Compounds of Formula (I): [structure] pharmaceutically acceptable salts thereof, deuterated derivatives of any of the foregoing, and metabolites of any of the foregoing are disclosed. Pharmaceutical compositions comprising the same, methods of treating cystic fibrosis using the same, and methods for making the same are also disclosed.

Description

154 parts

›This application claims priority to U.S. provisional application…

This application claims priority to U.S. provisional application 62/631,453, filed Feb. 15, 2018, the disclosure of which is incorporated herein by reference in its entirety.

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

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.

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.

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.

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.

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.

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.

Accordingly, there is a need for novel treatments of CFTR mediated diseases.

Disclosed herein are novel compounds, 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), pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing. For example, compounds of Formula (I) can be depicted as:

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(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…

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.

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

Also disclosed herein are pharmaceutical compositions comprising at least one of the novel compounds disclosed herein 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. Also disclosed are methods of treating the CFTR-mediated disease cystic fibrosis comprising administering at least one of the novel compounds disclosed herein 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.

Also disclosed are methods of treating the CFTR-mediated disease cystic fibrosis comprising administering at least one of the novel compounds disclosed herein 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.

›BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the structures of non-limiting examples of novel compounds disclosed herein.

FIG. 2 is a representative list of CFTR mutations.

›DEFINITIONS · 1 of 28

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.

As used herein, the term “haloalkyl group” refers to an alkyl group substituted with one or more halogen atoms.

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.

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.

As used herein, the term “haloalkoxyl group” refers to an alkoxy group substituted with one or more halogen atoms.

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.

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.

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.

“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.

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

As used herein, “CFTR” means cystic fibrosis transmembrane conductance regulator.

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).

The term “F508del” refers to a mutant CFTR protein which is lacking the amino acid phenylalanine at position 508.

As used herein, a patient who is “homozygous” for a particular gene mutation has the same mutation on each allele.

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.

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.

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.

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.

As used herein, the term “active pharmaceutical ingredient” (“API”) refers to a biologically active compound.

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.

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.

›DEFINITIONS · 2 of 28

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.

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.

The terms “patient” and “subject” are used interchangeably and refer to an animal including humans.

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).

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.

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.

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.

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).

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:

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.

›DEFINITIONS · 3 of 28

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.

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.

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.

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.”

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, relevant portions of which are independently incorporated herein by reference.

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).

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.

›DEFINITIONS · 4 of 28

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.

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 .

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.

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.

As stated above, disclosed 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:

each R a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

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:

In some embodiments, the compound of Formula I is a compound of Formula (II-A) or (II-B):

a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing,

›DEFINITIONS · 5 of 28

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:

each R a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

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 -C 2 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.

In some embodiments, the compound of Formula I is a compound of Formula (III-A) or (III-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 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, 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:

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 to 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.

In some embodiments, the compound of Formula I 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; 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:

›DEFINITIONS · 6 of 28

each R a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

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.

In some embodiments, the compound of Formula I 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:

each R a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

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.

In some embodiments, the compound of Formula I 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:

each R a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

›DEFINITIONS · 7 of 28

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.

In some embodiments, the compound of Formula I 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:

each R a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

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.

In some embodiments, the compound of Formula I 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:

each R a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

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.

In some embodiments, the compound of Formula I is a compound of Formula VI-A or VI-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:

›DEFINITIONS · 8 of 28

each R a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

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.

In some embodiments, the compound of Formula I is a compound of Formula VI-C or VI-D:

a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing,

wherein:

each R a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

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.

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

In some embodiments, at least one compound chosen from the novel compounds disclosed herein, 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 disclosed herein, 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 disclosed herein, 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 disclosed herein, 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 disclosed herein, 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.

In some embodiments, at least one novel compound (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:

›DEFINITIONS · 9 of 28

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;

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

and pharmaceutically acceptable salts thereof.

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 Formula (I) 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 Formula (I) 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 Formula (I) 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 Formula (I) 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 Formula (I) 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.

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.

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.

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.

Any of the novel compounds disclosed herein, such as for example, compounds of Formula (I) 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.

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.

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.

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.

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.

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 (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), 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.

›DEFINITIONS · 10 of 28

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

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.

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.

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

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.

In some embodiments, the methods of the disclosure employ administering to a patient in need thereof at least one compound chosen from any of the compounds of Formula I 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.

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, all of which are incorporated herein by reference. Some exemplary pharmaceutical compositions for Compound III and its pharmaceutically acceptable salts can be found in WO 2007/134279, WO 2010/019239, WO 2011/019413, WO 2012/027731, and WO 2013/130669, all of which are incorporated herein by reference. Exemplary compositions comprising Compound III-d and its pharmaceutically acceptable salts can be found in, e.g., WO 2014/078842 and WO2018/227049, incorporated herein by reference. Some exemplary pharmaceutical compositions for Compound IV and its pharmaceutically acceptable salts can be found in WO 2010/037066, WO 2011/127241, WO 2013/112804, and WO 2014/071122, all of which are incorporated herein by reference.

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, incorporated herein by reference. An exemplary embodiment is shown in the following Table 2:

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, incorporated herein by reference. An exemplary embodiment is shown in the following Table 3:

›DEFINITIONS · 11 of 28

Additional pharmaceutical compositions comprising Compound III are disclosed in PCT Publication No. WO 2013/130669, incorporated herein by reference. 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.

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

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.

In some embodiments, disclosed herein are methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a compound, pharmaceutically acceptable salt thereof, or a deuterated analog of any of the foregoing; or a 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.

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).

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.

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.

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%.

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.

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 Feb. 2016)

average sweat chloride>86 mmol/L, and prevalence of pancreatic insufficiency (PI)>50%

in vitro testing

mutations resulting in baseline chloride transport<10% of wild-type CFTR were considered minimal function mutations resulting in chloride transport<10% of wild-type CFTR following the addition of Compound II and/or Compound III were considered nonresponsive.

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.

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.

›DEFINITIONS · 12 of 28

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.

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.

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.

In some embodiments, the methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis disclosed herein are each independently produces an increase in chloride transport above the baseline chloride transport of the patient.

In some embodiments, in the methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis disclosed herein, the patient is heterozygous for F508del, and the other CFTR genetic mutation is any CF-causing mutation. In some embodiments, the patient 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 patient 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.

In some embodiments, in the methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis disclosed herein, the patient 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, I618T, I807M, I980K, L102R, L1324P, L1335P, L138ins, L1480P, LISP, L165S, L320V, L346P, L453S, L571S, L967S, M1101R, M152V, M1T, M1V, M265R, M9521, M952T, P574H, PSL, 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.

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.

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, I618T, I807M, I980K, L102R, L1324P, L1335P, L138ins, L1480P, LISP, L165S, L320V, L346P, L453S, L571S, L967S, M1101R, M152V, M1T, M1V, M265R, M9521, M952T, P574H, PSL, 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.

›DEFINITIONS · 13 of 28

In some embodiments, in the methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis disclosed herein, the patient 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, 41507, 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.

In some embodiments, in the methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis disclosed herein, the patient 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, 41507, 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.

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.

In some embodiments, in the methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis disclosed herein, 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.

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.

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.

›DEFINITIONS · 14 of 28

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.

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.

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:

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.

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.

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.

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.

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.

In some embodiments 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 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 (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 their deuterated derivatives), and (ii) Compound II, and/or Compound III, and/or Compound IV.

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.

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.

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.

›DEFINITIONS · 15 of 28

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, but other than F508del, listed in Table A, B, C, and FIG. 2 .

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 .

In some embodiments, the patient is homozygous for F508del.

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.

In some embodiments, the composition disclosed herein is useful for 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.

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.

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.

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.

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.

In some embodiments, this disclosure relates to a method of augmenting or inducing anion channel activity in vitro or in vivo, comprising contacting the channel with a 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.

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:

›DEFINITIONS · 16 of 28

In some embodiments, Compound III-d as used herein includes the deuterated compound disclosed in U.S. Pat. No. 8,865,902 (which is incorporated herein by reference) 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).

Exemplary embodiments of the disclosure include: The novel compounds disclosed herein (e.g., 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, 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 (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 can be prepared in a similar manner as those for 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 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, the relevant portions of which are incorporated herein by reference.

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.

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.

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 .

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.

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.

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.

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 .

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.

›DEFINITIONS · 17 of 28

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.

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).

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 performed in the presence of a base, such as sodium hydride.

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.

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.

Additional Embodiments Include

1. A compound 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:

each R a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

10. The compound of any one of embodiments 1 to 9, 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:

each R a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

›DEFINITIONS · 18 of 28

11. The compound of any one of embodiments 1 to 8, 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 , and 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, and 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.

16. The compound of any one of embodiments 1 to 14, 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, and:

each R 8 and R 9 is independently chosen from hydrogen and deuterium; and each R b is independently chosen from hydrogen and methyl.

17. The compound of any one of embodiments 1 to 14, 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, and wherein:

each R 8 and R 9 is independently chosen from hydrogen and deuterium; and each R b is hydrogen.

18. The compound of any one of embodiments 1 to 14, 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:

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

29. The compound of any one of embodiments 20 to 28, 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:

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

30. The compound of any one of embodiments 20 to 28, 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:

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:

›DEFINITIONS · 19 of 28

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.

35. The compound of any one of embodiments 20 to 33, 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.

36. The compound of any one of embodiments 20 to 33, 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.

37. The compound of any one of embodiments 20 to 33, 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:

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, 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:

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

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:

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:

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:

›DEFINITIONS · 20 of 28

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 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

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:

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:

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.

›DEFINITIONS · 21 of 28

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:

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:

each R a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

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:

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:

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.

›DEFINITIONS · 22 of 28

each R a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

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:

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:

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;

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:

each R a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

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:

›DEFINITIONS · 23 of 28

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:

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:

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:

each R a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

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:

›DEFINITIONS · 24 of 28

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:

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

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:

each R a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

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:

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:

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:

›DEFINITIONS · 25 of 28

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 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 to 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:

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:

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

(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

195. A method of treating cystic fibrosis comprising administering to a patient in need thereof a compound of any one of embodiments 1 to 191 or a pharmaceutical composition according to embodiment 194.

196. Use of at least one compound chosen from compounds of any one of embodiments 1-191 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:

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:

›DEFINITIONS · 26 of 28

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:

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

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:

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:

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 th , and the variables therein are as recited in embodiment 1.

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:

›DEFINITIONS · 27 of 28

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:

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:

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:

›DEFINITIONS · 28 of 28

Other embodiments include:

A. A compound of Formula I:

B. A pharmaceutically acceptable salt of a compound of Formula I

C. A pharmaceutical composition comprising:

(i) a compound of Formula I

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 I

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 I

V. A method of treating cystic fibrosis comprising administering to a patient in need thereof a pharmaceutically acceptable salt of a compound of Formula I

W. A method of treating cystic fibrosis comprising administering to a patient in need thereof a pharmaceutical composition comprising:

(A) a compound of Formula I

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 I

and

a pharmaceutically acceptable carrier.

General Experimental Procedures

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

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×0.25 mm×0.25 um_df) column, with a 2.0 mL/min flow rate (H 2 carrier gas), at an injection temperature of 220° C. and an oven temperature of 120° C., 15 minutes.

›SYNTHETIC EXAMPLES · 1 of 2

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

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

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

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 (2.68 g, 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

(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 N 2 . Then Pd-C (250 mg, 5% wt) was added. The reaction was flushed with nitrogen again and then stirred under H 2 (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

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 (3 g, 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

(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.

›SYNTHETIC EXAMPLES · 2 of 2

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

›Step 1: 2-Phenylaminomethylene-malonic Acid Diethyl Ester

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

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

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, 1H), 13.42 (s, 1H), 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

›Step 1: Carbonic Acid 2,4-di-tert-butyl-phenyl ester methyl ester

Methyl chloroformate (58 mL, 750 mmol) was added dropwise to a solution of 2,4-di-tert-butyl-phenol (103.2 g, 500 mmol), Et 3 N (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. 1 L) 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

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

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-nitro-phenol (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

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 · 1 of 2

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

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

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.

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.

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.

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.

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:

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.

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.

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.

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.

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.

›Step 5: N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide · 2 of 2

LC Method E: 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 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.

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.

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.

LC Method H: Kinetex C 18 4.6×50 mm 2.6 μm. 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.

LC Method I: Kinetex C 18 4.6×50 mm 2.6 μm. 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.

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.

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.

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.

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.

LC Method N: Zorbax C 18 4.6×50 mm 3.5 μm. 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.

LC Method O: Zorbax SB-C 18 4.6×50 mm 3.5 μm, 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.

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).

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).

LC Method R: Waters Cortex 2.7 μm C 18 (3.0 mm×50 mm), 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 0.5 min, equilibration to 5% B over 1.5 min.

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.

LC Method T: Zorbax C 18 4.6×50 mm 3.5 μM, Security Guard: AJO-4287 C 18 , 4×3.0 mm. 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.

LC Method U: Kinetex EVO C 18 4.6×50 mm 2.6 lam, 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.

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)

›Step 1: tert-Butyl 2,6-dichloropyridine-3-carboxylate

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 (2×300 mL), 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

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

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

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-d 6 ) 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

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

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 m/z 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

tert-Butyl-3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-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]ethoxy]-1H-pyrazole (612 mg, 86%). 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) 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

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

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

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 (500 mL), washed with 1N hydrogen chloride aqueous solution (100 mL) and brine (2×50 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 (250 MHz, CDCl 3 ) δ 2.48 (t, J=8.0 Hz, 2H), 1.85 (t, J=8.0 Hz, 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

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 (3×150 mL). The combined organic layers were washed with brine (2×50 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 (3×60 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 (0.92 g, 30%) as a colorless oil. 1 H NMR (250 MHz, 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

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 (4×80 mL). 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 (250 MHz, 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

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

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 (3×100 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 (500 MHz, 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

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 1 h. 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

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 6 h. 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 (2×40 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 (3×75 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) · 1 of 2

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

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 (590 mg, 3.639 mmol) were combined in tetrahydrofuran (15.3 mL) and stirred for 2 h. At this point, 6-fluoro-2-pyridinesulfonamide (534 mg, 3.03 mmol) was added followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (907 μL, 6.07 mmol) and the reaction was stirred for an additional 30 min at room temperature. The reaction was diluted with ethyl acetate and washed with a 1M citric acid solution, followed by brine. The organics were separated, dried over sodium sulfate, and evaporated to give a white solid. The solid was treated with ether, removed under reduced pressure and then dissolved in minimal hot dichloromethane. The reaction mixture was cooled slowly to room temperature, then in an ice-water bath giving a mass of white solid which was filtered and washed with hexanes. The solid was dried under reduced pressure to afford 2-chloro-N-[(6-fluoro-2-pyridyl)sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (1.48 g, 89%). ESI-MS m/z calc. 533.05475, found 543.3 (M+1) + ; Retention time: 0.72 min (LC Method A).

Step 19: 2-Chloro-N-[[6-[3-(5,5-dimethylpyrrolidin-2-yl)propyl-methyl-amino]-2-pyridyl]sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide

2-chloro-N-[(6-fluoro-2-pyridyl)sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (1.033 g, 1.876 mmol), 3-(5,5-dimethylpyrrolidin-2-yl)-N-methyl-propan-1-amine (di-trifluoroacetic acid salt) (747.3 mg, 1.876 mmol), potassium carbonate (1.556 g, 11.26 mmol) and dimethyl sulfoxide (5 mL) were added to a vial, capped, and heated to 50° C. for 20 min. The reaction was heated to 65° C. for 90 min. The reaction was cooled back to 50° C. and stirred for 32 h. The reaction was cooled to room temperature and 2-chloro-N-[(6-fluoro-2-pyridyl)sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (300 mg, 0.5451 mmol) was added and then warmed back to 50° C. and stirred overnight. The reaction was cooled to room temperature and poured into water giving a white precipitate. Concentrated hydrochloric acid was added to bring the pH to 4 and then the white solid was filtered off and washed with water followed by hexanes. The solid was dissolved in dichloromethane, dried (magnesium sulfate), filtered, and concentrated to a white solid. The solid was purified by silica gel chromatography using a shallow gradient from 100% dichloromethane to 20% Methanol/dichloromethane giving 2-chloro-N-[[6-[3-(5,5-dimethylpyrrolidin-2-yl)propyl-methyl-amino]-2-pyridyl]sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (350 mg, 27%) as a white solid. ESI-MS m/z calc. 683.2268, found 684.5 (M+1) + ; Retention time: 0.63 min (LC Method A).

Step 20: 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)

Combined 2-chloro-N-[[6-[3-(5,5-dimethylpyrrolidin-2-yl)propyl-methyl-amino]-2-pyridyl]sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (350 mg, 0.5116 mmol), potassium carbonate (353.5 mg, 2.558 mmol), cesium fluoride (116.6 mg, 28.34 μL, 0.7674 mmol), 3 Å molecular sieves and dimethyl sulfoxide (7.077 mL) in a vial, purged with nitrogen, capped, heated to 150° C. and stirred for 25 h. Cooled to room temperature then poured into 150 mL of water. Adjusted the pH to 4 by the dropwise addition of concentrated hydrochloric acid giving a tan precipitate which was filtered and washed with water then hexanes. Dissolved the solid in dichloromethane, dried (magnesium sulfate), filtered and concentrated to a tan solid which was purified by silica gel chromatography using a shallow gradient from 100% dichloromethane to 20% methanol/dichloromethane giving 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) (259.5 mg, 78%). 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.62 (s, 1H), 8.22 (d, J=2.8 Hz, 1H), 7.97 (s, 1H), 7.77 (dd, J=8.6, 7.3 Hz, 1H), 7.13 (d, J=7.2 Hz, 1H), 7.04 (s, 1H), 6.82 (d, J=8.7 Hz, 1H), 6.13 (d, J=2.8 Hz, 1H), 4.32 (t, J=7.1 Hz, 2H), 2.96 (s, 3H), 2.08 (t, J=7.0 Hz, 2H), 1.69 (s, 2H), 1.54 (d, J=9.7 Hz, 5H), 1.35 (s, 3H), 1.23 (s, 7H), 0.98-0.95 (m, 2H), 0.89 (td, J=5.8, 4.6, 3.0 Hz, 2H). ESI-MS m/z calc. 647.2502, found 648.2 (M+1) + ; Retention time: 2.05 min (LC Method B).

Example 2: Preparation of (15S)-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(24),5(10),6,8,20,22-hexaene-2,2,4-trione (Compound 10) and (15R)-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(24),5(10),6,8,20,22-hexaene-2,2,4-trione (Compound 11)

Step 1: (15S)-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(24),5(10),6,8,20,22-hexaene-2,2,4-trione (Compound 10) and (15R)-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(24),5(10),6,8,20,22-hexaene-2,2,4-trione (Compound 11)

›Step 17: 3-(5,5-Dimethylpyrrolidin-2-yl)-N-methyl-propan-1-amine (di-trifluoroacetic Acid Salt) · 2 of 2

Subjected racemic 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) (221.5 mg, 0.3420 mmol) to chiral separation by SFC chromatography using a ChiralPak AS-H (250×21.2 mm column, 5 μm particle size) with 15% Methanol/85% carbon dioxide mobile phase at 10 mL/min over 8.0 min (injection volume=500 μL of 32 mg/mL solution in methanol) giving as the first enantiomer to elute (15S)-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 (24),5(10),6,8,20,22-hexaene-2,2,4-trione (Compound 10) (82.3 mg, 74%) as a white solid; 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.64 (s, 1H), 8.22 (d, J=2.8 Hz, 1H), 7.98 (d, J=8.3 Hz, 1H), 7.77 (t, J=7.9 Hz, 1H), 7.12 (d, J=7.2 Hz, 1H), 7.04 (s, 1H), 6.82 (d, J=8.6 Hz, 1H), 6.13 (d, J=2.8 Hz, 1H), 4.32 (t, J=7.0 Hz, 2H), 3.60 (s, 1H), 2.99 (s, 1H), 2.96 (s, 3H), 2.08 (t, J=7.1 Hz, 2H), 1.96-1.84 (m, 1H), 1.69 (s, 3H), 1.52 (s, 6H), 1.35 (s, 3H), 1.02-0.83 (m, 5H), ESI-MS m/z calc. 647.2502, found 648.4 (M+1) + ; Retention time: 2.06 min (LC Method B), and as the second enantiomer to elute (15R)-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(24),5(10),6,8,20,22-hexaene-2,2,4-trione (Compound 11) (81.7 mg, 74%) as a white solid; 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.64 (s, 1H), 8.22 (d, J=2.8 Hz, 1H), 7.98 (d, J=8.3 Hz, 1H), 7.77 (t, J=8.0 Hz, 1H), 7.12 (d, J=7.3 Hz, 1H), 7.03 (s, 1H), 6.81 (d, J=8.6 Hz, 1H), 6.12 (d, J=2.7 Hz, 1H), 4.41 (s, 1H), 4.32 (t, J=7.0 Hz, 2H), 3.59 (s, 1H), 3.01 (s, 1H), 2.96 (s, 3H), 2.08 (t, J=7.1 Hz, 2H), 1.92 (d, J=8.7 Hz, 1H), 1.69 (s, 3H), 1.52 (s, 6H), 1.35 (s, 3H), 1.01-0.83 (m, 5H), ESI-MS m/z calc. 647.2502, found 648.4 (M+1) + ; Retention time: 2.06 min (LC Method B).

Example 3: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Compound 12)

›Step 1: (E)-(2-Oxotetrahydropyran-3-ylidene)methanolate (Sodium Salt)

A 5 L, 3-neck round bottom flask was fitted with a mechanical stirrer, a heating mantle, an addition funnel, a J-Kem temperature probe/controller and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with sodium hydride (59.91 g of 60% w/w, 1.498 mol) followed by heptane (1.5 L) which provided a grey suspension. Stirring was commenced and the pot temperature was recorded at 19° C. The vessel was then charged with ethyl alcohol (3.451 g, 74.91 mmol) added via syringe which resulted in gas evolution. The addition funnel was charged with a clear pale yellow solution of tetrahydropyran-2-one (150 g, 1.498 mol) and ethyl formate (111 g, 1.50 mol). The solution was added dropwise over 1 h which resulted in gas evolution and a gradual exotherm to 45° C. The resulting thick white suspension was then heated to 65° C. for 2 h and then allowed to cool to room temperature. The mixture was continued to stir at room temperature overnight (about 10 h). The reaction mixture was vacuum filtered through a glass frit Buchner funnel (medium porosity) under a stream of nitrogen. The filter cake was displacement washed with heptane (2×250 mL) and pulled for a few min. The slightly heptane wet cake was transferred to a glass tray and dried in a vacuum oven at 45° C. for 15 h to provide a white solid (205 g, 1.36 mol, 91% yield) as the desired product, (E)-(2-oxotetrahydropyran-3-ylidene)methanolate (sodium salt).

›Step 2: 3-Methylenetetrahydropyran-2-one

A 5 L, 3-neck round bottom flask was fitted with a mechanical stirrer, a heating mantle, an addition funnel, a J-Kem temperature probe/controller and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with (E)-(2-oxotetrahydropyran-3-ylidene)methanolate (sodium salt) (205 g, 1.366 mol) (205 g, 1.366 mol) and tetrahydrofuran (1640 mL) which provided a white suspension. Stirring was commenced and the pot temperature was recorded at 19° C. The vessel was then charged with paraformaldehyde (136.6 g, 4.549 mol) added as a solid in one portion. The resulting suspension was heated to 63° C. and the condition was maintained for 15 h. Upon heating the reaction mixture became slightly gelatinous. The white gelatinous mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran. The remaining residue was partitioned with ethyl acetate (1000 mL), saturated sodium chloride (500 mL) and saturated sodium hydrogen carbonate (500 mL) in a separatory funnel. The organic was removed and the residual aqueous was extracted with ethyl acetate (5×300 mL). The combined organic was dried over sodium sulfate (500 g) and then vacuum filtered through a glass frit Buchner funnel with a 20 mm layer of celite. The filter cake was displacement washed with ethyl acetate (250 mL). The clear filtrate was concentrated under reduced pressure to provide a clear pale yellow oil (135 g) as the desired crude product. The material was purified by silica gel column flash chromatography (liquid load) eluting with a gradient of 100% hexane to 60% ethyl acetate in hexane over 1 h collecting 450 mL fractions. The product was detected by TLC analysis on silica gel eluting with 3:1 hexanes/ethyl acetate and visualized under UV. The product fractions were combined and concentrated under reduced pressure to provide a clear, colorless oil (132 g, 1.18 mol, 72% yield containing 16 wt % residual ethyl acetate by NMR) as the desired product, 3-methylenetetrahydropyran-2-one. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 6.18 (q, J=1.9 Hz, 1H), 5.60 (q, J=1.9 Hz, 1H), 4.40-4.26 (m, 2H), 2.61 (ddt, J=7.0, 6.3, 2.0 Hz, 2H), 1.90-1.75 (m, 2H).

›Step 3: 3-(2-Methyl-2-nitro-propyl)tetrahydropyran-2-one

A 5000 mL, 3-neck round bottom flask was fitted with a mechanical stirrer, a cooling bath used as secondary containment, a J-Kem temperature probe, an addition funnel and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with 2-nitropropane (104.9 g, 1.177 mol). Stirring was commenced and the pot temperature was recorded at 19° C. The vessel was then charged with 1,8-diazabicyclo[5.4.0]undec-7-ene (22.41 g, 147.2 mmol) added neat in one portion which resulted in a clear light yellow solution. No exotherm was observed. The addition funnel was charged with a solution of 3-methylenetetrahydropyran-2-one (110 g, 981.0 mmol) in acetonitrile (1100 mL) which was added dropwise over 1 h which resulted in a clear light yellow solution and a gradual exotherm to 24° C. The reaction mixture was continued to stir at room temperature for 3.5 h and then concentrated under reduced pressure. The remaining residue was dissolved in dichloromethane (1000 mL) and partitioned with 500 mL of a 3:2 mixture of 1 molar citric acid solution/saturated sodium chloride solution. The resulting organic phase was a clear pale blue solution and the aqueous phase was a slightly cloudy very pale blue solution. The organic was removed and the residual aqueous was extracted with dichloromethane (300 mL). The combined organic was washed with saturated sodium chloride solution (300 mL), dried over sodium sulfate (250 g) and then filtered through a glass frit Buchner funnel. The filtrate was concentrated under reduced pressure to a volume of about 200 mL. The clear pale blue dichloromethane solution was diluted with methyl tert-butyl ether (1500 mL) and the cloudy solution was concentrated under reduced pressure to a volume of about 200 mL which provided a suspension. The mixture was again diluted with methyl tert-butyl ether (1500 mL) and concentrated under reduced pressure to a volume of about 250 mL. The resulting suspension was allowed to stand at room temperature overnight (about 12 h). The solid was collected by vacuum filtration in a glass frit Buchner funnel and the filter cake was displacement washed with cold methyl tert-butyl ether (2×150 mL) and then pulled for 30 min. The material was further dried in a vacuum oven at 45° C. for 5 h to provide (160 g, 0.795 mol, 81% yield) of a white solid as the desired product, 3-(2-methyl-2-nitro-propyl)tetrahydropyran-2-one. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 4.34 (ddd, J=11.1, 9.3, 4.3 Hz, 1H), 4.20 (dt, J=11.1, 5.1 Hz, 1H), 2.75-2.62 (m, 1H), 2.56 (dd, J=14.9, 5.2 Hz, 1H), 2.01-1.89 (m, 2H), 1.89-1.67 (m, 2H), 1.55 (d, J=6.0 Hz, 6H), 1.44 (dddd, J=12.8, 11.5, 8.1, 6.6 Hz, 1H).

›Step 4: 3-(3-Hydroxypropyl)-5,5-dimethyl-pyrrolidin-2-one

A 1000 mL, 3-neck round bottom flask was fitted with a Teflon stir bar, a heating mantle, a J-Kem temperature probe/controller and rubber septums. The vessel was charged with 3-(2-methyl-2-nitro-propyl)tetrahydropyran-2-one (25 g, 124.2 mmol) and ethyl alcohol (375 mL) which provided a white suspension. Stirring was commenced and the suspension was heated to 40° C. for 10 min which provided a clear colorless solution. The vessel was then fitted with a gas dispersion tube and the solution was degassed with nitrogen for 15 min. The vessel was then charged with Raney Nickel (8.019 g of 50% w/w, 68.31 mmol) and the vessel was then fitted with the septums. The vessel was evacuated and placed under a hydrogen atmosphere. The process was repeated for three cycles. The vessel was then placed under 1 atmosphere hydrogen and the reaction mixture was gradually heated to 60° C. The reaction was continued to stir at 60° C. for 24 h. After cooling to room temperature, the vessel was fitted with a gas dispersion tube and the reaction mixture was degassed with nitrogen for 15 min. The mixture was vacuum filtered through a glass frit Buchner funnel with a 20 mm layer of celite. The filter cake was displacement washed with ethanol (2×100 mL) and pulled until slightly ethyl alcohol wet, then wetted with water and the used Raney nickel catalyst was discarded under water. The clear pale amber filtrate was concentrated under reduced pressure to a clear viscous light amber oil. The oil was diluted with methyl tert-butyl ether (1500 mL) and the cloudy solution was concentrated under reduced pressure to a volume of about 150 mL which provided a suspension. The mixture was again diluted with methyl tert-butyl ether (1500 mL) and concentrated under reduced pressure to a volume of about 150 mL. The resulting suspension was allowed to stand at room temperature overnight (about 12 h). The solid was collected by vacuum filtration in a glass frit Buchner funnel and the filter cake was displacement washed with cold methyl tert-butyl ether (2×50 mL) and then pulled for 30 min. The material was further dried in a vacuum oven at 45° C. for 3 h to provide a white solid (19 g, 0.111 mol, 89% yield) as the product, 3-(3-hydroxypropyl)-5,5-dimethyl-pyrrolidin-2-one. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 7.63 (s, 1H), 3.38 (t, J=6.5 Hz, 2H), 2.37 (tdd, J=9.8, 8.5, 4.4 Hz, 1H), 2.02 (dd, J=12.3, 8.6 Hz, 1H), 1.72 (tdd, J=9.6, 7.5, 4.4 Hz, 1H), 1.52-1.32 (m, 3H), 1.28-1.03 (m, 7H).

›Step 5: 3-(5,5-Dimethylpyrrolidin-3-yl)propan-1-ol

A 5 L, 3-neck round bottom flask was fitted with a mechanical stirrer, a heating mantle, an addition funnel, a J-Kem temperature probe/controller and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with lithium aluminum hydride pellets (19.39 g, 510.9 mmol). The vessel was then charged with tetrahydrofuran (500 mL, 20 mL/g). Stirring was commenced and the pot temperature was recorded at 20° C. The mixture was allowed to stir at room temperature for 0.5 h to allow the pellets to dissolve. The pot temperature of the resulting grey suspension was recorded at 24° C. The addition funnel was charged with a solution of 3-(3-hydroxypropyl)-5,5-dimethyl-pyrrolidin-2-one (25 g, 146.0 mmol) in tetrahydrofuran (500 mL) and the clear pale yellow solution was added dropwise over 90 min. Slight heating was required to achieve homogeneity. After the completed addition the pot temperature of the resulting greyish suspension was recorded at 24° C. The mixture was then heated to a pot temperature of 65° C. and the condition was maintained for 72 h. Analysis of the reaction mixture at this point indicated some residual starting material still remaining and no change in product formation. The reaction was subsequently stopped at this point. The heating mantle was removed and the vessel was fitted with a cooling bath. The suspension was cooled to 0° C. with a crushed ice/water cooling bath and then quenched by the very slow dropwise addition of water (19.93 mL), followed by 15 wt % sodium hydroxide solution (19.93 mL) and then finally with water (59.79 mL). The pot temperature of the resulting white suspension was recorded at 5° C. The cooling bath was removed and the vessel was again fitted with a heating mantle. The suspension was warmed to 60° C. and the condition was maintained for 30 min. The warm suspension was vacuum filtered through a glass frit Buchner funnel with a 20 mm layer of celite. The filter cake was then displacement washed with 60° C. tetrahydrofuran (2×250 mL) and then pulled for 30 min. The clear filtrate was concentrated under reduced pressure to provide (23.5 g, 0.149 mol, 99% yield) of a clear light yellow viscous oil as the desired product, 3-(5,5-dimethylpyrrolidin-3-yl)propan-1-ol. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 3.37 (dt, J=8.3, 6.4 Hz, 3H), 2.95 (dd, J=10.6, 7.6 Hz, 1H), 2.40 (dd, J=10.7, 7.7 Hz, 1H), 2.04 (dt, J=16.1, 8.1 Hz, 1H), 1.69 (dd, J=12.2, 8.2 Hz, 1H), 1.50-1.24 (m, 5H), 1.11-0.94 (m, 7H).

›Step 6: tert-Butyl 4-(3-hydroxypropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

A 1 L, 3-neck round bottom flask was fitted with a mechanical stirrer, a cooling bath, an addition funnel, a J-Kem temperature probe and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with 3-(5,5-dimethylpyrrolidin-3-yl)propan-1-ol (15 g, 95.39 mmol) and dichloromethane (225 mL, 15 mL/g) which provided a clear light yellow solution. Stirring was commenced and the pot temperature was recorded at 19° C. The cooling bath was charged with crushed ice/water and the pot temperature was lowered to 0° C. The addition funnel was charged with triethylamine (12.55 g, 124.0 mmol) which was subsequently added neat dropwise over 5 min. No exotherm was observed. The addition funnel was then charged with di-tert-butyl dicarbonate (22.89 g, 104.9 mmol) dissolved in dichloromethane (225 mL). The clear pale yellow solution was then added dropwise over 30 min which resulted in gentle gas evolution. No exotherm was observed. The cooling bath was removed and the resulting clear light yellow solution was allowed to warm to room temperature and continue to stir at room temperature for 3 h. The reaction mixture was transferred to a separatory funnel and partitioned with water (75 mL). The organic was removed and washed with saturated sodium chloride solution (75 mL), dried over sodium sulfate (150 g) and then filtered through a glass frit Buchner funnel. The filtrate was concentrated under reduced pressure to provide (30 g) of a clear light yellow oil as the desired crude product. The material was purified by silica gel column flash chromatography (liquid load with dichloromethane) eluting with a gradient of 100% dichloromethane to 10% methyl alcohol in dichloromethane over 60 min collecting 50 mL fractions. The desired product fractions were combined and concentrated under reduced pressure to provide tert-butyl 4-(3-hydroxypropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (22 g, 0.0855 mol, 90% yield) as a clear pale yellow viscous oil. 1 H NMR (400 MHz, DMSO-d 6 ) δ 4.38 (td, J=5.2, 1.4 Hz, 1H), 3.54 (dt, J=10.3, 6.7 Hz, 1H), 3.38 (td, J=6.6, 3.5 Hz, 2H), 2.76 (q, J=10.3 Hz, 1H), 2.07 (td, J=11.6, 5.7 Hz, 1H), 1.87 (ddd, J=16.7, 12.1, 6.0 Hz, 1H), 1.37 (dd, J=14.2, 10.4 Hz, 17H), 1.24 (s, 3H).

›Step 7: tert-Butyl 2,2-dimethyl-4-(3-methylsulfonyl oxypropyl)pyrrolidine-1-carboxylate

tert-Butyl 4-(3-hydroxypropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (50.5 g, 196.22 mmol) and triethylamine (39.711 g, 54.698 mL, 392.44 mmol) were dissolved in dichloromethane (500 mL) and the resulting solution was chilled in an ice water bath for 30 min. Mesyl chloride (24.725 g, 16.706 mL, 215.84 mmol) was added dropwise over a 30 min period, then the ice bath was removed and the mixture stirred at room temperature for one hour. The reaction was then quenched with saturated sodium bicarbonate solution (200 mL). The phases were separated and the organic phase was extracted with saturated sodium bicarbonate (200 mL) and water (2×100 mL). The aqueous phases were discarded and the organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to obtain tert-butyl 2,2-dimethyl-4-(3-methylsulfonyl oxypropyl)pyrrolidine-1-carboxylate (64.2 g, 93%) as a pale yellow oil. ESI-MS m/z calc. 335.1766, found 336.4 (M+1) + ; Retention time: 5.54 min (LC Method Q).

›Step 8: tert-Butyl 4-(3-aminopropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

tert-Butyl 2,2-dimethyl-4-(3-methylsulfonyloxypropyl)pyrrolidine-1-carboxylate (64.2 g, 191.38 mmol) was dissolved in dioxane (650 mL) and then ammonium hydroxide (650 mL) was added and the resulting mixture heated to 45° C. for 18 h. After 18 h, the reaction was cooled to room temperature. The solution was diluted with 1M sodium hydroxide (200 mL) and then extracted with diethyl ether (3×650 mL). The aqueous phase was discarded and the combined organic phases were extracted with water (2×200 mL). The aqueous phases were discarded and the organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford tert-butyl 4-(3-aminopropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (48.9 g, 95%) as a pale yellow oil. ESI-MS m/z calc. 256.2151, found 257.3 (M+1) + ; Retention time: 3.70 min (LC Method Q).

›Step 9: tert-Butyl 2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate · 1 of 2

To tert-butyl 4-(3-aminopropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (8.91 g, 34.8 mmol) and 6-fluoropyridine-2-sulfonamide (6.13 g, 34.8 mmol) in dimethyl sulfoxide (75 mL) was added potassium carbonate (4.91 g, 35.5 mmol) and the mixture stirred at 100° C. for 12 h and then allowed to cool to ambient temperature and stirred for an additional 4 h (16 h total). The reaction mixture was slowly poured into hydrochloric acid (35 mL of 1 M, 35.00 mmol) in water (200 mL) (some foaming) and diluted with ethyl acetate (250 mL). The organic phase was separated and washed with 100 mL of brine. The organic phase was dried over magnesium sulfate, filtered over celite, and concentrated in vacuo to afford a dark yellow oil. The crude product was purified by silica gel chromatography eluting with 0%-100% ethyl acetate in hexanes. Collected both pure (9.0 g) and impure (3 g) fractions. Purified the impure fractions by silica gel chromatography eluting with 0%-100% ethyl acetate in hexanes affording, in total, tert-butyl 2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (10.0 g, 69%). 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 7.52 (dd, J=8.5, 7.2 Hz, 1H), 7.07 (s, 2H), 6.95 (dd, J=7.2, 0.7 Hz, 2H), 6.61 (d, J=8.5 Hz, 1H), 3.55 (q, J=9.1 Hz, 1H), 3.32-3.24 (m, 2H), 2.79 (q, J=10.0 Hz, 1H), 2.13 (d, J=16.1 Hz, 1H), 1.96-1.82 (m, 1H), 1.51 (dt, J=18.0, 9.3 Hz, 2H), 1.37 (dd, J=12.9, 10.6 Hz, 15H), 1.24 (s, 3H). ESI-MS m/z calc. 412.21442, found 413.1 (M+1) + ; Retention time: 2.34 min (LC Method D).

