COMPOUNDS TO INCREASE CFTR ACTIVITY

Abstract

Compounds that modulate, for example, those that are directed at the underlying defects in the cellular processing of CFTR activity.

Description

BACKGROUND [1] In cells, there is normally a balance between the synthesis, folding, trafficking, aggregation, and degradation of proteins, known as protein homeostasis, which is maintained by the presence of sensors and pathway networks (Sitia et al., Nature, 426: 891-894, 2003; Ron et al., Nat. Rev. Mol. Cell. Biol., 8: 519-529, 2007). The maintenance of protein homeostasis in cells, also known as proteostasis, is based on the control of the conformation of the individual proteins that make up the proteome, the binding interactions between them, their location, and their concentration.Protein folding in vivo occurs through interactions between the chains that make up the folded polypeptides and various macromolecular cellular components, such as different classes of chaperones and folding enzymes, which are useful for minimizing aggregation (Wiseman et al., Cell, 131: 809-821, 2007). Whether a particular protein folds in a specific cell type depends on the distribution, concentration, and subcellular localization of chaperones, folding enzymes, and various metabolites, among other components (Wiseman et al.).Cystic fibrosis and other diseases related to protein misfolding occur as a result of an imbalance in protein homeostasis (proteostasis), that is, in the ability to deal with the reduced energy stability of mutated proteins that have misfolded, which is fundamental to normal physiology (Balch et al., Science, 319, 916-9 (2008);. Powers et al., Annu. Rev. Biochem., 78, 959-91 (2009); Hutt et al., FEBS Lett., 583, 2639-46 (2009)). [2] Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel that spans the epithelial membrane multiple times (Riordan et al., Annu. Rev. Biochem., 77, 701-26 (2008)). Approximately 90 percent of patients have a deletion in the phenylalanine (Phe) residue at position 508 of at least one allele (AF508). This mutation results in altered energy characteristics related to the folding of the CFTR proteins, which in turn leads to their degradation in the endoplasmic reticulum (ER). Therefore, the AF508 mutation is associated with defects at the level of folding and trafficking and an increase in the degradation of the mutated variant of the protein that constitutes the CFTR (Qu et al., J. Biol. Chem., 272, 15739-44 (1997)).The loss of a functional channel formed by CFTR in the plasma membrane results in impaired ion homeostasis (Cl-, Na+, HCO3-) and surface hydration of the airways, which manifests as decreased lung function (Riordan et al.). The reduced volume of periciliary fluid and increased mucus viscosity impair mucociliary clearance, resulting in chronic infection and inflammation, which are the phenotypic characteristics of cystic fibrosis (Boucher, J. Intern. Med., 261, 5-16 (2007)). In addition to respiratory dysfunction, the AF508 mutation in CFTR also affects the normal function of other organs (the pancreas, intestine, gallbladder). Therefore, it can be concluded that the loss of function affects multiple downstream pathways and that it is necessary to correct it to provide a solution. [3] In addition to cystic fibrosis, mutations in the gene encoding CFTR and / or alterations in the activity of the channel constituted by CFTR have also been associated with other conditions, such as congenital bilateral absence of the vas deferens (CBAVD), acute, recurrent or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, tobacco-related lung diseases such as chronic obstructive pulmonary disease (COPD), dry eye disease, Sjogren's syndrome or chronic sinusitis, cholestatic liver disease (e.g., primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC)) (Sloane et al. (2012), PLoS ONE, 7 (6): e39809.doi:10,1371 / journal.pone,0039809; Bombieri et al. (2011), J. Cyst. Fibros., June 2011, 10, suppl. 2: S86-102; Albert et al. (2008), Clinical Respiratory Medicine, third edition, Mosby Inc; Levin et al. (2005), Invest. Ophthalmol. Vis. Sci., 46 (4): 1428-1434; Froussard (2007), Pancreas, 35 (1): 94-5), Son et al. (2017) J Med Chem 60(6):2401-10. [4] In the technique, there remains a need for compounds, compositions and methods that are useful for increasing CFTR activity and for treating CF, other CFTR-related diseases and other diseases related to protein misfolding. SUMMARY [5] This disclosure is directed in part to the compounds represented by Formula I: and pharmaceutically acceptable salts thereof, wherein A, X1, X2, X3, R1, R2, and R3 and R4 are as defined herein. [6] Also included here are pharmaceutical compositions that include a disclosed compound, such as those compounds having disclosed formulas such as Formula I, and a pharmaceutically acceptable vehicle or excipient. In certain embodiments, the compositions may include at least one additional CFTR modulator; for example, they may include one, two, three, four, five, or more additional CFTR modulators. [7] In certain embodiments, a method is provided comprising administering a disclosed compound to a subject (e.g., a human patient) suffering from a disease that is related to a decrease in CFTR activity (such as cystic fibrosis, congenital bilateral absence of the vas deferens (CBAVD), acute, recurrent or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, chronic obstructive pulmonary disease (COPD), chronic sinusitis, cholestatic liver disease (e.g., primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC)), dry eye disease, protein C deficiency, A-β-lipoproteinemia, lysosomal storage-related disease, chylomicronemia type 1, mild lung diseases, lipid processing deficiencies, hereditary angioedema type 1,coagulation-related fibrinolysis, hereditary hemochromatosis, CFTR-related metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, Sjögren's syndrome, familial hypercholesterolemia, l-cell / pseudo-Hurler disease, mucopolysaccharidosis, Sandhof / Tay-Sachs disease, Crigler-Najjar disease type II, polyendocrinopathy / hyperinsulinemia, diabetes mellitus, Laron dwarfism, myeloperoxidase deficiencies, primary hypoparathyroidism, melanoma, CDG glucanosis type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiencies, diabetes insipidus (DI), neurophyseal DI, nephrogenic DI, the Charcot-Marie-Tooth syndrome, Perlizaeus-Merzbacher disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,Progressive supranuclear palsy, Pick's disease, Huntington's disease, spinocerebellar ataxia type I, atrophy of the muscles of the spine and medulla oblongata, dentate rubro-pallido-Louisian atrophy, myotonic dystrophy, hereditary Creutzfeldt-Jakob disease (which is caused by a defect in the processing of prion proteins), Fabry disease, and Straussler-Scheinker syndrome). In certain embodiments, the disease is cystic fibrosis. For example, a method for treating a patient suffering from cystic fibrosis is contemplated herein, comprising administering to said patient an effective amount of a compound disclosed herein. [8] In some embodiments, the disclosed methods described herein may also include administering at least one additional CFTR modulator, for example, administer at least two, three, four, or five additional CFTR modulators. In certain embodiments, at least one additional CFTR modulator is a CFTR corrector (for example, VX-661 (tezacaftor), VX-152, VX-440, VX-445, VX-659, or VX-983) or, for example, VX-809 (lumacaftor) or, for example, GLPG2851, GLPG2665, GLPG2737, or GLPG2222, and the other is a CFTR enhancer (for example, ivacaftor and genistein). DETAILED DESCRIPTION [9] As used herein, the determinative “one” may be interpreted as referring to one or more elements, unless otherwise specified. For example, the term “an agent” may be interpreted as referring to a single agent or to a combination of two or more agents.

[10] As previously stated, the present invention relates in part to compounds as described in Formula I, as well as a pharmaceutically acceptable salt, prodrug or solvate thereof, to pharmaceutical compositions comprising them, to methods useful for increasing CFTR activity, and to methods useful for treating cystic fibrosis.

