How to Treat Cystic Fibrosis

Abstract

The present disclosure provides a method 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, e.g., administering about 1 mg to about 400 mg of Compound (I). 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. 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.

Description

[Technical field]

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 342,418, filed May 16, 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. Despite 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 membrane anion secretion, causing an imbalance in ion and fluid transport. The resulting reduced 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, 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 define them as disease-causing. The most common disease-causing mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, commonly referred to as the F508del mutation. This mutation occurs in many cases of cystic fibrosis and is associated with severe disease.

[0006] CFTR is a cAMP / ATP-mediated anion channel expressed in a variety of cell types, including absorptive and secretory epithelial cells, where it controls the flow of anions 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 consisting 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 a large, polar regulatory (R) domain to multiple phosphorylation sites that control channel activity and cellular trafficking.

[0007] Chloride transport is mediated by the coordinated activity of ENaC (epithelial sodium channel) and CFTR present on the apical membrane, and Na + -K + -ATPase pump and Cl -Secondary active transport of chloride from the luminal side leads to accumulation of intracellular chloride, which is then transported through the Cl - It can passively leave the cell through channels, resulting in vectorial transport. + / 2Cl - / K + Cotransporter, Na + -K + -ATPase pump and basolateral membrane K on the basolateral surface + The channel, and the positioning of CFTR on the luminal side, regulate 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. More recently, several CFTR modulators have been identified. These modulators are considered, for example, as potentiators, correctors, potentiators / co-potentiators, amplifiers, read-through agents, and nucleic acid therapies. CFTR modulators that increase the channel gating activity of mutant and wild-type CFTR at the epithelial cell surface are known as potentiators. Correctors improve defective protein processing and the resulting trafficking 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 potentiators is often required to enhance CFTR activity. Currently, only one CFTR potentiator 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)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (Compound I), its deuterated derivatives, and pharma- ceutically acceptable salts of any of the foregoing. Compound I may be represented as having the following structure: [ka]

[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 of treatment 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 is a method of treating the CFTR-mediated disease cystic fibrosis, comprising administering to a patient in need of treatment Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, either 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) 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-trimethylpyrazole-1-yl]-4-oxo-1,4-dihydroquinoline-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-trimethylpyrazole-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxamide (compound III-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), (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6-Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound VII), (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hexan-5-yl}-9-oxa-2λ 6 in combination with one or more additional CFTR modulating agents selected from -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione (Compound VIII), N-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound IX), and N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound X). In some embodiments, Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, is administered in the same composition with 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. 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, comprising administering to a patient in need of treatment 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, as disclosed in Journal of Cystic Fibrosis (2018), 17(5), 595-606, and nesoricaftor or PTI-428, as disclosed in WO2016 / 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 comprising administering to a patient in need of treatment 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 WO2018 / 065921, posenacaftor or PTI-801 disclosed in WO2017 / 062581, ABBV-2851 disclosed in WO2017 / 009804, GLPG2737, ABBV-3748, ABBV-3903, and ABBV-119 disclosed in U.S. Patent Application Publication No. 2017-0101405.

[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] 1 provides an X-ray powder diffraction (XRPD) pattern of crystalline Compound I, Form A (native). [Diagram 2] 1 provides a differential scanning calorimetry (DSC) analysis of crystalline Compound I, Form A (native). [Diagram 3] The study design for Part A of the first-in-human (FIH) study of Compound I is provided, and the doses studied are provided. [Figure 4] The study design for Part B of the FIH study of Compound I is provided and the doses studied are provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] definition “Compound I” as used throughout this disclosure refers to (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, which may be represented as having the following structure: [ka]

[0017] 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 for making and using Compound I are disclosed in PCT International Application No. PCT / US2021 / 072475, which is incorporated herein by reference.

[0018] "Compound II" as used herein 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 may be represented by the following structure: [ka] Compound II may be in the form of a pharma-ceutically acceptable salt. Compound II and methods of making and using Compound II are disclosed in WO2010 / 053471, WO2011 / 119984, WO2011 / 133751, WO2011 / 133951, and WO2015 / 160787, each of which is incorporated herein by reference.

[0019] "Compound III" as used throughout this disclosure refers to N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (also known as N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide), which is represented by the following structure: [ka] Compound III may also be in the form of a pharma- ceutically acceptable salt.Compound III and methods of making and using compound III are disclosed in WO2006 / 002421, WO2007 / 079139, WO2010 / 108162, and WO2010 / 019239, each of which is incorporated herein by reference.

[0020] In some embodiments, a deuterated derivative of compound III (compound III-d) is used in the compositions and methods disclosed herein. The chemical name of compound III-d is N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide and is represented by the following structure: [ka] Compound III-d may be in the form of a pharma-ceutically acceptable salt. Compound III-d and methods for making and using compound III-d are disclosed in WO2012 / 158885, WO2014 / 078842, WO2019 / 109021, and U.S. Patent No. 8,865,902, which are incorporated herein by reference.

[0021] "Compound IV" as used herein refers to 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, which is represented by the following chemical structure: [ka] Compound IV may be in the form of a pharma- ceutically acceptable salt.Compound IV and methods for making and using compound IV are disclosed in WO2007 / 056341, WO2009 / 073757, and WO2009 / 076142, which are incorporated herein by reference.

[0022] "Compound V" as used herein refers to N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, which is represented by the following chemical structure: [ka] Compound V may be in the form of a pharma- ceutically acceptable salt. Compound V and methods of making and using Compound V are disclosed in WO2018 / 107100 and WO2019 / 113476, which are incorporated herein by reference.

[0023] As used herein, "Compound VI" refers to N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, which is represented by the following chemical structure: [ka] Compound VI may be in the form of a pharma- ceutically acceptable salt. Compound VI and methods for making and using Compound VI are disclosed in WO2018 / 064632 and WO2019 / 113476, which are incorporated herein by reference.

[0024] As used herein, "Compound VII" refers to (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione, which is represented by the following chemical structure: [ka] Compound VII may be in the form of a pharma- ceutically acceptable salt. Compound VII and methods of making and using Compound VII are described in WO2019 / 161078, incorporated herein by reference. It is disclosed in WO2020 / 102346 and WO2021 / 030554.

[0025] As used herein, "Compound VIII" refers to (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hexan-5-yl}-9-oxa-2λ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione, which is represented by the following chemical structure: [ka] Compound VIII may be in the form of a pharma- ceutically acceptable salt.Compound VIII and methods for making and using compound VIII are disclosed in WO2020 / 206080, which is incorporated herein by reference.

[0026] "Compound IX" as used herein refers to N-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, which is represented by the following chemical structure: [ka] Compound IX may be in the form of a pharma-ceutically acceptable salt. Compound IX and methods for making and using compound IX are disclosed in WO2016 / 057572, which is incorporated herein by reference.

[0027] "Compound X" as used herein refers to N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, which is represented by the following chemical structure: [ka] Compound X may be in the form of a 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.

[0028] As used herein, "CFTR" means cystic fibrosis transmembrane conductance regulator.

[0029] 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.

[0030] 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.

[0031] As used herein, a patient who is "homozygous" for a particular genetic mutation has the same mutation in each allele.

[0032] 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.

[0033] As used herein, the terms "CFTR modulator," "CFTR-modulating compound," and "CFTR-modulating agent" refer interchangeably to compounds that directly or indirectly increase the activity of CFTR. CFTR modulators include, but are not limited to, compounds that correct, enhance, stabilize, and / or amplify CFTR.

[0034] 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.

[0035] 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.

[0036] As used herein, the term "active pharmaceutical ingredient" ("API") or "therapeutic agent" refers to a biologically active compound.

[0037] It is to be understood that certain compounds of the present invention may exist as separate stereoisomers or enantiomers and / or mixtures of such stereoisomers or enantiomers. As used in the chemical structures disclosed herein, a "wedge" to a stereoatom [ka] or "hash" [ka] The bond denotes a chiral center of known absolute stereochemistry (i.e., one stereoisomer). As used in the chemical structures disclosed herein, a "wavy" bond to a stereoatom. [ka] indicates a chiral center of unknown absolute stereochemistry (i.e., one stereoisomer). As used in the chemical structures disclosed herein, a "wavy" bond to a double bond carbon [ka] indicates a mixture of E / Z isomers. [ka] ("straight") bonds indicate where a mixture (e.g., a racemate or concentrate) exists. As used herein, two bonds to a double bond carbon [ka] A ("straight") bond indicates that the double bond possesses the E / Z stereochemistry as 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 whose point of attachment is at the terminus of the bond that terminates in the "wavy" line.

[0038] The terms "patient" and "subject" are used interchangeably and refer to animals, including humans.

[0039] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to the amount of a compound that produces a desired effect when the compound is administered (e.g., amelioration of CF or symptoms of CF, or 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).

[0040] As used herein, the terms "treatment", "treating" and the like generally refer to the amelioration of one or more symptoms of CF in a patient diagnosed with the disease, the reduction in the severity of CF or one or more of its symptoms in a subject, or the slowing of progression of the disease in a subject. As used herein, "treatment" includes, but is not limited to, the following: increasing the subject's growth, increasing weight gain, reducing mucus in the lungs, improving pancreatic and / or liver function, reducing chest infections, and / or reducing coughing or shortness of breath. Improvement of any of these symptoms, reducing the severity, or slowing of progression of the disease can be readily assessed according to standard methods and techniques known in the art.

[0041] 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.

[0042] 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 the specified dose, amount, or weight percent value, or range of doses, amounts, or weight percents, that would be recognized by one of ordinary skill in the art to provide an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percent. The terms "about" and "approximately" may refer to a margin of error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In some embodiments, the terms "about" and "approximately" mean within 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range. 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.

[0043] 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.

[0044] As used herein, "deuterated derivative" means the same chemical structure where one or more hydrogen atoms have been replaced by deuterium atoms.

[0045] As used herein, the term "pharmaceutically acceptable salts" refers to salt forms of the disclosed compounds or their deuterated derivatives, where the salts are non-toxic. Pharmaceutically acceptable salts of the disclosed compounds 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.

[0046] The phrase "deuterated derivatives 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 and deuterated derivatives thereof" is used interchangeably with "pharma- ceutically acceptable salts 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 a pharma- ceutical acceptable salt of any one of the reference compounds, a deuterated derivative of any one of the reference compounds, a deuterated derivative of a pharma- ceutical acceptable salt of any one of the reference compounds, and a pharma- ceutical acceptable salt of a deuterated derivative of any one of the reference compounds.

[0047] 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 an equivalent amount of its pharma- ceutically acceptable salt" includes 100 mg of compound I and the amount of pharma- ceutically acceptable salt of compound I equivalent to 100 mg of compound I.

[0048] 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]

[0049] 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- Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-butyl salts. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-butyl salts. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-butyl salts. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-butyl salts. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-butyl salts. + (C 1-4 Alkyl) 4The 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 pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0050] As used herein, the term "XRPD" refers to the analytical characterization method of X-ray powder diffraction. The XRPD patterns disclosed herein were recorded at ambient conditions using a diffractometer in either transmission or reflection geometry.

[0051] As used herein, the terms "X-ray powder diffractogram," "X-ray powder diffraction pattern," "XRPD pattern," and "XRPD spectrum" refer interchangeably to an experimentally obtained pattern that plots signal position (on the abscissa) versus signal intensity (on the ordinate). For amorphous materials, the X-ray powder diffractogram may include one or more broad signals, and for crystalline materials, the X-ray powder diffractogram may include one or more signals, each identified by its angular value, measured in degrees two-theta (°2θ), represented on the abscissa of the X-ray powder diffractogram, which may be expressed as "signals at ... degrees two-theta," "signals at [a] two-theta value of ...," and / or "signals at at least two-theta values ​​of ... selected from ...."