Step 10: tert-Butyl 4-[3-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

Part A: To 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (11.4 g, 30.34 mmol) in tetrahydrofuran (150 mL) was slowly added carbonyl diimidazole (5.9 g, 36 mmol). The mixture was stirred at ambient temperature for 1 hr. Additional carbonyl diimidazole (0.5 g, 3 mmol) was added and the reaction was stirred at ambient temperature for an additional 1 h (2 h total).

Part B: To the activated ester prepared in Part A was added tert-butyl 2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (10.0 g, 24.24 mmol) in tetrahydrofuran (50 mL) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (7.5 mL, 50. mmol) and the mixture stirred at ambient temperature for 16 hr. Citric acid (25.1 g, 130.6 mmol) in water (200 mL) was slowly added to the reaction mixture and acidified to pH=3. The mixture became cloudy but no precipitate formed. The mixture was extracted with ethyl acetate (400 mL) and the organic phase washed with brine, dried over magnesium sulfate, filtered over celite, and concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with 0-80% ethyl acetate/hexanes affording the product as a foam, tert-butyl 4-[3-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (13.82 g, 74%) 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.79 (s, 1H), 8.40 (t, J=2.7 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.62 (dd, J=8.5, 7.2 Hz, 1H), 7.21 (d, J=5.8 Hz, 1H), 7.17 (d, J=7.1 Hz, 1H), 6.74 (d, J=8.5 Hz, 1H), 6.19 (t, J=2.3 Hz, 1H), 4.34 (t, J=7.1 Hz, 2H), 3.50 (dt, J=18.3, 9.0 Hz, 1H), 3.23 (d, J=6.7 Hz, 2H), 2.80-2.69 (m, 1H), 2.09 (t, J=7.1 Hz, 2H), 1.79 (td, J=12.4, 6.1 Hz, 1H), 1.52 (dt, J=15.4, 8.0 Hz, 2H), 1.36 (d, J=11.4 Hz, 10H), 1.33-1.25 (m, 5H), 1.17 (s, 2H), 0.99-0.92 (m, 2H), 0.89 (d, J=5.0 Hz, 2H). ESI-MS m/z calc. 769.2636, found 770.1 (M+1) + ; Retention time: 3.48 min (LC Method D).

Step 11: 2-chloro-{N}-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propylamino]-2-pyridyl]sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (Dihydrochloride Salt)

To tert-butyl 4-[3-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (13.8 g, 17.92 mmol) in dichloromethane (75 mL) was added hydrochloric acid (15 mL of 4 M, 60.00 mmol) and the mixture stirred at ambient temperature for 16 hr. The solvent was removed in vacuo and the residue diluted with 100 mL of ethyl acetate. The solvent was removed in vacuo and repeated with an additional 100 mL of ethyl acetate affording a foam, 2-chloro-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propylamino]-2-pyridyl]sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (dihydrochloride salt) (13.5 g, 101%). 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.83 (s, 1H), 9.06 (s, 1H), 8.92 (s, 1H), 8.42 (d, J=2.8 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.63 (dd, J=8.5, 7.2 Hz, 1H), 7.29 (s, 1H), 7.18 (dd, J=7.2, 0.7 Hz, 1H), 6.76 (dd, J=8.5, 0.7 Hz, 1H), 6.21 (d, J=2.9 Hz, 1H), 4.95 (s, 2H), 4.35 (t, J=7.0 Hz, 2H), 3.41-3.28 (m, 1H), 3.24 (p, J=6.7 Hz, 2H), 2.80 (tt, J=11.8, 6.7 Hz, 1H), 2.35 (q, J=7.8, 7.3 Hz, 1H), 2.09 (t, J=7.1 Hz, 2H), 1.91 (dd, J=12.8, 7.6 Hz, 1H), 1.58-1.43 (m, 3H), 1.42-1.31 (m, 5H), 1.24 (s, 3H), 1.01-0.93 (m, 2H), 0.90 (dd, J=7.9, 3.2 Hz, 2H). ESI-MS m/z calc. 669.2112, found 670.0 (M+1) + ; Retention time: 2.26 min (LC Method D).

Step 12: 12,12-Dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Compound 12)

To the 2-chloro-N-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propylamino]-2-pyridyl]sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (dihydrochloride salt) (12.9 g, 17.36 mmol) in NMP (120 mL) was added potassium carbonate (9.64 g, 69.8 mmol) followed by cesium fluoride (2.69 g, 17.7 mmol) and the slurry was stirred at 150° C. for 16 hr. The reaction was then allowed to cool to ambient temperature. The mixture was diluted with water (100 mL) and poured into water (400 mL) and the mixture was slowly acidified with hydrochloric acid (27.0 mL of 6 M, 162.0 mmol). The precipitate was collected using a medium frit and washed 3× with 50 mL of water. The solid was air dried for 1 h and then dissolved in ethyl acetate (400 mL). The organic phase was concentrated in vacuo and the crude product purified by silica gel chromatography eluting with 0-100% ethyl acetate/hexanes. 6.3 g of pure product and 6 g of impure fractions were collected. The impure fractions were purified by silica gel chromatography eluting with 0-5% methanol/dichloromethane which provided good separation of product from impurities. The pure product fractions were combined affording 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Compound 12) (7.4 g, 67%). 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.52 (s, 1H), 8.22 (d, J=2.8 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.58 (dd, J=8.5, 7.2 Hz, 1H), 7.05 (d, J=7.0 Hz, 1H), 7.00 (s, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.2 Hz, 1H), 6.11 (d, J=2.8 Hz, 1H), 4.31 (t, J=7.0 Hz, 2H), 4.02-3.81 (m, 1H), 3.15 (dt, J=10.1, 3.8 Hz, 1H), 2.95 (d, J=13.7 Hz, 1H), 2.78-2.61 (m, 1H), 2.15 (dd, J=5.7, 2.9 Hz, 1H), 2.07 (d, J=6.4 Hz, 2H), 1.92-1.82 (m, 1H), 1.81-1.69 (m, 1H), 1.64-1.53 (m, 6H), 1.51 (s, 3H), 1.36-1.23 (m, 1H), 0.99-0.93 (m, 2H), 0.90 (d, J=10.8 Hz, 2H). ESI-MS m/z calc. 633.2345, found 634.2 (M+1) + ; Retention time: 2.23 min (LC Method E).

›Step 9: tert-Butyl 2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate · 2 of 2

Example 4: Preparation of (14R)-12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (Compound 13) and (14S)-12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (Compound 14)

Step 1: (14R)-12,12-Dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (Compound 13) and (14S)-12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (Compound 14)

Racemic 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1 (23),5(10),6,8,19,21-hexaene-2,2,4-trione (7.4 g) was dissolved in 150 mL of acetonitrile and subjected to chiral SFC purification. The sample was separated by chiral SFC chromatography using a ChiralPak AS-H (250×21.2 mm column, 5 μm particle size) with 25% acetonitrile:methanol (90:10))/75% carbon dioxide mobile phase at 70 mL/min giving as the first enantiomer to elute, (14R)-12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (Compound 13) (2.91 g, 53%); 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.51 (s, 1H), 8.21 (d, J=2.7 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.05 (d, J=7.0 Hz, 1H), 6.99 (d, J=5.8 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 6.11 (d, J=2.7 Hz, 1H), 4.31 (t, J=7.0 Hz, 2H), 3.93 (s, 1H), 3.16 (s, 1H), 2.95 (d, J=12.7 Hz, 1H), 2.80-2.64 (m, 1H), 2.10 (s, 1H), 2.08 (t, J=7.1 Hz, 2H), 1.86 (dd, J=11.5, 5.4 Hz, 1H), 1.81-1.71 (m, 1H), 1.60 (s, 6H), 1.51 (s, 3H), 1.31 (d, J=12.8 Hz, 1H), 0.95 (d, J=4.3 Hz, 2H), 0.89 (s, 2H); ESI-MS m/z calc. 633.2345, found 634.3 (M+1) + ; Retention time: 2.19 min; and as the second enantiomer to elute, (14S)-12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (Compound 14) (3.0 g, 54%) 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.52 (s, 1H), 8.22 (d, J=2.8 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.58 (dd, J=8.5, 7.1 Hz, 1H), 7.05 (d, J=7.2 Hz, 1H), 6.99 (s, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 6.11 (d, J=2.8 Hz, 1H), 4.31 (t, J=7.0 Hz, 2H), 3.92 (d, J=12.6 Hz, 1H), 3.15 (s, 1H), 2.95 (d, J=13.2 Hz, 1H), 2.78-2.64 (m, 1H), 2.08 (t, J=7.1 Hz, 3H), 1.86 (dd, J=11.9, 5.3 Hz, 1H), 1.77 (s, 1H), 1.60 (s, 6H), 1.51 (s, 3H), 1.31 (q, J=11.9 Hz, 1H), 1.00-0.92 (m, 2H), 0.90 (d, J=10.4 Hz, 2H). ESI-MS m/z calc. 633.2345, found 634.1 (M+1) + ; Retention time: 2.2 min (LC Method B).

Example 5: Preparation of 12,12-dimethyl-8-(3-{[1-(trifluoromethyl)cyclopropyl]methoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Compound 15)

›Step 1: tert-Butyl 3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1-carboxylate

A 5000 mL, 3-neck round bottom flask as fitted with a mechanical stirrer, a heating mantle, a J-Kem temperature probe/controller, an addition funnel, a water cooled reflux condenser and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with tert-butyl 5-oxo-1H-pyrazole-2-carboxylate (70 g, 0.3800 mol) and tetrahydrofuran (840 mL, 12 mL/g) which provided a clear pale yellow solution. Stirring was commenced and the pot temperature was recorded at 19° C. The vessel was then charged with [1-(trifluoromethyl)cyclopropyl]methanol (58.56 g, 0.4180 mol) added neat in one portion followed by triphenylphosphine (109.6 g, 0.4180 mol) added as a solid in one portion. The resulting clear pale yellow solution was then treated with diisopropyl azodicarboxylate (clear reddish-orange liquid) (82.3 mL, 0.4180 mol) added neat dropwise over 1 h which resulted in a gradual exotherm to 40° C. and a clear light amber solution. The reaction mixture was then heated to a pot temperature of 50° C. and the condition was maintained for 2 h when analysis by LC/MS indicated complete consumption of the starting material. The clear amber reaction mixture was concentrated under reduced pressure and the resulting clear dark amber oil was suspended in toluene (560 mL) and stirred at room temperature for 1 h during which time a solid (triphenylphosphine oxide MW=278.28) precipitated. The thick slurry was filtered through a glass frit Buchner funnel and the filter cake was displacement washed with toluene (150 mL) and then pulled for 30 min. The clear amber filtrate was concentrated under reduced pressure to provide a clear amber oil. The material was purified by silica gel column flash chromatography (solid load adsorbed on celite) eluting with a gradient of 100% hexane to 20% ethyl acetate in hexane collecting 450 mL fractions. The product elutes around 5% ethyl acetate in hexane. The desired fractions were combined and concentrated under reduced pressure to provide a clear pale yellow oil as the desired product, tert-butyl 3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1-carboxylate (81 g, 0.264 mol, 70%). 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 8.10 (d, J=2.9 Hz, 1H), 6.14 (d, J=3.0 Hz, 1H), 4.31 (s, 2H), 1.55 (s, 9H), 1.07 (dp, J=4.9, 1.3 Hz, 4H). ESI-MS m/z calc. 306.11914, found 307.0 (M+1) + ; Retention time: 1.75 min (LC Method B).

›Step 2: 3-[[1-(Trifluoromethyl)cyclopropyl]methoxy]-1H-pyrazole · 1 of 3

A 5000 mL, 3-neck round bottom flask was fitted with a mechanical stirrer, a heating mantle, a J-Kem temperature probe, a water cooled reflux condenser, an addition funnel and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with tert-butyl 3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1-carboxylate (80 g, 0.2612 mol), dichloromethane (320 mL, 4 mL/g) and methyl alcohol (320 mL, 4 mL/g) which provided a clear pale yellow solution. Stirring was commenced and the pot temperature was recorded at 19° C. The addition funnel was charged with 4 M hydrochloric acid in 1,4-dioxane (195.9 mL, 0.7836 mol) which was subsequently added dropwise over 1 h which resulted in a gradual exotherm to 30° C. The resulting clear pale yellow solution was heated to a pot temperature of 45° C. and the condition was maintained for 1 h when analysis by LC/MS indicated reaction completion. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The remaining residue was dissolved in tert-butyl methyl ether (640 mL) and then transferred to a separatory funnel and partitioned with 2 M sodium hydroxide solution (391.8 mL, 0.7836 mol). The organic layer was removed and the residual aqueous was extracted with tert-butyl methyl ether (2×200 mL). The combined organic was washed with saturated sodium chloride solution (500 mL), dried over sodium sulfate (300 g) and then filtered through a glass frit Buchner funnel. The clear pale yellow filtrate was concentrated under reduced pressure to provide a clear light yellow oil which solidified upon standing to provide a white solid (49.5 g, 0.240 mol, 92%) as the desired product, 3-[[1-(trifluoromethyl)cyclopropyl]methoxy]-1H-pyrazole. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 11.90 (s, 1H), 7.51 (d, J=2.4 Hz, 1H), 5.67 (d, J=2.4 Hz, 1H), 4.19 (s, 2H), 1.09-0.97 (m, 4H). ESI-MS m/z calc. 206.0667, found 207.0 (M+1) + ; Retention time: 1.08 min (LC Method B).

Step 3: tert-Butyl 2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylate

A 5000 mL, 3-neck round bottom flask was fitted with a mechanical stirrer, a cooling bath used as secondary containment, a J-Kem temperature probe, a water cooled reflux condenser, an addition funnel and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with 3-[[1-(trifluoromethyl)cyclopropyl]methoxy]-1H-pyrazole (45 g, 0.2183 mol) and N,N-dimethylformamide (540 mL, 12 mL/g) which provided a clear pale yellow solution. Stirring was commenced and the pot temperature was recorded at 17° C. The vessel was then charged with tert-butyl 2,6-dichloropyridine-3-carboxylate (54.16 g, 0.2183 mol) added as a solid in one portion. The resulting clear pale yellow solution was then treated with potassium carbonate (39.22 g, 0.2838 mol) added as a solid in one portion followed by 1,4-diazabicyclo[2.2.2]octane (3.67 g, 0.03274 mol) added as a solid in one portion. The resulting pale yellow suspension was allowed to stir at room temperature for 24 h. The reaction mixture was cooled to 10° C. with a crushed ice/water cooling bath. The addition funnel was charged with water (540 mL) added dropwise over 45 min which resulted in a thick suspension and an exotherm to 15° C. The resulting suspension was continued to stir at 15° C. for 30 min and then filtered through a glass frit Buchner funnel. The filter cake was displacement washed with water (2×500 mL) and then pulled in the Buchner funnel for 2 h. The material was then allowed to air dry overnight to provide (73 g, 0.175 mol, 80%) of a white granular solid, tert-butyl 2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylate. ESI-MS m/z calc. 417.1067, found 418.1 (M+1) + ; Retention time: 0.85 min (LC Method A).

Step 4: 2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic Acid

A 1000 mL, 3-neck round bottom flask as fitted with a mechanical stirrer, a heating mantle, a J-Kem temperature probe/controller, an addition funnel, a water cooled reflux condenser and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with tert-butyl 2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylate (70 g, 0.1675 mol) and 2-propanol (350 mL) which provided an off-white suspension. Stirring was commenced and the pot temperature was recorded at 19° C. The addition funnel was charged with aqueous 6 M hydrochloric acid (139.6 mL, 0.8375 mol) which was added dropwise over 10 min which resulted in an exotherm to 30° C. The resulting suspension was then heated to reflux (pot temperature˜82° C.) Upon heating the suspension turns to a clear pale yellow solution (pot temperature˜75° C. at this point). After stirring at reflux for 30 min a solid began to precipitate. The suspension was continued to stir at reflux for an additional 30 min at which point water (210 mL) was added dropwise over 15 min. The heat was then removed and the suspension was continued to stir and allowed to slowly cool to room temperature. The material was collected by vacuum filtration in a glass frit Buchner funnel and the filter cake was displacement washed with 1:1 water/2-propanol (100 mL) followed by water (2×100 mL) and then pulled in the Buchner funnel for 30 min. The material was further dried in a vacuum oven at 45° C. for 24 h to provide 2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (56 g, 0.155 mol, 92%) as a white solid. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 13.64 (s, 1H), 8.44 (d, J=2.9 Hz, 1H), 8.41 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 6.24 (d, J=2.9 Hz, 1H), 4.41 (s, 2H), 1.16-1.07 (m, 4H). ESI-MS m/z calc. 361.0441, found 362.1 (M+1) + ; Retention time: 0.66 min (LC Method A).

Step 5: tert-Butyl 4-[3-[[6-[[2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

›Step 2: 3-[[1-(Trifluoromethyl)cyclopropyl]methoxy]-1H-pyrazole · 2 of 3

2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (260 mg, 0.6973 mmol) and carbonyl diimidazole (113.1 mg, 0.6973 mmol) were combined in tetrahydrofuran (3.783 mL) and stirred for 1 h at 45° C. tert-Butyl 2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (287.7 mg, 0.6973 mmol) was added followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (212.4 mg, 208.6 μL, 1.395 mmol) and the reaction was heated at 45° C. for 4 hrs. The reaction was diluted with ethyl acetate and washed with a 1M citric acid solution, followed by brine. The organics were separated, dried over sodium sulfate, evaporated, then purified by silica gel chromatography (24 gram column) using a gradient from 100% hexanes to 70% ethyl acetate in hexanes to afford as a white solid, tert-butyl 4-[3-[[6-[[2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (232 mg, 44%). 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.78 (s, 1H), 8.41 (d, J=2.4 Hz, 1H), 8.11 (d, J=8.3 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.62 (dd, J=8.4, 7.3 Hz, 1H), 7.21 (s, 1H), 7.17 (d, J=7.1 Hz, 1H), 6.74 (d, J=8.5 Hz, 1H), 6.23 (s, 1H), 4.39 (s, 2H), 3.58-3.46 (m, 1H), 3.24 (s, 2H), 2.74 (t, J=10.5 Hz, 1H), 2.02 (s, 1H), 1.79 (td, J=12.2, 6.4 Hz, 1H), 1.50 (ddd, J=21.4, 10.3, 6.2 Hz, 2H), 1.36 (d, J=11.7 Hz, 9H), 1.30 (d, J=13.8 Hz, 6H), 1.17 (s, 3H), 1.11 (s, 2H), 1.09 (s, 2H). ESI-MS m/z calc. 755.248, found 756.5 (M+1) + ; Retention time: 2.31 min (LC Method E).

Step 6: 12,12-Dimethyl-8-(3-{[1-(trifluoromethyl)cyclopropyl]methoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Compound 15)

Part A: tert-Butyl 4-[3-[[6-[[2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (232 mg, 0.3068 mmol) was dissolved in dichloromethane (5.0 mL) and hydrochloric acid (4M in dioxane) (2.5 mL of 4 M, 10.00 mmol) was added to the mixture and allowed to stir at room temperature for 3 h. The reaction was concentrated to dryness under reduced pressure, redissolved in ethyl acetate, and then aqueous 2M sodium carbonate (5 mL) was added to adjust the solution to pH 10. The organic layer was extracted with ethyl acetate (2×10 mL), washed with brine, dried over sodium sulfate, and evaporated to dryness under reduced pressure.

Part B: To a vial was added the crude amine from Part A, potassium carbonate (235 mg, 1.70 mmol), cesium fluoride (75.3 mg, 0.4957 mmol), 3 Å molecular sieves, and dimethyl sulfoxide (7.0 mL). The vial was purged with nitrogen, capped, heated to 150° C. and stirred for 16 h. The reaction was cooled to room temperature. The reaction was diluted with ethyl acetate and washed with a 1M citric acid solution, followed by brine. The organics were separated, dried over sodium sulfate, evaporated, and then purified by silica gel chromatography (24 gram column) using a gradient from 100% hexanes to 80% ethyl acetate to afford as an off-white solid, 12,12-dimethyl-8-(3-{[1-(trifluoromethyl) cyclopropyl]methoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Compound 15) (101.9 mg, 54%). 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.51 (s, 1H), 8.22 (d, J=2.8 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.66-7.49 (m, 1H), 7.05 (d, J=7.2 Hz, 1H), 6.98 (d, J=5.5 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 6.16 (d, J=2.7 Hz, 1H), 4.36 (q, J=11.9 Hz, 2H), 3.92 (dd, J=24.2, 10.9 Hz, 1H), 3.24-3.07 (m, 1H), 2.95 (d, J=13.0 Hz, 1H), 2.78-2.64 (m, 1H), 2.22-2.08 (m, 1H), 1.86 (dd, J=11.8, 5.0 Hz, 1H), 1.76 (dd, J=15.9, 8.1 Hz, 1H), 1.65-1.54 (m, 6H), 1.51 (s, 3H), 1.31 (dd, J=24.7, 12.0 Hz, 1H), 1.10 (s, 4H). ESI-MS m/z calc. 619.2189, found 620.2 (M+1) + ; Retention time: 2.1 min (LC Method E).

Example 6: Preparation of 12,12-dimethyl-8-(3-{[1-(trifluoromethyl)cyclopropyl]methoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Enantiomer 1) (Compound 21) and 12,12-dimethyl-8-(3-{[1-(trifluoromethyl)cyclopropyl]methoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Enantiomer 2) (Compound 22)

Step 1: 12,12-Dimethyl-8-(3-{[1-(trifluoromethyl)cyclopropyl]methoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Enantiomer 1) (Compound 21) and 12,12-dimethyl-8-(3-{[1-(trifluoromethyl)cyclopropyl]methoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Enantiomer 2) (Compound 22)

Racemic 12,12-dimethyl-8-(3-{[1-(trifluoromethyl)cyclopropyl]methoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1 (23),5(10),6,8,19,21-hexaene-2,2,4-trione (Compound 15) (82.4 mg, 0.133 mmol) was subjected to chiral SFC chromatography using a ChiralPak AS-H (250×21.2 mm column, 5 μm particle size) with 20% acetonitrile (No modifier))/80% carbon dioxide mobile phase at 70 mL/min giving as the first enantiomer to elute, 12,12-dimethyl-8-(3-{[1-(trifluoromethyl)cyclopropyl]methoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (enantiomer 1) (Compound 21) (32.38 mg, 78%) as an off-white solid; 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.51 (s, 1H), 8.22 (d, J=2.7 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.72-7.67 (m, 1H), 7.62-7.50 (m, 1H), 7.05 (d, J=7.0 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 6.15 (d, J=2.7 Hz, 1H), 4.36 (q, J=11.9 Hz, 2H), 4.16-4.12 (m, 1H), 3.22-3.10 (m, 1H), 2.95 (d, J=12.9 Hz, 1H), 2.74-2.68 (m, 1H), 2.20-2.03 (m, 1H), 1.86 (dd, J=12.2, 5.0 Hz, 1H), 1.76 (dd, J=10.3, 4.8 Hz, 1H), 1.60 (s, 3H), 1.51 (s, 3H), 1.28 (s, 4H), 1.10 (s, 2H), 0.87 (d, J=5.1 Hz, 2H), ESI-MS m/z calc. 619.2189, found 620.2 (M+1) + ; Retention time: 2.1 min (LC Method E) and as the second enantiomer to elute, 12,12-dimethyl-8-(3-{[1-(trifluoromethyl)cyclopropyl]methoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (enantiomer 2) (Compound 22) (34.58 mg, 83%) as an off-white solid; 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.51 (s, 1H), 8.22 (d, J=2.8 Hz, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.69 (d, J=3.6 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.05 (d, J=7.2 Hz, 1H), 6.92 (d, J=8.3 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 6.16 (d, J=2.8 Hz, 1H), 4.36 (q, J=11.9 Hz, 2H), 4.14 (d, J=2.3 Hz, 1H), 3.16 (s, 1H), 2.95 (d, J=13.4 Hz, 1H), 2.76-2.68 (m, 1H), 2.19-2.07 (m, 1H), 1.86 (dd, J=11.8, 5.1 Hz, 1H), 1.75 (s, 1H), 1.60 (s, 3H), 1.51 (s, 3H), 1.28 (d, J=2.1 Hz, 4H), 1.10 (d, J=2.7 Hz, 2H), 0.88 (s, 2H), ESI-MS m/z calc. 619.2189, found 620.2 (M+1) + ; Retention time: 2.1 min (LC Method E).

›Step 2: 3-[[1-(Trifluoromethyl)cyclopropyl]methoxy]-1H-pyrazole · 3 of 3

Example 7: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.111,14.05,10]pentacosa-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (Compound 28)

›Step 1: Ethyl 1-(bromomethyl)-2-oxocyclopentanecarboxylate

A solution of ethyl 2-oxocyclopentanecarboxylate (70 g, 449 mmol) in dry tetrahydrofuran (300 mL) was added slowly to a suspension of 67.6% sodium hydride suspension in mineral oil (19.17 g, 540 mmol) in tetrahydrofuran (750 mL) containing hexamethylphosphoramide (97 g, 540 mmol) at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 1 h. Dibromomethane (392 g, 250 mmol) was added and the reaction mixture was refluxed at 80° C. for 16 h. The reaction was allowed to cool to room temperature and diethyl ether (1000 mL) was added and the organic layer was washed with water (5×500 mL), dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography using 0-10% hexanes-ethyl acetate to provide ethyl 1-(bromomethyl)-2-oxocyclopentanecarboxylate (85 g, 76%) of as a colorless oil. 1 H NMR (250 MHz, CDCl 3 ) δ 4.18 (q, J=7.0 Hz, 7.25 Hz, 2H); 3.68 (q, J=22.5 Hz, J=9.5 Hz, 2H); 2.58-2.00 (m, 6H); 1.25 (t, J=7.75 Hz, 3H).

›Step 2: Diethyl 2-methylenehexanedioate

Potassium carbonate (79 g, 572 mmol) was added to a solution of ethyl 1-(bromomethyl)-2-oxocyclopentanecarboxylate (85 g, 341 mmol) in dry ethanol (680 mL) and the mixture was stirred at room temperature for 16 h. The mixture was filtered, evaporated and purified by silica gel column chromatography using 0-5% hexanes-ethyl acetate to provide diethyl 2-methylenehexanedioate (72.7 g, 98%) as a colorless oil. 1 H NMR (250 MHz, CDCl 3 ) δ 6.16 (s, 1H); 5.54 (s, 1H); 4.24-4.07 (m, 4H); 2.36-2.28 (m, 4H), 1.83-1.77 (m, 2H), 1.32-1.21 (m, 6H).

›Step 3: Diethyl 2-(2-methyl-2-nitropropyl)hexanedioate

1,8-Diazabicycloundec-7-ene (23 g, 151 mmol) was added to a solution of diethyl 2-methylenehexanedioate (72.7 g, 340 mmol) and 2-nitropropane (36.3 g, 408 mmol) in dry acetonitrile (1000 mL) and the mixture was stirred at room temperature for 16 h. The mixture was evaporated and the residue was dissolved in ethyl acetate (1000 mL) and washed with saturated ammonium chloride (500 mL). The organic phase was concentrated and purified by silica gel column chromatography using 0-10% hexanes-ethyl acetate to provide diethyl 2-(2-methyl-2-nitropropyl)hexanedioate (86 g, 84%) as a colorless oil. 1 H NMR (250 MHz, CDCl 3 ) δ 4.17-4.07 (m, 4H); 2.41-2.05 (m, 5H), 1.72-1.44 (m, 4H), 1.56 (s, 3H), 1.51 (s, 3H), 1.28-1.21 (m, 6H).

›Step 4: 4-(4,4-Dimethyl-5-oxo-pyrrolidin-2-yl)-butyric acid ethyl ester

A mixture of diethyl 2-(2-methyl-2-nitropropyl)hexanedioate (43 g, 141.7 mmol) and Raney nickel slurry (12 g) in ethanol (860 mL) was heated at 80° C. for 18 h in a Parr reactor under 2 bar of hydrogen gas. Celite (50 g) was added and the resulting mixture was filtered. The solids were discarded and the filtrate was concentrated to obtain 4-(4,4-dimethyl-5-oxo-pyrrolidin-2-yl)-butyric acid ethyl ester (31.2 g, 97%) as an orange oil. The crude product was used in the next step without further purification. ESI-MS m/z calc. 227.3, found 228.3 (M+1) + . Retention time: 3.23 min (LC Method Q).

›Step 5: 4-(4,4-Dimethylpyrrolidin-2-yl)-butan-1-ol

To a solution of 4-(4,4-dimethyl-5-oxo-pyrrolidin-2-yl)-butyric acid ethyl ester (78.8 g, 345.3 mmol) in tetrahydrofuran (1200 mL) was added lithium aluminum hydride (39.3 g, 1036.0 mmol) in portions over a 45 min period and the resulting slurry was heated to reflux under nitrogen for 18 h. The cooled reaction mixture was carefully quenched with a saturated solution of sodium sulfate (100 mL) and the formed solid was filtered. The solids were discarded and the filtrate was concentrated under vacuum to obtain 4-(4,4-dimethylpyrrolidin-2-yl)-butan-1-ol (51.5 g, 87%) as a brown oil. The crude product was used in the next step without further purification. ESI-MS m/z calc. 171.28, found 172.3 (M+1) + . Retention time: 1.05 min (LC Method Q).

›Step 6: 2-(4-Hydroxybutyl)-4,4-dimethyl-pyrrolidine-1-carboxylic Acid tert-butyl ester

To a solution of 4-(4,4-dimethylpyrrolidin-2-yl)-butan-1-ol (51.5 g, 301 mmol) in dichloromethane (400 mL) was added a solution of sodium bicarbonate (50.6 g, 602 mmol) in water (300 mL) followed by di-tert-butyl dicarbonate (65.6 g, 301 mmol). The resulting biphasic mixture was stirred for 18 h at room temperature. The phases were separated and the aqueous phase was discarded. The organic phase was concentrated and purified by silica gel column chromatography using 0-45% hexanes-ethyl acetate to obtain 2-(4-hydroxybutyl)-4,4-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (57.2 g, 77%) as a clear oil. 1 H NMR (250 MHz, CDCl 3 ) δ 4.35 (t, 1H), 3.53 (m, 1H), 3.37 (m, 2H), 2.76 (m, 1H), 2.01-1.81 (m, 2H), 1.40-1.24 (m, 23H). ESI-MS m/z calc. 271.4, found 272.4 (M+1) + . Retention time: 4.67 min (LC Method Q).

›Step 7: tert-Butyl 2,2-dimethyl-4-(4-methylsulfonyloxybutyl)pyrrolidine-1-carboxylate

To a solution of tert-butyl 4-(4-hydroxybutyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (2.28 g, 8.401 mmol) in dichloromethane (19 mL) and triethylamine (8.0 mL, 57 mmol) chilled to 0° C. was added methanesulfonyl chloride (2.161 mL, 27.92 mmol) dropwise. The reaction mixture was stirred for 20 h allowing the reaction to warm to room temperature after 1 h (the clear solution turned cloudy orange after 10 min). The reaction mixture was quenched with ice-water and dichloromethane, followed by brine. The aqueous layer was extracted with further dichloromethane (2×20 mL) and the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was dried under vacuum for 1 h to provide tert-butyl 2,2-dimethyl-4-(4-methylsulfonyloxybutyl)pyrrolidine-1-carboxylate (2.9 g, 99%) as a yellow oil. ESI-MS m/z calc. 349.1923, found 350.2 (M+1) + ; Retention time: 1.82 min (LC Method E).

›Step 8: tert-Butyl 4-(4-aminobutyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

tert-Butyl 2,2-dimethyl-4-(4-methylsulfonyloxybutyl)pyrrolidine-1-carboxylate (2.9 g, 8.298 mmol) was dissolved in a mixture of dioxane (60 mL) and ammonium hydroxide (60 mL of 30% w/v, 510 mmol). The mixture was heated to 50° C. in a sealed vessel for 18 h. The dioxane was concentrated under vacuum and dichloromethane (50 mL) was added. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under vacuum. The crude material was purified by silica gel chromatography (80 gram column) using dichloromethane methanol (containing 5 mL/liter 30% ammonium hydroxide) gradient method (0 to 15% methanol in dichloromethane) to obtain tert-butyl 4-(4-aminobutyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (1.44 g, 64%) as an off-white foam. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 7.90 (s, 2H), 3.55 (dd, J=18.7, 11.1 Hz, 1H), 3.34 (s, 2H), 3.17 (s, 1H), 2.76 (dd, J=17.0, 9.5 Hz, 2H), 2.06 (s, 1H), 1.95-1.74 (m, 1H), 1.52 (t, J=18.4 Hz, 2H), 1.39 (d, J=9.9 Hz, 9H), 1.35 (s, 1H), 1.34 (s, 2H), 1.31-1.18 (m, 6H). ESI-MS m/z calc. 270.23074, found 271.2 (M+1) + ; Retention time: 1.21 min (LC Method E).

›Step 9: tert-Butyl 2,2-dimethyl-4-[4-[(6-sulfamoyl-2-pyridyl)amino]butyl]pyrrolidine-1-carboxylate · 1 of 2

In a 250 mL flask was combined 6-fluoropyridine-2-sulfonamide (894 mg, 5.07 mmol) in dimethyl sulfoxide (20 mL), followed by potassium carbonate (1.1 g, 8.0 mmol) and tert-butyl 4-(4-aminobutyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (1.44 g, 5.33 mmol) under nitrogen and a reflux condenser. The vessel was heated at 60° C. in an oil bath for 18 h. Added potassium carbonate (1.1 g, 8.0 mmol) and increased heat to 80° C. for an additional 4 h. Upon cooling, the reaction mixture was filtered then diluted with ethyl acetate and washed with a 1 M citric acid solution, followed by brine. The organics were separated, dried over sodium sulfate, filtered, evaporated and purified by silica gel chromatography (80 gram column GOLD) using a gradient from 100% hexanes to 75% ethyl acetate in hexanes to afford as a white solid, tert-butyl 2,2-dimethyl-4-[4-[(6-sulfamoyl-2-pyridyl)amino]butyl]pyrrolidine-1-carboxylate (475 mg, 22%). 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 7.51 (dd, J=8.4, 7.3 Hz, 1H), 7.07 (s, 2H), 6.94 (t, J=5.7 Hz, 2H), 6.61 (d, J=8.2 Hz, 1H), 3.54 (dd, J=18.2, 8.5 Hz, 1H), 3.28 (dd, J=12.6, 6.6 Hz, 2H), 2.78 (dd, J=19.7, 10.1 Hz, 1H), 2.07 (s, 1H), 1.94-1.80 (m, 1H), 1.52 (s, 2H), 1.44 (d, J=12.2 Hz, 1H), 1.38 (d, J=10.4 Hz, 9H), 1.35 (d, J=10.9 Hz, 6H), 1.21 (d, J=17.2 Hz, 4H). ESI-MS m/z calc. 426.23007, found 427.2 (M+1) + ; Retention time: 1.76 min (LC Method E).

Step 10: tert-Butyl 4-[4-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]butyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (425 mg, 1.13 mmol) and carbonyl diimidazole (217 mg, 1.34 mmol) were combined in tetrahydrofuran (7 mL) and stirred for 90 min at 50° C. Then tert-butyl 2,2-dimethyl-4-[4-[(6-sulfamoyl-2-pyridyl)amino]butyl]pyrrolidine-1-carboxylate (475 mg, 1.11 mmol) was added followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (350 μL, 2.34 mmol) and the reaction was heated at 50° C. for 18 h. The reaction was diluted with ethyl acetate and washed with a 1 M citric acid solution, followed by brine. The organics were separated, dried over sodium sulfate, filtered and evaporated then purified by silica gel chromatography (80 gram column) using a gradient from 100% hexanes to 70% ethyl acetate in hexanes to afford tert-butyl 4-[4-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]butyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (613 mg, 83%) as a white solid. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.80 (s, 1H), 8.41 (t, J=3.0 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.61 (dd, J=8.4, 7.3 Hz, 1H), 7.22 (s, 1H), 7.16 (d, J=7.0 Hz, 1H), 6.73 (d, J=8.5 Hz, 1H), 6.18 (d, J=2.9 Hz, 1H), 4.34 (t, J=7.0 Hz, 2H), 3.54-3.42 (m, 1H), 3.22 (t, J=6.8 Hz, 2H), 2.72-2.63 (m, 1H), 2.08 (t, J=7.1 Hz, 2H), 2.00-1.88 (m, 1H), 1.71 (td, J=11.2, 5.9 Hz, 1H), 1.53-1.45 (m, 2H), 1.40-1.34 (m, 9H), 1.25 (t, J=11.6 Hz, 6H), 1.20-1.18 (m, 1H), 1.17 (d, J=6.0 Hz, 4H), 0.98-0.92 (m, 2H), 0.88 (s, 2H). ESI-MS m/z calc. 783.27924, found 784.2 (M+1) + ; Retention time: 2.4 min (LC Method E).

Step 11: 12,12-Dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.111,14.05,10]pentacosa-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (Compound 28)

Part A: tert-Butyl 4-[4-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]butyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (538 mg, 0.686 mmol) was dissolved in dichloromethane (12 mL) and to the mixture was added hydrochloric acid (4 M in dioxane) (5 mL of 4 M, 20.0 mmol) and stirred at room temperature for 1 h. Concentrated mixture to dryness under reduced pressure, redissolved in ethyl acetate, then added aqueous 2 M sodium carbonate (5 mL), giving pH˜10. Extracted with ethyl acetate (2×10 mL), washed with brine, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure.

Part B: Combined material from Part A and potassium carbonate (474 mg, 3.43 mmol), cesium fluoride (156 mg, 1.03 mmol), 3 Å molecular sieves and dimethyl sulfoxide (11 mL) in a vial, purged with nitrogen, capped, heated to 150° C. and stirred for 18 h. Cooled to room temperature. The reaction was diluted with ethyl acetate and washed with a 1 M citric acid solution, followed by brine. The organics were separated, dried over sodium sulfate, filtered and evaporated then purified by silica gel chromatography (40 gram column) using a gradient from 100% hexanes to 80% ethyl acetate in hexanes to afford 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.111,14.05,10]pentacosa-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (Compound 28) (270 mg, 60%) as a white solid. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.45 (s, 1H), 8.21 (d, J=2.7 Hz, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.69 (t, J=7.9 Hz, 1H), 7.23 (d, J=7.2 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 6.81 (d, J=8.4 Hz, 1H), 6.12 (d, J=2.7 Hz, 1H), 4.32 (t, J=7.0 Hz, 2H), 3.51 (s, 2H), 3.30 (s, 1H), 2.76 (d, J=15.3 Hz, 1H), 2.69-2.58 (m, 1H), 2.14 (d, J=7.4 Hz, 1H), 2.08 (t, J=7.0 Hz, 2H), 1.85 (dd, J=11.6, 5.4 Hz, 1H), 1.56 (s, 2H), 1.55 (d, J=3.3 Hz, 6H), 1.46 (s, 2H), 1.26-1.16 (m, 2H), 0.96 (t, J=5.7 Hz, 2H), 0.89 (s, 2H). ESI-MS m/z calc. 647.2502, found 648.2 (M+1) + ; Retention time: 2.26 min (LC Method E).

