Methods of treating cystic fibrosis

Abstract

# imgabs0 # The disclosure provides a method of treating cystic fibrosis or CFTR mediated disease comprising administering Compound (I), a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, e.g., from 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 pharmaceutically acceptable salt of any of the foregoing, and optionally comprising one or more additional CFTR modulators.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 342,418, filed on May 16, 2022, the contents of which are incorporated by reference in their entirety.

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

[0003] Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 88,000 children and adults worldwide. Despite advances in treatment, CF remains incurable.

[0004] In CF patients, mutations in the endogenously expressed CFTR in the respiratory epithelium lead to reduced apical anion secretion, resulting in an imbalance in ion and fluid transport. The resulting reduction in anion transport leads to increased mucus accumulation in the lungs, and accompanied by microbial infections, ultimately leading to death in CF patients. In addition to respiratory diseases, CF patients often suffer from gastrointestinal problems and pancreatic insufficiency, which can lead to death if not treated. In addition, most men with cystic fibrosis are infertile, and women with cystic fibrosis have reduced fertility.

[0005] Sequence analysis of the CFTR gene has revealed a variety of pathogenic 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, more than 2000 mutations in the CF gene have been identified; currently, the CFTR2 database contains information on at least 322 of these identified mutations, with sufficient evidence to define at least 281 mutations as pathogenic. The most common pathogenic mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence and is often referred to as the F508del mutation. This mutation occurs in many cases of cystic fibrosis and is associated with severe disease.

[0006] CFTR is the cAMP / ATP-mediated anion channel expressed in various cell types comprising absorptive and secretory epithelial cells, wherein the CFTR regulates the anion flux across the membrane and the activity of other ion channels and proteins. In epithelial cells, the normal function of CFTR is most important for maintaining the transport of electrolytes throughout the body (comprising respiratory and digestive tissues). CFTR is composed of 1480 amino acids of coded proteins, and the protein is composed of tandem repeats of a transmembrane domain, and each transmembrane domain contains six transmembrane helices and nucleotide binding domains. Two transmembrane domains are connected with multiple phosphorylation sites by large polarity regulation (R) domains, which regulate channel activity and cellular transport.

[0007] Chloride transport is carried out by ENaC (epithelial sodium channel) and CFTR present on the apical membrane and by Na+ expressed on the basolateral surface of the cell. + -K + The coordinated activity of the Na-ATPase pump and the Cl- channels is responsible for the transport of chloride. Secondary active transport of chloride from the luminal side results in the accumulation of intracellular chloride, which can then passively leave the cell via the Cl- channels, thus mediating the transport of Na. + / 2Cl- / K + Co-transporter, Na + -K + -ATPase pump and basolateral membrane K on the basolateral surface + The arrangement of channels and CFTR on the luminal side coordinates the secretion of chloride. Since water itself may not be actively transported, its flow across the epithelium depends on the small transepithelial osmotic gradient created by the bulk flow of sodium and chloride.

[0008] A variety of CFTR modulators have been identified recently. These modulators can be characterized as, for example, potentiators, correctors, potentiator enhancers / 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 surface of epithelial cells are called potentiators. Correctors improve erroneous protein processing and the resulting transport to the epithelial surface. Ghelani and Schneider-Futschik (2020) ACS Pharmacology and Translational Science (ACS Pharmacol. Transl. Sci.) 3:4-10. The U.S. FDA has approved three CFTR correctors for the treatment of cystic fibrosis. However, monotherapy with some CFTR correctors has not been found to be effective enough, and therefore combination therapy with potentiators is generally required to enhance CFTR activity. Currently only one CFTR potentiator is approved for the treatment of cystic fibrosis. Therefore, novel treatments for cystic fibrosis and other CFTR-mediated diseases are needed.

[0009] Thus, one aspect of the present disclosure provides a CFTR modulating compound (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (Compound I), its deuterated derivatives, and pharmaceutically acceptable salts of any of the foregoing. Compound I can be depicted as having the following structure:

[0010]

[0011] Other aspects of the present disclosure provide pharmaceutical compositions comprising Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, which may further comprise at least one additional active pharmaceutical ingredient and / or at least one pharmaceutically acceptable carrier. Yet another aspect of the present disclosure is a method for treating CFTR-mediated disease cystic fibrosis, the method comprising administering Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing to a subject in need thereof, optionally as part of a pharmaceutical composition comprising at least one additional component.

[0012] Another aspect of the present invention provides a method for treating cystic fibrosis, a CFTR-mediated disease, comprising administering to a patient in need thereof Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, alone or in combination with one or more additional CFTR modulators selected from the group consisting of: (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylprop-2- 1H-indol-5-yl)cyclopropanecarboxamide (compound II), N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (also known as N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide) (compound III) or N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl)-1,1,1 ,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (Compound III-d), 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound IV), N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)- 2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound V), N-(phenylsulfonyl)-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]hept-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -thia-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), (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6-thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione (Compound VIII); N-(phenylsulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound IX) and N-[(6-amino-2-pyridinyl)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 pharmaceutically acceptable salt of any of the foregoing is administered in the same composition with at least one compound selected from the following: Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, a deuterated derivative thereof, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, a composition comprising Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing is co-administered with a separate composition comprising at least one compound selected from the following: Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, a deuterated derivative thereof, and a pharmaceutically acceptable salt of any of the foregoing.

[0013] Another aspect of the present invention provides a method for treating CFTR-mediated disease cystic fibrosis, the method comprising administering Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing to a patient in need thereof, and optionally further administering one or more additional CFTR modulators selected from the following: ASP-11, disclosed in Journal of Cystic Fibrosis (2018), 17(5), 595–606; and nesolicaftor or PTI-428, disclosed in WO 2016 / 105485. In one embodiment, the additional CFTR modulator is ASP-11. In one embodiment, the additional CFTR modulator comprises PTI-428.

[0014] Another aspect of the present invention provides a method for treating the CFTR-mediated disease cystic fibrosis, the method comprising administering to a patient in need thereof a pharmaceutically acceptable salt of Compound I, a deuterated derivative thereof, or any one of the foregoing, and optionally further administering one or more additional CFTR modulators selected from the following: galicaftor or ABBV-2222, disclosed in U.S. Patent Application Publication No. 2016-0120841; ABBV-3221, disclosed in WO 2018 / 065921; posenacaftor or PTI-801, disclosed in WO 2017 / 062581; ABBV-2851, disclosed in WO 2017 / 009804; GLPG2737, disclosed in U.S. Patent Application Publication No. 2017-0101405; ABBV-3748; ABBV-3903; and ABBV-119.

[0015] In certain embodiments, the pharmaceutical composition of the present invention includes Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing, and may optionally further include at least one compound selected from the following: Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, a deuterated derivative thereof, and a pharmaceutically acceptable salt of any one of the foregoing. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 An X-ray powder diffraction (XRPD) pattern of crystalline Compound 1 Form A (pure) is provided.

[0017] Figure 2 Provided is a Differential Scanning Calorimetry (DSC) analysis of crystalline Compound I Form A (pure).

[0018] Figure 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.

[0019] Figure 4 The study design for Part B of the FIH study of Compound I is provided, and the doses studied are provided.

[0020] definition

[0021] As used throughout this disclosure, "Compound I" refers to (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, which can be depicted as having the following structure:

[0022]

[0023] Compound I may be a racemic mixture or an enantiomerically enriched (e.g., >90% ee, >95% ee, >98% ee) mixture of isomers. Compound I or its deuterated derivative may be in the form of a pharmaceutically acceptable salt, solvate and / or hydrate. Compound I and methods for preparing and using Compound I are disclosed in PCT International Application No. PCT / US2021 / 072475, which is incorporated herein by reference.

[0024] As used herein, "Compound II" refers to (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, which can be depicted by the following structure:

[0025]

[0026] Compound II may be in the form of a pharmaceutically acceptable salt. Compound II and methods of making and using Compound II are disclosed in WO 2010 / 053471, WO 2011 / 119984, WO 2011 / 133751, WO 2011 / 133951 and WO 2015 / 160787, each of which is incorporated herein by reference.

[0027] As used throughout this disclosure, "Compound III" refers to N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (also known as N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide), which is depicted by the following structure:

[0028]

[0029] Compound III may also be in the form of a pharmaceutically acceptable salt.Compound III and methods of making and using Compound III are disclosed in WO 2006 / 002421, WO 2007 / 079139, WO 2010 / 108162 and WO 2010 / 019239, each of which is incorporated herein by reference.

[0030] 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, as depicted in the following structure:

[0031]

[0032] Compound III-d may be in the form of a pharmaceutically acceptable salt. Compound III-d and methods for preparing and using Compound III-d are disclosed in WO 2012 / 158885, WO 2014 / 078842, WO 2019 / 109021, and U.S. Pat. No. 8,865,902, which are incorporated herein by reference.

[0033] As used herein, "Compound IV" refers to 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, which is depicted by the following chemical structure:

[0034]

[0035] Compound IV may be in the form of a pharmaceutically acceptable salt. Compound IV and methods of making and using Compound IV are disclosed in WO 2007 / 056341, WO 2009 / 073757 and WO 2009 / 076142, which are incorporated herein by reference.

[0036] As used herein, "Compound V" refers to N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, which is depicted by the following chemical structure:

[0037]

[0038] Compound V may be in the form of a pharmaceutically acceptable salt. Compound V and methods of making and using Compound V are disclosed in WO 2018 / 107100 and WO 2019 / 113476, which are incorporated herein by reference.

[0039] 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 depicted by the following chemical structure:

[0040]

[0041] Compound VI may be in the form of a pharmaceutically acceptable salt. Compound VI and methods for preparing and using Compound VI are disclosed in WO 2018 / 064632 and WO 2019 / 113476, which are incorporated herein by reference.

[0042] As used herein, "Compound VII" refers to (14S)-8-[3-(2-{dispiro[2.0.2.1]hept-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]tetracosyl-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione, said compound being depicted by the following chemical structure:

[0043]

[0044] Compound VII may be in the form of a pharmaceutically acceptable salt. Compound VII and methods for preparing and using Compound VII are disclosed in WO 2019 / 161078, WO 2020 / 102346 and WO 2021 / 030554, which are incorporated herein by reference.

[0045] 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]nonadecan-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione, the compound being depicted by the following chemical structure:

[0046]

[0047] Compound VIII may be in the form of a pharmaceutically acceptable salt. Compound VIII and methods of making and using Compound VIII are disclosed in WO 2020 / 206080, which is incorporated herein by reference.

[0048] As used herein, "Compound IX" refers to N-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, which is depicted by the following chemical structure:

[0049]

[0050] Compound IX may be in the form of a pharmaceutically acceptable salt. Compound IX and methods of making and using Compound IX are disclosed in WO 2016 / 057572, which is incorporated herein by reference.

[0051] As used herein, "Compound X" refers to N-[(6-amino-2-pyridinyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, which is depicted by the following chemical structure:

[0052]

[0053] Compound X may be in the form of a pharmaceutically acceptable salt. Compound X and methods of making and using Compound X are disclosed in WO 2016 / 057572, which is incorporated herein by reference.

[0054] As used herein, "CFTR" means cystic fibrosis transmembrane conductance regulator.

[0055] As used herein, "mutation" may refer to a mutation in a CFTR gene or CFTR protein. "CFTR gene mutation" refers to a mutation in a CFTR gene, and "CFTR protein mutation" refers to a mutation in a CFTR protein. Genetic defects or mutations in a gene (i.e., changes in one or more nucleotides) typically result in mutations (i.e., changes in one or more amino acids) or frameshifts (i.e., changes in the reading frame that controls how the CFTR gene is translated into the CFTR protein).

[0056] As used herein, the term "F508del" refers to a mutant CFTR protein lacking the amino acid phenylalanine at position 508, or to a mutant CFTR gene encoding a CFTR protein lacking the amino acid phenylalanine at position 508.

[0057] As used herein, a patient who is "homozygous" for a particular genetic mutation has the same mutation on each allele.

