a colorless oil. ESI-MS m / z calculated 277.1314, found 278.3 (M+1). + ; Retention time: 2.86 min; LC method E.

[0226] Step 2: (2R)-2-(benzyloxycarbonylamino)-4-cyclopropyl-butanoate methyl ester [ka] A solution of EtZn / hexane (50 mL 1M, 50.000 mmol) was diluted with DCM (25 mL) and cooled to approximately -10 °C. A solution of TFA (5.7720 g, 3.9 mL, 50.621 mmol) in DCM (10 mL) was added dropwise. The mixture was stirred at <0 °C for 15 min. CHCl in DCM (25 mL) 2(A solution of (2R)-2-(benzyloxycarbonylamino)hex-5-enoate (12.968 g, 3.9 mL, 48.418 mmol) was added in small portions. The mixture was stirred at the same temperature for 15 minutes. Then, a solution of (2R)-2-(benzyloxycarbonylamino)-4-cyclopropyl-butanoate (3.9 g, 13.360 mmol) in DCM (25 mL) was added in small portions. The mixture was stirred for 15 hours (gradually reaching room temperature). HCl (0.2 N aqueous solution) was added in small portions (40 mL total). Additional DCM (60 mL) was added. The layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residual oil was purified by silica gel chromatography (80 g column) using 0–40% EtOAc / hexanes to give methyl (2R)-2-(benzyloxycarbonylamino)-4-cyclopropyl-butanoate (3.65 g, 89%) as a colorless oil. 1 H NMR(500 MHz,chloroform-d)δ 7.43-7.28(m, 5H), 5.31-5.20(m, 1H), 5.11(s, 2H), 4.49-4.35(m, 1H), 3.74(s, 3H), 2.02-1.86(m, 1H), 1.83-1.67(m, 1H), 1.32-1.19(m, 2H), 0.77-0.59(m, 1H), 0.52-0.35(m, 2H), 0.09--0.04(m, 2H).ESI-MS m / z calculated value 291.14706, measured value 292.5(M+1) + ; Retention time: 3.01 min; LC method E.

[0227] Step 3: Benzyl N-[(1R)-3-cyclopropyl-1-(hydroxymethyl)propyl]carbamate [ka] Methyl (2R)-2-(benzyloxycarbonylamino)-4-cyclopropylbutanoate (3.94 g, 12.847 mmol) was dissolved in THF (40 mL), and the solution was cooled in an ice-water bath and stirred under a nitrogen balloon. LiBH4 / THF solution (12 mL 2 M, 24.000 mmol) was added in small portions over 10 minutes. The ice bath was removed, and the mixture was stirred at room temperature for 2 hours. NH4Cl (20 mL, saturated aqueous solution) was added, followed by EtOAc (50 mL) and water (40 mL). The layers were separated. The organic layer was washed with additional water (30 mL × 2), brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to give crude benzyl N-[(1R)-3-cyclopropyl-1-(hydroxymethyl)propyl]carbamate (3.75 g, 100%) as a colorless oil. ESI-MS m / z calculated 263.15213, observed 264.4 (M+1) + ; Retention time: 2.65 min; LC method E.

[0228] Step 4: (2R)-2-Amino-4-cyclopropyl-butan-1-ol [ka] Benzyl N-[(1R)-3-cyclopropyl-1-(hydroxymethyl)propyl]carbamate (3.75 g, 12.817 mmol) was dissolved in EtOH (60 mL). Aqueous HCl (12.9 mL 1 M, 12.900 mmol) was added, followed by Pd-activated carbon (300 mg, 5% (w / w), 0.1410 mmol). The mixture was evacuated, refilled with a H2 balloon, and stirred at room temperature for 4 hours. It was then filtered through a Celite pad and washed with MeOH. The combined filtrate was concentrated to give (2R)-2-amino-4-cyclopropyl-butan-1-ol (hydrochloride salt) (2.15 g, 96%) as a colorless oil. ESI-MS m / z calculated 129.11537, found 130.4 (M+1). + ; Retention time: 1.09 min; LC method E.

[0229] Step 5: 3-[[4-[(2R)-2-amino-4-cyclopropyl-butoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [ka] 3-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (3 g, 7.1793 mmol) and (2R)-2-amino-4-cyclopropyl-butan-1-ol (hydrochloride) (2.15 g, 12.329 mmol) were mixed in THF (20 mL) at room temperature. Sodium t-butoxide (2.8 g, 29.135 mmol) was added in one portion. The mixture was stirred at room temperature for 1 hour. Additional sodium t-butoxide (1.4 g, 14.568 mmol) was added. The mixture was stirred at room temperature for 2 hours. Aqueous HCl (60 mL 1 M, 60.000 mmol) was added, followed by EtOAc (60 mL). The layers were separated. The aqueous layer was extracted with additional EtOAc (20 mL). The combined EtOAc solution was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was retaken in EtOAc (approximately 20 mL) and sonicated briefly. The supernatant was discarded. The precipitate was dissolved in THF, transferred to a shipping vial, and dried under high vacuum for 20 hours to give 3-[[4-[(2R)-2-amino-4-cyclopropyl-butoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride) (4.14 g, 95%) as a slightly yellowish solid. 1H NMR (500 MHz, DMSO-d6)δ 13.20(s, 1H), 8.44(s, 1H), 8.28-8.05(m, 5H), 7.69(t, J=.8, 7.8Hz, 1H), 7.25(t, J=7.6, 7.6 Hz, 1H), 7.12(d, J=7.6 Hz, 2H), 6.30(s, 1H), 4.36(dd, J=11.8, 3.3 Hz,1H), 4.21(dd, J=11.8, 6.6 Hz, 1H), 3.57-3.48(m, 1H), 1.99(d, J=8.5 Hz, 6H), 1.72-1.63(m, 2H), 1.33-1.19(m, 2H), 0.77-0.61(m, 1H), 0.47-0.34(m, 2H), 0.08--0.01(m, 2H).ESI-MS m / z Calculated value 510.1937, actual value 511.8 (M+1) + ; Retention time: 1.78 min; LC method H.

[0230] Example 13: 3-[[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonimidoyl]benzoic acid, isomer A Step 1: Methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfanylbenzoate [ka] A 500 mL single-necked round-bottom flask was charged with methyl 3-[(3-methoxycarbonylphenyl)disulfanyl]benzoate (26.5 g, 79.244 mmol), dichloromethane (167 mL), and pyridine (2.9340 g, 3 mL, 37.092 mmol) under a N atmosphere. To the resulting amber solution, sulfuryl chloride (10.7 g, 79.277 mmol) was added dropwise (no exotherm was observed). The solution turned deep orange and was stirred at room temperature for 10 minutes. A separate 2 L three-necked round-bottom flask was charged with 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (25.95 g, 111.04 mmol) and dichloromethane (618 mL) under a N atmosphere. The resulting pale yellow solution was cooled to 2 °C (internal temperature) using an ice bath. Triethylamine (47.335 g, 65.2 mL, 467.78 mmol) was then added dropwise, while maintaining the internal temperature below 10° C. When this solution again reached 2° C., the first solution was added dropwise, while maintaining the internal temperature below 10° C. (Exothermic). The resulting pale orange suspension was stirred at 2° C. for 1 h (the ice bath was not removed). The reaction was poured into 5 wt % aqueous sodium bicarbonate solution (585 mL, 63 vol). After phase separation, the aqueous phase was extracted with DCM (3×50 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated to dryness to give the crude product (76.54 g) as an amber viscous oil. The oil was mixed with silica gel (80 g, 1 part relative to the crude) and DCM. The suspension was concentrated to dryness to give a fine orange powder. The dry pack was loaded onto silica gel (460 g, 6 parts relative to the crude material) packed with heptane in a fritted glass. Elution began with 80 / 20 heptane / EtOAc (1 L), followed by 70 / 30 (5 L). The filtrate (light yellow) was concentrated to dryness. During concentration, a fine white solid formed. The solid was suspended in 50 mL of 95 / 5 heptane / EtOAc, cooled in an ice bath, and filtered. The off-white solid was washed with 50 mL of cold 95 / 5 heptane / EtOAc and dried under high vacuum to give methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfanylbenzoate (26.46 g, 83%) as a white powder.1 H NMR (400 MHz, CDCl3)δ 7.90-7.87(m, 1H), 7.84(dt, J=7.3, 1.6 ESI-MS m / z Calculated value 399.0808, actual value 400.0 (M+1) + ; Retention time: 2.018 min; LC method I.

[0231] Step 2: Methyl 3-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfinamoylbenzoate [ka] A 500 mL three-necked round-bottom flask equipped with an internal temperature probe was charged with methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfanylbenzoate (26 g, 65.017 mmol) and dichloromethane (624 mL) under a N atmosphere. The resulting pale yellow solution was cooled to 2 °C (internal temperature) using an ice bath. 3-Chloroperbenzoic acid (15.6 g, 69.608 mmol) was then added portionwise while maintaining the internal temperature below 5 °C (slight exotherm). The resulting pale yellow suspension was stirred at 2 °C for 1 h. A 5 wt % aqueous solution of NaSO (520 mL, 20 vol) was added to the reaction mixture. An exotherm was observed, and the internal temperature reached 10 °C. The mixture was poured into 5 wt % aqueous sodium bicarbonate (520 mL, 20 vol). After phase separation, the aqueous phase was extracted with DCM (3 × 100 mL). The combined organic phases were dried over sodium sulfate and concentrated to dryness to give the crude product as a yellow oil. The oil was mixed with heptane / EtOAc (95 / 5) (200 mL) and sonicated to give a white slurry. The slurry was stirred at room temperature for 30 minutes. The solid was collected by filtration, washed with cold heptane / EtOAc (95 / 5) (100 mL), and dried under high vacuum to give methyl 3-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfinamoylbenzoate (22.76 g, 84%) as a white powder. 1 H NMR (400 MHz, CDCl3)δ 8.48(t, J=1.7 Hz, 1H), 8.25(dt, J=7.7, 1.4 Hz, 1H), 8.07(dt, J=7.8, 1.5 Hz, 1H), 7.67(t, J=7.7 ESI-MS m / z Calculated value 415.07574, actual value 416.0 (M+1) + ; Retention time: 1.906 min; LC method I.