Example 8: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.111,14.05,10]pentacosa-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (Enantiomer 1) (Compound 29) and 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.111,14.05,10]pentacosa-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (Enantiomer 2) (Compound 30)

›Step 9: tert-Butyl 2,2-dimethyl-4-[4-[(6-sulfamoyl-2-pyridyl)amino]butyl]pyrrolidine-1-carboxylate · 2 of 2

Step 1: 12,12-Dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.111,14.05,10]pentacosa-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (Enantiomer 1) (Compound 29) and 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.111,14.05,10]pentacosa-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (Enantiomer 2) (Compound 30)

Racemic 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.111,14.05,10]pentacosa-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (Compound 28) (204 mg, 0.3150 mmol) was subjected to chiral SFC chromatography using a ChiralPak AS-H (250×21.2 mm column, 5 μm particle size) with 30% acetonitrile:methanol (90:10))/70% carbon dioxide mobile phase at 0.5 mL/min giving as the first enantiomer to elute, 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.111,14.05,10]pentacosa-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (enantiomer 1) (Compound 29) (94.1 mg, 91%) as an off-white solid; ESI-MS m/z calc. 647.2502, found 648.2 (M+1) + ; Retention time: 2.27 min (LC Method E) and as the second enantiomer to elute, 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.111,14.05,10]pentacosa-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (enantiomer 2) (Compound 30) (90.0 mg, 87%) as an off-white solid; 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.45 (s, 1H), 8.21 (d, J=2.8 Hz, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.69 (t, J=7.9 Hz, 1H), 7.23 (d, J=7.2 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 6.81 (d, J=8.1 Hz, 2H), 6.12 (d, J=2.7 Hz, 1H), 4.32 (t, J=7.0 Hz, 2H), 3.29 (dd, J=4.7, 2.4 Hz, 1H), 2.86-2.69 (m, 1H), 2.63 (dd, J=16.0, 11.6 Hz, 1H), 2.13 (s, 1H), 2.08 (t, J=7.1 Hz, 2H), 1.85 (dd, J=11.9, 5.5 Hz, 1H), 1.68-1.56 (m, 2H), 1.55 (d, J=2.9 Hz, 6H), 1.47 (dd, J=22.2, 10.1 Hz, 2H), 1.26-1.16 (m, 2H), 0.96 (dd, J=7.7, 3.7 Hz, 2H), 0.93 (d, J=9.2 Hz, 1H), 0.88 (t, J=5.8 Hz, 2H), ESI-MS m/z calc. 647.2502, found 648.2 (M+1) + ; Retention time: 2.27 min (LC Method E).

Example 9: Preparation of 12,12,17-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Diastereomer Pair 1) (Compound 35), 12,12,17-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Diastereomer Pair 2) (Compound 36), 12,12,17-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Diastereomer Pair 1, Enantiomer 1) (Compound 58), 12,12,17-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Diastereomer Pair 1, Enantiomer 2) (Compound 59), 12,12,17-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Diastereomer Pair 2, Enantiomer 1) (Compound 60) and 12,12,17-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Diastereomer Pair 2, Enantiomer 2) (Compound 61)

›Step 1: (3E)-3-(Hydroxymethylene)-6-methyl-tetrahydropyran-2-one (Sodium Salt)

To a suspension of sodium hydride (60% in mineral oil) (2.63 g of 60% w/w, 65.8 mmol) in diethyl ether (56 mL) was added absolute ethanol (300 μL) then a mixture of 6-methyltetrahydropyran-2-one (5.0 g, 43.80 mmol) and ethyl formate (6.0 mL, 74 mmol) was added dropwise at ambient temperature within 30 min. After addition was finished the reaction mixture stirred for 1 h at room temperature. The solid formed in the mixture (sodium salt of product) was collected by filtration, washed with diethyl ether and dried under high vacuum to afford (3E)-3-(hydroxymethylene)-6-methyl-tetrahydropyran-2-one (Sodium salt) (7.1 g, 99%). ESI-MS m/z calc. 142.06299, found 143.2 (M+1) + ; Retention time: 0.64 min (LC Method E).

›Step 2: 6-Methyl-3-methylene-tetrahydropyran-2-one

(3E)-3-(Hydroxymethylene)-6-methyl-tetrahydropyran-2-one (Sodium salt) (7.1 g, 43 mmol) was suspended in tetrahydrofuran (100 mL), treated with paraformaldehyde (4.2 g, 140 mmol) under nitrogen and the mixture was heated to 65° C. for 1 h. The mixture was cooled in an ice-water bath, quenched with aqueous saturated potassium carbonate (20 mL) and the organic phase was separated, then the aqueous phase was extracted with diethyl ether (4×10 mL). The organic fractions were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure by rotary evaporation with no heating. The residue obtained was purified by silica gel chromatography (120 gram column) using a gradient from 100% hexanes to 40% ethyl acetate in hexanes to afford as a colorless liquid, 6-methyl-3-methylene-tetrahydropyran-2-one (2.96 g, 55%). 1 H NMR (400 MHz, CDCl 3 ) δ 6.48-6.38 (m, 1H), 5.57 (dt, J=2.7, 1.5 Hz, 1H), 4.49 (dqd, J=10.4, 6.3, 2.6 Hz, 1H), 2.71 (dddt, J=16.2, 5.0, 3.5, 1.3 Hz, 1H), 2.65-2.52 (m, 1H), 2.03-1.93 (m, 1H), 1.67 (dddd, J=13.9, 12.4, 10.5, 5.1 Hz, 1H), 1.40 (d, J=6.3 Hz, 3H). ESI-MS m/z calc. 126.06808, found 127.0 (M+1) + ; Retention time: 0.66 min (LC Method E).

›Step 3: 6-Methyl-3-(2-methyl-2-nitro-propyl)tetrahydropyran-2-one

2-Nitropropane (2.6 mL, 29 mmol) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (550 μL, 3.68 mmol) and stirred for 5 min under nitrogen then a solution of 6-methyl-3-methylene-tetrahydropyran-2-one (2.96 g, 23.5 mmol) in acetonitrile (32 mL) was added dropwise at room temperature over 45 min. The solution was stirred at room temperature for 4 h. The mixture was evaporated and the residue was then purified by silica gel chromatography (120 gram column) using a gradient from 100% hexanes to 60% ethyl acetate in hexanes to isolate product which was then dried under vacuum to afford as a clear oil which turned into a white solid upon standing, 6-methyl-3-(2-methyl-2-nitro-propyl)tetrahydropyran-2-one (4.32 g, 85%). 1 H NMR (400 MHz, CDCl 3 ) δ 4.57-4.37 (m, 1H), 2.71-2.58 (m, 1H), 2.51-2.32 (m, 1H), 2.24 (dd, J=15.0, 6.9 Hz, 1H), 2.14-2.06 (m, 1H), 2.00-1.87 (m, 1H), 1.68-1.60 (m, 6H), 1.58 (dd, J=4.8, 2.7 Hz, 1H), 1.56-1.47 (m, 1H), 1.36 (dd, J=6.2, 3.2 Hz, 3H). ESI-MS m/z calc. 215.11575, found 216.2 (M+1) + ; Retention time: 1.11 min (LC Method E).

›Step 4: 3-(3-Hydroxybutyl)-5,5-dimethyl-pyrrolidin-2-one

6-methyl-3-(2-methyl-2-nitro-propyl)tetrahydropyran-2-one (4.32 g, 20.07 mmol) was dissolved in ethanol (78 mL) and wet Raney nickel (1.2 g, 20.45 mmol) was added under nitrogen atmosphere. Three vacuum/hydrogen cycles were performed and the resulting mixture was stirred at room temperature under hydrogen (1 atmosphere) for 10 min. Then the suspension was equipped with a reflux condenser and heated to 60° C. and stirred at this temperature under hydrogen for 24 h. Cooled to room temperature and filtered through Celite and washed with ethyl acetate. The filtrates were combined and concentrated under reduced pressure and the residue was purified by silica gel chromatography (120 gram column) using a shallow gradient from 100% dichloromethane to 10% methanol in dichloromethane giving 3-(3-hydroxybutyl)-5,5-dimethyl-pyrrolidin-2-one (2.5 g, 67%) as a white solid. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 7.63 (s, 1H), 4.36 (d, J=4.7 Hz, 1H), 3.56 (dt, J=11.9, 6.0 Hz, 1H), 2.35 (qd, J=9.3, 4.4 Hz, 1H), 2.01 (dd, J=12.3, 8.6 Hz, 1H), 1.85-1.59 (m, 1H), 1.45-1.35 (m, 1H), 1.31 (ddd, J=10.6, 8.1, 4.1 Hz, 2H), 1.28-1.20 (m, 1H), 1.18 (s, 3H), 1.13 (s, 3H), 1.03 (dd, J=6.2, 1.6 Hz, 3H). ESI-MS m/z calc. 185.14159, found 186.2 (M+1) + ; Retention time: 0.74 min (LC Method E).

›Step 5: 4-(5,5-Dimethylpyrrolidin-3-yl)butan-2-ol

A solution of 3-(3-hydroxybutyl)-5,5-dimethyl-pyrrolidin-2-one (2.5 g, 13.49 mmol) in anhydrous tetrahydrofuran (37 mL) was carefully added (within 20 min) to a suspension of lithium aluminum hydride (686.6 mg, 20.24 mmol) in dry tetrahydrofuran (37 mL) at room temperature under nitrogen atmosphere. After addition was finished the reaction mixture was heated to reflux for 72 h (two extra portions of lithium aluminum hydride (200 mg, 7.00 mmol) were added to the reaction mixture after 24 h and 48 h of refluxing). The mixture was cooled in an ice-water bath; more tetrahydrofuran (25 mL) was added to the mixture followed by slow addition of aqueous saturated sodium potassium tartrate tetrahydrate (Rochelle's salt, 30 mL). The resulting mixture was stirred vigorously for 2 h at room temperature until a clear separation of aqueous and organic phases was achieved; then the organic layer was separated and concentrated under vacuum. The residue was dissolved in dichloromethane (100 mL) and the obtained solution was washed with brine (2×15 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford as a yellow oil, 4-(5,5-dimethylpyrrolidin-3-yl)butan-2-ol (1.6 g, 69%). 1 H NMR (400 MHz, CDCl 3 ) δ 3.78 (dd, J=11.9, 5.8 Hz, 1H), 3.14 (ddd, J=10.4, 7.6, 2.8 Hz, 1H), 2.59 (dd, J=11.0, 8.1 Hz, 1H), 2.24-2.07 (m, 1H), 1.87-1.78 (m, 1H), 1.73 (s, 2H), 1.54-1.37 (m, 4H), 1.37-1.21 (m, 1H), 1.21-1.13 (m, 9H). ESI-MS m/z calc. 171.16231, found 172.2 (M+1) + ; Retention time: 0.53 min (LC Method E).

›Step 6: tert-Butyl 4-(3-hydroxybutyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

Di-tert-butyl dicarbonate (2.4 mL, 10.45 mmol) and triethylamine (1.7 mL, 12.20 mmol) were added to a solution of 4-(5,5-dimethylpyrrolidin-3-yl)butan-2-ol (1.6 g, 9.341 mmol) dissolved in dichloromethane (40 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. The mixture was washed with water (15 mL), saturated sodium bicarbonate (15 mL) and brine (15 mL) then extracted the organic, dried over sodium sulfate, filtered and concentrated the mixture. The residue was purified by silica gel chromatography (40 gram column) using a gradient from 100% dichloromethane to 10% methanol in dichloromethane to isolate as a clear oil, tert-butyl 4-(3-hydroxybutyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (2.4 g, 95%). 1 H NMR (400 MHz, CDCl 3 ) δ 3.79 (s, 1H), 3.75-3.56 (m, 1H), 3.00-2.77 (m, 1H), 2.18-2.04 (m, 1H), 1.89 (td, J=12.3, 6.0 Hz, 1H), 1.63 (s, 1H), 1.53 (s, 5H), 1.49-1.43 (m, 12H), 1.38 (s, 1H), 1.34 (dd, J=9.1, 4.5 Hz, 2H), 1.20 (t, J=5.5 Hz, 3H). ESI-MS m/z calc. 271.21475, found 272.2 (M+1) + ; Retention time: 1.64 min (LC Method E).

›Step 7: tert-Butyl 2,2-dimethyl-4-(3-methylsulfonyloxybutyl)pyrrolidine-1-carboxylate

To a solution in dichloromethane (6 mL) chilled to 0° C. of tert-butyl 4-(3-hydroxybutyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (346 mg, 1.275 mmol) and triethylamine (1.2 mL, 8.6 mmol) was added dropwise methanesulfonyl chloride (350 μL, 4.52 mmol). The reaction mixture was stirred for 20 h allowing to warm to room temperature after 1 h (the clear solution turned cloudy orange after 10 min). The reaction mixture was quenched with ice-water and dichloromethane, followed by brine. The aqueous layer was extracted with further dichloromethane (2×20 mL) and the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was dried under vacuum for 1 h to give as a yellow oil, tert-butyl 2,2-dimethyl-4-(3-methylsulfonyloxybutyl)pyrrolidine-1-carboxylate (440 mg, 99%). ESI-MS m/z calc. 349.1923, found 350.1 (M+1) + ; Retention time: 1.8 min (LC Method E).

›Step 8: tert-Butyl 4-(3-aminobutyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

tert-Butyl 2,2-dimethyl-4-(3-methylsulfonyloxybutyl)pyrrolidine-1-carboxylate (440 mg, 1.259 mmol) was dissolved in a mixture of dioxane (10 mL) and ammonium hydroxide (10 mL of 30% w/v, 85.60 mmol). The mixture was heated to 50° C. in a sealed vessel for 72 h. The dioxane was concentrated under vacuum and dichloromethane (50 mL) was added. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under vacuum. The crude material was purified by silica gel chromatography (24 gram column) using dichloromethane methanol (containing 5 mL/liter 30% ammonium hydroxide) gradient method (0 to 15% methanol) to obtain as a light yellow oil, tert-butyl 4-(3-aminobutyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (199 mg, 58%). 1 H NMR (400 MHz, dimethyl sulfoxide) δ 7.86 (s, 2H), 3.62-3.49 (m, 1H), 3.14 (dt, J=17.3, 5.3 Hz, 1H), 2.79 (dd, J=19.2, 10.2 Hz, 1H), 2.08-1.97 (m, 1H), 1.93-1.81 (m, 1H), 1.56 (ddd, J=25.3, 14.2, 6.6 Hz, 1H), 1.49-1.43 (m, 1H), 1.42-1.33 (m, 15H), 1.24 (d, J=5.9 Hz, 4H), 1.16 (d, J=6.5 Hz, 2H).

›Step 9: tert-Butyl 2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]butyl]pyrrolidine-1-carboxylate · 1 of 2

In a sealed 20 mL microwave vial, a solution of 6-fluoropyridine-2-sulfonamide (526 mg, 2.986 mmol), tert-butyl 4-(3-aminobutyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (800 mg, 2.958 mmol) and diisopropylethylamine (2.6 mL, 14.93 mmol) in dimethyl sulfoxide (8 mL) was stirred at 130° C. for 16 h. The solvent was removed in vacuo and the residue was dissolved in dichloromethane and washed with water. Organic extract was dried over sodium sulfate, evaporated and purified by silica gel chromatography using 12 g column (gradient from 0-85% ethyl acetate/hexanes) to afford tert-butyl 2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]butyl]pyrrolidine-1-carboxylate (490 mg, 38%). 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 7.49 (dd, J=8.4, 7.3 Hz, 1H), 7.03 (s, 2H), 6.93 (d, J=7.2 Hz, 1H), 6.78 (d, J=8.1 Hz, 1H), 6.59 (d, J=8.4 Hz, 1H), 4.02 (s, 1H), 3.53 (d, J=10.0 Hz, 1H), 2.78 (dd, J=18.9, 10.6 Hz, 1H), 2.02 (d, J=27.8 Hz, 1H), 1.88 (s, 1H), 1.55-1.42 (m, 2H), 1.42-1.29 (m, 16H), 1.23 (s, 3H), 1.11 (d, J=6.4 Hz, 3H). ESI-MS m/z calc. 426.23007, found 427.1 (M+1) + ; Retention time: 0.66 min (LC Method A).

Step 10: tert-Butyl 4-[3-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]butyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (160 mg, 0.4258 mmol) and carbonyl diimidazole (69 mg, 0.4255 mmol) were combined in tetrahydrofuran (2.5 mL) and stirred for 120 min at 50° C. Then tert-butyl 2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]butyl]pyrrolidine-1-carboxylate (145 mg, 0.3399 mmol) was added followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (110 μL, 0.7356 mmol) and the reaction was heated at 50° C. for 18 h. The reaction was diluted with ethyl acetate and washed with a 1 M citric acid solution, followed by brine. The organics were separated, dried over sodium sulfate, filtered and evaporated and then purified by reverse-phase preparative reverse-phase HPLC utilizing a C 18 column and method 30-99 A1-B1 (acetonitrile-water+5 mM hydrochloric acid) to afford tert-butyl 4-[3-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]butyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (97 mg, 36%) as a white solid. ESI-MS m/z calc. 783.27924, found 784.2 (M+1) + ; Retention time: 2.44 min (LC Method E).

Step 11: 12,12,17-Trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Diastereomer Pair 1) (Compound 35), 12,12,17-Trimethyl-8-(3-{2-[1-(trifluoromethyl) cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Diastereomer Pair 2) (Compound 36), 12,12,17-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Diastereomer Pair 1, Enantiomer 1) (Compound 58), 12,12,17-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Diastereomer Pair 1, Enantiomer 2) (Compound 59), 12,12,17-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Diastereomer Pair 2, Enantiomer 1) (Compound 60) and 12,12,17-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Diastereomer Pair 2, Enantiomer 2) (Compound 61)

Part A: tert-Butyl 4-[3-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]butyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (97 mg, 0.1237 mmol) was dissolved in dichloromethane (2.0 mL) and to the mixture was added hydrochloric acid (4 M in dioxane) (1000 μL of 4 M, 4.000 mmol) and stirred at room temperature for 3 h. Concentrated mixture to dryness under reduced pressure, redissolved in ethyl acetate, then added aqueous 2 M sodium carbonate (5 mL), giving pH˜10. Extracted organic layer with ethyl acetate (2×10 mL), washed with brine, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure.

Part B: Combined material from Part A and potassium carbonate (90 mg, 0.6512 mmol), cesium fluoride (30 mg, 0.1975 mmol), 3 Å molecular sieves and dimethyl sulfoxide (2.0 mL) in a vial, purged with nitrogen, capped, heated at 150° C. and stirred for 18 h. Cooled to room temperature. The reaction mixture was filtered and then purified by reverse-phase preparative chromatography (C 18 column, 20% to 99% acetonitrile (no modifier) in water (5 mM hydrochloric acid)) to afford as the first diastereomer pair of enantiomers to elute, 12,12,17-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (diastereomer pair 1) (Compound 35) (9.0 mg, 22%) as an off-white solid; 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.62 (s, 1H), 8.21 (d, J=2.8 Hz, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.57 (dd, J=8.5, 7.2 Hz, 1H), 7.05 (d, J=7.2 Hz, 1H), 6.97 (d, J=9.2 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.68 (d, J=8.5 Hz, 1H), 6.11 (d, J=2.8 Hz, 1H), 4.31 (t, J=7.2 Hz, 2H), 4.17 (s, 1H), 3.10 (d, J=9.4 Hz, 1H), 2.74-2.66 (m, 1H), 2.20-2.10 (m, 1H), 2.08 (t, J=7.1 Hz, 2H), 1.85 (dd, J=11.9, 5.2 Hz, 1H), 1.64 (d, J=7.1 Hz, 1H), 1.62-1.59 (m, 3H), 1.56 (d, J=12.9 Hz, 2H), 1.51 (s, 3H), 1.36-1.24 (m, 2H), 1.04 (d, J=6.3 Hz, 3H), 0.95 (d, J=4.6 Hz, 2H), 0.90 (d, J=11.1 Hz, 2H); ESI-MS m/z calc. 647.2502, found 648.2 (M+1) + ; Retention time: 2.25 min (LC Method E); and as the second diastereomer pair of enantiomers to elute, 12,12,17-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (diastereomer pair 2) (Compound 36) (33.6 mg, 82%) as an off-white solid; 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.41 (s, 1H), 8.21 (d, J=2.7 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.58 (dd, J=8.5, 7.3 Hz, 1H), 7.20 (dd, J=12.2, 7.3 Hz, 2H), 6.89 (d, J=8.2 Hz, 1H), 6.70 (d, J=8.2 Hz, 1H), 6.10 (d, J=2.7 Hz, 1H), 4.31 (t, J=7.0 Hz, 2H), 3.65 (d, J=5.0 Hz, 1H), 3.23-2.97 (m, 2H), 2.27 (dd, J=10.1, 5.1 Hz, 1H), 2.07 (t, J=7.1 Hz, 2H), 1.89 (dd, J=11.8, 5.8 Hz, 2H), 1.78-1.67 (m, 1H), 1.62 (s, 3H), 1.58 (d, J=12.0 Hz, 1H), 1.52 (s, 3H), 1.45 (dd, J=14.0, 6.8 Hz, 1H), 1.22 (d, J=6.6 Hz, 3H), 1.15-1.06 (m, 1H), 0.97-0.93 (m, 2H), 0.89 (d, J=11.4 Hz, 2H). ESI-MS m/z calc. 647.2502, found 648.2 (M+1) + ; Retention time: 2.29 min (LC Method E).

›Step 9: tert-Butyl 2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]butyl]pyrrolidine-1-carboxylate · 2 of 2

Part C: 12,12,17-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (diastereomer pair 1) (11.5 mg) was subjected to chiral separation by SFC chromatography using a ChiralPak AS-H (250×10 mm) column (5 μm particle size) with 16% acetonitrile/methanol (90:10)/84% carbon dioxide mobile phase at 10 mL/min over 8.0 min [injection volume=70 μL of 24 mg/mL solution in acetonitrile/methanol (90:10)] giving as the first enantiomer to elute, 12,12,17-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (diastereomer pair 1, enantiomer 1) (Compound 58) (2.6 mg, 45%; >98% ee) as an off-white solid; ESI-MS m/z calc. 647.2502, found 648.2 (M+1) + ; Retention time: 2.25 min (LC Method E) and as the second enantiomer to elute, 12,12,17-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (diastereomer pair 1, enantiomer 2) (Compound 59) (3.6 mg, 62%; >98% ee) as an off-white solid; ESI-MS m/z calc. 647.2502, found 648.2 (M+1) + ; Retention time: 2.25 min (LC Method E).

Part D: 12,12,17-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (diastereomer pair 2) (55 mg) was subjected to chiral separation by SFC chromatography using a ChiralPak AS-H (250×10 mm) column (5 μm particle size) with 16% acetonitrile/methanol (90:10)/84% carbon dioxide mobile phase at 10 mL/min over 8.0 min [injection volume=70 μL of 24 mg/mL solution in acetonitrile/methanol (90:10)] giving as the first enantiomer to elute, 12,12,17-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (diastereomer pair 2, enantiomer 1) (Compound 60) (17.9 mg, 64%, >98% ee) as an off-white solid; ESI-MS m/z calc. 647.2502, found 648.2 (M+1) + ; Retention time: 2.3 min (LC Method E) and as the second enantiomer to elute, 12,12,17-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1 (23),5(10),6,8,19,21-hexaene-2,2,4-trione (diastereomer pair 2, enantiomer 2) (Compound 61) (18.1 mg, 65%, >98% ee) as an off-white solid; 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.40 (s, 1H), 8.21 (d, J=2.7 Hz, 1H), 7.59 (dd, J=20.6, 12.9 Hz, 2H), 7.18 (d, J=7.2 Hz, 2H), 6.89 (d, J=8.1 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 6.10 (d, J=2.6 Hz, 1H), 4.31 (t, J=7.0 Hz, 2H), 3.63 (s, 1H), 3.12 (d, J=30.7 Hz, 2H), 2.28 (dd, J=21.3, 12.6 Hz, 1H), 2.07 (t, J=7.0 Hz, 2H), 2.03-1.81 (m, 2H), 1.79-1.67 (m, 1H), 1.62 (s, 3H), 1.57 (d, J=12.1 Hz, 1H), 1.52 (s, 3H), 1.49-1.39 (m, 1H), 1.21 (d, J=6.5 Hz, 3H), 1.10 (dd, J=12.8, 4.4 Hz, 1H), 0.99-0.93 (m, 2H), 0.88 (s, 2H), ESI-MS m/z calc. 647.2502, found 648.2 (M+1) + ; Retention time: 2.3 min (LC Method E).

Example 10: Preparation of 12,12-dimethyl-8-{3-[(2,2,3,3-tetramethylcyclopropyl) methoxy]-1H-pyrazol-1-yl}-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound 42)

›Step 1: tert-Butyl 3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazole-1-carboxylate

To a degassed solution of triphenylphosphine (51.28 g, 195.5 mmol) in toluene (360.0 mL) under nitrogen gas at 0° C. was added DIAD (39.53 g, 37.86 mL, 195.5 mmol) dropwise. The mixture was stirred at 0° C. for 30 min affording a white slurry. To the mixture was added a solution of (2,2,3,3-tetramethylcyclopropyl)methanol (29.84 g of 70% w/w, 162.9 mmol) and tert-butyl 3-hydroxypyrazole-1-carboxylate (30 g, 162.9 mmol) in toluene (600.0 mL) dropwise at 5° C. over 2 h. The mixture was allowed to warm to ambient temperature and was stirred for 18 h. The mixture was heated to 75° C. for a total of 6 h and then allowed to cool to ambient temperature. The slurry was diluted with heptane (900 mL) and stirred at ambient temperature for 3 h. The slurry was filtered over Celite and the precipitate washed 3× with 100 mL of heptane. The filtrate was concentrated in vacuo affording a thick yellow oil. The crude product was chromatographed on a 750 gram silica gel column loading with dichloromethane and eluting with a 0-20% ethyl acetate/hexanes gradient. Collected fractions containing product were concentrated in vacuo affording an off-white solid, tert-butyl 3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazole-1-carboxylate (30.1 g, 63%). 1 H NMR (400 MHz, Chloroform-d) δ 7.82 (d, J=3.0 Hz, 1H), 5.88 (d, J=2.9 Hz, 1H), 4.30 (d, J=7.7 Hz, 2H), 1.61 (s, 9H), 1.12 (s, 6H), 1.04 (s, 6H), 0.70 (t, J=7.8 Hz, 1H). ESI-MS m/z calc. 294.19434, found 295.0 (M+1) + ; Retention time: 2.19 min (LC Method B).

›Step 2: 3-[(2,2,3,3-Tetramethylcyclopropyl)methoxy]-1H-pyrazole · 1 of 3

To a solution of tert-butyl 3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazole-1-carboxylate (127 g, 431.4 mmol) in tetrahydrofuran (317.5 mL) and ethyl alcohol (635.0 mL) was slowly added sodium hydroxide (431.4 mL of 2 M, 862.8 mmol) and the mixture was stirred at room temperature overnight. Most of the solvent was removed under reduced pressure. The aqueous residue was diluted with water (400 mL) and extracted with methyl tert-butyl ether (762.0 mL). The organic phase was washed twice with brine (2×300 mL) and the aqueous phases were back extracted once with methyl tert-butyl ether (250 mL). The combined organic phases were dried, filtered and evaporated to give 3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]-1H-pyrazole (75 g, 89%) as a viscous oil. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 11.78 (s, 1H), 7.48 (t, J=2.1 Hz, 1H), 5.65 (s, 1H), 4.05 (d, J=7.7 Hz, 2H), 1.08 (s, 6H), 1.00 (s, 6H), 0.67 (t, J=7.7 Hz, 1H). ESI-MS m/z calc. 194.1419, found 195.0 (M+1) + ; Retention time: 1.43 min (LC Method B).

Step 3: 2,6-Dichloro-N-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propylamino]-2-pyridyl]sulfonyl]pyridine-3-carboxamide

Part A: To a solution of 2,6-dichloropyridine-3-carboxylic acid (200 mg, 1.042 mmol) in tetrahydrofuran (5 mL) was added di(imidazol-1-yl)methanone (169.0 mg, 1.042 mmol) and the reaction mixture was stirred for 90 min at 50° C. tert-Butyl 2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (343.9 mg, 0.8336 mmol) was added followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (237.9 mg, 233.7 μL, 1.563 mmol) and the reaction was heated at 50° C. for 18 hrs. The reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution followed by brine. The organics were separated, dried over sodium sulfate, filtered and evaporated. The resultant brown residue was purified by silica gel column chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate to afford tert-butyl 4-[3-[[6-[(2,6-dichloropyridine-3-carbonyl)sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (284 mg, 46%) as off white sticky material. ESI-MS m/z calc. 585.15796, found 586.5 (M+1) + ; Retention time: 0.79 min (LC Method A).

Part B: The material from Part A was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (1.782 g, 1.204 mL, 15.63 mmol) and stirred at room temperature for 5 hr. The solvent was removed and the residue was dissolved in ethyl acetate and the organics were washed with saturated aqueous sodium bicarbonate solution then brine. The organic layers were dried over anhydrous sodium sulfate, filtered and the solvent was removed. The material was dried under vacuum overnight to afford 2,6-dichloro-N-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propylamino]-2-pyridyl]sulfonyl]pyridine-3-carboxamide (233 mg, 100%) as an off white sticky material. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 9.31 (s, 1H), 9.15 (s, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.62 (dd, J=8.5, 7.2 Hz, 1H), 7.17 (d, J=7.2 Hz, 1H), 6.79 (d, J=8.5 Hz, 1H), 3.34 (dq, J=14.6, 5.7 Hz, 1H), 3.24 (dq, J=6.6, 4.1 Hz, 2H), 2.89-2.75 (m, 1H), 2.45-2.29 (m, 1H), 1.93 (dd, J=12.8, 7.7 Hz, 1H), 1.60-1.45 (m, 3H), 1.43-1.33 (m, 5H), 1.29 (s, 3H). ESI-MS m/z calc. 485.10553, found 486.5 (M+1) + ; Retention time: 0.5 min (LC Method A).

Step 4: 8-Chloro-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Hydrochloride Salt) (Compound C)

To a solution of 2,6-dichloro-N-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propylamino]-2-pyridyl]sulfonyl]pyridine-3-carboxamide (200 mg, 0.4112 mmol) in dimethyl sulfoxide (5.0 mL) and 3 Å molecular sieves was stirred at room temperature for 10 min. Cesium fluoride (194 mg, 1.277 mmol) and potassium carbonate (1703 mg, 12.32 mmol) were then added and the reaction mixture was heated at 140° C. overnight. The reaction mixture was filtered through Whatman filter disc (puradisc 25 TF) and the filtrate was purified by a reverse phase HPLC-MS method using a Luna C 18 (2) column (75×30 mm, 5 μm particle size) sold by Phenomenex (pn: 00C-4252-U0-AX) and a dual gradient run from 30-99% mobile phase B over 15.0 min. Mobile phase A=water (5 mM hydrochloric acid). Mobile phase B=acetonitrile. Flow rate=50 mL/min, injection volume=950 μL and column temperature=25° C. to afford 8-chloro-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (hydrochloride salt) (76 mg, 38%) as white solid. 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.69 (d, J=7.9 Hz, 1H), 7.54 (dd, J=8.5, 7.3 Hz, 1H), 7.16 (d, J=7.2 Hz, 1H), 6.67 (d, J=8.5 Hz, 1H), 6.56 (d, J=7.9 Hz, 1H), 4.14-3.93 (m, 1H), 3.26-3.15 (m, 1H), 3.09-2.98 (m, 1H), 2.78 (t, J=10.0 Hz, 1H), 2.19 (dd, J=15.6, 5.6 Hz, 1H), 1.92-1.77 (m, 2H), 1.72-1.60 (m, 2H), 1.61 (s, 3H), 1.51 (s, 3H), 1.49-1.34 (m, 2H). ESI-MS m/z calc. 449.12885, found 450.4 (M+1) + ; Retention time: 1.92 min (LC Method B).

Step 5: 12,12-Dimethyl-8-{3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]-1H-pyrazol-1-yl}-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound 42)

To a solution of 3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]-1H-pyrazole (11.98 mg, 0.06168 mmol) in dimethyl sulfoxide (1 mL) was added scandium triflate (6.073 mg, 0.01234 mmol) and sodium hydride (10.2 mg of 50% w/w, 0.2125 mmol) at 0° C. under a nitrogen atmosphere. The reaction was stirred for 30 min. 8-Chloro-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (hydrochloride salt) (30 mg, 0.06168 mmol) was then added and the reaction mixture was heated at 120° C. for 16 h. The reaction mixture was cooled to room temperature and quenched with a few drops of water. The resultant mixture was filtered through a Whatman filter disc (puradisc 25 TF) and the filtrate was purified by a reverse phase HPLC-MS method using a dual gradient run from 50-99% mobile phase B over 15.0 min (Mobile phase A=water (no modifier), Mobile phase B=acetonitrile) to afford 12,12-dimethyl-8-{3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]-1H-pyrazol-1-yl}-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound 42) (2.6 mg, 7%). 1 H NMR (400 MHz, Chloroform-d) δ 8.19 (s, 1H), 8.07 (s, 1H), 7.57 (s, 2H), 7.51 (s, 1H), 6.58 (s, 1H), 5.96 (s, 1H), 4.28 (d, J=7.8 Hz, 2H), 3.88 (brs, 1H), 3.41-3.27 (m, 2H), 3.21 (brs, 1H), 3.07 (brs, 1H), 2.61 (brs, 1H), 2.08 (brs, 1H), 1.63 (s, 6H), 1.71-1.53 (m, 3H), 1.26 (brs, 1H), 1.14 (d, J=2.5 Hz, 6H), 1.07 (s, 6H), 0.75 (t, J=7.7 Hz, 1H). ESI-MS m/z calc. 607.29407, found 608.5 (M+1) + ; Retention time: 2.86 min (LC Method B).

›Step 2: 3-[(2,2,3,3-Tetramethylcyclopropyl)methoxy]-1H-pyrazole · 2 of 3

Example 11: Preparation of 8-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound 43)

Step-1: (1-Cyclopropyl-2-methoxy-vinyl)cyclopropane

A 5000 mL round bottom flask was fitted with a mechanical stirrer, a cooling bath used as secondary containment, a J-Kem temperature probe, an addition funnel, water cooled reflux condenser and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with (methoxymethyl)triphenylphosphonium chloride (97.3 g, 284 mmol) and tetrahydrofuran (375 mL) which provided a white suspension. Stirring was commenced and the pot temperature was recorded at 19° C. The vessel was then charged with potassium tert-butoxide (31.85 g, 0.2838 mol) added as a solid in portions over 10 min which resulted in a reddish orange solution and an exotherm to 21° C. The mixture was continued to stir at room temperature for 30 min. The addition funnel was charged with dicyclopropyl ketone (dicyclopropylmethanone) (25.0 g, 227.0 mmol) which was subsequently added neat, dropwise over 25 min which resulted in a gradual exotherm to 35° C. The resulting reddish orange solution was allowed to gradually cool to room temperature and then continued to stir at room temperature for 4 h. The reaction was then quenched with cold water (375 mL) added dropwise over 25 min. The resulting biphasic mixture was transferred to a separatory funnel and allowed to stand for 5 min. The aqueous was drained and the remaining organic was washed with saturated sodium chloride solution (375 mL). The organic was removed and concentrated under reduced pressure to provide pale yellow oil which still contained some water. The mixture was diluted with ethyl acetate (500 mL) and then transferred to a separatory funnel and partitioned with water (150 mL). The organic was removed, dried over sodium sulfate (150 g) and then filtered through a glass frit Buchner funnel. The filtrate was concentrated under reduced pressure to provide a pale yellow oil with some suspended solids (triphenylphosphine oxide). The mixture was diluted with hexane (500 mL) and then filtered through a glass frit Buchner funnel with a 40 mm layer of silica gel. The filter cake was displacement washed with hexane (2×500 mL). The filtrate was concentrated under reduced pressure to provide (1-cyclopropyl-2-methoxy-vinyl)cyclopropane as a clear pale yellow oil (27 g, 0.1953 mol, 86% yield). ESI-MS m/z calc. 138.10446, found 138.0 (M+1) + ; Retention time: 1.73 min (LC Method B).

Step-2: 2,2-Dicyclopropylacetaldehyde

To a solution of (1-cyclopropyl-2-methoxy-vinyl)cyclopropane (128 g, 709.4 mmol) in tetrahydrofuran (700 mL) was added aqueous hydrochloric acid (250 mL of 3 M, 750.0 mmol) and the mixture was stirred at ambient temperature for 16 h then stirred at 55° C. for 4 h and then allowed to cool to ambient temperature over 12 h. The mixture was diluted with 500 mL of brine and the aqueous phase was separated. The aqueous phase was extracted with 500 mL of MTBE and the organic phases were combined. The organic phases were washed with 500 mL of brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was diluted with 250 mL of MTBE and the residual water was removed using a separatory funnel. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo affording 2,2-dicyclopropylacetaldehyde (99.2 g, 96%) as a light orange oil. 1 H NMR (400 MHz, Chloroform-d) δ 9.74 (d, J=2.9 Hz, 1H), 1.06 (td, J=8.9, 2.9 Hz, 1H), 0.94-0.81 (m, 2H), 0.64-0.49 (m, 4H), 0.32-0.20 (m, 4H).

Step-3: [(E)-1-Cyclopropyl-3-methoxy-allyl]cyclopropane

A 5000 mL round bottom flask was fitted with a mechanical stirrer, a heating mantle, a J-Kem temperature probe, an addition funnel, a water cooled reflux condenser and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with (methoxymethyl)triphenylphosphonium chloride (116.8 g, 340.7 mmol) and tetrahydrofuran (423 mL) which provided a white suspension. Stirring was commenced and the pot temperature was recorded at 19° C. The vessel was then charged with potassium tert-butoxide (38.22 g, 340.6 mmol) added as a solid in portions over 30 min (12.74 g portion added every 10 min) which resulted in a reddish orange solution and an exotherm to 40° C. The mixture was continued to stir at room temperature for 30 min. The pot temperature was recorded at 36° C. at this point. The addition funnel was then charged with 2,2-dicyclopropylacetaldehyde (47 g of 60% w/w contaminated with triphenylphosphine oxide from previous step, 227.1 mmol) which was subsequently added neat dropwise over 25 min which resulted in a gradual exotherm to 47° C. The resulting reddish orange solution was allowed to gradually cool to room temperature and then continued to stir at room temperature for 15 h. The reaction mixture (pot temp=19° C.) was then quenched with cold water (1000 mL) which resulted in an exotherm to 22° C. The mixture was continued to stir for 10 min. The resulting biphasic mixture was transferred to a separatory funnel and allowed to stand for 5 min. The organic was removed and the residual aqueous was extracted with ethyl acetate (2×300 mL). The combined organic layers were concentrated under reduced pressure to provide a dark amber oil which still contained some water. The mixture was diluted with ethyl acetate (500 mL) and then transferred to a separatory funnel and partitioned with water (150 mL). The organic was removed, washed with saturated sodium chloride solution (200 mL), dried over sodium sulfate (200 g) and then filtered through a glass frit Buchner funnel. The filtrate was concentrated under reduced pressure to provide pale amber oil with some suspended solids (triphenylphosphine oxide). The mixture was diluted with heptane (500 mL) and then allowed to stand at room temperature for 30 min. The suspension was filtered through a glass frit Buchner funnel and the filter cake was displacement washed with heptane (2×100 mL). The filtrate was concentrated under reduced pressure to a volume of about 200 mL. The pale amber solution was cooled to 0° C. in a crushed ice/water cooling bath for 30 min during which time more solids precipitated. The suspension was filtered through a glass frit Buchner funnel and the filter cake was displacement washed with heptane (2×50 mL). The filtrate was concentrated under reduced pressure to provide [(E)-1-cyclopropyl-3-methoxy-allyl]cyclopropane (30 g, 87%). 1 H NMR (400 MHz, Chloroform-d) δ 6.31 (dd, J=12.7, 1.1 Hz, 1H), 4.68 (dd, J=12.7, 7.6 Hz, 1H), 3.51 (s, 3H), 0.77 (qt, J=8.1, 5.0 Hz, 2H), 0.54-0.32 (m, 2H), 0.28-0.12 (m, 5H), 0.08 (ddd, J=9.3, 5.3, 4.1 Hz, 2H).

