Macrocycles used as modulators of the transmembrane conductance regulator in cystic fibrosis, their pharmaceutical compositions, their use in the treatment of cystic fibrosis, and associated manufacturing process

Description

[0001] This application claims priority to United States provisional application 62 / 631,453, filed February 15, 2018.

[0002] Disclosed herein is a modulator of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and its use in methods of treatment of cystic fibrosis, pharmaceutical compositions containing the modulator, and a process for making the modulator.

[0003] Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 70,000 children and adults worldwide. Despite progress in the treatment of CF, there is no cure.

[0004] In patients with CF, mutations in CFTR endogenously expressed in respiratory epithelia lead to reduced apical anion secretion causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to enhanced mucus accumulation in the lung and accompanying microbial infections that ultimately cause death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, result in death. In addition, the majority of males with cystic fibrosis are infertile, and fertility is reduced among females with cystic fibrosis.

[0005] Sequence analysis of the CFTR gene has revealed a variety of disease causing mutations (Cutting, G. R. et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem, B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, greater than 2000 mutations in the CF gene have been identified; currently, the CFTR2 database contains information on only 322 of these identified mutations, with sufficient evidence to define 281 mutations as disease causing. The most prevalent disease-causing mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is commonly referred to as the F508del mutation. This mutation occurs in approximately 70% of the cases of cystic fibrosis and is associated with severe disease.

[0006] The deletion of residue 508 in CFTR prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the endoplasmic reticulum (ER) and traffic to the plasma membrane. As a result, the number of CFTR channels for anion transport present in the membrane is far less than observed in cells expressing wild-type CFTR, i.e., CFTR having no mutations. In addition to impaired trafficking, the mutation results in defective channel gating. Together, the reduced number of channels in the membrane and the defective gating lead to reduced anion and fluid transport across epithelia. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). The channels that are defective because of the F508del mutation are still functional, albeit less functional than wild-type CFTR channels. (Dalemans et al. (1991), Nature Lond. 354: 526-528; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). In addition to F508del, other disease causing mutations in CFTR that result in defective trafficking, synthesis, and / or channel gating could be up- or down-regulated to alter anion secretion and modify disease progression and / or severity.

[0007] CFTR is a cAMP / ATP-mediated anion channel that is expressed in a variety of cell types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelial cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. CFTR is composed of approximately 1480 amino acids that encode a protein which is made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking.

[0008] Chloride transport takes place by the coordinated activity of ENaC and CFTR present on the apical membrane and the Na +< -K +< -ATPase pump and Cl -< channels expressed on the basolateral surface of the cell. Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which can then passively leave the cell via Cl -< channels, resulting in a vectorial transport. Arrangement of Na +< / 2Cl -< / K +< co-transporter, Na +< -K +< -ATPase pump and the basolateral membrane K +< channels on the basolateral surface and CFTR on the luminal side coordinate the secretion of chloride via CFTR on the luminal side. Because water is probably never actively transported itself, its flow across epithelia depends on tiny transepithelial osmotic gradients generated by the bulk flow of sodium and chloride.

[0009] US 2016 / 095858 A1 relates to compounds for the treatment of CFTR mediated diseases, such as cycstic fibrosis, as well as pharmaceutical compositions, methods of treating, and kits thereof.

[0010] WO 2017 / 173274 A1 relates to compounds for the treatment of CFTR mediated diseases, such as cycstic fibrosis, as well as pharmaceutical compositions, methods of treating, and kits thereof.

[0011] Accordingly, there is a need for novel treatments of CFTR mediated diseases. The invention features a compound of Formula (III-A) or (III-B): or or a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, as defined in the claims. The invention also provides compounds of Formulae (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), and (VI-D), pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing.

[0012] Not part of the invention but also described herein are compounds of Formulae (I), (II-A), and (II-B), pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing.

[0013] In some embodiments, Ring D in Formula (I) is pyridin-2(1H)-one, pyrrolidin-2-one, or imidazolidin-2-one.

[0014] The present invention also features pharmaceutical compositions comprising at least one of the novel compounds of Formula (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), or (VI-D) as defined in the claims and / or at least one pharmaceutically acceptable salt thereof, which compositions may further include at least one additional active pharmaceutical ingredient and / or at least one carrier. The present invention also features the compounds of Formula (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), or (VI-D) as defined in the claims for use in methods of treating the CFTR-mediated disease cystic fibrosis comprising administering at least one of the novel compounds of Formula (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), or (VI-D) and / or at least one pharmaceutically acceptable salt thereof, optionally as part of a pharmaceutical composition comprising at least one additional component, to a subject in need thereof.

[0015] The present invention also features the compounds of Formula (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), or (VI-D) as defined in the claims for use in methods of treating the CFTR-mediated disease cystic fibrosis comprising administering at least one of the novel compounds of Formula (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), or (VI-D) and / or at least one pharmaceutically acceptable salt thereof, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound II), and N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound III), optionally as part of at least one pharmaceutical composition comprising at least one additional component, to a patient in need thereof.

[0016] The references to methods of treatment in the subsequent paragraphs of this description are to be interpreted as references to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for treatment of the human (or animal) body by therapy (or for diagnosis).Brief Description of the Drawings

[0017] FIG. 1 shows the structures of non-limiting examples of novel compounds disclosed herein. FIG. 2 is a representative list of CFTR mutations. Definitions

[0018] As used herein, the term "alkyl group" refers to a saturated aliphatic hydrocarbon (containing, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms). Alkyl groups may be substituted or unsubstituted and branched or unbranched.

[0019] As used herein, the term "haloalkyl group" refers to an alkyl group substituted with one or more halogen atoms.

[0020] As used herein, the term "cycloalkyl group" refers to a cyclic non-aromatic hydrocarbon containing 3 to 12 carbons in a ring (such as, for example 3 to 10 carbons). Cycloalkyl groups encompass monocyclic, bicyclic, tricyclic, polycyclic, bridged, fused, and spiro rings, including mono spiro and dispiro rings. Non-limiting examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, spiro[2.2]pentane, and dispiro[2.0.2.1]heptane. Cycloalkyl groups may be substituted or unsubstituted.

[0021] The term "alkoxy group" as used herein refers to an alkyl or cycloalkyl group covalently bonded to an oxygen atom. Alkoxy groups may be substituted or unsubstituted and branched or unbranched.

[0022] As used herein, the term "haloalkoxyl group" refers to an alkoxy group substituted with one or more halogen atoms.

[0023] The term "heteroaryl ring" as used herein refers to an aromatic ring comprising at least one ring atom that is a heteroatom, such as O, N, or S.

[0024] As used herein, the term "heterocyclyl ring" refers to a non-aromatic hydrocarbon containing 3 to 12 atoms in a ring (such as, for example 3-10 atoms) comprising at least one ring atom that is a heteroatom, such as O, N, or S. "Heterocyclyl" rings encompass monocyclic, bicyclic, tricyclic, polycyclic, bridged, fused, and spiro rings, including mono spiro and dispiro rings.

[0025] Examples of protecting groups for nitrogen include, for example, t-butyl carbamate (Boc), benzyl (Bn), para-methoxybenzyl (PMB), tetrahydropyranyl (THP), 9-fluorenylmethyl carbamate (Fmoc), benzyl carbamate (Cbz), methyl carbamate, ethyl carbamate, 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), allyl carbamate (Aloc or Alloc), formamide, acetamide, benzamide, allylamine, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide. A comprehensive list of nitrogen protecting groups can be found in Wuts, P. G. M. "Greene's Protective Groups in Organic Synthesis: Fifth Edition," 2014, John Wiley and Sons.

[0026] "Substituted," whether preceded by the term "optionally" or not, indicates that at least one hydrogen of the "substituted" group is replaced by a substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent chosen from a specified group, the substituent may be either the same or different at each position.

[0027] As used herein, "deuterated derivative(s)" means the same chemical structure, but with one or more hydrogen atoms replaced by a deuterium atom.

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

[0029] As used herein, "mutations" can refer to mutations in the CFTR gene or the CFTR protein. A "CFTR gene mutation" refers to a mutation in the CFTR gene, and a "CFTR protein mutation" refers to a mutation in the CFTR protein. A genetic defect or mutation, or a change in the nucleotides in a gene in general results in a mutation in the CFTR protein translated from that gene, or a frame shift(s).

[0030] The term "F508del" refers to a mutant CFTR protein which is lacking the amino acid phenylalanine at position 508.

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

[0032] As used herein, a patient who is "heterozygous" for a particular gene mutation has this mutation on one allele, and a different mutation on the other allele.

[0033] As used herein, the term "modulator" refers to a compound that increases the activity of a biological compound or molecule such as a protein. For example, a CFTR modulator is a compound that increases the activity of CFTR. The increase in activity resulting from a CFTR modulator includes but is not limited to compounds that correct, potentiate, stabilize and / or amplify CFTR.

[0034] As used herein, the term "CFTR corrector" refers to a compound that facilitates the processing and trafficking of CFTR to increase the amount of CFTR at the cell surface. Compounds of Formulae (I), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), and (VI-D), Compound II, Compound IV, and their pharmaceutically acceptable salts thereof disclosed herein are CFTR correctors.

[0035] As used herein, the term "CFTR potentiator" refers to a compound that increases the channel activity of CFTR protein located at the cell surface, resulting in enhanced ion transport. Compound III disclosed herein is a CFTR potentiator.

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

[0037] As used herein, the term "pharmaceutically acceptable salt" refers to a salt form of a compound of this disclosure wherein the salt is nontoxic. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0038] As used herein, the term "amorphous" refers to a solid material having no long range order in the position of its molecules. Amorphous solids are generally supercooled liquids in which the molecules are arranged in a random manner so that there is no well-defined arrangement, e.g., molecular packing, and no long range order. Amorphous solids are generally isotropic, i.e. exhibit similar properties in all directions and do not have definite melting points. For example, an amorphous material is a solid material having no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of an amorphous solid. See, US 2004 / 0006237 for a comparison of XRPDs of an amorphous material and crystalline material.

[0039] As used herein, the term "substantially amorphous" refers to a solid material having little or no long range order in the position of its molecules. For example, substantially amorphous materials have less than 15% crystallinity (e.g., less than 10% crystallinity or less than 5% crystallinity). It is also noted that the term 'substantially amorphous' includes the descriptor, 'amorphous', which refers to materials having no (0%) crystallinity.

[0040] As used herein, the term "dispersion" refers to a disperse system in which one substance, the dispersed phase, is distributed, in discrete units, throughout a second substance (the continuous phase or vehicle). The size of the dispersed phase can vary considerably (e.g. colloidal particles of nanometer dimension, to multiple microns in size). In general, the dispersed phases can be solids, liquids, or gases. In the case of a solid dispersion, the dispersed and continuous phases are both solids. In pharmaceutical applications, a solid dispersion can include a crystalline drug (dispersed phase) in an amorphous polymer (continuous phase); or alternatively, an amorphous drug (dispersed phase) in an amorphous polymer (continuous phase). In some embodiments, a solid dispersion includes the polymer constituting the dispersed phase, and the drug constitute the continuous phase. Or, a solid dispersion includes the drug constituting the dispersed phase, and the polymer constituting the continuous phase.

[0041] The terms "patient" and "subject" are used interchangeably and refer to an animal including humans.

[0042] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to that amount of a compound that produces the desired effect for which it is administered (e.g., improvement in CF or a symptom of CF, or lessening the severity of CF or a symptom of CF). The exact amount of an effective dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0043] As used herein, the terms "treatment," "treating," and the like generally mean the improvement of CF or its symptoms or lessening the severity of CF or its symptoms in a subject. "Treatment," as used herein, includes, but is not limited to, the following: increased growth of the subject, increased weight gain, reduction of mucus in the lungs, improved pancreatic and / or liver function, reduction of chest infections, and / or reductions in coughing or shortness of breath. Improvements in or lessening the severity of any of these symptoms can be readily assessed according to standard methods and techniques known in the art.

[0044] As used herein, the term "in combination with," when referring to two or more compounds, agents, or additional active pharmaceutical ingredients, means the administration of two or more compounds, agents, or active pharmaceutical ingredients to the patient prior to, concurrent with, or subsequent to each other.

[0045] The terms "about" and "approximately," when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, include the value of a specified dose, amount, or weight percent or a range of the dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent.

[0046] One of ordinary skill in the art would 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 the amount equivalent to the concentration of the free base of the compound. It is noted that the disclosed amounts of the compounds or their pharmaceutically acceptable salts thereof herein are based upon their free base form. For example, "10 mg of at least one compound chosen from compounds of Formula (I) and pharmaceutically acceptable salts thereof" includes 10 mg of a compound of Formula (I) and a concentration of a pharmaceutically acceptable salt of compounds of Formula (I) equivalent to 10 mg of compounds of Formula (I).

[0047] Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, 1-19. For example, Table 1 of that article provides the following pharmaceutically acceptable salts: Table 1: AcetateHydrobromideStearateBenzenesulfonateHydrochlorideSubacetateBenzoateHydroxynaphthoateSuccinateBicarbonateIodideSulfateBitartrateIsethionateTannateBromideLactateTartrateCalcium edetateLactobionateTeociateCamsylateMalateTriethiodideCarbonateMaleateBenzathineChlorideMandelateChloroprocaineCitrateMesylateCholineDihydrochlorideMethylbromideDiethanolamineEdetateMethylnitrateEthylenediamineEdisylateMethylsulfateMeglumineEstolateMucateProcaineEsylateNapsylateAluminumFumarateNitrateCalciumGluceptatePamoate (Embonate)LithiumGluconatePantothenateMagnesiumGlutamatePhosphate / diphosphatePotassiumGlycollylarsanilatePolygalacturonateSodiumHexvlresorcinateSalicylateZincHydrabamine

[0048] Non-limiting examples of pharmaceutically acceptable salts derived from appropriate acids 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, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N +< (C 1-4 alkyl) 4 salts. This disclosure also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0049] The exact amount of a pharmaceutical composition required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular agent, its mode of administration, and the like. The compounds of this disclosure may be formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of this disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term "patient", as used herein, means an animal, such as a mammal, and even further such as a human.

[0050] In some embodiments, the disclosure also is directed to methods of treatment using isotope-labelled compounds of the afore-mentioned compounds, which have the same structures as disclosed herein except that one or more atoms therein have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs naturally (isotope labelled). Examples of isotopes which are commercially available and suitable for the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example 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, respectively.

[0051] The isotope-labelled compounds and salts can be used in a number of beneficial ways. They can be suitable for medicaments and / or various types of assays, such as substrate tissue distribution assays. For example, tritium ( 3< H)- and / or carbon-14 ( 14< C)-labelled compounds are particularly useful for various types of assays, such as substrate tissue distribution assays, due to relatively simple preparation and excellent detectability. For example, deuterium ( 2< H)-labelled ones are therapeutically useful with potential therapeutic advantages over the non- 2< H-labelled compounds. In general, deuterium ( 2< H)-labelled compounds and salts can have higher metabolic stability as compared to those that are not isotope-labelled owing to the kinetic isotope effect described below. Higher metabolic stability translates directly into an increased in vivo half-life or lower dosages, which could be desired. The isotope-labelled compounds and salts can usually be prepared by carrying out the procedures disclosed in the synthesis schemes and the related description, in the example part and in the preparation part in the present text, replacing a non-isotope-labelled reactant by a readily available isotope-labelled reactant.

[0052] In some embodiments, the isotope-labelled compounds and salts are deuterium ( 2< H)-labelled ones. In some specific embodiments, the isotope-labelled compounds and salts are deuterium ( 2< H)-labelled, wherein one or more hydrogen atoms therein have been replaced by deuterium. In chemical structures, deuterium is represented as " 2< H" or "D."

[0053] The deuterium ( 2< H)-labelled compounds and salts can manipulate the oxidative metabolism of the compound by way of the primary kinetic isotope effect. The primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies necessary for covalent bond formation after this isotopic exchange. Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially. For explanation: if deuterium is bonded to a carbon atom at a non-exchangeable position, rate differences of k M / k D = 2-7 are typical. For a further discussion, see S. L. Harbeson and R. D. Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417; and T.G. Gant "Using deuterium in drug discovery: leaving the label in the drug" J. Med. Chem. 2014, 57, 3595-3611.

[0054] The concentration of the isotope(s) (e.g., deuterium) incorporated into the isotope-labelled compounds and salt of the disclosure may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. In some embodiments, if a substituent in a compound of the disclosure is denoted 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).

[0055] When discovering and developing therapeutic agents, the person skilled in the art attempts to optimize pharmacokinetic parameters while retaining desirable in vitro properties. It may be reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism.

[0056] One of ordinary skill in the art would understand that deuteration of one or more metabolically labile positions on a compound or active metabolite may lead to improvement of one or more superior DMPK properties while maintaining biological activity as compared to the corresponding hydrogen analogs. The superior DMPK property or properties may have an impact on the exposure, half-life, clearance, metabolism, and / or even food requirements for optimal absorption of the drug product. Deuteration may also change the metabolism at other non-deuterated positions of the deuterated compound.

[0057] In some embodiments, the disclosure includes deuterated derivatives of the novel compounds disclosed herein and of their pharmaceutically acceptable salts. Non-limiting examples of deuterated compounds are disclosed in FIG. 1.

[0058] Each compound described herein, including compounds of Formulae (I), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), and (VI-D), Compounds II, III, and IV, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing can independently be administered once daily, twice daily, or three times daily. In some embodiments, at least one compound chosen from Compounds of Formulae (I), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), and (VI-D), pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing is administered once daily. In some embodiments, at least one compound chosen from Compounds of Formulae (I), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), and (VI-D), and pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing are administered twice daily. In some embodiments, at least one compound chosen from Compound II and pharmaceutically acceptable salts thereof is administered once daily. In some embodiments, at least one compound chosen from Compound II and pharmaceutically acceptable salts thereof is administered twice daily. In some embodiments, at least one compound chosen from Compound III and pharmaceutically acceptable salts thereof is administered once daily. In some embodiments, at least one compound chosen from Compound III and pharmaceutically acceptable salts thereof is administered twice daily. In some embodiments, at least one compound chosen from Compound IV and pharmaceutically acceptable salts thereof is administered once daily. In some embodiments, at least one compound chosen from Compound IV and pharmaceutically acceptable salts thereof is administered twice daily. In some embodiments, a deuterated derivative of Compound II, III, and / or IV or a pharmaceutically acceptable salt thereof is employed in any one of these embodiments.

[0059] In some embodiments, 10 mg to 1,500 mg of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a deuterated derivative of such compound or salt are administered daily.

[0060] Described herein are compounds of Formula (I): a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: Ring A is a phenyl, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; Ring B is a pyridinyl ring; Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; X is O, NH, or an N(C1-C4 alkyl); each R 1< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; m is 0, 1, 2, 3, or 4; each R 2< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; n is 0, 1, or 2; each R 3< is methyl; each R 4< is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y) k -R 7< groups, or optionally two R 4< , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens; q is 1, 2, 3 or 4; and Z is a divalent linker of formula (L) r , wherein: r is 1, 2, 3, 4, 5, or 6; each L is independently chosen from C(R 8< )(R 9< ) groups, -O-, and -NR b< - groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen, halogens, C 1 -C 2 haloalkyl groups, C 1 -C 2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups.

[0061] The compound of Formula I described herein may be a compound of Formula (II-A) or (II-B): or a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: the carbon denoted by ∗< has S-stereochemistry or R-stereochemistry; Ring A is a phenyl, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; Ring B is a pyridinyl ring; Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6-membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; each R 1< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; m is 0, 1, 2, 3, or 4; each R 2< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; n is 0, 1, or 2; each R 3< is methyl; each R 4< is independently chosen from halogens, a hydroxyl group, an oxo group, a cyano group, and -(Y) k -R 7< groups, or optionally two R 4< , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens; q is 1, 2, 3, or 4; Z is a divalent linker of formula (L) r , wherein: r is 1,2, 3, 4, 5, or 6; each L is independently chosen from C(R 8< )(R 9< ) groups, -O-, and -NR b< - groups , wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen, halogens, C 1 -C2 alkyl groups, C 1 -C 2 haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups.

[0062] The invention provides a compound of Formula (III-A) or (III-B): or a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: the carbon denoted by ∗< has S-stereochemistry or R-stereochemistry; Ring A is a phenyl, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; each R 1< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; m is 0, 1, 2, 3, or 4; each R 2< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; n is 0, 1, or 2; each R 3< is methyl; each R 4< is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y) k -R 7< groups or optionally two R 4< , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens; q is 1 or 2; Z is a divalent linker of formula (L) r , wherein: r is 3, 4, or 5; each L is independently chosen from C(R 8< )(R 9< ) groups, -O-, and -NR b< - groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen, halogens, C 1 -C 2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups.

[0063] The invention also provides a compound of Formula IV-A: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: the carbon denoted by ∗< has S-stereochemistry or R-stereochemistry; Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; each R 1< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; m is 0, 1, 2, 3, or 4; each R 2< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; n is 0, 1, or 2; each R 3< is methyl; each R 4< is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y) k -R 7< groups, or optionally two R 4< , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens; q is 1 or 2; Z is a divalent linker of formula (L) r , wherein: r is 3, 4, or 5; each L is independently chosen from C(R 8< )(R 9< ) groups, -O-, and -NR b< - groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen, halogens, C 1 -C 2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups.

[0064] The invention also provides a compound of Formula IV-B: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: the carbon denoted by ∗< has S-stereochemistry or R-stereochemistry; Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; each R 1< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; m is 0, 1, 2, 3, or 4; each R 2< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; n is 0, 1, or 2; each R 3< is methyl; each R 4< is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y) k -R 7< groups, or optionally two R 4< , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens; q is 1 or 2; r is 3 or 4; each R 8< and R 9< is independently chosen from hydrogen, halogens, C 1 -C 2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups.

[0065] The invention also provides a compound of Formula IV-C: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: the carbon denoted by ∗< has S-stereochemistry or R-stereochemistry; each R 1< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; m is 0, 1, 2, 3, or 4; each R 2< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; n is 0, 1, or 2; each R 3< is methyl; each R 4< is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y) k -R 7< groups, or optionally two R 4< , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens; q is 1 or 2; r is 3 or 4; each R 8< and R 9< is independently chosen from hydrogen, halogens, C 1 -C 2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups.

[0066] The invention also provides a compound of Formula V-A: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: the carbon denoted by ∗< has S-stereochemistry or R-stereochemistry; Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; each R 1< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; m is 0, 1, 2, 3, or 4; each R 2< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; n is 0, 1, or 2; each R 3< is methyl; each R 4< is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y) k -R 7< groups, or optionally two R 4< , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens; q is 1 or 2; Z is a divalent linker of formula (L) r , wherein: r is 3, 4, or 5; each L is independently chosen from C(R 8< )(R 9< ) groups, -O-, and -NR b< - groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen, halogens, C 1 -C 2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups.

[0067] The invention also provides a compound of Formula V-B: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: the carbon denoted by ∗< has S-stereochemistry or R-stereochemistry; Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; each R 1< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; m is 0, 1, 2, 3, or 4; each R 2< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; n is 0, 1, or 2; each R 3< is methyl; each R 4< is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y) k -R 7< groups, or optionally two R 4< , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens; q is 1 or 2; r is 3, 4, or 5; and each R 8< and R 9< is independently chosen from hydrogen, halogens, C 1 -C 2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups.

[0068] The invention also provides a compound of Formula VI-A or VI-B: or a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: the carbon denoted by ∗< has S-stereochemistry or R-stereochemistry; Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; each R 1< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; m is 0, 1, 2, 3, or 4; each R 2< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; n is 0, 1, or 2; each R 3< is methyl; each R 4< is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y) k -R 7< groups, or optionally two R 4< , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens; q is 1 or 2; Z is a divalent linker of formula (L) r , wherein: r is 3, 4, or 5; each L is independently chosen from C(R 8< )(R 9< ) groups, -O-, and -NR b< - groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen, halogens, C 1 -C 2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups.

[0069] The invention also provides a compound of Formula VI-C or VI-D: or a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: the carbon denoted by ∗< has S-stereochemistry or R-stereochemistry; Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; each R 1< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; m is 0, 1, 2, 3, or 4; each R 2< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; n is 0, 1, or 2; each R 3< is methyl; each R 4< is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y) k -R 7< groups, or optionally two R 4< , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens; q is 1 or 2; r is 3 or 4; and each R 8< and R 9< is independently chosen from hydrogen, halogens, C 1 -C 2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups.

[0070] Also disclosed herein are compounds having a formula chosen from any one of the formulae depicted in FIG. 1 and pharmaceutically acceptable salts thereof.