[11] For example, the compounds represented by Formula I are provided herein: Formula 1 or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, where: A is an 8- to 10-membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms, each selected from the group consisting of O, N, and S; wherein the bicyclic heteroaryl may be optionally substituted with one, two, or three substituents, each independently selected from RA1; X1 is selected from the group consisting of N and C(RX1); X2 is selected from the group consisting of N and C(RX2); X3 is selected from the group consisting of N and C(RX3); where only one of X1, X2 or X3 can be N; R1 is selected from the group consisting of -NRaRb, C3-6 alkyl, C3-6 cycloalkyl, phenyl, a 5-6 membered monocyclic heteroaryl having one, two, three, or four heteroatoms each independently selected from the group consisting of O, N, and S, and a 4-10 membered monocyclic, bridged bicyclic, spirocyclic heterocycle having one or two heteroatoms each independently selected from the group consisting of O, N, and S; wherein the 5-6 membered monocyclic heteroaryl may be optionally substituted with one or more substituents each independently selected from Ree; and wherein the 4-10 membered monocyclic, bridged bicyclic, spirocyclic heterocycle may be optionally substituted with one, two, three, or four substituents each independently selected from Rff;and wherein said heterocyclyl contains an -NH portion, said nitrogen may be optionally substituted with a substituent selected from the group consisting of Ci6alkyl, -C(O)-Ci-6alkyl, -C(O)-O-Ci-6alkyl, and -S(O)w-Ci-3alkyl (where w is; O, 1, or 2); and where C3-ealkyl, C3-6alkoxy, and C3-6C3-ealkyl can be optionally substituted with one, two, or three substituents, each independently selected from R; and where phenyl can be optionally substituted with one or more substituents, each independently selected from Rp; R2 is selected from the group consisting of hydrogen, halogen, cyano, Ci-6-alkyl, Ci-6-alkoxy, and C3-6-Cycloalkyl; wherein Ci-6-alkyl, Ci-6-alkoxy, and C3-6-Cycloalkyl may be optionally substituted with one or more substituents, each independently selected from the group consisting of halogen, hydroxyl, and phenyl; and wherein phenyl may be optionally substituted with one or more substituents, each independently selected from Rp; R3 is selected from the group consisting of hydrogen, halogen, hydroxyl, 6-Cycloalkoxy, -S(O)w-6-Cycloalkoxy (where w is 0, 1, or 2), NRa-6-Cycloalkoxy, -S(O)w-6-Cycloalkoxy (where w is 0, 1, or 2), -NRa-6-Cycloalkoxy, -O-phenyl, -S(O)w-phenyl (where w is 0, 1, or 2), -NRa-phenyl, C8-12-benzocycloalkoxy, -NRaRb, -OC(O)NRa-phenyl, -NRa-C(O)-O-phenyl, -NRaC(O)-6-alkyl-phenyl, -6-alkyl-NRa-phenyl, -NRa-Ci-6-alkyl-phenyl, and a monocyclic, bridged bicyclic, 4-10-membered spirocyclic heterocyclyl, heterocyclyl-NRa-, or a heterocyclyl-S(O)w- portion (where w is 0, 1, or 2) having one or two heteroatoms each independently selected from the group consisting of O, N, and S; wherein if said heterocyclyloxyl, heterocyclyl-NRa-, or heterocyclyl-S(O)w- ring contains an -NH portion, said nitrogen may be optionally substituted with a substituent selected from the group consisting of Ci-6-alkyl, -C(O)-Ci-6-alkyl, C(O)-OCi-6alkyl, and -S(O)w-Ci-3alkyl (where w is 0, 1, or 2); and wherein said heterocyclyloxyl, heterocyclyl-NRa-, and heterocyclyl-S(O)w may be optionally substituted with one, two, three, or four substituents each independently selected from Rff; and wherein said phenyl portion of -Ophenyl, -S(O)w-phenyl, -NRa-phenyl, -OC(O)NRa-phenyl, -NRa-C(O)-O-phenyl, -NRaC(O)-Ci-6alkyl-phenyl, -Ci-6alkyl-NRa-phenyl, and -NRa-Ci-6alkyl-phenyl may be optionally substituted with one, two, or three substituents each independently selected from Rp; and where Ci-6alkoxyl, -S(O)w-Ci-6alkyl (where w is 0, 1, or 2), -NRa-Ci-6alkyl, C3-6Ci-6alkoxyl, -S(O)W-C3-6Ci-6alkyl (where w is 0, 1, or 2), and -NRa-C3-6Ci-6alkyl can be optionally substituted with one, two, or three substituents each independently selected from R; R4 is selected from the group consisting of hydrogen and Ci-6alkyl, wherein Ci-6alkyl may be optionally substituted with one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, and Ci ealkoxyl; or R1 and R4, taken together with the sulfur and nitrogen to which they are respectively attached, form an optionally substituted 5-8 membered monocyclic heterocyclic ring which may optionally have an additional heteroatom selected from the group consisting of O, N, and S; Ree is selected independently, in each case, from the group consisting of Rp, hydrogen, C3-ealkyl, C3-6Cycloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6alkoxy, C3-6alkyl-S(O)w-, (where w is 0, 1 or 2), C16alkylcarbonyl-N(Ra)- and C1-6alkoxycarbonyl-N(Ra)-; where C1-6alkyl, C3ecycloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6alkoxy, C3-6alkyl-S(O)w-, C110 6-alkylcarbonyl-N(Ra)- and Ci-6-alkoxycarbonyl-N(Ra)- may be optionally substituted with one or more substituents selected from Rp; Rffse is selected independently in each case, from the group consisting of halogen, hydroxyl, -NRaRb, oxo, Ci-6alkyl and Ci-6alkoxy; R is selected independently in each case from the group consisting of halogen, hydroxyl, -NRaRb, C3-ealkyl, C3-6C3-ealkyl, C3-6C3-ealkyl (optionally substituted with one, two or three substituents selected independently from the group consisting of halogen, hydroxyl, C3-ealkyl and C3-ealkyl (optionally substituted with one, two or three fluorine atoms)), phenyl, a 5-6 membered monocyclic or 8-10 membered bicyclic heteroaryl with one, two or three heteroatoms each selected independently from the group consisting of O, N, and S, and a 4-10 membered monocyclic, bridged bicyclic, spirocyclic heterocyclic ring with one or two heteroatoms each selected independently from the group consisting of O, N, and S;wherein said heterocyclic ring contains an -NH portion, said nitrogen may be optionally substituted with a substituent selected from the group consisting of Ci-6alkyl, -C(O)-Ci6alkyl, -C(O)-O-Ci-6alkyl, and -S(O)w-Ci-3alkyl (where w is 0, 1, or 2); and wherein phenyl may be optionally substituted with one, two, or three substituents, each independently selected from Rhh; and wherein said monocyclic, bridged bicyclic, spirocyclic heterocyclic ring of 410 members may be optionally substituted with one, two, three, or four substituents, each independently selected from R; Rhh is selected independently in each case from the group consisting of halogen, cyano, Ci-ealkyl, Ci-6alkoxy, S(O)w-Ci-3alkyl, -S(O)W NRaRb, -NRa-S(O)w-Ci-3alkyl (where w is 0, 1, or 2), a 5-6 membered monocyclic heteroaryl having one, two, or three heteroatoms each independently selected from the group consisting of O, N, and S, and a 4-7 membered heterocyclic ring having one or two heteroatoms each independently selected from the group consisting of O, N, and S; wherein Ci-6alkoxy and S(O)w-Ci-3alkyl may be optionally substituted with one, two, or three halogens; R¡i is selected independently in each case, from the group consisting of halogen, hydroxyl, -NRaRb, oxo, Ci-6alkyl and Ci ealkoxyl; RA1 is selected independently for each case, from the group consisting of hydrogen, halogen, Ci-ealkyl, C2-6alkenyl, C2-6alkynyl, Ci6alkoxyl, C3-C6cycloalkyl, phenyl, -NRaRb, -OC(O)-NRa-phenyl, -NRa-C(O)phenyl, and -NRa-Ci-4alkyl-phenyl; wherein Ci-ealkyl, C2-6alkenyl, C2-6alkynyl, Ci6alkoxyl, C3-6cycloalkyl, and phenyl may be optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, phenyl, and -NRaRb; RX1 is selected from the group consisting of hydrogen, halogen, cyano, Ci-6alkyl, Ci-6alkoxy, -Ci-6alkoxyphenyl, C3-6cycloalkyl, C3-6cycloalkoxy, and phenyl; wherein Ci-6alkyl and Ci-6alkoxy may be optionally substituted with one, two, or three substituents selected from the group consisting of hydroxyl and halogen; and wherein phenyl may be optionally substituted with one or more substituents selected from Rp; RX2 is selected from the group consisting of hydrogen, halogen, C1ealkyl, Ci-6alkoxy, and -Ciealkoxyphenyl; wherein phenyl may be optionally substituted with one or more substituents selected from Rp; RX3 is selected from the group consisting of hydrogen, halogen, cyano, Ci-6alkyl, Ci-6alkoxy, -Ci-6Ci-alkoxyphenyl, C3-6Ci-6Ci-chloroalkyl, C3-6Ci-chloroalkoxy, and phenyl; wherein Ci-6alkyl and Ci-6Ci-alkoxy can be optionally substituted with one, two, or three substituents selected from the group consisting of hydroxyl and halogen; and wherein phenyl can be optionally substituted with one or more substituents selected from Rp; Rp is selected independently in each case, from the group consisting of halogen, hydroxyl, cyano, Ci-ealkyl, C3-6Cycloalkyl, Ci-6alkoxy, phenyl, C3-6Cycloalkoxy, -S(O)w-Cy-3alkyl (where w is 0, 1, or 2), -S(O)w-NRaRb, and -NRaRb; and Ra and Rb are independently selected from each other from the group consisting of hydrogen, C1-6 alkyl, phenyl, -C(O)-phenyl, and -C(O)-Ci-6alkyl; wherein C1-6 alkyl, phenyl, -C(O)-phenyl, and -C(O)-Ci-6alkyl may be optionally substituted with one or more substituents selected from halogen, cyano, oxo, and hydroxyl; or Ra and Rb taken together with the nitrogen to which they are attached form a heterocyclic ring.

[12] In some embodiments, A may be selected from the group consisting of: where: X4 is selected independently for each case, from the group consisting of O, S, and N(RX4); X5 is selected from the group consisting of N and C(RX5); RA1 is selected independently for each case, from the group consisting of hydrogen, halogen, C2-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, phenyl, -NRaRb, -OC(O)NRaRb, -NRa-C(O)-phenyl, and -OC(O)-NRa-phenyl; wherein C2-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6alkoxy, C3-6cycloalkyl, phenyl, -OC(O)NRaRb, -NRa-C(O)-phenyl, and -OC(O)-NRa-phenyl may be optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, phenyl, and NRaRb; RA2 is selected from the group consisting of hydrogen and Ci-6alkyl; RA3 and rA4 are independently selected from each other from the group consisting of hydrogen, halogen, Ci-6alkyl, Ci ealkoxyl, and NRaRb; wherein C1ealkyl and Ci ealkoxyl may be optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, phenyl, and NRaRb; RX4 is selected from the group consisting of hydrogen, Ci-6alkyl, C3-6cycloalkyl, phenyl, heterocycle, Ci-6alkyl-S(O)2-, and phenyl-S(O)2-; wherein C1ealkyl, C3-6cycloalkyl, phenyl, and heterocycle may be optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, phenyl, and NRaRb; and RX5 is selected from the group consisting of hydrogen, halogen, and C1ealkyl.

[13] In some embodiments, R1 can be selected, for example, from the group consisting of C3-6-alkyl and C3-6-chloroalkyl; wherein C3-6-alkyl and C3-6-chloroalkyl can be optionally substituted with one, two, or three substituents each independently selected from the group consisting of halogen and hydroxyl. For example, R1 can be selected from the group consisting of methyl, cyclopropyl, and Λ>^0H.

[14] In other embodiments, R1 may be, for example, a 4-10 membered monocyclic heterocycle with one or two heteroatoms each independently selected from the group consisting of O, N, and S, wherein the 4-10 membered monocyclic heterocycle may be optionally substituted with one, two, three, or four substituents each independently selected from Rff. For example, R1 may be selected from the group consisting of nh2

[15] In other embodiments, R1 may be, for example, phenyl, where phenyl may be optionally substituted with one or more substituents each independently selected from Rp. For example, R1 may be selected from the group consisting of i and 'T''.

[16] In other embodiments, R1 may be selected, for example, from the group consisting of: R, and R66 where X is independently selected from the group consisting of O and S; R” is hydrogen or Ci-4alkyl; and each R66 and R77 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, -NH2, and Ci-4alkyl.

[17] For example, R1 can be selected from the group consisting of: VVVV — ** — — _ . VVVV 1 , 1 , and 1

[18] In some embodiments, R2 can be selected, for example, from the group consisting of hydrogen, Ci-6 alkyl, Ci-6 cycloalkyl, and halogen. For example, R2 can be methyl.

[19] In other embodiments, R3 may be, for example, Ci-6-alkoxyl, where Ci-6-alkoxyl may be optionally substituted with one, two, or three substituents, each selected independently from R. For example, R may be phenyl, where phenyl may be optionally substituted with one or two substituents, each selected independently from Rhh. In some embodiments, X1 may be C(RX1), X2 may be C(RX2), and X3 may be C(RX3).

[20] In some additional embodiments, A can be selected, for example, from the group consisting of: /

[21] For example, A can be selected from the group consisting of:

[22] In some embodiments, a disclosed compound can be represented, for example, by Formula II: R1; Formula II where: Is X O or S? RA1 is selected from the group consisting of hydrogen and Ci-6alkyl; R2 is selected from the group consisting of hydrogen and Ci-6alkyl; r25 and r26 are independently selected from each other from the group consisting of hydrogen and Ci-2alkyl; B is selected from the group consisting of: a monocyclic, bridged bicyclic, spirocyclic heterocyclic ring of 4-10 members having one or two heteroatoms each independently selected from the group consisting of O, N, and S; wherein if said heterocyclic ring contains an -NH portion, said nitrogen may be optionally substituted with a substituent selected from the group consisting of Ci-6alkyl, -C(O)-Ci-6alkyl, -C(O)-O-Ci-6alkyl, and -S(O)w-Ci3alkyl (where w is 0, 1, or 2); and wherein said heterocyclic ring may be optionally substituted with one, two, three, or four substituents each independently selected from hydroxyl, Ci ealkyl, Ci-6alkoxy, and oxo; and phenyl, wherein phenyl may be optionally substituted with one or more substituents selected independently in each case, from the group consisting of halogen, hydroxyl, cyano, Ci-ealkyl, C3-6Cycloalkyl, Ci6alkoxyl, phenyl, C3-6Cycloalkoxyl, -S(O)w-Cy-3alkyl (where w is O, I, or 2), S(O)w-NRaRb, y-NRaRb; and Ra and Rb are independently selected from each other from the group consisting of hydrogen, C1-6 alkyl, phenyl, -C(O)-phenyl, and -C(O)-Ci-6alkyl; wherein C1-6 alkyl, phenyl, -C(O)-phenyl, and -C(O)-Ci-6alkyl may be optionally substituted with one or more substituents selected from halogen, cyano, oxo, and hydroxyl; or Ra and Rb taken together with the nitrogen to which they are attached form a heterocyclic ring.

[23] In some forms of realization, B can be, for example: / ' 44 R44R; where R11, R22, R33 and R44 are independently selected for each case, from the group consisting of hydrogen and Ci6alkyl.

[24] For example, B can be selected from the group consisting of

[25] In some embodiments, B can be phenyl.

