How to Treat Cystic Fibrosis

Abstract

The present disclosure provides methods of treating cystic fibrosis or a CFTR-mediated disease comprising administering Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing. The present disclosure also provides pharmaceutical compositions comprising Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, and optionally one or more additional CFTR modulating agents.

Description

[Technical field]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 306,344, filed February 3, 2022, the contents of which are incorporated herein by reference in their entirety. [Background technology]

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

[0003] Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 88,000 children and adults worldwide. Although there have been advances in the treatment of CF, there is no cure.

[0004] In patients with CF, mutations in CFTR endogenously expressed in respiratory epithelium reduce apical anion secretion, causing an imbalance in ion and fluid transport. The resulting reduction in anion transport contributes to increased mucus accumulation in the lungs, accompanied by microbial infections that ultimately lead to death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal disorders and pancreatic insufficiency that, if left untreated, can lead to death. In addition, the majority of men with cystic fibrosis are infertile, and fertility is reduced in women with cystic fibrosis.

[0005] Sequence analysis of the CFTR gene has revealed a variety of disease-causing mutations (Cutting, GR et al. (1990) Nature 346:366-369, Dean, M. et al. (1990) Cell 61:863:870, and Kerem, BS. et al. (1989) Science 245:1073-1080, Kerem, BS et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, over 2000 CF gene mutations have been identified, and the CFTR2 database currently contains information on at least 322 of these identified mutations, with at least 281 mutations having sufficient evidence to be defined as disease-causing. The most common disease-causing mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, commonly referred to as the F508del mutation. This mutation occurs in many cases of cystic fibrosis and is associated with severe disease.

[0006] CFTR is a cAMP / ATP-mediated anion channel expressed in various cell types, including absorptive and secretory epithelial cells, where it controls anion flux across the membrane and also regulates the activity of other ion channels and proteins. In epithelial cells, normal function of CFTR is essential for maintaining electrolyte transport throughout the body, including respiratory and digestive tissues. CFTR is composed of 1480 amino acids that encode a protein composed of tandem repeats of transmembrane domains, each of which contains six transmembrane helices and a nucleotide-binding domain. The two transmembrane domains are linked via large polar regulatory (R) domains to multiple phosphorylation sites that control channel activity and cellular trafficking.

[0007] Chloride transport occurs through the coordinated activity of ENaC (epithelial sodium channel) and CFTR present on the apical membrane, and of Na+-K+-ATPase pumps and Cl- channels expressed on the basolateral surface of the cell. Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which can then passively leave the cell via Cl- channels, resulting in vectorial transport. The arrangement of Na+ / 2Cl- / K+ cotransporters, Na+-K+-ATPase pumps and basolateral membrane K+ channels on the basolateral side, and CFTR on the luminal side, regulates chloride secretion. Presumably because water itself is not actively transported, its flow across the epithelium depends on a small transepithelial osmotic gradient generated by the bulk flow of sodium and chloride. Recently, several CFTR modulators have been identified. These modulators are considered, for example, as enhancers, correctors, enhancer / co-enhancers, amplifiers, read-through agents, and nucleic acid therapies. CFTR modulators that increase the channel gating activity of mutant and wild-type CFTR at the epithelial cell surface are known as enhancers. Correctors improve defective protein processing, resulting in transport to the epithelial surface. Ghelani and Schneider-Futschik (2020) ACS Pharmacol. Transl. Sci. 3:4-10. There are three CFTR correctors approved by the U.S. Food and Drug Administration for the treatment of cystic fibrosis. However, monotherapy with some CFTR correctors has proven to be ineffective, and as a result, combination therapy with enhancers is often necessary to enhance CFTR activity. Currently, only one CFTR enhancer is approved for the treatment of cystic fibrosis. Thus, there is a need for novel treatments for cystic fibrosis and other CFTR-mediated diseases. [Prior art documents] [Non-patent literature]

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

[0009] Accordingly, one aspect of the disclosure provides a CFTR modulating compound, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (Compound I), its deuterated derivatives, and pharma- ceutically acceptable salts of any of the foregoing. Compound I has the following structure: [ka] It can be shown as having:

[0010] Another aspect of the disclosure provides a pharmaceutical composition comprising Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, which may further comprise at least one additional active pharmaceutical ingredient and / or at least one pharma- ceutically acceptable carrier. Yet another aspect of the disclosure is a method of treating the CFTR-mediated disease cystic fibrosis, comprising administering to a subject in need thereof Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, optionally as part of a pharmaceutical composition comprising at least one additional ingredient.

[0011] Another aspect of the invention provides a method of treating the CFTR-mediated disease cystic fibrosis, comprising administering to a patient in need thereof Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, alone or in combination with (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound II), N -[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (also known as N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide) (Compound III) or N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline Phosphorus-3-carboxamide (compound III-d), 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide)-3-methylpyridin-2-yl)benzoic acid (compound IV), N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (compound V) ), N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (compound VI), (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound VII), (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hexan-5-yl}-9-oxa-2λ6-thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione (compound VIII), N-(beta In some embodiments, compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing is administered in the same composition as at least one compound selected from compound II, compound III, compound III-d, compound IV, compound V, compound VI, compound VII, compound VIII, compound IX, compound X, a deuterated derivative thereof, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, a composition comprising Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing is co-administered with a separate composition comprising at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, a deuterated derivative thereof, and a pharma- ceutically acceptable salt of any of the foregoing.

[0012] Another aspect of the invention provides a method of treating the CFTR-mediated disease cystic fibrosis, the method comprising administering to a patient in need thereof Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, and optionally further administering one or more additional CFTR modulating agents selected from ASP-11, disclosed in Journal of Cystic Fibrosis (2018), 17(5), 595-606, and nesoricaftor or PTI-428, disclosed in WO 2016 / 105485. In one embodiment, the additional CFTR modulating agent is ASP-11. In one embodiment, the additional CFTR modulating agent comprises PTI-428.

[0013] Another aspect of the invention provides a method of treating the CFTR mediated disease cystic fibrosis, the method comprising administering to a patient in need thereof Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, and optionally further administering one or more additional CFTR modulating agents selected from gallicaftor or ABBV-2222 disclosed in U.S. Patent Application Publication No. 2016-0120841; ABBV-3221 disclosed in WO 2018 / 065921; posenacaftor or PTI-801 disclosed in WO 2017 / 062581; ABBV-2851 disclosed in WO 2017 / 009804; GLPG2737 disclosed in U.S. Patent Application Publication No. 2017-0101405; ABBV-3748; ABBV-3903; and ABBV-119.

[0014] In certain embodiments, the pharmaceutical compositions of the present invention comprise Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, and may optionally further comprise at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, a deuterated derivative thereof, and a pharma- ceutically acceptable salt of any of the foregoing. [Brief description of the drawings]

[0015] [Figure 1] FIG. 1 provides the study design for Part A of the first-in-human (FIH) study of Compound I and provides the doses tested.

[0016] [Diagram 2] FIG. 2 provides the study design for Part B of the FIH study of Compound I and provides the doses tested.

[0017] [Diagram 3] FIG. 3 provides the study design for Part C of the FIH study of Compound I. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] definition As used throughout this disclosure, "Compound I" refers to the compound having the following structure: [ka]

[0043] This refers to (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, which may be illustrated as having the following structure:

[0019] Compound I may be a racemic mixture or an enantioenriched (e.g., >90% ee, >95% ee, >98% ee) mixture of isomers. Compound I or its deuterated derivatives may be in the form of a pharma- ceutically acceptable salt, solvate, and / or hydrate. Compound I and methods of making and using Compound I are disclosed in International Application PCT / US2021 / 044895, published as WO 2022 / 032068, which is incorporated herein by reference.

[0020] As used herein, "Compound II" refers to (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, which has the following structure: [ka] It can be expressed as: Compound II can be in the form of a pharma-ceutically acceptable salt.Compound II and the method of making and using compound II are disclosed in WO2010 / 053471, WO2011 / 119984, WO2011 / 133751, WO2011 / 133951 and WO2015 / 160787, each of which is incorporated herein by reference.

[0021] As used throughout this disclosure, “Compound III” refers to N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (also known as N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide), which has the following structure: [ka] It is expressed as: Compound III can also be in the form of a pharma-ceutically acceptable salt.Compound III and the method of making and using compound III are disclosed in WO2006 / 002421, WO2007 / 079139, WO2010 / 108162 and WO2010 / 019239, each of which is incorporated herein by reference.

[0022] In some embodiments, a deuterated derivative of compound III (compound III-d) is used in the compositions and methods disclosed herein. Compound III-d has the chemical name N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide and the following structure: [ka] It is expressed as: Compound III-d can be in the form of a pharma-ceutically acceptable salt.Compound III-d and the method of making and using compound III-d are disclosed in WO 2012 / 158885, WO 2014 / 078842, WO 2019 / 109021 and US Patent No. 8,865,902, which are incorporated herein by reference.

[0023] As used herein, "compound IV" refers to 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid and has the following chemical structure: [ka] It is expressed as: Compound IV can be in the form of a pharma-ceutically acceptable salt.Compound IV and the method of making and using compound IV are disclosed in WO2007 / 056341, WO2009 / 073757 and WO2009 / 076142, which are incorporated herein by reference.

[0024] As used herein, "Compound V" refers to N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide and has the following chemical structure: [ka] It is expressed as: Compound V may be in the form of a pharma- ceutically acceptable salt. Compound V and methods of making and using Compound V are disclosed in WO 2018 / 107100 and WO 2019 / 113476, which are incorporated herein by reference.

[0025] As used herein, "Compound VI" refers to N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide and has the following chemical structure: [ka] It is expressed as: Compound VI can be in the form of a pharma-ceutically acceptable salt. Compound VI and methods of making and using Compound VI are disclosed in WO2018 / 064632 and WO2019 / 113476, which are incorporated herein by reference.

[0026] As used herein, "Compound VII" refers to (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione and has the following chemical structure: [ka] It is expressed as: Compound VII can be in the form of a pharma- ceutically acceptable salt.Compound VII and the method of making and using compound VII are disclosed in International Publication No. WO2019 / 161078, International Publication No. WO2020 / 102346 and International Publication No. WO2021 / 030554, which are incorporated herein by reference.

[0027] As used herein, "compound VIII" refers to (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hexan-5-yl}-9-oxa-2λ6-thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione and has the following chemical structure: [ka] It is expressed as: Compound VIII can be in the form of a pharma-ceutically acceptable salt.Compound VIII and the method of making and using compound VIII are disclosed in International Publication No. WO2020 / 206080, which is incorporated herein by reference.

[0028] As used herein, "compound IX" refers to N-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, having the following chemical structure: [ka] It is expressed as: Compound IX may be in the form of a pharma-ceutically acceptable salt. Compound IX and methods of making and using compound IX are disclosed in International Publication No. WO 2016 / 057572, which is incorporated herein by reference.

[0029] As used herein, "Compound X" refers to N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide and has the following chemical structure: [ka] It is expressed as: Compound X may be in the form of a pharma- ceutically acceptable salt. Compound X and methods of making and using Compound X are disclosed in WO2016 / 057572, which is incorporated herein by reference.

[0030] As used herein, "CFTR" means cystic fibrosis transmembrane conductance regulator.

[0031] As used herein, "mutation" can refer to a mutation in the CFTR gene or CFTR protein. A "CFTR gene mutation" refers to a mutation in the CFTR gene, and a "CFTR protein mutation" refers to a mutation in the CFTR protein. A genetic defect or mutation in a gene (i.e., a change in one or more nucleotides) generally results in a mutation (i.e., a change in one or more amino acids) or a frameshift (i.e., a change in the reading frame that governs how the CFTR gene is translated into the CFTR protein) in the CFTR protein translated from that gene.

[0032] As used herein, the term "F508del" refers to a mutant CFTR protein lacking the amino acid phenylalanine at position 508, or a mutant CFTR gene encoding a CFTR protein lacking the amino acid phenylalanine at position 508.

[0033] As used herein, a patient who is "homozygous" for a particular genetic mutation has the same mutation in each allele.

[0034] As used herein, a patient who is "heterozygous" for a particular genetic mutation carries the mutation in one allele and a different mutation in the other allele.

[0035] As used herein, the terms "CFTR modulating agent," "CFTR modulating compound," and "CFTR modulating agent" refer interchangeably to compounds that directly or indirectly increase the activity of CFTR. CFTR modulating agents include, but are not limited to, compounds that correct, enhance, stabilize, and / or amplify CFTR.

[0036] As used herein, the term "CFTR corrector" refers to a compound that enhances the processing and trafficking of CFTR to increase the amount of CFTR at the cell surface. Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, and Compound X disclosed herein are CFTR correctors.

[0037] As used herein, the term "CFTR potentiator" refers to a compound that increases the channel activity of the CFTR protein located on the cell surface, resulting in enhanced ion transport. Compound III and compound III-d disclosed herein are CFTR potentiators.

[0038] As used herein, the term "active pharmaceutical ingredient" ("API") or "therapeutic agent" refers to a biologically active compound.

[0039] It is to be understood that certain compounds of the present invention may exist as separate stereoisomers or enantiomers and / or as mixtures of said stereoisomers or enantiomers. As used in the chemical structures disclosed herein, a "wedge" ( [ka] or "Hash" ( [ka] The bond denotes a chiral center of known absolute stereochemistry (i.e., one stereoisomer). As used in the chemical structures disclosed herein, a "wavy" bond ( [ka] indicates a chiral center of unknown absolute stereochemistry (i.e., one stereoisomer). As used in the chemical structures disclosed herein, a "wavy" bond ( [ka] indicates a mixture of E / Z isomers. [ka] A ("straight") bond indicates where a mixture (e.g., a racemate or concentrate) exists. As used herein, the term "straight" refers to two bonds to a double bond carbon. [ka] A ("straight") bond indicates that the double bond has the E / Z stereochemistry depicted. As used in the chemical structures disclosed herein, [ka] (i.e., a "wavy" line perpendicular to the "straight" bond to group "A") indicates that group "A" is a substituent, the point of attachment of which is the terminus of the bond that ends in the "wavy" line.

[0040] The terms "patient" and "subject" are used interchangeably and refer to animals, including humans.

[0041] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to the amount of a compound that, when administered, results in a desired effect (e.g., amelioration of CF or symptoms of CF, or a reduction in the severity of CF or symptoms of CF). The exact amount of an effective dose will depend on the purpose of the treatment and will be ascertainable by one of ordinary skill in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0042] As used herein, the terms "treatment", "treating" and the like generally refer to an improvement in CF or one or more of its symptoms, or a reduction in the severity of CF or one or more of its symptoms in a subject. As used herein, "treatment" includes, but is not limited to, increasing the subject's growth, improving weight gain, reducing mucus in the lungs, improving pancreatic and / or liver function, reducing lung infections, and / or reducing coughing or shortness of breath. Improvement or a reduction in the severity of any of these symptoms can be readily assessed according to standard methods and techniques known in the art.

[0043] As used herein, the term "in combination with" when referring to two or more compounds, agents, or additional APIs, means that the two or more compounds, agents, or APIs are administered to a patient before, simultaneously with, or after each other.

[0044] The terms "about" and "approximately", when used in connection with a dose, amount, or weight percent of a component of a composition or dosage form, include a particular dose, amount, or weight percent value, or a range of doses, amounts, or weight percents, that would be recognized by a person skilled in the art as providing an equivalent pharmacological effect to that obtained from the particular dose, amount, or weight percent. The terms "about" and "approximately" may also refer to an acceptable error for a particular value as determined by a person skilled in the art, which depends, in part, on how the value is measured or determined. In some embodiments, the terms "about" and "approximately" mean within 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range. In some embodiments, the terms "about" and "approximately" mean within 15% of a given value. In some embodiments, the terms "about" and "approximately" mean within 10% of a given value.

[0045] As used herein, "minimal function (MF) mutation" refers to a CFTR gene mutation associated with minimal CFTR function (a CFTR protein that has little or no function), including, for example, mutations associated with severe defects in the ability of the CFTR channel to open and close, known as channel gating defects or "gating mutations," mutations associated with severe defects in the cellular processing of CFTR and its delivery to the cell surface, mutations associated with no CFTR synthesis (or minimal CFTR synthesis), and mutations associated with severe defects in channel conductance.

[0046] As used herein, "deuterated derivative" refers to the same chemical structure where one or more hydrogen atoms have been replaced by deuterium atoms.

[0047] As used herein, the term "pharmaceutically acceptable salts" refers to the salt forms of the compounds of the present disclosure, or their deuterated derivatives, where the salts are non-toxic. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. The "free base" forms of the compounds do not include, for example, ionically bonded salts.

[0048] The phrase "deuterated derivatives thereof or pharma- ceutically acceptable salts thereof" is used interchangeably with "deuterated derivatives thereof or pharma- ceutically acceptable salts of any of the foregoing" in reference to one or more compounds or formulas of the invention. The phrase "pharma- ceutically acceptable salts thereof and deuterated derivatives thereof" is used interchangeably with "pharma- ceutically acceptable salts thereof and deuterated derivatives of any of the foregoing" in reference to one or more compounds or formulas of the invention. These phrases are intended to encompass pharma- ceutically acceptable salts of any one of the reference compounds, deuterated derivatives of any one of the reference compounds, deuterated derivatives of pharma- ceutically acceptable salts of any one of the reference compounds, and pharma- ceutically acceptable salts of deuterated derivatives of any one of the reference compounds.