[0058] As used herein, a patient who is "heterozygous" for a particular genetic mutation has that mutation on one allele and a different mutation on the other allele.

[0059] 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.

[0060] As used herein, the term "CFTR corrector" refers to a compound that promotes the processing and transport 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.

[0061] As used herein, the term "CFTR potentiator" refers to a compound that increases the channel activity of the CFTR protein located at the cell surface, thereby resulting in enhanced ion transport. Compound III and Compound III-d disclosed herein are CFTR potentiators.

[0062] As used herein, the term "active pharmaceutical ingredient" ("API") or "therapeutic agent" refers to a biologically active compound.

[0063] It should be understood that certain compounds of the present invention may exist as individual stereoisomers or enantiomers and / or mixtures of those stereoisomers or enantiomers. As used in the chemical structures disclosed herein, the "wedge" with respect to stereogenic atoms is or "hash" A bond indicates a chiral center of known absolute stereochemistry (ie, one stereoisomer). As used in the chemical structures disclosed herein, a "wavy" bond to a stereogenic atom indicates a chiral center of unknown absolute stereochemistry (i.e., one stereoisomer). As used in the chemical structures disclosed herein, a "wavy" bond to a double-bonded carbon indicates a mixture of E / Z isomers. As used in the chemical structures disclosed herein, the ("straight") bonds indicate that a mixture (e.g., a racemate or an enrichment) is present. As used herein, the two carbon atoms of a double bond are ("straight") bonds indicate that the double bond has the E / Z stereochemistry as drawn. As used in the chemical structures disclosed herein, (ie, a "wavy" line perpendicular to the "straight" bond of group "A") indicates that group "A" is a substituent whose point of attachment is at the end of the bond terminating at the "wavy" line.

[0064] The terms "patient" and "subject" are used interchangeably and refer to animals including humans.

[0065] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to the amount of a compound that produces the desired effect for which the compound is administered (e.g., improving CF or a symptom of CF, or reducing the severity of a symptom of CF). The exact amount of an effective dose will depend on the purpose of the treatment and will be determined by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0066] As used herein, the terms "treatment", "treating" and the like generally mean improving one or more CF symptoms in a patient diagnosed with CF, reducing the severity of CF or one or more symptoms thereof in a subject, or slowing the progression of the disease in a subject. As used herein, "treatment" includes, but is not limited to, the following: increased growth, increased weight gain, reduced mucus in the lungs, improved pancreatic and / or liver function, reduced chest infection, and / or reduced cough or shortness of breath in a subject. Improvement of any of these symptoms, reduction in severity, or slowing of disease progression can be readily assessed according to standard methods and techniques known in the art.

[0067] 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 the patient before, simultaneously with, or after each other.

[0068] When used in conjunction with the dosage, amount or weight percentage of the ingredients of a composition or dosage form, the terms "about" and "approximately" include a specified dosage, amount or weight percentage value or a range of the dosage, amount or weight percentage that is considered by a person of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from a specified dosage, amount or weight percentage. The terms "about" and "approximately" may refer to an acceptable error of a specific value determined by a person skilled in the art, which depends in part on how to measure or determine the value. 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.

[0069] As used herein, "minimally functional (MF) mutations" refer to CFTR gene mutations that are associated with minimal CFTR function (very low to no functional CFTR protein), and include, for example, mutations associated with severe defects in the ability of the CFTR channel to open and close, known as defective channel gating or "gating mutations"; mutations associated with severe defects in the cellular processing of CFTR and its delivery to the cell surface; mutations associated with no (or minimal) CFTR synthesis; and mutations associated with severe defects in channel transduction.

[0070] As used herein, "deuterated derivative" means the same chemical structure wherein one or more hydrogen atoms are replaced by deuterium atoms.

[0071] As used herein, the term "pharmaceutically acceptable salt" refers to a salt form of a compound of the present disclosure, or a deuterated derivative thereof, wherein the salt is non-toxic. Pharmaceutically acceptable salts of compounds of the present disclosure include salts derived from suitable inorganic and organic acids and bases. For example, a "free base" form of a compound does not contain ionically bonded salts.

[0072] With respect to one or more compounds or formulae of the invention, the phrase "a deuterated derivative or a pharmaceutically acceptable salt thereof" is used interchangeably with "a deuterated derivative thereof or a pharmaceutically acceptable salt of any of the foregoing." The phrase "a pharmaceutically acceptable salt and a deuterated derivative thereof" is used interchangeably with "a pharmaceutically acceptable salt thereof and a deuterated derivative of any of the foregoing" when referring to one or more compounds or formulae of the invention. These phrases are intended to encompass pharmaceutically acceptable salts of any of the cited compounds, deuterated derivatives of any of the cited compounds, deuterated derivatives of pharmaceutically acceptable salts of any of the cited compounds, and pharmaceutically acceptable salts of deuterated derivatives of any of the cited compounds.

[0073] One of ordinary skill in the art will recognize that when an amount of "a compound or a pharmaceutically acceptable salt thereof" is disclosed, the amount of the pharmaceutically acceptable salt form of the compound is an amount equivalent to the concentration of the free base of the compound. It should be noted that the amounts of the compounds or pharmaceutically acceptable salts thereof disclosed herein are based on their free base form. For example, "100 mg of Compound 1 or a pharmaceutically acceptable salt thereof" or "100 mg of Compound 1 or an equivalent amount of a pharmaceutically acceptable salt thereof" includes 100 mg of Compound 1 and an amount of a pharmaceutically acceptable salt of Compound 1 equivalent to 100 mg of Compound 1.

[0074] Suitable pharmaceutically acceptable salts are, for example, those disclosed in SM Berge et al., Journal of Pharmaceutical Sciences, 1977, 66, 1-19. For example, Table 1 of the article provides the following pharmaceutically acceptable salts:

[0075] Table 1:

[0076]

[0077] Non-limiting examples of pharmaceutically acceptable acid addition salts include: salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or perchloric acid; salts formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid; and salts formed by using other methods used in the art, such as ion exchange. Non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbic acid, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfuric acid, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4Salts. The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali metal and alkaline earth metal salts include sodium, lithium, potassium, calcium and magnesium. Additional non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include benzenesulfonates and glucosamine salts.

[0078] As used herein, the term "XRPD" refers to the analytical characterization method of X-ray powder diffraction. The XRPD patterns disclosed herein are recorded under ambient conditions using a diffractometer in transmission or reflection geometry.

[0079] As used herein, the terms "X-ray powder diffraction pattern", "X-ray powder diffraction pattern", "XRPD pattern", "XRPD spectrum" refer interchangeably to an experimentally obtained graph that plots signal position (on the abscissa) versus signal intensity (on the ordinate). For amorphous materials, an X-ray powder diffraction pattern may include one or more broad signals; and for crystalline materials, an X-ray powder diffraction pattern may include one or more signals, each identified by its angle value as measured in 2θ degrees (°2θ), depicted on the abscissa of the X-ray powder diffraction pattern, which signals may be represented as "signal at 2θ degrees ...", "signal at [a] 2θ value of ...", and / or "signal at at least ... selected from ... 2θ values ​​​​of ...".

[0080] As used herein, the term "DSC" refers to the analytical method of Differential Scanning Calorimetry.

[0081] As used herein, the term "melting temperature," "melting point," or "Tm" refers to the temperature at which a material transitions from a solid phase to a liquid phase. DETAILED DESCRIPTION

[0082] Treatment

[0083] Compound I, its deuterated derivative or any of the pharmaceutically acceptable salts of the foregoing can serve as CFTR regulators, i.e., it regulates the CFTR activity in vivo. Individuals mutated in the gene encoding CFTR can benefit from receiving CFTR regulators. CFTR mutations may affect CFTR amount, i.e., the number of CFTR channels at the cell surface, or they may affect CFTR function, i.e., the functional ability of each channel to open and transport ions. The mutations affecting the amount of CFTR include mutations that cause synthesis defects (class I defects), mutations that cause processing and transport defects (class II defects), mutations that cause CFTR synthesis to reduce (class V defects), and mutations that reduce the surface stability of CFTR (class VI defects). The mutations that affect CFTR function include mutations that cause gating defects (class III defects) and mutations that cause conduction defects (class IV defects). Some CFTR mutations show the characteristics of multiple categories. Some mutations in the CFTR gene cause CF.

[0084] Therefore, in some embodiments, the present invention provides a method for treating cystic fibrosis in a patient, reducing its severity, or treating symptoms thereof, the method comprising administering to the patient an effective amount of Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, alone or in combination with another active ingredient such as another CFTR modulator. In some embodiments, the patient has a F508del / minimal function (MF) genotype, a F508del / F508del genotype (homozygous for the F508del mutation), a F508del / gating genotype, or a F508del / residual function (RF) genotype. In some embodiments, the patient is heterozygous and has one F508del mutation. In some embodiments, the patient is homozygous for the F508del mutation. In some embodiments, the patient is homozygous for the N1303K mutation.

[0085] In some embodiments, 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 3.5mg, 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 mg, 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 1 85mg, 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 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 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 pharmaceutically acceptable salt of any of the foregoing.

[0086] 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, 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 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 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, 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 pharmaceutically acceptable salt of any of the foregoing.

[0087] In some embodiments, 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. 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 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 18 5mg, 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 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 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 pharmaceutically acceptable salt of any of the foregoing, is administered in a single dose.

[0088] 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, 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 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 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 155m g, 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 2 95 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 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 pharmaceutically acceptable salt of any of the foregoing, is administered in a single dose.

[0089] In some embodiments, 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. 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 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 18 5mg, 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 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 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 pharmaceutically acceptable salt of any of the foregoing is administered in two doses.

[0090] 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, 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 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 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 155m g, 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 2 95 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 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 pharmaceutically acceptable salt of any of the foregoing, is administered in two doses.

[0091] In some embodiments, the patient is heterozygous and has a F508del mutation on one allele and a mutation on the other allele selected from Table 2:

[0092] Table 2: CFTR mutations

[0093]

[0094]

[0095] In some embodiments, the present disclosure also relates to methods of treatment using isotopically labeled compounds of the aforementioned compounds or pharmaceutically acceptable salts thereof, wherein the formulas and variables of such compounds and salts are each and independently as described above or in any other embodiment above, with the proviso that one or more atoms are replaced by one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the atoms normally occurring in nature (isotopically labeled). Examples of commercially available isotopes suitable for use in the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, respectively. 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl.

[0096] Isotope-labeled compounds and salts can be used in a variety of beneficial ways. The compounds and salts can be suitable for use in pharmaceuticals and / or various types of assays, such as substrate tissue distribution assays. For example, tritium ( 3 H) and / or carbon-14 ( 14 Compounds labeled with deuterium (C) are particularly useful in various types of assays, such as substrate tissue distribution assays, because of their relatively simple preparation and excellent detectability. 2 H) The labeled compound is therapeutically useful and is comparable to non- 2 H-labeled compounds have potential therapeutic advantages. In general, deuterated compounds ( 2 H) labeled compounds and salts may have higher metabolic stability due to the kinetic isotope effect described below. Higher metabolic stability is directly converted into increased half-life in vivo or lower dosage, which may be desirable. Isotope-labeled compounds and salts may generally be prepared by replacing unisotope-labeled reactants with readily available isotope-labeled reactants by performing the procedures disclosed in the synthetic schemes and related descriptions, in the examples section, and in the preparation section.

[0097] In some embodiments, isotopically labeled compounds and salts are deuterated ( 2 In some embodiments, the isotopically labeled compounds and salts are deuterated with deuterium ( 2 H) labeled with one or more hydrogen atoms replaced by deuterium. In chemical structures, deuterium is represented by “ 2 "H" or "D".

[0098] When discovering and developing therapeutic agents, one skilled in the art attempts to optimize pharmacokinetic parameters while retaining desired in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic properties are susceptible to oxidative metabolism.