[0052] As used herein, the term "DSC" refers to the analytical method of Differential Scanning Calorimetry.

[0053] As used herein, the term "melting temperature," "melting point," or "Tm" refers to the temperature at which a substance transitions from a solid to a liquid phase.

[0054] 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), reduced synthesis of CFTR (class V defects), and reduced surface stability of CFTR (class VI defects). Mutations that affect CFTR function include those that cause gating defects (class III defects) and conductance defects (class IV defects). Some CFTR mutations exhibit characteristics of more than one class. Certain mutations in the CFTR gene result in CF.

[0055] Thus, in some embodiments, the present invention provides a method for 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, 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 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 F508del mutation. In some embodiments, the patient is homozygous for N1303K mutation.

[0056] In some embodiments, the amount of the active ingredient is from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, from about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg , about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17 mg, approx. 18 mg, approx. 19 mg, approx. 20 mg, approx. 25 mg, approx. 30 mg, approx. 31 mg, approx. 32 mg, approx. 33 mg, approx. 34 mg, approx. 35 mg, approx. 6mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, approx. 100mg, approx. 105mg, approx. 110mg, approx. 115mg, approx. 120mg, approx. 125mg, approx. 130mg, approx. 135mg, approx. 140mg, approx. 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, About 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg,Approximately 365mg, approximately 370mg, approximately 375mg, approximately 380mg, approximately 385mg, approximately 390mg, approximately 395mg, approximately 400mg, approximately 410mg, approximately 420mg, approximately 430mg, approximately 440mg, approximately 450mg, approximately 460m g, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 60 In one embodiment, about 0 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 mg of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing is administered daily.

[0057] In some embodiments, about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg, about 2 mg to about 40 mg, etc.) mg, about 5 mg to about 50 mg, about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 1 mg to about 30 mg, about 1 mg to about 30 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg , about 3 mg, about 3.5 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 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 25mg, about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg g, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg , about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, About 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, About 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing is administered daily.

[0058] In some embodiments, the amount of the active ingredient is from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, from about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg , about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17 mg, approx. 18 mg, approx. 19 mg, approx. 20 mg, approx. 25 mg, approx. 30 mg, approx. 31 mg, approx. 32 mg, approx. 33 mg, approx. 34 mg, approx. 35 mg, approx. 6mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, approx. 100mg, approx. 105mg, approx. 110mg, approx. 115mg, approx. 120mg, approx. 125mg, approx. 130mg, approx. 135mg, approx. 140mg, approx. 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, About 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg,Approximately 365mg, approximately 370mg, approximately 375mg, approximately 380mg, approximately 385mg, approximately 390mg, approximately 395mg, approximately 400mg, approximately 410mg, approximately 420mg, approximately 430mg, approximately 440mg, approximately 450mg, approximately 460mg , about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600m g, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 mg of Compound I, its deuterated derivative, or a pharma- ceutically acceptable salt of any of the foregoing, is administered as a single dose.

[0059] In some embodiments, about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg, about 2 mg to about 40 mg, etc.) mg, about 5 mg to about 50 mg, about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 1 mg to about 30 mg, about 1 mg to about 30 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg , about 3 mg, about 3.5 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 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 25mg, about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90m g, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, About 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, About 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about A total daily dose of about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 mg) of Compound I, its deuterated derivative, or a pharma- ceutically acceptable salt of any of the foregoing is administered as a single dose.

[0060] In some embodiments, the amount of the active ingredient is from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, from about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg , about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17 mg, approx. 18 mg, approx. 19 mg, approx. 20 mg, approx. 25 mg, approx. 30 mg, approx. 31 mg, approx. 32 mg, approx. 33 mg, approx. 34 mg, approx. 35 mg, approx. 6mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, approx. 100mg, approx. 105mg, approx. 110mg, approx. 115mg, approx. 120mg, approx. 125mg, approx. 130mg, approx. 135mg, approx. 140mg, approx. 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, About 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg,Approximately 365mg, approximately 370mg, approximately 375mg, approximately 380mg, approximately 385mg, approximately 390mg, approximately 395mg, approximately 400mg, approximately 410mg, approximately 420mg, approximately 430mg, approximately 440mg, approximately 450mg, approximately 460m g, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600 about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 mg of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing, is administered in two doses.

[0061] In some embodiments, about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg, about 2 mg to about 40 mg, etc.) mg, about 5 mg to about 50 mg, about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 1 mg to about 30 mg, about 1 mg to about 30 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg , about 3 mg, about 3.5 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 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 25mg, about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90 mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg , about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg , about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, A total daily dose of about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 mg) of Compound I, its deuterated derivative, or a pharma- ceutically acceptable salt of any of the foregoing, is administered in two doses.

[0062] 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]

[0063] In some embodiments, the present disclosure is also directed 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 in any other embodiment described 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 is normally found in nature. Examples of isotopes that are commercially available and suitable for the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Contains Cl.

[0064] Isotopically labeled compounds and salts can be used in a number of beneficial ways. They may be suitable for various types of assays, such as drug and / or substrate tissue distribution assays. For example, tritium ( 3 H) labeling and / or carbon-14 ( 14 C) labeled compounds are particularly useful in various types of assays, such as substrate tissue distribution assays, due to their relatively simple preparation and excellent detectability. 2 H) The labeled compound is therapeutically useful and non- 2 3H labeled compounds have potential therapeutic advantages over H labeled compounds. 2H) Labeled compounds and salts can have higher metabolic stability compared to those that are not isotopically labeled due to the kinetic isotope effect described below. Higher metabolic stability directly translates into increased in vivo half-life or lower dosage, which may be desirable. Isotopically labeled compounds and salts can be prepared by generally carrying out the procedures disclosed in the synthetic schemes and related descriptions, examples section, and preparation section of this specification, and replacing non-isotopically labeled reactants with readily available isotopically labeled reactants.

[0065] In some embodiments, the isotopically labeled compounds and salts contain deuterium ( 2 In some specific embodiments, the isotopically labeled compounds and salts are deuterium (H) labeled compounds, in which one or more hydrogen atoms are replaced by deuterium. 2 H) labeled. In the chemical structure, deuterium is 2 It is represented by "H" or "D".

[0066] 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.

[0067] deuterium( 2 H) labeled compounds and salts can modulate the oxidative metabolism of compounds through the primary kinetic isotope effect, which 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 in a non-exchangeable position, k M / k DRate differences of 2-7 are typical. For further discussion, see S.L. Harbeson and R.D. Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417, which is incorporated herein by reference.

[0068] 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 designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Combination therapy

[0069] 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).

[0070] Thus, in some embodiments, the present invention provides a method of treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient, comprising administering to the patient about 0.1 mg to about 800 mg (e.g., about 1 mg to about 400 mg, about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg, about 2 mg to about 40 mg). g, approx. 5 mg to approx. 50 mg, approx. 5 mg to approx. 20 mg, approx. 5 mg to approx. 10 mg, approx. 1 mg to approx. 30 mg, approx. 1 mg, approx. 1.5 mg, approx. 2 mg, approx. 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 25mg, about 30mg, about 31mg, about 32mg, about 33mg , about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 1 30mg, approx. 135mg, approx. 140mg, approx. 145mg, approx. 150mg, approx. 155mg, approx. 160mg, approx. 165mg, approx. 170mg, approx. 175mg, approx. 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg,310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 360mg, 365mg, 370mg, 375mg, 380mg, 385mg, 390mg, 395mg, 4 00mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580m g, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 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.

[0071] In some embodiments, the present invention provides a method of treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient, comprising administering to the patient about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 300 mg, about 30 mg to about 400 mg, or about 40 mg to about 50 mg). g ~ about 30 mg, about 30 mg - about 60 mg, about 1 mg - about 50 mg, about 2 mg - about 40 mg, about 5 mg - about 50 mg, about 5 mg - about 20 mg, about 5 mg - about 10 mg, about 1 mg - about 30 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 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 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 25 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 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, About 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg , about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325m g, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 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.

[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, comprising administering to the patient about 5 mg to about 375 mg (e.g., about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 5 mg to about 50 mg, about 5 mg to about 20 mg, about 5 mg to about 10 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 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 25mg, about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg 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 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165 mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235m g, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, The method includes administering about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, or about 375 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.

[0073] In some embodiments, the present invention provides a method of treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient, comprising administering to the patient about 15 mg to about 350 mg (e.g., about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 31 mg , about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, approx. 110mg, approx. 115mg, approx. 120mg, approx. 125mg, approx. 130mg, approx. 135mg, approx. 140mg, approx. 145mg, approx. 150mg, approx. 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 2 In one embodiment, the method comprises administering to a patient in need of a medicament for administration of at least one of the following active pharmaceutical ingredients: about 65 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, or about 350 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.

[0074] In some embodiments, the present invention provides a method of treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient, comprising administering to the patient about 30 mg to about 300 mg (e.g., about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 30 mg to about 60 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, 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 81 mg, about 82 mg, about 83 mg, about 84 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 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 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg , about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 1 75mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240m g, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, or about 300 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.

[0075] In some embodiments, the present invention provides a method of treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient, comprising administering to the patient about 50 mg to about 200 mg (e.g., about 50 mg to about 175 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 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 ... In one embodiment, the method comprises administering to a subject a therapeutically effective amount of Compound I, a deuterated derivative thereof, or a pharma- ceutical agent, such as a CFTR modulator, in an amount of about 10 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, or about 200 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.

[0076] In some embodiments, the present invention provides a method of treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient, comprising administering to the patient about 50 mg to about 175 mg (e.g., 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 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 500 mg, about 500 mg, about 500 mg, about 500 mg, about 510 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about g, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, or about 175 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.

[0077] In some embodiments, the present invention provides a method of treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient, comprising administering to the patient about 10 mg to about 200 mg (e.g., about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 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 25 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 mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 1 In one embodiment, the method comprises administering to a patient in need of a medicament for treatment with a CFTR modulator, the method comprising administering to the patient an amount of about 50 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, or about 200 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.

[0078] In some embodiments, the present invention provides a method of treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient, comprising administering to the patient about 20 mg to about 100 mg (e.g., about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 20 mg, about 25 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, In one embodiment, the method comprises administering 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 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, alone or in combination with at least one additional active pharmaceutical ingredient, such as, for example, a CFTR modulator.

[0079] In some embodiments, the present invention provides a method of treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient, comprising administering to the patient about 30 mg to about 60 mg (e.g., 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, or about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, In one embodiment, the method comprises administering to a patient in need of a medicament for treatment with a CFTR modulator, the method comprising administering to the patient an amount of 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, or about 60 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.

[0080] In some embodiments, the present invention provides a method of treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient, comprising administering to the patient about 1 mg to about 50 mg (e.g., about 2 mg to about 40 mg, about 5 mg to about 50 mg, about 20 mg to about 30 mg, about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 1 mg to about 30 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 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 11 mg, about 12 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 40 mg, about 5 mg, about 50 mg, about 20 mg, about 30 mg, about 40 mg, about 5 mg, about 50 mg, about 20 mg, about 30 mg, about 40 mg, about 5 mg, about 50 mg, about 50 mg, about 60 mg, about 60 mg, about 60 mg In one embodiment, the method comprises administering to a subject a therapeutically effective amount of Compound I, a deuterated derivative thereof, or a pharmacologic agent in an amount of about 1 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 25 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, or about 50 mg of Compound I, a deuterated derivative thereof, or a pharmacologically 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.