[0071] In some embodiments, at least one compound chosen from the novelcompounds of Formulae (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), or (VI-D), pharmaceutically acceptable salts thereof, and deuterated derivatives of the foregoing is administered in combination with at least one compound chosen from Compound II, pharmaceutically acceptable salts thereof, and deuterated derivatives of the foregoing. In some embodiments, at least one compound chosen from the novel compounds of Formulae (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), or (VI-D), pharmaceutically acceptable salts thereof, and deuterated derivatives of the foregoing is administered in combination with at least one compound chosen from Compound III and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound chosen from the novel compounds of Formulae (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), or (VI-D), pharmaceutically acceptable salts thereof, and deuterated derivatives of the foregoing is administered in combination with at least one compound chosen from Compound IV and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound chosen from the novel compounds of Formulae (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), or (VI-D), pharmaceutically acceptable salts, and deuterated derivatives of the foregoing thereof is administered in combination with Compounds II or a pharmaceutically acceptable salt or deuterated derivative thereof and at least one compound chosen from Compound III, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing. In some embodiments, at least one compound chosen from the novel compounds of Formulae (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), or (VI-D), pharmaceutically acceptable salts, and deuterated derivatives of any of the foregoing thereof is administered in combination with at least one compound chosen from Compound III, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing and at least one compound chosen from Compound IV, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing.

[0072] In some embodiments, at least one novel compound of Formulae (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), or (VI-D) (and / or at least one pharmaceutically acceptable salt thereof and / or at least one deuterated derivative of such compound or salt) can be administered in combination with at least one additional active pharmaceutical ingredient. In some embodiments, at least one additional active pharmaceutical ingredient is chosen from: (a) Compound II: and pharmaceutically acceptable salts thereof. A chemical name for Compound II is (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; (b) Compound III: and pharmaceutically acceptable salts thereof. A chemical name for Compound III is N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide; and (c) Compound IV: and pharmaceutically acceptable salts thereof.

[0073] A chemical name for Compound IV is 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamido)-3-methylpyridin-2-yl)benzoic acid. In some embodiments, a compound of Formulae (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), or (VI-D) and / or a pharmaceutically acceptable salt thereof can be administered in combination with Compound II and / or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formulae (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), or (VI-D) and / or a pharmaceutically acceptable salt thereof can be administered in combination with Compound III and / or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formulae (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), or (VI-D) and / or a pharmaceutically acceptable salt thereof can be administered in combination with Compound IV and / or a pharmaceutically acceptable salt thereof. In some embodiments a compound of Formulae (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), or (VI-D) and / or a pharmaceutically acceptable salt thereof can be administered in combination with Compounds II and / or a pharmaceutically acceptable salt thereof and Compound III and / or a pharmaceutically acceptable salt thereof. In some embodiments a compound of Formulae (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), or (VI-D) and / or a pharmaceutically acceptable salt thereof can be administered in combination with Compounds II and / or a pharmaceutically acceptable salt thereof and Compound IV and / or a pharmaceutically acceptable salt thereof.

[0074] In one aspect, the disclosure features a pharmaceutical composition comprising a compound of Formula (I) and / or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0075] In one aspect, the disclosure features a pharmaceutical composition comprising a compound of Formula (I) and / or a pharmaceutically acceptable salt thereof, Compound II and / or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0076] In one aspect, the disclosure features a pharmaceutical composition comprising a compound of Formula (I) and / or a pharmaceutically acceptable salt thereof, Compound III and / or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0077] In one aspect, the disclosure features a pharmaceutical composition comprising a compound of Formula (I) and / or a pharmaceutically acceptable salt thereof, Compound II and / or a pharmaceutically acceptable salt thereof, Compound III and / or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0078] Any of the novel compounds disclosed herein, such as for example, compounds of Formulae (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), or (VI-D) and their pharmaceutically acceptable salts thereof, and deuterated derivatives of such compounds and salts can be comprised in a single pharmaceutical composition or separate pharmaceutical compositions in combination with other additional active pharmaceutical ingredient(s) (e.g., Compound II, III, or IV, or its pharmaceutically acceptable salt thereof, or a deuterated derivative of such Compound or salt). Such pharmaceutical compositions can be administered once daily or multiple times daily, such as twice daily. In some embodiments, the disclosure features a pharmaceutical composition comprising at least one compound chosen from any of the compounds disclosed herein and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.

[0079] In some embodiments, the disclosure features a pharmaceutical composition comprising at least one compound chosen from the novel compounds disclosed herein and pharmaceutically acceptable salts thereof, at least one compound chosen from Compound II and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.

[0080] In some embodiments, the disclosure features a pharmaceutical composition comprising at least one compound chosen from the novel compounds disclosed herein and pharmaceutically acceptable salts thereof, at least one compound chosen from Compound III and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.

[0081] In some embodiments, the disclosure features a pharmaceutical composition comprising at least one compound chosen from the novel compounds disclosed herein and pharmaceutically acceptable salts thereof, at least one compound chosen from Compound II and pharmaceutically acceptable salts thereof, at least one compound chosen from Compound III and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.

[0082] In some embodiments, the disclosure features a pharmaceutical composition comprising at least one compound chosen from the novel compounds disclosed herein and pharmaceutically acceptable salts thereof, at least one compound chosen from Compound III and pharmaceutically acceptable salts thereof, at least one compound chosen from Compound IV and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.

[0083] In some embodiments, pharmaceutical compositions disclosed herein comprise at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR modulator. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR corrector. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR potentiator. In some embodiments, the pharmaceutical composition comprises (i) a compound of Formulae (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), and (VI-D), or a pharmaceutically acceptable salt thereof, or a deuterated derivative of such compound or salt; and (ii) at least two additional active pharmaceutical ingredients, one of which is a CFTR corrector and one of which is a CFTR potentiator.

[0084] In some embodiments, at least one additional active pharmaceutical ingredient is selected from mucolytic agents, bronchodialators, antibiotics, anti-infective agents, and anti-inflammatory agents.

[0085] A pharmaceutical composition may further comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is chosen from pharmaceutically acceptable vehicles and pharmaceutically acceptable adjuvants. In some embodiments, the at least one pharmaceutically acceptable is chosen from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, lubricants.

[0086] It will also be appreciated that a pharmaceutical composition of this disclosure, including a pharmaceutical composition comprising combinations described previously, can be employed in combination therapies; that is, the compositions can be administered concurrently with, prior to, or subsequent to, at least one additional active pharmaceutical ingredient or medical procedures.

[0087] Pharmaceutical compositions comprising these combinations are useful for treating cystic fibrosis.

[0088] As described above, pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be chosen from adjuvants and vehicles. The at least one pharmaceutically acceptable carrier, as used herein, includes any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surface active agents, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier is incompatible with the compounds of this disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this disclosure. Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffering agents (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives, and antioxidants.

[0089] In some embodiments, the present invention features at least one compound chosen from any of the compounds of Formulae (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), or (VI-D) and pharmaceutically acceptable salts thereof, and at least one compound chosen from Compound II, Compound III, Compound IV, and pharmaceutically acceptable salts of any of the foregoing, for use in methods of administering to a patient in need thereof at least one compound chosen from any of the compounds of Formulae (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), or (VI-D) and pharmaceutically acceptable salts thereof, and at least one compound chosen from Compound II, Compound III, Compound IV, and pharmaceutically acceptable salts of any of the foregoing.

[0090] Any suitable pharmaceutical compositions known in the art can be used for the novel compounds disclosed herein, Compound II, Compound III, Compound IV, and pharmaceutically acceptable salts thereof. Some exemplary pharmaceutical compositions for Compound II and its pharmaceutically acceptable salts can be found in WO 2011 / 119984 and WO 2014 / 015841. 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. Exemplary compositions comprising Compound III-d and its pharmaceutically acceptable salts can be fround in, e.g., WO 2014 / 078842 and WO2018 / 227049. Some exemplary pharmaceutical compositions for Compound IV and its pharmaceutically acceptable salts can be found in WO 2010 / 037066, WO 2011 / 127241, WO 2013 / 112804, and WO 2014 / 071122.

[0091] In some embodiments, a pharmaceutical composition comprising at least one compound chosen from the novel compounds disclosed herein and pharmaceutically acceptable salts thereof is administered with a pharmaceutical composition comprising Compound II and Compound III. Pharmaceutical compositions comprising Compound II and Compound III are disclosed in PCT Publication No. WO 2015 / 160787.

[0092] An exemplary embodiment is shown in the following Table 2: Table 2. Exemplary Tablet Comprising 100 mg Compound II and 150 mg Compound III.Ingredient Amount per tablet (mg) Intra-granularCompound II SDD (spray dried dispersion)125(80 wt % Compound II, 20 wt % HPMC)Compound III SDD187.5(80 wt % Compound III, 19.5 wt% HPMCAS-HG; 0.5 wt% sodium lauryl sulfate)Microcrystalline cellulose131.4Croscarmellose Sodium29.6Total 473.5 Extra-granularMicrocrystalline cellulose112.5Magnesium Stearate5.9Total 118.4 Total uncoated Tablet 591.9 Film coatOpadry17.7Total coated Tablet 609.6

[0093] In some embodiments, a pharmaceutical composition comprising at least one compound chosen from the novel compounds disclosed herein and pharmaceutical salts thereof is administered with a pharmaceutical composition comprising Compound III. Pharmaceutical compositions comprising Compound III are disclosed in PCT Publication No. WO 2010 / 019239. An exemplary embodiment is shown in the following Table 3: Table 3: Ingredients for Exemplary Tablet of Compound IIITablet Formulation Percent Dose % Wt. / Wt. Dose (mg) Batch (g) Compound III SDD34.09%187.523.86(80 wt % Compound III, 19.5 wt% HPMCAS-HG; 0.5 wt% sodium lauryl sulfate)Microcrystalline cellulose30.51%167.821.36Lactose30.40%167.221.28Sodium croscarmellose3.000%16.502.100SLS0.500%2.7500.3500Colloidal silicon dioxide0.500%2.7500.3500Magnesium stearate1.000%5.5000.7000Total 100% 550 70

[0094] Additional pharmaceutical compositions comprising Compound III are disclosed in PCT Publication No. WO 2013 / 130669. Exemplary mini-tablets (~2 mm diameter, ~2 mm thickness, each mini-tablet weighing about 6.9 mg) was formulated to have approximately 50 mg of Compound III per 26 mini-tablets and approximately 75 mg of Compound III per 39 mini-tablets using the amounts of ingredients recited in Table 4, below. Table 4: Ingredients for mini-tablets for 50 mg and 75 mg potency Tablet Formulation Percent Dose % Wt. / Wt. Dose (mg) 50 mg potency Dose (mg) 75 mg potency Batch (g) Compound III SDD3562.593.81753.4(80 wt % Compound III, 19.5 wt% HPMCAS-HG; 0.5 wt% sodium lauryl sulfate)Mannitol13.524.136.2675.2Lactose4173.2109.82050.2Sucralose2.03.65.4100.06Croscarmellose sodium6.010.716.1300.1Colloidal silicon dioxide1.01.82.750.0Magnesium stearate1.52.74.074.19Total 100 178.6 268 5003.15

[0095] In some embodiments, the pharmaceutical compositions are a tablet. In some embodiments, the tablets are suitable for oral administration.

[0096] The compounds, pharmaceutically acceptable salts thereof, and deuterated analogs of any of the foregoing, and pharmaceutical compositions, of this disclosure, either in monotherapies or in combo-therapies are useful for treating cystic fibrosis.

[0097] In some embodiments, disclosed herein is a compound, pharmaceutically acceptable salt thereof, or a deuterated analog of any of the foregoing; or a pharmaceutical composition, of this disclosure, for use in methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the compound, pharmaceutically acceptable salt thereof, or the deuterated analog of any of the foregoing; or the pharmaceutical composition, of this disclosure to a patient, such as a human, wherein said patient has cystic fibrosis. In some embodiments, the patient has an F508del / minimal function (MF) genotype, F508del / F508del genotype (homozygous for the F508del mutation), F508del / gating genotype, or F508del / residual function (RF) genotype. In some embodiments the patient is heterozygous and has one F508del mutation.

[0098] As used herein, "minimal function (MF) mutations" refer to CFTR gene mutations associated with minimal CFTR function (little-to-no functioning CFTR protein) and include, for example, mutations associated with severe defects in 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 conductance. Table C below includes a non-exclusive list of CFTR minimal function mutations, which are detectable by an FDA-cleared genotyping assay. In some embodiments, a mutation is considered a MF mutation if it meets at least 1 of the following 2 criteria: biological plausibility of no translated protein (genetic sequence predicts the complete absence of CFTR protein), or in vitro testing that supports lack of responsiveness to Compound II, Compound III or the combination of Compound II and Compound III, and evidence of clinical severity on a population basis (as reported in large patient registries).

[0099] In some embodiments, the minimal function mutations are those that result in little-to-no functioning CFTR protein and are not responsive in vitro to Compound II, Compound III, or the combination of Compound II and Compound III.

[0100] In some embodiments, the minimal function mutations are those that are not responsive in vitro to Compound II, Compound III, or the combination of Compound II and Compound III. In some embodiments, the minimal function mutations are mutations based on in vitro testing met the following criteria in in vitro experiments: baseline chloride transport that was <10% of wildtype CFTR, and an increase in chloride transport of <10% over baseline following the addition of Compound II, Compound III, or Compound II / Compound III in the assay.

[0101] In some embodiments, patients with at least one minimal function mutation exhibit evidence of clinical severity as defined as: average sweat chloride >86 mmol / L, and prevalence of pancreatic insufficiency (PI) >50%.

[0102] Patients with an F508del / minimal function genotype are defined as patients that are heterozygous F508del-CFTR with a second CFTR allele containing a minimal function mutation. In some embodiments, patients with an F508del / minimal function genotype are patients that are heterozygous F508del-CFTR with a second CFTR allele containing a mutation that results in a CFTR protein with minimal CFTR function (little-to-no functioning CFTR protein) and that is not responsive in vitro to Compound II, Compound III, or the combination of Compound II and Compound III.

[0103] In some embodiments, minimal function mutations can be determined using 3 major sources: biological plausibility for the mutation to respond (i.e., mutation class) evidence of clinical severity on a population basis (per CFTR2 patient registry; accessed on 15 February 2016) ∘ average sweat chloride >86 mmol / L, and ∘ prevalence of pancreatic insufficiency (PI) >50% in vitro testing o mutations resulting in baseline chloride transport <10% of wild-type CFTR were considered minimal function o mutations resulting in chloride transport <10% of wild-type CFTR following the addition of Compound II and / or Compound III were considered nonresponsive.

[0104] As used herein, a "residual function mutation" referred to are Class II through V mutations that have some residual chloride transport and result in a less severe clinical phenotype. Residual function mutations are mutations in the CFTR gene that result in reduced protein quantity or function at the cell surface which can produce partial CFTR activity.

[0105] Non-limiting examples of CFTR gene mutations known to result in a residual function phenotype include a CFTR residual function mutation selected from 2789+5G→A, 3849+10kbC→T, 3272-26A→G, 711+3A→G, E56K, P67L, R74W, D110E, Dl110H, R117C, L206W, R347H, R352Q, A455E, D579G, E831X, S945L, S977F, F1052V, R1070W, F1074L, D1152H, D1270N, E193K, and K1060T. For example, CFTR mutations that cause defective mRNA splicing, such as 2789+507 result in reduced protein synthesis, but deliver some functional CFTR to the surface of the cell to provide residual function. Other CFTR mutations that reduce conductance and / or gating, such as R117H, result in a normal quantity of CFTR channels at the surface of the cell, but the functional level is low, resulting in residual function. In some embodiments, the CFTR residual function mutation is selected from R117H, S1235R, I1027T, R668C, G576A, M470V, L997F, R75Q, R1070Q, R31C, D614G, G1069R, R1162L, E56K, A1067T, E193K, and K1060T. In some embodiments, the CFTR residual function mutation is selected from R117H, S1235R, I1027T, R668C, G576A, M470V, L997F, R75Q, R1070Q, R31C, D614G, G1069R, R1162L, E56K, and A1067T.

[0106] Residual CFTR function can be characterized at the cellular (in vitro) level using cell based assays, such as an FRT assay (Van Goor, F. et al. (2009) PNAS Vol. 106, No. 44, 18825-18830; and Van Goor, F. et al. (2011) PNAS Vol. 108, No. 46, 18843-18846), to measure the amount of chloride transport through the mutated CFTR channels. Residual function mutations result in a reduction but not complete elimination of CFTR dependent ion transport. In some embodiments, residual function mutations result in at least about 10% reduction of CFTR activity in an FRT assay. In some embodiments, the residual function mutations result in up to about 90% reduction in CFTR activity in an FRT assay.

[0107] Patients with an F508del / residual function genotype are defined as patients that are heterozygous F508del-CFTR with a second CFTR allele that contains a mutation that results in reduced protein quantity or function at the cell surface which can produce partial CFTR activity.

[0108] Patients with an F508del / gating mutation genotype are defined as patients that are heterozygous F508del-CFTR with a second CFTR allele that contains a mutation associated with a gating defect and clinically demonstrated to be responsive to Compound III. Examples of such mutations include: G178R, S549N, S549R, G551D, G551S, G1244E, S1251N, S1255P, and G1349D.

[0109] In some embodiments, the compounds and compositions of the invention may be used in methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis, each of which independently produce an increase in chloride transport above the baseline chloride transport of the patient.

[0110] In some embodiments, the compounds and compositions of the invention for use in the methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis are for use in methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient that is heterozygous for F508del, and the other CFTR genetic mutation is any CF-causing mutation. In some embodiments, the paitent is heterozygous for F508del, and the other CFTR genetic mutation is any CF-causing mutation, and is expected to be and / or is responsive to any of the novel compounds disclosed herein, such as a Compound of Formula (I), Compound II, Compound III and / or Compound IV genotypes based on in vitro and / or clinical data. In some embodiments, the paitent is heterozygous for F508del, and the other CFTR genetic mutation is any CF-causing mutation, and is expected to be and / or is responsive to any combinations of (i) the novel compounds disclosed herein, such as a Compound of Formula (I), and (ii) Compound II, and / or Compound III and / or Compound IV genotypes based on in vitro and / or clinical data.

[0111] In some embodiments, the compounds and compositions of the invention for use in the methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis are for use in methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient that possesses a CFTR genetic mutation selected from any of the mutations listed in Table A.

[0112] In some embodiments, the compounds and compositions of the invention for use in the methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis are for use in methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient that possesses a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, 621+3A->G, 1949del84, 3141del9, 3195del6, 3199del6, 3905InsT, 4209TGTT->A, A1006E, A120T, A234D, A349V, A613T, C524R, D192G, D443Y, D513G, D836Y, D924N, D979V, E116K, E403D, E474K, E588V, E60K, E822K, F1016S, F1099L, F191V, F311del, F311L, F508C, F575Y, G1061R, G1249R, G126D, G149R, G194R, G194V, G27R, G314E, G458V, G463V, G480C, G622D, G628R, G628R(G->A), G91R, G970D, H1054D, H1085P, H1085R, H1375P, H139R, H199R, H609R, H939R, I1005R, I1234V, I1269N, I1366N, I175V, I502T, I506S, I506T, I601F, 1618T, I807M, I980K, L102R, L1324P, L1335P, L138ins, L1480P, L15P, L165S, L320V, L346P, L453S, L571S, L967S, M1101R, M152V, MIT, M1V, M265R, M952I, M952T, P574H, P5L, P750L, P99L, Q1100P, Q1291H, Q1291R, Q237E, Q237H, Q452P, Q98R, R1066C, R1066H, R117G, R117L, R117P, R1283M, R1283S, R170H, R258G, R31L, R334L, R334Q, R347L, R352W, R516G, R553Q, R751L, R792G, R933G, S1118F, S1159F, S1159P, S13F, S549R(A->C), S549R(T->G), S589N, S737F, S912L, T1036N, T1053I, T1246I, T604I, V1153E, V1240G, V1293G, V201M, V232D, V456A, V456F, V562I, W1098C, W1098R, W1282R, W361R, W57G, W57R, Y1014C, Y1032C, Y109N, Y161D, Y161S, Y563D, Y563N, Y569C, and Y913C.

[0113] In some embodiments, the patient has at least one combination mutation chosen from: G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, and 621+3A->G.

[0114] In some embodiments, the patient has at least one combination mutation chosen from: 1949del84, 3141del9, 3195del6, 3199del6, 3905InsT, 4209TGTT->A, A1006E, A120T, A234D, A349V, A613T, C524R, D192G, D443Y, D513G, D836Y, D924N, D979V, E116K, E403D, E474K, E588V, E60K, E822K, F1016S, F1099L, F191V, F311del, F311L, F508C, F575Y, G1061R, G1249R, G126D, G149R, G194R, G194V, G27R, G314E, G458V, G463V, G480C, G622D, G628R, G628R(G->A), G91R, G970D, H1054D, H1085P, H1085R, H1375P, H139R, H199R, H609R, H939R, I1005R, I1234V, I1269N, I1366N, I175V, I502T, I506S, I506T, I601F, 1618T, I807M, I980K, L102R, L1324P, L1335P, L138ins, L1480P, L15P, L165S, L320V, L346P, L453S, L571S, L967S, M1101R, M152V, MIT, M1V, M265R, M952I, M952T, P574H, P5L, P750L, P99L, Q1100P, Q1291H, Q1291R, Q237E, Q237H, Q452P, Q98R, R1066C, R1066H, R117G, R117L, R117P, R1283M, R1283S, R170H, R258G, R31L, R334L, R334Q, R347L, R352W, R516G, R553Q, R751L, R792G, R933G, S1118F, S1159F, S1159P, S13F, S549R(A->C), S549R(T->G), S589N, S737F, S912L, T1036N, T1053I, T1246I, T604I, V1153E, V1240G, V1293G, V201M, V232D, V456A, V456F, V562I, W1098C, W1098R, W1282R, W361R, W57G, W57R, Y1014C, Y1032C, Y109N, Y161D, Y161S, Y563D, Y563N, Y569C, and Y913C.

[0115] In some embodiments, the compounds and compositions of the invention for use in the methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis are for use in methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient that possesses a CFTR genetic mutation G551D. In some embodiments, the patient is homozygous for the G551D genetic mutation. In some embodiments, the patient is heterozygous for the G551D genetic mutation. In some embodiments, the patient is heterozygous for the G551D genetic mutation, having the G551D mutation on one allele and any other CF-causing mutation on the other allele. In some embodiments, the patient is heterozygous for the G551D genetic mutation on one allele and the other CF-causing genetic mutation on the other allele is any one of F508del, G542X, N1303K, W1282X, R117H, R553X, 1717-1G->A, 621+1G->T, 2789+5G->A, 3849+10kbC->T, R1162X, G85E, 3120+1G->A, ΔI507, 1898+1G->A, 3659delC, R347P, R560T, R334W, A455E, 2184delA, or 711+1G->T. In some embodiments, the patient is heterozygous for the G551D genetic mutation, and the other CFTR genetic mutation is F508del. In some embodiments, the patient is heterozygous for the G551D genetic mutation, and the other CFTR genetic mutation is R117H.

[0116] In some embodiments, the compounds and compositions of the invention for use in in the methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis are for use in methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient that possesses a CFTR genetic mutation F508del. In some embodiments, the patient is homozygous for the F508del genetic mutation. In some embodiments, the patient is heterozygous for the F508del genetic mutation wherein the patient has the F508del genetic mutation on one allele and any CF-causing genetic mutation on the other allele. In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is any CF-causing mutation, including, but not limited to G551D, G542X, N1303K, W1282X, R117H, R553X, 1717-1G->A, 621+1G->T, 2789+5G->A, 3849+10kbC->T, R1162X, G85E, 3120+1G->A, ΔI507, 1898+1G->A, 3659delC, R347P, R560T, R334W, A455E, 2184delA, or 711+1G->T. In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is G551D. In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is R117H.

[0117] In some embodiments, the patient has at least one combination mutation chosen from: D443Y;G576A;R668C, F508C;S1251N, G576A; R668C, G970R; M470V, R74W;D1270N, R74W;V201M, and R74W;V201M;D1270N.

[0118] In some embodiments, the compounds and compositions of the invention for use in the methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis are for use in methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient that possesses a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V and G1069R. In some embodiments, the patient possesses a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R and S1251N. In some embodiments, the patient possesses a CFTR genetic mutation selected from E193K, F1052V and G1069R. In some embodiments, the compounds and compositions of the invention for use in the method produce an increase in chloride transport relative to baseline chloride transport of the patient of the patient.

[0119] In some embodiments, the compounds and compositions of the invention for use in the methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis are for use in methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient that possesses a CFTR genetic mutation selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N and D1152H.

[0120] In some embodiments, the patient possesses a CFTR genetic mutation selected from 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C and 621+3A->G. In some embodiments, the patient possesses a CFTR genetic mutation selected from 1717-1G->A, 1811+1.6kbA->G, 2789+5G->A, 3272-26A->G and 3849+10kbC->T. In some embodiments, the patient possesses a CFTR genetic mutation selected from 2789+5G->A and 3272-26A->G.