[0049] Those skilled in the art will recognize that when the amount of "a compound or its pharma- ceutically acceptable salt" is disclosed, the amount of the pharma- ceutically acceptable salt form of the compound is the amount equivalent to the concentration of the free base of the compound. Note that the disclosed amounts of compounds or their pharma- ceutically acceptable salts herein are based on their free base form. For example, "100 mg of compound I or its pharma- ceutically acceptable salt" or "100 mg of compound I or its equivalent amount of pharma- ceutically acceptable salt" includes 100 mg of compound I and the amount of pharma- ceutically acceptable salt of compound I that is equivalent to 100 mg of compound I.

[0050] Suitable pharma- ceutically acceptable salts are, for example, those disclosed in SM Berge, et al. J. Pharmaceutical Sciences, 1977, 66, 1-19. For example, Table 1 of that article provides the following pharma- ceutically acceptable salts: [Table 1]

[0051] Non-limiting examples of pharma- ceutically acceptable acid addition salts include salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid, salts formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, and salts formed using other methods used in the art, such as ion exchange. Non-limiting examples of pharma-ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- Salts include ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N+(C1-4 alkyl)4 salts. The present disclosure also contemplates the quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharma- ceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates, etc. Other suitable non-limiting examples of pharma-ceutically acceptable salts include besylate and glucosamine salts.

[0052] Detailed Description of the Embodiments Treatment method Compound I, its deuterated derivatives, or pharma- ceutically acceptable salts of any of the foregoing can act as CFTR modulators, i.e., modulate CFTR activity in the body. Individuals suffering from mutations in the gene encoding CFTR may benefit from receiving CFTR modulators. CFTR mutations can affect CFTR mass, i.e., the number of CFTR channels at the cell surface, or affect CFTR function, i.e., the functional ability of each channel to open and transport ions. Mutations that affect CFTR mass include those that cause synthesis defects (class I defects), processing and trafficking defects (class II defects), mutations that cause reduced synthesis of CFTR (class V defects), and mutations that reduce the surface stability of CFTR (class VI defects). Mutations that affect CFTR function include those that cause gating defects (class III defects) and conductance defects (class IV defects). Some CFTR mutations exhibit characteristics of more than one class. Certain mutations in the CFTR gene result in CF.

[0053] Thus, in some embodiments, the present invention provides a method of treating cystic fibrosis, reducing the severity of cystic fibrosis, or treating cystic fibrosis symptomatically in a patient, comprising administering to the patient an effective amount of Compound I, its deuterated derivative, or a pharma- ceutically acceptable salt of any of the foregoing, alone or in combination with another active ingredient, such as another CFTR modulator. In some embodiments, the patient has an F508del / minimal function (MF) genotype, an F508del / F508del genotype (homozygous for the F508del mutation), an F508del / gating genotype, or an F508del / residual function (RF) genotype. In some embodiments, the patient is heterozygous and has one F508del mutation. In some embodiments, the patient is homozygous for the N1303K mutation.

[0054] In some embodiments, 5 mg to 100 mg (e.g., 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing is administered daily. In some embodiments, 7 mg to 90 mg of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing is administered daily. In some embodiments, 10 mg to 80 mg of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing is administered daily. In some embodiments, 10 mg to 40 mg of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing is administered daily. In some embodiments, 30 mg to 60 mg of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing is administered daily, hi some embodiments, 50 mg to 80 mg of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing is administered daily.

[0055] In some embodiments, about 5 mg to about 100 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, is administered daily. In some embodiments, about 7 mg to about 90 mg of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, is administered daily. In some embodiments, about 10 mg to about 80 mg of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, is administered daily. In some embodiments, about 10 mg to about 40 mg of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof is administered daily. In some embodiments, about 30 mg to about 60 mg of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof is administered daily. In some embodiments, about 50 mg to about 80 mg of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof is administered daily.

[0056] In some embodiments, about 0.1 mg to about 50 mg (e.g., about 0.1 mg, about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing is administered daily. In some embodiments, about 0.25 mg to about 50 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing is administered daily. In some embodiments, about 0.25 mg to about 25 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg) of Compound I, its deuterated derivative, or any of the foregoing pharma- ceutically acceptable salts is administered daily. In some embodiments, about 1 mg to about 15 mg (e.g., about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg) of Compound I, its deuterated derivative, or any of the foregoing pharma- ceutically acceptable salts is administered daily. In some embodiments, about 1.5 mg to about 14 mg (e.g., about 1.5 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 14 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing is administered daily.In some embodiments, about 4 mg to about 13 mg (e.g., about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, its deuterated derivative, or any of the aforementioned pharma- ceutically acceptable salts is administered daily. In some embodiments, about 8 mg to about 13 mg (e.g., about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, its deuterated derivative, or any of the aforementioned pharma- ceutically acceptable salts is administered daily.

[0057] In some embodiments, a total daily dose of about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, about 50 mg to about 80 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing is administered once a day as a single dose. In some embodiments, a total daily dose of about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, about 50 mg to about 80 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing is administered in two doses.

[0058] In some embodiments, about 0.1 mg to about 50 mg (e.g., about 0.25 mg to about 50 mg, about 0.25 mg to about 25 mg, about 1 mg to about 15 mg, about 1.5 mg to about 14 mg, about 4 mg to about 13 mg, about 8 mg to about 13 mg, about 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg A total daily dose of about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing is administered as a single dose. In some embodiments, about 0.1 mg to about 50 mg (e.g., about 0.25 mg to about 50 mg, about 0.25 mg to about 25 mg, about 1 mg to about 15 mg, about 1.5 mg to about 14 mg, about 4 mg to about 13 mg, about 8 mg to about 13 mg, about 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 ... A total daily dose of about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg of Compound I, its deuterated derivatives, or a pharma- ceutically acceptable salt of any of the foregoing, is administered in two doses.

[0059] In some embodiments, the patient is heterozygous and carries an F508del mutation in one allele and a mutation selected from Table 2 in the other allele. [Table 2-1] [Table 2-2]

[0060] In some embodiments, the present disclosure also relates to methods of treatment using isotopically labeled compounds of the aforementioned compounds or pharma- ceutically acceptable salts thereof, wherein the formulas and variables of such compounds and salts are each independently as described above or as described in any other embodiment above, except that one or more atoms therein are replaced (isotopically labeled) by an atom having an atomic mass or mass number different from the atomic mass or mass number of the atom that normally occurs in nature. Examples of isotopes that are commercially available and suitable for the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively.

[0061] Isotopically labeled compounds and salts can be used in several beneficial ways. They may be suitable for various types of assays, such as drug and / or substrate tissue distribution assays. For example, tritium (3H)-labeled and / or carbon-14 (14C)-labeled compounds are particularly useful for various types of assays, such as substrate tissue distribution assays, due to their relatively simple preparation and excellent detectability. For example, deuterium (2H)-labeled compounds are therapeutically useful and have potential therapeutic advantages over non-2H-labeled compounds. In general, deuterium (2H)-labeled compounds and salts can have higher metabolic stability compared to non-isotopically labeled ones due to the kinetic isotope effect described below. Higher metabolic stability translates directly into increased in vivo half-life or lower dosage, which may be desirable. Isotopically labeled compounds and salts can be prepared by generally following the procedures disclosed in the synthetic schemes and related descriptions, examples section, and preparation section of this specification, replacing non-isotopically labeled reactants with readily available isotopically labeled reactants.

[0062] In some embodiments, the isotopically labeled compounds and salts are deuterium (2H) labeled compounds and salts. In some particular embodiments, the isotopically labeled compounds and salts are deuterium (2H) labeled, in which one or more hydrogen atoms have been replaced by deuterium. In the chemical structures, deuterium is represented by "2H" or "D".

[0063] In discovering and developing therapeutic agents, one skilled in the art attempts to optimize pharmacokinetic parameters while retaining desirable in vitro properties, and it may be reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism.

[0064] Deuterium (2H) labeled compounds and salts can modulate the oxidative metabolism of compounds through the primary kinetic isotope effect. The primary kinetic isotope effect is the change in the rate of a chemical reaction resulting from the exchange of an isotope nucleus, which is then caused by the change in the ground state energy required for covalent bond formation after this isotope exchange. The exchange of a heavier isotope usually results in a lowering of the ground state energy of the chemical bond, and therefore a decrease in the rate-limiting bond cleavage. If the bond cleavage occurs in or near a saddle point region along the configuration of a multi-product reaction, the product distribution ratio can change significantly. For illustrative purposes, when deuterium is attached to a carbon atom at a non-exchangeable position, a rate difference of kM / kD=2-7 is typical. For further discussion, see SL Harbeson and RD Tung, Deuterium In Drug Discovery and Development, Ann.Rep.Med.Rep.Med.Chem.2011,46,403-417, which is incorporated herein by reference in its entirety.

[0065] The concentration of an isotope (e.g., deuterium) incorporated into the isotopically labeled compounds and salts of the present disclosure may be defined by the isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specified isotope. In some embodiments, when a substituent of a compound of the disclosure is represented by deuterium, such compounds have an isotopic enrichment factor for each of the designated deuterium atoms of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0066] Combination therapy One embodiment disclosed herein provides a method of treating CF and other CFTR-mediated diseases using Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, in combination with at least one additional active pharmaceutical ingredient (API).

[0067] Accordingly, in some embodiments, the invention provides methods of treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient, the methods comprising administering to the patient about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, alone or in combination with at least one additional active pharmaceutical ingredient, such as, for example, a CFTR modulator.

[0068] In some embodiments, the invention provides a method of treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient, the method comprising administering to a subject a dose of about 0.1 mg to about 50 mg (e.g., about 0.25 mg to about 50 mg, about 0.25 mg to about 25 mg, about 0.5 mg to about 15 mg, about 1.5 mg to about 14 mg, about 4 mg to about 13 mg, about 8 mg to about 13 mg, about 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 ... The present invention includes administering to a patient an amount of about 1 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg of Compound I, a deuterated derivative thereof, or a pharma- ceutical acceptable salt of any of the foregoing, alone or in combination with at least one additional active pharmaceutical ingredient, such as a CFTR modulator.

[0069] In some embodiments, the invention provides a method of treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient, the method comprising administering a dose of from about 0.1 mg to about 50 mg (e.g., about 0.1 mg, about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 ... The present invention includes administering to a patient about 1 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg of Compound I, its deuterated derivative, or any pharma- ceutically acceptable salt of any of the foregoing, alone or in combination with at least one additional active pharmaceutical ingredient, such as a CFTR modulator.

[0070] In some embodiments, the invention provides a method of treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient, the method comprising administering to the patient about 0.25 mg to about 50 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, alone or in combination with at least one additional active pharmaceutical ingredient, such as a CFTR modulator.

[0071] In some embodiments, the invention provides a method of treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient, the method comprising administering to the patient about 0.25 mg to about 25 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, alone or in combination with at least one additional active pharmaceutical ingredient, such as a CFTR modulator.

[0072] In some embodiments, the invention provides a method of treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient, the method comprising administering to the patient about 1 mg to about 15 mg (e.g., about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg) of Compound I, its deuterated derivative, or any pharma- ceutically acceptable salt thereof, alone or in combination with at least one additional active pharmaceutical ingredient, such as a CFTR modulator.

[0073] In some embodiments, the invention provides a method of treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient, the method comprising administering to the patient about 1.5 mg to about 14 mg (e.g., about 1.5 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 14 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, alone or in combination with at least one additional active pharmaceutical ingredient, such as a CFTR modulator.

[0074] In some embodiments, the invention provides a method of treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient, the method comprising administering to the patient about 4 mg to about 13 mg (e.g., about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, alone or in combination with at least one additional active pharmaceutical ingredient, such as a CFTR modulator.

[0075] In some embodiments, the invention provides a method of treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient, the method comprising administering to the patient about 8 mg to about 13 mg (e.g., about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, alone or in combination with at least one additional active pharmaceutical ingredient, such as a CFTR modulator.

[0076] In some embodiments, the at least one additional API is selected from a mucolytic agent, a bronchodilator, an antibiotic, an anti-infective, an anti-inflammatory agent, and a nutritional agent.

[0077] In some embodiments, the additional agent is a mucolytic agent. Exemplary mucolytic agents useful herein include Pulmozyme®.

[0078] In some embodiments, the additional agent is a bronchodilator. Exemplary bronchodilators include albuterol, metaproterenol sulfate, pirbuterol acetate, salmeterol, and tetrabuline sulfate.

[0079] In some embodiments, the additional therapeutic agent is an antibiotic. Exemplary antibiotics useful herein include tobramycin, including tobramycin inhalation powder (TIP), azithromycin, aztreonam, including an aerosolized form of aztreonam, amikacin, including liposomal formulations of amikacin, ciprofloxacin, including formulations of ciprofloxacin suitable for administration by inhalation, levofloxacin, including an aerosolized formulation of levofloxacin, and combinations of two antibiotics, such as fosfomycin and tobramycin.

[0080] In some embodiments, the additional agent is an anti-inflammatory agent, i.e., an agent that can reduce inflammation in the lungs. Examples of such agents useful herein include ibuprofen, docosahexaenoic acid (DHA), sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine, and simavastatin.

[0081] In some embodiments, the additional agent is a nutritional agent. Exemplary nutritional agents include pancrelipase (pancreatic enzyme replacement), including Pancrease®, Pancreacarb®, Ultrase®, or Creon®, Liprotomase® (formerly Trizytek®), Aquadeks®, and glutathione inhalation. In one embodiment, the additional agent is pancrelipase.

[0082] In some embodiments, the at least one additional active pharmaceutical ingredient is selected from a CFTR modulating agent. In some embodiments, the CFTR modulating agent is a CFTR corrector. In some embodiments, the CFTR modulating agent is a CFTR enhancer / co-enhancer (e.g., ASP-11). In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR amplifier. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR read-through agent. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR nucleic acid therapy.

[0083] In some embodiments, the at least one additional active pharmaceutical ingredient is an ENaC inhibitor. In some embodiments, the at least one additional active pharmaceutical ingredient is a TMEM16A modulator. In some embodiments, the at least one additional active pharmaceutical ingredient is a GPR39 agonist.

[0084] In some embodiments, the at least one additional active pharmaceutical ingredient is (a) compound II, a deuterated derivative of compound II, and a pharma- ceutically acceptable salt of compound II and its deuterated derivative; (b) compound III, a deuterated derivative of compound III, and a pharma- ceutically acceptable salt of compound III and its deuterated derivative; (c) compound III-d, and a pharma- ceutically acceptable salt of compound III-d; (d) compound IV, a deuterated derivative of compound IV, and a pharma- ceutically acceptable salt of compound IV and its deuterated derivative; (e) compound V, a deuterated derivative of compound V, and a pharma- ceutically acceptable salt of compound V and its deuterated derivative; (f) compound III-d, and a pharma- ceutically acceptable salt of compound III-d; ) compound VI, a deuterated derivative of compound VI, and a pharma- ceutically acceptable salt of compound VI and its deuterated derivative; (g) compound VII, a deuterated derivative of compound VII, and a pharma- ceutically acceptable salt of compound VII and its deuterated derivative; (h) compound VIII, a deuterated derivative of compound VIII, and a pharma- ceutically acceptable salt of compound VIII and its deuterated derivative; (i) compound IX, a deuterated derivative of compound IX, and a pharma- ceutically acceptable salt of compound IX and its deuterated derivative; and (j) compound X, a deuterated derivative of compound X, and a pharma- ceutically acceptable salt of compound X and its deuterated derivative. Thus, in some embodiments, the combination therapy provided herein comprises administering at least one compound selected from Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; and Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof, and pharma- ceutically acceptable salts thereof.

[0085] In some embodiments, the combination therapy provided herein comprises: (a) about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) optionally at least one compound selected from the group consisting of compounds described in WO 2016 / 105485, U.S. Patent Application Publication No. 2016-013364, and / or U.S. Patent Application Publication No. 2016-013364. 20841, U.S. Patent Application Publication No. 2017-0101405, WO 2017 / 009804, WO 2018 / 065921, WO 2017 / 062581; WO 2022 / 076618; WO 2022 / 076620; WO 2022 / 076621; WO 2022 / 076622 ;WO 2022 / 076624;WO 2022 / 076625;WO 2022 / 076626;WO 2022 / 076627;WO 2022 / 076628;WO 2022 / 076629;U.S. Provisional Patent Applications Nos. 63 / 328,097 and 63 / 393,405;Phuan, P.-W. et al J.Cyst.Fibros.2018,17(5),595-606;Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669,Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640,Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32,Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,EJet al.PLoS One 2019,14(12),e0223954, Smith,NJ,Solovay,CF,Pharm.Pat.Anal.2017,6(4),179-188,Kunzelmann,K.et al.,Front.Pharmacol.2019, 10, 3; or Son, J.-H. et al., Eur. J. of Med. Chem. 2020, 112888., at least one compound selected from the compounds disclosed therein. .