[0081] In some embodiments, the present invention provides a method of treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient, comprising administering to the patient about 2 mg to about 40 mg (e.g., about 20 mg to about 30 mg, about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 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 1 ... In one embodiment, the method comprises administering to a patient in need of a medicament for use in a method for treating a chronic rheumatoid arthritis, the method comprising administering to a patient in need of a medicament for treatment with a ...

[0082] In some embodiments, the present invention provides a method of treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient, comprising administering to the patient about 5 mg to about 50 mg (e.g., about 20 mg to about 30 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, or about 10 mg, about 11 mg, about 12 mg, In one embodiment, the method comprises administering 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 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 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, for example, a CFTR modulator.

[0083] 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, comprising administering to the patient about 5 mg to about 20 mg (e.g., 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 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, or about 20 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.

[0084] 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, comprising administering to the patient about 5 mg to about 10 mg (e.g., 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, or about 10 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.

[0085] In some embodiments, the present invention provides a method of treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient, comprising administering to the patient about 1 mg to about 30 mg (e.g., about 5 mg to about 20 mg, about 20 mg to about 30 mg, about 5 mg to about 10 mg, about 1 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 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 In one embodiment, the method comprises administering to a patient in need of a medicament for treatment with a CFTR modulator, the method comprising administering to the patient an amount of about 8 mg, about 8.5 mg, about 9 mg, about 9.5 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 25 mg, or about 30 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.

[0086] 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.

[0087] In some embodiments, the additional agent is a mucolytic agent. Exemplary mucolytic agents useful herein include Pulmozyme®.

[0088] In some embodiments, the additional agent is a bronchodilator. Exemplary bronchodilators include albuterol, metaproterenol sulfate, pirbuterol acetate, salmeterol, and tetrabuline sulfate.

[0089] In some embodiments, the additional therapeutic agent is an antibiotic. Exemplary antibiotics useful herein include tobramycin, including tobramycin inhalation powder (TIP), azithromycin, aztreonam, including an aerosolized form of aztreonam, amikacin, including a liposomal formulation of amikacin, ciprofloxacin, including a formulation of ciprofloxacin suitable for administration by inhalation, levofloxacin, including an aerosolized formulation of levofloxacin, and combinations of two antibiotics, such as fosfomycin and tobramycin.

[0090] In some embodiments, the additional agent is an anti-inflammatory agent, i.e., an agent that can reduce inflammation in the lungs. Exemplary such agents useful herein include ibuprofen, docosahexaenoic acid (DHA), sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine, and simavastatin.

[0091] 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.

[0092] In some embodiments, the at least one additional active pharmaceutical ingredient is selected from a CFTR modulator. In some embodiments, the CFTR modulator is a CFTR corrector. In some embodiments, the CFTR modulator is a CFTR 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.

[0093] In some embodiments, at least one additional active pharmaceutical ingredient is an ENaC inhibitor. In some embodiments, at least one additional active pharmaceutical ingredient is a TMEM16A modulator. In some embodiments, at least one additional active pharmaceutical ingredient is a GPR39 agonist.

[0094] 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 Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any 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 and pharma- ceutically acceptable salts thereof.

[0095] In some embodiments, the combination therapies provided herein comprise (a) a dose of from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, from about 1 mg to about 1. 5mg, about 2mg, about 2.5mg, about 3mg, about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 25mg, about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, About 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg , about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 1 70mg, approx. 175mg, approx. 180mg, approx. 185mg, approx. 190mg, approx. 195mg, approx. 200mg, approx. 205mg, approx. 210mg, approx. 215mg, approx. 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, about 340mg, about 345mg,About 350mg, about 355mg, about 360mg, about 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395mg, about 400m g, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 51 0mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, about 700mg, about 710mg, about 720mg , about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 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 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 and pharma- ceutically acceptable salts thereof, as described in WO2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO 2018 / 065921, WO2017 / 062581, Phuan,P.-W.et al.J.Cyst.Fibros.2018,17(5),595-606, Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640, Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32, Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272, Brasell,EJet al.PLoS One 2019,14(12),e0223954, Smith,NJ,Solovay,CF,Pharm.Pat.Anal.2017,6(4),179-188,and at least one compound selected from the compounds disclosed in Kunzelmann, K. et al., Front.Pharmacol. 2019, 10, 3, or Son, J.-H. et al., Eur.J.of Med.Chem. 2020, 112888.

[0096] In some embodiments, the combination therapy provided herein comprises: (a) about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg, about 2 mg to about 40 mg, about 5 mg to about 50 mg, about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 1 mg to about 30 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg g, 3mg, 3.5mg, 4mg, 4.5mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 9.5mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16 mg, approx. 17 mg, approx. 18 mg, approx. 19 mg, approx. 20 mg, approx. 25 mg, approx. 30 mg, approx. 31 mg, approx. 32 mg, approx. 33 mg, approx. 34 mg, approx. 35 mg, approx. 5mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 1 80mg, approx. 185mg, approx. 190mg, approx. 195mg, approx. 200mg, approx. 205mg, approx. 210mg, approx. 215mg, approx. 220mg, approx. 225mg, approx. 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, about 340mg, about 345mg, about 350mg, about 355mg,about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; and (b) optionally, Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, and (c) at least one compound selected from compound X, and deuterated derivatives and pharma- ceutically acceptable salts thereof; and (d) optionally a compound selected from the group consisting of compounds described in WO2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO2017 / 062581, Phuan, P.-W. et al. al.J.Cyst.Fibros.2018,17(5),595-606, Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640, Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32, Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,EJet al.PLoS One 2019, 14(12), e0223954, Smith, NJ, Solovay, CF, Pharm. Pat. Anal. 2017, 6(4), 179-188, Kunzelmann, K. et al., Front. Pharmacol. 2019, 10, 3, or Son, J.-H. et al., Eur. J. of Med. Chem. 2020, 112888.

[0097] In some embodiments, the combination therapies provided herein comprise (a) a dose of about 5 mg to about 375 mg (e.g., about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 5 mg to about 50 mg, about 5 mg to about 20 mg, about 5 mg to about 10 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 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 25 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 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg , approx. 145 mg, approx. 150 mg, approx. 155 mg, approx. 160 mg, approx. 165 mg, approx. 170 mg, approx. 175 mg, approx. 180 mg, approx. 185 mg, approx. 190 mg, approx. 0 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, or about 375 mg of Compound I, a deuterated derivative thereof, or any of the foregoing pharma- ceutically acceptable and (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 and pharma- ceutically acceptable salts thereof; and (c) optionally a compound selected from the group consisting of compounds described in WO2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO2017 / 062581, Phuan, P.-W. et al. 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 et al., Front.Pharmacol. 2019,10,3, or Son, J.-H. et al., Eur.J.of Med.Chem. 2020,112888, and at least one compound selected from the compounds disclosed therein. .

[0098] In some embodiments, the combination therapy provided herein comprises (a) about 15 mg to about 350 mg (e.g., about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 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, 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 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about g, approx. 44 mg, approx. 45 mg, approx. 46 mg, approx. 47 mg, approx. 48 mg, approx. 49 mg, approx. 50 mg, approx. 51 mg, approx. 52 mg, approx. 53 mg, approx. 0mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170 mg, approx. 175 mg, approx. 180 mg, approx. 185 mg, approx. 190 mg, approx. 195 mg, approx. 200 mg, approx. 205 mg, approx. 210 mg, approx. 215 mg, approx. 60mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, about 340mg, about 345mg, or about 350 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 and pharma- ceutically acceptable salts thereof; and (c) optionally at least one compound selected from compounds described in WO2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804,WO2018 / 065921, WO2017 / 062581, WO2022 / 076618, WO2022 / 076620, WO2022 / 076621, WO2022 / 076622, WO2022 / 076624, WO2022 / 076625, WO2022 / 076626, WO2022 / 076627, WO2022 / 076628, WO2022 / 076629, PCT International Application No. PCT / US2023 / 017627, Phuan, P.-W. et al. J. Cyst. Fibros. 2018, 17(5), 595-606, Pedemonet, N. et al. 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 and at least one compound selected from the compounds disclosed in U.S. Pat. No. 6,313,623, and U.S. Pat. No. 6,313,623.

[0099] In some embodiments, the combination therapy provided herein comprises (a) about 30 mg to about 300 mg (e.g., about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 30 mg to about 60 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 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 14 0mg, approx. 145mg, approx. 150mg, approx. 155mg, approx. 160mg, approx. 165mg, approx. 170mg, approx. 175mg, approx. 180mg, approx. (b) about 30 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, or about 300 mg of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; and (c) optionally, a small amount 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 and pharma- ceutically acceptable salts thereof. and (c) optionally, WO2016 / 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,WO2022 / 076629, PCT International Application No. PCT / US2023 / 017627, 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.

[0100] In some embodiments, the combination therapy provided herein comprises: (a) about 50 mg to about 200 mg (e.g., about 50 mg to about 175 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 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about (b) optionally, Compound II, Compound III, Compound I, Compound II, Compound I ... II-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives and pharma- ceutically acceptable salts thereof; and (c) optionally a compound selected from the group consisting of compounds described in WO2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO 2017 / 062581, WO2022 / 076618, WO2022 / 076620, WO2022 / 076621, WO2022 / 076622, WO2022 / 076624, WO2022 / 076625, WO2022 / 076626, WO2022 / 076627, WO2022 / 076628, WO2022 / 076629, PCT International Application No. PCT / US2023 / 017627, Phuan, P.-W. et al. al.J.Cyst.Fibros.2018,17(5),595-606, Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640, Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32,Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272, Brasell,EJet al.PLoS One 2019,14(12),e0223954, Smith,NJ,Solovay,CF,Pharm.Pat.Anal.2017,6(4),179-188, Kunzelmann,K.et al.,Front.Pharmacol.2019,10,3, or Son,J.-H.et al.,Eur.J.of Med.Chem.2020,112888.

[0101] In some embodiments, the combination therapy provided herein comprises: (a) about 50 mg to about 175 mg (e.g., 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 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 65 mg, (b) about 15 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, or about 175 mg of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; and (c) optionally, Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VI-C, Compound VI-D, Compound VI-E, Compound VI-F, Compound VI-G, Compound VI-H, Compound VI-I, Compound VI-J ... and (c) at least one compound selected from compound VII, compound VIII, compound IX, compound X, and deuterated derivatives and pharma- ceutically acceptable salts thereof, and optionally a compound selected from the group consisting of compounds described in WO2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO2017 / 062581, WO2022 / 076618, WO2022 / 076620, WO2022 / 076621, WO2022 / 076622, WO2022 / 076624, WO2022 / 076625, WO2022 / 076626, WO2022 / 076627, WO2022 / 076628, WO2022 / 076629, PCT International Application No. PCT / US2023 / 017627, 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.and at least one compound selected from the compounds disclosed in 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.

[0102] In some embodiments, the combination therapy provided herein comprises: (a) about 10 mg to about 200 mg (e.g., about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 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 25 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 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg g, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, or about 200 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 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 and pharma- ceutically acceptable salts thereof, as described in WO2016 / 105485, U.S. Patent Application Publication No. 2016 / 023361, and / or U.S. Patent Application Publication No. 2016 / 023361. No. 16-0120841, 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, WO2022 / 076629, PCT International Application No. PCT / US2023 / 017627, 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.

