Modulators of cystic fibrosis transmembrane conductance regulators

Abstract

The present disclosure provides modulators of cystic fibrosis transmembrane conductance regulatory factor (CFTR), pharmaceutical compositions containing at least one such modulator, methods of treating CFTR-mediated diseases, including cystic fibrosis, using such modulators and pharmaceutical compositions, combination pharmaceutical compositions and combination therapies employing these modulators, and methods of treating CFTR-mediated diseases, including cystic fibrosis. And processes and intermediates for preparing such modulators.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of priority to U.S. application 63 / 328,097, filed April 6, 2022, and U.S. application 63 / 393,405, filed July 29, 2022, the disclosures of which are incorporated herein by reference in their entireties. Technical Field

[0003] The present disclosure relates to modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), pharmaceutical compositions containing the modulators, methods of using such modulators to treat CFTR-mediated diseases including cystic fibrosis, uses of such modulators, combination therapies and combination pharmaceutical compositions, and methods and intermediates for preparing such modulators. Background Art

[0004] Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 70,000 children and adults worldwide. Despite progress in treatment, CF remains incurable.

[0005] In CF patients, mutations in CFTR, an endogenously expressed gene in the respiratory epithelium, lead to reduced apical anion secretion, resulting in an imbalance in ion and fluid transport. The resulting reduction in anion transport leads to increased mucus accumulation in the lungs, accompanied by microbial infections, and ultimately leads to death in CF patients. In addition to respiratory problems, CF patients often suffer from gastrointestinal problems and pancreatic insufficiency, which can lead to death if left untreated. In addition, most men with cystic fibrosis are infertile, and women with cystic fibrosis have reduced fertility.

[0006] Sequence analysis of the CFTR gene has revealed numerous disease-causing mutations (Cutting, GR et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem, BS et al. (1989) Science 245:1073-1080; Kerem, BS et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, over 2,000 mutations in the CF gene have been identified; currently, the CFTR2 database contains information on only 432 of these identified mutations, with sufficient evidence to define 352 mutations as pathogenic. The most common pathogenic mutation is a phenylalanine deletion 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.

[0007] The deletion of residue 508 in CFTR prevents the nascent protein from folding correctly. This causes the mutant protein to be unable to leave the endoplasmic reticulum (ER) and be transported to the plasma membrane. Therefore, the number of CFTR channels present in the membrane for anion transport is much lower than the number observed in cells expressing wild-type CFTR, i.e., CFTR without mutation. In addition to impaired transport, mutations lead to defective channel gating. The reduction of the number of channels in the membrane and the gating defect together lead to a reduction in anion and fluid transepithelial transport. (Quinton, PM (1990), FASEB J.4:2709-2727). Due to the F508del mutation, the defective channel is still functional, although its function is less than that of the wild-type CFTR channel. (Dalemans et al. (1991), Nature Lond.354:526-528; Pasyk and Foskett (1995), J.Cell.Biochem.270:12347-50). In addition to F508del, other pathogenic mutations in CFTR that result in defective trafficking, synthesis, and / or channel gating may be upregulated to alter anion secretion and modify disease progression and / or severity.

[0008] CFTR is a cAMP / ATP-mediated anion channel expressed in various cell types comprising absorptive and secretory epithelial cells, wherein the CFTR regulates transmembrane anion flux and the activity of other ion channels and proteins. In epithelial cells, the normal function of CFTR is crucial for maintaining the transport of electrolytes throughout the body (comprising respiratory and digestive tissues). CFTR is composed of 1480 amino acids encoding a protein, and the protein is composed of tandem repeats of a transmembrane domain, each of which contains six transmembrane helices and a nucleotide binding domain. Two transmembrane domains are connected to multiple phosphorylation sites by large polarity regulation (R) domains, thereby regulating channel activity and cellular transport.

[0009] Chloride transport occurs through ENaC and CFTR present on the apical membrane and Na+ expressed on the basolateral surface of cells. + -K + -ATPase pump and Cl - Secondary active transport of chloride ions from the lumen leads to accumulation of chloride ions in the cell, which can then - The channel passively exits the cell, leading to mediator transport. + / 2Cl - / K + Co-transporter, Na + -K + -ATPase pump and basolateral membrane K on the basolateral surface +The arrangement of channels and CFTR on the luminal side coordinates chloride secretion via CFTR on the luminal side. Since water itself may not be actively transported, its flow across the epithelium depends on the small transepithelial osmotic gradient generated by the bulk flow of sodium and chloride ions.

[0010] A number of CFTR modulating compounds have recently been identified. However, there remains a need for compounds that can treat or alleviate cystic fibrosis and other CFTR-mediated diseases, and particularly the more severe forms of these diseases. Summary of the Invention

[0011] One aspect of the present disclosure provides novel compounds, including compounds of formula I, including compounds of any one of formulas 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 one of the foregoing. Another aspect of the present disclosure provides compounds of formula II, formula III, and formula IV, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any one of the foregoing. Another aspect of the present disclosure provides 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 one of the foregoing.

[0012] Formula I encompasses compounds within the following structures:

[0013]

[0014] Tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein:

[0015] Ring A is

[0016] Q is selected from -C- and -N-;

[0017] W is selected from -CH-, -C(F)-, -C(CF3)- and -N-;

[0018] X 1 、X 2 and X 3 are each independently selected from -CH- and -N-;

[0019] Y is selected from -N-, -N(R y )-、-C(R y )- and -O-, where

[0020] R y Selected from hydrogen, halogen, C1-C8 haloalkyl, cyano, -NH2, C3-C6 cycloalkyl, C1-C8 alkyl (which may be optionally substituted by a group selected from -OH and C1-C8 alkoxy), -NHC(O)OC1-C8 alkyl (which may be optionally substituted by a group selected from -OH and halogen);

[0021] Z is selected from -CH-, -O-, -S-, -S(O)-, -S(O)2-, -N- and -NR z ,in

[0022] R z Selected from hydrogen and C1-C8 alkyl;

[0023] R 1 Selected from: C3-C6 cycloalkyl, C1-C8 alkoxy and C1-C8 alkyl (which may be optionally substituted by a group selected from C4-C6 cycloalkyl, C5-C6 aryl, 4 to 6-membered heterocyclyl and 4 to 6-membered heteroaryl);

[0024] R 2 Selected from: hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl and C1-C8 alkoxy;

[0025] R 3a and R 3b independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl);

[0026] R 4 Selected from:

[0027] 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

[0028] C1-C9 alkyl, which may be optionally substituted with 1 to 2 groups independently selected from the following:

[0029] ●C3-C8 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0030] ●C1-C8 haloalkyl;

[0031] ●OC3-C7 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0032] ●phenyl (which may be optionally substituted by a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0033] ●C1-C8 alkoxy (which may be optionally substituted by a group selected from C3-C6 cycloalkyl and halogen);

[0034] ● 4 to 6 membered heterocyclyl (which may be optionally substituted with 1 to 2 groups independently selected from halogen, C1-C8 haloalkyl, C1-C8 alkyl and C1-C8 alkoxy); and

[0035] Silicon (which may be optionally substituted with 1 to 3 groups independently selected from C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 haloalkyl);

[0036] R 5a and R 5b independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl);

[0037] R 6 is selected from halogen, 4 to 6 membered heterocyclyl, C3-C8 cycloalkyl (which may be optionally substituted by a group selected from C1-C8 alkyl, C1-C8 haloalkyl and halogen); and C1-C8 alkyl (which may be optionally substituted by 1 to 2 groups independently selected from C1-C8 alkoxy, halogen, oxo, -OH, -NH2 and -SO2CH3); and

[0038] R 7 Selected from O and NR, where

[0039] R is selected from hydrogen and C1-C8 alkyl.

[0040] Formula I also includes compounds of V:

[0041]

[0042]

[0043]

[0044] Tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein all variables are as defined for Formula I.

[0045] In some embodiments, the compound of Formula I is selected from Compounds 1-1 to 1-265, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0046] Formula II encompasses compounds within the following structures:

[0047]

[0048] Tautomers thereof, or deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein:

[0049] Ring B is a 6-membered heteroaryl group, which is optionally substituted with 1 to 2 groups independently selected from:

[0050] Halogen

[0051] ◆4 to 10 membered heterocyclic group (which may be optionally substituted by 1 to 3 groups independently selected from halogen, oxo, C1-C4 alkyl)

[0052] ◆N(R x )2, where R x 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)

[0053] C1-C4 alkyl (optionally substituted by C3-C6 cycloalkyl (which may further optionally be substituted by a group selected from halogen, OH))

[0054] R 1 Selected from: C3-C6 cycloalkyl, C1-C6 alkoxy and C1-C6 alkyl (which may be optionally substituted by a group selected from C4-C6 cycloalkyl, C4-C6 aryl, 4 to 6-membered heterocyclyl and 4 to 6-membered heteroaryl);

[0055] R 2 Selected from: hydrogen, halogen, C1-C8 alkyl, C1-C4 haloalkyl and C1-C8 alkoxy;

[0056] R 3a and R 3b independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl);

[0057] R 4 Selected from:

[0058] 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

[0059] C1-C9 alkyl, which may be optionally substituted with 1 to 2 groups independently selected from the following:

[0060] ●C3-C8 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0061] ●C1-C8 haloalkyl;

[0062] ●phenyl (which may be optionally substituted by a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0063] ●C1-C8 alkoxy (which may be optionally substituted by a group selected from C3-C6 cycloalkyl and halogen);

[0064] ● 4 to 6 membered heterocyclyl (which may be optionally substituted with 1 to 2 groups independently selected from halogen, C1-C8 haloalkyl, C1-C8 alkyl and C1-C8 alkoxy); and

[0065] Silicon (which may be optionally substituted with 1 to 3 groups independently selected from C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 haloalkyl);

[0066] R 5a and R5b independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl).

[0067] In some embodiments, Ring B in the compound, tautomer, deuterated derivative, or salt of Formula II is selected from:

[0068]

[0069] In some embodiments, the compound of Formula II is selected from Compounds II-1 to II-38, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0070] Formula III encompasses compounds within the following structures:

[0071]

[0072] or a tautomer thereof, or a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0073] Ring C is selected from:

[0074]

[0075] and in

[0076] Each R c independently selected from hydrogen, halogen, cyano, amino, C1-C4 alkyl (which may be optionally substituted by a group selected from -OH, halogen and oxo) and C3-C6 alkenyl;

[0077] R 1 Selected from: C3-C6 cycloalkyl, C1-C6 alkoxy and C1-C6 alkyl (which may be optionally substituted by a group selected from C4-C6 cycloalkyl, C4-C6 aryl, 4 to 6-membered heterocyclyl and 4 to 6-membered heteroaryl);

[0078] R 2Selected from: hydrogen, halogen, C1-C8 alkyl, C1-C4 haloalkyl and C1-C8 alkoxy;

[0079] R 3a and R 3b independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl);

[0080] R 4 Selected from:

[0081] 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

[0082] C1-C9 alkyl, which may be optionally substituted with 1 to 2 groups independently selected from the following:

[0083] ●C3-C8 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0084] ●C1-C8 haloalkyl;

[0085] ●phenyl (which may be optionally substituted by a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0086] ●C1-C8 alkoxy (which may be optionally substituted by a group selected from C3-C6 cycloalkyl and halogen);

[0087] ● 4 to 6 membered heterocyclyl (which may be optionally substituted with 1 to 2 groups independently selected from halogen, C1-C8 haloalkyl, C1-C8 alkyl and C1-C8 alkoxy); and

[0088] Silicon (which may be optionally substituted with 1 to 3 groups independently selected from C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 haloalkyl);

[0089] R 5a and R 5bindependently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl).

[0090] In some embodiments, the compound of Formula III is selected from Compounds III-1 to III-25, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0091] Formula IV encompasses compounds within the following structures:

[0092]

[0093] or a tautomer thereof, or a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0094] Ring D is

[0095] Q is selected from -C- and -N-;

[0096] W is selected from -CH-, -C(F)-, -C(CF3)- and -N-;

[0097] X 1 、X 2 and X 3 are each independently selected from -CH- and -N-;

[0098] X 4 Selected from C and N;

[0099] Y is selected from -N-, -N(R y )-、-C(R y )- and -O-, where

[0100] R y Selected from hydrogen, halogen, C1-C8 haloalkyl, cyano, -NH2, C3-C6 cycloalkyl, C1-C8 alkyl (which may be optionally substituted by a group selected from -OH and C1-C8 alkoxy), -NHC(O)OC1-C8 alkyl (which may be optionally substituted by a group selected from -OH and halogen);

[0101] Z is selected from -CR z -, -O-, -S-, -S(O)-, -S(O)2-, -N- and -NR z ,in

[0102] R z is selected from hydrogen, halogen and C1-C8 alkyl (which may be optionally substituted by C1-C8 alkoxy);

[0103] R 0 Selected from C1-C2 alkyl;

[0104] R 1 Selected from: C3-C6 cycloalkyl, C1-C8 alkoxy and C1-C8 alkyl (which may be optionally substituted by a group selected from C1-C8 alkoxy, C4-C6 cycloalkyl, C5-C6 aryl, 4 to 6-membered heterocyclyl and 4 to 6-membered heteroaryl);

[0105] R 2 Selected from: hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl and C1-C8 alkoxy;

[0106] R 3a and R 3b independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl);

[0107] R 4 Selected from:

[0108] 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

[0109] C1-C9 alkyl, which may be optionally substituted with 1 to 2 groups independently selected from the following:

[0110] -OH

[0111] ●C3-C8 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0112] ●C1-C8 haloalkyl;

[0113] -OC3-C7 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0114] ●phenyl (which may be optionally substituted by a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0115] ●C1-C8 alkoxy (which may be optionally substituted by a group selected from C3-C6 cycloalkyl and phenyl; or which may be optionally substituted by 1 to 3 halogen atoms);

[0116] ● 4 to 6 membered heterocyclyl (which may be optionally substituted with 1 to 2 groups independently selected from halogen, C1-C8 haloalkyl, C1-C8 alkyl and C1-C8 alkoxy); and

[0117] Silicon (which may be optionally substituted with 1 to 3 groups independently selected from C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 haloalkyl);

[0118] R 5a and R 5b independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl);

[0119] 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 to 2 groups selected from C1-C8 alkyl), C3-C8 cycloalkyl (which may be optionally substituted with a group selected from C1-C8 alkyl, C1-C8 haloalkyl and halogen), phenyl and C1-C8 alkyl (which may be optionally substituted with 1 to 2 groups independently selected from C1-C8 alkoxy, C1-C8 haloalkyl, halogen, oxo, -OH, -NH2 and -SO2CH3); and

[0120] R 7 Selected from O and NR, where

[0121] R is selected from hydrogen and C1-C8 alkyl.

[0122] In some embodiments, the compound of Formula IV is selected from compounds IV-1 to IV-106, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0123] Another aspect of the present disclosure provides a pharmaceutical composition comprising at least one compound selected from the novel compounds disclosed herein, its tautomers, deuterated derivatives of these compounds and tautomers, and a pharmaceutically acceptable salt of any of the foregoing, and at least one pharmaceutically acceptable carrier, the composition 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.

[0124] Therefore, another aspect of the present disclosure provides a method for treating CFTR-mediated disease cystic fibrosis, comprising administering to a subject in need thereof at least one compound selected from the novel compounds disclosed herein, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one pharmaceutically acceptable carrier, optionally as part of a pharmaceutical composition comprising at least one additional component. In some embodiments, the at least one additional active pharmaceutical ingredient in the methods of treatment disclosed herein is at least one other CFTR modulator. In some embodiments, the at least one other CFTR modulator is selected from a CFTR potentiator and a CFTR corrector.

[0125] In certain embodiments, the pharmaceutical compositions of the present disclosure comprise at least one compound selected from the group consisting of compounds of Formula I, including compounds of any one of Formulas Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, and If(i), 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 the group consisting of compounds of Formula 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 the group consisting of compounds of Formula 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 the group consisting of: a compound of Formula IV, its tautomers, 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 the group consisting of: compounds I-1 to I-265, compounds II-1 to II-38, compounds III-1 to III-25, compounds IV-1 to IV-106, its tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0126] In some embodiments, the composition comprising at least one compound selected from the group consisting of compounds of Formula I (including compounds of any one 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 these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, may optionally further comprise (a) at least one (i.e., one or more) compounds selected from the group consisting of: (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2- (1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (tizzacato), 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (lumacato), tizzacato and deuterated derivatives of lumacato, and pharmaceutically acceptable salts of any of the foregoing; and / or (b) at least one (i.e., one or more) compound selected from the group consisting of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (ivacato), 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 (deuteroticator), (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-tetraazatricyclo[[12.3.1.12,5]nonadeca-1(18),2,4 ,14,16-pentaen-6-ol; ivacaftor, deuterated ivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives of (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol; and pharmaceutically acceptable salts of any of the foregoing.

[0127] In some embodiments, the 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 may optionally further comprise (a) at least one (i.e., one or more) compounds selected from the following: (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylprop-2-yl)-1 (i) benzoic acid (rumacato), tizacato and deuterated derivatives of rumacato, and pharmaceutically acceptable salts of any of the foregoing; and / or (b) at least one (i.e., one or more) compounds selected from the group consisting of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (ivacato), N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)prop- 2-amino-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (deuteroticator), (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-tetraazatricyclo[[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol 6-pentaen-6-ol; ivacaftor, deuterated ivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives of (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol; and pharmaceutically acceptable salts of any of the foregoing.

[0128] Another aspect of the present disclosure provides a method of treating the CFTR-mediated disease cystic fibrosis, comprising administering to a patient in need thereof at least one compound selected from the novel compounds disclosed herein, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing, and optionally further administering one or more additional CFTR modulators selected from tizacator, ivacaftor, and lumacaftor.

[0129] On the other hand, 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 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 pharmaceutical compositions comprising these compounds and optionally further comprising one or more CFTR modulators are used in treatment or for the manufacture of a medicament. In some embodiments, the one or more additional CFTR modulators are selected from CFTR potentiators. In some embodiments, the one or more additional CFTR modulators are selected from CFTR correctors. In some embodiments, the one or more additional CFTR modulators are selected from tizacator, lumacator, ivacaftor, deuterated tizacator, (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-tetraazatricyclo[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.

[0130] Additional aspects of the disclosure provide intermediates and methods for preparing the compounds and compositions disclosed herein.

[0131] definition

[0132] As used herein, "tizacator" refers to (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, which can be depicted by the following structure:

[0133]

[0134] Tizacator may be in the form of a deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative. Tizacator and methods of making and using tizacator are disclosed in WO 2010 / 053471, WO 2011 / 119984, WO 2011 / 133751, WO 2011 / 133951, WO 2015 / 160787, and US 2009 / 0131492, each of which is incorporated herein by reference.

[0135] "Ivacaftor" as used throughout this disclosure is N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, which is depicted by the following structure:

[0136]

[0137] Ivacaftor can 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 WO 2006 / 002421, WO 2007 / 079139, WO 2010 / 108162, and WO 2010 / 019239, each of which is incorporated herein by reference.

[0138] In some embodiments, a deuterated derivative of ivacaftor (deuterated ivacaftor) is used in the compositions and methods disclosed herein. The chemical name of deuterated 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, as depicted in the following structure:

[0139]

[0140] Deuterated cattor can be in the form of another deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative. Deuterated cattor and methods of making and using deuterated cattor are disclosed in WO 2012 / 158885, WO 2014 / 078842, and U.S. Patent No. 8,865,902, each of which is incorporated herein by reference.

[0141] As used herein, "lumacatol" refers to 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, the chemical structure of which is depicted below:

[0142]

[0143] Lumacator may be in the form of a deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative. Lumacator and methods of making and using lumacator are disclosed in WO 2007 / 056341, WO 2009 / 073757, and WO 2009 / 076142, which are incorporated herein by reference.

[0144] (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives and pharmaceutically acceptable salts are described in WO 2022 / 032068, which is incorporated herein by reference.

[0145] (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[12.3.1.12,5]nonadecan-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.

[0146] 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), which may contain double (alkenyl) or tris (alkynyl) bonds between one or more sets of adjacent carbon atoms. Alkyl groups may be substituted or unsubstituted.

[0147] As used herein, the term "aliphatic" or "aliphatic group" means a straight chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or an aromatic (also referred to herein as "alicyclic," "carbocycle," or "cycloalkyl") monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units but is not 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 still 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, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C 2-4 aliphatic carbon atom that is fully saturated or contains one or more unsaturated units. 3-8 Hydrocarbon or bicyclic or tricyclic C 8-14 A hydrocarbon, but not aromatic, having a single point of attachment to the rest of the molecule, wherein any individual ring in the bicyclic ring system has 3-7 members. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, and (cycloalkyl)alkenyl. Suitable cycloaliphatic groups include cycloalkyl, bicyclic cycloalkyl (e.g., decalin), bridged bicyclic cycloalkyl (e.g., norbornyl or [2.2.2]bicyclo-octyl), and bridged tricyclic (e.g., adamantyl).

[0148] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0149] As used herein, the term "π bond" refers to a covalent bond formed by the p orbitals of adjacent atoms. A π bond exists when there are multiple bonds (i.e., double or triple bonds) 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.

[0150] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms, such as a fluoroalkyl group, which refers to an alkyl group substituted with one or more fluorine atoms. In certain embodiments, one carbon atom of an alkyl group is substituted with one or more halogen atoms. In certain embodiments, each carbon atom of an alkyl group is substituted with one or more halogen atoms. In certain embodiments, one or more carbon atoms of an alkyl group is a perhalogenated carbon atom (i.e., all hydrogen atoms of an alkyl group are substituted with halogen atoms). In certain embodiments, each carbon atom of an alkyl group is a perhalogenated carbon atom. Non-limiting examples of fluoroalkyl groups include -CHF2, -CH2F, -CF3, -CF2- and perhalogenated alkyl groups, such as -CF2CF3.

[0151] As used herein, the term "halogen" or "halo" means F, Cl, Br, or I.

[0152] As used herein, the terms "oxo" and "=0" refer to a substituent oxygen atom attached to another atom through a double bond.

[0153] As used herein, the term "alkoxy" refers to an alkyl or cycloalkyl group covalently bonded to an oxygen atom. An alkoxy group may be substituted or unsubstituted.

[0154] As used herein, " cycloalkyl " refers to a cyclic, bicyclic, tricyclic or polycyclic non-aromatic hydrocarbon group with 3 to 12 carbons (such as 3-10 carbons) and can include one or more unsaturated bonds." cycloalkyl " encompasses monocycle, bicyclic, tricyclic, bridged ring, fused ring and spirocycle, including single spirocycle and dispirocycle. The limiting examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, two spiral [2.0.2.1] heptane, bicyclo [1.1.1] pentane and spiral [2,3] hexane. Cycloalkyl can be substituted or unsubstituted.

[0155] As used herein, the term "aryl" is a functional group or substituent derived from an aromatic ring and encompasses monocyclic aromatic rings and bicyclic, tricyclic and fused ring systems, wherein at least one ring in the system is aromatic. Aryl may optionally be substituted with one or more substituents. Non-limiting examples of aryl include phenyl, naphthyl and 1,2,3,4-tetrahydronaphthyl.

[0156] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substituent of a heterocyclic ring, such as nitrogen N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl)).

[0157] As used herein, the term "heteroaliphatic" refers to an aliphatic group in which one or two carbon atoms are independently replaced by 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 "heterocycloaliphatic" groups.

[0158] As used herein, the term "heteroaryl ring" refers to an aromatic ring comprising at least one ring atom that is a heteroatom such as O, N or S. Heteroaryl encompasses monocyclic and bicyclic, tricyclic, bridged, fused and spirocyclic systems (including monospiro and dispiro) having a total of five to fourteen ring members, wherein 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 three to seven ring members. Non-limiting examples of heteroaryl rings include pyridine, quinoline, indole and dihydroindole. Heteroaryl can optionally be substituted with one or more substituents. In certain embodiments, the term "heteroaryl ring" encompasses heteroaryl rings with various oxidation states, such as heteroaryl rings containing N-oxides and sulfoxides. Non-limiting examples of such heteroaryl rings include pyrimidine N-oxides, quinoline N-oxides, thiophene S-oxides and pyrimidine N-oxides.