[0099] Deuterium 2 H) labeled compounds and salts can modulate the oxidative metabolism of compounds via the primary kinetic isotope effect. The primary kinetic isotope effect is a change in the rate of a chemical reaction caused by the exchange of isotopic nuclei, which in turn causes a change in the ground state energy required to form a covalent bond after this isotope exchange. The exchange of heavier isotopes generally lowers the ground state energy of a chemical bond and, therefore, reduces rate-limiting bond breakage. If bond breakage occurs in or near a saddle point region along the coordinates of a multi-product reaction, the product distribution ratio can change significantly. Explanation: If deuterium is bonded to a carbon atom at a non-exchangeable position, then k M / k D = 2-7 ​​rate differences are typical. For further discussion, see SL Harbeson and RD Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417, incorporated herein by reference.

[0100] The concentration of an isotope (e.g., deuterium) incorporated into the isotopically labeled compounds and salts of the present disclosure can be defined by an isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a particular isotope. In some embodiments, if a substituent in a compound of the present disclosure is represented as deuterium, such compound has 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).

[0101] Combination therapy

[0102] One aspect disclosed herein provides methods of treating CF and other CFTR-mediated diseases using Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing in combination with at least one additional active pharmaceutical ingredient (API).

[0103] Thus, in some embodiments, the present invention provides a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, the method 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 400 mg) of CFTR alone or in combination with at least one additional active pharmaceutical ingredient, such as a CFTR modulator. 0mg, about 5mg to about 50mg, about 5mg to about 20mg, about 5mg to about 10mg, about 1mg to about 30mg, about 1mg, 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 g, 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, 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 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 530 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 pharmaceutically acceptable salt of any of the foregoing.

[0104] In some embodiments, the present invention provides a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, the method 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 20mg to about 30mg, about 30mg to about 60mg, about 1mg to about 50mg, about 2mg to about 40mg, about 5mg to about 50mg, about 5mg to about 20mg, about 5mg to about 10mg, about 1mg to about 30mg, about 1mg, 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 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 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, 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 pharmaceutically acceptable salt of any of the foregoing.

[0105] In some embodiments, the present invention provides a method of treating, lessening the severity of, or treating the symptoms of cystic fibrosis in a patient, the method 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 mg, 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 14 0mg, 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 2 70 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 a pharmaceutically acceptable salt of any of the foregoing.

[0106] In some embodiments, the present invention provides a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, the method 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 to about 30 mg, about 20 mg to about 60 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg to about 30 mg, about 20 mg to about 30 mg, about 20 mg to about 60 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg to about 30 mg, about 20 mg to about 30 mg, about 20 mg to about 30 mg, about 20 mg to about 60 mg, about 20 mg, about 20 mg to about 3 ... 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 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 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, 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 705 mg, about 710 mg, about 715 mg, about 720 mg, about 725 mg, about 730 mg, about 735 mg, about 740 mg, about 750 mg, or about 760 mg) of Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0107] In some embodiments, the present invention provides a method of treating, lessening the severity of, or treating the symptoms of cystic fibrosis in a patient, the method 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 ... 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 g, 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 g, 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 or about 300 mg) of Compound I, its deuterated derivative, or a pharmaceutically acceptable salt of any one of the foregoing.

[0108] In some embodiments, the present invention provides a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, the method 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 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 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 103 mg, about 104 mg, about 105 mg, about 106 mg, about 107 mg, about 108 mg, about 109 mg, about 110 mg, about 111 mg, about 112 mg, about 113 mg, about 114 mg, about 115 mg, about 116 mg, about 117 mg, about 118 mg, about 119 mg, about 120 mg, about 121 mg, about 122 mg, about 123 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, its deuterated derivative or a pharmaceutically acceptable salt of any one of the foregoing.

[0109] In some embodiments, the present invention provides a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, the method 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 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 103 mg, about 104 mg, about 105 mg, about 106 mg, about 107 mg, about 108 mg, about 109 mg, about 110 mg, about 111 mg, about 112 mg, about 113 mg, about 114 mg, about 115 mg, about 116 mg, about 117 mg, 0 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 or about 175 mg) of Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0110] In some embodiments, the present invention provides a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, the method 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, 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 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 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, its deuterated derivative, or a pharmaceutically acceptable salt of any one of the foregoing.

[0111] In some embodiments, the present invention provides a method of treating, lessening the severity of, or treating the symptoms of cystic fibrosis in a patient, the method 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) of the compound of claim 1, alone or in combination with at least one additional active pharmaceutical ingredient, such as a CFTR modulator. or about 100 mg) of Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0112] In some embodiments, the present invention provides a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, the method comprising administering to the patient from 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 pharmaceutically acceptable salt of any of the foregoing, alone or in combination with at least one additional active pharmaceutical ingredient, such as a CFTR modulator.

[0113] In some embodiments, the present invention provides a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, the method comprising administering to the patient from about 1 mg to about 50 mg (e.g., from about 2 mg to about 40 mg, from about 5 mg to about 50 mg, from about 20 mg to about 30 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 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 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 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 pharmaceutically acceptable salt of any of the foregoing.

[0114] In some embodiments, the present invention provides a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, the method 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 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 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 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 or about 40 mg) of Compound I, its deuterated derivative, or a pharmaceutically acceptable salt of any of the foregoing.

[0115] In some embodiments, the present invention provides a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, the method comprising administering to the patient from 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 pharmaceutically acceptable salt of any of the foregoing, alone or in combination with at least one additional active pharmaceutical ingredient, such as a CFTR modulator.

[0116] In some embodiments, the present invention provides a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, the method 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 pharmaceutically acceptable salt of any of the foregoing, alone or in combination with at least one additional active pharmaceutical ingredient, such as a CFTR modulator.

[0117] In some embodiments, the present invention provides a method for treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, the method 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 pharmaceutically acceptable salt of any of the foregoing, alone or in combination with at least one additional active pharmaceutical ingredient, such as a CFTR modulator.

[0118] In some embodiments, the present invention provides a method of treating, lessening the severity of, or treating the symptoms of cystic fibrosis in a patient, the method 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 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 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 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 47 mg, about 48 mg, about 49 mg, about 50 ... 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 pharmaceutically acceptable salt of any of the foregoing.

[0119] In some embodiments, the at least one additional API is selected from a mucolytic agent, a bronchodilator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, and a nutritional agent.

[0120] In some embodiments, the additional agent is a mucolytic agent. Exemplary mucolytic agents useful herein include

[0121] In some embodiments, the additional agent is a bronchodilator. Exemplary bronchodilators include albuterol, metaprotenol sulfate, pirbuterolacetate, salmeterol, and tetrabuline sulfate.

[0122] In certain embodiments, the additional therapeutic agent is an antibiotic. Exemplary antibiotics available herein include tobramycin, including tobramycin inhalation powder (TIP); azithromycin; aztreonam, including aerosolized forms of aztreonam; amikacin, including liposomal formulations thereof; ciprofloxacin, including formulations thereof suitable for administration by inhalation; levoflaxacin, including aerosolized formulations thereof; and combinations of two antibiotics, such as fosfomycin and tobramycin.

[0123] In some embodiments, the additional agent is an anti-inflammatory agent, i.e., an agent that can reduce lung inflammation. Exemplary such agents useful herein include ibuprofen, docosahexaenoic acid (DHA), sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine, and simvastatin.

[0124] In some embodiments, the additional agent is a nutritional agent. Exemplary nutritional agents include pancreatic lipase (a pancreatic enzyme substitute), including or (Previously ), and glutathione inhalers. In one embodiment, the additional nutritional agent is pancreatic lipase.

[0125] In some embodiments, at least one additional active pharmaceutical ingredient is selected from CFTR modulators. In some embodiments, the CFTR modulator is a CFTR corrector. In some embodiments, the CFTR modulator is a CFTR potentiator enhancer / co-potentiator (e.g., ASP-11). In some embodiments, at least one additional active pharmaceutical ingredient is a CFTR amplifier. In some embodiments, at least one additional active pharmaceutical ingredient is a CFTR read-through agent. In some embodiments, at least one additional active pharmaceutical ingredient is a CFTR nucleic acid therapy.

[0126] 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.

[0127] In some embodiments, at least one additional active pharmaceutical ingredient is selected from: (a) Compound II, deuterated derivatives of Compound II, and pharmaceutically acceptable salts of Compound II and its deuterated derivatives; (b) Compound III, deuterated derivatives of Compound III, and pharmaceutically acceptable salts of Compound III and its deuterated derivatives; (c) Compound III-d and pharmaceutically acceptable salts of Compound III-d; (d) Compound IV, deuterated derivatives of Compound IV, and pharmaceutically acceptable salts of Compound IV and its deuterated derivatives; (e) Compound V, deuterated derivatives of Compound V, and pharmaceutically acceptable salts of Compound V and its deuterated derivatives. The invention further comprises a pharmaceutically acceptable salt of compound IX, a deuterated derivative of compound IX, and a pharmaceutically acceptable salt of compound IX and a deuterated derivative thereof; (f) compound VI, a deuterated derivative of compound VI, and a pharmaceutically acceptable salt of compound VI and a deuterated derivative thereof; (g) compound VII, a deuterated derivative of compound VII, and a pharmaceutically acceptable salt of compound VII and a deuterated derivative thereof; (h) compound VIII, a deuterated derivative of compound VIII, and a pharmaceutically acceptable salt of compound VIII and a deuterated derivative thereof; (i) compound IX, a deuterated derivative of compound IX, and a pharmaceutically acceptable salt of compound IX and a deuterated derivative thereof; and (j) compound X, a deuterated derivative of compound X, and a pharmaceutically acceptable salt of compound X and a deuterated derivative thereof. Thus, in some embodiments, the combination therapies provided herein comprise administering Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing; and at least one compound selected from the group consisting of Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives and pharmaceutically acceptable salts thereof.

[0128] In some embodiments, the combination therapies provided herein comprise administering: (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 1.5 mg, about 2 mg to about 30 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 2 ... g, 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 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 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 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 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 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670 (a) about 100 mg, about 150 mg, about 100 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg, about 150 mg 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO 2017 / 009804, WO 2018 / 065921, WO 2017 / 062581; Phuan, P.-W. et al. Journal of Cystic Fibrosis 2018, 17(5), 595–606; Pedemonte, N. et al. Science Advances 2020, 6(8), Paper 9669; Phuan, P.-W. et al. Scientific Reports 2019, 9(1), 17640; Bose, S. et al. Journal of Cystic Fibrosis 2020, 19 Suppl 1, S25–S32; Crawford, D.K. Pharmacology and Experimental Therapeutics Journal of Pharmaceutical Sciences 2020, 374(2), 264–272; Brasell, EJ et al., PLoS ONE 2019, 14(12), e0223954; Smith, NJ, Solovay, CF, Pharmaceutical Patent Analysis 2017, 6(4), 179-188; Kunzelmann, K. et al., Frontiers in Pharmacology 2019, 10, 3; or Son, J.-H. et al., European Journal of Medicinal Chemistry 2020, 112888.

[0129] In some embodiments, the combination therapies provided herein comprise administering: (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 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 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 mg, 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 1 85mg, 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 330mg, about 335mg, about 340mg, about 345mg, about 350mg, about 355mg, about 360mg,(a) optionally at least one compound selected from the group consisting of Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives and pharmaceutically acceptable salts thereof; and (c) optionally at least one compound selected from the group consisting of compounds disclosed in WO 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO 2017 / 009804, WO 2018 / 065921, WO 2017 / 062581; Phuan, P.-W. et al. Journal of Cystic Fibrosis 2018, 17(5), 595–606; Pedemonte, N. et al. Science Advances 2020, 6(8), paper 9669; Phuan, P.-W. et al. Scientific Reports 2019, 9(1), 17640; Bose, S. et al. Journal of Cystic Fibrosis 2020, 19 Supplement 1, S25–S32; Crawford, D.K. Pharmacology and Experimental Therapeutics Journal of Pharmaceutical Sciences 2020, 374(2), 264–272; Brasell, EJ et al., PLoS ONE 2019, 14(12), e0223954; Smith, NJ, Solovay, CF, Pharmaceutical Patent Analysis 2017, 6(4), 179-188; Kunzelmann, K. et al., Frontiers in Pharmacology 2019, 10, 3; or Son, J.-H. et al., European Journal of Medicinal Chemistry 2020, 112888.