[0103] In some embodiments, the combination therapy provided herein comprises: (a) about 20 mg to about 100 mg (e.g., about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 20 mg, about 25 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 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; and (b) optionally, Compound II, Compound III, Compound IV ... III-d, IV, V, VI, VII, VIII, IX, X, and deuterated derivatives and pharma- ceutically acceptable salts thereof; and (c) optionally a compound selected from the group consisting of compounds described in WO2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO 2017 / 062581, WO2022 / 076618, WO2022 / 076620, WO2022 / 076621, WO2022 / 076622, WO2022 / 076624, WO2022 / 076625, WO2022 / 076626, WO2022 / 076627, WO2022 / 076628, WO2022 / 076629, PCT International Application No. PCT / US2023 / 017627, Phuan, P.-W. et al. al.J.Cyst.Fibros.2018,17(5),595-606, Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640, Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32,Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272, Brasell,EJet al.PLoS One 2019,14(12),e0223954, Smith,NJ,Solovay,CF,Pharm.Pat.Anal.2017,6(4),179-188, Kunzelmann,K.et al.,Front.Pharmacol.2019,10,3, or Son,J.-H.et al.,Eur.J.of Med.Chem.2020,112888.

[0104] In some embodiments, the combination therapy provided herein comprises (a) about 30 mg to about 60 mg (e.g., 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, or 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, or about 60 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; and (b) optionally, Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound I X, compound X, and deuterated derivatives and pharma- ceutically acceptable salts thereof; and (c) optionally a compound selected from WO2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO2017 / 062581, WO2022 / 07 6618, WO2022 / 076620, WO2022 / 076621, WO2022 / 076622, WO2022 / 076624, WO2022 / 076625, WO2022 / 076626, WO2022 / 076627, WO2022 / 076628, WO2022 / 076629, PCT International Application No. PCT / US2023 / 017627, 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.

[0105] In some embodiments, the combination therapies provided herein comprise (a) a dose of about 1 mg to about 50 mg (e.g., about 2 mg to about 40 mg, about 5 mg to about 50 mg, about 5 mg to about 20 mg, about 20 mg to about 30 mg, about 5 mg to about 10 mg, about 1 mg to about 30 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 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 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 25 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, or about 50 mg of Compound I, its deuterium derivatives, 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 and pharma- ceutically acceptable salts thereof; and (c) optionally at least one compound selected from the group consisting of compounds described in WO2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO201 7 / 009804, WO2018 / 065921, WO2017 / 062581, WO2022 / 076618, WO2022 / 076620, WO2022 / 076621, WO2022 / 076622, WO2022 / 076624, WO2022 / 076625, WO2022 / 076626, WO2022 / 076627, WO2022 / 076628, WO2022 / 076629, PCT International Application No. PCT / US2023 / 017627, 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, DK JPharmacol. 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.

[0106] In some embodiments, the combination therapies provided herein comprise (a) about 2 mg to about 40 mg (e.g., about 5 mg to about 20 mg, about 20 mg to about 30 mg, about 5 mg to about 10 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 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 11 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 ... 2 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 25 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, or about 40 mg of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; and (b) optionally, Compound II, Compound III, Compound II I-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives and pharma- ceutically acceptable salts thereof; and (c) optionally, at least one compound selected from WO2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO2 017 / 062581, WO2022 / 076618, WO2022 / 076620, WO2022 / 076621, WO2022 / 076622, WO2022 / 076624, WO2022 / 076625, WO2022 / 076626, WO2022 / 076627, WO2022 / 076628, WO2022 / 076629, PCT International Application No. PCT / US2023 / 017627, Phuan, P.-W. et al. al.J.Cyst.Fibros.2018,17(5),595-606, Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640, Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32, Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,E.and at least one compound selected from the compounds disclosed in J. et 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.

[0107] In some embodiments, the combination therapy provided herein comprises (a) about 5 mg to about 50 mg (e.g., about 20 mg to about 30 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, or 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 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 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) optionally, Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, Compound XI, Compound IX, Compound IXIII ... and deuterated derivatives and pharma- ceutically acceptable salts thereof; and (c) optionally, at least one compound selected from WO2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO2017 / 062581, WO2022 / 07661 8, WO2022 / 076620, WO2022 / 076621, WO2022 / 076622, WO2022 / 076624, WO2022 / 076625, WO2022 / 076626, WO2022 / 076627, WO2022 / 076628, WO2022 / 076629, PCT International Application No. PCT / US2023 / 017627, 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.

[0108] In some embodiments, the combination therapy provided herein comprises (a) about 5 mg to about 20 mg (e.g., 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 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, or about 20 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; and (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 and pharma- ceutically acceptable salts thereof. and (c) optionally at least one compound selected from WO2016 / 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 / 076 620, WO2022 / 076621, WO2022 / 076622, WO2022 / 076624, WO2022 / 076625, WO2022 / 076626, WO2022 / 076627, WO2022 / 076628, WO2022 / 076629, PCT International Application No. PCT / US2023 / 017627, 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 at least one compound selected from the compounds disclosed in.

[0109] In some embodiments, the combination therapy provided herein comprises: (a) about 5 mg to about 10 mg (e.g., 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, or about 10 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 and pharma- ceutically acceptable salts thereof; and (c) optionally, W WO2016 / 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 / 0766 21, WO2022 / 076622, WO2022 / 076624, WO2022 / 076625, WO2022 / 076626, WO2022 / 076627, WO2022 / 076628, WO2022 / 076629, PCT International Application No. PCT / US2023 / 017627, 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.and administering at least one compound selected from the compounds disclosed in US Pat. No. 6,202,112,888.

[0110] In some embodiments, the combination therapies provided herein comprise (a) about 1 mg to about 30 mg (e.g., about 5 mg to about 20 mg, about 20 mg to about 30 mg, about 5 mg to about 10 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 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 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 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 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 70 mg, about 75 mg, about 76 mg, about 7 (b) optionally, Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VI-c, Compound VI-d, Compound VI-e, Compound VI-f, Compound VI-g, Compound VI-h, Compound VI-i, Compound VI-j ... and (c) at least one compound selected from compound VII, compound VIII, compound IX, compound X, and deuterated derivatives and pharma- ceutically acceptable salts thereof, optionally comprising a compound selected from the group consisting of compounds described in WO2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO2017 / 062581, W No. PCT / US2023 / 017627, Phuan, P.-W. et al. al.J.Cyst.Fibros.2018,17(5),595-606, Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640, Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32, Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272, Brasell,EJet al.PLoS One 2019,14(12),e0223954, Smith,N.and at least one compound selected from the compounds disclosed in 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.

[0111] In some embodiments, the combination therapies provided herein comprise (a) a dose of from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, from about 1 mg to about 1. 5mg, about 2mg, about 2.5mg, about 3mg, about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 25mg, about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, About 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg , about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 1 70mg, approx. 175mg, approx. 180mg, approx. 185mg, approx. 190mg, approx. 195mg, approx. 200mg, approx. 205mg, approx. 210mg, approx. 215mg, approx. 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, about 340mg, about 345mg,About 350mg, about 355mg, about 360mg, about 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395mg, about 400mg, about 410mg, about 420mg, About 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 mg of compound I, (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 and pharma- ceutically acceptable salts thereof; and (c) optionally at least one compound selected from PTI-428, ASP-11, ABBV-2222, ABV-2223, ABV-2224, ABV-2225, ABV-2226, ABV-2228, ABV-2229 ... BV-2851,GLPG2737,ABBV-3221,ABBV-3748,ABBV-3903,ABBV-119,FDL-169,ARN5562,ARN21586,ARN22081,AR N22652, 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-2.5 Rx, BI 1265162, ARO-ENaC1001, ETD002, and at least one compound selected from DS-1039.

[0112] In some embodiments, the combination therapy provided herein comprises (a) about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg, about 2 mg to about 40 mg, about 5 mg to about 50 mg, about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 1 mg to about 30 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg g, 3mg, 3.5mg, 4mg, 4.5mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 9.5mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16 mg, approx. 17 mg, approx. 18 mg, approx. 19 mg, approx. 20 mg, approx. 25 mg, approx. 30 mg, approx. 31 mg, approx. 32 mg, approx. 33 mg, approx. 34 mg, approx. 35 mg, approx. 5mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 1 80mg, approx. 185mg, approx. 190mg, approx. 195mg, approx. 200mg, approx. 205mg, approx. 210mg, approx. 215mg, approx. 220mg, approx. 225mg, approx. 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, about 340mg, about 345mg, about 350mg, about 355mg,about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 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 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-11 9, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, ARN23766, PTI-801, FDL-176 , PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW251(Icenticaftor), GLPG3067 / AB and at least one compound selected from BV-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-2.5 Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0113] In some embodiments, the combination therapy provided herein comprises: (a) about 5 mg to about 375 mg (e.g., about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 5 mg to about 50 mg, about 5 mg to about 20 mg, about 5 mg to about 10 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 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 25mg, about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg g, approx. 65 mg, approx. 70 mg, approx. 75 mg, approx. 80 mg, approx. 85 mg, approx. 90 mg, approx. 95 mg, approx. 100 mg, approx. 105 mg, approx. 5mg, approx. 160mg, approx. 165mg, approx. 170mg, approx. 175mg, approx. 180mg, approx. 185mg, approx. 190mg, approx. 195mg, approx. 200mg, approx. (b) optionally, Compound II, Compound III, Compound IV ...and (c) at least one compound selected from Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives and pharma- ceutically acceptable salts thereof; and (d) optionally, PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, ARN23766, PTI-801, FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW251(Icenticaftor), GLPG3067 / ABBV-3067(Navocaftor), ABBV-191, EL X-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-2.5 Rx, BI 1265162, ARO-ENaC1001, ETD002, and at least one compound selected from DS-1039.

[0114] In some embodiments, the combination therapy provided herein comprises: (a) about 15 mg to about 350 mg (e.g., about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 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 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg , approx. 85 mg, approx. 90 mg, approx. 95 mg, approx. 100 mg, approx. 105 mg, approx. 110 mg, approx. 115 mg, approx. 120 mg, approx. 125 mg, approx. 130 mg, approx. 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, or about 350 mg. (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 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-2451, QBW251(Icenticaftor), GLPG3067 / ABB and at least one compound selected from V-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-2.5 Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0115] In some embodiments, the combination therapy provided herein comprises (a) about 30 mg to about 300 mg (e.g., about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 30 mg to about 60 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 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 1 40mg, approx. 145mg, approx. 150mg, approx. 155mg, approx. 160mg, approx. 165mg, approx. 170mg, approx. 175mg, approx. 180mg, approx. 185mg, approx. about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, or about 300 mg of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; and (b) optionally, 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 deuterated derivatives and pharma- ceutically acceptable salts thereof. and (c) optionally, PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, ARN23766, PTI-801, FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW251 (Icenticaftor),and 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-2.5 Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0116] In some embodiments, the combination therapy provided herein comprises: (a) about 50 mg to about 200 mg (e.g., about 50 mg to about 175 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 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about (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 (c) at least one compound selected from the group consisting of 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, GLPG18 and at least one compound selected from: GLPG37 / 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-2.5 Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0117] In some embodiments, the combination therapies provided herein comprise (a) about 50 mg to about 175 mg (e.g., 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 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 500 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 55 mg, about 56 mg, about 57 mg, about (b) about 35 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, or about 175 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; and (c) optionally, a small amount 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 and pharma- ceutically acceptable salts thereof. and (c) optionally, 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, and at least one compound selected from 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-2.5 Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0118] In some embodiments, the combination therapy provided herein comprises: (a) about 10 mg to about 200 mg (e.g., about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 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 25 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 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg (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 and pharma- ceutically acceptable salts thereof; and (c) optionally, at least one compound selected from PTI-428, ASP-11, ABBV-222, 2, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, ARN23766, PTI- 801, FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW251 (Icenticaftor), GLPG3067 / ABBV-3067 (Navocaftor), ABBV-191, ELX-02,and at least one compound selected from MRT5005, Lunar-CF, RCT223, amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5 Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0119] In some embodiments, the combination therapy provided herein comprises (a) about 20 mg to about 100 mg (e.g., about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 20 mg, about 25 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, 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 81 mg, about 82 mg, about 83 mg, about 84 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 101 mg, about 102 mg, about 1 (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 (c) at least one compound selected from hydrogenated derivatives and pharma- ceutically acceptable salts, and optionally 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, GLPG1 and at least one compound selected from: 837 / 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-2.5 Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0120] In some embodiments, the combination therapies provided herein comprise (a) about 30 mg to about 60 mg (e.g., 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, or 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, or about 60 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 and pharma- ceutically acceptable salts thereof; and (c) any Optionally, PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, FDL-169, ARN 5562, ARN21586, ARN22081, 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-2.5 Rx, BI 1265162, ARO-ENaC1001, ETD002, and at least one compound selected from DS-1039.