[0121] In some embodiments, the compounds and compositions of the invention for use in the methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis are for use in methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient that possesses a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C and 621+3A->G, and human CFTR mutations selected from F508del, R117H, and G551D.

[0122] In some embodiments, the compounds and compositions of the invention for use in the methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis are for use in methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient that possesses a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, 621+3A->G, and a CFTR mutation selected from F508del, R117H, and G551D; and a CFTR mutations selected from F508del, R117H, and G551D.

[0123] In some embodiments, the patient possesses a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V and G1069R, and a human CFTR mutation selected from F508del, R117H, and G551D. In some embodiments, the patient possesses a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R and S1251N, and a human CFTR mutation selected from F508del, R117H, and G551D. In some embodiments, the patient possesses a CFTR genetic mutation selected from E193K, F1052V and G1069R, and a human CFTR mutation selected from F508del, R117H, and G551D.

[0124] In some embodiments, the patient possesses a CFTR genetic mutation selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N and D1152H, and a human CFTR mutation selected from F508del, R117H, and G551D.

[0125] In some embodiments, the patient possesses a CFTR genetic mutation selected from 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C and 621+3A->G, and a human CFTR mutation selected from F508del, R117H, and G551D. In some embodiments, the patient possesses a CFTR genetic mutation selected from 1717-1G->A, 1811+1.6kbA->G, 2789+5G->A, 3272-26A->G and 3849+10kbC->T, and a human CFTR mutation selected from F508del, R117H, and G551D. In some embodiments, the patient possesses a CFTR genetic mutation selected from 2789+5G->A and 3272-26A->G, and a human CFTR mutation selected from F508del, R117H.

[0126] In some embodiments, the patient is heterozygous having a CF-causing mutation on one allele and a CF-causing mutation on the other allele. In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is any CF-causing mutation, including, but not limited to F508del on one CFTR allele and a CFTR mutation on the second CFTR allele that is associated with minimal CFTR function, residual CFTR function, or a defect in CFTR channel gating activity. In some embodiments, the CF-causing mutation is selected from Table A. In some embodiments, the CF-causing mutation is selected from Table B. In some embodiments, the CF-causing mutation is selected from Table C. In some embodiments, the CF-causing mutation is selected from FIG. 2. In some embodiments, the patient is heterozygous having a CF-causing mutation on one CFTR allele selected from the mutations listed in the table from FIG. 2 and a CF- causing mutation on the other CFTR allele is selected from the CFTR mutations listed in Table B: Table B: CFTR Mutations Q39X621+1G->TA559TW57X1248+1G->AR560TE60X1341+1G-AR560SR75X1717-1G-AA561EE92X1811+1.6kbA→GY569DQ98X1811+1G→CL1065PY122X1812-1G-AR1066CL218X1898+1G-AR1066MQ220X2622+1G→AL1077PC276X3120+1G→AH1085RQ290X3120G→AM1101KG330X3850-1G→AN1303KW401X4005+1G→A3849+10kbC→TQ414X4374+1G→T3272-26A→GS434X663delT711+3A→GS466X2183AA→GE56KS489XCFTRdel2,3P67LQ493X3659delCR74WW496X394delTTD110EQ525X2184insAD110HG542X3905insTR117CQ552X2184delAL206WR553X1078delTR347HE585X1154insTCR352QG673X2183delAA→GA455ER709X2143delTD579GK710X1677delTAE831XL732X3876delAS945LR764X2307insAS977FR785X4382delAF1052VR792X4016insTR1070WE822X2347delGF1074LW846X3007delGD1152HR851X574delAD1270NQ890X2711delTG178RS912X3791delCS549NW1089XCFTRdele22-23S549RY1092X457TAT→GG551DE1104X2043delGG551SR1158X2869insGG1244ER1162X3600+2insTS1251NS1196X3737delAS1255PW1204X4040delAG1349DS1255X541delCW1282XA46DQ1313XT338I621+1G->TR347P711+1G→TL927P711+5G→AG85E712-1G→TS341P405+1G→AL467P405+3A→C 406-1G→A1507del V520F Table C: CFTR Mutations Criteria Mutation Truncation mutationsS4XC276XG542XR792XE1104X• %PI >50% and / or SwCl -< >86 mmol / LG27XQ290XG550XE822XR1158XQ39XG330XQ552XW846XR1162XW57XW401XR553XY849XS1196X• no full-length proteinE60XQ414XE585XR851XW1204XR75XS434XG673XQ890XL1254XE92XS466XQ685XS912XS1255XQ98XS489XR709XY913XW1282XY122XQ493XK710XW1089XQ1313XE193XW496XL732XY1092XE1371XL218XC524XR764XW1098XQ1382XQ220XQ525XR785XR1102XQ1411XSplice mutations185+1G→T711+5G→A1717-8G→A2622+1G→A3121-1G→A• %PI >50% and / or SwCl -< >86 mmol / L296+1G→A712-1G→T1717-1G→A2790-1G→C3500-2A→G405+1G→A1248+1G→A1811+1G→C3040G→C3600+2insT405+3A→C1249-1G→A1811+1.6kbA→G(G970R)3850-1G→A• no or little mature mRNA406-1G→A1341+1G→A1812-1G→A3120G→A4005+1G→A621+1G→T1525-2A→G1898+1G→A3120+1G→A4374+1G→T711+1G→T1525-1G→A1898+1G→C3121-2A→GSmall (≤3 nucleotide) insertion / deletion (ins / del) frameshift mutations182delT1119delA1782delA2732insA3876delA306insA1138insG1824delA2869insG3878delG365-366insT1154insTC2043delG2896insAG3905insT394delTT1161delC2143delT2942insT4016insT• %PI >50% and / or SwCl -< >86 mmol / L442delA1213delT2183AA→G a< 2957delT4021dupT444delA1259insA2184delA3007delG4040delA• garbled and / or truncated protein457TAT→G1288insTA2184insA3028delA4279insA541delC1471delA2307insA3171delC4326delTC574delA1497delGG2347delG3659delC663delT1548delG2585delT3737delA935delA1609del CA2594delGT3791delC1078delT1677delTA2711delT3821delTNon-small (>3 nucleotide) insertion / deletion (ins / del) frameshift mutationsCFTRdele2,31461ins42991del32CFTRdele22,231924del73667ins4124del23bp2055del9→A4010de14852de1222105- 117del13insAGAAA24209TGTT→AA• %PI >50% and / or SwCl -< >86 mmol / L991del52721del11• garbled and / or truncated protein Criteria Mutation Class II, III, IV mutations not responsive to Compound III alone or in combination with Compound II or Compound IVA46D b< V520FY569D b< N1303KG85EA559T b< L1065PR347PR560TR1066CL467P b< R560SL1077P b< I507delA561EM1101K• %PI>50% and / or SwCl >86 mmol / L AND• Not responsive in vitro to Compound III alone or in combination with Compound II or Compound IV Note: %PI: percentage of F508del-CFTR heterozygous patients in the CFTR2 patient registry who are pancreatic insufficient; SwCl -< : mean sweat chloride of F508del-CFTR heterozygous patients in the CFTR2 patient registry a< Also known as 2183delAA→G. b< Unpublished data.

[0127] In some embodiments, the patient is: with F508del / MF (F / MF) genotypes (heterozygous for F508del and an MF mutation not expected to respond to CFTR modulators, such as Compound III); with F508del / F508del (F / F) genotype (homozygous for F508del); and / or with F508del / gating (F / G) genotypes (heterozygous for F508del and a gating mutation known to be CFTR modulator-responsive (e.g., Compound III-responsive). In some embodiments, the patient with F508del / MF (F / MF) genotypes has a MF mutation that is not expected to respond to Compound II, Compound III, and both of Compound II and Compound III. In some embodiments, the patient with F508del / MF (F / MF) genotypes has any one of the MF mutations in Table C.

[0128] In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is any CF-causing mutation, including truncation mutations, splice mutations, small (≤3 nucleotide) insertion or deletion (ins / del) frameshift mutations; non-small (>3 nucleotide) insertion or deletion (ins / del) frameshift mutations; and Class II, III, IV mutations not responsive to Compound III alone or in combination with Compound II or Compound IV.

[0129] In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is a truncation mutation. In some specific embodiments, the truncation mutation is a truncation mutation listed in Table C.

[0130] In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is a splice mutation. In some specific embodiments, the splice mutation is a splice mutation listed in Table C.

[0131] In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is a small (≤3 nucleotide) insertion or deletion (ins / del) frameshift mutation. In some specific embodiments, the small (≤3 nucleotide) insertion or deletion (ins / del) frameshift mutation is a small (≤3 nucleotide) insertion or deletion (ins / del) frameshift mutation listed in Table C.

[0132] In some embodiments compounds of Formulae (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), and (VI-D), and pharmaceutically acceptable salts thereof, and their deuterated, the patient is heterozygous for F508del, and the other CFTR genetic mutation is any CF-causing mutation expected to be and / or is responsive to, based on in vitro and / or clinical data, any combination of (i) a novel compound chosen from those disclosed herein (e.g., compounds of Formulae (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), and (VI-D), and pharmaceutically acceptable salts thereof, and their deuterated derivatives), and (ii) Compound II, and / or Compound III, and / or Compound IV.

[0133] In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is any CF-causing mutation expected to be and / or is responsive, based on in vitro and / or clinical data, to the triple combination of a novel compound chosen from those disclosed herein (e.g., derivatives), and Compound II, and Compound III.

[0134] In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is a non-small (>3 nucleotide) insertion or deletion (ins / del) frameshift mutation. In some specific embodiments, the non-small (>3 nucleotide) insertion or deletion (ins / del) frameshift mutation is a non-small (>3 nucleotide) insertion or deletion (ins / del) frameshift mutation listed in Table C.

[0135] In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is a Class II, III, IV mutations not responsive to Compound III alone or in combination with Compound II or Compound IV. In some specific embodiments, the Class II, III, IV mutations not responsive to Compound III alone or in combination with Compound II or Compound IV is a Class II, III, IV mutations not responsive to Compound III alone or in combination with Compound II or Compound IV listed in Table C.

[0136] In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is any mutation listed in Table C.

[0137] In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is any mutation, but other than F508del, listed in Table A, B, C, and FIG. 2.

[0138] In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is any mutation listed in Table A. In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is any mutation listed in Table B. In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is any mutation listed in Table C. In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is any mutation listed in FIG. 2.

[0139] In some embodiments, the patient is homozygous for F508del.

[0140] In some embodiments, the patient is heterozygous having one CF-causing mutation on one CFTR allele selected from the mutations listed in the table from FIG. 2 and another CF-causing mutation on the other CFTR allele is selected from the CFTR mutations listed in Table C.

[0141] In some embodiments, the composition disclosed herein is useful for use in treating, lessening the severity of, or symptomatically treating cystic fibrosis in patients who exhibit residual CFTR activity in the apical membrane of respiratory and non-respiratory epithelia. The presence of residual CFTR activity at the epithelial surface can be readily detected using methods known in the art, e.g., standard electrophysiological, biochemical, or histochemical techniques. Such methods identify CFTR activity using in vivo or ex vivo electrophysiological techniques, measurement of sweat or salivary Cl -< concentrations, or ex vivo biochemical or histochemical techniques to monitor cell surface density. Using such methods, residual CFTR activity can be readily detected for patients that are heterozygous or homozygous for a variety of different mutations, including patients heterozygous for the most common mutation, F508del, as well as other mutations such as the G551D mutation, or the R117H mutation. In some embodiments, compositions disclosed herein are useful for treating, lessening the severity of, or symptomatically treating cystic fibrosis in patients who exhibit little to no residual CFTR activity. In some embodiments, compositions disclosed herein are useful for treating, lessening the severity of, or symptomatically treating cystic fibrosis in patients who exhibit little to no residual CFTR activity in the apical membrane of respiratory epithelia.

[0142] In some embodiments, the compositions disclosed herein are useful for treating or lessening the severity of cystic fibrosis in patients who exhibit residual CFTR activity using pharmacological methods. Such methods increase the amount of CFTR present at the cell surface, thereby inducing a hitherto absent CFTR activity in a patient or augmenting the existing level of residual CFTR activity in a patient.

[0143] In some embodiments, the compositions disclosed herein are useful for treating or lessening the severity of cystic fibrosis in patients with certain genotypes exhibiting residual CFTR activity.

[0144] In some embodiments, compositions disclosed herein are useful for treating, lessening the severity of, or symptomatically treating cystic fibrosis in patients within certain clinical phenotypes, e.g., a mild to moderate clinical phenotype that typically correlates with the amount of residual CFTR activity in the apical membrane of epithelia. Such phenotypes include patients exhibiting pancreatic sufficiency.

[0145] In some embodiments, the compositions disclosed herein are useful for treating, lessening the severity of, or symptomatically treating patients diagnosed with pancreatic sufficiency, idiopathic pancreatitis and congenital bilateral absence of the vas deferens, or mild lung disease wherein the patient exhibits residual CFTR activity.

[0146] In some embodiments, this disclosure relates to a composition for use in a method of augmenting or inducing anion channel activity in vitro or in vivo, comprising contacting the channel with the composition disclosed herein. In some embodiments, the anion channel is a chloride channel or a bicarbonate channel. In some embodiments, the anion channel is a chloride channel.

[0147] In some embodiments, the patient is heterozygous and has an F508del mutation on one allele and a mutation on the other allele selected from Table 5: Table 5: CFTR Mutations Mutation Q2XL218XQ525XR792XE1104XS4XQ220XG542XE822XW1145XW19XY275XG550XW882XR1158XG27XC276XQ552XW846XR1162XQ39XQ290XR553XY849XS1196XW57XG330XE585XR851XW1204XE60XW401XG673XQ890XL1254XR75XQ414XQ685XS912XS1255XL88XS434XR709XY913XW1282XE92XS466XK710XQ1042XQ1313XQ98XS489XQ715XW1089XQ1330XY122XQ493XL732XY1092XE1371XE193XW496XR764XW1098XQ1382XW216XC524XR785XR1102XQ1411X185+1G→T711+5G→A1717-8G→A2622+1G→A3121-1G→A296+1G→A712-1G→T1717-1G→A2790-1G→C3500-2A→G296+1G→T1248+1G→A1811+1G→C3040G→C3600+2insT405+1G→A1249-1G→A1811+1.6kbA→G(G970R)3850-1G→A405+3A→C1341+1G→A1811+1643G→T3120G→A4005+1G→A406-1G→A1525-2A→G1812-1G→A3120+1G→A4374+1G→T621+1G->T1525-1G→A1898+1G→A3121-2A→G711+1G→T1898+1G→C182delT1078delT1677delTA2711delT3737delA306insA1119delA1782delA2732insA3791delC306delTAGA1138insG1824delA2869insG3821delT365-366insT1154insTC1833delT2896insAG3876delA394delTT1161delC2043delG2942insT3878delG442delA1213delT2143delT2957delT3905insT444delA1259insA2183AA→G3007delG4016insT457TAT→G1288insTA2184delA3028delA4021dupT541delC1343delG2184insA3171delC4022insT574delA1471delA2307insA3171insC4040delA663delT1497delGG2347delG3271delGG4279insA849delG1548delG2585delT3349insT4326delTC935delA1609del CA2594delGT3659delCCFTRdelelCFTRdele16-17b1461ins4CFTRdele2CFTRdele17a, 17b1924del7Mutation CFTRdele2,3CFTRdele17a-182055de19→ACFTRdele2-4CFTRdelel92105-2117del13insAGAAACFTRdele3-10,14b-16CFTRdelel9-212372del8CFTRdele4-7CFTRdele212721del11CFTRdele4-11CFTRdele22-242991del32CFTR50kbdelCFTRdele22,233667ins4CFTRdup6b-10124del23bp4010del4CFTRdele11602del144209TGTT→AACFTRdele13,14a852de122CFTRdele14b-17b991del5A46DV520FY569DN1303KG85EA559TL1065PR347PR560TR1066CL467PR560SL1077PI507delA561EM1101K

[0148] The exact amount of a pharmaceutical composition required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular agent, its mode of administration, and the like. The compounds of this disclosure may be formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of this disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term "patient", as used herein, means an animal, such as a mammal, and even further such as a human.

[0149] In some embodiments, the disclosure includes deuterated derivatives of the novel compounds disclosed herein and of their pharmaceutically acceptable salts. Nonlimiting examples of deuterated compounds are disclosed in FIG. 1.

[0150] In some embodiments, Compound III-d as used herein includes the deuterated compound disclosed in U.S. Patent No. 8,865,902 as: Clinical efficacy of Compound III-d in combination with other CFTR correctors, including combinations with Compound II, have been described in Davies et al., New Engl. J. Med. 379(17):1599-1611 (2018) and Davies et al., New Engl. J. Med. 379(17):1612-1620 (2018).

[0151] Exemplary embodiments of the disclosure include: The novel compounds disclosed herein (e.g., compounds of Formulae (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), and (VI-D), pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing, including the compounds in FIG. 1 and those specifically depicted herein) can be prepared by suitable methods known in the art. For example, they can be prepared in accordance with the exemplary syntheses described below in the Examples. For example, deuterated derivatives of the novel compounds of Formulae (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), and (VI-D) and pharmaceutically acceptable salts thereof can be prepared in a similar manner as those for compounds of Formulae (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), and (VI-D) and pharmaceutically acceptable salts thereof by employing intermediates and / or reagents where one or more hydrogen atoms are replaced with deuterium. For example, see T.G. Gant "Using deuterium in drug discovery: leaving the label in the drug," J. Med. Chem. 2014, 57, 3595-3611.

[0152] In some embodiments, compounds disclosed herein and pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing are prepared as depicted in Schemes 1-12, wherein the variables therein are each and independently are as those for Formula (I). Suitable condition(s) known in the art can be employed for each step depicted in the schemes. The methods disclosed herein can be used to prepare compounds of Formulae (I), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), and (VI-D), and any compounds depicted in Table 5 and FIG. 1, salts thereof, or deuterated derivatives of any of the foregoing.

[0153] In some embodiments, as shown in Scheme 1, the methods comprise reacting a compound of Formula (A) or a salt thereof with a compound of Formula (B) or a salt thereof to generate a compound of Formula (Y), a salt thereof, or a deuterated derivative of any of the foregoing. The reaction of Formula (A) and Formula (B) can be performed under any suitable coupling reaction between carboxylic acid and sulfonamide, such as with CDI. In some embodiments, the coupling reaction is performed in the presence of a base, such as DBU.

[0154] In some embodiments, as shown in Scheme 2, the methods comprise deprotection of a compound of Formula (Y) to generate a compound of Formula (Y-1), a salt thereof, or a deuterated derivative of any of the foregoing. The deprotection of Formula (Y) can be performed under any suitable deprotection conditions, which are readily apparent to a person of skill in the art depending on the protecting group R 10< . In some embodiments, the protecting group R 10< is Boc, and the deprotection conditions are acidic. In some embodiments, as shown in Scheme 2, the methods comprise reacting a compound of Formula (Y-1) to generate a compound of Formula (I), a salt thereof, or a deuterated derivative of any of the foregoing. The reaction of Formula (Y-1) can be performed under any suitable coupling reaction between an amine and halogen. In some embodiments, this coupling reaction is performed in the presence of a base, such as K 2 CO 3 .

[0155] In some embodiments, as shown in Scheme 3, the methods comprise reacting a compound of Formula (A) or a salt thereof with a compound of Formula (B-2) or a salt thereof to generate a compound of Formula (Y-2), a salt thereof, or a deuterated derivative of any of the foregoing. The reaction of Formula (A) and Formula (B-2) can be performed under any suitable coupling reaction between a carboxylic acid and sulfonamide, such as with CDI. In some embodiments, the coupling reaction is performed in the presence of a base, such as DBU.

[0156] In some embodiments, as shown in Scheme 4, the methods comprise reacting a compound of Formula (D) or a salt thereof with a compound of Formula (E-2) or a salt thereof to generate a compound of Formula (B-2), a salt thereof, or a deuterated derivative of any of the foregoing. The reaction of Formula (D) and Formula (E-2) can be performed under any suitable coupling reaction between an amine and Rd.

[0157] In some embodiments, as shown in Scheme 5, the methods comprise reacting a compound of Formula (A) or a salt thereof with a compound of Formula (B-3) or a salt thereof to generate a compound of Formula (Y-3), a salt thereof, or a deuterated derivative of any of the foregoing. The reaction of Formula (A) and Formula (B-3) can be performed under any suitable coupling reaction between a carboxylic acid and sulfonamide, such as with CDI. In some embodiments, the coupling reaction is performed in the presence of a base, such as DBU.

[0158] In some embodiments, as shown in Scheme 6, the methods comprise reacting a compound of Formula (D) or a salt thereof with a compound of Formula (E-3) or a salt thereof to generate a compound of Formula (B-3), a salt thereof, or a deuterated derivative of any of the foregoing. The reaction of Formula (A) and Formula (B-3) can be performed under any suitable coupling reaction between an alcohol and R d< .

[0159] In some embodiments, as shown in Scheme 7, the methods comprise reacting a compound of Formula (Z-1) with a compound of Formula (X) to generate a compound of Formula (I), a salt thereof, or a deuterated derivative of any of the foregoing. The reaction of Formula (Z-1) with a compound of Formula (X) can be performed under any suitable coupling reaction between an nitrogen and halogen.

[0160] In some embodiments, as shown in Scheme 8, the methods comprise reacting a compound of Formula (Z-1) with a compound of Formula (X-1) to generate a compound of Formula (IV-C), a salt thereof, or a deuterated derivative of any of the foregoing. The reaction of Formula (Z-1) with a compound of Formula (X-1) can be performed under any suitable coupling reaction between a nitrogen and halogen.

[0161] In some embodiments, as shown in Scheme 9, the methods comprise reacting a compound of Formula (F) or a salt thereof with a compound of Formula (G) or a salt thereof to generate a compound of Formula (H), a salt thereof, or a deuterated derivative of any of the foregoing. The reaction of Formula (F) and Formula (G) can be performed under any suitable reaction between an anide and sulfur atom, such as with bromine. In some embodiments, the reaction is performed in the presence of a base, such as pyridine. A compound of Formula (H) or a salt thereof can be oxidized to form a compound of Formula (J) or a salt thereof. In some embodiment, the oxidizing agent is meta-chloroperoxybenzoic acid (m-CPBA).

[0162] In some embodiments, as shown in Scheme 10, the methods comprise reaction of a compound of Formula (J) with a compound of Formula (L) to generate a compound of Formula (M), a salt thereof, or a deuterated derivative of any of the foregoing. In some embodiments, the reaction is perfoemed in the presence of a base, such as sodium hydride.

[0163] In some embodiments, as shown in Scheme 11, the methods comprise reacting a compound of Formula (M) or a salt thereof with an amine to produce a compound of Formula (N), a salt thereof, or a deuterated derivative of any of the foregoing, wherein X is NH or an N(C 1 -C 4 alkyl). In some embodiments, the reaction of Formula (M) and the amine can be performed in the presence of N-chlorosuccinimide. The compound of Formula (N) can be converted to a compound of Formula (O), a salt thereof, or a deuterated derivative of any of the foregoing. In some embodiments, the reaction is performed under reducing conditions. In some embodiments, the reaction is performed in the presence of palladium on carbon and hydrogen.

[0164] In some embodiments, as shown in Scheme 12, the methods comprise reacting a compound of Formula (O) or a salt thereof to generate a compound of Formula (P), a salt thereof, or a deuterated derivative of any of the foregoing. In some embodiments, the reaction of Formula (O) can be performed in the presence of a base. In some embodiments, the base is triethylamine. In some embodiments, the reaction of Formula (O) can be performed with heating.