[0232] Step 3: Methyl 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonimidoyl]benzoate [ka] A 3 L three-necked round-bottom flask equipped with an addition funnel and an internal temperature probe was charged with methyl 3-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfinamoylbenzoate (22.5 g, 54.100 mmol) and dichloromethane (833 mL) under a N atmosphere. To the resulting pale yellow solution was added 1-chloropyrrolidine-2,5-dione (10.11 g, 75.712 mmol) in small portions. The milky mixture was stirred at room temperature for 7 hours. The reaction was then cooled to 0 °C (ice bath) and ammonia (0.4 M in dioxane) (1.2 L, 0.4 M, 480.00 mmol) was added dropwise over 35 minutes. The reaction was stirred overnight at room temperature. The reaction was poured into a 1:1 mixture of 5 wt % aqueous sodium bicarbonate / brine (1 L). After phase separation, the aqueous phase was extracted with DCM (3 x 150 mL). The combined organic phases were washed with brine (250 mL), dried over sodium sulfate, filtered, and concentrated to dryness to give the crude product as a yellow oil. The oil was dissolved in EtOAc and concentrated to dryness. A mixture of 95 / 5 heptane / EtOAc was added (resulting in a white solid) and the solvent was concentrated to dryness. The solid was triturated with 95 / 5 heptane / EtOAc (200 mL). The white solid was collected by filtration as an off-white powder. 1Methyl 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonimidoyl]benzoate (23.399 g, 81%) was obtained, containing approximately 15% by weight succinimide by H NMR. Methyl 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonimidoyl]benzoate (23.399 g, 49.577 mmol) was dissolved in EtOAc (250 mL) by sonication at 40 °C. The organic phase was washed with saturated aqueous sodium bicarbonate (2 × 100 mL). The aqueous phase was back-washed with EtOAc (100 mL). The combined organic phases were washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give methyl 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonimidoyl]benzoate (21.98 g, 97%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3)δ 8.69(t, J=1.8 Hz, 1H), 8.28(ddd, J=8.0, 1.9, 1.1 Hz, 1H), 8.23(dt, J=7.9, 1.3 Hz, 1H), 7.56(t, J=7.8 Hz, 1H), 7.21-7.15(m, 1H), 7.04(d, J=7.6 Hz, 2H), 6.74(s, 1H), 6.00(br.s., 2H), 3.90(s, 3H), 2.02-1.84(m, 6H).ESI-MS m / z Calculated value 430.08664, actual value 431.1 (M+1) + ;Retention time: 3.975 minutes;LC method J.

[0233] Step 4: Methyl 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonimidoyl]benzoate, Isomer A, and Methyl 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonimidoyl]benzoate, Isomer B [ka] Racemic methyl 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonimidoyl]benzoate (21.98 g, 47.948 mmol) was dissolved in a 1:1 mixture of MeOH / MeCN (concentration: 1.2 g / 25 mL) and subjected to chiral SFC separation (flow rate: 75 mL / min, 15% MeOH, column: Cellulose 1, temperature = 40 °C, outlet pressure: 100 bar, injection volume: 600 μL). The fastest eluting peak by SFC gave methyl 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonimidoyl]benzoate, Isomer A (8.38 g, 78%) as a pale yellow solid after evaporation to dryness and coevaporation with 2-methyltetrahydrofuran. 1 H NMR (400 MHz, DMSO-d6)δ 8.39(t, J=1.6 Hz, 1H), 8.15-8.07(m, 2H), 7.89(s, 2H), 7.67(t, J=7.8 Hz, 1H), 7.22-7.15(m, 1H), 7.03(d, J=7.6 Hz, 2H), 6.91(s, 1H), 3.83(s, 3H), 1.93-1.51(m, 6H).ESI-MS m / z calculated value 430.0866, actual value 431.1(M+1) + retention time: 3.99 min. The slowest eluting peak by SFC gave, after evaporation to dryness and co-evaporation with 2-methyltetrahydrofuran, methyl 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonimidoyl]benzoate, Isomer B (8.52 g, 76%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.38(t,J=1.6Hz,1H),8.14-8.07(m,2H),7.89(s,2H),7.67(t,J=7.8Hz,1 ESI-MS m / z calculated value 430.0866, measured value 431.1(M+1) + ;Retention time: 3.99 minutes;LC method J.

[0234] Step 5: 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonimidoyl]benzoic acid, isomer A [ka] To a solution of methyl 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonimidoyl]benzoate, Isomer A (8.38 g, 18.125 mmol) in tetrahydrofuran (170 mL) and water (170 mL) was added lithium hydroxide hydrate (1.9 g, 45.277 mmol) at 0 °C. The resulting pale yellow solution was stirred at room temperature for 16 h. The reaction mixture was diluted with saturated aqueous NH4Cl (250 mL) and some 1 N HCl to bring the pH to 4. The product was extracted with EtOAc (3×150 mL) and the combined organic phases were washed with brine (200 mL), dried over magnesium sulfate, filtered and concentrated to dryness to give 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonimidoyl]benzoic acid, Isomer A (7.82 g, 96%) as a pale beige solid. 1 H NMR (400 MHz, DMSO-d6)δ 8.44(br.s., 1H), 8.11(br.s., 1H), 7.93(d, J=7.6 Hz, 1H), 7.72(br.s., 2H), 7.53(t, J=7.6 Hz, 1H), 7.21-7.11(m, 1H), 7.02(d, J=6.8 Hz, 2H), 6.88(s, 1H), 1.77(br.s., 6H).ESI-MS m / z Calculated value 416.07098, Actual value 417.1(M+1) + ; Retention time: 3.57 min; LC method J.

[0235] Step 6: 3-[[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonimidoyl]benzoic acid, isomer A [ka] 3-[[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonimidoyl]benzoic acid, Isomer A (4 g, 8.5012 mmol) was dissolved in 2-MeTHF (36 mL) and DMF (4 mL). The reaction mixture was cooled to 0° C., and sodium tert-butoxide (4.8 g, 49.946 mmol) was added, followed by (2R)-2-amino-4,4-dimethyl-pentan-1-ol (hydrochloride) (1.8 g, 10.735 mmol). The reaction was then warmed to room temperature and stirred for 5.5 hours. Additional sodium tert-butoxide (817 mg, 8.5013 mmol) was added, and the reaction mixture was stirred at room temperature for 15 minutes. The reaction was cooled to 0° C. and quenched by the addition of aqueous hydrochloric acid (2 M, 60 mL). The reaction mixture was allowed to stand at room temperature overnight, after which the mixture was evaporated to dryness and the residue was purified by 120 g C using a 10-100% MeCN / acidified water (0.1% HCl) gradient. 18 Two purifications by reverse-phase chromatography on an Aq cartridge gave, after lyophilization, 3-[[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonimidoyl]benzoic acid (hydrochloride), Isomer A (2.24 g, 46%) as a pale beige solid. 1 H NMR (400 MHz, DMSO-d6)δ 8.62-8.31(m, 5H), 8.30-8.21(m, 2H), 7.83(t, J=7.8 Hz, 1H), 7.38-7.30(m, 1H), 7.19(d, J=7.6 Hz, 2H), 6.55(br.s., 1H), 4.48(d, J=12.0 Hz, 1H), 3.80(dd, J=11.6, 7.5 Hz, 1H), 3.53(br.s., 1H), 2.08(br.s, 6H), 1.52(d, J=5.6 Hz, 2H), 0.92(s, 9H).ESI-MS m / z Calculated value 511.2253, measured value 512.2 (M+1) + ; Retention time: 2.11 min; LC method J.

[0236] Example 14: Preparation of 3-[[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonimidoyl]benzoic acid, isomer B Step 1: 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonimidoyl]benzoic acid, isomer B [ka] To a solution of methyl 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonimidoyl]benzoate, Isomer B (8.52 g, 17.637 mmol) in tetrahydrofuran (170 mL) and water (170 mL) was added lithium hydroxide hydrate (1.85 g, 44.086 mmol) at 0 °C. The resulting pale yellow solution was stirred at room temperature for 16 h. The reaction mixture was diluted with saturated aqueous NH4Cl (200 mL) and some 1 N HCl (approximately 30 mL) to bring the pH to 4. The product was extracted with EtOAc (3×200 mL) and the combined organic phases were washed with brine (200 mL), dried over magnesium sulfate, filtered and concentrated to dryness to give 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonimidoyl]benzoic acid, Isomer B (7.62 g, 96%) as a beige solid. 1 H NMR (400 MHz, DMSO-d6)δ 8.42(br.s., 1H), 8.10(d, J=6.8 Hz, 1H), 7.95(d, J=7.8 Hz, 1H), 7.74(br.s., 2H), 7.55(t, J=7.7 Hz, 1H), 7.20-7.13(m, 1H), 7.03(d, J=7.3 Hz, 2H), 6.89(s, 1H), 1.95-1.56(m, 6H).ESI-MS m / z calculated value 416.07098, measured value 417.1(M+1) + ; Retention time: 3.58 min; LC method J.

[0237] Step 2: 3-[[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonimidoyl]benzoic acid, isomer B [ka] 3-[[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonimidoyl]benzoic acid, Isomer B (3.97 g, 8.4279 mmol) was dissolved in 2-MeTHF (36 mL) and DMF (4 mL). The reaction mixture was cooled to 0° C., and sodium tert-butoxide (4.05 g, 42.142 mmol) was added, followed by (2R)-2-amino-4,4-dimethyl-pentan-1-ol (hydrochloride) (1.7 g, 10.139 mmol). The reaction was then warmed to room temperature and stirred for 6 hours. Additional sodium tert-butoxide (2 g, 20.811 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction was cooled to 0° C. and quenched by the addition of aqueous hydrochloric acid (2 M, 70 mL). The mixture was evaporated to dryness and the residue was purified by 120 g C using a 5-100% MeCN / acidified water (0.1% HCl) gradient. 18 Two purifications by reverse-phase chromatography on an Aq cartridge gave, after lyophilization, 3-[[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonimidoyl]benzoic acid (hydrochloride), isomer B (2.13 g, 45%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6)δ 8.55-8.33(m, 5H), 8.29-8.20(m, 2H), 7.82(t, J=7.8 Hz, 1H), 7.36-7.29(m, 1H), 7.18(d, J=7.6 Hz, 2H), 6.53(br.s., 1H), 4.32(dd, J=11.7, 7.6 Hz, 1H), 3.96(d, J=11.5 Hz, 1H), 3.49(br.s., 1H), 2.07(br.s., 6H), 1.58-1.47(m, 2H), 0.93(s, 9H).ESI-MS m / z Calculated value 511.2253, measured value 512.3 (M+1)+ ; Retention time: 2.13 min; LC method J.

