EA044967B1 - MACROCYCLES AS MODULATORS OF CYSTIC FICID TRANSMEMBRANCE CONDUCTION REGULATOR, THEIR PHARMACEUTICAL COMPOSITIONS, THEIR APPLICATION FOR THE TREATMENT OF CYSTIC FIDOSIS AND THEIR PRODUCTION METHOD - Google Patents

Description

Disclosed herein is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, pharmaceutical compositions containing the modulator, methods for treating cystic fibrosis, and a method 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 MB, there is no complete cure.

In patients with MB, mutations in CFTR, endogenously expressed in the respiratory epithelium, lead to decreased apical anion secretion, causing an imbalance in ion and fluid transport. The resulting reduction in anion transport promotes mucus accumulation in the lungs and associated microbial infections, which ultimately cause death in patients with MB. In addition to respiratory problems, patients with MB typically suffer from gastrointestinal problems and pancreatic failure, which, if left untreated, lead to death. Additionally, most men with cystic fibrosis are infertile, and women with cystic fibrosis have reduced fertility.

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, more than 2000 mutations in the CF gene have been identified; the CFTR2 database currently contains information for only 322 of these identified mutations, with sufficient evidence to identify 281 mutations as disease-causing. The most common disease-causing mutation is a phenylalanine deletion 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 cystic fibrosis cases and is associated with severe disease.

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 move to the plasma membrane. As a result, the number of CFTR channels for anion transport present in the membrane is significantly less than that observed in cells expressing wild-type CFTR, i.e. CFTR without mutations. In addition to impaired migration, the mutation results in defects in ion channel gating. Together, the reduced number of channels in the membrane and the defective ion channel gating mechanism lead to decreased anion and fluid transport across the epithelium. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). The defective channels due to the F508del mutation are still functional, although 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 migration, synthesis, and/or gating of ion channels may be increased or decreased to alter anion secretion and alter 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 epithelial cells, where it regulates the flux of anions across the membrane as well as the activity of other ion channels and proteins. In epithelial cells, normal CFTR function is critical for maintaining electrolyte transport throughout the body, including respiratory and digestive tissues. CFTR consists of approximately 1,480 amino acids that encode a protein that consists of tandem repeat 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 cell migration.

Chloride transport is accomplished through 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 cell surface. Secondary active transport of chloride from the inside leads to the accumulation of intracellular chloride, which can then passively leave the cell through Cl channels, resulting in vectorial transport. The arrangement of the Na ⁺ /2Cl ^- K ⁺ cotransporter, Na ⁺ -K ⁺ ATPase pump and basolateral surface K ⁺ channels on the basolateral surface and CFTR on the inner side coordinates chloride secretion through CFTR on the inner side. Because water is probably never actively transported on its own, its flow across the epithelium depends on tiny transepithelial osmotic gradients generated by the bulk flow of sodium and chloride.

Accordingly, there is a need for new methods of treating CFTR-mediated diseases.

New compounds are disclosed herein, including compounds of formulas (I), (II-A), (II-B),

- 1 044967 (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) may be described as:

a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein ring A is 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 represents O, NH or N(C ₁ -C ₄ -alkyl);

each R ¹ is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and independently substituted with one or more groups selected from halogens, C1- _C2 alkyl groups, haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups; where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3_5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected 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 bivalent linker of formula (L) _r , where r is 1, 2, 3, 4, 5 or 6;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C ₁ -C ₂ haloalkyl groups, C1 -C2 alkyl groups, hydroxyl group, C ₁ -C ₂ alkoxy groups and C ₁ -C ₂ haloalkoxy groups; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

In some embodiments, ring D in formula (I) is pyridin-2(III)one, pyrrolidin-2-one, or imidazolidin-2-one.

Also disclosed herein are pharmaceutical compositions containing at least one of the novel compounds described 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 CFTR-mediated cystic fibrosis, comprising administering

- 2 044967 at least one of the new compounds described herein, and/or at least one pharmaceutically acceptable salt thereof, optionally as part of a pharmaceutical composition containing at least one additional component, in a subject in need thereof.

Also disclosed are methods of treating CFTR-mediated cystic fibrosis, comprising administering at least one of the novel compounds described herein and/or at least one pharmaceutically acceptable salt thereof, (R)-1-(2,2-difluorobenzo[d ][1,3]dioxol-5-yl)-N-(1-(2,3dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5yl) cyclopropanecarboxamide (compound II) and N-[2,4-bis(1,1-dimemulemul)-5-hydroxyphenyl]-1,4dihydro-4-oxoquinoline-3-carboxamide (compound III), optionally as part of at least one a pharmaceutical composition containing at least one additional component in a patient in need thereof.

Brief description of graphic materials

Fig. 1 shows the structures of non-limiting examples of new compounds disclosed herein.

Fig. 2 is a representative list of CFTR mutations.

Definitions

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, 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 from 3 to 12 carbon atoms in the ring (eg, for example, from 3 to 10 carbon atoms). Cycloalkyl groups include monocyclic, bicyclic, tricyclic, polycyclic, bridged, fused and spirocyclic rings, including monospiro and dispiro rings. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, spiro[2.2]pentane and dispiro[2.0.2.1]heptane. Cycloalkyl groups may be substituted or unsubstituted.

As used herein, the term alkoxy group refers to an alkyl or cycloalkyl group covalently bonded to an oxygen atom. Alkoxy groups may be substituted or unsubstituted, branched or unbranched.

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

As used herein, the term heteroaryl ring refers to an aromatic ring containing 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 having 3 to 12 ring atoms (e.g., 3 to 10 atoms) containing at least one ring atom that is a heteroatom, such as O, N, or S. Heterocyclyl rings include monocyclic, bicyclic, tricyclic, polycyclic, bridged, fused and spiro rings, including monospiro and dispiro rings.

Examples of nitrogen protecting groups include, for example, tert-butylcarbamate (Boc), benzyl (Bn), para-methoxybenzyl (PMB), tetrahydropyranyl (THP), 9-fluorenylmethylcarbamate (Fmoc), benzylcarbamate (Cbz), methylcarbamate, ethylcarbamate, 2 ,2,2-trichloroethylcarbamate (Troc), 2trimethylsilylethylcarbamate (Teos), allylcarbamate (Aloc or Alloc), formamide, acetamide, benzamide, allylamine, trifluoroacetamide, triphenylmethylamine, benzylideneamine and p-toluenesulfonamide. A complete 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, preceded by the term optionally or not, indicates that at least one hydrogen in 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 can be substituted by more than one substituent selected from the specified group, the substituent may be the same or different at each position .

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

As used herein, the term CFTR refers to the cystic fibrosis transmembrane conductance regulator.

As used herein, the term mutations may refer to mutations in the CFTR gene or CFTR protein. A CFTR gene mutation refers to a mutation in the CFTR gene, and a CFTR protein mutation refers to a mutation in the CFTR protein. Genetic defect or mutation, or change in nucleotides in a gene in

- 3 044967 generally leads to a mutation in the CFTR protein translated from this gene, or to a frameshift.

The term F508del refers to a mutant CFTR protein that lacks the amino acid phenylalanine at position 508.

In this context, a patient who is homozygous for a mutation in a particular gene has the same mutation for each allele.

In this context, a patient who is heterozygous for a mutation in a particular gene has that mutation on one allele and another mutation on another 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 CFTR activity. Increased activity resulting from a CFTR modulator includes, but is not limited to, compounds that correct, potentiate, stabilize and/or enhance 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 formulas (I), (II-A), (II-B), (Ш-А), (Ш-В), (IV-A), (IV-B), (IV-C), (V-A ), (V-B), (VI-A), (VIB), (VI-C) and (VI-D), compound II, compound IV and their pharmaceutically acceptable salts disclosed herein are CFTR correctors.

As used herein, the term CFTR enhancer refers to a compound that increases the activity of a CFTR protein channel located on the cell surface, resulting in increased ion transport. Compound III disclosed herein is a CFTR enhancer.

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, where the salt is non-toxic. Pharmaceutically acceptable salts of the compounds of this disclosure include salts 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 that does not have long-range order in the position of its molecules. Amorphous solids are typically supercooled liquids in which the molecules are arranged randomly so that there is no well-defined arrangement, such as molecular packing, and there is no long-range order. Amorphous solids are usually isotropic, that is, they exhibit the same properties in all directions and do not have specific melting points. For example, an amorphous material is a solid material that does not have characteristic sharp crystalline peaks in an X-ray powder diffraction (XRPD) pattern (ie, is not crystalline as defined by XRPD). Instead, one or more broad peaks (such as halos) appear in its XRPD diagram. Broad peaks are characteristic of an amorphous solid. See US 2004/0006237 for a comparison of XRPD of amorphous material and crystalline material.

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 a crystallinity of less than 15% (e.g., crystallinity of less than 10% or crystallinity of less than 5%). It should also be 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 dispersed system in which one substance, the dispersed phase, is distributed in discrete units throughout a second substance (the continuous phase or carrier). The size of the dispersed phase can vary significantly (for example, colloidal particles ranging in size from a nanometer to several microns). Typically, dispersed phases can be solids, liquids or gases. In the case of a solid dispersion, both the dispersed and continuous phases are solid. In pharmaceutical applications, the solid dispersion may comprise 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, the solid dispersion includes a polymer constituting the dispersed phase and the drug constituting the continuous phase. Or, the 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 a human.

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 (eg, reducing MB or symptom of MB or reducing severity of MB or symptom

- 4 044967

MB). The exact amount of the effective dose will depend on the purpose of treatment and will be determined by one skilled in the art using known techniques (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

As used herein, the terms treatment, treat, etc. usually means relief of MB or its symptoms or reduction in the severity of MB or its symptoms in the subject. Treatment as used herein includes, but is not limited to, the following: increasing the subject's height, increasing weight, decreasing mucus in the lungs, improving pancreatic and/or liver function, decreasing chest infections, and/or decreasing cough or shortness of breath. Improvement or reduction in the severity of any of these symptoms can be easily assessed by standard methods and techniques known in the art.

As used herein, in combination with, when applied 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 a patient before, concurrently with, or after each other.

The terms about, about, and approximately, when used in connection with doses, amounts, or weight percentages of the ingredients of a composition or dosage form, include the meaning of said dose, amount, or weight percent, or the range of dose, amount, or weight percent that is recognized by one skilled in the art. areas, provide a pharmacological effect equivalent to that obtained from the indicated dose, amount or weight percentage.

One of ordinary skill in the art will understand that when the amount of a compound or a pharmaceutically acceptable salt thereof is disclosed, the amount of the pharmaceutically acceptable salt form of the compound is an amount equivalent to the concentration of the free base of the compound. It should be noted that the amounts of compounds or pharmaceutically acceptable salts thereof disclosed herein are based on their free base form. For example, 10 mg of at least one compound selected from the compounds of formula (I) and its pharmaceutically acceptable salts includes 10 mg of the compound of formula (I) and a concentration of a pharmaceutically acceptable salt of the compounds of formula (I) equivalent to 10 mg of the compound of formula (I).

Suitable pharmaceutically acceptable salts are, for example, those disclosed in SM Berge, et al. J. Pharmaceutical Sciences, 1977, 66, 1-19. For example, in table. 1 of this article the following pharmaceutically acceptable salts are presented:

Table 1

Acetate Hydrobromide Stearate Benzenesulfonate Hydrochloride Subacetate Benzoate Hydroxynaphthoate Succinate Bicarbonate Iodide Sulfate Bitartrate Isethionate Tannat Bromide Lactate Tartrate Calcium edetate Lactobionate Theocyate Kamzilat Malate Triethiodide Carbonate Maleate Benzathine Chloride Mandelat Chloroprocaine Citrate Mesilate Kholin Dihydrochloride Methyl bromide Diethanolamine Edetat Methyl nitrate Ethylenediamine Edisilate Methyl sulfate Meglumine Estolate Mukat Procaine Ezilat Napsylate Aluminum Fumarate Nitrate Calcium G luceptate Pamoate (Embonate) Lithium Gluconate Pantothenate Magnesium Glutamate Phosphate/diphosphate Potassium

- 5 044967

Glycollylarsanilate

Polygalacturonate

Sodium

Hexylresorcinate

Salicylate

Zinc

Hydrabamine

Non-limiting examples of pharmaceutically acceptable salts derived from corresponding 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; as well as salts formed 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, dodecyl sulfate, ethanesulfonate, formate, fumarate, gluco heptonate, glycerophosphate, gluconate, semisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, 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 ⁺ (C1.4 alkyl) ₄ salts. This disclosure also provides for 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. Other 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 arylsulfonate. Other suitable non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

The exact amount of the 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 route of administration, and the like. The compositions of this invention may be formulated in unit dosage form for ease of administration and uniformity of dosage. The expression unit dosage form as used herein refers to a physically discrete unit of agent suitable for the patient being treated. However, it should be understood that the general daily use of the compounds and compositions of this disclosure will be determined by the attending physician in the exercise of sound medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors, including the disorder being treated and the severity of the disease; the activity of the specific API being used; the specific composition used; the age, body weight, general health, gender and diet of the patient; time of administration, route of administration and rate of excretion of the particular compound used; duration of treatment; drugs used in combination or coincident with the specific compound used, and similar factors well known in medicine. The term patient as used herein means an animal such as a mammal, and even more so such as a human.

In some embodiments of the invention, the disclosure is also directed to methods of treatment using isotopically labeled compounds of the above compounds that have the same structures as those disclosed herein, except that one or more atoms therein have been replaced by an atom or atoms having an atomic a mass or mass number that differs from the atomic mass or mass number of an atom that is commonly found in nature (isotopic label). Examples of isotopes that are commercially available and suitable for this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example ^{, 2H} , ^3H , 13C, ^14C , ^15N , ^18O , ¹⁷ 0, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl, respectively.

Isotopically labeled compounds and salts can be used in a variety of useful ways. They may be suitable for drugs and/or various types of assays, such as substrate tissue distribution assays. For example, compounds labeled with tritium ( ^3H ) and/or carbon-14 ( ^14C ) are particularly useful for various types of assays, such as substrate tissue distribution assays, due to their relatively simple preparation and excellent detectability. For example, compounds labeled with deuterium ( ^2H ) are therapeutically useful with potential therapeutic advantages over compounds not labeled with ^2H . In general, compounds and salts labeled with deuterium ( ^2H ) may have higher metabolic stability compared to with those that are not isotope labeled, due to the kinetic isotope effect described below. Higher metabolic stability directly translates into increased in vivo half-life or lower dosages, which may be desirable. Isotope-labeled compounds and salts can generally be prepared by following the procedures disclosed in the synthesis schemes and accompanying description, in the Example and in the preparation portions of this text, by replacing the non-isotopically labeled reagent with a readily available isotopically labeled reagent.

In some embodiments, the isotope-labeled compounds and salts are deuterium-labeled ( ^2H ). In some specific embodiments, the isotopically labeled compounds and salts are labeled with deuterium ( ^2H ) wherein one or more of the hydrogen atoms therein are replaced with deuterium. In chemical structures, deuterium is represented as ^2H or D.

Compounds and salts labeled with deuterium ( ^2H ) can influence the oxidative metabolism of the compound through a primary kinetic isotope effect. The primary kinetic isotope effect is a change in the rate of a chemical reaction that results from the exchange of isotopic nuclei, which in turn is caused by a change in the ground state energy required to form a covalent bond after this isotope exchange. Exchange of a heavier isotope usually results in a decrease in the ground state energy of the chemical bond and thus causes a decrease in rate-limiting bond breaking. If bond cleavage occurs at or near the saddle point region along the multiproduct reaction coordinate, the product distribution ratios can be significantly altered. To explain: if deuterium is bonded to a carbon atom in a non-substituted position, the typical rate differences are k _M /k _D =2-7. For further discussion, see S. L. Harbeson and R. D. Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417; and TG 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 isotopes (eg, deuterium) included in the isotopically labeled compounds and salt herein can be determined using 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 particular isotope. In some embodiments, if a substituent in a compound of the disclosure is designated deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium inclusion in each designated deuterium atom), at least 4000 (60% deuterium inclusion %), not less than 4500 (deuterium inclusion 67.5%), not less than 5000 (deuterium inclusion 75%), not less than 5500 (deuterium inclusion 82.5%), not less than 6000 (deuterium inclusion 90%), not less than 6333 .3 (95% deuterium inclusion), not less than 6466.7 (97% deuterium inclusion), not less than 6600 (99% deuterium inclusion) or not less than 6633.3 (99.5% deuterium inclusion).

In the discovery and development of therapeutic agents, one skilled in the art attempts to optimize pharmacokinetic parameters while maintaining the desired properties in vitro. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism.

One of ordinary skill in the art will appreciate that deuteration of one or more metabolically labile positions in a compound or active metabolite can result in enhancement of one or more of the superior properties of DMPK while maintaining biological activity compared to the corresponding hydrogen analogues. The superior property or properties of DMPK may influence exposure, half-life, clearance, metabolism, and/or even dietary requirements for optimal drug absorption. Deuteration may also alter 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 their pharmaceutically acceptable salts. Non-limiting examples of deuterated compounds are disclosed in FIG. 1.

Each compound described herein, including compounds of formulas (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, their pharmaceutically acceptable salts and deuterated derivatives of any of the above can be independently administered once daily, twice daily or thrice daily. In some embodiments, at least one compound selected from compounds of formulas (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), their pharmaceutically acceptable salts and deuterated derivatives of any of the above, administered once a day. In some embodiments, at least one compound selected from compounds of formulas (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 their pharmaceutically acceptable salts, and deuterated derivatives any of the above, administered twice daily. In some embodiments, at least one compound selected from Compound II and its pharmaceutically acceptable salts is administered once daily. In some embodiments, at least one compound selected from Compound II and its pharmaceutically acceptable salts is administered twice daily. In some embodiments, according to

- 7 044967 at least one compound selected from compound III and its pharmaceutically acceptable salts is administered once a day. In some embodiments, at least one compound selected from Compound III and its pharmaceutically acceptable salts is administered twice daily. In some embodiments, at least one compound selected from Compound IV and its pharmaceutically acceptable salts is administered once daily. In some embodiments, at least one compound selected from Compound IV and its pharmaceutically acceptable salts is administered twice daily. In some embodiments, a deuterated derivative of Compound II, III, and/or IV, or a pharmaceutically acceptable salt thereof, is used in any of these embodiments.

In some embodiments, from 10 mg to 1500 mg of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a deuterated derivative of such compound or salt is administered daily.

As stated above, compounds of formula (I) are disclosed herein:

a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein ring A is 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 represents O, NH or N(C ₁ -C ₄ -alkyl);

each R ¹ is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C 2 alkoxy groups, C 1 -C ₂ haloalkyl groups, C 1 -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and independently substituted with one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl group, C1- _C2 alkoxy groups and C1- _C2 haloalkoxy groups; where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C 1 -C ₂ alkyl groups, C 1 -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C 1 -C ₂ haloalkoxy groups ; and each R ^a is independently selected from hydrogen and C1- _C2 alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected 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 bivalent linker of formula (L) _r , where r is 1, 2, 3, 4, 5 or 6;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C1-C ₂ -haloalkyl groups, C1-C2 alkyl groups, hydroxyl group, C1-C ₂ -alkoxy groups and C1-C ₂ -haloalkoxy

- 8 044967 groups; and each R ^b is independently selected from hydrogen and C1-C2 alkyl groups.

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 above, wherein the carbon labeled * has S-stereochemistry or R-stereochemistry;

ring A is 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 selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

each R ⁴ is independently selected from halogens, hydroxyl group, oxo group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and is independently substituted with one or more groups selected from halogens, C1- _C2 alkyl groups, haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups, where k is 0.1 , 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected 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 bivalent linker of formula (L) _r , where r is 1, 2, 3, 4, 5 or 6;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C ₁ -C ₂ -alkyl groups, C1-C2 haloalkyl groups, hydroxyl group, C ₁ -C ₂ -alkoxy groups and C1-C2- 9 044967 haloalkoxy groups; and each R ^b is independently selected from hydrogen and C1-C2 alkyl groups.

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

(SH-A) or a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein the carbon labeled * has S-stereochemistry or R-stereochemistry;

ring A is 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 R1 is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C _{2 alkoxy groups, C 1 -C 2} haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which optionally independently substituted with one or more groups selected from halogens, C1- _C2 alkyl groups, haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups, where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C ₂ alkoxy groups and C ₁ - C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens;

q is equal to 1 or 2;

Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C ₁ -C ₂ -alkyl groups, hydroxyl group, C ₁ -C ₂ -alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^b is independently selected from hydrogen and C1- _C2 alkyl groups.

- 10 044967

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 above, wherein the carbon labeled * 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 represents O, NH or N(C ₁ -C ₄ -alkyl);

each R ¹ is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and is independently substituted with one or more groups selected from halogens, C1- _C2 alkyl groups, haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups, where k is 0.1 , 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C 1 -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens;

q is equal to 1 or 2;

Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C ₁ -C ₂ -alkyl groups, hydroxyl group, C ₁ -C ₂ -alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^b is independently selected 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 above, wherein the carbon labeled * 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 selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and is independently substituted with one or more groups selected from halogens, C1- _C2 alkyl groups, haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups, where k is 0.1 , 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R5)(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups and halogens;

q is equal to 1 or 2;

r is 3 or 4;

each R ⁸ and R ⁹ is independently selected from hydrogen, halogens, C ₁ -C ₂ alkyl groups, hydroxyl group, C ₁ -C ₂ alkoxy groups and C ₁ -C ₂ haloalkoxy groups; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

In some embodiments, the compound of Formula I is a compound of Formula IV-C:

'(CR^ ⁹ )^ R ^b a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein the carbon labeled * has S-stereochemistry or R-stereochemistry;

each R ¹ is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and is independently substituted with one or more groups selected from halogens, C1- _C2 alkyl groups, haloalkyl groups,

- 12 044967 hydroxyl group, C1-C2 alkoxy groups and C1-C2 haloalkoxy groups, where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R5)(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y) _k -R ⁷ is not bonded to another heteroatom in -(Y) _k -R ⁷ where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo ;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens;

q is equal to 1 or 2;

r is 3 or 4;

each R ⁸ and R ⁹ is independently selected from hydrogen, halogens, C ₁ -C ₂ alkyl groups, hydroxyl group, C ₁ -C ₂ alkoxy groups and C ₁ -C ₂ haloalkoxy groups; and each R ^b is independently selected 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 above, wherein the carbon labeled * 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 selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C ₁ -C ₂ haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C 2 alkoxy groups, C 1 -C ₂ haloalkyl groups, C 1 -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and is independently substituted with one or more groups selected from halogens, _CrC2 -alkyl groups, haloalkyl groups, hydroxyl group, _CrC2 -alkoxy groups and _C1 -C2 _- haloalkoxy groups, where k is 0, 1, 2, 3 , 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y) _k -R ⁷ , wherein each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, Q-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from _{C 2} alkyl groups, C 1 -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C 1 -C ₂ haloalkoxy groups ; and each R ^a is independently selected from hydrogen and C _g C ₂ -alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from _{C 2} -alkyl groups, C 1 -C 2 haloalkyl groups and halogens;

q is equal to 1 or 2;

- 13 044967

Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C ₁ -C ₂ alkyl groups, hydroxyl group, C ₁ -C ₂ alkoxy groups and C ₁ -C ₂ haloalkoxy groups; and each R ^b is independently selected 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 above, wherein the carbon labeled * 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 selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and is independently substituted with one or more groups selected from halogens, C1- _C2 alkyl groups, haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups, where k is 0.1 , 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens;

q is equal to 1 or 2;

r is 3, 4 or 5; and each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C ₁ -C ₂ alkyl groups, hydroxyl group, C ₁ -C ₂ alkoxy groups and C ₁ -C ₂ haloalkoxy groups.

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

- 14 044967 (VI-A) or

R ³ ^/ with its pharmaceutically acceptable salt or deuterated derivative of any of the above, where the carbon labeled * 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 selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C ₂ haloalkyl groups, C 1 -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C1- _C2 alkyl groups, C1- _C2 alkoxy groups, C1-C2 haloalkyl groups, C1- _C2 haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and is independently substituted with one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl group, C1- _C2 alkoxy groups and C1- _C2 haloalkoxy groups, where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3.5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a _C3-5 cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C 1 -C ₂ alkyl groups, C 1 -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C ₂ alkoxy groups and C 1 -C ₂ - haloalkoxy groups; and each R ^a is independently selected from hydrogen and C1- _C2 alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C 1 -C ₂ alkyl groups, C 1 -C ₂ haloalkyl groups and halogens;

q is equal to 1 or 2;

Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C1-C ₂ alkyl groups, hydroxyl group, C1-C ₂ alkoxy groups and C1-C ₂ haloalkoxy groups; and each R ^b is independently selected from hydrogen and C1- _C2 alkyl groups.

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

- 15 044967 (cr*r9>;

(cr ^s r ⁹ );

a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein the carbon labeled * 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 represents O, NH or N(C ₁ -C ₄ -alkyl);

each R ¹ is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C 2 alkoxy groups, C 1 -C ₂ haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y) _k -R ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optionally and independently substituted with one or more groups selected from halogens, C ₁ -C ₂ -alkyl groups, haloalkyl groups, hydroxyl group, C 1 -C 2 -alkoxy groups and C ₁ -C ₂ -haloalkoxy groups, where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens;

q is equal to 1 or 2;

r is 3 or 4; and each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C ₁ -C ₂ -alkyl groups, hydroxyl group, C ₁ -C ₂ -alkoxy groups and C ₁ -C ₂ -haloalkoxy groups.

Also disclosed herein are compounds having a formula selected from any of the formulas depicted in FIG. 1 and their pharmaceutically acceptable salts.

In some embodiments, at least one compound selected from the novel compounds described herein, pharmaceutically acceptable salts thereof, and deuterated derivatives thereof is administered in combination with at least one compound selected from Compound II, pharmaceutically acceptable salts thereof, and deuterated derivatives thereof. derivatives of the above. In some embodiments, at least one compound selected from the novel compounds described herein, pharmaceutically acceptable salts thereof, and deuterated

- 16 044967 derivatives of the above, are administered in combination with at least one compound selected from compound III and its pharmaceutically acceptable salts. In some embodiments, at least one compound selected 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 selected from Compound IV and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound selected from the novel compounds described herein, pharmaceutically acceptable salts thereof, and deuterated derivatives thereof, is administered in combination with Compounds II or a pharmaceutically acceptable salt or deuterated derivative thereof, and at least one compound selected from compound III, its pharmaceutically acceptable salts and deuterated derivatives of any of the above. In some embodiments, at least one compound selected from the novel compounds disclosed herein, pharmaceutically acceptable salts, and deuterated derivatives of any of the foregoing is administered in combination with at least one compound selected from Compound III, its pharmaceutically acceptable salts and deuterated derivatives of any of the above and at least one compound selected from compound IV, pharmaceutically acceptable salts thereof and deuterated derivatives of any of the above.

In some embodiments, at least one new compound (and/or at least one pharmaceutically acceptable salt thereof and/or at least one deuterated derivative of such compound or salt) may be administered in combination with at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is selected from the following.

(a) compounds II:

and its pharmaceutically acceptable salts.

The chemical name of 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;

Compound III:

and its pharmaceutically acceptable salts.

The chemical name of compound III is X-(5-hydroxy-2,4-di-tert-butylphenyl)-4oxo-1H-quinoline-3-carboxamide; and Compound IV:

and its pharmaceutically acceptable salts.

The chemical name of compound IV is 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5yl)cyclopropan-1-carboxamido)-3-methylpyridin-2-yl)benzoic acid. In some embodiments, a compound of formula (I) and/or a pharmaceutically acceptable salt thereof may be administered in combination with a compound II and/or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of formula (I) and/or a pharmaceutically acceptable salt thereof may 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 may be administered in combination with a compound IV and/or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of formula (I) and/or a pharmaceutically acceptable salt thereof may be administered in combination with compound 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 may be administered in combination with compound II and/or its

- 17 044967 pharmaceutically acceptable salt and compound IV and/or a pharmaceutically acceptable salt thereof.

In one aspect, the disclosure provides 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 provides a pharmaceutical composition comprising a compound of formula (I) and/or a pharmaceutically acceptable salt thereof, a compound II and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In one aspect, the disclosure provides a pharmaceutical composition comprising a compound of formula (I) and/or a pharmaceutically acceptable salt thereof, a compound III and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In one aspect, the disclosure provides a pharmaceutical composition comprising a compound of formula (I) and/or a pharmaceutically acceptable salt thereof, compound II and/or a pharmaceutically acceptable salt thereof, compound III and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Any of the new compounds described herein, such as, for example, the compounds of formula (I) and their pharmaceutically acceptable salts, as well as deuterated derivatives of such compounds and salts, can be included in a single pharmaceutical composition or separate pharmaceutical compositions in combination with other additional active pharmaceutical ingredients (eg, compound II, III or IV or a pharmaceutically acceptable salt thereof or a deuterated derivative of such a compound or salt). Such pharmaceutical compositions can be administered once a day or several times a day, for example, twice a day. In some embodiments, the disclosure relates to a pharmaceutical composition comprising at least one compound selected from any of the compounds disclosed herein and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.