[0165] The present invention is defined in the claims. Additional embodiments include: 39. A compound of Formula (III-A) or (III-B): or a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: the carbon denoted by ∗< has S-stereochemistry or R-stereochemistry; Ring A is a phenyl, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; each R 1< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; m is 0, 1, 2, 3, or 4; each R 2< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; n is 0, 1, or 2; each R 3< is methyl; each R 4< is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y) k -R 7< groups or optionally two R 4< , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< -groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens; q is 1 or 2; Z is a divalent linker of formula (L) r , wherein: r is 3, 4, or 5; each L is independently chosen from C(R 8< )(R 9< ) groups, -O-, and -NR b< -groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen, halogens, C 1 -C2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups. 40. The compound of embodiment 39, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring A is a phenyl ring, a pyridyl ring, or a pyrazolyl ring, wherein Ring A is optionally substituted with (R 1< ) m . 41. The compound of embodiment 39 or 40, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 1< is independently chosen from deuterium, C 1 -C 2 alkyl groups, and a hydroxyl group, and m is 0 or 1. 42. The compound of any one of embodiments 39 to 41, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein n is 0. 43. The compound of any one of embodiments 39 to 42, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is a 5-membered heteroaryl ring substituted with (R 4< ) q . 44. The compound of any one of embodiments 39 to 42, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is a pyrazolyl ring substituted with (R 4< ) q . 45. The compound of any one of embodiments 39 to 42, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is wherein indicates the point of attachment of Ring D to Ring B . 46. The compound of any one of embodiments 39 to 42, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is wherein indicates the point of attachment of Ring D to Ring B . 47. The compound of any one of embodiments 39 to 46, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from an oxo group or -(Y) k -R 7< groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< -groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y)k-R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens. 48. The compound of any one of embodiments 39 to 47, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from an oxo group or -(Y) k -R 7< groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< -groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y)k-R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens. 49. The compound of any one of embodiments 39 to 47, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from an oxo group or -O-(Y) k -R 7< groups, wherein: k is 0, 1, 2, 3, 4, or 5; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< -groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y)k-R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens. 50. The compound of any one of embodiments 39 to 47, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from and wherein indicates the point of attachment of R 4< to Ring D. 51. The compound of any one of embodiments 39 to 50, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein k is 3, 4, 5, or 6. 52. The compound of any one of embodiments 39 to 51, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein q is 1. 53. The compound of any one of embodiments 39 to 52, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Z is a divalent linker of formula (L) r , wherein: r is 3, 4, or 5; each L is independently chosen from C(R 8< )(R 9< ) groups, -O-, and -NR b< -groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen and deuterium; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups. 54. The compound of any one of embodiments 39 to 52, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Z is a divalent linker of formula (L) r , wherein: r is 3, 4, or 5; each L is independently chosen from C(R 8< )(R 9< ) groups and -NR b< - groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen and deuterium; and each R b< is independently chosen from hydrogen and methyl. 55. The compound of any one of embodiments 39 to 52, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Z is a divalent linker of formula (L) r , wherein: r is 3, 4, or 5; each L is independently chosen from C(R 8< )(R 9< ) groups and -NR b< - groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen and deuterium; and each R b< is hydrogen. 56. The compound of any one of embodiments 39 to 52, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Z is a divalent linker of formula (L) r , wherein: r is 3, 4, or 5; each L is independently chosen from C(R 8< )(R 9< ) groups, -O-, and -NR b< -groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is hydrogen; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups. 57. The compound of any one of embodiments 39 to 56, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 3< is independently CD 3 . 58. The compound of embodiment 39, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein the compound of Formula (III-A) or (III-B) is a compound of Formula IV-A: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: the carbon denoted by ∗< has S-stereochemistry or R-stereochemistry; Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; each R 1< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; m is 0, 1, 2, 3, or 4; each R 2< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; n is 0, 1, or 2; each R 3< is methyl; each R 4< is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y) k -R 7< groups, or optionally two R 4< , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< -groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens; q is 1 or 2; Z is a divalent linker of formula (L) r , wherein: r is 3, 4, or 5; each L is independently chosen from C(R 8< )(R 9< ) groups, -O-, and -NR b< -groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen, halogens, C 1 -C2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups. 59. The compound of embodiment 58, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 1< is independently chosen from deuterium, C 1 -C 2 alkyl groups, and a hydroxyl group, and m is 0 or 1. 60. The compound of embodiment 58 or 59, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein n is 0. 61. The compound of any one of embodiments 58 to 60, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is a 5-membered heteroaryl ring substituted with (R 4< ) q . 62. The compound of any one of embodiments 58 to 60, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is a pyrazolyl ring substituted with (R 4< ) q . 63. The compound of any one of embodiments 58 to 60, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is wherein indicates the point of attachment of Ring D to Ring B. 64. The compound of any one of embodiments 58 to 60, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is wherein indicates the point of attachment of Ring D to Ring B . 65. The compound of any one of embodiments 58 to 64, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from an oxo group or -(Y) k -R 7< groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< -groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y)k-R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens. 66. The compound of any one of embodiments 58 to 65, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from an oxo group or -(Y) k -R 7< groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< -groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y)k-R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens. 67. The compound of any one of embodiments 58 to 66, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from an oxo group or -O-(Y) k -R 7< groups, wherein: k is 0, 1, 2, 3, 4, or 5; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< -groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y)k-R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens. 68. The compound of any one of embodiments 58 to 67, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from wherein indicates the point of attachment of R 4< to Ring D. 69. The compound of any one of embodiments 58 to 68, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein k is 3, 4, 5, or 6. 70. The compound of any one of embodiments 58 to 69, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein q is 1. 71. The compound of any one of embodiments 58 to 70, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Z is a divalent linker of formula (L) r , wherein: r is 3, 4, or 5; each L is independently chosen from C(R 8< )(R 9< ) groups, -O-, and -NR b< -groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen and deuterium; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups. 72. The compound of any one of embodiments 58 to 70, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Z is a divalent linker of formula (L) r , wherein: r is 3, 4, or 5; each L is independently chosen from C(R 8< )(R 9< ) groups and -NR b< - groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen and deuterium; and each R b< is independently chosen from hydrogen and methyl. 73. The compound of any one of embodiments 58 to 70, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Z is a divalent linker of formula (L) r , wherein: r is 3, 4, or 5; each L is independently chosen from C(R 8< )(R 9< ) groups and -NR b< - groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen and deuterium; and each R b< is hydrogen. 74. The compound of any one of embodiments 58 to 70, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Z is a divalent linker of formula (L) r , wherein: r is 3, 4, or 5; each L is independently chosen from C(R 8< )(R 9< ) groups, -O-, and -NR b< -groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is hydrogen; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups. 75. The compound of any one of embodiments 58 to 74, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 3< is independently CD 3 . 76. The compound of embodiment 39, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein the compound of Formula (III-A) or (III-B) is a compound of Formula IV-B: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: the carbon denoted by ∗< has S-stereochemistry or R-stereochemistry; Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; each R 1< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; m is 0, 1, 2, 3, or 4; each R 2< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; n is 0, 1, or 2; each R 3< is methyl; each R 4< is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y) k -R 7< groups, or optionally two R 4< , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< -groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens; q is 1 or 2; r is 3 or 4; each R 8< and R 9< is independently chosen from hydrogen, halogens, C 1 -C 2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups. 77. The compound of embodiment 76, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 8< and R 9< is independently chosen from hydrogen, deuterium, halogens, C 1 -C 2 alkyl groups, a hydroxyl group, C 1 -C2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups. 78. The compound of embodiment 76 or 77, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 8< and R 9< is H. 79. The compound of any one of embodiments 76 to 78, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 1< is independently chosen from deuterium, C 1 -C 2 alkyl groups, and a hydroxyl group, and m is 0 or 1. 80. The compound of any one of embodiments 76 to 79, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein n is 0. 81. The compound of any one of embodiments 76 to 80, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is 5-membered heteroaryl ring substituted with (R 4< ) q . 82. The compound of any one of embodiments 76 to 80, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is a pyrazolyl ring substituted with (R 4< ) q . 83. The compound of any one of embodiments 76 to 80, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is wherein indicates the point of attachment of Ring D to Ring B . 84. The compound of any one of embodiments 76 to 80, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is wherein indicates the point of attachment of Ring D to Ring B . 85. The compound of any one of embodiments 76 to 84, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from an oxo group or -(Y) k -R 7< groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and - NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in - (Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens. 86. The compound of any one of embodiments 76 to 84, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from an oxo group or -(Y) k -R 7< groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and - NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in - (Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens. 87. The compound of any one of embodiments 76 to 84, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from an oxo group or -O-(Y) k -R 7< groups, wherein: k is 0, 1, 2, 3, 4, or 5; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and - NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens. 88. The compound of any one of embodiments 76 to 84, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently wherein indicates the point of attachment of R 4< to Ring D. 89. The compound of any one of embodiments 76 to 88, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein k is 3, 4, 5, or 6. 90. The compound of any one of embodiments 76 to 89, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein q is 1. 91. The compound of any one of embodiments 76 to 90, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: r is 3, 4, or 5; each R 8< and R 9< is independently chosen from hydrogen and deuterium; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups. 92. The compound of any one of embodiments 76 to 90, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: r is 3, 4, or 5; each R 8< and R 9< is independently chosen from hydrogen and deuterium; and each R b< is independently chosen from hydrogen and methyl. 93. The compound of any one of embodiments 76 to 90, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: r is 3, 4, or 5; each R 8< and R 9< is independently chosen from hydrogen and deuterium; and each R b< is hydrogen. 94. The compound of any one of embodiments 76 to 90, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: r is 3, 4, or 5; each R 8< and R 9< is hydrogen; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups. 95. The compound of any one of embodiments 76 to 94, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 3< is independently CD 3 . 96. The compound of embodiment 39 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein the compound of Formula (III-A) or (III-B) is a compound of Formula IV-C: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: the carbon denoted by ∗< has S-stereochemistry or R-stereochemistry; each R 1< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; m is 0, 1, 2, 3, or 4; each R 2< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; n is 0, 1, or 2; each R 3< is methyl; each R 4< is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y) k -R 7< groups, or optionally two R 4< , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< -groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3-5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3-5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens; q is 1 or 2; r is 3 or 4; each R 8< and R 9< is independently chosen from hydrogen, halogens, C 1 -C2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups. 97. The compound of embodiment 96, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 8< and R 9< is independently chosen from hydrogen, deuterium, halogens, C 1 -C 2 alkyl groups, a hydroxyl group, C 1 -C2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups. 98. The compound of embodiment 96 or 97, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 8< and R 9< is H. 99. The compound of any one of embodiments 96 to 98, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 1< is independently chosen from deuterium, C 1 -C 2 alkyl groups, and a hydroxyl group, and m is 0 or 1. 100. The compound of any one of embodiments 96 to 99, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein n is 0. 101. The compound of any one of embodiments 96 to 100, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from an oxo group or -(Y) k -R 7< groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and - NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in - (Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3-5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3-5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens. 102. The compound of any one of embodiments 96 to 100, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from an oxo group or -(Y) k -R 7< groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and - NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in - (Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens. 103. The compound of any one of embodiments 96 to 100, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from an oxo group or -O-(Y) k -R 7< groups, wherein: k is 0, 1, 2, 3, 4, or 5; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and - NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in - (Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3-5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3-5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens. 104. The compound of any one of embodiments 96 to 100, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from wherein indicates the point of attachment of R 4< to Ring D. 105. The compound of any one of embodiments 96 to 104, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein k is 3, 4, 5, or 6. 106. The compound of any one of embodiments 96 to 105, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein q is 1. 107. The compound of any one of embodiments 96 to 106, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: r is 3, 4, or 5; each R 8< and R 9< is independently chosen from hydrogen and deuterium; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups. 108. The compound of any one of embodiments 96 to 106, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: r is 3, 4, or 5; each R 8< and R 9< is independently chosen from hydrogen and deuterium; and each R b< is independently chosen from hydrogen and methyl. 109. The compound of any one of embodiments 96 to 106, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein wherein: r is 3, 4, or 5; each R 8< and R 9< is independently chosen from hydrogen and deuterium; and each R b< is hydrogen. 110. The compound of any one of embodiments 96 to 106, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: r is 3, 4, or 5; each R 8< and R 9< is hydrogen; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups. 111. The compound of any one of embodiments 96 to 110, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 3< is independently CD 3 . 112. The compound of embodiment 39, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein the compound of Formula (III-A) or (III-B) is a compound of Formula V-A: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: the carbon denoted by ∗< has S-stereochemistry or R-stereochemistry; Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; each R 1< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; m is 0, 1, 2, 3, or 4; each R 2< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; n is 0, 1, or 2; each R 3< is methyl; each R 4< is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y) k -R 7< groups, or optionally two R 4< , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< -groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3-5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3-5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens; q is 1 or 2; Z is a divalent linker of formula (L) r , wherein: r is 3, 4, or 5; each L is independently chosen from C(R 8< )(R 9< ) groups, -O-, and -NR b< -groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen, halogens, C 1 -C 2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups. 113. The compound of embodiment 112, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 1< is independently chosen from deuterium, C 1 -C 2 alkyl groups, and a hydroxyl group, and m is 0 or 1. 114. The compound of embodiment 112 or 113, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein n is 0. 115. The compound of any one of embodiments 112 to 114, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is 5-membered heteroaryl ring substituted with (R 4< ) q . 116. The compound of any one of embodiments 112 to 114, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is a pyrazolyl ring substituted with (R 4< ) q . 117. The compound of any one of embodiments 112 to 114, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is wherein indicates the point of attachment of Ring D to Ring B . 118. The compound of any one of embodiments 112 to 117, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is wherein indicates the point of attachment of Ring D to Ring B . 119. The compound of any one of embodiments 112 to 118, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from an oxo group or -(Y) k -R 7< groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and - NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in - (Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens. 120. The compound of any one of embodiments 112 to 118, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from an oxo group or -(Y) k -R 7< groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and - NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in - (Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens. 121. The compound of any one of embodiments 112 to 118, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from an oxo group or -O-(Y) k -R 7< groups, wherein: k is 0, 1, 2, 3, 4, or 5; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and - NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in - (Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens. 122. The compound of any one of embodiments 112 to 118, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from wherein indicates the point of attachment of R 4< to Ring D. 123. The compound of any one of embodiments 112 to 122, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein k is 3, 4, 5, or 6. 124. The compound of any one of embodiments 112 to 123, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein q is 1. 125. The compound of any one of embodiments 112 to 124, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Z is a divalent linker of formula (L) r , wherein: r is 3, 4, or 5; each L is independently chosen from C(R 8< )(R 9< ) groups, -O-, and - NR b< - groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen and deuterium; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups. 126. The compound of any one of embodiments 112 to 124, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Z is a divalent linker of formula (L) r , wherein: r is 3, 4, or 5; each L is independently chosen from C(R 8< )(R 9< ) groups and -NR b< -groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen and deuterium; and each R b< is independently chosen from hydrogen and methyl. 127. The compound of any one of embodiments 112 to 124, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Z is a divalent linker of formula (L) r , wherein: r is 3, 4, or 5; each L is independently chosen from C(R 8< )(R 9< ) groups and -NR b< -groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen and deuterium; and each R b< is hydrogen. 128. The compound of any one of embodiments 112 to 124, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Z is a divalent linker of formula (L) r , wherein: r is 3, 4, or 5; each L is independently chosen from C(R 8< )(R 9< ) groups, -O-, and - NR b< - groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is hydrogen; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups. 129. The compound of any one of embodiments 112 to 128, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 3< is independently CD 3 . 130. The compound of embodiment 39, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein the compound of Formula (III-A) or (III-B) is a compound of Formula V-B: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: the carbon denoted by ∗< has S-stereochemistry or R-stereochemistry; Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; each R 1< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; m is 0, 1, 2, 3, or 4; each R 2< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; n is 0, 1, or 2; each R 3< is methyl; each R 4< is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y) k -R 7< groups, or optionally two R 4< , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< -groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3-5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens; q is 1 or 2; r is 3, 4, or 5; and each R 8< and R 9< is independently chosen from hydrogen, halogens, C 1 -C2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups. 131. The compound of embodiment 130, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 8< and R 9< is independently chosen from hydrogen, deuterium, halogens, C 1 -C 2 alkyl groups, a hydroxyl group, C 1 -C2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups. 132. The compound of embodiment 130 or 131, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 8< and R 9< is H. 133. The compound of any one of embodiments 130 to 132, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 1< is independently chosen from deuterium, C 1 -C 2 alkyl groups, and a hydroxyl group, and m is 0 or 1. 134. The compound of any one of embodiments 130 to 133, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein n is 0. 135. The compound of any one of embodiments 130 to 134, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is a 5-membered heteroaryl ring substituted with (R 4< ) q . 136. The compound of any one of embodiments 130 to 134, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is a pyrazolyl ring substituted with (R 4< ) q . 137. The compound of any one of embodiments 130 to 134, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is wherein indicates the point of attachment of Ring D to Ring B . 138. The compound of any one of embodiments 130 to 137, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is wherein indicates the point of attachment of Ring D to Ring B . 139. The compound of any one of embodiments 130 to 138, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from an oxo group or -(Y) k -R 7< groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and - NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in - (Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens. 140. The compound of any one of embodiments 130 to 138, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from an oxo group or -(Y) k -R 7< groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and - NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in - (Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens. 141. The compound of any one of embodiments 130 to 138, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from an oxo group or -O-(Y) k -R 7< groups, wherein: k is 0, 1, 2, 3, 4, or 5; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and - NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in - (Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3-5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3-5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens. 142. The compound of any one of embodiments 130 to 138, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from wherein indicates the point of attachment of R 4< to Ring D. 143. The compound of any one of embodiments 130 to 142, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein k is 3, 4, 5, or 6. 144. The compound of any one of embodiments 130 to 143, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein q is 1. 145. The compound of any one of embodiments 130 to 144, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: r is 3, 4, or 5; and each R 8< and R 9< is independently chosen from hydrogen and deuterium. 146. The compound of any one of embodiments 130 to 144, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: r is 3, 4, or 5; and each R 8< and R 9< is hydrogen. 147. The compound of any one of embodiments 130 to 144, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: r is 3, 4, or 5; and each R 8< and R 9< is deuterium. 148. The compound of any one of embodiments 130 to 144, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: r is 3 or 4; and each R 8< and R 9< is hydrogen. 149. The compound of any one of embodiments 130 to 148, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 3< is independently CD 3 . 150. The compound of embodiment 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein the compound of Formula I is a compound of Formula VI-A or VI-B: or a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: the carbon denoted by ∗< has S-stereochemistry or R-stereochemistry; Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; each R 1< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; m is 0, 1, 2, 3, or 4; each R 2< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; n is 0, 1, or 2; each R 3< is methyl; each R 4< is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y) k -R 7< groups, or optionally two R 4< , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< -groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3-5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3-5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens; q is 1 or 2; Z is a divalent linker of formula (L) r , wherein: r is 3, 4, or 5; each L is independently chosen from C(R 8< )(R 9< ) groups, -O-, and -NR b< -groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen, halogens, C 1 -C2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups. 151. The compound of embodiment 150, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 1< is independently chosen from deuterium, C 1 -C 2 alkyl groups, and a hydroxyl group, and m is 0 or 1. 152. The compound of embodiment 150 or 151, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein n is 0. 153. The compound of any one of embodiments 150 to 152, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is a 5-membered heteroaryl ring substituted with (R 4< ) q . 154. The compound of any one of embodiments 150 to 152, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is a pyrazolyl ring substituted with (R 4< ) q . 155. The compound of any one of embodiments 150 to 152, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is wherein indicates the point of attachment of Ring D to Ring B . 156. The compound of any one of embodiments 150 to 152, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is wherein indicates the point of attachment of Ring D to Ring B . 157. The compound of any one of embodiments 150 to 156, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from an oxo group or -(Y) k -R 7< groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and - NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in - (Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3-5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3-5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens. 158. The compound of any one of embodiments 150 to 156, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from an oxo group or -(Y) k -R 7< groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and - NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in - (Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens. 159. The compound of any one of embodiments 150 to 156, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from an oxo group or -O-(Y) k -R 7< groups, wherein: k is 0, 1, 2, 3, 4, or 5; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and - NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in - (Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3-5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3-5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens. 160. The compound of any one of embodiments 150 to 156, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from wherein indicates the point of attachment of R 4< to Ring D. 161. The compound of any one of embodiments 150 to 160, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein k is 3, 4, 5, or 6. 162. The compound of any one of embodiments 150 to 161, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein q is 1. 163. The compound of any one of embodiments 150 to 162, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Z is a divalent linker of formula (L) r , wherein: r is 3, 4, or 5; each L is independently chosen from C(R 8< )(R 9< ) groups, -O-, and - NR b< - groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen and deuterium; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups. 164. The compound of any one of embodiments 150 to 162, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Z is a divalent linker of formula (L) r , wherein: r is 3, 4, or 5; each L is independently chosen from C(R 8< )(R 9< ) groups and -NR b< -groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen and deuterium; and each R b< is independently chosen from hydrogen and methyl. 165. The compound of any one of embodiments 150 to 162, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Z is a divalent linker of formula (L) r , wherein: r is 3, 4, or 5; each L is independently chosen from C(R 8< )(R 9< ) groups and -NR b< -groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen and deuterium; and each R b< is hydrogen. 166. The compound of any one of embodiments 150 to 162, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Z is a divalent linker of formula (L) r , wherein: r is 3, 4, or 5; each L is independently chosen from C(R 8< )(R 9< ) groups, -O-, and - NR b< - groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is hydrogen; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups. 167. The compound of any one of embodiments 150 to 166, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 3< is independently CD 3 . 168. The compound of embodiment 39, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein the compound of Formula (III-A) or (III-B) is a compound of Formula VI-C or VI-D: or a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: the carbon denoted by ∗< has S-stereochemistry or R-stereochemistry; Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; each R 1< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; m is 0, 1, 2, 3, or 4; each R 2< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; n is 0, 1, or 2; each R 3< is methyl; each R 4< is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y) k -R 7< groups, or optionally two R 4< , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< -groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens; q is 1 or 2; r is 3 or 4; and each R 8< and R 9< is independently chosen from hydrogen, halogens, C 1 -C2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups. 169. The compound of embodiment 168, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 8< and R 9< is independently chosen from hydrogen, deuterium, halogens, C 1 -C 2 alkyl groups, a hydroxyl group, C 1 -C2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups. 170. The compound of embodiment 169 or 169, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 8< and R 9< is H. 171. The compound of any one of embodiments 168 to 170, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 1< is independently chosen from deuterium, C 1 -C 2 alkyl groups, and a hydroxyl group, and m is 0 or 1. 172. The compound of any one of embodiments 168 to 171, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein n is 0. 173. The compound of any one of embodiments 168 to 172, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D a 5-membered heteroaryl ring substituted with (R 4< ) q . 174. The compound of any one of embodiments 168 to 172, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is a pyrazolyl ring substituted with (R 4< ) q . 175. The compound of any one of embodiments 168 to 172, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is wherein indicates the point of attachment of Ring D to Ring B . 176. The compound of any one of embodiments 168 to 172, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is wherein indicates the point of attachment of Ring D to Ring B . 177. The compound of any one of embodiments 168 to 172, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from an oxo group or -(Y) k -R 7< groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and - NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in - (Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens. 178. The compound of any one of embodiments 168 to 176, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from an oxo group or -(Y) k -R 7< groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and - NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in - (Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens. 179. The compound of any one of embodiments 168 to 176, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from an oxo group or -O-(Y) k -R 7< groups, wherein: k is 0, 1, 2, 3, 4, or 5; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and - NR a< - groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in - (Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens. 180. The compound of any one of embodiments 168 to 176, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4< is independently chosen from wherein indicates the point of attachment of R 4< to Ring D. 181. The compound of any one of embodiments 168 to 180, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein k is 3, 4, 5, or 6. 182. The compound of any one of embodiments 168 to 181, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein q is 1. 183. The compound of any one of embodiments 168 to 182, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: r is 3, 4, or 5; and each R 8< and R 9< is independently chosen from hydrogen and deuterium. 184. The compound of any one of embodiments 168 to 182, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: r is 3, 4, or 5; and each R 8< and R 9< is hydrogen. 185. The compound of any one of embodiments 168 to 182, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: r is 3, 4, or 5; and each R 8< and R 9< is deuterium;. 186. The compound of any one of embodiments 168 to 182, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: r is 3 or 4; and each R 8< and R 9< is hydrogen. 187. The compound of any one of embodiments 168 to 186, wherein each R 3< is independently CD 3 . 188. The compound of any one of embodiments 39-57, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein the carbon denoted by ∗< of formula (II-A) or (III-A) has S-stereochemistry, and wherein the carbon denoted by ∗< of formula (II-B) or (III-B) has R-stereochemistry. 189. The compound of any one of embodiments 58-187, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein the carbon denoted by ∗< of any one of formulae (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), and (VI-D) has S-stereochemistry. 190. The compound of any one of embodiments 58-187, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein the carbon denoted by ∗< of any one of formulae (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), and (VI-D) has R-stereochemistry. 191. A compound chosen from compounds Nos. 1-97, 99-261, 264, 265, 268-270, 273-302 depicted in Figure 1, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing. 192. A compound chosen from compounds Nos. 304-309 depicted in Figure 1, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing. 193. A compound selected from: pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing. 194. A pharmaceutical composition comprising at least one compound chosen from compounds of any one of embodiments 39-191 a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, and optionally one or more of: (a) Compound II: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing; (b) Compound III: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing; and (c) a pharmaceutically acceptable carrier. 195. A compound of any one of embodiments 39 to 191 or a pharmaceutical composition according to embodiment 194 for use in a method of treating cystic fibrosis comprising administering to a patient in need thereof the compound of any one of embodiments 39 to 191 or the pharmaceutical composition according to embodiment 194. 196. At least one compound chosen from compounds of any one of embodiments 39-191 a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, and optionally one or more of: (a) Compound II: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing; (b) Compound III: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing; for use in treating cystic fibrosis. 197. A compound of Formula (X): a salt thereof, or a deuterated derivative of any of the foregoing, wherein: Q a< is a halogen; Ring A is a phenyl, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; Ring B is a pyridinyl ring; X is O, NH, or an N(C 1 -C 4 alkyl); each R 1< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; m is 0, 1, 2, 3, or 4; each R 2< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; n is 0, 1, or 2; each R 3< is methyl; Z is a divalent linker of formula (L) r , wherein: r is 1, 2, 3, 4, 5, or 6; each L is independently chosen from C(R 8< )(R 9< ) groups, -O-, and -NR b< -groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen, halogens, C 1 -C2 haloalkyl groups, C 1 -C 2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups. 198. A compound of Formula (Y): a salt thereof, or a deuterated derivative of any of the foregoing, wherein: Q b< is a halogen; R 10< is hydrogen or a protecting group; Ring A is a phenyl, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; Ring B is a pyridinyl ring; Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; X is O, NH, or an N(C 1 -C 4 alkyl); each R 1< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; m is 0, 1, 2, 3, or 4; each R 2< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; n is 0, 1, or 2; each R 3< is methyl; each R 4< is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y) k -R 7< groups, or optionally two R 4< , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< -groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3-5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3-5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens; q is 1, 2, 3 or 4; and Z is a divalent linker of formula (L) r , wherein: r is 1, 2, 3, 4, 5, or 6; each L is independently chosen from C(R 8< )(R 9< ) groups, -O-, and -NR b< -groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen, halogens, C 1 -C2 haloalkyl groups, C 1 -C 2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups. 199. A method of preparing a compound of Formula (I): a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, comprising coupling the NH group of Ring C and the Q b< group of Ring B of a compound of Formula (Y-I ): a salt thereof, or a deuterated derivative of any of the foregoing, wherein: Q b< is a halogen; Ring A is a phenyl, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; Ring B is a pyridinyl ring; Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; X is O, NH, or an N(C 1 -C 4 alkyl); each R 1< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; m is 0, 1, 2, 3, or 4; each R 2< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; n is 0, 1, or 2; each R 3< is methyl; each R 4< is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y) k -R 7< groups, or optionally two R 4< , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< -groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3 - 5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3 - 5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens; q is 1, 2, 3 or 4; and Z is a divalent linker of formula (L) r , wherein: r is 1, 2, 3, 4, 5, or 6; each L is independently chosen from C(R 8< )(R 9< ) groups, -O-, and -NR b< -groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen, halogens, C 1 -C2 haloalkyl groups, C 1 -C 2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; to form a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing. 200. The method of embodiment 198, wherein said coupling is performed in the presence of a base. 201. A method of preparing a compound of Formula (Y) a salt thereof, or a deuterated derivative of any of the foregoing, comprising reacting a compound of Formula (A), a salt thereof, or a deuterated derivative of any of the foregoing, with a compound of Formula (B), a salt thereof, or a deuterated derivative of any of the foregoing, to form said compound of Formula (Y), a salt thereof, or a deuterated derivative of any of the foregoing: and optionally deprotecting the N-protecting group of Ring C of Formula (Y), wherein Q b< is a halogen; R 10< of Formula (Y) is hydrogen or a N-protecting group; R 10< of Formula (B) is a N-protecting group, and Ring A, Ring B, Ring D, X, R 1< , m, R 2< , n, R 3< , R 4< , q, Z, R 10< , and the variables therein are as recited in embodiment 39. 202. The method of embodiment 201, wherein said reacting a compound of Formula (A), a salt thereof, or a deuterated derivative of any of the foregoing, with a compound of Formula (B), a salt thereof, or a deuterated derivative of any of the foregoing, is performed in the presence of a base. 203. The method of embodiment 201, wherein said reacting a compound of Formula (A), salt thereof, or a deuterated derivative of any of the foregoing, with a compound of Formula (B), a salt thereof, or a deuterated derivative of any of the foregoing, comprises reacting a compound of Formula (A ) , salt thereof, or a deuterated derivative of any of the foregoing, with a coupling reagent and subsequently with a compound of Formula (B ) , salt thereof, or a deuterated derivative of any of the foregoing, in the presence of a base. 204. A method of preparing a compound of Formula (Y-2): a salt thereof, or a deuterated derivative of any of the foregoing, wherein: Q b< is a halogen; Ring A is a phenyl, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; Ring B is a pyridinyl ring; Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; X is O, NH, or an N(C 1 -C 4 alkyl); each R 1< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; m is 0, 1, 2, 3, or 4; each R 2< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; n is 0, 1, or 2; each R 3< is methyl; each R 4< is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y) k -R 7< groups, or optionally two R 4< , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< -groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3-5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3-5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens; q is 1, 2, 3 or 4; r is 1, 2, 3, 4 or 5; each R 8< and R 9< is independently chosen from hydrogen, halogens, C 1 -C 2 haloalkyl groups, C 1 -C 2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and R 10< is hydrogen or a protecting group; comprising reacting a compound of Formula (A), a salt thereof, or a deuterated derivative of any of the foregoing, with a compound of Formula (B-2), a salt thereof, or a deuterated derivative of any of the foregoing, to form said compound of Formula (Y- 2), a salt thereof, or a deuterated derivative of any of the foregoing: 205. The method of embodiment 204, wherein said reacting a compound of Formula (A), a salt thereof, or a deuterated derivative of any of the foregoing, with a compound of Formula (B-2), salt thereof, or a deuterated derivative of any of the foregoing, is performed in the presence of a base. 206. The method of embodiment 205, wherein said reacting a compound of Formula (A), a salt thereof, or a deuterated derivative of any of the foregoing, with a compound of Formula (B-2), a salt thereof, or a deuterated derivative of any of the foregoing, comprises reacting a compound of Formula (A), a salt thereof, or a deuterated derivative of any of the foregoing, with a coupling reagent and subsequently with a compound of Formula (B-2), a salt thereof, or a deuterated derivative of any of the foregoing, in the presence of a base. 207. The method of any one of embodiments 204-206, further comprising reacting a compound of Formula (D), a salt thereof, or a deuterated derivative of any of the foregoing, with a compound of Formula (E-2),a salt thereof, or a deuterated derivative of any of the foregoing, to form said compound of Formula (B-2), a salt thereof, or a deuterated derivative of any of the foregoing: wherein R d< is a halogen. 208. A method of preparing a compound of Formula (Y-3): a salt thereof, or a deuterated derivative of any of the foregoing, comprising reacting a compound of Formula (A), a salt thereof, or a deuterated derivative of any of the foregoing, with a compound of Formula (B-3), a salt thereof, or a deuterated derivative of any of the foregoing, to form said compound of Formula (Y-3), a salt thereof, or a deuterated derivative of any of the foregoing: 209. The method of embodiment 208 wherein said reacting a compound of Formula (A), a salt thereof, or a deuterated derivative of any of the foregoing, with a compound of Formula (B-3), a salt thereof, or a deuterated derivative of any of the foregoing, is performed in the presence of a base. 210. The method of embodiment 208, wherein said reacting a compound of Formula (A), a salt thereof, or a deuterated derivative of any of the foregoing, with a compound of Formula (B-3), a salt thereof, or a deuterated derivative of any of the foregoing, comprises reacting a compound of Formula (A), a salt thereof, or a deuterated derivative of any of the foregoing, with a coupling reagent and subsequently with a compound of Formula (B-3), a salt thereof, or a deuterated derivative of any of the foregoing, in the presence of a base. 211. The method of any one of embodiments 208-210, further comprising reacting a compound of Formula (D), a salt thereof, or a deuterated derivative of any of the foregoing, with a compound of Formula (E-3), a salt thereof, or a deuterated derivative of any of the foregoing, to form said compound of Formula (B-3), a salt thereof, or a deuterated derivative of any of the foregoing: 212. A method of preparing a compound of Formula (I) a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is comprising reacting a compound of Formula (X), a salt thereof, or a deuterated derivative of any of the foregoing, with a compound of Formula (Z-1 ), a salt thereof, or a deuterated derivative of any of the foregoing: wherein: Q a< is a halogen; Ring A is a phenyl, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; Ring B is a pyridinyl ring; Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; X is O, NH, or an N(C1-C4 alkyl); each R 1< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; m is 0, 1, 2, 3, or 4; each R 2< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; n is 0, 1, or 2; each R 3< is methyl; each R 4< is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y) k -R 7< groups, or optionally two R 4< , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< -groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3-5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3-5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens; q is 1, 2, 3 or 4; and Z is a divalent linker of formula (L) r , wherein: r is 1, 2, 3, 4, 5, or 6; each L is independently chosen from C(R 8< )(R 9< ) groups, -O-, and -NR b< -groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: each R 8< and R 9< is independently chosen from hydrogen, halogens, C 1 -C2 haloalkyl groups, C 1 -C 2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups. 213. A method of preparing a compound of Formula (IV-C): , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing comprising reacting a compound of Formula (X-1 ), a salt thereof, or a deuterated derivative of any of the foregoing with a compound of Formula (Z-1 ), a salt thereof, or a deuterated derivative of any of the foregoing wherein: Q a< is a halogen; the carbon denoted by ∗< has S-stereochemistry or R-stereochemistry; Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; each R 1< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; m is 0, 1, 2, 3, or 4; each R 2< is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; n is 0, 1, or 2; each R 3< is methyl; each R 4< is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y) k -R 7< groups, or optionally two R 4< , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups, wherein: k is 0, 1, 2, 3, 4, 5, or 6; each Y is independently chosen from C(R 5< )(R 6< ) groups, -O-, and -NR a< -groups, wherein a heteroatom in -(Y) k -R 7< is not bonded to another heteroatom in -(Y) k -R 7< , wherein: each R 5< and R 6< is independently chosen from hydrogen, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3-5 cycloalkyl groups, or R 5< and R 6< on the same carbon together form a C 3-5 cycloalkyl group or oxo; each of R 5< and R 6< is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R a< is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and R 7< is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens; q is 1 or 2; r is 3 or 4; each R 8< and R 9< is independently chosen from hydrogen, halogens, C 1 -C 2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and each R b< is independently chosen from hydrogen and C 1 -C 2 alkyl groups. 214. The compound of any one of embodiments 39-190, wherein the compound is in the form of a pharmaceutically acceptable salt. 215. The compound of embodiment 214, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt. 216. The compound of embodiment 215, wherein the pharmaceutically acceptable salt is a calcium salt. 217. The compound of embodiment 191, wherein the compound is in the form of a pharmaceutically acceptable salt. 218. The compound of embodiment 217, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt. 219. The compound of embodiment 218, wherein the pharmaceutically acceptable salt is a calcium salt. 220. The compound of embodiment 192, wherein the compound is in the form of a pharmaceutically acceptable salt. 221. The compound of embodiment 220, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt. 222. The compound of embodiment 221, wherein the pharmaceutically acceptable salt is a calcium salt. 223. The compound of embodiment 193, wherein the compound is in the form of a pharmaceutically acceptable salt. 224. The compound of embodiment 223, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt. 225. The compound of embodiment 224, wherein the pharmaceutically acceptable salt is a calcium salt. 226. The compound of embodiment 193, wherein the compound is 227. The compound of embodiment 193, wherein the compound is in the form of a calcium salt of: 228. The compound of embodiment 193, wherein the compound is 229. The compound of embodiment 193, wherein the compound is in the form of a calcium salt of: 230. The compound of embodiment 193, wherein the compound is 231. The compound of embodiment 193, wherein the compound is in the form of a calcium salt of: 232. The compound of embodiment 193, wherein the compound is 233. The compound of embodiment 193, wherein the compound is in the form of a calcium salt of: 234. The compound of embodiment 193, wherein the compound is 235. The compound of embodiment 193, wherein the compound is in the form of a calcium salt of: 236. The compound of embodiment 193, wherein the compound is 237. The compound of embodiment 193, wherein the compound is in the form of a calcium salt of: 238. The compound of embodiment 193, wherein the compound is 239. The compound of embodiment 193, wherein the compound is in the form of a calcium salt of: 240. The compound of embodiment 193, wherein the compound is 241. The compound of embodiment 193, wherein the compound is in the form of a calcium salt of: 242. The compound of embodiment 193, wherein the compound is 243. The compound of embodiment 193, wherein the compound is in the form of a calcium salt of: 244. The compound of embodiment 193, wherein the compound is 245. The compound of embodiment 193, wherein the compound is in the form of a calcium salt of: 246. The compound for use in a method of treating cystic fibrosis of embodiment 195, wherein the compound is in the form of a pharmaceutically acceptable salt. 247. The compound for use in a method of embodiment 246, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt. 248. The compound for use in a method of embodiment 247, wherein the pharmaceutically acceptable salt is a calcium salt. 249. A compound of embodiment 192 for use in a method of treating cystic fibrosis comprising administering to a patient in need thereof the compound of embodiment 192. 250. A compound of any one of embodiments 193 or 226-245 for use in a method of treating cystic fibrosis comprising administering to a patient in need thereof the compound of any one of embodiments 193 or 226-245. 251. The compound for use in a method of treating cystic fibrosis of embodiment 249 or 250, wherein the compound is in the form of a pharmaceutically acceptable salt. 252. The compound for use in a method of embodiment 251, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt. 253. The compound for use in a method of embodiment 252, wherein the pharmaceutically acceptable salt is a calcium salt. 254. A compound of any one of embodiments 39-190 for use in a method of treating cystic fibrosis comprising administering to a patient in need thereof the compound of any one of embodiments 39-190, wherein the compound is administered in combination with Compound III or a pharmaceutically acceptable salt or deuterated derivative thereof. 255. A compound of embodiment 191 for use in a method of treating cystic fibrosis comprising administering to a patient in need thereof the compound of embodiment 191, wherein the compound is administered in combination with Compound III or a pharmaceutically acceptable salt or deuterated derivative thereof. 256. A compound of embodiment 192 for use in a method of treating cystic fibrosis comprising administering to a patient in need thereof the compound of embodiment 192, wherein the compound is administered in combination with Compound III or a pharmaceutically acceptable salt or deuterated derivative thereof. 257. A compound of any one of embodiments 193 or 226-245 for use in a method of treating cystic fibrosis comprising administering to a patient in need thereof the compound of any one of embodiments 193 or 226-245, wherein the compound is administered in combination with Compound III or a pharmaceutically acceptable salt or deuterated derivative thereof. 258. The compound for use in a method of any one of embodiments 254-257, wherein the deuterated derivative of Compound III is Compound III-d. 259. A compound of any one of embodiments 39-190 for use in a method of treating cystic fibrosis comprising administering to a patient in need thereof the compound of any one of embodiments 39-190, wherein the compound is administered in combination with (a) Compound II and (b) Compound III or a deuterated derivative thereof. 260. A compound of embodiment 191 for use in a method of treating cystic fibrosis comprising administering to a patient in need thereof the compound of embodiment 191, wherein the compound is administered in combination with (a) Compound II and (b) Compound III or a deuterated derivative thereof. 261. A compound of embodiment 192 for use in a method of treating cystic fibrosis comprising administering to a patient in need thereof the compound of embodiment 192, wherein the compound is administered in combination with (a) Compound II and (b) Compound III or a deuterated derivative thereof. 262. A compound of any one of embodiments 193 or 226-245 for use in a method of treating cystic fibrosis comprising administering to a patient in need thereof the compound of any one of embodiments 193 or 226-245, wherein the compound is administered in combination with (a) Compound II and (b) Compound III or a deuterated derivative thereof. 263. The compound for use in a method of any one of embodiments 259-262, wherein the deuterated derivative of Compound III is Compound III-d. 264. The compound for use in a method of any one of embodiments 254-262, wherein the compound is in the form of a pharmaceutically acceptable salt. 265. The compound for use in a method of embodiment 264, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt. 266. The compound for use in a method of embodiment 265, wherein the pharmaceutically acceptable salt is a calcium salt. 267. A pharmaceutical composition comprising the compound of embodiment 191 and a pharmaceutically acceptable carrier. 268. A pharmaceutical composition comprising the compound of embodiment 192 and a pharmaceutically acceptable carrier. 269. A pharmaceutical composition comprising the compound of any one of embodiments 193 or 226-245 and a pharmaceutically acceptable carrier. 270. The pharmaceutical composition of any one of embodiments 267-269, wherein the compound in the form of a pharmaceutically acceptable salt. 271. The pharmaceutical composition of embodiment 270, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt. 272. The pharmaceutical composition of embodiment 271, wherein the pharmaceutically acceptable salt is a calcium salt. 273. The pharmaceutical composition of any one of embodiments 267-272, further comprising Compound III or pharmaceutically acceptable salt or deuterated derivative thereof. 274. The pharmaceutical composition of embodiment 273, wherein the deuterated derivative of Compound III is Compound III-d. 275. The pharmaceutical composition of any one of embodiments 267-272, further comprising (a) Compound II and (b) Compound III or a deuterated derivative thereof. 276. The pharmaceutical composition of embodiment 275, wherein the deuterated derivative of Compound III is Compound III-d. 277. The compound of any one of embodiments 39-190 for use in the treatment of cystic fibrosis. 278. The compound of embodiment 191 for use in the treatment of cystic fibrosis. 279. The compound embodiment 192 for use in the treatment of cystic fibrosis. 280. The compound of any one of embodiments 193 or 226-245 for use in the treatment of cystic fibrosis. 281. The compound for use of any one of embodiments 277-280, wherein the compound is in the form of a pharmaceutically acceptable salt. 282. The compound for use of embodiment 281, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt. 283. The compound for use of embodiment 282, wherein the pharmaceutically acceptable salt is a calcium salt. 284. The compound for use of any one of embodiments 277-283, wherein the treatment further comprises administration of Compound III. 285. The compound for use of any one of embodiments 277-283, wherein the treatment further comprises administration of Compound III-d. 286. The compound for use of any one of embodiments 277-283, wherein the treatment further comprises administration of Compound II and Compound III. 287. The compound for use of any one of embodiments 277-283, wherein the treatment further comprises administration of Compound II and Compound III-d.