[0159] As used herein, the term "heterocyclyl ring" refers to a non-aromatic hydrocarbon containing 3 to 12 atoms (e.g., 3-10 atoms) in the ring, the ring including at least one ring atom which is a heteroatom such as O, N, or S and which may contain one or more unsaturated bonds. "Heterocyclyl" rings encompass monocyclic, bicyclic, tricyclic, polycyclic, bridged, fused, and spirocyclic rings, including monospirocyclic and dispirocyclic rings.

[0160] Key Name It is intended to reflect the presence of an aromatic (ie, conjugated) ring system. It is understood that Ring A in Formula I comprises a six-membered aryl or heteroaryl ring fused to a five-membered aryl or heteroaryl ring.

[0161] It is understood that certain compounds of the present disclosure may exist as individual stereoisomers or enantiomers and / or mixtures of such stereoisomers or enantiomers. As used in the chemical structures disclosed herein, the "wedge" of the stereoisomers is not necessarily the same as the "wedge" of the stereoisomers. or "hash" A bond indicates a chiral center of known absolute stereochemistry (ie, one stereoisomer). As used in the chemical structures disclosed herein, a "wavy" bond to a stereogenic atom 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-bonded carbon indicates a mixture of E / Z isomers. As used in the chemical structures disclosed herein, the A ("straight") bond indicates that a mixture (eg, a racemate or an enrichment) is present. As used herein, the two carbon atoms of a double bond are ("straight") bonds indicate double bonds with E / Z stereochemistry as drawn. As used in the chemical structures disclosed herein, (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 end of the bond that ends at the "wavy" line. As used herein, stereoatoms labeled with (R) or (S) indicate the stereochemical designation of the stereoatom under the Cahn-Ingold-Perlog convention.

[0162] Some compounds can exist as atropisomers. It should be understood that some compounds of the present disclosure can exist as separated atropisomers and / or mixtures of these atropisomers, that is, subclasses of stereoisomers, which are caused by hindered rotation around a single bond or chiral axis and can be separated into separate chemical species. As used herein, the stereoisomerization source unit represented by (P) or (M) indicates the stereochemical nomenclature of the stereoisomerization source unit according to the Cahn-Ingold-Prelog rule (basic terms of stereochemistry, IUPAC Recommendations 1996, Pure & Appl. Chem., Vol. 68, No. 12, pp. 2193-2222, 1996).

[0163] Certain compounds disclosed herein may exist as tautomers, and both tautomeric forms are contemplated, even if only a single tautomeric structure is depicted. For example, a description of compound X should be understood to encompass its tautomer, compound Y, and vice versa, as well as mixtures thereof:

[0164]

[0165] Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0166] "Tert" and "t-" are used interchangeably and mean tertiary.

[0167] The compounds described herein may be optionally substituted with one or more substituents, as generally shown above, or as exemplified by specific classes, subclasses, and species of the present disclosure. It should be understood that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." "Substituted," whether or not preceded by the term "optionally," indicates that at least one hydrogen in 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 more than one position in any given structure can be substituted by more than one substituent selected from a specified group, the substituent at each position may be the same or different. The combination of substituents contemplated by the present disclosure is preferably a combination of substituents that results in the formation of stable or chemically feasible compounds.

[0168] As used herein, the term "stable" refers to a compound that is not substantially altered when subjected to conditions that allow for its production, detection, and preferably its recovery, purification, and use for one or more of the purposes disclosed herein.

[0169] As used herein, the term "stable compound" refers to a compound that has sufficient stability to allow its manufacture and is capable of maintaining the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into a therapeutic product, an intermediate for producing a therapeutic compound, an isolatable or storable intermediate, and / or treatment of a disease or condition responsive to a therapeutic agent).

[0170] 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 indicated, when a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen in its natural abundance isotopic composition.

[0171] As used herein, the term "derivative" refers to a collection of molecules having the same chemical structure as the compounds of the present disclosure, except that one or more atoms of the molecule may have been replaced by another atom. In addition, unless otherwise indicated, structures described herein are also intended to encompass compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to replacing hydrogen with deuterium or tritium or replacing 13 C or 14 Compounds having the present structures except for the substitution of carbon by C are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools, probes in biological assays, or compounds with improved therapeutic properties.

[0172] As used herein, a "deuterated derivative" refers to a compound having the same chemical structure as a reference compound, with one or more hydrogen atoms replaced by a deuterium atom. In some embodiments, the one or more hydrogen atoms replaced by deuterium are part of an alkyl group. In some embodiments, the one or more hydrogen atoms replaced by deuterium are part of a methyl group. In chemical structures, deuterium can be represented as "D."

[0173] As used herein, "CFTR" means cystic fibrosis transmembrane conductance regulator.

[0174] As used herein, the term "modulator" refers to a compound that increases the activity of a biological compound or molecule, such as a protein.

[0175] As used herein, the term "CFTR modulator" refers to a compound that increases CFTR activity. Increased activity caused by a CFTR modulator includes, but is not limited to, compounds that correct, enhance, stabilize, and / or amplify CFTR.

[0176] As used herein, the terms "corrector" and "CFTR corrector" are used interchangeably and refer to compounds that promote the processing and trafficking of CFTR to increase the amount of CFTR on the cell surface. The novel compounds disclosed herein are CFTR correctors. Tizacator and lumacator, as referred to herein, and their deuterated derivatives and pharmaceutically acceptable salts, are correctors.

[0177] As used herein, the terms "potentiator" and "CFTR potentiator" refer to compounds that increase the channel activity of the CFTR protein located on the cell surface, thereby enhancing ion transport. As mentioned herein, ivacaftor, deuterated vacaftor, (6R, 12R) -17-amino-12-methyl-6, 15-bis (trifluoromethyl) -13, 19-dioxa-3, 4, 18-triazatricyclo [12.3.1.12, 5] 19-deca-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-tetraazatricyclo [12.3.1.12, 5] 19-deca-1 (18), 2, 4, 14, 16-pentaen-6-ol are CFTR potentiators. It will be understood that descriptions of combinations of compounds including 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 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) will generally, but not necessarily, include CFTR potentiators, e.g., ivacaftor, deuterated tautomer, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxolane, Hetero-3,4,18-triazatricyclo[12.3.1.12,5]nonadecan-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-tetraazatricyclo[[12.3.1.12,5]nonadecan-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-tetraazatricyclo[[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 will generally, but not necessarily, contain only a single potentiator, but may contain more than one corrector.Thus, in some embodiments, a combination of at least one compound of the present disclosure (e.g., a compound selected from the group consisting of 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) will include a potentiator selected from the group consisting of ivacaftor, deuterated tautomer, (6R,12R)-17-amino-1 2-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]19-dec-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-tetraazatricyclo[[12.3.1.12,5]19-dec-1(18),2,4,14,16-pentaen-6-ol; or a deuterated derivative or pharmaceutically acceptable salt thereof, and may further include another CFTR corrector, such as a corrector compound selected from tizzacato, lumacato, and deuterated derivatives and pharmaceutically acceptable salts thereof. In some embodiments, such combinations may further include a CFTR potentiator enhancer.

[0178] As used herein, the terms "CFTR potentiator enhancer," "CFTR potentiator enhancer," and "CFTR co-potentiator" are used interchangeably and refer to a compound that enhances the potentiation effect of CFTR.

[0179] When referring to the compounds of the present disclosure, the term "compound" refers to a collection of molecules having the same chemical structure except for possible isotopic variations among the constituent atoms of the molecules.

[0180] The phrase "novel compounds of the present disclosure" refers to compounds selected from the following: compounds of any 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. The phrase "novel compounds of the present disclosure" specifically excludes any compound disclosed in PCT / US2021 / 053858 (incorporated herein by reference).

[0181] As used herein, the term "at least one compound selected from..." means selecting one or more compounds from a specific group. "Selected from" and "selected from" are used interchangeably herein.

[0182] References herein to "compounds 1-1 to 1-265" are intended to refer to each of compounds 1 to 264 encompassed by Formula I, either individually or as a group. Similarly, references to "compounds II-1 to II-38" refer to compounds 1 to 38 encompassed by Formula II, either as a group or as each compound individually. References to "compounds III-1 to III-24" refer to compounds 1 to 24 encompassed by Formula III, either as a group or as each compound individually. References to "compounds IV-1 to IV-106" refer to compounds 1 to 106 encompassed by Formula IV, either as a group or as each compound individually. References to "compounds 1-1 to 1-265, compounds II-1 to II-38, compounds III-1 to III-25, and compounds IV-1 to IV-106" are intended to refer to compounds falling within each of Formulas I, II, III, and IV, either individually or as three separate groups of compounds.

[0183] As used herein, the term "active pharmaceutical ingredient" or "therapeutic agent" ("API") refers to a biologically active compound.

[0184] The terms "patient" and "subject" are used interchangeably and refer to animals, including humans.

[0185] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to the amount of a compound that produces the desired effect for which the compound is administered (e.g., improvement in CF or a symptom of CF, or a decrease in the severity of CF or a symptom of CF). The exact amount of an effective dose will depend on the purpose of the treatment and will be determined by one skilled in the art using known techniques (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0186] As used herein, the terms "treatment," "treating," and the like generally refer to improving one or more symptoms of CF in a subject, or reducing the severity of CF or one or more symptoms of CF. As used herein, "treatment" includes, but is not limited to, the following: increased growth, increased weight gain, reduced lung mucus, improved pancreatic and / or liver function, reduced chest infection, and / or reduced cough or shortness of breath in a subject. Improvement in any of these symptoms or reduction in their severity can be readily assessed according to standard methods and techniques known in the art.

[0187] It should be understood that references herein to methods of treatment (e.g., methods of treating a CFTR-mediated disease or methods of treating cystic fibrosis) using one or more compounds of the present disclosure, optionally in combination with one or more additional CFTR modulators (e.g., a compound selected from the group consisting of compounds of Formula I, 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, optionally in combination with one or more additional CFTR modulators) should also be construed as references to:

[0188] - one or more compounds of the present disclosure (e.g., a compound selected from the group consisting of 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 of treating, for example, cystic fibrosis; optionally in combination with one or more additional CFTR modulators; and / or

[0189] - Use of one or more compounds of the present disclosure (e.g., a compound selected from the group consisting of: a compound of any 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) in the manufacture of a medicament for treating, for example, cystic fibrosis.

[0190] It should also be understood that references herein to methods of treatment (e.g., methods of treating a CFTR-mediated disease or methods of treating cystic fibrosis) using the pharmaceutical compositions of the present disclosure (e.g., pharmaceutical compositions comprising at least one compound selected from the group consisting of: 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) should also be construed as references to:

[0191] - a pharmaceutical composition for use in a method of treating, for example, cystic fibrosis (e.g., a pharmaceutical composition comprising at least one compound selected from the group consisting 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 optionally further comprising one or more additional CFTR modulators); and / or

[0192] - Use of a pharmaceutical composition (e.g., a pharmaceutical composition comprising at least one compound selected from the group consisting 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 optionally further comprising one or more additional CFTR modulators) in the manufacture of a medicament for treating, for example, cystic fibrosis.

[0193] 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 the patient before, simultaneously with or after each other.

[0194] As used herein, when used in conjunction with amount, volume, reaction time, reaction temperature, etc., the terms "about" and "approximately" mean the acceptable error of a particular value determined by one of ordinary skill in the art, which depends in part on how to measure or determine the value. In some embodiments, the terms "about" or "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 "~" that appears immediately before a numerical value has the same meaning as the terms "about" and "approximately."

[0195] The term "at least one" means one or more.

[0196] As used herein, the term "solvent" refers to any liquid in which the product is at least partially soluble (solubility of the product > 1 g / L).

[0197] Non-limiting examples of suitable solvents that can be used in the present disclosure include, for example, water (H2O), methanol (MeOH), dichloromethane (DCM; CH2Cl2), acetonitrile (MeCN; CH3CN), 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 (Et2O), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0198] As used herein, the term "ambient conditions" means room temperature, open air conditions, and uncontrolled humidity conditions. As used herein, the term "room temperature" or "ambient temperature" means 15°C to 30°C.

[0199] As used herein, "mutation" can refer to a mutation in the CFTR gene or the 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. Typically, a gene defect or mutation, or a change in nucleotides in a gene, produces a mutation or frameshift in the CFTR protein translated from the gene.

[0200] As used herein, "minimally functional (MF) mutations" refer to CFTR gene mutations that are associated with minimal CFTR function (very low to no functional CFTR protein) and include, for example, mutations associated with severe defects in the ability of the CFTR channel to open and close, referred to as defective channel gating or "gating mutations"; mutations associated with severe defects in the cellular processing of CFTR and its delivery to the cell surface; mutations associated with no (or minimal) CFTR synthesis; and mutations associated with severe defects in channel transduction.

[0201] As used herein, the term "F508del" refers to a mutant CFTR protein lacking the amino acid phenylalanine at position 508, or to a mutant CFTR gene encoding a CFTR protein lacking the amino acid phenylalanine at position 508.

[0202] The present disclosure also provides methods for preparing salts of compounds of the present disclosure. Salts of compounds of the present disclosure are formed between an acid and a basic group of the compound, such as an amino functional group, or 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.

[0203] As used herein, the term "pharmaceutically acceptable" refers to compositions that are, within the scope of sound medical judgment, suitable for contact with the tissues of humans and other mammals without excessive toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit / risk ratio.

[0204] As used herein, the term "pharmaceutically acceptable salt" means any non-toxic salt that is capable of providing, directly or indirectly, a compound of the present disclosure when administered to a recipient. Pharmaceutically acceptable salts of the compounds of the present disclosure include salts derived from suitable inorganic and organic acids and bases. A "pharmaceutically acceptable counterion" is an ionic portion of a salt that is non-toxic when released from the salt when administered to a recipient. One of ordinary skill in the art will recognize that when the amount of a "compound or a pharmaceutically acceptable salt thereof" is disclosed, the amount of the pharmaceutically acceptable salt form of the compound is an amount equivalent to the concentration of the free base of the compound.

[0205] For example, the "free base" form of a compound does not contain an ionically bonded salt. It should be noted that the disclosed amounts of a compound or a pharmaceutically acceptable salt thereof herein are based on its free base form. For example, "10 mg of at least one compound selected from Compound 1 and a pharmaceutically acceptable salt thereof" includes 10 mg of Compound 1 and a pharmaceutically acceptable salt of Compound 1 in a concentration equivalent to 10 mg of Compound 1.

[0206] Suitable pharmaceutically acceptable salts are, for example, those disclosed in SM Berge et al., J. Pharmaceutical Sciences, 1977, 66, 1-19. For example, Table 1 of that article provides the following pharmaceutically acceptable salts:

[0207] Table 1:

[0208]

[0209]

[0210] Non-limiting examples of pharmaceutically acceptable acid addition salts include salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid; salts formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid; and salts formed by using other methods used in the art, such as ion exchange. Non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbic acid, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts. 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. Additional 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 benzenesulfonates and glucosamine salts.

[0211] CFTR modulator compounds

[0212] In some embodiments, the present disclosure provides compounds of Formula I:

[0213]

[0214] Tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein:

[0215] Ring A is

[0216] Q is selected from -C- and -N-;

[0217] W is selected from -CH-, -C(F)-, -C(CF3)- and -N-;

[0218] X 1 、X 2 and X 3 are each independently selected from -CH- and -N-;

[0219] Y is selected from -N-, -N(R y )-、-C(R y )- and -O-, where

[0220] R y Selected from hydrogen, halogen, C1-C8 haloalkyl, cyano, -NH2, C3-C6 cycloalkyl, C1-C8 alkyl (which may be optionally substituted by a group selected from -OH and C1-C8 alkoxy), -NHC(O)OC1-C8 alkyl (which may be optionally substituted by a group selected from -OH and halogen);

[0221] Z is selected from -CH-, -O-, -S-, -S(O)-, -S(O)2-, -N- and -NR z ,in

[0222] R z Selected from hydrogen and C1-C8 alkyl;

[0223] R 1 Selected from: C3-C6 cycloalkyl, C1-C8 alkoxy and C1-C8 alkyl (which may be optionally substituted by a group selected from C4-C6 cycloalkyl, C5-C6 aryl, 4 to 6-membered heterocyclyl and 4 to 6-membered heteroaryl);

[0224] R 2 Selected from: hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl and C1-C8 alkoxy;

[0225] R 3a and R 3bindependently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl);

[0226] R 4 Selected from:

[0227] 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

[0228] C1-C9 alkyl, which may be optionally substituted with 1 to 2 groups independently selected from the following:

[0229] ●C3-C8 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0230] ●C1-C8 haloalkyl;

[0231] ●OC3-C7 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0232] ●phenyl (which may be optionally substituted by a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0233] ●C1-C8 alkoxy (which may be optionally substituted by a group selected from C3-C6 cycloalkyl and halogen);

[0234] ● 4 to 6 membered heterocyclyl (which may be optionally substituted with 1 to 2 groups independently selected from halogen, C1-C8 haloalkyl, C1-C8 alkyl and C1-C8 alkoxy); and

[0235] Silicon (which may be optionally substituted with 1 to 3 groups independently selected from C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 haloalkyl);

[0236] R 5a and R 5bindependently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl);

[0237] R 6 is selected from halogen, 4 to 6 membered heterocyclyl, C3-C8 cycloalkyl (which may be optionally substituted by a group selected from C1-C8 alkyl, C1-C8 haloalkyl and halogen); and C1-C8 alkyl (which may be optionally substituted by 1 to 2 groups independently selected from C1-C8 alkoxy, halogen, oxo, -OH, -NH2 and -SO2CH3); and

[0238] R 7 Selected from O and NR, where

[0239] R is selected from hydrogen and C1-C8 alkyl; provided that the compound of formula I is not selected from:

[0240]

[0241]

[0242] and tautomers, deuterated derivatives, and pharmaceutically acceptable salts thereof.

[0243] In some embodiments, Ring A in the compound of Formula I is selected from:

[0244]

[0245] And where R 6 , W, X 2 、X 3 , Y, R y and Z are as defined above. In some embodiments, ring A in the compound of formula I is selected from:

[0246] where R y and R 6 As defined above.

[0247] In some embodiments, the compound of Formula I is selected from Formula Ia: Or formula Ia(i): Compounds and tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0248] In some embodiments, the compound of Formula I is selected from Formula Ib: and formula Ib(i): Compounds and tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0249] In some embodiments, the compound of Formula I is selected from Formula Ic: And formula Ic(i): Compounds and tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0250] In some embodiments, the compound of Formula I is selected from Formula Id: and formula Id(i): Compounds and tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0251] In some embodiments, the compound of Formula I is selected from Formula Ie: and formula Ie(i): Compounds and tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0252] In some embodiments, the compound of Formula I is selected from

[0253] Formula If: Japanese form If(i): Compounds

[0254] and tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0255] In some embodiments, R in the compound of any of Formula 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 by a group selected from halogen, haloalkyl, and C1-C4 alkoxy. In some embodiments, R in the compound of any one of Formulas I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, and If(i) 4is selected from C1-C6 alkyl substituted by 1 to 2 groups independently selected from C3-C5 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from halogen, haloalkyl and C1-C4 alkyl). In some embodiments, R in the compound of any one of Formula 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 by phenyl (which may be optionally substituted by a group selected from C1-C4 alkyl, C1-C4 alkoxy, halogen and haloalkyl). In some embodiments, R in the compound of any one of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If and If(i) 4 Selected from C1-C6 alkyl substituted by 4- to 6-membered heterocyclic groups (which may be optionally substituted by 1 to 2 groups independently selected from halogen, haloalkyl and C1-C4 alkyl).

[0256] In some embodiments, R in the compound of any of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie(i), If, and If(i) 4 Selected from

[0257]

[0258] as well as

[0259] In some embodiments of Formula I, R y is selected from bromine, chlorine, hydrogen, cyano, NH2, butyl, cyclopropyl, CH3 and CF3. In some embodiments, R y Selected from hydrogen, chlorine, amino, methyl and butyl.

[0260] In some embodiments, R in the compound of any of Formula 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 the compound of any one of Formulas I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If and If(i) 6is selected from C1-C6 alkyl (which may be optionally substituted with 1 to 2 groups independently selected from C1-C4 alkoxy, halogen, -OH, oxo, -NH2 and -SO2CH3). In some embodiments, R in the compound of any one of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie(i), If and If(i) 6 Selected from:

[0261]

[0262] as well as

[0263] In some embodiments of Formula I, the compound is selected from compounds 1-1 to 1-265 and tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287] In some embodiments, the present disclosure provides compounds of Formula II:

[0288]

[0289] or a tautomer thereof, or a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0290] Ring B is a 6-membered heteroaryl group, which is optionally substituted with 1 to 2 groups independently selected from:

[0291] Halogen

[0292] ◆4 to 10 membered heterocyclic group (which may be optionally substituted by 1 to 3 groups independently selected from halogen, oxo, C1-C4 alkyl)

[0293] ◆N(R x )2, where R x 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)

[0294] C1-C4 alkyl (optionally substituted by C3-C6 cycloalkyl (which may further optionally be substituted by a group selected from halogen, -OH))

[0295] R 1 Selected from: C3-C6 cycloalkyl, C1-C6 alkoxy and C1-C6 alkyl (which may be optionally substituted by a group selected from C4-C6 cycloalkyl, C4-C6 aryl, 4 to 6-membered heterocyclyl and 4 to 6-membered heteroaryl);

[0296] R 2 Selected from: hydrogen, halogen, C1-C8 alkyl, haloalkyl and C1-C8 alkoxy;

[0297] R 3a and R 3bindependently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl);

[0298] R 4 Selected from:

[0299] 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

[0300] C1-C9 alkyl, which may be optionally substituted with 1 to 2 groups independently selected from the following:

[0301] ●C3-C8 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0302] ●C1-C8 haloalkyl;

[0303] ●phenyl (which may be optionally substituted by a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0304] ●C1-C8 alkoxy (which may be optionally substituted by a group selected from C3-C6 cycloalkyl and halogen);

[0305] ● 4 to 6 membered heterocyclyl (which may be optionally substituted with 1 to 2 groups independently selected from halogen, C1-C8 haloalkyl, C1-C8 alkyl and C1-C8 alkoxy); and

[0306] Silicon (which may be optionally substituted with 1 to 3 groups independently selected from C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 haloalkyl);

[0307] R 5a and R 5bindependently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl).

[0308] In some embodiments, Ring B in the compound, tautomer, deuterated derivative, or salt of Formula II is a heteroaryl group selected from:

[0309]

[0310] wherein Ring B is optionally substituted by 1 to 2 groups independently selected from:

[0311] Halogen

[0312] ◆4 to 10 membered heterocyclic group (which may be optionally substituted by 1 to 3 groups independently selected from halogen, oxo, C1-C4 alkyl)

[0313] ◆N(R x )2, where R x is selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl (which may be optionally substituted by a group selected from halogen, C1-C4 haloalkyl and C1-C4 alkyl)

[0314] ◆ C1-C4 alkyl (optionally substituted by C3-C6 cycloalkyl (which may be further optionally substituted by a group selected from halogen, OH)).