[0121] In some embodiments, the combination therapy provided herein comprises: (a) about 1 mg to about 50 mg (e.g., about 2 mg to about 40 mg, about 5 mg to about 50 mg, about 5 mg to about 20 mg, about 20 mg to about 30 mg, about 5 mg to about 10 mg, about 1 mg to about 30 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 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 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 25 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, or about 50 mg of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; and (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 and pharma- ceutically acceptable salts thereof; and (c) optionally, PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, ARN23766, PTI -801, FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW251 (Icenticaftor), GLPG3067 / ABBV-3067 (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-2.5 Rx, and at least one compound selected from BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0122] In some embodiments, the combination therapies provided herein comprise (a) about 2 mg to about 40 mg (e.g., about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 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 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 20 mg, about 22 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 ... (b) optionally, 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 medicaments; and (c) optionally, at least one compound selected from the group consisting of 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 / and at least one compound selected from 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-2.5 Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0123] In some embodiments, the combination therapies provided herein comprise: (a) about 5 mg to about 50 mg (e.g., about 20 mg to about 30 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, or 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 25 mg, about 30 mg, about 35 mg, about 40 mg, about 4 ... (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 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 and pharma- ceutically acceptable salts thereof. I-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 / AB and at least one compound selected from BV-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-2.5 Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0124] In some embodiments, the combination therapy provided herein comprises: (a) about 5 mg to about 20 mg (e.g., 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 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, or about 20 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 and pharma- ceutical acceptable salts thereof; and (c) optionally, at least one compound selected from PTI-428, ASP-11, ABBV-2222, ABV-2222, ABV-2224, ABV-2226, ABV-2228 ... BV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, FDL-169, ARN5562, ARN21586, ARN22081, A RN22652, ARN23765, ARN23766, PTI-801, FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW25 and at least one compound selected from: 1 (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-2.5 Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0125] In some embodiments, the combination therapy provided herein comprises: (a) about 5 mg to about 10 mg (e.g., 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, or about 10 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 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-4222, ABBV-4223, ABBV-4224, ABBV-4225, ABBV-4226, ABBV-4227, ABBV-4228, ABBV-4229, ABBV-5220, ABBV-5221, ABBV-5222, ABBV-5223, ABBV-5224, ABBV-5225, ABBV-5226, ABBV-5227, ABBV-5228, ABBV-5229 ... V-3748, ABBV-3903, ABBV-119, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, ARN237 66, 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-2.5 Rx, BI 1265162, ARO-ENaC1001, ETD002, and at least one compound selected from DS-1039.

[0126] In some embodiments, the combination therapies provided herein comprise (a) about 1 mg to about 30 mg (e.g., about 5 mg to about 20 mg, about 20 mg to about 30 mg, about 5 mg to about 10 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 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 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 25 mg, or about 30 mg) of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt of any of the foregoing; and (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 and pharma- ceutically acceptable salts thereof. and (c) optionally, 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, and at least one compound selected from 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-2.5 Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0127] In some embodiments, the amount of the active ingredient is from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, from about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg , about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17 mg, approx. 18 mg, approx. 19 mg, approx. 20 mg, approx. 25 mg, approx. 30 mg, approx. 31 mg, approx. 32 mg, approx. 33 mg, approx. 34 mg, approx. 35 mg, approx. 6mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, approx. 100mg, approx. 105mg, approx. 110mg, approx. 115mg, approx. 120mg, approx. 125mg, approx. 130mg, approx. 135mg, approx. 140mg, approx. 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, About 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg,About 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480 mg, approx. 490 mg, approx. 500 mg, approx. 510 mg, approx. 520 mg, approx. 530 mg, approx. 540 mg, approx. 550 mg, approx. 560 mg, approx. 570 mg, approx. 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 mg of Compound I, its deuterated derivative, or any pharma- ceutically acceptable salt thereof, is administered in combination with at least one compound selected from Compound II, and its pharma- ceutically acceptable salts and deuterated derivatives.

[0128] In some embodiments, the amount of the active ingredient is from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, from about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg , about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17 mg, approx. 18 mg, approx. 19 mg, approx. 20 mg, approx. 25 mg, approx. 30 mg, approx. 31 mg, approx. 32 mg, approx. 33 mg, approx. 34 mg, approx. 35 mg, approx. 6mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, approx. 100mg, approx. 105mg, approx. 110mg, approx. 115mg, approx. 120mg, approx. 125mg, approx. 130mg, approx. 135mg, approx. 140mg, approx. 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, About 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg,About 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480 mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 6 40 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 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 and deuterated derivatives thereof.

[0129] In some embodiments, the amount of the active ingredient is from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, from about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg , about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17 mg, approx. 18 mg, approx. 19 mg, approx. 20 mg, approx. 25 mg, approx. 30 mg, approx. 31 mg, approx. 32 mg, approx. 33 mg, approx. 34 mg, approx. 35 mg, approx. 6mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, approx. 100mg, approx. 105mg, approx. 110mg, approx. 115mg, approx. 120mg, approx. 125mg, approx. 130mg, approx. 135mg, approx. 140mg, approx. 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, About 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg,Approx. 365 mg, approx. 370 mg, approx. 375 mg, approx. 380 mg, approx. 385 mg, approx. 390 mg, approx. 395 mg, approx. 400 mg, approx. 410 mg, approx. 420 mg, approx. g, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 64 In one embodiment, the compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing is administered in an amount of about 0 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 mg in combination with at least one compound selected from compound III-d, and pharmaceutically acceptable salts and deuterated derivatives thereof.

[0130] In some embodiments, the amount of the active ingredient is from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, from about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg , about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17 mg, approx. 18 mg, approx. 19 mg, approx. 20 mg, approx. 25 mg, approx. 30 mg, approx. 31 mg, approx. 32 mg, approx. 33 mg, approx. 34 mg, approx. 35 mg, approx. 6mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, approx. 100mg, approx. 105mg, approx. 110mg, approx. 115mg, approx. 120mg, approx. 125mg, approx. 130mg, approx. 135mg, approx. 140mg, approx. 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, About 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg,About 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480 mg, approx. 490 mg, approx. 500 mg, approx. 510 mg, approx. 520 mg, approx. 530 mg, approx. 540 mg, approx. 550 mg, approx. 560 mg, approx. 570 mg, approx. 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 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 pharma- ceutically acceptable salts and deuterated derivatives.

[0131] In some embodiments, the amount of the active ingredient is from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, from about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg , about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17 mg, approx. 18 mg, approx. 19 mg, approx. 20 mg, approx. 25 mg, approx. 30 mg, approx. 31 mg, approx. 32 mg, approx. 33 mg, approx. 34 mg, approx. 35 mg, approx. 6mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, approx. 100mg, approx. 105mg, approx. 110mg, approx. 115mg, approx. 120mg, approx. 125mg, approx. 130mg, approx. 135mg, approx. 140mg, approx. 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, About 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg,About 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480 mg, approx. 490 mg, approx. 500 mg, approx. 510 mg, approx. 520 mg, approx. 530 mg, approx. 540 mg, approx. 550 mg, approx. 560 mg, approx. 570 mg, approx. 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 mg of Compound I, its deuterated derivative, or any of the foregoing pharmaceutically acceptable salts, is administered in combination with at least one compound selected from Compound V, and pharmaceutically acceptable salts and deuterated derivatives thereof.

[0132] In some embodiments, the amount of the active ingredient is from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, from about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg , about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17 mg, approx. 18 mg, approx. 19 mg, approx. 20 mg, approx. 25 mg, approx. 30 mg, approx. 31 mg, approx. 32 mg, approx. 33 mg, approx. 34 mg, approx. 35 mg, approx. 6mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, approx. 100mg, approx. 105mg, approx. 110mg, approx. 115mg, approx. 120mg, approx. 125mg, approx. 130mg, approx. 135mg, approx. 140mg, approx. 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, About 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg,About 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480 mg, approx. 490 mg, approx. 500 mg, approx. 510 mg, approx. 520 mg, approx. 530 mg, approx. 540 mg, approx. 550 mg, approx. 560 mg, approx. 570 mg, approx. 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 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 pharma- ceutically acceptable salts and deuterated derivatives thereof.

[0133] In some embodiments, the amount of the active ingredient is from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, from about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg , about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17 mg, approx. 18 mg, approx. 19 mg, approx. 20 mg, approx. 25 mg, approx. 30 mg, approx. 31 mg, approx. 32 mg, approx. 33 mg, approx. 34 mg, approx. 35 mg, approx. 6mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, approx. 100mg, approx. 105mg, approx. 110mg, approx. 115mg, approx. 120mg, approx. 125mg, approx. 130mg, approx. 135mg, approx. 140mg, approx. 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, About 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg,About 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480 mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 6 40 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 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 pharma- ceutically acceptable salts and deuterated derivatives.

[0134] In some embodiments, the amount of the active ingredient is from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, from about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg , about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17 mg, approx. 18 mg, approx. 19 mg, approx. 20 mg, approx. 25 mg, approx. 30 mg, approx. 31 mg, approx. 32 mg, approx. 33 mg, approx. 34 mg, approx. 35 mg, approx. 6mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, approx. 100mg, approx. 105mg, approx. 110mg, approx. 115mg, approx. 120mg, approx. 125mg, approx. 130mg, approx. 135mg, approx. 140mg, approx. 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, About 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg,About 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480 mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 6 40 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 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 pharma- ceutically acceptable salts and deuterated derivatives thereof.

[0135] In some embodiments, the amount of the active ingredient is from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, from about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg , about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17 mg, approx. 18 mg, approx. 19 mg, approx. 20 mg, approx. 25 mg, approx. 30 mg, approx. 31 mg, approx. 32 mg, approx. 33 mg, approx. 34 mg, approx. 35 mg, approx. 6mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, approx. 100mg, approx. 105mg, approx. 110mg, approx. 115mg, approx. 120mg, approx. 125mg, approx. 130mg, approx. 135mg, approx. 140mg, approx. 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, About 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg,About 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480 mg, approx. 490 mg, approx. 500 mg, approx. 510 mg, approx. 520 mg, approx. 530 mg, approx. 540 mg, approx. 550 mg, approx. 560 mg, approx. 570 mg, approx. 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 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 pharma- ceutically acceptable salts and deuterated derivatives.

[0136] In some embodiments, the amount of the active ingredient is from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, from about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg , about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17 mg, approx. 18 mg, approx. 19 mg, approx. 20 mg, approx. 25 mg, approx. 30 mg, approx. 31 mg, approx. 32 mg, approx. 33 mg, approx. 34 mg, approx. 35 mg, approx. 6mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, approx. 100mg, approx. 105mg, approx. 110mg, approx. 115mg, approx. 120mg, approx. 125mg, approx. 130mg, approx. 135mg, approx. 140mg, approx. 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, About 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg,About 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480 mg, approx. 490 mg, approx. 500 mg, approx. 510 mg, approx. 520 mg, approx. 530 mg, approx. 540 mg, approx. 550 mg, approx. 560 mg, approx. 570 mg, approx. 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 mg of Compound I, its deuterated derivative, or any pharma- ceutically acceptable salt thereof, is administered in combination with at least one compound selected from Compound X, and its pharma- ceutically acceptable salts and deuterated derivatives.