[0238] Example 15 Preparation of 3-[[4-[(2R)-2-amino-3-(1-methylcyclobutyl)propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid Step 1: N-Methoxy-N,1-dimethyl-cyclobutanecarboxamide [ka] To a solution of 1-methylcyclobutanecarboxylic acid (18 g, 157.70 mmol) in DMF (200 mL) was added N-methoxymethanamine hydrochloride (31 g, 317.81 mmol), followed by HATU (70 g, 184.10 mmol) and triethylamine (50.820 g, 70 mL, 502.22 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes and then at room temperature for 18 hours. Water (400 mL) and EtOAc (400 mL) were added, and the mixture was extracted with EtOAc (3 x 200 mL), washed with 1N aqueous HCl (2 x 400 mL), saturated aqueous sodium bicarbonate (2 x 400 mL), water (2 x 400 mL), and brine (2 x 400 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give N-methoxy-N,1-dimethyl-cyclobutanecarboxamide (20.5 g, 75%) as a yellow oil. ESI-MS m / z calculated 157.11028, found 158.4 (M+1). + ; Retention time: 1.49 min; LC method I.

[0239] Step 2: 1-Methylcyclobutanecarbaldehyde [ka] A solution of N-methoxy-N,1-dimethyl-cyclobutanecarboxamide (20 g, 115.01 mmol) in dry dioxane (100 mL) was added to a suspension of LAH (6.5 g, 171.26 mmol) in dry dioxane (200 mL) at 0 °C. The mixture was stirred at 0 °C for 5 minutes and then at room temperature for 2 hours. The mixture was then cooled to 0 °C, and water (6.5 mL) was added, followed by aqueous NaOH (15%, 6.5 mL), followed by water (19.5 mL). The mixture was stirred at room temperature for 30 minutes, and magnesium sulfate (10 g) was added. The mixture was filtered through Celite, and the filter cake was rinsed with dioxane (100 mL) to give a 1-methylcyclobutanecarbaldehyde / dioxane solution (11.28 g, 100%). This solution was used directly as a dioxane solution in the next reaction.

[0240] Step 3: Methyl 2-(tert-butoxycarbonylamino)-3-(1-methylcyclobutyl)prop-2-enoate [ka] To a stirred solution of 1-methylcyclobutanecarbaldehyde (dioxane solution) (11.28 g, 114.93 mmol) at 0° C. was added 2-(tert-butoxycarbonylamino)-2-dimethoxyphosphoryl-methyl acetate (11.5 g, 38.689 mmol), followed by 1,1,3,3-tetramethylguanidine (13.311 g, 14.5 mL, 115.57 mmol). The reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 24 hours. Water (100 mL) and EtOAc (250 mL) were added, and the mixture was extracted with EtOAc (3×250 mL). The combined organic layers were washed with brine (250 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude mixture was purified by flash chromatography on a silica gel cartridge (120 g Gold) using a gradient of 0-40% EtOAc / heptane to give, after evaporation, methyl 2-(tert-butoxycarbonylamino)-3-(1-methylcyclobutyl)prop-2-enoate (8.6 g, 82%) as a white solid. ESI-MS m / z calculated 269.1627, found 214.2 (M-55).+ ; Retention time: 1.84 minutes, LC method I.

[0241] Step 4: (2R)-2-(tert-butoxycarbonylamino)-3-(1-methylcyclobutyl)propanoate methyl ester [ka] Methyl 2-(tert-butoxycarbonylamino)-3-(1-methylcyclobutyl)prop-2-enoate (18 g, 65.962 mmol) was dissolved in ethanol (180 mL) and dioxane (90 mL). Nitrogen was passed through for 15 minutes, and then 1,2-bis[(2R,5R)-2,5-diethylphosphorano]benzene(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (2.5 g, 3.4596 mmol) was added. Nitrogen was passed through for 5 minutes, and then the mixture was hydrogenated under 65 psi hydrogen pressure at room temperature for 4 hours. The mixture was concentrated to dryness in vacuo, and then a solution of EtOAc and heptane (1:1, 200 mL) was added to the mixture. The crude solution was filtered through a silica pad and the pad was rinsed with a solution of EtOAc and heptane (1:1, 400 mL) to give methyl (2R)-2-(tert-butoxycarbonylamino)-3-(1-methylcyclobutyl)propanoate (17.5 g, 93%) after evaporation as a yellow oil. 1 H NMR (400 MHz, CDCl3)δ 4.91-4.77(m, 1H), 4.39-4.24(m, 1H), 3.72(s, 3H), 2.01-1.76(m, 5H), 1.75-1.64(m, 3H), 1.45(s, 9H), 1.23(s, 3H).ESI-MS m / z calculated value 271.1784, measured value 294.2 (M+23) + ; Retention time: 1.9 min; LC method I.

[0242] Step 5: tert-Butyl N-[(1R)-1-(hydroxymethyl)-2-(1-methylcyclobutyl)ethyl]carbamate [ka] A solution of methyl (2R)-2-(tert-butoxycarbonylamino)-3-(1-methylcyclobutyl)propanoate (17.5 g, 61.267 mmol) in THF (40 mL) was added to a suspension of LAH (3.5 g, 92.216 mmol) in THF (160 mL) at 0° C. The mixture was stirred at 0° C. for 15 minutes and then at room temperature for 2 hours. The mixture was then cooled to 0° C., and water (3.5 mL) was added, followed by aqueous NaOH (15%, 3.5 mL), and then water (10.5 mL). The mixture was stirred at room temperature for 30 minutes, and then magnesium sulfate (2 g) was added. The mixture was filtered through Celite, and the filter cake was washed with EtOAc (100 mL). The filtrate was then concentrated in vacuo to give crude tert-butyl N-[(1R)-1-(hydroxymethyl)-2-(1-methylcyclobutyl)ethyl]carbamate (15.3 g, 97%) as a colorless oil. 1 H NMR (400 MHz, CDCl3)δ 4.51(br.s, 1H), 3.72(br.s, 1H), 3.65-3.56(m, 1H), 3.51-3.41(m, 1H), 2.47(br.s, 1H), 2.00-1.90 (m, 1H), 1.89-1.76(m, 3H), 1.74-1.65(m, 2H), 1.61-1.49(m, 2H), 1.44(s, 9H), 1.19(s, 3H).ESI-MS m / z calculated value 243.1834, measured value 188.2 (M-55) + ; Retention time: 1.74 min; LC method I.

[0243] Step 6: (2R)-2-Amino-3-(1-methylcyclobutyl)propan-1-ol [ka] To a solution of tert-butyl N-[(1R)-1-(hydroxymethyl)-2-(1-methylcyclobutyl)ethyl]carbamate (15.3 g, 59.731 mmol) in dry DCM (150 mL) was added HCl (4 M in dioxane) (150 mL, 600.00 mmol) at room temperature. After 18 h, the solvent was removed in vacuo to give (2R)-2-amino-3-(1-methylcyclobutyl)propan-1-ol (hydrochloride) (11 g, 97%) as a white solid after coevaporation with MeCN (2 × 100 mL). 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (br.s, 3H), 5.33 (br.s, 1H), 3.56 (dd, J = 11.5, 3.4 Hz, 1H), 3.39-3.31 (m, 1H, overlap with water), 3.04 (br.s, 1H), 1.95-1.79 (m, 3H), 1.78-1.56 (m, 5H), 1.12 (s, 3H). Several batches of (2R)-2-amino-3-(1-methylcyclobutyl)propan-1-ol (hydrochloride) from three different reactions (1.25 g, 6.6087 mmol, 1.28 g, 6.7673 mmol, and 11 g, 58.156 mmol) were combined in water (75 mL). The resulting mixture was then lyophilized to give (2R)-2-amino-3-(1-methylcyclobutyl)propan-1-ol (hydrochloride salt) (12.8 g, 95%) as a white solid. 1 H NMR (400 MHz, DMSO-d6)δ 7.97(br.s, 3H), 5.33(br.s, 1H), 3.60-3.52(m, 1H), 3.39-3.30(m, 1H, overlaps with water) , 3.04(br.s, 1H), 1.94-1.79(m, 3H), 1.78-1.57(m, 5H), 1.12(s, 3H).ESI-MS m / z calculated value 143.13101, actual value 144.4(M+1) + ; Retention time: 0.56 min; LC method I.