[26] For example, RA1 can be methyl. For example, R2 can be methyl.

[27] Compounds disclosed in the Examples are also provided here.

[28] Pharmaceutical compositions comprising a disclosed compound, such as those with Formula I, and a pharmaceutically acceptable vehicle or excipient are also contemplated herein. In certain embodiments, the compositions may include at least one additional CFTR modulator as described elsewhere herein, or at least two additional CFTR modulators, each independently as described elsewhere herein.

[29] The features and other details of the invention will be described later. Before providing a detailed description of the present disclosure, definitions of some of the terms used in the specification, examples, and appended claims will be provided. These definitions are to be interpreted in the context of the invention and should be familiar to those skilled in the art. Unless otherwise indicated, all technical and scientific terms used herein have the meanings commonly given to them by those skilled in the art.

[30] Obviously, the description in this disclosure must be interpreted in accordance with the laws and principles governing chemical bonds.

[31] The term “alkyl”, as used herein, unless otherwise indicated, refers to a saturated, branched or linear-chain hydrocarbon group comprising the specified number of carbon atoms; for example, the term “C1-C10 alkyl” refers to an alkyl group comprising from 1 to 10 carbon atoms, whereas linear or branched hydrocarbon groups comprising from 1 to 6, from 1 to 4 or from 1 to 3 carbon atoms are referred to herein as C1-6, C1-4 or C1-3 alkyl groups, respectively. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl.

[32] The term “alkylcarbonyl” as used herein refers to a linear or branched alkyl group attached to a carbonyl group (alkyl-C(O)-). Examples of alkylcarbonyl groups include, but are not limited to, alkylcarbonyl groups of 1 to 6 atoms, referred to herein as Ci-6-alkylcarbonyl groups. Examples of alkylcarbonyl groups include, but are not limited to, acetyl, propanoyl, isopropanoyl, butanoyl, etc.

[33] The term “carbonyl” as used herein refers to the radical -C(O)-.

[34] The term “cyano” as used herein refers to the radical -CN.

[35] The term “alkenyl,” as used herein, refers to a linear or branched chain unit comprising the specified number of carbon atoms and having at least one double bond between any two carbon atoms. By way of non-limiting example, an alkenyl group may be linear or branched and may comprise from 2 to 6 or 3 to 4 carbon atoms, in which case it is referred to herein as a C2-6 or C3-4 alkenyl group, respectively. Non-limiting examples of alkenyl groups include vinyl, allyl, butenyl, pentenyl, and so forth.

[36] The term “alkynyl”, as used herein, refers to a linear or branched chain unit comprising the specified number of carbon atoms and having at least one triple bond between a pair of carbon atoms.

[37] The term cycloalkyl, as used herein, refers to cyclic saturated alkyl portions having three or more carbon atoms, for example, between 3 and 10, between 3 and 6, or between 4 and 6 carbons, referred to herein as C3-10 cycloalkyl, C3-6 cycloalkyl, or C4-6 cycloalkyl, respectively. Unless otherwise stated, such cyclic saturated alkyl portions may contain up to 18 carbon atoms and include monocycloalkyl, polycycloalkyl, and benzocycloalkyl structures. Monocycloalkyl refers to groups having a single ring group. Polycycloalkyl indicates hydrocarbon systems containing two or more ring systems with one or more ring carbon atoms in common; that is, a spiro, fused, or bridged structure. Benzocycloalkyl means a monocyclic alkyl group fused to a benzene ring, referred to herein as C8-12benzocycloalkyl, for example.Examples of monocycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentadecyl, cyclohexadecyl, cycloheptadecyl, and cyclooctadecyl. Examples of polycycloalkyl groups include, but are not limited to, decahydronaphthalene, spiro[4,5]decyl, bicyclo[2,2,1]heptyl, bicyclo[3,2,1]octyl, pinanyl, norbornyl, adamantyl, and bicyclo[2,2,2]octyl. Examples of benzocycloalkyl groups. These include, but are not limited to, tetrahydronaphthyl, indanyl, and 1,2-benzocycloheptanyl.

[38] The term “cycloalkoxyl” refers to a cycloalkyl group, as previously described, having a monocycloalkyl, polycycloalkyl, or benzocycloalkyl structure, attached to the rest of the molecule through an ether oxygen atom. Examples of cycloalkoxyl groups include, but are not limited to, cycloalkoxyl groups of 3 to 6 carbon atoms, referred to herein as C3-6Cycloalkoxyl groups. Examples of cycloalkoxyl groups include, but are not limited to, cyclopropoxyl, cyclobutoxyl, cyclohexyloxyl, etc. The term “benzocycloalkoxyl” refers to a monocyclic cycloalkoxyl group fused to a benzene ring, referred to herein, for example, as C3-2benzocycloalkoxyl. Examples of benzocycloalkoxyl groups include, but are not limited to, tetrahydronaphthyloxyl, indaniloxyl, and 1,2-benzocycloheptaniloxyl.

[39] The term “cycloalkenyl”, as used herein, refers to a cyclic alkenyl group comprising 3 or more carbon atoms.

[40] The term “cycloalkynyl”, as used herein, refers to a cyclic alkynyl group comprising 5 or more carbon atoms.

[41] The term “alkylene” refers to a saturated, linear or branched, divalent aliphatic radical comprising the indicated number of carbon atoms. The term “cycloalkylene” refers to a saturated, divalent, carbocyclic hydrocarbon group comprising the indicated number of carbon atoms.

[42] The term “alkoxyl”, as used herein, refers to a linear or branched alkyl group attached to an oxygen atom (alkyl-O). By way of non-limiting example, an alkoxyl group may comprise from 1 to 6 or from 2 to 6 carbon atoms, in which case it is referred to herein as a C1-6 or C2-6 alkoxyl group, respectively. Non-limiting examples of alkoxyl groups include methoxyl, ethoxyl, isopropoxyl, etc.

[43] The term “alkoxyalkyl” as used herein refers to a linear or branched alkyl group attached to oxygen, bonded to a second linear or branched alkyl group (alkyl-O-alkyl-). Examples of alkoxyalkyl groups include, but are not limited to, alkoxyalkyl groups wherein each of the alkyl groups independently contains between 1 and 6 carbon atoms, referred to herein as Ci-6-alkoxy-Ci-6-alkyl. Examples of alkoxyalkyl groups include, but are not limited to, methoxymethyl, 2-methoxyethyl, 1-methoxyethyl, 2-methoxypropyl, ethoxymethyl, 2-isopropoxyethyl, etc.

[44] The term “alkoxycarbonyl” as used herein refers to a linear or branched alkyl group attached to oxygen, bonded to a carbonyl group (alkyl-OC(O)-). Examples of alkoxycarbonyl groups include, but are not limited to, alkoxycarbonyl groups of 1 to 6 carbon atoms, referred to herein as Ci-6-alkoxycarbonyl. Examples of alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.

[45] The term “alkenyloxyl” as used herein refers to a linear or branched alkenyl group attached to oxygen (alkenyl-O-). Examples of alkenyloxyl groups include, but are not limited to, groups with an alkenyl group of between 3 and 6 carbon atoms, referred to herein as C3-6alkenyloxyl. Examples of “alkenyloxyl” groups include, but are not limited to, allyloxyl, butenyloxyl, etc.

[46] The term “alkynyloxyl” as used herein refers to a linear or branched alkynyl group attached to oxygen (alkynyl-O). Examples of alkynyloxyl groups include, but are not limited to, groups with an alkynyl group of between 3 and 6 carbon atoms, referred to herein as C3-6 alkynyloxyl. Examples of alkynyloxyl groups include, but are not limited to, propynyloxyl, butynyloxyl, etc.

[47] The term “heterocycle” or “heterocyclyl” refers to a heterocycloalkyl, heterocycloalkenyl, heterobicycloalkyl, heterobicycloalkenyl, heteropolycycloalkyl, or heteropolycycloalkenyl group, among others, unless otherwise specified. The term “heterocycloalkyl” refers to a cycloalkyl group comprising one or more heteroatoms or N in the rings. The term “heterocycloalkenyl,” as used herein, refers to a cycloalkenyl group comprising one or more heteroatoms (O, S, or N) in the rings. The term “heterobicycloalkyl” refers to a bicycloalkyl group comprising one or more heteroatoms (O, S, or N) in the rings. The term “heterobicycloalkenyl,” as used herein, refers to a bicycloalkenyl group comprising one or more heteroatoms (O, S, or N) in the rings.For example, the term “heterocycle” can refer to a saturated or partially unsaturated ring comprising between 4 and 12 or between 4 and 10 members, including monocyclic, bridged bicyclic, fused bicyclic, and spirocyclic rings, whose ring structures include between one and three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, heterocyclyl rings may be linked to an adjacent radical through a carbon or nitrogen atom. Non-limiting examples of heterocyclyl groups include pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxethane, azetidine, tetrahydrofuran, and dihydrofuran, among others.

[48] ​​The term “oxo” as used herein refers to the radical =0.

[49] Cycloalkyl, cycloalkenyl and heterocyclic groups can also take the form of groups that are like those described above in the context of the respective definitions but are substituted with one or more oxo units.

[50] The term “heteroaryl,” as used herein, refers to an aromatic carbocyclic group comprising one or more heteroatoms (O, S, or N) in the rings. Unless otherwise stated, a heteroaryl group may be monocyclic or polycyclic. A heteroaryl group may also be substituted or unsubstituted. Heteroaryl groups according to the present invention may also take the form of ring systems substituted with one or more oxo units. A polycyclic heteroaryl group may comprise fused rings, rings joined by covalent bonds, or combinations thereof. A polycyclic heteroaryl group is a polycyclic ring system comprising at least one aromatic ring in which there is one or more heteroatoms.Non-limiting examples of heteroaryl groups include pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naftiridinyl, dihydroquinolyl, tetrahydroquinolyl, and dihydroisoquinolyl. tetrahydroisoquinolyl, benzofuryl, furopyrimidinyl, pyrolopyrimidinyl, thiazolopyrimidinyl, oxazolopyrimidinyl, and azaindolyl. The heteroaryl groups described can be attached to a C atom or a heteroatom (when possible).For example, a group derived from a pyrrole can take the form of a pyrrole-1-yl group (bonded to an N atom) or a pyrrole-3-yl group (bonded to a C atom). In some embodiments, a heteroaryl group comprises between 4 and 12 members. In still other embodiments, a heteroaryl group takes the form of a monocyclic or bicyclic heteroaryl group comprising between 4 and 10 members.

[51] The term “heterocyclyloxyl” as used herein refers to a heterocyclyl group attached to oxygen (heterocyclyl-O-).

[52] The term “heteroaryloxyl” as used herein refers to a heteroaryl group attached to oxygen (heteroaryl-O-).

[53] The terms “halo” and “halogen”, as used herein, refer to atoms of F, Cl, Br, or I.

[54] The term “haloalkyl” as used herein refers to an alkyl group comprising between 1 and (2n+1) substituents, which are independently selected from the atoms of F, Cl, of Br or I, where n is the maximum number of carbon atoms that can be in the alkyl group. It should be understood that a haloalkyl group is a specific example of an optionally substituted alkyl group.

[55] The term “hydroxyl”, as used herein, refers to an OH radical.

[56] Those versed in the technology will know that “H” is the symbol for hydrogen, “N” is the symbol for nitrogen, “S” is the symbol for sulfur, and “O” is the symbol for oxygen. “Me” is the abbreviation for methyl.