In some embodiments, the present invention discloses a pharmaceutical composition comprising at least one compound selected from the novel compounds disclosed herein and pharmaceutically acceptable salts thereof, at least one compound selected from Compound II and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.

In some embodiments, the disclosure relates to a pharmaceutical composition comprising at least one compound selected from novel compounds disclosed herein and pharmaceutically acceptable salts thereof, at least one compound selected from Compound III and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.

In some embodiments, the disclosure relates to a pharmaceutical composition comprising at least one compound selected from the novel compounds described herein and pharmaceutically acceptable salts thereof, at least one compound selected from Compound II and pharmaceutically acceptable salts thereof, at least one compound selected from compound III and its pharmaceutically acceptable salts and at least one pharmaceutically acceptable carrier.

In some embodiments, the disclosure relates to a pharmaceutical composition comprising at least one compound selected from the novel compounds disclosed herein and pharmaceutically acceptable salts thereof, at least one compound selected from Compound III and pharmaceutically acceptable salts thereof, at least one compound selected from Compound IV and its pharmaceutically acceptable salts and at least one pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical compositions disclosed herein contain at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR modulator. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR corrector. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR enhancer. In some embodiments, the pharmaceutical composition contains (i) a compound of formulas (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 pharmaceutically acceptable salts 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 enhancer.

In some embodiments, the at least one additional active pharmaceutical ingredient is selected from mucolytics, bronchodilators, antibiotics, anti-infectives, and anti-inflammatory agents.

The pharmaceutical composition may further comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from pharmaceutically acceptable carriers and pharmaceutically acceptable adjuvants. In some embodiments, the at least one pharmaceutically acceptable product is selected from pharmaceutically acceptable excipients, disintegrants, surfactants, binders, lubricants.

It will also be understood that the pharmaceutical composition of the present disclosure, including a pharmaceutical composition containing the combinations described previously, can be used in combination therapy; that is, the compositions can be administered simultaneously, before or after at least one additional active pharmaceutical ingredient or medical procedure.

Pharmaceutical compositions containing these combinations are useful for the treatment of cystic fibrosis.

As described above, the pharmaceutical compositions described herein may optionally further contain at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be selected from adjuvants and carriers. The at least one pharmaceutically acceptable carrier used in this disclosure includes any and all solvents, diluents, other liquid carriers, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifying agents, preservatives, solid binders and lubricants depending on the specific 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 vehicles used in the formulation of pharmaceutical compositions and known methods for their preparation. Except that any standard carrier may be incompatible with the substance or its derivatives, for example, causing any undesirable biological effect or otherwise interacting in a harmful manner with any other component(s) of the pharmaceutical composition, its use is also contemplated by the present invention. Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum albumin), buffers (such as phosphates, glycine, sorbic acid and potassium sorbate), mixtures partial glycerides 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 silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, 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 carboxymethylcellulose, ethylcellulose and cellulose acetate), tragacanth powder, 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), complex ethers (such as ethyl oleate and ethyl laurate), agar, buffering agents (such as magnesium hydroxide and aluminum hydroxide), 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), colors, release agents, coating agents, sweeteners, flavors, fragrances, preservatives and antioxidants.

In some embodiments, the methods of the disclosure involve administering to a patient in need thereof at least one compound selected from any of the compounds of Formula I and pharmaceutically acceptable salts thereof, and at least one compound selected from Compound II, Compound III, compound IV and pharmaceutically acceptable salts of any of the above.

Any suitable pharmaceutical compositions known in the art can be used for the new compounds described herein, Compound II, Compound III, Compound IV, and pharmaceutically acceptable salts thereof. Some examples of pharmaceutical compositions of 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 in their entirety. Some examples of pharmaceutical compositions of 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 in their entirety by links. Examples of compositions containing compound III-d and its pharmaceutically acceptable salts can be found, for example, in WO 2014/078842 and WO 2018/227049, incorporated herein by reference. Some examples of pharmaceutical compositions of 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 their entirety.

In some embodiments, a pharmaceutical composition comprising at least one compound selected 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 containing Compound II and Compound III are disclosed in PCT Publication No. WO 2015/160787, incorporated herein by reference. An illustrative example of an embodiment is illustrated in Table. 2 further.

table 2

Exemplary tablets containing 100 mg of compound II and 150 mg of compound III

Ingredient Amount per tablet (mg) Internal game Compound II SDD (spray-dried dispersion) (80 wt% Compound II, 20 wt% HPMC) 125 Compound III SDD (80 wt% Compound III, 19.5 wt% HPMCAS-HG; 0.5 wt% sodium lauryl sulfate) 187.5 Microcrystalline cellulose 131.4 Croscarmellose sodium 29.6 Total 473.5 Extragranular Microcrystalline cellulose 112.5 Magnesium stearate 5.9 Total 118.4 Total, tablet without coatings 591.9 Film coating Opadray 17.7 Total coated tablets 609.6

In some embodiments, a pharmaceutical composition comprising at least one compound selected from the novel compounds disclosed herein and pharmaceutical salts thereof is administered with a pharmaceutical composition containing Compound III. Pharmaceutical compositions containing compound III are disclosed in PCT Publication No. WO 2010/019239, incorporated herein by reference. An illustrative example of an embodiment is illustrated in Table. 3 further:

- 20 044967

Table 3

Ingredients for Compound III Tablet Examples

Composition of the tablet Dose percentage % w/w Dose (mg) Batch number (G) Compound III SDD (80 wt% Compound III, 19.5 wt% HPMCAS-HG; 0.5 wt% sodium lauryl sulfate) 34.09% 187.5 23.86 Microcrystalline cellulose 30.51% 167.8 21.36 Lactose 30.40% 167.2 21.28 Croscarmellose sodium 3.000% 16.50 2.100 linen 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

Additional pharmaceutical compositions containing Compound III are disclosed in PCT Publication No. WO 2013/130669, incorporated herein by reference. Typical mini-tablets (~2 mm diameter, ~2 mm thickness, each mini-tablet weighing about 6.9 mg) were formulated to contain approximately 50 mg of Compound III per 26 mini-tablets and approximately 75 mg of Compound III per 39 mini-tablets using the quantities of ingredients indicated in the table. 4 below.

Table 4

Ingredients for 50 and 75 mg mini tablets

Composition of the tablet Dose percentage % w/w Dose (mg) contents of the current substances 50 Dose (mg) content of active substance 75 Batch number (G) mg mg Compound III SDD (80% wt., compound III, 19.5% wt. HPMCAS-HG; 0.5% by weight, sodium lauryl sulfate) 35 62.5 93.8 1753.4 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 dioxide silicon 1.0 1.8 2.7 50.0 Magnesium stearate 1.5 2.7 4.0 74.19 Total 100 178.6 268 5003.15

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

The compounds, their pharmaceutically acceptable salts and deuterated analogues of any of the above and the pharmaceutical compositions of the present disclosure, either in monotherapy or in combination therapy, are useful for the treatment of cystic fibrosis.

- 21 044967

In some embodiments, disclosed herein are methods of treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a deuterated analogue of any of the foregoing; or a pharmaceutical composition described herein, to a patient, such as a human, wherein said patient has cystic fibrosis. In some embodiments, the patient has the F508del/minimal function (MF) genotype, the F508del/F508del genotype (homozygous for the F508del mutation), the F508del/modulation genotype, or the F508del/residual function (RF) genotype. In some embodiments, the patient is heterozygous and contains a single F508del mutation.

In this context, minimal function (MF) mutations refer to mutations in the CFTR gene associated with minimal CFTR function (virtually non-functional CFTR protein) and include, for example, mutations associated with severe defects in the ability of the CFTR channel to open and close, known as defective modulation channel or mutation modulation; mutations associated with severe defects in cellular processing of CFTR and its delivery to the cell surface; mutations associated with the absence (or minimal) synthesis of CFTR; and mutations associated with severe channel conduction defects. Table C below includes a non-exclusive list of CFTR minimal function mutations that can be detected using an FDA-approved genotyping assay. In some embodiments, a mutation is considered an MF mutation if it meets at least 1 of the following 2 criteria:

biological certainty of absence of translated protein (genetic sequence predicts complete absence of CFTR protein), or in vitro testing that confirms lack of response to Compound II, Compound III, or a 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, minimal functional mutations are those that cause the CFTR protein to be substantially nonfunctional and unresponsive in vitro to Compound II, Compound III, or a combination of Compound II and Compound III.

In some embodiments, minimal functional mutations are those that do not respond in vitro to Compound II, Compound III, or a combination of Compound II and Compound III. In some embodiments, minimal functional mutations are mutations based on in vitro testing that meet the following criteria in in vitro experiments:

a baseline chloride transport that was <10% of wild-type CFTR, and an increase in chloride transport of <10% over baseline following the addition of Compound II, Compound III, or Compound II/Compound III to the assay.

In some embodiments, patients with at least one minimal functional mutation demonstrate evidence of clinical severity, defined as:

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

Patients with the F508del/minimal function genotype are defined as patients who are heterozygous for F508del-CFTR with a second CFTR allele containing a minimal function mutation. In some embodiments, patients with the F508del/minimal function genotype are patients who are heterozygous for F508del-CFTR with a second CFTR allele containing a mutation that results in the production of a CFTR protein with minimal CFTR function (little to no functional CFTR protein) and which does not respond in vitro on compound II, compound III or a combination of compound II and compound III.

In some embodiments, minimal functional mutations can be determined using 3 main sources:

biological likelihood of response to the mutation (eg, class of mutation), population-based evidence of clinical severity (according to the CFTR2 patient registry; accessed February 15, 2016), mean sweat chloride >86 mmol/L, and prevalence of pancreatic insufficiency ( PI) >50%, in vitro testing, mutations resulting in initial chloride transport <10% wild-type CFTR were considered minimal function, mutations resulting in chloride transport <10% wild-type CFTR after addition of Compound II and/or Compound III, were considered insensitive.

As used herein, the term residual function mutation refers to class II-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 a decrease in the amount or function of the protein on the cell surface, which can cause partial activation

- 22 044967 CFTR.

Non-limiting examples of CFTR gene mutations known to result in a residual function phenotype include the CFTR residual function mutation selected from 2789'5G >A, 3849+10kbC>T, 3272-26A >G, 7IG3A >G, E56K, P67L, R74W, D110E, D1110H, R117C, L206W, R347H, R352Q, A455E, D579G, E831X, S945L, S977F, F1052V, R1070W, F1074L, D1152H, D1270N, E193K and K1060T. For example, CFTR mutations that cause defective splicing of mRNAs such as 2789+507 result in decreased protein synthesis but deliver some functional CFTR to the cell surface to provide residual function. Other CFTR mutations that reduce conductance and/or disrupt gating, such as R117H, result in normal numbers of CFTR channels on the cell surface, 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 K10 60T. 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.

Residual CFTR function can be characterized at the cellular (in vitro) level using cell-based assays such as the FRT assay (Van Goor, F. et al. (2009) PNAS Vol. 106, No. 44, 1882518830; and Van Goor , F. et al (2011) PNAS Vol. 108, No. 46, 18843-18846) to measure the amount of chloride transport through mutated CFTR channels. Residual function mutations reduce, but do not completely eliminate, CFTR-dependent ion transport. In some embodiments, the residual function mutations result in a reduction in CFTR activity of at least about 10% in the FRT assay. In some embodiments, residual function mutations result in approximately 90% reduction in CFTR activity in an FRT assay.

Patients with the F508de1/residual function genotype are defined as patients who are heterozygous for F508del-CFTR with a second CFTR allele that contains a mutation that results in a decrease in the amount or function of the cell surface protein, which may cause partial CFTR activity.

Patients with the F508de1/modulation mutation genotype are defined as patients who are heterozygous for F508del-CFTR with a second CFTR allele that contains a mutation associated with a modulation defect and have been clinically demonstrated to be susceptible to Compound III. Examples of such mutations include: G178R, S549N, S549R, G551D, G551S, G1244E, S1251N, S1255P, and G1349D.

In some embodiments, methods disclosed herein for treating, ameliorating, or symptomatically treating cystic fibrosis independently result in an increase in chloride transport above the patient's baseline chloride transport level.

In some embodiments, in the methods described herein for treating, ameliorating, or symptomatically treating cystic fibrosis, the patient is heterozygous for F508del and the other CFTR genetic mutation is any mutation that causes CF. 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 will respond 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 will respond to any combination of (i) of the novel compounds disclosed herein, such as a compound of formula (I) and (ii) compounds II and/or compounds III and/or compounds IV genotypes based on in vitro and/or clinical data.

In some embodiments, in the methods of treating, reducing the severity or symptomatic treatment of cystic fibrosis described herein, the patient has a CFTR genetic mutation selected from any of the mutations in table. A.

- 23 044967

Table A CF Mutations 1949del84 3121-2 A^G 3121-977_3499+248 del2515 078delT 2043 delG 1078delT 2055del9^A 11234V 2105- 2117dell3insAGAAA 3132delTG 1154insTC 2118dell4 1161delC 3141del9 1213delT 2143 del T 3171delC 1248+1A 2183AA->G+ 3195del6 1249-1G^A 2183AA^G 3199del6 124del23bp 2I83AA^G ^:1 1259insA 3272-26A->G 1288insTA 2183delAA->G# 3 500-2A^G 1341+1G->A 2183delAA^G 3600+2insT 1342-2A->C 2184delA 365-366insT 2184ms A 3659delC 1461ins4 2307insA 3667ins4 147 Idel A 3737delA 1497delGG 2347delG 3 791 del C 1507del 2556insAT 3 821 del T 1525-1G^A 2585delT 1525-2A^G 2594delGT 3849+1 OkbC^T 1548delG 2622+1G-+A 3849+10kbC->T 1577delTA 1609del CA 2622+1G-+A 3850-1G^A 1677delTA 3850-3T->G 1716G/A 2659delC 3850-1G-+A 1717-1G—>A 2711 del T 3876delA 1717-8G^A 271 del T 1782delA 272 Idel 11 3878delG 1811+1.6kbA->G 1811+1G->C 2732insA 3905InsT 2789+2insA 3905insT 1811+1.6kbA—>G 2789+5G^A 394delTT 1811+1G—>C 2790-IG^C 4005+1G-+A 4005+2T- >C 1812-1G->A 1898+1G- >A 279O-1G->C 2869insG 4005+1G^A 1812-lG^A 2896insAG 4005+1G-+A 1824delA 2942insT 401 Odel 4 2957delT 182delT 1119delA 4015delA 185+lG^T 296+1G^A 1898+1G->T 2991del32 4016insT 3007delG 4021dupT 1898+1G^A 3028delA 4040delA 1898+1 G^C 3040G^C 405+1G^A 1898+3 A->G 306insA 405+3A^C 1898+5G->T 306insA 1138insG 4O5+1G->A 3120G^A 406-1G^A 1924del7 3121-lG^A 4O6-1G->A

- 24 044967

4209TGTT->A

4209TGTT—>AA

4279insA_____________

4326delTC___________

4374+1 G^T

4374+1G-+T

4382delA

4428insGA

442delA

457TAT^G_______

541 del C_______________

574delA_____________

5T_________________

621+1G—»T_________

621+3A->G

663delT

663delT 1548delG

675del4_______________

711+1G->T 711+3A->G

711+1G—>T_________

711+3 A^G________

7H+5G^A_______

712-1G->T

7T

852del22______________

935delA_____________

991del5_______________

A1006E

A120T

A234D

A349V

A455E

A613T

A46D

A46Db____________

A559T_____________

A559Tb____________

A561E_____________

C276X___________

C524R

C524X

CFTRdel2,3__________

CFTRdele22-23_______

D110E

D110H G1061R D1152H G1069R D1270N G1244E G1249R D192G G126D D443Y G1349D D513G G149R D579G D614G G178R G194R D836Y G194V D924N G27R D979V G27X E1104X G314E E116K G330X E1371X G458V E193K G463V E193X E403D G480C E474K G542X G550X E56K G551D E585X G551S E588V G576A E60K G622D E822K G628R E822X G628R(G->A) G970D E831X G673X E92K G85E E92X G91R F1016S G970R F1052V G970R F1074L H1054D F1099L H1085P F191V H1085R F311del H1375P F311L H139R F508C H199R F508del H199Y F575Y

- 25 044967

H609R L346P Q414X E585X H939R L453S Q493X I1005R L467P Q525X L467Pb Q552X I1027T L558S Q685X I1234V L571S Q890X Q890X I1269N L732X L927P Q98R I1366N L967S Q98X I148T L997F I175V R1066CR1066H I3336K M1101K R1066M M1101R R1070Q I502T M152V R1070W I506S I506T M1TM1V R1102X M265R R1158X I507del R1162L I507del M470V I601F M952I R1162X I618T M952T R117C I807M N1303K R117G I980K P205S R117H IVS14b+5G->A P574H R117L K710X P5L R117P K710X P67L R1283M K710X P750L R1283S L102R P99L R170H L1065P QI 100P R258G L1077P L1077Pb Q1291H R31C L1254X Q1291R R31L L1324P Q1313X R334L L1335P Q1382X R334Q Q1411X L138ins R334W Q1412X L1480P R347H Q220X L15P R347L Q237E L165S Q237H Q452P R347P R352Q L206W Q290X R352W L218X Q359K/T360K L227R Q39X R516G L320V Q414

- 26 044967

R553Q S977F Y569C R553X T1036N Y569D R560K Y569Db R560S T1053I Y849X R560T T12461 Y913C R668C T338I Y913X R709X T604I R74W V1153E V1240G R751L V1293G R75Q R75X V201M R764X V232D V456A R792G V456F R792X V520F R851X V562I R933G V754M S1118F W1089X S1159F W1098C S1159P W1098R S1196X W1098X S1235R W1204X W1282R S1251N W1282X S1255P W361R S1255X S13F W401X W496X S341P W57G S434X S466X W57R S489X W57X S492F W846X S4X S549N Y1014C S549R Y1032C S549R(A->C) Y1092X S549R(T->G) Y109N S589N Y122X Y161D S737F Y161S S912L Y563D S912X S945L Y563N

In some embodiments, in the methods of treating, ameliorating, or symptomatic treatment of cystic fibrosis described herein, the patient has a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069 R , 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, 327226A->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, F 508C, 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, H 609R, H939R, I1005R, I1234V, I1269N, I1366N, I175V, I502T, I506S, I506T, I601F, I618T, I807M, I980K, L102R, L1324P, L1335P, L138ins, L1480P, L15P, L165S, L320V, L34 6P, L453S, L571S, L967S, M1101R, M152V, M1T, M1V, M265R, M952I, M952T, P574H, P5L, P750L, P99L, Q1100P, Q1291H, Q1291R, Q237E, Q237H, Q452P, Q98R, R1066C, R1066H, R117G,

- 27 044967

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 of mutations selected from: G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352 Q, 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, 327226A->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 of mutations selected from: 1949del84, 3141del9, 3195del6, 3199del6, 3905InsT, 4209TGTT->A, A1006E, A120T, A234D, A349V, A613T, C524R, D192G, D443 Y, 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, I136 6N, I175V, I502T, I506S, I506T , I601F, I618T, I807M, I980K, L102R, L1324P, L1335P, L138ins, L1480P, L15P, L165S, L320V, L346P, L453S, L571S, L967S, M1101R, M152V, M1T, M1V, M 265R, M952I, M952T, P574H, P5L , P750L, P99L, Q1100P, Q1291H, Q1291R, Q237E, Q237H, Q452P, Q98R, R1066C, R1066H, R117G, R117L, R117P, R1283M, R1283S, R170H, R258G, R31L, R3 34L, 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, V1 240G, V1293G , V201M, V232D, V456A, V456F, V562I, W1098C, W1098R, W1282R, W361R, W57G, W57R, Y1014C, Y1032C, Y109N, Y161D, Y161S, Y563D, Y563N, Y569C and Y91 3C.

In some embodiments, in the methods of treating, ameliorating, or symptomatic treatment of cystic fibrosis described herein, the patient possesses the 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 MB-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, AI507, 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, ameliorating, or symptomatic treatment of cystic fibrosis described herein, the patient possesses the 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, where the patient has the F508del genetic mutation on one allele and any MB-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, AI507, 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 of mutations selected from:

D443Y; G576A; R668C,

F508C; S1251N,

G576A; R668C,

- 28 044967

G970R; M470V,

R74W; D1270N,

R74W; V201M, and

R74W; V201M; D1270N.

In some embodiments, in the methods of treating, ameliorating, or symptomatic treatment of cystic fibrosis described herein, the patient has a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, and G1069 R . In some embodiments, the patient has a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, and S1251N. In some embodiments, the patient has a CFTR genetic mutation selected from E193K, F1052V, and G1069R. In some embodiments, the method results in an increase in chloride transport compared to the patient's baseline chloride transport level.

In some embodiments, in the methods of treating, reducing the severity or symptomatic treatment of cystic fibrosis described herein, the patient has 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 has 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 has 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 has a CFTR genetic mutation selected from 2789+5G>A and 3272-26A->G.

In some embodiments, in the methods of treating, reducing the severity or symptomatic treatment of cystic fibrosis described herein, the patient has a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069 R , 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, 327226A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+ 3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G/A, 1811+1G->C, 1898+5G->T, 3850-3T->G , IVS14b+5G->A, 1898+1G->T, 4005+2T->C and 621+3A->G, and human CFTR mutations selected from F508del, R117H and G551D.

In some embodiments, in the methods of treating, ameliorating, or symptomatic treatment of cystic fibrosis described herein, the patient has a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069 R , 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, 327226A->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 CFTR mutation selected from F508del, R117H and G551D; and CFTR mutations selected from F508del, R117H and G551D.

In some embodiments, the patient has a genetic CFTR mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, and G1069R, and a human CFTR mutation selected from F508del, R117 H and G551D. In some embodiments, the patient has a genetic CFTR 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 has a genetic CFTR mutation selected from E193K, F1052V, and G1069R, and a human CFTR mutation selected from F508del, R117H, and G551D.

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

In some embodiments, the patient has 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,

- 29 044967

3121-1G->A, 4374+lG->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G >A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G/A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C and 621+3A->G, and human CFTR mutation selected from F508del, R117H and G551D. In some embodiments, the patient has a CFTR genetic mutation selected from 1717-1G->A, 1811+l.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 has a genetic CFTR 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 and has a mutation causing MB on one allele and a mutation causing MB on the other allele. In some embodiments, the patient is heterozygous for F508del and the other CFTR genetic mutation is any mutation that causes MB, including, but not limited to, F508del on one CFTR allele and a CFTR mutation on a second CFTR allele that is associated with minimal CFTR function, residual function CFTR or a defect in CFTR channel modulation 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 in FIG. 2 and MV-causing mutation on another CFTR allele is selected from the CFTR mutations listed in Table. IN.

Table B

CFTR mutations

Q39X S912X 3659delC W57X W1089X 394delTT E60X Y1092X 2184insA R75X E1104X 3905insT E92X R1158X 2184delA Q98X R1162X 1078delT Y122X S1196X 1154insTC L218X W1204X 2183delAA^G Q220X S1255X 2143 del T S276X W1282X 1677delTA Q290X Q1313X 3876delA G330X 621+lG^T 2307insA W401X 711+1G—>T 4382delA Q414X 711+5G^A 4016insT S434X 712-lG^T 2347delG S466X 405+1G^A 3007delG S489X 405+3A^C 574delA Q493X 406-1G^A 2711 del T W496X 621+lG^T 3 791 del C Q525X 1248+1G^A CFTRdele22-23 G542X 1341+1G^A 457TAT—>G Q552X 1717-lG^A 2043 delG R553X 1811+1.6kbA—»G 2869insG E585X 1811+lG^C 3600+2insT G673X 1812-lG^A 3737delA R709X 1898+1G^A 4040delA K710X 2622+1G^A 541 del C L732X 3120+lG^A A46D R764X 3120G^A T338I

- 30 044967

R785X 3850-1G^A R347P R792X 4005+1G^A L927P E822X 4374+1 G^T G85E W846X 663delT S341P R851X 2183AA—>G L467P Q890X V520F A559T R560T R560S A561E Y569D L1065P R1066C R1066M L1077P H1085R M1101K N1303K 3 849+1 OkbC^T 3 272-26A^G 711+3 A^G E56K P67L R74W D110E D110H R117C L206W R347H R352Q A455E D579G E831X S945L S977F F1052V R1070W F1074L D1152H D1270N CFTRdel2,3 G178R S549N S549R G551D G551S G1244E S1251N S1255P G1349D I507del

- 31 044967

Table C

CFTR mutations

Criteria Mutation S4X S276X G542X R792X E1104X G27X Q290X G550X E822X R1158X Q39X G330X Q552X W846X R1162X Truncating mutations W57X W401X R553X Y849X S1196X % P1> 50% and/or E60X Q414X E585X R851X W1204X SwCl >86 mmol/l R75X S434X G673X Q890X L1254X No E92X S466X Q685X S912X S1255X full size Q98X S489X R709X Y913X W1282X squirrel Y122X Q493X K710X W1089X Q1313X E193X W496X L732X Y1092X E1371X L218X S524X R764X W1098X Q1382X Q220X Q525X R785X R1102X Q1411X 185+1G^ 711+5G 1717-8G^A 2622+1G^A 3121- T ^A IG^A 296+1G^ 712- 1717-lG^A 2790-IG^C 3500- A IG^T 2A^G Splice mutations 405+1G^ 1248+1G 1811+1G—>C 3600+2in A ^A 3040G^C sT % P1> 50% and/or 405+ZA^ 1249- 1811+1.6kb (G970R) 3850- SwCl >86 mmol/l no or little mature WITH IG^A A^G IG^A 406- 1341+1G 4005+1G mRNA IG^A ^A 1812-lG^A 3120G^A ^A 621+1G—► 1525- 1898+1G^ 3120+1G^A 4374+1G T 2A^G A —>T 711+1G—> 1525- 1898+1 G^C 3121-2 A^G T IG^A

Small (<3 182delT 1119delA 1782delA 2732insA 3876delA nucleotides) 306insA 1138insG 1824delA 2869insG 3878delG shift mutations 365- 1154insT 2043 delG 2896insAG 3905insT reading frames 366insT C with insert or 394delTT 1161delC 2143 del T 2942insT 4016insT deletion (ins/del) 2183AA^G 4021dup 442delA 1213delT 2957delT % P1> 50% and/or a T

- 32 044967

SwCl > 86 mmol/l 444delA 1259insA 2184delA 3007delG 4040delA distorted and/or truncated protein 457TAT^ G 1288insT A 2184ms A 3028delA 4279insA 54 Idel C 147 Idel A 2307insA 3171delC 4326delT C 574delA 1497delG G 2347delG 3659delC 663delT 1548delG 2585delT 3737delA 935delA 1609del C.A. 2594delGT 3 791 del C 1078delT 1677delT A 2711 del T 3 821 del T

Large (> 3 CFTRdele2,3 1461ins4 2991del32 nucleotides) CFTRdele22,23 1924del7 3667ins4 shift mutations reading frames 124del23bp 2055del9^A 2105- 401 Odel 4 with insertion or deletion (ins/del) 852del22 2117dell3insAGAA A 4209TGTT^AA % P1> 50% and/or SwCl'> 86 mmol/l distorted and/or truncated protein 991del5 272 Idel 11

Class Mutations P, A46D ^b V520F Y569D ^b N1303K III, IV, Not G85E A559T ^b L1065P responding on R347P R560T R1066C compound III L467P ^b R560S L1077P ^b separately or V I507del A561E M1101K combinations With

compound II or compound IV % P1> 50% and/or

SwCl> 86 mmol/l

AND

Does not react 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 registry who have pancreatic insufficiency; SwCl ^- : mean sweat chloride of F508del-CFTR heterozygous patients in the CFTR2 patient registry.

^a Also known as 2183delAA^G. ^b Unpublished data.

In some embodiments, the patient: has the F508del/MF(F/MF) genotypes (heterozygous for F508del and the MF mutation unresponsive to CFTR modulators such as Compound III); with the F508del/F508del (F/F) genotype (homozygous for F508del); and/or with F508del/modulation (F/G) genotypes (heterozygous for F508del and a modulation mutation known to be sensitive to CFTR modulators (e.g., sensitive to Compound III). In some embodiments, a patient with F508del/MF genotypes (F/MF) there is an MF mutation that is not expected to respond to Compound II, Compound III, and Compound II and Compound III. In some embodiments, a patient with F508del/MF genotypes (F /MF) has one of the MF mutations listed in Table C.