[0244] Step 7: Benzyl N-[(1R)-1-(hydroxymethyl)-2-(1-methylcyclobutyl)ethyl]carbamate [ka] To a stirred suspension of (2R)-2-amino-3-(1-methylcyclobutyl)propan-1-ol (12.3 g, 81.584 mmol) in dry THF (250 mL) at 0° C., triethylamine (25.410 g, 35 mL, 251.11 mmol) was added, followed by N-(benzyloxycarbonyloxy)succinimide (24.5 g, 98.307 mmol). The reaction was stirred at 0° C. for 15 minutes and then at room temperature for 4 hours. Water (250 mL) and EtOAc (250 mL) were added, and the mixture was extracted with EtOAc (3×250 mL). The combined organic layers were washed with water (3×250 mL) and brine (250 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude mixture was purified by flash chromatography on a 330 g silica gel cartridge eluting with a 0-100% EtOAc / heptane gradient, followed by 275 g C elution with a 40-100% MeOH / acidified water (0.1% (v / v) aqueous formic acid) gradient. 18 The product was purified twice by reverse-phase chromatography on a GOLD cartridge. Fractions containing the desired product were combined, and the organic solvent was evaporated. EtOAc (500 mL) was then added, and the mixture was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (1 × 500 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The product was then separated by SFC (Column Lux 5 μm, Cellulose 4, 250 × 21.2 mm, 21.5 mg / injection, concentration 53.8 mg / mL, injection volume 400 μL, column temperature = 40 °C, flow rate 75 mL / min, 20% MeOH). Fractions containing the desired product were combined, and the solvent was evaporated to give benzyl N-[(1R)-1-(hydroxymethyl)-2-(1-methylcyclobutyl)ethyl]carbamate (13.5 g, 58%) as a yellow oil. 1H NMR (400 MHz, CDCl3)δ 7.40-7.29(m, 5H), 5.10(s, 2H), 4.81(br.s, 1H), 3.87-3.75(m, 1H), 3.70-3.60(m, 1H), 3.54-3.46(m, 1H), 2.2 3(br.s, 1H), 2.01-1.90(m, 1H), 1.90-1.75(m, 3H), 1.74-1.65(m, 2H), 1.64-1.52(m, 2H), 1.19(s, 3H).ESI-MS m / z calculated value 277.1678, measured value 278.2(M+1) + Retention time: 1.74 min; LC Method I. Fractions containing the other enantiomer were combined and the solvent was concentrated in vacuo. The product was purified by elution with a gradient of 50-100% MeOH / acidified water (0.1% (v / v) formic acid in water) on 80 g C 18 GOLD cartridge, then eluted with a 50–100% MeCN / acidified water (0.1% (v / v) formic acid in water) gradient. 18 The product was purified twice by reverse-phase chromatography on a GOLD cartridge. Fractions containing the desired product were combined, and the organic solvent was evaporated. EtOAc (50 mL) was then added, and the mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give benzyl N-[(1S)-1-(hydroxymethyl)-2-(1-methylcyclobutyl)ethyl]carbamate (525 mg, 2%) as a yellow oil. 1 H NMR (400 MHz, CDCl) δ 7.38-7.31 (m, 5H), 5.11 (s, 2H), 4.80 (br.s, 1H), 3.86-3.76 (m, 1H), 3.71-3.62 (m, 1H), 3.55-3.47 (m, 1H), 2.00-1.90 (m, 1H), 1.88-1.76 (m, 3H), 1.74-1.65 (m, 2H), 1.64-1.52 (m, 2H), 1.19 (s, 3H), one proton missing (labile proton). ESI-MS m / z calculated 277.1678, found 278.2 (M+1); retention time: 1.75 min; LC method I.

[0245] Step 8: (2R)-2-Amino-3-(1-methylcyclobutyl)propan-1-ol [ka] To a degassed solution of N-[(1R)-1-(hydroxymethyl)-2-(1-methylcyclobutyl)ethyl]benzylcarbamate (13.5 g, 47.165 mmol) in methanol (250 mL) was added 50% wet palladium on carbon (5.2 g, 2.4431 mmol). After purging with nitrogen for 5 minutes, hydrogen was bubbled through the solution for 5 minutes, after which the mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 6 hours. The mixture was filtered through a Celite® pad, and the pad was rinsed with methanol (100 mL). The filtrate was concentrated in vacuo, and then the product was acidified with hydrogen chloride solution (50 mL of 3 M in methanol, 150.00 mmol) added. The mixture was stirred at room temperature for 5 minutes and then concentrated in vacuo to give (2R)-2-amino-3-(1-methylcyclobutyl)propan-1-ol (hydrochloride salt) (7.68 g, 86%) as a white solid after lyophilization. 1 H NMR (400 MHz, DMSO-d6)δ 7.28(br.s, 3H), 5.23(br.s, 1H), 3.57-3.47(m, 1H), 3.34-3.25(m, 1H), 3.05-2.95( m, 1H), 1.95-1.70(m, 4H), 1.70-1.58(m, 3H), 1.58-1.50(m, 1H), 1.11(s, 3H).ESI-MS m / z calculated value ESI-MS m / z calculated value 143.13101, actual value 144.4(M+1) + ; Retention time: 0.64 min; LC method I.

[0246] Step 9: 3-[[4-[(2R)-2-amino-3-(1-methylcyclobutyl)propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [ka] A solution of (2R)-2-amino-3-(1-methylcyclobutyl)propan-1-ol (7.65 g, 50.741 mmol) in anhydrous N,N-dimethylformamide (40 mL) was added to a solution of 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (23 g, 55.042 mmol) in 2-methyltetrahydrofuran (200 mL). The mixture was cooled to 10-15 °C, and then sodium tert-butoxide (30 g, 312.16 mmol) was added. The reaction was stirred at 10-15 °C for 2 h, then cooled to 0 °C and quenched by the addition of 1 N aqueous HCl (300 mL). The biphasic mixture was stirred for 30 min. The layers were then separated, and the aqueous layer was extracted with 2-methyltetrahydrofuran (5 × 500 mL). The combined organic layers were washed with water (3 x 500 mL) and brine (1 x 500 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude mixture was purified by eluting with a 20-100% MeOH / acidic water (0.1% aqueous hydrochloric acid) gradient to give 275 g C 18 Purification by reverse phase chromatography on a GOLD cartridge gave, after evaporation, 3-[[4-[(2R)-2-amino-3-(1-methylcyclobutyl)propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride) (24.25 g, 78%) as a white solid. 1 H NMR (400 MHz, DMSO-d6)δ 8.48-8.35(m, 4H), 8.13(t, J=9.3 Hz, 2H), 7.71(t, J=7.7 Hz, 1H), 7.25(t, J=7.6 Hz, 1H), 7.12(d, J=7.6 Hz, 2H), 6.33(s, 1H), 4.32(dd, J=11.6, 2.6 Hz, 1H), 4.06(dd, J=11.7, 6.1 Hz, 1H), 3.47(br.s, 1H), 2.00(s, 6H), 1.93-1.83(m, 2H), 1.82-1.62(m, 5H), 1.58-1.47(m, 1H), 1.16(s, 3H).2H missing, unstable proton. ESI-MS m / z calculated value 524.20935, measured value 525.3(M+1) + ; Retention time: 2.49 min; LC method J.

[0247] Example 16: Preparation of 3-[[4-(2-amino-5-fluoro-5-methyl-hexoxy)-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid Step 1: Ethyl 3-hydroxy-3-methyl-butanoate [ka] Ethyl acetate (5.0512 g, 5.6 mL, 57.332 mmol) was added dropwise to a solution of (bis(trimethylsilyl)amino)lithium in THF (39 mL 1.5 M, 58.500 mmol) in THF (56 mL) at −78° C. The reaction mixture was stirred at this temperature for 30 minutes. Acetone (3.9550 g, 5 mL, 68.097 mmol) was added, and the reaction mixture was allowed to stir for 10 minutes. HCl (2 M, 35 mL) was added to the reaction mixture, which was then allowed to warm to room temperature. The reaction mixture was extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with saturated aqueous sodium bicarbonate (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl 3-hydroxy-3-methyl-butanoate (7.84 g, 89%) as a clear yellow oil. 1 H NMR(400MHz,CDCl3)δ4.18(q,J=7.1Hz,2H),3.59(s,1H),2.48(s,2H),1.31-1.26(m,9H).ESI-MS m / z Calculated value 146.0943, Actual value 169.2(M+23) + ; Retention time: 1.3 min; LC method I.

[0248] Step 2: Ethyl 3-fluoro-3-methyl-butanoate [ka] Deoxo-Fluor (toluene solution) (26 g, 50% (w / w), 58.759 mmol) was added to a solution of ethyl 3-hydroxy-3-methyl-butanoate (7.5 g, 48.740 mmol) in DCM (125 mL) at −78° C. The reaction was then allowed to warm to room temperature and stirred for 4 h. The reaction mixture was quenched with aqueous sodium bicarbonate (200 mL). The aqueous phase was extracted with DCM (2×100 mL), and the combined organic phases were washed with saturated aqueous ammonium chloride (100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give crude ethyl 3-fluoro-3-methyl-butanoate (4.8 g, 53%) as a clear oil. 1 H NMR (400 MHz, CDCl) δ 4.16 (q, J = 7.2 Hz, 2H), 2.66 (d, J = 16.1 Hz, 2H), 1.49 (d, J = 21.8 Hz, 6H), 1.28 (t, J = 7.2 Hz, 3H). This was used directly in the next step without further purification.

[0249] Step 3: 3-Fluoro-3-methyl-butanal [ka] DIBAL (toluene solution) (8.7 mL of 1 M, 8.7000 mmol) was slowly added to a solution of ethyl 3-fluoro-3-methylbutanoate (1 g, 5.3990 mmol) in DCM (10 mL) at −78° C. The reaction mixture was stirred at this temperature for 1 hour. The reaction mixture was quenched with concentrated aqueous ammonium chloride (20 mL) and 1N HCl (5 mL). The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. DCM (100 mL) was added to the mixture and shaken. The aqueous phase was separated and washed with additional DCM (25 mL). The combined organic phase was dried over sodium sulfate overnight and then filtered to give a solution of approximately 0.3% 3-fluoro-3-methylbutanal (185 g, 99%) as a clear solution. This solution was used directly in the next step.

[0250] Step 4: 2-(tert-butoxycarbonylamino)-5-fluoro-5-methyl-hex-2-enoic acid methyl ester [ka] To a stirred solution of 3-fluoro-3-methyl-butanal (3% solution in DCM) (185 g, 5.3302 mmol) at 0° C., 2-(tert-butoxycarbonylamino)-2-dimethoxyphosphoryl-methyl acetate (500 mg, 1.6821 mmol) was added, followed by 1,1,3,3-tetramethylguanidine (580 mg, 5.0357 mmol). The reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 18 hours. Water (100 mL) and DCM (100 mL) were added, and the mixture was extracted with DCM (3×100 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on a 40 g silica gel cartridge using a 0-40% EtOAc / heptane gradient to afford methyl 2-(tert-butoxycarbonylamino)-5-fluoro-5-methyl-hex-2-enoate (383 mg, 83%) as a white solid. 1 H NMR(400MHz,CDCl3)δ6.62(t,J=7.3Hz,1H),6.11(br.s.,1H),3.80(s,3H),2.54(dd,J=20.3,7.6Hz,2H),1.47(s,9H),1.40(d,J=21.5Hz,6H).19F NMR(377MHz, CDCl3)δ-138.20(br.s., 1F).ESI-MS m / z calculated value 275.1533, measured value 298.2(M+23) + ; Retention time: 1.73 min; LC method I.