[0086] In some embodiments, the combination therapy provided herein comprises: (a) about 0.1 mg to about 50 mg (e.g., about 0.1 mg, about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) optionally, a compound according to any one of International Publication Nos. WO 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO 2017 / 009804, WO 2018 / 065921, WO 2017 / 062581; WO 2022 / 076618; WO 2022 / 076620; WO 2022 / 0 76621;WO 2022 / 076622;WO 2022 / 076624;WO 2022 / 076625;WO 2022 / 076626;WO 2022 / 076627;WO 2022 / 076628;WO 2022 / 076629;U.S. Provisional Patent Applications Nos. 63 / 328,097 and 63 / 393,405;Phuan, P.-W. et al J.Cyst.Fibros.2018,17(5),595-606;Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669,Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640,Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32,Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,EJet al.PLoS One 2019,14(12),e0223954,Smith,N.J, Solovay, CF, Pharm. Pat. Anal. 2017, 6(4), 179-188; Kunzelmann, K. et al., Front. Pharmacol. 2019, 10, 3; or Son, J.-H. et al., Eur. J. of Med. Chem. 2020, 112888., or at least one compound selected from the compounds disclosed therein. .

[0087] In some embodiments, the combination therapy provided herein comprises: (a) about 0.25 mg to about 50 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and and (c) optionally, WO 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO 2017 / 009804, WO 2018 / 065921, WO 2017 / 062581; WO 2022 / 076618; WO 2022 / 076620; WO 2022 / 076 621;WO 2022 / 076622;WO 2022 / 076624;WO 2022 / 076625;WO 2022 / 076626;WO 2022 / 076627;WO 2022 / 076628;WO 2022 / 076629;U.S. Provisional Patent Applications Nos. 63 / 328,097 and 63 / 393,405;Phuan, P.-W. et al.J.Cyst.Fibros.2018,17(5),595-606;Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640,Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32,Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,EJet al.PLoS One 2019,14(12),e0223954,Smith,N.J, Solovay, CF, Pharm. Pat. Anal. 2017, 6(4), 179-188; Kunzelmann, K. et al., Front. Pharmacol. 2019, 10, 3; or Son, J.-H. et al., Eur. J. of Med. Chem. 2020, 112888., or at least one compound selected from the compounds disclosed therein. .

[0088] In some embodiments, the combination therapy provided herein comprises: (a) about 0.25 mg to about 25 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) optionally at least one compound selected from the International Publication No. 2002 / 0022662 and the International Publication No. 2002 / 0022662. US Patent Application Publication No. 2016 / 105485, US Patent Application Publication No. 2016-0120841, US Patent Application Publication No. 2017-0101405, International Publication No. 2017 / 009804, WO2018 / 065921, WO2017 / 062581, WO2022 / 076618, WO2022 / 076620, WO2022 / 076621 ;WO2022 / 076622;WO2022 / 076624;WO2022 / 076625;WO2022 / 076626;WO2022 / 076627;WO2022 / 076628;International Publication No. 2022 / 076629;U.S. Provisional Patent Application Nos. 63 / 328,097 and 63 / 393,405;Phuan, P.-W. et al.J.Cyst.Fibros.2018,17(5),595-606;Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640,Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32,Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,EJet al.PLoS One 2019,14(12),e0223954, Smith,NJ,Solovay,CF,Pharm.Pat.Anal.2017,6(4),179-188,Kunzelmann,K.et al.,Front.Pharmacol.2019,10,3;or Son,J.-H.et al.,Eur.J.of Med. Chem. 2020, 112888., at least one compound selected from the compounds disclosed in.

[0089] In some embodiments, the combination therapy provided herein comprises: (a) about 1 mg to about 15 mg (e.g., about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) optionally at least one compound selected from the group consisting of compounds described in WO 2016 / 105485, U.S. Pat. US Patent Application Publication No. 2016-0120841, US Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO2017 / 062581; WO2022 / 076618; WO2022 / 076620; WO2022 / 076621; WO2022 / 07 6622;WO2022 / 076624;WO2022 / 076625;WO2022 / 076626;WO2022 / 076627;WO2022 / 076628;WO 2022 / 076629;U.S. Provisional Patent Application Nos. 63 / 328,097 and 63 / 393,405;Phuan, P.-W. et al.J.Cyst.Fibros.2018,17(5),595-606;Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640,Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32,Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,EJet al.PLoS One 2019,14(12),e0223954, Smith,NJ,Solovay,CF,Pharm.Pat.Anal.2017,6(4),179-188,Kunzelmann,K.et al.,Front.Pharmacol.2019,10,3;or Son,J.-H.et al.,Eur.J.of Med.Chem.2020,112888., or at least one compound selected from the compounds disclosed in .

[0090] In some embodiments, the combination therapy provided herein comprises: (a) about 1.5 mg to about 14 mg (e.g., about 1.5 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 14 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; , U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO2017 / 062581; WO2022 / 076618; WO2022 / 076620; WO2022 / 076621; WO2022 / 0 76622;WO2022 / 076624;WO2022 / 076625;WO2022 / 076626;WO2022 / 076627;WO2022 / 076628;WO 2022 / 076629;U.S. Provisional Patent Application Nos. 63 / 328,097 and 63 / 393,405;Phuan, P.-W. et al.J.Cyst.Fibros.2018,17(5),595-606;Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640,Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32,Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,EJet al.PLoS One 2019,14(12),e0223954, Smith,NJ,Solovay,CF,Pharm.Pat.Anal.2017,6(4),179-188,Kunzelmann,K.et al.,Front.Pharmacol.2019,10,3;or Son,J.-H.et al.,Eur.J.of Med.Chem.2020,112888., or at least one compound selected from the compounds disclosed in .

[0091] In some embodiments, the combination therapy provided herein comprises: (a) about 4 mg to about 13 mg (e.g., about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; and (b) at least one compound, optionally selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof. and (c) optionally a compound selected from the group consisting of compounds disclosed in WO 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO2017 / 062581; WO2022 / 076618; WO2022 / 076620; WO20 22 / 076621;WO2022 / 076622;WO2022 / 076624;WO2022 / 076625;WO2022 / 076626;WO2022 / 076627;WO2022 / 076628;WO Publication No. 2022 / 076629;U.S. Provisional Patent Application Nos. 63 / 328,097 and 63 / 393,405;Phuan, P.-W. et al.J.Cyst.Fibros.2018,17(5),595-606;Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640,Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32,Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,EJet al.PLoS One 2019,14(12),e0223954, Smith,NJ,Solovay,CF,Pharm.Pat.Anal.2017,6(4),179-188,Kunzelmann,K.et al.,Front.Pharmacol.2019, 10, 3; or Son, J.-H. et al., Eur. J. of Med. Chem. 2020, 112888., at least one compound selected from the compounds disclosed therein. .

[0092] In some embodiments, the combination therapy provided herein comprises: (a) about 8 mg to about 13 mg (e.g., about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) optionally at least one compound selected from WO 2006 / 023666, 016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405,,WO2017 / 009804,WO2018 / 065921,WO2017 / 062581;WO2022 / 076618;WO2022 / 076620;WO2022 / 076621;WO 2022 / 076622;WO2022 / 076624;WO2022 / 076625;WO2022 / 076626;WO2022 / 076627;WO2022 / 076628;WO Publication No. 2022 / 076629;U.S. Provisional Patent Application Nos. 63 / 328,097 and 63 / 393,405;Phuan, P.-W. et al.J.Cyst.Fibros.2018,17(5),595-606;Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640,Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32,Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,EJet al.PLoS One 2019,14(12),e0223954, Smith,NJ,Solovay,CF,Pharm.Pat.Anal.2017,6(4),179-188,Kunzelmann,K.et al.,Front.Pharmacol.2019,10,3;or Son,J.-H.et al.,Eur.J.of Med.Chem.2020,112888., or at least one compound selected from the compounds disclosed in .

[0093] In some embodiments, the combination therapy provided herein comprises: (a) about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) optionally at least one compound selected from PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV- 3748,ABBV-3903,ABBV-119,FDL-169,ARN5562,ARN21586,ARN22081,ARN22652,ARN23765,ARN2376 6, PTI-801, FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW251 (Icenticaftor), The method comprises administering at least one compound selected from GLPG3067 / ABBV-3067 (navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0094] In some embodiments, the combination therapies provided herein comprise (a) a dose of about 0.1 mg to about 50 mg (e.g., about 0.1 mg, about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47. (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) optionally at least one compound selected from PTI-428, ASP- 11,ABBV-2222,ABBV-2851,GLPG2737,ABBV-3221,ABBV-3748,ABBV-3903,ABBV-119,FDL-169,ARN5562,ARN21586 ,ARN22081,ARN22652,ARN23765,ARN23766,PTI-801,FDL-176,PTI-808,GLPG1837 / ABBV-974,GLPG2451 / ABBV-24 51, QBW251 (Icenticaftor), GLPG3067 / ABBV-3067 (navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and at least one compound selected from DS-1039.

[0095] In some embodiments, the combination therapies provided herein comprise (a) about 0.25 mg to about 50 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or (b) at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) optionally at least one compound selected from PTI-428, ASP-11, ABBV-2222,ABBV-2851,GLPG2737,ABBV-3221,ABBV-3748,ABBV-3903,ABBV-119,FDL-169,ARN5562,ARN21586,A RN22081, ARN22652, ARN23765, ARN23766, PTI-801, FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451 , QBW251 (Icenticaftor), GLPG3067 / ABBV-3067 (Navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0096] In some embodiments, the combination therapy provided herein comprises: (a) about 0.25 mg to about 25 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) optionally at least one compound selected from PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3 221,ABBV-3748,ABBV-3903,ABBV-119,FDL-169,ARN5562,ARN21586,ARN22081,ARN22652,ARN23765, ARN23766,PTI-801,FDL-176,PTI-808,GLPG1837 / ABBV-974,GLPG2451 / ABBV-2451,QBW251(Icenticaf tor), GLPG3067 / ABBV-3067 (navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0097] In some embodiments, the combination therapy provided herein comprises: (a) about 1 mg to about 15 mg (e.g., about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) optionally at least one compound selected from PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-4221, ABBV-4222, ABBV-4223, ABBV-4224, ABBV-4225, ABBV-4226, ABBV-4227, ABBV-4228, ABBV-4229 ...9, ABBV-4229, ABBV-4229, ABBV-4229, ABBV-4229, ABBV-4229, ABBV-4229, ABBV-4229, ABBV-4229, ABBV-4229, ABB V-3903,ABBV-119,FDL-169,ARN5562,ARN21586,ARN22081,ARN22652,ARN23765,ARN23766,PTI- 801,FDL-176,PTI-808,GLPG1837 / ABBV-974,GLPG2451 / ABBV-2451,QBW251(Icenticaftor),GLPG 3067 / ABBV-3067 (navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0098] In some embodiments, the combination therapy provided herein comprises: (a) about 1.5 mg to about 14 mg (e.g., about 1.5 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 14 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) optionally at least one compound selected from PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, AB ... BV-3903,ABBV-119,FDL-169,ARN5562,ARN21586,ARN22081,ARN22652,ARN23765,ARN23766,PTI -801,FDL-176,PTI-808,GLPG1837 / ABBV-974,GLPG2451 / ABBV-2451,QBW251(Icenticaftor),GLP The method comprises administering at least one compound selected from G3067 / ABBV-3067 (navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0099] In some embodiments, the combination therapy provided herein comprises: (a) about 4 mg to about 13 mg (e.g., about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) optionally at least one compound selected from PTI-428, ASP-11, ABBV-2222, ABBV- 2851,GLPG2737,ABBV-3221,ABBV-3748,ABBV-3903,ABBV-119,FDL-169,ARN5562,ARN21586,ARN22081,ARN 22652, ARN23765, ARN23766, PTI-801, FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW251 (Icenticaftor), GLPG3067 / ABBV-3067 (navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0100] In some embodiments, the combination therapy provided herein comprises: (a) about 8 mg to about 13 mg (e.g., about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) optionally at least one compound selected from PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748,ABBV-3903,ABBV-119,FDL-169,ARN5562,ARN21586,ARN22081,ARN22652,ARN23765,ARN 23766,PTI-801,FDL-176,PTI-808,GLPG1837 / ABBV-974,GLPG2451 / ABBV-2451,QBW251(Icenticafto r), GLPG3067 / ABBV-3067 (navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and at least one compound selected from DS-1039.

[0101] In some embodiments, about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, its deuterated derivative, or any of the aforementioned pharma- ceutically acceptable salts is administered in combination with at least one compound selected from Compound II and its pharma- ceutically acceptable salts and their deuterated derivatives. In some embodiments, about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, its deuterated derivative, or any of the aforementioned pharma- ceutically acceptable salts is administered in combination with at least one compound selected from Compound III and its pharma- ceutically acceptable salts and their deuterated derivatives. In some embodiments, about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, its deuterated derivative, or any of the aforementioned pharmaceutically acceptable salts is administered in combination with at least one compound selected from Compound III-d and its pharmaceutically acceptable salts. In some embodiments, about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, its deuterated derivative, or any of the aforementioned pharmaceutically acceptable salts is administered in combination with at least one compound selected from Compound IV and its deuterated derivatives and their pharmaceutically acceptable salts. In some embodiments, about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or any of the foregoing pharma- ceutically acceptable salts is administered in combination with at least one compound selected from Compound V and its deuterated derivatives, and pharma- ceutically acceptable salts thereof.In some embodiments, about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, its deuterated derivative, or any of the aforementioned pharmaceutically acceptable salts is administered in combination with at least one compound selected from Compound VI and its deuterated derivatives and their pharmaceutically acceptable salts. In some embodiments, about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, its deuterated derivative, or any of the aforementioned pharmaceutically acceptable salts is administered in combination with at least one compound selected from Compound VII and its deuterated derivatives and their pharmaceutically acceptable salts. In some embodiments, about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, its deuterated derivative, or any of the aforementioned pharmaceutically acceptable salts is administered in combination with at least one compound selected from Compound VIII and its deuterated derivatives and their pharmaceutically acceptable salts. In some embodiments, about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, its deuterated derivative, or any of the aforementioned pharmaceutically acceptable salts is administered in combination with at least one compound selected from Compound IX and its deuterated derivatives and their pharmaceutically acceptable salts. In some embodiments, about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or any of the foregoing pharma- ceutically acceptable salts is administered in combination with at least one compound selected from Compound X and its deuterated derivatives, and pharma- ceutically acceptable salts thereof.

[0102] In some embodiments, about 0.1 mg to about 50 mg (e.g., about 0.25 mg to about 50 mg, about 0.25 mg to about 25 mg, about 0.5 mg to about 15 mg, about 1.5 mg to about 14 mg, about 4 mg to about 13 mg, about 8 mg to about 13 mg, about 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, g, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, is administered in combination with at least one compound selected from Compound II and pharma- ceutically acceptable salts thereof, and deuterated derivatives thereof. In some embodiments, about 0.1 mg to about 50 mg (e.g., about 0.25 mg to about 50 mg, about 0.25 mg to about 25 mg, about 0.5 mg to about 15 mg, about 1.5 mg to about 14 mg, about 4 mg to about 13 mg, about 8 mg to about 13 mg, about 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, g, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, its deuterated derivative, or a pharma- ceutically acceptable salt of any of the foregoing, is administered in combination with at least one compound selected from Compound IV and its deuterated derivatives, and pharma- ceutically acceptable salts thereof.In some embodiments, about 0.1 mg to about 50 mg (e.g., about 0.25 mg to about 25 mg, about 0.5 mg to about 15 mg, about 1.5 mg to about 14 mg, about 4 mg to about 13 mg, about 8 mg to about 13 mg, about 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg , about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, its deuterated derivative, or a pharma- ceutically acceptable salt of any of the foregoing, is administered in combination with at least one compound selected from Compound V and its deuterated derivatives, and pharma- ceutically acceptable salts thereof. In some embodiments, about 0.1 mg to about 50 mg (e.g., about 0.25 mg to about 50 mg, about 0.25 mg to about 25 mg, about 0.5 mg to about 15 mg, about 1.5 mg to about 14 mg, about 4 mg to about 13 mg, about 8 mg to about 13 mg, about 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, g, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, its deuterated derivative, or a pharma- ceutically acceptable salt of any of the foregoing, is administered in combination with at least one compound selected from Compound VI and its deuterated derivatives, and pharma- ceutically acceptable salts thereof.In some embodiments, about 0.1 mg to about 50 mg (e.g., about 0.25 mg to about 50 mg, about 0.25 mg to about 25 mg, about 0.5 mg to about 15 mg, about 1.5 mg to about 14 mg, about 4 mg to about 13 mg, about 8 mg to about 13 mg, about 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg , about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg of Compound I, its deuterated derivative, or a pharma- ceutically acceptable salt of any of the foregoing, is administered in combination with at least one compound selected from Compound VII and its deuterated derivatives, and pharma- ceutically acceptable salts thereof. In some embodiments, about 0.1 mg to about 50 mg (e.g., about 0.25 mg to about 50 mg, about 0.25 mg to about 25 mg, about 0.5 mg to about 15 mg, about 1.5 mg to about 14 mg, about 4 mg to about 13 mg, about 8 mg to about 13 mg, about 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg , about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, its deuterated derivative, or a pharma- ceutically acceptable salt of any of the foregoing, is administered in combination with at least one compound selected from Compound VIII and its deuterated derivatives, and pharma- ceutically acceptable salts thereof.In some embodiments, about 0.1 mg to about 50 mg (e.g., about 0.25 mg to about 50 mg, about 0.25 mg to about 25 mg, about 0.5 mg to about 15 mg, about 1.5 mg to about 14 mg, about 4 mg to about 13 mg, about 8 mg to about 13 mg, about 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, g, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, its deuterated derivative, or a pharma- ceutically acceptable salt of any of the foregoing, is administered in combination with at least one compound selected from Compound IX and its deuterated derivatives, and pharma- ceutically acceptable salts thereof. In some embodiments, about 0.1 mg to about 50 mg (e.g., about 0.25 mg to about 50 mg, about 0.25 mg to about 25 mg, about 0.5 mg to about 15 mg, about 1.5 mg to about 14 mg, about 4 mg to about 13 mg, about 8 mg to about 13 mg, about 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, g, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, its deuterated derivative, or a pharma- ceutically acceptable salt of any of the foregoing, is administered in combination with at least one compound selected from Compound X and its deuterated derivatives, and pharma- ceutically acceptable salts thereof.