›Step 2: 3-[(2,2,3,3-Tetramethylcyclopropyl)methoxy]-1H-pyrazole · 3 of 3

Step-4: 3,3-Dicyclopropylpropanal

To a solution of [(E)-1-cyclopropyl-3-methoxy-allyl]cyclopropane (141 g, 555.7 mmol) in tetrahydrofuran (500 mL) was added aqueous hydrochloric acid (100 mL of 3 M, 300.0 mmol) and the mixture warmed to 50° C. for 2 h. The mixture was cooled to ambient temperature and the tetrahydrofuran removed in vacuo. The residue was diluted with dichloromethane (700 mL) and the aqueous phase separated (slight emulsion). The organic phase was washed with 500 mL of brine, dried over magnesium sulfate and filtered. To the filtrate was added MgCl 2 (50 g, 525.1 mmol) and the mixture was stirred at ambient temperature for 12 h. The slurry was filtered over Celite (blinded the Celite and needed to be scraped off). The filtrate was slightly cloudy and was washed with brine, dried over magnesium sulfate, filtered and concentrated to afford 3,3-dicyclopropylpropanal (76.8 g, 100%), 1 H NMR (400 MHz, Chloroform-d) δ 9.83 (t, J=2.7 Hz, 1H), 2.71-2.39 (m, 2H), 0.73 (ddt, J=5.5, 4.2, 2.9 Hz, 3H), 0.56-0.47 (m, 2H), 0.42 (dddd, J=9.2, 7.6, 4.0, 2.6 Hz, 2H), 0.28-0.21 (m, 2H), 0.11-0.04 (m, 2H).

Step-5: 3,3-Dicyclopropylpropan-1-ol

To a slurry of lithium aluminum hydride (10.4 g, 266.9 mmol) in tetrahydrofuran (500 mL) was added dropwise a solution of 3,3-dicyclopropylpropanal (76 g, 549.9 mmol) in tetrahydrofuran (150 mL) allowing for a gentle reflux. The mixture was stirred at ambient temperature for 2 h. The reaction was chilled with an ice bath and quenched with the slow addition of water (10.4 mL, 577.3 mmol) followed by aqueous sodium hydroxide (10.4 mL of 4 M, 41.60 mmol), then water (31.2 mL, 1.732 mol). The slurry was filtered over celite, washed with tetrahydrofuran and concentrated in vacuo to afford 3,3-dicyclopropylpropan-1-ol (112 g, 73%), 1 H NMR (400 MHz, Chloroform-d) δ 3.81 (t, J=6.9 Hz, 2H), 1.76 (q, J=6.9 Hz, 2H), 0.63 (dtt, J=8.8, 8.0, 5.1 Hz, 2H), 0.50-0.34 (m, 4H), 0.27-0.14 (m, 3H), 0.14-0.02 (m, 2H).

Step-6: tert-Butyl 3-(3,3-dicyclopropylpropoxy)pyrazole-1-carboxylate

To tert-butyl 3-hydroxypyrazole-1-carboxylate (36.5 g, 198.2 mmol) in tetrahydrofuran (450 mL) under nitrogen was added 3,3-dicyclopropylpropan-1-ol (28.0 g, 199.7 mmol) and triphenylphosphine (57.0 g, 217.3 mmol). To the mixture was added DIAD (43.0 mL, 218.4 mmol) dropwise allowing the mixture to gradually exotherm to 45° C. After the addition, the mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with hexanes (450 mL) and removed approximately 50% of the solvent in vacuo affording a slurry. The slurry was filtered using a medium frit and the solid was washed with hexanes (3×50 mL). The filtrate was concentrated in vacuo affording an amber oil. The crude oil was diluted with dichloromethane and chromatographed on a 750 g silica gel column eluting with a gradient from 0%-40% ethyl acetate in hexanes. Collected two main fractions, the second fraction was pure product. The first fraction contained triphenylphosphine and was rechromatographed on a 750 g silica gel column eluting with a gradient from 0%-25% ethyl acetate in hexanes. Combined product from the second column with product obtained from the first column affording as a clear oil, tert-butyl 3-(3,3-dicyclopropylpropoxy)pyrazole-1-carboxylate (39.0 g, 64%). ESI-MS m/z calc. 306.19434, found 307.1 (M+1) + ; Retention time: 2.26 min (LC Method B).

Step-7: 3-(3,3-Dicyclopropylpropoxy)-1H-pyrazole (Trifluoroacetate Salt)

A solution of tert-butyl 3-(3,3-dicyclopropylpropoxy)pyrazole-1-carboxylate (255 mg, 0.8322 mmol) and trifluoroacetic acid (325.0 μL, 4.218 mmol) in dichloromethane (1 mL) was stirred for 2.5 h. The volatiles were removed under vacuum, affording 3-(3,3-dicyclopropylpropoxy)-1H-pyrazole (trifluoroacetate salt) (266 mg, 100%) as a colorless oil which was used directly in the next reaction. ESI-MS m/z calc. 206.1419, found 207.2 (M+1) + ; Retention time: 0.59 minutes (LC Method A).

›Step 8: tert-Butyl 2-chloro-6-[3-(3,3-dicyclopropylpropoxy) pyrazol-1-yl]pyridine-3-carboxylate

A mixture of tert-butyl 2,6-dichloropyridine-3-carboxylate (220.0 mg, 0.8867 mmol), 3-(3,3-dicyclopropylpropoxy)-1H-pyrazole (trifluoroacetate salt) (266.0 mg, 0.8305 mmol), potassium carbonate (230 mg, 1.664 mmol) and 1,4-diazabicyclo[2.2.2]octane (20 mg, 0.1783 mmol) in dimethyl sulfoxide (10 mL) was stirred at room temperature for 15 h. The reaction was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography using a gradient from 100% hexanes to 20% ethyl acetate in hexanes to afford tert-butyl 2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridine-3-carboxylate (245 mg, 71%) as a colorless oil. ESI-MS m/z calc. 417.18192, found 418.4 (M+1) + ; Retention time: 1.28 min (LC Method J).

›Step 9: 2-Chloro-6-[3-(3,3-dicyclopropylpropoxy) pyrazol-1-yl]pyridine-3-carboxylic Acid

A solution of tert-butyl 2-chloro-6-[3-(3,3-dicyclopropylpropoxy) pyrazol-1-yl]pyridine-3-carboxylate (245.0 mg, 0.5862 mmol) in trifluoroacetic acid (500.0 μL, 6.490 mmol) and dichloromethane (1.5 mL) was stirred for 4 h at room temperature. The solvent was evaporated, and twice the residue was taken up in tetrahydrofuran and concentrated under vacuum to afford 2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (204 mg, 96%) as a white solid which was used directly in the next reaction. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.47-8.32 (m, 2H), 7.73 (d, J=8.5 Hz, 1H), 6.03 (d, J=2.9 Hz, 1H), 4.45 (t, J=6.7 Hz, 2H), 1.98 (q, J=7.0 Hz, 2H), 0.75-0.64 (m, 2H), 0.50-0.39 (m, 4H), 0.35-0.26 (m, 1H), 0.26-0.19 (m, 2H), 0.15-0.06 (m, 2H). ESI-MS m/z calc. 361.11932, found 362.3 (M+1) + ; Retention time: 0.8 min (LC Method A).

Step-10: tert-Butyl 4-[3-[[6-[[2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

To a solution of 2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (505.1 mg, 1.382 mmol) in tetrahydrofuran (5 mL) was added carbonyl diimidazole (224.1 mg, 1.382 mmol) and the mixture was stirred for 120 min at 50° C. Then, tert-butyl 2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (380 mg, 0.9211 mmol) in tetrahydrofuran (5 mL) was added followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (280.4 mg, 275.4 μL, 1.842 mmol) and the reaction was heated at 50° C. for 16 h. The reaction was diluted with ethyl acetate and washed with a small amount of 1:1 saturated aqueous ammonium chloride/brine. The organics were separated, dried over sodium sulfate, filtered and evaporated. The resultant brown residue was purified by silica gel chromatography using a shallow gradient from 100% dichloromethane to 20% methanol in dichloromethane to afford tert-butyl 4-[3-[[6-[[2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (356 mg, 51%) as a white solid. 1 H NMR (400 MHz, Chloroform-d) δ 8.31 (d, J=2.9 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.58-7.50 (m, 2H), 6.55 (dd, J=7.7, 1.6 Hz, 1H), 5.95 (d, J=2.9 Hz, 1H), 4.92 (s, 1H), 4.42 (t, J=6.9 Hz, 2H), 4.02 (dd, J=10.7, 7.3 Hz, 1H), 3.64-3.54 (m, 1H), 3.17 (t, J=11.7 Hz, 1H), 2.88 (t, J=10.7 Hz, 1H), 2.19 (d, J=9.5 Hz, 1H), 1.97 (q, J=6.8 Hz, 2H), 1.82 (dt, J=15.1, 7.6 Hz, 2H), 1.55 (tdd, J=16.3, 10.8, 5.0 Hz, 1H), 1.40 (s, 11H), 1.30 (s, 3H), 1.25 (s, 3H), 0.76-0.60 (m, 2H), 0.55-0.40 (m, 4H), 0.33 (ddd, J=15.9, 9.0, 6.9 Hz, 1H), 0.20 (dtd, J=9.5, 4.9, 3.6 Hz, 2H), 0.14-0.04 (m, 2H). ESI-MS m/z calc. 755.3232, found 756.5 (M+1) + ; Retention time: 0.6 min (LC Method L).

Step-11: 8-[3-(3,3-Dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound 43)

A solution of tert-butyl 4-[3-[[6-[[2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (350 mg, 0.4627 mmol) in dichloromethane (2.917 mL) and trifluoroacetic acid (527.6 mg, 354.1 μL, 4.627 mmol) was stirred at room temperature for 4 h. The solvents were removed in vacuo and the residue was dissolved in ethyl acetate. Washed with 2 mL of saturated aqueous sodium bicarbonate solution and the organic layers were collected and the solvent was removed under vacuum. The material was dissolved in dimethyl sulfoxide (17.50 mL) and 3 Å molecular sieves, cesium fluoride (210.8 mg, 1.388 mmol) and potassium carbonate (191.8 mg, 1.388 mmol) were added and the reaction mixture was heated at 130° C. overnight. The reaction mixture was filtered through Whatman filter disc (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS using a dual gradient run from 20%-80% mobile phase B over 15.0 min (mobile phase A=water (0.05% hydrochloric acid), mobile phase B=acetonitrile) to afford 8-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound 43) (158 mg, 55%) as an off-white solid. 1 H NMR (400 MHz, Chloroform-d) δ 9.99 (s, 1H), 8.19 (d, J=2.8 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.50 (d, J=7.2 Hz, 1H), 7.31-7.19 (m, 1H), 6.60 (d, J=8.3 Hz, 1H), 5.91 (d, J=2.8 Hz, 1H), 4.43 (t, J=6.8 Hz, 2H), 3.91 (s, 1H), 3.35 (t, J=8.7 Hz, 1H), 3.18 (d, J=13.9 Hz, 1H), 3.03 (t, J=9.9 Hz, 1H), 2.60 (d, J=18.4 Hz, 1H), 2.07 (dd, J=12.2, 7.8 Hz, 1H), 1.97 (q, J=6.8 Hz, 2H), 1.62 (d, J=6.2 Hz, 11H), 0.73-0.61 (m, 2H), 0.51-0.38 (m, 4H), 0.38-0.29 (m, 1H), 0.24-0.16 (m, 2H), 0.15-0.06 (m, 2H). ESI-MS m/z calc. 619.29407, found 620.4 (M+1) + ; Retention time: 1.32 min (LC Method J)

Example 12: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-18-oxa-2λ 6 -thia-3,9,11,23-tetraazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Enantiomer 1) (Compound 48) and 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-18-oxa-2λ 6 -thia-3,9,11,23-tetraazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Enantiomer 2) (Compound 49)

›Step 1: tert-Butyl 2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)oxy]propyl]pyrrolidine-1-carboxylate · 1 of 2

To the tert-butyl 4-(3-hydroxypropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (257 mg, 0.9986 mmol) stirring under nitrogen atmosphere in N,N-dimethylformamide (2.056 mL) was portionwise added sodium hydride (79.87 mg, 1.997 mmol) (Caution: gas evolution) and the mixture was stirred at room temperature for 20 min. 6-Fluoropyridine-2-sulfonamide (175.9 mg, 0.9986 mmol) was then added and the resulting mixture was stirred at room temperature for 2 h and 20 min then sodium hydride (23.96 mg, 0.9984 mmol) was added (Caution: gas evolution) and the resulting mixture was stirred 20 min then poured into 1N citric acid and extracted with ethyl acetate (2×). Combined organic fractions, dried (sodium sulfate), filtered and concentrated to a clear oil which was purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate giving tert-butyl 2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)oxy]propyl]pyrrolidine-1-carboxylate (275.2 mg, 67%). ESI-MS m/z calc. 413.19846, found 414.2 (M+1) + ; Retention time: 0.69 min (LC Method A).

Step 2: tert-Butyl 4-[3-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]oxy]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

In a 20 mL vial, 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (96.86 mg, 0.2578 mmol) and carbonyl diimidazole (45.81 mg, 0.2825 mmol) were combined in tetrahydrofuran (1.53 mL) and stirred for 120 min at 50° C. with a loose cap. Then tert-butyl 2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)oxy]propyl]pyrrolidine-1-carboxylate (193.8 mg, 0.2578 mmol) in tetrahydrofuran (2.04 mL) was added followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (80.81 mg, 79.38 μL, 0.5308 mmol) and the reaction was heated at 50° C. for 16 hrs. The reaction was diluted with ethyl acetate and washed with a 1M citric acid solution, followed by brine. The organics were separated, dried over sodium sulfate, filtered and evaporated then purified by silica gel chromatography using a shallow gradient from 100% dichloromethane to 20% methanol/dichloromethane. Product co-eluted with some impurities. Fractions containing product were combined and re-purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate giving tert-butyl 4-[3-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]oxy]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (64.7 mg, 33%). ESI-MS m/z calc. 770.2476, found 771.2 (M+1) + ; Retention time: 0.94 min (LC Method A).

Step 3: 2-Chloro-N-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propoxy]-2-pyridyl]sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide

tert-Butyl 4-[3-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]oxy]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (132.5 mg, 0.1718 mmol) was dissolved in dichloromethane (578.2 μL) and to the mixture was added trifluoroacetic acid (898.7 mg, 607.2 μL, 7.882 mmol) and the mixture was stirred at room temperature for 60 min. Concentrated the mixture to dryness under reduced pressure, took up in saturated aqueous sodium bicarbonate and ethyl acetate and separated the layers. Washed the organic layer with a small amount of brine then dried (sodium sulfate), filtered and concentrated to a white solid, 2-chloro-N-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propoxy]-2-pyridyl]sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (110 mg, 95%). ESI-MS m/z calc. 670.1952, found 671.2 (M+1) + ; Retention time: 0.64 min (LC Method A).

Step 4: 12,12-Dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-18-oxa-2λ 6 -thia-3,9,11,23-tetraazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound 40)

To a solution of 2-chloro-N-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propoxy]-2-pyridyl]sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (126.6 mg, 0.1886 mmol) in dimethyl sulfoxide (5.063 mL) was added potassium carbonate (130.3 mg, 0.9430 mmol), cesium fluoride (34.38 mg, 0.2263 mmol) and a small amount of 3 Å molecular sieves. The resulting mixture was capped and heated to 150° C. for 6.5 h then cooled to room temperature and stirred overnight. The mixture was then heated to 165° C. for 90 min then cooled to room temperature, diluted with ethyl acetate and washed with 1:1 saturated aqueous NH 4 Cl/1M citric acid then brine. The organic phase was dried (sodium sulfate), filtered and concentrated to an orange oil which was purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate (product elutes after reaching 100% ethyl acetate) to give 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-18-oxa-2λ 6 -thia-3,9,11,23-tetraazatetracyclo[17.3.1.111,14.05,10]tetracosa-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound 40) (58.2 mg, 48%) as a white solid. ESI-MS m/z calc. 634.2185, found 635.2 (M+1) + ; Retention time: 2.29 min (LC Method B).

Step 5: 12,12-Dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-18-oxa-2λ 6 -thia-3,9,11,23-tetraazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Enantiomer 1) (Compound 48) and 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-18-oxa-2λ 6 -thia-3,9,11,23-tetraazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Enantiomer 2) (Compound 49)

Subjected racemic 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-18-oxa-2λ 6 -thia-3,9,11,23-tetraazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound 40) (45.3 mg, 0.07052 mmol) to chiral separation by SFC chromatography using a ChiralPak AS-H (250×10 mm column, 5 μm particle size) with 25% acetonitrile/methanol (90:10)/75% carbon dioxide mobile phase at 10 mL/min over 8.0 min (injection volume=70 μL of 24 mg/mL solution in acetonitrile/methanol (90:10)) giving as the first enantiomer to elute. 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-18-oxa-2λ 6 -thia-3,9,11,23-tetraazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (enantiomer 1) (Compound 48) (22.20 mg, 97%) as a white solid; ESI-MS m/z calc. 634.2185, found 635.0 (M+1) + ; Retention time: 2.30 min (LC Method B) and as the second enantiomer to elute 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-18-oxa-2λ 6 -thia-3,9,11,23-tetraazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (enantiomer 2) (Compound 49) (22.33 mg, 100%) as a white solid; 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.81 (s, 1H), 8.21 (d, J=2.8 Hz, 1H), 8.01 (t, J=7.9 Hz, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.63 (d, J=7.4 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 6.12 (d, J=2.8 Hz, 1H), 5.17 (t, J=12.1 Hz, 1H), 4.32 (t, J=7.0 Hz, 2H), 4.11 (d, J=6.5 Hz, 1H), 3.93 (d, J=11.1 Hz, 1H), 3.19-3.15 (m, 4H), 2.18 (s, 1H), 2.08 (t, J=7.0 Hz, 2H), 1.86 (dd, J=11.9, 5.3 Hz, 1H), 1.68 (t, J=13.6 Hz, 2H), 1.60 (s, 3H), 1.51 (s, 3H), 1.00-0.93 (m, 2H), 0.92-0.85 (m, 2H), ESI-MS m/z calc. 634.2185, found 635.1 (M+1) + ; Retention time: 2.29 min (LC Method B).

›Step 1: tert-Butyl 2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)oxy]propyl]pyrrolidine-1-carboxylate · 2 of 2

Example 13: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl) cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11-triazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound 53)

›Step 1: tert-Butyl 2,2-dimethyl-4-(3-oxopropyl)pyrrolidine-1-carboxylate

Dess-Martin Periodinane (9.95 g, 23.46 mmol) was added to a stirred solution of tert-butyl 4-(3-hydroxypropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (5.20 g, 20.20 mmol) in anhydrous CH 2 Cl 2 (40 mL) at 0° C. (ice-water bath) under nitrogen. After 15 min, the reaction was allowed to warm to ambient temperature and stirring continued for another 2 h. The reaction was diluted with ether (200 mL) and saturated aqueous sodium bicarbonate (100 mL) was added slowly (to mitigate carbon dioxide gas evolution). Then 10% sodium thiosulfate (50 mL) was added and stirred at ambient temperature for 30 min. The layers were separated and the aqueous layer was extracted with ether (2×100 mL). The combined organics were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude material. The crude was purified from medium pressure silica gel chromatography (330 g silica gel column, 5-35% Ethyl acetate in hexanes over 35 min) to furnish desired tert-butyl 2,2-dimethyl-4-(3-oxopropyl)pyrrolidine-1-carboxylate (3.96 g, 77%) as clear viscous material, tert-butyl 2,2-dimethyl-4-(3-oxopropyl)pyrrolidine-1-carboxylate (3.96 g, 77%). 1 H NMR (400 MHz, Methanol-d 4 ) δ 4.48 (t, J=5.4 Hz, 1H), 3.66 (dd, J=11.2, 6.9 Hz, 1H), 2.87 (q, J=10.7 Hz, 1H), 2.31 (t, J=7.6 Hz, 1H), 2.22-2.07 (m, 1H), 1.95 (ddt, J=17.2, 12.1, 6.1 Hz, 1H), 1.66 (q, J=7.9 Hz, 1H), 1.62-1.55 (m, 1H), 1.54-1.48 (m, 2H), 1.47 (s, 4H), 1.43 (s, 6H), 1.41 (s, 2H), 1.31 (s, 3H). ESI-MS m/z calc. 255.18344, found 256.2 (M+1) + ; Retention time: 1.57 min (LC Method B).

›Step 2: tert-Butyl 4-but-3-ynyl-2,2-dimethyl-pyrrolidine-1-carboxylate

To a solution of tert-butyl 2,2-dimethyl-4-(3-oxopropyl)pyrrolidine-1-carboxylate (1.33 g, 5.208 mmol) in Methanol (31 mL) at 0° C. was added potassium carbonate (1.62 g, 11.72 mmol) followed by dropwise addition of (1-dimethoxyphosphoryl-2-oxo-propylidene)-imino-ammonium (12.5 mL of 10% w/v, 6.473 mmol). On completion of addition, the mixture was warmed to room temperature and stirred 4 h. Removed solvent under reduced pressure and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate (1×). The aqueous layer was back extracted twice with ethyl acetate and the organic layers were combined, dried (sodium sulfate), filtered and concentrated to a clear oil which was purified by silica gel chromatography using a gradient from 100% hexanes to 50% ethyl acetate in hexanes giving as a clear oil tert-butyl 4-but-3-ynyl-2,2-dimethyl-pyrrolidine-1-carboxylate (1.15 g, 88%). ESI-MS m/z calc. 251.18852, found 252.2 (M+1) + ; Retention time: 1.96 min. 1 H NMR (400 MHz, CDCl 3 ) δ 3.82-3.56 (m, 1H), 2.99-2.80 (m, 1H), 2.35-2.23 (m, 1H), 2.21 (dd, J=9.5, 4.6 Hz, 2H), 1.96 (s, 1H), 1.95-1.86 (m, 1H), 1.63-1.55 (m, 2H), 1.53-1.36 (m, 13H), 1.30 (t, J=10.8 Hz, 3H).

›Step 3: tert-Butyl 2,2-dimethyl-4-[4-(3-sulfamoylphenyl)but-3-ynyl]pyrrolidine-1-carboxylate

Nitrogen was bubbled through a stirring mixture of 3-iodobenzenesulfonamide (308.0 mg, 1.088 mmol), tert-butyl 4-but-3-ynyl-2,2-dimethyl-pyrrolidine-1-carboxylate (156.3 mg, 0.6218 mmol), Pd(PPh 3 ) 2 Cl 2 (26.19 mg, 0.03731 mmol), iodocopper (11.84 mg, 0.06218 mmol) and N,N-dimethylformamide (1.563 mL) in a vial for 5 min then N-isopropylpropan-2-amine (69.21 mg, 95.86 μL, 0.6840 mmol) was added and the vial was sealed and stirred at 50° C. for 2.5 h then cooled to room temperature and stirred overnight. Cooled to room temperature and poured into water (200 mL) and extracted with dichloromethane (2×100 mL), combined organic layers, washed with water (2×100 mL), dried (magnesium sulfate), filtered and concentrated to an orange oil which was purified by silica gel chromatography using a gradient from 100% hexanes to 100% ethyl acetate giving tert-butyl 2,2-dimethyl-4-[4-(3-sulfamoylphenyl)but-3-ynyl]pyrrolidine-1-carboxylate (307.9 mg, 92%) as a yellow oil. ESI-MS m/z calc. 406.19263, found 407.2 (M+1) + ; Retention time: 0.71 min (LC Method A).

›Step 4: tert-Butyl 2,2-dimethyl-4-[4-(3-sulfamoylphenyl)butyl]pyrrolidine-1-carboxylate

To tert-butyl 2,2-dimethyl-4-[4(3-sulfamoylphenyl)but-3-ynyl]pyrrolidine-1-carboxylate (307.9 mg, 0.5744 mmol) was added platinum oxide (65.20 mg, 0.2871 mmol) followed by EtOH (2.188 mL) and nitrogen was bubbled through the mixture for 1 min followed by hydrogen bubbled through the mixture for 5 min. The mixture was then capped with a hydrogen balloon and stirred for 3 h. Purged with nitrogen, added celite, stirred 1 min then filtered over a pad of celite. Concentrated the filtrate to tert-butyl 2,2-dimethyl-4-[4-(3-sulfamoylphenyl)butyl]pyrrolidine-1-carboxylate (320.4 mg, 82%), an orange oil which was taken directly into the next step. ESI-MS m/z calc. 410.22394, found 411.3 (M+1) + ; Retention time: 0.73 min (LC Method A).

Step 5: tert-Butyl 4-[4-[3-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]phenyl]butyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

In a 20 mL vial 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (95.96 mg, 0.2554 mmol) and carbonyl diimidazole (41.41 mg, 0.2554 mmol) were combined in tetrahydrofuran (1.00 mL) and stirred for 120 min at 50° C. with a loose cap. Then tert-butyl 2,2-dimethyl-4-[4-(3-sulfamoylphenyl)butyl]pyrrolidine-1-carboxylate (69.9 mg, 0.1703 mmol) in tetrahydrofuran (1.338 mL) was added followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (50.93 μL, 0.3406 mmol) and the reaction was heated at 50° C. for 16 hrs. The reaction was diluted with ethyl acetate and washed with a small amount of 1:1 saturated aqueous ammonium chloride/brine. The organics were separated, dried over sodium sulfate, filtered and evaporated then purified by silica gel chromatography using a shallow gradient from 100% dichloromethane to 20% methanol/dichloromethane giving tert-butyl 4-[4-[3-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]phenyl]butyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (110.5 mg, 84%) as a white solid. ESI-MS m/z calc. 767.27313, found 768.2 (M+1) + ; Retention time: 0.95 min (LC Method A).

Step 6: 2-Chloro-N-[3-[4-(5,5-dimethyl pyrrolidin-3-yl)butyl]phenyl]sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (Trifluoroacetic Acid Salt)

tert-Butyl 4-[4-[3-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]phenyl]butyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (110.5 mg, 0.1438 mmol) was dissolved in dichloromethane (482.2 μL) and to the mixture was added trifluoroacetic acid (508.3 μL, 6.598 mmol) and stirred at room temperature for 40 min. Concentrated mixture to dryness under reduced pressure, took up in sat. aq. sodium bicarbonate and ethyl acetate and separated the layers. Aqueous layer was neutralized with saturated aqueous ammonium chloride and extracted with ethyl acetate. Organic fraction was dried (sodium sulfate), filtered and concentrated to an orange oil which was filtered and purified using a reverse phase HPLC-MS method using a Luna C 18 (2) column (75×30 mm, 5 μm particle size) sold by Phenomenex (pn: 00C-4252-U0-AX) and a dual gradient run from 1-99% mobile phase B over 15.0 min (mobile phase A=water (5 mM hydrochloric acid), mobile phase B=acetonitrile, flow rate=50 mL/min, injection volume=950 μL and column temperature=25° C.) to give 2-chloro-N-[3-[4-(5,5-dimethylpyrrolidin-3-yl)butyl]phenyl]sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (trifluoroacetic acid salt) (104.5 mg, 93%). ESI-MS m/z calc. 667.2207, found 668.2 (M+1) + ; Retention time: 0.67 min (LC Method A).

Step 7: 12,12-Dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11-triazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound 53)

To a solution of 2-chloro-N-[3-[4-(5,5-dimethylpyrrolidin-3-yl)butyl]phenyl]sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide trifluoroacetic acid salt (112.5 mg, 0.1438 mmol) in dimethyl sulfoxide (4.499 mL) was added potassium carbonate (119.2 mg, 0.8625 mmol), cesium fluoride (26.22 mg, 0.1726 mmol) and a small amount of 3 Å molecular sieves. The resulting mixture was capped and heated to 165° C. for 6 h. The mixture was then cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and brine. The organic phase was dried (sodium sulfate), filtered and concentrated to an orange oil which was purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate to give 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11-triazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound 53) (46.5 mg, 51%) as a yellow solid. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.44 (s, 1H), 8.21 (d, J=2.8 Hz, 1H), 7.84 (s, 1H), 7.81 (s, 1H), 7.78-7.74 (m, 1H), 7.59 (s, 2H), 6.93 (d, J=8.2 Hz, 1H), 6.12 (d, J=2.8 Hz, 1H), 4.31 (t, J=7.0 Hz, 2H), 2.75 (s, 3H), 2.65 (s, 1H), 2.08 (t, J=7.0 Hz, 3H), 1.82 (td, J=13.9, 12.7, 6.0 Hz, 2H), 1.59 (s, 3H), 1.53 (s, 1H), 1.51 (s, 3H), 1.47 (s, 2H), 1.14 (d, J=8.7 Hz, 1H), 1.01-0.93 (m, 3H), 0.90-0.86 (m, 2H), 0.72 (s, 1H). ESI-MS m/z calc. 631.244, found 632.1 (M+1) + ; Retention time: 2.44 min (LC Method B).

Example 14: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl) cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11-triazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(21),5,7,9,19,22-hexaene-2,2,4-trione (Enantiomer 1) (Compound 54) and 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11-triazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(21),5,7,9,19,22-hexaene-2,2,4-trione (Enantiomer 2) (Compound 55)

›Step 1: tert-Butyl 2,2-dimethyl-4-[4-(4-sulfamoylphenyl)but-3-ynyl]pyrrolidine-1-carboxylate

Nitrogen was bubbled through a stirring mixture of 4-bromobenzenesulfonamide (256.9 mg, 1.088 mmol), tert-butyl 4-but-3-ynyl-2,2-dimethyl-pyrrolidine-1-carboxylate (156.3 mg, 0.6218 mmol), Pd(PPh 3 ) 2 Cl 2 (26.19 mg, 0.03731 mmol), iodocopper (11.84 mg, 0.06218 mmol) and N,N-dimethylformamide (1.563 mL) in a vial for 5 min then N-isopropylpropan-2-amine (69.21 mg, 95.86 μL, 0.6840 mmol) was added and the vial was sealed and stirred at 50° C. for 75 min then cooled to room temperature and stirred overnight. Cooled to room temperature and poured into water (200 mL) and extracted with dichloromethane (2×100 mL), combined organic layers, washed with water (2×100 mL), dried (magnesium sulfate), filtered and concentrated to an orange oil which was purified by silica gel chromatography using a gradient from 100% hexanes to 100% ethyl acetate giving tert-butyl 2,2-dimethyl-4-[4-(4-sulfamoylphenyl)but-3-ynyl]pyrrolidine-1-carboxylate (192.5 mg, 76%) as a white solid. ESI-MS m/z calc. 406.19263, found 407.1 (M+1) + ; Retention time: 0.71 min (LC Method A).

›Step 2: tert-Butyl 2,2-dimethyl-4-[4-(4-sulfamoylphenyl)butyl]pyrrolidine-1-carboxylate · 1 of 2

To tert-butyl 2,2-dimethyl-4-[4-(4-sulfamoylphenyl)but-3-ynyl]pyrrolidine-1-carboxylate (192.5 mg, 0.4735 mmol) was added palladium oxide (53.75 mg, 0.2367 mmol) followed by EtOH (1.804 mL) and nitrogen was bubbled through the mixture for 1 min followed by hydrogen bubbled through the mixture for 5 min. The mixture was then capped with a hydrogen balloon and stirred for 3 h. Purged with nitrogen, added celite, stirred 1 min then filtered over a pad of celite. Concentrated the filtrate to tert-butyl 2,2-dimethyl-4-[4-(4-sulfamoylphenyl)butyl]pyrrolidine-1-carboxylate (179.5 mg, 92%), an off-white solid. ESI-MS m/z calc. 410.22394, found 411.2 (M+1) + ; Retention time: 0.75 min (LC Method A).

Step 3: tert-Butyl 4-[4-[4-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]phenyl]butyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

In a 20 mL vial, 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (164.3 mg, 0.4372 mmol) and carbonyl diimidazole (77.70 mg, 0.4792 mmol) were combined in tetrahydrofuran (2.576 mL) and stirred for 120 min at 50° C. with a loose cap. Then tert-butyl 2,2-dimethyl-4-[4-(4-sulfamoylphenyl)butyl]pyrrolidine-1-carboxylate (179.5 mg, 0.4372 mmol) in tetrahydrofuran (3.436 mL) was added followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (137.0 mg, 134.6 μL, 0.9002 mmol) and the reaction was heated at 50° C. for 16 hrs. The reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride followed by brine. The organic layer was dried over sodium sulfate, evaporated then purified using a reverse phase HPLC-MS method using a Luna C 18 (2) column (75×30 mm, 5 μm particle size) sold by Phenomenex (pn: 00C-4252-U0-AX) and a dual gradient run from 30-99% mobile phase B over 15.0 min (mobile phase A=water (5 mM hydrochloric acid), mobile phase B=acetonitrile, flow rate=50 mL/min, injection volume=950 μL and column temperature=25° C.). Fractions of intended product were combined and acetonitrile was removed under reduced pressure. The material was then diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate (1×) and brine (1×), dried (sodium sulfate), filtered and concentrated to provide tert-butyl 4-[4-[4-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]phenyl]butyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (132.8 mg, 40%), a clear oil. ESI-MS m/z calc. 767.27313, found 768.2 (M+1) + ; Retention time: 0.96 min (LC Method A).

Step 4: 2-Chloro-N-[4-[4-(5,5-dimethylpyrrolidin-3-yl)butyl]phenyl]sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide

tert-Butyl 4-[4-[4-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]phenyl]butyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (132.8 mg, 0.1729 mmol) was dissolved in dichloromethane (579.5 μL) and to the mixture was added trifluoroacetic acid (904.5 mg, 611.1 μL, 7.933 mmol) and the mixture was stirred at room temperature for 60 min. Concentrated the mixture to dryness under reduced pressure, took up in saturated aqueous sodium bicarbonate and ethyl acetate and separated the layers. Dried the organic layer (sodium sulfate), filtered and concentrated to a white solid, 2-chloro-N-[4-[4-(5,5-dimethylpyrrolidin-3-yl)butyl]phenyl]sulfonyl-6-[3-[2-[1-(trifluoromethyl) cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (99.8 mg, 86%). ESI-MS m/z calc. 667.2207, found 668.3 (M+1) + ; Retention time: 0.66 min (LC Method A).

Step 5: 12,12-Dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11-triazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(21),5,7,9,19,22-hexaene-2,2,4-trione (Compound 52)

To a solution of 2-chloro-N-[4-[4-(5,5-dimethylpyrrolidin-3-yl)butyl]phenyl]sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (99.8 mg, 0.1494 mmol) in dimethyl sulfoxide (3.991 mL) was added potassium carbonate (103.2 mg, 0.7470 mmol), cesium fluoride (27.24 mg, 0.1793 mmol) and a small amount of 3 Å molecular sieves. The resulting mixture was capped and heated to 155° C. overnight. Cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and brine. The organic phase was dried (sodium sulfate), filtered and concentrated to an orange oil which was purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate to give 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11-triazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(21),5,7,9,19,22-hexaene-2,2,4-trione (Compound 51) (25 mg, 26%) as a white solid. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.21 (s, 1H), 8.17 (d, J=2.8 Hz, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.46 (d, J=16.6 Hz, 2H), 6.89 (d, J=8.3 Hz, 1H), 6.10 (d, J=2.8 Hz, 1H), 4.31 (t, J=7.0 Hz, 2H), 2.92-2.80 (m, 1H), 2.74 (dt, J=13.9, 6.9 Hz, 1H), 2.19 (s, 1H), 2.07 (t, J=7.1 Hz, 2H), 1.94-1.85 (m, 2H), 1.80 (s, 1H), 1.70 (dd, J=11.7, 5.3 Hz, 1H), 1.60-1.52 (m, 1H), 1.49 (s, 6H), 1.44-1.34 (m, 2H), 1.02 (dt, J=12.8, 6.7 Hz, 1H), 0.98-0.93 (m, 2H), 0.89 (d, J=10.8 Hz, 2H), 0.77 (q, J=11.6 Hz, 1H), 0.36 (s, 1H). ESI-MS m/z calc. 631.244, found 632.1 (M+1) + ; Retention time: 2.46 min (LC Method B).

Step 6: 12,12-Dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11-triazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(21),5,7,9,19,22-hexaene-2,2,4-trione (Enantiomer 1) (Compound 54) and 12,12-Dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11-triazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(21),5,7,9,19,22-hexaene-2,2,4-trione (Enantiomer 2) (Compound 55)

Subjected racemic 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11-triazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(21),5,7,9,19,22-hexaene-2,2,4-trione (21.9 mg, 0.03411 mmol) to chiral separation by SFC chromatography using a ChiralPak AS-H (250×10 mm column, 5 μm particle size) with 25% acetonitrile/methanol (90:10)/75% carbon dioxide mobile phase at 10 mL/min over 6.0 min (injection volume=70 μL of 24 mg/mL solution in 85% acetonitrile/methanol (90:10)/15% dimethyl sulfoxide) giving as the first enantiomer to elute, 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11-triazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(21),5,7,9,19,22-hexaene-2,2,4-trione (enantiomer 1) (Compound 54) (10.01 mg, 92%) as a white solid; ESI-MS m/z calc. 631.244, found 632.2 (M+1) + ; Retention time: 2.44 min (LC Method B) and as the second enantiomer to elute, 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11-triazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(21),5,7,9,19,22-hexaene-2,2,4-trione (enantiomer 2) (Compound 55) (8.59 mg, 80%) as a white solid; 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.20 (s, 1H), 8.17 (d, J=2.8 Hz, 1H), 8.07 (dd, J=8.0, 2.1 Hz, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.76 (dd, J=8.1, 2.0 Hz, 1H), 7.49 (d, J=8.2 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 6.90 (d, J=8.3 Hz, 1H), 6.10 (d, J=2.7 Hz, 1H), 4.31 (t, J=7.0 Hz, 2H), 2.87 (dt, J=13.4, 6.4 Hz, 1H), 2.74 (dt, J=14.0, 7.0 Hz, 1H), 2.19 (t, J=10.4 Hz, 1H), 2.07 (t, J=7.1 Hz, 2H), 1.89 (dt, J=13.4, 6.0 Hz, 2H), 1.80 (d, J=8.4 Hz, 1H), 1.70 (dd, J=11.8, 5.4 Hz, 1H), 1.55 (dt, J=14.0, 7.0 Hz, 1H), 1.49 (s, 6H), 1.39 (t, J=12.3 Hz, 2H), 1.02 (dt, J=12.8, 6.5 Hz, 1H), 0.96 (td, J=4.9, 4.4, 3.1 Hz, 2H), 0.91-0.85 (m, 2H), 0.77 (q, J=10.7 Hz, 1H), 0.36 (s, 1H), ESI-MS m/z calc. 631.244, found 632.2 (M+1) + ; Retention time: 2.44 min (LC Method B).