In some embodiments, the patient is heterozygous for F508del and the other CFTR genetic mutation is any mutation that causes MB, including truncation mutations, splicing mutations, small (<3 nucleotides) insertion or deletion frameshift mutations (ins/del); large (>3 nucleotides) frameshift mutations with insertion or deletion (ins/del); and class II, III, IV mutations not responding 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 splicing mutation. In some specific embodiments, the splicing mutation is a splicing 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 frameshift mutation (ins/del) is a small (<3 nucleotide) insertion or deletion frameshift mutation (ins/del) as listed in Table C .

In some embodiments, compounds of formulas (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 their pharmaceutically acceptable salts and their deuterated derivatives, the patient is heterozygous for F508del, and another genetic a CFTR mutation is any MB-causing mutation that is expected to respond to and/or responds, based on in vitro and/or clinical data, to any combination of (i) a novel compound selected from those disclosed herein (e.g., a compound of formulas (I), (II-A), (II-B), (III-A), (IIIB), (IV-A), (IV-B), (IV-C), (V-A), (V-B ), (VI-A), (VI-B), (VI-C) and (VI-D) and their pharmaceutically acceptable salts and deuterated derivatives), and (ii) compound II and/or compound III and/or compounds IV.

In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is any CF-causing mutation that is expected to be and/or is sensitive, based on in vitro and/or clinical data, to the triple combination of a new a compound selected from those disclosed herein (eg, a derivative) and Compound II and Compound III.

In some embodiments, the patient is heterozygous for F508del and the other CFTR genetic mutation is a large (>3 nucleotide) insertion or deletion (ins/del) frameshift mutation. In some specific embodiments, the large (>3 nucleotide) insertion or deletion frameshift mutation (ins/del) is a large (>3 nucleotide) insertion or deletion frameshift mutation (ins/del) as set forth in Table. WITH.

In some embodiments, the patient is heterozygous for F508del and the other CFTR genetic mutation is a class II, III, IV mutation that does not respond to Compound III alone or in combination with Compound II or Compound IV. In some specific embodiments, class II, III, IV mutations not responding to compound III alone or in combination with compound II or compound IV are class II, III, IV mutations not responding to compound III alone or in combination with compound II or compound IV, given in table. WITH.

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

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

In some embodiments, the patient is homozygous for F508del.

In some embodiments, the patient is heterozygous and has one MB-causing mutation on one CFTR allele, selected from the mutations listed in the table on

- 34 044967 fig. 2 and another MB-causing mutation on a different CFTR allele selected from the CFTR mutations listed in Table. WITH.

In some embodiments, a composition disclosed herein is useful for the treatment, amelioration, or symptomatic treatment of cystic fibrosis in patients who exhibit residual CFTR activity in the apical membrane of respiratory and non-respiratory epithelium. The presence of residual CFTR activity on the epithelial surface can be readily detected using methods known in the art, for example, standard electrophysiological, biochemical or histochemical methods. Such methods determine CFTR activity using in vivo or ex vivo electrophysiological methods, measurement of Cl ⁻ concentrations in sweat or saliva, or ex vivo biochemical or histochemical methods to monitor cell surface density. Using such methods, residual CFTR activity can be easily detected in patients who are heterozygous or homozygous for many different mutations, including patients heterozygous for the most common F508del mutation, as well as other mutations such as the G551D mutation or the R117H mutation. In some embodiments, the compositions disclosed herein are useful for the treatment, amelioration, or symptomatic treatment of cystic fibrosis in patients who exhibit little or no residual CFTR activity. In some embodiments, the compositions disclosed herein are useful for the treatment, amelioration, or symptomatic treatment of cystic fibrosis in patients who exhibit little or no residual CFTR activity in the apical membrane of the respiratory epithelium.

In some embodiments, the compositions disclosed herein are useful for treating or reducing the severity of cystic fibrosis in patients who have residual CFTR activity using pharmacological methods. Such methods increase the amount of CFTR present on the cell surface, thereby inducing previously absent CFTR activity in the patient or increasing the existing level of residual CFTR activity in the patient.

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

In some embodiments, the compositions disclosed herein are useful for treating, reducing the severity of, or symptomatically treating cystic fibrosis in patients with certain clinical phenotypes, e.g., a mild to moderate clinical phenotype that generally correlates with the amount of residual CFTR activity in the apical membrane of the epithelium. Such phenotypes include patients with pancreatic insufficiency.

In some embodiments, the compositions disclosed herein are useful for the treatment, amelioration, or symptomatic treatment of patients diagnosed with pancreatic insufficiency, idiopathic pancreatitis and congenital bilateral absence of the vas deferens, or mild lung disease in which the patient exhibits residual CFTR activity.

In some embodiments, this disclosure relates to a method of increasing or inducing the activity of an anion channel 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 the F508del mutation on one allele and a mutation on the other allele selected from Table 1. 5.

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Table 5 CFTR Mutations

Mutation Q2X L218X Q525X R792X E1104X S4X Q220X G542X E822X W1145X W19X Y275X G550X W882X R1158X G27X S276X 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 S524X R785X R1102X Q1411X 185+lG^T 711+5G^A 1717-8G^A 2622+1G^A 3121-lG^A 296+1G^A 712-1G—>T 1717-lG^A 2790-1 G^C 3500-2A^G 296+1 G^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+ZA^S 1341+lG^A I8II + I643G^T 3120G^A 4005+1G^A 406-1G^A 1525-2A^G 1812-lG^A 3120+1G^A 4374+1 G^T 621+lG^T 711+1G—>T 1525-1G^A 1898+1G^A 3121-2A^G 1898+1 G^C

182delT 1078delT 1677delTA 2711 del T 3737delA 306insA 1119delA 1782delA 2732insA 3 791 del C 306delTAGA 1138insG 1824delA 2869insG 3 821 del T 365-366insT 1154insTC 1833delT 2896insAG 3876delA 394delTT 1161delC 2043 delG 2942insT 3878delG 442delA 1213delT 2143 del T 2957delT 3905insT 444delA 1259insA 2183AA^G 3007delG 4016insT 457TAT^G 1288insTA 2184delA 3028delA 4021dupT

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Mutation 541 del C 1343delG 2184insA 3171delC 4022insT 574delA 147 Idel A 2307insA 3171insC 4040delA 663delT 1497delGG 2347delG 3271 del GG 4279insA 849delG 1548delG 2585delT 3349insT 4326delTC 935delA 1609del CA 2594delGT 3659delC CFTRdelel CFTRdelel 6-17b 1461ins4 CFTRdele2 CFTRdelel 7a, 17b 1924del7 CFTRdele2,3 CFTRdelel 7a-18 2055del9^A CFTRdele2-4 CFTRdelel 9 2105-2117dell3insAGAAA CFTRdele3-10,14b-16 CFTRdelel 9-21 2372del8 CFTRdele4-7 CFTRdele21 272 Idel 11 CFTRdele4-ll CFTRdele22-24 2991del32 CFTR50kbdel CFTRdele22,23 3667ins4 CFTRdup6b-10 124del23bp 401 Odel 4 CFTRdelel 1 602dell4 4209TGTT^AA CFTRdelel 3.14a 852del22 CFTRdelel 4b-17b 991del5 A46D V520F Y569D N1303K G85E A559T L1065P R347P R560T R1066C L467P R560S L1077P I507del A561E M1101K

The exact amount of the 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 route of administration, and the like. The compositions of this invention may be formulated in unit dosage form for ease of administration and uniformity of dosage. The expression unit dosage form as used herein refers to a physically discrete unit of agent suitable for the patient being treated. However, it should be understood that the general daily use of the compounds and compositions of this disclosure will be determined by the attending physician in the exercise of sound medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors, including the disorder being treated and the severity of the disease; the activity of the specific API being used; the specific composition used; the age, body weight, general health, gender and diet of the patient; time of administration, route of administration and rate of excretion of the particular compound used; duration of treatment; drugs used in combination or coincident with the specific compound used, and similar factors well known in medicine. The term patient as used herein means an animal such as a mammal, and even more so such as a human.

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

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

The clinical efficacy of Compound III-d in combination with other CFTR correctors, including combinations with Compound II, was 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).

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Exemplary embodiments of the present disclosure include: novel compounds disclosed herein (e.g., compounds of formulas (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), their pharmaceutically acceptable forms salts and deuterated derivatives of any of the above, including the compounds of Fig. 1 and 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 in the Examples below. For example, deuterated derivatives of new compounds of formulas (I), (II-A), (II-B), (III-A), (IIIB), (IV-A), (IV-B), (IV-C) , (V-A), (V-B), (VI-A), (VI-B), (VI-C) and (VI-D) and their pharmaceutically acceptable salts can be prepared similarly in the same manner as for the compounds of the formulas (I), (IIA), (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, using intermediates and/or reagents wherein one or more hydrogen atoms are replaced by 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, relevant portions of which are incorporated herein by reference.

In some embodiments, the compounds disclosed herein and their pharmaceutically acceptable salts, as well as deuterated derivatives of any of the above, are prepared as shown in Schemes 1-12, wherein each of the variables therein independently corresponds to those of formula (I). Suitable conditions known in the art can be used for each step depicted in the diagrams. The methods disclosed herein can be used to prepare compounds of formulas (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), as well as any compounds presented in table. 5 and fig. 1, their salts or deuterated derivatives of any of the above.

In some embodiments, as shown in Scheme 1, the methods involve reacting a compound of formula (A) or a salt thereof with a compound of formula (B) or a salt thereof to form 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 carried out in any suitable coupling reaction of a carboxylic acid and a sulfonamide, such as with CDI. In some embodiments, the coupling reaction is carried out in the presence of a base, such as DBU.

Scheme 1

In some embodiments, as shown in Scheme 2, the methods include deprotecting a compound of formula (Y) to form a compound of formula (Y-1), a salt thereof, or a deuterated derivative of any of the foregoing. Deprotection of formula (Y) can be performed under any suitable deprotection conditions that are readily apparent to one skilled in the art, depending on the protecting group R10. In some embodiments, the protecting group R10 is Boc and the deprotection conditions are acidic. In some embodiments, as shown in Scheme 2, the methods involve reacting a compound of formula (Y-1) to form 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 carried out by any suitable coupling reaction between an amine and a halogen. In some embodiments, this coupling reaction is carried out in the presence of a base, such as K2CO3.

- 38 044967

Scheme 2

(Y-D

In some embodiments, as shown in Scheme 3, the methods involve reacting a compound of formula (A) or a salt thereof with a compound of formula (B-2) or a salt thereof to form a compound of formula (Y-2), a salt thereof, or a deuterated derivative of any of the above. The reaction of formula (A) and formula (B-2) can be carried out in any suitable coupling reaction of a carboxylic acid and a sulfonamide, such as with CDI. In some embodiments, the coupling reaction is carried out in the presence of a base, such as DBU.

Scheme 3

In some embodiments, as shown in Scheme 4, the methods involve reacting a compound of formula (D) or a salt thereof with a compound of formula (E-2) or a salt thereof to form a compound of formula (B-2), a salt thereof, or a deuterated derivative of any of the above. The reaction of formula (D) and formula (E-2) can be carried out according to any suitable coupling reaction between the amine and Rd.

Scheme 4

In some embodiments, as shown in Scheme 5, the methods involve reacting a compound of formula (A) or a salt thereof with a compound of formula (B-3) or a salt thereof to form a compound of formula (Y-3), a salt thereof, or a deuterated derivative of any of the above. The reaction of formula (A) and formula (B-3) can be carried out in any suitable coupling reaction of a carboxylic acid and a sulfonamide, such as with CDI. In some embodiments

- 39 044967 the coupling reaction is carried out in the presence of a base such as DBU.

Scheme 5

In some embodiments, as shown in Scheme 6, the methods involve reacting a compound of formula (D) or a salt thereof with a compound of formula (E-3) or a salt thereof to form a compound of formula (B-3), a salt thereof, or a deuterated derivative of any of the above. The reaction of formula (A) and formula (B-3) can be carried out according to any suitable coupling reaction between an alcohol and R ^d .

Scheme 6

In some embodiments, as shown in Scheme 7, the methods involve reacting a compound of formula (Z-1) with a compound of formula (X) to form 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 carried out by any suitable coupling reaction between nitrogen and halogen.

Scheme 7

In some embodiments, as shown in Scheme 8, the methods involve reacting a compound of formula (Z-1) with a compound of formula (X-1) to form a compound of formula (IVC), 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 carried out by any suitable coupling reaction between nitrogen and halogen.

- 40 044967

Scheme 8

In some embodiments, as shown in Scheme 9, the methods involve reacting a compound of formula (F) or a salt thereof with a compound of formula (G) or a salt thereof to form 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 carried out by any suitable reaction between the amide and a sulfur atom, for example with bromine. In some embodiments, the reaction is carried out 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 embodiments, the oxidizing agent is meta-chloroperoxybenzoic acid (m-CPBA).

Scheme 9

In some embodiments, as shown in Scheme 10, the methods involve reacting a compound of formula (J) with a compound of formula (L) to form 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.

- 41 044967

Scheme 10

In some embodiments, as shown in Scheme 11, the methods involve 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 above, wherein X is NH or N(C ₁ -C ₄ -alkyl). In some embodiments, the reaction of formula (M) and an amine can be carried out in the presence of N-chlorosuccinimide. The compound of formula (N) can be converted into the compound of formula (O), a salt thereof, or a deuterated derivative of any of the above. In some embodiments, the reaction is carried out under reducing conditions. In some embodiments, the reaction is carried out in the presence of palladium on carbon and hydrogen.

Scheme 11

In some embodiments, as shown in Scheme 12, the methods involve reacting a compound of formula (O) or a salt thereof to form 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 carried out in the presence of a base. In some embodiments, the base is triethylamine. In some embodiments, the reaction of formula (O) can be carried out by heating.

Scheme 12

Additional options include the following. 1. Compound of formula (I)

a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein ring A is 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 represents O, NH or N(C ₁ -C ₄ -alkyl);

each R ¹ is independently selected from C1- _C2 alkyl groups, _C1 - _C2 alkoxy groups, C1-C2 haloalkyl groups, C1- _C2 haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C1- _C2 alkyl groups, C1- _C2 alkoxy groups, C1-C2 haloalkyl groups, C1- _C2 haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and independently substituted with one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl group, C1- _C2 alkoxy groups and C1- _C2 haloalkoxy groups; where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from

- 43 044967

C1-C2 alkyl groups, C ₁ -C2 haloalkyl groups, halogens, hydroxyl group, C1-C2 alkoxy groups and C ₁ -C ₂ haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected 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 bivalent linker of formula (L) _r , where r is 1, 2, 3, 4, 5 or 6;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C ₁ -C ₂ haloalkyl groups, C1 -C2 alkyl groups, hydroxyl group, C ₁ -C ₂ alkoxy groups and C ₁ -C ₂ haloalkoxy groups; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

2. The compound of Embodiment 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring A is a phenyl ring, a pyridyl ring, or a pyrazole ring, wherein ring A is optionally substituted with (R1)m.

3. The compound of Embodiment 1 or 2, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ¹ is independently selected from deuterium, C ₁ -C ₂ alkyl groups and a hydroxyl group and m is 0 or 1.

4. The compound of any one of embodiments 1-3, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, where n is 0.

5. The compound of any one of embodiments 1-4, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is a 5-membered heteroaryl ring substituted with (R4) _q .

6. The compound of any one of embodiments 1-4, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein the D ring is a phenyl ring, a pyridinyl ring, a pyrazolyl ring, an imidazolidinone ring, a pyrrolidinone ring, or a pyridinone ring, wherein the D ring is substituted (R ⁴ ) _q .

7. The compound of any one of embodiments 1-4, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is where indicates the point of attachment of ring D to ring B

8. The compound of Embodiment 7, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is where indicates the point of attachment of ring D to ring B.

9. The compound of any one of embodiments 1-8, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ and where each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from

- 44 044967

C1-C2 alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C1-C2 alkoxy groups and C ₁ -C ₂ haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁ o-cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C _{2 -α} alkyl groups, C 1 -C 2 haloalkyl groups and halogens.

10. The compound of any one of embodiments 1-9, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y) _k -R ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ and wherein each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1C4 alkyl groups, and O3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ -cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ -α alkyl groups, C 1 -C 2 -haloalkyl groups and halogens.

11. The compound of any one of embodiments 1-8, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -O-(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4 or 5;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y) _k -R ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ and wherein each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1C4 alkyl groups, and O3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group, or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ -cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ -α alkyl groups, C 1 -C 2 -haloalkyl groups and halogens.

12. The compound of any one of embodiments 1-8, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from

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- 46 044967

where indicates the point of attachment of R ⁴ to ring D.

13. The compound of any one of embodiments 1-12, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, where k is 3, 4, 5 or 6.

14. The compound of any one of embodiments 1-13, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein q is 1.

15. The compound of any one of embodiments 1-14, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, wherein the heteroatom at Z is not bonded to another heteroatom at Z and wherein R ⁸ and R ⁹ are each independently selected from hydrogen and deuterium; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

16. The compound according to any one of embodiments 1-14, its pharmaceutically acceptable

- 47 044967 salt or deuterated derivative of any of the above, where Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from C(R ⁸ )(R ⁹ ) groups and -NR ^b groups, where the heteroatom at Z is not bonded to another heteroatom at Z, and:

R ⁸ and R ⁹ are each independently selected from hydrogen and deuterium; and each R ^b is independently selected from hydrogen and methyl.

17. The compound of any one of embodiments 1-14, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from C(R ⁸ )(R ⁹ ) groups and -NR ^b groups, wherein the heteroatom in Z is not bonded to another heteroatom in Z and wherein each R ⁸ and R ⁹ are independently selected from hydrogen and deuterium; and each R ^b is hydrogen.

18. The compound of any one of embodiments 1-14, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, wherein the heteroatom at Z is not bonded to another heteroatom at Z, wherein each R ⁸ and R ⁹ is hydrogen; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

19. The compound of any one of embodiments 1-18, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, 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 above, 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 above, wherein the carbon labeled * has S-stereochemistry or R-stereochemistry;

ring A is 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 selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

each R ⁴ is independently selected from halogens, hydroxyl group, oxo group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and is independently substituted with one or more groups selected from halogens, C1- _C2 alkyl groups, haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups, where k is 0.1 , 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where

- 48 044967 R ⁵ and R ⁶ are each independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C ₃ . ₅ cycloalkyl groups, or ^R5 and ^R6 on the same carbon atom together form _C3 . ₅ cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected 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 bivalent linker of formula (L) _r , where r is 1, 2, 3, 4, 5 or 6;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C ₁ -C ₂ alkyl groups, C1-C2 haloalkyl groups, hydroxyl group, C ₁ -C ₂ alkoxy groups and C1-C2 haloalkoxy groups; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

21. The compound of Embodiment 20, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring A is a phenyl ring, a pyridyl ring, or a pyrazolyl ring, wherein ring A is optionally substituted with (R1) _m .

22. The compound of Embodiment 20 or 21, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ¹ is independently selected from deuterium, C ₁ -C ₂ alkyl groups and a hydroxyl group and m is 0 or 1.

23. The compound of any one of embodiments 20-22, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, where n is 0.

24. The compound of any one of embodiments 20-23, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Ring D is a 5-membered heteroaryl ring substituted with (R ⁴ ) _q .

25. The compound of any one of embodiments 20-23, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein the D ring is a pyrazolyl ring or a pyridinone ring, wherein the D ring is substituted with R ⁴ .

26. The compound of any one of embodiments 20-23, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is

where indicates the point of attachment of ring D to ring B.

27. The compound of any one of embodiments 20-23, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is where indicates the point of attachment of ring D to ring B.

28. The compound of any one of embodiments 20-27, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or a -(Y) _k -R ⁷ group, wherein

- 49 044967 k equals 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y) _k -R ⁷ is not bonded to another heteroatom in -(Y) _k -R ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1O4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C ₁ -C ₂ alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ C ₂ haloalkyl groups and halogens.

29. The compound of any one of embodiments 20-28, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1C4 alkyl groups, and C3.5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form C3. ₅ cycloalkyl group;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C ₁ -C ₂ alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups and halogens.

30. The compound of any one of embodiments 20-28, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -O-(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4 or 5;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1C4 alkyl groups, and C3.5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form C3. ₅ cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C ₁ -C ₂ alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups and halogens.

31. The compound of any one of embodiments 20-28, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from

- 50 044967

- 51 044967

- 52 044967

where indicates the point of attachment of R ⁴ to ring D.

32. The compound of any one of embodiments 20-31, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, where k is 3, 4, 5 or 6.

33. The compound of any one of embodiments 20-32, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein q is 1.

34. The compound of any one of embodiments 20-33, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen and deuterium; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

35. The compound of any one of embodiments 20-33, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from C(R ⁸ )(R ⁹ ) groups and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen and deuterium; and each R ^b is independently selected from hydrogen and methyl.

36. The compound of any one of embodiments 20-33, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from C(R ⁸ )(R ⁹ ) groups and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen and deuterium; and each R ^b is hydrogen.

37. The compound according to any of embodiments 20-33, its pharmaceutically acceptable

- 53 044967 salt or deuterated derivative of any of the above, where Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, wherein the heteroatom at Z is not bonded to another heteroatom at Z, wherein each R ⁸ and R ⁹ is hydrogen; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

38. The compound of any one of embodiments 20-37, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, 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 above, wherein the compound of formula I is a compound of formula (W-A) or (W-B):

a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein the carbon labeled * has S-stereochemistry or R-stereochemistry;

ring A is 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 selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C ₁ -C ₂ haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which optionally independently substituted with one or more groups selected from halogens, C1- _C2 alkyl groups, haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups, where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano group and C ₃ -C ₁₀ -cycloalkyl groups, optional

- 54 044967 substituted with one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups and halogens;

q is equal to 1 or 2;

Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from the C(R8)(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen, halogens , C ₁ -C ₂ -alkyl groups, hydroxyl group, C ₁ -C ₂ -alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

40. The compound of Embodiment 39, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring A is a phenyl ring, a pyridyl ring, or a pyrazolyl ring, wherein ring A is optionally substituted with (R1)m.

41. The compound of Embodiment 39 or 40, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ¹ is independently selected from deuterium, C ₁ -C ₂ alkyl groups and a hydroxyl group and m is 0 or 1.

42. The compound of any one of embodiments 39-41, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, where n is 0.

43. The compound of any one of embodiments 39-42, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is a 5-membered heteroaryl ring substituted with (R ⁴ ) _q .

44. The compound of any one of embodiments 39-42, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is a pyrazolyl ring substituted with (R ⁴ ) _q .

45. The compound of any one of embodiments 39-42, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is wherein indicates the point of attachment of ring D to ring B.

46. The compound of any one of embodiments 39-42, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is (R ⁴ ) _q wherein indicates the point of attachment of ring D to ring B.

47. The compound of any one of embodiments 39-46, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C ₁ -C ₄ alkyl groups, and C _3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form C _3-5 cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

- 55 044967

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens.

48. The compound of any one of embodiments 39-47, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1C4 alkyl groups, and C3.5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form C3. ₅ cycloalkyl group;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens.

49. The compound of any one of embodiments 39-47, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -O-(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4 or 5;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1C4 alkyl groups, and C3.5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form C3. ₅ cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups and halogens.

50. The compound of any one of embodiments 39-47, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from

- 56 044967

- 57 044967

where indicates the point of attachment of R ⁴ to ring D.

51. The compound of any one of embodiments 39-50, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, where k is 3, 4, 5 or 6.

52. The compound of any one of embodiments 39-51, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein q is 1.

53. The compound of any one of embodiments 39-52, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen and deuterium; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

54. The compound of any one of embodiments 39-52, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from C(R ⁸ )(R ⁹ ) groups and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen and deuterium; and each R ^b is independently selected from hydrogen and methyl.

55. The compound of any one of embodiments 39-52, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Z is a bivalent linker of formula (L)r, where r is 3, 4 or 5;

each L is independently selected from C(R ⁸ )(R ⁹ ) groups and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen and deuterium; and each R ^b is hydrogen.

56. The compound according to any one of embodiments 39-52, its pharmaceutically acceptable

- 58 044967 salt or deuterated derivative of any of the above, where Z represents a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, wherein the heteroatom at Z is not bonded to another heteroatom at Z, wherein each R ⁸ and R ⁹ is hydrogen; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

57. The compound of any one of embodiments 39-56, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, 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 above, 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 above, wherein the carbon labeled * 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 represents O, NH or N(C ₁ -C ₄ -alkyl);

each R ¹ is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and is independently substituted with one or more groups selected from halogens, C1- _C2 alkyl groups, haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups, where k is 0.1 , 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C _r C ₂ haloalkyl groups and halogens;

q is equal to 1 or 2;

Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C ₁ -C ₂ -alkyl groups, hydroxyl group, C ₁ -C ₂ -alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

59. The compound of embodiment 58, a pharmaceutically acceptable salt or deuteron thereof

- 59 044967 ri derivative of any of the above, where each R ¹ is independently selected from deuterium,

C ₁ -C ₂ -alkyl groups and hydroxyl group and m is 0 or 1.

60. The compound of Embodiment 58 or 59, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, where n is 0.

61. The compound of any one of embodiments 58-60, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is a 5-membered heteroaryl ring substituted with (R ⁴ )q.

62. The compound of any one of embodiments 58-60, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is a pyrazolyl ring substituted with (R ⁴ ) _q .

63. The compound of any one of embodiments 58-60, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D represents a co-

64. The compound of any one of embodiments 58-60, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is

where indicates the point of attachment of ring D to ring B.

65. The compound of any one of embodiments 58-64, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens.

66. The compound of any one of embodiments 58-65, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens.

- 60 044967

67. The compound of any one of embodiments 58-66, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -O-(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4 or 5;

each Y is independently selected from the C(R5)(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C _r C ₂ alkoxy groups and C ₁ - C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens.

68. The compound of any one of embodiments 58-67, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from

- 61 044967 where

indicates the point of attachment of R ⁴ to ring D.

69. The compound of any one of embodiments 58-68, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein k is 3, 4, 5, or 6.

- 62 044967

70. The compound of any one of embodiments 58-69, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein q is 1.

71. The compound of any one of embodiments 58-70, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen and deuterium; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

72. The compound of any one of embodiments 58-70, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from C(R ⁸ )(R ⁹ ) groups and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen and deuterium; and each R ^b is independently selected from hydrogen and methyl.

73. The compound of any one of embodiments 58-70, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from C(R ⁸ )(R ⁹ ) groups and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen and deuterium; and each R ^b is hydrogen.

74. The compound of any one of embodiments 58-70, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, wherein the heteroatom at Z is not bonded to another heteroatom at Z, wherein each R ⁸ and R ⁹ is hydrogen; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

75. The compound of any one of embodiments 58-74, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, 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 above, 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 above, wherein the carbon labeled * 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 selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

- 63 044967 each R ³ represents methyl;

each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and is independently substituted with one or more groups selected from halogens, C1- _C2 alkyl groups, haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups, where k is 0.1 , 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens;

q is equal to 1 or 2;

r is 3 or 4;

each R ⁸ and R ⁹ is independently selected from hydrogen, halogens, C ₁ -C ₂ alkyl groups, hydroxyl group, C ₁ -C ₂ alkoxy groups and C ₁ -C ₂ haloalkoxy groups; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

77. The compound of embodiment 76, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁸ and R ⁹ is independently selected from hydrogen, deuterium, halogens, C ₁ -C ₂ alkyl groups, hydroxyl group, C ₁ - C ₂ -alkoxy groups and C ₁ -C ₂ -haloalkoxy groups.

78. The compound of Embodiment 76 or 77, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ^R8 and ^R9 are each H.

79. The compound of any one of embodiments 76-78, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ¹ is independently selected from deuterium, C ₁ -C ₂ alkyl groups and a hydroxyl group and m is 0 or 1 .

80. The compound of any one of embodiments 76-79, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, where n is 0.

81. The compound of any one of embodiments 76-80, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is a 5-membered heteroaryl ring substituted with (R ⁴ ) _q .

82. The compound of any one of embodiments 76-80, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is a pyrazolyl ring substituted with (R ⁴ ) _q .

83. The compound of any one of embodiments 76-80, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is o

where indicates the point of attachment of ring D to ring B.

84. The compound of any one of embodiments 76-80, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is

- 64 044967 where

indicates the point of attachment of ring D to ring B.

85. The compound of any one of embodiments 76-84, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y) _k - ^R7 is not bonded to another heteroatom in -(Y) ^kR7 , wherein each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group, or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C 1 -C ₂ alkyl groups, C 1 -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C 1 -C ₂ haloalkoxy groups ; and each R ^a is independently selected from hydrogen and C1- _C2 alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C 1 -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens.