[0166] Other embodiments include: A. A compound of Formula III-A or III-B: B. A pharmaceutically acceptable salt of a compound of Formula III-A or III-B C. A pharmaceutical composition comprising: (i) a compound of Formula III-A or III-B: and (ii) a pharmaceutically acceptable carrier. D. The pharmaceutical composition of embodiment C further comprising Compound II: E. The pharmaceutical composition of embodiment C further comprising a pharmaceutically acceptable salt of Compound II: F. The pharmaceutical composition of embodiment C further comprising Compound III: G. The pharmaceutical composition of embodiment C further comprising a pharmaceutically acceptable salt of Compound III: H. The pharmaceutical composition of embodiment D further comprising Compound III: I. The pharmaceutical composition of embodiment D further comprising a pharmaceutically acceptable salt of Compound III: J. The pharmaceutical composition of embodiment E further comprising Compound III: K. The pharmaceutical composition of embodiment E further comprising a pharmaceutically acceptable salt of Compound III: L. A pharmaceutical composition comprising: (A) a pharmaceutically acceptable salt of a compound of Formula III-A or III-B and (B) a pharmaceutically acceptable carrier. M. The pharmaceutical composition of embodiment L further comprising Compound II: N. The pharmaceutical composition of embodiment L further comprising a pharmaceutically acceptable salt of Compound II: O. The pharmaceutical composition of embodiment L further comprising Compound III: P. The pharmaceutical composition of embodiment L further comprising a pharmaceutically acceptable salt of Compound III: Q. The pharmaceutical composition of embodiment M further comprising Compound III: R. The pharmaceutical composition of embodiment M further comprising a pharmaceutically acceptable salt of Compound III: S. The pharmaceutical composition of embodiment M further comprising Compound III: T. The pharmaceutical composition of embodiment M further comprising a pharmaceutically acceptable salt of Compound III: U. A method of treating cystic fibrosis comprising administering to a patient in need thereof a compound of Formula III-A or III-B: or V. A method of treating cystic fibrosis comprising administering to a patient in need thereof a pharmaceutically acceptable salt of a compound of Formula III-A or III-B: W. A method of treating cystic fibrosis comprising administering to a patient in need thereof a pharmaceutical composition comprising: (A) a compound of Formula III-A or III-B and (B) a pharmaceutically acceptable carrier. X. A method of treating cystic fibrosis comprising administering to a patient in need thereof a pharmaceutical composition comprising: a pharmaceutically acceptable salt of a compound of Formula III-A or III-B and a pharmaceutically acceptable carrier. General Experimental Procedures

[0167] The definitions of certain abbreviations for the Examples below are summarized below: Boc anhydride ((Boc) 2 O): di-tert-butyl dicarbonate CDI: carbonyl diimidazole DABCO: 1,4-diazabicyclo[2.2.2]octane DBU: 1,8-diazabicyclo(5.4.0)undec-7-ene DCM: dichloromethane DIAD: diisopropyl azodicarboxylate DIEA (DIPEA; N,N-diisopropylethylamine) DMA: N,N-Dimethylacetamide DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide Et 2 O: diethyl ether EtOH: ethanol HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate IPA: isoproanol MeOH: methanol NMP: N-methyl-2-pyrrolidone MTBE: methyl tert-butyl ether TBS-Cl: tert-Butyldimethylsilyl chloride TFA: trifluoroacetic acid THF: tetrahydrofuran) p-TsOH: p-Toluenesulfonic Acid TPPO-DIAD complex: a complex of triphenylphosphine oxide with diisopropyl azodicarboxylate

[0168] Reagents and starting materials were obtained by commercial sources unless otherwise stated and were used without purification. Proton and carbon NMR spectra were acquired on either of a Bruker Biospin DRX 400 MHz FTNMR spectrometer operating at a 1< H and 13< C resonant frequency of 400 and 100 MHz respectively, or on a 300 MHz NMR spectrometer. One dimensional proton and carbon spectra were acquired using a broadband observe (BBFO) probe with 20 Hz sample rotation at 0.1834 and 0.9083 Hz / Pt digital resolution respectively. All proton and carbon spectra were acquired with temperature control at 30°C using standard, previously published pulse sequences and routine processing parameters. Final purity of compounds was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50 × 2.1 mm, 1.7 µm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 3.0 minutes. Mobile phase A = H 2 O (0.05 % CF 3 CO 2 H). Mobile phase B = CH 3 CN (0.035 % CF 3 CO 2 H). Flow rate = 1.2 mL / min, injection volume = 1.5 µL, and column temperature = 60 °C. Final purity was calculated by averaging the area under the curve (AUC) of two UV traces (220 nm, 254 nm). Low-resolution mass spectra were reported as [M+H] +< species obtained using a single quadrupole mass spectrometer equipped with an electrospray ionization (ESI) source capable of achieving a mass accuracy of 0.1 Da and a minimum resolution of 1000 (no units on resolution) across the detection range. Optical purity of methyl (2S)-2,4-dimethyl-4-nitro-pentanoate was determined using chiral gas chromatography (GC) analysis on an Agilent 7890A / MSD 5975C instrument, using a Restek Rt-βDEXcst (30m × 0.25mm × 0.25um_df) column, with a 2.0 mL / min flow rate (H2 carrier gas), at an injection temperature of 220°C and an oven temperature of 120°C, 15 minutes.Synthetic Examples Synthesis of Compound II: (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

[0169] Step 1: (R)-Benzyl 2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate and ((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)methyl 2-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate

[0170] Cesium carbonate (8.23 g, 25.3 mmol) was added to a mixture of benzyl 2-(6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate (3.0 g, 8.4 mmol) and (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (7.23 g, 25.3 mmol) in DMF (N,N-dimethylformamide) (17 mL). The reaction was stirred at 80 °C for 46 hours under a nitrogen atmosphere. The mixture was then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over MgSO 4 , filtered and concentrated. The crude product, a viscous brown oil which contains both of the products shown above, was taken directly to the next step without further purification. (R)-Benzyl 2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate, ESI-MS m / z calc. 470.2, found 471.5 (M+1) +< . Retention time 2.20 minutes. ((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)methyl 2-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate, ESI-MS m / z calc. 494.5, found 495.7 (M+1) +< . Retention time 2.01 minutes.Step 2: (R)-2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropan-1-ol

[0171] The crude reaction mixture obtained in step (A) was dissolved in THF (tetrahydrofuran) (42 mL) and cooled in an ice-water bath. LiAlH 4 (16.8 mL of 1 M solution, 16.8 mmol) was added drop-wise. After the addition was complete, the mixture was stirred for an additional 5 minutes. The reaction was quenched by adding water (1 mL), 15% NaOH solution (1 mL) and then water (3 mL). The mixture was filtered over Celite, and the solids were washed with THF and ethyl acetate. The filtrate was concentrated and purified by column chromatography (30-60% ethyl acetate-hexanes) to obtain (R)-2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropan-1-ol as a brown oil (2.68g, 87 % over 2 steps). ESI-MS m / z calc. 366.4, found 367.3 (M+1) +< . Retention time 1.68 minutes. 1< H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 13.4 Hz, 1H), 6.57 (s, 1H), 4.94 (t, J = 5.4 Hz, 1H), 4.64 - 4.60 (m, 1H), 4.52 - 4.42(m, 2H), 4.16 - 4.14 (m, 1H), 3.76 - 3.74 (m, 1H), 3.63 - 3.53 (m, 2H), 1.42 (s, 3H), 1.38 - 1.36 (m, 6H) and 1.19 (s, 3H) ppm. (DMSO is dimethylsulfoxide).Step 3: (R)-2-(5-amino-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-1H-indol-2-yl)-2-methylpropan-1-ol