›Step 2: tert-Butyl 2,2-dimethyl-4-[4-(4-sulfamoylphenyl)butyl]pyrrolidine-1-carboxylate · 2 of 2

Example 15: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11-triazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Enantiomer 1) (Compound 56) and 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11-triazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Enantiomer 2) (Compound 57)

Step 1: 12,12-Dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11-triazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Enantiomer 1) (Compound 56) and 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11-triazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Enantiomer 2) (Compound 57)

Subjected racemic 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11-triazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (41.7 mg, 0.06575 mmol) to chiral separation by SFC chromatography using a ChiralPak AS-H (250×10 mm column, 5 μm particle size) with 25% acetonitrile/methanol (90:10)/75% carbon dioxide mobile phase at 10 mL/min over 8.0 min (injection volume=70 μL of 24 mg/mL solution in 85% acetonitrile/methanol (90:10)/15% dimethyl sulfoxide) giving as the first enantiomer to elute, 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11-triazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (enantiomer 1) (Compound 56) (20.2 mg, 97%); ESI-MS m/z calc. 631.244, found 632.2 (M+1) + ; Retention time: 2.44 min (LC Method B) and as the second enantiomer to elute, 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11-triazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (enantiomer 2) (Compound 57) (15.9 mg, 75%); 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.44 (s, 1H), 8.21 (d, J=2.8 Hz, 1H), 7.87-7.75 (m, 3H), 7.63-7.57 (m, 2H), 6.93 (dd, J=8.2, 1.2 Hz, 1H), 6.12 (dd, J=2.8, 0.9 Hz, 1H), 4.31 (t, J=7.0 Hz, 2H), 2.75 (d, J=6.0 Hz, 2H), 2.68-2.62 (m, 1H), 2.11-2.05 (m, 3H), 1.83 (dt, J=12.6, 6.3 Hz, 2H), 1.58 (s, 3H), 1.51 (s, 6H), 1.15 (t, J=8.9 Hz, 1H), 0.97 (d, J=3.4 Hz, 1H), 0.97-0.95 (m, 2H), 0.91 (s, 1H), 0.90 (s, 2H), 0.72 (s, 1H). ESI-MS m/z calc. 631.244, found 632.2 (M+1) + ; Retention time: 2.43 min (LC Method B).

Example 16: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,20,25-pentaazatetracyclo[19.3.1.111,14.05,10]hexacosa-1(24),5,7,9,21(25),22-hexaene-2,2,4-trione (Enantiomer 1) (Compound 63) and 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,20,25-pentaazatetracyclo[19.3.1.111,14.05,10]hexacosa-1(24),5,7,9,21(25),22-hexaene-2,2,4-trione (Enantiomer 2) (Compound 64)

›Step 1: Ethyl 1-(bromomethyl)-2-oxo-cyclohexanecarboxylate

A solution of ethyl 2-cyclohexanonecarboxylate (84.0 g, 493 mmol) in tetrahydrofuran (350 mL) of was added dropwise to a slurry of 60% sodium hydride (25.7 g, 641 mmol) and hexamethylphosphoramide (112 mL, 641 mmol) in tetrahydrofuran (850 mL) over a four h period and the resulting mixture stirred at room temperature for one h. Dibromomethane (173 mL, 2470 mmol) was then added dropwise over a one h period and the mixture was refluxed at 70° C. for 16 h. The reaction mixture was diluted with diethyl ether (6 L) and the organic layer was washed with water (5×850 mL), the aqueous phases were discarded and the organic phase was dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography using a 0-15% hexanes/ethyl acetate gradient to obtain ethyl 1-(bromomethyl)-2-oxo-cyclohexanecarboxylate (68 g, 52%) as a clear oil. Purity was determined to be approx. 80% by 1 H NMR. 1 H NMR (250 MHz, CDCl 3 ) δ 4.35-4.15 (m, 2H), 3.88-3.50 (dd, 2H), 2.75-2.64 (dd, 1H), 2.49-2.41 (m, 2H), 2.30-2.17 (p, 2H), 2.10-1.75 (m, 2H), 1.74-1.53 (m, 2H), 1.32-1.22 (m, 3H). The crude material was used in the next step without further purification.

›Step 2: Diethyl 2-methyleneheptanedioate

A slurry of ethyl 1-(bromomethyl)-2-oxo-cyclohexanecarboxylate (68 g, 258 mmol) and potassium carbonate (71.4 g, 517 mmol) in ethanol (600 mL) was stirred for 16 h at room temperature. The resulting mixture was filtered, the solids were discarded and the filtrate was concentrated and purified by silica gel chromatography using a 0-15% hexanes/ethyl acetate gradient to obtain diethyl 2-methyleneheptanedioate (45.2 g, 77%) as a clear oil. 1 H NMR (250 MHz, CDCl 3 ) δ 6.17 (s, 1H), 5.54 (s, 1H), 4.23-4.06 (m, 4H), 2.35-2.15 (t, 4H), 1.73-1.40 (m, 4H), 1.29-1.07 (m, 6H). ESI-MS m/z calc. 228.29, found 229.0 (M+1) + . Retention time: 4.97 min (LC Method Q).

›Step 3: Diethyl 2-(2-methyl-2-nitro-propyl)heptanedioate

A mixture of diethyl 2-methyleneheptanedioate (48.6 g, 213 mmol), 2-nitropropane (58 mL, 639 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.2 mL, 21 mmol) was heated at 85° C. for five h. The mixture was concentrated and purified by silica gel chromatography using a 0-15% hexanes/ethyl acetate gradient to obtain diethyl 2-(2-methyl-2-nitro-propyl)heptanedioate (58 g, 85%) as a clear oil. ESI-MS m/z calc. 317.38, found 318.1 (M+1) + . Retention time: 5.19 min (LC Method Q).

›Step 4: Ethyl 5-(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)pentanoate

To a solution of diethyl 2-(2-methyl-2-nitro-propyl)heptanedioate (19 g, 59.8 mmol) in ethanol (400 mL) was added Raney Nickel slurry (9 g) and the resulting mixture was heated to 80° C. for 22 h in a Parr reactor under 2 bar of hydrogen. Celite (50 g) was added to the reactor and the mixture was filtered. The solids were discarded and the filtrate was concentrated under vacuum to obtain ethyl 5-(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)pentanoate (13.2 g, 91% yield) as a pale oil. ESI-MS m/z calc. 241.33, found 242.1 (M+1) + . Retention time: 3.79 min (LC Method Q). The crude product was used in the next step without further purification.

›Step 5: 5-(5,5-Dimethylpyrrolidin-3-yl)pentan-1-ol

To a solution of ethyl 5-(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)pentanoate (13.2 g, 54.7 mmol) in tetrahydrofuran (200 mL) was added lithium aluminum hydride (6.2 g, 164.1 mmol) in portions, then the resulting slurry was refluxed under nitrogen atmosphere for 17 h. The mixture was carefully quenched with saturated aqueous sodium sulfate solution (50 mL) and filtered. The solids were discarded and the aqueous phase was separated and discarded. The organic phase was concentrated to obtain 5-(5,5-dimethylpyrrolidin-3-yl)-pentan-1-ol (8.8 g) as a pale yellow oil. ESI-MS m/z calc. 185.31, found 186.3 (M+1) + . Retention time: 1.98 min (LC Method Q). The crude product was used in the next step without further purification.

›Step 6: tert-Butyl 4-(5-hydroxypentyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

To a solution of 5-(5,5-dimethylpyrrolidin-3-yl)-pentan-1-ol (27.0 g, 145.7 mmol) in dichloromethane (200 mL) was added a solution of sodium bicarbonate (24.5 g, 291.4 mmol) in water (150 mL), followed addition of di-tert-butyl dicarbonate (31.8 g, 145.7 mmol). The resulting heterogeneous mixture was stirred at room temperature for two h. The phases were separated and the aqueous phase was discarded. The organic phase was concentrated under vacuum and purified by silica gel chromatography using a 0-45% hexanes/ethyl acetate gradient to obtain tert-butyl 4-(5-hydroxypentyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (32.0 g, 77%) as a clear oil. 1 H NMR (250 MHz, CDCl 3 ) δ 4.29 (q, 1H), 3.53 (s, 1H), 3.37 (q, 2H), 2.75 (q, 1H), 2.05 (s, 2H), 1.87 (m, 1H), 1.43-1.17 (m, 23H). ESI-MS m/z calc. 285.43, found 286.4 (M+1) + . Retention time: 5.20 min (LC Method Q).

›Step 7: tert-Butyl 2,2-dimethyl-4-(5-methylsulfonyloxypentyl)pyrrolidine-1-carboxylate

A solution of tert-butyl 4-(5-hydroxypentyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (10.5 g, 36.8 mmol) and triethylamine (10.3 mL, 73.6 mmol) in dichloromethane (100 mL) was chilled in an ice water bath. Then methanesulfonyl chloride (3.2 mL, 40.5 mmol) was added dropwise over a 15 min period and the resulting mixture was stirred for one h in the ice bath. The reaction was quenched with saturated sodium bicarbonate solution (50 mL). The aqueous phase was discarded and the organic phase was concentrated to obtain tert-butyl 2,2-dimethyl-4-(5-methylsulfonyloxypentyl)pyrrolidine-1-carboxylate (13.3 g, 99%) as a yellow oil. ESI-MS m/z calc. 363.16, found 364.3 (M+1) + . Retention time: 5.77 min The crude product was used in the next step without further purification (LC Method Q).

›Step 8: tert-Butyl 4-(5-aminopentyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

A solution of tert-butyl 2,2-dimethyl-4-(5-methylsulfonyloxypentyl)pyrrolidine-1-carboxylate (13.3 g, 36.6 mmol) in tetrahydrofuran (275 mL) and 28% aqueous ammonium hydroxide (275 mL was stirred at 50° C. for 24 h. Tetrahydrofuran and ammonia were removed under vacuum and the remaining aqueous phase was extracted with dichloromethane (3×100 mL) and the combined organics were concentrated to an oil and purified by silica gel chromatography using a 0-15% dichloromethane/methanol (0.25% ammonium hydroxide) gradient to obtain tert-butyl 4-(5-aminopentyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (5.4 g, 52%) as a pale oil. 1 H NMR (250 MHz, CDCl 3 ) δ 3.53 (q, 1H), 2.75 (q, 1H), 2.05 (s, 2H), 1.86 (m, 1H), 1.43-1.10 (m, 23H). ESI-MS m/z calc. 284.45, found 285.4 (M+1) + . Retention time: 4.07 min (LC Method Q).

›Step 9: tert-Butyl 2,2-dimethyl-4-[5-[(6-sulfamoyl-2-pyridyl)amino]pentyl]pyrrolidine-1-carboxylate · 1 of 3

A 100 mL round bottom flask was charged with tert-butyl 4-(5-aminopentyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (1.028 g, 3.614 mmol), 6-fluoropyridine-2-sulfonamide (636 mg, 3.610 mmol) and anhydrous dimethyl sulfoxide (10 mL). Potassium carbonate (519 mg, 3.755 mmol) (freshly ground in a mortar) was added and the mixture stirred at 100° C. for 20 h. After cooling down, the reaction was diluted with ethyl acetate (50 mL) and poured into saturated aqueous ammonium chloride (50 mL). The two phases were separated. The aqueous phase was extracted with ethyl acetate (20 mL) and the combined extracts were washed with brine (40 mL). After drying over sodium sulfate and evaporation, the residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0 to 100% over 30 min) in hexanes. The pure fractions were collected and the solvents evaporated to give tert-butyl 2,2-dimethyl-4-[5-[(6-sulfamoyl-2-pyridyl)amino]pentyl]pyrrolidine-1-carboxylate (1.184 g, 74%) as a white solid foam. ESI-MS m/z calc. 440.24573, found 441.3 (M+1) + ; Retention time: 1.86 min (LC Method B).

Step 10: tert-Butyl 4-[5-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]pentyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

In a 20 mL vial, 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (19.8 mg, 0.8511 mmol) and carbonyl diimidazole (138.0 mg, 0.8511 mmol) were combined in tetrahydrofuran (3.588 mL) and stirred for 120 min at 50° C. with a loose cap. Then tert-butyl 2,2-dimethyl-4-[5-[(6-sulfamoyl-2-pyridyl)amino]pentyl]pyrrolidine-1-carboxylate (250 mg, 0.5674 mmol) in tetrahydrofuran (4.785 mL) was added followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (169.7 μL, 1.135 mmol) and the reaction was heated at 50° C. for 16 hrs. The reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride followed by brine. The organics were separated, dried over sodium sulfate, filtered and evaporated then purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate giving tert-butyl 4-[5-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]pentyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (416.8 mg, 92%). ESI-MS m/z calc. 797.2949, found 798.3 (M+1) + ; Retention time: 0.92 min (LC Method A).

Step 11: 2-Chloro-N-[[6-[5-(5,5-dimethylpyrrolidin-3-yl)pentylamino]-2-pyridyl]sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide

tert-Butyl 4-[5-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]pentyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (416.8 mg, 0.5221 mmol) was dissolved in dichloromethane (1.189 mL) and to the mixture was added trifluoroacetic acid (1.845 mL, 23.95 mmol) and stirred the mixture at room temperature for 60 min. Concentrated mixture to dryness under reduced pressure, took up in saturated aqueous sodium bicarbonate and ethyl acetate and separated the layers. Organic layer was dried (sodium sulfate), filtered and concentrated to a white solid, 2-chloro-N-[[6-[5-(5,5-dimethylpyrrolidin-3-yl)pentylamino]-2-pyridyl]sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (361 mg, 91%). ESI-MS m/z calc. 697.2425, found 698.2 (M+1) + ; Retention time: 0.64 min (LC Method A).

Step 12: 12,12-Dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,20,25-pentaazatetracyclo[19.3.1.111,14.05,10]hexacosa-1(24),5,7,9,21(25),22-hexaene-2,2,4-trione (Enantiomer 1) (Compound 63) and 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,20,25-pentaazatetracyclo[19.3.1.111,14.05,10]hexacosa-1(24),5,7,9,21(25),22-hexaene-2,2,4-trione (Enantiomer 2) (Compound 64)

To a solution of 2-chloro-N-[[6-[5-(5,5-dimethylpyrrolidin-3-yl)pentylamino]-2-pyridyl]sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (361 mg, 0.4736 mmol) in dimethyl sulfoxide (13.22 mL) was added potassium carbonate (392.6 mg, 2.841 mmol), cesium fluoride (86.33 mg, 0.5683 mmol) and a small amount of 3 Å molecular sieves. The resulting mixture was capped and heated to 165° C. for 16 h. The mixture was then cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and brine. The organic phase was dried (sodium sulfate), filtered and concentrated to 422 mg of a tan amorphous solid which was subjected to chiral separation by SFC chromatography using a LUX 3 (250×21 mm column, 5 μm particle size) with 60% methanol (20 mM NH 3 additive))/40% carbon dioxide mobile phase at 30 mL/min giving as the first enantiomer to elute, 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,20,25-pentaazatetracyclo[19.3.1.111,14.05,10]hexacosa-1(24),5,7,9,21(25),22-hexaene-2,2,4-trione (enantiomer 1) (Compound 63) (74.4 mg, 47%) as a white solid; 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.69 (bs, 1H), 8.19 (d, J=2.7 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.48 (s, 1H), 7.08 (d, J=6.9 Hz, 2H), 6.85 (d, J=8.0 Hz, 1H), 6.58 (s, 1H), 6.07 (d, J=2.6 Hz, 1H), 4.31 (t, J=7.0 Hz, 2H), 3.84 (d, J=14.2 Hz, 1H), 3.06 (s, 1H), 2.89 (s, 1H), 2.79 (s, 1H), 2.08 (t, J=7.1 Hz, 3H), 1.81 (dd, J=11.6, 5.4 Hz, 1H), 1.60 (d, J=9.1 Hz, 1H), 1.55 (d, J=6.2 Hz, 6H), 1.47 (d, J=12.5 Hz, 3H), 1.27 (d, J=26.3 Hz, 3H), 1.01 (s, 1H), 0.98-0.93 (m, 2H), 0.93-0.84 (m, 3H), ESI-MS m/z calc. 661.2658, found 662.2 (M+1) + ; Retention time: 2.29 min (LC Method B) and as the second enantiomer to elute, 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,20,25-pentaazatetracyclo[19.3.1.111,14.05,10]hexacosa-1(24),5,7,9,21(25),22-hexaene-2,2,4-trione (enantiomer 2) (Compound 64) (79.2 mg, 50%) as a white solid; 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.50 (s, 1H), 8.21 (d, J=2.8 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.56 (s, 1H), 7.14 (s, 1H), 6.91 (d, J=7.8 Hz, 2H), 6.70 (s, 1H), 6.11 (s, 1H), 4.31 (t, J=7.0 Hz, 2H), 3.88 (s, 1H), 3.06 (s, 1H), 2.74 (s, 1H), 2.62 (d, J=32.1 Hz, 1H), 2.08 (t, J=7.1 Hz, 2H), 1.83 (dd, J=11.8, 5.3 Hz, 1H), 1.67-1.57 (m, 1H), 1.55 (d, J=10.5 Hz, 6H), 1.48 (t, J=12.1 Hz, 3H), 1.30 (s, 2H), 1.23 (s, 1H), 1.01 (d, J=9.5 Hz, 1H), 0.98-0.95 (m, 2H), 0.95-0.87 (m, 3H), ESI-MS m/z calc. 661.2658, found 662.2 (M+1) + ; Retention time: 2.29 min (LC Method B).

›Step 9: tert-Butyl 2,2-dimethyl-4-[5-[(6-sulfamoyl-2-pyridyl)amino]pentyl]pyrrolidine-1-carboxylate · 2 of 3

Example 17: Preparation of (14S)-8-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound 66)

Step 1: tert-Butyl (4S)-2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate

Subjected racemic tert-butyl 2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (7 g, 16.97 mmol) to chiral separation by SFC chromatography using a ChiralPak IG (250×21.2 mm column, 5 μm particle size) with 40% methanol/60% carbon dioxide mobile phase at 70 mL/min over 11.0 min (injection volume=500 μL of 32 mg/mL solution in methanol) giving as the first peak to elute, tert-butyl (4S)-2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (3.4481 g, 99%). ESI-MS m/z calc. 412.21442, found 413.2 (M+1); Retention time: 0.63 min (LC Method A).

Step 2: tert-Butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

Part A: To 2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (8.9 g, 24.60 mmol) in tetrahydrofuran (80 mL) was slowly added carbonyl diimidazole (4.4 g, 27.14 mmol). The mixture was stirred at ambient temperature for 1 hr.

Part B: To tert-butyl (4S)-2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (10.1 g, 24.48 mmol) in tetrahydrofuran (40 mL) was added 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (11.0 mL, 73.56 mmol) followed by the activated ester from Part A and the mixture was stirred at ambient temperature for 16 hr. The reaction was quenched with 50 mL of water and most of the tetrahydrofuran was removed under vacuum. The remaining mixture was diluted with water (250 mL) containing hydrochloric acid (26 mL of 6 M, 156.0 mmol) and acidified to pH=2-3. The clear dark yellow solution was extracted with ethyl acetate (400 mL). The organic phase was washed with 300 mL of brine, dried over magnesium sulfate, filtered and concentrated under vacuum affording a thick yellow oil. The crude reaction mixture was chromatographed on a C 18 415 g reverse phase column eluting with 50-100% water/acetonitrile to afford tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (11.2 g, 60%). ESI-MS m/z calc. 755.3232, found 756.3 (M+1) + ; Retention time: 2.53 min (LC Method B).

Step 3: 2-Chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]-N-[[6-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2-pyridyl]sulfonyl]pyridine-3-carboxamide (Trifluoroacetic Acid Salt)

To tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (16.7 g, 22.08 mmol) in dichloromethane (80 mL) and toluene (40 mL) was added trifluoroacetic acid (10 mL, 129.8 mmol) and the mixture was stirred at ambient temperature for 22 h. The solvent was removed by rotary evaporation at 35° C. affording a thick yellow oil. The oil was diluted with dichloromethane (80 mL) and toluene (120 mL) and the solvent removed by rotary evaporation at 55° C. The process was repeated with dichloromethane and toluene affording 2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]-N-[[6-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2-pyridyl]sulfonyl]pyridine-3-carboxamide (trifluoroacetate salt) (22.6 g, 133%, product contaminated with residual toluene and trifluoroacetic acid) as thick oil. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.73 (s, 1H), 8.60 (s, 2H), 8.39 (d, J=2.9 Hz, 1H), 8.11 (d, J=8.3 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.63 (dd, J=8.5, 7.2 Hz, 1H), 7.26-7.22 (m, 1H), 6.75 (dd, J=8.5, 0.7 Hz, 1H), 6.20 (d, J=2.9 Hz, 1H), 4.40 (t, J=6.8 Hz, 2H), 3.36 (dq, J=12.0, 5.3 Hz, 1H), 3.24 (hept, J=6.7 Hz, 2H), 2.80 (td, J=11.8, 10.8, 6.1 Hz, 1H), 2.41-2.32 (m, 1H), 2.02-1.85 (m, 3H), 1.61-1.28 (m, 8H), 1.24 (d, J=6.2 Hz, 4H), 0.69 (qt, J=8.3, 5.0 Hz, 2H), 0.49-0.34 (m, 3H), 0.34-0.25 (m, 1H), 0.25-0.14 (m, 2H), 0.11-0.00 (m, 2H). ESI-MS m/z calc. 655.27075, found 656.3 (M+1) + ; Retention time: 1.71 min (LC Method B).

Step 4: (14S)-8-[3-(3,3-Dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound 66)

To a solution of 2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]-N-[[6-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2-pyridyl]sulfonyl]pyridine-3-carboxamide (trifluoroacetate salt) (17.5 g, 22.72 mmol) in NMP (300 mL) was added potassium carbonate (15.3 g, 110.7 mmol) followed by cesium fluoride (3.8 g, 25.02 mmol). The mixture was purged with nitrogen for 5 min. The mixture was heated at 150° C. for 20 hr. The reaction mixture was cooled to room temperature, added to water (1200 mL) (used a 5 L flask chilled with an ice-bath) and acidified by careful addition of hydrochloric acid (20 mL of 6 M, 120.0 mmol) and then solid citric acid (45 g, 234.2 mmol). The mixture was stirred in an ice bath for 1 hr. The solid was collected by filtration using a medium frit (slow filtration) and the wet filter cake was dissolved in ethyl acetate (1,000 mL) and washed with 500 mL of brine. The aqueous phase was separated and the organic phase was dried over magnesium sulfate, filtered over Celite and concentrated under vacuum affording a light yellow foam. The crude product was diluted with acetonitrile and split into 3 equal volumes (15 mL) and chromatographed on a C 18 415 g reverse phase Column eluting with 50-100% acetonitrile/water to afford (14S)-8-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound 66) (8.91 g, 63%). 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.48 (s, 1H), 8.20 (d, J=3.2 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.05 (d, J=7.0 Hz, 1H), 6.97 (s, 2H), 6.71 (d, J=8.4 Hz, 1H), 6.10 (d, J=3.2 Hz, 1H), 4.37 (t, J=6.7 Hz, 2H), 3.91 (s, 1H), 3.15 (s, 1H), 2.95 (d, J=13.3 Hz, 1H), 2.71 (s, 1H), 2.12 (s, 1H), 1.95-1.71 (m, 4H), 1.60 (d, J=3.3 Hz, 6H), 1.51 (s, 3H), 1.39-1.25 (m, 1H), 0.67 (dt, J=8.5, 4.1 Hz, 2H), 0.47-0.33 (m, 4H), 0.30 (t, J=8.0 Hz, 1H), 0.20 (dd, J=9.7, 4.4 Hz, 2H), 0.04 (d, J=8.3 Hz, 2H). ESI-MS m/z calc. 619.29407, found 620.3 (M+1) + ; Retention time: 10.3 min (LC Method F).

›Step 9: tert-Butyl 2,2-dimethyl-4-[5-[(6-sulfamoyl-2-pyridyl)amino]pentyl]pyrrolidine-1-carboxylate · 3 of 3

Example 18: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,20-pentaazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Enantiomer 1) (Compound 72) and 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,20-pentaazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Enantiomer 2) (Compound 73)

›Step 1: tert-Butyl 2,2-dimethyl-4-[3-[(5-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate · 1 of 2

To tert-butyl 4-(3-aminopropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (400 mg, 1.560 mmol) and 6-chloropyridine-3-sulfonamide (300.5 mg, 1.560 mmol) in dimethyl sulfoxide (3.368 mL) was added potassium carbonate (219.9 mg, 1.591 mmol) and the mixture stirred at 100° C. for 20 h then allowed to cool to room temperature. Diluted with ethyl acetate and poured into saturated aqueous ammonium chloride. Separated the layers then washed the organic layer with saturated aqueous brine, dried (sodium sulfate), filtered and concentrated to a yellow foam which was purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate giving tert-butyl 2,2-dimethyl-4-[3-[(5-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (347 mg, 54%) as a white solid. ESI-MS m/z calc. 412.21442, found 413.2 (M+1) + ; Retention time: 0.52 min (LC Method A).

Step 2: tert-Butyl 4-[3-[[5-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

In a 20 mL vial 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (474.2 mg, 1.262 mmol) and carbonyl diimidazole (204.6 mg, 1.262 mmol) were combined in tetrahydrofuran (4.979 mL) and stirred for 120 min at 50° C. with a loose cap. Then tert-butyl 2,2-dimethyl-4-[3-[(5-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (347 mg, 0.8411 mmol) in tetrahydrofuran (6.642 mL) was added followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (251.6 μL, 1.682 mmol) and the reaction was heated at 50° C. for 16 hrs. The reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride followed by brine. The organics were separated, dried over sodium sulfate, filtered and evaporated then purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate giving pure product as well as mixed fractions. Mixed fractions were concentrated and repurified using a reverse phase HPLC-MS method using a Luna C 18 (2) column (75×30 mm, 5 μm particle size) sold by Phenomenex (pn: 00C-4252-U0-AX) and a dual gradient run from 30-99% mobile phase B over 15.0 min (mobile phase A=water (5 mM hydrochloric acid), mobile phase B=acetonitrile, flow rate=50 mL/min, injection volume=950 μL and column temperature=25° C.). Pure fractions from reverse-phase prep purification were combined and acetonitrile was removed by rotary evaporation. The residue was dissolved in ethyl acetate and washed with a small amount of saturated aqueous sodium bicarbonate then dried (sodium sulfate), filtered and concentrated to a white solid which was combined with the pure product from the silica gel column to give tert-butyl 4-[3-[[5-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (539.2 mg, 83%) as a white solid. ESI-MS m/z calc. 769.2636, found 770.2 (M+1) + ; Retention time: 0.84 min (LC Method A).

Step 3: 2-Chloro-N-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propylamino]-3-pyridyl]sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide

tert-Butyl 4-[3-[[5-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (539.2 mg, 0.7000 mmol) was dissolved in dichloromethane (2.353 mL) and to the mixture was added trifluoroacetic acid (2.474 mL, 32.11 mmol) and the mixture was stirred at room temperature for 60 min. Concentrated mixture to dryness under reduced pressure, took up in saturated aqueous sodium bicarbonate and ethyl acetate and separated the layers (solubility of product in ethyl acetate under these conditions is poor, addition of some methanol helps, needed to evaporate the organic layer without using solid drying agent). Concentrated the organic layer by rotary evaporation followed by drying under vacuum giving 2-chloro-N-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propylamino]-3-pyridyl]sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (423.3 mg, 90%) as an off-white solid. ESI-MS m/z calc. 669.2112, found 670.2 (M+1) + ; Retention time: 0.56 min (LC Method A).

Step 4: 12,12-Dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,20-pentaazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound 62)

To a solution of 2-chloro-N-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propylamino]-3-pyridyl]sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (423.3 mg, 0.6317 mmol) in dimethyl sulfoxide (16.93 mL) was added potassium carbonate (523.8 mg, 3.790 mmol), cesium fluoride (115.1 mg, 0.7577 mmol) and a small amount of 3 Å molecular sieves. The resulting mixture was capped and heated to 165° C. for 16 h. Increased the temperature to 175° C. and stirred 3 h then cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and brine. The organic phase was dried (sodium sulfate), filtered and concentrated to 500 mg of a tan amorphous solid which was filtered and purified using a reverse phase HPLC-MS method using a Luna C 18 (2) column (75×30 mm, 5 μm particle size) sold by Phenomenex (pn: 00C-4252-U0-AX) and a dual gradient run from 30-99% mobile phase B over 15.0 min (mobile phase A=water (5 mM hydrochloric acid), mobile phase B=acetonitrile, flow rate=50 mL/min, injection volume=950 μL and column temperature=25° C.) giving 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,20-pentaazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound 62) (24.2 mg, 6%) as a white solid. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.13 (s, 1H), 8.38 (s, 1H), 8.17 (d, J=2.8 Hz, 1H), 7.91-7.64 (m, 2H), 7.42 (s, 1H), 6.63 (d, J=8.8 Hz, 1H), 6.09 (d, J=2.7 Hz, 1H), 4.30 (t, J=7.1 Hz, 2H), 3.64 (s, 1H), 2.88 (s, 1H), 2.07 (t, J=7.1 Hz, 3H), 2.03-1.92 (m, 2H), 1.80-1.71 (m, 1H), 1.54 (s, 3H), 1.48 (s, 3H), 1.38 (q, J=13.8, 11.4 Hz, 4H), 0.98-0.92 (m, 2H), 0.92-0.85 (m, 3H). ESI-MS m/z calc. 633.2345, found 634.2 (M+1) + ; Retention time: 2.03 min (LC Method B).

›Step 1: tert-Butyl 2,2-dimethyl-4-[3-[(5-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate · 2 of 2

Step 5: 12,12-Dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,20-pentaazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Enantiomer 1) (Compound 72) and 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,20-pentaazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Enantiomer 2) (Compound 73)

Subjected racemic 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,20-pentaazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (17 mg, 0.02565 mmol) to chiral separation by SFC chromatography using a ChiralPak AS-H (250×10 mm column, 5 μm particle size) with 18% methanol (20 mM NH 3 additive)/82% carbon dioxide mobile phase at 10 mL/min over 8.0 min (injection volume=70 μL of 24 mg/mL solution in 90% methanol/10% dimethyl sulfoxide giving as the first enantiomer to elute, 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,20-pentaazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (enantiomer 1) (Compound 72) (6.34 mg, 78%) as a white solid; ESI-MS m/z calc. 633.2345, found 634.4 (M+1) + ; Retention time: 2.08 min (LC Method B) and as the second enantiomer to elute, 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,20-pentaazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (enantiomer 2) (Compound 73) (5.54 mg, 68%) as a white solid. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.13 (s, 1H), 8.63 (s, 1H), 8.43 (s, 1H), 8.18 (d, J=2.8 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.54 (s, 1H), 6.90 (dd, J=8.3, 3.5 Hz, 1H), 6.67 (dd, J=9.0, 3.1 Hz, 1H), 6.11 (d, J=2.8 Hz, 1H), 4.31 (t, J=7.0 Hz, 2H), 3.66 (s, 1H), 2.90 (s, 1H), 2.08 (d, J=7.1 Hz, 2H), 1.92 (s, 3H), 1.77 (d, J=12.5 Hz, 1H), 1.64 (d, J=13.8 Hz, 1H), 1.55 (s, 3H), 1.48 (s, 3H), 1.46-1.34 (m, 3H), 1.34 (s, 1H), 0.97-0.94 (m, 2H), 0.88 (s, 2H). ESI-MS m/z calc. 633.2345, found 634.3 (M+1) + ; Retention time: 2.08 min (LC Method B).

Example 19: Preparation of (14S)-12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl) cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-18-oxa-2λ 6 -thia-3,9,11-triazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Compound 77)

From: (3S)-3-(3-Hydroxypropyl)-5,5-dimethyl-pyrrolidin-2-one

Racemic 3-(3-hydroxypropyl)-5,5-dimethyl-pyrrolidin-2-one (100 g, 566.5 mmol) was separated by chiral SFC chromatography using a ChiralPak AD-H (2×25 cm column) with 30% methanol/carbon dioxide mobile phase at 60 mL/min (injection volume=1 mL of 20 mg/mL solution in methanol giving as the first enantiomer to elute, (3S)-3-(3-hydroxypropyl)-5,5-dimethyl-pyrrolidin-2-one (47 g, 48%) as an off white solid. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 7.63 (s, 1H), 4.38 (t, J=5.1 Hz, 1H), 3.39 (t, J=5.6 Hz, 2H), 2.37 (ddt, J=13.9, 9.6, 4.4 Hz, 1H), 2.02 (dd, J=12.3, 8.6 Hz, 1H), 1.78-1.64 (m, 1H), 1.42 (td, J=12.8, 12.3, 8.4 Hz, 3H), 1.16 (d, J=17.9 Hz, 7H). ESI-MS m/z calc. 171.12593, found 172.0 (M+1) + ; Retention time: 0.61 min (LC Method B).

›Step 2: 3-[(3S)-5,5-Dimethylpyrrolidin-3-yl]propan-1-ol

A 5 L, 3-neck round bottom flask was fitted with a mechanical stirrer, a heating mantle, an addition funnel, a J-Kem temperature probe/controller and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with lithium aluminum hydride pellets (46.53 g, 1.226 mol) pellets. The vessel was then charged with tetrahydrofuran (500 mL, 20 mL/g). Stirring was commenced and the pot temperature was recorded at 20° C. The mixture was allowed to stir at room temperature for 0.5 h to allow the pellets to dissolve. The pot temperature of the resulting grey suspension was recorded at 24° C. The addition funnel was charged with a solution of (3S)-3-(3-hydroxypropyl)-5,5-dimethyl-pyrrolidin-2-one (60 g, 350.4 mmol) in tetrahydrofuran (600 mL) and the clear pale yellow solution was added dropwise over 90 min. Slight heating was required to get into solution. After the completed addition the pot temperature of the resulting greyish suspension was recorded at 24° C. The mixture was then heated to a pot temperature of 65° C. and the condition was maintained for 72 h. Analysis of the reaction mixture at this point indicated some residual starting material still remaining and no change in product formation. The reaction was subsequently stopped at this point. The heating mantle was removed and the vessel was fitted with a cooling bath. The suspension was cooled to 0° C. with a crushed ice/water cooling bath and then quenched by the very slow dropwise addition of water (46.53 mL), followed by 15 wt % sodium hydroxide solution (46.53 mL) and then finally with water (139.59 mL). The pot temperature of the resulting white suspension was recorded at 5° C. The cooling bath was removed and the vessel was again fitted with a heating mantle. The suspension was warmed to 60° C. and the condition was maintained for 30 min. The warm suspension was vacuum filtered through a glass frit Buchner funnel with a 25 mm layer of celite. The filter cake was then displacement washed with 60° C. tetrahydrofuran (2×350 mL) and then pulled for 30 min. The clear filtrate was concentrated under reduced pressure to provide (55 g, 0.349 mol, 99% yield) of a clear light yellow viscous oil as the desired product, 3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propan-1-ol (55 g, 100%). 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 3.36 (t, J=6.3 Hz, 3H), 2.95 (dd, J=10.6, 7.6 Hz, 1H), 2.40 (dd, J=10.6, 7.7 Hz, 1H), 2.12-1.97 (m, 1H), 1.69 (dd, J=12.1, 8.2 Hz, 1H), 1.47-1.25 (m, 5H), 1.08 (s, 3H), 1.02 (s, 3H).

›Step 3: tert-Butyl (4S)-4-(3-hydroxypropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

A 1 L, 3-neck round bottom flask was fitted with a mechanical stirrer, a cooling bath, an addition funnel, a J-Kem temperature probe and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with 3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propan-1-ol (25 g, 159.0 mmol) and dichloromethane (250 mL) which provided a clear light yellow solution. Stirring was commenced and the pot temperature was recorded at 19° C. The cooling bath was charged with crushed ice/water and the pot temperature was lowered to 0° C. The addition funnel was charged with triethylamine (22.16 mL, 159.0 mmol) which was subsequently added neat dropwise over 5 min. No exotherm was observed. The addition funnel was then charged with di-tert-butyl dicarbonate (31.32 g, 143.5 mmol) dissolved in dichloromethane (150 mL). The clear pale yellow solution was then added dropwise over 30 min which resulted in gentle gas evolution. No exotherm was observed. The cooling bath was removed and the resulting clear light yellow solution was allowed to warm to room temperature and continue to stir at room temperature for 3 h. The reaction mixture was transferred to a separatory funnel and partitioned with water (75 mL). The organic was removed and washed with saturated sodium chloride solution (75 mL), dried over sodium sulfate (150 g) and then filtered through a glass frit Buchner funnel. The filtrate was concentrated under reduced pressure to provide (45 g) of a clear light yellow oil as the desired crude product. The material was purified by silica gel column flash chromatography (liquid load with dichloromethane) eluting with a gradient of 100% dichloromethane to 10% methyl alcohol in dichloromethane over 60 min collecting 50 mL fractions. The desired product fractions were combined and concentrated under reduced pressure to provide tert-butyl (4S)-4-(3-hydroxypropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (39 g, 95%). 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 4.35 (t, J=5.2 Hz, 1H), 3.54 (dt, J=12.2, 6.3 Hz, 1H), 3.38 (t, J=5.8 Hz, 2H), 2.76 (q, J=10.2 Hz, 1H), 1.47 (s, 3H), 1.44-1.28 (m, 18H), 1.24 (s, 3H). ESI-MS m/z calc. 257.1991, found 258.1 (M+1) + ; Retention time: 1.55 min (LC Method B).