[0315] In some embodiments, Ring B in the compound, tautomer, deuterated derivative, or salt of Formula II is selected from:

[0316]

[0317]

[0318] In some embodiments, the compound of Formula II is selected from compounds II-1 to II-38, tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0319]

[0320]

[0321]

[0322]

[0323] In some embodiments, the present disclosure provides compounds of Formula III:

[0324]

[0325] or a tautomer thereof, or a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0326] Ring C is selected from:

[0327]

[0328] in

[0329] Each R c independently selected from hydrogen, halogen, cyano, amino, C1-C4 alkyl (which may be optionally substituted by a group selected from -OH, halogen and oxo) and C3-C6 alkenyl;

[0330] R 1 Selected from: C3-C6 cycloalkyl, C1-C6 alkoxy and C1-C6 alkyl (which may be optionally substituted by a group selected from C4-C6 cycloalkyl, C4-C6 aryl, 4 to 6-membered heterocyclyl and 4 to 6-membered heteroaryl);

[0331] R 2 Selected from: hydrogen, halogen, C1-C8 alkyl, haloalkyl and C1-C8 alkoxy;

[0332] R 3a and R 3b independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl);

[0333] R 4 Selected from:

[0334] 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

[0335] C1-C9 alkyl, which may be optionally substituted with 1 to 2 groups independently selected from the following:

[0336] ●C3-C8 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0337] ●C1-C8 haloalkyl;

[0338] ●phenyl (which may be optionally substituted by a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0339] ●C1-C8 alkoxy (which may be optionally substituted by a group selected from C3-C6 cycloalkyl and halogen);

[0340] ● 4 to 6 membered heterocyclyl (which may be optionally substituted with 1 to 2 groups independently selected from halogen, C1-C8 haloalkyl, C1-C8 alkyl and C1-C8 alkoxy); and

[0341] Silicon (which may be optionally substituted with 1 to 3 groups independently selected from C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 haloalkyl);

[0342] R 5a and R 5b independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl);

[0343] In some embodiments, the compound of Formula III is selected from Compounds III-1 to III-25, tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0344]

[0345]

[0346]

[0347] In some embodiments, the present disclosure provides compounds of Formula IV:

[0348]

[0349] Tautomers thereof, or deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein:

[0350] Ring D is

[0351] Q is selected from -C- and -N-;

[0352] W is selected from -CH-, -C(F)-, -C(CF3)- and -N-;

[0353] X 1 、X 2 and X 3 are each independently selected from -CH- and -N-;

[0354] X 4 Selected from C and N;

[0355] Y is selected from -N-, -N(R y )-、-C(R y )- and -O-, where

[0356] R y Selected from hydrogen, halogen, C1-C8 haloalkyl, cyano, -NH2, C3-C6 cycloalkyl, C1-C8 alkyl (which may be optionally substituted by a group selected from -OH and C1-C8 alkoxy), -NHC(O)OC1-C8 alkyl (which may be optionally substituted by a group selected from -OH and halogen);

[0357] Z is selected from -CR z -, -O-, -S-, -S(O)-, -S(O)2-, -N- and -NR z ,in

[0358] R z is selected from hydrogen, halogen and C1-C8 alkyl (which may be optionally substituted by C1-C8 alkoxy);

[0359] R 0 Selected from C1-C2 alkyl;

[0360] R 1Selected from: C3-C6 cycloalkyl, C1-C8 alkoxy and C1-C8 alkyl (which may be optionally substituted by a group selected from C1-C8 alkoxy, C4-C6 cycloalkyl, C5-C6 aryl, 4 to 6-membered heterocyclyl and 4 to 6-membered heteroaryl);

[0361] R 2 Selected from: hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl and C1-C8 alkoxy;

[0362] R 3a and R 3b independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl);

[0363] R 4 Selected from:

[0364] 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

[0365] C1-C9 alkyl, which may be optionally substituted with 1 to 2 groups independently selected from the following:

[0366] -OH

[0367] ●C3-C8 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0368] ●C1-C8 haloalkyl;

[0369] -OC3-C7 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0370] ●phenyl (which may be optionally substituted by a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0371] ●C1-C8 alkoxy (which may be optionally substituted by a group selected from C3-C6 cycloalkyl and phenyl; or which may be optionally substituted by 1 to 3 halogen atoms);

[0372] ● 4 to 6 membered heterocyclyl (which may be optionally substituted with 1 to 2 groups independently selected from halogen, C1-C8 haloalkyl, C1-C8 alkyl and C1-C8 alkoxy); and

[0373] Silicon (which may be optionally substituted with 1 to 3 groups independently selected from C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 haloalkyl);

[0374] R 5a and R 5b independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl);

[0375] 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 to 2 groups selected from C1-C8 alkyl), C3-C8 cycloalkyl (which may be optionally substituted with a group selected from C1-C8 alkyl, C1-C8 haloalkyl and halogen), phenyl and C1-C8 alkyl (which may be optionally substituted with 1 to 2 groups independently selected from C1-C8 alkoxy, C1-C8 haloalkyl, halogen, oxo, -OH, -NH2 and -SO2CH3); and

[0376] R 7 Selected from O and NR, where

[0377] R is selected from hydrogen and C1-C8 alkyl;

[0378] Provided that the compound of formula IV is not selected from:

[0379]

[0380]

[0381]

[0382] and tautomers, deuterated derivatives, and pharmaceutically acceptable salts thereof.

[0383] In some embodiments, the compound of Formula IV is selected from compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393] Treatment

[0394] Any novel compound disclosed herein (e.g., a compound selected from the group consisting of compounds of Formula I, Ia, Ia(i), Ib, Ib(i), Ic, Ic(i), Id, Id(i), Ie, Ie(i), If, If(i), a compound of any one of 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) can act as a CFTR modulator, i.e., it modulates CFTR activity in vivo. Individuals with mutations in the gene encoding CFTR may benefit from receiving CFTR modulators. CFTR mutations may affect CFTR amount, i.e., the number of CFTR channels at the cell surface, or they may affect CFTR function, i.e., the functional ability of each channel to open and transport ions. Mutations that affect the amount of CFTR include mutations that lead to synthesis defects (Class I defects), mutations that lead to processing and transport defects (Class II defects), mutations that lead to reduced CFTR synthesis (Class V defects), and mutations that reduce the surface stability of CFTR (Class VI defects). Mutations that affect CFTR function include mutations that lead to gating defects (Class III defects) and mutations that lead to transduction defects (Class IV defects). Some CFTR mutations exhibit the characteristics of multiple classes. Certain mutations in the CFTR gene lead to cystic fibrosis.

[0395] Thus, in some embodiments, the present disclosure provides a method of treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient, comprising administering to the patient an effective amount of any novel compound disclosed herein, such as a compound selected from the group consisting 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, 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, deuterated tautomer, lumacaftor, and tautomer. In some embodiments, the patient has a F508del / minimal function (MF) genotype, a F508del / F508del genotype (homozygous for the F508del mutation), a F508del / gating genotype, or a F508del / residual function (RF) genotype. In some embodiments, the patient is heterozygous and has one F508del mutation. In some embodiments, the patient is homozygous for the N1303K mutation.

[0396] In some embodiments, 5 mg to 500 mg of a compound disclosed herein, a tautomer thereof, a deuterated derivative of the compound and tautomer, or a pharmaceutically acceptable salt of any of the foregoing is administered daily.

[0397] In some embodiments, the patient has at least one F508del mutation in the CFTR gene. In some embodiments, based on in vitro data, the patient has a CFTR gene mutation that responds to the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the invention. In some embodiments, the patient is heterozygous and has an F508del mutation on one allele and a mutation on the other allele selected from Table 2:

[0398] Table 2: CFTR mutations

[0399]

[0400]

[0401] a Also known as 2183delAA→G.

[0402] CFTR: cystic fibrosis transmembrane conductance regulator; IVA: ivacaftor.

[0403] SwCl: sweat chloride.

[0404] TEZ: Tizhakato.

[0405] Source: CFTR2.org [Internet]. Baltimore (MD): Clinical and Functional Translation of CFTR. Clinical and Functional Translation of CFTR (CFTR2), Cystic Fibrosis Foundation, Johns Hopkins University, The Hospital for Sick Children. Available at http: / / www.cftr2.org / . Accessed May 15, 2018.

[0406] Note: %PI: percentage of F508del-CFTR heterozygous patients with pancreatic insufficiency in the CFTR2 Patient Registry; SwCl: mean sweat chloride in F508del-CFTR heterozygous patients in the CFTR2 Patient Registry.

[0407] In some embodiments, the present disclosure also relates to methods of treatment using isotopically labeled compounds of the aforementioned compounds or pharmaceutically acceptable salts thereof, wherein the chemical formulas and variables of such compounds and salts are each independently as described above or in any other embodiment above, with the proviso that one or more atoms 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 found in nature. Examples of commercially available isotopes suitable for the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, respectively. 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl.

[0408] Isotope-labeled compounds and salts can be used in a variety of beneficial ways. They can be suitable for pharmaceutical and / or various types of assays, such as substrate tissue distribution assays. For example, tritium ( 3 H) and / or carbon-14 ( 14 C) labeled compounds are particularly useful in various types of assays, such as substrate tissue distribution assays, due to their relative ease of preparation and excellent detectability. For example, deuterium ( 2 H) labeled compounds are therapeutically useful and are comparable to non 2H-labeled compounds have potential therapeutic advantages. In general, deuterium ( 2 H) labeled compounds and salts can have higher metabolic stability due to the kinetic isotope effect described below. Higher metabolic stability directly translates into increased in vivo half-life or lower dosage, which can be desirable. Isotope-labeled compounds and salts can generally be prepared by performing the procedures disclosed in the synthetic schemes and related descriptions herein, in the Examples section, and in the Preparation section, replacing non-isotope-labeled reactants with readily available isotope-labeled reactants.

[0409] In some embodiments, isotopically labeled compounds and salts are deuterated ( 2 In some embodiments, isotope-labeled compounds and salts are deuterated ( 2 H) label, in which one or more hydrogen atoms have been replaced by deuterium. Deuterium is represented by "D" in chemical structures.

[0410] The concentration of an isotope (e.g., deuterium) incorporated into the isotopically labeled compounds and salts of the present disclosure can be defined by an 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, where a substituent in a compound of the present disclosure is represented as deuterium, such compound has an isotopic enrichment factor per 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).

[0411] Combination therapy

[0412] One aspect disclosed herein provides methods for treating cystic fibrosis and other CFTR-mediated diseases using any of the novel compounds disclosed herein (e.g., compounds 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) in combination with at least one additional active pharmaceutical ingredient.

[0413] In some embodiments, the at least one additional active pharmaceutical ingredient is selected from mucolytics, bronchodilators, antibiotics, anti-infectives, and anti-inflammatory agents.

[0414] In some embodiments, the additional therapeutic agent is an antibiotic. Exemplary antibiotics useful herein include tobramycin, including tobramycin inhalation powder (TIP); azithromycin; aztreonam, including aerosolized forms of aztreonam; amikacin, including liposomal formulations thereof; ciprofloxacin, including formulations thereof suitable for administration by inhalation; levofloxacin, including aerosolized formulations thereof; and combinations of two antibiotics, such as fosfomycin and tobramycin.

[0415] In some embodiments, the additional agent is a mucolytic agent. Exemplary mucolytic agents useful herein include

[0416] In some embodiments, the additional agent is a bronchodilator. Exemplary bronchodilators include albuterol, metaproterol sulfate, pirbuterolacetate, salmeterol, or tetrabuline sulfate.

[0417] In some embodiments, the additional agent is an anti-inflammatory agent, i.e., an agent that can reduce lung inflammation. Exemplary such agents useful herein include ibuprofen, docosahexaenoic acid (DHA), sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine, or simvastatin.

[0418] In some embodiments, the additional agent is a nutritional agent. Exemplary nutritional agents include pancrelipase (a pancreatic enzyme substitute), including or (Previous ), Or glutathione inhalation. In some embodiments, the additional nutritional agent is pancrelipase.

[0419] In some embodiments, at least one additional active pharmaceutical ingredient is selected from a CFTR modulator. In some embodiments, the at least one additional active pharmaceutical ingredient is selected from a CFTR potentiator. In some embodiments, the potentiator is selected from ivacaftor, deuterated vacaftor, (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-tetraazatricyclo[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 corrector is selected from lumacaftor, tizacaftor, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.

[0420] In some embodiments, the at least one additional active pharmaceutical ingredient is selected from (a) tizacator, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof; and / or (b) ivacaftor, deuterated tizacator, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nineteen Carbon-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-tetraazatricyclo[12.3.1.12,5]nonadecan-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.

[0421] Thus, in some embodiments, the combination therapies provided herein comprise (a) a compound selected from the group consisting of 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 the group consisting of tizancator, lumacaftor, and deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing. or (c) at least one compound selected from the group consisting of ivacaftor, deuterated ivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-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-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any one of the foregoing. In other embodiments, the combination therapies provided herein comprise (a) at least one compound selected from the group consisting of 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 the group consisting of tevacator and pharmaceutically acceptable salts thereof; and (c) at least one compound selected from the group consisting of ivacaftor, deuterated tevacator, and pharmaceutically acceptable salts thereof.In other embodiments, the combination therapies provided herein comprise (a) at least one compound selected from the group consisting of 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 the group consisting of tizancator, lumacaftor, and deuterated derivatives thereof. and pharmaceutically acceptable salts thereof; and / or (c) at least one compound selected from the group consisting of: (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-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-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives thereof and pharmaceutically acceptable salts thereof.

[0422] In some embodiments, at least one compound selected from the group consisting of 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 tezcator and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound selected from the group consisting of 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 lumacaftor and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound selected from the group consisting of 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 ivacaftor and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound selected from the group consisting of 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 deuterated tadalafil and pharmaceutically acceptable salts thereof.In some embodiments, at least one compound selected from the group consisting of 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 combined with at least one compound selected from the group consisting of (6R,12R)-1 The compounds of 7-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-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and their deuterated derivatives and pharmaceutically acceptable salts are administered in combination.

[0423] In some embodiments, at least one compound selected from the group consisting of 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 tizacator 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 the group consisting of 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 tezcator and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one compound selected from deuterated tezcator and deuterated derivatives and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound selected from the group consisting of 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 the group consisting of tezcato and deuterated derivatives thereof, and pharmaceutically acceptable salts thereof. 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-tetraazatricyclo[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 combination.

[0424] In some embodiments, at least one compound selected from the group consisting of 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 lumacaftor and its deuterated derivatives and pharmaceutically acceptable salts, and at least one compound selected from ivacaftor and its deuterated derivatives and pharmaceutically acceptable salts. In some embodiments, at least one compound selected from the group consisting of 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 lumacator and its deuterated derivatives and pharmaceutically acceptable salts, and at least one compound selected from deuterated tautomer and its deuterated derivatives and pharmaceutically acceptable salts. In some embodiments, at least one compound selected from the group consisting of 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 the group consisting of lumacatolide and its deuterated derivatives and pharmaceutically acceptable salts. 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-tetraazatricyclo[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 combination.

[0425] Each of the 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 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) can independently be administered once daily, twice daily, or three times daily. In some embodiments, at least one compound selected from the group consisting of 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 once daily. In some embodiments, at least one compound selected from the group consisting of 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 twice daily.

[0426] In some embodiments, at least one compound selected from the group consisting of 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 are administered once daily with at least one compound selected from tezcator and deuterated derivatives and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound selected from the group consisting of 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 are administered twice daily with at least one compound selected from tezcator and deuterated derivatives and pharmaceutically acceptable salts thereof.

[0427] In some embodiments, at least one compound selected from the group consisting 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 are administered with at least one compound selected from the group consisting of ivacaftor, deuterated tautomer, (6R,12R)- A compound of 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-tetraazatricyclo[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 are administered once a day. In some embodiments, at least one compound selected from the group consisting 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 are administered with at least one compound selected from the group consisting of ivacaftor, deuterated tautomer, (6R,12 The compounds of (R)-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-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and their deuterated derivatives and pharmaceutically acceptable salts are administered twice a day.

[0428] In some embodiments, at least one compound selected from the group consisting 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 the group consisting of tezcator and its deuterated derivatives and pharmaceutically acceptable salts, and at least one compound selected from the group consisting of The compounds of ivacaftor, deuterated ivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-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-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and their deuterated derivatives and pharmaceutically acceptable salts are administered once a day. In some embodiments, at least one compound selected from the group consisting 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 tezcato and pharmaceutically acceptable salts thereof, and at least one compound selected from ivacaftor. The compounds of toluidine, deuterated toluidine, (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-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and their deuterated derivatives and pharmaceutically acceptable salts are administered twice a day.

[0429] In some embodiments, at least one compound selected from the group consisting 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 ivacaftor, deuterated tautomer, (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-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and their deuterated derivatives and pharmaceutically acceptable salts and at least one compound selected from lumacator and its deuterated derivatives and pharmaceutically acceptable salts are administered once a day. In some embodiments, at least one compound selected from the group consisting 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 ivacaftor, deuterated tautomer, (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-tetraazatricyclo[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 lumacator and deuterated derivatives and pharmaceutically acceptable salts thereof are administered twice a day.

[0430] In some embodiments, at least one compound selected from the group consisting of 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 are administered once a day with at least one compound selected from tizacator and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one compound selected from ivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof is administered twice a day. In some embodiments, at least one compound selected from the group consisting of 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 are administered once a day with at least one compound selected from lumacaftor and pharmaceutically acceptable salts thereof, and at least one compound selected from ivacaftor and pharmaceutically acceptable salts thereof is administered twice a day.

[0431] In some embodiments, at least one compound selected from the group consisting of 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 tezcator and deuterated derivatives and pharmaceutically acceptable salts thereof are administered once a day, and 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-tetraazatricyclo[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 or twice a day. In some embodiments, at least one compound selected from the group consisting 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 lumacatolide and deuterated derivatives and pharmaceutically acceptable salts thereof are administered once a day, 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-tetraazatricyclo[[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 or twice a day.

[0432] 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 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 additional CFTR modulator compounds (e.g., tezcator, lumacaftor, ivacaftor, deuteroticator, (6R,12 (R)-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-tetraazatricyclo[[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and 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, such as twice a day. As used herein, a given amount of an API (e.g., tizacator, lumacaftor, ivacaftor, deutecator, (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-tetraazatricyclo[[12.3.1.12,5]nonadecan-1(18),2,4,14,16-pentaen-6-ol and its deuterated derivatives and pharmaceutically acceptable salts) administered once or twice a day means that the given amount is administered once or twice a day in each administration.

[0433] 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 tizacator 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.

[0434] 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 tezcator and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition; and at least one compound selected from deuterated tezcator and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.

[0435] In some embodiments, at least one compound selected from the group consisting of 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 the group consisting of tezcator and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition. at least one compound selected from the group consisting of (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]19-dec-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-tetraazatricyclo[[12.3.1.12,5]19-dec-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.

[0436] In some embodiments, at least one compound selected from the group consisting of 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 are administered in a first pharmaceutical composition; at least one compound selected from the group consisting of ivacaftor, deuterated tautomer, (6R,12R)-17-amino-12-methyl-6,15 -bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]19-carbon-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-tetraazatricyclo[[12.3.1.12,5]19-carbon-1(18),2,4,14,16-pentaen-6-ol and their deuterated derivatives and pharmaceutically acceptable salts are administered in the second pharmaceutical composition; at least one compound selected from lumacator and its deuterated derivatives and pharmaceutically acceptable salts is administered in the third pharmaceutical composition.

[0437] In some embodiments, at least one compound selected from the group consisting of 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 are administered in a first pharmaceutical composition; and at least one compound selected from the group consisting of tezcator and its deuterated derivatives and pharmaceutically acceptable salts and at least one A compound selected from ivacaftor, deuterated ivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-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-tetraazatricyclo[[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. In some embodiments, the second pharmaceutical composition comprises half of the daily dose of the at least one compound selected from ivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, and the other half of the daily dose of the at least one compound selected from ivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.

[0438] In some embodiments, at least one compound selected from 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 thereof, at least one compound selected from tevacaftor and pharmaceutically acceptable salts thereof, and at least one compound selected from ivacaftor, deuterated tevacaftor, and pharmaceutically acceptable salts thereof are 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, the first pharmaceutical composition is administered once daily, and when the first composition includes ivacaftor, the second composition including only ivacaftor is administered once daily.

[0439] Any suitable pharmaceutical composition can be used for 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, tevacator, ivacaftor, deuterated derivatives of tautomers, lumacaftor, and tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. Some exemplary pharmaceutical compositions for tevacator and pharmaceutically acceptable salts thereof can be found in WO 2011 / 119984 and WO 2014 / 014841, all of which are incorporated herein by reference. Some exemplary pharmaceutical compositions for ivacaftor and pharmaceutically acceptable salts thereof can be found in WO 2007 / 134279, WO 2010 / 019239, WO 2011 / 019413, WO 2012 / 027731, and WO 2013 / 130669, and some exemplary pharmaceutical compositions for deuteratedicator and pharmaceutically acceptable salts thereof can be found in US 8,865,902, US 9,181,192, US 9,512,079, WO 2017 / 053455, and WO 2018 / 080591, all of which are incorporated herein by reference. Some exemplary pharmaceutical compositions for lumacato and pharmaceutically acceptable salts thereof can be found in WO 2010 / 037066, WO 2011 / 127421, and WO 2014 / 071122, each of which is incorporated herein by reference.

[0440] Pharmaceutical composition

[0441] Another aspect of the present disclosure provides a pharmaceutical composition comprising at least one novel compound of the present disclosure (e.g., a compound selected from 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 pharmaceutically acceptable carrier.

[0442] In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from the group consisting 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, in combination with at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR modulator. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR corrector. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR potentiator. In some embodiments, the pharmaceutical composition comprises at least one compound selected from the group consisting of 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 two additional active pharmaceutical ingredients, one of which is a CFTR corrector and the other of which is a CFTR potentiator.

[0443] In some embodiments, the present disclosure provides a pharmaceutical composition comprising (a) at least one compound selected from the group consisting of 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 tizacator and pharmaceutically acceptable salts thereof, and (c) at least one pharmaceutically acceptable carrier.

[0444] In some embodiments, the present disclosure provides a pharmaceutical composition comprising (a) at least one compound selected from the group consisting 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 the group consisting of ivacaftor, deuterated tautomer, (6R,1 (2R)-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-tetraazatricyclo[[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, and (c) at least one pharmaceutically acceptable carrier.

[0445] In some embodiments, the present disclosure provides a pharmaceutical composition comprising (a) at least one compound selected from the group consisting of 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 tizacator 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.

[0446] In some embodiments, the present disclosure provides a pharmaceutical composition comprising (a) at least one compound selected from the group consisting 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 tezcator and deuterated derivatives and pharmaceutically acceptable salts thereof, (c) at least one compound selected from deuterated tezcator and deuterated derivatives and pharmaceutically acceptable salts thereof, and (d) at least one pharmaceutically acceptable carrier.

[0447] In some embodiments, the present disclosure provides a pharmaceutical composition comprising (a) at least one compound selected from the group consisting 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 the group consisting of tezcator and deuterated derivatives thereof and pharmaceutically acceptable salts. (c) at least one compound selected from the group consisting of (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-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-tetraazatricyclo[[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives and pharmaceutically acceptable salts thereof, and (d) at least one pharmaceutically acceptable carrier.

[0448] In some embodiments, the present disclosure provides a pharmaceutical composition comprising (a) at least one compound selected from the group consisting 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 the group consisting of ivacaftor, deuterated tautomer, (6R,12R)-17-amino-12-methyl- (c) at least one compound selected from lumacator and its deuterated derivatives and pharmaceutically acceptable salts, and (d) at least one pharmaceutically acceptable carrier.

[0449] Any pharmaceutical composition disclosed herein may include at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable vehicle and a pharmaceutically acceptable adjuvant. In some embodiments, the at least one pharmaceutically acceptable agent is selected from a pharmaceutically acceptable filler, a disintegrant, a surfactant, a binder, and a lubricant.

[0450] The pharmaceutical compositions described herein are useful for treating cystic fibrosis and other CFTR-mediated diseases.

[0451] 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 an adjuvant and a vehicle. As used herein, the at least one pharmaceutically acceptable carrier comprises any and all solvents, diluents, other liquid vehicles, dispersing aids, suspending aids, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders, and lubricants suitable for the desired particular dosage form. Various carriers for formulating pharmaceutical compositions and known techniques for preparing the same are disclosed in Remington: The Science and Practice of Pharmacy, 21st ed., 2005, edited by D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York. Unless any conventional carrier is incompatible with the compounds of the present disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component of the pharmaceutical composition, its use is contemplated to be within the scope of the present disclosure.Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates, glycine, sorbic acid, and potassium sorbate), mixtures of saturated vegetable fatty acid partial glycerides, water salts and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, lanolin, sugars (such as lactose, glucose, and sucrose), Starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, phosphate buffer, nontoxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, release agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives and antioxidants.