[0251] Step 5: Methyl 2-(tert-butoxycarbonylamino)-5-fluoro-5-methyl-hexanoate [ka] Palladium on carbon (400 mg, 0.1879 mmol) was added to a solution of methyl 2-(tert-butoxycarbonylamino)-5-fluoro-5-methyl-hex-2-enoate (380 mg, 1.3802 mmol) in methanol (4 mL), and hydrogen was continuously injected into the suspension with a hydrogen balloon equipped with a thin needle for 30 minutes. The crude mixture was filtered through a syringe filter and concentrated under reduced pressure. The resulting residue was purified by C using 5-100% acetonitrile / acidified water (containing 0.1% formic acid). 18 Purification by reverse phase column chromatography gave methyl 2-(tert-butoxycarbonylamino)-5-fluoro-5-methyl-hexanoate (250 mg, 65%) as a clear oil. 1 H NMR(400MHz,CDCl3)δ5.03(d,J=7.1Hz,1H),4.38-4.26(m,1H),3.76(s,3H),2.04-1.89( m,1H),1.80-1.71(m,1H),1.69-1.57(m,2H),1.45(s,9H),1.34(d,J=21.5Hz,6H).ESI-MS m / z calculated value 277.1689, actual value 300.2 (M+23) + ; Retention time: 1.76 min; LC method I.

[0252] Step 6: tert-butyl N-[4-fluoro-1-(hydroxymethyl)-4-methyl-pentyl]carbamate [ka] Lithium borohydride (340 mg, 15.608 mmol) was added to a solution of methyl 2-(tert-butoxycarbonylamino)-5-fluoro-5-methylhexanoate (230 mg, 0.8293 mmol) in ethanol (6 mL) at 0 °C. The reaction mixture was stirred at this temperature for 1 hour, then allowed to warm to room temperature and stirred for an additional 30 minutes. Water (20 mL) was then added to the reaction mixture, which was then allowed to stir at room temperature overnight. The reaction mixture was transferred to cold 0.1 N aqueous HCl (40 mL), and the mixture was extracted with DCM (3 × 50 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl N-[4-fluoro-1-(hydroxymethyl)-4-methyl-pentyl]carbamate (240 mg, 99%) as a clear oil. 1 H NMR(400MHz,CDCl3)δ4.66(br.s.,1H),3.78-3.53(m,3H),2.32(br.s.,1H),1.82-1.58(m,4H),1.46(s,9H),1.36(d,J=21.8Hz,6H).19F NMR(377MHz, CDCl3)δ-139.16(br.s., 1F).ESI-MS m / z calculated value 249.174, measured value 272.2(M+23) + ; Retention time: 1.63 min; LC method I.

[0253] Step 7: 2-Amino-5-fluoro-5-methyl-hexan-1-ol [ka] Hydrogen chloride (dioxane solution) (2 mL 4 M, 8.0000 mmol) was added to a solution of tert-butyl N-[4-fluoro-1-(hydroxymethyl)-4-methyl-pentyl]carbamate (240 mg, 0.8182 mmol) in DCM (2 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in pure water and concentrated under reduced pressure. The resulting residue was then redissolved in water and lyophilized to give 2-amino-5-fluoro-5-methyl-hexan-1-ol (hydrochloride) (138 mg, 86%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ7.95(br.s.,3H),5.30(t,J=5.0Hz,1H),3.59(dt,J=11.5,4.4Hz,1H), 3.45(dt,J=11.4,5.7Hz,1H),3.10-2.99(m,1H),1.71-1.57(m,4H),1.30(d,J=22.0Hz,6H).19F NMR(377MHz,DMSO-d6)δ-136.12(nonu,J=20.4Hz,1F).ESI-MS m / z calculated value 149.1216, actual value 150.2(M+1) + ; Retention time: 0.29 min; LC method I.

[0254] Step 8: 3-[[4-(2-amino-5-fluoro-5-methyl-hexoxy)-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [ka] A flame-dried flask was charged with 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (325 mg, 0.7778 mmol), 2-amino-5-fluoro-5-methyl-hexan-1-ol (hydrochloride salt) (134 mg, 0.6856 mmol), 2-MeTHF (15 mL), and anhydrous DMF (1.5 mL) under a nitrogen atmosphere. The reaction mixture was cooled to 0°C, and then sodium tert-butoxide (375 mg, 3.9020 mmol) was added. The reaction was stirred at 0°C for 5 minutes, then allowed to reach room temperature and stirred at room temperature for 45 minutes. The reaction was then cooled to 0°C, then diluted with 2-methyltetrahydrofuran (150 mL) and quenched by the addition of 1 N aqueous hydrochloric acid (150 mL). The layers were separated and the aqueous layer was extracted with 2-methyltetrahydrofuran (2 x 150 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by C chromatography using a 50 g Gold column eluting with a 5-100% acetonitrile / acidified water (containing 0.1% (v / v) hydrochloric acid) gradient. 18The resulting mixture was purified by reverse-phase chromatography at RT. The desired fractions were concentrated under reduced pressure and then freeze-dried to give 3-[[4-(2-amino-5-fluoro-5-methyl-hexoxy)-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride) (305 mg, 64%) as a white fluffy solid. 1 H NMR(400MHz,DMSO-d6)δ13.32(br.s.,1H),12.60-11.86(m,1H),8.45(t,J=1. 6Hz,1H),8.40-8.03(m,5H),7.69(t,J=7.7Hz,1H),7.32-7.20(m,1H),7.18-7. 06(m,2H),6.32(br.s.,1H),4.49-4.34(m,1H),4.28(dd,J=11.9,6.2Hz,1H), 3.61-3.50(m,1H),2.00(br.s.,6H),1.83-1.61(m,4H),1.38-1.27(m,6H).19F NMR(377MHz,DMSO-d6)δ-136.46(s,1F).ESI-MS m / z calculated value 530.1999, measured value 531.1(M+1) + ; Retention time: 2.42 min; LC method J. Example 17: Preparation of 3-[[4-(2-amino-4,4-dimethyl-hexoxy)-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[0255] Step 1: Diethyl 2-(1,1-dimethylpropyl)propanedioate [ka] To a solution of diethyl isopropylidenemalonate (2 g, 9.9884 mmol) in THF (60 mL) was added CuI (2.85 g, 14.965 mmol). After stirring at 0 °C for 30 min, ethylmagnesium bromide / THF solution (30 mL 1 M, 30.000 mmol) was added dropwise, and the mixture was stirred at 0 °C for 3 h. The mixture was quenched with 1 N HCl (50 mL) and extracted with ethyl acetate (2 × 60 mL). The combined organic phases were washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give diethyl 2-(1,1-dimethylpropyl)propanedioate (2.4 g, 99%) as a brownish oil. 1 H NMR (400 MHz, CDCl3)δ 4.18(q, J=7.2 Hz, 4H), 3.33(s, 1H), 1.48(q, J=7.4 Hz, 2H), 1.27(t, J=7.2 Hz, 6H), 1.09(s, 6H), 0.87(t, J=7.6 Hz, 3H).ESI-MS m / z calculated value 230.15181, measured value 231.2(M+1) + ; Retention time: 1.98 min; LC method I.

[0256] Step 2: 3,3-Dimethylpentanoic Acid [ka] To a solution of diethyl 2-(1,1-dimethylpropyl)propanedioate (2.4 g, 9.9001 mmol) in DMSO (50 mL) and water (10 mL) was added lithium hydroxide hydrate (2.1 g, 50.043 mmol), and the mixture was stirred at 120 °C for 22 h. The mixture was acidified to pH 2-3 with 1 N hydrochloric acid and extracted with ethyl acetate (2 × 40 mL). The combined organic layers were washed with brine (3 × 30 mL) and water (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 3,3-dimethylpentanoic acid (1.23 g, 91%) as a yellow oil. 1H NMR (400 MHz, CDCl) δ 2.23 (s, 2H), 1.39 (q, J = 7.4 Hz, 2H), 1.02 (s, 6H), 0.87 (t, J = 7.5 Hz, 3H); one labile proton missing. ESI-MS m / z calculated 130.09938, found 131.2 (M+1). + ; Retention time: 1.6 min; LC method I.

[0257] Step 3: N-Methoxy-N,3,3-trimethyl-pentanamide [ka] To a solution of 3,3-dimethylpentanoic acid (1.23 g, 8.9757 mmol) in DMF (28 mL), N-methoxymethanamine (hydrochloride) (1.1 g, 11.277 mmol), DIPEA (3.6358 g, 4.9 mL, 28.132 mmol), and then HATU (5.39 g, 14.176 mmol) were added at 15-20 °C (water bath). The mixture was stirred at room temperature for 16 h. The mixture was diluted with water (50 mL) and extracted with MTBE (2 × 75 mL). The combined organic phase was washed with brine (5 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (column: 100 g, gradient: 0-20% ethyl acetate / heptane) gave N-methoxy-N,3,3-trimethyl-pentanamide (1.19 g, 76%) as a colorless oil. 1 H NMR(400 MHz, CDCl3)δ 3.67(s, 3H), 3.18(s, 3H), 2.31(s, 2H), 1.40(q, J=7.4 Hz, 2H), 1.00(s, 6H), 0.86(t, J=7.5 Hz, 3H).ESI-MS m / z Calculated value 173.14159, actual value 174.2 (M+1) + ; Retention time: 1.72 min; LC method I.

[0258] Step 4: 3,3-Dimethylpentanal [ka] To a solution of N-methoxy-N,3,3-trimethyl-pentanamide (1.12 g, 6.3999 mmol) in THF (20 mL) was added lithium aluminum hydride (736 mg, 19.392 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. The reaction mixture was slowly quenched with water (40 mL) and extracted with MTBE (2×30 mL). The combined organic layers were washed with brine (3×45 mL), dried over sodium sulfate, and filtered to give crude 3,3-dimethylpentanal (730.77 mg, 100%) as a colorless MTBE / THF solution.