[57] The compounds according to the invention may comprise one or more chiral centers, and thus may take the form of stereoisomers. The term “stereoisomers,” as used herein, may be interpreted as referring to either an enantiomer or a diastereomer. Such compounds may be designated by the symbols “(+),” “R,” or “S,” depending on the configuration of the substituents around the stereogenic carbon atoms, although those skilled in the art should also recognize that a structure may have an implicit chiral center. The scope of the present invention includes both the various individual stereoisomers of the compounds and mixtures thereof.Mixtures of enantiomers or diastereomers may be designated by the symbol “(±)”, although once again, those versed in the technique must recognize that a structure may have an implicit chiral center.

[58] The compounds according to the invention may contain one or more double bonds between pairs of carbon atoms, and depending on the arrangement of substituents around them, may take the form of various geometric isomers. Herein, single, double, and triple bonds are represented by a variety of hyphen-based symbols. Based on IUPAC nomenclature and the position of substituents around the double bonds between pairs of carbon atoms, the compounds are assigned a “Z” or “E” designation. Unless otherwise specified, structures with double bonds may correspond to either “E” or “Z” isomers.Alternatively, depending on the position of the substituents around a double bond between a pair of carbon atoms, a designation of “cis” or “trans” can be assigned, where “cis” represents the presence of the substituents on the same side of a double bond and “trans” represents the presence of the substituents on opposite sides.

[59] The compounds according to the invention may contain a carbocyclic or heterocyclic ring, and depending on the arrangement of the substituents around it, they may take the form of various geometric isomers. Based on IUPAC nomenclature and the position of the substituents around the carbocyclic or heterocyclic rings, the compounds are assigned a “Z” or “E” designation. Unless otherwise specified, structures with carbocyclic or heterocyclic rings may correspond to either “E” or “Z” isomers. Alternatively, depending on the position of the substituents around a carbocyclic or heterocyclic ring, a “cis” or “trans” designation may be assigned, where “cis” represents the presence of the substituents on the same side of a ring and “trans” represents the presence of the substituents on opposite sides. Mixtures comprising compounds whose substituents Enantiomers and diastereomers of the compounds of the present invention can be synthesized from commercially available starting materials containing asymmetric or stereogenic centers, or as a result of resolving racemic mixtures containing them, according to methods well known to those skilled in the art.By way of example, these methods may include (1) combining a mixture of enantiomers with a chiral auxiliary, separating the resulting diastereomer mixture by recrystallization or chromatography, and releasing the optically pure product from the auxiliary, (2) forming a salt using an optically active resolving agent, (3) subjecting a mixture of optical enantiomers to a direct separation procedure on chiral or liquid chromatography columns, or (4) resorting to a kinetic resolution procedure using stereoselective chemical or enzymatic reagents. Racemic mixtures may also be resolved to obtain their constituent enantiomers according to other known methods, such as liquid chromatography in a chiral phase or crystallization in a chiral solvent.Those versed in the technique should know that, in a stereoselective synthesis procedure based on a chemical or enzymatic reaction, a single reagent produces an unequal mixture of various stereoisomers as a result of the creation of a new stereocenter or the transformation of a pre-existing one. A stereoselective synthesis procedure may involve an enantioselective transformation or... The diastereoselective synthesis may be based on the use of chiral auxiliaries. Useful examples can be found in Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH, Weinheim, 2009. When describing or representing a particular compound, the scope of the invention must include both its chemical structure and all its tautomers.

[61] The term “pure enantiomer” applies to a compound that is present as a pure stereoisomer in a composition. By way of example, a compound that takes the form of a pure stereoisomer in a composition is free or substantially free of the other possible stereoisomers. In another example, a compound comprising a chiral center is said to take the form of a pure enantiomer in a composition when it is free or substantially free of the other possible enantiomer. In another example, a compound comprising two chiral centers is said to take the form of a pure enantiomer in a composition when it is free or substantially free of the other possible diastereomers.

[62] When a particular stereochemistry is illustrated or represented, this should be interpreted as indicating that one of the enantiomers is present in excess relative to the other. A compound exhibits an R configuration at a specific position when it is present in excess relative to the compound exhibiting an S configuration at the same position. Conversely, a compound exhibits an S configuration at a specific position when it is present in excess relative to the compound exhibiting an R configuration at the same position.

[63] The compounds described herein may be in non-solvated forms or in solvated forms in combination with pharmaceutically acceptable solvents, such as water or ethanol, and all such forms are included within the scope of the invention. In one embodiment, a compound is amorphous. In one embodiment, a compound is in the form of a single polymorphic form. In another embodiment, the compound is in the form of a mixture of polymorphic forms. In another embodiment, the compound is in a crystalline form.

[64] Also within the scope of the present invention are compounds labeled with isotopes, which are identical to those described herein but have had one or more of their original atoms replaced by atoms having an atomic mass or mass number different from that which can normally be found in nature. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, or 36Cl. For example, a disclosed compound may have one or more H atoms replaced by deuterium.

[65] Some isotope-labeled compounds (e.g., those labeled with 3H or 14C) can be useful for analyzing the presence and / or distribution of parent compounds. The isotopes tritium (i.e., 3H) and carbon-14 (i.e., 14C) are particularly suitable in this context because they are easy to prepare and detect. Furthermore, substitution with heavier isotopes, such as deuterium (i.e., 2H), can offer certain therapeutic advantages, such as increased metabolic stability (e.g., as a result of an increased in vivo half-life or the possibility of using a lower dose), and may therefore be suitable under certain circumstances.To label the compounds of the invention with isotopes, one can generally resort to procedures analogous to those described in the examples herein, with the substitution of the original reagents for identical reagents labeled with isotopes.

[66] In some embodiments of the invention, one or more of the nitrogen atoms in a compound such as those described herein can be oxidized to obtain an N-oxide.

[67] Representative synthetic routes for the preparation of the compounds described herein are provided throughout the Examples section. Those skilled in the art should be aware of the possibility of separating the diastereomers from the reaction mixtures by means of column chromatography procedures.

[68] The disclosed compounds can also be prepared according to various methods described in the literature, including, without limitation, those described in J. Med. Chem., 2011, 54 (13), 4350-64, in Russian Journal of Organic Chemistry, 2011, 47 (8), 1199-1203, in U.S. Patent Application Publication No. 2009 / 0036451 A1, in WO 2008 / 046072 A2 and in U.S. Patent No. 4336264, the contents of which are expressly incorporated herein by reference.

[69] As mentioned above, the present document contemplates a form of implementation of a method for increasing CFTR activity in a subject comprising administering an effective amount of a disclosed compound, as well as a method useful for treating a patient suffering from a CFTR activity-related condition, which involves administering to the patient an effective amount of a compound such as those described herein.

[70] The term “treatment” refers to the prevention or delay of symptoms, complications, or biochemical signs of disease, the relief or improvement of symptoms, or the interruption or inhibition of The further development of a disease, condition, or disorder. The term “subject” refers to an animal that needs treatment. The term “patient” refers to a human subject who needs treatment.

[71] The term “effective amount” refers to a quantity of an agent that is sufficient to achieve a desired and / or predetermined effect. In the context of a treatment method, the term “effective amount,” applied to a particular therapeutic agent, refers to a quantity that is sufficient to improve one or more symptoms of a disorder, to prevent the progression of a disorder, to bring about the regression of a disorder, and / or to achieve a desired effect of another kind.

[72] The term “modulation” may be interpreted as referring to an increase, an improvement, an inhibition, a decrease, a suppression, or some other similar effect. The terms “increase” and “improvement” refer to the attainment of a net gain by direct or indirect means. As used herein, the terms “inhibition” and “decrease” refer to the attainment of a net decrease by direct or indirect means.

[73] In some examples, CFTR activity in a patient improves as a result of the administration of a compound such as those described herein when CFTR activity is observed to be higher than that determined in the absence of the compound. CFTR activity can be determined, for example, based on chloride channel activity, which is characteristic of CFTR, and / or based on other activity related to ion transport (e.g., HCO3- transport). In some of these embodiments, the activity of one or more (for example, one or two) mutated variants of CFTR is enhanced (for example, CFTR AF508, S549N, G542X, G551D, R117H, N1303K, W1282X, R553X, 621+1OT, 1717-1G>A, 3849+10kbC>T, 2789+5G>A, 3120+1G>A, l507del, R1162X, 1898+1 G>A, 3659delC, G85E, D1152H, R560T, R347P, 2184insA, A455E, R334W, Q493X or 2184delA).Patients undergoing treatment may have one or more CFTR mutations belonging to one or more classes, including, but not limited to, class I, class II, class III, class IV, class V, and class VI mutations. The CFTR genotype of treated subjects (who, for example, may be human subjects) may include, but is not limited to, homozygous mutations (e.g., AF508 / F508 or R117H / R117H) or compound heterozygous mutations (e.g., AF508 / G551D, AF508 / A455E, AF508 / G542X, A508F / W1204X). R553X / W1316X, W1282X / N1303K, 591Δ18 / Ε831Χ, AF508del / R117H / N1303K / 3849+10kbC>T, Δ303Κ / 384 or DF508 / G178R).

[74] In certain embodiments, the mutation is of class I, for example, a G542X mutation, or a class II / I mutation, for example, a compound heterozygous mutation AF508 / G542X. In other embodiments, the mutation is a class III mutation, for example, a G551D mutation, or a class II / III mutation, for example, a compound heterozygous mutation AF508 / G551D. In still other embodiments, the mutation is a class V mutation, for example, an A455E mutation, or a class II / V mutation, for example, a compound heterozygous mutation AF508 / A455E. Of the more than 1000 known mutations for the gene encoding CFTR, the AF508 mutation is the most frequent and results in misfolding of the protein and disruption of trafficking from the endoplasmic reticulum to the apical membrane (Dormer et al. (2001), J. Cell Sci., 114, 4073-4081, http: / / www.genet.sickkids.on.ca / app).In certain embodiments, the activity of CFTR AF508 is improved (e.g., increased). In certain embodiments, the activity of CFTR AF508, CFTR G542X, CFTR G551D and / or CFTR A455E is improved (e.g., increased). An improvement in CFTR activity can be determined, for example, with methods such as those described in the literature, such as Ussing chamber studies, membrane fixation-based studies, or determination of leq in hBE cells (Devor et al. (2000), Am. J. Physiol. Cell Physiol., 279 (2): C461-79; Dousmanis et al. (2002), J. Gen. Physiol., 119 (6): 545-59; Bruscia et al. (2005), PNAS, 103 (8): 2965-2971).

[75] As discussed above, the disclosure also covers a method for treating cystic fibrosis, as well as methods useful for treating conditions associated with CFTR activity, encompassing those conditions that occur as a result of a deficiency in CFTR activity, which involve administering an effective amount of a disclosed compound.

[76] For example, a method is provided herein for treating a condition associated with a deficiency or decrease in CFTR activity, comprising administering an effective amount of a compound as described herein to increase CFTR activity. Non-limiting examples of conditions resulting from a deficiency in CFTR activity include cystic fibrosis, congenital bilateral absence of the vas deferens (CBAVD), acute, recurrent, or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, chronic obstructive pulmonary disease (COPD), chronic sinusitis, cholestatic liver disease (e.g., primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC)), dry eye disease, protein C deficiencies, α-β-lipoproteinemia, and lysosomal storage-related disease.Chylomicronemia type 1, mild lung diseases, lipid processing deficiencies, hereditary angioedema type 1, coagulation-related fibrinolysis, hereditary hemochromatosis, CFTR-related metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, and Sjogren's syndrome.