[0137] In some embodiments, about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg, about 2 ... g ~ about 40mg, about 5mg - about 50mg, about 5mg - about 20mg, about 5mg - about 10mg, about 1mg - about 30mg, about 1mg, about 1.5mg, about 2mg, about 2.5mg, about 3 mg, about 3.5 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 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 25 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 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, About 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg , about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325m g, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 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 pharma- ceutically acceptable salts and deuterated derivatives thereof.

[0138] In some embodiments, about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg, about 2 ... g ~ about 40mg, about 5mg - about 50mg, about 5mg - about 20mg, about 5mg - about 10mg, about 1mg - about 30mg, about 1mg, about 1.5mg, about 2mg, about 2.5mg, about 3 mg, about 3.5 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 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 25 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 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, About 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg , about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325m g, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 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 and deuterated derivatives thereof.

[0139] In some embodiments, about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg, about 2 ... g ~ about 40mg, about 5mg - about 50mg, about 5mg - about 20mg, about 5mg - about 10mg, about 1mg - about 30mg, about 1mg, about 1.5mg, about 2mg, about 2.5mg, about 3 mg, about 3.5 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 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 25 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 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, About 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, About 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 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-d, and pharma- ceutically acceptable salts and deuterated derivatives thereof.

[0140] In some embodiments, about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg, about 2 ... g ~ about 40mg, about 5mg - about 50mg, about 5mg - about 20mg, about 5mg - about 10mg, about 1mg - about 30mg, about 1mg, about 1.5mg, about 2mg, about 2.5mg, about 3 mg, about 3.5 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 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 25 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 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, About 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg , about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325m g, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 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 pharma- ceutically acceptable salts and deuterated derivatives thereof.

[0141] In some embodiments, about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg, about 2 ... g ~ about 40mg, about 5mg - about 50mg, about 5mg - about 20mg, about 5mg - about 10mg, about 1mg - about 30mg, about 1mg, about 1.5mg, about 2mg, about 2.5mg, about 3 mg, about 3.5 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 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 25mg, about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg , about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, About 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg , about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250m g, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 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 pharma- ceutically acceptable salts and deuterated derivatives thereof.

[0142] In some embodiments, about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg, about 2 ... g ~ about 40mg, about 5mg - about 50mg, about 5mg - about 20mg, about 5mg - about 10mg, about 1mg - about 30mg, about 1mg, about 1.5mg, about 2mg, about 2.5mg, about 3 mg, about 3.5 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 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 25 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 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, About 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg , about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325m g, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 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 pharma- ceutically acceptable salts and deuterated derivatives thereof.

[0143] In some embodiments, about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg, about 2 ... g ~ about 40mg, about 5mg - about 50mg, about 5mg - about 20mg, about 5mg - about 10mg, about 1mg - about 30mg, about 1mg, about 1.5mg, about 2mg, about 2.5mg, about 3 mg, about 3.5 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 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 25 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 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, About 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg , about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325m g, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 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 pharma- ceutically acceptable salts and deuterated derivatives thereof.

[0144] In some embodiments, about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg, about 2 ... g ~ about 40mg, about 5mg - about 50mg, about 5mg - about 20mg, about 5mg - about 10mg, about 1mg - about 30mg, about 1mg, about 1.5mg, about 2mg, about 2.5mg, about 3 mg, about 3.5 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 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 25 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 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, Approximately 255 mg, approximately 260 mg, approximately 265 mg, approximately 270 mg, approximately 275 mg, approximately 280 mg, approximately 285 mg, approximately 290 mg, approximately 295 mg, approximately 300 mg, approximately 305 mg, approximately 310 mg, approximately 315 mg, approximately 320 mg, approximately 325 mg , about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 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 pharma- ceutically acceptable salts and deuterated derivatives thereof.

[0145] In some embodiments, about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg, about 2 ... g ~ about 40mg, about 5mg - about 50mg, about 5mg - about 20mg, about 5mg - about 10mg, about 1mg - about 30mg, about 1mg, about 1.5mg, about 2mg, about 2.5mg, about 3 mg, about 3.5 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 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 25 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 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, About 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg , about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325m g, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 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 pharma- ceutically acceptable salts and deuterated derivatives thereof.

[0146] In some embodiments, about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg, about 2 ... g ~ about 40mg, about 5mg - about 50mg, about 5mg - about 20mg, about 5mg - about 10mg, about 1mg - about 30mg, about 1mg, about 1.5mg, about 2mg, about 2.5mg, about 3 mg, about 3.5 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 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 25mg, about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg , about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, About 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg , about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250m g, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 In one embodiment, about 300 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 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 X, and pharma- ceutically acceptable salts and deuterated derivatives thereof.

[0147] In some embodiments, the amount of the active ingredient is from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, from about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg , about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17 mg, approx. 18 mg, approx. 19 mg, approx. 20 mg, approx. 25 mg, approx. 30 mg, approx. 31 mg, approx. 32 mg, approx. 33 mg, approx. 34 mg, approx. 35 mg, approx. 6mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, approx. 100mg, approx. 105mg, approx. 110mg, approx. 115mg, approx. 120mg, approx. 125mg, approx. 130mg, approx. 135mg, approx. 140mg, approx. 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, About 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg,Approx. 365 mg, approx. 370 mg, approx. 375 mg, approx. 380 mg, approx. 385 mg, approx. 390 mg, approx. 395 mg, approx. 400 mg, approx. 410 mg, approx. 00mg, 510mg, 520mg, 530mg, 540mg, 550mg, 560mg, 570mg, 580mg, 590mg, 600mg, 610mg, 620mg, 630mg, 640mg, 650mg, 660mg, 670 In one embodiment, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 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 pharma- ceutically acceptable salts and deuterated derivatives, and at least one compound selected from Compound V and its pharma- ceutically acceptable salts and deuterated derivatives.

[0148] In some embodiments, the amount of the active ingredient is from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, from about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg , about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17 mg, approx. 18 mg, approx. 19 mg, approx. 20 mg, approx. 25 mg, approx. 30 mg, approx. 31 mg, approx. 32 mg, approx. 33 mg, approx. 34 mg, approx. 35 mg, approx. 6mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, approx. 100mg, approx. 105mg, approx. 110mg, approx. 115mg, approx. 120mg, approx. 125mg, approx. 130mg, approx. 135mg, approx. 140mg, approx. 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, About 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg,Approx. 365 mg, approx. 370 mg, approx. 375 mg, approx. 380 mg, approx. 385 mg, approx. 390 mg, approx. 395 mg, approx. 400 mg, approx. 410 mg, approx. 00mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670m g, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 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 pharma- ceutically acceptable salts and deuterated derivatives, and at least one compound selected from Compound VI and its pharma- ceutically acceptable salts and deuterated derivatives.

[0149] In some embodiments, the amount of the active ingredient is from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, from about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg , about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17 mg, approx. 18 mg, approx. 19 mg, approx. 20 mg, approx. 25 mg, approx. 30 mg, approx. 31 mg, approx. 32 mg, approx. 33 mg, approx. 34 mg, approx. 35 mg, approx. 6mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, approx. 100mg, approx. 105mg, approx. 110mg, approx. 115mg, approx. 120mg, approx. 125mg, approx. 130mg, approx. 135mg, approx. 140mg, approx. 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, About 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg,Approx. 365 mg, approx. 370 mg, approx. 375 mg, approx. 380 mg, approx. 385 mg, approx. 390 mg, approx. 395 mg, approx. 400 mg, approx. 410 mg, approx. 00mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670m g, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 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 pharma- ceutically acceptable salts and deuterated derivatives, and at least one compound selected from Compound VII and its pharma- ceutically acceptable salts and deuterated derivatives.

[0150] In some embodiments, the amount of the active ingredient is from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, from about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg , about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17 mg, approx. 18 mg, approx. 19 mg, approx. 20 mg, approx. 25 mg, approx. 30 mg, approx. 31 mg, approx. 32 mg, approx. 33 mg, approx. 34 mg, approx. 35 mg, approx. 6mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, approx. 100mg, approx. 105mg, approx. 110mg, approx. 115mg, approx. 120mg, approx. 125mg, approx. 130mg, approx. 135mg, approx. 140mg, approx. 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, About 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg,Approx. 365 mg, approx. 370 mg, approx. 375 mg, approx. 380 mg, approx. 385 mg, approx. 390 mg, approx. 395 mg, approx. 400 mg, approx. 410 mg, approx. 0mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg , about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 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 pharma- ceutically acceptable salts and deuterated derivatives, and at least one compound selected from Compound VIII and its pharma- ceutically acceptable salts and deuterated derivatives.

[0151] In some embodiments, about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg, about 2 ... g ~ about 40mg, about 5mg - about 50mg, about 5mg - about 20mg, about 5mg - about 10mg, about 1mg - about 30mg, about 1mg, about 1.5mg, about 2mg, about 2.5mg, about 3 mg, about 3.5 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 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 25 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, Approx. 54 mg, approx. 55 mg, approx. 56 mg, approx. 57 mg, approx. 58 mg, approx. 59 mg, approx. 60 mg, approx. 65 mg, approx. 70 mg, approx. 75 mg, approx. 80 mg, approx. g, approx. 120 mg, approx. 125 mg, approx. 130 mg, approx. 135 mg, approx. 140 mg, approx. 145 mg, approx. 150 mg, approx. 155 mg, approx. 160 mg, approx. 165 mg, approx. 5mg, approx. 200mg, approx. 205mg, approx. 210mg, approx. 215mg, approx. 220mg, approx. 225mg, approx. 230mg, approx. 235mg, approx. 240mg, approx. 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, about 340mg, about 345mg, about 350mg , about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 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 pharma- ceutically acceptable salts and deuterated derivatives, and at least one compound selected from Compound V and its pharma- ceutically acceptable salts and deuterated derivatives.

[0152] In some embodiments, about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg, about 2 ... g ~ about 40mg, about 5mg - about 50mg, about 5mg - about 20mg, about 5mg - about 10mg, about 1mg - about 30mg, about 1mg, about 1.5mg, about 2mg, about 2.5mg, about 3 mg, about 3.5 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 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 25 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, Approx. 54 mg, approx. 55 mg, approx. 56 mg, approx. 57 mg, approx. 58 mg, approx. 59 mg, approx. 60 mg, approx. 65 mg, approx. 70 mg, approx. 75 mg, approx. 80 mg, approx. g, approx. 120 mg, approx. 125 mg, approx. 130 mg, approx. 135 mg, approx. 140 mg, approx. 145 mg, approx. 150 mg, approx. 155 mg, approx. 160 mg, approx. 165 mg, approx. 5mg, approx. 200mg, approx. 205mg, approx. 210mg, approx. 215mg, approx. 220mg, approx. 225mg, approx. 230mg, approx. 235mg, approx. 240mg, approx. 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, about 340mg, about 345mg, about 350mg , about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 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 pharma- ceutically acceptable salts and deuterated derivatives, and at least one compound selected from Compound VI and its pharma- ceutically acceptable salts and deuterated derivatives.