86. The compound of any one of embodiments 76-84, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y) _k - ^R7 is not bonded to another heteroatom in -(Y) ^kR7 , wherein each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C 1 -C ₂ alkyl groups, C 1 -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C 1 -C ₂ haloalkoxy groups ; and each R ^a is independently selected from hydrogen and C1- _C2 alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C 1 -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens.

87. The compound of any one of embodiments 76-84, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -O-(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4 or 5;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y) _k - ^R7 is not bonded to another heteroatom in -(Y) ^kR7 , wherein each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group, or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C 1 -C ₂ alkyl groups, C 1 -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C 1 -C ₂ haloalkoxy groups ; and each R ^a is independently selected from hydrogen and C1- _C2 alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C 1 -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens.

88. The compound of any one of embodiments 76-84, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ independently represents

- 65 044967

- 66 044967

- 67 044967 where indicates the point of attachment of R ⁴ to ring D.

89. The compound of any one of embodiments 76-88, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein k is 3, 4, 5, or 6.

90. The compound of any one of embodiments 76-89, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein q is 1.

91. The compound of any one of embodiments 76-90, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein r is 3, 4 or 5;

R ⁸ and R ⁹ are each independently selected from hydrogen and deuterium; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

92. The compound of any one of embodiments 76-90, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein r is 3, 4 or 5;

R ⁸ and R ⁹ are each independently selected from hydrogen and deuterium; and each R ^b is independently selected from hydrogen and methyl.

93. The compound of any one of embodiments 76-90, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein r is 3, 4 or 5;

R ⁸ and R ⁹ are each independently selected from hydrogen and deuterium; and each R ^b is hydrogen.

94. The compound of any one of embodiments 76-90, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein r is 3, 4 or 5;

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

95. The compound of any one of embodiments 76-94, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, 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 above, 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 above, wherein the carbon marked * has S-stereochemistry or R-stereochemistry;

each R ¹ is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and is independently substituted with one or more groups selected from halogens, C1- _C2 alkyl groups, haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups, where k is 0.1 , 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R5)(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and ^R6 are independently selected from hydrogen, halogens, hydroxyl group, C1-C4-68044967 alkyl groups, and _C3-5 cycloalkyl groups, or ^R5 and ^R6 on the same carbon atom together form _C3 . ₅ cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from

C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C1-C2 alkoxy groups and C ₁ -C ₂ haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens;

q is equal to 1 or 2;

r is 3 or 4;

each R ⁸ and R ⁹ is independently selected from hydrogen, halogens, C ₁ -C ₂ alkyl groups, hydroxyl group, C ₁ -C ₂ alkoxy groups and C ₁ -C ₂ haloalkoxy groups; and each R ^b is independently selected 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 above, wherein each R ⁸ and R ⁹ is independently selected from hydrogen, deuterium, halogens, C ₁ -C ₂ alkyl groups, hydroxyl group, C ₁ - C ₂ -alkoxy groups and C ₁ -C ₂ -haloalkoxy groups.

98. The compound of Embodiment 96 or 97, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ^R8 and ^R9 are each H.

99. The compound of any one of embodiments 96-98, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ¹ is independently selected 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 96-99, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, where n is 0.

101. The compound of any one of embodiments 96-100, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y) _k - ^R7 is not bonded to another heteroatom in -(Y) ^kR7 , wherein each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1C4 alkyl groups, and C3.5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form C3. ₅ cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups and halogens.

102. The compound of any one of embodiments 96-100, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -(Y)kR ⁷ group, where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y) _k -R ⁷ , wherein each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1C4 alkyl groups, and C3_5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3_ ₅ cycloalkyl group;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens.

103. The compound of any one of embodiments 96-100, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -O-(Y) _k -R ⁷ group, wherein

- 69 044967 k equals 0, 1, 2, 3, 4 or 5;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y) _k -R ⁷ is not bonded to another heteroatom in -(Y) _k -R ⁷ , wherein each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens.

104. The compound of any one of embodiments 96-100, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from

- 70 044967 where

indicates the point of attachment of R ⁴ to ring D.

105. The compound of any one of embodiments 96-104, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein k is 3, 4, 5, or 6.

106. The compound of any one of embodiments 96-105, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein q is 1.

107. The compound of any one of embodiments 96-106, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein r is 3, 4 or 5;

R ⁸ and R ⁹ are each independently selected from hydrogen and deuterium; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

108. The compound of any one of embodiments 96-106, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein r is 3, 4 or 5;

R ⁸ and R ⁹ are each independently selected from hydrogen and deuterium; And

- 71 044967 each R ^b is independently selected from hydrogen and methyl.

109. The compound of any one of embodiments 96-106, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein r is 3, 4 or 5;

R ⁸ and R ⁹ are each independently selected from hydrogen and deuterium; and each R ^b is hydrogen.

110. The compound of any one of embodiments 96-106, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein r is 3, 4 or 5;

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

111. The compound of any one of embodiments 96-110, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, 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 above, 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 above, wherein the carbon labeled * 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 selected from C ₁ -C ₂ -alkyl groups, C ₁ -C 2 -alkoxy groups, C 1 -C ₂ -haloalkyl groups, C ₁ -C ₂ -haloalkoxy groups, halogens, cyano group and hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and is independently substituted with one or more groups selected from halogens, C1- _C2 alkyl groups, haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups, where k is 0.1 , 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ -cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ -α alkyl groups, C 1 -C 2 -haloalkyl groups and halogens;

q is equal to 1 or 2;

Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom at Z is not bonded to another heteroatom at Z, where

- 72 044967 each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C ₁ -C ₂ alkyl groups, hydroxyl group, C ₁ -C ₂ alkoxy groups and C ₁ -C ₂ haloalkoxy groups; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

113. The compound of Embodiment 112, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ¹ is independently selected from deuterium, C ₁ -C ₂ alkyl groups, and a hydroxyl group, and m is 0 or 1.

114. The compound of Embodiment 112 or 113, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, where n is 0.

115. The compound of any one of embodiments 112-114, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is a 5-membered heteroaryl ring substituted with (R ⁴ ) _q .

116. The compound of any one of embodiments 112-114, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is a pyrazolyl ring substituted with (R ⁴ )q.

117. The compound of any one of embodiments 112-114, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is

where indicates the point of attachment of ring D to ring B.

118. The compound of any one of embodiments 112-117, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is where indicates the point of attachment of ring D to ring B.

119. The compound of any one of embodiments 112-118, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y) _k - ^R7 is not bonded to another heteroatom in -(Y) ^kR7 , wherein each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C ₁ -C ₄ alkyl groups, and C _3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom 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 selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C _r C ₂ alkoxy groups and C ₁ - C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens.

120. The compound of any one of embodiments 112-118, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where

- 73 044967 each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C ₁ C ₄ alkyl groups, and C _3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C _3-5 cycloalkyl group;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁ o-cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens.

121. The compound of any one of embodiments 112-118, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -O-(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4 or 5;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens.

122. The compound of any one of embodiments 112-118, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from

- 74 044967

- 75 044967

Where

indicates the point of attachment of R ⁴ to ring D.

123. The compound of any one of embodiments 112-122, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, where k is 3, 4, 5 or 6.

124. The compound of any one of embodiments 112-123, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein q is 1.

125. The compound of any one of embodiments 112-124, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Z is a bivalent linker of formula (L) _r where r is 3, 4 or 5;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen and deuterium; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

126. The compound of any one of embodiments 112-124, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from C(R ⁸ )(R ⁹ ) groups and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen and deuterium; and each R ^b is independently selected from hydrogen and methyl.

127. The compound of any one of embodiments 112-124, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from C(R ⁸ )(R ⁹ ) groups and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen and deuterium; and each R ^b is hydrogen.

128. The compound of any one of embodiments 112-124, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, wherein the heteroatom at Z is not bonded to another heteroatom at Z, wherein each R ⁸ and R ⁹ is hydrogen; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

129. The compound of any one of embodiments 112-128, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, 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 above, 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 above, wherein the carbon marked * 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 selected from C1-C2 alkyl groups, C1- _C2 alkoxy groups, Ci- _C2 haloalkyl groups, C1- _C2 haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C1- _C2 alkyl groups, C1- _C2 alkoxy groups, C1-C2 haloalkyl groups, C1- _C2 haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and is independently substituted with one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl group, C1- _C2 alkoxy groups and C1- _C2 haloalkoxy groups, where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y) _k - ^R7 is not bonded to another heteroatom in -(Y) ^kR7 , wherein each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a _C3-5 cycloalkyl group or oxo ;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C 1 -C ₂ alkyl groups, C 1 -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ haloalkoxy groups groups; and each R ^a is independently selected from hydrogen and C1- _C2 alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C 1 -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens;

q is equal to 1 or 2;

r is 3, 4 or 5; and each R ⁸ and R ⁹ is independently selected from hydrogen, halogens, C1-C ₂ alkyl groups, hydroxyl group, C1-C ₂ alkoxy groups and C1-C ₂ haloalkoxy groups.

131. The compound of Embodiment 130, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁸ and R ⁹ is independently selected from hydrogen, deuterium, halogens, C1- _C2 alkyl groups, hydroxyl group, C1- _C2 -alkoxy groups and C ₁ -C ₂ -haloalkoxy groups.

132. The compound of Embodiment 130 or 131, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ^R8 and ^R9 are each H.

133. The compound of any one of embodiments 130-132, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ¹ is independently selected from deuterium, C1-C2 alkyl groups and a hydroxyl group and m is 0 or 1.

134. The compound of any one of embodiments 130-133, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, where n is 0.

135. The compound of any one of embodiments 130-134, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is a 5-membered heteroaryl ring substituted with (R4) _q .

136. The compound of any one of embodiments 130-134, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is a pyrazolyl ring substituted with (R ⁴ ) _q .

137. The compound of any one of embodiments 130-134, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is

- 77 044967

where indicates the point of attachment of ring D to ring B.

138. The compound of any one of embodiments 130-137, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is where indicates the point of attachment of ring D to ring B.

139. The compound of any one of embodiments 130-138, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, Q -C 2 haloalkyl groups and halogens.

140. The compound of any one of embodiments 130-138, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y) _k -R ⁷ , wherein each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C _r C ₂ haloalkyl groups and halogens.

141. The compound of any one of embodiments 130-138, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -O-(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4 or 5;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y) _k -R ⁷ , wherein each ^R5 and ^R6 are independently selected from hydrogen, deuterium, halogens, hydroxyl group, _C1C4 alkyl groups, and _C3-5 cycloalkyl groups, or ^R5 and ^R6 on the same carbon atom together

- 78 044967 form a C3-5cycloalkyl group or oxo;

each of R5 and ^R6 is optionally independently substituted with one or more groups selected from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, hydroxyl group, C1-C2 alkoxy groups and C1-C2 haloalkoxy groups; and each R ^a is independently selected from hydrogen and C1- _C2 alkyl groups; and R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁ o-cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups and halogens .

142. The compound of any one of embodiments 130-138, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from

- 79 044967

where indicates the point of attachment of R ⁴ to ring D.

143. The compound of any one of embodiments 130-142, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, where k is 3, 4, 5 or 6.

144. The compound of any one of embodiments 130-143, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein q is 1.

145. The compound of any one of embodiments 130-144, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein r is 3, 4 or 5; and each R ⁸ and R ⁹ is independently selected from hydrogen and deuterium.

146. The compound of any one of embodiments 130-144, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein r is 3, 4 or 5; and R ⁸ and R ⁹ are each hydrogen.

147. The compound of any one of embodiments 130-144, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein r is 3, 4 or 5; and each R ⁸ and R ⁹ represents deuterium.

148. The compound of any one of embodiments 130-144, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein r is 3 or 4; and R ⁸ and R ⁹ are each hydrogen.

149. The compound of any one of embodiments 130-148, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, 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 above, wherein the compound of formula I is a compound of formula VI-A or VI-B:

(VI-A) or a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein the carbon marked * 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 selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and is independently substituted with one or more groups selected from halogens, C1- _C2 alkyl groups, haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups, where k is 0.1 , 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y) _k -R ⁷ is not

- 81 044967 is bonded to another heteroatom at -(Y) _k -R ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C ₁ -C ₄ alkyl groups, and C ₃ . ₅ cycloalkyl groups, or ^R5 and ^R6 on the same carbon atom together form _C3 . ₅ cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups and halogens;

q is equal to 1 or 2;

Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C ₁ -C ₂ -alkyl groups, hydroxyl group, C ₁ -C ₂ -alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

151. The compound of Embodiment 150, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ¹ is independently selected from deuterium, C ₁ -C ₂ alkyl groups and a hydroxyl group and m is 0 or 1.

152. The compound of Embodiment 150 or 151, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, where n is 0.

153. The compound of any one of embodiments 150-152, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is a 5-membered heteroaryl ring substituted with (R ⁴ ) _q .

154. The compound of any one of embodiments 150-152, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is a pyrazolyl ring substituted with (R ⁴ ) _q .

155. The compound of any one of embodiments 150-152, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is o

where indicates the point of attachment of ring D to ring B.

156. The compound of any one of embodiments 150-152, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is

where indicates the point of attachment of ring D to ring B.

157. The compound of any one of embodiments 150-156, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y) _k -R ⁷ , Where

- 82 044967 each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, a hydroxyl group, C1H-alkyl groups, and ^.alkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form C ₃ . ₅ cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens.

158. The compound of any one of embodiments 150-156, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1C4 alkyl groups, and C3.5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form C3. ₅ cycloalkyl group;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, Ci-C ₂ haloalkyl groups and halogens.

159. The compound of any one of embodiments 150-156, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -O-(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4 or 5;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y) _k - ^R7 is not bonded to another heteroatom in -(Y) ^kR7 , wherein each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1C4 alkyl groups, and C3.5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form C3. ₅ cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C1-C2 alkyl groups; and R ⁷ is selected from hydrogen, halogens, cyano groups and C3-C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C1C ₂ haloalkyl groups and halogens.

160. The compound of any one of embodiments 150-156, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from

- 83 044967

- 84 044967

where indicates the point of attachment of R ⁴ to ring D.

161. The compound of any one of embodiments 150-160, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, where k is 3, 4, 5 or 6.

162. The compound of any one of embodiments 150-161, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein q is 1.

163. The compound of any one of embodiments 150-162, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen and deuterium; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

164. The compound of any one of embodiments 150-162, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Z is a bivalent linker of formula (L)r, where r is 3, 4 or 5;

each L is independently selected from C(R ⁸ )(R ⁹ ) groups and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen and deuterium; and each R ^b is independently selected from hydrogen and methyl.

- 85 044967

165. The compound of any one of embodiments 150-162, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5;

each L is independently selected from C(R ⁸ )(R ⁹ ) groups and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen and deuterium; and each R ^b is hydrogen.

166. The compound of any one of embodiments 150-162, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein Z is a bivalent linker of formula (L)r, where r is 3, 4 or 5;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, wherein the heteroatom at Z is not bonded to another heteroatom at Z, wherein each R ⁸ and R ⁹ is hydrogen; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

167. The compound of any one of embodiments 150-166, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, 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 above, wherein the compound of formula I is a compound of formula VI-C or VI-D:

-(cr ^s r ⁹ )J a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein the carbon labeled * 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 represents O, NH or N(C ₁ -C ₄ -alkyl);

each R ¹ is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and is independently substituted with one or more groups selected from halogens, C1- _C2 alkyl groups, haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups, where k is 0.1 , 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y) _k - ^R7 is not bonded to another heteroatom in -(Y) ^kR7 , wherein each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo;

- 86 044967 each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from

C1- _C2 alkyl groups, _C1 - _C2 haloalkyl groups, halogens, hydroxyl group, C1-C2 alkoxy groups and _C1 - _C2 haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups and halogens;

q is equal to 1 or 2;

r is 3 or 4; and each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C ₁ -C ₂ alkyl groups, hydroxyl group, C ₁ -C ₂ alkoxy groups and C ₁ -C ₂ haloalkoxy groups.

169. The compound of embodiment 168, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁸ and R ⁹ is independently selected from hydrogen, deuterium, halogens, C ₁ -C ₂ alkyl groups, hydroxyl group, C ₁ - C ₂ -alkoxy groups and C ₁ -C ₂ -haloalkoxy groups.

170. The compound of Embodiment 169, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ^R8 and ^R9 are each H.

171. The compound of any one of embodiments 168-170, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ¹ is independently selected from deuterium, C ₁ -C ₂ alkyl groups and a hydroxyl group and m is 0 or 1 .

172. The compound of any one of embodiments 168-171, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, where n is 0.

173. The compound of any one of embodiments 168-172, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is a 5-membered heteroaryl ring substituted with (R ⁴ ) _q .

174. The compound of any one of embodiments 168-172, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is a pyrazolyl ring substituted with (R ⁴ ) _q .

175. The compound of any one of embodiments 168-172, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is o

cr cr dr / g (R ⁴ )q (R ⁴ )q (R ⁴ )q (R ⁴ )q ,

O o nAa (R ⁴ )q (R ⁴ )q where indicates the point of attachment of ring D to ring B.

176. The compound of any one of embodiments 168-172, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is where

indicates the point of attachment of ring D to ring B.

177. The compound of any one of embodiments 168-172, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C ₁ C ₄ alkyl groups, and C _3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form C _{3 -5} cycloalkyl group or oxo;

- 87 044967 each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from

C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C1-C2 alkoxy groups and C ₁ -C ₂ haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens.

178. The compound of any one of embodiments 168-176, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens.

179. The compound of any one of embodiments 168-176, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or -O-(Y) _k -R ⁷ group, where k is 0, 1, 2, 3, 4 or 5;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y) _k -R ⁷ , wherein each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group, or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens.

180. The compound of any one of embodiments 168-176, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from

- 88 044967

- 89 044967

Where

indicates the point of attachment of R ⁴ to ring D.

181. The compound of any one of embodiments 168-180, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, where k is 3, 4, 5, or 6.

182. The compound of any one of embodiments 168-181, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein q is 1.

183. The compound of any one of embodiments 168-182, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein r is 3, 4 or 5; and each R ⁸ and R ⁹ is independently selected from hydrogen and deuterium.

184. The compound of any one of embodiments 168-182, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein r is 3, 4 or 5; and R ⁸ and R ⁹ are each hydrogen.

185. The compound of any one of embodiments 168-182, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein r is 3, 4 or 5; and each R ⁸ and R ⁹ represents deuterium.

186. The compound of any one of embodiments 168-182, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein r is 3 or 4; and R ⁸ and R ⁹ are each hydrogen.

187. The compound of any one of embodiments 168-186, 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 above, wherein the *-labeled carbon of formula (II-A) or (III-A) has S-stereochemistry, and where the *-labeled carbon 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 above, wherein the carbon labeled * is any of formulas (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 above, wherein the carbon labeled * is any of formulas (IV-A), (IV-B), (IV-C), (V-A ), (V-B), (VI-A), (VI-B), (VI-C), and (VI-D) have R stereochemistry.

191. A compound selected from compounds No. 302 shown in FIG. 1, its pharmaceutically acceptable salts and deuterated derivatives of any of the above.

192. A compound selected from compounds Nos. 303-309 shown in FIG. 1, its pharmaceutically acceptable salts and deuterated derivatives of any of the above.

193. Connection selected from:

- 90 044967

pharmaceutically acceptable salts thereof or deuterated derivatives of any of the above.

194. A pharmaceutical composition containing at least one compound selected from the compounds of any of embodiments 1-191, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, and optionally one or more of:

(a) compounds II:

a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above;

(b) compounds III:

a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above; and (c) a pharmaceutically acceptable carrier.

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

196. The use of at least one compound selected from the compounds of any of embodiments 1-191, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, and optionally one or more of:

(a) compounds II:

- 91 044967 a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above;

(b) compounds III:

a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above;

for the treatment of cystic fibrosis.

197. Compound of formula (X)

a salt thereof or a deuterated derivative of any of the above, wherein Q ^a represents a halogen;

ring A is phenyl, a 5-membered heteroaryl ring or a 6-membered heteroaryl ring;

ring B is a pyridinyl ring;

X represents O, NH or N(C ₁ -C ₄ -alkyl);

each R ¹ is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

Z is a bivalent linker of formula (L) _r , where r is 1, 2, 3, 4, 5 or 6;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C ₁ -C ₂ haloalkyl groups, C1 -C2 alkyl groups, hydroxyl group, C ₁ -C ₂ alkoxy groups and C ₁ -C ₂ haloalkoxy groups; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

198. Compound of formula (Y):

a salt thereof or a deuterated derivative of any of the above, where

Q ^b represents halogen;

R ¹⁰ represents hydrogen or a protecting group;

ring A is phenyl, a 5-membered heteroaryl ring or a 6-membered heteroaryl ring;

- 92 044967 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 represents O, NH or N(C ₁ -C ₄ -alkyl);

each R ¹ is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C 2 alkoxy groups, C 1 -C ₂ haloalkyl groups, C 1 -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C1- _C2 alkyl groups, C1- _C2 alkoxy groups, C1- _C2 haloalkyl groups, C1- _C2 haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and independently substituted with one or more groups selected from halogens, C1-C2 alkyl groups, haloalkyl groups, hydroxyl group, C1- _C2 alkoxy groups and C1- _C2 haloalkoxy groups; where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C 1 -C ₂ - haloalkoxy groups; and each R ^a is independently selected from hydrogen and C1- _C2 alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected 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 bivalent linker of formula (L) _r , where r is 1, 2, 3, 4, 5 or 6;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C1- _C2 haloalkyl groups, C1-C2alkyl groups, hydroxyl group, C1- _C2 alkoxy groups and C^C^haloalkoxy groups; and each R ^b is independently selected from hydrogen and C1- _C2 alkyl groups.

199. A method for preparing a compound of formula (I) its pharmaceutically acceptable salt or a deuterated derivative of any of the above containing a combination of the NH group of the C ring and the Q ^b group of the B ring of the compound of formula (YI):

^Qb

HN' is a salt thereof or a deuterated derivative of any of the above, where

Q ^b represents halogen;

ring A is 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 represents O, NH or N(C ₁ -C ₄ -alkyl);

each R ¹ is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and independently substituted with one or more groups selected from halogens, C1- _C2 alkyl groups, haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups; where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C ₁ -C ₂ alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁ o-cycloalkyl groups, optionally substituted by one or more groups selected 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 bivalent linker of formula (L)r, where r is 1, 2, 3, 4, 5 or 6;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C ₁ -C ₂ -haloalkyl groups, C1-C2 alkyl groups, hydroxyl group, C ₁ -C ₂ -alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups;

to form a compound of formula (I), a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above.

200. The method of embodiment 198, wherein said combination is performed in the presence of a base.

201. A process for preparing a compound of formula (Y), a salt thereof, or a deuterated derivative of any of the above, wherein reacting a compound of formula (A), a salt thereof, or a deuterated derivative of any of the above with a compound of formula (B), a salt thereof, or a deuterated derivative of any of the above with by forming said compound of formula (Y), a salt thereof, or a deuterated derivative of any of the above:

- 94 044967

and optionally deprotecting the N-protecting group of the C ring of formula (Y) wherein Q ^b is halogen;

R ¹⁰ of formula (Y) represents hydrogen or an N-protecting group; R ¹⁰ of formula (B) represents an N-protecting group, and ring A, ring B, ring D, X, R ¹ , m, R ² , n, R ³ , R ⁴ , q, Z, R ¹⁰ and variables thereof such as specified in embodiment 1.

202. The method of embodiment 201, wherein said reaction of 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 carried out in the presence of a base.

203. The method of Embodiment 201, wherein said reaction of 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 involves reacting a compound of formula (A), its a salt or a deuterated derivative of any of the above with a coupling reagent and subsequently with a compound of formula (B), a salt thereof or a deuterated derivative of any of the above, in the presence of a base.

204. Method for preparing a compound of formula (Y-2):

a salt thereof or a deuterated derivative of any of the above, where

Q ^b represents halogen;

ring A is 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 represents O, NH or N(C ₁ -C ₄ -alkyl);

each R ¹ is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y) _k -R ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6-95 044967 membered cycloalkyl or a heterocyclyl ring which is optionally and independently substituted with one or more groups selected from halogen, C ₁ -C ₂ alkyl groups, haloalkyl groups, hydroxyl group, C ₁ -C ₂ alkoxy groups and C ₁ -C ₂ haloalkoxy groups ; where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3.5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form C3. ₅ cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C ₁ -C ₂ alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups and halogens;

q is 1, 2, 3 or 4;

r is 1, 2, 3, 4 or 5;

each R ⁸ and R ⁹ is independently selected from hydrogen, halogens, C ₁ -C ₂ haloalkyl groups, C 1 -C 2 alkyl groups, hydroxyl group, C ₁ -C ₂ alkoxy groups and C ₁ -C ₂ haloalkoxy groups; And

R ¹⁰ represents hydrogen or a protecting group;

comprising reacting a compound of formula (A), a salt thereof, or a deuterated derivative of any of the above with a compound of formula (B-2), a salt thereof, or a deuterated derivative of any of the above to form said compound of formula (Y-2), a salt thereof, or a deuterated derivative of any of the above from the above:

205. The method of embodiment 204, wherein said reaction of a compound of formula (A), a salt thereof, or a deuterated derivative of any of the above with a compound of formula (B-2), a salt thereof, or a deuterated derivative of any of the above is carried out in the presence of a base.

206. The method of embodiment 205, wherein said reaction of a compound of formula (A), a salt thereof, or a deuterated derivative of any of the foregoing with a compound of formula (B-2), a salt thereof, or a deuterated derivative of any of the above comprises reacting a compound of formula (A) , a salt thereof, or a deuterated derivative of any of the above with a coupling reagent and subsequently with a compound of formula (B-2), a salt thereof, or a deuterated derivative of any of the above, in the presence of a base.

207. The method according to any one of claims 204-206, further comprising reacting a compound of formula (D), a salt thereof or a deuterated derivative of any of the above with a compound of formula (E-2), a salt thereof or a deuterated derivative of any of the above to form said compound formula (B-2), a salt thereof or a deuterated derivative of any of the above:

- 96 044967 o x

V

O h ₂ n

where R ^d represents halogen.

208. Method for preparing a compound of formula (Y-3):

a salt thereof or a deuterated derivative of any of the above, wherein reacting a compound of formula (A), a salt thereof or a deuterated derivative of any of the above with a compound of formula (B-3), a salt thereof or a deuterated derivative of any of the above to form said compound of formula (Y- 3), a salt thereof or a deuterated derivative of any of the above:

209. The method of embodiment 208, wherein said reaction of 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 carried out in the presence of a base.

210. The method of embodiment 208, wherein said reaction of 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 above involves reacting a compound of formula ( A), a salt thereof or a deuterated derivative of any of the above with a coupling reagent and subsequently with a compound of formula (B-3), a salt thereof or a deuterated derivative of any of the above, in the presence of a base.

211. The method according to any one of claims 208-210, further comprising reacting a compound of formula (D), a salt thereof or a deuterated derivative of any of the above with a compound of formula (E-3), a salt thereof or a deuterated derivative of any of the above to form said compound formula (B-3), a salt thereof or a deuterated derivative of any of the above:

- 97 044967

a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein ring D is

containing the reaction of a compound of formula (X), a salt thereof, or a deuterated derivative of any of the above with a compound of formula (Z-1), a salt thereof, or a deuterated derivative of any of the above:

where Q ^a represents halogen;

ring A is 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 represents O, NH or N(C ₁ -C ₄ -alkyl);

each R ¹ is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C ₁ -C ₂ haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y) _k -R ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and independently substituted

- 98 044967 one or more groups selected from halogens, C1- _C2 alkyl groups, haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups; where k is 0, 1, 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y) _k -R ⁷ is not bonded to another heteroatom in -(Y) _k -R ⁷ , wherein each ^R5 and ^R6 are independently selected from hydrogen, halogens, hydroxyl group, C1-C4alkyl groups, and C3-5cycloalkyl groups, or ^R5 and ^R6 on the same carbon atom together form a C3-5cycloalkyl group, or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, CrC ₂ alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected 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 bivalent linker of formula (L) _r , where r is 1, 2, 3, 4, 5 or 6;

each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C ₁ -C ₂ haloalkyl groups, C1 -C2 alkyl groups, hydroxyl group, C ₁ -C ₂ alkoxy groups and C ₁ -C ₂ haloalkoxy groups; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

213. Method for preparing a compound of formula (IV-C):

a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, containing the interaction of a compound of formula (X-1), a salt thereof or a deuterated derivative of any of the above with a compound of formula (Z-1), a salt thereof or a deuterated derivative of any of the above:

where Q ^a represents halogen;

the carbon marked * 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 selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

m is 0, 1, 2, 3 or 4;

each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C1 -C2 haloalkyl groups, C1 -C2 haloalkoxy groups, halogens, a cyano group and a hydroxyl group;

n is 0, 1 or 2;

each R ³ represents methyl;

each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and is independently substituted with one or more groups selected from halogens, C1- _C2 alkyl groups, haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups, where k is 0.1 , 2, 3, 4, 5 or 6;

each Y is independently selected from the C(R5)(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y) _k - ^R7 is not bonded to another heteroatom in -(Y) ^kR7 , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3_5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3_ ₅ cycloalkyl group or oxo;

each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And

R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups and halogens;

q is equal to 1 or 2;

r is 3 or 4;

each R ⁸ and R ⁹ is independently selected from hydrogen, halogens, C ₁ -C ₂ alkyl groups, hydroxyl group, C ₁ -C ₂ alkoxy groups and C ₁ -C ₂ haloalkoxy groups; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups.