[77] In some embodiments, treatment methods based on administering a compound as described herein to a patient may also include administering an additional therapeutic agent. By way of example, in one embodiment, a method is provided herein comprising administering a compound as described herein and at least one additional therapeutic agent. In certain respects, the invention relates to a method comprising administering a compound as described herein and at least two additional therapeutic agents.Additional therapeutic agents include, for example, mucolytics, bronchodilators, antibiotics, anti-infectives, anti-inflammatory agents, agents that modulate ion channels, agents used in gene therapy, CFTR correctors, CFTR enhancers, or other agents that modulate CFTR activity. In some embodiments, at least one of the additional therapeutic agents is selected from the group consisting of a CFTR corrector and a CFTR enhancer.Non-limiting examples of CFTR correctors and enhancers include VX-770 (Ivacaftor), deuterated Ivacaftor, GLPG2851, GLPG2737, GLPG2451, VX-809 (3-(6(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, VX-661 (1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropane]-6-fluoro-2-(2-hydroxy-1,1-dmethylethyl)-1-indole-5-yl]cyclopropanecarboxamide), VX-983, VX-152, VX-440, VX-445, VX-659, and Ataluren (PTC124) (3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid), FDL169, GLPG1837 / ABBV-974 (e.g., a CFTR enhancer). GLPG2665, GLPG2222 (for example, a CFTR corrector); and the compounds described in, for example, WO2014 / 144860 and 2014 / 176553, incorporated herein by reference. Non-limiting examples of modulators include GLPG3067, QBW-251, QR-010, NB-124, riociquat, and the compounds described in WO2014 / 081821, WO2014 / 160478, WO2011 / 113894. W02014 / 081820, US2014027933; WO2013 / 038386; for example, in WO2014 / 152213; WO2014 / 0228376, and WO2014 / 180562 WO2014 / 045283; WO2014 / 160440, WO2013 / 038390, which are incorporated herein by reference, where all modulators may be used as additional therapeutic agents. Non-limiting examples of anti-inflammatory agents include N6022 (3-(5-(4-(1-Himidazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1-H-pyrrole-2-yl)propanoic acid), CTX4430, N1861, N1785, and N91115.

[78] In some embodiments, the methods described herein may also comprise administering an additional therapeutic agent targeting CFTR or administering at least two additional therapeutic agents targeting CFTR. In some embodiments, the methods described herein may also comprise administering an additional CFTR modulator or administering at least two modulators of the Additional CFTR agents. In certain embodiments, at least one of the CFTR modulators is a CFTR corrector (e.g., VX-809, VX-661, VX-983, VX-152, VX-440, VX-445, VX-659, and GLPG2222 or GLPG2665) or an enhancer (e.g., ivacaftor, genistein, and GLPG1837). In some of these embodiments, one of the at least two additional therapeutic agents is a CFTR corrector (e.g., VX-809, VX-661, VX-152, VX-440, VX-445, VX-659, and VX-983) and the other is a CFTR enhancer (e.g., ivacaftor and genistein). In some of these embodiments, one of the at least two additional therapeutic agents is a CFTR corrector (e.g., GLPG2222) and the other is a CFTR enhancer (e.g., GLPG1837). In some of these embodiments, one of the at least two additional therapeutic agents is a CFTR corrector (e.g., VX-809 or VX-661) and the other is a CFTR enhancer (e.g., ivacaftor). In some of these embodiments, at least one of the CFTR modulators is an agent that is useful for improving readout through the stop codons (e.g., NB124 or ataluren). NB124 has the structure:

[79] In other embodiments, the methods described herein may also include administering an epithelial sodium channel inhibitor (ENaC) (e.g., VX-371). In other embodiments, the methods described herein may also include administering gene or RNA therapies, including SHP-636.

[80] Consequently, in another aspect, the invention provides a method for treating a condition associated with a deficiency or decrease in CFTR activity (e.g., cystic fibrosis), comprising administering to the subject in need (e.g., a human patient) an effective amount of a compound as described herein and at least one or two additional CFTR-targeting therapeutic agents (e.g., at least one or two additional CFTR-targeting therapeutic agents, one of which may be a CFTR corrector or modulator (e.g., VX-809, VX-661, VX-983, VX-445, VX-659, GLPG2222, NB124, or ataluren), where more precisely one of them may be GLPG2222 and the other may be GLPG1837 or GLPG3067, or one may be VX-809 or VX661, and the other is ivacaftor).Other agents, such as amplifiers, are disclosed in co-pending applications PCT / US14 / 044100, PCT / US15 / 020460, PCT / US15 / 020499, and PCT / US15 / 036691, each of which is incorporated by reference. For example, an example of an amplifier is / V-(3-(5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)propyl)-5-phenylisoxazol-3-carboxamide (“Compound A”). In certain forms of implementation, the CFTR genotype of the subjects being treated presents one or more class I mutations in CFTR, one or more class II mutations in CFTR, one or more class III mutations in CFTR, one or more class IV mutations in CFTR, one or more class V mutations in CFTR or one or more class VI mutations in CFTR, among other possibilities.In certain embodiments, the genotype of the subjects being treated presents one or more homozygous mutations (e.g., AF508 / F508 or R117H / R117H) and / or one or more compound heterozygous mutations (e.g., AF508 / G551D, AF508 / A455E, AF508 / G542X, A508F / W1204X, R553X / W1316X, W1282X / N1303K,. AF508del / R117H, N1303K / 3849+10kbC>T, AF508 / R334W, DF508 / G178R, or 591Δ18 / E831X). In certain embodiments, the subject's CFTR genotype carries a class I mutation, for example, a class I mutation G542X or a compound heterozygous mutation AF508 / G542X. In other embodiments, the subject's CFTR genotype carries a class III mutation, for example, a class III mutation G551D or a compound heterozygous mutation AF508 / G551D. In still other embodiments, the subject's CFTR genotype exhibits a class V mutation, for example, a class V A455E mutation or a compound heterozygous AF508 / A455E mutation. In certain embodiments, the activity of CFTR AF508, CFTR G542X, CFTR G551D, and / or CFTR A455E is enhanced (e.g., increased).In certain embodiments, the improvement in activity (e.g., the increase in activity) that occurs as a result of administering a combination of a compound such as those described herein and one or two additional therapeutic agents is greater than that which could be expected by adding the improvements in activity that could be obtained with each of them individually. separate therapeutic components. Class Effect on the protein that constitutes CFTR Example of mutation I The protein is shortened W1282X: instead of inserting the amino acid tryptophan (W), the protein sequence is prematurely interrupted (represented by X) II The protein does not reach the AF508 membrane: an amino acid phenylalanine is deleted (0 The channel cannot be properly regulated The conductance of chloride is reduced The protein is shortened due to an incorrect excision of the gene The protein shortens due to protein instability G551D: a missense mutation: instead of an amino acid glycine (G), an aspartate (D) is added. Missense mutation R117H 3120+1G>A: mutation at the cleavage site in intron 16 of the gene N287Y: mutation of A to T at position 991 Genotype Description Possible Symptoms A508F / A508F homozygous Severe lung disease, pancreatic insufficiency R117H / R117H homozygous Bilateral absence Congenital vas deferens defect, absence of lung or pancreatic disease WT / A508F heterozygote No effects WT / 3120+1 G>A heterozygote No effects A508F / W1204X compound heterozygote No effects R553Xy W1316X 591Δ18 / E831Χ compound heterozygote compound heterozygote diseases in the Lungs, pancreatic insufficiency. Mild lung disease, pancreatic insufficiency. Absence of lung disease or pancreatic insufficiency, nasal polyps.

[81] By way of example, a method is provided herein for treating a patient who has one or more of the following mutations in the gene encoding CFTR: G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, G970R or R117H, and / or has one or two copies of the AF508del mutation, one copy of the AF508 mutation and a second mutation that results in an opening effect on the protein constituting CFTR (e.g., is a patient heterozygous for the AF508 and G551D mutations) or one copy of the AF508 mutation and a second mutation that results in residual CFTR activity, comprising administering an effective amount of a compound as described herein.As described herein, these methods (which, for example, may be applied in a patient with one or more mutations such as those described above) may include, for example, subjecting the patient to combination therapy, such as the (simultaneous or sequential) administration of an effective amount of ivacaftor and an effective amount of a compound such as those described herein, which may act as an amplifier, or a disclosed compound that may act as a corrector. This administration may result, for example, in an increase in chloride transport in the bronchial epithelial cells of patients with one or two copies of mutations such as the AF508 mutation, compared to the result that could be obtained by administering ivacaftor alone.Another combination therapy that can be applied in the context of the present invention is based on the administration of an effective amount of an agent useful for improving reading (for example, ataluren or NB124) and an effective amount of a compound such as those described herein, which can act as an amplifier or as a corrector.

[82] Unconstrained by theory, a disclosed compound may be advantageous compared to known CFTR correctors. For example, using relative quantification of the F508del-CFTR protein, exposure to a disclosed compound may result, at least in some embodiments, in a higher proportion of CFTR protein on the cell surface compared to a known corrector. In another embodiment, the use of, for example, F508del-CFTR HBE, may enhance the CFTR function of a disclosed compound administered with, for example, ivacaftor. For example, a disclosed compound combined with ivacaftor (or another corrector) may restore chloride transport to a level equal to, or greater than, the combination of lumacaftor and ivacaftor in CFTR HBE cells.In another embodiment, the combination of a disclosed compound, lumacaftor, and vacaftor can increase chloride transport, for example, by more than 1-fold, for example, by 1.4-fold. The disclosed compounds, for example, can maintain, in some embodiments, a similar functional benefit with either 24-hour or acute administration of vacaftor, in contrast to the lumacaftor-vacaftor combination, which has an attenuated response at 24 hours compared to acute administration of vacaftor.

[83] The term “combination therapy,” as used herein, refers to a process in which a patient is concurrently administered a compound such as those described herein, a CFTR-enhancing agent (e.g., ivacaftor), and optionally one or more CFTR-correcting agents (e.g., VX-661 or lumacaftor) as part of a specified treatment regimen, so as to produce a beneficial effect resulting from the simultaneous action of the therapeutic agents. By way of example, the beneficial effect of a combination may include, without limitation, a superior pharmacokinetic or pharmacodynamic effect resulting from the simultaneous action of the therapeutic agents. For example, administration of a disclosed compound with ivacaftor alone or with a CFTR-correcting agent (e.g., lumacaftor or VX-661) may result in a level of operation (e.g.,measured by chloride activity in HBE cells or patients having an AF508 mutation, achieving clinical progress (or improvement) compared to the chloride activity level in cells or patients with a G551D mutation receiving ivacaftor alone, or ivacaftor and a corrector agent (lumacaftor or VX-661); or, for example, administration of a disclosed compound with ivacaftor alone or ivacaftor with a CFTR corrector (e.g., lumacaftor or VX-661) may result in an operating level (e.g., measured by chloride activity in HBE cells or patients having an A455E mutation) achieving clinical progress (or improvement) compared to the chloride activity level in, for example, 50% or more of wild-type cells; or following administration of a described compound and ivacaftor to a patient (e.g.,that has a G551D class III mutation) may result in a twofold or greater increase in ivacaftor activity compared to ivacaftor administration alone. The administration of the combination therapeutic agents described is normally carried out over a defined period of time (usually one day, several days, several weeks, several months, or several years, depending on the combination selected). Combination therapy may involve the sequential administration of multiple therapeutic agents, meaning that each is administered at a different time, as well as the substantially simultaneous administration of all, or at least two, of the therapeutic agents. Substantially simultaneous administration may result, for example, from the administration of a single tablet or capsule.in which each of the therapeutic agents is present in a fixed proportion, or it may be the result of administering multiple therapeutic agents in separate capsules. The consecutive or substantially simultaneous administration of each of the therapeutic agents may be carried out by any appropriate route, including, but not limited to, oral, inhalation, intravenous, intramuscular, and direct absorption through mucous membrane tissues. The therapeutic agents may be administered via identical or different routes. For example, the first therapeutic agent in a particular combination may be administered by intravenous injection, inhalation, or nebulizer, while the other therapeutic agents in the combination may be administered orally. Alternatively, for example, all the therapeutic agents may be administered orally.through intravenous injection, inhalation, or nebulization.