[0103] In some embodiments, about 0.1 mg to about 50 mg (e.g., about 0.25 mg to about 50 mg, about 0.25 mg to about 25 mg, about 0.5 mg to about 15 mg, about 1.5 mg to about 14 mg, about 4 mg to about 13 mg, about 8 mg to about 13 mg, about 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg , about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, its deuterated derivative, or a pharma- ceutically acceptable salt of any of the foregoing, is administered in combination with at least one compound selected from Compound III and pharma- ceutically acceptable salts thereof, and deuterated derivatives thereof. In some embodiments, about 0.1 mg to about 50 mg (e.g., about 0.25 mg to about 50 mg, about 0.25 mg to about 25 mg, about 0.5 mg to about 15 mg, about 1.5 mg to about 14 mg, about 4 mg to about 13 mg, about 8 mg to about 13 mg, about 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about

[0034] Compound I, its deuterated derivative, or a pharma- ceutical acceptable salt of any of the foregoing, is administered in combination with at least one compound selected from compound III-d and a pharma- ceutical acceptable salt thereof.

[0104] In some embodiments, about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or any of the aforementioned pharma- ceutically acceptable salts is administered in combination with at least one compound selected from Compound II and its deuterated derivatives and pharma- ceutically acceptable salts thereof, and at least one compound selected from Compound V and its pharma- ceutically acceptable salts and deuterated derivatives thereof. In some embodiments, about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or any of the aforementioned pharmaceutical acceptable salts is administered in combination with at least one compound selected from Compound II and its deuterated derivatives and pharmaceutical acceptable salts thereof, and at least one compound selected from Compound VI and its deuterated derivatives and pharmaceutical acceptable salts thereof. In some embodiments, about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or any of the aforementioned pharmaceutical acceptable salts is administered in combination with at least one compound selected from Compound II and its deuterated derivatives and pharmaceutical acceptable salts thereof, and at least one compound selected from Compound VII and its deuterated derivatives and pharmaceutical acceptable salts thereof. In some embodiments, about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, its deuterated derivative, or any of the aforementioned pharmaceutical acceptable salts is administered in combination with at least one compound selected from Compound II and its deuterated derivatives and pharmaceutical acceptable salts thereof, and at least one compound selected from Compound VIII and its deuterated derivatives and pharmaceutical acceptable salts thereof.

[0105] In some embodiments, about 0.1 mg to about 50 mg (e.g., about 0.25 mg to about 50 mg, about 0.25 mg to about 25 mg, about 0.5 mg to about 15 mg, about 1.5 mg to about 14 mg, about 4 mg to about 13 mg, about 8 mg to about 13 mg, about 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 40 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 50 mg, about 50 mg, about 50 mg, about 50 mg, about g, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, its deuterated derivative, or a pharma- ceutically acceptable salt of any of the foregoing, is administered in combination with at least one compound selected from Compound II and its deuterated derivatives, and pharma- ceutically acceptable salts thereof, and at least one compound selected from Compound V and its pharma- ceutically acceptable salts, and deuterated derivatives thereof.In some embodiments, about 0.1 mg to about 50 mg (e.g., about 0.25 mg to about 50 mg, about 0.25 mg to about 25 mg, about 0.5 mg to about 15 mg, about 1.5 mg to about 14 mg, about 4 mg to about 13 mg, about 8 mg to about 13 mg, about 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg , about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, its deuterated derivative, or a pharma- ceutically acceptable salt of any of the foregoing, is administered in combination with at least one compound selected from Compound II and its deuterated derivatives, and a pharma- ceutically acceptable salt thereof, and at least one compound selected from Compound VI and its deuterated derivatives, and a pharma- ceutically acceptable salt thereof.In some embodiments, about 0.1 mg to about 50 mg (e.g., about 0.25 mg to about 50 mg, about 0.25 mg to about 25 mg, about 0.5 mg to about 15 mg, about 1.5 mg to about 14 mg, about 4 mg to about 13 mg, about 8 mg to about 13 mg, about 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg , about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, its deuterated derivative, or a pharma- ceutically acceptable salt of any of the foregoing, is administered in combination with at least one compound selected from Compound II and its deuterated derivatives, and a pharma- ceutically acceptable salt thereof, and at least one compound selected from Compound VII and its deuterated derivatives, and a pharma- ceutically acceptable salt thereof.In some embodiments, about 0.1 mg to about 50 mg (e.g., about 0.25 mg to about 50 mg, about 0.25 mg to about 25 mg, about 0.5 mg to about 15 mg, about 1.5 mg to about 14 mg, about 4 mg to about 13 mg, about 8 mg to about 13 mg, about 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, About 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, its deuterated derivative, or a pharma- ceutically acceptable salt of any of the foregoing, is administered in combination with at least one compound selected from Compound II and its deuterated derivatives, and pharma- ceutically acceptable salts thereof, and at least one compound selected from Compound VIII and its deuterated derivatives, and pharma- ceutically acceptable salts thereof.

[0106] Each of Compound I, its deuterated derivatives, or any pharma- ceutically acceptable salts of the foregoing, and compounds selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and their deuterated derivatives and pharma- ceutically acceptable salts thereof, may be administered independently once a day, twice a day, or three times a day.

[0107] In some embodiments, compound I, its deuterated derivative, or any pharma- ceutically acceptable salt of the foregoing is administered once a day. In some embodiments, compound I, its deuterated derivative, or any pharma- ceutically acceptable salt of the foregoing is administered twice a day. In some embodiments, compound I, its deuterated derivative, or any pharma- ceutically acceptable salt of the foregoing, and at least one compound selected from compound II, compound III, compound III-d, compound IV, compound V, compound VI, compound VII, compound VIII, compound IX, compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof are administered once a day. In some embodiments, compound I, its deuterated derivative, or any pharma- ceutically acceptable salt of the foregoing, and at least one compound selected from compound II, compound III, compound III-d, compound IV, compound V, compound VI, compound VII, compound VIII, compound IX, compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof are administered twice a day. In some embodiments, at least one compound selected from compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, and compound II and its deuterated derivative and their pharma- ceutically acceptable salts are administered once daily, in some embodiments, at least one compound selected from compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, and compound II and its deuterated derivative and their pharma- ceutically acceptable salts are administered twice daily.

[0108] Compound I, its deuterated derivative, or any pharma- ceutically acceptable salt thereof, and the additional therapeutic agent may be administered in a single pharmaceutical composition or in separate pharmaceutical compositions. Thus, (a) about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, its deuterated derivative, or any pharma- ceutically acceptable salt thereof, and (b) a compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and its deuterated derivatives and pharma- ceutically acceptable salts thereof, may be administered in a single pharmaceutical composition comprising (a) and (b), or in separate pharmaceutical compositions, in which a first composition comprises (a) and a second composition comprises (b). Such pharmaceutical compositions may be administered once a day or multiple times a day, such as twice or three times a day. As used herein, the phrase that a given amount of an API (e.g., Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing) is administered daily or once or twice per day means that the given amount is administered per dose, and that the dosing can occur once or twice daily.

[0109] Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, and the additional therapeutic agent may be administered in a single pharmaceutical composition or in separate pharmaceutical compositions. Therefore, (a) about 0.1 mg to about 50 mg (for example, about 0.25 mg to about 50 mg, about 0.25 mg to about 25 mg, about 0.5 mg to about 15 mg, about 1.5 mg to about 14 mg, about 4 mg to about 13 mg, about 8 mg to about 13 mg, about 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg g, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, its deuterated derivative, or a pharma- ceutically acceptable salt of any of the foregoing, and (b) a compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and its deuterated derivatives and pharma- ceutically acceptable salts thereof, can be administered in a single pharmaceutical composition comprising (a) and (b), or in separate pharmaceutical compositions, a first composition comprising (a) and a second composition comprising (b). Such pharmaceutical compositions can be administered once a day or multiple times a day, such as twice or three times a day. As used herein, the phrase that a given amount of an API (e.g., Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing) is administered daily or once or twice per day means that the given amount is administered per dose, and that the dosing can occur once or twice daily.

[0110] In some embodiments, (a) about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing is administered in a first pharmaceutical composition; and at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof is administered in a second pharmaceutical composition.

[0111] In some embodiments, (a) from about 0.1 mg to about 50 mg (e.g., from about 0.25 mg to about 50 mg, from about 0.25 mg to about 25 mg, from about 0.5 mg to about 15 mg, from about 1.5 mg to about 14 mg, from about 4 mg to about 13 mg, from about 8 mg to about 13 mg, from about 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 17 mg, about 5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, its deuterated derivative, or a pharma- ceutically acceptable salt of any of the foregoing, is administered in a first pharmaceutical composition; and at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof, is administered in a second composition.

[0112] Any suitable pharmaceutical composition known in the art can be used for Compound I, Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof. Some exemplary pharmaceutical compositions of Compound II and its pharma- ceutically acceptable salts can be found in WO 2011 / 119984 and WO 2014 / 014841, which are incorporated herein by reference. Some exemplary pharmaceutical compositions of compound III and pharma- ceutically acceptable salts thereof can be found in WO 2007 / 134279, WO 2010 / 019239, WO 2011 / 019413, WO 2012 / 027731, and WO 2013 / 130669, and some exemplary pharmaceutical compositions of compound III-d and pharma- ceutically acceptable salts thereof can be found in U.S. Pat. No. 8,865,902, U.S. Pat. No. 9,181,192, U.S. Pat. No. 9,512,079, WO 2017 / 053455, and WO 2018 / 080591, all of which are incorporated herein by reference. Some exemplary pharmaceutical compositions of compound IV and its pharma- ceutically acceptable salts can be found in WO 2010 / 037066, WO 2011 / 127421, and WO 2014 / 071122, which are incorporated herein by reference. Some exemplary pharmaceutical compositions of compound V and its pharma- ceutically acceptable salts can be found in WO 2019 / 152940, which are incorporated herein by reference. Some exemplary pharmaceutical compositions of compound VI and its pharma- ceutically acceptable salts can be found in WO 2019 / 079760, which are incorporated herein by reference.

[0113] Pharmaceutical Compositions Another aspect of the present invention provides a pharmaceutical composition comprising Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, and at least one pharma- ceutically acceptable carrier.

[0114] In some embodiments, the disclosure provides a pharmaceutical composition comprising (a) about 5 mg to 100 mg of compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt of the foregoing, and (b) at least one pharma- ceutically acceptable carrier. In some embodiments, the disclosure provides a pharmaceutical composition comprising (a) about 7 mg to 90 mg of compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt of the foregoing, and (b) at least one pharma- ceutically acceptable carrier. In some embodiments, the disclosure provides a pharmaceutical composition comprising (a) about 10 mg to 80 mg of compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt of the foregoing, and (b) at least one pharma- ceutically acceptable carrier. In some embodiments, the disclosure provides a pharmaceutical composition comprising (a) about 10 mg to 40 mg of compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt of the foregoing, and (b) at least one pharma- ceutically acceptable carrier. In some embodiments, the disclosure provides a pharmaceutical composition comprising: (a) about 30 mg to 60 mg of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; and (b) at least one pharma- ceutically acceptable carrier. In some embodiments, the disclosure provides a pharmaceutical composition comprising: (a) about 50 mg to 80 mg of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; and (b) at least one pharma- ceutically acceptable carrier.

[0115] In some embodiments, the disclosure provides a pharmaceutical composition comprising: (a) about 0.1 mg to about 50 mg (e.g., about 0.1 mg, about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; and (b) at least one pharma- ceutically acceptable carrier.

[0116] In some embodiments, the disclosure provides a pharmaceutical composition comprising: (a) about 0.25 mg to about 50 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; and (b) at least one pharma- ceutically acceptable carrier.

[0117] In some embodiments, the disclosure provides pharmaceutical compositions comprising: (a) about 0.25 mg to about 25 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; and (b) at least one pharma- ceutically acceptable carrier.

[0118] In some embodiments, the disclosure provides pharmaceutical compositions comprising: (a) about 1 mg to about 15 mg (e.g., about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; and (b) at least one pharma- ceutically acceptable carrier.

[0119] In some embodiments, the disclosure provides pharmaceutical compositions comprising: (a) about 1.5 mg to about 14 mg (e.g., about 1.5 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 14 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; and (b) at least one pharma- ceutically acceptable carrier.

[0120] In some embodiments, the disclosure provides a pharmaceutical composition comprising: (a) about 4 mg to about 13 mg (e.g., about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; and (b) at least one pharma- ceutically acceptable carrier.

[0121] In some embodiments, the disclosure provides a pharmaceutical composition comprising: (a) about 8 mg to about 13 mg (e.g., about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; and (b) at least one pharma- ceutically acceptable carrier.

[0122] In some embodiments, the present invention provides a pharmaceutical composition comprising about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, and optionally at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR modulator. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR corrector. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR enhancer. In some embodiments, the at least one additional active pharmaceutical ingredient is a compound that enhances CFTR enhancement, i.e., a CFTR enhancer enhancer / co-enhancement agent. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR amplifier. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR read-through agent. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR nucleic acid therapy. In some embodiments, the at least one additional active pharmaceutical ingredient is an ENaC inhibitor. In some embodiments, the at least one additional active pharmaceutical ingredient is a TMEM16A modulator. In some embodiments, the at least one additional active pharmaceutical ingredient is a GPR39 agonist. In some embodiments, the pharmaceutical composition comprises Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, and at least one additional active pharmaceutical ingredient that is a CFTR corrector. In some embodiments, the pharmaceutical composition comprises Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, and at least two additional active pharmaceutical ingredients, each of which is a CFTR corrector.

[0123] In some embodiments, the present invention provides a method for treating a patient having a pulmonary circulation comprising administering to the patient ... The present invention provides a pharmaceutical composition comprising about 1 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, and optionally at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR modulator. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR corrector. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR enhancer. In some embodiments, the at least one additional active pharmaceutical ingredient is a compound that enhances a CFTR enhancer, i.e., a CFTR enhancer enhancer / co-enhancer. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR amplifier. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR read-through agent. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR nucleic acid therapy. In some embodiments, the at least one additional active pharmaceutical ingredient is an ENaC inhibitor. In some embodiments, the at least one additional active pharmaceutical ingredient is a TMEM16A modulator. In some embodiments, the at least one additional active pharmaceutical ingredient is a GPR39 agonist. In some embodiments, the pharmaceutical composition comprises Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, and at least one additional active pharmaceutical ingredient that is a CFTR corrector.In some embodiments, the pharmaceutical composition comprises Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, and at least two additional active pharmaceutical ingredients, each of which is a CFTR corrector.

[0124] In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or any of the foregoing pharma- ceutically acceptable salts; (b) at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the present invention provides pharmaceutical compositions comprising: (a) Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) at least two compounds selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0125] In some embodiments, the present invention provides a method for treating a pulmonary circulation comprising administering to a patient a therapeutically effective amount of a pulmonary circulation comprising administering to the patient a therapeutically effective amount of a pulmonary circulation comprising administering to the patient a therapeutically effective amount of a pulmonary circulation comprising administering to the patient a therapeutically effective amount of a pulmonary circulation comprising administering to the patient a therapeutically effective amount of a pulmonary circulation comprising administering to the patient a therapeutically effective amount of a pulmonary circulation comprising administering to the patient a therapeutically effective amount of a pulmonary circulation or a pharma- ceutically acceptable salt of any of the foregoing; (b) at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the present invention provides a method for treating a pulmonary circulation comprising administering to a patient a therapeutically effective amount of a pulmonary circulation comprising administering to the patient a therapeutically effective amount of a pulmonary circulation comprising administering to the patient a therapeutically effective amount of a pulmonary circulation comprising administering to the patient a therapeutically effective amount of a pulmonary circulation comprising administering to the patient a therapeutically effective amount of a pulmonary circulation comprising administering to the patient a therapeutically effective amount of a pulmonary circulation comprising administering to the patient a therapeutically effective amount of a pulmonary circulation or a pharma- ceutical acceptable salt of any of the foregoing; (b) at least two compounds selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutical acceptable salts thereof; and (c) at least one pharma- ceutical composition comprising at least one pharma- ceutical acceptable carrier.