[0452] List of Exemplary Embodiments

[0453] 1. A compound of formula I:

[0454]

[0455] Tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein:

[0456] Ring A is

[0457] Q is selected from -C- and -N-;

[0458] W is selected from -CH-, -C(F)-, -C(CF3)- and -N-;

[0459] X 1 、X 2 and X 3 are each independently selected from -CH- and -N-;

[0460] Y is selected from -N-, -N(R y )-、-C(R y )- and -O-, where

[0461] R ySelected from hydrogen, halogen, C1-C8 haloalkyl, cyano, -NH2, C3-C6 cycloalkyl, C1-C8 alkyl (which may be optionally substituted by a group selected from -OH and C1-C8 alkoxy), -NHC(O)OC1-C8 alkyl (which may be optionally substituted by a group selected from -OH and halogen);

[0462] Z is selected from -CH-, -O-, -S-, -S(O)-, -S(O)2-, -N- and -NR z ,in

[0463] R z Selected from hydrogen and C1-C8 alkyl;

[0464] R 1 Selected from: C3-C6 cycloalkyl, C1-C8 alkoxy and C1-C8 alkyl (which may be optionally substituted by a group selected from C4-C6 cycloalkyl, C5-C6 aryl, 4 to 6-membered heterocyclyl and 4 to 6-membered heteroaryl);

[0465] R 2 Selected from: hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl and C1-C8 alkoxy;

[0466] R 3a and R 3b independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl);

[0467] R 4 Selected from:

[0468] 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

[0469] C1-C9 alkyl, which may be optionally substituted with 1 to 2 groups independently selected from the following:

[0470] ●C3-C8 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0471] ●C1-C8 haloalkyl;

[0472] ●OC3-C7 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0473] ●phenyl (which may be optionally substituted by a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0474] ●C1-C8 alkoxy (which may be optionally substituted by a group selected from C3-C6 cycloalkyl and halogen);

[0475] ● 4 to 6 membered heterocyclyl (which may be optionally substituted with 1 to 2 groups independently selected from halogen, C1-C8 haloalkyl, C1-C8 alkyl and C1-C8 alkoxy); and

[0476] Silicon (which may be optionally substituted with 1 to 3 groups independently selected from C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 haloalkyl);

[0477] R 5a and R 5b independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl);

[0478] R 6 is selected from halogen, 4 to 6 membered heterocyclyl, C3-C8 cycloalkyl (which may be optionally substituted by a group selected from C1-C8 alkyl, C1-C8 haloalkyl and halogen); and C1-C8 alkyl (which may be optionally substituted by 1 to 2 groups independently selected from C1-C8 alkoxy, halogen, oxo, -OH, -NH2 and -SO2CH3); and

[0479] R 7 Selected from O and NR, where

[0480] R is selected from hydrogen and C1-C8 alkyl;

[0481] Provided that the compound of formula I is not selected from:

[0482]

[0483]

[0484]

[0485] and tautomers, deuterated derivatives, and pharmaceutically acceptable salts thereof.

[0486] 2. The compound, tautomer, deuterated derivative or salt according to embodiment 1, wherein R1 is selected from C1-C4 alkyl.

[0487] 3. The compound, tautomer, deuterated derivative or salt of embodiment 1, wherein R1 is CH3.

[0488] 4. The compound, tautomer, deuterated derivative or salt of any one of embodiments 1 to 3, wherein R 2 Selected from: hydrogen, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy.

[0489] 5. The compound, tautomer, deuterated derivative or salt of any one of embodiments 1 to 4, wherein R 2 Selected from: hydrogen and C1-C4 alkyl.

[0490] 6. The compound, tautomer, deuterated derivative or salt of any one of embodiments 1 to 5, wherein R 2 Selected from: hydrogen and methyl.

[0491] 7. The compound, tautomer, deuterated derivative or salt according to embodiment 1, wherein R 3a and R 3b Independently selected from hydrogen, halogen, C1-C4 alkyl and C3-C7 cycloalkyl.

[0492] 8. The compound, tautomer, deuterated derivative or salt according to embodiment 1, wherein R 3a and R 3b It's hydrogen.

[0493] 9. The compound, tautomer, deuterated derivative or salt of any one of embodiments 1 to 8, wherein R 4 is selected from C1-C6 alkyl optionally substituted by a group selected from halogen, haloalkyl and C1-C4 alkoxy.

[0494] 10. The compound, tautomer, deuterated derivative or salt of any one of embodiments 1 to 8, wherein R 4 is selected from C1-C4 alkyl substituted by C3-C5 cycloalkyl.

[0495] 11. The compound, tautomer, deuterated derivative or salt of any one of embodiments 1 to 8, wherein R 4 Selected from C1-C4 alkyl substituted by 1 to 2 groups independently selected from C3-C5 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from halogen, haloalkyl and C1-C4 alkyl).

[0496] 12. The compound, tautomer, deuterated derivative or salt of any one of embodiments 1 to 8, wherein R 4 Selected from C1-C6 alkyl groups optionally substituted by phenyl groups (which may be optionally substituted by groups selected from C1-C4 alkyl groups, C1-C4 alkoxy groups, halogen groups and haloalkyl groups).

[0497] 13. The compound, tautomer, deuterated derivative or salt of any one of embodiments 1 to 8, wherein R 4 Selected from C1-C6 alkyl substituted by 4- to 6-membered heterocyclic groups (which may be optionally substituted by 1 to 2 groups independently selected from halogen, haloalkyl and C1-C4 alkyl).

[0498] 14. The compound, tautomer, deuterated derivative or salt of any one of embodiments 1 to 8, wherein R 4 Selected from:

[0499]

[0500] as well as

[0501] 15. The compound, tautomer, deuterated derivative or salt of any one of embodiments 1 to 14, wherein R 5a and R 5b Independently selected from hydrogen, halogen, C1-C4 alkyl and C3-C7 cycloalkyl.

[0502] 16. The compound, tautomer, deuterated derivative or salt of any one of embodiments 1 to 15, wherein R5a and R 5b It's hydrogen.

[0503] 17. The compound, tautomer, deuterated derivative or salt of any one of embodiments 1 to 16, wherein R 6 is selected from C3-C8 cycloalkyl (which may be optionally substituted by a group selected from C1-C4 alkyl, haloalkyl and halogen).

[0504] 18. The compound, tautomer, deuterated derivative or salt of any one of embodiments 1 to 16, wherein R 6is selected from C3-C6 cycloalkyl (which may be optionally substituted with a group selected from C1-C4 alkyl).

[0505] 19. The compound, tautomer, deuterated derivative or salt of any one of embodiments 1 to 16, wherein R 6 is selected from C1-C6 alkyl (which may be optionally substituted by a group selected from C1-C4 alkoxy, halogen, -OH, oxo, -NH2 and -SO2CH3).

[0506] 20. The compound, tautomer, deuterated derivative or salt of any one of embodiments 1 to 16, wherein R 6 Selected from C1-C6 alkyl and C3-C6 cycloalkyl.

[0507] 21. The compound, tautomer, deuterated derivative or salt of any one of embodiments 1 to 16, wherein R 6 is selected from C1-C4 alkyl (which may be optionally substituted by -OH) and C4 cycloalkyl (which may be optionally substituted by a group selected from C1-C4 alkyl).

[0508] 22. The compound, tautomer, deuterated derivative or salt of any one of embodiments 1 to 16, wherein R 6 is selected from C3 alkyl and C3 cycloalkyl (which may be optionally substituted with a group selected from C1-C4 alkyl).

[0509] 23. The compound, tautomer, deuterated derivative or salt of any one of embodiments 1 to 16, wherein R 6 is selected from C3-C4 cycloalkyl groups optionally substituted by methyl groups.

[0510] 24. The compound, tautomer, deuterated derivative or salt of any one of embodiments 1 to 16, wherein R 6 Selected from:

[0511]

[0512] as well as

[0513] 25. The compound, tautomer, deuterated derivative or salt of any one of embodiments 1 to 24, wherein R 7 It is O.

[0514] 26. The compound, tautomer, deuterated derivative or salt of any one of embodiments 1 to 24, wherein X 1 For C.

[0515] 26. The compound, tautomer, deuterated derivative or salt of any one of embodiments 1 to 24, wherein Q is C.

[0516] 27. The compound, tautomer, deuterated derivative or salt of embodiment 1 selected from compounds of formula Ia:

[0517]

[0518] and its tautomers, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein R 4 and R 6 As defined in Example 1.

[0519] 28. The compound, tautomer, deuterated derivative or salt of embodiment 1 selected from compounds of formula Ia(i):

[0520]

[0521] and its tautomers, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein R 4 and R 6 As defined in Example 1.

[0522] 29. The compound, tautomer, deuterated derivative or salt of embodiment 1 selected from compounds of formula Ib:

[0523]

[0524] and its tautomers, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein R 4 and R 6 As defined in Example 1.

[0525] 30. The compound, tautomer, deuterated derivative or salt of embodiment 1 selected from compounds of formula Ib(i):

[0526]

[0527] and its tautomers, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein R 4 and R 6 As defined in Example 1.

[0528] 31. The compound, tautomer, deuterated derivative or salt of embodiment 1 selected from compounds of formula Ic:

[0529]

[0530] and its tautomers, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein R 4 and R 6 As defined in Example 1.

[0531] 32. The compound, tautomer, deuterated derivative or salt of embodiment 1 selected from compounds of formula Ic(i):

[0532]

[0533] and its tautomers, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein R 4 and R 6 As defined in Example 1.

[0534] 33. The compound, tautomer, deuterated derivative or salt of embodiment 1 selected from compounds of formula Id:

[0535]

[0536] and its tautomers, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein R 4 and R 6 As defined in Example 1.

[0537] 34. The compound, tautomer, deuterated derivative or salt of embodiment 1 selected from compounds of formula Id(i):

[0538]

[0539] and its tautomers, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein R 4 and R 6 As defined in Example 1.

[0540] 35. The compound, tautomer, deuterated derivative or salt of embodiment 1 selected from compounds of formula 1e:

[0541]

[0542] and its tautomers, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein R 4 and R 6As defined in Example 1.

[0543] 36. The compound, tautomer, deuterated derivative or salt of embodiment 1 selected from compounds of formula Ie(i):

[0544]

[0545] and its tautomers, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein R 4 and R 6 As defined in Example 1.

[0546] 37. The compound, tautomer, deuterated derivative or salt of embodiment 1 selected from compounds of formula If:

[0547]

[0548] and its tautomers, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein R 4 and R 6 As defined in Example 1.

[0549] 38. The compound, tautomer, deuterated derivative or salt of embodiment 1 selected from compounds of formula If(i):

[0550]

[0551] and its tautomers, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein R 4 and R 6 As defined in Example 1.

[0552] 39. The compound, tautomer, deuterated derivative or salt of embodiment 1, wherein Ring A is selected from:

[0553]

[0554] And where R 6 , W, X 2 、X 3 , Y, R y and Z are as defined in Example 1.

[0555] 40. The compound, tautomer, deuterated derivative or salt of embodiment 1, wherein Ring A is selected from:

[0556]

[0557] where R y and R 6 As defined in Example 1.

[0558] 41. The compound, tautomer, deuterated derivative or salt of embodiment 1, 39 or 40, wherein R y Selected from:

[0559]

[0560] 42. The compound, tautomer, deuterated derivative or salt of embodiment 1, wherein

[0561] Ring A is selected from:

[0562] where R 6 As defined in Example 1,

[0563] And R 4 is selected from C1-C6 alkyl groups substituted by C3-C6 cycloalkyl groups which are optionally substituted by methyl groups.

[0564] 43. The compound, tautomer, deuterated derivative or salt of any one of embodiments 27 to 41, wherein R 4 is selected from C1-C6 alkyl groups optionally substituted by 1 to 3 halogens.

[0565] 44. The compound, tautomer, deuterated derivative or salt of any one of embodiments 27 to 41, wherein R 4 is selected from C1-C6 alkyl groups substituted by C1-C4 alkoxy groups.

[0566] 45. The compound, tautomer, deuterated derivative or salt of any one of embodiments 27 to 41, wherein R 4 is selected from C1-C6 alkyl groups substituted by C3-C6 cycloalkyl groups which are optionally substituted by methyl groups.

[0567] 46. ​​The compound, tautomer, deuterated derivative or salt of any one of embodiments 27 to 41, wherein R 4 is selected from C1-C6 alkyl groups substituted by 5- to 6-membered heterocyclic groups.

[0568] 47. The compound, tautomer, deuterated derivative or salt of any one of embodiments 27 to 41, wherein R 4 Selected from C1-C6 alkyl substituted by OC3-C6 cycloalkyl.

[0569] 48. A compound selected from compounds 1-1 to 1-265, tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any one of the foregoing.

[0570] 49. The compound according to embodiment 48, which is selected from compound 1-4:

[0571]

[0572] and tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0573] 50. The compound according to embodiment 48, which is selected from compound 1-23:

[0574]

[0575] and tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0576] 51. The compound according to embodiment 48, which is selected from compound 1-34:

[0577]

[0578] and tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0579] 52. The compound according to embodiment 48, which is selected from compound 1-35:

[0580]

[0581] and tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0582] 53. The compound according to embodiment 48, which is selected from compound 1-40:

[0583]

[0584] and tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0585] 54. The compound according to embodiment 48, which is selected from compound 1-49:

[0586]

[0587] and tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0588] 55. The compound according to embodiment 48, which is selected from compound 1-52:

[0589]

[0590] and tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0591] 56. The compound according to embodiment 48, which is selected from compound 1-88:

[0592]

[0593] and tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0594] 57. The compound according to embodiment 48, which is selected from compound 1-96:

[0595]

[0596] and tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0597] 58. The compound according to embodiment 48, which is selected from compound 1-97:

[0598]

[0599] and tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0600] 59. The compound according to embodiment 48, which is selected from compound 1-98:

[0601]

[0602] and tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0603] 60. The compound according to embodiment 48, which is selected from compound 1-99:

[0604]

[0605] and tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0606] 61. The compound according to embodiment 48, which is selected from compound I-139:

[0607]

[0608] and tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0609] 62. The compound according to embodiment 48, which is selected from compound I-158:

[0610]

[0611] and tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0612] 63. The compound according to embodiment 48, which is selected from compound I-188:

[0613]

[0614] and tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0615] 64. The compound according to embodiment 48, which is selected from compound 1-206:

[0616]

[0617] and tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0618] 65. The compound according to embodiment 48, which is selected from compound I-255:

[0619]

[0620] and tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0621] 66. The compound according to embodiment 48, which is selected from compound I-256:

[0622]

[0623] and tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0624] 67. A compound of formula II:

[0625]

[0626] or a tautomer thereof, or a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0627] Ring B is a 6-membered heteroaryl group, which is optionally substituted with 1 to 2 groups independently selected from:

[0628] Halogen

[0629] ◆4 to 10 membered heterocyclic group (which may be optionally substituted by 1 to 3 groups independently selected from halogen, oxo, C1-C4 alkyl)

[0630] ◆N(R x )2, where R x 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)

[0631] C1-C4 alkyl (optionally substituted by C3-C6 cycloalkyl (which may further optionally be substituted by a group selected from halogen, OH))

[0632] R 1 Selected from: C3-C6 cycloalkyl, C1-C6 alkoxy and C1-C6 alkyl (which may be optionally substituted with C4-C6 cycloalkyl);

[0633] R 2 Selected from: hydrogen, halogen, C1-C2 alkyl, C1-C4 haloalkyl and C1-C2 alkoxy;

[0634] R 3a and R 3b independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl);

[0635] R 4 Selected from:

[0636] 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

[0637] C1-C9 alkyl, which may be optionally substituted with 1 to 2 groups independently selected from the following:

[0638] ●C3-C8 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0639] ●C1-C8 haloalkyl;

[0640] ●phenyl (which may be optionally substituted by a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0641] ●C1-C8 alkoxy (which may be optionally substituted by a group selected from C3-C6 cycloalkyl and halogen);

[0642] ● 4 to 6 membered heterocyclyl (which may be optionally substituted with 1 to 2 groups independently selected from halogen, C1-C8 haloalkyl, C1-C8 alkyl and C1-C8 alkoxy); and

[0643] Silicon (which may be optionally substituted with 1 to 3 groups independently selected from C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 haloalkyl);

[0644] R 5a and R 5b independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl);

[0645] And wherein 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.

[0646] 68. A compound of formula III:

[0647]

[0648] or a tautomer thereof, or a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0649] Ring C is selected from:

[0650]

[0651] in

[0652] Each R c independently selected from hydrogen, halogen, cyano, amino, C1-C4 alkyl (which may be optionally substituted by a group selected from -OH, halogen and oxo) and C3-C6 alkenyl;

[0653] R 1 Selected from: C3-C6 cycloalkyl, C1-C6 alkoxy and C1-C6 alkyl (which may be optionally substituted with C4-C6 cycloalkyl);

[0654] R 2 Selected from: hydrogen, halogen, C1-C2 alkyl, C1-C4 haloalkyl and C1-C2 alkoxy;

[0655] R 3a and R 3b independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl);

[0656] R 4 Selected from:

[0657] 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

[0658] C1-C9 alkyl, which may be optionally substituted with 1 to 2 groups independently selected from the following:

[0659] ●C3-C8 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0660] ●C1-C8 haloalkyl;

[0661] ●phenyl (which may be optionally substituted by a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0662] ●C1-C8 alkoxy (which may be optionally substituted by a group selected from C3-C6 cycloalkyl and halogen);

[0663] ● 4 to 6 membered heterocyclyl (which may be optionally substituted with 1 to 2 groups independently selected from halogen, C1-C8 haloalkyl, C1-C8 alkyl and C1-C8 alkoxy); and

[0664] Silicon (which may be optionally substituted with 1 to 3 groups independently selected from C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 haloalkyl);

[0665] R 5a and R 5b independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl);

[0666] And wherein 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.

[0667] 69. A compound of formula IV:

[0668]

[0669] or a tautomer thereof, or a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0670] Ring D is

[0671] Q is selected from -C- and -N-;

[0672] W is selected from -CH-, -C(F)-, -C(CF3)- and -N-;

[0673] X 1 、X 2 and X 3 are each independently selected from -CH- and -N-;

[0674] X 4 Selected from C and N;

[0675] Y is selected from -N-, -N(R y )-、-C(R y )- and -O-, where

[0676] R y Selected from hydrogen, halogen, C1-C8 haloalkyl, cyano, -NH2, C3-C6 cycloalkyl, C1-C8 alkyl (which may be optionally substituted by a group selected from -OH and C1-C8 alkoxy), -NHC(O)OC1-C8 alkyl (which may be optionally substituted by a group selected from -OH and halogen);

[0677] Z is selected from -CR z -, -O-, -S-, -S(O)-, -S(O)2-, -N- and -NR z ,in

[0678] R z is selected from hydrogen, halogen and C1-C8 alkyl (which may be optionally substituted by C1-C8 alkoxy);

[0679] R 0 Selected from C1-C2 alkyl;

[0680] R 1 Selected from: C3-C6 cycloalkyl, C1-C8 alkoxy and C1-C8 alkyl (which may be optionally substituted by a group selected from C1-C8 alkoxy, C4-C6 cycloalkyl, C5-C6 aryl, 4 to 6-membered heterocyclyl and 4 to 6-membered heteroaryl);

[0681] R 2 Selected from: hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl and C1-C8 alkoxy;

[0682] R 3a and R 3bindependently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl);

[0683] R 4 Selected from:

[0684] 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

[0685] C1-C9 alkyl, which may be optionally substituted with 1 to 2 groups independently selected from the following:

[0686] -OH

[0687] ●C3-C8 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0688] ●C1-C8 haloalkyl;

[0689] -OC3-C7 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0690] ●phenyl (which may be optionally substituted by a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl);

[0691] ●C1-C8 alkoxy (which may be optionally substituted by a group selected from C3-C6 cycloalkyl and phenyl; or which may be optionally substituted by 1 to 3 halogen atoms);

[0692] ● 4 to 6 membered heterocyclyl (which may be optionally substituted with 1 to 2 groups independently selected from halogen, C1-C8 haloalkyl, C1-C8 alkyl and C1-C8 alkoxy); and

[0693] Silicon (which may be optionally substituted with 1 to 3 groups independently selected from C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 haloalkyl);

[0694] R5a and R 5b independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl);

[0695] 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 to 2 groups selected from C1-C8 alkyl), C3-C8 cycloalkyl (which may be optionally substituted with a group selected from C1-C8 alkyl, C1-C8 haloalkyl and halogen), phenyl and C1-C8 alkyl (which may be optionally substituted with 1 to 2 groups independently selected from C1-C8 alkoxy, C1-C8 haloalkyl, halogen, oxo, -OH, -NH2 and -SO2CH3); and

[0696] R 7 Selected from O and NR, where

[0697] R is selected from hydrogen and C1-C8 alkyl;

[0698] Provided that the compound of formula IV is not selected from:

[0699]

[0700]

[0701]

[0702] and tautomers, deuterated derivatives, and pharmaceutically acceptable salts thereof.

[0703] 70. A compound selected from compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0704] 71. A method of treating cystic fibrosis comprising administering a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 to 70.

[0705] 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.

[0706] 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.

[0707] 74. The method of embodiment 72, wherein the at least one additional active pharmaceutical ingredient is selected from a CFTR potentiator.

[0708] 75. The method of embodiment 74, wherein the CFTR potentiator is selected from ivacaftor, deuterated ivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-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-tetraazatricyclo[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.

[0709] 76. The method of embodiment 72, wherein the at least one additional active pharmaceutical ingredient is selected from a CFTR corrector.

[0710] 77. The method of embodiment 76, wherein the calibrator is selected from lumacator, tizzacator, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.

[0711] 78. A method of treating cystic fibrosis comprising administering a combination therapy comprising:

[0712] (a) a compound selected from the group consisting of 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

[0713] (b) at least one compound selected from tiazacator, lumacator and deuterated derivatives and pharmaceutically acceptable salts thereof; and / or

[0714] (c) at least one compound selected from the group consisting of ivacaftor, deuterated ivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-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-tetraazatricyclo[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.

[0715] 79. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 70 for use in treating cystic fibrosis.

[0716] 80. A compound selected from the group consisting of 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, for use in combination with the following compounds for treating cystic fibrosis:

[0717] (a) at least one compound selected from the group consisting of tiazacator, lumacator, and deuterated derivatives and pharmaceutically acceptable salts thereof; and / or

[0718] (b) at least one compound selected from the group consisting of ivacaftor, deuterated ivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-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-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any one of the foregoing.

[0719] 81. Use of a compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1 to 70 in the manufacture of a medicament for treating cystic fibrosis.

[0720] 82. Use of a compound selected from the group consisting of 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, for the manufacture of a medicament for treating cystic fibrosis in combination with:

[0721] (a) at least one compound selected from the group consisting of tiazacator, lumacator, and deuterated derivatives and pharmaceutically acceptable salts thereof; and / or

[0722] (b) at least one compound selected from the group consisting of ivacaftor, deuterated ivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-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-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any one of the foregoing.

[0723] 83. A pharmaceutical composition comprising the compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of embodiments 1 to 70 and a pharmaceutical carrier.

[0724] 84. A pharmaceutical composition comprising:

[0725] (a) a compound selected from the group consisting of 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;

[0726] (b) at least one compound selected from tiazacator, lumacator and deuterated derivatives and pharmaceutically acceptable salts thereof; and / or

[0727] (c) at least one compound selected from the group consisting of ivacaftor, deuterated ivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-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-tetraazatricyclo[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. DETAILED DESCRIPTION

[0728] Examples

[0729] I. List of Abbreviations

[0730] ACN: acetonitrile

[0731] Boc2O: di-tert-butyl dicarbonate

[0732] CDMT: 2-chloro-4,6-dimethoxy-1,3,5-triazine

[0733] Cmpd: Compound

[0734] DBU: 1,8-diazabicyclo(5.4.0)undec-7-ene

[0735] DCM: dichloromethane

[0736] DI: Deionization

[0737] DIEA: (DIPEA, DiPEA): N,N-diisopropylethylamine

[0738] DMA: N,N-dimethylacetamide

[0739] DMAP: 4-dimethylaminopyridine

[0740] DMF: N,N-dimethylformamide

[0741] DMSO: dimethyl sulfoxide

[0742] EA: ethyl acetate

[0743] Diethyl ether: ethyl ether

[0744] EtOAc: ethyl acetate

[0745] EtOH: ethanol

[0746] GC: Gas chromatography

[0747] GCMS: Gas chromatography mass spectrometry

[0748] HOTU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-hexafluorophosphate oxide

[0749] HPLC: High Performance Liquid Chromatography

[0750] IPA: Isopropyl alcohol

[0751] LAH: lithium aluminum hydride

[0752] LC: Liquid chromatography

[0753] LCMS: Liquid chromatography mass spectrometry

[0754] LCMS Rt: LCMS retention time

[0755] MeCN: acetonitrile

[0756] MeOH: methanol

[0757] MTBE: Methyl tert-butyl ether

[0758] MeTHF or 2-MeTHF: 2-methyltetrahydrofuran

[0759] NMP: N-methyl-2-pyrrolidone

[0760] NMM: N-methylmorpholine

[0761] Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0762] RBF: Round Bottom Flask

[0763] rt, RT: room temperature

[0764] SFC: Supercritical fluid chromatography

[0765] TEA: triethylamine

[0766] TFA: trifluoroacetic acid

[0767] THF: Tetrahydrofuran

[0768] TLC: Thin layer chromatography

[0769] TMS: trimethylsilyl

[0770] T3P: Propanephosphonic anhydride

[0771] UPLC: Ultra-Performance Liquid Chromatography

[0772] Xantphos:4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0773] II. General Methods

[0774] Unless otherwise noted, reagents and starting materials were obtained from commercial sources and used without purification.