[84] Combination therapy may also involve administering the therapeutic agents described above in conjunction with other biologically active ingredients or with non-pharmacological therapies. When combination therapy also includes non-pharmacological treatment, the latter may be administered at any appropriate time to achieve a beneficial effect resulting from the simultaneous action of the therapeutic agents and the non-pharmacological treatment. In appropriate cases, the beneficial effect is achieved when the non-pharmacological treatment is temporarily discontinued at the time the therapeutic agents are administered, for example, for a period of one day, several days, or even several weeks.

[85] The components of a combination such as those described herein may be administered to a patient simultaneously or sequentially. It should be noted that the components may be present in the same pharmaceutically acceptable vehicle, in which case they may be administered simultaneously. Alternatively, the active ingredients may be present in separate pharmaceutical vehicles, in which case they may be present in conventional oral dosage forms, which may be administered simultaneously or sequentially.

[86] In a further aspect, a method is provided for determining whether a candidate agent is useful for increasing CFTR activity, comprising (i) contacting a cell expressing a protein constituting a CFTR with the candidate agent and a compound as described herein; (ii) measuring the CFTR activity in the cell in the presence of the candidate agent and the compound described herein; and (iii) comparing the CFTR activity with that determined in the absence of the candidate agent, wherein an increase in CFTR activity in the presence of the candidate agent is an indication that it is a useful agent for increasing CFTR activity. In certain embodiments, a protein constituting a mutated variant of CFTR is expressed in the cell.In certain embodiments, CFTR activity is determined based on chloride channel activity, which is characteristic of CFTR, and / or on other ion transport-related activity. In some of these embodiments, the method is characterized by high yield. In some of these embodiments, the candidate agent is a CFTR corrector or a CFTR enhancer.

[87] A method for treating a patient suffering from, or suspected of having, CF or a condition associated with deficient or decreased CFTR activity is provided herein in one embodiment. The method comprises testing the patient (e.g., by analyzing the patient's cells, mucosa, and / or body fluids) for a specific functional or molecular profile, optionally evaluating the results of such testing, and administering a disclosed compound to the patient based on the testing and / or evaluation. For example, a method for treating a patient with CF or a condition associated with deficient or decreased CFTR activity and a specific functional or molecular profile is provided herein, comprising administering a disclosed compound to the patient.

[88] The expression “pharmaceutically acceptable salt(s)” as used herein refers to salts of acidic or basic groups that may be present in the disclosed compounds and that are used in the disclosed compositions. The compounds included in the compositions herein that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.The acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, which include, but are not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-s-(2-hydroxy-3-naphthoate)). The compounds included in the compositions herein that are acidic in nature are capable of forming basic salts with various pharmacologically acceptable cations.Examples of such salts include alkali metal or alkaline earth metal salts, for example, salts of calcium, magnesium, sodium, lithium, zinc, potassium, and iron. Examples of such salts also include, for example, ammonium salts and quaternary ammonium salts. Compounds included in the compositions herein that include a basic or acidic unit may also form pharmaceutically acceptable salts with various amino acids. The compounds of the invention may contain both acidic and basic groups; for example, an amino group and a carboxylic acid group. In such a case, the compound may exist as an acid addition salt, a dipole, or a basic salt.

[89] In one embodiment, the contemplated methods may include, for example, administering prodrugs of the compounds described herein, for example, prodrugs of a compound of Formula I, or a pharmaceutical composition thereof.

[90] The term “prodrug” refers to compounds that are transformed in vivo to give a disclosed compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound. The transformation can occur by various mechanisms (e.g., by esterases, amidases, phosphatases, oxidative and / or reductive metabolism) in various locations (e.g., in the intestinal lumen or during intestinal transit, in the blood, or in the liver). Prodrugs are well known in the art (e.g., see Rautio, Kumpulainen, et al., Nature Reviews Drug Discovery 2008, 7, 255).For example, if a disclosure compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound contains a carboxylic acid functional group, a prodrug may comprise an ester formed by replacing the hydrogen atom of the acid group with a group such as (C1-8)alkyl, (C2-12)alkylcarbonyloxymethyl, 1-(alkylcarbonyloxy)ethyl with 4 to 9 carbon atoms, 1-methyl-1-(alkylcarbonyloxy)ethyl with 5 to 10 carbon atoms, alkoxycarbonyloxymethyl with 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl with 4 to 7 carbon atoms, 1-methyl-1(alkoxycarbonyloxy)ethyl with 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl with 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl with between 4 and 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-2)alkylamino-(C2-3)alkyl (e.g. β-dimethylaminoethyl), carbamoyl-(Ci-2)alkyl, N,N-di(Ci-. 2)alkylcarbamoyl-(C2-2)alkyl and piperidino-, pyrrolidine- or morpholino-(C2-3)alkyl.

[91] Similarly, if a compound of the invention contains an alcohol functional group, a prodrug can be formed by replacing the hydrogen atom of the alcohol group with a group such as (Ci-6)alkylcarbonyloxymethyl, 1-((Ci-6)alkylcarbonyloxy)ethyl, 1-methyl-1-((Ci- 6)alkylcarbonyloxy)ethyl (Ci-6)alkoxycarbonyloxy)methyl, N-(Ci6)alkoxycarbonylaminomethyl, succinoyl, (Ci-6)alkylcarbonyl, α-amino(Ci4)alkylcarbonyl, arylalkylcarbonyl and α-aminoalkylcarbonyl, or α-aminoalkylcarbonyl-α-aminoalkylcarbonyl, wherein each α-aminoalkylcarbonyl group is independently selected from naturally occurring Lamino Acids, P(O)(OH)2, -P(O)(O(Ci-6)alkyl)2 or glycosyl (where the radical is the result of the removal of a hydroxyl group from the hemiacetal form of a carbohydrate).

[92] If a compound of the invention incorporates an amine functional group, a prodrug can be formed, for example, by creating an amide or carbamate derivative, an N-alkylcarbonyloxyalkyl, a (oxodioxolenyl)methyl derivative, an N-Mannich base, an imine, or an enamine. Furthermore, a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can be metabolically cleaved to generate a bioactive primary or secondary amine. For examples, see Simplicio et al., Molecules 2008, 13, 519 and references therein.

[93] Certain embodiments also include the use of clathrates of the compounds described herein, pharmaceutical compositions comprising the clathrates, and methods of using the clathrates. Clathrates of a disclosed compound or a pharmaceutical composition thereof are also included herein.

[94] The term “pharmaceutically or pharmacologically acceptable” includes molecular entities and compositions that do not produce an adverse, allergic, or other undesired reaction when administered to an animal or a human, as appropriate. For administration to humans, preparations must meet standards of sterility, pyrogenicity, and general safety and purity as required by the FDA Office of Biologics Standards.

[95] The term “pharmaceutically acceptable vehicle” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic agents, absorption retarders, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Compositions may also contain other active compounds that provide supplementary, additional, or augmented therapeutic functions.

[96] The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable vehicles.

[97] As described above, this document also covers the administration of pharmaceutical compositions comprising a pharmaceutically acceptable vehicle or excipient and a compound such as those described herein. A compound such as those described herein, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, may be administered via pharmaceutical compositions comprising a pharmaceutically acceptable vehicle or excipient. The excipient may be selected based on the route by which the composition is to be administered for a therapeutic application. In turn, the route by which a composition is administered depends on the condition to be treated. By way of example, intravenous injection may be appropriate for treating a systemic disorder, while oral administration may be appropriate for treating a gastrointestinal disorder.The route of administration and the dosage of the composition can be determined by those skilled in the technique without unnecessary experimentation, based on the results of conventional dose-response studies. The circumstances to be considered in making these determinations include the nature of the condition(s) to be treated, the nature of the composition to be administered, the age and weight of the patient to be treated, their response to treatment, and the severity of their symptoms.A pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, may be administered via various routes, including, but not limited to, parenteral, oral, pulmonary, ophthalmic, nasal, rectal, vaginal, auricular, topical, buccal, transdermal, intravenous, intramuscular, subcutaneous, intradermal, infraocular, intracerebral, intralymphatic, intra-articular, intrathecal, or intraperitoneal routes. Depending on the formulation to be administered, the compositions may also include pharmaceutically acceptable, non-toxic vehicles or diluents, which are defined as those vehicles commonly used to formulate pharmaceutical compositions suitable for administration to animals, and particularly to humans.Diluents are selected so as not to affect the biological activity of the drug agent or the composition. Examples of diluents that may be used include distilled water, phosphate-buffered saline solutions, Ringer's solution, dextrose-based solutions, and Hank's solution. Furthermore, a pharmaceutical composition or formulation may also include other non-toxic vehicles, adjuvants, or stabilizers, which may be non-therapeutic in nature and must not be immunogenic, among other characteristics.Pharmaceutical compositions may also comprise macromolecules that are slowly processed by metabolism, such as proteins, polysaccharides such as chitosan, polylactic acids, polyglycolic acids or acid copolymers (e.g. SEPHAROSE™, agarose or cellulose functionalized with latex, among other possibilities), polymeric amino acids, amino acid copolymers or lipid aggregates (e.g. oil droplets or liposomes).

[98] The disclosed compositions may be administered parenterally, for example, intravenously, intramuscularly, intrathecally, or subcutaneously. Parenteral administration may be carried out by incorporating a composition into a solution or suspension. Such solutions or suspensions may also comprise sterile diluents such as water for injection, saline solutions, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other solvents of synthetic origin. Formulations that may be administered parenterally may also comprise antibacterial agents such as benzyl or methyl alcohol, antioxidants such as ascorbic acid or sodium bisulfite, and chelating agents such as EDTA. Acetate-, citrate-, or phosphate-based buffers and tonicity-adjusting agents such as sodium chloride or dextrose may also be added.A preparation that can be administered parenterally can be placed in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

[99] On the other hand, excipients may be present in the compositions, for example, wetting agents, emulsifying agents, surfactants, or substances useful for buffering pH. Other components that may be present in a pharmaceutical composition include oils derived from petroleum, animals, or plants, and synthetic oils, such as peanut oil, soybean oil, or mineral oils. In general, glycols, such as propylene glycol or polyethylene glycol, are suitable liquid vehicles, particularly in the case of injectable solutions. [i 00] Injectable formulations may be prepared as liquid solutions or suspensions, or as solid forms that can be dissolved or suspended in liquid vehicles for subsequent injection. A preparation may also be emulsified or encapsulated in liposomes or microparticles, which, for example, may be composed of polylactides, polyglycolides, or copolymers, to achieve a superior adjuvant effect, as previously described (Langer, Science, 249: 1527, 1990; Hanes, Advanced Drug Delivery Reviews, 28: 97-119, 1997). The compositions and pharmacological agents described herein may be administered by depot injection or by means of implants and may be formulated to provide sustained or pulsed release of the active ingredients.