[0126] In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) about 0.25 mg to about 50 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) about 0.25 mg to about 50 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) at least two compounds selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0127] In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) about 0.25 mg to about 25 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) about 0.25 mg to about 25 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg) of Compound I, its deuterated derivative, or any of the foregoing pharma- ceutically acceptable salts; (b) at least two compounds selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0128] In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) about 1 mg to about 15 mg (e.g., about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg) of Compound I, its deuterated derivative, or any of the foregoing pharma- ceutically acceptable salts; (b) at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) about 1 mg to about 15 mg (e.g., about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg) of Compound I, its deuterated derivative, or any of the foregoing pharma- ceutically acceptable salts; (b) at least two compounds selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0129] In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) about 1.5 mg to about 14 mg (e.g., about 1.5 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 14 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) about 1.5 mg to about 14 mg (e.g., about 1.5 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 14 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) at least two compounds selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0130] In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) about 4 mg to about 13 mg (e.g., about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) about 4 mg to about 13 mg (e.g., about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) at least two compounds selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0131] In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) about 8 mg to about 13 mg (e.g., about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, its deuterated derivative, or any of the foregoing pharma- ceutically acceptable salts; (b) at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) about 8 mg to about 13 mg (e.g., about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, its deuterated derivative, or any of the foregoing pharma- ceutically acceptable salts; (b) at least two compounds selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0132] In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or any of the foregoing pharma- ceutically acceptable salts; (b) at least one compound selected from Compound II, a deuterated derivative thereof, and a pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0133] In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) about 0.1 mg to about 50 mg (e.g., about 0.1 mg, about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) at least one compound selected from Compound II, and a deuterated derivative thereof, and a pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0134] In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) about 0.25 mg to about 50 mg (e.g., about about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) at least one compound selected from Compound II, a deuterated derivative thereof, and a pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0135] In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) about 0.25 mg to about 25 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) at least one compound selected from Compound II, and a deuterated derivative thereof, and a pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0136] In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) about 1 mg to about 15 mg (e.g., about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg) of Compound I, its deuterated derivative, or any of the foregoing pharma- ceutically acceptable salts; (b) at least one compound selected from Compound II and its deuterated derivatives, and pharma- ceutically acceptable salts thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0137] In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) about 1.5 mg to about 14 mg (e.g., about 1.5 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 14 mg) of Compound I, its deuterated derivative, or any of the foregoing pharma- ceutically acceptable salts; (b) at least one compound selected from Compound II and its deuterated derivatives, and pharma- ceutically acceptable salts thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0138] In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) about 4 mg to about 13 mg (e.g., about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) at least one compound selected from Compound II, and a deuterated derivative thereof, and a pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0139] In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) about 8 mg to about 13 mg (e.g., about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, its deuterated derivative, or any of the foregoing pharma- ceutically acceptable salts; (b) at least one compound selected from Compound II and its deuterated derivatives, and pharma- ceutically acceptable salts thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0140] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (a) about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or any of the foregoing pharma- ceutically acceptable salts; (b) at least one compound selected from Compound II, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; (c) at least one compound selected from Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (d) at least one pharma- ceutically acceptable carrier.

[0141] In some embodiments, the disclosure provides: (a) about 0.1 mg to about 50 mg (e.g., about 0.1 mg, about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any of the foregoing. (b) at least one compound selected from Compound II, and deuterated derivatives thereof, and pharma- ceutically acceptable salts thereof; (c) at least one compound selected from Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof, and pharma- ceutically acceptable salts thereof; and (d) at least one pharma- ceutically acceptable carrier.

[0142] In some embodiments, the disclosure provides a method for administering to a patient a therapeutically effective amount of Compound I, a deuterated derivative thereof, or any of the foregoing compounds, comprising administering to a patient a therapeutically effective amount of Compound I, a deuterated derivative thereof, or any of the foregoing compounds, comprising administering to a patient a therapeutically effective amount of Compound I, a deuterated derivative thereof, or any of the foregoing compounds, wherein the deuterated derivative thereof is administered in an amount of from about 0.25 mg to about 50 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) ... In one aspect, the present invention provides a pharmaceutical composition comprising: (a) at least one compound selected from Compound II, and deuterated derivatives thereof, and pharma- ceutically acceptable salts thereof; (b) at least one compound selected from Compound II, and deuterated derivatives thereof, and pharma- ceutically acceptable salts thereof; (c) at least one compound selected from Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof, and pharma- ceutically acceptable salts thereof; and (d) at least one pharma- ceutically acceptable carrier.

[0143] In some embodiments, the disclosure provides a pharmaceutical composition comprising: (a) about 0.25 mg to about 25 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg) of Compound I, its deuterated derivative, or any pharma- ceutically acceptable salt thereof; (b) at least one compound selected from Compound II, and its deuterated derivatives and pharma- ceutically acceptable salts thereof; (c) at least one compound selected from Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and its deuterated derivatives and pharma- ceutically acceptable salts thereof; and (d) at least one pharma- ceutically acceptable carrier.

[0144] In some embodiments, the disclosure provides a pharmaceutical composition comprising: (a) about 1 mg to about 15 mg (e.g., about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg) of Compound I, its deuterated derivative, or any pharma- ceutically acceptable salt thereof; (b) at least one compound selected from Compound II, and its deuterated derivatives and pharma- ceutically acceptable salts thereof; (c) at least one compound selected from Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and its deuterated derivatives and pharma- ceutically acceptable salts thereof; and (d) at least one pharma- ceutically acceptable carrier.

[0145] In some embodiments, the disclosure provides a pharmaceutical composition comprising: (a) about 1.5 mg to about 14 mg (e.g., about 1.5 mg, about 4 mg, about 6.5 mg, about 9 mg, about 11.5 mg, or about 14 mg) of Compound I, its deuterated derivative, or any pharma- ceutically acceptable salt thereof; (b) at least one compound selected from Compound II, and its deuterated derivatives and pharma- ceutically acceptable salts thereof; (c) at least one compound selected from Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and its deuterated derivatives and pharma- ceutically acceptable salts thereof; and (d) at least one pharma- ceutically acceptable carrier.

[0146] In some embodiments, the disclosure provides a pharmaceutical composition comprising: (a) about 4 mg to about 13 mg (e.g., about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, its deuterated derivative, or a pharma- ceutically acceptable salt of any of the foregoing; (b) at least one compound selected from Compound II, and its deuterated derivatives and pharma- ceutically acceptable salts thereof; (c) at least one compound selected from Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and its deuterated derivatives and pharma- ceutically acceptable salts thereof; and (d) at least one pharma- ceutically acceptable carrier.

[0147] In some embodiments, the disclosure provides a pharmaceutical composition comprising: (a) about 8 mg to about 13 mg (e.g., about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, its deuterated derivative, or any pharma- ceutically acceptable salt thereof; (b) at least one compound selected from Compound II, and its deuterated derivatives and pharma- ceutically acceptable salts thereof; (c) at least one compound selected from Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and its deuterated derivatives and pharma- ceutically acceptable salts thereof; and (d) at least one pharma- ceutically acceptable carrier.

[0148] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; (c) optionally at least one compound selected from the group consisting of Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; 05485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO2017 / 062581; WO2022 / 076618; WO2022 / 076620; WO2022 / 076621; WO202 2 / 076622;WO2022 / 076624;WO2022 / 076625;WO2022 / 076626;WO2022 / 076627;WO2022 / 076628;WO 2022 / 076629;U.S. Provisional Patent Application Nos. 63 / 328,097 and 63 / 393,405;Phuan, P.-W. et al.J.Cyst.Fibros.2018,17(5),595-606;Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640,Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32,Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,EJet al.PLoS One 2019,14(12),e0223954, Smith,NJ,Solovay,CF,Pharm.Pat.Anal.2017,6(4),179-188,Kunzelmann,K.et al.,Front.Pharmacol.2019,10,3;or Son,J.-H.et al.,Eur.J.of Med.Chem.2020,112888; and (d) at least one compound selected from the compounds disclosed in the above-mentioned US Pat. No. 6,200,112888; and (d) at least one pharma- ceutically acceptable carrier.

[0149] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.1 mg to about 50 mg (e.g., about 0.1 mg, about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally, Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutical acceptable salts thereof; and (c) at least one compound selected from the group consisting of compounds having an acceptable salt form according to the invention, as described in WO 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO 2017 / 009804, WO2018 / 065921, WO2017 / 062581; WO2022 / 076618; WO2022 / 07 6620;WO2022 / 076621;WO2022 / 076622;WO2022 / 076624;WO2022 / 076625;WO2022 / 076626;WO2022 / 076627;WO2022 / 076628;International Publication No. 2022 / 076629;U.S. Provisional Patent Application Nos. 63 / 328,097 and 63 / 393,405;Phuan, P.-W. et al.J.Cyst.Fibros.2018,17(5),595-606;Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640,Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32,Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,EJet al.PLoS One 2019,14(12),e0223954, Smith,NJ,Solovay,CF,Pharm.Pat.Anal.2017, 6(4), 179-188, Kunzelmann, K. et al., Front.Pharmacol.2019, 10, 3; or Son, J.-H. et al., Eur.J.of Med.Chem.2020, 112888; and (d) at least one pharma- ceutically acceptable carrier.

[0150] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 50 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally, Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; and (c) at least one compound selected from acceptable salts thereof, as disclosed in WO 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO2017 / 062581; WO2022 / 076618; WO2022 / 0766 20;WO2022 / 076621;WO2022 / 076622;WO2022 / 076624;WO2022 / 076625;WO2022 / 076626;WO2022 / 076627;WO2022 / 076628;International Publication No. 2022 / 076629;U.S. Provisional Patent Application Nos. 63 / 328,097 and 63 / 393,405;Phuan, P.-W. et al.J.Cyst.Fibros.2018,17(5),595-606;Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640,Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32,Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,EJet al.PLoS One 2019,14(12),e0223954, Smith,NJ,Solovay,CF,Pharm.Pat.Anal.2017, 6(4), 179-188, Kunzelmann, K. et al., Front.Pharmacol.2019, 10, 3; or Son, J.-H. et al., Eur.J.of Med.Chem.2020, 112888; and (d) at least one pharma- ceutically acceptable carrier.

[0151] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 25 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg) of Compound I, its deuterated derivative, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; (c) optionally at least one compound selected from the group consisting of Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; Publication No. 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO2017 / 062581; WO2022 / 076618; WO2022 / 076620; WO2022 / 076621; WO2022 / 076622;WO2022 / 076624;WO2022 / 076625;WO2022 / 076626;WO2022 / 076627;WO2022 / 076628;WO 2022 / 076629;U.S. Provisional Patent Application Nos. 63 / 328,097 and 63 / 393,405;Phuan, P.-W. et al.J.Cyst.Fibros.2018,17(5),595-606;Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640,Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32,Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,EJet al.PLoS One 2019,14(12),e0223954, Smith,NJ,Solovay,CF,Pharm.Pat.Anal.2017,6(4),179-188,Kunzelmann,K.et al.,Front.Pharmacol.2019,10,3;or Son,J.-H.et al.,Eur.J.of Med.Chem. 2020, 112888; and (d) at least one pharma- ceutically acceptable carrier.

[0152] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 1 mg to about 15 mg (e.g., about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg) of Compound I, its deuterated derivative, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; (c) optionally at least one compound selected from the group consisting of compounds described in WO 2016 / 105485, U.S. Pat. No. 6,333,363, and the like; US Patent Application Publication No. 2016-0120841, US Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO2017 / 062581; WO2022 / 076618; WO2022 / 076620; WO2022 / 076621; WO2022 / 076 622;WO2022 / 076624;WO2022 / 076625;WO2022 / 076626;WO2022 / 076627;WO2022 / 076628;International Publication No. 2022 / 076629;U.S. Provisional Patent Application Nos. 63 / 328,097 and 63 / 393,405;Phuan, P.-W. et al.J.Cyst.Fibros.2018,17(5),595-606;Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640,Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32,Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,EJet al.PLoS One 2019,14(12),e0223954, Smith,NJ,Solovay,CF,Pharm.Pat.Anal.2017,6(4),179-188,Kunzelmann,K.et al.,Front.Pharmacol.2019,10,3;or Son,J.-H.et al.,Eur.J.of Med.Chem.2020,112888; and (d) at least one compound selected from the compounds disclosed in the above-mentioned US Pat. No. 6,200,112888; and (d) at least one pharma- ceutically acceptable carrier.

[0153] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 1.5 mg to about 14 mg (e.g., about 1.5 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 14 mg) of Compound I, its deuterated derivative, or any of the foregoing pharma- ceutical acceptable salts; (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutical acceptable salts thereof; (c) optionally at least one compound selected from the group consisting of compounds described in WO 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO2017 / 062581; WO2022 / 076618; WO2022 / 076620; WO2022 / 076621; WO2022 / 07 6622;WO2022 / 076624;WO2022 / 076625;WO2022 / 076626;WO2022 / 076627;WO2022 / 076628;WO 2022 / 076629;U.S. Provisional Patent Application Nos. 63 / 328,097 and 63 / 393,405;Phuan, P.-W. et al.J.Cyst.Fibros.2018,17(5),595-606;Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640,Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32,Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,EJet al.PLoS One 2019,14(12),e0223954, Smith,NJ,Solovay,CF,Pharm.Pat.Anal.2017,6(4),179-188,Kunzelmann,K.et al.,Front.Pharmacol.2019,10,3;or Son,J.-H.et al.,Eur.J.of Med.Chem.2020,112888; and (d) at least one compound selected from the compounds disclosed in the above-mentioned US Pat. No. 6,200,112888; and (d) at least one pharma- ceutically acceptable carrier.

[0154] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 4 mg to about 13 mg (e.g., about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally at least one selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; (c) optionally a compound selected from the group consisting of compounds disclosed in International Publication No. 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO2017 / 062581; WO2022 / 076618; WO2022 / 076620; WO202 2 / 076621;WO2022 / 076622;WO2022 / 076624;WO2022 / 076625;WO2022 / 076626;WO2022 / 076627;WO2022 / 076628;WO Publication No. 2022 / 076629;U.S. Provisional Patent Application Nos. 63 / 328,097 and 63 / 393,405;Phuan, P.-W. et al.J.Cyst.Fibros.2018,17(5),595-606;Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640,Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32,Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,EJet al.PLoS One 2019,14(12),e0223954, Smith,NJ,Solovay,CF,Pharm.Pat.Anal.2017,6(4),179-188,Kunzelmann,K.et al.,Front.Pharmacol.2019, 10, 3; or Son, J.-H. et al., Eur. J. of Med. Chem. 2020, 112888; and (d) at least one compound selected from the compounds disclosed in; and (d) at least one pharma- ceutically acceptable carrier.

[0155] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 8 mg to about 13 mg (e.g., about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, its deuterated derivative, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; (c) optionally at least one compound selected from the group consisting of Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO2017 / 062581; WO2022 / 076618; WO2022 / 076620; WO2022 / 076621; WO 2022 / 076622;WO2022 / 076624;WO2022 / 076625;WO2022 / 076626;WO2022 / 076627;WO2022 / 076628;WO Publication No. 2022 / 076629;U.S. Provisional Patent Application Nos. 63 / 328,097 and 63 / 393,405;Phuan, P.-W. et al.J.Cyst.Fibros.2018,17(5),595-606;Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640,Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32,Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,EJet al.PLoS One 2019,14(12),e0223954, Smith,NJ,Solovay,CF,Pharm.Pat.Anal.2017,6(4),179-188,Kunzelmann,K.et al.,Front.Pharmacol.2019,10,3;or Son,J.-H.et al.,Eur.J.of Med.Chem.2020,112888; and (d) at least one compound selected from the compounds disclosed in the above-mentioned US Pat. No. 6,200,112888; and (d) at least one pharma- ceutically acceptable carrier.

[0156] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; or (c) optionally at least one compound selected from PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV- 3748,ABBV-3903,ABBV-119,FDL-169,ARN5562,ARN21586,ARN22081,ARN22652,ARN23765,ARN2376 6, PTI-801, FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW251 (Icenticaftor), at least one compound selected from GLPG3067 / ABBV-3067 (navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039; and (d) at least one pharma- ceutically acceptable carrier.

[0157] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) a dose of about 0.1 mg to about 50 mg (e.g., about 0.1 mg, about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47 mg, about 50 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 82 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 100 mg, about 101 mg, about 102 mg, about 103 mg, about 104 mg, about 105 mg, about 106 mg, about 107 mg, about 108 mg, about 10 (b) at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; (c) optionally at least one compound selected from PTI-428, ASP-1 1,ABBV-2222,ABBV-2851,GLPG2737,ABBV-3221,ABBV-3748,ABBV-3903,ABBV-119,FDL-169,ARN5562,ARN21586, ARN22081, ARN22652, ARN23765, ARN23766, PTI-801, FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-245 1, at least one compound selected from QBW251 (Icenticaftor), GLPG3067 / ABBV-3067 (Navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039; and (d) at least one pharma- ceutically acceptable carrier.