[0153] In some embodiments, about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg, about 2 ... g ~ about 40mg, about 5mg - about 50mg, about 5mg - about 20mg, about 5mg - about 10mg, about 1mg - about 30mg, about 1mg, about 1.5mg, about 2mg, about 2.5mg, about 3 mg, about 3.5 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 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 25 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, Approx. 54 mg, approx. 55 mg, approx. 56 mg, approx. 57 mg, approx. 58 mg, approx. 59 mg, approx. 60 mg, approx. 65 mg, approx. 70 mg, approx. 75 mg, approx. 80 mg, approx. g, approx. 120 mg, approx. 125 mg, approx. 130 mg, approx. 135 mg, approx. 140 mg, approx. 145 mg, approx. 150 mg, approx. 155 mg, approx. 160 mg, approx. mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, about 2 75mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, about 340mg, about 345mg, about 350mg, About 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 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 pharma- ceutically acceptable salts and deuterated derivatives, and at least one compound selected from Compound VII and its pharma- ceutically acceptable salts and deuterated derivatives.

[0154] In some embodiments, about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg, about 2 ... g ~ about 40mg, about 5mg - about 50mg, about 5mg - about 20mg, about 5mg - about 10mg, about 1mg - about 30mg, about 1mg, about 1.5mg, about 2mg, about 2.5mg, about 3 mg, about 3.5 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 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 25 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, Approx. 54 mg, approx. 55 mg, approx. 56 mg, approx. 57 mg, approx. 58 mg, approx. 59 mg, approx. 60 mg, approx. 65 mg, approx. 70 mg, approx. 75 mg, approx. 80 mg, approx. g, approx. 120 mg, approx. 125 mg, approx. 130 mg, approx. 135 mg, approx. 140 mg, approx. 145 mg, approx. 150 mg, approx. 155 mg, approx. 160 mg, approx. mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, about 2 75mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, about 340mg, about 345mg, about 350mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 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 pharma- ceutically acceptable salts and deuterated derivatives, and at least one compound selected from Compound VIII and its pharma- ceutically acceptable salts and deuterated derivatives.

[0155] Each of Compound I, its deuterated derivatives, or any of the foregoing pharma- ceutically acceptable salts, and 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 their deuterated derivatives and pharma- ceutically acceptable salts, can be administered independently once daily, twice daily, or three times daily.

[0156] In some embodiments, compound I, its deuterated derivative, or any pharma- ceutically acceptable salt thereof is administered once a day. In some embodiments, compound I, its deuterated derivative, or any pharma- ceutically acceptable salt thereof is administered twice a day. In some embodiments, compound I, its deuterated derivative, or any pharma- ceutically acceptable salt thereof, 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 and pharma- ceutically acceptable salt thereof, are administered once a day. In some embodiments, compound I, its deuterated derivative, or any pharma- ceutically acceptable salt thereof, 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 and pharma- ceutically acceptable salt 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 derivatives and pharma- ceutically acceptable salts is 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 derivatives and pharma- ceutically acceptable salts is administered twice daily.

[0157] Compound I, its deuterated derivative, or any of the aforementioned pharma- ceutically acceptable salts, and the additional therapeutic agent can be administered in a single pharmaceutical composition or in separate pharmaceutical compositions. Thus, (a) about 0.1 mg to about 800 mg (e.g., about 1 mg to about 400 mg, about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg, about 2 mg to about 40 mg, about 5 mg to about 50 mg, about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 1 mg to about 30 mg, about 1 mg, about 1.5 mg , about 2 mg, about 2.5 mg, about 3 mg, about 3.5 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 11 mg, about 12 mg, About 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 25mg, about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, About 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 22 5mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg,About 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, about 340mg, about 345mg, about 350mg, about 355mg, about 360mg, about 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395mg, about 400mg, about 410mg, about 420mg, about 430mg, about 44 0mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg (a) about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 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 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 two 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 dose can occur once or twice per day.

[0158] In some embodiments, the amount of the active ingredient is from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, from about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg , about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17 mg, approx. 18 mg, approx. 19 mg, approx. 20 mg, approx. 25 mg, approx. 30 mg, approx. 31 mg, approx. 32 mg, approx. 33 mg, approx. 34 mg, approx. 35 mg, approx. 6mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, approx. 100mg, approx. 105mg, approx. 110mg, approx. 115mg, approx. 120mg, approx. 125mg, approx. 130mg, approx. 135mg, approx. 140mg, approx. 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, About 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg,Approx. 365 mg, approx. 370 mg, approx. 375 mg, approx. 380 mg, approx. 385 mg, approx. 390 mg, approx. 395 mg, approx. 400 mg, approx. 410 mg, approx. 10mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690m g, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 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 and pharma- ceutically acceptable salts thereof is administered in a second pharmaceutical composition.

[0159] Compound I, its deuterated derivative, or any of the aforementioned pharma- ceutically acceptable salts, and the additional therapeutic agent can be administered in a single pharmaceutical composition or in separate pharmaceutical compositions. Thus, (a) about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg, about 2 mg to about 40 mg, about 5 mg to about 50 mg, about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 1 mg to about 30 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3mg, about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 1 5mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 25mg, about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42 mg, approx. 43mg, approx. 44mg, approx. 45mg, approx. 46mg, approx. 47mg, approx. 48mg, approx. 49mg, approx. 50mg, approx. 51mg, approx. 52mg, approx. g, approx. 70 mg, approx. 75 mg, approx. 80 mg, approx. 85 mg, approx. 90 mg, approx. 95 mg, approx. 100 mg, approx. 105 mg, approx. 110 mg, approx. 115 mg, approx. 120 mg, approx. About 155mg, about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 23 5mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg,About 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 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, 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 two 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 dose can occur once or twice per day.

[0160] In some embodiments, about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg, about 2 ... g ~ about 40mg, about 5mg - about 50mg, about 5mg - about 20mg, about 5mg - about 10mg, about 1mg - about 30mg, about 1mg, about 1.5mg, about 2mg, about 2.5mg, about 3 mg, about 3.5 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 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 25mg, about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 20 5mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285 mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, about 340mg, about 345mg, about 350mg, about 355mg, about 360mg, about 365mg , about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 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 and pharma- ceutically acceptable salts thereof is administered in a second pharmaceutical composition.

[0161] 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 and pharma- ceutically acceptable salts thereof. Some exemplary pharmaceutical compositions of Compound II and pharma- ceutically acceptable salts thereof can be found in WO2011 / 119984 and WO2014 / 014841, which are incorporated herein by reference. Some exemplary pharmaceutical compositions of compound III and pharma- ceutically acceptable salts thereof can be found in WO2007 / 134279, WO2010 / 019239, WO2011 / 019413, WO2012 / 027731, and WO2013 / 130669, and some exemplary pharmaceutical compositions of compound III-d and pharma- ceutically acceptable salts thereof can be found in US8,865,902, US9,181,192, US9,512,079, WO2017 / 053455, and WO2018 / 080591, all of which are incorporated herein by reference. Some exemplary pharmaceutical compositions of compound IV and its pharma- ceutically acceptable salts can be found in WO2010 / 037066, WO2011 / 127421, and WO2014 / 071122, which are incorporated herein by reference. Some exemplary pharmaceutical compositions of compound V and its pharma- ceutically acceptable salts can be found in WO2019 / 152940, which are incorporated herein by reference. Some exemplary pharmaceutical compositions of compound VI and its pharma- ceutically acceptable salts can be found in WO2019 / 079760, which are incorporated herein by reference.

[0162] 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.

[0163] In some embodiments, the present disclosure provides (a) from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 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 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 25 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 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg,About 355mg, about 360mg, about 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 4 60mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610 The present invention provides a pharmaceutical composition comprising: about 600 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 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.

[0164] In some embodiments, the present disclosure provides a method for the preparation of a medicament for use in a patient with a disease comprising administering to the patient (a) from about 1 mg to about 400 mg (e.g., from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg , about 2 mg to about 40 mg, about 5 mg to about 50 mg, about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 1 mg to about 30 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, About 3mg, about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5 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 25 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 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg , about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 17 0mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg , about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 3 The present invention provides a pharmaceutical composition comprising: (a) about 15 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 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.

[0165] In some embodiments, the disclosure provides a method for the treatment of atopic dermatitis, comprising administering to a patient a therapeutically effective amount of a medicament comprising administering to a patient a therapeutically effective amount of a medicament, the medicament being administered in an amount of (a) about 5 mg to about 375 mg (e.g., about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 5 mg to about 50 mg, about 5 mg to about 20 mg, about 5 mg to about 10 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 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 25mg, about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg mg, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85m g, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg , about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225m g, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295 The present invention provides a pharmaceutical composition comprising: (a) about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, or about 375 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.

[0166] In some embodiments, the present disclosure provides a method for the preparation of a medicament for use in a patient with a medicament for which the medicament for use in the present invention is administered in a dose range of (a) about 15 mg to about 350 mg (e.g., about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 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 38mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115m g, approx. 120 mg, approx. 125 mg, approx. 130 mg, approx. 135 mg, approx. 140 mg, approx. 145 mg, approx. 150 mg, approx. 155 mg, approx. 160 mg, approx. 90mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, or about 350 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.

[0167] In some embodiments, the present disclosure provides a method for the preparation of a medicament for use in a patient with a medicament for which the medicament for use in the present invention is administered orally, in a dose range of about 30 mg to about 300 mg (e.g., about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 30 mg to about 60 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, 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 81 mg, about 82 mg, about 83 mg, about 84 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, 5mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 12 0mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, about 1 80mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 2 In one embodiment, the pharmaceutical composition comprises about 40 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, or about 300 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.

[0168] In some embodiments, the present disclosure provides a method for the preparation of a medicament for use in a patient with a medicament for which the medicament for use in the present invention is administered orally, in a dose range of (a) about 50 mg to about 200 mg (e.g., about 50 mg to about 175 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 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg) , about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, or about 200 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.

[0169] In some embodiments, the disclosure provides a method of treating a patient with a pulmonary circulation comprising administering to the patient a dose of about 50 mg to about 175 mg (e.g., 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 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg In one embodiment, the pharmaceutical composition comprises at least one of Compound I, a deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, and (b) at least one pharma- ceutically acceptable carrier.

[0170] In some embodiments, the present disclosure provides a method of treating a patient with a pulmonary circulation comprising administering to the patient a dose of (a) about 10 mg to about 200 mg (e.g., about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 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 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 60 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 7 9mg, about 20mg, about 25mg, about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg, about 52mg, about 53 In one embodiment, the pharmaceutical composition comprises about 50 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 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, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, or about 200 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.

[0171] In some embodiments, the disclosure provides a method of treating or preventing atopic dermatitis, comprising administering to a patient a dose of (a) about 20 mg to about 100 mg (e.g., about 30 mg to about 60 mg, about 20 mg, about 25 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 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; and (b) at least one pharma- ceutically acceptable carrier.

[0172] In some embodiments, the disclosure provides a pharmaceutical composition comprising: (a) about 30 mg to about 60 mg (e.g., 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, or 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, or about 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.

[0173] In some embodiments, the disclosure provides a method for the preparation of a medicament for use in a patient with a medicament for which the medicament for use in the present invention is administered in a dose range of (a) about 1 mg to about 50 mg (e.g., about 2 mg to about 40 mg, about 5 mg to about 50 mg, about 5 mg to about 20 mg, about 20 mg to about 30 mg, about 5 mg to about 10 mg, about 1 mg to about 30 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 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 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 ... In one embodiment, the pharmaceutical composition comprises about 1 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 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, 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.

[0174] In some embodiments, the present disclosure provides a method for the preparation of a medicament for use in a patient with a medicament for which the medicament for use in the present invention is administered in a dose range of (a) about 2 mg to about 40 mg (e.g., about 5 mg to about 20 mg, about 20 mg to about 30 mg, about 5 mg to about 10 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 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 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 ... In one embodiment, the pharmaceutical composition comprises about 4 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 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, or about 40 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.