[0775] At 400MHz and 100MHz respectively 1 H and 13 Proton and carbon NMR spectra were obtained on a Bruker Biospin DRX 400 MHz FTNMR spectrometer operated at the C resonance frequency or on a 300 MHz NMR spectrometer. One-dimensional proton and carbon spectra were acquired at a digital resolution of 0.1834 and 0.9083 Hz / Pt, respectively, using a broadband observe (BBFO) probe at 20 Hz sample rotation. All proton and carbon spectra were acquired at 30°C under temperature control using standard, previously published pulse sequences and conventional processing parameters.

[0776] 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.

[0777] Also recorded on a Varian Mercury NMR instrument at 300 MHz using a 45 degree pulse angle, 4800 Hz spectral width, and 28860 acquisition points. 1 The 1H NMR spectrum was recorded using a 190 nm spectral analyzer (190 nm) with 100 nm spectral width (190 nm) of the 190 nm spectral analyzer (190 nm). The 190 nm spectral analyzer (190 nm) was used to analyze the 190 nm spectral analyzer (190 nm) using a 190 nm spectral analyzer (190 nm) of the 190 nm spectral analyzer (190 nm). The 190 nm spectral analyzer (190 nm) was used to analyze the 190 nm spectral analyzer (190 nm) of ...

[0778] Also recorded at 400 MHz on a Bruker Avance III HD NMR instrument using a 30 degree pulse angle, 8000 Hz spectral width, and 128k acquisition points 1The 1H NMR spectrum was recorded at 377 MHz using a 30 degree pulse angle, 89286 Hz spectral width, and 128 k acquisition points. The 19F NMR spectrum was recorded at 377 MHz using a 30 degree pulse angle, 89286 Hz spectral width, and 128 k acquisition points. The 19F NMR spectrum was recorded at 377 MHz using a 30 degree pulse angle, 89286 Hz spectral width, and 128 k acquisition points. The 19F NMR spectrum was recorded at 377 MHz using a 30 degree pulse angle, 89286 Hz spectral width, and 128 k acquisition points.

[0779] 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 an ID PFG, 5 mm, 50-202 / 500 MHz probe (Model / Part No. 99337300).

[0780] III. General UPLC / HPLC Analysis Methods

[0781] LC method A: using Acquity UPLC BEH C manufactured by Waters 18 Column (50×2.1 mm, 1.7 μm particles) (pn: 186002350) and analytical reversed-phase UPLC with a dual gradient from 1% to 99% mobile phase B over 3.0 minutes. Mobile phase A = H₂O (0.05% CF₃CO₂H). Mobile phase B = CH₃CN (0.035% CF₃CO₂H). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, and column temperature = 60°C.

[0782] LC Method B: Acquity UPLC BEH C manufactured by Waters 18 Column (30×2.1 mm, 1.7 μm particles) (pn: 186002349) and a dual gradient run from 1-99% mobile phase B over 1.0 minute. 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.

[0783] LC Method C: Using Acquity UPLC BEH C manufactured by Waters 18Column (50×2.1 mm, 1.7 μm particles) (pn: 186002350) and reversed-phase UPLC with a dual gradient from 30% to 99% mobile phase B over 2.9 minutes. Mobile phase A = H₂O (0.05% CF₃CO₂H). Mobile phase B = CH₃CN (0.035% CF₃CO₂H). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, and column temperature = 60°C.

[0784] LC Method D: Merckmillipore Chromolith SpeedROD C 18 Column (50 x 4.6 mm) and dual gradient run from 5-100% mobile phase B over 12 minutes. Mobile phase A = water (0.1% CF3CO2H). Mobile phase B = acetonitrile (0.1% CF3CO2H).

[0785] LC Method E: Merckmillipore Chromolith SpeedROD C 18 Column (50 x 4.6 mm) and dual gradient run from 5-100% mobile phase B over 6 minutes. Mobile phase A = water (0.1% CF3CO2H). Mobile phase B = acetonitrile (0.1% CF3CO2H).

[0786] LC Method F: Kinetex Polar C 18 3.0×50 mm 2.6 μm, 6 minutes, 5%-95% ACN / H2O (0.1% formic acid) 1.2 ml / min.

[0787] LC Method G: Acquity UPLC BEH C manufactured by Waters 18 Column (50×2.1 mm, 1.7 μm particles) (pn: 186002350) and dual gradient run from 1-30% mobile phase B over 2.9 minutes. Mobile phase A = H₂O (0.05% CF₃CO₂H). Mobile phase B = CH₃CN (0.035% CF₃CO₂H). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, and column temperature = 60°C.

[0788] LC method H: water Cortex 2.7μC 18 (3.0 mm × 50 mm), temperature: 55 ° C; flow rate: 1.2 ml / min; mobile phase: 100% water containing 0.1% trifluoroacetic (TFA) acid, followed by 100% acetonitrile containing 0.1% TFA acid, gradient: 5% to 100% B over 4 minutes, stay at 100% B for 0.5 minutes, and equilibrate to 5% B over 1.5 minutes.

[0789] LC Method I: UPLC Luna C 18 (2) 50 × 3 mm 3 μm. Run: 2.5 min. Mobile phase: Initial 95% H2O 0.1% FA / 5% MeCN 0.1% FA, linear gradient to 95% MeCN 0.1% FA over 1.3 min, hold 95% CH3CN 0.1% FA for 1.2 min, T: 45°C, flow rate: 1.5 ml / min

[0790] LC Method J: UPLC SunFire C 18 75×4.6mm 3.5μm, run: 6 minutes. Mobile phase conditions: initial 95% H2O + 0.1% FA / 5% CH3CN + 0.1% FA, linear gradient to 95% CH3CN for 4 minutes, hold at 95% CH3CN for 2 minutes. T: 45°C, flow: 1.5 ml / min

[0791] LC Method K: XBridge C 18 4.6 x 75 mm, 5 μm, initial gradient 95% NH4HCO3 / 5% MeCN, 6 min run, 1 min equilibrium gradient 0 to 3 min 95% MeCN, hold for 3 min. Flow rate 1.5 ml / min.

[0792] LC Method L: Luna C 18 3.0×50 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.

[0793] LC Method M: Using Acquity UPLC-MS BEH C manufactured by Waters 18 Analytical reversed-phase UPLC-MS (pn: 186002350) using a 50×2.1 mm column (50×2.1 mm, 1.7 μm particle size) and a dual gradient run from 1% to 99% mobile phase B over 5.0 minutes. 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.

[0794] IV. Synthesis of Common Intermediates

[0795] Example 1: Preparation of 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[0796]

[0797] Step 1: tert-Butyl N-tert-butoxycarbonyl-N-(4,6-dichloropyrimidin-2-yl)carbamate

[0798]

[0799] To a solution of 4,6-dichloropyrimidine-2-amine (300g, 1.829mol) in DCM (2.1L) was added (BOC) 2O (838g, 3.840mol) and then DMAP (5.6g, 45.84mmol) was added. The mixture was stirred at ambient temperature for 6 hours. Additional DMAP (5.6g, 45.84mmol) was added and the reactant was continued to stir at ambient temperature for 24 hours. The mixture was diluted with water (2.1L) and the organic phase was separated. The organic phase was washed with water (2.1L) and 2.1L of brine, dried over magnesium sulfate, filtered through diatomaceous earth and concentrated in a vacuum to obtain a light orange oil with silt in the slurries. The mixture was diluted with about 500mL of heptane and filtered using an M filter. The precipitate (SM) was washed with 250mL of heptane. The filtrate was concentrated in vacuo to give a thick orange oil which was seeded with solid from a previous experiment and allowed to crystallize on standing to give tert-butyl N-tert-butoxycarbonyl-N-(4,6-dichloropyrimidin-2-yl)carbamate (645 g, 97%) as a light orange hard solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 1.44 (s, 18H). ESI-MS m / z calculated value 363.07526, found value 364.1 (M+1) + ; Retention time: 2.12 minutes (LC method A).

[0800] Step 2: tert-Butyl N-tert-butoxycarbonyl-N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]carbamate

[0801]

[0802] All solvents were degassed before use. To a slurry of N-tert-butyloxycarbonyl-N-(4,6-dichloropyrimidin-2-yl)carbamic acid tert-butyl ester (88 g, 241.6 mmol) was added DME (704 mL) and water (176 mL) containing (2,6-dimethylphenyl)boronic acid (approximately 36.24 g, 241.6 mmol) and Cs CO (approximately 196.8 g, 604.0 mmol). Pd (dppf) Cl (approximately 8.839 g, 12.08 mmol) was added and the mixture was vigorously stirred under nitrogen at 80 ° C (reflux) for 1 hour (no SM remained). The reactant 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 / hexane. Product fractions (eluting with 15% EtOAc) were combined and concentrated under vacuum to give the product as a clear oil that crystallized upon 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, found value 434.1 (M+1) + ; Retention time: 2.32 minutes (LC method A).

[0803] Step 3: 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (hydrochloride)

[0804]

[0805] 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). 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 under vacuum to give 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine hydrochloride (213.5 g, 64%) as a white solid (213.5 g, 82%). 1HNMR (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, found value 234.1 (M+1) + ; Retention time: 2.1 minutes (LC method C).

[0806] Step 4: 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine

[0807]

[0808] 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 of 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 x 500 mL). The combined brown DCM phases were stirred over 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 creamy suspension. The cream suspension was stirred at room temperature for 1 hour, filtered, washed with cold heptane and dried to give 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (157 g, 91%) as a cream solid. 1 HNMR (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, found value 234.0 (M+1) + ; Retention time: 1.45 minutes (LC method A).

[0809] Step 5: 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[0810]

[0811] 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (235 g, 985.5 mmol) was dissolved in MeTHF (2.3 L) under stirring and nitrogen and cooled in an ice bath. To the cold solution was added methyl 3-chlorosulfonylbenzoate (347 g, 1.479 mol) in one portion (appears slightly endothermic), and to the cold, pale yellow solution was added dropwise a solution of 2-methyl-butan-2-ol (lithium salt) (875 mL of 3.1 M, 2.712 mol) in heptane over 1.25 hours (exothermic, internal temperature 0 to 10°C). The ice bath was removed and the green solution was stirred at room temperature for 4 hours. To the green solution was added cold HCl (2 L of 1.5 M, 3.000 mol), the phases separated, and the organic phase washed once with water (1 L) and once with brine (500 mL). The aqueous phase was back extracted once with MeTHF (350 mL) and the organic phases were combined. The yellow MeTHF solution of methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoate (ESI-MS m / z calculated value 431.07065, found value 432.0 (M+1)) was added to the 1% ethanol solution. + ; retention time: 1.81 minutes) was treated with NaOH (2.3 L of 2M, 4.600 mol) and stirred at room temperature for 1 hour. The phases were separated and the NaOH phase was washed twice with MeTHF (2×500 mL), and the combined organic phases were extracted once with 2M NaOH (1×250 mL). The combined NaOH phases were combined, stirred in an ice bath, and slowly acidified by adding HCl (416 mL of 36% w / w, 4.929 mol) while maintaining the internal temperature between 10 and 20°C. At the end of the addition (pH approximately 5-6), the final pH was adjusted to 2-3 by adding solid citric acid. The resulting yellow viscous suspension was stirred at room temperature overnight to give a creamy shortbread suspension. The solid was collected by filtration, washed with copious amounts of water, and sucked dry for 3 hours. The solid was dried under reduced pressure at 45-50°C with a nitrogen leak for 120 hours. 3-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (395 g, 96%) was isolated 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, found value 418.0 (M+1)+ ; Retention time: 1.56 min. (LC method A).

[0812] Example 2: Preparation of [[4-[(2R)-2-(tert-Butoxycarbonylamino)-4-methyl-pentyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[0813]

[0814] Step 1: 3-[[4-[(2R)-2-(tert-Butoxycarbonylamino)-4-methyl-pentyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[0815]

[0816] To a stirred solution of (2R)-2-amino-4-methyl-pentane-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 and 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 water bath preheated to 60° C. and stirred for 20 minutes. After cooling to room temperature, di-tert-butyl dicarbonate (69.381 g, 317.90 mmol) was added and the reaction mixture was stirred for 3 hours. The reactant was quenched with saturated aqueous ammonium chloride solution (150 mL). The volatiles were removed under vacuum and the aqueous layer was acidified to a pH of about 3 with 10% aqueous citric acid solution. The product was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, and concentrated to a residual volume of approximately 250 mL. The product was precipitated into excess hexanes (750 mL) and collected by vacuum filtration. The obtained white solid was repurified by silica gel chromatography using a 0-40% acetone (0.15% acetate buffer) gradient in hexanes (0.15% acetate buffer) to give 3-[[4-[(2R)-2-(tert-butoxycarbonylamino)-4-methyl-pentyloxy]-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, found 599.4 (M+1) + ; Retention time: 5.85 minutes (LC method D).

[0817] Step 2: 3-[[4-[(2R)-2-amino-4-methyl-pentyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride)

[0818]

[0819] To a stirred solution of 3-[[4-[(2R)-2-(tert-butoxycarbonylamino)-4-methyl-pentyloxy]-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 of a 4M solution in 1,4-dioxane, 346.24 mmol) at room temperature. The reaction mixture was stirred for 2 hours. The volatiles were removed under vacuum and the obtained solid was ground with diethyl ether (150 mL). After removing the volatiles, the product was dried under vacuum to give 3-[[4-[(2R)-2-amino-4-methyl-pentyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride) (19.68 g, 100%) as a white solid. 1 H NMR (250 MHz, DMSO-d6) δ 8.56-8.27 (m, 4H), 8.14 (t, J = 6.8 Hz, 2H), 7.70 (t, J = 7.8 Hz, 1H), 7.34-7.18 (m, 1H), 7.17-7.02 (m, 2H), 6.31 (s, 1H), 4.42-4.23 (m, 1H), 4.23-4.06 (m, 1H), 3.5-3.4 (m, 1H, overlapped with water), 2.01 (s, 6H), 1.82-1.31 (m, 3H), 1.02-0.78 (m, 6H). ESI-MS m / z calculated value 498.1937, found value 499.3 (M+1) + ; Retention time: 1.63 minutes (LC method E).

[0820] Example 3: Preparation of 3-[[4-[(2R)-2-amino-4,4-dimethyl-pentyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[0821]

[0822] Step 1: (2R)-2-Amino-4,4-dimethyl-pentan-1-ol

[0823] To a solution of (2R)-2-amino-4,4-dimethyl-pentanoic acid (15g, 103.3mmol) in THF (150mL) was added dropwise borane-THF (260mL of 1M, 260.0mmol) at 0°C, keeping the reaction temperature <10°C. The addition time was approximately 30 minutes. The mixture was warmed to ambient temperature and stirred for 22 hours. The reactant was quenched by slowly adding methanol (80mL, 1.975mol) and the solvent was removed in vacuo. The residue was co-evaporated 3 times with methanol (200mL, 4.937mol). The crude residue was diluted with HCl (200mL of 1M, 200.0mmol) and washed with 200mL of MTBE. The aqueous phase was evaporated to remove residual organic solvent. Water was further removed in vacuo to obtain an off-white solid. The solid was further dried using an acetonitrile azeotrope. The solid was made into a slurry in 200mL of ACN and the precipitate was collected with M glass frit. The solid was air-dried for 1 hour and then dried in vacuo at 45°C for 20 hours to afford (2R)-2-amino-4,4-dimethyl-pentan-1-ol (hydrochloride salt) (14.73 g, 85%). 1 HNMR (400 MHz, DMSO-d6) δ 7.80 (s, 3H), 5.36 (t, J = 5.1 Hz, 1H), 3.59 (dt, J = 11.7, 4.1 Hz, 1H), 3.42-3.34 (m, 1H), 3.10 (dq, J = 7.7, 3.8 Hz, 1H), 1.46 (dd, J = 14.5, 7.1 Hz, 1H), 1.33 (dd, J = 14.5, 3.5 Hz, 1H), 0.91 (s, 9H). ESI-MS m / z calculated value 131.13101, found value 132.1 (M+1) + ; Retention time: 0.51 min (LC method A).

[0824] Step 2: 3-[[4-[(2R)-2-amino-4,4-dimethyl-pentyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[0825]

[0826] 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), cooled to 5 ° C and added over 10 minutes, followed by (2R)-2-amino-4,4-dimethyl-pentan-1-ol (hydrochloride) (8.02 g, 47.830 mmol). The reaction was then warmed to 10 ° C and stirred for 4 hours. The reaction was then cooled to 0 ° C and quenched by adding aqueous hydrochloric acid (2 M, 200 mL) over 10 minutes. The phases were separated and the aqueous phase was extracted with 2-methyltetrahydrofuran (200 mL). The organic phases were combined and washed with 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-pentyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride) (22.29 g, 80%). 1 H NMR (400MHz, DMSO-d6) δ13.26(br.s.,2H),8.45(t,J=1.6Hz,1H),8.28-8.06(m,5H),7.69(t,J=7.8Hz,1H),7.31-7.21(m,1H),7.13(d,J=7.6Hz,2H) ,6.29(br.s.,1H),4.30(dd,J=11.7,2.7Hz,1H),4.10(dd,J=11.5,7.1Hz, 1H),3.56(br.s.,1H),2.13-1.90(s,6H),1.62-1.47(m,2H),0.94(s,9H). ESI-MS m / z calculated value 512.20935, found value 513.0 (M+1) + ; Retention time: 2.334 minutes; LC method F.

[0827] Example 4: Preparation of 3-[[4-[(2R)-2-amino-5,5,5-trifluoro-4,4-dimethyl-pentyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[0828]

[0829] Step 1: 4,4,4-Trifluoro-3,3-dimethyl-butyraldehyde

[0830]

[0831] 4,4,4-trifluoro-3,3-dimethyl-butane-1-ol (8.987 g, 57.555 mmol), DCM (63 mL), water (63 mL), NaBr (544 mg, 5.2870 mmol), sodium bicarbonate (12.32 g, 146.66 mmol) and TEMPO (92 mg, 0.5888 mmol) were charged into a 1L three-necked flask. The mixture was cooled with an ice-water bath. At 2.5-4.4 ° C, a NaOCl aqueous solution (47 mL of 1.31 M, 61.570 mmol) was added dropwise over 2 hours. After the addition, the mixture was stirred for 10 minutes. 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 (about 80 mL) of crude product in DCM, which was used directly in the next step. 1 H NMR (300MHz, CDCl3) δ9.82-9.78 (m, 1H), 2.54 (d, J = 2.6Hz, 2H), 1.28 (s, 6H). 19 F NMR (282MHz, CDCl3) δ-79.11 (s, 3F).

[0832] Step 2: (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]valeronitrile and (2S)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]valeronitrile

[0833]

[0834] To a solution of 4,4,4-trifluoro-3,3-dimethyl-butyraldehyde (113.7 g, 57.540 mmol) (purity of about 7.8%) in DCM (80 mL) was added MeOH (110 mL). The mixture was cooled with an ice-water bath. (1R)-1-phenylethylamine (8.46 g, 69.814 mmol) was added, followed by acetic acid (4.41 g, 73.436 mmol). The mixture was stirred at 0 ° C for 10 minutes, and then NaCN (3.56 g, 72.642 mmol) was added. The mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was cooled to 0 ° C and a solution of potassium carbonate (4 g) in water (20 mL) was added dropwise, followed by brine (40 mL). The mixture was extracted with DCM (2 × 100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (120 g silica gel, heptane / EtOAc 0-30%) to give a 4:1 mixture of (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]valeronitrile and (2S)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]valeronitrile as a colorless oil (14.87 g, 91%). ESI-MS m / z calcd 284.15002, found 285.2 (M+1) + ; Retention time: 3.38 minutes; LC method F.

[0835] 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

[0836]

[0837] To a 4:1 mixture of (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]valeronitrile and (2S)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]valeronitrile (14.87 g, 52.300 mmol) in DCM (105 mL) was added sulfuric acid (56.3 g, 551.06 mmol). The mixture was stirred at room temperature overnight, poured into crude ice (200 g) and neutralized to pH 9 with 28% NH in water (100 mL). The mixture was extracted with DCM (500 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (330 g silica gel, heptane / EtOAc 20-50%) to give (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanamide (10.77 g, 68%) as a white solid. 1 H NMR (300MHz, CDCl3) δ7.39-7.22(m,5H),6.35(br.s.,1H),5.55(br.s.,1H),3.65(q,J=6.5Hz,1H),2.93(dd,J=7 .6,3.8Hz,1H),1.87(dd,J=15.0,3.8Hz,1H),1.65-1.56(m,2H),1.35(d,J=6.5Hz,3H),1.04(s,3H),1.00(s,3H). 19 F NMR (282 MHz, CDCl3) δ -78.77 (s, 3F). 99.4% de was determined by 19F NMR.

[0838] Step 4: (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanoic acid

[0839]

[0840] 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. More concentrated HCl (40 mL of 11.8 M, 472.00 mmol) and HOAc (10 mL) were added. The mixture was stirred at 100 ° C overnight. More HCl aqueous solution (20 mL of 6 M, 120.00 mmol) was added. After 7 hours at 100 ° C, more HCl aqueous solution (20 mL of 6 M, 120.00 mmol) was added. The mixture was stirred at 100 ° C overnight. The mixture became a clear solution. More HCl aqueous solution (20mL of 6M, 120.00mmol) was added. The mixture was stirred at 100°C for 7 hours, and more HCl aqueous solution (20mL of 6M, 120.00mmol) was added. The mixture was stirred at 100°C overnight. The mixture was concentrated and co-evaporated with water (50mL). The residue (17g) was mixed with water (25mL) at 50°C for 20 minutes, cooled with an ice-water bath for 20 minutes and filtered. The crude product was mixed with 1,4-dioxane (60mL). The mixture was concentrated and dried under vacuum overnight to give (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanoic acid (hydrochloride) (13.04g, 97%) as an off-white solid. 1 H NMR(300MHz,DMSO-d6)δ10.09(br.s.,1H),7.54-7.31(m,5H),7.29-7.05(m,1H),4.07(q,J=5.9 Hz, 1H), 3.16-2.98 (m, 1H), 2.08-1.83 (m, 2H), 1.49 (d, J = 6.5Hz, 3H), 0.99 (s, 3H), 0.92 (s, 3H). 19 F NMR (282 MHz, DMSO-d6) δ -78.28 (s, 3F). ESI-MS m / z calculated value 303.14462, found value 304.2 (M+1) + ; Retention time: 1.98 minutes; LC method F.

[0841] Step 5: (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentan-1-ol

[0842]

[0843] To a suspension of (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanoic acid (hydrochloride) (13.04 g, 36.267 mmol) in THF (200 mL) was added dropwise LAH in THF (100 mL of 1 M, 100.00 mmol) at 35 ° C. The mixture was stirred at 40 ° C for 2 hours, cooled to 10 ° C with an ice-water bath and diluted with THF (200 mL). A mixture of water (3.8 g) and THF (50 mL) was added dropwise, followed by the addition of 25% aqueous NaOH solution (3.8 g) and water (10 g). The resulting mixture was stirred at room temperature for 30 minutes and at 50 ° C for 1 hour, filtered and washed with warm THF. The filtrate was concentrated to give 12.02 g of the product (free amine) as a colorless oil. 1 H NMR (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 (quintet, 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 ether (20 mL) and diluted with heptane (80 mL) and cooled in an ice-water bath. HCl in 1,4-dioxane (10.5 mL of 4M, 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. 1 H NMR(300MHz,DMSO-d6)δ9.57(br.s.,1H),9.25(t,J=9.8Hz,1H),7.80-7.59(m,2H),7.53-7.32(m,3H),5.63(br.s.,1H),4.58(t,J=6.3Hz,1H), 3.81-3.65(m,1H),3.64-3.51(m,1H),2.91-2.74(m,1H),1.98-1.85(m, 1H), 1.85-1.74 (m, 1H), 1.63 (d, J = 6.8Hz, 3H), 0.91 (s, 3H), 0.88 (s, 3H). 19F NMR (282 MHz, DMSO-d6) δ -77.71 (s, 3F). ESI-MS m / z calculated value 289.16534, found value 290.2 (M+1) + ; Retention time: 2.08 minutes; LC method F.