[0158] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) a dose of about 0.25 mg to about 50 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg 50 mg or about 50 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; (c) optionally at least one compound selected from PTI-428, ASP-11,A BBV-2222,ABBV-2851,GLPG2737,ABBV-3221,ABBV-3748,ABBV-3903,ABBV-119,FDL-169,ARN5562,ARN21586,AR N22081, ARN22652, ARN23765, ARN23766, PTI-801, FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451 , QBW251 (Icenticaftor), GLPG3067 / ABBV-3067 (Navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039; and (d) at least one pharma- ceutically acceptable carrier.

[0159] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 25 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; or (c) optionally at least one compound selected from PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-32, 21,ABBV-3748,ABBV-3903,ABBV-119,FDL-169,ARN5562,ARN21586,ARN22081,ARN22652,ARN23765,A RN23766,PTI-801,FDL-176,PTI-808,GLPG1837 / ABBV-974,GLPG2451 / ABBV-2451,QBW251(Icenticaft or), GLPG3067 / ABBV-3067 (navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039; and (d) at least one pharmaceutically acceptable carrier.

[0160] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 1 mg to about 15 mg (e.g., about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; or (c) optionally at least one compound selected from PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV- 3903,ABBV-119,FDL-169,ARN5562,ARN21586,ARN22081,ARN22652,ARN23765,ARN23766,PTI-80 1,FDL-176,PTI-808,GLPG1837 / ABBV-974,GLPG2451 / ABBV-2451,QBW251(Icenticaftor),GLPG3 067 / ABBV-3067 (navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039; and (d) at least one pharma- ceutically acceptable carrier.

[0161] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 1.5 mg to about 14 mg (e.g., about 1.5 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 14 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; or (c) optionally at least one compound selected from PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-4221, ABBV-4222, ABBV-4223, ABBV-4224, ABBV-4225, ABBV-4226, ABBV-4227, ABBV-4228, ABBV-4229 ...9, ABBV-4229, ABBV-4229, ABBV-4229, ABBV-4229, ABBV-4229, ABBV-4229, ABBV-4229, ABBV-4229, ABBV-422 V-3903,ABBV-119,FDL-169,ARN5562,ARN21586,ARN22081,ARN22652,ARN23765,ARN23766,PTI- 801,FDL-176,PTI-808,GLPG1837 / ABBV-974,GLPG2451 / ABBV-2451,QBW251(Icenticaftor),GLPG 3067 / ABBV-3067 (navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039; and (d) at least one pharma- ceutically acceptable carrier.

[0162] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 4 mg to about 13 mg (e.g., about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutical acceptable salt of any of the foregoing; (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutical acceptable salts thereof; (c) optionally at least one compound selected from PTI-428, ASP-11, ABBV-2222, ABBV-2223, ABBV-2224, ABBV-2225, ABBV-2226, ABBV-2227, ABBV-2228, ABBV-2229 ... 851,GLPG2737,ABBV-3221,ABBV-3748,ABBV-3903,ABBV-119,FDL-169,ARN5562,ARN21586,ARN22081,ARN2 2652,ARN23765,ARN23766,PTI-801,FDL-176,PTI-808,GLPG1837 / ABBV-974,GLPG2451 / ABBV-2451,QBW251( at least one compound selected from Icenticaftor), GLPG3067 / ABBV-3067 (navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039; and (d) at least one pharmaceutically acceptable carrier.

[0163] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 8 mg to about 13 mg (e.g., about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof; (c) optionally at least one compound selected from PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748,ABBV-3903,ABBV-119,FDL-169,ARN5562,ARN21586,ARN22081,ARN22652,ARN23765,ARN 23766,PTI-801,FDL-176,PTI-808,GLPG1837 / ABBV-974,GLPG2451 / ABBV-2451,QBW251(Icenticafto r), GLPG3067 / ABBV-3067 (navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039; and (d) at least one pharma- ceutically acceptable carrier.

[0164] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or any of the foregoing pharma- ceutically acceptable salts; (b) Compound II, a deuterated derivative thereof, or any of the foregoing pharma- ceutically acceptable salts; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound III, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or any of the foregoing pharma- ceutically acceptable salts; (b) Compound III-d, a deuterated derivative thereof, or any of the foregoing pharma- ceutically acceptable salts; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or any of the foregoing pharma- ceutically acceptable salts; (b) Compound IV, a deuterated derivative thereof, or any of the foregoing pharma- ceutically acceptable salts; and (c) at least one pharma- ceutically acceptable carrier.In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or any of the foregoing pharma- ceutically acceptable salts; (b) Compound V, a deuterated derivative thereof, or any of the foregoing pharma- ceutically acceptable salts; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or any of the foregoing pharma- ceutically acceptable salts; (b) Compound VI, a deuterated derivative thereof, or any of the foregoing pharma- ceutically acceptable salts; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or any of the foregoing pharma- ceutically acceptable salts; (b) Compound VII, a deuterated derivative thereof, or any of the foregoing pharma- ceutically acceptable salts; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or any of the foregoing pharma- ceutically acceptable salts; (b) Compound VIII, a deuterated derivative thereof, or any of the foregoing pharma- ceutically acceptable salts; and (c) at least one pharma- ceutically acceptable carrier.In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or any of the foregoing pharma- ceutically acceptable salts; (b) Compound IX, a deuterated derivative thereof, or any of the foregoing pharma- ceutically acceptable salts; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound X, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0165] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.1 mg to about 50 mg (e.g., about 0.1 mg, about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.1 mg to about 50 mg (e.g., about 0.1 mg, about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound III, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.1 mg to about 50 mg (e.g., about 0.1 mg, about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound III-d, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier.In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.1 mg to about 50 mg (e.g., about 0.1 mg, about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound IV, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.1 mg to about 50 mg (e.g., about 0.1 mg, about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound V, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.1 mg to about 50 mg (e.g., about 0.1 mg, about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound VI, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier.In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.1 mg to about 50 mg (e.g., about 0.1 mg, about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound VII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.1 mg to about 50 mg (e.g., about 0.1 mg, about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound VIII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.1 mg to about 50 mg (e.g., about 0.1 mg, about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound IX, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier.In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.1 mg to about 50 mg (e.g., about 0.1 mg, about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound X, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0166] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 50 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 50 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound III, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 50 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound III-d, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier.In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 50 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound IV, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 50 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound V, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 50 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound VI, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier.In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 50 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound VII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 50 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound VIII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 50 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound IX, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier.In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 50 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound X, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0167] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 25 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 25 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound III, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 25 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound III-d, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 0.25 mg to about 25 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound IV, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier.In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 25 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound V, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 25 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound VI, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 25 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound VII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 25 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound VIII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier.In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 25 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound IX, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 25 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound X, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0168] In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1 mg to about 15 mg (e.g., about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1 mg to about 15 mg (e.g., about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound III, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1 mg to about 15 mg (e.g., about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound III-d, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1 mg to about 15 mg (e.g., about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound IV, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1 mg to about 15 mg (e.g., about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound V, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (c) at least one pharma- ceutically acceptable carrier.In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1 mg to about 15 mg (e.g., about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound VI, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1 mg to about 15 mg (e.g., about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound VII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1 mg to about 15 mg (e.g., about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound VIII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1 mg to about 15 mg (e.g., about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound IX, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1 mg to about 15 mg (e.g., about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound X, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0169] In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1.5 mg to about 14 mg (e.g., about 1.5 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 14 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1.5 mg to about 14 mg (e.g., about 1.5 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 14 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound III, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1.5 mg to about 14 mg (e.g., about 1.5 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 14 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound III-d, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1.5 mg to about 14 mg (e.g., about 1.5 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 14 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound IV, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (c) at least one pharma- ceutically acceptable carrier.In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1.5 mg to about 14 mg (e.g., about 1.5 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 14 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound V, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1.5 mg to about 14 mg (e.g., about 1.5 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 14 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound VI, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1.5 mg to about 14 mg (e.g., about 1.5 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 14 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound VII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1.5 mg to about 14 mg (e.g., about 1.5 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 14 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound VIII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (c) at least one pharma- ceutically acceptable carrier.In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1.5 mg to about 14 mg (e.g., about 1.5 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 14 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound IX, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1.5 mg to about 14 mg (e.g., about 1.5 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 14 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound X, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (c) at least one pharma- ceutically acceptable carrier.

[0170] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 4 mg to about 13 mg (e.g., about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 4 mg to about 13 mg (e.g., about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound III, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 4 mg to about 13 mg (e.g., about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound III-d, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier.In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 4 mg to about 13 mg (e.g., about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound IV, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 4 mg to about 13 mg (e.g., about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound V, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 4 mg to about 13 mg (e.g., about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound VI, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier.In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 4 mg to about 13 mg (e.g., about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound VII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 4 mg to about 13 mg (e.g., about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound VIII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 4 mg to about 13 mg (e.g., about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound IX, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier.In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 4 mg to about 13 mg (e.g., about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound X, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0171] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 8 mg to about 13 mg (e.g., about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 8 mg to about 13 mg (e.g., about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound III, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 8 mg to about 13 mg (e.g., about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound III-d, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 8 mg to about 13 mg (e.g., about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound IV, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier.In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 8 mg to about 13 mg (e.g., about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound V, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 8 mg to about 13 mg (e.g., about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound VI, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 8 mg to about 13 mg (e.g., about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound VII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 8 mg to about 13 mg (e.g., about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound VIII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier.In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 8 mg to about 13 mg (e.g., about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound IX, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 8 mg to about 13 mg (e.g., about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound X, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0172] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (c) Compound V, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (d) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (c) Compound VI, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (d) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (c) Compound VII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (d) at least one pharma- ceutically acceptable carrier.In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 5 mg to about 100 mg (e.g., about 7 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 30 mg to about 60 mg, or about 50 mg to about 80 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (c) Compound VIII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (d) at least one pharma- ceutically acceptable carrier.

[0173] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.1 mg to about 50 mg (e.g., about 0.1 mg, about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (c) Compound V, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (d) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.1 mg to about 50 mg (e.g., about 0.1 mg, about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (c) Compound VI, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (d) at least one pharma- ceutically acceptable carrier.In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.1 mg to about 50 mg (e.g., about 0.1 mg, about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (c) Compound VII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (d) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.1 mg to about 50 mg (e.g., about 0.1 mg, about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (c) Compound VIII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (d) at least one pharma- ceutically acceptable carrier.

[0174] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 50 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (c) Compound V, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (d) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 50 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (c) Compound VI, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (d) at least one pharma- ceutically acceptable carrier.In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 50 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (c) Compound VII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (d) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 50 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (c) Compound VIII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (d) at least one pharma- ceutically acceptable carrier.

[0175] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 25 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (c) Compound V, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (d) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 25 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (c) Compound VI, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (d) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 25 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (c) Compound VII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (d) at least one pharma- ceutically acceptable carrier.In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 0.25 mg to about 25 mg (e.g., about 0.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (c) Compound VIII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (d) at least one pharma- ceutically acceptable carrier.

[0176] In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1 mg to about 15 mg (e.g., about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (c) Compound V, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (d) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1 mg to about 15 mg (e.g., about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (c) Compound VI, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (d) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1 mg to about 15 mg (e.g., about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (c) Compound VII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (d) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1 mg to about 15 mg (e.g., about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (c) Compound VIII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (d) at least one pharma- ceutically acceptable carrier.

[0177] In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1.5 mg to about 14 mg (e.g., about 1.5 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 14 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (c) Compound V, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (d) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1.5 mg to about 14 mg (e.g., about 1.5 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 14 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (c) Compound VI, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (d) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1.5 mg to about 14 mg (e.g., about 1.5 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 14 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (c) Compound VII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (d) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise (a) about 1.5 mg to about 14 mg (e.g., about 1.5 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 14 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, (c) Compound VIII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof, and (d) at least one pharma- ceutically acceptable carrier.

[0178] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 4 mg to about 13 mg (e.g., about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (c) Compound V, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (d) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 4 mg to about 13 mg (e.g., about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (c) Compound VI, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (d) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 4 mg to about 13 mg (e.g., about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (c) Compound VII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (d) at least one pharma- ceutically acceptable carrier.In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 4 mg to about 13 mg (e.g., about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (c) Compound VIII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (d) at least one pharma- ceutically acceptable carrier.

[0179] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 8 mg to about 13 mg (e.g., about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (c) Compound V, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (d) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 8 mg to about 13 mg (e.g., about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (c) Compound VI, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (d) at least one pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 8 mg to about 13 mg (e.g., about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (c) Compound VII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (d) at least one pharma- ceutically acceptable carrier.In some embodiments, the pharmaceutical compositions provided herein comprise: (a) about 8 mg to about 13 mg (e.g., about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 13 mg) of Compound I, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (b) Compound II, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; (c) Compound VIII, a deuterated derivative thereof, or any pharma- ceutically acceptable salt thereof; and (d) at least one pharma- ceutically acceptable carrier.

[0180] Any pharmaceutical composition disclosed herein may include at least one pharma- ceutically acceptable carrier. In some embodiments, the at least one pharma- ceutically acceptable carrier is selected from a pharma- ceutically acceptable vehicle and a pharma- ceutically acceptable adjuvant. In some embodiments, the at least one pharma- ceutically acceptable is selected from a pharma- ceutically acceptable filler, disintegrant, surfactant, binder, and lubricant.

[0181] The pharmaceutical compositions described herein are useful for the treatment of cystic fibrosis and other CFTR-mediated diseases.