214. The compound of any one of embodiments 1-190, wherein the compound is in the form of a pharmaceutically acceptable salt.

215. The compound of embodiment 214, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt.

216. The compound of embodiment 215, wherein the pharmaceutically acceptable salt is a calcium salt.

217. The compound of any one of embodiments 191, wherein the compound is in the form of a pharmaceutically acceptable salt.

218. The compound of embodiment 217, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt.

219. The compound of embodiment 218, wherein the pharmaceutically acceptable salt is a calcium salt.

220. The compound of any one of embodiments 192, wherein the compound is in the form of a pharmaceutically acceptable salt.

221. The compound of embodiment 220, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt.

222. The compound of embodiment 221, wherein the pharmaceutically acceptable salt is a calcium salt.

223. The compound of any one of embodiments 193, wherein the compound is in the form of a pharmaceutically acceptable salt.

224. The compound of embodiment 223, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt.

225. The compound of embodiment 224, wherein the pharmaceutically acceptable salt is a calcium salt.

226. The connection of embodiment 193, wherein the connection is

OOO

227. The compound of any one of embodiments 193, wherein the compound is in the form of a calcium salt:

- 100 044967

OOO

228. The connection of embodiment 193, wherein the connection is

229. The compound of any one of embodiments 193, wherein the compound is in calcium salt form:

OOO

230. The connection of embodiment 193, wherein the connection is

OOO

231. The compound of any one of embodiments 193, wherein the compound is in calcium salt form:

OOO

232. The connection of embodiment 193, wherein the connection is

233. The compound of any one of embodiments 193, wherein the compound is in calcium salt form:

234. The connection of embodiment 193, wherein the connection is

235. The compound of any one of embodiments 193, wherein the compound is in calcium salt form:

- 101 044967

Ooo

236. The connection of embodiment 193, wherein the connection is

OOO

237. The compound of any one of embodiments 193, wherein the compound is in the form of a calcium salt:

238. The connection of embodiment 193, wherein the connection is

239. The compound of any one of embodiments 193, wherein the compound is in the form of a calcium salt:

240. The connection of embodiment 193, wherein the connection is

241. The compound of any one of embodiments 193, wherein the compound is in the form of a calcium salt:

OOO

242. The connection of embodiment 193, wherein the connection is

243. The compound of any one of embodiments 193, wherein the compound is in the form of a calcium salt:

- 102 044967

244. The connection of embodiment 193, wherein the connection is

OOO

245. The compound of any one of embodiments 193, wherein the compound is in the form of a calcium salt:

ooo

246. The method of treating cystic fibrosis according to embodiment 195, wherein the compound is in the form of a pharmaceutically acceptable salt.

247. The method of embodiment 246, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt.

248. The method of embodiment 247, wherein the pharmaceutically acceptable salt is a calcium salt.

249. A method of treating cystic fibrosis, comprising administering to a patient in need thereof a compound of embodiment 192.

250. A method of treating cystic fibrosis, comprising administering to a patient in need thereof a compound of any of embodiments 193 or 226-245.

251. The compound of any one of embodiments 249 or 250, wherein the compound is in the form of a pharmaceutically acceptable salt.

252. The method of embodiment 251, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt.

253. The method of embodiment 252, wherein the pharmaceutically acceptable salt is a calcium salt.

254. A method of treating cystic fibrosis, comprising administering to a patient in need thereof a compound of any one of embodiments 1-190, wherein the compound is administered in combination with Compound III or a pharmaceutically acceptable salt or deuterated derivative thereof.

255. A method of treating cystic fibrosis, comprising administering to a patient in need thereof a compound of Embodiment 191, wherein the compound is administered in combination with Compound III or a pharmaceutically acceptable salt or deuterated derivative thereof.

256. A method of treating cystic fibrosis, comprising administering to a patient in need thereof a compound of Embodiment 192, wherein the compound is administered in combination with Compound III or a pharmaceutically acceptable salt or deuterated derivative thereof.

257. A method of treating cystic fibrosis, comprising administering to a patient in need thereof a compound of any one of embodiments 193 or 226-245, wherein the compound is administered in combination with compound III or a pharmaceutically acceptable salt or deuterated derivative thereof.

258. The method of any one of embodiments 254-257, wherein the deuterated derivative of compound III is compound III-d.

259. A method of treating cystic fibrosis, comprising administering to a patient in need thereof a compound according to any one of claims 1 to 190, wherein the compound is administered in combination with (a) compound II and (b) compound III or a deuterated derivative thereof.

260. A method of treating cystic fibrosis, comprising administering to a patient in need thereof a compound according to embodiment 191, wherein the compound is administered in combination with (a) compound II and (b) compound III or a deuterated derivative thereof.

261. A method of treating cystic fibrosis, comprising administering to a patient in need thereof a compound according to embodiment 192, wherein the compound is administered in combination with (a) compound II and (b) compound III or a deuterated derivative thereof.

262. A method of treating cystic fibrosis, comprising administering to a patient in need thereof a compound according to any one of claims 193 or 226-245, wherein the compound is administered in combination with (a) compound II and (b) compound III or a deuterated derivative thereof.

- 103 044967

263. The method of any one of embodiments 259-262, wherein the deuterated derivative of compound III is compound III-d.

264. The method of any one of embodiments 254-262, wherein the compound is in the form of a pharmaceutically acceptable salt.

265. The method of embodiment 264, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt.

266. The method of embodiment 265, wherein the pharmaceutically acceptable salt is a calcium salt.

267. A pharmaceutical composition comprising the compound of Embodiment 191 and a pharmaceutically acceptable carrier.

268. A pharmaceutical composition comprising the compound of embodiment 192 and a pharmaceutically acceptable carrier.

269. A pharmaceutical composition containing a compound according to any one of claims 193 or 226-245 and a pharmaceutically acceptable carrier.

270. The pharmaceutical composition of any one of embodiments 267-269, wherein the compound is in the form of a pharmaceutically acceptable salt.

271. The pharmaceutical composition of embodiment 270, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt.

272. The pharmaceutical composition of embodiment 271, wherein the pharmaceutically acceptable salt is a calcium salt.

273. The pharmaceutical composition according to any one of paragraphs 267-272, further containing compound III or a pharmaceutically acceptable salt or deuterated derivative thereof.

274. The pharmaceutical composition of embodiment 273, wherein the deuterated derivative of compound III is compound III-d.

275. The pharmaceutical composition according to any one of paragraphs 267-272, further containing (a) compound II and (b) compound III or a deuterated derivative thereof.

276. The pharmaceutical composition of embodiment 275, wherein the deuterated derivative of compound III is compound III-d.

277. The compound of any one of embodiments 1-190 for use in the treatment of cystic fibrosis.

278. The compound of embodiment 191 for use in the treatment of cystic fibrosis.

279. The compound of embodiment 192 for use in the treatment of cystic fibrosis.

280. The compound of any one of embodiments 193 or 226-245 for use in the treatment of cystic fibrosis.

281. A compound for use according to any one of embodiments 277-280, wherein the compound is in the form of a pharmaceutically acceptable salt.

282. The compound for use in embodiment 281, wherein the pharmaceutically acceptable salt is a sodium salt, a calcium salt, or a potassium salt.

283. The compound for use in embodiment 282, wherein the pharmaceutically acceptable salt is a calcium salt.

284. A compound for use according to any one of claims 277 to 283, wherein the treatment further comprises administering compound III.

285. A compound for use according to any one of claims 277 to 283, wherein the treatment further comprises administering compound III-d.

286. A compound for use according to any one of claims 277 to 283, wherein the treatment further comprises administering a compound II and a compound III.

287. A compound for use according to any one of claims 277 to 283, wherein the treatment further comprises administering compound II and compound III-d.

Other options include a compound of formula I:

a pharmaceutically acceptable salt of a compound of formula I

- 104 044967

(ii) a pharmaceutically acceptable carrier.

The pharmaceutical composition according to embodiment C, further containing compound II:

The pharmaceutical composition of embodiment C, further comprising a pharmaceutically acceptable salt of compound II:

The pharmaceutical composition according to embodiment C, further containing compound III:

The pharmaceutical composition according to embodiment C, further comprising a pharmaceutically acceptable salt of compound III:

The pharmaceutical composition according to embodiment D, further comprising compound III:

The pharmaceutical composition of embodiment D, further comprising a pharmaceutically acceptable salt of compound III:

The pharmaceutical composition according to embodiment E, additionally containing the compound - 105 044967

The pharmaceutical composition of embodiment E, further comprising a pharmaceutically acceptable salt of compound III:

tion III:

Pharmaceutical composition containing: a pharmaceutically acceptable salt of a compound of formula I

pharmaceutically acceptable carrier.

The pharmaceutical composition according to embodiment L, further comprising compound II:

The pharmaceutical composition of embodiment L, further comprising a pharmaceutically acceptable salt of compound II:

The pharmaceutical composition according to embodiment L, further comprising compound III:

The pharmaceutical composition of embodiment L, further comprising a pharmaceutically acceptable salt of compound III:

Pharmaceutical composition according to embodiment M, further containing compound III:

The pharmaceutical composition of embodiment M, further comprising a pharmaceutically acceptable salt of compound III:

- 106 044967

Pharmaceutical composition according to embodiment M, further containing compound III:

The pharmaceutical composition of embodiment M, further comprising a pharmaceutically acceptable salt of compound III:

A method of treating cystic fibrosis, comprising administering to a patient in need thereof a compound of formula I

A method of treating cystic fibrosis, comprising administering to a patient in need thereof a pharmaceutically acceptable salt of a compound of formula I

A method of treating cystic fibrosis, comprising administering to a patient in need thereof a pharmaceutical composition containing: a compound of formula I:

pharmaceutically acceptable carrier.

A method of treating cystic fibrosis, comprising administering to a patient in need of it a pharmaceutical composition containing:

a pharmaceutically acceptable salt of a compound of formula I

pharmaceutically acceptable carrier.

- 107 044967

General experimental procedures

The definitions of some of the abbreviations in the examples below are summarized below:

Boc: anhydride ((Boc) _2O ): di-tert-butyl dicarbonate;

CDI: carbonyldiimidazole;

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: hexafluorophosphate 1 -[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3 hexafluorophosphate oxide;

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: complex of triphenylphosphine oxide with diisopropyl azodicarboxylate.

Reagents and starting materials were obtained from commercial sources unless otherwise stated and were used without purification. Proton and carbon NMR spectra were obtained either on a Bruker Biospin DRX 400 MHz FT-NMR spectrometer operating at 1H and ¹³ C resonance frequencies of 400 and 100 MHz, respectively, or on a 300 MHz NMR spectrometer. One-dimensional proton and carbon spectra were acquired using a broadband observation probe (BBFO) with a sample rotation of 20 Hz and a digital resolution of 0.1834 and 0.9083 Hz/Pt, respectively. All proton and carbon spectra were acquired under temperature control at 30°C using standard previously published pulse sequences and standard processing parameters. The final purity of the compounds was determined by reverse phase HPLC using an Acquity UPLC BEN C ₁₈ column (50x2.1 mm, 1.7 μm particle size) manufactured by Waters (part number: 186002350) and a dual gradient with a mobile phase change of 1-99% B for 3.0 min. Mobile phase A=H2O (0.05% CF3CO2H). Mobile phase B=CH ₃ CN (0.035% CF3CO2H). Flow rate=1.2 ml/min, injection volume=1.5 µl and column temperature=60°C. The final purity was calculated by averaging the area under the curve (AUC) of two UV curves (220 nm, 254 nm). Low resolution mass spectra are presented as [M+H]+ samples obtained using a single quadrupole mass spectrometer equipped with an electrospray ionization (ESI) source capable of providing a mass accuracy of 0.1 Da and a minimum resolution of 1000 (no resolution units) throughout the entire detection range. The optical purity of methyl (2S)-2,4-dimethyl-4-nitropentanoate was determined by chiral gas chromatography (GC) analysis on an Agilent 7890A/MSD 5975C instrument using Restek Rt-PDEXcst (30 mx0.25 mmx0.25 μm_df) with flow rate 2.0 ml/min (carrier gas _H2 ), at an injection temperature of 220°C and a thermostat temperature of 120°C, 15 min.

Synthetic examples

Synthesis of compound II: (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxynropyl)-6fluoro-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-2yl)- 2-methylpropanoate and ((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl-2-(1-(((R)-2,2-dimethyl-1,3- 108 044967 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)-2methylpropanoate (3.0 g, 8.4 mmol) and (8)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl-4methylbenzenesulfonate (7.23 g, 25.3 mmol) in DMF (Ni,Ni-dimethylformamide) (17 ml). The reaction mixture 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 containing both of the above products, was sent directly to the next step without further purification. (R)-benzyl 2-(1-((2,2-dimethyl-1,3-dioxolan-4yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate, MS-ESI m/z calc. 470.2, found 471.5 (M+1)+. Hold time 2.20 minutes. ((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl 2-(1-(((R)-2,2dimethyl-1,3-dioxolan-4-yl)methyl)- 6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate, ESI-MS m/z cal. 494.5, found 495.7 (M+1) ⁺ . Hold 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)- 2methylpropan-1-ol.

The crude reaction mixture obtained in step (A) was dissolved in THF (42 ml) and cooled in an ice water bath. LiAlH ₄ (16.8 ml of 1 M solution, 16.8 mmol) was added dropwise. After 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 through 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 give (R)-2-(1-((2,2-dimethyl-1,3-dioxolan-4yl)methyl)-6-fluoro-5 -nitro-1H-indol-2-yl)-2-methylpropan-1-ol as a brown oil (2.68 g, 87% in 2 steps). MS-ESI m/z calc. 366.4, found 367.3 (M+1) ⁺ . Retention time 1.68 minutes.

1H NMR (400 MHz, DMSO-d ₆ ) 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 dimethyl sulfoxide).

Step 3: (R)-2-(5-amino-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-1H-indol-2-yl) -2methylpropan-1-ol.

(R)-2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropan1 -ol (2.5 g, 6.82 mmol) was dissolved in ethanol (70 ml) and the reaction mixture was washed with N2. Pd-C (250 mg, 5% wt) was then added. The reaction mixture was again purged with nitrogen and then stirred under H ₂ (atm). After 2.5 hours, only partial conversion to product was observed by LCMS. The reaction was filtered through celite and concentrated. The residue was re-subjected to the above conditions. After 2 hours, LCMS showed complete conversion to product. The reaction mixture was filtered through celite. The filtrate was concentrated to give the product (1.82 g, 79%). MS-ESI m/z calc. 336.2, found 337.5 (M+1) ⁺ . Retention time 0.86 minutes.

1H NMR (400 MHz, DMSO-d ₆ ) 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-4yl )methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide.

DMF (3 drops) was added to a stirred 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 formed. The solution was concentrated in vacuo, then toluene (3 ml) was added and the mixture was concentrated again. The toluene step was repeated once more and the residue was placed under high vacuum for 10 minutes. The acid chloride was then dissolved in dichloromethane (10 ml) and added to the mixture of (R)-2-(5amino-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 mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with 1 N. HCl solution, saturated NaHCO ₃ solution and brine, dried over MgSO ₄ and concentrated to give the product (3 g, 100%).

MS-ESI m/z calc. 560.6, found 561.7 (M+1) ⁺ . Hold time 2.05 min.

1H 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-( 1Hydroxy-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-fluoro2-(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 mixture was heated at 80°C for 45 minutes. Reactionary

- 109 044967 the mixture was then evaporated at room temperature and partitioned between saturated aqueous NaHCO ₃ and ethyl acetate. The ethyl acetate layer was separated, dried over MgSO ₄ , filtered and evaporated. The residue was purified by column chromatography (50-100% ethyl acetate-hexanes) to give the product. (1.3 g, 47%, ee >98% by SKZHK). MS-ESI m/z calc. 520.5, found 521.7 (M+1)+. Retention time 1.69 minutes.

¹ H NMR (400 MHz, DMSO-f,) δ 8.31 (s, 1H), 7.53 (s, 1H), 7.42-7.38 (m, 2H), 7.33-7.30 (m, 2H), 6.22 (s, 1H ), 5.01 (d, J=5.2 Hz, 1H), 4.90 (t, J=5.5 Hz, 1H), 4.75 (t, J=5.8 Hz, 1H), 4.40 (dd, J=2.6, 15.1 Hz, 1H ), 4.10 (dd, J=8.7, 15.1 Hz, 1H), 3.90 (s, 1H), 3.65-3.54 (m, 2H), 3.48-3.33 (m, 2H), 1.48-1.45 (m, 2H), 1.35 (s, 3H), 1.32 (s, 3H) and 1.14-1.11 (m, 2H) ppm.

Synthesis of compound III: N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3carboxamide.

Part A: Synthesis of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid

Step 1: 2-phenylaminomethylene diethyl malonic acid 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 hours. The mixture was cooled to room temperature and dried at reduced pressure to obtain 2-phenylaminomethylenemalonic acid diethyl ester as a solid, which was used in the next step without further purification.

1H NMR (DMSO-b6) 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), 4.174.33 (m , 4H), 1.18-1.40 (m, 6H).

Step 2: 4-hydroxyquinoline-3-carboxylic acid ethyl ester.

A 1 L three-neck flask equipped 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 hours. The solution was cooled to room temperature and filtered. The residue was treated with an aqueous solution of Na ₂ CO ₃ , 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 for the 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 (2 N, 150 ml) and stirred for 2 hours at reflux. After cooling, the mixture was filtered and the filtrate was acidified to pH 4 with 2N. HCl. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to give 4-oxo-1,4dihydroquinoline-3-carboxylic acid as a pale white solid (10.5 g, 92%).

1H NMR (DMSO-d6) 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 K-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3carboxamide

Pd-C, EtOH

Step 1: 2,4-di-tert-butylphenylcarbonate methyl ester.

Methyl chloroformate (58 ml, 750 mmol) was added dropwise to a solution of 2,4-di-tert-butylphenol (103.2 g, 500 mmol), Et ₃ N (139 ml, 1000 mmol) and DMAP (3.05 g, 25 mmol) in dichloromethane (400 ml) was cooled in an ice-water bath to 0°C. The mixture was allowed to warm to room temperature with stirring overnight, then filtered through silica gel (approximately 1 L) using 10% ethyl acetate-hexanes (~4 L) as eluent. The combined filtrates were concentrated to give methyl 2,4-di-tert-butylphenyl phenyl ester as a yellow oil (132 g, col).

1H 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: 2,4-di-tert-butyl-5-nitro-phenyl carbonate methyl ester and 2,4-di-tert-butyl-6-nitrophenyl carbonate methyl ester.

To a stirred 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, a cooled mixture of sulfuric acid (2 ml) and nitric acid (2 ml) was added. The addition was done slowly so that the reaction temperature did not exceed 50°C. The reaction mixture was stirred for 2 hours 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 obtain a mixture of 2,4-di-tert-butyl-5-nitrophenylcarbonate methyl ester and methyl ester 2, 4-di-tert-butyl-6-nitrophenyl carbonate 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.

A mixture of 2,4-di-tert-butyl-5-nitrophenyl carbonate methyl ester and 2,4-di-tert-butyl-6-nitrophenyl methyl ester (4.2 g, 14.0 mmol) was dissolved in MeOH (65 ml) before adding KOH (2.0 g, 36 mmol). The mixture was stirred at room temperature for 2 hours. Then the reaction mixture was acidified (pH 2-3) by adding conc. HCl and partitioned between water and diethyl ether. The ether layer was dried (MgSO4), concentrated and purified by column chromatography (0-5% ethyl acetate-hexanes) to give 2,4-di-tert-butyl-5-nitrophenol (1.31 g, 29% over 2 steps) and 2 ,4-di-tert-butyl-6-nitrophenol. 2,4-di-tert-butyl-5-nitrophenol.

1H 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-5-nitrophenol: ^1H 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.

Pd-5% was added to a reflux solution of 2,4-di-tert-butyl-5-nitrophenol (1.86 g, 7.40 mmol) and ammonium formate (1.86 g) in ethanol (75 ml). wt. on activated carbon (900 mg). The reaction mixture was stirred at reflux for 2 hours, cooled to room temperature and filtered through celite. The celite was washed with methanol and the combined filtrates were concentrated to give 5-amino-2,4-di-tert-butylphenol as a gray solid (1.66 g, quant.).

1H 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 d6) δ 8.64 (s, 1H, OH), 6.84 (s, 1H), 6.08 (s, 1H), 4.39 (s, 2H, NH2), 1.27 (m, 18H); HPLC time beat 2.72 min., 10-99% CH3CN, 5 min. processed; ESI-MS 222.4 m/z [M+H]+.

Step 5: N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide

Et ₃ N (63.0 ml, 451 mmol) at ambient temperature. The mixture became homogeneous and was left stirring for 10 minutes before 5amino-2,4-di-tert-butylphenol (50.0 g, 226 mmol) was added in small portions. The mixture was stirred overnight at ambient temperature. During the reaction, the mixture became heterogeneous. After all the acid had been consumed (LC-MS analysis, MH+190, 1.71 min), the solvent was removed in vacuo. EtOH (ethyl alcohol) was added to the orange solid to form a slurry. The mixture was stirred on a rotary evaporator (bath temperature 65°C) for 15 min without placing the system under vacuum. The mixture was filtered and the captured solid was washed with hexane to obtain a white solid which was an EtOH crystal. Et2O (diethyl ether) was added to the above solid to form a suspension. The mixture was stirred on a rotary evaporator (bath temperature 25°C) for 15 min without placing the system under vacuum. The mixture was filtered and the solid was captured. This procedure was performed a total of five times. The solid obtained from the fifth precipitation was placed under vacuum overnight to provide N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamideα (38 g, 52% ). HPLC time beat 3.45 min., 10-99% CH3CN, 5 min. processed;

1H NMR (400 MHz, DMSO-dg) δ 12.88 (s, 1H), 11.83 (s, 1H), 9.20 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J=8.2,

- 111 044967

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); MS-ESI m/z calc. 392.21; found 393.3 [M+H]+.

Synthesis of compound IV: 3-(6-(1-(2,2-difluorobenzo[b][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3methylpyridin-2-yl)benzoic acid.

Compound IV can be prepared by coupling the acid chloride moiety to the amine moiety according to Schemes IV-A to IV-D.

Scheme IV-A. Synthesis of the acid chloride fragment.

F 0-¾¾ recovery 1. S0C1? _{with η Λ}

X 1 J ------*- χΊΪΊ -----=-* % ^υ 7ίΊ

F 0 ССХ ₂ _ _Na0H F сг-Сж..О ⁿ _{2 F 0} -CA^CI

1. NaCN

_2.H2O

T ^F F ^X O^CN > _q XX _cn

SOC1 ₂

F Cr -'-^ X C

Scheme IV-A shows the preparation of 1-(2,2-difluorobenzo[b][1,3]dioxol-5yl)cyclopropanecarbonyl chloride, which is used in Scheme IV-C to form the amide bond of compound IV.

The starting material, 2,2-difluorobenzo[b][1,3]dioxole-5-carboxylic acid, is commercially available from Saltigo (a subsidiary of Lanxess Corporation). Reduction of the carboxylic acid moiety in 2,2-difluorobenzo[b][1,3]dioxole-5-carboxylic acid to the primary alcohol followed by conversion to the corresponding chloride using thionyl chloride (SOCl2) gives 5-(chloromethyl)-2,2difluorobenzo [b][1,3]dioxole, which is then converted to 2-(2,2-difluorobenzo[b][1,3]dioxol-5yl)acetonitrile upon addition of sodium cyanide. Treatment of 2-(2,2-difluorobenzo[b][1,3]dioxol-5yl)acetonitrile with base and 1-bromo-2-chloroethane gives 1-(2,2-difluorobenzo[b][1,3]dioxol- 5yl)cyclopropanecarbonitrile. The nitrile moiety in 1-(2,2-difluorobenzo[b][1,3]dioxol-5yl)cyclopropanecarbonitrile is converted to a carboxylic acid using a base to give 1-(2,2-difluorobenzo[b][1,3]dioxol -5-yl)cyclopropanecarboxylic acid, which is converted to the desired acid chloride using thionyl chloride.

Scheme IV-B

Alternative synthesis of the acid chloride fragment.

Scheme IV-B depicts an alternative synthesis of the required acid chloride. 5-Bromomethyl-2,2difluoro-1,3-benzodioxole combines with ethyl cyanoacetate in the presence of a palladium catalyst to form the corresponding alpha-cyanoethyl ester. Saponification of the ester moiety to a carboxylic acid gives cyanoethyl compound IV. Alkylation of a cyanoethyl compound with 1 bromo-2-chloroethane in the presence of a base gives the cyanocyclopropyl compound. Treatment of the cyano-112 044967 cyclopropyl compound with a base produces a carboxylate salt, which is converted to a carboxylic acid by treatment with an 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

Synthesis of amino group.

1. K ₂ CO ₃ .PdCdppf)Cl ₂ /у ιΉύ^-Α 2. aq.MsOH

- V V

COjtBu ► CO^Bu urea peroxyhydrate phthalic anhydride EtOAc.

T

1. M^RUDSKH I UJ

C02tBu 2. ethanolamine ^α - cQ-tBu

Scheme IV-C shows the preparation of the required tert-butyl 3-(6-amino-3-methylpyridin-2yl)benzoate, which is combined with 1-(2,2-difluorobenzo[b][1,3]dioxol-5yl) cyclopropanecarbonyl chloride in Scheme IV-C to give compound IV. The palladium-catalyzed coupling of 2-bromo-3-methylpyridine with 3-(tert-butoxycarbonyl)phenylboronic acid produces tert-butyl 3-(3-methylpyridin-2-yl)benzoate, which is then converted to the desired compound.

Scheme IV-D

Formation of the acid salt of 3-(6-(1-(2,2-difluorobenzo[b][1,3]dioxol-5yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid.

. X Wy

CO^i CO^Bi acid acid

Scheme IV-D depicts the coupling of 1-(2,2-difluorobenzo[b][1,3]dioxol-5yl)cyclopropanecarbonyl chloride with tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate using triethylamine and 4-dimethylaminopyridine to initially prepare the tert-butyl ester of compound IV.

Syntheses of compounds

General analytical methods UHPLC/HPLC.

Unless otherwise stated, yields of enantiomers separated by chiral LCLC are given as a percentage of the theoretical yield for one racemate enantiomer.

LC Method A: Analytical reverse phase HPLC using an Acquity UPLC BEN C ₁₈ column (30 x 2.1 mm, 1.7 µm particle size) manufactured by Waters (art. no.: 186002349), and a dual gradient mobile phase change B 1-99 % for 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 HPLC using an Acquity UPLC BEN C ₁₈ column (50x2.1 mm, 1.7 µm particle size) manufactured by Waters (part number: 186002350), and dual gradient mobile phase change B 1-99 % for 3.0 min. 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 (50x3.0 mm) and a double 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). Flow rate=1.5 ml/min, injection volume=2 µl and column temperature=30°C.

LC Method D: Analytical reverse phase HPLC using an Acquity UPLC BEN C ₁₈ column (50x2.1 mm, 1.7 µm particle size) manufactured by Waters (P/N: 186002350), and dual gradient mobile phase change B 1-99 % for 5.0 min. 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 E: Analytical reverse phase HPLC using an Acquity UPLC BEN Cis column (50x2.1 mm, 1.7 µm particle size) manufactured by Waters (art. no.: 186002350), and a dual gradient with a mobile phase variation of 1-99% B for 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 HPLC using an Acquity UPLC BEN C ₁₈ column (50 x 2.1 mm, 1.7 µm particle size) manufactured by Waters (P/N: 186002350), and a dual gradient mobile phase change B 1-99 % for 15.0 min. 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 HPLC using an Acquity UPLC BEN C ₁₈ column (50x2.1 mm, 1.7 µm particle size) manufactured by Waters (art. no.: 186002350), and a dual gradient with mobile phase change B 30-99 % for 3.0 min. 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 4.6x50 mm 2.6 microns. Temperature: 45°C, flow: 2.0 ml/min, operating 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) over 4.0 min, then hold at 95% acetonitrile (0.1% formic acid) for 2.0 min.