[0844] Step 6: (2R)-2-Amino-5,5,5-trifluoro-4,4-dimethyl-pentan-1-ol

[0845]

[0846] To a solution of (2R) -5,5,5- trifluoro -4,4- dimethyl -2- [[(1R) -1- phenylethyl] amino] pentane -1- alcohol (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 at room temperature for 9 hours under 40 psi hydrogen in a Parr shaker hydrogenation apparatus. More 10% palladium on carbon, 50% wet (1 g, 0.4698 mmol) was added. The mixture was vibrated 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 ground 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 under vacuum to give (2R)-2-amino-5,5,5-trifluoro-4,4-dimethyl-pentan-1-ol (hydrochloride) (7.66 g, 93%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ8.08(br.s.,3H),5.46(t,J=5.0Hz,1H),3.67-3.52(m,1H),3.43(dt,J=11 .7,5.8Hz,1H),3.29-3.16(m,1H),1.88-1.73(m,1H),1.72-1.58(m,1H),1.15(s,3H),1.10(s,3H). 19 F NMR (282 MHz, DMSO-d6) δ -78.07 (s, 3F). ESI-MS m / z calculated value 185.10275, found value 186.2 (M+1) + ; Retention time: 0.64 min; LC method F.

[0847] Step 7: 3-[[4-[(2R)-2-amino-5,5,5-trifluoro-4,4-dimethyl-pentyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[0848]

[0849] 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-pentane-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 to induce rapid partial dissolution of the solid. After 5 minutes, the cooling bath was removed and the reactants were stirred at room temperature for 1 hour (90% conversion). More (2R)-2-amino-5,5,5-trifluoro-4,4-dimethyl-pentane-1-ol (hydrochloride) (363 mg, 1.638 mmol) was added and the mixture was stirred for one hour (no change). More 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 two phases were separated. The organic phase was washed with brine (50 mL), dried over sodium sulfate and concentrated. The residue was triturated in EtOAc / MeOH / hexanes and the solvent was evaporated to give 3-[[4-[(2R)2-amino-5,5,5-trifluoro-4,4-dimethyl-pentyloxy]-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, found value 567.62 (M+1) + ; Retention time: 1.13 minutes (LC method A).

[0850] Example 5: Preparation of 3-[[4-[(2R)-2-amino-3-[1-(trifluoromethyl)cyclopropyl]propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[0851]

[0852] Step 1: 2-[1-(Trifluoromethyl)cyclopropyl]ethanol

[0853]

[0854] Under nitrogen, LAH (49.868 g, 1.3139 mol) is added to THF (1700 mL) and the mixture is stirred for 30 minutes, then cooled to 0° C. THF (500 mL) containing 2-[1-(trifluoromethyl)cyclopropyl]acetic acid (190.91 g, 1.0107 mol) is added dropwise while controlling the temperature to <5° C. The mixture is warmed to room temperature and stirred for 24 hours. The resulting suspension is cooled to 0° C., water (50 mL) is added very slowly, followed by 15% w / w sodium hydroxide (50 mL) and water (150 mL). The mixture is stirred at 0° C. for 30 minutes and filtered through a pad of celite, and the filter cake is 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) δ4.57 (t, J = 5.2 Hz, 1H), 3.55-3.39 (m, 2H), 1.74 (t, J = 7.3 Hz, 2H), 1.00-0.58 (m, 4H).

[0855] Step 2: 2-[1-(Trifluoromethyl)cyclopropyl]acetaldehyde

[0856]

[0857] A solution of 2-[1-(trifluoromethyl)cyclopropyl]ethanol (80g, 467.1mmol) in dichloromethane (1.1L) was stirred at room temperature and treated with Dess-Martin periodinane (250g, 589.4mmol) in portions (exothermic! Cool in an ice bath and keep T < 15°C). Water (12mL, 666.1mmol) was added to the mixture and slowly added over 0.5 hours (exothermic to 33°C during addition, maintained between 20 and 33°C by cooling with cold water) to obtain a dense suspension. After addition, the light yellow fine suspension was stirred at room temperature for 18 hours. The yellow suspension was diluted with ether (500mL) (yellow suspension) and stirred for 30 minutes. The slurry was filtered through diatomaceous earth and the precipitate was washed with 100mL of ether. The organic phase was carefully treated with saturated aqueous sodium carbonate solution (500ml, strong gas release, final pH of about 10). The three-phase mixture is stirred at room temperature for 1 hour, and solid is removed by filtration (large glass frit).By phase (yellow turbid ether phase, colorless water) separation and organic phase is washed once with sodium carbonate saturated aqueous solution (250mL), washed once with 1M sodium thiosulfate (250mL) and washed once with salt solution (250mL).Aqueous phase is stripped once with ether (150mL), and the organic phase merged is dried, filtered and evaporated, obtain 2- [1- (trifluoromethyl) cyclopropyl] acetaldehyde (40g, 56%) in yellow liquid.

[0858] Step 3: 2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propionitrile

[0859]

[0860] 2-[1-(trifluoromethyl)cyclopropyl]acetaldehyde (102g, 670.5mmol) in MeOH (700mL) is treated with (1R)-1-phenylethylamine (86mL, 667.1mmol) and cooled in an ice bath. The solution is treated with acetic acid (38mL, 668.2mmol), stirred in an ice bath for 20 minutes, then solid NaCN (note, 33g, 673.4mmol) is added once and the suspension is stirred in a melting ice bath for 14 hours. The solution is concentrated under reduced pressure and residue is extracted with MTBE (1000mL) and saturated sodium carbonate / water 1:1 (1000mL) and washed with brine (350mL). 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]propionitrile (180.8 g, 96%) as a 3:1 mixture of diastereomers. ESI-MS m / z calculated value 282.13437, found value 283.0 (M+1)+ ; Retention times: 1.69 min (major isomer) and 1.62 min (minor isomer), LC method A.

[0861] Step 4: (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]acrylamide

[0862]

[0863] In a 2L flask equipped with mechanical stirring and temperature probe, sulfuric acid (285mL of 18M, 5.130mol) is added and cooled in an ice bath. At an internal temperature of 5°C, a solution of 2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propionitrile (180.8g, 640.4mmol, a 3:1 mixture of diastereomers) in DCM (900mL) was added dropwise over 20 minutes. The ice bath was removed, and the dark orange emulsion was stirred at room temperature for 18 hours and at 30-40°C for 2 hours. Under mechanical stirring, the dark orange emulsion was carefully added to a mixture of ice and water (2.2L) to give a yellow three-phase mixture, which was alkalized under ice cooling by slowly adding ammonium hydroxide (30% w / w 1.33L, 10.25mol) (very exothermic, the internal temperature was maintained between 10 and 25°C by adding ice). The yellow emulsion was stirred at room temperature (pH of about 10) for 10 minutes, 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 phase was washed once with water / brine 1:1 (500 mL). The DCM phase was dried, filtered and evaporated to give crude 2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propionamide (189.5 g, 99%) as a yellow-orange oil. ESI-MS m / z calculated value 300.14496, found value 301.0 (M+1) + Retention time: 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 quickly treated with HCl (240 mL of 4 M, 960.0 mmol) (4 M in dioxane) and the resulting dense suspension was mechanically stirred overnight at room temperature. The solid was collected by filtration, washed with cold ethanol and dried under vacuum at 40-45° C. with nitrogen bleed to give (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propionamide (hydrochloride) (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 Hz, 1H), 1.85 (dd, J = 15.1, 10.4 Hz, 1H), 1.58 (d, J = 6.7 Hz, 3H), 0.89 (pd, J = 9.6, 9.2, 4.3 Hz, 2H), 0.84-0.66 (m, 2H). ESI-MS m / z calcd 300.14496, found 301.0 (M+1) + ; Retention time: 1.40 min (major isomer) and 1.40 min (minor isomer), 97:3 mixture of diastereomers (LC method G).

[0864] Step 5: (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propanoic acid

[0865]

[0866] In a 5 L flask equipped with mechanical stirring, (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propionamide (hydrochloride) (147 g, 436.5 mmol) was added to acetic acid (735 mL) under stirring and the dense 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 foaming, acetic acid (145 mL) was added) and the suspension was stirred at 60-65 ° C for 16 hours. The suspension was then slowly heated to 100 ° C (over 4 hours, strong foaming) and the resulting solution was stirred at 100 ° C for another 20 hours. The light yellow solution was concentrated under reduced pressure at 65 ° C to a semi-solid material and treated with water (1.5 L). The dense suspension was heated to 70-80 ° C and cooled to room temperature under stirring for 2 hours. The solid was collected by filtration, washed with water and sucked dry overnight. The wet solid was further dried at 50-60 ° C under reduced pressure 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 value 301.12897, found value 302.0 (M+1) + ; Retention time: 1.82 minutes; (LC method G).

[0867] Step 6: (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol

[0868]

[0869] In a 5 L flask equipped with mechanical stirring, 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) (pellet) was added slowly over 1 hour while maintaining the internal temperature between 30 and 40° C. by external cooling. The mixture was stirred at 30-40° C. for 1 hour (almost no more hydrogen evolution, gray suspension, most of the starting material was in solution) and heated at 50-55° C. for 1 hour. The gray suspension was stirred overnight in a cooling heating mantle. The gray suspension was cooled in an ice bath and quenched by carefully adding water (44 mL, 2.442 mol), NaOH (41 mL of 6 M, 246.0 mmol) and water (44 mL, 2.442 mol) (the exotherm was high when water was first added and kept between 5 ° C and 30 ° C by cooling). The gray suspension was heated to 50-55 ° C for 1 hour, at which time a colorless suspension was obtained. The warm suspension was filtered through a celite pad covered with magnesium sulfate. The solid was washed with hot THF and evaporated to give crude (2R) -2- [[(1R) -1- phenylethyl] amino] -3- [1- (trifluoromethyl) cyclopropyl] propane-1-ol (121 g, 105%) as an oil. The crude product was dissolved in ether (1 L, clear solution) and slowly treated with HCl (101 mL of 4 M, 404.0 mmol) (4 M in dioxane) under cooling. The resulting thick suspension was stirred at room temperature for 1 hour, and the solid was collected by filtration, washed with diethyl ether and dried at 40-45°C under reduced pressure with nitrogen purge 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, found value 288.0 (M+1) + ; Retention time: 0.99 min (LC method A).

[0870] Step 7: (2R)-2-amino-3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol

[0871]

[0872] 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 in EtOH (630 mL) (under warming) and treated with Pd / C (6.3 g of 10% w / w, 5.920 mmol) (12.5 g of 50% water wet) and the reaction was stirred at 40° C. under 2 bar of hydrogen for 24 hours. The reaction mixture was filtered through celite. The pad was washed with ethanol and the colorless filtrate was evaporated to a solid material, which was triturated with diethyl ether. The suspension was stirred at room temperature for 1 hour. The solid was filtered, washed with copious amounts of ether and dried to give (2R)-2-amino-3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol (hydrochloride) (41.8 g, 97%) as an off-white solid. 1 H 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 Hz, 1H), 2.08 (dd, J = 15.1, 5.4 Hz, 1H), 1.69 (dd, J = 15.1, 9.4 Hz, 1H), 0.97 (h, J = 6.5, 5.9 Hz, 2H), 0.86 (s, 2H). ESI-MS m / z calculated value 183.0871, found value 184.0 (M+1) + ; Retention time: 0.65 min; LC method A.

[0873] Step 8: 3-[[4-[(2R)-2-amino-3-[1-(trifluoromethyl)cyclopropyl]propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[0874]

[0875] 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 of 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 value 564.1654, found value 565.1 (M+1) + ; Retention time: 0.48 minutes; LC method B.

[0876] Example 6: Preparation of 3-[[4-[(2R)-2-amino-3-cyclopropyl-propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[0877] Step 1: tert-Butyl N-[(1R)-1-(cyclopropylmethyl)-2-hydroxy-ethyl]carbamate

[0878]

[0879] A solution of (2R)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propionic 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 three hours. 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 under vacuum to give tert-butyl N-[(1R)-1-(cyclopropylmethyl)-2-hydroxy-ethyl]carbamate (89 mg, 43%). ESI-MS m / z calculated value 215.15215, found value 216.2 (M+1)+ ; Retention time: 0.47 minutes; LC method B.

[0880] Step 2: 3-[[4-[(2R)-2-(tert-Butoxycarbonylamino)-3-cyclopropyl-propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[0881]

[0882] 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-hydroxy-ethyl]carbamate (89 mg, 0.4134 mmol) and sodium tert-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 a reverse phase HPLC-MS method using a Luna C 18 (2) column (75×30 mm, 5 μm particle size) (pn: 00C-4252-U0-AX) and a dual gradient repurification run from 1-99% mobile phase B over 15.0 minutes. Mobile phase A = H 2 O (5 mM HCl). Mobile phase B = CH 3 CN. Flow rate = 50 ml / min, and column temperature = 25° C. to obtain 3-[[4-[(2R)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (45 mg, 18%) as a colorless solid. ESI-MS m / z calculated value 596.23047, found value 597.3 (M+1) + ; Retention time: 0.68 minutes; LC method B.

[0883] Step 3: 3-[[4-[(2R)-2-amino-3-cyclopropyl-propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[0884]

[0885] 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 of 4 M, 12.00 mmol) in dioxane was stirred for four hours. The solvent was removed under vacuum, and the resulting solid was triturated with diethyl ether and dried under vacuum to give 3-[[4-[(2R)-2-amino-3-cyclopropyl-propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride) (53 mg, 132%). ESI-MS m / z calculated value 496.17804, found value 497.3 (M+1) + ; Retention time: 0.41 min; LC method B.

[0886] Example 7: Preparation of (2R)-2-amino-5,5-dimethyl-hexan-1-ol

[0887] Step 1: 2-(tert-Butoxycarbonylamino)-5,5-dimethyl-hex-2-enoic acid methyl ester

[0888]

[0889] To a stirred solution of 2-(tert-butoxycarbonylamino)-2-dimethoxyphosphoryl-acetic acid methyl ester (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-dimethylbutanal (5.0274 g, 6.3 mL, 50.194 mmol) at 0 ° C (ice bath). The reaction mixture was stirred at room temperature for 16 hours. HCl aqueous solution (1N) (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 by passing through a 50 g pad of silica gel using a gradient of 15% EtOAc / heptane to afford methyl 2-(tert-butoxycarbonylamino)-5,5-dimethyl-hex-2-enoate (13.6 g, 95%) as a clear oil that crystallized as a white solid. 1 H NMR (400MHz, CDCl3) δ6.66(t,J=7.6Hz,1H),5.86(br.s,1H),3.79(s,3H),2.12(d,J=7.6Hz,2H),1.47(s,9H),0.95(s,9H).

[0890] Step 2: (2R)-2-(tert-Butoxycarbonylamino)-5,5-dimethyl-hexanoic acid methyl ester

[0891]

[0892] Nitrogen was bubbled through a solution of methyl 2-(tert-butoxycarbonylamino)-5,5-dimethyl-hex-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-diethylphosphono]benzene(1,5-cyclooctadiene)trifluoromethanesulfonate rhodium(I) (363 mg, 0.5023 mmol) was added under nitrogen, and the mixture was placed in an ultrasonic bath for 5 minutes. The reaction mixture was then purged with nitrogen (3 x 30 psi) and then hydrogen (3 x 50 psi). Hydrogen pressure was maintained at 50 psi (3.5 bar) and the reaction was stirred at room temperature for 16 h, at which time the volatiles were removed under reduced pressure and the residue was passed through a plug of silica gel (80 g) using 15% EtOAc / heptane eluent to afford (2R)-2-(tert-butoxycarbonylamino)-5,5-dimethyl-hexanoic acid methyl ester (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 Hz, 1H), 3.74 (s, 3H), 1.87-1.71 (m, 1H), 1.64-1.54 (m, 1H), 1.45 (s, 9H), 1.28-1.15 (m, 2H), 0.87 (s, 9H). ESI-MS m / z calculated value 273.194, found value 296.2 (M+23) + ; Retention time: 4.58 minutes; LC method J.

[0893] Step 3: tert-Butyl N-[(1R)-1-(hydroxymethyl)-4,4-dimethyl-pentyl]carbamate

[0894]

[0895] To a solution of (2R)-2-(tert-butoxycarbonylamino)-5,5-dimethyl-hexanoic acid methyl ester (14 g, 48.652 mmol) in THF (145 mL) was added LiBH4 (2M solution in THF) (61 mL of 2M, 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 a saturated NH4Cl aqueous solution (50 mL) at 0 ° C (with a large amount of gas released, but no exotherm). 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 N-[(1R)-1-(hydroxymethyl)-4,4-dimethyl-pentyl]carbamic acid tert-butyl ester (13.23 g, 89%) as a clear oil. ESI-MS m / z calculated value 245.1991, found value 268.2 (M+23) + ; Retention time: 1.8 minutes. 1 H NMR (400MHz, CDCl3) δ4.62(br.s,1H),3.68(d,J=7.1Hz,1H),3.55(d,J=8.1Hz,2 H), 2.57 (br.s, 1H), 1.55-1.29 (m, 11H), 1.28-1.19 (m, 2H), 0.88 (s, 9H); LC method I.

[0896] Step 4: (2R)-2-Amino-5,5-dimethyl-hexan-1-ol

[0897]

[0898] 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 in 1,4-dioxane) (63 mL of 4M, 252.00 mmol). The reaction mixture was stirred at room temperature for 16 hours, and then the mixture was evaporated to dryness under reduced pressure. The residue was triturated in THF and then filtered to give (2R)-2-amino-5,5-dimethyl-hexan-1-ol (hydrochloride) (8.137 g, 98%) as a white solid. 1HNMR (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, found value 146.3 (M+1) + ; Retention time: 1.78 minutes; LC method J.

[0899] Example 8: Preparation of 3-[[4-[(2R)-2-amino-5,5-dimethyl-hexyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[0900] Step 1: 3-[[4-[(2R)-2-amino-5,5-dimethyl-hexyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[0901]

[0902] 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 reactants were stirred at 10-15 ° C for 2 hours, then cooled to 0 ° C and quenched at 0 ° C by adding 1N HCl aqueous solution (180 mL). This biphasic mixture was stirred for 30 minutes. 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 (3×500 mL) and brine (1×500 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 on a glass frit (por. 4) and the residue was collected using MeOH to dissolve it. The crude mixture was purified by reverse phase chromatography on 275 g C 18Purification on cartridge eluting with a gradient of 0 to 80% CH3CN in acidic water (0.1% HCl in water) gave, after evaporation, 3-[[4-[(2R)-2-amino-5,5-dimethyl-hexyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride) as a white solid (10.2 g, 70%). 1 H 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 value 526.225, found value 527.2 (M+1) + ; Retention time: 2.58 minutes; LC method A.

[0903] Example 9: Preparation of (2R)-2-amino-3-(1-methylcyclopropyl)propan-1-ol

[0904] Step 1: 2-(1-methylcyclopropyl)ethanol

[0905]

[0906] At 0-15 ℃, in 30 minutes, 3-methylbut-3-ene-1-ol (135g, 1.5674mol) was added to a solution of diethylzinc (hexane solution) (2L of 1M, 2.0000mol). The mixture was then warmed to 15 ℃, and after stirring for 20 minutes, diiodomethane (482.7g, 1.8022mol) was added as a DCM (270mL) solution over 1 hour. The reactant was then warmed to 25 ℃ and stirred for 20 hours. After cooling to 5 ℃, the reaction mixture was quenched with HCl aqueous solution (2M, 1.35L). Each phase was separated, and the aqueous phase was extracted with DCM (2×675mL). The hexane extract was washed with sodium thiosulfate (10% w / w, 1.35L) and concentrated in vacuo. The sodium thiosulfate solution was then extracted in sequence with two DCM extracts. The DCM extract was then merged with the product obtained from the concentration of the hexane extract. Water (1.35 L) was then added to the combined organic phases. The mixture was cooled to 2° C., and an aqueous solution of sodium permanganate (83.5 g, 40% w / w, 235.34 mmol) was added. The mixture was stirred at 2° C. for 15 minutes, 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 (400MHz, CDCl3) δ3.75 (t, J = 7.0 Hz, 2H), 1.51 (t, J = 7.0 Hz, 3H), 1.04 (s, 3H), 0.32-0.22 (m, 4H).

[0907] Step 2: 2-(1-Methylcyclopropyl)acetaldehyde

[0908]

[0909] 2-(1-Methylcyclopropyl)ethanol (106 g, 1.0319 mol) was added to a mixture of water (800 mL) and DCM (800 mL), followed by 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 hour (T=1.0 to 8.2° C.). After 1 hour, the mixture was filtered through celite (0.5 parts) and the phases were separated. The aqueous phase was extracted with DCM (2×3.5 vol). 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 DCM solution of 2-(1-methylcyclopropyl)acetaldehyde (101.27 g, 100%) with a 4.15% w / w content. 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).

[0910] Step 3: 3-(1-Methylcyclopropyl)-2-[[(1R)-1-phenylethyl]amino]propionitrile

[0911]

[0912] 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 was added (1R)-1-phenylethylamine (122.20 g, 130 mL, 1.0084 mol) (T increased from 3 ° C to 9 ° C). Acetic acid (68.640 g, 65 mL, 1.1430 mol) (T increased from 3 ° C to 5 ° C) was added dropwise, followed by the addition of sodium cyanide (53 g, 1.0815 mol) (T increased from 1 ° C to 5 ° C). The mixture was warmed to room temperature and stirred overnight. The mixture was concentrated under vacuum (rotary evaporator was connected to a scrubber containing 6M sodium hydroxide solution). MTBE (5 vol.) and potassium carbonate aqueous solution (10% w / w, 5 vol) were added to the residue. The mixture was stirred for 5 minutes and then the phases were separated. The organic layer was washed with brine (15% w / w, 3×5 vol.), dried over sodium sulfate (0.5 parts), and concentrated under reduced pressure to give 3-(1-methylcyclopropyl)-2-[[(1R)-1-phenylethyl]amino]propionitrile (diastereomeric mixture 70:30, 245.86 g, 92%) as a slightly amber oil. ESI-MS m / z calculated value 228.16264, found value 229.2 (M+1) + ; Retention time: 2.935 minutes; LC method F.

[0913] Step 4: (2R)-3-(1-methylcyclopropyl)-2-[[(1R)-1-phenylethyl]amino]propionamide

[0914]

[0915] To a solution of two batches of 3-(1-methylcyclopropyl)-2-[[(1R)-1-phenylethyl]amino]propionitrile (diastereomeric mixture 70:30, 245 g, 948.53 mmol and 19 g, 68.899 mmol) combined in a mixture of DMSO (1.2 L) and water (250 mL) stirred at 50° C. was added potassium carbonate (33 g, 238.77 mmol). An aqueous solution of hydrogen peroxide (220 mL of 9.8 M, 2.1560 mol) was added dropwise over 1.5 hours. The mixture was stirred at 50° C. for 1 hour. The mixture was cooled to room temperature and then 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 separated and extracted with aqueous HCl (2×1.5 L of 1 M, 2×6 vol). The acidic aqueous layers were combined and slowly stirred at 5° C. for 2 hours. The resulting suspension was filtered, and the recovered solid was dried at 50° C. under reduced pressure for 2 hours to give (2R)-3-(1-methylcyclopropyl)-2-[[(1R)-1-phenylethyl]amino]propanamide (hydrochloride) (151.24 g, 52%) as a white powder. ESI-MS m / z calculated value 246.1732, found value 274.2 (M+1) + ; Retention time: 1.391 minutes. 1 H NMR(400MHz,DMSO-d6)δ10.04-9.89(m,1H),9.56-9.37(m,1H),8.05(s,1H),7.77-7.56(m,3H),7.47-7.37(m,3H),4.28-4.14(m,1H) ,3.45-3.28(m,1H),2.20-2.07(m,1H),1.59(d,J=6.8Hz,3H),1.44(dd,J=13.4,10.8Hz,1H),0.92(s,3H),0.35-0.11(m,4H); LC method F.