›Step 4: tert-Butyl (4S)-2,2-dimethyl-4-(3-methylsulfonyloxypropyl)pyrrolidine-1-carboxylate

A 500 mL, 3-neck round bottom flask was fitted with a mechanical stirrer, a cooling bath, an addition funnel, a J-Kem temperature probe and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with tert-butyl (4S)-4-(3-hydroxypropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (25 g, 97.14 mmol) and dichloromethane (250 mL) which provided a clear colorless solution. Stirring was commenced and the pot temperature was recorded at 19° C. The cooling bath was charged with crushed ice/water and the pot temperature was lowered to 0° C. The addition funnel was charged with triethylamine (17.60 mL, 126.3 mmol) which was added neat dropwise over 5 min. No exotherm was observed. The addition funnel was then charged with methanesulfonyl chloride (8.277 mL, 106.9 mmol) which was added neat dropwise over 15 min which resulted in a light yellow suspension and an exotherm to 4° C. The mixture was continued to stir at <5° C. for 1 h when analysis by LC/MS indicated complete consumption of the starting material. The reaction mixture was further diluted with dichloromethane (200 mL) and then poured into saturated ammonium chloride solution (250 mL). The biphasic mixture was then transferred to a separatory funnel. The organic was removed, washed with saturated ammonium chloride solution (150 mL), dried over sodium sulfate (150 g) and then filtered through a glass frit Buchner funnel. The filtrate was concentrated under reduced pressure to provide tert-butyl (4S)-2,2-dimethyl-4-(3-methylsulfonyloxypropyl)pyrrolidine-1-carboxylate (29 g, 89%) as a clear amber oil. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 4.19 (t, J=6.4 Hz, 2H), 3.16 (s, 3H), 2.79 (q, J=10.2 Hz, 1H), 2.11 (s, 1H), 1.90 (td, J=13.5, 6.0 Hz, 1H), 1.66 (ddd, J=15.8, 7.6, 4.0 Hz, 2H), 1.51-1.22 (m, 20H). ESI-MS m/z calc. 335.17664, found 336.1 (M+1) + ; Retention time: 1.74 min (LC Method B).

›Step 5: tert-Butyl (4S)-2,2-dimethyl-4-[3-(3-sulfamoylphenoxy)propyl]pyrrolidine-1-carboxylate

In a 100 mL flask was added 3-hydroxybenzenesulfonamide (750 mg, 4.331 mmol) and N,N-dimethylformamide (15 mL). To the mixture was added potassium carbonate (1.8 g, 13.02 mmol) and tert-butyl (4S)-2,2-dimethyl-4-(3-methylsulfonyloxypropyl)pyrrolidine-1-carboxylate (1.5 g, 4.471 mmol) at room temperature. The resulting mixture was stirred at room temperature for 48 h, then heated to 50° C. for 5 h. The mixture was then poured into 1 N citric acid and extracted with ethyl acetate (2×). Combined organic fractions, dried (sodium sulfate), filtered and concentrated to a yellow oil which was purified via silica gel column chromatography (80 gram column) using a gradient from 100% hexanes to 65% ethyl acetate in hexanes to afford tert-butyl (4S)-2,2-dimethyl-4-[3-(3-sulfamoylphenoxy)propyl]pyrrolidine-1-carboxylate (868 mg, 49%) as a light yellow foam. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 7.47 (t, J=8.0 Hz, 1H), 7.40-7.36 (m, 1H), 7.34 (d, J=3.7 Hz, 3H), 7.15 (d, J=8.3 Hz, 1H), 4.02 (t, J=6.1 Hz, 2H), 3.58 (dd, J=17.4, 7.1 Hz, 1H), 2.81 (q, J=10.3 Hz, 1H), 2.15 (s, 1H), 1.99-1.85 (m, 1H), 1.74 (dt, J=13.3, 6.4 Hz, 2H), 1.46 (dd, J=14.6, 9.4 Hz, 3H), 1.38 (t, J=10.4 Hz, 12H), 1.25 (s, 3H). ESI-MS m/z calc. 412.2032, found 413.2 (M+1) + ; Retention time: 1.86 min (LC Method E).

Step 6: tert-Butyl (4S)-4-[3-[3-[[2-chloro-6-[3-[2-[1-(trifluoromethyl) cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]phenoxy]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (342 mg, 0.9102 mmol) and carbonyl diimidazole (148 mg, 0.9127 mmol) were combined in tetrahydrofuran (5.5 mL) and stirred for 1 h at 50° C. Then tert-butyl (4S)-2,2-dimethyl-4-[3-(3-sulfamoylphenoxy)propyl]pyrrolidine-1-carboxylate (250 mg, 0.6060 mmol) was added followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (230 μL, 1.538 mmol) and the reaction was heated at 50° C. for 18 h. The reaction was diluted with ethyl acetate and washed with a 1 M citric acid solution, followed by brine. The organics were separated, dried over sodium sulfate, filtered and evaporated and then purified via silica gel chromatography (40 gram column) using a gradient from 100% hexanes to 75% ethyl acetate in hexanes to afford tert-butyl (4S)-4-[3-[3-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]phenoxy]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (368 mg, 79%) as an off-white solid. ESI-MS m/z calc. 769.2524, found 770.2 (M+1) + ; Retention time: 2.12 min (LC Method G).

Step 7: (14S)-12,12-Dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-18-oxa-2λ 6 -thia-3,9,11-triazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Compound 77)

Part A: tert-Butyl (4S)-4-[3-[3-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]phenoxy]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (368 mg, 0.4778 mmol) was dissolved in dichloromethane (7.6 mL) and to the mixture was added hydrochloric acid (4 M in dioxane) (4.0 mL of 4 M, 16.00 mmol) and stirred at room temperature for 30 min. Concentrated mixture to dryness under reduced pressure, redissolved in ethyl acetate, then added aqueous 2 M sodium carbonate (5 mL) to give pH˜10. Extracted organic layer with ethyl acetate (2×10 mL), washed with brine, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure.

Part B: Combined material from Part A and potassium carbonate (345 mg, 2.496 mmol), cesium fluoride (115 mg, 0.7571 mmol), 3 Å molecular sieves and dimethyl sulfoxide (7.6 mL) in a vial, purged with nitrogen, capped, heated at 150° C. and stirred for 20 h. Cooled to room temperature. The mixture was filtered, then purified by reverse-phase preparative HPLC utilizing a C 18 column and method 30-99 A1-B1 (acetonitrile-water+5 mM hydrochloric acid) to afford (14S)-12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-18-oxa-2λ 6 -thia-3,9,11-triazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Compound 77) (62.1 mg, 20%) as an off-white solid. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.40 (s, 1H), 8.21 (d, J=2.8 Hz, 1H), 7.85 (d, J=8.3 Hz, 1H), 7.57 (t, J=6.5 Hz, 2H), 7.50 (s, 1H), 7.46-7.32 (m, 1H), 6.94 (d, J=8.2 Hz, 1H), 6.12 (d, J=2.7 Hz, 1H), 4.34 (dt, J=14.1, 5.6 Hz, 3H), 4.21-4.04 (m, 1H), 2.90-2.78 (m, 1H), 2.71 (dd, J=19.5, 9.2 Hz, 1H), 2.26-2.12 (m, 1H), 2.08 (t, J=7.1 Hz, 2H), 1.85 (dd, J=11.8, 5.5 Hz, 1H), 1.75-1.64 (m, 2H), 1.55 (s, 6H), 1.50 (d, J=12.4 Hz, 1H), 1.47-1.36 (m, 1H), 1.28-1.19 (m, 1H), 0.98-0.93 (m, 2H), 0.88 (t, J=5.2 Hz, 2H). ESI-MS m/z calc. 633.22327, found 634.2 (M+1) + ; Retention time: 2.3 min (LC Method E).

Example 20: Preparation of (14S)-8-[3-(3,3-dimethylbutyl)-2-oxopyrrolidin-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (Compound 79)

›Step 1: 3-(3,3-Dimethylbutyl)pyrrolidin-2-one · 1 of 2

To a solution of 2-pyrrolidone (32.0 g, 0.376 mol) in anhydrous tetrahydrofuran (900 mL) was added n-butyllithium (2.3 M in hexane, 343 mL, 0.790 mol) at −78° C. The reaction mixture was stirred at the same temperature for 1 h. A solution of 1-chloro-3,3-dimethylbutane (45.3 g, 0.376 mol) in anhydrous tetrahydrofuran (100 mL) was added to the reaction mixture dropwise at −78° C. The reaction was stirred for 10 min at −78° C. and then slowly raised to room temperature. The reaction was quenched with 20% ammonium chloride aqueous solution (500 mL). Two layers were separated and the aqueous layer was extracted with ethyl acetate (2×250 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was triturated with hexane (50 mL) to yield 3-(3,3-dimethylbutyl)pyrrolidin-2-one (9.091 g, 14%) as a white crystalline solid. 1 H-NMR (250 MHz, CDCl 3 ) δ 5.70 (s, br, 1H), 3.32 (m, 2H), 2.29 (m, 2H), 1.86 (m, 1H), 1.79 (m, 1H), 1.26 (m, 3H), 0.90 (s, 9H). ESI-MS m/z: calc. 169.1, found 169.9 (M+1) + .

Step 2: tert-Butyl (4S)-4-[3-[[6-[(2,6-dichloropyridine-3-carbonyl)sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

A 250 mL round bottom flask was charged under nitrogen with 2,6-dichloropyridine-3-carboxylic acid (1.14 g, 5.937 mmol) and anhydrous tetrahydrofuran (20 mL). Added carbonyl diimidazole (964 mg, 5.945 mmol) and the mixture was stirred under nitrogen at room temperature for 2 h. In a separate 100 mL flask, a solution of tert-butyl (4S)-2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (1.529 g, 3.706 mmol) in anhydrous tetrahydrofuran (10 mL) was prepared under a nitrogen atmosphere and it was subsequently added via syringe into the activated ester solution. Added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.2 mL, 8.024 mmol) via a syringe and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 16 h. The solvents were removed under reduced pressure and the resulting thick oil was treated with ethyl acetate (50 mL) and water (30 mL). Added hydrochloric acid (4 mL of 6 M, 24.00 mmol) and the two phases were separated. The aqueous phase was washed with brine (30 mL) and dried over sodium sulfate. After evaporation of the solvents, the residue was dissolved in dichloromethane and purified by flash chromatography on silica gel (80 g column) using a gradient of ethyl acetate (0 to 100% over 30 min) in hexanes. Evaporation of the solvents provided tert-butyl (4S)-4-[3-[[6-[(2,6-dichloropyridine-3-carbonyl)sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (1.934 g, 89%) as a white foamy solid. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.90 (broad s, 1H), 8.06 (dt, J=8.0, 3.1 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.61 (dd, J=8.5, 7.2 Hz, 1H), 7.22 (broad s, 1H), 7.16 (d, J=7.2 Hz, 1H), 6.74 (d, J=8.5 Hz, 1H), 3.61-3.41 (m, 1H), 3.31-3.13 (m, 2H), 2.76 (td, J=10.5, 4.8 Hz, 1H), 2.11-1.99 (m, 1H), 1.83 (td, J=14.1, 13.5, 5.9 Hz, 1H), 1.60-1.44 (m, 2H), 1.44-1.26 (m, 15H), 1.21 (s, 3H). ESI-MS m/z calc. 585.15796, found 586.1 (M+1) + ; Retention time: 2.02 min (LC Method B). The product was used for the next step without any further purification.

Step 3: 2,6-Dichloro-N-[[6-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2-pyridyl]sulfonyl]pyridine-3-carboxamide (Dihydrochloride Salt)

n a 100 mL round bottom flask, tert-butyl (4S)-4-[3-[[6-[(2,6-dichloropyridine-3-carbonyl)sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (1.923 g, 3.279 mmol) was stirred at room temperature in dichloromethane (10 mL) and hydrochloric acid (3 mL of 4 M in dioxane solution, 12.00 mmol). A white gummy precipitate formed rapidly. More dichloromethane (10 mL) was added and the mixture was stirred at room temperature for an additional 2.5 h. An additional 2 mL of hydrochloric acid was added and the mixture was stirred for an additional 2 h. The volatiles were removed by evaporation and the residue was evaporated in the presence of tetrahydrofuran/ethyl acetate/dichloromethane/methanol/hexanes until a foamy solid was obtained. Drying under high vacuum over the weekend provided 2,6-dichloro-N-[[6-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2-pyridyl]sulfonyl]pyridine-3-carboxamide (dihydrochloride salt) (1.933 g, 105%) as a foamy off-white solid (approx. 90% pure by LCMS). 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 9.13 (broad s, 1H), 8.98 (broad s, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.62 (dd, J=8.5, 7.2 Hz, 1H), 7.17 (d, J=7.1 Hz, 1H), 6.77 (dd, J=8.5, 0.8 Hz, 1H), 3.34 (dq, J=11.2, 5.6 Hz, 1H), 3.24 (q, J=6.0 Hz, 2H), 2.80 (td, J=11.8, 11.1, 6.0 Hz, 1H), 2.42-2.29 (m, 1H), 2.14 (tt, J=7.8, 6.9 Hz, 1H), 1.93 (dd, J=12.8, 7.8 Hz, 1H), 1.56-1.32 (m, 7H), 1.28 (s, 3H). ESI-MS m/z calc. 485.10553, found 486.2 (M+1) + ; Retention time: 0.89 min (LC Method B).

Step 4: (14S)-8-chloro-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (Compound D)

To a 20 mL microwave vial under nitrogen was added 2,6-dichloro-N-[[6-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2-pyridyl]sulfonyl]pyridine-3-carboxamide (dihydrochloride salt) (859 mg, 1.536 mmol), anhydrous NMP (13.5 mL), potassium carbonate (1.4 g, 10.13 mmol) (325 mesh), 3 Å molecular sieves and cesium fluoride (285 mg, 1.876 mmol). The vial was sealed under nitrogen and the mixture was vigorously stirred in an oil bath at 150° C. for 22 h. The mixture was poured into cooled water (85 mL) and it was acidified by adding hydrochloric acid (2.1 mL of 6 M, 12.60 mmol) (mild foaming). The resulting suspension was filtered through a ceramic funnel using a paper filter and the solid was briefly air dried. The solid was dissolved in dichloromethane and dried over sodium sulfate. After concentration, the solution was diluted with dichloromethane and purified by chromatography on silica gel using a gradient of ethyl acetate (0 to 100% over 30 min) in hexanes. The product eluted between 55-65% ethyl acetate in hexanes. Evaporation of the solvents and further concentration provided (14S)-8-chloro-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (320 mg, 54%). 1 H NMR (400 MHz, Chloroform-d) δ 9.19 (s, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.44 (d, J=7.2 Hz, 1H), 6.66 (d, J=7.9 Hz, 1H), 6.59 (d, J=8.3 Hz, 1H), 3.93 (d, J=11.0 Hz, 1H), 3.25 (dd, J=10.1, 7.2 Hz, 1H), 3.17 (d, J=13.6 Hz, 1H), 2.96 (t, J=10.1 Hz, 1H), 2.39 (d, J=9.7 Hz, 1H), 1.96 (dd, J=12.1, 6.8 Hz, 1H), 1.63 (d, J=8.1 Hz, 3H), 1.57 (d, J=15.4 Hz, 7H), 1.47 (d, J=9.5 Hz, 1H). ESI-MS m/z calc. 449.12885, found 450.4 (M+1) + ; Retention time: 1.76 min (LC Method E).

›Step 1: 3-(3,3-Dimethylbutyl)pyrrolidin-2-one · 2 of 2

Step 5: (14S)-8-[3-(3,3-Dimethylbutyl)-2-oxopyrrolidin-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (Compound 79)

A 4 mL vial was charged with (14S)-8-chloro-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (25 mg, 0.05556 mmol), 3-(3,3-dimethylbutyl)pyrrolidin-2-one (12 mg, 0.07090 mmol), Pd 2 (dba) 3 (8 mg, 0.008736 mmol), Xantphos (5 mg, 0.008641 mmol), cesium carbonate (99 mg, 0.3038 mmol) and anhydrous dioxane (400 μL). The mixture was sparged with nitrogen for 1-2 min, capped and stirred at 120° C. for 21 h. The reaction was diluted with dimethyl sulfoxide (900 μL), microfiltered and subjected to reverse phase preparative HPLC (C 18 ) using a gradient of acetonitrile in water (1 to 99% over 15 min) and hydrochloric acid as a modifier. The pure fractions were collected and the solvents evaporated to give 4.3 mg of off-white solid. The product was further purified by flash chromatography on silica gel (4 g column) using a gradient of methanol (0 to 5% over 30 min) in dichloromethane. The pure fractions were collected and the solvents evaporated to give (14S)-8-[3-(3,3-dimethylbutyl)-2-oxopyrrolidin-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (Compound 79) (2 mg, 6%) as an off-white solid (diastereomeric mixture). 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.41 (s, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.63-7.44 (m, 2H), 7.04 (d, J=7.1 Hz, 1H), 6.97 (broad s, 1H), 6.70 (d, J=8.5 Hz, 1H), 4.16-3.64 (m, 3H), 3.10 (br s, 1H), 2.94 (d, J=13.3 Hz, 1H), 2.74-2.54 (m, 2H), 2.29-2.17 (m, 1H), 2.10 (br s, 1H), 1.87-1.43 (m, 11H), 1.37-1.12 (m, 6H), 0.88 (d, J=3.6 Hz, 9H). ESI-MS m/z calc. 582.2988, found 583.4 (M+1) + ; Retention time: 2.25 min (LC Method B).

Example 21: Preparation of 12,12-dimethyl-8-(4-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.111,14.05,10]pentacosa-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (Enantiomer 1) (Compound 82) and 12,12-dimethyl-8-(4-{2-[1-(trifluoromethyl) cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.111,14.05,10]pentacosa-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (Enantiomer 2) (Compound 83)

›Step 1: tert-Butyl 4-hydroxypyrazole-1-carboxylate

Sodium hydroxide (16.32 g, 408.0 mmol) was added to a cold solution (0° C.) of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (60 g, 204.0 mmol) in tetrahydrofuran (450 mL) followed by slow addition of hydrogen peroxide (46.26 g, 41.68 mL of 30% w/v, 408.0 mmol). Reaction mixture was stirred at 0° C. for 10 min then at room temperature for 45 min. Reaction was cooled to 0° C. and diluted with dichloromethane (800 mL). 3M hydrochloric acid was added until pH=2 and the organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated in a small amount of dichloromethane and solid was filtrated under vacuum, washed well with more dichloromethane and dried under reduced pressure to afford tert-butyl 4-hydroxypyrazole-1-carboxylate (19.904 g, 53%) as a white solid. 1 H NMR (300 MHz, dimethyl sulfoxide-d 6 ) δ 1.52 (s, 9H), 7.45 (d, J=0.9 Hz, 1H), 7.51 (d, J=0.9 Hz, 1H), 9.28 (s, 1H). ESI-MS m/z calc. 184.0848, found 129.1 (M-C 4 H 8 +1) + ; Retention time: 1.73 min (LC Method H).

›Step 2: tert-Butyl 4-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-1-carboxylate

2-[1-(Trifluoromethyl)cyclopropyl]ethanol (28.2 g, 183.0 mmol) was added to a solution of tert-butyl 4-hydroxypyrazole-1-carboxylate (23.7 g, 128.7 mmol) and triphenylphosphine (50.6 g, 192.9 mmol) in tetrahydrofuran (250 mL) at 0° C. Diisopropyl azodicarboxylate (39.03 g, 38.00 mL, 193.0 mmol) was slowly added at 0° C. and the reaction mixture was stirred at 0° C. for 10 min. The reaction was then heated at 70° C. overnight. The reaction was cooled to room temperature and the reaction mixture was diluted with dichloromethane (300 mL) and quenched by addition of 5% aqueous citric acid (150 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure (155 g of yellow oil). The residue was triturated with heptanes and a small amount of ethyl acetate (less than 10%). The solid was filtered and washed with heptane. The filtrate was concentrated under reduced pressure (55 g of yellow oil). The residue was purified by silica gel chromatography using a gradient from 0% to 20% of ethyl acetate in heptanes to afford tert-butyl 4-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-1-carboxylate (27.31 g, 66%) as a white solid. 1 H NMR (300 MHz, dimethyl sulfoxide-d 6 ) δ 0.80-0.97 (m, 4H), 1.54 (s, 9H), 2.00 (t, J=6.9 Hz, 2H), 3.99 (t, J=6.8 Hz, 2H), 7.61-7.70 (m, 1H), 7.90 (s, 1H). 19F NMR (282 MHz, dimethyl sulfoxide-d 6 ) δ−68.6 (s, 3F). ESI-MS m/z calc. 320.1348, found 265.1 (M-C 4 H 8 +1) + ; Retention time: 2.18 min (LC Method I).

›Step 3: 4-[2-[1-(Trifluoromethyl)cyclopropyl]ethoxy]-1H-pyrazole (Hydrochloric Acid Salt) · 1 of 2

Hydrogen chloride (80 mL of 4 M, 320.0 mmol) was added to a solution of tert-butyl 4-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-1-carboxylate (10.63 g, 33.19 mmol) in dichloromethane (50 mL) and reaction mixture was stirred at room temperature overnight. Reaction mixture was concentrated under reduced pressure to afford 4-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]-1H-pyrazole (hydrochloric acid salt) (8.71 g, 100%) as an off-white solid. 1 H NMR (300 MHz, dimethyl sulfoxide-d 6 ) δ 0.77-0.96 (m, 4H), 1.98 (t, J=6.9 Hz, 2H), 3.91 (t, J=6.9 Hz, 2H), 7.41 (s, 2H). ESI-MS m/z calc. 220.0823, found 221.2 (M+1) + ; Retention time: 2.43 min (LC Method H).

Step 4: tert-Butyl 2-chloro-6-[4-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylate

4-[2-[1-(Trifluoromethyl)cyclopropyl]ethoxy]-1H-pyrazole (hydrochloric acid salt) (10 g, 38.963 mmol) was added to N,N-dimethylformamide (80 mL). The reaction was chilled to 0° C. and sodium hydride (1.87 g, 60% w/w, 46.754 mmol) was added portionwise and was allowed to stir for 10 min. A solution of tert-butyl 2,6-dichloropyridine-3-carboxylate (9.67 g, 38.975 mmol) in N,N-dimethylformamide (20 mL) was added and the reaction was heated at 75° C. and allowed to stir overnight. Once cooled to room temperature, the reaction was quenched with brine (100 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient from 0% to 10% of ethyl acetate in heptanes to afford tert-butyl 2-chloro-6-[4-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylate (7.68 g, 46%) as white solid. 1 H NMR (300 MHz, CDCl 3 ) δ 0.73 (s, 2H), 0.98-1.10 (m, 2H), 1.62 (s, 9H), 2.03-2.13 (m, 2H), 4.09 (t, J=7.0 Hz, 2H), 7.51 (s, 1H), 7.84 (d, J=8.5 Hz, 1H), 8.12 (s, 1H), 8.21 (d, J=8.5 Hz, 1H). 19F NMR (282 MHz, CDCl 3 ) δ−69.9 (br. s., 3F). ESI-MS m/z calc. 431.1224, found 432.1 (M+1)++; Retention time: 2.56 min (LC Method I).

Step 5: 2-Chloro-6-[4-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic Acid

Trifluoroacetic acid (46.620 g, 31.5 mL, 408.86 mmol) was added to a solution of tert-butyl 2-chloro-6-[4-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylate (17.59 g, 40.733 mmol) in dichloromethane (150 mL) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (175 mL) and the organic layer was washed with brine (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude 2-chloro-6-[4-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (14.82 g, 77%) as a white solid. 1 H NMR (300 MHz, dimethyl sulfoxide-d 6 ) δ 0.81-0.97 (m, 4H), 2.04 (t, J=6.9 Hz, 2H), 4.04-4.13 (m, 2H), 7.77 (s, 1H), 7.86 (d, J=8.5 Hz, 1H), 8.25 (s, 1H), 8.37 (d, J=8.5 Hz, 1H). ESI-MS m/z calc. 375.0598, found 376.1 (M+1) + ; Retention time: 3.14 min (LC Method H).

Step 6: tert-Butyl 4-[4-[[6-[[2-chloro-6-[4-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]butyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

To a round bottom flask was added 2-chloro-6-[4-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (97 mg, 0.2582 mmol), carbonyl diimidazole (45 mg, 0.2775 mmol) and tetrahydrofuran (3.0 mL). The reaction was heated at 40° C. for 90 min. A solution of tert-butyl 2,2-dimethyl-4-[4-[(6-sulfamoyl-2-pyridyl)amino]butyl]pyrrolidine-1-carboxylate (95 mg, 0.2227 mmol) in tetrahydrofuran (2 mL) was added dropwise followed by 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (120 μL, 0.8024 mmol). The reaction was stirred overnight at room temperature. The reaction was quenched with 1N citric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude reaction mixture was purified via HPLC (20%-99% acetonitrile:water with a 0.1% hydrochloric acid modifier) giving tert-butyl 4-[4-[[6-[[2-chloro-6-[4-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]butyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (82.7 mg, 49%) as a white solid. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.81 (s, 1H), 8.24 (s, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.77 (d, J=0.9 Hz, 1H), 7.61 (dd, J=8.5, 7.2 Hz, 1H), 7.20 (d, J=4.9 Hz, 1H), 7.16 (d, J=7.2 Hz, 1H), 6.73 (d, J=8.5 Hz, 1H), 4.09 (t, J=6.9 Hz, 2H), 3.54-3.41 (m, 1H), 3.22 (q, J=6.5 Hz, 2H), 2.74-2.63 (m, 1H), 2.05 (t, J=6.9 Hz, 2H), 1.96 (s, 1H), 1.73 (td, J=11.5, 6.0 Hz, 1H), 1.49 (p, J=7.7, 7.3 Hz, 2H), 1.37 (d, J=12.8 Hz, 9H), 1.30-1.12 (m, 11H), 0.98-0.84 (m, 4H). ESI-MS m/z calc. 783.27924, found 784.3 (M+1) + ; Retention time: 2.28 min (LC Method B).

Step 7: 2-Chloro-N-[[6-[4-(5,5-dimethylpyrrolidin-3-yl)butylamino]-2-pyridyl]sulfonyl]-6-[4-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide

To a round bottom flask containing tert-butyl 4-[4-[[6-[[2-chloro-6-[4-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]butyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (118 mg, 0.1505 mmol) was added dichloromethane (5 mL) and trifluoroacetic acid (650 μL, 8.437 mmol). The reaction was allowed to stir at room temperature for 1 h. The reaction was evaporated to dryness. A solution of saturated sodium bicarbonate was added followed by ethyl acetate. The reaction was extracted 3 times with ethyl acetate, dried over sodium sulfate, filtered and evaporated giving 2-chloro-N-[[6-[4-(5,5-dimethylpyrrolidin-3-yl)butylamino]-2-pyridyl]sulfonyl]-6-[4-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (102 mg, 99%) which was taken on without further purification. ESI-MS m/z calc. 683.2268, found 684.4 (M+1) + ; Retention time: 1.51 min (LC Method B).

›Step 3: 4-[2-[1-(Trifluoromethyl)cyclopropyl]ethoxy]-1H-pyrazole (Hydrochloric Acid Salt) · 2 of 2

Step 8: 12,12-Dimethyl-8-(4-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.111,14.05,10]pentacosa-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (Compound 70)

To a microwave vial was added potassium carbonate (92 mg, 0.6657 mmol), cesium fluoride (45 mg, 0.2962 mmol), five 3 Å molecular sieves and a solution of 2-chloro-N-[[6-[4-(5,5-dimethylpyrrolidin-3-yl)butylamino]-2-pyridyl]sulfonyl]-6-[4-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (90 mg, 0.1315 mmol) in dimethyl sulfoxide (0.8 mL). The reaction was sealed and placed in a preheated 150° C. oil bath overnight. The reaction was cooled to room temperature, filtered and purified via HPLC (10%-99% acetonitrile:water with a 0.1% hydrochloric acid modifier) giving 12,12-dimethyl-8-(4-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.111,14.05,10]pentacosa-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (Compound 70) (20.8 mg, 24%) as a white solid. ESI-MS m/z calc. 647.2502, found 648.4 (M+1) + ; Retention time: 2.1 min (LC Method B).

Step 9: 12,12-Dimethyl-8-(4-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.111,14.05,10]pentacosa-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (Enantiomer 1) (Compound 82) and 12,12-dimethyl-8-(4-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.111,14.05,10]pentacosa-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (Enantiomer 2) (Compound 83)

Racemic 12,12-dimethyl-8-(4-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.111,14.05,10]pentacosa-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (17 mg, 0.02625 mmol) was subjected to chiral SFC chromatography using a ChiralPak AS-H (250×21.2 mm column, 5 μm particle size) with 20%-25% methanol (NH 3 modifier))/carbon dioxide mobile phase at 50 mL/min giving as the first enantiomer to elute, 12,12-dimethyl-8-(4-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.111,14.05,10]pentacosa-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (enantiomer 1) (Compound 82) (7.7 mg, 90%); ESI-MS m/z calc. 647.2502, found 648.2 (M+1) + ; Retention time: 3.18 min (LC Method D) and as the second enantiomer to elute, 12,12-dimethyl-8-(4-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.111,14.05,10]pentacosa-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (enantiomer 2) (Compound 83) (7.6 mg, 89%); 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.49 (s, 1H), 7.96 (d, J=1.0 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.62 (d, J=26.0 Hz, 2H), 7.14 (s, 1H), 6.98 (s, 1H), 6.69 (d, J=44.0 Hz, 2H), 4.06 (t, J=7.1 Hz, 2H), 2.86 (s, 1H), 2.04 (t, J=7.0 Hz, 3H), 1.88-1.78 (m, 1H), 1.65-1.47 (m, 7H), 1.21 (d, J=14.6 Hz, 3H), 1.01-0.82 (m, 4H), ESI-MS m/z calc. 647.2502, found 648.2 (M+1) + ; Retention time: 3.18 min (LC Method D).

Example 22: Preparation of (18R)-20,20-dimethyl-4-(3-{2-[1-(trifluoromethyl) cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-10λ 6 -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docosa-2,4,6,11(22),12-pentaene-8,10,10-trione (Compound 84) and (18S)-20,20-dimethyl-4-(3-{2-[1-(trifluoromethyl) cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-10λ 6 -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docosa-2,4,6,11(22),12-pentaene-8,10,10-trione (Compound 85)

›Step 1: tert-Butyl 2,2-dimethyl-4-[3-(3-sulfamoylpyrazol-1-yl)propyl]pyrrolidine-1-carboxylate · 1 of 2

Part A: To a 250 mL round bottom flask tert-butyl 4-(3-hydroxypropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (10 g, 38.85 mmol) in dry dichloromethane (100 mL) was added triethylamine (8.3 mL, 59.55 mmol). The reaction was cooled to 0° C. over 10 min and methanesulfonyl chloride (3.7 mL, 47.80 mmol) was added dropwise (exothermic, formed white slurry) and the reaction was stirred for 1 h while warming to room temperature. The reaction was then quenched with cold water (150 mL) and extracted with dichloromethane (200 mL) twice. The organic layer was dried over sodium sulfate, filtered and evaporated to provide the mesylate as a yellowish oil.

Part B: The crude mesylate from Part A was dissolved in N,N-dimethylformamide (50 mL) and 1H-pyrazole-3-sulfonamide (5.8 g, 39.41 mmol) was added followed by potassium carbonate (16.3 g, 117.9 mmol) and the reaction mixture was stirred at 70° C. for 20 h. The reaction mixture was cooled to room temperature and poured into crushed ice and extracted with ethyl acetate (3×100 mL), combined organic layers, washed with water (2=×100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The brown residue was purified by silica gel chromatography (330 gram column) using a gradient from 100% hexanes to 100% ethyl acetate to afford tert-butyl 2,2-dimethyl-4-[3-(3-sulfamoylpyrazol-1-yl)propyl]pyrrolidine-1-carboxylate (7.6 g, 51%) as a white solid. ESI-MS m/z calc. 386.19876, found 387.25 (M+1) + ; Retention time: 0.61 min (LC Method A).

Step 2: tert-Butyl 4-[3-[3-[[2-chloro-6-[3-[2-[1-(trifluoromethyl) cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]pyrazol-1-yl]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (458 mg, 1.219 mmol) and di(imidazol-1-yl)methanone (208 mg, 1.283 mmol) were combined in tetrahydrofuran (5 mL) and stirred for 120 min at 50° C. Then, tert-butyl 2,2-dimethyl-4-[3-(3-sulfamoylpyrazol-1-yl) propyl]pyrrolidine-1-carboxylate (388 mg, 1.004 mmol) was added followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (300 μL, 2.006 mmol) and the reaction was stirred at room temperature for 20 h. The reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution, followed by brine. The organics were separated, dried over sodium sulfate, filtered and evaporated and then purified by silica gel chromatography using a gradient from 100% hexanes to 90% ethyl acetate in hexanes to afford tert-butyl 4-[3-[3-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]pyrazol-1-yl]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (247 mg, 33%) as a white solid. 1 H NMR (400 MHz, Chloroform-d) δ 9.82 (s, 1H), 8.30 (d, J=2.9 Hz, 1H), 8.22 (d, J=8.5 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.47 (d, J=2.4 Hz, 1H), 7.04 (d, J=2.3 Hz, 1H), 5.96 (d, J=2.9 Hz, 1H), 4.39 (t, J=7.2 Hz, 2H), 4.19 (t, J=7.1 Hz, 2H), 3.75-3.51 (m, 1H), 2.83 (t, J=10.3 Hz, 1H), 2.08 (t, J=7.2 Hz, 2H), 1.87 (ddt, J=19.6, 12.7, 6.9 Hz, 3H), 1.67 (s, 2H), 1.43 (s, 9H), 1.33 (s, 3H), 1.30 (d, J=13.3 Hz, 2H), 1.23 (s, 3H), 1.05-1.00 (m, 2H), 0.76-0.70 (m, 2H). ESI-MS m/z calc. 743.248, found 744.3 (M+1) + ; Retention time: 0.86 min (LC Method A).

Step 3: 20,20-Dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-10λ 6 -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docosa-2,4,6,11(22),12-pentaene-8,10,10-trione

Part A: A solution of tert-butyl 4-[3-[3-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]pyrazol-1-yl]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (247 mg, 0.3319 mmol) in dichloromethane (1 mL) and trifluoroacetic acid (260 μL, 3.398 mmol) was stirred at room temperature for 4 h. The solvents were then evaporated. The residue was dissolved in ethyl acetate, washed with 2 mL of saturated sodium bicarbonate solution and solvent was removed and dried under high vacuum.

Part B: The residue from Part A was dissolved in dimethyl sulfoxide (6 mL) and 3 Å molecular sieves were added and the reaction mixture was stirred for 10 min. Then cesium fluoride (153 mg, 1.007 mmol) and potassium carbonate (142 mg, 1.027 mmol) were added and the reaction mixture was heated at 130° C. overnight. The reaction mixture was filtered through a Whatman filter disc (puradisc 25 TF) and the filtrate was purified by a reverse phase HPLC-MS method using a dual gradient run from 50-90% mobile phase B over 15.0 min (mobile phase A=water (0.05% hydrochloric acid), mobile phase B=acetonitrile) to afford 20,20-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-10λ 6 -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docosa-2(7),3,5,11(22),12-pentaene-8,10,10-trione (80 mg, 40%) as a white solid. ESI-MS m/z calc. 607.2189, found 608.1 (M+1) + ; Retention time: 2.07 min (LC Method B).

Step 4: (18R)-20,20-Dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-10λ 6 -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docosa-2,4,6,11(22),12-pentaene-8,10,10-trione (Compound 84) and (18S)-20,20-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-10λ 6 -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docosa-2,4,6,11(22),12-pentaene-8,10,10-trione (Compound 85)

Subjected racemic 20,20-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-10λ 6 -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docosa-2(7),3,5,11(22),12-pentaene-8,10,10-trione (80 mg) to chiral separation by SFC chromatography using Chiral Pak AS-H (250×10 mm), column, 5 μm particle size) with 27% acetonitrile:methanol, 73% carbon dioxide mobile phase at 10 mL/min over 8.0 min (injection volume=70 μL of 24 mg/mL in acetonitrile:methanol (90:10)) giving as the first enantiomer to elute (18R)-20,20-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-10λ 6 -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docosa-2,4,6,11(22),12-pentaene-8,10,10-trione (Compound 84) (27 mg, 27%); 1 H NMR (400 MHz, Chloroform-d) δ 8.82 (s, 1H), 8.16 (d, J=2.8 Hz, 1H), 7.66 (d, J=8.2 Hz, 1H), 7.46 (d, J=2.4 Hz, 1H), 7.06 (d, J=2.3 Hz, 1H), 6.96 (d, J=8.2 Hz, 2H), 5.86 (d, J=2.8 Hz, 1H), 4.39 (d, J=7.1 Hz, 2H), 4.31 (dt, J=13.3, 3.3 Hz, 1H), 3.91 (td, J=12.8, 2.7 Hz, 2H), 2.81-2.66 (m, 2H), 2.19-2.07 (m, 3H), 1.97 (t, J=10.1 Hz, 1H), 1.75 (dd, J=11.7, 5.3 Hz, 1H), 1.57 (s, 3H), 1.54 (s, 3H), 1.46 (t, J=12.2 Hz, 1H), 1.08-0.99 (m, 2H), 0.81-0.71 (m, 4H), ESI-MS m/z calc. 607.2189, found 608.1 (M+1) + ; Retention time: 2.07 min (LC Method B) and as the second enantiomer to elute (18S)-20,20-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-10λ 6 -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docosa-2,4,6,11(22),12-pentaene-8,10,10-trione (Compound 85) (31.5 mg, 31%); 1 H NMR (400 MHz, Chloroform-d) δ 8.44 (s, 1H), 8.17 (d, J=2.7 Hz, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.48 (d, J=2.3 Hz, 1H), 7.07 (d, J=2.3 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H), 5.86 (d, J=2.7 Hz, 1H), 4.39 (d, J=7.2 Hz, 2H), 4.33 (d, J=3.5 Hz, 1H), 3.93 (t, J=12.3 Hz, 1H), 2.74 (s, 1H), 2.22-2.12 (m, 2H), 2.09 (t, J=7.2 Hz, 2H), 1.99 (t, J=10.3 Hz, 2H), 1.76 (dd, J=11.9, 5.3 Hz, 1H), 1.59 (s, 3H), 1.55 (s, 3H), 1.47 (t, J=12.2 Hz, 1H), 1.06-1.00 (m, 2H), 0.89-0.68 (m, 4H), ESI-MS m/z calc. 607.2189, found 608.1 (M+1) + ; Retention time: 2.07 minutes (LC Method B).