[0130] In some embodiments, the combination therapies provided herein comprise administering: (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, 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 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, 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 pharmaceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from the following: 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 pharmaceutically acceptable salts thereof; and (c) optionally at least one compound selected from the compounds disclosed in the following documents: WO 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO 2017 / 009804, WO 2018 / 065921, WO 2017 / 062581; Phuan, P.-W.et al. Journal of Cystic Fibrosis 2018, 17(5), 595–606; Pedemonte, N. et al. Science Advances 2020, 6(8), paper 9669; Phuan, P.-W. et al. Scientific Reports 2019, 9(1), 17640; Bose, S. et al. Journal of Cystic Fibrosis 2020, 19 Supplement 1, S25–S32; Crawford, D.K. Journal of Pharmacology and Experimental Therapeutics 2020, 37 4(2), 264–272; Brasell, EJ et al., PLoS ONE 2019, 14(12), e0223954; Smith, NJ, Solovay, CF, Pharmaceutical Patent Analysis 2017, 6(4), 179-188; Kunzelmann, K. et al., Frontiers in Pharmacology 2019, 10, 3; or Son, J.-H. et al., European Journal of Medicinal Chemistry 2020, 112888. .

[0131] In some embodiments, the combination therapies provided herein comprise administering: (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 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 250mg, about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 29 (b) optionally at least one compound selected from the group consisting of Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives and pharmaceutically acceptable salts thereof;and (c) optionally at least one compound selected from the group consisting of compounds disclosed in WO 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO 2017 / 009804, WO 2018 / 065921, WO 2017 / 062581; WO 2022 / 076618; WO 2022 / 076620; WO 2022 / 076621; WO 2022 / 076622; WO 2022 / 076624; WO 2022 / 076625; WO 2022 / 076626; WO 2022 / 076627; WO 2022 / 076628; WO 2022 / 076629; PCT International Application No. PCT / US2023 / 017627; Phuan, P.-W. et al. Journal of Cystic Fibrosis 2018, 17(5), 595–606; Pedemonte, N. et al. Science Advances 2020, 6(8), Paper 9669; Phuan, P.-W. et al. Scientific Reports 2019, 9(1), 17640; Bose, S. et al. Journal of Cystic Fibrosis 2020, 19 Supplement 1, S25–S32; Crawford rd, DK Journal of Pharmacology and Experimental Therapeutics 2020, 374(2), 264–272; Brasell, EJ et al. PLoS ONE 2019, 14(12), e0223954; Smith, NJ, Solovay, CF, Pharmaceutical Patent Analysis 2017, 6(4), 179-188; Kunzelmann, K. et al. Frontiers in Pharmacology 2019, 10, 3; or Son, J.-H. et al. European Journal of Medicinal Chemistry 2020, 112888. ;

[0132] In some embodiments, the combination therapies provided herein comprise administering: (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 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 250mg, about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about (b) optionally at least one compound selected from the group consisting of Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives and pharmaceutically acceptable salts thereof; and (c) optionally at least one compound selected from the group consisting of compounds disclosed in the following documents: WO 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO 2017 / 009804, WO 2018 / 065921, WO 2017 / 062581; WO 2022 / 076618; WO 2022 / 076620; WO 2022 / 076621; WO 2022 / 076622; WO 2022 / 076624; WO 2022 / 076625; WO 2022 / 076626; WO 2022 / 076627; WO 2022 / 076628;WO 2022 / 076629; PCT International Application No. PCT / US2023 / 017627; Phuan, P.-W. et al. Journal of Cystic Fibrosis 2018, 17(5), 595–606; Pedemonte, N. et al. Science Advances 2020, 6(8), Paper 9669; Phuan, P.-W. et al. Scientific Reports 2019, 9(1), 17640; Bose, S. et al. Journal of Cystic Fibrosis 2020, 19 Supplement 1, S25–S32; Crawford rd, DK Journal of Pharmacology and Experimental Therapeutics 2020, 374(2), 264–272; Brasell, EJ et al. PLoS ONE 2019, 14(12), e0223954; Smith, NJ, Solovay, CF, Pharmaceutical Patent Analysis 2017, 6(4), 179-188; Kunzelmann, K. et al. Frontiers in Pharmacology 2019, 10, 3; or Son, J.-H. et al. European Journal of Medicinal Chemistry 2020, 112888. ;

[0133] In some embodiments, the combination therapies provided herein comprise administering: (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 15 (a) about 150 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 pharmaceutically acceptable salt of any one of the foregoing; (b) optionally at least one compound selected from the following: 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 pharmaceutically acceptable salts thereof; and (c) optionally at least one compound selected from the compounds disclosed in the following documents: WO 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO 2017 / 009804, WO 2018 / 065921, WO 2017 / 062581; WO 2022 / 076618; WO 2022 / 076620; WO 2022 / 076621; WO 2022 / 076622; WO 2022 / 076624; WO 2022 / 076625; WO 2022 / 076626; WO 2022 / 076627; WO 2022 / 076628; WO 2022 / 076629; PCT International Application No. PCT / US2023 / 017627; Phuan, P.-W. et al. Journal of Cystic Fibrosis 2018, 17(5), 595–606; Pedemonte, N. et al. Science Advances 2020, 6(8), Paper 9669; Phuan, P.-W. et al. Scientific Reports 2019, 9(1), 17640; Bose, S. et al. Journal of Cystic Fibrosis 2020, 19 Supplement 1, S25–S32; Crawford, D.K. Journal of Pharmacology and Experimental Therapeutics 2020, 374(2), 264–272; Brasell, E.J. et al. PLoS One 2019, 14(12), e0223954; Smith, N.J, Solovay, CF, Pharmaceutical Patent Analysis 2017, 6(4), 179-188; Kunzelmann, K. et al., Frontiers in Pharmacology 2019, 10, 3; or Son, J.-H. et al., European Journal of Medicinal Chemistry 2020, 112888. .

[0134] In some embodiments, the combination therapies provided herein comprise administering: (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 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, its deuterated derivative or a pharmaceutically acceptable salt of any one of the foregoing; (b) optionally at least one compound selected from the following: 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 pharmaceutically acceptable salts thereof; and (c) optionally at least one compound selected from the compounds disclosed in the following documents: WO 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO 2017 / 009804, WO 2018 / 065921, WO 2017 / 062581; WO 2022 / 076618; WO 2022 / 076620; WO 2022 / 076621; WO 2022 / 076622; WO 2022 / 076624; WO 2022 / 076625; WO 2022 / 076626; WO 2022 / 076627; WO 2022 / 076628; WO 2022 / 076629; PCT International Application No. PCT / US2023 / 017627; Phuan, P.-W. et al. Cystic Fibrosis Journal 2018, 17(5), 595–606; Pedemonte, N. et al. Science Advances 2020, 6(8), Paper 9669; Phuan, P.-W. et al. Scientific Reports 2019, 9(1), 17640; Bose, S. et al. Cystic Fibrosis Journal 2020, 19 Supplement 1, S25–S32; Crawford, DK. Journal of Pharmacology and Experimental Therapeutics 2020, 374(2), 264–272; Brasell, EJ et al. PLoS One 2019, 14(12), e0223954; Smith, NJ, Solovay, CF, Pharmaceutical Patent Analysis 2017, 6(4), 179-188; Kunzelmann, K. et al., Frontiers in Pharmacology 2019, 10, 3; or Son, J.-H. et al., European Journal of Medicinal Chemistry 2020, 112888. .

[0135] In some embodiments, the combination therapies provided herein comprise administering: (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 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 g, about 195 mg or about 200 mg) of Compound I, its deuterated derivative or a pharmaceutically acceptable salt of any one of the foregoing; (b) optionally at least one compound selected from the following: 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 pharmaceutically acceptable salts thereof; and (c) optionally at least one compound selected from the compounds disclosed in the following documents: WO 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO 2017 / 009804, WO 2018 / 065921, WO 2017 / 062581; WO 2022 / 076618; WO 2022 / 076620; WO 2022 / 076621; WO 2022 / 076622; WO 2022 / 076624; WO 2022 / 076625; WO 2022 / 076626; WO 2022 / 076627; WO 2022 / 076628; WO 2022 / 076629; PCT International Application No. PCT / US2023 / 017627;Phuan, P.-W. et al. Journal of Cystic Fibrosis 2018, 17(5), 595–606; Pedemonte, N. et al. Science Advances 2020, 6(8), paper 9669; Phuan, P.-W. et al. Scientific Reports 2019, 9(1), 17640; Bose, S. et al. Journal of Cystic Fibrosis 2020, 19 Supplement 1, S25–S32; Crawford, D.K. Journal of Pharmacology and Experimental Therapeutics 20 20, 374(2), 264–272; Brasell, EJ et al., PLoS ONE 2019, 14(12), e0223954; Smith, NJ, Solovay, CF, Pharmaceutical Patent Analysis 2017, 6(4), 179-188; Kunzelmann, K. et al., Frontiers in Pharmacology 2019, 10, 3; or Son, J.-H. et al., European Journal of Medicinal Chemistry 2020, 112888. ;

[0136] In some embodiments, the combination therapies provided herein comprise administering: (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 g, 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, its deuterated derivative or a pharmaceutically acceptable salt of any one of the foregoing; (b) optionally at least one compound selected from the following: 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 pharmaceutically acceptable salts thereof; and (c) optionally at least one compound selected from the compounds disclosed in the following documents: WO 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO 2017 / 009804, WO 2018 / 065921, WO 2017 / 062581; WO 2022 / 076618; WO 2022 / 076620; WO 2022 / 076621; WO 2022 / 076622; WO 2022 / 076624; WO 2022 / 076625; WO 2022 / 076626; WO 2022 / 076627; WO 2022 / 076628; WO 2022 / 076629; PCT International Application No. PCT / US2023 / 017627; Phuan, P.-W. et al. Journal of Cystic Fibrosis 2018, 17(5), 595–606; Pedemonte, N. et al. Science Advances 2020, 6(8), Paper 9669; Phuan, P.-W. et al. Scientific Reports 2019, 9(1), 17640; Bose, S. et al. Journal of Cystic Fibrosis 2020, 19 Supplement 1, S25–S32; Crawford, D.K. Journal of Pharmacology and Experimental Therapeutics 2020, 374(2), 264–272; Brasell, E.J.et al., PLOS ONE, 2019, 14(12), e0223954; Smith, NJ, Solovay, CF, Pharmaceutical Patent Analysis, 2017, 6(4), 179-188; Kunzelmann, K. et al., Frontiers in Pharmacology, 2019, 10, 3; or Son, J.-H. et al., European Journal of Medicinal Chemistry, 2020, 112888. .

[0137] In some embodiments, the combination therapies provided herein comprise administering: (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 g, about 56 mg, about 57 mg, about 58 mg, about 59 mg or about 60 mg) of Compound I, its deuterated derivative or a pharmaceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from the following: 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 pharmaceutically acceptable salts thereof; and (c) optionally at least one compound selected from the compounds disclosed in the following documents: WO 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO 2017 / 009804, WO 2018 / 065921, WO 2017 / 062581; WO 2022 / 076618; WO 2022 / 076620; WO 2022 / 076621; WO 2022 / 076622; WO 2022 / 076624; WO 2022 / 076625; WO 2022 / 076626; WO 2022 / 076627; WO 2022 / 076628; WO2022 / 076629; PCT International Application No. PCT / US2023 / 017627; Phuan, P.-W. et al. Journal of Cystic Fibrosis 2018, 17(5), 595–606; Pedemonte, N. et al. Science Advances 2020, 6(8), paper 9669; Phuan, P.-W. et al. Scientific Reports 2019, 9(1), 17640; Bose, S. et al. Journal of Cystic Fibrosis 2020 , 19 Supplement 1, S25–S32; Crawford, DK Journal of Pharmacology and Experimental Therapeutics 2020, 374(2), 264–272; Brasell, EJ et al. PLoS ONE 2019, 14(12), e0223954; Smith, NJ, Solovay, CF, Pharmaceutical Patent Analysis 2017, 6(4), 179-188; Kunzelmann, K. et al. Frontiers in Pharmacology 2019, 10, 3; or Son, J.-H. et al., European Journal of Medicinal Chemistry 2020, 112888. .