LC method I: Kinetex C ₁₈ 4.6x50 mm 2.6 µm. Temperature: 45°C, flow: 2.0 ml/min, operating 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) over 2.0 min, then hold at 95% acetonitrile (0.1% formic acid) for 1.0 min.

LC Method J: Analytical reverse phase HPLC using an Acquity UPLC BEN C ₁₈ column (50x2.1 mm, 1.7 µm particle size) manufactured by Waters (P/N: 186002350), and a dual gradient mobile phase change of B 50-99 % for 3.0 min. 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 HPLC using an Acquity UPLC BEN C ₁₈ column (50x2.1 mm, 1.7 µm particle size) manufactured by Waters (art. no.: 186002350), and a dual gradient mobile phase change B 30-99 % for 1.0 min. 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 HPLC using an Acquity UPLC BEN C ₁₈ column (50x2.1 mm, 1.7 µm particle size) manufactured by Waters (art. no.: 186002350), and a dual gradient with mobile phase variation B 50-99 % for 1.0 min. 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 x 3.0 mm) and a double 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 4.6x50 mm 3.5 µm. Flow: 2.0 ml/min, gradient 95% water (0.1% trifluoroacetic acid) + 5% acetonitrile (0.1% trifluoroacetic acid) to 95% acetonitrile (0.1% trifluoroacetic acid) (2.0 min ), then hold at 95% acetonitrile (0.1% trifluoroacetic acid) for 1.0 min.

LC method O: Zorbax SB-C ₁₈ 4.6x50 mm 3.5 µm, temperature: 45°C, flow 2.0 ml/min, operating 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) over 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 (50x4.6 mm) and double 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 (50x4.6 mm) and 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 mmχ50 mm), temperature: 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 minutes, holding at 100% B for 0.5 minutes, equilibrating to 5% B over 1.5 minutes.

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LC Method S: Poroshell 120 EC-C ₁₈ 3.0x50 mm 2.7 µM, temperature: 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) over 4.0 min, then soak in 95% acetonitrile (0.1% trifluoroacetic acid) for 2.0 minutes.

LC method T: Zorbax C ₁₈ 4.6x50 mm 3.5 µM, pre-column: AJO-4287 C ₁₈ , 4x3.0 mm. Temperature: 45°C, flow: 2.0 ml/min, operating 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) over 4.0 min, then hold for 2.0 min.

LC method U: Kinetex EVO C ₁₈ 4.6 &times; 50 mm, 2.6 µm, temperature: 45°C, flow rate: 2.0 ml/min, operating 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) over 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}-1Hpyrazol-1 - yl)-2λ ⁶ -thia-3,9,11,19 ,24-pentaazatetracyclo[18.3.1.05,10.011,15]tetracose1(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 sequentially 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, 1 N was added. hydrochloric acid (400 ml) and the mixture was stirred vigorously for about 10 minutes. The product was extracted with ethyl acetate (2x300 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) tert- butyl 2,6dichloropyridine-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). MS-ESI 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

The 50 L reactor was started and the jacket was set at 20°C, with stirring at 150 rpm, reflux condenser (10°C) and nitrogen purge. Methanol (2.860 L) and methyl (E)-3methoxyprop-2-enoate (2.643 kg, 22.76 mol) were added and the reactor was capped. The reaction mixture was heated to an internal temperature of 40°C and the system was set to maintain a jacket temperature of 40°C. Hydrazine hydrate (1300 g, 55 wt%, 22.31 mol) was added portionwise through a dropping funnel over 30 min. The reaction mixture was heated to 60°C for 1 hour. The reaction mixture was cooled to 20°C and triethylamine (2.483 kg, 3.420 L, 24.54 mol) was added in portions, maintaining the 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 in portions while maintaining the temperature <45°C. The reaction mixture was stirred at 20°C for 16 hours. The reaction solution was partially concentrated to remove methanol, resulting in a clear, light amber oil. The resulting oil was transferred to a 50 L reactor, stirred and water (7.150 L) and heptane (7.150 L) were added. The additives caused a small amount of product to precipitate. The aqueous layer was poured 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 acetic acid (1.474 kg, 1.396 L, 24.54 mol) was charged, which was added dropwise. The jacket was set at 0°C to absorb the exothermic quench reaction. After addition was complete (pH 5), the reaction mixture was stirred for 1 hour. 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 to a 20 L rotary valve flask and heptane (7.150 L) was added. The mixture was suspended at 45°C for 30 minutes and 1-2 volumes of the solvent were distilled off. The suspension in the rotary flask was filtered and the solids were washed with heptane (3.575 L). The solid was further dried under vacuum (50°C, 15 mbar) to provide tert-butyl 5-oxo-1H-pyrazole-2carboxylate (2921 g, 71%) as a coarse crystalline solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 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-fluoropyridine

2,6-Difluoropyridine (200 g, 1.738 mol) was dissolved in dimethyl sulfoxide (2 L) in a 5 L three-neck round bottom 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 through a dropping funnel. An exothermic effect was observed during addition. The temperature rose to approximately 40°C. The reaction was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with dichloromethane. The extract was washed twice with water and filtered through a small layer of silica gel. The plug was eluted with dichloromethane and the filtrate was evaporated in vacuo to give 2-benzylsulfanyl-6-fluoropyridine (366 g, 96%) as a peach oil that solidified in vacuo to large blocky plates.

¹ H NMR (400 MHz, chloroform-d) δ 7.58 (kv, 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-fluoropyridine (303.2 g, 1.383 mol) was dissolved in chloroform (2.0 L) in a 12 L three-neck round bottom 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 stirred vigorously. Chlorine gas from the bottle was vigorously bubbled into the reaction using a Pasteur pipette inserted through the septum on the third neck of the flask. A white precipitate quickly formed. An exothermic effect was observed during addition. The addition of chlorine was stopped when the temperature increased to

- 116 044967

20°C. The reaction mixture was allowed to cool again before adding more chlorine gas. Dosing was continued until the reaction turned yellowish-green in color and remained so after stirring for 30 minutes. No additional ectotherms have been observed at this time. The reaction mixture was poured into a solution of 40% aqueous sodium bisulfite. The organic layer was separated and the aqueous layer was extracted with another portion of chloroform. The organic layers were combined, dried over magnesium sulfate, filtered and evaporated in vacuo to give a slightly yellow oil. The oil was dissolved in dichloromethane (1.5 L) and added dropwise to ammonium hydroxide (1.5 L, 40% w/v, 17.12 mol) in a 12 L three-neck round bottom flask equipped with an overhead stirrer, temperature probe and an additional funnel. The ammonium hydroxide solution was cooled to 0°C in an ice bath before addition. The rate of addition was adjusted so that the reaction temperature remained below 10°C. The resulting greenish-yellow solution was stirred for an hour and poured onto ice.

The layers were separated (the organic layer was dark green) and the aqueous layer was extracted with more dichloromethane. Organic layers were removed. The aqueous layer was cooled in an ice bath, and concentrated aqueous hydrochloric acid was added to the aqueous layer in portions until the pH became 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 give a light brown solid. The solid was mixed with dichloromethane (approximately 500 ml) and stirred using a magnetic stirrer until most of the large lumps were broken up. Approximately 1.5 L of pentane was added, resulting in a large amount of light brown solid precipitating. The resulting mixture was quickly stirred and then filtered. The filter cake was washed with pentane and dried in vacuo to give 6-fluoropyridine-2-sulfonamide (204.1 g, 84%) as a light brown solid.

¹ H NMR (300 MHz, DMSO-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 was added dropwise 2-[1-(trifluoromethyl)cyclopropyl]acetic acid (1.002 g, 5.948 mmol) in tetrahydrofuran (3.0 ml) for 30 min, maintaining the reaction temperature below 20°C. The reaction mixture was allowed to gradually warm to ambient temperature and stirred for 18 hours. The mixture was cooled in an ice bath and quenched successively with water (294 mg, 295 μl, 16.36 mmol), sodium hydroxide (297 μl 6 M, 1.784 mmol) and then with water (884.0 μL, 49.07 mmol) to obtain 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, filtered and concentrated in vacuo to obtain a product with residual tetrahydrofuran and ether. The mixture was transferred to the next stage 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 to tetrahydrofuran (10.48 ml) and the reaction mixture 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 mixture was allowed to warm to room temperature over 16 hours. The mixture was evaporated and the resulting material was partitioned between ethyl acetate (30 mL) and 1 N. 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 chromatography on silica gel, eluting with a gradient of ethyl acetate in hexanes (0-30%), to give tert-butyl 3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-1carboxylate (1.03 g, 57 %). MS-ESI 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 mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated and the resulting oil was partitioned between ethyl acetate (10 ml) and 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, DMSO-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). MS-ESI 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). 1,4Diazabicyclo[2.2.2]octane (62 mg, 0.5540 mmol) was added and the mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was diluted with water (20 ml) and stirred for 15 minutes. 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%) . MS-ESI m/z calc. 431.12, detected 432.1 (M+1) ⁺ ; Retention time: 0.88 min (LC method A).

Step 9: carboxylic acid

2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-

tert-Butyl-2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3carboxylate (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 hours. The reaction mixture 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]pyridin-3-carboxylic acid (873 mg, 99%) MSER m /z calc. 375.06, detected 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-dimethylaminopyridine (9.19 g, 42.1 mmol) and triethylamine (4.26 g, 42.1 mmol) was dissolved in anhydrous dichloromethane (140 ml), then di-tert-butyl dicarbonate (27.6 g, 0.126 mol) was added. The reaction mixture was stirred at room temperature for 48 hours. The reaction solution was diluted with dichloromethane (500 ml), washed with 1 N. aqueous solution of hydrogen chloride (100 ml) and saline solution (2x50 ml). The organic layers were dried over magnesium sulfate, filtered and concentrated. The resulting residue was subjected to silica gel chromatography using a hexane-ethyl acetate gradient method (0 to 20% ethyl acetate in hexanes) to give tert-butyl 2,2-dimethyl-5-oxopyrrolidine-1-carboxylate (5.48 g, 58% ) as a white solid.

1H 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). MS-ESI 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-dimethylpyrrolidine-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. Diisobutylaluminum hydride (14.1 mmol, 14 ml, 1.0 M in toluene) was slowly added to the above solution, and the resulting solution was stirred at -78°C for 4 hours, and then warmed to room temperature and further stirred for 3 hours Then p-toluenesulfonic acid monohydrate (18 mg) in methyl alcohol (40 ml) was added and the resulting solution was stirred for 19 hours.

- 118 044967 the solvents were removed under reduced pressure. A saturated aqueous solution of potassium sodium tartrate (100 ml) was added to the resulting residue and stirred for 3 hours. The solution was extracted with diethyl ether (3x150 ml). The combined organic layers were washed with brine (2x50 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the intermediate as a 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. Boron trifluoride diethyl etherate (1.72 g, 12.1 mmol) was then added slowly. After addition was complete, the reaction solution was stirred at -78°C for 2 hours and then for another 2 hours 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 (3x60 ml). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography using a hexane-ethyl acetate gradient method (0 to 15% ethyl acetate) to give tert-butyl-5-allyl-2,2-dimethylpyrrolidine-1-carboxylate (0.92 g, 30%) in in the form of 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). MS-ESI 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 ^os Boc/° ^H

ΕγΑ f= ______- D-N /— ⁷

9-BBN (15.38 mmol, 30 .8 ml, 0.5 M in tetrahydrofuran). The resulting solution was stirred at room temperature for 3 hours. The reaction solution was cooled to 0°C, an aqueous solution of hydrogen peroxide (38.5 mmol, 4.4 ml, 30% in water) was added, followed by sodium hydroxide (19.25 mmol , 3.9 ml, 20% in water). The reaction mixture was then stirred at room temperature for 1.5 hours. Water (50 ml) was added and the aqueous solution was extracted with diethyl ether (4x80 ml). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using hexanes and ethyl acetate (0 to 35% ethyl acetate in hexanes) to give tert-butyl 5-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate (834 mg, 84%) as colorless oil.

1H NMR (250 MHz, DMSO) 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). MS-ESI 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.

|Boc, / ''—on _Vos A'-o o nA ----* nA _z s ^z —gD °' ⁴ 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 dichloromethane and cooled in an ice bath. Methanesulfonyl chloride (1.2 mL, 15.0 mmol) was added dropwise over 10 minutes and the resulting mixture was stirred in an ice bath for 20 minutes. The mixture was quenched with saturated sodium bicarbonate (10 ml) and the organic layer was washed with water (10 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give tert-butyl-2,2-dimethyl-5-(3((methylsulfonyl )hydroxy)propyl)pyrrolidine-1-carboxylate (4.9 g, quantitative yield) as an orange oil. The crude product was used for the next step without further purification. MS-ESI 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 |Boc^ Ο _{ύ x} O Boc NHj nA X ---* nA > o ^x Ϊ >

A 30% aqueous solution of ammonium hydroxide (70 ml), and the resulting mixture was heated in a closed container at 60°C for 20 hours. The mixture was concentrated in vacuo and extracted with dichloromethane (3x100 ml). The combined organic layers were concentrated to an oil and purified by silica gel column chromatography using a 0-15% dichloromethane-methanol gradient to give tert-butyl 5-(3-aminopropyl)-2,2dimethyl-pyrrolidine-1-carboxylate (2.14 d, yield 61% in two stages) in the form of a light oil.

1H NMR (500 MHz, DMSO) δ 53.66 (d, 1H), 2.85 (b, s, 2H), 2.58-2.48 (m, 2H), 1.85-1.18 (m, 22H). MS-ESI m/z calc. 256.4, found 257.4 (M+1) ⁺ ; Retention time: 3.50 min (LC method Q).

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Step 15: tert-butyl 5-[3-(tert-butoxycarbonylamino)propyl]-2,2-dimethyl-pyrrolidine-1carboxylate

tert-Butyl 5-(3-aminopropyl)-2,2-dimethylpyrrolidine-1-carboxylate (640 mg, 2.496 mmol) was dissolved in dichloromethane (6.4 ml) under a nitrogen atmosphere and triethylamine (1.01 g) was added , 9.981 mmol), followed by di-tert-butyl dicarbonate (1.362 g, 6.241 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture 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 to give tert-butyl-5-[ 3-(tert-butoxycarbonylamino)propyl]-2,2-dimethylpyrrolidine-1carboxylate (720 mg, 81%) as a clear oil. MS-ESI m/z calc. 356.26752, detected 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-dimethylpyrrolidine 1-carboxylate.

tert-Butyl 5-[3-(tert-butoxycarbonylamino)propyl]-2,2-dimethylpyrrolidine-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 left stirring at room temperature for 16 hours. Potassium carbonate (1.396 g, 10.10 mmol) was added. , then methyl iodide (860.2 mg, 6.060 mmol), and the reaction mixture was stirred overnight. Sodium hydride (404 mg, 10.1 mmol) was added and stirred for 6 hours. Sodium hydride (121 mg, 5.04 mmol) was added and the reaction mixture was placed in a refrigerator at 4°C for 3 days. The reaction mixture was warmed to room temperature, methyl iodide (860.2 mg, 6.060 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane and then washed with water (2 x 40 ml). The organic layer was washed twice with brine and then with saturated aqueous sodium carbonate to bring the reaction mixture to pH ~12. The reaction mixture was then extracted using dichloromethane (3x75 ml). The combined organic fractions were dried over sodium sulfate, filtered and concentrated to give 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-dimethylpyrrolidine-1- carboxylate (695 mg, 93%) as a yellow oil. MS-ESI 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-methylpronan-1-amine (ditrifluoroacetic acid salt).

To a stirred solution of tert-butyl 5-[3-[tert-butoxycarbonyl(methyl)amino]propyl]-2,2dimethylpyrrolidine-1-carboxylate (695 mg, 1.876 mmol) in methylene chloride (6.95 ml) at 0°C trifluoroacetic acid (2.891 mL, 37.52 mmol) was added and the mixture was stirred at room temperature for 5 hours. Volatiles were removed under reduced pressure and then evaporated from the ether 3 times to give 3-(5,5-dimethylpyrrolidine-2- yl)-N-methylpropan-1-amine (ditrifluoroacetic acid salt) (747.3 mg, 100%). MS-ESI 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]pyridin-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 carbonyldiimidazole (590 mg , 3.639 mmol) were combined in tetrahydrofuran (15.3 ml) and stirred for 2 hours. At this point, 6-fluoro-2-pyridine sulfonamide (534 mg, 3.03 mmol) was added, then 1,8-diazabicyclo[5.4. 0]undec-7-ene (907 μL, 6.07 mmol) and the reaction mixture was stirred for an additional 30 min at room temperature. The reaction was diluted with ethyl acetate and

- 120 044967 was washed with a 1M solution of citric acid, and then with saline solution. The organic layers 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 a minimal amount of hot dichloromethane. The reaction mixture was slowly cooled to room temperature, then in an ice water bath, yielding a mass of white solid, which was filtered and washed with hexane. The solid was dried under reduced pressure to give 2-chloro-H-[(6-fluoro-2pyridyl)sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine -3 carboxamide (1.48 g, 89%). MS-ESI m/z calc. 533.05475, detected 543.3 (M+1)+; Retention time: 0.72 min (LC method A).

Step 19: 2-χλορ-Ν-[[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]pyrazol1-yl]pyridin-3-carboxamide (1.033 g, 1.876 mmol), 3-(5,5-dimethylpyrrolidin-2-yl)-N-methylpropan-1amine (ditrifluoroacetic acid salt) (747.3 mg, 1.876 mmol), potassium carbonate (1.556 g, 11.26 mmol) and dimethyl sulfoxide (5 ml) was added to the vial, capped and heated to 50°C for 20 min. The reaction mixture was heated to 65°C for 90 minutes. The reaction mixture was again cooled to 50°C and stirred for 32 hours. The reaction mixture was cooled to room temperature and 2-chloro-N-[(6-fluoro-2-niridyl)sulfonyl]-6-[3-[2- [1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (300 mg, 0.5451 mmol) was then warmed back to 50°C and stirred overnight. The reaction mixture was cooled to room temperature and poured into water to obtain a white precipitate. Concentrated hydrochloric acid was added to adjust the pH to 4 and then the white solid was filtered off and washed with water and then hexane. 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 to give 2-chloro-A[6-[3-(5,5dimethylpyrrolidin-2-yl)propylmethyl-amino]-2-pyridyl ]sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (350 mg, 27%) as a white solid. MS-ESI 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)2X ⁶ -thia-3,9,11,19 ,24-pentaazatetracyclo[18.3.1.05,10.011,15]tetracose-1(23),5,7,9,20(24),21-hexaene-2,2,4trione (compound 9)

Combined 2-chloro-N-[[6-[3-(5,5-dimethylpyrrolidin-2-yl)propylmethylamino]-2pyridyl]sulfonyl]-6-[3-[2-[1 -(trifluoromethyl)cyclopropyl]ethoxy ] pyrazol-1-yl] pyridin-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 A molecular sieves and dimethyl sulfoxide (7.077 ml) in a vial, purged with nitrogen, capped, heated to 150 ° C and stirred for 25 hours. Cooled to room temperature, then poured into ~ 150 ml of water. The pH was adjusted to 4 by adding concentrated hydrochloric acid dropwise to obtain a tan precipitate, which was filtered and washed with water, then with hexane. The solid was dissolved in dichloromethane, dried (magnesium sulfate), filtered and concentrated to a tan solid, which was purified by silica gel chromatography using a shallow gradient of 100% dichloromethane to 20% methanol/dichloromethane to give 12,12,19-trimethyl -8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}1 H-pyrazol-1 -yl)-2Х ⁶ -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.05, 10.011,15]tetracose1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (compound 9) (259.5 mg, 78%).

1H NMR (400 MHz, DMSO) 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), 0.980.95 (m, 2H), 0.89 (td, J=5.8, 4.6, 3.0 Hz, 2H). MS-ESI 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}-1Hpyrazol-1 -yl)-2X ⁶ -thia-3,9 ,11,19,24-pentaazatetracyclo[18.3.1.05,10.011.15]tetracose- 121 044967

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}-1 H-pyrazol-1-yl)-2Х ⁶ -thia-3,9,11,19,24pentaazatetracyclo[18.3.1.05,10.011,15]tetracose-1 (24 ),5(10),6,8,20,22-hexaene-2,2,4-trione (compound

eleven)

Step 1: (15S)-12,12,19-trimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 yl)-2λ ⁶ -thia-3, 9,11,19,24-pentaazatetracyclo[18.3.1.05,10.011,15]tetracose-1(24),5(10),6,8,20,22-hexaene2,2,4-trione (compound 10) and (15R)-12,12,19-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}1 H-pyrazol-1 -yl)-2Х ⁶ -thia-3,9,11 ,19,24-pentaazatetracyclo[18.3.1.05,10.011,15]tetracose1(24),5(10),6,8,20,22-hexaene-2,2,4-trione (compound 11)

Racemic 12,12,19-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1 -yl)-2λ ⁶ -thia-3,9,11,19,24 was subjected to -pentaazatetracyclo[18.3.1.05,10.011.15]tetracose1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (compound 9) (221.5 mg, 0. 3420 mmol) chiral separation by SLC chromatography using ChiralPak AS-H (250x21.2 mm column, 5 µm particle size) with a mobile phase of 15% methanol/85% carbon dioxide at 10 ml/min for 8.0 min (injection volume = 500 μl of 32 mg/ml solution in methanol) yielding (15S)-12,12,19-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy as the first enantiomer eluted }-1 H-pyrazol-1 -yl)-2Х ⁶ thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.05,10.011,15]tetracose-1(24),5(10),6, 8,20,22-hexaene-2,2,4trione (compound 10) (82.3 mg, 74%) as a white solid;

1H NMR (400 MHz, dimethylsulfoxide-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 the second enantiomer eluted (15R)-12,12,19-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H- pyrazol-1-ul)-2λ ⁶ -thia-3,9,11,19,24-pentazatetracyclo[18.3.1.05,10.011,15]tetracose1(24),5(10),6,8,20,22- hexaene-2,2,4-trione (compound 11) (81.7 mg, 74%) as a white solid;

1H NMR (400 MHz, dimethyl sulfoxide-I6) 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), MS-ESM 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-1ul)-2λ ⁶ -thia-3,9,11,18,23 -nentaazatetracyclo[17.3.1.111,14.05,10]tetrakose-1(23),5(10),6,8,19,21-hexaene2,2,4-trione (compound 12)

Step 1: (E)-(2-oxotetrahydropyran-3-ylidene)methanolate (sodium salt)

- 122 044967

A 5 L three-neck round bottom flask was equipped with a mechanical stirrer, heating hood, dropping funnel, J-Kem temperature sensor/controller, and nitrogen inlet/outlet. Sodium hydride (59.91 g, 60 wt%, 1.498 mol) followed by heptane (1.5 L) was charged into the vessel under a nitrogen atmosphere to give a gray suspension. Stirring was started and the temperature in the vessel was recorded at 19°C. The vessel was then loaded with ethyl alcohol (3.451 g, 74.91 mmol) added via a syringe, resulting in gas evolution. A clear yellow solution of tetrahydropyran-2-one (150 g, 1.498 mol) and ethyl formate (111 g, 1.50 mol) was added to an additional funnel. The solution was added dropwise over 1 hour, resulting in gas evolution and gradual heating to 45°C. The resulting dense white suspension was heated to 65°C for 2 hours and then allowed to cool to room temperature. The mixture was continued to stir at room temperature overnight (about 10 hours). The reaction mixture was filtered under vacuum through a Buchner funnel with a glass frit (medium porosity) under a stream of nitrogen. The filter cake was washed by displacement with heptane (2x250 ml) and drawn out for several minutes. The wet cake containing little heptane was transferred to a glass tray and dried in a vacuum oven at 45°C for 15 hours to give 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 o o ο'ΑΑ'ό

Na ⁺ C/

A 5 L three-neck round bottom flask was equipped with a mechanical stirrer, heating hood, dropping funnel, J-Kem temperature sensor/controller, and nitrogen inlet/outlet. (E)-(2-oxotetrahydropyran-3-ylidene)methanolate (sodium salt) (205 g, 1.366 mol) and tetrahydrofuran (1640 ml) were charged into the vessel under a nitrogen atmosphere to give a white suspension. Stirring was started and the temperature in the vessel was recorded at 19°C. Paraformaldehyde (136.6 g, 4.549 mmol) was then added to the vessel as a solid in one portion. The resulting suspension was heated to 63°C and the conditions were maintained for 15 hours. Upon heating, the reaction mixture became slightly gel-like. The white jelly mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran. The residue was partitioned between ethyl acetate (1000 ml), saturated sodium chloride (500 ml) and saturated sodium hydrogen carbonate (500 ml) in a separatory funnel. The organic phase was removed and the remaining aqueous layer was extracted with ethyl acetate (5x300 ml). The combined organic compounds were dried over sodium sulfate (500 g) and then vacuum filtered through a Buchner funnel fitted with a 20 mm Celite glass frit. The filter cake was washed by displacing with ethyl acetate (250 ml). The clear filtrate was concentrated under reduced pressure to give a clear pale yellow oil (135 g) as the expected crude product. The material was purified by flash chromatography on a silica gel column (liquid loading), eluting with a gradient of 100% hexanes to 60% ethyl acetate in hexanes over 1 hour, collecting 450 ml fractions. The product was detected by TLC analysis on silica gel, eluting with hexanes/ethyl acetate 3:1, 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, 3methylenetetrahydropyran-2-one.

^1H NMR(400 MHz, DMSO-06) δ 6.18 (k, J=1.9 Hz, 1H), 5.60 (k, 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 o o

O'T'l kJ no ₂

A 5000 mL three-neck round bottom flask was equipped with a mechanical stirrer, a cooling bath used as a secondary containment, a J-Kem temperature probe, a dropping funnel, and a nitrogen inlet/outlet. 2nitropropane (104.9 g, 1.177 mol) was charged into the vessel under a nitrogen atmosphere. Stirring was started and the temperature in the vessel 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, resulting in a clear, light yellow solution. No exotherm was observed. A solution of 3-methylenetetrahydropyran-2-one (110 g, 981.0 mmol) in acetonitrile (1100 ml) was loaded into the addition funnel, which was added dropwise over 1 hour, resulting in a clear light yellow solution and a gradual exotherm until 24°C. The reaction mixture was continued to stir at room temperature for 3.5 hours and then concentrated

- 123 044967 at 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/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 layer was removed and the residual aqueous layer was extracted with dichloromethane (300 ml). The combined organic compounds were washed with brine (300 ml), dried over sodium sulfate (250 g) and then filtered through a Buchner funnel fitted with a glass frit. The filtrate was concentrated under reduced pressure to a volume of approximately 200 ml. The clear pale blue dichloromethane solution was diluted with methyl tert-butyl ether (1500 ml) and the opaque solution was concentrated under reduced pressure to a volume of approximately 200 ml to give a suspension. The mixture was again diluted with methyl t-butyl ether (1500 ml) and concentrated under reduced pressure to a volume of approximately 250 ml. The resulting suspension was left overnight at room temperature (about 12 hours). The solid was collected by vacuum filtration in a Buchner funnel fitted with a glass frit, the filter cake was washed with cold methyl tert-butyl ether (2x150 ml) and then stretched for 30 min. The material was further dried in a vacuum oven at 45°C for 5 hours to obtain (160 g, 0.795 mol, 81% yield) a white solid as the desired product, 3-(2-methyl-2nitropropyl)tetrahydropyran-2-one.