›Step 1: tert-Butyl 2,2-dimethyl-4-[3-(3-sulfamoylpyrazol-1-yl)propyl]pyrrolidine-1-carboxylate · 2 of 2

Example 23: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-19-oxa-2λ 6 -thia-3,9,11-triazatetracyclo[18.2.2.111,14.05,10]pentacosa-1(22),5,7,9,20,23-hexaene-2,2,4-trione (Enantiomer 1) (Compound 95) and 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-19-oxa-2λ 6 -thia-3,9,11-triazatetracyclo[18.2.2.111,14.05,10]pentacosa-1(22),5,7,9,20,23-hexaene-2,2,4-trione (Enantiomer 2) (Compound 96)

›Step 1: tert-Butyl 2,2-dimethyl-4-[4-(4-sulfamoylphenoxy)butyl]pyrrolidine-1-carboxylate · 1 of 2

In a 50 mL flask was added 4-hydroxybenzenesulfonamide (319 mg, 1.842 mmol) and N,N-dimethylformamide (12.88 mL). To the mixture was added tert-butyl 2,2-dimethyl-4-(4-methylsulfonyloxybutyl)pyrrolidine-1-carboxylate (643.8 mg, 1.842 mmol) and potassium carbonate (891 mg, 6.447 mmol) at room temperature and stirred at 50° C. overnight. Cooled to room temperature and poured into water (100 mL) and extracted with ethyl acetate (2×100 mL), combined organic layers, washed with water (2×100 mL), dried (sodium sulfate), filtered and concentrated to a brown residue which was purified by silica gel chromatography using a gradient from 100% hexanes to 100% ethyl acetate to afford tert-butyl 2,2-dimethyl-4-[4-(4-sulfamoylphenoxy)butyl]pyrrolidine-1-carboxylate (416.1 mg, 53%) as a light orange oil. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 7.46 (t, J=8.0 Hz, 1H), 7.39-7.33 (m, 2H), 7.31 (s, 2H), 7.13 (d, J=7.8 Hz, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.85-3.67 (m, 1H), 1.88 (dd, J=11.8, 6.6 Hz, 2H), 1.79-1.61 (m, 4H), 1.51 (dd, J=37.7, 5.8 Hz, 2H), 1.38 (s, 12H), 1.24 (s, 3H). ESI-MS m/z calc. 426.21884, found 427.3 (M+1) + ; Retention time: 0.75 min (LC Method A).

Step 2: tert-Butyl 4-[4-[4-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]phenoxy]butyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

In a 20 mL vial, 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (549.7 mg, 1.463 mmol) and carbonyl diimidazole (237.2 mg, 1.463 mmol) were combined in tetrahydrofuran (5.971 mL) and stirred for 120 min at 50° C. with a loose cap. Then tert-butyl 2,2-dimethyl-4-[4-(4-sulfamoylphenoxy)butyl]pyrrolidine-1-carboxylate (416.1 mg, 0.9755 mmol) in tetrahydrofuran (7.964 mL) was added followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (297.0 mg, 291.7 μL, 1.951 mmol) and the reaction was heated at 50° C. for 16 hrs. The reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride followed by brine. The organics were separated, dried over sodium sulfate, filtered and evaporated then purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate giving very poor separation. Fractions containing product were combined and concentrated then repurified by silica gel chromatography using a shallow gradient from 100% dichloromethane to 20% methanol/dichloromethane giving tert-butyl 4-[4-[4-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]phenoxy]butyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (596 mg, 78%) as a light yellow solid. ESI-MS m/z calc. 783.268, found 784.2 (M+1) + ; Retention time: 2.54 min (LC Method B).

Step 3: 2-chloro-N-[4-[4-(5,5-dimethylpyrrolidin-3-yl)butoxy]phenyl]sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide

tert-Butyl 4-[4-[4-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]phenoxy]butyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (596 mg, 0.7599 mmol) was dissolved in dichloromethane (2.600 mL) and to the mixture was added trifluoroacetic acid (3.975 g, 2.686 mL, 34.86 mmol) and stirred at room temperature for 60 min. Concentrated mixture to dryness under reduced pressure, took up in saturated aqueous sodium bicarbonate and ethyl acetate containing a small amount of methanol for solubility and separated the layers. Concentrated the organic layer by rotary evaporation followed by high vacuum pump giving 2-chloro-N-[4-[4-(5,5-dimethylpyrrolidin-3-yl)butoxy]phenyl]sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (403.3 mg, 78%) as an off-white solid. ESI-MS m/z calc. 683.2156, found 684.2 (M+1) + ; Retention time: 0.66 min (LC Method A).

Step 4: 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-19-oxa-2λ 6 -thia-3,9,11-triazatetracyclo[18.2.2.111,14.05,10]pentacosa-1(22),5,7,9,20,23-hexaene-2,2,4-trione (Compound 89)

To a solution of 2-chloro-N-[4-[4-(5,5-dimethylpyrrolidin-3-yl)butoxy]phenyl]sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (403.3 mg, 0.5895 mmol) in dimethyl sulfoxide (16.13 mL) was added potassium carbonate (488.7 mg, 3.536 mmol), cesium fluoride (107.5 mg, 0.7077 mmol) and a small amount of 3 Å molecular sieves. The resulting mixture was capped and heated to 165° C. for 18 h. The mixture was then cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and brine. The organic phase was dried (sodium sulfate), filtered and concentrated to a tan amorphous solid which was purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate giving 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-19-oxa-2λ 6 -thia-3,9,11-triazatetracyclo[18.2.2.111,14.05,10]pentacosa-1(22),5,7,9,20,23-hexaene-2,2,4-trione (Compound 89) (80 mg, 21%). 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.22 (s, 1H), 8.19 (d, J=2.8 Hz, 1H), 8.08 (dd, J=8.6, 2.5 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.77 (dd, J=8.7, 2.5 Hz, 1H), 7.34 (ddd, J=16.6, 8.7, 2.5 Hz, 2H), 6.92 (d, J=8.3 Hz, 1H), 6.11 (d, J=2.7 Hz, 1H), 4.40 (t, J=4.8 Hz, 2H), 4.31 (t, J=7.0 Hz, 2H), 2.40 (s, 1H), 2.07 (t, J=7.1 Hz, 2H), 1.95 (d, J=29.5 Hz, 2H), 1.76 (t, J=6.5 Hz, 2H), 1.59 (s, 1H), 1.52 (d, J=6.7 Hz, 6H), 1.46 (d, J=12.3 Hz, 1H), 1.33 (s, 1H), 1.24 (s, 1H), 1.08-1.00 (m, 1H), 0.96 (q, J=4.7, 4.0 Hz, 2H), 0.88 (s, 2H), 0.67 (s, 1H). ESI-MS m/z calc. 647.23895, found 648.2 (M+1) + ; Retention time: 2.37 min (LC Method B).

Step 5: 12,12-Dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-19-oxa-2λ 6 -thia-3,9,11-triazatetracyclo[18.2.2.111,14.05,10]pentacosa-1(22),5,7,9,20,23-hexaene-2,2,4-trione (Enantiomer 1) (Compound 95) and 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-19-oxa-2λ 6 -thia-3,9,11-triazatetracyclo[18.2.2.111,14.05,10]pentacosa-1(22),5,7,9,20,23-hexaene-2,2,4-trione (Enantiomer 2) (Compound 96)

›Step 1: tert-Butyl 2,2-dimethyl-4-[4-(4-sulfamoylphenoxy)butyl]pyrrolidine-1-carboxylate · 2 of 2

Subjected racemic 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-19-oxa-2λ 6 -thia-3,9,11-triazatetracyclo[18.2.2.111,14.05,10]pentacosa-1(22),5,7,9,20,23-hexaene-2,2,4-trione (Compound 89) (72.1 mg, 0.1101 mmol) to chiral separation by SFC chromatography using a ChiralCel OD-H (250×10 mm column, 5 μm particle size) with 35% acetonitrile/methanol (90:10)/65% carbon dioxide mobile phase at 10 mL/min over 8.0 min (injection volume=70 μL of 24 mg/mL solution in acetonitrile/methanol (90:10) giving as the first enantiomer to elute, 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-19-oxa-2λ 6 -thia-3,9,11-triazatetracyclo[18.2.2.111,14.05,10]pentacosa-1(22),5,7,9,20,23-hexaene-2,2,4-trione (enantiomer 1) (Compound 95) (21.9 mg, 61%); 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.23 (s, 1H), 8.19 (d, J=2.8 Hz, 1H), 8.08 (dd, J=8.6, 2.4 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.76 (dd, J=8.7, 2.4 Hz, 1H), 7.34 (ddd, J=16.3, 8.7, 2.5 Hz, 2H), 6.92 (d, J=8.3 Hz, 1H), 6.11 (d, J=2.7 Hz, 1H), 4.40 (t, J=4.9 Hz, 2H), 4.31 (t, J=7.0 Hz, 2H), 3.17 (d, J=5.2 Hz, 1H), 2.40 (d, J=10.3 Hz, 1H), 2.07 (t, J=7.1 Hz, 2H), 1.92 (d, J=5.4 Hz, 2H), 1.81-1.72 (m, 2H), 1.58 (d, J=15.1 Hz, 1H), 1.53 (s, 3H), 1.51 (s, 3H), 1.33 (t, J=13.3 Hz, 1H), 1.12-0.98 (m, 2H), 0.98-0.94 (m, 2H), 0.88 (tt, J=5.6, 2.4 Hz, 2H), 0.66 (d, J=13.0 Hz, 1H), ESI-MS m/z calc. 647.23895, found 648.2 (M+1) + ; Retention time: 2.34 min (LC Method B) and as the second enantiomer to elute, 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-19-oxa-2λ 6 -thia-3,9,11-triazatetracyclo[18.2.2.111,14.05,10]pentacosa-1(22),5,7,9,20,23-hexaene-2,2,4-trione (enantiomer 2) (Compound 96) (18.75 mg, 52%); ESI-MS m/z calc. 647.23895, found 648.2 (M+1) + ; Retention time: 2.33 min (LC Method B).

Example 24: Preparation of (14S)-8-[3-(3,3-dimethylbutyl)-4,4-dimethyl-2-oxopyrrolidin-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (hydrochloric acid salt) (Compound 98)

›Step 1: 1-Benzyl-4,4-dimethyl-pyrrolidin-2-one

To a 100 mL round bottom flask charged with 4,4-dimethylpyrrolidin-2-one (524 mg, 4.631 mmol) was added tetrahydrofuran (25 mL), followed by 2-methylpropan-2-olate sodium salt) (590 mg, 6.139 mmol) and the mixture was stirred at room temperature for 30 min. Bromomethylbenzene (1000 μL, 8.408 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with water (˜15 mL) and the crude mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The crude reaction mixture was purified via silica gel chromatography (0%-60% ethyl acetate in hexanes gradient) affording 1-benzyl-4,4-dimethyl-pyrrolidin-2-one (834 mg, 89%) as a clear oil. ESI-MS m/z calc. 203.13101, found 204.1 (M+1) + ; Retention time: 1.3 min (LC Method B).

›Step 2: 1-Benzyl-3-(3,3-dimethylbutyl)-4,4-dimethyl-pyrrolidin-2-one

A 100 mL round bottom flask was charged with 1-benzyl-4,4-dimethyl-pyrrolidin-2-one (834 mg, 4.103 mmol) and tetrahydrofuran (20 mL) and the reaction flask was purged with nitrogen for 5 min. The reaction flask was cooled to −78° C. and butyllithium (2.1 mL of 2.5 M, 5.250 mmol) in hexanes was added dropwise and the mixture was stirred at −78° C. for 1 h. 1-bromo-3,3-dimethyl-butane (700 μL, 4.970 mmol) was added dropwise and the reaction mixture was stirred and slowly warmed to room temperature over a period of 18 h. The reaction was quenched with water (10 mL) and brine (10 mL) and extracted with ethyl acetate (3×40 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The crude reaction mixture was purified by silica gel chromatography (0%-40% ethyl acetate in hexanes gradient) affording 1-benzyl-3-(3,3-dimethylbutyl)-4,4-dimethyl-pyrrolidin-2-one (107 mg, 9%) as a clear oil. ESI-MS m/z calc. 287.2249, found 288.1 (M+1) + ; Retention time: 2.15 min (LC Method B).

›Step 3: 3-(3,3-Dimethylbutyl)-4,4-dimethyl-pyrrolidin-2-one

To a nitrogen-purged 50 mL flask charged with 1-benzyl-3-(3,3-dimethylbutyl)-4,4-dimethyl-pyrrolidin-2-one (107 mg, 0.3723 mmol) was added propan-1-amine (3 mL) and ethane-1,2-diamine (200 μL, 2.992 mmol). The solution was cooled to −30° C. and a strip of lithium wire (4 cm, cut into 4 smaller pieces and rinsed with hexanes to remove excess oil) was added. The flask was re-fitted with a septum and the reaction mixture stirred vigorously, with slight warming to −20° C. A blue color eventually formed around the lithium wire, with blue color leeching out into the solution briefly and the reaction was allowed to stir until the solution remained a deep blue color (˜20 min). Water (˜15 mL) was added and the larger pieces of lithium were removed and the mixture was warmed to room temperature and stirred for 10 min. The crude mixture was extracted with ethyl acetate (3×20 mL), the combined organic extracts washed with water (15 mL), dried over sodium sulfate, filtered and concentrated in vacuo affording crude 3-(3,3-dimethylbutyl)-4,4-dimethyl-pyrrolidin-2-one (115 mg, 157% (crude product containing impurities)) as a yellow oil, which was used without further purification. ESI-MS m/z calc. 197.17796, found 198.1 (M+1) + ; Retention time: 1.58 min (LC Method B).

Step 4: (14S)-8-[3-(3,3-Dimethylbutyl)-4,4-dimethyl-2-oxopyrrolidin-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Hydrochloric Acid Salt) (Compound 98)

To a 4 mL vial charged with crude 3-(3,3-dimethylbutyl)-4,4-dimethyl-pyrrolidin-2-one (45 mg, 0.2281 mmol) was added (14S)-8-chloro-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (25 mg, 0.05373 mmol), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (8 mg, 0.01383 mmol), tris(dibenzylideneacetone)dipalladium(0) (13 mg, 0.01420 mmol), cesium carbonate (25 mg, 0.07673 mmol) and dioxane (1 mL). The headspace was purged with nitrogen, the vial capped and the reaction mixture stirred at 120° C. for 18 h. After cooling to room temperature, the crude mixture was diluted with ethyl acetate (˜30 mL) and washed with 1.0M aqueous citric acid (5 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was taken up in a minimal amount of dimethyl sulfoxide (0.4-1 mL) and subjected to HPLC purification (C 18 reverse-phase, 99:1-1:99 water: acetonitrile, hydrochloric acid modifier). The fractions were then concentrated in vacuo and the residue purified by silica gel chromatography (0%-70%) ethyl acetate in hexanes gradient affording (14S)-8-[3-(3,3-dimethylbutyl)-4,4-dimethyl-2-oxopyrrolidin-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (hydrochloric acid salt) (Compound 98) (4 mg, 11%) as an off-white solid. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.42 (s, 1H), 7.66 (dd, J=8.3, 3.2 Hz, 1H), 7.52 (ddd, J=22.6, 14.8, 8.2 Hz, 2H), 7.03 (d, J=7.2 Hz, 1H), 6.92 (d, J=32.0 Hz, 1H), 6.69 (d, J=8.7 Hz, 1H), 4.46-3.82 (m, 3H), 3.83-3.41 (m, 3H), 3.09 (s, 1H), 2.93 (d, J=13.3 Hz, 1H), 2.80-2.63 (m, 1H), 2.40-2.23 (m, 1H), 2.17-1.98 (m, 1H), 1.90-1.68 (m, 2H), 1.68-1.38 (m, 8H), 1.28 (d, J=40.1 Hz, 5H), 1.18 (d, J=5.6 Hz, 2H), 1.02-0.70 (m, 9H). ESI-MS m/z calc. 610.33014, found 611.2 (M+1) + ; Retention time: 2.38 min (LC Method B).

Example 25: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-18-oxa-2λ 6 -thia-3,9,11-triazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(21),5,7,9,19,22-hexaene-2,2,4-trione (Enantiomer 1) (Compound 99) and 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-18-oxa-2λ 6 -thia-3,9,11-triazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(21),5,7,9,19,22-hexaene-2,2,4-trione (Enantiomer 2) (Compound 100)

›Step 1: tert-Butyl 2,2-dimethyl-4-[3-(4-sulfamoylphenoxy)propyl]pyrrolidine-1-carboxylate · 1 of 2

In a 50 mL flask was added 4-hydroxybenzenesulfonamide (471.1 mg, 2.720 mmol) and N,N-dimethylformamide (13.69 mL). To the mixture was added tert-butyl 2,2-dimethyl-4-(3-methylsulfonyloxypropyl)pyrrolidine-1-carboxylate (912.4 mg, 2.720 mmol) and potassium carbonate (1.316 g, 9.520 mmol) at room temperature and stirred at room temperature for 3 h then heated to 50° C. overnight. Cooled to room temperature and poured into water (100 mL) and extracted with ethyl acetate (2×100 mL), combined organic layers, washed with water (2×100 mL), dried (sodium sulfate), filtered and concentrated to a brown residue which was purified by silica gel chromatography using a gradient from 100% hexanes to 100% ethyl acetate to afford tert-butyl 2,2-dimethyl-4-[3-(4-sulfamoylphenoxy)propyl]pyrrolidine-1-carboxylate (578.3 mg, 52%) as a light orange oil. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 7.46 (t, J=8.0 Hz, 1H), 7.39-7.33 (m, 2H), 7.31 (s, 2H), 7.13 (d, J=7.8 Hz, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.85-3.67 (m, 1H), 1.88 (dd, J=11.8, 6.6 Hz, 2H), 1.79-1.61 (m, 4H), 1.51 (dd, J=37.7, 5.8 Hz, 2H), 1.38 (s, 12H), 1.24 (s, 3H). ESI-MS m/z calc. 412.2032, found 413.3 (M+1) + ; Retention time: 0.71 min (LC Method A).

Step 2: tert-Butyl 4-[3-[4-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]phenoxy]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

In a 20 mL vial, 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (790.2 mg, 2.103 mmol) and carbonyl diimidazole (341.0 mg, 2.103 mmol) were combined in tetrahydrofuran (6 mL) and stirred for 120 min at 50° C. with a loose cap. Then tert-butyl 2,2-dimethyl-4-[3-(4-sulfamoylphenoxy)propyl]pyrrolidine-1-carboxylate (578.3 mg, 1.402 mmol) in tetrahydrofuran (10 mL) was added followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (426.9 mg, 419.4 μL, 2.804 mmol) and the reaction was heated at 50° C. for 16 hrs. The reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride followed by brine. The organics were separated, dried over sodium sulfate, filtered and evaporated then purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate giving very poor separation. Fractions containing product were combined and concentrated then repurified by silica gel chromatography using a shallow gradient from 100% dichloromethane to 20% methanol/dichloromethane giving tert-butyl 4-[3-[4-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]phenoxy]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (953.1 mg, 88%) as a light yellow solid. ESI-MS m/z calc. 769.2524, found 770.1 (M+1) + ; Retention time: 2.49 min (LC Method B).

Step 3: 2-Chloro-N-[4-[3-(5,5-dimethylpyrrolidin-3-yl)propoxy]phenyl]sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide

tert-Butyl 4-[3-[4-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]phenoxy]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (953.1 mg, 1.237 mmol) was dissolved in dichloromethane (4.158 mL) and to the mixture was added trifluoroacetic acid (6.471 g, 4.372 mL, 56.75 mmol) and the mixture was stirred at room temperature for 60 min. Concentrated mixture to dryness under reduced pressure, took up in saturated aqueous sodium bicarbonate and ethyl acetate containing a small amount of methanol for solubility and separated the layers. Concentrated the organic layer by rotary evaporation followed by drying on vacuum giving 2-chloro-N-[4-[3-(5,5-dimethylpyrrolidin-3-yl)propoxy]phenyl]sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (738.1 mg, 89%) as an off-white solid. ESI-MS m/z calc. 669.19995, found 670.3 (M+1) + ; Retention time: 0.65 min (LC Method A).

Step 4: 12,12-Dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-18-oxa-2λ 6 -thia-3,9,11-triazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(21),5,7,9,19,22-hexaene-2,2,4-trione (Compound 88)

To a solution of 2-chloro-N-[4-[3-(5,5-dimethylpyrrolidin-3-yl)propoxy]phenyl]sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (738.1 mg, 1.101 mmol) in dimethyl sulfoxide (29.52 mL) was added potassium carbonate (912.8 mg, 6.605 mmol), cesium fluoride (200.7 mg, 1.321 mmol) and a small amount of 3 Å molecular sieves. The resulting mixture was capped and heated to 130° C. for 16 h. Continued heating at 150° C. for 16 h. Heated to 170° C. and stirred 3 h then cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and brine. The organic phase was dried (sodium sulfate), filtered and concentrated to a tan amorphous solid which was purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate giving 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-18-oxa-2λ 6 -thia-3,9,11-triazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(21),5,7,9,19,22-hexaene-2,2,4-tri one (30 mg, 4%) as a white solid. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.13 (s, 1H), 8.17 (d, J=2.8 Hz, 1H), 8.06 (d, J=7.8 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.30 (dd, J=8.8, 2.4 Hz, 1H), 7.19 (dd, J=8.6, 2.4 Hz, 1H), 6.89 (d, J=8.3 Hz, 1H), 6.10 (d, J=2.7 Hz, 1H), 4.52 (d, J=12.1 Hz, 1H), 4.30 (t, J=7.0 Hz, 2H), 4.27-4.17 (m, 1H), 2.07 (t, J=7.1 Hz, 2H), 1.96 (s, 2H), 1.75 (s, 1H), 1.69 (d, J=12.2 Hz, 1H), 1.53 (s, 5H), 1.46 (s, 3H), 1.44-1.36 (m, 2H), 1.05 (s, 1H), 0.98-0.93 (m, 2H), 0.90-0.84 (m, 2H). ESI-MS m/z calc. 633.22327, found 634.1 (M+1) + ; Retention time: 2.28 min (LC Method B).

Step 5: 12,12-Dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-18-oxa-2λ 6 -thia-3,9,11-triazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(21),5,7,9,19,22-hexaene-2,2,4-trione (Enantiomer 1) (Compound 99) and 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-18-oxa-2λ 6 -thia-3,9,11-triazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(21),5,7,9,19,22-hexaene-2,2,4-trione (Enantiomer 2) (Compound 100)

›Step 1: tert-Butyl 2,2-dimethyl-4-[3-(4-sulfamoylphenoxy)propyl]pyrrolidine-1-carboxylate · 2 of 2

Subjected racemic 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-18-oxa-2λ 6 -thia-3,9,11-triazatetracyclo [17.2.2.111,14.05,10]tetracosa-1(21),5,7,9,19,22-hexaene-2,2,4-trione (27.2 mg, 0.04292 mmol) to chiral separation by SFC chromatography using a ChiralCel OD-H (250×10 mm column, 5 μm particle size) with 42% acetonitrile/methanol (90:10)/58% carbon dioxide mobile phase at 10 mL/min over 8.0 min (injection volume=70 μL of 24 mg/mL solution in acetonitrile/methanol (90:10) giving as the first enantiomer to elute, 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-18-oxa-2λ 6 -thia-3,9,11-triazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(21),5,7,9,19,22-hexaene-2,2,4-trione (enantiomer 1) (Compound 99) (10.22 mg, 75%) as a white solid; 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.13 (s, 1H), 8.17 (d, J=2.8 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.31 (dd, J=8.8, 2.5 Hz, 1H), 7.20 (dd, J=8.6, 2.4 Hz, 1H), 6.90 (d, J=8.3 Hz, 1H), 6.10 (d, J=2.8 Hz, 1H), 4.52 (d, J=11.9 Hz, 1H), 4.30 (t, J=7.1 Hz, 2H), 4.26-4.16 (m, 1H), 2.07 (t, J=7.1 Hz, 2H), 1.96 (s, 2H), 1.77-1.64 (m, 2H), 1.55 (s, 1H), 1.53 (s, 3H), 1.48 (s, 1H), 1.46 (s, 3H), 1.38 (dd, J=22.7, 11.1 Hz, 2H), 1.04 (d, J=8.2 Hz, 1H), 0.99-0.92 (m, 2H), 0.89 (d, J=11.6 Hz, 2H), ESI-MS m/z calc. 633.22327, found 634.1 (M+1) + ; Retention time: 2.25 min (LC Method B) and as the second enantiomer to elute, 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-18-oxa-2λ 6 -thia-3,9,11-triazatetracyclo[17.2.2.111,14.05,10]tetracosa-1(21),5,7,9,19,22-hexaene-2,2,4-trione (enantiomer 2) (Compound 100) (9.72 mg, 71%) as a white solid; ESI-MS m/z calc. 633.22327, found 634.1 (M+1) + ; Retention time: 2.25 min (LC Method B).

Example 26: Preparation of (14S)-8-[3-(4,4-dimethylpentyl)-2-oxopyrrolidin-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound 102)

›Step 1: 3-(4,4-Dimethylpentyl)pyrrolidin-2-one

To a solution of pyrrolidin-2-one (4.64 g, 54.52 mmol) in anhydrous tetrahydrofuran (300 mL) at −78° C. was added 2.5 M n-butyllithium solution in hexane (43.6 mL, 0.109 mol) dropwise and the reaction solution was stirred at this temperature for 1 h. A solution of 1-chloro-4,4-dimethylpentane (7.34 g, 54.52 mmol) in anhydrous tetrahydrofuran (20 mL) was added slowly. After the addition was finished, the solution was stirred at −78° C. for 20 min before it was gradually warmed up to ambient temperature. 20% Aqueous ammonium chloride solution (100 mL) was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×150 mL) and the combined organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue obtained was purified by silica gel column chromatography using a 0-100% ethyl acetate in hexanes gradient to afford 3-(4,4-dimethylpentyl)pyrrolidin-2-one (3.86 g, 39%) as a white solid. 1 H NMR (250 MHz, CDCl 3 ) δ (ppm): 7.51 (s, 1H), 3.12 (m, 2H), 2.15 (m, 2H), 1.60 (m, 2H), 1.29-1.11 (m, 5H), 0.86 (s, 9H). ESI-MS m/z calc. 183.16, found 184.2 (M+1) + . Retention time: 4.66 min (LC Method Q).

Step 2: (14S)-8-[3-(4,4-Dimethylpentyl)-2-oxopyrrolidin-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound 102)

A 4 mL vial was charged with (14S)-8-chloro-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (25 mg, 0.05373 mmol), 3-(4,4-dimethylpentyl)pyrrolidin-2-one (29 mg, 0.1582 mmol) (crude material, purity unknown), Pd 2 (dba) 3 (10 mg, 0.01092 mmol), Xantphos (6 mg, 0.01037 mmol), cesium carbonate (87.52 mg, 0.2686 mmol) and anhydrous dioxane (0.4 mL). The mixture was sparged with nitrogen for 1-2 min, capped and stirred at 120° C. for 21 h. The reaction was diluted with dimethyl sulfoxide (700 μL), microfiltered and subjected to reverse phase preparative HPLC (C 18 ) using a gradient of acetonitrile in water (1 to 99% over 15 min) and hydrochloric acid as a modifier. The pure fractions were collected, a bit of brine was added and the organic solvents were evaporated. The product was extracted with dichloromethane and the organic phase was dried over sodium sulfate. Evaporation of the solvents gave 8 mg of solid. The product was purified by flash chromatography on silica gel (4 g column) using a gradient of methanol (0 to 5% over 30 min) in dichloromethane. The pure fractions were collected and the solvents evaporated to give (14S)-8-[3-(4,4-dimethylpentyl)-2-oxopyrrolidin-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound 102) (5.5 mg, 17%) as a white solid mixture of diastereomers. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.42 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.61-7.48 (m, 2H), 7.04 (d, J=7.1 Hz, 1H), 6.96 (broad s, 1H), 6.70 (d, J=8.5 Hz, 1H), 4.08-3.72 (m, 3H), 3.10 (br d, J=8.8 Hz, 1H), 2.94 (d, J=13.2 Hz, 1H), 2.74-2.60 (m, 2H), 2.33-2.18 (m, 1H), 2.10 (br s, 1H), 1.86-1.66 (m, 4H), 1.65-1.44 (m, 9H), 1.37-1.15 (m, 6H), 0.87 (d, J=1.8 Hz, 9H). ESI-MS m/z calc. 596.31445, found 597.4 (M+1) + ; Retention time: 2.29 min (LC Method B).

Example 27: Syntheses of 8-[3-({dispiro[2.0.2.1]heptan-7-yl}methoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Enantiomer 1) (Compound 106) and 8-[3-({dispiro[2.0.2.1]heptan-7-yl}methoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Enantiomer 2) (Compound 107)

›Step 1: 1-Cyclopropylcyclopropanol

To a solution of methyl cyclopropanecarboxylate (75 g, 749.1 mmol) in ether (450 mL) was added titanium(IV) isopropoxide (55.3 mL, 187.4 mmol). To the mixture was slowly added ethyl magnesium bromide (1.6 L of 1 M, 1.60 mol) over 2 h. The addition is exothermic and controlled with monitoring the addition rate and using a cooling bath. The reaction temperature was kept between 21° C.-26° C. during addition. After addition, the mixture was stirred an additional 2 h at ambient temperature. Next, the mixture was chilled to −5° C. using an acetone/dry ice bath and slowly quenched with sulfuric acid (970 g of 10% w/w, 990 mmol). The reaction mixture was cooled in a dry ice/acetone bath to keep the reaction vessel below 0° C. during the quench. As the quench progressed, a grey/purple solid formed. Following complete addition of aqueous sulfuric acid, the mixture was stirred at 0° C. for 1 h. The precipitate was filtered through Celite using a medium frit and the precipitate washed with diethyl ether (900 mL). The filtrate was transferred to a separatory funnel and the organic phase was washed with brine (1 L), saturated sodium bicarbonate (1 L) and brine (1 L). The organic phase was dried over magnesium sulfate, filtered over Celite and the solvent was evaporated by rotary evaporation at 100 torr and the water bath set at 20° C. The crude product was stored at −23° C. overnight and used without further purification. The product, 1-cyclopropylcyclopropanol (61 g, 83%) was found to contain 50% solvent (tetrahydrofuran and PrOH) and used as such in the next step. 1 H NMR (400 MHz, Chloroform-d) δ 1.32 (tt, J=8.2, 5.1 Hz, 1H), 0.71-0.61 (m, 2H), 0.51-0.43 (m, 2H), 0.43-0.33 (m, 2H), 0.23-0.14 (m, 2H).

›Step 2: 1-Bromo-1-cyclopropyl-cyclopropane

A solution of triphenylphosphine (56.1 g, 213.9 mmol) in dichloromethane (200 mL) was cooled to −10° C. A solution of bromine (11.0 mL, 214 mmol) in dichloromethane (40 mL) was added and the reaction was stirred at −10° C. for an additional 15 min. The reaction was then cooled to −30° C. and pyridine (3.3 mL, 41 mmol) was added. A solution of 1-cyclopropylcyclopropanol (20.0 g, 204 mmol), pyridine (17.3 mL, 214 mmol) and dichloromethane (100 mL) was added dropwise while maintaining the temperature between −15° C. to −20° C. After 30 min, the addition was complete and the reaction was allowed to gradually warm to room temperature. The reaction was then allowed to stir at 40° C. overnight. The reaction was then cooled to room temperature and quenched with water (100 mL). The reaction was then stirred for 10 min and the phases were separated. The organic phase was successively washed with 1 M hydrochloric acid (102 mL) then saturated sodium bicarbonate (50 mL), dried over sodium sulfate, filtered and concentrated (30° C./house vacuum˜300 torr) to remove most of the dichloromethane. The crude reaction mixture was flash distilled (40° C./20 torr) to remove further dichloromethane. The solid residue (Ph 3 PO and product) was re-heated and distilled (50-60° C./20 torr) to afford 21.5 g (65% yield) of 1-bromo-1-cyclopropyl-cyclopropane as a turbid, colorless liquid. 1 H NMR (400 MHz, Chloroform-d) δ 1.61 (tt, J=8.2, 5.0 Hz, 1H), 1.07-1.02 (m, 2H), 0.78-0.66 (m, 2H), 0.67-0.51 (m, 2H), 0.35-0.21 (m, 2H).

›Step 3: Cyclopropylidenecyclopropane

A solution of potassium tert-butoxide (16.7 g, 148.8 mmol) in dimethyl sulfoxide (100 mL) was stirred at room temperature in a 3-neck 250-mL round bottom flask. 1-Bromo-1-cyclopropyl-cyclopropane (20.0 g, 124.2 mmol) was added dropwise and the reaction immediately turned dark and then brown. The reaction was mildly exothermic (maintained temperature between 18° C. to 22° C. using an ice-water bath). After 10 min, the addition was completed. The ice-water bath was removed and the reaction was allowed to stir at room temperature. After 90 min, the reaction mixture was vacuum distilled using a bulb-to-bulb distillation. The distillation took place from 60° C. to 80° C. between 40 and 100 torr. The distillate slowly collected in the receiver to afford 18.2 g (7.3 g of product as a 42 wt % solution in t-BuOH) of a colorless liquid. The distillate was further washed with water (5×10 mL). Dichloromethane (4 g) was added and mixture was dried over magnesium sulfate, filtered (washing with 2 additional portions of 3 g of dichloromethane each) to afford 17.30 g (6.9 g product as a 39.6 wt % solution in dichloromethane; 69% yield) as a colorless liquid. 1 H NMR (400 MHz, Chloroform-d) δ 1.19 (s, 8H). The 1H NMR confirms the presence of dichloromethane and a small amount of tert-butanol.

›Step 4: Ethyl dispiro[2.0.2.1]heptane-7-carboxylate

To a solution of cyclopropylidenecyclopropane (49.5 g, 617.8 mmol) in dichloromethane (110 mL) at 0° C. under a nitrogen atmosphere was added rhodium(II) acetate (4.2 g, 9.503 mmol). To the mixture at 0° C. was added ethyl 2-diazoacetate (106.8 mL, 1.016 mol) using a syringe pump set at an addition rate of 0.02 mL/min (1.2 mL/h). The addition was continuous for 89 hr. The crude reaction mixture was filtered through a plug of silica, washing 3× with 150 mL of dichloromethane each. The volatile materials were removed in vacuo affording a crude, dark yellow oil, ethyl dispiro[2.0.2.1]heptane-7-carboxylate (100 g, 97%, contains ˜20% dichloromethane, diethyl (E)-but-2-enedioate and diethyl (Z)-but-2-enedioate as contaminants) which was used directly in the next step. 1 H NMR (400 MHz, Chloroform-d) δ 4.13 (q, J=7.1 Hz, 2H), 2.23 (s, 1H), 1.24 (t, J=7.1 Hz, 3H), 1.08-0.93 (m, 4H), 0.90-0.82 (m, 2H), 0.77 (ddd, J=8.2, 5.0, 3.5 Hz, 2H).

›Step 5: Dispiro[2.0.2.1]heptan-7-yl methanol

To a slurry of lithium aluminum hydride (7.8 g, 200.2 mmol) in diethyl ether (300 mL) chilled with an ice-water bath was slowly added ethyl dispiro[2.0.2.1]heptane-7-carboxylate (10.77 g, 64.79 mmol). The mixture was allowed to warm to a gentle reflux during the addition and continued to stir at ambient temperature for 1 h. The reaction was chilled with an ice-water bath and slowly quenched with the addition of water (8.0 mL, 440 mmol), followed by sodium hydroxide (8.0 mL of 2 M, 16 mmol) and then water (24.0 mL, 1.33 mol). The light yellow slurry was filtered over Celite and washed 3× with 150 mL of methyl tert-butyl ether. The filtrate was concentrated in vacuo affording 8.87 g of a clear oil, dispiro[2.0.2.1]heptan-7-yl methanol (8.87 g, quantitative yield).

1 H NMR (400 MHz, Chloroform-d) δ 3.71 (dd, J=6.7, 5.5 Hz, 2H), 1.76-1.65 (m, 1H), 1.46 (t, J=5.6 Hz, 1H), 0.87 (q, J=1.9 Hz, 4H), 0.72-0.61 (m, 2H), 0.60-0.50 (m, 2H).

›Step 6: tert-Butyl 3-(dispiro[2.0.2.1]heptan-7-yl methoxy)-1H-pyrazole-1-carboxylate

A solution of dispiro[2.0.2.1]heptan-7-yl methanol (1.36 g, 11.0 mmol), tert-butyl 3-hydroxypyrazole-1-carboxylate (2.3 g, 12 mmol) and triphenylphosphine (3.2 g, 12 mmol) in tetrahydrofuran (28 mL) was cooled in an ice bath and diisopropyl azodicarboxylate (2.4 mL, 12 mmol) was slowly added. The cooling bath was removed and the reaction was stirred for 15 h. The reaction was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and evaporated under vacuum. The residue was purified by silica gel chromatography eluting with a gradient of 0-20% ethyl acetate in hexanes to give tert-butyl 3-(dispiro[2.0.2.1]heptan-7-yl methoxy)-1H-pyrazole-1-carboxylate (1.57 g, 49% yield) as a colorless oil. ESI-MS m/z calc. 290.16306, found 291.3 (M+1) + ; Retention time: 0.76 min (LC Method A).

›Step 7: 3-(Dispiro[2.0.2.1]heptan-7-ylmethoxy)-1H-pyrazole

A solution of tert-butyl 3-(dispiro[2.0.2.1]heptan-7-yl methoxy)-1H-pyrazole-1-carboxylate (1.57 g, 5.41 mmol) and trifluoroacetic acid (2.2 mL, 29 mmol) in dichloromethane (20 mL) was stirred for three h. The volatiles were removed under vacuum and the residue was basified with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and evaporated to give 3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)-1H-pyrazole (0.94 g, 91% yield) as pale yellow oil. ESI-MS m/z calc. 190.11061, found 191.1 (M+1) + ; Retention time: 0.52 min (LC Method A).

›Step 8: Ethyl 2-chloro-6-(3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)-1H-pyrazol-1-yl)nicotinate

A mixture of 3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)-1H-pyrazole (0.94 g, 4.9 mmol), ethyl 2,6-dichloropyridine-3-carboxylate (1.15 g, 5.23 mmol), potassium carbonate (0.83 g, 6.0 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.12 g, 1.1 mmol) in dimethyl sulfoxide (16 mL) was stirred for 24 h. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine and water, dried over sodium sulfate, filtered and evaporated under vacuum. The residue was purified by silica gel column chromatography eluting with a gradient from 0-20% ethyl acetate in hexanes to give ethyl 2-chloro-6-(3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)-1H-pyrazol-1-yl)nicotinate (1.39 g, 75% yield) as a colorless solid. 1 H NMR (400 MHz, Chloroform-d) δ 8.36 (d, J=2.8 Hz, 1H), 8.27 (d, J=8.5 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 5.96 (d, J=2.9 Hz, 1H), 4.41 (q, J=7.1 Hz, 2H), 4.30 (d, J=7.0 Hz, 2H), 1.94 (t, J=7.0 Hz, 1H), 1.42 (t, J=7.1 Hz, 3H), 1.02-0.89 (m, 4H), 0.75-0.65 (m, 2H), 0.65-0.53 (m, 2H). ESI-MS m/z calc. 373.11932, found 374.2 (M+1) + ; Retention time: 0.87 min (LC Method A).