[0138] In some embodiments, the combination therapies provided herein comprise administering: (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 (a) optionally at least one compound selected from the group consisting of Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives and pharmaceutically acceptable salts thereof; and (c) optionally at least one compound selected from the group consisting of Compounds disclosed in the following documents: WO 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO 2017 / 009804, WO 2018 / 065921, WO 2017 / 062581; WO 2022 / 076618; WO 2022 / 076620; WO 2022 / 076621; WO 2022 / 076622; WO 2022 / 076624; WO 2022 / 076625; WO 2022 / 076626; WO 2022 / 076627; WO 2022 / 076628; WO 2022 / 076629; PCT International Application No. PCT / US2023 / 017627; Phuan, P.-W. et al. Journal of Cystic Fibrosis 2018, 17(5), 595–606; Pedemonte, N. et al. Science Advances 2020, 6(8), paper 9669; Phuan, P.-W. et al. Scientific Reports 2019, 9(1), 17640; Bose, S.et al. Journal of Cystic Fibrosis 2020, 19 Supplement 1, S25–S32; Crawford, DK. Journal of Pharmacology and Experimental Therapeutics 2020, 374(2), 264–272; Brasell, EJ. et al. PLoS ONE 2019, 14(12), e0223954; Smith, NJ, Solovay, CF. Pharmaceutical Patent Analysis 2017, 6(4), 179-188; Kunzelmann, K. et al. Frontiers in Pharmacology 2019, 10, 3; or Son, J.-H. et al. European Journal of Medicinal Chemistry 2020, 112888. .

[0139] In some embodiments, the combination therapies provided herein comprise administering: (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 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 pharmaceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from the following: 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 pharmaceutically acceptable salts thereof; and (c) optionally at least one compound selected from the compounds disclosed in the following documents: WO 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO 2017 / 009804, WO 2018 / 065921, WO 2017 / 062581; WO 2022 / 076618; WO 2022 / 076620; WO 2022 / 076621; WO 2022 / 076622; WO 2022 / 076624; WO 2022 / 076625; WO 2022 / 076626; WO 2022 / 076627; WO 2022 / 076628; WO 2022 / 076629; PCT International Application No. PCT / US2023 / 017627; Phuan, P.-W. et al. Journal of Cystic Fibrosis 2018, 17(5), 595–606; Pedemonte, N. et al. Science Advances 2020, 6(8), Paper 9669; Phuan, P.-W. et al. Scientific Reports 2019, 9(1), 17640; Bose, S. et al. Journal of Cystic Fibrosis 2020, 19 Supplement 1, S25–S32; Crawford, D.K. Journal of Pharmacology and Experimental Therapeutics 2020, 374(2), 264–272; Brasell, E.J. et al. PLoS One 2019, 14(12), e0223954; Smith, N.J, Solovay, CF, Pharmaceutical Patent Analysis 2017, 6(4), 179-188; Kunzelmann, K. et al., Frontiers in Pharmacology 2019, 10, 3; or Son, J.-H. et al., European Journal of Medicinal Chemistry 2020, 112888. .

[0140] In some embodiments, the combination therapies provided herein comprise administration of: (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 g, about 35 mg, about 40 mg, about 45 mg or about 50 mg) of Compound I, its deuterated derivative or a pharmaceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from the following: 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 pharmaceutically acceptable salts thereof; and (c) optionally at least one compound selected from the compounds disclosed in the following documents: WO 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO 2017 / 009804, WO 2018 / 065921, WO 2017 / 062581; WO 2022 / 076618; WO 2022 / 076620; WO 2022 / 076621; WO 2022 / 076622; WO 2022 / 076624; WO 2022 / 076625; WO 2022 / 076626; WO 2022 / 076627; WO 2022 / 076628; WO 2022 / 076629; PCT International Application No. PCT / US2023 / 017627; Phuan, P.-W. et al. Journal of Cystic Fibrosis 2018, 17(5), 595–606; Pedemonte, N. et al. Science Advances 2020, 6(8), Paper 9669; Phuan, P.-W. et al. Scientific Reports 2019, 9(1), 17640; Bose, S. et al. Journal of Cystic Fibrosis 2020, 19 Supplement 1, S2 5–S32; Crawford, DK Journal of Pharmacology and Experimental Therapeutics 2020, 374(2), 264–272; Brasell, EJ et al. PLoS ONE 2019, 14(12), e0223954; Smith, NJ, Solovay, CF, Pharmaceutical Patent Analysis 2017, 6(4), 179-188; Kunzelmann, K. et al. Frontiers in Pharmacology 2019, 10, 3; Or Son, J.-H.et al., European Journal of Medicinal Chemistry 2020, 112888. .

[0141] In some embodiments, the combination therapy provided herein comprises administering: (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 pharmaceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from the following: 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 pharmaceutically acceptable salts thereof; and (c) optionally at least one compound selected from the compounds disclosed in the following documents: WO 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO 2017 / 009804, WO 2018 / 065921, WO 2017 / 062581; WO 2022 / 076618; WO 2022 / 076620; WO 2022 / 076621; WO 2022 / 076622; WO 2022 / 076624; WO 2022 / 076625; WO 2022 / 076626; WO 2022 / 076627; WO 2022 / 076628; WO2022 / 076629; PCT International Application No. PCT / US2023 / 017627; Phuan, P.-W. et al. Journal of Cystic Fibrosis 2018, 17(5), 595–606; Pedemonte, N. et al. Science Advances 2020, 6(8), Paper 9669; Phuan, P.-W. et al. Scientific Reports 2019, 9(1), 17640; Bose, S. et al. Journal of Cystic Fibrosis 2020, 19 Supplement 1, S25–S32 ; Crawford, DK, Journal of Pharmacology and Experimental Therapeutics, 2020, 374(2), 264–272; Brasell, EJ, et al., PLoS One, 2019, 14(12), e0223954; Smith, NJ, Solovay, CF, Pharmaceutical Patent Analysis, 2017, 6(4), 179-188; Kunzelmann, K., et al., Frontiers in Pharmacology, 2019, 10, 3; or Son, J.-H., et al., European Journal of Medicinal Chemistry, 2020, 112888.

[0142] In some embodiments, the combination therapy provided herein comprises administering: (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 pharmaceutically 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 pharmaceutically acceptable salts thereof; and (c) optionally at least one compound selected from the compounds disclosed in WO 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO 2017 / 009804, WO 2018 / 065921, WO 2017 / 062581; WO 2022 / 076618; WO 2022 / 076620; WO 2022 / 076621; WO 2022 / 076622; WO 2022 / 076624; WO 2022 / 076625; WO 2022 / 076626;WO 2022 / 076627;WO 2022 / 076628;WO 2022 / 076629; PCT International Application No. PCT / US2023 / 017627; Phuan, P.-W. et al. Journal of Cystic Fibrosis 2018, 17(5), 595–606; Pedemonte, N. et al. Science Advances 2020, 6(8), Paper 9669; Phuan, P.-W. et al. Scientific Reports 2019, 9(1), 17640; Bose, S. et al. Journal of Cystic Fibrosis 2020, 19 Supplement 1, S25–S32; Crawford rd, DK, Journal of Pharmacology and Experimental Therapeutics, 2020, 374(2), 264–272; Brasell, EJ, et al., PLoS One, 2019, 14(12), e0223954; Smith, NJ, Solovay, CF, Pharmaceutical Patent Analysis, 2017, 6(4), 179-188; Kunzelmann, K., et al., Frontiers in Pharmacology, 2019, 10, 3; or Son, J.-H., et al., European Journal of Medicinal Chemistry, 2020, 112888.

[0143] In some embodiments, the combination therapies provided herein comprise administering: (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 pharmaceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from the following: 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 pharmaceutically acceptable salts thereof; and (c) optionally at least one compound selected from the compounds disclosed in the following documents: WO2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO 2017 / 009804, WO 2018 / 065921, WO 2017 / 062581; WO 2022 / 076618; WO 2022 / 076620; WO 2022 / 076621; WO 2022 / 076622; WO 2022 / 076624; WO 2022 / 076625;WO 2022 / 076626;WO 2022 / 076627;WO 2022 / 076628;WO 2022 / 076629; PCT International Application No. PCT / US2023 / 017627; Phuan, P.-W. et al. Cystic Fibrosis Journal 2018, 17(5), 595–606; Pedemonte, N. et al. Science Advances 2020, 6(8), Paper 9669; Phuan, P.-W. et al. Scientific Reports 2019, 9(1), 17640; Bose, S. et al. Cystic Fibrosis Journal 2020, 19 Supplement 1, S25–S32; Crawford, DK. Journal of Pharmacology and Experimental Therapeutics 2020, 374(2), 264–272; Brasell, EJ et al. PLoS One 2019, 14(12), e0223954; Smith, NJ, Solovay, CF, Pharmaceutical Patent Analysis 2017, 6(4), 179-188; Kunzelmann, K. et al., Frontiers in Pharmacology 2019, 10, 3; or Son, J.-H. et al., European Journal of Medicinal Chemistry 2020, 112888. .

[0144] In some embodiments, the combination therapies provided herein comprise administering: (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 1.5 mg, about 2 mg to about 30 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 2 ... g, 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 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 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 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 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 620mg, about 630mg , 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 pharmaceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from the following: Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound Compound X and its deuterated derivatives and pharmaceutically acceptable salts; and (c) optionally at least one compound selected from the following: 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, GL PG2451 / ABBV-2451, QBW251 (Icenticaftor), GLPG3067 / ABBV-3067 (Navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0145] In some embodiments, the combination therapies provided herein comprise administering: (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 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 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 mg, 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 1 85mg, 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 330mg, about 335mg, about 340mg, about 345mg, about 350mg, about 355mg, about 360mg,(a) optionally at least one compound selected from the group consisting of Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives and pharmaceutically acceptable salts thereof; 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 / ABBV-974, GLPG2451 / ABBV-2451, QBW251 (Esenkato), GLPG3067 / ABBV-30 67 (Navocato), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, Amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0146] In some embodiments, the combination therapies provided herein comprise administering: (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 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 355 mg, about 360 mg, about 365 mg, about 370 mg or about 375 mg) of Compound 1, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing;(b) optionally at least one compound selected from the following: 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 pharmaceutically acceptable salts thereof; and (c) optionally at least one compound selected from the following: PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN2 3765, ARN23766, PTI-801, FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW251 (Isencato), GLPG3067 / ABBV-3067 (Navocato), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, Amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002 and DS-1039. ;

[0147] In some embodiments, the combination therapies provided herein comprise administering: (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 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 250mg, about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 29 (b) optionally at least one compound selected from the group consisting of Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives and pharmaceutically acceptable salts thereof;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 / ABB V-974, GLPG2451 / ABBV-2451, QBW251 (Isencato), GLPG3067 / ABBV-3067 (Navocato), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, Amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039. ;

[0148] In some embodiments, the combination therapies provided herein comprise administering: (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 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 250mg, about 255mg, about 260mg, about 265m g, 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 pharmaceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from the following: 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 pharmaceutically acceptable salts thereof;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 / ABB V-974, GLPG2451 / ABBV-2451, QBW251 (Isencato), GLPG3067 / ABBV-3067 (Navocato), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, Amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039. ;

[0149] In some embodiments, the combination therapies provided herein comprise administering: (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 pharmaceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from the following: 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 pharmaceutically acceptable salts; and (c) optionally at least one compound selected from the following: 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, GLP G1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW251 (Isencatto), GLPG3067 / ABBV-3067 (Navocato), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, Amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0150] In some embodiments, the combination therapies provided herein comprise administering: (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 135 mg, about 1 (a) about 40 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 pharmaceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from the following: 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 pharmaceutically acceptable salts thereof; and (c) optionally at least one compound selected from the following: PT I-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, FDL-169, ARN5562, ARN2158 6. ARN22081, ARN22652, ARN23765, ARN23766, PTI-801, FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW25 1(Esencato), GLPG3067 / ABBV-3067(Navocato), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, Amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037(VX-371), P-1055(VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0151] In some embodiments, the combination therapies provided herein comprise administering: (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 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 7mg, 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 1 (a) about 150 mg, about 200 mg, about 150 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 75 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 pharmaceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from the following: 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 pharmaceutically acceptable salts thereof;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 / ABB V-974, GLPG2451 / ABBV-2451, QBW251 (Isencato), GLPG3067 / ABBV-3067 (Navocato), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, Amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039. ;