[101] Suitable formulations may also be prepared for oral, intranasal, pulmonary, suppository, transdermal, or ocular administration. Suitable binders and vehicles for suppositories include, for example, polyalkylene glycols and triglycerides, and suppositories may be prepared from mixtures containing the active ingredients in a proportion ranging from approximately 0.5% to approximately 10%, or in the range of approximately 1% to approximately 2%. Orally administered formulations include excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, or pharmaceutical-grade magnesium carbonate. Topical application may be appropriate for transdermal or intradermal administration. Transdermal administration can be achieved through the use of a skin patch or transferosomes (Paul et al., Eur. J. Immunol., 25: 3521-24, 1995; Cevc et al., Biochem. Biophys. Acta, 1368: 201-15, 1998).

[102] For oral therapeutic administration, pharmaceutical compositions may be combined with excipients and may be used in the form of tablets, lozenges, capsules, elixirs, suspensions, syrups, coated tablets, or chewing gum, among other possibilities. Tablets, pills, capsules, lozenges, and other similar forms may also contain binders, excipients, disintegrating agents, lubricants, gluing agents, sweetening agents, or flavoring agents. Examples of binders that may be used in this context include microcrystalline cellulose, tragacanth gum, and gelatin. Examples of excipients that may be used include starch and lactose. Examples of disintegrating agents that may be used include alginic acid and corn starch. Examples of lubricants that may be used in this context include magnesium stearate and potassium stearate.An example of a useful glide is colloidal silicon dioxide. Examples of sweetening agents that may be used include sucrose and saccharin. Examples of flavoring agents that may be used include mint, methyl salicylate, and orange flavoring. The materials used to prepare the described compositions must be pharmaceutically pure and non-toxic in the quantities applied. In another embodiment, the composition is administered as a tablet or capsule.

[103] Other materials may be used as coatings or to modify the physical form of an individual dosage form. For example, tablets may be coated with shellac and / or sugars. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetener, methylparaben or propylparaben as a preservative, a colorant, and a flavoring such as cherry or orange, among other components. In the context of vaginal administration, a pharmaceutical composition may take the form of a pessary, tampon, cream, gel, paste, foam, or spray.

[104] A pharmaceutical composition may also be administered nasally. In this context, nasal administration encompasses the application of a composition to the mucous membranes of the nostrils or nasal cavity of the patient. In the practice of the present invention, pharmaceutical compositions administered nasally comprise therapeutically effective quantities of the compounds, are prepared according to well-known methods, and take the form, for example, of nasal sprays, nasal drops, suspensions, gels, ointments, creams, or powders. A composition may also be administered by means of a nasal tampon or nasal sponge.

[105] In the context of topical administration, appropriate formulations may include oils, waxes, gels, powders, polymers, or any other biocompatible liquid or solid vehicle. Such formulations may be administered by applying them directly to the affected tissues; for example, they may be administered as drops into the subject's eyes, in the form of liquid formulations appropriate for treating infections of the conjunctival tissue, or they may be administered to the skin in the form of creams.

[106] Rectal administration encompasses the administration of pharmaceutical compositions into the rectum or large intestine. This may result from the use of suppositories or enemas. Suppository formulations can be readily prepared according to methods known in the art. By way of example, suppository formulations can be prepared by heating glycerin to approximately 120°C, dissolving the desired pharmaceutical composition in the glycerin, mixing with the hot glycerin, adding purified water, and pouring the hot mixture into a suppository mold.

[107] Transdermal administration encompasses the percutaneous absorption of a composition, that is, its absorption through the skin. Formulations that can be administered transdermally include patches, ointments, creams, gels, and salves, among others.

[108] In addition to the meaning usually given to the term “pulmonary administration” in the context of administering the formulations described herein, which relates to their application to any part, tissue, or organ whose primary function is gas exchange with the external environment, for the purposes of the present invention, the term may also apply to administration to any tissue or cavity adjacent to the respiratory tract, particularly the paranasal sinuses. For pulmonary administration, an aerosol formulation containing the desired active agents, a hand-pumped atomizer, a pressurized nebulizer, a metered-dose inhaler, or a dry powder formulation may be used.Appropriate formulations in this context may include other agents, such as anti-aesthetic agents, in order to preserve the effectiveness of the compounds described herein during their application in aerosol form.

[109] A suitable device for administering drugs in aerosol form takes the form of a container holding an aerosolized pharmaceutical formulation as described herein, housed in a suitable enclosure, and equipped with a metering valve suitable for effecting administration. The empty space in the upper portion of the described device represents more than approximately 15% of its total volume. For pulmonary administration, the compounds are typically dissolved, suspended, or emulsified in a mixture of a solvent, a surfactant, and a propellant. The mixture is maintained under pressure in a container sealed with a suitable metering valve.

[110] The invention also encompasses the treatment of a condition associated with proteostasis dysfunction in a subject, comprising administering to said subject an effective amount of a disclosed compound that enhances, improves, or restores the proteostasis of a protein. Proteostasis refers to the homeostasis of proteins. Dysfunction in protein homeostasis results from protein misfolding, protein aggregation, defective protein trafficking, or protein degradation. For example, the invention contemplates administering a disclosed compound, for instance, with Formula I, that corrects protein misfolding, reduces protein aggregation, corrects or restores protein trafficking, and / or affects protein degradation for the treatment of a condition associated with proteostasis dysfunction. In some respects, a disclosed compound, for example, is administeredwith Formula I, which corrects protein misfolding and / or corrects or restores protein trafficking. In cystic fibrosis, the mutated or defective enzyme is the cystic fibrosis transmembrane conductance regulator (CFTR). One of the most common mutations of this protein is AF508, which is a three-nucleotide deletion (Δ) resulting in the loss of the amino acid phenylalanine (F) at position 508a (508) of the protein. As described earlier, the mutated cystic fibrosis transmembrane conductance regulator exists in a misfolded state and is characterized by altered trafficking compared to wild-type CFTR. Additional indicative proteins that may exhibit proteostasis dysfunction, for example, that may exist in a misfolded state, include, but are not limited to, glucocerebrosidase, hexosamine A,aspartylglucosaminidase, α-galactosidase A, cistern vehicle, acid ceramidase, acid α-L-fucosidase, protective protein, cathepsin A, acid β-glucosidase, acid β-galactosidase, iduronate 2-sulfatase, α-L-iduronidase, galactocerebrosidase, acid α-mannosidase, acid β-mannosidase, arylsulfatase B, arylsulfatase A, β-acetylgalactosamine-6-sulfate sulfatase, acid β-galactosidase, β-acetylglucosamine-L-phosphotransferase, acid sphingomyelinase, NPC-1, acid α-glucosidase, β-hexosamine B, heparin β-sulfatase α-N-acetylglucosaminidase, α-glucosaminidase / β-acetyltransferase, N-acetylglucosamine-6-sulfate sulfatase, α-acetylgalactosaminidase, aneuramidase, β-glucuronidase, β-hexosamine, acid lipase, polyglutamine, asynuclein, TDP-43, superoxide dismutase (SOD), α-β peptide, tau protein, transthyretin, and insulin. Compounds of formula I can be used to restore proteostasis (e.g.,to obtain correct folding and / or alter the trafficking) of the proteins described above.

[111] Conformational diseases of proteins encompass both gain-of-function and loss-of-function disorders. In one embodiment, a conformational disease of a protein is a gain-of-function disorder. The terms “gain-of-function disorder,” “gain-of-function disease,” “gain-of-function disorder with toxic effect,” and “gain-of-function disease with toxic effect” are used here synonymously. A gain-of-function disorder is a disease characterized by increased proteotoxicity associated with aggregation. In such diseases, aggregation outweighs elimination within and / or outside the cell. Gain-of-function diseases include, but are not limited to, neurodegenerative diseases associated with polyglutamine aggregation, Lewy body diseases, amyotrophic lateral sclerosis,Transthyretin aggregation-associated diseases, Alzheimer's disease, Machado-Joseph disease, Bamyloid cerebral angiopathy, retinal ganglion cell degeneration, tauopathies (progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobar degeneration), cerebral hemorrhage with amyloidosis, Alexander disease, serpinopathies, familial amyloid neuropathy, senile systemic amyloidosis, ApoA1 amyloidosis, ApoAII amyloidosis, ApoAIV amyloidosis, Finnish-type familial amyloidosis, lysozyme-induced amyloidosis, fibrinogen amyloidosis, dialysis amyloidosis, inclusion body myositis / myopathy, cataracts, medullary thyroid carcinoma, cardiac atrial amyloidosis, pituitary prolactinoma, hereditary reticular corneal dystrophy, lichen Cutaneous amyloidosis, lactoferrin corneal amyloidosis, alveolar pulmonary proteinosis,Amyloid-producing odontogenic tumor, seminal vesicle amyloidosis, sickle cell disease, critical illness myopathy, von Hippel-Lindau disease, spinocerebellar ataxia type 1, Angelman syndrome, giant axonal neuropathy, inclusion body myopathy with Paget's disease of bone, frontotemporal dementia (IBMPFD), and prion diseases. Neurodegenerative diseases associated with polyglutamine aggregation include, but are not limited to, Huntington's disease, dentate rubropallidolulian atrophy, various forms of spinocerebellar ataxia, and spinal and bulbar muscular atrophy. Alzheimer's disease is characterized by the formation of two types of aggregates: extracellular aggregates of Aβ peptide and intracellular aggregates of microtubule-associated tau protein. Diseases associated with transthyretin aggregation include, for example,Senile systemic amyloidosis and familial amyloid neuropathy. Lewy body diseases are characterized by aggregation of the α-synuclein protein and include, for example, Parkinson's disease, Lewy body dementia (LBD), and multiple system atrophy (SMA). Prion diseases (also known as transmissible spongiform encephalopathies or TSEs) are characterized by aggregation of prion proteins. In humans, some indicative prion diseases are Creutzfeldt-Jakob disease (CJD), variant forms of Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, and kuru. In another embodiment, the misfolded protein is alpha-1 antitrypsin.

[112] In a further embodiment, the disease due to protein conformation is a loss-of-function disorder. The terms “loss-of-function disease” and “loss-of-function disorder” are used here synonymously. Loss-of-function diseases are a group of diseases characterized by the inefficient folding of a protein, resulting in excessive protein degradation. Loss-of-function diseases include, for example, lysosomal storage diseases. Lysosomal storage diseases are a group of diseases characterized by a deficiency of a specific lysosomal enzyme, which can occur in a variety of tissues, resulting in the accumulation of molecules that are normally degraded by the deficient enzyme.A deficiency in a lysosomal enzyme can be a deficiency in a lysosomal hydrolase or a protein related to lysosomal trafficking. Lysosomal storage diseases include, but are not limited to, aspartylglucosaminuria, Fabry disease, Batten disease, cystinosis, Farber disease, fucosidosis, galactasidosis, Gaucher disease (including Types 1, 2, and 3), GM1 gangliosidosis, Hunter disease, Hurler-Scheie disease, Krabbe disease, α-Mannosidosis, β-Mannosidosis, Maroteaux-Lamy disease, metachromatic leukodystrophy, Morquio syndrome A, Morquio syndrome B, mucolipidosis II, mucolipidosis III, Neimann-Pick disease (including Types A, B, and C), Pompe disease, Sandhoff disease, Sanfilippo syndrome (including Types A, B, C, and D), Schindler disease, Schindler-Kanzaki disease, sialidosis, Sly syndrome, and Tay-Sachs disease. Wolman disease.

[113] In another embodiment, a disease associated with proteostasis dysfunction is a cardiovascular disease. Cardiovascular diseases include, but are not limited to, coronary artery disease, myocardial infarction, stroke, restenosis, and arteriosclerosis. Conditions associated with proteostasis dysfunction also include ischemic conditions, such as ischemia / reperfusion injury, myocardial ischemia, stable angina, unstable angina, stroke, ischemic heart disease, and cerebral ischemia.