[0182] As mentioned above, the pharmaceutical composition disclosed herein may further include at least one pharma- ceutically acceptable carrier. The at least one pharma- ceutically acceptable carrier may be selected from adjuvants and vehicles. As used herein, at least one pharma- ceutically acceptable carrier includes any solvent, diluent, other liquid vehicle, dispersing aid, suspending aid, surfactant, isotonicity agent, thickener, emulsifier, preservative, solid binder, and lubricant suitable for the specific dosage form desired. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York disclose various carriers used in the formulation of pharmaceutical compositions and known techniques for their preparation. Except insofar as any conventional carrier is incompatible with the compounds of the present disclosure, for example, by imparting any undesirable biological effects or otherwise interacting in a deleterious manner with any other components of the pharmaceutical composition, its use is contemplated within the scope of the present disclosure.Non-limiting examples of suitable pharma- ceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates, glycine, sorbic acid, and potassium sorbate, etc.), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., carboxymethylcellulose, cellulose acetate, cellulose esters ... Examples of suitable lubricants include, but are not limited to, sodium hydroxide, ethylcellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository waxes), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (e.g., propylene glycol and polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions, non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), colorants, releasing agents, coating agents, sweetening agents, flavoring agents, fragrances, preservatives, and antioxidants. Non-Limiting Exemplary Embodiments 1. A method for treating cystic fibrosis comprising administering to a patient in need thereof about 5 mg to about 100 mg of Compound I: [ka] or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily. 2. The method of embodiment 1, wherein the method comprises administering from about 7 mg to about 90 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily. 3. The method of embodiment 1 or 2, wherein the method comprises administering from about 10 mg to about 80 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily. 4. The method according to any one of embodiments 1-3, wherein the method comprises administering from about 10 mg to about 40 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily. 5. The method according to any one of embodiments 1 to 3, wherein the method comprises administering from about 30 mg to about 60 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily. 6. The method according to any one of embodiments 1-3, wherein the method comprises administering from about 50 mg to about 80 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily. 7. The method according to any one of embodiments 1-3, wherein about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, or about 80 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, is administered daily. 8. The method of any one of embodiments 1-3, wherein about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, or about 80 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, is administered daily. 9. A method for treating cystic fibrosis, comprising administering to a patient in need thereof from about 0.1 mg to about 50 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily. 10. The method of embodiment 9, wherein the method comprises administering from about 0.25 mg to about 50 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily. 11. The method of embodiment 9 or 10, wherein the method comprises administering from about 0.25 mg to about 25 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily. 12. The method according to any one of embodiments 9 to 11, wherein the method comprises administering daily from about 1 mg to about 15 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 13. The method according to any one of embodiments 9 to 12, wherein the method comprises administering from about 1.5 mg to about 14 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily. 14. The method according to any one of embodiments 9 to 13, wherein the method comprises administering from about 4 mg to about 13 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily. 15. The method according to any one of embodiments 9 to 14, wherein the method comprises administering from about 8 mg to about 13 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily. 16. About 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7. 5mg, about 8mg, about 8.5mg, about 9, about 9.5mg, about 10mg, about 10.5mg, about 11mg, about 11.5mg, about 12mg, about 12.5mg, about 13mg, about 14mg, about The method of embodiment 9, wherein 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, is administered daily. 17. A method for treating cystic fibrosis comprising administering to a patient in need thereof about 5 mg to about 100 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily, wherein the patient is heterozygous and has one F508del mutation. 18. The method of embodiment 17, wherein the method comprises administering from about 7 mg to about 90 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily, and the patient is heterozygous and has one F508del mutation. 19. The method of embodiment 17 or embodiment 18, wherein the method comprises administering from about 10 mg to about 80 mg of compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily, and the patient is heterozygous and has one F508del mutation. 20. The method according to any one of embodiments 17-19, wherein the method comprises administering from about 10 mg to about 40 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily, and the patient is heterozygous and has one F508del mutation. 21. The method according to any one of embodiments 17-19, wherein the method comprises administering from about 30 mg to about 60 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily, and the patient is heterozygous and has one F508del mutation. 22. The method according to any one of embodiments 17-19, wherein the method comprises administering from about 50 mg to about 80 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily, and the patient is heterozygous and has one F508del mutation. 23. The method according to any one of embodiments 17-19, wherein about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, or about 80 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, is administered daily, and the patient is heterozygous and has one F508del mutation. 24. The method according to any one of embodiments 17-19, wherein about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, or about 80 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, is administered daily, and the patient is heterozygous and has one F508del mutation. 25. A method for treating cystic fibrosis, comprising administering to a patient in need thereof from about 0.1 mg to about 50 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, wherein the patient is heterozygous and has one F508del mutation. 26. The method of embodiment 25, wherein the method comprises administering from about 0.25 mg to about 50 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily, and the patient is heterozygous and has one F508del mutation. 27. The method of embodiment 25 or embodiment 26, wherein the method comprises administering from about 0.25 mg to about 25 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily, and the patient is heterozygous and has one F508del mutation. 28. The method according to any one of embodiments 25 to 27, wherein the method comprises administering from about 1 mg to about 15 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily, and the patient is heterozygous and has one F508del mutation. 29. The method according to any one of embodiments 25 to 28, wherein the method comprises administering from about 1.5 mg to about 14 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily, and the patient is heterozygous and has one F508del mutation. 30. The method according to any one of embodiments 25 to 29, wherein the method comprises administering from about 4 mg to about 13 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily, and the patient is heterozygous and has one F508del mutation. 31. The method according to any one of embodiments 25 to 30, wherein the method comprises administering from about 8 mg to about 13 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily, and the patient is heterozygous and has one F508del mutation. 32. About 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg , about 8.5mg, about 9, about 9.5mg, about 10mg, about 10.5mg, about 11mg, about 11.5mg, about 12mg, about 12.5mg, about 13mg, about 14mg, about 15mg, about 17.5mg, about 20 26. The method of embodiment 25, wherein about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, is administered daily, and the patient is heterozygous and has an F508del mutation. 33. The method according to any one of embodiments 1-33, wherein compound I or a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, is administered once daily as a single dose. 34. The method according to any one of embodiments 1-33, wherein compound I or a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, is administered twice daily. 35. The method of any of embodiments 1-34, further comprising administering one or more additional therapeutic agents. 36. The method of embodiment 35, wherein the one or more additional therapeutic agents comprises a compound having CFTR modulating activity, or a deuterated derivative or a pharma- ceutically acceptable salt thereof. 37. The method of embodiment 35 or 36, wherein the one or more additional therapeutic agents comprises a CFTR corrector. 38. One or more additional therapeutic agents (a) (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (compound II): [ka] (b) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound IV): [ka] (c) N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (compound V): [ka] (d) N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (compound VI): [ka] (e) (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound VII): [ka] (f) (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hexan-5-yl}-9-oxa-2λ6-thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione (Compound VIII): [ka] (g) N-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound IX): [ka] (h) N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound X): [ka] and deuterated derivatives thereof, and pharma- ceutically acceptable salts thereof. 39. The method of any one of embodiments 35-38, wherein the one or more additional therapeutic agents comprises at least one compound selected from PTI-428, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, ABBV-2851, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, ARN23766, and PTI-801. 40. The method of any one of embodiments 35-39, wherein the one or more additional therapeutic agents comprises a CFTR enhancer. 41. The method of any one of embodiments 35-40, wherein the one or more additional therapeutic agents comprises ASP-11. 42. The method of any one of embodiments 35-41, wherein the one or more additional therapeutic agents comprises a CFTR enhancer. 43. One or more additional therapeutic agents (a) N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (compound III): [ka] (b) N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (compound III-d): [ka] and deuterated derivatives thereof, and pharma- ceutically acceptable salts thereof. 44. The method of any one of embodiments 35-43, wherein the one or more additional therapeutic agents comprises at least one compound selected from FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW251 (Icenticaftor), GLPG3067 / ABBV-3067 (navocaftor), and ABBV-191. 45. The method of any one of embodiments 35-44, wherein the one or more additional therapeutic agents comprises a CFTR amplifier. 46. ​​The method of any one of embodiments 35-45, wherein the one or more additional therapeutic agents comprises PTI-428. 47. The method of any one of embodiments 35-46, wherein the one or more additional therapeutic agents comprises a CFTR readthrough agent. 48. The method of any one of embodiments 35-46, wherein the one or more additional therapeutic agents comprises ELX-02. 49. The method of any one of embodiments 35-48, wherein the one or more additional therapeutic agents comprises a nucleic acid therapy. 50. The pharmaceutical composition of any one of embodiments 35-49, wherein the one or more additional therapeutic agents comprises at least one agent selected from MRT5005, Lunar-CF, and RCT223. 51. The method of any one of embodiments 35-50, wherein the one or more additional therapeutic agents comprises an ENaC inhibitor. 52. The pharmaceutical composition of any one of embodiments 35-51, wherein the one or more additional therapeutic agents comprises amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5 Rx, BI 1265162, or ARO-ENaC1001. 53. The method of any one of embodiments 35-52, wherein the one or more additional therapeutic agents comprises a TMEM16A modulating agent. 54. The method of any one of embodiments 35-53, wherein the one or more additional therapeutic agents comprises ETD002. 55. The method of any one of embodiments 35-54, wherein the one or more additional therapeutic agents comprises a GPR39 agonist. 56. The method of any one of embodiments 35-55, wherein the one or more additional therapeutic agents comprises DS-1039. 57. A pharmaceutical composition comprising about 5 mg to about 100 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 58. The pharmaceutical composition according to embodiment 57, wherein the composition comprises from about 7 mg to about 90 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 59. The pharmaceutical composition according to embodiment 57 or embodiment 58, wherein the composition comprises from about 10 mg to about 80 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 60. The pharmaceutical composition according to any one of embodiments 57-59, wherein the composition comprises from about 10 mg to about 40 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 61. The pharmaceutical composition according to any one of embodiments 57-59, wherein the composition comprises from about 30 mg to about 60 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 62. The pharmaceutical composition according to any one of embodiments 57-59, wherein the composition comprises from about 50 mg to about 80 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 63. The pharmaceutical composition according to any one of embodiments 57-59, wherein the composition comprises about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, or about 80 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 64. The pharmaceutical composition according to any one of embodiments 57-59, wherein the composition comprises about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, or about 80 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 65. A pharmaceutical composition comprising about 0.1 mg to about 50 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 66. The pharmaceutical composition according to embodiment 65, wherein the composition comprises from about 0.25 mg to about 50 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 67. The pharmaceutical composition according to embodiment 65 or embodiment 66, wherein the composition comprises from about 0.25 mg to about 25 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 68. The pharmaceutical composition according to any one of embodiments 65 to 67, wherein the composition comprises from about 1 mg to about 15 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 69. The pharmaceutical composition according to any one of embodiments 65 to 68, wherein the composition comprises from about 1.5 mg to about 14 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 70. The pharmaceutical composition according to any one of embodiments 65-69, wherein the composition comprises from about 4 mg to about 13 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 71. The pharmaceutical composition according to any one of embodiments 65 to 70, wherein the composition comprises from about 8 mg to about 13 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 72. The composition comprises about 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 66. The pharmaceutical composition of embodiment 65, comprising about 1 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 73. The pharmaceutical composition according to any one of embodiments 57-72, wherein the composition further comprises one or more additional therapeutic agents. 74. The pharmaceutical composition according to embodiment 73, wherein the one or more additional therapeutic agents comprise a compound having CFTR modulating activity or a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 75. The pharmaceutical composition according to embodiment 73 or embodiment 74, wherein the one or more additional therapeutic agents comprises a CFTR corrector. 76. One or more additional therapeutic agents (a) Compound II, (b) compound IV, (c) compound V, (d) compound VI, (e) compound VII, (f) compound VIII, (g) Compound IX, and (i) The pharmaceutical composition according to any one of embodiments 73 to 75, comprising a compound selected from compound X, and its deuterated derivatives, and pharma- ceutically acceptable salts thereof. 77. The pharmaceutical composition of any one of embodiments 73 to 76, wherein the one or more additional therapeutic agents comprises at least one compound selected from PTI-428, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, ABBV-2851, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, ARN23766, and PTI-801. 78. The pharmaceutical composition of any one of embodiments 73-77, wherein the one or more additional therapeutic agents comprises a CFTR enhancer potentiator. 79. The pharmaceutical composition according to any one of embodiments 73 to 78, wherein the one or more additional therapeutic agents comprises ASP-11. 80. The pharmaceutical composition of any one of embodiments 73-79, wherein the one or more additional therapeutic agents comprises a CFTR enhancer. 81. The pharmaceutical composition according to any one of embodiments 73 to 80, wherein the one or more additional therapeutic agents comprises a compound selected from compound III, compound III-d, and deuterated derivatives thereof, and pharma- ceutically acceptable salts thereof. 82. The pharmaceutical composition of any one of embodiments 73 to 81, wherein the one or more additional therapeutic agents comprises at least one compound selected from FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW251 (Icenticaftor), GLPG3067 / ABBV-3067 (navocaftor), and ABBV-191. 83. The pharmaceutical composition of any one of embodiments 73-82, wherein the one or more additional therapeutic agents comprises a CFTR amplifier. 84. The pharmaceutical composition according to any one of embodiments 73-83, wherein the one or more additional therapeutic agents comprises PTI-428. 85. The pharmaceutical composition of any one of embodiments 73-84, wherein the one or more additional therapeutic agents comprises a CFTR read-through agent. 86. The pharmaceutical composition according to any one of embodiments 73-85, wherein the one or more additional therapeutic agents comprises ELX-02. 87. The pharmaceutical composition of any one of embodiments 73-86, wherein the one or more additional therapeutic agents comprises a nucleic acid therapy. 88. The pharmaceutical composition of any one of embodiments 73-87, wherein the one or more additional therapeutic agents comprises at least one agent selected from MRT5005, Lunar-CF, and RCT223. 89. The pharmaceutical composition according to any one of embodiments 73-88, wherein the one or more additional therapeutic agents comprises an ENaC inhibitor. 90. The one or more additional therapeutic agents are amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5 Rx, BI 1265162, or A pharmaceutical composition according to any one of embodiments 73 to 89, comprising ARO-ENaC1001. 91. The pharmaceutical composition of any one of embodiments 73-90, wherein the one or more additional therapeutic agents comprises a TMEM16A modulating agent. 92. The pharmaceutical composition according to any one of embodiments 73-91, wherein the one or more additional therapeutic agents comprises ETD002. 93. The pharmaceutical composition according to any one of embodiments 73-92, wherein the one or more additional therapeutic agents comprises a GPR39 agonist. 94. The pharmaceutical composition according to any one of embodiments 73-93, wherein the one or more additional therapeutic agents comprises DS-1039. 95. Compound I or a deuterated derivative thereof or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition according to any one of embodiments 57 to 94, for use in a method for treating cystic fibrosis in a patient, comprising daily administration of about 5 mg to about 100 mg of compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutical acceptable salt thereof. 96. The compound, deuterated derivative, salt, or composition for use according to embodiment 95, wherein the method comprises daily administration of about 7 mg to about 90 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 97. The compound, deuterated derivative, salt, or composition for use according to embodiment 95 or embodiment 96, wherein the method comprises daily administration of about 10 mg to about 80 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 98. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 95 to 97, wherein the method comprises administering daily from about 10 mg to about 40 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 99. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 95 to 97, wherein the method comprises administering daily about 30 mg to about 60 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 100. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 95 to 97, wherein the method comprises administering daily from about 50 mg to about 80 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 101. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 95-97, wherein the method comprises daily administration of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, or about 80 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 102. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 95-97, wherein the method comprises daily administration of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, or about 80 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 103. Compound I or a deuterated derivative thereof or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition according to any one of embodiments 57-94, for use in a method for treating cystic fibrosis in a patient, comprising administering daily from about 0.1 mg to about 50 mg of compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutical acceptable salt thereof. 104. The compound, deuterated derivative, salt, or composition for use according to embodiment 103, wherein the method comprises administering daily from about 0.25 mg to about 50 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 105. The compound, deuterated derivative, salt, or composition for use according to embodiment 103 or embodiment 104, wherein the method comprises daily administration of about 0.25 mg to about 25 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 106. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 103 to 105, wherein the method comprises administering daily from about 1 mg to about 15 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 107. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 103 to 106, wherein the method comprises administering daily from about 1.5 mg to about 14 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 108. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 103 to 107, wherein the method comprises administering daily from about 4 mg to about 13 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 109. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 103 to 108, wherein the method comprises administering daily from about 8 mg to about 13 mg of compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 110. The method comprises administering to a subject a dose of about 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 17.5 mg 104. The compound, deuterated derivative, salt, or composition for use according to embodiment 103, comprising daily administration of about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 111. Compound I or a deuterated derivative thereof or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition according to any one of embodiments 57 to 94, for use in a method for treating cystic fibrosis in a patient, the method comprising daily administration of about 5 mg to about 100 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutical acceptable salt thereof, wherein the patient is heterozygous and has one F508del mutation. 112. The compound, deuterated derivative, salt or composition for use according to embodiment 111, wherein the method comprises administering daily from about 7 mg to about 90 mg of compound I or an equivalent amount of a deuterated derivative thereof or a pharma- ceutically acceptable salt thereof, and the patient is heterozygous and has one F508del mutation. 113. The compound, deuterated derivative, salt or composition for use according to embodiment 111 or embodiment 112, wherein the method comprises daily administration of about 10 mg to about 80 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, and the patient is heterozygous and has one F508del mutation. 114. The compound, deuterated derivative, salt or composition for use according to any one of embodiments 111 to 113, wherein the method comprises daily administration of about 10 mg to about 40 mg of compound I or an equivalent amount of a deuterated derivative thereof or a pharma- ceutically acceptable salt thereof, and the patient is heterozygous and has one F508del mutation. 115. The compound, deuterated derivative, salt or composition for use according to any one of embodiments 111 to 113, wherein the method comprises administering daily about 30 mg to about 60 mg of compound I or an equivalent amount of a deuterated derivative thereof or a pharma- ceutically acceptable salt thereof, and the patient is heterozygous and has one F508del mutation. 116. The compound, deuterated derivative, salt or composition for use according to any one of embodiments 111 to 113, wherein the method comprises administering daily about 50 mg to about 80 mg of compound I or an equivalent amount of a deuterated derivative thereof or a pharma- ceutically acceptable salt thereof, and the patient is heterozygous and has one F508del mutation. 117. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 111 to 113, wherein the method comprises administering daily about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, or about 80 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, and wherein the patient is heterozygous and has one F508del mutation. 118. The compound, deuterated derivative, salt or composition for use according to any one of embodiments 111 to 113, wherein the method comprises administering about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, or about 80 mg of compound I or an equivalent amount of a deuterated derivative thereof or a pharma- ceutically acceptable salt thereof, and the patient is heterozygous and has one F508del mutation. 119. Compound I or a deuterated derivative thereof or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition according to any one of embodiments 57 to 94, for use in a method for treating cystic fibrosis in a patient, the method comprising daily administration of about 0.1 mg to about 50 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutical acceptable salt thereof, wherein the patient is heterozygous and has one F508del mutation. 120. The compound, deuterated derivative, salt, or composition for use according to embodiment 119, wherein the method comprises daily administration of about 0.25 mg to about 50 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, and the patient is heterozygous and has one F508del mutation. 121. The compound, deuterated derivative, salt or composition for use according to embodiment 119 or embodiment 120, wherein the method comprises daily administration of about 0.25 mg to about 25 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, and the patient is heterozygous and has one F508del mutation. 122. The compound, deuterated derivative, salt or composition for use according to any one of embodiments 119 to 121, wherein the method comprises daily administration of about 1 mg to about 15 mg of compound I or an equivalent amount of a deuterated derivative thereof or a pharma- ceutically acceptable salt thereof, and the patient is heterozygous and has one F508del mutation. 123. The compound, deuterated derivative, salt or composition for use according to any one of embodiments 119 to 122, wherein the method comprises daily administration of about 1.5 mg to about 14 mg of compound I or an equivalent amount of a deuterated derivative thereof or a pharma- ceutically acceptable salt thereof, and the patient is heterozygous and has one F508del mutation. 124. The compound, deuterated derivative, salt or composition for use according to any one of embodiments 119 to 123, wherein the method comprises administering daily from about 4 mg to about 13 mg of compound I or an equivalent amount of a deuterated derivative thereof or a pharma- ceutically acceptable salt thereof, and the patient is heterozygous and has one F508del mutation. 125. The compound, deuterated derivative, salt or composition for use according to any one of embodiments 119 to 124, wherein the method comprises administering daily from about 8 mg to about 13 mg of compound I or an equivalent amount of a deuterated derivative thereof or a pharma- ceutically acceptable salt thereof, and the patient is heterozygous and has one F508del mutation. 126. The method comprises administering to a subject a dose of about 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, The compound, deuterated derivative, salt or composition for use according to embodiment 119, comprising daily administration of about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, wherein the patient is heterozygous and has one F508del mutation. 127. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 95 to 127, wherein the method comprises administering compound I or a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, once daily as a single dose. 128. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 95 to 127, wherein the method comprises administering compound I or a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, twice daily. 129. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 95-129, wherein the method further comprises administering one or more additional therapeutic agents. 130. The compound, deuterated derivative, salt, or composition for use according to embodiment 129, wherein the one or more additional therapeutic agents comprises a compound having CFTR modulating activity or a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 131. The compound, deuterated derivative, salt, or composition for use according to embodiment 129 or embodiment 130, wherein the one or more additional therapeutic agents comprises a CFTR corrector. 132. One or more additional therapeutic agents (a) Compound II, (b) compound IV, (c) compound V, (d) compound VI, (e) compound VII, (f) compound VIII, (g) Compound IX, and (h) A compound, deuterated derivative, salt, or composition for use according to any one of embodiments 129-131, comprising a compound selected from compound X, and deuterated derivatives thereof, and pharma- ceutically acceptable salts of any of the foregoing. 133. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 129 to 132, wherein the one or more additional therapeutic agents comprises at least one compound selected from PTI-428, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, ABBV-2851, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, ARN23766, and PTI-PTI-801. 134. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 129-133, wherein the one or more additional therapeutic agents comprises a CFTR potentiator. 135. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 129-134, wherein the one or more additional therapeutic agents comprises ASP-11. 136. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 129-135, wherein the one or more additional therapeutic agents comprises a CFTR enhancer. 137. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 129-136, wherein the one or more additional therapeutic agents comprises a compound selected from compound III, compound III-d, and pharma- ceutically acceptable salts thereof, and deuterated derivatives thereof. 138. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 129-137, wherein the one or more additional therapeutic agents comprises at least one compound selected from FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW251 (Icenticaftor), GLPG3067 / ABBV-3067 (navocaftor), and ABBV-191. 139. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 129-138, wherein the one or more additional therapeutic agents comprises a CFTR amplifier. 140. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 129-139, wherein the one or more additional therapeutic agents comprises PTI-428. 141. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 129-140, wherein the one or more additional therapeutic agents comprises a read-through agent. 142. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 129-141, wherein the one or more additional therapeutic agents comprises ELX-02. 143. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 129-142, wherein the one or more additional therapeutic agents comprises a nucleic acid therapy. 144. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 129-143, wherein the one or more additional therapeutic agents comprises at least one agent selected from MRT5005, Lunar-CF, and RCT223. 145. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 129-144, wherein the one or more additional therapeutic agents comprises an ENaC inhibitor. 146. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 129 to 145, wherein the one or more additional therapeutic agents comprise amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5 Rx, BI 1265162, and ARO-ENaC1001. 147. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 129-146, wherein the one or more additional therapeutic agents comprises a TMEM16A modulating agent. 148. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 129-147, wherein the one or more additional therapeutic agents comprises ETD002. 149. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 129-148, wherein the one or more additional therapeutic agents comprises a GPR39 agonist. 150. The compound, deuterated derivative, salt, or composition for use according to any one of embodiments 129-149, wherein the one or more additional therapeutic agents comprises DS-1039. 151. Use of compound I or an equivalent amount of its deuterated derivative or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to any one of embodiments 57-94, in the manufacture of a medicament for treating cystic fibrosis, wherein the medicament comprises from about 5 mg to about 100 mg of compound I or an equivalent amount of its deuterated derivative or a pharma- ceutically acceptable salt thereof. 152. The use according to embodiment 151, wherein the medicament comprises from about 7 mg to about 90 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 153. The use according to embodiment 151 or embodiment 152, wherein the medicament comprises from about 10 mg to about 80 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 154. The use according to any one of embodiments 151 to 153, wherein the medicament comprises from about 10 mg to about 40 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 155. The use according to any one of embodiments 151 to 153, wherein the medicament comprises from about 30 mg to about 60 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 156. The use according to any one of embodiments 151 to 153, wherein the medicament comprises from about 50 mg to about 80 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 157. The use according to any one of embodiments 151 to 153, wherein the medicament comprises administering about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, or about 80 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 158. The use according to any one of embodiments 151 to 153, wherein the medicament comprises daily administration of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, or about 80 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 159. Use of compound I or a deuterated derivative thereof or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition according to any one of embodiments 57 to 94, in the manufacture of a medicament for treating cystic fibrosis, wherein the medicament comprises from about 0.1 mg to about 50 mg of compound I or an equivalent amount of a deuterated derivative thereof or a pharma- ceutical acceptable salt thereof. 160. The use according to embodiment 159, wherein the medicament comprises from about 0.25 mg to about 50 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 161. The use according to embodiment 159 or embodiment 160, wherein the medicament comprises from about 0.25 mg to about 25 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 162. The use according to any one of embodiments 159-161, wherein the medicament comprises from about 1 mg to about 15 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 163. The use according to any one of embodiments 159-162, wherein the medicament comprises from about 1.5 mg to about 14 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 164. The use according to any one of embodiments 159-162, wherein the medicament comprises from about 4 mg to about 13 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 165. The use according to any one of embodiments 159 to 163, wherein the medicament comprises from about 8 mg to about 13 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 166. The drug is about 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, The use of embodiment 159, comprising administering about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 167. The use according to any one of embodiments 151 to 166, wherein the medicament is formulated to be administered once a day as a single dose. 168. The use according to any one of embodiments 151 to 166, wherein the medicament is formulated to be administered twice a day. 169. The use according to any one of embodiments 151 to 168, wherein the medicament is formulated to be administered in combination with one or more additional therapeutic agents. 170. The use according to embodiment 169, wherein the one or more additional therapeutic agents comprise a compound having CFTR modulating activity or a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof. 171. The use according to embodiment 169 or embodiment 170, wherein the one or more additional therapeutic agents comprises a CFTR corrector. 172. One or more additional therapeutic agents (a) Compound II, (b) compound IV, (c) compound V, (d) compound VI, (e) compound VII, (f) compound VIII, (g) Compound IX, and (h) The method according to any one of embodiments 169-171, comprising a compound selected from compound X, and its deuterated derivatives and pharma- ceutically acceptable salts thereof. 173. The use of any one of embodiments 169 to 172, wherein the one or more additional therapeutic agents comprises at least one compound selected from PTI-428, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, ABBV-2851, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, ARN23766, and PTI-801. 174. The use according to any one of embodiments 169 to 173, wherein the one or more additional therapeutic agents comprises a CFTR enhancer potentiator. 175. The use according to any one of embodiments 169 to 174, wherein the one or more additional therapeutic agents comprises ASP-11. 176. The use according to any one of embodiments 169-175, wherein the one or more additional therapeutic agents comprises a CFTR enhancer. 177. The use according to any one of embodiments 169 to 176, wherein the one or more additional therapeutic agents comprise a compound selected from compound III, compound III-d, and deuterated derivatives thereof, and pharma- ceutically acceptable salts thereof. 178. The use according to any one of embodiments 169 to 177, wherein the one or more additional therapeutic agents comprises at least one compound selected from FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW251 (Icenticaftor), GLPG3067 / ABBV-3067 (navocaftor), and ABBV-191. 179. The use according to any one of embodiments 169 to 178, wherein the one or more additional therapeutic agents comprises a CFTR amplifier. 180. The use according to any one of embodiments 169-179, wherein the one or more additional therapeutic agents comprises PTI-428. 181. The use according to any one of embodiments 169-180, wherein the one or more additional therapeutic agents comprises a CFTR read-through agent. 182. The use according to any one of embodiments 169-181, wherein the one or more additional therapeutic agents comprises ELX-02. 183. The use according to any one of embodiments 169 to 182, wherein the one or more additional therapeutic agents comprise a nucleic acid therapy. 184. The use according to any one of embodiments 169 to 183, wherein the one or more additional therapeutic agents comprises at least one agent selected from MRT5005, Lunar-CF, and RCT223. 185. The use according to any one of embodiments 169 to 184, wherein the one or more additional therapeutic agents comprises an ENaC inhibitor. 186. The use of any one of embodiments 169 to 185, wherein the one or more additional therapeutic agents comprise amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5 Rx, BI 1265162, or ARO-ENaC1001. 187. The use according to any one of embodiments 169-186, wherein the one or more additional therapeutic agents comprises a TMEM16A modulating agent. 188. The use according to any one of embodiments 169 to 187, wherein the one or more additional therapeutic agents comprises ETD002. 189. The use according to any one of embodiments 169-188, wherein the one or more additional therapeutic agents comprises a GPR39 agonist. 190. The use according to any one of embodiments 169 to 189, wherein the one or more additional therapeutic agents comprises DS-1039. EXAMPLES