[0152] In some embodiments, the combination therapies provided herein comprise administering: (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 g, 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 pharmaceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from the following: 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 pharmaceutically acceptable salts thereof 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 / ABBV-974, GLPG2451 / AB BV-2451, QBW251 (Isencatto), GLPG3067 / ABBV-3067 (Navocato), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, Amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0153] In some embodiments, the combination therapies provided herein comprise administering: (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 pharmaceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from the following: 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 pharmaceutically acceptable salts thereof; and (c) optionally at least one compound selected from the following: P TI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, FDL-169, ARN55 62. ARN21586, ARN22081, ARN22652, ARN23765, ARN23766, PTI-801, FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2 451 / ABBV-2451, QBW251 (Isencatto), GLPG3067 / ABBV-3067 (Navocato), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, Amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0154] In some embodiments, the combination therapies provided herein comprise administering: (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 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 pharmaceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from the group consisting of Compound II, Compound II I, compound III-d, compound IV, compound V, compound VI, compound VII, compound VIII, compound IX, compound X and deuterated derivatives and pharmaceutically acceptable salts thereof; and (c) optionally at least one compound selected from the following: 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, P TI-801, FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW251 (Isencatto), GLPG3067 / ABBV-3067 (Navocato), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, Amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0155] In some embodiments, the combination therapies provided herein comprise administering: (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 (a) about 15 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 pharmaceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from the following: 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 biologically and pharmaceutically acceptable salts; 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, GLPG18 37 / ABBV-974, GLPG2451 / ABBV-2451, QBW251 (Isencatto), GLPG3067 / ABBV-3067 (Navocato), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, Amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0156] In some embodiments, the combination therapies provided herein comprise administering: (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 ... (a) about 100 mg, about 200 mg, about 40 mg, about 50 mg, about 60 mg, about 80 mg, about 150 mg, about 250 mg, about 300 mg, about 450 mg, or about 500 mg) of Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from the group consisting of Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives and pharmaceutically acceptable salts thereof; 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, AR N21586, ARN22081, ARN22652, ARN23765, ARN23766, PTI-801, FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW251 (Isencatto), GLPG3067 / ABBV-3067 (Navocato), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, Amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0157] In some embodiments, the combination therapies provided herein include administering: (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 pharmaceutically 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 pharmaceutically acceptable salts thereof; and (c) optionally at least one compound selected from PTI-428, ASP-11, ABBV-2222, ABBV-28 51. 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, QB W251 (Isencatto), GLPG3067 / ABBV-3067 (Navcatto), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, Amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0158] In some embodiments, the combination therapies provided herein include administering: (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 pharmaceutically 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 pharmaceutically acceptable salts thereof; and (c) optionally at least one compound selected from PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-374 8. 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 (Ethankato), GLPG 3067 / ABBV-3067 (Navocato), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, Amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0159] In some embodiments, the combination therapies provided herein comprise administering: (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 (a) 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 pharmaceutically acceptable salt of any of the foregoing; (b) optionally at least one compound selected from the following: 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 pharmaceutically acceptable salts thereof; and (c) optionally at least one compound selected from the following: PTI -428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, FDL-169, ARN5562, ARN2158 6. ARN22081, ARN22652, ARN23765, ARN23766, PTI-801, FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW25 1(Esencato), GLPG3067 / ABBV-3067(Navocato), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, Amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037(VX-371), P-1055(VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI1265162, ARO-ENaC1001, ETD002, and DS-1039.

[0160] In some embodiments, 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. 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 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 18 5mg, 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 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 g, 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 pharmaceutically acceptable salt of any one of the foregoing, and at least one compound selected from Compound II and a pharmaceutically acceptable salt and deuterated derivative thereof.

[0161] In some embodiments, 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. 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 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 18 5mg, 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 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 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 pharmaceutically acceptable salt of any one of the foregoing, and at least one compound selected from Compound III and a pharmaceutically acceptable salt and deuterated derivative thereof.

[0162] In some embodiments, 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. 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 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 18 5mg, 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 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 0mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg or about 800mg) of Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing, and at least one compound selected from Compound III-d and a pharmaceutically acceptable salt thereof.

[0163] In some embodiments, 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. 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 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 18 5mg, 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 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 g, 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 pharmaceutically acceptable salt of any one of the foregoing, and at least one compound selected from Compound IV and a deuterated derivative thereof and a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, 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. 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 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 18 5mg, 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 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 g, 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 pharmaceutically acceptable salt of any one of the foregoing, and at least one compound selected from Compound V and a deuterated derivative thereof and a pharmaceutically acceptable salt thereof.

[0165] In some embodiments, 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. 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 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 18 5mg, 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 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 g, 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 pharmaceutically acceptable salt of any one of the foregoing, and at least one compound selected from Compound VI and a deuterated derivative thereof and a pharmaceutically acceptable salt thereof.

[0166] In some embodiments, 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. 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 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 18 5mg, 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 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 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 pharmaceutically acceptable salt of any one of the foregoing, and at least one compound selected from Compound VII and a deuterated derivative thereof and a pharmaceutically acceptable salt thereof.

[0167] In some embodiments, 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. 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 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 18 5mg, 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 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 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 pharmaceutically acceptable salt of any one of the foregoing, and at least one compound selected from Compound VIII and deuterated derivatives and pharmaceutically acceptable salts thereof.

[0168] In some embodiments, 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. 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 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 18 5mg, 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 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 g, 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 pharmaceutically acceptable salt of any one of the foregoing, in combination with at least one compound selected from Compound IX and a deuterated derivative thereof and a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, 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. 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 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 18 5mg, 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 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 g, 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 pharmaceutically acceptable salt of any one of the foregoing, in combination with at least one compound selected from Compound X and a deuterated derivative thereof and a pharmaceutically acceptable salt thereof.

[0170] 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, 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 9.5mg, 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 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 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 pharmaceutically acceptable salt of any one of the foregoing, is administered in combination with at least one compound selected from Compound II and a pharmaceutically acceptable salt and deuterated derivative thereof.

[0171] 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, 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 9.5mg, 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 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 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 pharmaceutically acceptable salt of any one of the foregoing, and at least one compound selected from Compound III and pharmaceutically acceptable salts and deuterated derivatives thereof.

[0172] 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, 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 9.5mg, 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 0mg, 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 1 65mg, 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 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 pharmaceutically acceptable salt of any one of the foregoing, in combination with at least one compound selected from Compound III-d and a pharmaceutically acceptable salt thereof.

[0173] 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, 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 9.5mg, 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 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 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 pharmaceutically acceptable salt of any of the foregoing, in combination with at least one compound selected from Compound IV and deuterated derivatives and pharmaceutically acceptable salts thereof.

[0174] 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, 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 9.5mg, 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 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 16 5mg, 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 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 pharmaceutically acceptable salt of any of the foregoing, in combination with at least one compound selected from Compound V and a deuterated derivative and a pharmaceutically acceptable salt thereof.

[0175] 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, 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 9.5mg, 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 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 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 pharmaceutically acceptable salt of any of the foregoing, in combination with at least one compound selected from Compound VI and a deuterated derivative and a pharmaceutically acceptable salt thereof.

[0176] 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, 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 9.5mg, 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 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 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 pharmaceutically acceptable salt of any of the foregoing, in combination with at least one compound selected from Compound VII and a deuterated derivative and a pharmaceutically acceptable salt thereof.

[0177] 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, 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 9.5mg, 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 g, 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 165m g, 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 3 10 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 pharmaceutically acceptable salt of any of the foregoing, in combination with at least one compound selected from Compound VIII and deuterated derivatives and pharmaceutically acceptable salts thereof.

[0178] 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, 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 9.5mg, 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 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 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 pharmaceutically acceptable salt of any of the foregoing, in combination with at least one compound selected from Compound IX and deuterated derivatives and pharmaceutically acceptable salts thereof.

[0179] 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, 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 9.5mg, 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 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 16 5mg, 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 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 pharmaceutically acceptable salt of any of the foregoing, in combination with at least one compound selected from Compound X and a deuterated derivative and a pharmaceutically acceptable salt thereof.

[0180] In some embodiments, 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. 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 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 18 5mg, 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 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 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg or about 800mg) of Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing, and at least one compound selected from Compound II and its deuterated derivatives and pharmaceutically acceptable salts, and at least one compound selected from Compound V and its pharmaceutically acceptable salts and deuterated derivatives.

[0181] In some embodiments, 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. 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 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 18 5mg, 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 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 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg or about 800mg) of Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing, in combination with at least one compound selected from Compound II and its deuterated derivatives and pharmaceutically acceptable salts, and at least one compound selected from Compound VI and its deuterated derivatives and pharmaceutically acceptable salts.

[0182] In some embodiments, 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. 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 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 18 5mg, 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 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 620mg, about 630mg, about 6 40mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg or about 800mg) of Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing, and at least one compound selected from Compound II and its deuterated derivatives and pharmaceutically acceptable salts, and at least one compound selected from Compound VII and its deuterated derivatives and pharmaceutically acceptable salts.

[0183] In some embodiments, 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. 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 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 18 5mg, 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 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 620mg, about 630mg, about 6 40mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg or about 800mg) of Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing, in combination with at least one compound selected from Compound II and its deuterated derivatives and pharmaceutically acceptable salts, and at least one compound selected from Compound VIII and its deuterated derivatives and pharmaceutically acceptable salts.

[0184] 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, 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 9.5mg, 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 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 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 pharmaceutically acceptable salt of any one of the foregoing, in combination with at least one compound selected from Compound II and its deuterated derivatives and pharmaceutically acceptable salts, and at least one compound selected from Compound V and its pharmaceutically acceptable salts and deuterated derivatives. .

[0185] 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, 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 9.5mg, 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 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 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 pharmaceutically acceptable salt of any of the foregoing, in combination with at least one compound selected from Compound II and its deuterated derivatives and pharmaceutically acceptable salts, and at least one compound selected from Compound VI and its deuterated derivatives and pharmaceutically acceptable salts. .

[0186] 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, 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 9.5mg, 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 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 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 pharmaceutically acceptable salt of any one of the foregoing, in combination with at least one compound selected from Compound II and its deuterated derivatives and pharmaceutically acceptable salts, and at least one compound selected from Compound VII and its deuterated derivatives and pharmaceutically acceptable salts. .

[0187] 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, 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 9.5mg, 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 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 pharmaceutically acceptable salt of any one of the foregoing, in combination with at least one compound selected from Compound II and its deuterated derivatives and pharmaceutically acceptable salts and at least one compound selected from Compound VIII and its deuterated derivatives and pharmaceutically acceptable salts. .

[0188] Compound I, its deuterated derivative, or a pharmaceutically acceptable salt of any one of the foregoing, and each of the compounds selected from the following can be independently administered once a day, twice a day, or three times a day: 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 pharmaceutically acceptable salts thereof.

[0189] In some embodiments, Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing is administered once a day. In some embodiments, Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing is administered twice a day. In some embodiments, Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing, and at least one compound selected from the following are administered once a day: 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 pharmaceutically acceptable salts thereof. In some embodiments, Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing, and at least one compound selected from the following are administered twice a day: 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 pharmaceutically acceptable salts thereof. In some embodiments, Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing, and at least one compound selected from Compound II and a deuterated derivative thereof and a pharmaceutically acceptable salt thereof are administered once a day. In some embodiments, Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing, and at least one compound selected from Compound II and a deuterated derivative thereof and a pharmaceutically acceptable salt thereof are administered twice a day.