[114] In yet another embodiment, the treatment is contemplated as a disease associated with a dysfunction in proteostasis that is diabetes and / or complications of diabetes, including but not limited to diabetic retinopathy, cardiomyopathy, neuropathy, nephropathy, and impaired wound healing.

[115] In a further embodiment, the treatment of a disease associated with proteostasis dysfunction is contemplated, which is an eye disease that includes, but is not limited to, age-related macular degeneration (AMD), diabetic macular edema (DME), diabetic retinopathy, glaucoma, cataracts, retinitis pigmentosa (RP), and dry macular degeneration.

[116] In some further embodiments, the disclosed method is intended for the treatment of a disease associated with proteostasis dysfunction, where the disease affects the respiratory system or the pancreas. In certain further embodiments, the method is intended to treat a condition selected from the group consisting of polyendocrinopathy / hyperinsulinemia, diabetes mellitus, Charcot-Marie-Tooth syndrome, Pelizaeus-Merzbacher disease, and Gorham syndrome.

[117] Additional conditions associated with proteostasis dysfunction include hemoglobinopathies, inflammatory diseases, intermediate filament diseases, drug-induced lung injury, and hearing loss. For example, methods for the treatment of hemoglobinopathies (e.g., sickle cell anemia), inflammatory diseases (e.g., inflammatory bowel disease, colitis, ankylosing spondylitis), intermediate filament diseases (e.g., non-alcoholic and alcoholic fatty liver disease), and drug-induced lung injury (e.g., lung injury induced by methotrexate). In another embodiment, methods are provided for treating hearing loss, such as noise-induced hearing loss, aminoglycoside-induced hearing loss, and cisplatin-induced hearing loss, comprising administering a disclosed compound.

[118] Additional conditions include those associated with a defect in protein trafficking and that can be treated according to the methods disclosed include: PGP mutations, hERG trafficking mutations, mutations in the arginine-vasopressin receptor 2 that cause nephrogenic diabetes insipidus, mutations in the sulfonylurea receptor 1 and α1AT that cause persistent hyperinsulinemic hypoglycemia of infancy (PHH1).

[119] Disclosure is illustrated by the following examples, which should not be considered limiting in any way. EXAMPLES

[120] The compounds described herein may be prepared in various ways, based on the instructions provided herein or according to other synthetic procedures known in the art. In the description of the synthetic methods provided below, it is to be understood that all the proposed conditions for carrying out the reactions, including the choice of solvents, the atmosphere in which the reactions are performed, the temperature at which the reactions are carried out, the duration of the experiments, and the approaches to effecting the treatments, may be selected to be conventional conditions for the reactions in question, unless otherwise indicated. Those versed in the art of the Those involved in organic synthesis must understand that the functionalities present in the various portions of a molecule must be compatible with the proposed reagents and reactions. Substituents that are incompatible with the proposed reaction conditions must be obvious to those skilled in the art, and in these cases, alternative methods are detailed. The starting materials used in the examples are commercially available or can be readily prepared from known materials using conventional methods. It is contemplated that at least some of the compounds described as “intermediates” herein may also be compounds of the invention. Example 1: Synthesis procedures:

[121] The general procedures for the preparation of the compounds considered are described in Scheme I and Scheme II. The disclosed compounds can be prepared, for example, by base-mediated condensation of an aromatic aldehyde with a suitably functionalized isatin derivative (Scheme I), or by three-component coupling between an aromatic aldehyde, a functionalized aniline, and an alpha-keto acid as shown in Scheme II. Conversion of the additional functional group provides the sulfonamide. Scheme I: Scheme II: A: Ry i o=s=o Yo o< R1 •JOH O4 R1 ^nr6 R2\ ΙΐΊ M Steps _ R2\ ΙΐΊ A_r5 'N Het ^3 N Het r4 r4

[122] For example, Ri R2, R3, R4, Rs, R6, R7, and Het can be groups readily considered by a specialist in the art. For example, R7 can be, for example, C3-6-alkyl, C3-6-cycloalkyl, phenyl, heteroaryl (for example, pyridinyl, pyrrazolyl, or thiazolyl), or heterocyclyl (for example, morpholinyl or thiazolyl). For example, Re can be, for example, hydrogen or C3-6-alkyl. For example, R1 can be C3-6-alkoxyl, where C3-6-alkoxyl can be optionally substituted with phenyl or a 5-6-membered monocyclic heteroaryl (for example, tetrahydropyranyl, optionally substituted with one, two, three, or four substituents, each independently selected from hydroxyl, C3-6-alkyl, C3-6-alkoxyl, and oxo). For example, R2, R3, R4, and Rs can be independently selected from either hydrogen or Ci-6 alkyl. For example, Het can be, for instance, benzofuranyl or benothiofuranyl.

[123] Using the general procedures described above, the following compounds representative of disclosure were prepared with reagents, starting materials and conditions familiar to practitioners in the art: Compound No. Structure OH Ν Y =s= i 0=S=0 0=S=0 OH s=c o=s=o o=s=o OH

Claims

1. A compound represented by Formula II: FOLLOWS FORMULA 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: X is O or S; R1 is selected from the group consisting of -NR to Rb, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, phenyl, a 5-6 membered monocyclic heteroaryl having one, two, three, or four heteroatoms each independently selected from the group consisting of O, N, and S, and a 4-10 membered monocyclic, bridged bicyclic, spirocyclic heterocyclyl having one or two heteroatoms each independently selected from the group consisting of O, N, and S; wherein the 5-6 membered monocyclic heteroaryl may be optionally substituted with one or more substituents each independently selected from R ee ;and wherein the 4-10 membered monocyclic, bridged bicyclic, spirocyclic heterocycle may be optionally substituted with one, two, three, or four substituents, each independently selected from Rff; and wherein if said heterocycle contains an -NH portion, said nitrogen may be optionally substituted with a substituent selected from the group consisting of C1-6 alkyl, -C(O)-C1-6 alkyl, -C(O)-O-C1-6 alkyl, and -S(O)w-C1-3 alkyl (where w is 0, 1, or 2); and wherein C1-6 alkyl, C1-6 alkoxy, and C3-6 cycloalkyl may be optionally substituted with one, two, or three substituents, each independently selected from Rgg; and wherein phenyl may be optionally substituted with one or more substituents, each independently selected from Rp;R4 is selected from the group consisting of hydrogen and C1-6 alkyl, wherein C1-6 alkyl may be optionally substituted with one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-6 alkoxy; or R1 and R4, taken together with the sulfur and nitrogen to which they are respectively attached, form an optionally substituted 5-8-membered monocyclic heterocyclic ring that may optionally have an additional heteroatom selected from the group consisting of O, N, and S; R1 is selected from the group consisting of hydrogen and C1-6 alkyl; R2 is selected from the group consisting of hydrogen and C1-6 alkyl; R25 and R26 are independently selected from each other from the group consisting of hydrogen and C1-2 alkyl;B is selected from the group consisting of: a 4-10 membered monocyclic, bridged bicyclic, spirocyclic heterocyclic ring with one or two heteroatoms, each independently selected from the group consisting of O, N, and S; wherein if said heterocyclic ring contains an -NH portion, said nitrogen may be optionally substituted with a substituent selected from the group consisting of C1-6 alkyl, -C(O)-C1-6 alkyl, -C(O)-O-C1-6 alkyl, and -S(O)w-C1-3 alkyl (where w is 0, 1, or 2); and wherein said heterocyclic ring may be optionally substituted with one, two, three, or four substituents each independently selected from hydroxyl, C1-6 alkyl, C1-6 alkoxy, and oxo;and phenyl, wherein phenyl may be optionally substituted with one or more substituents selected independently in each case from the group consisting of halogen, hydroxyl, cyano, C1-6alkyl, C3-6cycloalkyl, C1-6alkoxy, phenyl, C3-6cycloalkoxy, -S(O)w-C1-3alkyl (where w is 0, 1, or 2), -S(O)w-NR a R b , and -NR a R b ; R ee is selected independently in each case from the group consisting of RP, hydrogen, C1-6alkyl, C3-6cycloalkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkyl-S(O)w-, (where w is 0, 1 or 2), C1-6alkylcarbonyl-N(R a )- and C1-6alkoxycarbonyl-N(R a )-; where C1-6alkyl, C3-6cycloalkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkyl-S(O)w-, C1-6alkylcarbonyl-N(R a )-, C1-6alkoxycarbonyl-N(R a )- may be optionally substituted with one or more substituents selected from RP;R ff is selected independently in each case from the group consisting of halogen, hydroxyl, -NR a R b , oxo, C1-6 alkyl and C1-6 alkoxy; R gg is independently selected in each case from the group consisting of halogen, hydroxyl, -NR a R b , C1-6alkyl, C1-6alkoxy, C3-6cycloalkyl (optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, hydroxyl, C1-3alkyl and C1-3alkoxy (optionally substituted with one, two or three fluorine atoms)), phenyl, a 5-6 membered monocyclic or 8-10 membered bicyclic heteroaryl with one, two or three heteroatoms each independently selected from the group consisting of O, N, and S, and a 4-10 membered monocyclic, bridged bicyclic, spirocyclic heterocyclic ring with one or two heteroatoms each independently selected from the group consisting of O, N, and S;wherein said heterocyclic ring contains an -NH portion, said nitrogen may be optionally substituted with a substituent selected from the group consisting of C1-6 alkyl, -C(O)-C1-6 alkyl, -C(O)-O-C1-6 alkyl, and -S(O)w-C1-3 alkyl (where w is 0, 1, or 2); and wherein phenyl may be optionally substituted with one, two, or three substituents each independently selected from R hh ; and wherein said 4-10 membered monocyclic, bridged bicyclic, spirocyclic heterocyclic ring may be optionally substituted with one, two, three, or four substituents each independently selected from R ii ;R hh is independently selected in each case from the group consisting of halogen, cyano, C1-6 alkyl, C1-6 alkoxy, S(O)w-C1-3 alkyl, -S(O)w-NR a R b , -NR a -S(O)w-C1-3 alkyl (where w is 0, 1, or 2), a 5-6 membered monocyclic heteroaryl having one, two, or three heteroatoms each independently selected from the group consisting of O, N, and S, and a 4-7 membered heterocyclic ring having one or two heteroatoms each independently selected from the group consisting of O, N, and S; wherein C1-6 alkoxy and S(O)w-C1-3 alkyl may be optionally substituted with one, two, or three halogens; R ii is selected independently in each case from the group consisting of halogen, hydroxyl, -NR a R b , oxo, C1-6 alkyl and C1-6 alkoxy;R p is independently selected in each case from the group consisting of halogen, hydroxyl, cyano, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, phenyl, C3-6 cycloalkoxy, -S(O)w-C1-3 alkyl (where w is 0, 1, or 2), -S(O)w-NR a R b , and -NR a R b ; and Ra and R b are independently selected from each other from the group consisting of hydrogen, C1-6 alkyl, phenyl, -C(O)-phenyl, and -C(O)-C1-6 alkyl; where C1-6 alkyl, phenyl, -C(O)-phenyl, and -C(O)-C1-6 alkyl may be optionally substituted with one or more substituents selected from halogen, cyano, oxo, and hydroxyl; or R a and R b taken together with the nitrogen to which they are attached form a heterocyclic ring characterized in that the compound is selected from the group consisting of: 60 FORMULAS FOLLOW, and a pharmaceutically acceptable salt or stereoisomer thereof. 2 Claims follow;