[0172] (R)-2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropan-1-ol (2.5 g, 6.82 mmol) was dissolved in ethanol (70 mL) and the reaction was flushed with N2. Then Pd-C (250 mg, 5% wt) was added. The reaction was flushed with nitrogen again and then stirred under H2 (atm). After 2.5 hours only partial conversion to the product was observed by LCMS. The reaction was filtered through Celite and concentrated. The residue was re-subjected to the conditions above. After 2 hours LCMS indicated complete conversion to product. The reaction mixture was filtered through Celite. The filtrate was concentrated to yield the product (1.82 g, 79 %). ESI-MS m / z calc. 336.2, found 337.5 (M+1) +< . Retention time 0.86 minutes. 1< H NMR (400 MHz, DMSO-d6) δ 7.17 (d, J = 12.6 Hz, 1H), 6.76 (d, J = 9.0 Hz, 1H), 6.03 (s, 1H), 4.79 - 4.76 (m, 1H), 4.46 (s, 2H), 4.37 - 4.31 (m, 3H),4.06 (dd, J = 6.1, 8.3 Hz, 1H), 3.70 - 3.67 (m, 1H), 3.55 - 3.52 (m, 2H), 1.41 (s, 3H), 1.32 (s, 6H) and 1.21 (s, 3H) ppm.Step 4: (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide

[0173] DMF (3 drops) was added to a stirring mixture of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (1.87 g, 7.7 mmol) and thionyl chloride (1.30 mL, 17.9 mmol). After 1 hour a clear solution had formed. The solution was concentrated under vacuum and then toluene (3 mL) was added and the mixture was concentrated again. The toluene step was repeated once more and the residue was placed on high vacuum for 10 minutes. The acid chloride was then dissolved in dichloromethane (10 mL) and added to a mixture of (R)-2-(5-amino-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-1H-indol-2-yl)-2-methylpropan-1-ol (1.8 g, 5.4 mmol) and triethylamine (2.24 mL, 16.1 mmol) in dichloromethane (45 mL). The reaction was stirred at room temperature for 1 hour. The reaction was washed with 1N HCl solution, saturated NaHCO 3 solution and brine, dried over MgSO 4 and concentrated to yield the product (3g, 100%). ESI-MS m / z calc. 560.6, found 561.7 (M+1) +< . Retention time 2.05 minutes. 1< H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.53 (s, 1H), 7.42 - 7.40 (m, 2H), 7.34 - 7.30 (m, 3H), 6.24 (s, 1H), 4.51 - 4.48 (m, 1H), 4.39 - 4.34 (m,2H), 4.08 (dd, J = 6.0, 8.3 Hz, 1H), 3.69 (t, J = 7.6 Hz, 1H), 3.58 - 3.51 (m, 2H), 1.48 - 1.45 (m, 2H), 1.39 (s, 3H), 1.34 - 1.33 (m, 6H), 1.18 (s, 3H) and 1.14 - 1.12 (m, 2H) ppm.Step 5: (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

[0174] (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (3.0 g, 5.4 mmol) was dissolved in methanol (52 mL). Water (5.2 mL) was added followed by p-TsOH.H 2 O (p-toluenesulfonic acid hydrate) (204 mg, 1.1 mmol). The reaction was heated at 80 °C for 45 minutes. The solution was concentrated and then partitioned between ethyl acetate and saturated NaHCO 3 solution. The ethyl acetate layer was dried over MgSO 4 and concentrated. The residue was purified by column chromatography (50-100 % ethyl acetate - hexanes) to yield the product. (1.3 g, 47 %, ee >98% by SFC). ESI-MS m / z calc. 520.5, found 521.7 (M+1) +< . Retention time 1.69 minutes. 1< H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.53 (s, 1H), 7.42 - 7.38 (m, 2H), 7.33 - 7.30 (m, 2H), 6.22 (s, 1H), 5.01 (d, J = 5.2 Hz, 1H), 4.90 (t, J = 5.5 Hz, 1H), 4.75 (t, J = 5.8 Hz, 1H), 4.40 (dd, J = 2.6, 15.1 Hz, 1H), 4.10 (dd, J = 8.7, 15.1 Hz, 1H), 3.90 (s, 1H), 3.65 - 3.54 (m, 2H), 3.48 - 3.33 (m, 2H), 1.48 - 1.45 (m, 2H), 1.35 (s, 3H), 1.32 (s, 3H) and 1.14 - 1.11 (m, 2H) ppm.Synthesis of Compound III: N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide Part A: Synthesis of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid

[0175] Step 1: 2-Phenylaminomethylene-malonic acid diethyl ester

[0176] A mixture of aniline (25.6 g, 0.275 mol) and diethyl 2-(ethoxymethylene)malonate (62.4 g, 0.288 mol) was heated at 140-150 °C for 2 h. The mixture was cooled to room temperature and dried under reduced pressure to afford 2-phenylaminomethylene-malonic acid diethyl ester as a solid, which was used in the next step without further purification. 1< H NMR (DMSO-d 6 ) δ 11.00 (d, 1H), 8.54 (d, J = 13.6 Hz, 1H), 7.36-7.39 (m, 2H), 7.13-7.17 (m, 3H), 4.17-4.33 (m, 4H), 1.18-1.40 (m, 6H).Step 2: 4-Hydroxyquinoline-3-carboxylic acid ethyl ester

[0177] A 1 L three-necked flask fitted with a mechanical stirrer was charged with 2-phenylaminomethylene-malonic acid diethyl ester (26.3 g, 0.100 mol), polyphosphoric acid (270 g) and phosphoryl chloride (750 g). The mixture was heated to 70 °C and stirred for 4 h. The mixture was cooled to room temperature and filtered. The residue was treated with aqueous Na 2 CO 3 solution, filtered, washed with water and dried. 4-Hydroxyquinoline-3-carboxylic acid ethyl ester was obtained as a pale brown solid (15.2 g, 70%). The crude product was used in next step without further purification.Step 3: 4-Oxo-1,4-dihydroquinoline-3-carboxylic acid

[0178] 4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h at reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HCl. The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a pale white solid (10.5 g, 92 %). 1< H NMR (DMSO-d 6 ) δ 15.34 (s, 1 H), 13.42 (s, 1 H), 8.89 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.60 (m, 1H).Part B: Synthesis of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

[0179] Step 1: Carbonic acid 2,4-di-tert-butyl-phenyl ester methyl ester

[0180] Methyl chloroformate (58 mL, 750 mmol) was added dropwise to a solution of 2,4-di-tert-butyl-phenol (103.2 g, 500 mmol), Et3N (139 mL, 1000 mmol) and DMAP (3.05 g, 25 mmol) in dichloromethane (400 mL) cooled in an ice-water bath to 0 °C. The mixture was allowed to warm to room temperature while stirring overnight, then filtered through silica gel (approx. 1L) using 10% ethyl acetate - hexanes (~ 4 L) as the eluent. The combined filtrates were concentrated to yield carbonic acid 2,4-di-tert-butyl-phenyl ester methyl ester as a yellow oil (132 g, quant.). 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.35 (d, J = 2.4 Hz, 1H), 7.29 (dd, J = 8.5, 2.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 3.85 (s, 3H), 1.30 (s, 9H), 1.29 (s, 9H).Step 2: Carbonic acid 2,4-di-tert-butyl-5-nitro-phenyl ester methyl ester and Carbonic acid 2,4-di-tert-butyl-6-nitro-phenyl ester methyl ester

[0181] To a stirring mixture of carbonic acid 2,4-di-tert-butyl-phenyl ester methyl ester (4.76 g, 180 mmol) in conc. sulfuric acid (2 mL), cooled in an ice-water bath, was added a cooled mixture of sulfuric acid (2 mL) and nitric acid (2 mL). The addition was done slowly so that the reaction temperature did not exceed 50 °C. The reaction was allowed to stir for 2 h while warming to room temperature. The reaction mixture was then added to ice-water and extracted into diethyl ether. The ether layer was dried (MgSO 4 ), concentrated and purified by column chromatography (0 - 10% ethyl acetate - hexanes) to yield a mixture of carbonic acid 2,4-di-tert-butyl-5-nitro-phenyl ester methyl ester and carbonic acid 2,4-di-tert-butyl-6-nitro-phenyl ester methyl ester as a pale yellow solid (4.28 g), which was used directly in the next step.Step 3: 2,4-Di-tert-butyl-5-nitro-phenol and 2,4-Di-tert-butyl-6-nitro-phenol

[0182] The mixture of carbonic acid 2,4-di-tert-butyl-5-nitro-phenyl ester methyl ester and carbonic acid 2,4-di-tert-butyl-6-nitro-phenyl ester methyl ester (4.2 g, 14.0 mmol) was dissolved in MeOH (65 mL) before KOH (2.0 g, 36 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction mixture was then made acidic (pH 2-3) by adding conc. HCl and partitioned between water and diethyl ether. The ether layer was dried (MgSO 4 ), concentrated and purified by column chromatography (0 - 5 % ethyl acetate - hexanes) to provide 2,4-di-tert-butyl-5-nitrophenol (1.31 g, 29% over 2 steps) and 2,4-di-tert-butyl-6-nitro-phenol. 2,4-Di-tert-butyl-5-nitro-phenol: 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.14 (s, 1H, OH), 7.34 (s, 1H), 6.83 (s, 1H), 1.36 (s, 9H), 1.30 (s, 9H). 2,4-Di-tert-butyl-6-nitro-phenol: 1< H NMR (400 MHz, CDCl 3 ) δ 11.48 (s, 1H), 7.98 (d, J = 2.5 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 1.47 (s, 9H), 1.34 (s, 9H).Step 4: 5-Amino-2,4-di-tert-butyl-phenol

[0183] To a refluxing solution of 2,4-di-tert-butyl-5-nitro-phenol (1.86 g, 7.40 mmol) and ammonium formate (1.86 g) in ethanol (75 mL) was added Pd-5% wt. on activated carbon (900 mg). The reaction mixture was stirred at reflux for 2 h, cooled to room temperature and filtered through Celite. The Celite was washed with methanol and the combined filtrates were concentrated to yield 5-amino-2,4-di-tert-butyl-phenol as a grey solid (1.66 g, quant.). 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.64 (s, 1H, OH), 6.84 (s, 1H), 6.08 (s, 1H), 4.39 (s, 2H, NH 2 ), 1.27 (m, 18H); HPLC ret. time 2.72 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 222.4 m / z [M+H] +< .Step 5: N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide

[0184]

[0185] To a suspension of 4-oxo-1,4-dihydroquinolin-3-carboxylic acid (35.5 g, 188 mmol) and HBTU (85.7 g, 226 mmol) in DMF (280 mL) was added Et 3 N (63.0 mL, 451 mmol) at ambient temperature. The mixture became homogeneous and was allowed to stir for 10 min before 5-amino-2,4-di-tert-butyl-phenol (50.0 g, 226 mmol) was added in small portions. The mixture was allowed to stir overnight at ambient temperature. The mixture became heterogeneous over the course of the reaction. After all of the acid was consumed (LC-MS analysis, MH+ 190, 1.71 min), the solvent was removed in vacuo. EtOH (ethyl alcohol) was added to the orange solid material to produce a slurry. The mixture was stirred on a rotovap (bath temperature 65 °C) for 15 min without placing the system under vacuum. The mixture was filtered and the captured solid was washed with hexanes to provide a white solid that was the EtOH crystalate. Et 2 O (diethyl ether) was added to the solid obtained above until a slurry was formed. The mixture was stirred on a rotovapor (bath temperature 25 °C) for 15 min without placing the system under vacuum. The mixture was filtered and the solid captured. This procedure was performed a total of five times. The solid obtained after the fifth precipitation was placed under vacuum overnight to provide N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (38 g, 52%). HPLC ret. time 3.45 min, 10-99% CH 3 CN, 5 min run; 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.88 (s, 1H), 11.83 (s, 1H), 9.20 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J = 8.2, 1.0 Hz, 1H), 7.83-7.79 (m, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.54-7.50 (m, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 1.38 (s, 9H), 1.37 (s, 9H); ESI-MS m / z calc'd 392.21; found 393.3 [M+H] +< .Synthesis of Compound IV: 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid

[0186] Compound IV may be prepared by coupling an acid chloride moiety with an amine moiety according to Schemes IV-A through IV-D.

[0187] Scheme IV-A depicts the preparation of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride, which is used in Scheme IV-C to make the amide linkage of Compound IV.

[0188] The starting material, 2,2-difluorobenzo[d][1,3]dioxole-5-carboxylic acid, is commercially available from Saltigo (an affiliate of the Lanxess Corporation). Reduction of the carboxylc acid moiety in 2,2-difluorobenzo[d][1,3]dioxole-5-carboxylic acid to the primary alcohol, followed by conversion to the corresponding chloride using thionyl chloride (SOCl 2 ), provides 5-(chloromethyl)-2,2-difluorobenzo[d][1,3]dioxole, which is subsequently converted to 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetonitrile using sodium cyanide. Treatment of 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetonitrile with base and 1-bromo-2-chloroethane provides 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile. The nitrile moiety in 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile is converted to a carboxylic acid using base to give 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid, which is converted to the desired acid chloride using thionyl chloride.

[0189] Scheme IV-B depicts an alternative synthesis of the requisite acid chloride. 5-bromomethyl-2,2-difluoro-1,3-benzodioxole is coupled with ethyl cyanoacetate in the presence of a palladium catalyst to form the corresponding alpha cyano ethyl ester. Saponification of the ester moiety to the carboxylic acid gives the cyanoethyl Compound IV. Alkylation of the cyanoethyl compound with 1-bromo-2-chloro ethane in the presence of base gives the cyanocyclopropyl compound. Treatment of the cyanocyclopropyl compound with base gives the carboxylate salt, which is converted to the carboxylic acid by treatment with acid. Conversion of the carboxylic acid to the acid chloride is then accomplished using a chlorinating agent such as thionyl chloride or the like.

[0190] Scheme IV-C depicts the preparation of the requisite tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate, which is coupled with 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride in Scheme IV-C to give Compound IV. Palladium-catalyzed coupling of 2-bromo-3-methylpyridine with 3-(tert-butoxycarbonyl)phenylboronic acid gives tert-butyl 3-(3-methylpyridin-2-yl)benzoate, which is subsequently converted to the desired compound.

[0191] Scheme IV-D depicts the coupling of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride with tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate using triethyl amine and 4-dimethylaminopyridine to initially provide the tert-butyl ester of Compound IV.Syntheses of Compounds General UPLC / HPLC Analytical Methods:

[0192] Unless indicated, yields of enantiomers separated by chiral SFC are given as a percentage of the theoretical yield for a single enantiomer of the racemate.

[0193] LC Method A: Analytical reverse phase UPLC using an Acquity UPLC BEH C 18 column (30 × 2.1 mm, 1.7 µm particle) made by Waters (pn: 186002349), and a dual gradient run from 1-99% mobile phase B over 1.2 minutes. Mobile phase A = water (0.05% trifluoroacetic acid). Mobile phase B = acetonitrile (0.035% trifluoroacetic acid). Flow rate = 1.5 mL / min, injection volume = 1.5 µL, and column temperature = 60 °C.

[0194] LC Method B: Analytical reverse phase UPLC using an Acquity UPLC BEH C 18 column (50 × 2.1 mm, 1.7 µm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 3.0 minutes. Mobile phase A = water (0.05% trifluoroacetic acid). Mobile phase B = acetonitrile (0.035% trifluoroacetic acid). Flow rate = 1.2 mL / min, injection volume = 1.5 µL, and column temperature = 60 °C.

[0195] LC Method C: Analytical reverse phase HPLC using a Kinetex C 18 column (50 × 3.0 mm) and a dual gradient run from 5-100% mobile phase B over 6 min. Mobile phase A = water (0.1% trifluoroacetic acid). Mobile phase B = acetonitrile (0.1% trifluoroacetic acid). Flow rate = 1.5 mL / min, injection volume = 2 µL, and column temperature = 30 °C.

[0196] LC Method D: Analytical reverse phase UPLC using an Acquity UPLC BEH C 18 column (50 × 2.1 mm, 1.7 µm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 5.0 minutes. Mobile phase A = water (0.05% trifluoroacetic acid). Mobile phase B = acetonitrile (0.035% trifluoroacetic acid). Flow rate = 1.2 mL / min, injection volume = 1.5 µL, and column temperature = 60 °C.

[0197] LC Method E: Analytical reverse phase UPLC using an Acquity UPLC BEH C18 column (50 × 2.1 mm, 1.7 µm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 2.5 minutes. Mobile phase A = water (0.05% trifluoroacetic acid). Mobile phase B = acetonitrile (0.035% trifluoroacetic acid). Flow rate = 1.2 mL / min, injection volume = 1.5 µL, and column temperature = 60 °C.

[0198] LC Method F: Analytical reverse phase UPLC using an Acquity UPLC BEH C 18 column (50 × 2.1 mm, 1.7 µm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 15.0 minutes. Mobile phase A = water (0.05% trifluoroacetic acid). Mobile phase B = acetonitrile (0.035% trifluoroacetic acid). Flow rate = 1.2 mL / min, injection volume = 1.5 µL, and column temperature = 60 °C.

[0199] LC Method G: Analytical reverse phase UPLC using an Acquity UPLC BEH C 18 column (50 × 2.1 mm, 1.7 µm particle) made by Waters (pn: 186002350), and a dual gradient run from 30-99% mobile phase B over 3.0 minutes. Mobile phase A = water (0.05% trifluoroacetic acid). Mobile phase B = acetonitrile (0.035% trifluoroacetic acid). Flow rate = 1.2 mL / min, injection volume = 1.5 µL, and column temperature = 60 °C.

[0200] LC Method H: Kinetex C 18 4.6 × 50mm 2.6µm. Temp: 45 °C, Flow: 2.0 mL / min, Run Time: 6 min. Mobile phase: Initial 95% water (0.1% formic acid) and 5% acetonitrile (0.1% formic acid) linear gradient to 95% acetonitrile (0.1% formic acid) for 4.0 min then hold at 95% acetonitrile (0.1% formic acid) for 2.0 min.

[0201] LC Method I: Kinetex C 18 4.6 × 50mm 2.6µm. Temp: 45 °C, Flow: 2.0 mL / min, Run Time: 3 min. Mobile phase: Initial 95% water (0.1% formic acid) and 5% acetonitrile (0.1% formic acid) linear gradient to 95% acetonitrile (0.1% formic acid) for 2.0 min then hold at 95% acetonitrile (0.1% formic acid) for 1.0 min.

[0202] LC Method J: Analytical reverse phase UPLC using an Acquity UPLC BEH C 18 column (50 × 2.1 mm, 1.7 µm particle) made by Waters (pn: 186002350), and a dual gradient run from 50-99% mobile phase B over 3.0 minutes. Mobile phase A = water (0.05% trifluoroacetic acid). Mobile phase B = acetonitrile (0.035% trifluoroacetic acid). Flow rate = 1.2 mL / min, injection volume = 1.5 µL, and column temperature = 60 °C.

[0203] LC Method K: Analytical reverse phase UPLC using an Acquity UPLC BEH C 18 column (50 × 2.1 mm, 1.7 µm particle) made by Waters (pn: 186002350), and a dual gradient run from 30-99% mobile phase B over 1.0 minutes. Mobile phase A = water (0.05% trifluoroacetic acid). Mobile phase B = acetonitrile (0.035% trifluoroacetic acid). Flow rate = 1.2 mL / min, injection volume = 1.5 µL, and column temperature = 60 °C.

[0204] LC Method L: Analytical reverse phase UPLC using an Acquity UPLC BEH C 18 column (50 × 2.1 mm, 1.7 µm particle) made by Waters (pn: 186002350), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A = water (0.05% trifluoroacetic acid). Mobile phase B = acetonitrile (0.035% trifluoroacetic acid). Flow rate = 1.2 mL / min, injection volume = 1.5 µL, and column temperature = 60 °C.

[0205] LC Method M: Analytical reverse phase HPLC using a Kinetex C 18 column (50 × 3.0 mm) and a dual gradient run from 5-100% mobile phase B over 6 min. Mobile phase A = water (0.1% trifluoroacetic acid). Mobile phase B = acetonitrile (0.1% trifluoroacetic acid). Flow rate = 1.5 mL / min, injection volume = 10 µL, and column temperature = 30 °C.

[0206] LC Method N: Zorbax C 18 4.6 × 50mm 3.5µm. Flow: 2.0 mL / min, 95% water (0.1% trifluoroacetic acid) + 5% acetonitrile (0.1% trifluoroacetic acid) to 95% acetonitrile (0.1% trifluoroacetic acid) gradient (2.0 min) then hold at 95% acetonitrile (0.1% trifluoroacetic acid) for 1.0 min.

[0207] LC Method O: Zorbax SB- C 18 4.6 × 50mm 3.5µm, Temp: 45 °C, Flow 2.0 mL / min, Run Time: 4 min. Mobile Phase Conditions: Initial 95% water (0.1% formic acid) and 5% acetonitrile (0.1% formic acid) linear gradient to 95% acetonitrile (0.1% formic acid) for 2.0 min then hold at 95% acetonitrile (0.1% formic acid) for 2.0 min.

[0208] LC Method P: Merckmillipore Chromolith SpeedROD C 18 column (50 × 4.6 mm) and a dual gradient run from 5 - 100% mobile phase B over 6 minutes. Mobile phase A = water (0.1 % trifluoroacetic acid). Mobile phase B = acetonitrile (0.1 % trifluoroacetic acid).

[0209] LC Method Q: Merckmillipore Chromolith SpeedROD C 18 column (50 × 4.6 mm) and a dual gradient run from 5 - 100% mobile phase B over 12 minutes. Mobile phase A = water (0.1 % trifluoroacetic acid). Mobile phase B = acetonitrile (0.1 % trifluoroacetic acid).

[0210] LC Method R: Waters Cortex 2.7µm C 18 (3.0mm × 50mm), Temp: 55 °C; Flow: 1.2 mL / min; Mobile phase A: 100% water with 0.1% trifluoroacetic acid. Mobile phase B: 100% acetonitrile with 0.1% trifluoroacetic acid. Gradient: 5% to 100% B over 4 min, with stay at 100% B for 0.5min, equilibration to 5% B over 1.5min.

[0211] LC Method S: Poroshell 120 EC-C 18 3.0 × 50 mm 2.7 µM, Temp: 45 °C, Flow: 2.0 mL / min, Run time: 6 min. Mobile phase conditions: Initial 95% water (0.1% trifluoroacetic acid) and 5% acetonitrile (0.1% trifluoroacetic acid) linear gradient to 95% acetonitrile (0.1% trifluoroacetic acid) for 4.0 min then hold at 95% acetonitrile (0.1% trifluoroacetic acid) for 2.0 min.

[0212] LC Method T: Zorbax C 18 4.6 × 50mm 3.5µM, Security Guard: AJO-4287 C 18 , 4 × 3.0mm. Temp: 45 °C, Flow: 2.0 mL / min, Run time: 6 min. Mobile phase: 95% water (0.1% formic acid) and 5% acetonitrile (0.1% formic acid) linear gradient to 95% acetonitrile (0.1% formic acid) for 4.0 min then hold for 2.0 min.