[0175] In some embodiments, the disclosure provides a pharmaceutical composition comprising: (a) about 5 mg to about 50 mg (e.g., about 20 mg to about 30 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, or 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 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 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.

[0176] In some embodiments, the disclosure provides a pharmaceutical composition comprising: (a) about 5 mg to about 20 mg (e.g., 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 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, or about 20 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.

[0177] In some embodiments, the disclosure provides a pharmaceutical composition comprising: (a) about 5 mg to about 10 mg (e.g., 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, or about 10 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.

[0178] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (a) about 1 mg to about 30 mg (e.g., about 5 mg to about 20 mg, about 20 mg to about 30 mg, about 5 mg to about 10 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 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 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 25 mg, or about 30 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.

[0179] In some embodiments, the present invention provides a compound having a concentration of from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, from about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg g, 3mg, 3.5mg, 4mg, 4.5mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 9.5mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16 mg, approx. 17 mg, approx. 18 mg, approx. 19 mg, approx. 20 mg, approx. 25 mg, approx. 30 mg, approx. 31 mg, approx. 32 mg, approx. 33 mg, approx. 34 mg, approx. 35 mg, approx. 5mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 1 80mg, approx. 185mg, approx. 190mg, approx. 195mg, approx. 200mg, approx. 205mg, approx. 210mg, approx. 215mg, approx. 220mg, approx. 225mg, approx. 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, about 340mg, about 345mg, about 350mg, about 355mg,About 360mg, about 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, About 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about The present invention provides a pharmaceutical composition comprising about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 mg of Compound I, its deuterated derivative, 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- ceutical 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 comprisesThe present invention 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.

[0180] In some embodiments, the present invention provides a compound that is effective to treat a patient with a medicament for a dose of about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg, about 2 mg to about 40 mg, about 5 mg to about 50 mg, about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 1 mg to about 30 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, About 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg , 19mg, 20mg, 25mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47m g, approx. 48 mg, approx. 49 mg, approx. 50 mg, approx. 51 mg, approx. 52 mg, approx. 53 mg, approx. 54 mg, approx. 55 mg, approx. 56 mg, approx. 57 mg, approx. 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 1 90mg, approx. 195mg, approx. 200mg, approx. 205mg, approx. 210mg, approx. 215mg, approx. 220mg, approx. 225mg, approx. 230mg, approx. 235mg, approx. 240mg, approx. 245mg, approx. 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, about 340mg, about 345mg, about 350mg, about 355mg, about 360mg, about 365mg,A pharmaceutical composition is provided comprising about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 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, at least one additional active pharmaceutical ingredient is a TMEM16A modulator. In some embodiments, at least one additional active pharmaceutical ingredient is a GPR39 agonist. In some embodiments, the pharmaceutical composition comprises 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.

[0181] In some embodiments, the present invention provides (a) from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 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 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 25 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 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg,About 355mg, about 360mg, about 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395mg, about 400 mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 5 00mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg , about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690 The present invention provides a pharmaceutical composition comprising: (a) about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 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 and pharma- ceutically acceptable salts thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0182] In some embodiments, the present invention provides (a) from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 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 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 25 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 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg,About 355mg, about 360mg, about 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395mg, about 400 mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 5 00mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg , about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690 The present invention provides a pharmaceutical composition comprising: (a) about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 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 and pharma- ceutically acceptable salts thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0183] In some embodiments, the present invention provides a method for treating a patient having a disease comprising administering to the patient a dose of about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg) , about 2 mg to about 40 mg, about 5 mg to about 50 mg, about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 1 mg to about 30 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, About 3mg, about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 25mg, about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg g, approx. 56 mg, approx. 57 mg, approx. 58 mg, approx. 59 mg, approx. 60 mg, approx. 65 mg, approx. 70 mg, approx. 75 mg, approx. 80 mg, approx. 85 mg, approx. , about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 21 0mg, approx. 215mg, approx. 220mg, approx. 225mg, approx. 230mg, approx. 235mg, approx. 240mg, approx. 245mg, approx. 250mg, approx. , about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 3 The present invention provides a pharmaceutical composition comprising: (a) about 75 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 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 and pharma- ceutically acceptable salts thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0184] In some embodiments, the present invention provides a method for treating a patient having a disease comprising administering to the patient a dose of about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg) , about 2 mg to about 40 mg, about 5 mg to about 50 mg, about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 1 mg to about 30 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, About 3mg, about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 25mg, about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg g, approx. 56 mg, approx. 57 mg, approx. 58 mg, approx. 59 mg, approx. 60 mg, approx. 65 mg, approx. 70 mg, approx. 75 mg, approx. 80 mg, approx. 85 mg, approx. , about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 21 0mg, approx. 215mg, approx. 220mg, approx. 225mg, approx. 230mg, approx. 235mg, approx. 240mg, approx. 245mg, approx. 250mg, approx. , about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 3 The present invention provides a pharmaceutical composition comprising: (a) about 75 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 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 and pharma- ceutically acceptable salts thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0185] In some embodiments, the present invention provides (a) from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 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 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 25 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 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg,Approx. 355 mg, approx. 360 mg, approx. 365 mg, approx. 370 mg, approx. 375 mg, approx. 380 mg, approx. 385 mg, approx. 390 mg, approx. 395 mg, approx. 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 65 The present invention provides a pharmaceutical composition comprising: (a) about 0 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 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 deuterated derivatives and pharma- ceutically acceptable salts thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0186] In some embodiments, the present invention provides a method for treating a patient having a disease comprising administering to the patient a dose of about 1 mg to about 400 mg (e.g., about 5 mg to about 375 mg, about 15 mg to about 350 mg, about 30 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 10 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg, about 1 mg to about 50 mg) , about 2 mg to about 40 mg, about 5 mg to about 50 mg, about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 1 mg to about 30 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, About 3mg, about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 25mg, about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110m g, approx. 115 mg, approx. 120 mg, approx. 125 mg, approx. 130 mg, approx. 135 mg, approx. 140 mg, approx. 145 mg, approx. 150 mg, approx. 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265 mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, about 340mg, The present invention provides a pharmaceutical composition comprising: (a) about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 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 deuterated derivatives and pharma-ceutically acceptable salts thereof; and (c) at least one pharma-ceutically acceptable carrier.

[0187] In some embodiments, the present disclosure provides (a) from about 0.1 mg to about 800 mg (e.g., from about 1 mg to about 400 mg, from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg, from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 1 mg to about 30 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 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 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 25 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 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg,About 355mg, about 360mg, about 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395mg, about 400mg, about 41 0mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, About 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 62 0mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, about 700mg, about 710mg, about 720mg, The present invention provides a pharmaceutical composition comprising about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 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 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 deuterated derivatives and pharma- ceutically acceptable salts thereof; and (d) at least one pharma- ceutically acceptable carrier.

[0188] In some embodiments, the present disclosure provides a method for the preparation of a medicament for use in a patient with a disease comprising administering to the patient (a) from about 1 mg to about 400 mg (e.g., from about 5 mg to about 375 mg, from about 15 mg to about 350 mg, from about 30 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 175 mg, from about 10 mg to about 200 mg, from about 20 mg to about 100 mg, from about 20 mg to about 30 mg, from about 30 mg to about 60 mg, from about 1 mg to about 50 mg , about 2 mg to about 40 mg, about 5 mg to about 50 mg, about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 1 mg to about 30 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, About 3mg, about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 25mg, about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg g, approx. 58 mg, approx. 59 mg, approx. 60 mg, approx. 65 mg, approx. 70 mg, approx. 75 mg, approx. 80 mg, approx. 85 mg, approx. 90 mg, approx. 95 mg, approx. 0mg, approx. 145mg, approx. 150mg, approx. 155mg, approx. 160mg, approx. 165mg, approx. 170mg, approx. 175mg, approx. 180mg, approx. g, approx. 230 mg, approx. 235 mg, approx. 240 mg, approx. 245 mg, approx. 250 mg, approx. 255 mg, approx. 260 mg, approx. 265 mg, approx. 270 mg, approx. 275 mg, approx. 280 mg, approx. about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or The present invention provides a pharmaceutical composition comprising: (a) about 400 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 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 deuterated derivatives and pharma- ceutically acceptable salts thereof; and (d) at least one pharma- ceutically acceptable carrier.

[0189] In some embodiments, the pharmaceutical compositions provided herein comprise: (a) a dose of about 0.1 mg to about 800 mg (e.g., about 1 m...

Claims

1. Compound I in the manufacture of drugs for treating cystic fibrosis: 【Transformation 38】 Alternatively, the use of a deuterated derivative thereof or any of the aforementioned pharmaceutically acceptable salts, wherein the agent contains about 0.1 mg to about 800 mg of compound I or an equivalent amount thereof of a deuterated derivative thereof or a pharmaceutically acceptable salt.

2. The use according to claim 1, characterized in that the drug is administered daily in an amount of about 1 mg to about 50 mg of compound I or an equivalent amount thereof, such as a deuterated derivative or a pharmaceutically acceptable salt.

3. The use according to claim 1, wherein the patient is heterozygous and has one F508del mutation.

4. The use according to claim 1, characterized in that compound I or its deuterated derivative or a pharmaceutically acceptable salt is administered once daily as a single dose.

5. The use according to claim 1, characterized in that compound I or its deuterated derivative or a pharmaceutically acceptable salt is administered daily in two doses.

6. The use according to claim 1, characterized in that the drug is administered in combination with one or more additional therapeutic agents.

7. The one or more additional therapeutic agents mentioned above (a) (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropane-2-yl)-1H-indole-5-yl)cyclopropanecarboxamide (compound II): 【Chemistry 39】 (b) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide)-3-methylpyridine-2-yl)benzoic acid (compound IV): 【Chemistry 40】 (c) N-(1,3-dimethylpyrazole-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazole-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidine-1-yl]pyridine-3-carboxamide (compound V): 【Chemistry 41】 (d) N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidine-1-yl]pyridine-3-carboxamide (compound VI): 【Chemistry 42】 (e) (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazole-1-yl]-12,12-dimethyl-2λ ６ -Tia-3,9,11,18,23-pentazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound VII): 【Chemistry 43】 (f)(11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2,3]hexane-5-yl}-9-oxa-2λ ６ -Tia-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 44】 (g) N-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidine-1-yl]pyridine-3-carboxamide (compound IX): 【Chemistry 45】 (h) N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidine-1-yl]pyridine-3-carboxamide (compound X): 【Chemistry 46】 (i) N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide (compound III): 【Chemistry 47】 (j) 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 48】 The use according to claim 6, further comprising a compound selected from the deuterated derivative thereof and any of the aforementioned pharmaceutically acceptable salts.

8. A pharmaceutical composition comprising approximately 0.1 mg to approximately 800 mg of compound I or an equivalent amount thereof, such as its deuterated derivative or a pharmaceutically acceptable salt.

9. The pharmaceutical composition according to claim 8, wherein the composition comprises about 1 mg to about 50 mg of compound I or an equivalent amount thereof, a deuterated derivative, or a pharmaceutically acceptable salt.

10. The pharmaceutical composition according to claim 8, wherein the composition further comprises one or more additional therapeutic agents.

11. The one or more additional therapeutic agents mentioned above (a) Compound II, (b) compound IV, (c) compound V, (d) compound VI, (e) Compound VII, (f) compound VIII, (g) Compound IX, (h) Compound X, (i) Compound III, (j) compound III-d, The pharmaceutical composition according to claim 10, further comprising a deuterated derivative thereof and a compound selected from any of the aforementioned pharmaceutically acceptable salts.

12. The pharmaceutical composition according to claim 8, for use in the treatment of cystic fibrosis.

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