[0259] Step 5: 2-(benzylamino)-4,4-dimethyl-hexanenitrile [ka] A three-necked round-bottom flask equipped with a 6N NaOH trap was charged with a 3:1 MTBE / THF solution (approximately 80 mL) of 3,3-dimethylpentanal (730.77 mg, 6.3999 mmol) and benzylamine (765.18 mg, 0.78 mL, 7.1410 mmol). To the mixture was slowly added acetic acid (411.84 mg, 0.39 mL, 6.8581 mmol), followed by trimethylsilyl cyanide (642.33 mg, 0.81 mL, 6.4747 mmol) at 0°C. The mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (2 × 40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by chromatography on silica gel (column: 120 g, gradient: 0-10% methanol / dichloromethane) gave 2-(benzylamino)-4,4-dimethyl-hexanenitrile (761 mg, 49%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3)δ 7.40-7.28(m, 5H), 4.08(d, J=12.7 Hz, 1H), 3.83(d, J=13.0 Hz, 1H), 3.51(dd, J=7.6, 5.6 Hz, 1H), 1.83(dd, J=14.2, 7.6 Hz, 1H), 1.66(dd, J=14.1, 5.5 Hz, 1H), 1.34-1.25(m, 3H), 0.94(s, 6H), 0.84(t, J=7.6 Hz, 3H).ESI-MS m / z Calculated value 230.1783, Actual value 231.4(M+1) + ;Retention time: 1.95 minutes;LC method I.

[0260] Step 6: 2-(benzylamino)-4,4-dimethyl-hexanoic acid [ka] 2-(Benzylamino)-4,4-dimethyl-hexanenitrile (761 mg, 3.1319 mmol) was dissolved in acetic acid (4.2240 g, 4 mL, 70.339 mmol) and hydrochloric acid (24 mL 12 M, 288.00 mmol) and stirred at 100° C. for 96 h. The solution was cooled to 10-15° C., the pH was raised to 3-4 with saturated aqueous sodium bicarbonate, and the mixture was filtered and dried under vacuum to give 2-(benzylamino)-4,4-dimethyl-hexanoic acid (685 mg, 88%) as a white powder. 1 H NMR (400 MHz, MeOH-d) δ 7.52-7.42 (m, 5H), 4.15 (d, J = 13.2 Hz, 1H), 4.05 (d, J = 13.2 Hz, 1H), 3.50 (dd, J = 9.3, 3.4 Hz, 1H), 1.94 (dd, J = 14.1, 9.4 Hz, 1H), 1.51 (dd, J = 13.8, 3.5 Hz, 1H), 1.38-1.29 (m, 2H), 0.93 (s, 6H), 0.84 (t, J = 7.5 Hz, 3H); two labile protons missing. ESI-MS m / z calculated 249.17288, found 250.2 (M+1). + ;Retention time: 1.32 minutes;LC method I.

[0261] Step 7: 2-(benzylamino)-4,4-dimethyl-hexan-1-ol [ka] To a solution of 2-(benzylamino)-4,4-dimethyl-hexanoic acid (685 mg, 2.7444 mmol) in anhydrous THF (10 mL) was added borane tetrahydrofuran complex / THF solution (8.3 mL 1 M, 8.3000 mmol) dropwise at 0° C. The reaction was stirred at 0° C. for 30 minutes and then at room temperature for 18 hours. The reaction was cooled to 0° C. and then quenc...

Claims

1. A compound of formula I, 【Chemical 840】 During the ceremony, Ring A is 【Chemical 841】 And, Q is selected from -C- and -N-. W is -CH-, -C(F)-, -C(CF ３ ) -, and -N- are selected, X １ , X ２ , and X ３ However, each is independently selected from -CH- and -N-, Y is -N-, -N(R ｙ )-,-C(R ｙ ) -, and -O- are selected, R ｙ is hydrogen, halogen, C １ to C ８ haloalkyl, cyano, -NH ２ , C ３ to C ６ cycloalkyl, C １ to C ８ alkyl (optionally substituted with a group selected from -OH and C １ to C ８ alkoxy), -NHC(O)OC １ to C ８ alkyl (optionally substituted with a group selected from -OH and halogen), and is selected from: Z is -CH-, -O-, -S-, -S(O)-, -S(O) ２ - and -N- are selected, R １ However, C ３ ~C ６ Cycloalkyl, C １ ~C ８ Alkoxy and C １ ~C ８ Alkyl (C ４ ~C ６ Cycloalkyl, C ５ ~C ６ (Can be optionally substituted with groups selected from aryl, 4-6 membered heterocyclyl, and 4-6 membered heteroaryl groups.) R ２ However, hydrogen, halogen, C １ ~C ８ Alkyl, C １ ~C ８ Haloalkyl and C １ ~C ８ Selected from alkoxy, R ３ａ and R ３ｂ These independently produce hydrogen, halogen, and C. １ ~C ８ Alkyl (halogen, hydroxyl, oxo, C) ３ ~C ６ Cycloalkyl, C ５ ~C ６ (Can be optionally substituted with aryl and 1-2 groups selected from 3-6 membered heterocyclyl groups) C １ ~C ８ Alkoxy (halogen, hydroxyl, oxo, C) ３ ~C ６ Cycloalkyl, C ５ ~C ６ (Can be optionally substituted with 1-2 groups selected from aryl and 3-6 membered heterocyclyl groups) or together, oxo and C ３ ~C ７ Cycloalkyl (halogen, hydroxyl, oxo, C) １ ~C ４ Alkyl, C １ ~C ４ Haloalkyl, C ３ ~C ６ Cycloalkyl, C ５ ~C ６ A group may be formed which is optionally substituted with one or two groups selected from aryl and 3- to 6-membered heterocyclyl groups. R ４ but, Halogen, C １ ~C ８ Haloalkyl and C １ ~C ８ C can be optionally substituted with 1 to 3 groups independently selected from the alkyl group. ３ ~C ６ Cycloalkyl, and ・C １ ~C ９ Alkyl, ・C ３ ~C ８ Cycloalkyl (C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogens, and C １ ~C ８ (Can be optionally substituted with one or two groups selected from haloalkyl groups.) ・C １ ~C ８ Haloalkyl, OC ３ ~C ７ Cycloalkyl (C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogens, and C １ ~C ８ (Can be optionally substituted with one or two groups selected from haloalkyl groups.) ・ Phenyl (C １ -C ８ alkyl, C １ -C ８ alkoxy, halogen, and C １ -C ８ haloalkyl, and may be optionally substituted with a group selected therefrom), - C １ - C ８ alkoxy (C ３ - C ６ which may be optionally substituted with a group selected from cycloalkyl and halogen). 4-6 member heterocycline (halogen, C) １ ~C ８ Haloalkyl, C １ ~C ８ Alkyl and C １ ~C ８ (Can be optionally substituted with one or two groups independently selected from the alkoxy), and • Silicon (C) １ ~C ８ Alkyl, C １ ~C ８ Alkoxy and C １ ~C ８ C １ ~C ９ Selected from alkyl groups, R ５ａ and R ５ｂ These independently produce hydrogen, halogen, and C. １ ~C ８ Alkyl (halogen, hydroxyl, oxo, C) ３ ~C ６ Cycloalkyl, C ５ ~C ６ (Can be optionally substituted with aryl and 1-2 groups selected from 3-6 membered heterocyclyl groups) C １ ~C ８ Alkoxy (halogen, hydroxyl, oxo, C) ３ ~C ６ Cycloalkyl, C ５ ~C ６ (Can be optionally substituted with 1-2 groups selected from aryl and 3-6 membered heterocyclyl groups) or together, oxo and C ３ ~C ７ Cycloalkyl (halogen, hydroxyl, oxo, C) １ ~C ４ Alkyl, C １ ~C ４ Haloalkyl, C ３ ~C ６ Cycloalkyl, C ５ ~C ６ A group may be formed which is optionally substituted with one or two groups selected from aryl and 3- to 6-membered heterocyclyl groups. R ６ However, halogens, 4-6 member heterocyclines, C ３ ~C ８ Cycloalkyl (C １ ~C ８ Alkyl, C １ ~C ８ (Can be optionally substituted with a group selected from haloalkyl and halogen groups), and C １ ~C ８ Alkyl (C １ ~C ８ Alkoxy, halogen, oxo, -OH, -NH ２ , and -SO ２ CH ３ (Can be arbitrarily substituted by one or two elements independently selected from) R ７ However, selected from O and NR, R is hydrogen and C １ ~C ８ Selected from alkyl groups, However, if the compound of formula I is Table 17-1 Table 17-2 A compound of formula I, a compound of formula I, a compound of formula I, a compound of formula I, a compound of formula I, a compound of formula I, a compound of formula I, a compound of formula I, a compound of formula I, a compound of formula I, a compound of formula I, or

2. Compounds of formula Ia: 【Chemical 842】 The tautomer, the deuterated derivative of the compound or tautomer, and any pharmaceutically acceptable salt of the foregoing, or Compounds of formula Ia(i): 【Chemical 843】 A compound, tautomer, deuterated derivative, or salt according to claim 1, selected from the tautomer, the compound or tautomer, and any pharmaceutically acceptable salt of the foregoing.

3. Compounds of formula Ib: 【Chemical 844】 The tautomer, the deuterated derivative of the compound or tautomer, and any pharmaceutically acceptable salt of the foregoing, or Compounds of formula Ib(i): 【Chemical 845】 A compound, tautomer, deuterated derivative, or salt according to claim 1, selected from the tautomer, the compound or tautomer, and any pharmaceutically acceptable salt of the foregoing.

4. Compounds of formula Ic: 【Chemical 846】 The tautomer, the deuterated derivative of the compound or tautomer, and any pharmaceutically acceptable salt of the foregoing, or Compounds of formula Ic(i): 【Chemical 847】 A compound, tautomer, deuterated derivative, or salt according to claim 1, selected from the tautomer, the compound or tautomer, and any pharmaceutically acceptable salt of the foregoing.