[0190] Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing 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 2 mg, about 2 mg, about 30 mg, about 30 mg to about 60 mg) .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 4 2mg, 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 15 5mg, 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 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 mg, 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 6 (a) 60mg, about 670mg, about 680mg, about 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg or about 800mg) of Compound I, its deuterated derivative or a pharmaceutically acceptable salt of any of the foregoing; and (b) a compound selected from the following: 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 pharmaceutically acceptable salts thereof, which can be administered as a single pharmaceutical composition comprising (a) and (b), or as a separate pharmaceutical composition in which the first composition comprises (a) and the second composition comprises (b). Such pharmaceutical compositions can be administered once a day or multiple times a day, such as twice or three times a day. As used herein, the phrases a given amount of API (e.g., Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing) is administered once or twice daily or is administered daily means that the given amount is administered by daily dosing, which may occur once or twice daily.

[0191] In some embodiments, 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. 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 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 18 5mg, 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 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 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 6 70mg, about 680mg, about 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg or about 800mg) of Compound I, its deuterated derivative or a pharmaceutically acceptable salt of any of the foregoing is administered as 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 pharmaceutically acceptable salts thereof are administered as a second pharmaceutical composition. ,

[0192] Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing 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 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 g, 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 16 5mg, 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 330mg,(a) 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 or about 400mg) of Compound I, its deuterated derivative or a pharmaceutically acceptable salt of any of the foregoing; and (b) a compound selected from the following: 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 pharmaceutically acceptable salts thereof, which can be administered as a single pharmaceutical composition comprising (a) and (b), or as a separate pharmaceutical composition in which the first composition comprises (a) and the second composition comprises (b). Such pharmaceutical compositions can be administered once a day or multiple times a day, such as twice or three times a day. As used herein, the phrases a given amount of API (e.g., Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing) is administered once or twice daily or is administered daily means that the given amount is administered by daily dosing, which may occur once or twice daily.

[0193] 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, 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 9.5mg, 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 g, 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 330mg, about 335mg, about 340mg, about 345mg, about 3 50mg, about 355mg, about 360mg, about 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395mg or about 400mg) of Compound I, its deuterated derivative or a pharmaceutically acceptable salt of any of the foregoing is administered as 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 pharmaceutically acceptable salts thereof are administered as a second pharmaceutical composition. .

[0194] 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 pharmaceutically acceptable salts thereof. Some exemplary pharmaceutical compositions for Compound II and pharmaceutically acceptable salts thereof can be found in WO 2011 / 119984 and WO 2014 / 014841, which are incorporated herein by reference. Some exemplary pharmaceutical compositions for compound III and its pharmaceutically acceptable salts can be found in WO 2007 / 134279, WO 2010 / 019239, WO 2011 / 019413, WO 2012 / 027731 and WO 2013 / 130669, and some exemplary pharmaceutical compositions for compound III-d and its pharmaceutically acceptable salts can be found in US 8,865,902, US 9,181,192, US 9,512,079, WO 2017 / 053455 and WO 2018 / 080591, all of which are incorporated herein by reference. Some exemplary pharmaceutical compositions for compound IV and its pharmaceutically acceptable salts can be found in WO 2010 / 037066, WO 2011 / 127421 and WO 2014 / 071122, which are incorporated herein by reference. Some exemplary pharmaceutical compositions for Compound V and pharmaceutically acceptable salts thereof can be found in WO 2019 / 152940, which is incorporated herein by reference. Some exemplary pharmaceutical compositions for Compound VI and pharmaceutically acceptable salts thereof can be found in WO 2019 / 079760, which is incorporated herein by reference.

[0195] Pharmaceutical composition

[0196] Another aspect of the present invention provides a pharmaceutical composition comprising Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing, and at least one pharmaceutically acceptable carrier.

[0197] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (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 50 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg); , 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 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 16 5mg, 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 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 58 0mg, 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 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg or about 800mg) of Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing; and (b) at least one pharmaceutically acceptable carrier.

[0198] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (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 g 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 9.5mg, 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 1 60mg, 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 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 pharmaceutically acceptable salt of any of the foregoing; and (b) at least one pharmaceutically acceptable carrier.

[0199] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (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 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 9mg, 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 g, 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 1, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing; and (b) at least one pharmaceutically acceptable carrier.

[0200] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (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 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 mg, 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 2 about 45 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) of Compound 1, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing; and (b) at least one pharmaceutically acceptable carrier.

[0201] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (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 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 10 2mg, 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 1 05mg, 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 220 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 or about 300 mg) of Compound 1, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing; and (b) at least one pharmaceutically acceptable carrier.

[0202] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (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); g, 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 1, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing; and (b) at least one pharmaceutically acceptable carrier.

[0203] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (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 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 or about 175 mg) of Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing; and (b) at least one pharmaceutically acceptable carrier.

[0204] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (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 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 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 1, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing; and (b) at least one pharmaceutically acceptable carrier.

[0205] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (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 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 about 7 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 pharmaceutically acceptable salt of any of the foregoing; and (b) at least one pharmaceutically acceptable carrier.

[0206] In some embodiments, the present 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 1, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing; and (b) at least one pharmaceutically acceptable carrier.

[0207] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (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 1, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing; and (b) at least one pharmaceutically acceptable carrier.

[0208] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (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); g, 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 or about 40 mg) of Compound I, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing; and (b) at least one pharmaceutically acceptable carrier.

[0209] In some embodiments, the present 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 pharmaceutically acceptable salt of any of the foregoing; and (b) at least one pharmaceutically acceptable carrier.

[0210] In some embodiments, the present 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 pharmaceutically acceptable salt of any of the foregoing; and (b) at least one pharmaceutically acceptable carrier.

[0211] In some embodiments, the present 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 pharmaceutically acceptable salt of any of the foregoing; and (b) at least one pharmaceutically acceptable carrier.

[0212] 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 pharmaceutically acceptable salt of any one of the foregoing; and (b) at least one pharmaceutically acceptable carrier.

[0213] In some embodiments, the present invention provides a pharmaceutical composition comprising: 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 to about 5 .... g, 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 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 1 70mg, 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 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 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg or about 800mg) of Compound I, its deuterated derivative or a pharmaceutically acceptable salt of any of the foregoing; and optionally at least one additional active pharmaceutical ingredient. In some embodiments, at least one additional active pharmaceutical ingredient is a CFTR modulator. In some embodiments, at least one additional active pharmaceutical ingredient is a CFTR corrector. In some embodiments, at least one additional active pharmaceutical ingredient is a CFTR potentiator. In some embodiments, at least one additional active pharmaceutical ingredient is a compound that enhances CFTR potentiation, that is, a CFTR potentiator enhancer / co-potentiator. In some embodiments, at least one additional active pharmaceutical ingredient is a CFTR amplifier. In some embodiments, at least one additional active pharmaceutical ingredient is a CFTR read-through agent. In some embodiments, at least one additional active pharmaceutical ingredient is a CFTR nucleic acid therapy. 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. In some embodiments, the pharmaceutical composition comprises: Compound I, a deuterated derivative thereof, or a pharmaceutically 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 pharmaceutically acceptable salt of any of the foregoing; and at least two additional active pharmaceutical ingredients, each of which is a CFTR corrector. 、

[0214] In some embodiments, the present invention provides a pharmaceutical composition comprising: 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 45 mg, 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 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 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 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 pharmaceutically acceptable salt of any of the foregoing; and optionally at least one additional active pharmaceutical ingredient. In some embodiments, at least one additional active pharmaceutical ingredient is a CFTR modulator. In some embodiments, at least one additional active pharmaceutical ingredient is a CFTR corrector. In some embodiments, at least one additional active pharmaceutical ingredient is a CFTR potentiator. In some embodiments, at least one additional active pharmaceutical ingredient is a compound that enhances CFTR potentiation, i.e., a CFTR potentiator enhancer / co-potentiator. In some embodiments, at least one additional active pharmaceutical ingredient is a CFTR amplifier. In some embodiments, at least one additional active pharmaceutical ingredient is a CFTR read-through agent. In some embodiments, at least one additional active pharmaceutical ingredient is a CFTR nucleic acid therapy. 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. In some embodiments, the pharmaceutical composition comprises: Compound I, a deuterated derivative thereof, or a pharmaceutically 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 pharmaceutically acceptable salt of any of the foregoing; and at least two additional active pharmaceutical ingredients, each of which is a CFTR corrector.

[0215] In some embodiments, the present invention provides a pharmaceutical composition comprising: (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 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg); , 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 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 16 5mg, 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 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 620mg, about 630mg, about 640mg, about 65 (a) about 100 mg, about 200 mg, about 25 ...

[0216] In some embodiments, the present invention provides a pharmaceutical composition comprising: (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 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg); , 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 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 16 5mg, 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 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 620mg, about 630mg, about 640mg, about 65 (a) about 100 mg, about 200 mg, about 25 ...

[0217] In some embodiments, the present invention provides a pharmaceutical composition comprising: (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 g 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 9.5mg, 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 1 95mg, 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 330mg, about 335mg, about 340mg, about 345mg, 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 pharmaceutically acceptable salt of any of the foregoing; (b) at least one compound selected from the following: 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 pharmaceutically acceptable salts thereof; and (c) at least one pharmaceutically acceptable carrier. .

[0218] In some embodiments, the present invention provides a pharmaceutical composition comprising: (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 g 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 9.5mg, 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 1 95mg, 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 330mg, about 335mg, about 340mg, about 345mg, 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 pharmaceutically acceptable salt of any of the foregoing; (b) at least two compounds selected from the following: 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 pharmaceutically acceptable salts thereof; and (c) at least one pharmaceutically acceptable carrier. .

[0219] In some embodiments, the present invention provides a pharmaceutical composition comprising: (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 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg); , 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 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 16 5mg, 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 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 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 pharmaceutically acceptable salt of any of the foregoing; (b) at least one compound selected from Compound II and its deuterated derivatives and pharmaceutically acceptable salts; and (c) at least one pharmaceutically acceptable carrier.

[0220] In some embodiments, the present invention provides a pharmaceutical composition comprising: (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 g 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 9.5mg, 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 1mg, 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 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 pharmaceutically acceptable salt of any of the foregoing; (b) at least one compound selected from Compound II and a deuterated derivative and a pharmaceutically acceptable salt thereof; and (c) at least one pharmaceutically acceptable carrier.

[0221] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (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 50 mg to about 100 mg, about 20 mg to about 30 mg, about 30 mg to about 60 mg); , 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 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 16 5mg, 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 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 620mg, about 630mg, about 640mg, about 650mg, about 660mg, 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 pharmaceutically acceptable salt of any of the foregoing; (b) at least one compound selected from Compound II and its deuterated derivatives and pharmaceutically acceptable salts; (c) at least one compound selected from the following: Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X and its deuterated derivatives and pharmaceutically acceptable salts; and (d) at least one pharmaceutically acceptable carrier.

[0222] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (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 g 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 9.5mg, 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 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 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 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 pharmaceutically acceptable salt of any of the foregoing; (b) at least one compound selected from Compound II and its deuterated derivatives and pharmaceutically acceptable salts; (c) at least one compound selected from the following: Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X and its deuterated derivatives and pharmaceutically acceptable salts; and (d) at least one pharmaceutically acceptable carrier. .

[0223] In some embodiments, the pharmaceutical compositions provided herein include: (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 1.5 mg, about 2 mg to about 30 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 2 mg to about 30 mg, about 2 mg to about 50 mg, about 2 mg to about 30 mg, about 2 mg to about 10 mg, about 1 mg to about 30 mg, about 2 ... g, 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 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, ab...

Claims

1. A method for treating cystic fibrosis, the method comprising administering to a patient in need thereof from about 0.1 mg to about 800 mg of Compound I per day: Or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the method comprises administering from about 1 mg to about 400 mg of Compound I or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof per day.

3. The method of claim 1 or claim 2, wherein the method comprises administering from about 5 mg to about 375 mg of Compound I or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof per day.