¹ H NMR (400 MHz, DMSO-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), 2.752.62 (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 three-neck round bottom flask was equipped with a Teflon stir bar, heating cap, J-Kem temperature sensor/controller, and rubber diaphragms. 3-(2-methyl-2-nitro-propyl)tetrahydropyran-2-one (25 g, 124.2 mmol) and ethyl alcohol (375 ml) were charged into the vessel to give a white suspension. Stirring was started and the suspension was heated to 40°C for 10 minutes, which gave a clear, colorless solution. The vessel was then fitted with a gas dispersion tube and the solution was degassed with nitrogen for 15 minutes. Raney nickel (8.019 g, 50% w/w, 68.31 mmol) was then charged into the vessel and the vessel was then baffled. The vessel was evacuated and placed in a hydrogen atmosphere. The process was repeated for three cycles. The vessel was then placed under 1 atmosphere of hydrogen and the reaction mixture was gradually heated to 60°C. The reaction mixture was continued to stir at 60°C for 24 hours. After cooling to room temperature, the vessel was equipped with a gas dispersion tube and the reaction mixture was degassed with nitrogen for 15 minutes. The mixture was filtered under vacuum through a Buchner funnel fitted with a glass frit containing a 20 mm layer of celite. The filter cake was washed by displacement with ethanol (2x100 ml) and drawn until it was slightly wet with ethyl alcohol, then wetted with water, and the used Raney nickel catalyst was drained 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 opaque solution was concentrated under reduced pressure to a volume of approximately 150 ml to give a suspension. The mixture was again diluted with methyl tert-butyl ether (1500 ml) and concentrated under reduced pressure to a volume of approximately 150 ml. The resulting suspension was left overnight at room temperature (about 12 hours). The solid was collected by vacuum filtration on a Buchner funnel fitted with a glass frit, the filter cake was washed with cold methyl tert-butyl ether (2x50 ml) and then pulled for 30 min. The material was further dried in a vacuum oven at 45°C for 3 hours to obtain a white solid (19 g, 0.111 mol, 89% yield) as the product, 3-(3-hydroxypropyl)-5,5-dimethyl-pyrrolidine- 2-on.

¹ H NMR (400 MHz, DMSO-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 three-neck round bottom flask was equipped with a mechanical stirrer, heating hood, dropping funnel, J-Kem temperature sensor/controller, and nitrogen inlet/outlet. Lithium aluminum hydride granules (19.39 g, 510.9 mmol) were loaded into the vessel under a nitrogen atmosphere. Tetrahydrofuran (500 ml, 20 ml/g) was then charged into the vessel. Stirring was started and the temperature in the vessel was recorded at 20°C. The mixture was left stirring at room temperature for 0.5 h to allow the granules to dissolve. The reactor temperature of the resulting sulfur suspension was 24°C. A solution of 3-(3-hydroxypropyl)-5.5 was loaded into the dropping funnel

- 124 044967 dimethylpyrrolidin-2-one (25 g, 146.0 mmol) in tetrahydrofuran (500 ml) and the clear pale yellow solution was added dropwise over 90 minutes. Little heating was required to achieve uniformity. After addition was completed, the reservoir temperature of the resulting grayish slurry was recorded at 24°C. The mixture was then heated to a kettle temperature of 65°C and conditions were maintained for 72 hours. Analysis of the reaction mixture at this point indicated that some residual starting material still remained and no change in product formation. The reaction was subsequently stopped at this stage. The heating mantle was removed and the vessel was provided with a cooling bath. The suspension was cooled to 0°C using a crushed ice/water cooling bath and then quenched by very slowly adding water (19.93 ml) dropwise, then 15 wt% sodium hydroxide solution (19.93 ml) and then water again (59.79 ml). The temperature of the resulting white suspension was 5°C. The cooling bath was removed and the vessel was again fitted with a heating mantle. The suspension was heated to 60°C and kept for 30 minutes. The warm suspension was filtered under vacuum through a Buchner funnel fitted with a glass frit containing a 20 mm layer of celite. The filter cake was then washed with tetrahydrofuran displacement at 60°C (2x250 ml) and then stretched for 30 min. The clear filtrate was concentrated under reduced pressure to give (23.5 g, 0.149 mol, 99% yield) a clear light yellow viscous oil as the desired product, 3(5,5-dimethylpyrrolidin-3-yl)propan-1-ol.

1H NMR (400 MHz, DMSO-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 three-neck round bottom flask was equipped with a mechanical stirrer, cooling bath, dropping funnel, J-Kem temperature probe, and nitrogen inlet/outlet. 3-(5,5-dimethylpyrrolidin-3-yl)propan-1-ol (15 g, 95.39 mmol) and dichloromethane (225 ml, 15 ml/g) were charged into a vessel under a nitrogen atmosphere, which gave a clear, light-colored yellow solution. Stirring was started and the temperature in the vessel was recorded at 19°C. Crushed ice/water was loaded into the cooling bath and the temperature in the container was lowered to 0°C. The addition funnel was loaded with triethylamine (12.55 g, 124.0 mmol), which was then added neat dropwise over 5 min. No exotherm was observed. Di-tert-butyl dicarbonate (22.89 g, 104.9 mmol) dissolved in dichloromethane (225 ml) was then charged into the addition funnel. A clear, pale yellow solution was then added dropwise over 30 minutes, causing a gentle evolution of gas. No exotherm was observed. The cooling bath was removed and the resulting clear light yellow solution was allowed to warm to room temperature and stirring was continued at room temperature for 3 hours. The reaction mixture was transferred to a separatory funnel and partitioned with water (75 ml). The organic layer was removed and washed with brine (75 ml), dried over sodium sulfate (150 g) and then filtered through a Buchner funnel with a glass frit. The filtrate was concentrated under reduced pressure to obtain (30 g) a clear light yellow oil as the desired crude product. The material was purified by flash chromatography on a silica gel column (liquid loading with dichloromethane), eluting with a gradient of 100% dichloromethane to 10% methyl alcohol in dichloromethane over 60 min, collecting 50 ml fractions. Fractions of the desired product were combined and concentrated under reduced pressure to give tert-butyl 4-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate (22 g, 0.0855 mol, 90% yield) as a clear, pale color. yellow viscous oil.

1H 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 (k, 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-methylsulfonyloxypropyl)pyrrolidine-1-carboxylate

tert-Butyl-4-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-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 cooled in an ice water bath for 30 min. Mesyl chloride (24.725 g, 16.706 mL, 215.84 mmol) was added dropwise over 30 minutes, then the ice bath was removed and the mixture was 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 (2x100 ml). The aqueous phases were discarded and the organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to give tert-butyl 2,2-dimethyl-4-(3methylsulfonyloxypropyl)pyrrolidine-1-carboxylate (64.2 g, 93%) as pale yellow oil. MS-ESI m/z calc. 335.1766, found 336.4 (M+1)+; Retention time: 5.54 min (LC method Q).

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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), then ammonium hydroxide (650 ml) was added and the resulting mixture was heated to 45°C for 18 hours. After 18 hours, the reaction mixture was cooled to room temperature. The solution was diluted with 1 M sodium hydroxide (200 ml) and then extracted with diethyl ether (3x650 ml). The aqueous phase was discarded and the combined organic phases were extracted with water (2x 200 ml). The aqueous phases were discarded and the organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to give tert-butyl 4-(3-aminopropyl)-2,2-dimethylpyrrolidine-1carboxylate (48.9 g, 95%) as a pale yellow oil. MS-ESI 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

To tert-butyl-4-(3-aminopropyl)-2,2-dimethylpyrrolidine-1-carboxylate (8.91 g, 34.8 mmol) and 6fluoropyridine-2-sulfonamide (6.13 g, 34.8 mmol) in dimethyl sulfoxide (75 ml), potassium carbonate (4.91 g, 35.5 mmol) was added and the mixture was stirred at 100°C for 12 hours and then allowed to cool to ambient temperature and stirred for an additional 4 hours (total 16 h). The reaction mixture was slowly poured into hydrochloric acid (35 ml 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 brine. The organic phase was dried over magnesium sulfate, filtered through celite and concentrated in vacuo to give a dark yellow oil. The crude product was purified by chromatography on silica gel, eluting with 0-100% ethyl acetate in hexane. Both pure (9.0 g) and impure (3 g) fractions were collected. Purify the contaminated fractions by chromatography on silica gel, eluting with 0.100% ethyl acetate in hexanes to give the total product tert-butyl-2,2-dimethyl-4-[3-[(6-sulfamoyl-2pyridyl)amino]propyl]pyrrolidine-1-carboxylate (10.0 g, 69%).

^1H NMR (400 MHz, DMSO-th 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 (k, J=9.1 Hz, 1H), 3.32-3.24 (m, 2H), 2.79 (k, 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). MS-ESI m/z calc. 412.21442, detected 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-1yl]pyridin-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-3carboxylic acid (11.4 g, 30.34 mmol) in tetrahydrofuran ( 150 ml) carbonyldiimidazole (5.9 g, 36 mmol) was added slowly. The mixture was stirred at ambient temperature for 1 hour. Additional carbonyldiimidazole (0.5 g, 3 mmol) was added and the reaction mixture was stirred at ambient temperature for an additional 1 hour (2 hours total).

Part B: To the activated ester obtained in part A was added tert-butyl-2,2dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (10.0 g, 24.24 mmol) in tetrahydrofuran (50 ml), then 1,8-diazabicyclo[5.4.0]undec-7-ene (7.5 ml, 50 mmol) and the mixture was stirred at ambient temperature for 16 h 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 was washed with brine, dried over magnesium sulfate, filtered through celite and concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with 0-80% ethyl acetate/hexanes to give tert-butyl 4-[3-[[6-[[2-chloro-6-[3-[2-[1(trifluoromethyl) as a foam )cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (13.82 g, 74%).

1H NMR (400 MHz, DMSO-a 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,

- 126 044967

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), 2.802.69 (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). MS-ESI 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)

K tert-butyl-4-[3-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl] -2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (13.8 g, 17.92 mmol) in dichloromethane (75 ml) was added hydrochloric acid (15 ml 4 M, 60.00 mmol) and the mixture was stirred at ambient temperature for 16 hours. The solvent was removed in vacuo and the residue was diluted with 100 ml of ethyl acetate. The solvent was removed in vacuo and repeated with an additional 100 ml of ethyl acetate to give a foam, 2-chloro-{N}-[[6-[3-(5,5-dimethylpyrrolidin-3yl)propylamino]-2-pyridyl]sulfonyl]-6 -[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridine-3-carboxamide (dihydrochloride salt) (13.5 g, 101%).

1H NMR (400 MHz, DMSO-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 (k, 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). MS-ESI m/z calc. 669.2112, detected 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]tetracose-1 (23),5(10),6,8,19,21 -hexaene-2,2,4trione (compound 12)

K 2-chloro-N-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propylamino]-2-pyridyl]sulfonyl]-6-[3-[2-[1(trifluoromethyl)cyclopropyl] ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (dihydrochloride salt) (12.9 g, 17.36 mmol) in NMP (120 ml) was added potassium carbonate (9.64 g, 69.8 mmol), and then cesium fluoride (2.69 g, 17.7 mmol) and the suspension was stirred at 150°C for 16 hours. The reaction mixture 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 6 M, 162.0 mmol). The precipitate was collected using a medium frit and washed 3 times with 50 ml water. The solid was air dried for 1 hour and then dissolved in ethyl acetate (400 ml). The organic phase was concentrated in vacuo and the crude product was purified by chromatography on silica gel, eluting with 0-100% ethyl acetate/hexanes. 6.3 g of pure product and 6 g of impure fractions were collected. Fractions containing impurities were purified by chromatography on silica gel, eluting with a mixture of 0-5% methanol/dichloromethane, which ensured good separation of the product from impurities. The pure product fractions were combined to give 12,12-dimethyl-8-(3{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ ⁶ -thia-3,9,11, 18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23),5(10),6,8,19,21-hexaene-2,2,4-trione (compound 12) (7.4 g , 67%).

1H NMR (400 MHz, DMSO-de) 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

- 127 044967 settlement 633.2345, detected 634.2 (M+1)+; Retention time: 2.23 min (LC method E).

Example 4: Preparation of (14R)-12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclononyl]ethoxy}-1Hpyrazol-1-yl)-2λ ⁶ -thia-3,9,11 ,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21hexaene-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]tetracose1(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} -1 H-pyrazol-1 -yl)2λ ⁶ -thia-3,9, 11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23),5,7,9,19,21-hexaene-2,2,4trione (compound 13) and (14S)-12 ,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3. 1.111,14.05,10]tetracose-1(23),5,7,9,19,21hexaene-2,2,4-trione (compound 14)

Racemic 12,12-dimethyl-8-(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)2λ ⁶ -thia-3,9,11,18,23- pentaazαtetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4trione (7.4 g) was dissolved in 150 ml of acetonitrile and subjected to chiral purification of SLC. The sample was separated by chiral SGC chromatography using ChiralPak AS-H (250x21.2 mm column, 5 µm particle size) with 25% acetonitrile:methanol (90:10)/75% carbon dioxide mobile phase at 70 ml/min. to give the first eluted enantiomer (14R)-12,12-dimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ ⁶ -thia-3,9 ,11,18,23pentaazatetracyclo[17,3,1,111,14,05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,2,4-trione (compound 13) ( 2.91 g, 53%);

Ή NMR (400 MHz, DMSO-b 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); MS-ESI m/z calc. 633.2345, detected 634.3 (M+1) ⁺ ; Hold time: 2.19 min; and the second eluted enantiomer, (148)-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]tetracose1(23),5,7,9,19,21-hexaene-2,2,4-trione (compound 14) (3.0 g, 54%);

1H NMR (400 MHz, DMSO-a 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 (k, J=11.9 Hz, 1H), 1.00-0.92 (m, 2H), 0.90 (d, J=10.4 Hz, 2H). MS-ESI m/z calc. 633.2345, found 634.1 (M+1) ⁺ ; Retention time: 2.2 min (LC method B).

- 128 044967

Example 5: Preparation of 12,12-dimethyl-8-(3-{[1-(trifluoromethyl)cyclopropyl]methoxy}-1H-pyrazol-1yl)-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo [17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene2,2,4-trione (compound 15)

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

F F

5000 mL three-neck round bottom flask equipped with mechanical stirrer, heating hood, J-Kem temperature sensor/controller, dropping funnel, water-cooled reflux condenser and nitrogen inlet/outlet. Tert-butyl-5oxo-III-pyrazole-2-carboxylate (70 g, 0.3800 mol) and tetrahydrofuran (840 ml, 12 ml/g) were charged into the vessel under a nitrogen atmosphere, giving a clear, pale yellow solution. Stirring was started and the temperature in the vessel 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 solids 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 dropwise over 1 hour, resulting in a gradual exotherm to 40°C and a clear, light-colored solution. -yellow solution. The reaction mixture was then heated to a temperature of 50°C and the conditions were maintained for 2 hours, when LC/MS analysis showed 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 hour, during which time a precipitate formed (MW of triphenylphosphine = 278.28). The thick suspension was filtered through a Buchner funnel fitted with a glass frit and the filter cake was washed with toluene (150 ml) and then drawn for 30 min. The pure amber filtrate was concentrated under reduced pressure to obtain a clear amber oil. The material was purified by flash chromatography on a silica gel column (solid load adsorbed onto celite), eluting with a gradient of 100% hexanes to 20% ethyl acetate in hexanes, collecting 450 mL fractions. The product was eluted with about 5% ethyl acetate in hexane. The desired fractions were combined and concentrated under reduced pressure to give 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, DMSO-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). MS-ESI m/z calc. 306.11914, detected 307.0 (M+1)+; Retention time: 1.75 min (LC method B).

Step 2: 3-[[1-(trifluoromethyl)cyclopropyl]methoxy]-1H-pyrazole

I-F

A 5000 mL three-neck round bottom flask was equipped with a mechanical stirrer, heating hood, J-Kem temperature probe, water reflux condenser, addition funnel, and nitrogen inlet/outlet. Tert-butyl-3-[[1(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1-carboxylate (80 g, 0.2612 mol), dichloromethane (320 ml, 4

- 129 044967 ml/g) and methyl alcohol (320 ml, 4 ml/g), which gave a clear pale yellow solution. Stirring was started and the temperature in the vessel 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 then added dropwise over 1 hour, resulting in a gradual exotherm to 30°C. The resulting clear, pale yellow solution was heated to 45°C and the conditions were maintained for 1 hour when LC/MS analysis indicated completion of the reaction. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The remaining residue was dissolved in t-butyl methyl ether (640 ml), 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 layer was extracted with tert-butyl methyl ether (2x200 ml). The combined organic compounds were washed with brine (500 ml), dried over sodium sulfate (300 g) and then filtered through a Buchner funnel fitted with a glass frit. The clear pale yellow filtrate was concentrated under reduced pressure to give a clear light yellow oil which solidified on standing to give 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, DMSO-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). MS-ESI m/z calc. 206.0667, detected 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

and F

A 5000 mL three-neck round bottom flask was equipped with a mechanical stirrer, a cooling bath used as a secondary containment, a J-Kem temperature probe, a water reflux condenser, a dropping funnel, and a nitrogen inlet/outlet. 3-[[1-(trifluoromethyl)cyclopropyl]methoxy]-1H-pyrazole (45 g, 0.2183 mol) and N,N-dimethylformαmide (540 ml, 12 ml/g) were loaded into a vessel under a nitrogen atmosphere, which gave transparent pale yellow solution. Stirring was started and the temperature in the vessel 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) as a solid in one portion followed by the addition of 1,4diazabicyclo[2,2,2]octane (3.67 g, 0.03274 mol) as a solid in one portion. The resulting pale yellow suspension was left stirring at room temperature for 24 hours. The reaction mixture was cooled to 10° C. using a crushed ice/water cooling bath. Water (540 mL) was added dropwise into the addition funnel over 45 min, resulting in the formation of a thick suspension and an exothermic reaction up to 15 °C. The resulting suspension was continued to stir at 15°C for 30 minutes and then filtered through a Buchner funnel fitted with a glass frit.

The filter cake was washed by displacement with water (2x500 ml) and then drawn into a Buchner funnel for 2 hours. The material was then allowed to air dry overnight to yield (73 g, 0.175 mol, 80%) a white granular solid, tert-butyl 2-chloro-6-[3-[[1(trifluoromethyl)cyclopropyl]methoxy]pyrazole -1-yl]pyridin-3-carboxylate. MS-ESI m/z calc. 417.1067, detected 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-3carboxylic acid

1000 mL three-neck round bottom flask equipped with mechanical stirrer, heating hood, J-Kem temperature sensor/controller, dropping funnel, water-cooled reflux condenser and nitrogen inlet/outlet. Tert-butyl-2chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridin-3-carboxylate (70 g, 0.1675 mol) and 2 -propanol (350 ml), which gave an off-white suspension. Stirring was started and the temperature in the vessel was recorded at 19°C. Aqueous 6 M hydrochloric acid (139.6 ml, 0.8375 mol) was loaded into the addition funnel, which was added dropwise over 10 min, resulting in exotherm to 30°C. Then the resulting suspension was heated under reflux (temperature of the container

- 130 044967 ~ 82°C). When heated, the suspension turned into a transparent pale yellow solution (the temperature of the container at this moment was ~ 75°C). After stirring under reflux for ~30 min, a solid precipitate began to precipitate. The suspension continued to stir at reflux for an additional 30 minutes, after which water (210 ml) was added dropwise over 15 minutes. Then the heating was stopped and the suspension continued to be stirred and allowed to slowly cool to room temperature. The material was collected by vacuum filtration in a Buchner funnel with a glass frit and the filter cake was washed by displacing 1:1 water/2propanol (100 ml), then water (2x100 ml), and then drawn into the Buchner funnel for 30 min. The material was further dried in a vacuum oven at 45°C for 24 hours to obtain 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.

1H NMR (400 MHz, DMSO-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). MS-ESI m/z calc. 361.0441, detected 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-1yl]pyridin-3-carbonyl]sulfamoyl] - 2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridin-3-carboxylic acid (260 mg, 0.6973 mmol) and carbonyldiimidazole (113.1 mg, 0 .6973 mmol) were combined in tetrahydrofuran (3.783 ml) and stirred for 1 hour at 45°C. Tert-butyl 2,2-dimethyl-4-[3-[(6sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (287.7 mg, 0.6973 mmol) was added followed by 1,8diazabicyclo [5.4.0]undec-7-ene (212.4 mg, 208.6 μL, 1.395 mmol), and the reaction mixture was heated at 45°C for 4 hours. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution, and then - saline solution. The organic layers were separated, dried over sodium sulfate, evaporated, then purified by silica gel chromatography (24 g column) using a gradient of 100% hexanes to 70% ethyl acetate in hexanes to give tert-butyl4-[3-[ as a white solid. [6-[[2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2, 2-dimethylpyrrolidine-1-carboxylate (232 mg, 44%).

¹ H NMR (400 MHz, DMSO-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 (dd, 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). MS-ESI 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}-1 H-pyrazol-1-yl)-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo [17.3.1.111,14.05,10]tetracose-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-1yl]pyridin-3-carbonyl]sulfamoyl ]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (232 mg, 0.3068 mmol) was dissolved in dichloromethane (5.0 ml) and hydrochloric acid (4 M in dioxane) (2.5 ml 4 M, 10.00 mmol) was added to the mixture and left to stir at room temperature for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate, and then aqueous 2 M sodium carbonate (5 ml) was added to bring solution to pH ~ 10. The organic layer was extracted with ethyl acetate (2x10 ml), washed with brine, dried over sodium sulfate and evaporated to dryness under reduced pressure.

Part B: Crude amine from Part A, potassium carbonate (235 mg, 1.70 mmol), cesium fluoride (75.3 mg, 0.4957 mmol), 3 A molecular sieves, and dimethyl sulfoxide (7.0 mL) were added to the vial. . The vessel was purged with nitrogen, closed with a lid, heated to 150°C and stirred for 16 hours. Reaction

- 131 044967 the mixture was cooled to room temperature. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution, and then with saline solution. The organic layers were separated, dried over sodium sulfate, evaporated and then purified by silica gel chromatography (24 g column) using a gradient of 100% hexanes to 80% ethyl acetate to give 12,12-dimethyl-8- as an off-white solid. (3-{ [ 1 -(trifluoromethyl)cyclopropyl]methoxy}-1 H-pyrazol-1 -yl)-2λ ⁶ thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose -1(23),5(10),6,8,19,21-hexaene-2,2,4trione (compound 15) (101.9 mg, 54%).

1H NMR (400 MHz, DMSO-b 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 (k, 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), 1.651.54 (m, 6H), 1.51 (s, 3H), 1.31 (dd, J=24.7, 12.0 Hz, 1H), 1.10 (s, 4H). MS-ESI m/z calc. 619.2189, detected 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-1yl)-2X ⁶ -thia-3,9,11,18,23-pentaazatetracyclo [17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene2,2,4-trione (enantiomer 1) (compound 21) and 12,12-dimethyl -8-(3-{[1(trifluoromethyl)cyclopropyl]methoxy}-1H-pyrazol-1-yl)-2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose -1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (enantiomer 2) (compound 22)

enantiomer 1 enantiomer 2

Step 1: 12,12-dimethyl-8-(3-{[1-(trifluoromethyl)cyclopropyl]methoxy}-1H-pyrazol-1-yl)-2X ⁶ -thia3,9,11,18,23-pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-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}-1Hpyrazol-1-yl)-2Х ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10 ]tetracose1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (enantiomer 2) (compound 22)

enantiomer 1 enantiomer 2

Racemic 12,12-dimethyl-8-(3- {[ 1 -(trifluoromethyl)cyclopropyl] methoxy} -1Hpyrazol-1 -yl)-2X ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17] was subjected to ,3,1,111,14,05,10]tetracose1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (compound 15) (82.4 mg, 0.133 mmol ) chiral SLC chromatography using ChiralPak AS-H (250x21.2 mm column, 5 µm particle size) with 20% acetonitrile (no modifier)/80% carbon dioxide as mobile phase at 70 ml/min, obtaining the first enantiomer eluted 12,12-dimethyl-8-(3-{[1-(trifluoromethyl)cyclopropyl]methoxy}-1 H-pyrazol-1 -yl)-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[ 17,3,1,111,14,05,10]tetracose1(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;

^1H NMR (400 MHz, DMSO-f,) 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 (k, 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), MS-ESM m/z calc. 619.2189, detected 620.2 (M+1) ⁺ ; Retention time: 2.1 min (LC method E), and the second enantiomer eluted, 12,12-dimethyl-8-(3-{[1-(trifluoromethyl)cyclopropyl]methoxy}-1H-pyrazol-1-yl) -2X ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17,3,1,111,14,05,10]tetracose1(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, DMSO-a 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 (k, 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), MS-ESM m/z calculated . 619.2189, found 620.2 (M+1)+; Retention time: 2.1 min (LC method E).

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Example 7: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1yl)-2λ ⁶ -thia-3,9,11,19,24 -pentaazatetracyclo[18.3.1.111,14.05,10]pentacose-1(23),5,7,9,20(24),21-hexaene2,2,4-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 slowly added to a suspension of 67.6% sodium hydride in mineral oil (19.17 g, 540 mmol) in tetrahydrofuran (750 ml) containing hexamethylphosphoramide (97 g, 540 mmol) at room temperature under argon. The reaction mixture was stirred at room temperature for 1 hour. Dibromomethane (392 g, 250 mmol) was added and the reaction mixture was refluxed at 80°C for 16 hours. The reaction mixture was allowed to cool to room temperature and diethyl ether (1000 ml) was added ), and the organic layer was washed with water (5x500 ml), dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography using 0-10% hexane-ethyl acetate to give ethyl 1-(bromomethyl)-2-oxocyclopentanecarboxylate (85 g , 76%) in the form of a colorless oil.

Ή NMR (250 MHz, CDCl3) δ 5 4.18 (k, J=7.0 Hz, 7.25 Hz, 2H); 3.68 (k, J=22.5 Hz, J=9.5 Hz, 2H); 2.582.00 (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)-2oxocyclopentanecarboxylate (85 g, 341 mmol) in dry ethanol (680 ml) and the mixture was stirred at room temperature for 16 hours. The mixture was filtered, evaporated and Purify by silica gel column chromatography using 0-5% hexane-ethyl acetate to give diethyl 2-methylenehexanedioate (72.7 g, 98%) as a colorless oil.

1H NMR (250 MHz, CDCl3) 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 hours. 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% hexane-ethyl acetate to give 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).

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Step 4: 4-(4,4-dimethyl-5-oxopyrrolidin-2-yl)butyric acid ethyl ester

A mixture of diethyl 2-(2-methyl-2-nitropropyl) hexanedioate (43 g, 141.7 mmol) and a suspension of Raney nickel (12 g) in ethanol (860 ml) was heated at 80°C for 18 h in a Parr reactor under 2 bars of hydrogen gas. Celite (50 g) was added and the resulting mixture was filtered. The solids were discarded and the filtrate was concentrated to give 4-(4,4-dimethyl-5-oxopyrrolidin-2yl)butyric acid ethyl ester (31.2 g, 97%) as an orange oil. The crude product was used for the next step without further purification. MS-ESI 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

Lithium aluminum hydride (39.3 g, 1036 0 mmol) in portions over 45 minutes, and the resulting suspension was refluxed under nitrogen for 18 hours. The cooled reaction mixture was carefully quenched with saturated sodium sulfate solution (100 ml) and the resulting solid was filtered. The solids were discarded and the filtrate was concentrated in vacuo to give 4-(4,4-dimethylpyrrolidin-2-yl)butan-1-ol (51.5 g, 87%) as a brown oil. The crude product was used for the next step without further purification. MS-ESI 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-dimethylpyrrolidine-1carboxylic 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 two-phase mixture was stirred for 18 hours 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% hexane-ethyl acetate to give 2-(4-hydroxybutyl)-4,4-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (57.2 g, 77 %) in the form of a clear oil.

Ή 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, 23Н).MS-ESI 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 cooled to 0°C solution of tert-butyl 4-(4-hydroxybutyl)-2,2-dimethylpyrrolidine-1carboxylate (2.28 g, 8.401 mmol) in dichloromethane (19 ml) and triethylamine (8.0 ml, 57 mmol), methanesulfonyl chloride (2.161 mL, 27.92 mmol) was added dropwise. The reaction mixture was stirred for 20 hours, allowing the reaction mixture to warm to room temperature after 1 hour (the clear solution turned cloudy orange after 10 minutes). The reaction mixture was quenched with ice water and dichloromethane, and then with saline. The aqueous layer was further extracted with dichloromethane (2 x 20 ml), and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was dried under vacuum for 1 hour to give tert-butyl2,2-dimethyl-4-(4-methylsulfonyloxybutyl)pyrrolidine-1-carboxylate (2.9 g, 99%) as a yellow oil. MS-ESI m/z calc. 349.1923, detected 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 30% wt./ vol., 510 mmol). The mixture was heated to 50°C in a closed vessel for 18 hours. The dioxane was concentrated in vacuo and dichloromethane (50 ml) was added. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (80 g column) using a dichloromethane-methanol gradient method (containing 5 ml/liter 30% ammonium hydroxide) (0 to 15% methanol in dichloromethane) to give tert-butyl-4-(4aminobutyl )-2,2-dimethylpyrrolidine-1-carboxylate (1.44 g, 64%) as an off-white foam.