[0213] LC Method U: Kinetex EVO C 18 4.6 × 50 mm 2.6 µm, Temp: 45 °C, Flow: 2.0 mL / min, Run time: 4 min. Mobile phase: Initial 95% water (0.1% formic acid) and 5% acetonitrile (0.1% formic acid) linear gradient to 95% acetonitrile (0.1% formic acid) for 2.0 min then hold at 95% acetonitrile (0.1% formic acid) for 2.0 min. Compounds 262, 263, 266, 267, 271 and 272, the syntheses of which are described in examples 87 and 90, are provided for reference.Example 1: Preparation of 12,12,19-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6< -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.05,10.011,15]tetracosa-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (Compound 9)

[0214] Step 1: tert-Butyl 2,6-dichloropyridine-3-carboxylate

[0215]

[0216] A solution of 2,6-dichloropyridine-3-carboxylic acid (10 g, 52.08 mmol) in tetrahydrofuran (210 mL) was treated successively with di-tert-butyl dicarbonate (17 g, 77.89 mmol) and 4-(dimethylamino)pyridine (3.2 g, 26.19 mmol) and stirred overnight at room temperature. At this point, hydrochloric acid 1N (400 mL) was added, and the mixture was stirred vigorously for about 10 min. The product was extracted with ethyl acetate (2 × 300mL), and the combined organic layers were washed with water (300 mL) and brine (150 mL) and dried over sodium sulfate, filtered and concentrated under reduced pressure to give 12.94 g (96% yield) of tert-butyl 2,6-dichloropyridine-3-carboxylate as a colorless oil. 1< H NMR (300 MHz, CDCl 3 ) δ 1.60 (s, 9H), 7.30 (d, J=7.9 Hz, 1H), 8.05 (d, J=8.2 Hz, 1H). ESI-MS m / z calc. 247.02, found 248.1 (M+1) +< ; Retention time: 1.79 min (LC Method B).Step 2: tert-Butyl 3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate

[0217]

[0218] A 50 L reactor was started, and the jacket was set to 20 °C, with stirring at 150 rpm, reflux condenser (10 °C) and nitrogen purge. Methanol (2.860 L) and methyl (E)-3-methoxyprop-2-enoate (2.643 kg, 22.76 mol) were added, and the reactor was capped. The reaction was heated to an internal temperature of 40 °C and the system was set to hold jacket temperature at 40 °C. Hydrazine hydrate (1300 g of 55% w / w, 22.31 mol) was added portion-wise via addition funnel over 30 min. The reaction was heated to 60 °C for 1 h. The reaction mixture was cooled to 20 °C and triethylamine (2.483 kg, 3.420 L, 24.54 mol) was added portion-wise, maintaining reaction temperature < 30 °C. A solution of Boc anhydride (4.967 kg, 5.228 L, 22.76 mol) in methanol (2.860 L) was added portion-wise maintaining temperature < 45 °C. The reaction mixture was stirred at 20 °C for 16 h. The reaction solution was partially concentrated to remove methanol, resulting in a clear, light amber oil. The resulting oil was transferred to the 50 L reactor, stirred and water (7.150 L) and heptane (7.150 L) were added. The additions caused a small amount of the product to precipitate. The aqueous layer was drained into a clean container and the interface and heptane layer were filtered to separate the solid (product). The aqueous layer was transferred back to the reactor, and the collected solid was placed back into the reactor and mixed with the aqueous layer. A dropping funnel was added to the reactor and loaded with acetic acid (1.474 kg, 1.396 L, 24.54 mol) which was added dropwise. The jacket was set to 0 °C to absorb the quench exotherm. After the addition was complete (pH = 5), the reaction mixture was stirred for 1 h. The solid was collected by filtration and washed with water (7.150 L) then washed a second time with water (3.575 L). The crystalline solid was transferred into a 20 L rotovap bulb and heptane (7.150 L) was added. The mixture was slurried at 45 °C for 30 min and 1-2 volumes of solvent were distilled off. The slurry in the rotovap flask was filtered and the solids were washed with heptane (3.575 L). The solid was further dried in vacuo (50 °C, 15 mbar) to give tert-butyl 5-oxo-1H-pyrazole-2-carboxylate (2921 g, 71%) as a coarse, crystalline solid. 1< H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.95 (s, 1H), 7.98 (d, J = 2.9 Hz, 1H), 5.90 (d, J = 2.9 Hz, 1H), 1.54 (s, 9H).Step 3: 2-Benzylsulfanyl-6-fluoro-pyridine

[0219]

[0220] 2,6-Difluoropyridine (200 g, 1.738 mol) was dissolved in dimethyl sulfoxide (2 L) in a 5 L three-necked round-bottomed flask equipped with an overhead stirrer, temperature probe and addition funnel. Cesium carbonate (572.4 g, 1.757 mol) was added. Phenylmethanethiol (206 mL, 1.755 mol) was added dropwise via addition funnel. An exotherm was observed during the addition. The temperature rose to approximately 40 °C. The reaction was stirred overnight at room temperature. The reaction was poured into water and extracted with dichloromethane. The extract was washed twice with water and filtered over a small plug of silica gel. The plug was eluted with dichloromethane and the filtrate was evaporated in vacuo to afford 2-benzylsulfanyl-6-fluoro-pyridine (366 g, 96%) as a peach-colored oil that solidified under vacuum to huge blocky plates. 1< H NMR (400 MHz, Chloroform-d) δ 7.58 (q, J = 7.9 Hz, 1H), 7.48 - 7.41 (m, 2H), 7.36 - 7.25 (m, 4H), 7.06 (dd, J = 7.6, 2.1 Hz, 1H), 6.62 (dd, J = 7.9, 2.6 Hz, 1H), 4.43 (s, 2H).Step 4: 6-Fluoropyridine-2-sulfonamide

[0221]

[0222] 2-Benzylsulfanyl-6-fluoro-pyridine (303.2 g, 1.383 mol) was dissolved in chloroform (2.0 L) in a 12 L three-necked round-bottomed flask equipped with an overhead stirrer and temperature probe. Water (1.5 L) was added and the mixture was cooled in an ice bath to 0 °C and vigorously stirred. Chlorine gas from a lecture bottled was bubbled vigorously into the reaction by way of a Pasteur pipet inserted through a septum on the third neck of the flask. A white precipitate rapidly formed. An exotherm was observed during the addition. The chlorine addition was stopped when the temperature rose to 20 °C. The reaction was allowed to cool again before the addition of more chlorine gas. Dosing was continued until the reaction turned a yellowish-green color and stayed that way after stirring for 30 min. At this point, no further exotherms were observed. The reaction was poured into a solution of 40% aqueous sodium bisulfite. The organic layer was separated and the aqueous was extracted with another portion of chloroform. The organic layers were combined, dried over magnesium sulfate, filtered, and evaporated in vacuo to afford a slightly yellow oil. The oil was dissolved in dichloromethane (1.5 L) and added dropwise to ammonium hydroxide (1.5 L of 40% w / v, 17.12 mol) in a 12 L three-necked round-bottomed flask equipped with an overhead stirrer, temperature probe, and addition funnel. The ammonium hydroxide solution was cooled to 0 °C in an ice-bath before the addition. The addition rate was adjusted so the temperature of the reaction stayed below 10 °C. The resulting greenish-yellow solution was stirred for an hour and poured into ice. The layers were separated (the organic layer was dark green) and the aqueous layer was extracted with more dichloromethane. The organic layers were discarded. The aqueous layer was cooled in an ice bath and concentrated aqueous hydrochloric acid was added in portions to the aqueous layer until the pH was strongly acidic. The resulting mixture was stirred as each portion was added. The resulting aqueous solution was extracted twice with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered, and evaporated in vacuo to afford a light brown solid. The solid was mixed with dichloromethane (approximately 500 mL) and stirred with a magnetic stirbar until most of the large clumps had broken up. Approximately 1.5 L of pentane was added which precipitated a lot of light brown solid. The resulting mixture was stirred briefly and then filtered. The filter cake was washed with pentane and dried in vacuo to afford 6-fluoropyridine-2-sulfonamide (204.1 g, 84%) as a light brown solid. 1< H NMR (300 MHz, dimethyl sulfoxide-d6) δ 8.52 - 8.11 (m, 1H), 7.89 (dd, J = 7.8, 2.7 Hz, 1H), 7.67 (s, 2H), 7.57 - 7.44 (m, 1H).Step 5: 2-[1-(Trifluoromethyl)cyclopropyl]ethanol

[0223]

[0224] To a solution of lithium aluminum hydride (293 mg, 7.732 mmol) in tetrahydrofuran (10.00 mL) in an ice-bath, 2-[1-(trifluoromethyl)cyclopropyl]acetic acid (1.002 g, 5.948 mmol) in tetrahydrofuran (3.0 mL) was added dropwise over a period of 30 min keeping the reaction temperature below 20 °C. The mixture was allowed to gradually warm to ambient temperature and was stirred for 18 h. The mixture was cooled with an ice-bath and sequentially quenched with water (294 mg, 295 µL, 16.36 mmol), sodium hydroxide (297 µL of 6 M, 1.784 mmol), and then water (884.0 µL, 49.07 mmol) to afford a granular solid in the mixture. The solid was filtered off using celite, and the precipitate was washed with ether. The filtrate was further dried with magnesium sulfate and filtered and concentrated in vacuo to afford the product with residual tetrahydrofuran and ether. The mixture was taken directly into the next step without further purification.Step 6: tert-Butyl 3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-1-carboxylate

[0225] tert-Butyl 5-oxo-1H-pyrazole-2-carboxylate (1.043 g, 5.660 mmol), 2-[1-(trifluoromethyl)cyclopropyl]ethanol (916 mg, 5.943 mmol), and triphenylphosphine (1.637 g, 6.243 mmol) were combined in tetrahydrofuran (10.48 mL) and the reaction was cooled in an ice-bath. Diisopropyl azodicarboxylate (1.288 g, 1.254 mL, 6.368 mmol) was added dropwise to the reaction mixture, and the reaction was allowed to warm to room temperature for 16 h. The mixture was evaporated, and the resulting material was partitioned between ethyl acetate (30 mL) and 1N sodium hydroxide (30 mL). The organic layer was separated, washed with brine (30 mL), dried over sodium sulfate, and concentrated. The crude material was purified by silica gel chromatography eluting with a gradient of ethyl acetate in hexanes (0- 30%) to give tert-butyl 3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-1-carboxylate (1.03 g, 57%). ESI-MS mlz calc. 320.13, found 321.1 (M+1) +< ; Retention time: 0.72 min (LC Method A).Step 7: 3-[2-[1-(Trifluoromethyl)cyclopropyl]ethoxy]-1H-pyrazole

[0226] tert-Butyl-3-[2-[1-(trifluoromethyl)cyclopropyllethoxylpyrazole-1-carboxylate (1.03 g, 3.216 mmol) was dissolved in dichloromethane (10.30 mL) with trifluoroacetic acid (2.478 mL, 32.16 mmol), and the reaction was stirred at room temperature for 2 h. The reaction was evaporated, and the resulting oil was partitioned between ethyl acetate (10 mL) and a saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated to give 3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxyl-1H-pyrazole (612 mg, 86%). 1< H NMR (400 MHz, dimethyl sulfoxide-d6) δ 11.86 (s, 1H), 7.50 (t, J = 2.1 Hz, 1H), 5.63 (t, J = 2.3 Hz, 1H), 4.14 (t, J = 7.1 Hz, 2H), 2.01 (t, J = 7.1 Hz, 2H), 0.96 - 0.88 (m, 2H), 0.88 - 0.81 (m, 2H). ESI-MS m / z calc. 220.08, found 221.0 (M+1) +< ; Retention time: 0.5 min (LC Method A).Step 8: tert-Butyl 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylate

[0227] tert-Butyl 2,6-dichloropyridine-3-carboxylate (687 mg, 2.770 mmol), 3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]-1H-pyrazole (610 mg, 2.770 mmol), and freshly ground potassium carbonate (459 mg, 3.324 mmol) were combined in anhydrous dimethyl sulfoxide (13.75 mL). 1,4-diazabicyclo[2.2.2]octane (62 mg, 0.5540 mmol) was added, and the mixture was stirred at room temperature under nitrogen for 16 h. The reaction mixture was diluted with water (20 mL) and stirred for 15 min. The resulting solid was collected and washed with water. The solid was dissolved in dichloromethane and dried over magnesium sulfate. The mixture was filtered and concentrated to give tert-butyl 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylate (1.01 g, 84%). ESI-MS m / z calc. 431.12, found 432.1 (M+1) +< ; Retention time: 0.88 min (LC Method A).Step 9: 2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid

[0228] tert-Butyl 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylate (1.01 g, 2.339 mmol) and trifluoroacetic acid (1.8 mL, 23.39 mmol) were combined in dichloromethane (10 mL) and heated at 40 °C for 3 h. The reaction was concentrated. Hexanes were added, and the mixture was concentrated again to give 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (873 mg, 99%) ESI-MS m / z calc. 375.06, found 376.1 (M+1) +< ; Retention time: 0.69 min (LC Method A).Step 10: tert-Butyl 2,2-dimethyl-5-oxopyrrolidine-1-carboxylate

[0229]

[0230] 5,5-Dimethylpyrrolidin-2-one (4.77 g, 42.1 mmol), 4-N,N-dimethylamino pyridine (9.19 g, 42.1 mmol) and triethylamine (4.26 g, 42.1 mmol) were dissolved in anhydrous dichloromethane (140 mL) followed by di-tert-butyl dicarbonate (27.6 g, 0.126 mol) . The reaction mixture was stirred at room temperature for 48 h. The reaction solution was diluted with dichloromethane (500mL), washed with 1N hydrogen chloride aqueous solution (100 mL,) and brine (2 X 50 mL). The organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue obtained was subjected to silica gel chromatography using hexanes - ethyl acetate gradient method (0 to 20% ethyl acetate in hexanes) to afford tert-butyl 2,2-dimethyl-5-oxopyrrolidine-1-carboxylate (5.48 g, 58%) as a white solid. 1< H NMR (250MHz, CDCl 3 ) δ 2.48 (t, J = 8.0Hz, 2H), 1.85 (t, J = 8.0Hz, 2H), 1.54 (s, 9H), 1.47 (s, 6H). ESI-MS m / z calc. 213.1, found 214.1 (M+1) +< . Retention time: 2.36 min (LC Method C).Step 11: tert-Butyl 5 -allyl-2,2-dimethyl -pyrrolidine-1-carboxylate

[0231] tert-Butyl 2,2-dimethyl-5-oxopyrrolidine-1-carboxylate (2.72 g, 12.8 mmol) was dissolved in anhydrous ether (36 mL) and anhydrous tetrahydrofuran (36 mL), and then cooled to -78 °C. To the above solution was slowly added diisobutylaluminum hydride (14.1 mmol, 14 mL, 1.0M in toluene) and the resulting solution was stirred at - 78 °C for 4 h and then warmed to room temperature and further stirred for 3 h. Then, p-toluenesulfonic acid monohydrate (18 mg) in methyl alcohol (40 mL) was added, and the resulting solution was stirred for 19 h. All solvents were removed under reduced pressure. To the residue obtained was added saturated potassium sodium tartrate aqueous solution (100 mL) and stirred for 3 h. The solution was extracted with diethyl ether (3 X 150 mL). The combined organic layers were washed with brine (2 X 50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford an intermediate as pale yellow oil (2.65 g). This intermediate and allyltrimethylsilane (2.34 g, 20.5 mmol) were dissolved in anhydrous dichloromethane (60 mL) and cooled to -78 °C. Then, boron trifluoride diethyl etherate (1.72 g, 12.1 mmol) was added slowly. After the addition was finished, the reaction solution was stirred at -78 °C for 2 h, and then an additional 2 h at room temperature. 1M Aqueous potassium carbonate solution (25 mL) was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3 X 60 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and, concentrated under reduced pressure. The residue obtained was subjected to silica gel chromatography using hexanes - ethyl acetate gradient method (0 to 15% ethyl acetate) to afford tert-butyl 5-allyl-2,2-dimethyl-pyrrolidine-1-carboxylate (0.92g, 30%) as a colorless oil. 1< H NMR (250MHz, CDCl 3 ) δ 5.76 (m, 1H), 5.08-5.01 (m, 2H), 3.94-3.82 (m, 1H), 2.43 (m, 1H), 2.13 (m, 1H), 2.00 (m, 2H), 1,70 (m, 2H), 1.57 (s, 9H), 1.41 (s, 3H), 1.28 (s, 3H). ESI-MS m / z calc. 239.2, found 240.1 (M+1) +< . Retention time: 3.83 min (LC Method C).Step 12: tert-Butyl 5 -(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate

[0232]

[0233] To a solution of tert-butyl 5-allyl-2,2-dimethylpyrrolidine-1-carboxylate (920 mg, 3.85 mmol) in anhydrous tetrahydrofuran (38 mL) at 0 °C was added 9-BBN (15.38 mmol, 30.8 mL, 0.5M in tetrahydrofuran). The resulting solution was stirred at room temperature for 3 h. The reaction solution cooled to 0 °C, hydrogen peroxide aqueous solution (38.5 mmol, 4.4 mL, 30% in water) was added followed by sodium hydroxide (19.25 mmol, 3.9 mL, 20% in water). Then, the reaction solution was stirred at room temperature for 1.5 h. Water (50 mL) was added, and the aqueous solution was extracted with diethyl ether (4 X 80mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography using hexanes and ethyl acetate (0 to 35% ethyl acetate in hexanes) to afford tert-butyl 5-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate (834 mg, 84%) as a colorless oil. 1< H NMR (250MHz, dimethyl sulfoxide) δ 4.39 (m, 1H), 3.67 (m, 1H), 3.37 (m, 2H), 1.88-1.49 (m, 6H), 1.40 (s, 6H), 1.38 (s, 3H), 1.31-1.28 (m, 2H), 1.24 (s, 3H). ESI-MS m / z calc. 257.2, found 258.1 (M+1) +< . Retention time: 2.79 min (LC Method C).Step 13: tert-Butyl 2,2-dimethyl-5-(3-methylsulfonyloxypropyl)pyrrolidine-1-carboxylate

[0234] tert-Butyl 5-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate (3.5 g, 13.6 mmol) and triethylamine (3.8 mL, 27.2 mmol) were dissolved in 40 mL of dichloromethane and chilled in an ice bath. Methanesulfonyl chloride (1.2 mL, 15.0 mmol) was added dropwise over a 10 min period and the resulting mixture was stirred in the ice bath for 20 min. The mixture was quenched with saturated sodium bicarbonate solution (10 mL) and the organic layer was washed with water (10 mL), dried over sodium sulfate, filtered and concentrated under vacuum to obtain tert-butyl 2,2-dimethyl-5-(3-((methylsulfonyl)oxy)propyl)pyrrolidine-1-carboxylate (4.9 g, quantitative yield) as an orange oil. The crude product was used in the next step without further purification. ESI-MS m / z calc. 335.5, found 336.3 (M+1) +< ; Retention time: 4.24 min (LC Method Q).Step 14: tert- Butyl 5-(3-aminopropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

[0235]

[0236] To a solution of 5-(3-methanesulfonyloxy-propyl)-2,2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (4.9 g, 13.6 mmol) in 1.4-dioxane (70 mL) was added 30% aqueous ammonium hydroxide solution (70 mL) and the resulting mixture was heated in a sealed container at 60°C for 20 h. The mixture was concentrated under vacuum and extracted with dichloromethane (3 X 100 mL). The combined organics were concentrated to an oil and purified by silica gel column chromatography using a 0-15% dichloromethane - methanol gradient to obtain tert-butyl 5-(3-aminopropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (2.14 g, 61% yield over two steps) as a pale oil. 1< H NMR (500MHz, dimethyl sulfoxide) δ 3.66 (d, 1H), 2.85 (br s, 2H), 2.58- 2.48 (m, 2H), 1.85- 1.18 (m, 22H). ESI-MS m / z calc. 256.4, found 257.4 (M+1) +< ; Retention time: 3.50 min (LC Method Q).Step 15: tert-Butyl 5-[3-(tert-butoxycarbonylamino)propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

[0237] tert-Butyl 5-(3-aminopropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (640 mg, 2.496 mmol) was dissolved in dichloromethane (6.4 mL) under nitrogen and to it was added triethylamine (1.01 g, 9.981 mmol) followed by di-tert-butyl dicarbonate (1.362 g, 6.241 mmol). The mixture was stirred at room temperature for 1h. The reaction was diluted with ether and saturated aqueous ammonium chloride and separated. The aqueous layer was washed twice more with ether, the combined organic phases were dried over sodium sulfate, filtered, and concentrated to a light yellow oil which was purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% Ethyl acetate giving tert-butyl 5-[3-(tert-butoxycarbonylamino)propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (720 mg, 81%) as a clear oil. ESI-MS m / z calc. 356.26752, found 357.3 (M+1) +< ; Retention time: 1.73 min (LC Method B).Step 16: tert-Butyl 5-[3-[tert-butoxycarbonyl(methyl)amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

[0238] tert-Butyl 5-[3-(tert-butoxycarbonylamino)propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (720 mg, 2.020 mmol) was dissolved in N,N-dimethylformamide (14.4 mL). Potassium carbonate (837.5 mg, 6.060 mmol) was added followed by methyl iodide (860.2 mg, 6.060 mmol) and the reaction mixture was allowed to stir at room temperature for 16 h. Potassium carbonate (1.396 g, 10.10 mmol) was added followed by methyl iodide (860.2 mg, 6.060 mmol) and the reaction was stirred overnight. Sodium hydride (404 mg, 10.1 mmol) was added and stirred for 6h. Sodium hydride (121 mg, 5.04 mmol) was added and the reaction was placed in a refrigerator at 4 °C for 3 days. The reaction was warmed to room temperature, methyl iodide (860.2 mg, 6.060 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was diluted with dichloromethane and then washed with water (2 X 40 mL). The organic layer was washed with brine twice followed by saturated aqueous sodium carbonate to bring the reaction mixture to pH ∼12. The reaction mixture was then extracted with dichloromethane (3 X 75 mL). The combined organic fractions were dried over sodium sulfate, filtered, and concentrated to a yellow oil. The residue was purified by silica gel chromatography using a shallow gradient from 100% dichloromethane to 20% methanol / dichloromethane to isolate the product, tert-butyl 5-[3-[tert-butoxycarbonyl(methyl)amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (695 mg, 93%) as a yellow oil. ESI-MS m / z calc. 370.28317, found 371.5 (M+1) +< ; Retention time: 0.83 min (LC Method A).Step 17: 3-(5,5-Dimethylpyrrolidin-2-yl)-N-methyl-propan-1-amine (di-trifluoroacetic acid salt)

[0239]

[0240] To a stirring solution of tert-butyl 5-[3-[tert-butoxycarbonyl(methyl)amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (695 mg, 1.876 mmol) in methylene chloride (6.95 mL) at 0 °C was added trifluoroacetic acid (2.891 mL, 37.52 mmol) and the mixture was stirred at room temperature for 5 h. The volatiles were removed under reduced pressure and then evaporated from ether 3 times giving 3-(5,5-dimethylpyrrolidin-2-yl)-N-methyl-propan-1-amine (di-trifluoroacetic acid salt) (747.3 mg, 100%). ESI-MS m / z calc. 170.1783, found 171.3 (M+1) +< ; Retention time: 0.09 min (LC Method A).Step 18: 2-Chloro-N-[(6-fluoro-2-pyridyl)sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide

[0241]

[0242] 2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (1.14 g, 3.03 mmol) and carbonyl diimidazole...

Claims

1. A compound of Formula (III-A) or (III-B): or a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: - the carbon denoted by ∗ has S-stereochemistry or R-stereochemistry; - Ring A is a phenyl, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; - Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; - each R1 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - m is 0, 1, 2, 3, or 4; - each R2 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - n is 0, 1, or 2; - each R3 is methyl; - each R4 is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y)k-R7 groups or optionally two R4, together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C1-C2 alkyl groups, haloalkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups, wherein: - k is 0, 1, 2, 3, 4, 5, or 6; - each Y is independently chosen from C(R5)(R6) groups, -O-, and -NRa-groups, wherein a heteroatom in -(Y)k-R7 is not bonded to another heteroatom in -(Y)k-R7, wherein: - each R5 and R6 is independently chosen from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Ra is independently chosen from hydrogen and C1-C2 alkyl groups; and - R7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens; - q is 1 or 2; - Z is a divalent linker of formula (L)r, wherein: - r is 3, 4, or 5; - each L is independently chosen from C(R8)(R9) groups, -O-, and -NRb-groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: - each R8 and R9 is independently chosen from hydrogen, halogens, C1-C2 alkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Rb is independently chosen from hydrogen and C1-C2 alkyl groups.

2. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein the compound of Formula (III-A) is a compound of Formula IV-A: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: - the carbon denoted by ∗ has S-stereochemistry or R-stereochemistry; - Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6-membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; - each R1 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - m is 0, 1, 2, 3, or 4; - each R2 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - n is 0, 1, or 2; - each R3 is methyl; - each R4 is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y)k-R7 groups, or optionally two R4, together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C1-C2 alkyl groups, haloalkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups, wherein: - k is 0, 1, 2, 3, 4, 5, or 6; - each Y is independently chosen from C(R5)(R6) groups, -O-, and -NRa-groups, wherein a heteroatom in -(Y)k-R7 is not bonded to another heteroatom in -(Y)k-R7, wherein: - each R5 and R6 is independently chosen from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Ra is independently chosen from hydrogen and C1-C2 alkyl groups; and - R7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens; - q is 1 or 2; - Z is a divalent linker of formula (L)r, wherein: - r is 3, 4, or 5; - each L is independently chosen from C(R8)(R9) groups, -O-, and -NRb- groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: - each R8 and R9 is independently chosen from hydrogen, halogens, C1-C2 alkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Rb is independently chosen from hydrogen and C1-C2 alkyl groups.

3. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein the compound of Formula (III-A) is a compound of Formula IV-B: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: - the carbon denoted by ∗ has S-stereochemistry or R-stereochemistry; - Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6-membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; - each R1 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - m is 0, 1, 2, 3, or 4; - each R2 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - n is 0, 1, or 2; - each R3 is methyl; - each R4 is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y)k-R7 groups, or optionally two R4, together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C1-C2 alkyl groups, haloalkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups, wherein: - k is 0, 1, 2, 3, 4, 5, or 6; - each Y is independently chosen from C(R5)(R6) groups, -O-, and -NRa- groups, wherein a heteroatom in -(Y)k-R7 is not bonded to another heteroatom in -(Y)k-R7 , wherein: - each R5 and R6 is independently chosen from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Ra is independently chosen from hydrogen and C1-C2 alkyl groups; and - R7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens; - q is 1 or 2; - r is 3 or 4; - each R8 and R9 is independently chosen from hydrogen, halogens, C1-C2 alkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Rb is independently chosen from hydrogen and C1-C2 alkyl groups.

4. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein the compound of Formula (III-A) is a compound of Formula IV-C: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: - the carbon denoted by ∗ has S-stereochemistry or R-stereochemistry; - each R1 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - m is 0, 1, 2, 3, or 4; - each R2 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - n is 0, 1, or 2; - each R3 is methyl; - each R4 is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y)k-R7 groups, or optionally two R4, together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C1-C2 alkyl groups, haloalkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups, wherein: - k is 0, 1, 2, 3, 4, 5, or 6; - each Y is independently chosen from C(R5)(R6) groups, -O-, and -NRa- groups, wherein a heteroatom in -(Y)k-R7 is not bonded to another heteroatom in -(Y)k-R7, wherein: - each R5 and R6 is independently chosen from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Ra is independently chosen from hydrogen and C1-C2 alkyl groups; and - R7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens; - q is 1 or 2; - r is 3 or 4; - each R8 and R9 is independently chosen from hydrogen, halogens, C1-C2 alkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Rb is independently chosen from hydrogen and C1-C2 alkyl groups.

5. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein the compound of Formula (III-A) is a compound of Formula V-A: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: - the carbon denoted by ∗ has S-stereochemistry or R-stereochemistry; - Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; - each R1 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - m is 0, 1, 2, 3, or 4; - each R2 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - n is 0, 1, or 2; - each R3 is methyl; - each R4 is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y)k-R7 groups, or optionally two R4, together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C1-C2 alkyl groups, haloalkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups, wherein: - k is 0, 1, 2, 3, 4, 5, or 6; - each Y is independently chosen from C(R5)(R6) groups, -O-, and -NRa- groups, wherein a heteroatom in -(Y)k-R7 is not bonded to another heteroatom in -(Y)k-R7, wherein: - each R5 and R6 is independently chosen from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Ra is independently chosen from hydrogen and C1-C2 alkyl groups; and - R7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens; - q is 1 or 2; - Z is a divalent linker of formula (L)r, wherein: - r is 3, 4, or 5; - each L is independently chosen from C(R8)(R9) groups, -O-, and -NRb- groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: - each R8 and R9 is independently chosen from hydrogen, halogens, C1-C2 alkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Rb is independently chosen from hydrogen and C1-C2 alkyl groups.

6. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein the compound of Formula (III-A) is a compound of Formula V-B: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: - the carbon denoted by ∗ has S-stereochemistry or R-stereochemistry; - Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; - each R1 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - m is 0, 1, 2, 3, or 4; - each R2 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - n is 0, 1, or 2; - each R3 is methyl; - each R4 is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y)k-R7 groups, or optionally two R4, together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C1-C2 alkyl groups, haloalkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups, wherein: - k is 0, 1, 2, 3, 4, 5, or 6; - each Y is independently chosen from C(R5)(R6) groups, -O-, and -NRa- groups, wherein a heteroatom in -(Y)k-R7 is not bonded to another heteroatom in -(Y)k-R7, wherein: - each R5 and R6 is independently chosen from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Ra is independently chosen from hydrogen and C1-C2 alkyl groups; and - R7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens; - q is 1 or 2; - r is 3, 4, or 5; and - each R8 and R9 is independently chosen from hydrogen, halogens, C1-C2 alkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups.

7. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein the compound of Formula (III-A) is a compound of Formula VI-A or VI-B: or a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: - the carbon denoted by ∗ has S-stereochemistry or R-stereochemistry; - Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; - each R1 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - m is 0, 1, 2, 3, or 4; - each R2 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - n is 0, 1, or 2; - each R3 is methyl; - each R4 is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y)k-R7 groups, or optionally two R4, together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C1-C2 alkyl groups, haloalkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups, wherein: - k is 0, 1, 2, 3, 4, 5, or 6; - each Y is independently chosen from C(R5)(R6) groups, -O-, and -NRa- groups, wherein a heteroatom in -(Y)k-R7 is not bonded to another heteroatom in -(Y)k-R7, wherein: - each R5 and R6 is independently chosen from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Ra is independently chosen from hydrogen and C1-C2 alkyl groups; and - R7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens; - q is 1 or 2; - Z is a divalent linker of formula (L) r, wherein: - r is 3, 4, or 5; - each L is independently chosen from C(R8)(R9) groups, -O-, and -NRb- groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: - each R8 and R9 is independently chosen from hydrogen, halogens, C1-C2 alkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Rb is independently chosen from hydrogen and C1-C2 alkyl groups.

8. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein the compound of Formula (III-A) is a compound of Formula VI-C or VI-D: or a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: - the carbon denoted by ∗ has S-stereochemistry or R-stereochemistry; - Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; - each R1 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - m is 0, 1, 2, 3, or 4; - each R2 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - n is 0, 1, or 2; - each R3 is methyl; - each R4 is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y)k-R7 groups, or optionally two R4, together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C1-C2 alkyl groups, haloalkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups, wherein: - k is 0, 1, 2, 3, 4, 5, or 6; - each Y is independently chosen from C(R5)(R6) groups, -O-, and -NRa- groups, wherein a heteroatom in -(Y)k-R7 is not bonded to another heteroatom in -(Y)k-R7, wherein: - each R5 and R6 is independently chosen from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Ra is independently chosen from hydrogen and C1-C2 alkyl groups; and - R7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens; - q is 1 or 2; - r is 3 or 4; and - each R8 and R9 is independently chosen from hydrogen, halogens, C1-C2 alkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups.

9. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring A is a phenyl ring, a pyridyl ring, or a pyrazolyl ring, wherein Ring A is optionally substituted with (R1)m.

10. The compound of any one of claims 1-9, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: (a) each R1 is independently chosen from deuterium, C1-C2 alkyl groups, and a hydroxyl group, and m is 0 or 1; or (b) n is 0.

11. The compound of any one of claims 1-3 and 5-8, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is a 5-membered heteroaryl ring substituted with (R4)q.

12. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: (a) Ring D is a phenyl ring, pyridinyl ring, pyrazolyl ring, imidazolidinone ring, a pyrrolidinone ring, or a pyridinone ring, wherein Ring D is substituted with (R4)q; or (b) Ring D is a pyrazolyl ring, or a pyridinone ring, wherein Ring D is substituted with R4.

13. The compound of any one of claims 1-3 and 5-8, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: (a) Ring D is a pyrazolyl ring, wherein Ring D is substituted with (R4)q; or (b) Ring D is: wherein indicates the point of attachment of Ring D to Ring B; optionally wherein Ring D is: wherein indicates the point of attachment of Ring D to Ring B .

14. The compound of any one of claims 1-13, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: (a) each R4 is independently chosen from an oxo group or -(Y)k-R7 groups, wherein: - k is 0, 1, 2, 3, 4, 5, or 6; - each Y is independently chosen from C(R5)(R6) groups, -O-, and -NRa- groups, wherein a heteroatom in -(Y)k-R7 is not bonded to another heteroatom in -(Y)k-R7, and wherein: - each R5 and R6 is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Ra is independently chosen from hydrogen and C1-C2 alkyl groups; and - R7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens, optionally wherein each R5 and R6 is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R5 and R6 on the same carbon together form a C3-5 cycloalkyl group; or (b) each R4 is independently chosen from an oxo group or -O-(Y)k-R7 groups, wherein: - k is 0, 1, 2, 3, 4, or 5; - each Y is independently chosen from C(R5)(R6) groups, -O-, and -NRa- groups, wherein a heteroatom in -(Y)k-R7 is not bonded to another heteroatom in -(Y)k-R7, and wherein: - each R5 and R6 is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Ra is independently chosen from hydrogen and C1-C2 alkyl groups; and - R7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens; and / or (c) each R4 is independently chosen from: wherein indicates the point of attachment of R4 to Ring D.

15. The compound of any one of claims 1-14, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: (a) k is 3, 4, 5, or 6; and / or (b) q is 1.

16. The compound of any one of claims 1-15, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Z is a divalent linker of formula (L)r, wherein: (a) - r is 3 or 4; - each L is independently chosen from C(R8)(R9) groups, -O-, and -NRb- groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, and wherein: - each R8 and R9 is independently chosen from hydrogen and deuterium; and - each Rb is independently chosen from hydrogen and C1-C2 alkyl groups; (b) - r is 3 or 4; - each L is independently chosen from C(R8)(R9) groups and -NRb- groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, and: - each R8 and R9 is independently chosen from hydrogen and deuterium; and - each Rb is independently chosen from hydrogen and methyl; (c) - r is 3 or 4; - each L is independently chosen from C(R8)(R9) groups and -NRb- groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, and wherein: - each R8 and R9 is independently chosen from hydrogen and deuterium; and - each Rb is hydrogen; or (d) - r is 3 or 4; - each L is independently chosen from C(R8)(R9) groups, -O-, and -NRb- groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: - each R8 and R9 is hydrogen; and - each Rb is independently chosen from hydrogen and C1-C2 alkyl groups.

17. The compound of any one of claims 1-16, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R3 is independently CD3.

18. The compound of claim 3 or claim 4, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: (a) r is 3 or 4; each R8 and R9 is independently chosen from hydrogen and deuterium; and each Rb is independently chosen from hydrogen and C1-C2 alkyl groups; (b) r is 3 or 4; each R8 and R9 is independently chosen from hydrogen and deuterium; and each Rb is independently chosen from hydrogen and methyl; (c) r is 3 or 4; each R8 and R9 is independently chosen from hydrogen and deuterium; and each Rb is hydrogen; or (d) r is 3 or 4; each R8 and R9 is hydrogen; and each Rb is independently chosen from hydrogen and C1-C2 alkyl groups.

19. The compound of claim 6 or claim 8, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: (a) r is 3 or 4; and each R8 and R9 is independently chosen from hydrogen and deuterium; (b) r is 3 or 4; and each R8 and R9 is hydrogen; or (c) r is 3 or 4; and each R8 and R9 is deuterium.

20. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein the compound of Formula (III-A) or (III-B) is selected from: or a deuterated derivative thereof or a pharmaceutically acceptable salt of any of those compounds or deuterated derivatives.

21. A pharmaceutical composition comprising at least one compound chosen from compounds of any one of claims 1-20, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, and optionally one or more of: (a) Compound II: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing; (b) Compound III or Compound III-d: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing; and (c) a pharmaceutically acceptable carrier.

22. A compound of any one of claims 1-20 or the pharmaceutical composition according to claim 21 for use in a method of treating cystic fibrosis comprising administering to a patient in need thereof the compound of any one of claims 1-20 or the pharmaceutical composition according to claim 21.

23. At least one compound chosen from compounds of any one of claims 1-20, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, and optionally one or more of: (a) Compound II: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing; (b) Compound III or Compound III-d: a deuterated derivative thereof or a pharmaceutically acceptable salt of any of the foregoing; for use in treating cystic fibrosis.

24. A compound of Formula (X): a deuterated derivative thereof or a salt of any of the foregoing, wherein: - Qa is a halogen; - Ring A is a phenyl, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; - Ring B is a pyridinyl ring; - X is O, NH, or an N(C1-C4 alkyl); - each R1 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - m is 0, 1, 2, 3, or 4; - each R2 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - n is 0, 1, or 2; - each R3 is methyl; - Z is a divalent linker of formula (L)r, wherein: - r is 1, 2, 3, 4, 5, or 6; - each L is independently chosen from C(R8)(R9) groups, -O-, and -NRb- groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: - each R8 and R9 is independently chosen from hydrogen, halogens, C1-C2 haloalkyl groups, C1-C2 alkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Rb is independently chosen from hydrogen and C1-C2 alkyl groups.

25. A compound of Formula (Y): a salt thereof, or a deuterated derivative of any of the foregoing, wherein: - Qb is a halogen; - R10 is hydrogen or a protecting group; - Ring A is a phenyl, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; - Ring B is a pyridinyl ring; - Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; - X is O, NH, or an N(C1-C4 alkyl); - each R1 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - m is 0, 1, 2, 3, or 4; - each R2 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - n is 0, 1, or 2; - each R3 is methyl; - each R4 is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y)k-R7 groups, or optionally two R4, together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C1-C2 alkyl groups, haloalkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; wherein: - k is 0, 1, 2, 3, 4, 5, or 6; - each Y is independently chosen from C(R5)(R6) groups, -O-, and -NRa- groups, wherein a heteroatom in -(Y)k-R7 is not bonded to another heteroatom in -(Y)k-R7, wherein: - each R5 and R6 is independently chosen from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Ra is independently chosen from hydrogen and C1-C2 alkyl groups; and - R7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens; - q is 1, 2, 3 or 4; and - Z is a divalent linker of formula (L)r, wherein: - r is 1, 2, 3, 4, 5, or 6; - each L is independently chosen from C(R8)(R9) groups, -O-, and -NRb- groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: - each R8 and R9 is independently chosen from hydrogen, halogens, C1-C2 haloalkyl groups, C1-C2 alkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Rb is independently chosen from hydrogen and C1-C2 alkyl groups.

26. A method of preparing a compound of Formula (I): a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, comprising coupling the NH group of Ring C and the Qb group of Ring B of a compound of Formula (Y-I): a salt thereof, or a deuterated derivative of any of the foregoing, wherein: - Qb is a halogen; - Ring A is a phenyl, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; - Ring B is a pyridinyl ring; - Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; - X is O, NH, or an N(C1-C4 alkyl); - each R1 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - m is 0, 1, 2, 3, or 4; - each R2 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - n is 0, 1, or 2; - each R3 is methyl; - each R4 is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y)k-R7 groups, or optionally two R4, together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C1-C2 alkyl groups, haloalkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; wherein: - k is 0, 1, 2, 3, 4, 5, or 6; - each Y is independently chosen from C(R5)(R6) groups, -O-, and -NRa- groups, wherein a heteroatom in -(Y)k-R7 is not bonded to another heteroatom in -(Y)k-R7, wherein: - each R5 and R6 is independently chosen from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Ra is independently chosen from hydrogen and C1-C2 alkyl groups; and - R7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens; - q is 1, 2, 3 or 4; and - Z is a divalent linker of formula (L)r, wherein: - r is 1, 2, 3, 4, 5, or 6; - each L is independently chosen from C(R8)(R9) groups, -O-, and -NRb- groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: - each R8 and R9 is independently chosen from hydrogen, halogens, C1-C2 haloalkyl groups, C1-C2 alkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Rb is independently chosen from hydrogen and C1-C2 alkyl groups; to form a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing.

27. The method of claim 26, wherein said coupling is performed in the presence of a base.

28. A method of preparing a compound of Formula (Y) a salt thereof, or a deuterated derivative of any of the foregoing, comprising reacting a compound of Formula (A), a salt thereof, or a deuterated derivative of any of the foregoing, with a compound of Formula (B), a salt thereof, or a deuterated derivative of any of the foregoing, to form said compound of Formula (Y), a salt thereof, or a deuterated derivative of any of the foregoing: and optionally deprotecting the N-protecting group of Ring C of Formula (Y), wherein Qb is a halogen; R10 of Formula (Y) is hydrogen or a N-protecting group; R10 of Formula (B) is a N-protecting group, and Ring A, Ring B, Ring D, X, R1, m, R2, n, R3, R4, q, Z, R10, and the variables therein are as recited in claim 1.

29. The method of claim 28, wherein: (a) said reacting a compound of Formula (A), a salt thereof, or a deuterated derivative of any of the foregoing, with a compound of Formula (B), a salt thereof, or a deuterated derivative of any of the foregoing, is performed in the presence of a base; or (b) said reacting a compound of Formula (A), salt thereof, or a deuterated derivative of any of the foregoing, with a compound of Formula (B), a salt thereof, or a deuterated derivative of any of the foregoing, comprises reacting a compound of Formula (A), salt thereof, or a deuterated derivative of any of the foregoing, with a coupling reagent and subsequently with a compound of Formula (B), salt thereof, or a deuterated derivative of any of the foregoing, in the presence of a base.

30. A method of preparing a compound of Formula (Y-2): a salt thereof, or a deuterated derivative of any of the foregoing, wherein: - Qb is a halogen; - Ring A is a phenyl, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; - Ring B is a pyridinyl ring; - Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; - X is O, NH, or an N(C1-C4 alkyl); - each R1 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - m is 0, 1, 2, 3, or 4; - each R2 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - n is 0, 1, or 2; - each R3 is methyl; - each R4 is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y)k-R7 groups, or optionally two R4, together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C1-C2 alkyl groups, haloalkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; wherein: - k is 0, 1, 2, 3, 4, 5, or 6; - each Y is independently chosen from C(R5)(R6) groups, -O-, and -NRa- groups, wherein a heteroatom in -(Y)k-R7 is not bonded to another heteroatom in -(Y)k-R7, wherein: - each R5 and R6 is independently chosen from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Ra is independently chosen from hydrogen and C1-C2 alkyl groups; and - R7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens; - q is 1, 2, 3 or 4; - r is 1, 2, 3, 4 or 5; - each R8 and R9 is independently chosen from hydrogen, halogens, C1-C2 haloalkyl groups, C1-C2 alkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - R10 is hydrogen or a protecting group; comprising reacting a compound of Formula (A), a salt thereof, or a deuterated derivative of any of the foregoing, with a compound of Formula (B-2), a salt thereof, or a deuterated derivative of any of the foregoing, to form said compound of Formula (Y-2), a salt thereof, or a deuterated derivative of any of the foregoing:

31. The method of claim 30, wherein: (a) said reacting a compound of Formula (A), a salt thereof, or a deuterated derivative of any of the foregoing, with a compound of Formula (B-2), salt thereof, or a deuterated derivative of any of the foregoing, is performed in the presence of a base; or (b) said reacting a compound of Formula (A), a salt thereof, or a deuterated derivative of any of the foregoing, with a compound of Formula (B-2), a salt thereof, or a deuterated derivative of any of the foregoing, comprises reacting a compound of Formula (A), a salt thereof, or a deuterated derivative of any of the foregoing, with a coupling reagent and subsequently with a compound of Formula (B-2), a salt thereof, or a deuterated derivative of any of the foregoing, in the presence of a base; optionally wherein the method further comprises reacting a compound of Formula (D), a salt thereof, or a deuterated derivative of any of the foregoing, with a compound of Formula (E-2),a salt thereof, or a deuterated derivative of any of the foregoing, to form said compound of Formula (B-2), a salt thereof, or a deuterated derivative of any of the foregoing: wherein Rd is a halogen.

32. A method of preparing a compound of Formula (Y-3): a salt thereof, or a deuterated derivative of any of the foregoing, comprising reacting a compound of Formula (A), a salt thereof, or a deuterated derivative of any of the foregoing, with a compound of Formula (B-3), a salt thereof, or a deuterated derivative of any of the foregoing, to form said compound of Formula (Y-3), a salt thereof, or a deuterated derivative of any of the foregoing:

33. The method of claim 32, wherein: (a) said reacting a compound of Formula (A), a salt thereof, or a deuterated derivative of any of the foregoing, with a compound of Formula (B-3), a salt thereof, or a deuterated derivative of any of the foregoing, is performed in the presence of a base; or (b) said reacting a compound of Formula (A), a salt thereof, or a deuterated derivative of any of the foregoing, with a compound of Formula (B-3), a salt thereof, or a deuterated derivative of any of the foregoing, comprises reacting a compound of Formula (A), a salt thereof, or a deuterated derivative of any of the foregoing, with a coupling reagent and subsequently with a compound of Formula (B-3), a salt thereof, or a deuterated derivative of any of the foregoing, in the presence of a base; optionally wherein the method further comprises reacting a compound of Formula (D), a salt thereof, or a deuterated derivative of any of the foregoing, with a compound of Formula (E-3), a salt thereof, or a deuterated derivative of any of the foregoing, to form said compound of Formula (B-3), a salt thereof, or a deuterated derivative of any of the foregoing: wherein Rd is a halogen.

34. A method of preparing a compound of Formula (I) a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is comprising reacting a compound of Formula (X), a salt thereof, or a deuterated derivative of any of the foregoing, with a compound of Formula (Z-1), a salt thereof, or a deuterated derivative of any of the foregoing: wherein: - Qa is a halogen; - Ring A is a phenyl, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; - Ring B is a pyridinyl ring; - Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; - X is O, NH, or an N(C1-C4 alkyl); - each R1 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - m is 0, 1, 2, 3, or 4; - each R2 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - n is 0, 1, or 2; - each R3 is methyl; - each R4 is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y)k-R7 groups, or optionally two R4, together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C1-C2 alkyl groups, haloalkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; wherein: - k is 0, 1, 2, 3, 4, 5, or 6; - each Y is independently chosen from C(R5)(R6) groups, -O-, and -NRa- groups, wherein a heteroatom in -(Y)k-R7 is not bonded to another heteroatom in -(Y)k-R7, wherein: - each R5 and R6 is independently chosen from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Ra is independently chosen from hydrogen and C1-C2 alkyl groups; and - R7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens; - q is 1, 2, 3 or 4; and - Z is a divalent linker of formula (L)r, wherein: - r is 1, 2, 3, 4, 5, or 6; - each L is independently chosen from C(R8)(R9) groups, -O-, and -NRb- groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: - each R8 and R9 is independently chosen from hydrogen, halogens, C1-C2 haloalkyl groups, C1-C2 alkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Rb is independently chosen from hydrogen and C1-C2 alkyl groups.

35. A method of preparing a compound of Formula (IV-C): a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing comprising reacting a compound of Formula (X-1), a salt thereof, or a deuterated derivative of any of the foregoing with a compound of Formula (Z-1), a salt thereof, or a deuterated derivative of any of the foregoing wherein: - Qa is a halogen; - the carbon denoted by ∗ has S-stereochemistry or R-stereochemistry; - Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6- membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring; - each R1 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - m is 0, 1, 2, 3, or 4; - each R2 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - n is 0, 1, or 2; - each R3 is methyl; - each R4 is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y)k-R7 groups, or optionally two R4, together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C1-C2 alkyl groups, haloalkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups, wherein: - k is 0, 1, 2, 3, 4, 5, or 6; - each Y is independently chosen from C(R5)(R6) groups, -O-, and -NRa- groups, wherein a heteroatom in -(Y)k-R7 is not bonded to another heteroatom in -(Y)k-R7 , wherein: - each R5 and R6 is independently chosen from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Ra is independently chosen from hydrogen and C1-C2 alkyl groups; and - R7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens; - q is 1 or 2; - r is 3 or 4; - each R8 and R9 is independently chosen from hydrogen, halogens, C1-C2 alkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Rb is independently chosen from hydrogen and C1-C2 alkyl groups.

36. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein the compound of Formula (III-A) or (III-B) is selected from: pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing.

37. The compound of any one of claims 1-20 or 36, wherein the compound is in the form of a pharmaceutically acceptable salt; optionally wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt; optionally wherein the pharmaceutically acceptable salt is a calcium salt.

38. The compound of claim 36, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein the compound of Formula (III-A) or (III-B) is selected from: pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing.

39. The compound of claim 38, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt.

40. The compound of claim 38 or claim 39, wherein: is in the form of a calcium salt.

41. The compound of any one of claims 1-20 or 36-40 for use in a method of treating cystic fibrosis comprising administering to a patient in need thereof the compound of any one of claims 1-20 or 36-40, wherein the compound is administered in combination with Compound III or Compound III-d.

42. The compound of any one of claims 1-20 or 36-40 for use in a method of treating cystic fibrosis comprising administering to a patient in need thereof the compound of any one of claims 1-20 or 36-40, wherein the compound is administered in combination with (a) Compound II and (b) Compound III or Compound III-d.

43. The compound of any one of claims 1-20 or 36-40 for use in the treatment of cystic fibrosis.

44. The compound for use of any one of claims 22 or 41-43, wherein the compound is in the form of a pharmaceutically acceptable salt, optionally wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt, optionally wherein the pharmaceutically acceptable salt is a calcium salt.

45. The compound for use of claim 43 or claim 44, wherein the treatment further comprises: (a) administration of Compound III; (b) administration of Compound III-d; (c) administration of Compound II and Compound III; or (d) administration of Compound II and Compound III-d.