4. The method according to any one of claims 1 to 3, wherein the method comprises administering from about 30 mg to about 300 mg of Compound I or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof per day.

5. The method of any one of claims 1 to 4, wherein the method comprises administering from about 50 mg to about 200 mg of Compound I or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof per day.

6. The method of any one of claims 1 to 5, wherein the method comprises administering from about 50 mg to about 175 mg of Compound I or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof per day.

7. The method of any one of claims 1 to 3, wherein the method comprises administering from about 10 mg to about 200 mg of Compound I or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof per day.

8. The method of any one of claims 1 to 3 or 7, wherein the method comprises administering from about 20 mg to about 100 mg of Compound I or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof per day.

9. The method of any one of claims 1 to 3, 7 or 8, wherein the method comprises administering from about 30 mg to about 60 mg of Compound 1 or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof per day.

10. The method of claim 1 or claim 2, wherein the method comprises administering from about 1 mg to about 50 mg of Compound I or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof per day.

11. The method of any one of claims 1, 2 or 10, wherein the method comprises administering from about 2 mg to about 40 mg of Compound 1 or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof per day.

12. The method of any one of claims 1 to 3 or 10, wherein the method comprises administering from about 5 mg to about 50 mg of Compound I or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof per day.

13. The method of any one of claims 1 to 3 or 10 to 12, wherein the method comprises administering from about 5 mg to about 20 mg of Compound 1 or an equivalent amount of a deuterated derivative or pharmaceutically acceptable salt thereof per day.

14. The method of any one of claims 1 to 3 or 10 to 13, wherein the method comprises administering from about 5 mg to about 10 mg of Compound I or an equivalent amount of a deuterated derivative or pharmaceutically acceptable salt thereof per day.

15. The method of any one of claims 1, 2 or 10, wherein the method comprises administering from about 1 mg to about 30 mg of Compound 1 or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof per day.

16. The method of any one of claims 1 to 4 or 7 to 9, wherein 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 1 or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof is administered daily.

17. The method according to any one of claims 1 to 16, wherein the patient is heterozygous and has one F508del mutation.

18. The method of any one of claims 1 to 17, wherein Compound 1 or a deuterated derivative or pharmaceutically acceptable salt thereof is administered in a single dose once daily.

19. The method of any one of claims 1 to 17, wherein Compound 1 or a deuterated derivative or pharmaceutically acceptable salt thereof is administered in two doses per day.

20. The method of any one of claims 1 to 19, further comprising administering one or more additional therapeutic agents.

21. The method of claim 20, wherein the one or more additional therapeutic agents comprises a compound having CFTR modulating activity or a deuterated derivative or a pharmaceutically acceptable salt thereof.

22. The method of claim 20 or claim 21, wherein the one or more additional therapeutic agents comprises a CFTR corrector.

23. The method of any one of claims 20 to 22, wherein the one or more additional therapeutic agents comprises a compound selected from: (a) (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylprop-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound II): (b) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound IV): (c) N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound V): (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): (e) (14S)-8-[3-(2-{dispiro[2.0.2.1]hept-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -Thia-3,9,11,18,23-pentazatetracyclo[17.3.1.111,14.05,10]tetracosyl-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound VII): (f) (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]nonadecan-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione (Compound VIII): (g) N-(Benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound IX): as well as (h) N-[(6-amino-2-pyridinyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound X): and deuterated derivatives and pharmaceutically acceptable salts thereof.

24. The method of any one of claims 20 to 23, wherein the one or more additional therapeutic agents comprises at least one compound selected from the group consisting of PTI-428, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, ABBV-2851, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, ARN23766, and PTI-801.

25. The method of any one of claims 20 to 24, wherein the one or more additional therapeutic agents comprises a CFTR potentiator enhancer.

26. The method of any one of claims 20 to 25, wherein the one or more additional therapeutic agents comprises ASP-11.

27. The method of any one of claims 20 to 26, wherein the one or more additional therapeutic agents comprises a CFTR potentiator.

28. The method of any one of claims 20 to 27, wherein the one or more additional therapeutic agents comprises a compound selected from: (c) N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (Compound III): as well as (d) 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): and deuterated derivatives and pharmaceutically acceptable salts thereof.

29. The method of any one of claims 20 to 28, wherein the one or more additional therapeutic agents comprises at least one compound selected from the group consisting of FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW251 (Icenticaftor), GLPG3067 / ABBV-3067 (Navocaftor), and ABBV-191.

30. The method of any one of claims 20 to 29, wherein the one or more additional therapeutic agents comprises a CFTR amplifying agent.

31. The method of any one of claims 20 to 30, wherein the one or more additional therapeutic agents comprises PTI-428.

32. The method of any one of claims 20 to 31, wherein the one or more additional therapeutic agents comprises a CFTR read-through agent.

33. The method of any one of claims 20 to 32, wherein the one or more additional therapeutic agents comprises ELX-02.

34. The method of any one of claims 20 to 33, wherein the one or more additional therapeutic agents comprises a nucleic acid therapy.

35. The method of any one of claims 20 to 34, wherein the one or more additional therapeutic agents comprises at least one agent selected from MRT5005, Lunar-CF, and RCT223.

36. The method of any one of claims 20 to 35, wherein the one or more additional therapeutic agents comprises an ENaC inhibitor.

37. The method of any one of claims 20 to 36, wherein the one or more additional therapeutic agents comprises amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162, or ARO-ENaC1001.

38. The method of any one of claims 20 to 37, wherein the one or more additional therapeutic agents comprises a TMEM16A modulator.

39. The method of any one of claims 20 to 38, wherein the one or more additional therapeutic agents comprises ETD002.

40. The method of any one of claims 20 to 39, wherein the one or more additional therapeutic agents comprises a GPR39 agonist.

41. The method of any one of claims 20 to 40, wherein the one or more additional therapeutic agents comprises DS-1039.

42. A pharmaceutical composition comprising about 0.1 mg to about 800 mg of Compound I or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof.

43. The pharmaceutical composition of claim 42, wherein the composition comprises about 1 mg to about 400 mg of Compound I or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof.

44. A pharmaceutical composition according to claim 42 or claim 43, wherein the composition comprises from about 5 mg to about 375 mg of Compound 1 or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof.

45. The pharmaceutical composition of any one of claims 42 to 44, wherein the composition comprises about 30 mg to about 300 mg of Compound I or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof.

46. ​​The pharmaceutical composition of any one of claims 42 to 45, wherein the composition comprises about 50 mg to about 200 mg of Compound I or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof.

47. The pharmaceutical composition of any one of claims 42 to 46, wherein the composition comprises about 50 mg to about 175 mg of Compound I or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof.

48. The pharmaceutical composition of any one of claims 42 to 44, wherein the composition comprises about 10 mg to about 200 mg of Compound I or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof.

49. The pharmaceutical composition of any one of claims 42 to 44 or 48, wherein the composition comprises about 20 mg to about 100 mg of Compound I or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof.

50. The pharmaceutical composition of any one of claims 42 to 44, 48 or 49, wherein the composition comprises about 30 mg to about 60 mg of Compound 1 or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof.

51. The pharmaceutical composition of claim 42 or claim 43, wherein the composition comprises about 1 mg to about 50 mg of Compound I or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof.

52. The pharmaceutical composition of any one of claims 42, 43 or 51, wherein the composition comprises about 2 mg to about 40 mg of Compound 1 or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof.

53. The pharmaceutical composition of any one of claims 42 to 44 or 51, wherein the composition comprises about 5 mg to about 50 mg of Compound I or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof.

54. A pharmaceutical composition according to any one of claims 42 to 44 or 51 to 53, wherein the composition comprises about 5 mg to about 20 mg of Compound I or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof.

55. The pharmaceutical composition of any one of claims 42 to 44 or 51 to 54, wherein the composition comprises about 5 mg to about 10 mg of Compound I or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof.

56. The pharmaceutical composition of any one of claims 42, 43 or 51, wherein the composition comprises about 1 mg to about 30 mg of Compound I or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof.

57. A pharmaceutical composition according to any one of claims 42 to 45 or 48 to 50, wherein the composition comprises 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 1 or an equivalent amount of a deuterated derivative or a pharmaceutically acceptable salt thereof.

58. A pharmaceutical composition according to any one of claims 42 to 57, wherein the composition further comprises one or more additional therapeutic agents.

59. The pharmaceutical composition of claim 58, wherein the one or more additional therapeutic agents comprises a compound having CFTR modulating activity or a deuterated derivative or a pharmaceutically acceptable salt thereof.

60. The pharmaceutical composition of claim 58 or claim 59, wherein the one or more additional therapeutic agents comprises a CFTR corrector.

61. A pharmaceutical composition according to any one of claims 58 to 60, wherein the one or more additional therapeutic agents comprises a compound selected from: (a) Compound II; (b) Compound IV; (c) Compound V; (d) Compound VI; (e) Compound VII; (f) Compound VIII; (g) Compound IX; as well as (i) Compound X; and deuterated derivatives and pharmaceutically acceptable salts thereof.

62. A pharmaceutical composition according to any one of claims 58 to 61, wherein the one or more additional therapeutic agents include at least one compound selected from the group consisting of PTI-428, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, ABBV-2851, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, ARN23766, and PTI-801.

63. The pharmaceutical composition of any one of claims 58 to 62, wherein the one or more additional therapeutic agents comprises a CFTR potentiator enhancer.

64. The pharmaceutical composition of any one of claims 58 to 63, wherein the one or more additional therapeutic agents comprises ASP-11.

65. The pharmaceutical composition of any one of claims 58 to 64, wherein the one or more additional therapeutic agents comprises a CFTR potentiator.

66. The pharmaceutical composition of any one of claims 58 to 65, wherein the one or more additional therapeutic agents comprises a compound selected from Compound III, Compound III-d, and deuterated derivatives and pharmaceutically acceptable salts thereof.

67. A pharmaceutical composition according to any one of claims 58 to 66, wherein the one or more additional therapeutic agents include at least one compound selected from the group consisting of FDL-176, PTI-808, GLPG1837 / ABBV-974, GLPG2451 / ABBV-2451, QBW251 (Isencattor), GLPG3067 / ABBV-3067 (Navocattor), and ABBV-191.

68. A pharmaceutical composition according to any one of claims 58 to 67, wherein the one or more additional therapeutic agents comprises a CFTR amplifying agent.

69. The pharmaceutical composition of any one of claims 58 to 68, wherein the one or more additional therapeutic agents comprises PTI-428.

70. The pharmaceutical composition of any one of claims 58 to 69, wherein the one or more additional therapeutic agents comprises a CFTR read-through agent.

71. The pharmaceutical composition of any one of claims 58 to 70, wherein the one or more additional therapeutic agents comprises ELX-02.

72. A pharmaceutical composition according to any one of claims 58 to 71, wherein the one or more additional therapeutic agents comprises a nucleic acid therapy.

73. The pharmaceutical composition of any one of claims 58 to 72, wherein the one or more additional therapeutic agents comprises at least one agent selected from MRT5005, Lunar-CF, and RCT223.

74. The pharmaceutical composition of any one of claims 58 to 73, wherein the one or more additional therapeutic agents comprises an ENaC inhibitor.

75. A pharmaceutical composition according to any one of claims 58 to 74, wherein the one or more additional therapeutic agents comprises amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI 1265162 or ARO-ENaC1001.

76. The pharmaceutical composition of any one of claims 58 to 75, wherein the one or more additional therapeutic agents comprises a TMEM16A modulator.

77. The pharmaceutical composition of any one of claims 58 to 76, wherein the one or more additional therapeutic agents comprises ETD002.

78. A pharmaceutical composition according to any one of claims 58 to 77, wherein the one or more additional therapeutic agents comprises a GPR39 agonist.

79. The pharmaceutical composition of any one of claims 58 to 78, wherein the one or more additional therapeutic agents comprises DS-1039.

80. Compound 1 or a deuterated derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 42 to 79, for use in a method for treating cystic fibrosis.

81. Use of Compound 1 or a deuterated derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 42 to 79, for preparing a medicament for treating cystic fibrosis.

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