[0916] Sodium chloride (500 g, 2 parts) was added to the mother liquor, and the aqueous solution was stirred at 5°C overnight. The resulting suspension was filtered, and the recovered solid was dried with air flow for 2 hours to give 3-(1-methylcyclopropyl)-2-[[(1R)-1-phenylethyl]amino]propanamide (hydrochloride) (89.42 g, 31%) as a white powder isomeric mixture. ESI-MS m / z calculated value 246.1732, found value 247.2 (M+1) + ; Retention time: 1.541 minutes; LC method F.

[0917] Step 5: (2R)-3-(1-methylcyclopropyl)-2-[[(1R)-1-phenylethyl]amino]propanoic acid

[0918]

[0919] At 70 ° C, to a solution of lithium hydroxide monohydrate (324 g, 7.7210 mol) in water (5 L), (2R) -3- (1- methylcyclopropyl) -2- [[(1R) -1- phenylethyl] amino] propionamide (hydrochloride) (228.9 g, 809.38 mmol) was added. The reactant was heated to 97 ° C and stirred for 68 hours. The reaction mixture was then cooled to room temperature and neutralized to pH 6 using a 3M HCl aqueous solution, and the product was recovered by filtration. The product was then recrystallized four times by dissolving it in a 0.5M NaOH aqueous solution (5 L) and neutralized to pH 6 using a 3M HCl aqueous solution. The resulting product was then dried in a vacuum at 45 ° C for 72 hours, and (2R) -3- (1- methylcyclopropyl) -2- [[(1R) -1- phenylethyl] amino] propionic acid (161.5 g, 65%) was obtained as a white solid. 1 H 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 is unstable. ESI-MS m / z calculated 247.15723, found 248.2 (M+1). + ; Retention time: 1.68 minutes; LC method F.

[0920] Step 6: (2R)-3-(1-methylcyclopropyl)-2-[[(1R)-1-phenylethyl]amino]propan-1-ol

[0921]

[0922] 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 LiAlH4 (40 g, 1.0539 mol) over 3 hours at 20-25°C. After stirring at room temperature for another hour, the reaction mixture was cooled to 10°C and water (38.000 g, 38 mL, 2.1093 mol) was added over 150 minutes. NaOH (35 mL of 6 M, 210.00 mmol) and water (38.000 g, 38 mL, 2.1093 mol) were then added sequentially. The mixture was stirred at room temperature overnight. The reaction mixture was then filtered over a bed of celite (bottom, 80 g) and magnesium sulfate (top, 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 a solution of HCl in dioxane (130 mL of 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 recovered 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) (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 .48-7.35(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, 2.2 Hz, 1H), 1.62 (d, J = 6.6 Hz, 3H), 1.26 (dd, J = 13.7, 11.2 Hz, 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, found value 234.2 (M+1) + ; Retention time: 1.82 minutes; LC method F.

[0923] Step 7: (2R)-2-amino-3-(1-methylcyclopropyl)propan-1-ol

[0924]

[0925] 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 reactants were stirred at 50 ° C for 24 hours. The mixture was filtered through a Pall filter 0.45 um, washed with EtOH (2×500 mL), and the filtrate was concentrated in vacuo. The obtained white solid was triturated with MTBE (625 mL) over 1 hour, then filtered, washed with MTBE (500 mL) and dried in vacuo to give (2R)-2-amino-3-(1-methylcyclopropyl)propan-1-ol (hydrochloride) (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, found value 130.2 (M+1) + ; Retention time: 0.34 min; LC method F.

[0926] Example 10: Preparation of 3-[[4-[(2R)-2-amino-4-fluoro-4-methyl-pentyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[0927] Step 1: (3R)-3-(tert-Butoxycarbonylamino)-4-hydroxy-butyric acid benzyl ester

[0928]

[0929] A stirred solution of (2R)-4-benzyloxy-2-(tert-butoxycarbonylamino)-4-oxo-butanoic 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 reactant was stirred at -50 ° C for 2 hours, then filtered, and the filtrate was cooled to -10 ° C. Sodium borohydride (3.50 g, 92.513 mmol) was added, and the reactant was allowed to reach room temperature and stirred at room temperature for 4 hours. The reactant was quenched at 0 ° C by the addition of water (200 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (5 × 150 mL). The combined organic layers were washed with brine (250 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford (3R)-3-(tert-butoxycarbonylamino)-4-hydroxy-butyric acid benzyl ester (17.857 g, 49%) as a viscous, translucent oil, which was used in the next step without further purification. ESI-MS m / z calculated value 309.1576, found value 332.2 (M+23) +; 210.2 (M-99) + ; Retention time: 1.7 minutes; LC method I.

[0930] Step 2: Benzyl 2-[(4R)-2-oxooxazolidin-4-yl]acetate

[0931]

[0932] At 0 ° C under a nitrogen atmosphere, pyridine (23.472 g, 24 mL, 296.74 mmol) and methanesulfonic anhydride (10 g, 57.407 mmol) were added to a stirred solution of crude (3R) -3- (tert-butoxycarbonylamino) -4-hydroxy-butyric acid benzyl ester (17.9 g, 30.667 mmol) in anhydrous 1,2-dichloroethane (140 mL) at 0 ° C. The reactant was stirred at 0 ° C for 15 minutes, then at room temperature for 2 hours, and finally at 90 ° C. overnight. The reactant was then cooled to room temperature, diluted with dichloromethane (140 mL), and quenched by adding an aqueous solution of 1N 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 which was purified by flash chromatography on silica gel using a 120 g HP Gold column and eluting with an ethyl acetate / heptane gradient (15 to 100% in 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, found value 236.2 (M+1) + ; Retention time: 1.51 minutes; LC method I.

[0933] Step 3: (4R)-4-(2-Hydroxy-2-methyl-propyl)oxazolidin-2-one

[0934]

[0935] The flask is flame dried, then cooled to room temperature with a stream of nitrogen, then anhydrous toluene (30mL) and anhydrous tetrahydrofuran (30mL) are loaded.Then the solvent mixture is cooled to -50 DEG C. A solution of methylmagnesium bromide in ether (29mL of 3M, 87.000mmol) is added to the mixture by cannula, and stirred at -50 DEG C for 30 minutes, followed by addition of a solution of 2- [(4R) -2- oxoxazolidin-4-yl] benzyl acetate (5.01g, 18.678mmol) in anhydrous tetrahydrofuran (15mL) by cannula. The reactant is stirred at -50 DEG C for 30 minutes, then the reactant is brought to room temperature and stirred at room temperature overnight. The reactant is then cooled to 0 DEG C, and quenched by dropping a solution of acetic acid (7.9200g, 7.5mL, 131.89mmol) in water (20mL). The reaction mixture is vigorously stirred at room temperature for 1 hour. Then sodium chloride is added to saturate the water layer. The reaction was then dried over sodium sulfate and filtered on 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 120 g HP Gold posts and eluted with an isopropanol / dichloromethane gradient (0 to 6% in 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, found value 160.2 (M+1) + ; Retention time: 0.74 min; LC method I.

[0936] Step 4: (4R)-4-(2-Fluoro-2-methyl-propyl)oxazolidin-2-one

[0937]

[0938] To a stirred solution of (diethylamino) sulfur trifluoride (4.1480 g, 3.4 mL, 25.734 mmol) in anhydrous dichloromethane (70 mL) was added a solution of (4R)-4-(2-hydroxy-2-methyl-propyl) oxazolidin-2-one (4.29 g, 25.603 mmol) in anhydrous dichloromethane (25 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 reactant was then slowly added to a saturated aqueous sodium bicarbonate solution (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 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, found value 162.2 (M+1) + ; Retention time: 1.28 minutes; LC method I.

[0939] Step 5: (2R)-2-Amino-4-fluoro-4-methyl-pentan-1-ol

[0940]

[0941] 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 reactants were then allowed to reach room temperature and concentrated under reduced pressure. The residue was co-evaporated with toluene (3 × 10 mL) to give a light orange residue, which was filtered on 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. 1H NMR (400 MHz, CD3OD) δ 3.50 (dd, J = 10.6, 4.8 Hz, 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 (377 MHz, CD3OD) δ -139.34 (s, 1F). ESI-MS m / z calculated value 135.10594, found value 136.2 (M+1) + ; Retention time: 0.23 min; LC method I.

[0942] Step 6: 3-[[4-[(2R)-2-amino-4-fluoro-4-methyl-pentyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[0943]

[0944] 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. Sodium tert-butoxide (1.05 g, 10.93 mmol) was added to the resulting turbid solution in one portion, causing the solid to dissolve and a slightly exothermic reaction to occur. The mixture was stirred at room temperature for 2.5 hours. The reactants were diluted with ethyl acetate (20 mL), HCl (20 mL of 1 M, 20.00 mmol) and brine (20 mL) and the 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 in 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-pentyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride) (1.238 g, 94%) as a brown solid. ESI-MS m / z calculated value 516.18427, found value 517.45 (M+1) + ; Retention time: 0.99 minutes; LC method A.

[0945] Example 11: Preparation of 3-[[4-[(2R)-2-amino-5-methyl-hexyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[0946] Step 1: (2R)-2-Amino-5-methyl-hexan-1-ol

[0947]

[0948] Borane tetrahydrofuran complex in THF (58mL of 1M, 58.000mmol) is slowly added to a suspension of (2R)-2-amino-5-methyl-hexanoic acid (4.05g, 27.893mmol) in 2-methyltetrahydrofuran (40mL). The reactant is stirred at room temperature for 16 hours. An aqueous solution of HCl (28mL of 3M, 84.00mmol) is added, the temperature is maintained at below 25°C, and the reactant is stirred at room temperature for 45 minutes. MeTHF (100mL) is added, and excess THF is removed by evaporation. The solution is alkalized with a 25% aqueous solution of NaOH (10mL) at a pH of about 9. The organic phase is separated. The aqueous layer is extracted with MeTHF (2×50mL). The combined organic layer is washed with brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Aqueous HCl (14 mL of 3M, 42.000 mmol) was added to the residue, water was evaporated to dryness, and then co-evaporated 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 HNMR (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, found value 132.2 (M+1) + ; Retention time: 2.022 minutes. 25% NaOH aqueous solution (3 mL) was added to the aqueous phase, 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 under vacuum. Aqueous HCl solution (14 mL of 3 M, 42.000 mmol) was added to the residue, the water was evaporated to dryness, and then co-evaporated 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) (2.227 g, 45%) as a white solid. 1H 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, found value 132.2 (M+1) + Retention time: 1.994 minutes. Total amount: 4.458 g, and overall yield: 95%. LC Method K.

[0949] Step 2: 3-[[4-[(2R)-2-amino-5-methyl-hydroxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[0950]

[0951] 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. Sodium tert-butoxide (1.01 g, 10.51 mmol) was added once to the resulting turbid solution, causing the solid to dissolve rapidly and a slightly exothermic reaction to occur. The mixture was stirred at room temperature for 1 hour. More (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 reactant was diluted with ethyl acetate (20 mL), HCl (20 mL of 1 M, 20.00 mmol) and brine (20 mL) and the 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 ground in a mixture of EtOAc and hexane (1: 3, v: v), and the resulting suspension was stirred at room temperature for 1 hour. The solid was filtered and dried to give 3-[[4-[(2R)-2-amino-5-methyl-hexyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride) (1.32 g, 82%) as an off-white solid. ESI-MS m / z calculated value 512.20935, experimental value 513.59 (M+1) + ; Retention time: 1.1 minutes; LC method A.

[0952] Example 12: Preparation of 3-[[4-[(2R)-2-amino-4-cyclopropyl-butoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[0953] Step 1: Methyl (2R)-2-(benzyloxycarbonylamino)hex-5-enoate

[0954]

[0955] (2R)-2-amino hex-5-enoic acid (2g, 15.485mmol) is mixed in methanol (40mL) and cooled in an acetone dry ice bath of about-10 ℃.Thionyl chloride (4.0775g, 2.5mL, 34.273mmol) is added dropwise.Then the clarified mixture is made to reach room temperature and stirred for 24 hours.Then it is concentrated.The off-white solid obtained is transferred to DCM (30mL) and water (15mL), and cooled in an ice-water bath.Sodium bicarbonate (8.6g, 102.37mmol) is added, followed by CbzOSu (4.68g, 18.779mmol).The slightly yellow mixture is effectively stirred for 15 hours (ice bath temperature reaches room temperature during the process).DCM and water (each 50ml) are added.Separate each layer.DCM solution is 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 calcd 277.1314, found 278.3 (M+1) + ; Retention time: 2.86 minutes; LC method E.

[0956] Step 2: (2R)-2-(Benzyloxycarbonylamino)-4-cyclopropyl-butyric acid methyl ester

[0957]

[0958] The hexane (1M, 50.000mmol) containing EtZn is diluted with DCM (25mL) and cooled to about -10 ℃.DCM (10mL) containing TFA (5.7720g, 3.9mL, 50.621mmol) is added dropwise.The mixture is stirred at <0 ℃ for 15 minutes.DCM (25mL) containing CHI (12.968g, 3.9mL, 48.418mmol) is added in batches.The mixture is stirred at the same temperature for 15 minutes.Then DCM (25mL) containing (2R)-2-(benzyloxycarbonylamino) hex-5-enoic acid methyl ester (3.9g, 13.360mmol) is added in batches.The mixture is stirred for 15 hours (gradually reaching room temperature).HCl (0.2N aqueous solution) (40ml in total) is added in batches.Add more DCM (60ml).Separate each layer. 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 (2R)-2-(benzyloxycarbonylamino)-4-cyclopropyl-butyric acid methyl ester (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, found value 292.5 (M+1) + ; Retention time: 3.01 minutes; LC method E.

[0959] Step 3: Benzyl N-[(1R)-3-cyclopropyl-1-(hydroxymethyl)propyl]carbamate

[0960]

[0961] (2R)-2-(Benzyloxycarbonylamino)-4-cyclopropyl-butyric acid methyl ester (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. A THF solution of LiBH4 (12 mL of 2M, 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 more water (30 ml × 2), brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give crude N-[(1R)-3-cyclopropyl-1-(hydroxymethyl)propyl]carbamic acid benzyl ester (3.75 g, 100%) as a colorless oil. ESI-MS m / z calculated value 263.15213, found value 264.4 (M+1) + ; Retention time: 2.65 minutes; LC method E.

[0962] Step 4: (2R)-2-Amino-4-cyclopropyl-butan-1-ol

[0963]

[0964] N-[(1R)-3-cyclopropyl-1-(hydroxymethyl)propyl]benzyl carbamate (3.75g, 12.817mmol) was dissolved in EtOH (60mL). HCl aqueous solution (12.9mL of 1M, 12.900mmol) was added, followed by Pd / activated carbon (300mg, 5% w / w, 0.1410mmol). The mixture was vacuumed and refilled with 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) (2.15g, 96%) as a colorless oil. ESI-MS m / z calculated value 129.11537, found value 130.4 (M+1) + ; Retention time: 1.09 minutes; LC method E.

[0965] Step 5: 3-[[4-[(2R)-2-amino-4-cyclopropyl-butoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[0966]

[0967] 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 tert-butoxide (2.8 g, 29.135 mmol) was added in one go. The mixture was stirred at room temperature for 1 hour. More sodium tert-butoxide (1.4 g, 14.568 mmol) was added. The mixture was stirred at room temperature for 2 hours. Aqueous HCl solution (60 mL of 1 M, 60.000 mmol) was added, followed by EtOAc (60 ml). The layers were separated. The aqueous layer was extracted with more EtOAc (20 ml). The combined EtOAc solutions were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was redissolved in EtOAc (about 20 ml) and briefly sonicated. The supernatant was discarded. The precipitate was dissolved in THF and transferred to a shipping bottle 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 yellow solid. 1 H NMR(500MHz,DMSO-d6)δ13.20(s,1H),8.44(s,1H),8.28–8.05(m,5H),7.69(t,J=.8,7.8H z,1H),7.25(t,J=7.6,7.6Hz,1H),7.12(d,J=7.6Hz,2H),6.30(s,1H),4.36(dd,J=11.8,3 .3Hz,1H),4.21(dd,J=11.8,6.6Hz,1H),3.57–3.48(m,1H),1.99(d,J=8.5Hz,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, found value 511.8(M+1) + ; Retention time: 1.78 minutes; LC method H.

[0968] Example 13: Preparation of 3-[[[4-[(2R)-2-amino-4,4-dimethyl-pentyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonylimino]benzoic acid isomer A

[0969] Step 1: Methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonylbenzoate

[0970]

[0971] Under N2 atmosphere, 3-[(3-methoxycarbonylphenyl)disulfonyl]benzoic acid methyl ester (26.5g, 79.244mmol), dichloromethane (167mL) and pyridine (2.9340g, 3mL, 37.092mmol) were added to a 500ml single-neck round-bottom flask. Thionyl chloride (10.7g, 79.277mmol) was added dropwise to the obtained amber solution (no exotherm was observed). The solution turned dark orange and was stirred at room temperature for 10 minutes. Under N2 atmosphere, 4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-amine (25.95g, 111.04mmol) and dichloromethane (618mL) were charged into another 2L three-necked round-bottom flask. The light yellow solution obtained was cooled to 2°C (internal temperature) using an ice bath. Then, triethylamine (47.335 g, 65.2 mL, 467.78 mmol) was added dropwise, keeping the internal temperature below 10°C. Once the solution reached 2°C again, the first solution was added dropwise (exothermic), keeping the internal temperature below 10°C. The resulting light orange suspension was stirred at 2°C for 1 hour (the ice bath was not removed). The reaction was poured into a 5% wt. aqueous sodium bicarbonate solution (585 ml, 63 vol.). After the phases were separated, the aqueous phase was extracted with DCM (3 x 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 product) and DCM. The suspension was concentrated to dryness to give a fine orange powder. This dry pack was loaded onto silica gel (460 g, 6 parts relative to the crude product) filled with heptane in a sintered glass. Elution was started with heptane / EtOAc (80 / 20) (1L), followed by 70 / 30 (5L). The filtrate (light yellow) was concentrated to dryness. During concentration, a fine white solid was formed. The solid was suspended in heptane / EtOAc (95 / 5) (50ml), cooled and filtered in an ice bath. The off-white solid was washed with cold heptane / EtOAc (95 / 5) (50ml) and dried under high vacuum to obtain 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonylbenzoic acid methyl ester (26.46g, 83%) as a white powder. 1H NMR (400 MHz, CDCl3) δ 7.90-7.87 (m, 1H), 7.84 (dt, J = 7.3, 1.6 Hz, 1H), 7.46-7.33 (m, 2H), 7.22-7.12 (m, 1H), 7.09-6.99 (m, 3H), 6.80 (s, 1H), 3.90 (s, 3H), 2.05 (s, 6H). ESI-MS m / z calculated value 399.0808, found value 400.0 (M+1) + ; Retention time: 2.018 minutes; LC method I.

[0972] Step 2: Methyl 3-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminesulfinylbenzoate

[0973]

[0974] Under N2 atmosphere, a 500ml 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]sulfonylbenzoate (26g, 65.017mmol) and dichloromethane (624mL). The resulting light yellow solution was cooled to 2°C (internal temperature) using an ice bath. 3-chloroperbenzoic acid (15.6g, 69.608mmol) was then added in portions (photoexothermic), maintaining the internal temperature below 5°C. The resulting light yellow suspension was stirred at 2°C for 1 hour. A 5% wt. aqueous solution of Na2S2O3 (520ml, 20vol.) was added to the reaction mixture. An exotherm was observed, and the internal temperature reached 10°C. The mixture was poured into a 5% wt. aqueous solution of sodium bicarbonate (520ml, 20vol.). After the phases were separated, the aqueous phase was extracted with DCM (3×100ml). The combined organic phases were dried over sodium sulfate and concentrated to dryness to give a crude product as a yellow oil. The oil was mixed with heptane / EtOAc (95 / 5) (200 ml) and sonicated to obtain a white slurry. The slurry was stirred at room temperature for 30 minutes. The solid was recovered 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]aminesulfinylbenzoate (22.76 g, 84%) as a white powder. 1H 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 Hz, 1H), 7.35 (s, 1H), 7.26-7.21 (m, 1H), 7.12 (d, J = 7.6 Hz, 2H), 6.96 (s, 1H), 3.96 (s, 3H), 2.15 (s, 6H). ESI-MS m / z calculated value 415.07574, found value 416.0 (M+1) + ; Retention time: 1.906 minutes; LC method I.

[0975] Step 3: Methyl 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonylimino]benzoate

[0976]

[0977] Under N2 atmosphere, a 3L three-necked round-bottom flask equipped with a dropping funnel and an internal temperature probe was charged with methyl 3-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminesulfinylbenzoate (22.5 g, 54.100 mmol) and dichloromethane (833 mL). 1-Chloropyrrolidine-2,5-dione (10.11 g, 75.712 mmol) was added in portions to the resulting pale yellow solution. The milky white mixture was stirred at room temperature for 7 hours. The reactant was then cooled to 0°C (ice bath) and ammonia (0.4 M in dioxane) (1.2 L of 0.4 M, 480.00 mmol) was added dropwise over 35 minutes. The reactant was stirred at room temperature overnight. The reactant was poured into a mixture of 5% wt. sodium bicarbonate aqueous solution / brine 1:1 (1 L). After the phases were separated, the aqueous phase was extracted with DCM (3×150 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 heptane / EtOAc 95 / 5 was added (a white solid appeared), and the solvent was concentrated to dryness. The solid was triturated with heptane / EtOAc 95 / 5 (200 ml). The white solid was recovered by filtration to give methyl 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonylimino]benzoate (23.399 g, 81%) as an off-white powder, according to 1H NMR, which contains about 15% wt of succinimide. 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonylimino]benzoic acid methyl ester (23.399 g, 49.577 mmol) was dissolved in EtOAc (250 mL) by ultrasonic treatment at 40 ° C. The organic phase was washed with saturated sodium bicarbonate aqueous solution (2 × 100 mL). The aqueous phase was backwashed with EtOAc (100 mL). The combined organic phase was washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonylimino]benzoic acid methyl ester (21.98 g, 97%) as a light 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 calcd 430.08664, found 431.1 (M+1) + ; Retention time: 3.975 minutes; LC method J.

[0978] Step 4: Methyl 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonylimino]benzoate, Isomer A, and Methyl 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonylimino]benzoate, Isomer B

[0979]

[0980] Racemic methyl 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonylimino]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 from SFC was evaporated to dryness and co-evaporated with 2-methyltetrahydrofuran to give methyl 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonylimino]benzoate Isomer A (8.38 g, 78%) as a light yellow solid. 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, found value 431.1 (M+1) + Retention time: 3.99 minutes. The slowest eluting peak was evaporated to dryness and co-evaporated with 2-methyltetrahydrofuran to afford methyl 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonylimino]benzoate Isomer B (8.52 g, 76%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (t, J = 1.6 Hz, 1H), 8.14-8.07 (m, 2H), 7.89 (s, 2H), 7.67 (t, J = 7.8 Hz, 1H), 7.21-7.15 (m, 1H), 7.03 (d, J = 7.6 Hz, 2H), 6.91 (s, 1H), 3.83 (s, 3H), 1.89-1.59 (m, 6H). ESI-MS m / z calculated value 430.0866, found value 431.1 (M+1) + ; Retention time: 3.99 minutes; LC method J.

[0981] Step 5: 3-[[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonylimino]benzoic acid isomer A

[0982]

[0983] To a solution of methyl 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonylimino]benzoate isomer A (8.38 g, 18.125 mmol) in tetrahydrofuran (170 mL) and 0°C water (170 mL) was added lithium hydroxide hydrate (1.9 g, 45.277 mmol). The resulting light yellow solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous NH4Cl solution (250 mL) and some HCl 1N to reach pH = 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]sulfonylimino]benzoic acid isomer A (7.82 g, 96%) as a light 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, found value 417.1 (M+1) + ; Retention time: 3.57 minutes; LC method J.