5. The aforementioned compound is a compound of formula Id: 【Chemical 848】 The tautomer, the deuterated derivative of the compound or tautomer, and any pharmaceutically acceptable salt of the foregoing, or Compounds of formula Id(i): 【Chemical 849】 A compound, tautomer, deuterated derivative, or salt according to claim 1, selected from the tautomer, the compound or tautomer, and any pharmaceutically acceptable salt of the foregoing.

6. Compounds of formula Ie: 【Chemical 850】 The tautomer, the deuterated derivative of the compound or tautomer, and any pharmaceutically acceptable salt of the foregoing, or Compounds of formula Ie(i): 【Chemical 851】 A compound, tautomer, deuterated derivative, or salt according to claim 1, selected from the tautomer, the compound or tautomer, and any pharmaceutically acceptable salt of the foregoing.

7. Compounds of formula If: 【Chemical 852】 The tautomer, the deuterated derivative of the compound or tautomer, and any pharmaceutically acceptable salt of the foregoing, or Compounds of formula If(i): 【Chemical 853】 A compound, tautomer, deuterated derivative, or salt according to claim 1, selected from the tautomer, the compound or tautomer, and any pharmaceutically acceptable salt of the foregoing. 【Request Item 8】 【Chemistry 877-1】 【Chemistry 877-2】 【Chemistry 877-3】 【Chemistry 877-4】 【Chemistry 877-5】 【Chemistry 877-6】 【Chemistry 877-7】 【Chemistry 877-8】 【Chemistry 877-9】 【Chemistry 877-10】 【Chemistry 877-11】 【Chemistry 877-12】 【Chemistry 877-13】 【Chemistry 877-14】 【Chemistry 877-15】 【Chemistry 877-16】 【Chemistry 877-17】 【Chemistry 877-18】 【Chemistry 877-19】 【Chemistry 877-20】 【Chemistry 877-21】 【Chemistry 877-22】 【Chemistry 877-23】 【Chemistry 877-24】 【Chemistry 877-25】 【Chemistry 877-26】 【Chemistry 877-27】 【Chemistry 877-28】 【Chemistry 877-29】 【Chemistry 877-30】 【Chemistry 877-31】 【Chemistry 877-32】 【Chemistry 877-33】 【Chemistry 877-34】 【Chemistry 877-35】 【Chemistry 877-36】 【Chemistry 877-37】 【Chemistry 877-38】 【Chemistry 877-39】 【Chemistry 877-40】 【Chemistry 877-41】 【Chemistry 877-42】 【Chemistry 877-43】 【Chemistry 877-44】 【Chemistry 877-45】 【Chemistry 877-46】 【Chemistry 877-47】 【Chemistry 877-48】 【Chemistry 877-49】 【Chemistry 877-50】 【Chemistry 877-51】 【Chemistry 877-52】 【Chemistry 877-53】 【Chemistry 877-54】 【Chemistry 877-55】 【Chemistry 877-56】 【Chemistry 877-57】 【Chemistry 877-58】 【Chemistry 877-59】 【Chemistry 877-60】 【Chemistry 877-61】 【Chemistry 877-62】 【Chemistry 877-63】 【Chemistry 877-64】 【Chemistry 877-65】 【Chemistry 877-66】 A compound selected from the tautomer, the compound or a deuterated derivative of the tautomer, and any pharmaceutically acceptable salt of the foregoing.

9. Compound I-4: 【Chemical 854】 Compound I-23: 【Chemical 855】 Compound I-34: 【Chemical 856】 Compound I-35: 【Chemical 857】 Compound I-40: 【Chemical 858】 Compound I-49: 【Chemical 859】 Compound I-52: 【Chemical 860】 Compound I-88: 【Chemistry 861】 Compound I-96: 【Chemical 862】 Compound I-97: 【Chemical 863】 Compound I-98: 【Chemical 864】 Compound I-99: 【Chemistry 865】 Compound I-139: 【Chemical 866】 Compound I-158: 【Chemical 867】 I-188: 【Chemical 868】 Compound I-206: 【Chemical 869】 Compound I-255: 【Chemical 870】 Compound I-256: 【Chemistry 871】 The compound according to claim 8, selected from the tautomer, the compound or a deuterated derivative of the tautomer, and any pharmaceutically acceptable salt of the foregoing.

10. A compound of formula II, 【Chemical 872】 During the ceremony, Ring B is ·halogen 4-10 member heterocyclyl (halogen, oxo, C) １ ~C ４ (It can be optionally substituted with 1 to 3 groups independently selected from the alkyl group.) ・N(R) ｘ ) ２ , (R ｘ These are independently hydrogen and C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl (halogen, C １ ~C ４ Haloalkyl and C １ ~C ４ (Can be optionally substituted with a group selected from alkyl groups) ・C １ ~C ４ Alkyl (C ３ ~C ６ A six-membered heteroaryl molecule that is optionally substituted with one or two groups independently selected from cycloalkyl groups (which can be optionally substituted with groups selected from halogens and OH groups), R １ However, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkoxy and C １ ~C ６ Alkyl (C ４ ~C ６ Selected from (which can be optionally substituted with cycloalkyl groups), R ２ However, hydrogen, halogen, C １ ~C ２ Alkyl, C １ ~C ４ Haloalkyl and C １ ~C ２ Selected from alkoxy, R ３ａ and R ３ｂ These independently produce hydrogen, halogen, and C. １ ~C ８ Alkyl (halogen, hydroxyl, oxo, C) ３ ~C ６ Cycloalkyl, C ５ ~C ６ (Can be optionally substituted with aryl and 1-2 groups selected from 3-6 membered heterocyclyl groups) C １ ~C ８ Alkoxy (halogen, hydroxyl, oxo, C) ３ ~C ６ Cycloalkyl, C ５ ~C ６ (Can be optionally substituted with aryl and 1-2 groups selected from 3-6 membered heterocyclyls) or together, C ３ ~C ７ Cycloalkyl (halogen, hydroxyl, oxo, C) １ ~C ４ Alkyl, C １ ~C ４ Haloalkyl, C ３ ~C ６ Cycloalkyl, C ５ ~C ６ They may be optionally substituted with aryl groups and 1-2 groups selected from 3-6 membered heterocyclines. R ４ but, Halogen, C １ ~C ８ Haloalkyl and C １ ~C ８ C can be optionally substituted with 1 to 3 groups independently selected from the alkyl group. ３ ~C ６ Cycloalkyl, and ・C １ ~C ９ Alkyl, ・C ３ ~C ８ Cycloalkyl (C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogens, and C １ ~C ８ (Can be optionally substituted with one or two groups selected from haloalkyl groups.) ・C １ ~C ８ Haloalkyl, Phenyl (C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogens, and C １ ~C ８ (Can be optionally substituted with a group selected from haloalkyl groups.) ・C １ ~C ８ Alkoxy (C ３ ~C ６ (Can be optionally substituted with a group selected from cycloalkyl and halogen groups.) 4-6 member heterocycline (halogen, C) １ ~C ８ Haloalkyl, C １ ~C ８ Alkyl and C １ ~C ８ (Can be optionally substituted with one or two groups independently selected from the alkoxy), and • Silicon (C) １ ~C ８ Alkyl, C １ ~C ８ Alkoxy and C １ ~C ８ C １ ~C ９ Selected from alkyl groups, R ５ａ and R ５ｂ These independently produce hydrogen, halogen, and C. １ ~C ８ Alkyl (halogen, hydroxyl, oxo, C) ３ ~C ６ Cycloalkyl, C ５ ~C ６ (Can be optionally substituted with aryl and 1-2 groups selected from 3-6 membered heterocyclyl groups) C １ ~C ８ Alkoxy (halogen, hydroxyl, oxo, C) ３ ~C ６ Cycloalkyl, C ５ ~C ６ (Can be optionally substituted with aryl and 1-2 groups selected from 3-6 membered heterocyclyls) or together, C ３ ~C ７ Cycloalkyl (halogen, hydroxyl, oxo, C) １ ~C ４ Alkyl, C １ ~C ４ Haloalkyl, C ３ ~C ６ Cycloalkyl, C ５ ~C ６ They may be optionally substituted with aryl groups and 1-2 groups selected from 3-6 membered heterocyclines. The compound of formula II is 【Chemical Engineering 878-1】 【Chemistry 878-2】 【Chemistry 878-3】 【Chemistry 878-4】 【Chemistry 878-5】 【Chemistry 878-6】 【Chemistry 878-7】 【Chemistry 878-8】 A compound of formula II, its tautomer, a deuterated derivative of the compound or its tautomer, or any pharmaceutically acceptable salt selected from any of the aforementioned.