›Step 9: 2-Chloro-6-[3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)pyrazol-1-yl]pyridine-3-carboxylic Acid · 1 of 2

A solution of ethyl 2-chloro-6-(3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)-1H-pyrazol-1-yl)nicotinate (1.39 g, 3.72 mmol) and sodium hydroxide (7.5 mL of 1 M solution, 7.5 mmol) in tetrahydrofuran (6 mL) and ethanol (3 mL) was stirred for 90 min. The volatiles were removed under vacuum and water was added. The reaction was cooled in an ice bath and hydrochloric acid (7.5 mL of 1 M solution, 7.5 mmol) was slowly added. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give 2-chloro-6-[3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (1.16 g, 82% yield) as a colorless solid. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 8.41 (d, J=2.9 Hz, 1H), 8.38 (d, J=8.4 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 6.19 (d, J=2.8 Hz, 1H), 4.27 (d, J=7.0 Hz, 2H), 1.93 (t, J=7.0 Hz, 1H), 0.97-0.79 (m, 4H), 0.76-0.66 (m, 2H), 0.65-0.56 (m, 2H). ESI-MS m/z calc. 345.088, found 346.1 (M+1) + ; Retention time: 0.73 min (LC Method A).

Step 10: tert-Butyl 4-[3-[[6-[[2-chloro-6-[3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

A 100 mL flask was charged under nitrogen with 2-chloro-6-[3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (300 mg, 0.8676 mmol) and anhydrous tetrahydrofuran (4 mL). Carbonyl diimidazole (214 mg, 1.320 mmol) was added and the mixture was stirred under nitrogen at room temperature for 2 h. In a separate 20 mL vial maintained under nitrogen atmosphere, a solution of tert-butyl 2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (358 mg, 0.8678 mmol) in anhydrous tetrahydrofuran (2 mL) was prepared and added via syringe to the activated ester solution. Added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.29 mL, 1.939 mmol) and the mixture was stirred at room temperature for 19 h. The solvent was evaporated and the residue was treated with water (50 mL), ethyl acetate (50 mL) and hydrochloric acid (1 mL of 6 M, 6.000 mmol). The two phases were separated. The aqueous phase was further extracted with ethyl acetate (25 mL). The combined organics were washed with brine (30 mL), dried over sodium sulfate and the solvents were evaporated. The product was dissolved in dichloromethane and purified by flash chromatography on silica gel using a gradient of ethyl acetate (0 to 100% over 30 min) in hexanes. The pure fractions were collected and the solvents were evaporated to give 408 mg of product as a foamy solid. LCMS showed that the material contained 6% of starting carboxylic acid. The product was purified a second time using the same method to give tert-butyl 4-[3-[[6-[[2-chloro-6-[3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (364 mg, 57%) as a colorless resin. ESI-MS m/z calc. 739.2919, found 740.3 (M+1) + : Retention time: 2.45 min (LC Method B).

Step 11: 2-Chloro-N-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propylamino]-2-pyridyl]sulfonyl]-6-[3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)pyrazol-1-yl]pyridine-3-carboxamide (Dihydrochloride Salt)

A 100 mL round bottom flask was charged with tert-butyl 4-[3-[[6-[[2-chloro-6-[3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)pyrazol-1-yl]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (364 mg, 0.4917 mmol), dichloromethane (5 mL) and hydrochloric acid (0.5 mL of 4 M, 2.000 mmol) (4 M in dioxane). The vial was capped and stirred at room temperature for 5 h. An additional amount of hydrochloric acid (0.5 mL of 4 M, 2.000 mmol) was added and the mixture was stirred for another h. The volatiles were removed by rotary evaporation under vacuum at room temperature. The residue was triturated with dichloromethane/hexanes and the solvents evaporated. The operation was repeated until a white solid was obtained. Drying under vacuum gave 2-chloro-N-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propylamino]-2-pyridyl]sulfonyl]-6-[3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)pyrazol-1-yl]pyridine-3-carboxamide (dihydrochloride salt) (325 mg, 93%) as a white solid. ESI-MS m/z calc. 639.23944, found 640.3 (M+1) + ; Retention time: 1.58 min (LC Method B).

Step 12: 8-[3-({Dispiro[2.0.2.1]heptan-7-yl}methoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Enantiomer 1) (Compound 106) and 8-[3-({dispiro[2.0.2.1]heptan-7-yl}methoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Enantiomer 2) (Compound 107)

A 100 mL round bottom flask equipped with a magnetic stirbar was charged under nitrogen with 2-chloro-N-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propylamino]-2-pyridyl]sulfonyl]-6-[3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)pyrazol-1-yl]pyridine-3-carboxamide (dihydrochloride salt) (325 mg, 0.4557 mmol), anhydrous NMP (3 mL), potassium carbonate (269 mg, 1.946 mmol) (freshly ground in a mortar) and cesium fluoride (70 mg, 0.4608 mmol). The mixture was vigorously stirred at 140° C. under nitrogen for 15 h. The mixture was diluted with water (20 mL) and it was acidified by slowly adding hydrochloric acid (500 μL of 6 M, 3.000 mmol, final pH=4-5). The resulting solid was filtered and briefly air dried. The solid was dissolved in dichloromethane/ethyl acetate (total volume 75 mL) dried over sodium sulfate, filtered and concentrated to give a solution that was purified by flash chromatography on silica gel using a gradient of methanol (0 to 5% over 30 min) in dichloromethane. Evaporation of the solvents gave racemic 8-[3-({dispiro[2.0.2.1]heptan-7-yl}methoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound 105) (102 mg, 36%) as a white solid. 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.51 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.58 (dd, J=8.5, 7.2 Hz, 1H), 7.05 (broad d, J=7.2 Hz, 1H), 6.97 (s, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 6.11 (d, J=2.7 Hz, 1H), 4.24 (d, J=7.0 Hz, 2H), 4.0-3.85 (m, 1H), 3.15 (br s, 1H), 2.95 (br d, J=13.3 Hz, 1H), 2.75-2.65 (m, 1H), 2.12 (br s, 1H), 1.91 (t, J=7.0 Hz, 1H), 1.89-1.67 (m, 2H), 1.67-1.41 (m, 9H), 1.37-1.26 (m, 1H), 0.97-0.81 (m, 4H), 0.74-0.65 (m, 2H), 0.66-0.53 (m, 2H). ESI-MS m/z calc. 603.26276, found 604.2 (M+1) + ; Retention time: 2.26 min (LC Method B). This racemic material (97 mg) was subjected to chiral SFC separation (ChiralPak column AS-H (250×10 mm), 5 μm, 35° C., mobile phase 38% acetonitrile:methanol (90:10 no modifier), 62% carbon dioxide, 10 mL/min, 24 mg/mL in acetonitrile:methanol (90:10 no modifier), injection volume 70 μL, 100 bar). The first enantiomer to elute was collected and the solvents were evaporated and the residue triturated in dichloromethane/hexanes. Evaporation gave 8-[3-({dispiro[2.0.2.1]heptan-7-yl}methoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (enantiomer 1) (Compound 106) (46 mg, 32%). 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.50 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.05 (d, J=7.2 Hz, 1H), 6.98 (broad d, J=7.3 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 6.10 (d, J=2.7 Hz, 1H), 4.23 (d, J=7.0 Hz, 2H), 3.99-3.82 (m, 1H), 3.15 (br s, 1H), 2.95 (br d, J=13.4 Hz, 1H), 2.80-2.62 (m, 1H), 2.12 (br s, 1H), 1.91 (t, J=7.0 Hz, 1H), 1.89-1.68 (m, 2H), 1.68-1.44 (m, 9H), 1.38-1.24 (m, 1H), 0.98-0.81 (m, 4H), 0.75-0.64 (m, 2H), 0.66-0.53 (m, 2H). ESI-MS m/z calc. 603.26276, found 604.3 (M+1) + ; Retention time: 2.27 min (LC Method E). The second enantiomer to elute was collected and the solvents were evaporated and the residue triturated in dichloromethane/hexanes. Evaporation gave 8-[3-({dispiro[2.0.2.1]heptan-7-yl}methoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (enantiomer 2) (Compound 107) (43 mg, 31%). 1 H NMR (400 MHz, dimethyl sulfoxide-d 6 ) δ 12.50 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.57 (t, J=7.9 Hz, 1H), 7.05 (d, J=7.2 Hz, 1H), 6.98 (broad d, J=8.5 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 6.10 (d, J=2.7 Hz, 1H), 4.23 (d, J=7.0 Hz, 2H), 4.02-3.82 (m, 1H), 3.23-3.06 (m, 1H), 2.95 (br d, J=13.1 Hz, 1H), 2.80-2.62 (m, 1H), 2.12 (br s, 1H), 1.91 (t, J=7.0 Hz, 1H), 1.88-1.68 (m, 2H), 1.68-1.42 (m, 9H), 1.39-1.24 (m, 1H), 0.96-0.81 (m, 4H), 0.74-0.64 (m, 2H), 0.64-0.53 (m, 2H). ESI-MS m/z calc. 603.26276, found 604.3 (M+1) + ; Retention time: 2.27 min (LC Method B).

›Step 9: 2-Chloro-6-[3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)pyrazol-1-yl]pyridine-3-carboxylic Acid · 2 of 2

Example 28: Preparation of 12,12,20-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Enantiomer 1) (Compound 114) and 12,12,20-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (Enantiomer 2) (Compound 115)

›Step 1: 2-Chloro-6-iodo-3-methyl-pyridine

A solution of 2-(dimethylamino)ethanol (13.02 g, 14.7 mL, 146.1 mmol) in hexanes (120 mL) was cooled to −5° C. and treated with butyllithium (132 mL of 2.5 M in hexanes, 330.0 mmol) over a period of 45 min. The flask was kept between −5 and 0° C. for 1 h then cooled to −78° C. A solution of 2-chloro-3-methyl-pyridine (7 g, 54.87 mmol) in hexanes (70 mL+10 mL rinse) was added dropwise during 30 min and the mixture was stirred at −78° C. for 2 h. A solution of iodine (56 g, 11.36 mL, 220.6 mmol) in tetrahydrofuran (200 mL) was added dropwise over a period of about 1 h and the reaction mixture was left to gradually warm up to room temperature overnight. The mixture was cooled in an ice bath and quenched slowly with water (250 mL). Transferred to a 1000 mL separatory funnel and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×250 mL) and the organic layers were combined, washed with water containing 10% aqueous sodium thiosulfate (organic layer becomes clear), water (200 mL) and brine (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography on a 220 g column, eluting from 0% to 15% ethyl acetate in heptanes to afford pure and mixed fractions. The mixed fractions were further purified by silica gel chromatography on a 120 g column, eluting from 0% to 15% ethyl acetate in heptanes then triturated in heptanes, dried and combined to the previous pure fractions from the first silica gel column to afford 2-chloro-6-iodo-3-methyl-pyridine (9.7 g, 68%) as a pale yellow solid. 1 H NMR (300 MHz, CDCl 3 ) ppm 2.32 (s, 3H), 7.18 (d, J=7.6 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H). ESI-MS m/z calc. 252.9155, found 254.0 (M+1) + ; Retention time: 2.71 min (LC Method H).

›Step 2: 2-Ethylhexyl 3-[(6-chloro-5-methyl-2-pyridyl)sulfanyl]propanoate

A solution of 2-chloro-6-iodo-3-methyl-pyridine (15.4 g, 60.76 mmol) and diisopropylethylamine (15.73 g, 21.2 mL, 121.7 mmol) in toluene (300 mL) was degassed by bubbling nitrogen for 10 min. Tris(dibenzylideneacetone)dipalladium(0) (1.7 g, 1.856 mmol), Xantphos (2.1 g, 3.629 mmol) and 2-ethylhexyl 3-sulfanylpropanoate (14.6 g, 66.86 mmol) were added and the mixture was heated at 110° C. overnight. The residue was concentrated under reduced pressure and purified by silica-gel column chromatography on a 220 g column, eluting from 0% to 20% ethyl acetate in heptanes to afford 2-ethylhexyl 3-[(6-chloro-5-methyl-2-pyridyl)sulfanyl]propanoate (15.8 g, 76%) as a yellow oil. 1 H NMR (300 MHz, CDCl 3 ) ppm 0.88 (t, J=7.3 Hz, 6H), 1.20-1.44 (m, 9H), 2.30 (s, 3H), 2.77 (t, J=7.0 Hz, 2H), 3.40 (t, J=6.9 Hz, 2H), 3.97-4.06 (m, 2H), 7.00 (d, J=7.9 Hz, 1H), 7.33 (d, J=7.9 Hz, 1H). ESI-MS m/z calc. 343.912, found 344.2 (M+1) + ; Retention time: 2.76 min (LC Method I).

›Step 3: 2-Ethylhexyl 3-[(6-chloro-5-methyl-2-pyridyl)sulfonyl]propanoate

m-Chloroperbenzoic acid (21.6 g, 96.38 mmol) was slowly added to a solution of 2-ethylhexyl 3-[(6-chloro-5-methyl-2-pyridyl)sulfanyl]propanoate (15.8 g, 45.94 mmol) in dichloromethane (135 mL) at room temperature. The mixture was stirred at this temperature for 5 h. Ethyl acetate (500 mL) was added and the resulting mixture was washed with saturated sodium bicarbonate solution (250 mL) then 0.5 M sodium hydroxide solution (2×250 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography on a 220 g column, eluting from 0% to 40% ethyl acetate in heptanes to afford 2-ethylhexyl 3-[(6-chloro-5-methyl-2-pyridyl)sulfonyl]propanoate (12.36 g, 72%) as a clear oil. 1 H NMR (300 MHz, CDCl 3 ) ppm 0.82-0.94 (m, 6H), 1.20-1.41 (m, 9H), 2.49 (s, 3H), 2.78-2.89 (m, 2H), 3.66-3.76 (m, 2H), 4.01 (dd, J=6.0, 1.9 Hz, 2H), 7.77-7.84 (m, 1H), 7.89-7.96 (m, 1H). ESI-MS m/z calc. 375.911, found 376.1 (M+1) + ; Retention time: 2.43 min (LC Method I).

›Step 4: 6-Chloro-5-methyl-pyridine-2-sulfonamide

Sodium methoxide (7.1 g, 131.4 mmol) was added to a solution of 2-ethylhexyl 3-[(6-chloro-5-methyl-2-pyridyl)sulfonyl]propanoate (12.36 g, 32.88 mmol) in tetrahydrofuran (100 mL) and methanol (35 mL) at room temperature. The reaction mixture was stirred for 4 h then the mixture was concentrated under reduced pressure to afford a white solid intermediate. To this intermediate was added hydroxylamine-O-sulfonic acid (7.4 g, 65.43 mmol) and sodium acetate (8.1 g, 98.74 mmol) in water (240 mL) at 0° C. The mixture was stirred at room temperature overnight then extracted with ethyl acetate (2×300 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography on a 120 g column, eluting from 20% to 80% of ethyl acetate in heptanes to afford 6-chloro-5-methyl-pyridine-2-sulfonamide (5.9 g, 86%) as a white solid. 1 H NMR (300 MHz, dimethyl sulfoxide-d 6 ) ppm 2.40 (s, 3H), 7.59 (s, 2H), 7.82 (d, J=7.6 Hz, 1H), 8.04 (d, J=7.6 Hz, 1H). ESI-MS m/z calc. 206.65, found 207.1 (M+1) + ; Retention time: 1.44 min (LC Method I).

Step 5: tert-Butyl 2,2-dimethyl-4-[3-[(3-methyl-6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate

In a 5 mL microwave vial, 6-chloro-5-methyl-pyridine-2-sulfonamide (460 mg, 2.226 mmol), tert-butyl 4-(3-aminopropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (380 mg, 1.482 mmol) and diisopropylethylamine (1.3 mL, 7.463 mmol) were dissolved in n-BuOH (3 mL). The vial was sealed and stirred at 160° C. overnight. The mixture was filtere

›Tables in the description — 30

TABLE 1

Acetate	Hydrobromide	Stearate
Benzenesulfonate	Hydrochloride	Subacetate
Benzoate	Hydroxynaphthoate	Succinate
Bicarbonate	Iodide	Sulfate
Bitartrate	Isethionate	Tannate
Bromide	Lactate	Tartrate
Calcium edetate	Lactobionate	Teociate
Camsylate	Malate	Triethiodide
Carbonate	Maleate	Benzathine
Chloride	Mandelate	Chloroprocaine
Citrate	Mesylate	Choline
Dihydrochloride	Methylbromide	Diethanolamine
Edetate	Methylnitrate	Ethylenediamine
Edisylate	Methylsulfate	Meglumine
Estolate	Mucate	Procaine
Esylate	Napsylate	Aluminum
Fumarate	Nitrate	Calcium
Gluceptate	Pamoate (Embonate)	Lithium
Gluconate	Pantothenate	Magnesium
Glutamate	Phosphate/diphosphate	Potassium
Glycollylarsanilate	Polygalacturonate	Sodium
Hexylresorcinate	Salicylate	Zinc
Hydrabamine

TABLE 2 — Exemplary Tablet Comprising 100 mg Compound II and 150 mg Compound III. Amount per

	Ingredient	tablet (mg)
Intra-granular	Compound II SDD (spray	125
	dried dispersion)
	(80 wt % Compound II, 20
	wt % HPMC)
	Compound III SDD	187.5
	(80 wt % Compound III,
	19.5 wt % HPMCAS-HG;
	0.5 wt % sodium lauryl
	sulfate)
	Microcrystalline cellulose	131.4
	Croscarmellose Sodium	29.6
	Total	473.5
Extra-granular	Microcrystalline cellulose	112.5
	Magnesium Stearate	5.9
	Total	118.4
Total uncoated Tablet		591.9
Film coat	Opadry	17.7
Total coated Tablet		609.6

TABLE 3 — Ingredients for Exemplary Tablet of Compound III

	Percent Dose	Dose	Batch
Tablet Formulation	% Wt./Wt.	(mg)	(g)
Compound III SDD	34.09%	187.5	23.86
(80 wt % Compound III, 19.5 wt %
HPMCAS-HG; 0.5 wt % sodium
lauryl sulfate)
Microcrystalline cellulose	30.51%	167.8	21.36
Lactose	30.40%	167.2	21.28
Sodium croscarmellose	3.000%	16.50	2.100
SLS	0.500%	2.750	0.3500
Colloidal silicon dioxide	0.500%	2.750	0.3500
Magnesium stearate	1.000%	5.500	0.7000
Total	100%	550	70

TABLE 4 — Ingredients for mini-tablets for 50 mg and 75 mg potency

	Percent	Dose (mg)	Dose (mg)
	Dose	50 mg	75 mg	Batch
Tablet Formulation	% Wt./Wt.	potency	potency	(g)
Compound III SDD	35	62.5	93.8	1753.4
(80 wt % Compound
III, 19.5 wt %
HPMCAS-HG; 0.5
wt % sodium lauryl
sulfate)
Mannitol	13.5	24.1	36.2	675.2
Lactose	41	73.2	109.8	2050.2
Sucralose	2.0	3.6	5.4	100.06
Croscarmellose sodium	6.0	10.7	16.1	300.1
Colloidal silicon	1.0	1.8	2.7	50.0
dioxide
Magnesium stearate	1.5	2.7	4.0	74.19
Total	100	178.6	268	5003.15

TABLE B CFTR Mutations

Q39X	1248+1G→A	R560S
W57X	1341+1G→A	A561E
E60X	1717−1G→A	Y569D
R75X	1811+1.6kbA→G	L1065P
E92X	1811+1G→C	R1066C
Q98X	1812−1G→A	R1066M
Y122X	1898+1G→A	L1077P
L218X	2622+1G→A	H1085R
Q220X	3120+1G→A	M1101K
C276X	3120G→A	N1303K
Q290X	3850−1G→A	3849+10kbC→T
G330X	4005+1G→A	3272−26A→G
W401X	4374+1G→T	711+3A→G
Q414X	663delT	E56K
S434X	2183AA→G	P67L
S466X	CFTRdel2,3	R74W
S489X	3659delC	D110E
Q493X	394delTT	D110H
W496X	2184insA	R117C
Q525X	3905insT	L206W
G542X	2184delA	R347H
Q552X	1078delT	R352Q
R553X	1154insTC	A455E
E585X	2183delAA→G	D579G
G673X	2143delT	E831X
R709X	1677delTA	S945L
K710X	3876delA	S977F
L732X	2307insA	F1052V
R764X	4382delA	R1070W
R785X	4016insT	F1074L
R792X	2347delG	D1152H
E822X	3007delG	D1270N
W846X	574delA	G178R
R851X	2711delT	S549N
Q890X	3791delC	S549R
S912X	CFTRdele22−23	G551D
W1089X	457TAT→G	G551S
Y1092X	2043delG	G1244E
E1104X	2869insG	S1251N
R1158X	3600+2insT	S1255P
R1162X	3737delA	G1349D
S1196X	4040delA
W1204X	541delC
S1255X	A46D
W1282X	T338I
Q1313X	R347P
621+1G→T	L927P
711+1G→T	G85E
711+5G→A	S341P
712−1G→T	L467P
405+1G→A	I507del
405+3A→C	V520F
406−1G→A	A559T
621+1G→T	R560T

TABLE C — CFTR Mutations a Also known as 2183delAA→G. b Unpublished data.

Criteria	Mutation
Truncation	S4X	C276X	G542X	R792X	E1104X
mutations	G27X	Q290X	G550X	E822X	R1158X
% PI > 50%	Q39X	G330X	Q552X	W846X	R1162X
and/or	W57X	W401X	R553X	Y849X	S1196X
SwCl − > 86	E60X	Q414X	E585X	R851X	W1204X
mmol/L	R75X	S434X	G673X	Q890X	L1254X
no full-length	E92X	S466X	Q685X	S912X	S1255X
protein	Q98X	S489X	R709X	Y913X	W1282X
	Y122X	Q493X	K710X	W1089X	Q1313X
	E193X	W496X	L732X	Y1092X	E1371X
	L218X	C524X	R764X	W1098X	Q1382X
	Q220X	Q525X	R785X	R1102X	Q1411X
Splice mutations	185+1G→T	711+5G→A	1717−8G→A	2622+1G→A	3121−1G→A
% PI > 50%	296+1G→A	712−1G→T	1717−1G→A	2790−1G→C	3500−2A→G
and/or	405+1G→A	1248+1G→A	1811+1G→C	3040G→C	3600+2insT
SwCl − > 86	405+3A→C	1249−1G→A	1811+1.6kbA→G	(G970R)	3850−1G→A
mmol/L	406−1G→A	1341+1G→A	1812−1G→A	3120G→A	4005+1G→A
no or little	621+1G→T	1525−2A→G	1898+1G→A	3120+1G→A	4374+1G→T
mature mRNA	711+1G→T	1525−1G→A	1898+1G→C	3121−2A→G
Small (≤3	182delT	1119delA	1782delA	2732insA	3876delA
nucleotide)	306insA	1138insG	1824delA	2869insG	3878delG
insertion/deletion	365−366insT	1154insTC	2043delG	2896insAG	3905insT
(ins/del) frameshift	394delTT	1161delC	2143delT	2942insT	4016insT
mutations	442delA	1213delT	2183AA→G a	2957delT	4021dupT
% PI > 50%	444delA	1259insA	2184delA	3007delG	4040delA
and/or	457TAT→G	1288insTA	2184insA	3028delA	4279insA
SwCl − > 86	541delC	1471delA	2307insA	3171delC	4326delTC
mmol/L	574delA	1497delGG	2347delG	3659delC
garbled and/or	663delT	1548delG	2585delT	3737delA
truncated	935delA	1609del CA	2594delGT	3791delC
protein	1078delT	1677delTA	2711delT	3821delT
Non-small (>3	CFTRdele2,3	1461ins4	2991del32
nucleotide)	CFTRdele22,23	1924del7	3667ins4
insertion/deletion	124del23bp	2055del9→A	4010del4
(ins/del) frameshift	852del22	2105−	4209TGTT→AA
mutations		2117del13insAGAAA
% PI > 50% and/or	991del5	2721del11
SwCl − > 86
mmol/L
garbled and/or
truncated
protein
Class II, III, IV	A46D b	V520F	Y569D b	N1303K
mutations not	G85E	A559T b	L1065P
responsive to	R347P	R560T	R1066C
Compound III	L467P b	R560S	L1077P b
alone or in	I507del	A561E	M1101K
combination with
Compound II or
Compound IV
% 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

TABLE 5 — CFTR Mutations Mutation

Q2X	L218X	Q525X	R792X	E1104X
S4X	Q220X	G542X	E822X	W1145X
W19X	Y275X	G550X	W882X	R1158X
G27X	C276X	Q552X	W846X	R1162X
Q39X	Q290X	R553X	Y849X	S1196X
W57X	G330X	E585X	R851X	W1204X
E60X	W401X	G673X	Q890X	L1254X
R75X	Q414X	Q685X	S912X	S1255X
L88X	S434X	R709X	Y913X	W1282X
E92X	S466X	K710X	Q1042X	Q1313X
Q98X	S489X	Q715X	W1089X	Q1330X
Y122X	Q493X	L732X	Y1092X	E1371X
E193X	W496X	R764X	W1098X	Q1382X
W216X	C524X	R785X	R1102X	Q1411X
185+1G→T	711+5G→A	1717−8G→A	2622+1G→A	3121−1G→A
296+1G→A	712−1G→T	1717−1G→A	2790−1G→C	3500−2A→G
296+1G→T	1248+1G→A	1811+1G→C	3040G→C	3600+2insT
405+1G→A	1249−1G→A	1811+1.6kbA→G	(G970R)	3850−1G→A
405+3A→C	1341+1G→A	1811+1643G→T	3120G→A	4005+1G→A
406−1G→A	1525−2A→G	1812−1G→A	3120+1G→A	4374+1G→T
621+1G→T	1525−1G→A	1898+1G→A	3121−2A→G
711+1G→T		1898+1G→C
182delT	1078delT	1677delTA	2711delT	3737delA
306insA	1119delA	1782delA	2732insA	3791delC
306delTAGA	1138insG	1824delA	2869insG	3821delT
365−366insT	1154insTC	1833delT	2896insAG	3876delA
394delTT	1161delC	2043delG	2942insT	3878delG
442delA	1213delT	2143delT	2957delT	3905insT
444delA	1259insA	2183AA→G	3007delG	4016insT
457TAT→G	1288insTA	2184delA	3028delA	4021dupT
541delC	1343delG	2184insA	3171delC	4022insT
574delA	1471delA	2307insA	3171insC	4040delA
663delT	1497delGG	2347delG	3271delGG	4279insA
849delG	1548delG	2585delT	3349insT	4326delTC
935delA	1609del CA	2594delGT	3659delC
CFTRdele1	CFTRdele16−17b	1461ins4
CFTRdele2	CFTRdele17a,17b	1924del7
CFTRdele2,3	CFTRdele17a−18	2055del9→A
CFTRdele2−4	CFTRdele19	2105−2117del13insAGAAA
CFTRdele3−10,14b−16	CFTRdele19−21	2372del8
CFTRdele4−7	CFTRdele21	2721del11
CFTRdele4−11	CFTRdele22−24	2991del32
CFTR50kbdel	CFTRdele22,23	3667ins4
CFTRdup6b−10	124del23bp	4010del4
CFTRdele11	602del14	4209TGTT→AA
CFTRdele13,14a	852del22
CFTRdele14b−17b	991del5
A46D	V520F	Y569D	N1303K
G85E	A559T	L1065P
R347P	R560T	R1066C
L467P	R560S	L1077P
I507del	A561E	M1101K

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 to 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.
12. The compound of any one of embodiments 1 to 8, 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.	13. The compound of any one of embodiments 1 to 12, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein k is 3, 4, 5, or 6.	14. The compound of any one of embodiments 1 to 13, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein q is 1.	15. The compound of any one of embodiments 1 to 14, 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:

each R 8 and R 9 is hydrogen; and each R b is independently chosen from hydrogen and C 1 -C 2 alkyl groups.

19. The compound of any one of embodiments 1 to 18, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 3 is independently CD 3 .	20. 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 (II-A) or (II-B):
a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing,	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 R5 and R6 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.
31. The compound of any one of embodiments 20 to 28, 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.	32. The compound of any one of embodiments 20 to 31, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein k is 3, 4, 5, or 6.	33. The compound of any one of embodiments 20 to 32, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein q is 1.	34. The compound of any one of embodiments 20 to 33, 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:

each R 8 and R 9 is hydrogen; and each R b is independently chosen from hydrogen and C 1 -C 2 alkyl groups.

38. The compound of any one of embodiments 20 to 37, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 3 is independently CD 3 .	39. 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 (III-A) or (III-B):
a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing,	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 to 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
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:

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 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 IV-A:
a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing,	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 to 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:

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 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 IV-B:
a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing,	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.
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:

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 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 IV-C:
a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing,	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 to 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.
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 -C 2 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:

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 to 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:

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 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 V-A:
a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing,	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.
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:

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 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 V-B:
a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing,	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.
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:

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:
a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing,	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.
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:

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 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-C or VI-D:
a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing,	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.
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:

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 20-57, 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. 1-302 depicted in FIG. 1 , pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing.	192. A compound chosen from compounds Nos. 303-309 depicted in FIG. 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 1-191 a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, and optionally one or more of:

a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing;	for treating cystic fibrosis.	197. A compound of Formula (X):
a salt thereof, or a deuterated derivative of any of the foregoing,	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.
198. A compound of Formula (Y):
a salt thereof, or a deuterated derivative of any of the foregoing,	wherein:

description truncated at 500,000 characters. 2 of 154 part labels are ours — the grant heads the rest

Stored text is truncated at the source; the tail of the description is not held.

Claims as granted

41 claims

Classifications

6 codes

LexDana classificationderived from the 10 nearest patents by meaning — ours, not an office code

Heterocyclic compounds containing two or more hetero rings50%
Drugs for disorders of the respiratory system40%
Heterocyclic compounds containing six-membered rings40%
Heterocyclic compounds containing nitrogen atoms as the only ring40%

IPC · International Patent Classification

Section A — Human necessities

A61K31/404
A61K31/439
A61K31/47
A61P11/00

Section C — Chemistry; metallurgy

C07D513/22
C07D515/22

As published → as granted

1 → 41 claims

The claims as they stood in the application’s own pre-grant publication (US-2022106331-A1), 2022, beside the claims that issued in 2024. Both are the same application. Claims are matched on their text, not their number.

41 added1 not granted

removedadded

›Claim by claim — 42

not grantedpublished claim 1no counterpart in the grant

m . 35 . The method of claim 24 , 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. 36 . The method of claim 24 , wherein n is 0. 37 . The method of claim 24 , wherein Ring D is a 5-membered heteroaryl ring substituted with (R 4 ) q . 38 . The method of claim 24 , wherein 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 (R 4 ) q . 39 . The method of claim 24 , wherein Ring D is a pyrazolyl ring, or a pyridinone ring, wherein Ring D is substituted with (R 4 ) q . 40 . The method of claim 24 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is a pyrazolyl ring, wherein Ring D is substituted with (R 4 ) q . 41 . The method of claim 24 , wherein Ring D is wherein indicates the point of attachment of Ring D to Ring B. 42 . The method of claim 24 , wherein Ring D is wherein indicates the point of attachment of Ring D to Ring B. 43 . The method of claim 42 , 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 , and 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. 44 . The method of claim 42 , 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 , and 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. 45 . The method of claim 42 , wherein each R 4 is independently chosen from wherein indicates the point of attachment of R 4 to Ring D. 46 . The method of claim 24 , wherein k is 3, 4, 5, or 6. 47 . The method of claim 24 , wherein q is 1. 48 . The method of claim 24 , 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, and 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. 49 . The method of claim 24 , 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, and: each R 8 and R 9 is independently chosen from hydrogen and deuterium; and each R b is independently chosen from hydrogen and methyl. 50 . The method of claim 24 , 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, and wherein: each R 8 and R 9 is independently chosen from hydrogen and deuterium; and each R b is hydrogen. 51 . The method of claim 24 , 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. 52 . The method of claim 24 , wherein each R 3 is independently CD 3 . 53 . The method of claim 28 , wherein: r is 3 or 4; 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 method of claim 28 , wherein: each R 8 and R 9 is independently chosen from hydrogen and deuterium; and each R b is hydrogen. 55 . The method of claim 29 , wherein each R 8 and R 9 is independently chosen from hydrogen and deuterium. 56 . The method of claim 29 , each R 8 and R 9 is hydrogen. 57 . The method of claim 24 , wherein the compound is selected from: a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the compounds, or a pharmaceutically acceptable salt of any deuterated derivatives of those compounds. 58 . The method of claim 24 , wherein the compound is in the form of a pharmaceutically acceptable salt. 59 . The method of claim 24 , wherein the compound is administered in combination with one or more of: (a) Compound II: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing; and (b) Compound III or Compound III-d: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing. 60 . A method of treating cystic fibrosis comprising administering to a patient in need thereof a compound of the formula: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing. 61 . The method of claim 60 , wherein the compound is in the form of a pharmaceutically acceptable salt. 62 . The method of claim 61 , wherein the pharmaceutically acceptable salt is a calcium salt. 63 . The method of claim 60 , wherein the compound is administered in combination with one or more of: (a) Compound II: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing; and (b) Compound III or Compound III-d: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing. 64 . The method of claim 63 , wherein the compound is administered in combination with Compound II and Compound III-d.

addedgranted claim 1independentno counterpart in the publication

A method of treating cystic fibrosis comprising administering to a patient in need thereof a compound 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.

addedgranted claim 2no counterpart in the publication

The method of claim 1 , wherein the compound of Formula (I) is a compound of Formula II-A or II-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 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 -C 2 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.

addedgranted claim 3no counterpart in the publication

The method of claim 1 , wherein the compound of Formula I is a compound of Formula III-A or III-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 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.

addedgranted claim 4no counterpart in the publication

The method of claim 1 , wherein the compound of Formula I 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 -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.

addedgranted claim 5no counterpart in the publication

The method of claim 1 , wherein the compound of Formula I 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

addedgranted claim 6no counterpart in the publication

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. 6. The method of claim 1 , wherein the compound of Formula I 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 -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.

addedgranted claim 7no counterpart in the publication

The method of claim 1 , wherein the compound of Formula I 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.

addedgranted claim 8no counterpart in the publication

The method of claim 1 , wherein the compound of Formula I 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, a6-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.

addedgranted claim 9no counterpart in the publication

The method of claim 1 , wherein the compound of Formula I is a compound of Formula VI-A or VI-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; 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.

addedgranted claim 10no counterpart in the publication

The method of claim 1 , wherein the compound of Formula I is a compound of Formula VI-C or VI-D: 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.

addedgranted claim 11no counterpart in the publication

The method of claim 1 , wherein Ring A is a phenyl ring, a pyridyl ring, or a pyrazolyl ring, wherein Ring A is optionally substituted with (R 1 ) m .

addedgranted claim 12no counterpart in the publication

The method of claim 1 , 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.

addedgranted claim 13no counterpart in the publication

The method of claim 1 , wherein n is 0.

addedgranted claim 14no counterpart in the publication

The method of claim 1 , wherein Ring D is a 5-membered heteroaryl ring substituted with (R 4 ) q .

addedgranted claim 15no counterpart in the publication

The method of claim 1 , wherein 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 (R 4 ) q .

addedgranted claim 16no counterpart in the publication

The method of claim 1 , wherein Ring D is a pyrazolyl ring, or a pyridinone ring, wherein Ring D is substituted with (R 4 ) q .

addedgranted claim 17no counterpart in the publication

The method of claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is a pyrazolyl ring, wherein Ring D is substituted with (R 4 ) q .

addedgranted claim 18no counterpart in the publication

The method of claim 1 , wherein Ring D is wherein indicates the point of attachment of Ring D to Ring B.

addedgranted claim 19no counterpart in the publication

The method of claim 1 , wherein Ring D is wherein indicates the point of attachment of Ring D to Ring B.

addedgranted claim 20no counterpart in the publication

The method of claim 19 , 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 , and 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.

addedgranted claim 21no counterpart in the publication

The method of claim 19 , 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 , and 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.

addedgranted claim 22no counterpart in the publication

The method of claim 19 , wherein each R 4 is independently chosen from wherein indicates the point of attachment of R 4 to Ring D.

addedgranted claim 23no counterpart in the publication

The method of claim 1 , wherein k is 3, 4, 5, or 6.

addedgranted claim 24no counterpart in the publication

The method of claim 1 , wherein q is 1.

addedgranted claim 25no counterpart in the publication

The method of claim 1 , 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, and 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.

addedgranted claim 26no counterpart in the publication

The method of claim 1 , 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, and: each R 8 and R 9 is independently chosen from hydrogen and deuterium; and each R b is independently chosen from hydrogen and methyl.

addedgranted claim 27no counterpart in the publication

The method of claim 1 , 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, and wherein: each R 8 and R 9 is independently chosen from hydrogen and deuterium; and each R b is hydrogen.

addedgranted claim 28no counterpart in the publication

The method of claim 1 , 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.

addedgranted claim 29no counterpart in the publication

The method of claim 1 , wherein each R 3 is independently CD 3 .

addedgranted claim 30no counterpart in the publication

The method of claim 5 , wherein: r is 3 or 4; 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.

addedgranted claim 31no counterpart in the publication

The method of claim 5 , wherein: each R 8 and R 9 is independently chosen from hydrogen and deuterium; and each R b is hydrogen.

addedgranted claim 32no counterpart in the publication

The method of claim 6 , wherein each R 8 and R 9 is independently chosen from hydrogen and deuterium.

addedgranted claim 33no counterpart in the publication

The method of claim 6 , each R 8 and R 9 is hydrogen.

addedgranted claim 34no counterpart in the publication

The method of claim 1 , wherein the compound is selected from: a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the compounds, or a pharmaceutically acceptable salt of any deuterated derivatives of those compounds.

addedgranted claim 35no counterpart in the publication

The method of claim 1 , wherein the compound is in the form of a pharmaceutically acceptable salt.

addedgranted claim 36no counterpart in the publication

The method of claim 1 , wherein the compound is administered in combination with one or more of: (a) Compound II: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing; and (b) Compound III or Compound III-d: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing.

addedgranted claim 37independentno counterpart in the publication

A method of treating cystic fibrosis comprising administering to a patient in need thereof a compound of the formula: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing.

addedgranted claim 38no counterpart in the publication

The method of claim 37 , wherein the compound is in the form of a pharmaceutically acceptable salt.

addedgranted claim 39no counterpart in the publication

The method of claim 38 , wherein the pharmaceutically acceptable salt is a calcium salt.

addedgranted claim 40no counterpart in the publication

The method of claim 37 , wherein the compound is administered in combination with one or more of: (a) Compound II: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing; and (b) Compound III or Compound III-d: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing.

addedgranted claim 41no counterpart in the publication

The method of claim 40 , wherein the compound is administered in combination with Compound II and Compound III-d.

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John S Kenyon

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