[0984] Step 6: 3-[[[4-[(2R)-2-amino-4,4-dimethyl-pentyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonylimino]benzoic acid isomer A

[0985]

[0986] 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonylimino]benzoic acid isomer A (4g, 8.5012mmol) was dissolved in 2-MeTHF (36mL) and DMF (4mL). The reaction mixture was cooled to 0°C and sodium tert-butoxide (4.8g, 49.946mmol) was added, followed by (2R)-2-amino-4,4-dimethyl-pentan-1-ol (hydrochloride) (1.8g, 10.735mmol). The reactant was then warmed to room temperature and stirred for 5.5 hours. More sodium tert-butoxide (817mg, 8.5013mmol) was added and the reaction mixture was stirred at room temperature for 15 minutes. The reactant was cooled to 0°C and quenched by adding aqueous hydrochloric acid solution (2M, 60mL). The reaction mixture was allowed to stand overnight at room temperature, then the mixture was evaporated to dryness, and the residue was purified by reverse phase chromatography on 120g C 18 Purification was performed twice on an Aq cartridge using a 10-100% MeCN / acidic water (0.1% HCl) gradient to afford 3-[[[4-[(2R)-2-amino-4,4-dimethyl-pentyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonylimino]benzoic acid (hydrochloride) Isomer A as a light beige solid after lyophilization (2.24 g, 46%). 1 HNMR (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, found value 512.2 (M+1) + ; Retention time: 2.11 minutes; LC method J.

[0987] Example 14: Preparation of 3-[[[4-[(2R)-2-amino-4,4-dimethyl-pentyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonylimino]benzoic acid isomer B

[0988] Step 1: 3-[[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonylimino]benzoic acid isomer B

[0989]

[0990] To a solution of methyl 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonylimino]benzoate, isomer B (8.52 g, 17.637 mmol) in tetrahydrofuran (170 mL) and water (170 mL) at 0° C., lithium hydroxide hydrate (1.85 g, 44.086 mmol) was added. The resulting light yellow solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous NH4Cl (200 mL) and some HCl 1N (approximately 30 mL) to reach pH = 4. The product was extracted with EtOAc (3 x 200 mL), and the combined organic phases were washed with brine (200 mL), dried over magnesium sulfate, filtered and concentrated to dryness to afford 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonylimino]benzoic acid Isomer B (7.62 g, 96%) as a light 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, found value 417.1 (M+1) + ; Retention time: 3.58 minutes; LC method J.

[0991] Step 2: 3-[[[4-[(2R)-2-amino-4,4-dimethyl-pentyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonylimino]benzoic acid isomer B

[0992]

[0993] 3-[[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonylimino]benzoic acid isomer B (3.97g, 8.4279mmol) was dissolved in 2-MeTHF (36mL) and DMF (4mL). The reaction mixture was cooled to 0°C and sodium tert-butoxide (4.05g, 42.142mmol) was added, followed by (2R)-2-amino-4,4-dimethyl-pentan-1-ol (hydrochloride) (1.7g, 10.139mmol). The reactant was then warmed to room temperature and stirred for 6 hours. More sodium tert-butoxide (2g, 20.811mmol) was added and the mixture was stirred at room temperature for 18 hours. The reactant was cooled to 0°C and quenched by adding aqueous hydrochloric acid solution (2M, 70mL). The mixture was evaporated to dryness and the residue was purified twice by reverse phase chromatography on a 120 g C18 Aq cartridge using a 5-100% MeCN / acidic water (0.1% HCl) gradient to afford after lyophilization 3-[[[4-[(2R)-2-amino-4,4-dimethyl-pentyloxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]amino]sulfonylimino]benzoic acid (hydrochloride) Isomer B as an off-white solid (2.13 g, 45%). 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, found value 512.3 (M+1) + ; Retention time: 2.13 minutes; LC method J.

[0994] Example 15: Preparation of 3-[[4-[(2R)-2-amino-3-(1-methylcyclobutyl)propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[0995] Step 1: N-methoxy-N,1-dimethyl-cyclobutanecarboxamide

[0996]

[0997] To a solution of 1-methylcyclobutanecarboxylic acid (18 g, 157.70 mmol) in DMF (200 mL) was added N-methoxymethylamine 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 (3×200 mL), washed with 1N aqueous HCl (2×400 mL), saturated aqueous sodium bicarbonate (2×400 mL), water (2×400 mL), and brine (2×400 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford N-methoxy-N,1-dimethyl-cyclobutanecarboxamide (20.5 g, 75%) as a yellow oil. ESI-MS m / z calculated value 157.11028, found value 158.4 (M+1) + ; Retention time: 1.49 minutes; LC method I.

[0998] Step 2: 1-Methylcyclobutanecarboxaldehyde

[0999]

[1000] 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) and water (19.5 mL). This 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 dioxane solution of 1-methylcyclobutanecarboxaldehyde (11.28 g, 100%). This solution was used directly in the next reaction as the dioxane solution.

[1001] Step 3: Methyl 2-(tert-butoxycarbonylamino)-3-(1-methylcyclobutyl)prop-2-enoate

[1002]

[1003] To a stirred solution of 1-methylcyclobutanecarboxaldehyde (in dioxane solution) (11.28 g, 114.93 mmol) at 0 ° C was added 2-(tert-butoxycarbonylamino)-2-dimethoxyphosphoryl-acetic acid methyl ester (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 0 to 40% EtOAc / heptane gradient to afford, 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.

[1004] Step 4: Methyl (2R)-2-(tert-butoxycarbonylamino)-3-(1-methylcyclobutyl)propanoate

[1005]

[1006] 2-(tert-butoxycarbonylamino)-3-(1-methylcyclobutyl)prop-2-enoic acid methyl esters (18g, 65.962mmol) is dissolved in ethanol (180mL) and dioxanes (90mL).Nitrogen is passed through 15 minutes, then add 1,2-bis[(2R, 5R)-2,5-diethylphosphono] benzene (1,5-cyclooctadiene) trifluoromethanesulfonic acid rhodium (I) (2.5g, 3.4596mmol).Nitrogen is passed through 5 minutes, then make mixture under 65psi hydrogen pressure and at room temperature hydrogenate 4 hours.Mixture is concentrated to dryness in a vacuum, then the solution of EtOAc and heptane (1:1,200mL) is added in mixture. The crude solution was filtered over a pad of silica and the pad was rinsed with a solution of EtOAc and heptane (1:1, 400 mL) to afford after evaporation methyl (2R)-2-(tert-butoxycarbonylamino)-3-(1-methylcyclobutyl)propanoate (17.5 g, 93%) as a yellow oil. 1HNMR (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, found value 294.2 (M+23) + ; Retention time: 1.9 minutes; LC method I.

[1007] Step 5: tert-Butyl N-[(1R)-1-(hydroxymethyl)-2-(1-methylcyclobutyl)ethyl]carbamate

[1008]

[1009] A solution of (2R) -2- (tert-butoxycarbonylamino) -3- (1- methylcyclobutyl) propionic acid methyl ester (17.5g, 61.267mmol) in THF (40mL) is added to a suspension of LAH (3.5g, 92.216mmol) in THF (160mL) at 0°C. The mixture is stirred at 0°C for 15 minutes and then stirred at room temperature for 2 hours. The mixture is then cooled to 0°C, and water (3.5mL) is added, followed by addition of the NaOH aqueous solution (15%, 3.5mL) and then water (10.5mL). The mixture is stirred at room temperature for 30 minutes and magnesium sulfate (2g) is then added. The mixture is filtered on diatomaceous earth, and the filter cake is washed with EtOAc (100mL). The filtrate was 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 HNMR (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, found value 188.2 (M-55) + ; Retention time: 1.74 minutes; LC method I.

[1010] Step 6: (2R)-2-amino-3-(1-methylcyclobutyl)propan-1-ol

[1011]

[1012] To a solution of tert-butyl N-[(1R)-1-(hydroxymethyl)-2-(1-methylcyclobutyl)ethyl]carbamate (15.3 g, 59.731 mmol) in anhydrous DCM (150 mL) was added HCl (in dioxane) (150 mL of 4 M, 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 x 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, overlapped 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) (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, overlapped 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, found value 144.4 (M+1) + ; Retention time: 0.56 min; LC method I.

[1013] Step 7: Benzyl N-[(1R)-1-(hydroxymethyl)-2-(1-methylcyclobutyl)ethyl]carbamate

[1014]

[1015] To a stirred suspension of (2R)-2-amino-3-(1-methylcyclobutyl)propan-1-ol (12.3 g, 81.584 mmol) in anhydrous THF (250 mL) was added triethylamine (25.410 g, 35 mL, 251.11 mmol) followed by N-(benzyloxycarbonyloxy)succinimide (24.5 g, 98.307 mmol) at 0°C. 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 x 250 mL). The combined organic layers were washed with water (3 x 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 to 100% EtOAc / heptane gradient, followed by reverse phase chromatography on a 275 g C 18 The product was purified twice on a GOLD cartridge using a gradient elution of 40 to 100% MeOH / acidic water (water containing 0.1% v / v formic acid). The 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 x 500 mL). The combined organic layers were washed with brine (1 x 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 x 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. 1 H 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), 2.23 (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, found value 278.2 (M+1) + ; Retention time: 1.74 minutes; LC method I. The fractions containing the other enantiomer were combined and the solvent was concentrated in vacuo. The product was purified by reverse phase chromatography on 80 g C 18GOLD cartridge with gradient elution from MeOH to 50% 100 / acidic water (water containing 0.1% v / v formic acid) and then on 80 g C 18 The GOLD cartridge was purified twice with a gradient elution of MeOH to 50% 100 / acidic water (water containing 0.1% v / v formic acid). The 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, CDCl3) 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), 1 missing proton (labile proton). ESI-MS m / z calcd 277.1678, found 278.2 (M+1); retention time: 1.75 min; LC method I.

[1016] Step 8: (2R)-2-amino-3-(1-methylcyclobutyl)propan-1-ol

[1017]

[1018] To a degassed solution of benzyl N-[(1R)-1-(hydroxymethyl)-2-(1-methylcyclobutyl)ethyl]carbamate (13.5 g, 47.165 mmol) in methanol (250 mL) was added 10% palladium on carbon 50% wet (5.2 g, 2.4431 mmol). After purging with nitrogen for 5 minutes, hydrogen was bubbled into 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 stirred by In 40mL 40mL 4-amino-3-(1-methylcyclobutyl)propan-1-ol (hydrochloride) (7.68g, 86%) of 2-amino-3-(1-methylcyclobutyl)propan-1-ol (hydrochloride) (7.68g, 86%) of white solid was obtained after lyophilization. 1H 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, found value 144.4 (M+1) + ; Retention time: 0.64 min; LC method I.

[1019] Step 9: 3-[[4-[(2R)-2-amino-3-(1-methylcyclobutyl)propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[1020]

[1021] 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 reactants were stirred at 10-15 ° C for 2 hours, then cooled to 0 ° C and quenched by adding 1N HCl aqueous solution (300 mL). The biphasic mixture was stirred for 30 minutes. 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 passed through 275 g of C 18 Purification by reverse phase chromatography on a GOLD cartridge eluting with a gradient of 20 to 100% MeOH in acidic water (0.1% hydrochloric acid in water) gave, after evaporation, 3-[[4-[(2R)-2-amino-3-(1-methylcyclobutyl)propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride) as a white solid (24.25 g, 78%). 1H 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 is missing, unstable proton. ESI-MS m / z calculated value 524.20935, found value 525.3 (M+1) + ; Retention time: 2.49 minutes; LC method J.

[1022] Example 16: Preparation of 3-[[4-(2-amino-5-fluoro-5-methyl-hexyloxy)-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[1023] Step 1: 3-Hydroxy-3-methyl-butyric acid ethyl ester

[1024]

[1025] Ethyl acetate (5.0512 g, 5.6 mL, 57.332 mmol) was added dropwise to a solution of (bis(trimethylsilyl)amide)lithium (in THF) (39 mL of 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 stirred for 10 minutes. HCl (2 M, 35 ml) was added to the reaction mixture, and the mixture was then warmed 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 solution (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3-hydroxy-3-methyl-butyric acid ethyl ester (7.84 g, 89%) as a clear yellow oil. 1 H NMR (400 MHz, CDCl3) δ 4.18 (q, J = 7.1 Hz, 2H), 3.59 (s, 1H), 2.48 (s, 2H), 1.31-1.26 (m, 9H). ESI-MS m / z calculated value 146.0943, found value 169.2 (M+23) + ; Retention time: 1.3 minutes; LC method I.

[1026] Step 2: 3-Fluoro-3-methyl-butyric acid ethyl ester

[1027]

[1028] At -78 ° C, deoxyfluorine (Deoxo-Fluor) (solution in toluene) (26g, 50% w / w, 58.759mmol) is added to a solution of 3-hydroxy-3-methyl-butyric acid ethyl ester (7.5g, 48.740mmol) in DCM (125mL).Then the reactant is warmed to room temperature and stirred for 4 hours.The reaction mixture is quenched with sodium bicarbonate aqueous solution (200mL).The aqueous phase is extracted with DCM (2 × 100mL), and the combined organic phase is washed with saturated ammonium chloride aqueous solution (100mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain crude 3-fluoro-3-methyl-butyric acid ethyl ester (4.8g, 53%) as a clear oil. 1 H NMR (400 MHz, CDCl 3 ) 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). It was used in the next step without further purification.

[1029] Step 3: 3-Fluoro-3-methyl-butyraldehyde

[1030]

[1031] At -78 ℃, DIBAL (in toluene) (8.7mL of 1M, 8.7000mmol) is slowly added to a solution of 3-fluoro-3-methyl-butyric acid ethyl ester (1g, 5.3990mmol) in DCM (10mL). The reaction mixture is stirred at this temperature for 1 hour. The reaction mixture is quenched with concentrated aqueous ammonium chloride solution (20mL) and 1N HCl (5mL). The reaction mixture is warmed to room temperature and stirred for 30 minutes. DCM (100mL) is added to the mixture and vibrated. The aqueous phase is separated and washed with more DCM (25mL). The combined organic phase is dried overnight with sodium sulfate and then filtered to provide about 0.3% solution (185g, 99%) of 3-fluoro-3-methyl-butyraldehyde in a clear solution. This solution is directly used in the next step.

[1032] Step 4: 2-(tert-Butoxycarbonylamino)-5-fluoro-5-methyl-hex-2-enoic acid methyl ester

[1033]

[1034] To a stirred solution of 3-fluoro-3-methyl-butyraldehyde (3% in DCM) (185 g, 5.3302 mmol) was added 2-(tert-butoxycarbonylamino)-2-dimethoxyphosphoryl-acetic acid methyl ester (500 mg, 1.6821 mmol) at 0 ° C., 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 ...

Claims

1. A compound of formula I: Tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein: Ring A is 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 selected from -N-, -N(R y )-、-C(R y )- and -O-, where R y Selected from hydrogen, halogen, C1-C8 haloalkyl, cyano, -NH2, C3-C6 cycloalkyl, C1-C8 alkyl (which may be optionally substituted by a group selected from -OH and C1-C8 alkoxy), -NHC(O)OC1-C8 alkyl (which may be optionally substituted by a group selected from -OH and halogen); Z is selected from -CH-, -O-, -S-, -S(O)-, -S(O)2-, -N- and -NR z ,in R z is selected from hydrogen and C1-C8 alkyl; R 1 Selected from: C3-C6 cycloalkyl, C1-C8 alkoxy and C1-C8 alkyl (which may be optionally substituted by a group selected from C4-C6 cycloalkyl, C5-C6 aryl, 4 to 6-membered heterocyclyl and 4 to 6-membered heteroaryl); R 2 Selected from: hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl and C1-C8 alkoxy; R 3a and R 3b independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl); R 4 Selected from: ◆ 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, which may be optionally substituted by 1 to 2 groups independently selected from the following: ●C3-C8 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl); ●C1-C8 haloalkyl; ●OC3-C7 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl); ●phenyl (which may be optionally substituted by a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl); ●C1-C8 alkoxy (which may be optionally substituted by a group selected from C3-C6 cycloalkyl and halogen); ●4 to 6 membered heterocyclyl (which may be optionally substituted by 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 independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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 to 6 membered heterocyclyl, C3-C8 cycloalkyl (which may be optionally substituted by a group selected from C1-C8 alkyl, C1-C8 haloalkyl and halogen); and C1-C8 alkyl (which may be optionally substituted by 1 to 2 groups independently selected from C1-C8 alkoxy, halogen, oxo, -OH, -NH2 and -SO2CH3); and R 7 Selected from O and NR, where R is selected from hydrogen and C1-C8 alkyl; Provided that the compound of formula I is not selected from: and tautomers, deuterated derivatives and pharmaceutically acceptable salts thereof.

2. The compound, tautomer, deuterated derivative or salt according to claim 1, which is selected from the compound of formula Ia: and its tautomers, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and a compound of formula Ia(i): and tautomers thereof, or deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

3. The compound, tautomer, deuterated derivative or salt according to claim 1, which is selected from the compound of formula Ib: and its tautomers, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and a compound of formula Ib(i): and tautomers thereof, or deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

4. The compound, tautomer, deuterated derivative or salt according to claim 1, which is selected from the compound of formula Ic: and its tautomers, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and a compound of formula Ic(i): and tautomers thereof, or deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

5. The compound, tautomer, deuterated derivative or salt according to claim 1, which is selected from the compound of formula Id: and its tautomers, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and a compound of formula Id(i): and its tautomers, or deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein R 4 and R 6 As defined in claim 1.

6. The compound, tautomer, deuterated derivative or salt according to claim 1, which is selected from the compound of formula Ie: and its tautomers, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and a compound of formula Ie(i): and its tautomers, or deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein R 4 and R 6 As defined in claim 1.

7. The compound, tautomer, deuterated derivative or salt according to claim 1, which is selected from the compound of formula If: and its tautomers, or deuterated derivatives of said compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, And a compound of formula If(i): and its tautomers, or deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein R 4 and R 6 As defined in claim 1.

8. A compound selected from compounds I-1 to I-265, tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

9. The compound according to claim 8, which is selected from compound I-4: Compound I-23: Compound I-34: Compound I-35: Compound I-40: Compound I-49: Compound I-52: Compound I-88: Compound I-96: Compound I-97: Compound I-98: Compound I-99: Compound I-139: Compound I-158: I-188： Compound I-206: Compound I-255: Compound I-256: and tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

10. A compound of formula II: or a tautomer thereof, or a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Ring B is a 6-membered heteroaryl group, which is optionally substituted by 1 to 2 groups independently selected from: Halogen ◆4 to 10 membered heterocyclic group (which may be optionally substituted by 1 to 3 groups independently selected from halogen, oxo, C1-C4 alkyl) ◆N(R x )2, where R x independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl (which may be optionally substituted by a group selected from halogen, C1-C4 haloalkyl and C1-C4 alkyl) ◆C1-C4 alkyl (optionally substituted by C3-C6 cycloalkyl (which may be further optionally substituted by a group selected from halogen, OH)) R 1 Selected from: C3-C6 cycloalkyl, C1-C6 alkoxy and C1-C6 alkyl (which may be optionally substituted by C4-C6 cycloalkyl); R 2 is selected from the group consisting of: hydrogen, halogen, C1-C2 alkyl, C1-C4 haloalkyl and C1-C2 alkoxy; R 3a and R 3b independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl); R 4 Selected from: ◆ 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, which may be optionally substituted by 1 to 2 groups independently selected from the following: ●C3-C8 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl); ●C1-C8 haloalkyl; ●phenyl (which may be optionally substituted by a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl); ●C1-C8 alkoxy (which may be optionally substituted by a group selected from C3-C6 cycloalkyl and halogen); ●4 to 6 membered heterocyclyl (which may be optionally substituted by 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 by 1 to 3 groups independently selected from C1-C8 alkyl, C1-C8 alkoxy and C1-C8 haloalkyl); R 5a and R 5b independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted by 1-2 groups selected from halogen, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), C1-C8 alkoxy (which may be optionally substituted by 1-2 groups selected from halogen, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclic groups), or may together form a C3-C7 cycloalkyl group (which may be optionally substituted by 1-2 groups selected from halogen, hydroxyl, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclic group); And wherein the compound of formula II is selected from compounds II-1 to II-38 and their tautomers, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

11. A compound of formula III: or a tautomer thereof, or a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Ring C is selected from: in Each R c independently selected from hydrogen, halogen, cyano, amino, C1-C4 alkyl (which may be optionally substituted by a group selected from -OH, halogen and oxo) and C3-C6 alkenyl; R 1 Selected from: C3-C6 cycloalkyl, C1-C6 alkoxy and C1-C6 alkyl (which may be optionally substituted by C4-C6 cycloalkyl); R 2 is selected from the group consisting of: hydrogen, halogen, C1-C2 alkyl, C1-C4 haloalkyl and C1-C2 alkoxy; R 3a and R 3b independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl); R 4 Selected from: ◆ 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, which may be optionally substituted by 1 to 2 groups independently selected from the following: ●C3-C8 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl); ●C1-C8 haloalkyl; ●phenyl (which may be optionally substituted by a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl); ●C1-C8 alkoxy (which may be optionally substituted by a group selected from C3-C6 cycloalkyl and halogen); ●4 to 6 membered heterocyclyl (which may be optionally substituted by 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 independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl); And wherein the compound of formula III is selected from compounds III-1 to III-25 and their tautomers, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

12. A compound of formula IV: or a tautomer thereof, or a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Ring D is 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 Selected from C and N; Y is selected from -N-, -N(R y )-、-C(R y )- and -O-, where R y Selected from hydrogen, halogen, C1-C8 haloalkyl, cyano, -NH2, C3-C6 cycloalkyl, C1-C8 alkyl (which may be optionally substituted by a group selected from -OH and C1-C8 alkoxy), -NHC(O)OC1-C8 alkyl (which may be optionally substituted by a group selected from -OH and halogen); Z is selected from -CR z -, -O-, -S-, -S(O)-, -S(O)2-, -N- and -NR z , where R z is selected from hydrogen, halogen and C1-C8 alkyl (which may be optionally substituted by C1-C8 alkoxy); R 0 Selected from C1-C2 alkyl; R 1 Selected from: C3-C6 cycloalkyl, C1-C8 alkoxy and C1-C8 alkyl (which may be optionally substituted by 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 Selected from: hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl and C1-C8 alkoxy; R 3a and R 3b independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl); R 4 Selected from: ◆ 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, which may be optionally substituted by 1 to 2 groups independently selected from the following: -OH ●C3-C8 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl); ●C1-C8 haloalkyl; ●-OC3-C7 cycloalkyl (which may be optionally substituted by 1 to 2 groups selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl groups); ●phenyl (which may be optionally substituted by a group selected from C1-C8 alkyl, C1-C8 alkoxy, halogen and C1-C8 haloalkyl); ●C1-C8 alkoxy (which may be optionally substituted by a group selected from C3-C6 cycloalkyl and phenyl; or which may be optionally substituted by 1 to 3 halogen atoms); ●4 to 6 membered heterocyclyl (which may be optionally substituted by 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 independently selected from hydrogen, halogen, C1-C8 alkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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, hydroxy, oxo, C3-C6 cycloalkyl, C5-C6 aryl and 3-6 membered heterocyclyl), or may together form a group selected from oxo and C3-C7 cycloalkyl (which may be optionally substituted with 1-2 groups selected from halogen, hydroxy, 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 to 2 groups selected from C1-C8 alkyl), C3-C8 cycloalkyl (which may be optionally substituted with a group selected from C1-C8 alkyl, C1-C8 haloalkyl and halogen), phenyl and C1-C8 alkyl (which may be optionally substituted with 1 to 2 groups independently selected from C1-C8 alkoxy, C1-C8 haloalkyl, halogen, oxo, -OH, -NH2 and -SO2CH3); and R 7 Selected from O and NR, where R is selected from hydrogen and C1-C8 alkyl; Provided that wherein the compound of formula IV is not selected from: and tautomers, deuterated derivatives and pharmaceutically acceptable salts thereof.

13. A compound selected from compounds IV-1 to IV-106, tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

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

15. A method of treating cystic fibrosis comprising administering a compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 13.

16. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 13 for use in treating cystic fibrosis.

17. 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 medicament for treating cystic fibrosis.

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