11. A compound of formula III, 【Chemical 873】 During the ceremony, Ring C is 【Chemistry 874】 Selected from, Each R ｃ These independently produce hydrogen, halogen, cyano, amino, and C. １ ~C ４ Alkyl (which can be optionally substituted with a group selected from -OH, halogen, and oxo), and C ３ ~C ６ Selected from Alkeny, R １ However, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkoxy and C １ ~C ６ Alkyl (C ４ ~C ６ Selected from (which can be optionally substituted with cycloalkyl groups), R ２ However, hydrogen, halogen, C １ ~C ２ Alkyl, C １ ~C ４ Haloalkyl and C １ ~C ２ Selected from alkoxy, R ３ａ and R ３ｂ These independently produce hydrogen, halogen, and C. １ ~C ８ Alkyl (halogen, hydroxyl, oxo, C) ３ ~C ６ Cycloalkyl, C ５ ~C ６ (Can be optionally substituted with aryl and 1-2 groups selected from 3-6 membered heterocyclyl groups) C １ ~C ８ Alkoxy (halogen, hydroxyl, oxo, C) ３ ~C ６ Cycloalkyl, C ５ ~C ６ (Can be optionally substituted with aryl and 1-2 groups selected from 3-6 membered heterocyclyls) or together, C ３ ~C ７ Cycloalkyl (halogen, hydroxyl, oxo, C) １ ~C ４ Alkyl, C １ ~C ４ Haloalkyl, C ３ ~C ６ Cycloalkyl, C ５ ~C ６ They may be optionally substituted with aryl groups and 1-2 groups selected from 3-6 membered heterocyclines. R ４ but, Halogen, C １ ~C ８ Haloalkyl and C １ ~C ８ C can be optionally substituted with 1 to 3 groups independently selected from the alkyl group. ３ ~C ６ Cycloalkyl, and ・C １ ~C ９ Alkyl, ・C ３ ~C ８ Cycloalkyl (C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogens, and C １ ~C ８ (Can be optionally substituted with one or two groups selected from haloalkyl groups.) ・C １ ~C ８ Haloalkyl, Phenyl (C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogens, and C １ ~C ８ (Can be optionally substituted with a group selected from haloalkyl groups.) ・C １ ~C ８ Alkoxy (C ３ ~C ６ (Can be optionally substituted with a group selected from cycloalkyl and halogen groups.) 4-6 member heterocycline (halogen, C) １ ~C ８ Haloalkyl, C １ ~C ８ Alkyl and C １ ~C ８ (Can be optionally substituted with one or two groups independently selected from the alkoxy), and • Silicon (C) １ ~C ８ Alkyl, C １ ~C ８ Alkoxy and C １ ~C ８ C １ ~C ９ Selected from alkyl groups, R ５ａ and R ５ｂ These independently produce hydrogen, halogen, and C. １ ~C ８ Alkyl (halogen, hydroxyl, oxo, C) ３ ~C ６ Cycloalkyl, C ５ ~C ６ (Can be optionally substituted with aryl and 1-2 groups selected from 3-6 membered heterocyclyl groups) C １ ~C ８ Alkoxy (halogen, hydroxyl, oxo, C) ３ ~C ６ Cycloalkyl, C ５ ~C ６ (Can be optionally substituted with aryl and 1-2 groups selected from 3-6 membered heterocyclyls) or together, C ３ ~C ７ Cycloalkyl (halogen, hydroxyl, oxo, C) １ ~C ４ Alkyl, C １ ~C ４ Haloalkyl, C ３ ~C ６ Cycloalkyl, C ５ ~C ６ They may be optionally substituted with aryl groups and 1-2 groups selected from 3-6 membered heterocyclines. The compound of formula III mentioned above, 【Chemistry 879-1】 【Chemistry 879-2】 【Chemistry 879-3】 【Chemistry 879-4】 【Chemistry 879-5】 【Chemistry 879-6】 A compound of formula III, a tautomer thereof, or a deuterated derivative of the compound or tautomer thereof, or a pharmaceutically acceptable salt of any of the aforementioned, selected from the tautomers thereof, or deuterated derivatives of the compound or tautomer thereof, and any of the aforementioned pharmaceutically acceptable salts.

12. A compound of formula IV, 【Chemical 875】 During the ceremony, Ring D is 【Chemical 876】 And, Q is selected from -C- and -N-. W is -CH-, -C(F)-, -C(CF ３ ) -, and -N- are selected, X １ , X ２ , and X ３ However, each is independently selected from -CH- and -N-, X ４ However, selected from C and N, Y is -N-, -N(R ｙ )-,-C(R ｙ ) -, and -O- are selected, R ｙ However, hydrogen, halogen, C １ ~C ８ Haloalkyl, cyano, -NH ２ , C ３ ~C ６ Cycloalkyl, C １ ~C ８ Alkyl (-OH and C １ ~C ８ (Can be optionally substituted with a group selected from alkoxy groups), -NHC(O)OC １ ~C ８ Selected from alkyl groups (which can be optionally substituted with groups selected from -OH and halogens), Z is -CR ｚ -, -O-, -S-, -S(O)-, -S(O) ２ - and -N- are selected, R ｚ However, hydrogen, halogens, and C １ ~C ８ Alkyl (C １ ~C ８ Selected from which can be optionally substituted with an alkoxy, R ０ However, C １ ~C ２ Selected from alkyl groups, R １ However, C ３ ~C ６ Cycloalkyl, C １ ~C ８ Alkoxy and C １ ~C ８ Alkyl (C １ ~C ８ Alkoxy, C ４ ~C ６ Cycloalkyl, C ５ ~C ６ (Can be optionally substituted with groups selected from aryl, 4-6 membered heterocyclyl, and 4-6 membered heteroaryl groups.) R ２ However, hydrogen, halogen, C １ ~C ８ Alkyl, C １ ~C ８ Haloalkyl and C １ ~C ８ Selected from alkoxy, R ３ａ and R ３ｂ These independently produce hydrogen, halogen, and C. １ ~C ８ Alkyl (halogen, hydroxyl, oxo, C) ３ ~C ６ Cycloalkyl, C ５ ~C ６ (Can be optionally substituted with aryl and 1-2 groups selected from 3-6 membered heterocyclyl groups) C １ ~C ８ Alkoxy (halogen, hydroxyl, oxo, C) ３ ~C ６ Cycloalkyl, C ５ ~C ６ (Can be optionally substituted with 1-2 groups selected from aryl and 3-6 membered heterocyclyl groups) or together, oxo and C ３ ~C ７ Cycloalkyl (halogen, hydroxyl, oxo, C) １ ~C ４ Alkyl, C １ ~C ４ Haloalkyl, C ３ ~C ６ Cycloalkyl, C ５ ~C ６ A group may be formed which is optionally substituted with one or two groups selected from aryl and 3- to 6-membered heterocyclyl groups. R ４ but, Halogen, C １ ~C ８ Haloalkyl and C １ ~C ８ C can be optionally substituted with 1 to 3 groups independently selected from the alkyl group. ３ ~C ８ Cycloalkyl, and ・C １ ~C ９ Alkyl, -OH ・C ３ ~C ８ Cycloalkyl (C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogens, and C １ ~C ８ (Can be optionally substituted with one or two groups selected from haloalkyl groups.) ・C １ ~C ８ Haloalkyl, -OC ３ ~C ７ Cycloalkyl (C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogens, and C １ ~C ８ (Can be optionally substituted with one or two groups selected from haloalkyl groups.) Phenyl (C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogens, and C １ ~C ８ (Can be optionally substituted with a group selected from haloalkyl groups.) ・C １ ~C ８ Alkoxy (C ３ ~C ６ They can be optionally substituted with groups selected from cycloalkyl and phenyl groups, or optionally substituted with 1 to 3 halogen atoms. 4-6 member heterocycline (halogen, C) １ ~C ８ Haloalkyl, C １ ~C ８ Alkyl and C １ ~C ８ (Can be optionally substituted with one or two groups independently selected from the alkoxy), and • Silicon (C) １ ~C ８ Alkyl, C １ ~C ８ Alkoxy and C １ ~C ８ C １ ~C ９ Selected from alkyl groups, R ５ａ and R ５ｂ These independently produce hydrogen, halogen, and C. １ ~C ８ Alkyl (halogen, hydroxyl, oxo, C) ３ ~C ６ Cycloalkyl, C ５ ~C ６ (Can be optionally substituted with aryl and 1-2 groups selected from 3-6 membered heterocyclyl groups) C １ ~C ８ Alkoxy (halogen, hydroxyl, oxo, C) ３ ~C ６ Cycloalkyl, C ５ ~C ６ (Can be optionally substituted with 1-2 groups selected from aryl and 3-6 membered heterocyclyl groups) or together, oxo and C ３ ~C ７ Cycloalkyl (halogen, hydroxyl, oxo, C) １ ~C ４ Alkyl, C １ ~C ４ Haloalkyl, C ３ ~C ６ Cycloalkyl, C ５ ~C ６ A group may be formed which is optionally substituted with one or two groups selected from aryl and 3- to 6-membered heterocyclyl groups. R ６ However, cyano, halogen, 4-6 member heterocyclyl, 5-6 member heteroaryl (C) １ ~C ８ (Can be optionally substituted with one or two groups selected from alkyl groups), C ３ ~C ８ Cycloalkyl (C １ ~C ８ Alkyl, C １ ~C ８ Phenylen, and C (which can be optionally substituted with a group selected from haloalkyl and halogen groups). １ ~C ８ Alkyl (C １ ~C ８ Alkoxy, C １ ~C ８ Haloalkyl, halogen, oxo, -OH, -NH ２ , and -SO ２ CH ３ (Can be arbitrarily substituted by one or two elements independently selected from) R ７ However, selected from O and NR, R is hydrogen and C １ ~C ８ Selected from alkyl groups, However, if the compound of formula IV is, Table 18-1 Table 18-2 A compound of formula IV, a compound of formula IV, a compound of formula IV, a compound of formula IV, a compound of formula IV, a compound of formula IV, a compound of formula IV, a compound of formula IV, a compound of formula IV, or a salt of formula IV that is not selected from the tautomer, the compound or a deuterated derivative of the tautomer, or any of the aforementioned pharmaceutically acceptable salts. 【Request Item 13】 【Chemistry 880-1】 【Chemical 880-2】 【Chemical 880-3】 【Chemical 880-4】 【Chemical 880-5】 【Chemical 880-6】 【Chemical 880-7】 【Chemistry 880-8】 【Chemistry 880-9】 【Chemical 880-10】 【Chemical 880-11】 【Chemistry 880-12】 【Chemistry 880-13】 【Chemistry 880-14】 【Chemical 880-15】 【Chemistry 880-16】 【Chemistry 880-17】 【Chemistry 880-18】 【Chemistry 880-19】 【Chemical 880-20】 【Chemistry 880-21】 【Chemistry 880-22】 A compound selected from the tautomer, the deuterated derivative of the compound and its tautomer, and any pharmaceutically acceptable salt of the foregoing.

14. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 13, and a pharmaceutical carrier.

15. The pharmaceutical composition according to claim 14, for use in treating cystic fibrosis.

16. Use of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 13 in the manufacture of a drug for the treatment of cystic fibrosis.

17. Formula: 【Chemical Formula 881】 The tautomer, the compound or a deuterated derivative of the tautomer, or any pharmaceutically acceptable salt of any of the above.

18. A pharmaceutical composition comprising the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in Claim 17, and a pharmaceutically acceptable carrier.

19. A composition or pharmaceutical composition for use in treating cystic fibrosis, comprising the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in claim 17, or the pharmaceutical composition described in claim 18.

20. Use of the pharmaceutical composition according to claim 18 in the manufacture of a drug for treating cystic fibrosis.

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