[0183] Abbreviation AE: Adverse event AUC: area under the concentration versus time curve AUC0-∞: AUC extrapolated from the time of administration to infinity AUC0-24 hours: AUC from time of administration to 24 hours AUC0-tlast: AUC from time of administration to the final measurable concentration Boc anhydride ((Boc)2O): Di-tert-butyl dicarbonate Boc: tert-butyloxycarbonyl Cmax: maximum observed concentration DCE: 1,2-dichloroethane DDI: Drug-drug interactions DIAD: Diisopropyl azodicarboxylate DMSO: Dimethyl sulfoxide DMSO-d6: Dimethylsulfoxide-d6 EtOAc: ethyl acetate ESI-MS: Electrospray ionization mass spectrometry FIH: First in Human (trial) HBE: Human bronchial epithelium (cells) HPLC: High-performance ...

Claims

1. A method for treating cystic fibrosis comprising administering to a patient in need thereof from 0.1 mg to about 50 mg of Compound I: 【Chemical 36】 or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily.

2. 10. The method of claim 1, wherein the method comprises daily administration of about 0.25 mg to about 50 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof.

3. 3. The method of claim 1 or claim 2, wherein the method comprises daily administration of about 0.25 mg to about 25 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof.

4. 4. The method of any one of claims 1 to 3, wherein the method comprises daily administration of about 1 mg to about 15 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof.

5. 5. The method of any one of claims 1 to 4, wherein the method comprises daily administration of about 1.5 mg to about 14 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof.

6. 6. The method of any one of claims 1 to 5, wherein the method comprises daily administration of about 4 mg to about 13 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof.

7. 7. The method of any one of claims 1 to 6, wherein the method comprises daily administration of about 8 mg to about 13 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof.

8. 10. The method of claim 1, wherein the method comprises administering from about 10 mg to about 40 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily.

9. About 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 m g, about 8 mg, about 8.5 mg, about 9, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 1 2. The method of claim 1, wherein 5 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, is administered daily.

10. 1. A method of treating cystic fibrosis comprising administering to a patient in need thereof from about 0.1 mg to about 50 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily, said patient being heterozygous and carrying an F508del mutation.

11. 11. The method of claim 10, wherein the method comprises administering from about 0.25 mg to about 50 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily, and the patient is heterozygous and carries an F508del mutation.

12. 12. The method of claim 10 or claim 11, wherein the method comprises administering from about 0.25 mg to about 25 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily, and the patient is heterozygous and carries an F508del mutation.

13. 13. The method of any one of claims 10 to 12, wherein the method comprises administering from about 1 mg to about 15 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily, and the patient is heterozygous and carries an F508del mutation.

14. 14. The method of any one of claims 10 to 13, wherein the method comprises administering from about 1.5 mg to about 14 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily, and the patient is heterozygous and carries an F508del mutation.

15. 15. The method of any one of claims 10 to 14, wherein the method comprises administering from about 4 mg to about 13 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily, and the patient is heterozygous and carries an F508del mutation.

16. 16. The method of any one of claims 10 to 15, wherein the method comprises administering from about 8 mg to about 13 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, daily, and the patient is heterozygous and carries an F508del mutation.

17. 11. The method of claim 10, wherein the method comprises daily administration of about 10 mg to about 40 mg of Compound I, or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof.

18. About 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5mg, about 9, about 9.5mg, about 10mg, about 10.5mg, about 11mg, about 11.5mg, about 12mg, about 12.5mg, about 13mg, about 14mg, about 15mg, about 17.5mg, about 20mg 11. The method of claim 10, wherein about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, is administered daily, and the patient is heterozygous and has an F508del mutation.

19. 19. The method of any one of claims 1 to 18, wherein Compound I or a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, is administered once daily as a single dose.

20. 19. The method of any one of claims 1 to 18, wherein Compound I or a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, is administered twice daily.

21. The method of any one of claims 1 to 20, further comprising administering one or more additional therapeutic agents.

22. 22. The method of claim 21, wherein the one or more additional therapeutic agents comprise a compound having CFTR modulating activity or a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof.

23. 23. The method of claim 21 or claim 22, wherein the one or more additional therapeutic agents comprises a CFTR correcting agent.

24. the one or more additional therapeutic agents (a) (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound II): 【Chemical 37】 (b) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound IV): 【Chemical Formula 38】 (c) N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound V): 【Chemical Formula 39】 (d) N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound VI). 【Chemistry 40】 (e) (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound VII): 【Chemistry 41】 (f) (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hexan-5-yl}-9-oxa-2λ6-thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione (Compound VIII): 【Chemistry 42】 (g) N-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound IX): 【Chemistry 43】 (h) N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound X). 【Chemistry 44】 and deuterated derivatives thereof and pharma- ceutically acceptable salts thereof.

25. The method of any one of claims 21 to 24, wherein the one or more additional therapeutic agents comprises a CFTR enhancer.

26. the one or more additional therapeutic agents (a) N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (Compound III): 【Chemistry 45】 (b) N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (compound III-d): 【Chemistry 46】 and deuterated derivatives thereof and pharma-ceutically acceptable salts thereof.

27. A pharmaceutical composition comprising from about 0.1 mg to about 50 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof.

28. 28. The pharmaceutical composition of claim 27, wherein the composition comprises from about 0.25 mg to about 50 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof.

29. 29. The pharmaceutical composition of claim 27 or claim 28, wherein the composition comprises about 0.25 mg to about 25 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof.

30. 30. The pharmaceutical composition of any one of claims 27 to 29, wherein the composition comprises from about 1 mg to about 15 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof.

31. 31. The pharmaceutical composition of any one of claims 27 to 30, wherein the composition comprises from about 1.5 mg to about 14 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof.

32. 32. The pharmaceutical composition of any one of claims 27 to 31, wherein the composition comprises from about 4 mg to about 13 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof.

33. 33. The pharmaceutical composition of any one of claims 27 to 32, wherein the composition comprises from about 8 mg to about 13 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof.

34. 28. The pharmaceutical composition of claim 27, wherein the composition comprises about 10 mg to about 40 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof.

35. The composition may comprise about 0.1 mg, about 0.25 mg, about 1 mg, about 1.5 mg, about 2.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg 28. The pharmaceutical composition of claim 27, comprising about 1 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, or about 50 mg of Compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof.

36. The pharmaceutical composition of any one of claims 27 to 35, wherein the composition further comprises one or more additional therapeutic agents.

37. 37. The pharmaceutical composition of claim 36, wherein the one or more additional therapeutic agents comprise a compound having CFTR modulating activity or a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof.

38. 38. The pharmaceutical composition of claim 36 or claim 37, wherein the one or more additional therapeutic agents comprises a CFTR correcting agent.

39. the one or more additional therapeutic agents (h) Compound II, (i) Compound IV, (j) compound V, (k) compound VI, (l) Compound VII, (m) compound VIII, (n) compound IX, and 39. The pharmaceutical composition of any one of claims 36 to 38, comprising a compound selected from (i) compound X, and its deuterated derivatives and pharma- ceutically acceptable salts thereof.

40. The pharmaceutical composition of any one of claims 36 to 39, wherein the one or more additional therapeutic agents comprises a CFTR enhancer.

41. 41. The pharmaceutical composition of any one of claims 36-40, wherein the one or more additional therapeutic agents comprise a compound selected from compound III, compound III-d, and deuterated derivatives thereof, and pharma- ceutically acceptable salts thereof.

42. 42. Compound I or a deuterated derivative thereof or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition according to any one of claims 27 to 41, for use in a method for treating cystic fibrosis in a patient comprising daily administration of about 0.1 mg to about 50 mg of compound I or an equivalent amount of a deuterated derivative thereof, or a pharma- ceutical acceptable salt thereof.

43. 42. Use of compound I or a deuterated derivative thereof or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition according to any one of claims 27 to 41, in the manufacture of a medicament for treating cystic fibrosis, wherein the medicament comprises from about 0.1 mg to about 50 mg of compound I or an equivalent amount of a deuterated derivative thereof or a pharma- ceutical acceptable salt thereof.

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