¹ H NMR (400 MHz, DMSO-d6) 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). MS-ESI m/z calc. 270.23074, detected 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-1carboxylate

In a 250 mL flask, combine 6-fluoropyridine-2-sulfonamide (894 mg, 5.07 mmol) in dimethyl sulfoxide (20 mL), then potassium carbonate (1.1 g, 8.0 mmol) and tert-butyl-4- (4-aminobutyl)-2,2dimethylpyrrolidine-1-carboxylate (1.44 g, 5.33 mmol) under nitrogen and reflux. The vessel was heated at 60°C in an oil bath for 18 hours. Potassium carbonate (1.1 g, 8.0 mmol) was added and the heat was increased to 80°C for an additional 4 hours. After cooling, the reaction mixture was filtered, then diluted with ethyl acetate and washed with 1 M citric acid solution and then with saline solution. The organic layers were separated, dried over sodium sulfate, filtered, evaporated and purified by silica gel chromatography (80 g GOLD column) using a gradient of 100% hexanes to 75% ethyl acetate in hexanes to give tert-butyl 2,2-dimethyl as a white solid -4-[4-[(6-sulfamoyl-2-pyridyl)amino]butyl]pyrrolidine-1-carboxylate (475 mg, 22%).

Ή NMR (400 MHz, DMSO-dg) 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). MS-ESI 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-1yl]pyridin-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 carbonyldiimidazole (217 mg, 1 .34 mmol) were combined in tetrahydrofuran (7 ml) and stirred for 90 min at 50°C. Tert-butyl 2,2-dimethyl-4-[4-[(6sulfamoyl-2-pyridyl)amino]butyl]pyrrolidine-1-carboxylate (475 mg, 1.11 mmol) was then added followed by 1,8diazabicyclo[ 5.4.0]undec-7-ene (350 μl, 2.34 mmol), and the reaction mixture was heated at 50°C for 18 hours. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution, followed by saline. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography (80 g column) using a gradient of 100% hexanes to 70% ethyl acetate in hexanes to give tert-butyl-4-[4-[[ 6-[[2-chloro-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]butyl]-2,2 -dimethylpyrrolidine-1-carboxylate (613 mg, 83%) as a white solid.

¹ H NMR (400 MHz, DMSO-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). MS-ESI 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]pentacose-1(23),5,7,9,20(24),21-hexaene-2,2,4trione (compound 28)

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Part A: tert-butyl 4-[4-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-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 hydrochloric acid (4 M in dioxane) was added to the mixture (5 ml 4 M, 20.0 mmol) and stirred at room temperature for 1 h. The mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate, then aqueous 2 M sodium carbonate (5 ml) was added to obtain a pH of ~ 10. Extracted with ethyl acetate (2x10 ml), washed with brine, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure.

Part B: Combine materials from Part A and potassium carbonate (474 mg, 3.43 mmol), cesium fluoride (156 mg, 1.03 mmol), 3 A molecular sieves and dimethyl sulfoxide (11 ml) in a vial, purged with nitrogen, capped, heated to 150 °C and stirred for 18 hours. Cooled to room temperature. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution, and then with saline solution. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography (40 g column) using a gradient of 100% hexanes to 80% ethyl acetate in hexanes to give 12,12-dimethyl-8-(3- {2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-2λ ⁶ -thia-3,9,11,19,24pentaazatetracyclo[18.3.1.111,14.05,10]pentacose-1( 23),5,7,9,20(24),21-hexaene-2,2,4-trione (compound 28) (270 mg, 60%) as a white solid.

1H NMR (400 MHz, DMSO-Y6) 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). MS-ESI 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-1yl)-2λ ⁶ -thia-3,9,11,19,24 -pentaazatetracyclo[18.3.1.111,14.05,10]pentacose-1(23),5,7,9,20(24),21-hexaene2,2,4-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]pentacose1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (enantiomer 2) (compound 30)

enantiomer 1 enantiomer 2

Step 1: 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ ⁶ -thia3,9,11,19,24- pentaazatetracyclo[18.3.1.111,14.05,10]pentacose-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}-1Hpyrazol-1-yl)-2λ ⁶ -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.111 ,14.05,10]pentacose1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (enantiomer 2) (compound 30)

enantiomer 1 enantiomer 2

Racemic 12,12-dimethyl-8-(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)2λ ⁶ -thia-3,9,11,19,24- pentaazatetracyclo[18.3.1.111,14.05,10]pentacose-1(23),5,7,9,20(24),21-hexaene-2,2,4trione (compound 28) (204 mg, 0.3150 mmol) subjected to chiral SLC chromatography using ChiralPak AS-H (250x21.2 mm column, 5 µm particle size) with a mobile phase of 30% acetonitrile:methanol (90:10))/70% carbon dioxide at 0.5 ml/min, giving as the first enantiomer, 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl) ^-2λ6- thia3,9,11 ,19,24-pentaazatetracyclo[18.3.1.111,14.05,10]pentacose-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; MS-ESI m/z calc. 647.2502, detected 648.2 (M+1) ⁺ ; Retention time: 2.27 min (LC method E) and as the second eluted enantiomer 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)- 2λ ⁶ -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.111,14.05,10]pentacose1(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;

1H NMR (400 MHz, DMSO-d6) 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), MS-ESI 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}-1Hpyrazol-1-yl)-2λ ⁶ -thia-3,9,11,18 ,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(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-3,9,11,18,23pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (pair of diastereomers 2) (compound 36), 12,12 ,17-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1 -yl)-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3. 1.111,14.05,10]tetracose1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (pair of diastereomers 1, enantiomer 1) (compound 58), 12,12, 17 -trimethyl-8-(3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[17.3. 1.111,14.05,10]tetracose-1 (23),5(10),6,8,19,21-hexaene-2,2,4-trione (pair of diastereomers 1, enantiomer 2) (compound 59), 12, 12,17-trimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3 .1.111,14.05,10]tetracose-1 (23),5(10),6,8,19,21-hexaene-2,2,4-trione (pair of diastereomers 2, enantiomer 1) (compound 60) and 12 ,12,17-trimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1 (23),5(10),6,8,19,21-hexaene-2,2,4-trione (pair of diastereomers 2, enantiomer 2) (compound 61)

Step 1: (3E)-3-(hydrokCymethylene)-6-methyl-tetrahydropyran-2-one (sodium salt).

To a suspension of sodium hydride (60% in mineral oil) (2.63 g of 60% wt., 65.8 mmol) in diethyl ether (56 ml) was added absolute ethanol (300 μl), then a mixture of 6-methyltetrahydropyran-2-one (5.0

- 137 044967 g, 43.80 mmol) and ethyl formate (6.0 ml, 74 mmol) were added dropwise at ambient temperature over 30 min. After addition was complete, the reaction mixture was stirred for 1 hour at room temperature. The solid formed in the mixture (sodium salt of the product) was collected by filtration, washed with diethyl ether and dried under high vacuum to give (3E)-3(hydroxymethylene)-6-methyltetrahydropyran-2-one (sodium salt) (7.1 g , 99%). MS-ESI m/z calc. 142.06299, detected 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-methyltetrahydropyran-2-one (sodium salt) (7.1 g, 43 mmol) was suspended in tetrahydrofuran (100 ml), treated with paraformaldehyde (4.2 g, 140 mmol) in nitrogen and the mixture was heated to 65°C for 1 hour. The mixture was cooled in an ice water bath, quenched with saturated aqueous potassium carbonate (20 ml) and the organic phase was separated, then the aqueous phase was extracted with diethyl ether (4 x 10 ml). The organic fractions were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure by rotary evaporation without heating. The resulting residue was purified by silica gel chromatography (120 g column) using a gradient of 100% hexanes to 40% ethyl acetate in hexanes to give 6-methyl-3-methylenetetrahydropyran-2-one (2.96 g, 55 %).

1H 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).MS-ESI 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 solution 6 -methyl-3methylenetetrahydropyran-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 hours. The mixture was evaporated and the residue was then purified by silica gel chromatography (120 g column) using a gradient of 100% hexanes to 60% ethyl acetate in hexanes to isolate the product, which was then dried in vacuo to give a clear oil which turned into a white solid on standing, 6-methyl-3-(2-methyl-2-nitropropyl)tetrahydropyran-2-one (4.32 g, 85%).

1H 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).MS-ESI 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) was added , 20.45 mmol) in a nitrogen atmosphere. Three vacuum/hydrogen cycles were performed and the resulting mixture was stirred at room temperature under a hydrogen atmosphere (1 atmosphere) for 10 minutes. The suspension was then refluxed, heated to 60°C and stirred at this temperature under a hydrogen atmosphere for 24 hours. Cooled to room temperature, 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 of 100% dichloromethane to 10% methanol in dichloromethane to give 3-(3-hydroxybutyl)-5,5-dimethylpyrrolidine-2- it (2.5 g, 67%) as a white solid.

1H NMR (400 MHz, DMSO-de) 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, T=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).MS-ESI m/z calc. . 185.14159, detected 186.2 (M+1) ⁺ ; Retention time: 0.74 min (LC method E).

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

- 138 044967

To a suspension of lithium aluminum hydride (686.6 mg, 20.24 mmol) in anhydrous tetrahydrofuran (37 ml), a solution of 3-(3-hydroxybutyl)-5,5-dimethylpyrrolidin-2-one (2 5 g, 13.49 mmol) in anhydrous tetrahydrofuran (37 ml) at room temperature under nitrogen. After addition was complete, the reaction mixture was refluxed for 72 hours (two additional portions of lithium aluminum hydride (200 mg, 7.00 mmol) were added to the reaction mixture after 24 hours and 48 hours of reflux). The mixture was cooled in an ice water bath; More tetrahydrofuran (25 ml) was added to the mixture, followed by the slow addition of aqueous saturated sodium potassium tartrate tetrahydrate (Rochelle's salt, 30 ml). The resulting mixture was intensively stirred for 2 hours at room temperature until a clear separation of the aqueous and organic phases was achieved; the organic layer was then separated and concentrated in vacuo. The residue was dissolved in dichloromethane (100 ml) and the resulting solution was washed with saline (2x15 ml). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4-(5,5-dimethylpyrrolidin-3-yl)butan-2-ol (1.6 g, 69%) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.78 (dd, J=l 1.9, 5.8 Hz, 1H), 3.14 (dd, 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). MS-ESI m/z calc. 171.16231, detected 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

Ν—\

HE

HE

Di-tert-butyl dicarbonate (2.4 ml, 10.45 mmol) and triethylamine (1.7 ml, 12.20 mmol) were added to the 4-(5,5-dimethylpyrrolidin-3-yl)butan-2-ol solution (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 minutes. The mixture was washed with water (15 ml), saturated sodium bicarbonate (15 ml) and brine (15 ml), then the organic matter was extracted, dried over sodium sulfate, filtered and the mixture was concentrated. The residue was purified by silica gel chromatography (40 g column) using a gradient of 100% dichloromethane to 10% methanol in dichloromethane to isolate tert-butyl-4-(3-hydroxybutyl)-2,2-dimethyl-pyrrolidine as a clear oil -1-carboxylate (2.4 g, 95%).

1H 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). MS-ESI m/z calc. 271.21475, detected 272.2 (M+1) ⁺ ; Retention time: 1.64 min (LCC method).

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

To a solution in dichloromethane (6 ml), cooled to 0°C, tert-butyl 4-(3-hydroxybutyl)-2,2dimethylpyrrolidine-1-carboxylate (346 mg, 1.275 mmol) and triethylamine (1.2 ml, 8 .6 mmol), methanesulfonyl chloride (350 μL, 4.52 mmol) was added dropwise. The reaction mixture was stirred for 20 hours, allowing it to warm to room temperature after 1 hour (the clear solution turned cloudy orange after 10 minutes). The reaction mixture was quenched with ice water and dichloromethane, and then with saline. The aqueous layer was further extracted with dichloromethane (2 x 20 ml) and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was dried in vacuo for 1 hour to obtain tert-butyl 2,2-dimethyl-4-(3-methylsulfonyloxybutyl)pyrrolidine-1-carboxylate (440 mg, 99%) as a yellow oil. MS-ESI m/z calc. 349.1923, detected 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

- 139 044967 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% wt. /vol., 85.60 mmol). The mixture was heated to 50°C in a closed vessel for 72 hours. The dioxane was concentrated in vacuo and dichloromethane (50 ml) was added. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (24 gram column) using a dichloromethane-methanol gradient method (containing 5 ml/liter 30% ammonium hydroxide) (0 to 15% methanol) to give tert-butyl as a light yellow oil. 4-(3-aminobutyl)-2,2-dimethylpyrrolidine-1-carboxylate (199 mg, 58%).

1H 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), 1.491.43 (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-1carboxylate

G ² °' θ /GL

Boc-nQ^X^ ⁺ / ^NH

A— ^{1 4 2} NX Boc-N ^FX

In a sealed 20 mL microwave-safe vial, a solution of 6-fluoropyridine-2sulfonamide (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) were stirred at 130°C for 16 hours. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and washed with water. The organic extract was dried over sodium sulfate, evaporated and purified by silica gel chromatography using a 12 g column (0-85% ethyl acetate/hexanes gradient) to give tert-butyl-2,2-dimethyl-4-[3-[(6-sulfamoyl -2-pyridyl)amino]butyl]pyrrolidine-1-carboxylate (490 mg, 38%).

¹ H NMR (400 MHz, DMSO-th 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). MS-ESI 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-1yl]pyridin-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-[(6sulfamoyl-2-pyridyl)amino]butyl]pyrrolidine-1-carboxylate (145 mg, 0.3399 mmol) was added, followed by 1,8diazabicyclo[ 5.4.0]undec-7-ene (110 μl, 0.7356 mmol), and the reaction mixture was heated at 50°C for 18 hours. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution, followed by saline. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by preparative reverse phase HPLC using a C ₁₈ column and Method 30-99 A1-B1 (acetonitrile-water + 5 mM hydrochloric acid) to give tert-butyl -4-[3-[[6-[[2chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino ]butyl]-2,2-dimethylpyrrolidine-1-carboxylate (97 mg, 36%) as a white solid. MS-ESI 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-pentaazαtetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4trione (diastereomer pair 1) (compound 35), 12,12,17-trimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1H-pyrazol-1 -yl)-2λ ⁶ -tuα-3,9,11,18,23pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (pair of diastereomers 2) (compound 36), 12,12 ,17-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3. 1.111,14.05,10]tetracose1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (pair of diastereomers 1, enantiomer 1) (compound 58), 12,12, 17-trimethyl-8-(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-2λ ⁶ -tua3,9,11,18,23-pentaazatetracyclo[17.3. 1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (pair of diastereomers 1, enantiomer 2) (compound 59), 12, 12,17-trimethyl-8-(3-{2-[1- 140 044967 (trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-2λ ⁶ -thia-3,9,11,18, 23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (pair of diastereomers 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, 23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (pair of diastereomers 2, enantiomer 2) (compound 61 )

Part A: tert-butyl 4-[3-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-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 hydrochloric acid (4 M in dioxane) (1000 µl 4 M, 4,000 mmol) and stirred at room temperature for 3 hours. The mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate, then aqueous 2 M sodium carbonate (5 ml) was added to give a pH of ~10. Extract the organic layer with ethyl acetate (2x10 ml), wash with brine, then dry over sodium sulfate, filter and evaporate to dryness under reduced pressure.

Part B: Combine materials from Part A and potassium carbonate (90 mg, 0.6512 mmol), cesium fluoride (30 mg, 0.1975 mmol), 3 A molecular sieves and dimethyl sulfoxide (2.0 ml) in a vial, purged with nitrogen , sealed, heated to 150°C and stirred for 18 hours. Cooled to room temperature. The reaction mixture was filtered and then purified by preparative reverse phase chromatography ( _C18 column, 20% to 99% acetonitrile (no modifier) in water (5 mM hydrochloric acid)) to yield eluting enantiomers 12,12 as the first pair of diastereomers. 17-trimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[17.3.1.111 ,14.05,10]tetracose-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;

1H NMR (400 MHz, DMSO-th 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 pair of eluting diastereomers, 12,12,17-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-2λ ⁶ -thia- 3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-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;

1H NMR (400 MHz, DMSO-a 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, detected 648.2 (M+1) ⁺ ; Retention time: 2.29 min (LC method E).

Part C: 12,12,17-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclononyl]ethoxy}-1H-pyrazol-1-yl)-2λ ⁶ thia-3,9,11,18 ,23-pentaazatetracyclo[17,3,1,111,14,05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4trione (diastereomer pair 1) ( 11.5 mg) were subjected to chiral separation using SGC chromatography

- 141 044967 graphics using a ChiralPak AS-H column (250x10 mm) (5 µm particle size) with 16% acetonitrile/methanol (90:10)/84% carbon dioxide as mobile phase at 10 ml/min, for 8 ,0 min. [injection volume=70 µl of a 24 mg/ml solution in acetonitrile/methanol (90:10)] to give the first eluted enantiomer 12,12,17-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl] ethoxy}-1Hpyrazol-1-yl)-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17,3,1,111,14,05,10]tetracose1(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; MS-ESI m/z calc. 647.2502, detected 648.2 (M+1)+; Retention time: 2.25 min (LC method E) and the second enantiomer eluted, 12,12,17trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl) -2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17,3,1,111,14,05,10]tetracose-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; MS-ESI m/z calc. 647.2502, detected 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}-1 H-pyrazol-1 -yl)-2X ⁶ thia-3,9,11, 18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4trione (diastereomer pair 2) (55 mg) subjected to chiral separation by SLC chromatography using a ChiralPak AS-H (250x10 mm) column (particle size 5 μm) with a mobile phase of 16% acetonitrile/methanol (90:10)/84% carbon dioxide at a rate of 10 ml/min, more than 8 .0 min [injection volume = 70 μl of a 24 mg/ml solution in acetonitrile/methanol (90:10)] to obtain 12,12,17-trimethyl-8-(3-{2-[1 - (trifluoromethyl)cyclopropyl]ethoxy} 1 H-pyrazol-1 -yl)-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(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 inorganic white solid substances MS-ESI m/z calc. 647.2502, detected 648.2 (M+1)+; Retention time: 2.3 min (LC method E) and as the second enantiomer eluted 12,12,17-trimethyl-8-(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol- 1 -yl)-2Х ⁶ -thia3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-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, DMSO-de) 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), MS-ESI 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-pyrazol1-yl}-2X ⁶ -thia-3,9,11,18, 23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-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 atmosphere at 0°C, DIAD (39.53 g, 37.86 mL, 195.5 mmol) was added dropwise. . The mixture was stirred

- 142 044967 at 0°C for 30 minutes, obtaining a white suspension. A solution of (2,2,3,3tetramethylcyclopropyl)methanol (29.84 g 70% w/w, 162.9 mmol) and tert-butyl 3-hydroxypyrazole-1-carboxylate (30 g, 162.9 mmol) was added to the mixture. in toluene (600.0 ml) dropwise at ~5°C for 2 hours. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 hours. The mixture was heated to 75°C for 6 hours and then allowed to cool to ambient temperature. The suspension was diluted with heptane (900 ml) and stirred at ambient temperature for 3 hours. The suspension was filtered through celite and the precipitate was washed 3 times with 100 ml of heptane. The filtrate was concentrated in vacuo to give a thick yellow oil. The crude product was chromatographed on a 750 gram silica gel column loaded with dichloromethane, eluting with a 0-20% ethyl acetate/hexanes gradient. The collected product containing fractions were concentrated in vacuo to yield 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). MS-ESI 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

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) sodium hydroxide (431.4 ml 2M, 862.8 mmol) was added slowly 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 (2x300 ml) and the aqueous phases were again extracted with methyl tert-butyl ether (250 ml). The combined organic phases were dried, filtered and evaporated to give 3-[(2,2,3,3tetramethylcyclopropyl)methoxy]-1H-pyrazole (75 g, 89%) as a viscous oil.

¹ H NMR (400 MHz, DMSO-de) 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). MS-ESI m/z calc. 194.1419, detected 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), add di(imidazol-1-yl)methanone (169.0 mg, 1.042 mmol) and the reaction mixture stirred for 90 min at 50°C. Tert-butyl 2,2-dimethyl-4-[3-[(6-sulfamoyl-2pyridyl)amino]propyl]pyrrolidine-1-carboxylate (343.9 mg, 0.8336 mmol) was added followed by 1,8diazabicyclo [5.4.0]undec-7-ene (237.9 mg, 233.7 μL, 1.563 mmol), and the reaction mixture was heated at 50°C for 18 hours. The reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride, and after - saline solution. The organic phases were separated, dried over sodium sulfate, filtered and evaporated. The resulting brown residue was purified by silica gel column chromatography using a shallow gradient of 100% hexanes to 100% ethyl acetate to give tert-butyl-4-[3-[[6-[(2,6-dichloropyridine-3-carbonyl)sulfamoyl] -2-pyridyl]amino]propyl]-2,2dimethylpyrrolidine-1-carboxylate (284 mg, 46%) as an off-white sticky material. MS-ESI m/z calc. 585.15796, detected 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 hours. The solvent was removed, the residue was dissolved in ethyl acetate, and the organic layers washed with a saturated aqueous solution of sodium bicarbonate, and then with saline solution. The organic layers were dried over anhydrous sodium sulfate, filtered and the solvent was removed. The material was dried in vacuo overnight to give 2,6dichloro-N-[[6-[3-(5,5-Dimethylpyrrolidin-3-yl)propylamino]-2-pyridyl]sulfonyl]pyridine-3 carboxamide (233 mg, 100%) in the form of an off-white sticky material.

¹ H NMR (400 MHz, DMSO-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 (dk, J=14.6, 5.7 Hz, 1H), 3.24

- 143 044967 (dk, 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). MS-ESI 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]tetracose-1(22),5,7,9, 19(23),20-hexaene-2,2,4-trione (hydrochloride salt) (compound C)

2,6-Dichloro-N-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propylamino]-2-pyridyl]sulfonyl]pyridine-3-carboxamide solution (200 mg, 0.4112 mmol) in dimethyl sulfoxide (5.0 ml) and 3 A molecular sieves were stirred at room temperature for 10 minutes. 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 a Whatman disk filter (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS using a Luna C ₁₈ (2) column (75x30 mm, 5 μm particle size) sold by Phenomenex. (art. no.: 00C-4252-U0-AX), double gradient run of 30-99% mobile phase B for 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 8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3 .1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (hydrochloride salt) (76 mg, 38%) as white solid matter.

1H 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). MS-ESI 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]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4trione (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, 50% wt., 0.2125 mmol) at 0°C in a nitrogen atmosphere. The reaction mixture was stirred for 30 minutes. 8chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14,05,10]tetracose1(22),5,7,9,19(23) ,20-hexaene-2,2,4-trione (hydrochloride salt) (30 mg, 0.06168 mmol) and the reaction mixture was heated at 120°C for 16 hours. The reaction mixture was cooled to room temperature and quenched with a few drops of water. The resulting mixture was filtered through a Whatman disk filter (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS using a dual gradient run of 50-99% mobile phase B over 15.0 min (mobile phase A=water (without modifier), mobile phase B = acetonitrile) to obtain 12,12-dimethyl-8-{3-[(2,2,3,3tetramethylcyclopropyl)methoxy] -1 H-pyrazol-1 -yl} -2λ ⁶ -thia- 3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 42 ) (2.6 mg, 7%).

1H 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). MS-ESI m/z calc. 607.29407, found 608.5 (M+1) ⁺ ; Retention time: 2.86 min (LC method B).

Example 11: Preparation of 8-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[17.3.1.111 ,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 43)

- 144 044967

Step 1: (1-cyclopropyl-2-methoxyvinyl)cyclopropane

The 5000 mL round bottom flask was equipped with a mechanical stirrer, a cooling bath used as a secondary containment vessel, a J-Kem temperature probe, a dropping funnel, a water-cooled reflux condenser, and a nitrogen inlet/outlet. (methoxymethyl)triphenylphosphonium chloride (97.3 g, 284 mmol) and tetrahydrofuran (375 ml) were charged into a vessel under a nitrogen atmosphere to give a white suspension. Stirring began and the temperature in the vessel 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, resulting in a reddish orange solution and an exothermic reaction at 21°C. The mixture was continued to stir at room temperature for 30 minutes. Dicyclopropyl ketone (dicyclopropylmethanone) (25.0 g, 227.0 mmol) was loaded into the addition funnel, which was then added neat dropwise over 25 min, resulting in a gradual exotherm to 35°C. The resulting reddish-orange solution was allowed to gradually cool to room temperature and then stirring was continued at room temperature for 4 hours. The reaction was then quenched by adding cold water (375 ml) dropwise over 25 minutes. The resulting two-phase mixture was transferred to a separatory funnel and left for 5 min. The aqueous layer was discarded and the remaining organic layer was washed with brine (375 mL). The organic layer was removed and concentrated under reduced pressure to give a pale yellow oil that still contained some water. The mixture was diluted with ethyl acetate (500 ml), then transferred to a separatory funnel and separated with water (150 ml). The organic layer was removed, dried over sodium sulfate (150 g) and then filtered through a Buchner funnel fitted with a glass frit. The filtrate was concentrated under reduced pressure to give a pale yellow oil with some suspended solids (triphenylphosphine oxide). The mixture was diluted with hexane (500 ml) and then filtered through a Buchner funnel fitted with a glass frit containing a 40 mm thick layer of silica gel. The filter cake was washed by displacement with hexane (2x500 ml). The filtrate was concentrated under reduced pressure to give (1-cyclopropyl-2-methoxyvinyl)cyclopropane as a clear, pale yellow oil (27 g, 0.1953 mol, 86% yield). MS-ESI 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-methoxyvinyl)cyclopropane (128 g, 709.4 mmol) in tetrahydrofuran (700 ml) was added aqueous hydrochloric acid (250 ml, 3 M, 750.0 mmol) and the mixture was stirred at ambient temperature for 16 hours, then stirred at 55°C for 4 hours and then allowed to cool to ambient temperature over 12 hours. The mixture was diluted with 500 ml salt

- 145 044967 solution and the aqueous phase was separated. The aqueous phase was extracted with 500 ml MTBE and the organic phases were combined. The organic phases were washed with 500 ml 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 to give 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

The 5000 mL round bottom flask was equipped with a mechanical stirrer, heating hood, J-Kem temperature probe, dropping funnel, water-cooled reflux condenser, and nitrogen inlet/outlet. (methoxymethyl) triphenylphosphonium chloride (116.8 g, 340.7 mmol) and tetrahydrofuran (423 ml) were charged into a vessel under a nitrogen atmosphere to give a white suspension. Stirring was started and the temperature in the vessel 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 portions added every 10 min), resulting in a reddish-orange solution and an exotherm up to 40°C. The mixture was continued to stir at room temperature for 30 minutes. At this point, the temperature in the pot was recorded at 36°C. 2,2-Dicyclopropylacetaldehyde (47 g of 60% w/w contaminated with triphenylphosphine oxide from the previous step, 227.1 mmol) was then loaded into the dropping funnel, which was then carefully added dropwise over 25 min, resulting in a gradual release heat and heating up 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 hours. The reaction mixture (vessel temperature = 19°C) was then quenched with cold water (1000 ml), resulting in an exotherm of up to 22° WITH. The mixture was continued to stir for 10 minutes. The resulting two-phase mixture was transferred to a separatory funnel and left for 5 min. The organic layer was removed and the residual aqueous layer was extracted with ethyl acetate (2x300 ml). The combined organic layers were concentrated under reduced pressure to give a dark amber oil that still contained some water. The mixture was diluted with ethyl acetate (500 ml), then transferred to a separatory funnel and separated with water (150 ml). The organic layer was removed, washed with brine (200 ml), dried over sodium sulfate (200 g) and then filtered through a Buchner funnel fitted with a glass frit. The filtrate was concentrated under reduced pressure to give a pale amber oil with some suspended solids (triphenylphosphine oxide). The mixture was diluted with heptane (500 ml) and then left at room temperature for 30 minutes. The suspension was filtered through a Buchner funnel fitted with a glass frit and the filter cake was washed with heptane (2x100 ml). The filtrate was concentrated under reduced pressure to a volume of approximately 200 ml. The pale amber solution was cooled to 0°C in a crushed ice/water bath for 30 min, during which time more solids precipitated. The suspension was filtered through a Buchner funnel fitted with a glass frit and the filter cake was washed with heptane (2x50 ml). The filtrate was concentrated under reduced pressure to give [(E)-1cyclopropyl-3-methoxy-allyl]cyclopropane (30 g, 87%).

1H 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 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 3 M, 300.0 mmol) and the mixture heated to 50°C for 2 hours. The mixture was cooled to ambient temperature and the tetrahydrofuran was removed in vacuo. The residue was diluted with dichloromethane (700 ml) and the aqueous phase was separated (slight emulsion). The organic phase was washed with 500 ml brine, dried over magnesium sulfate and filtered. MgCl ₂ (50 g, 525.1 mmol) was added to the filtrate and the mixture was stirred at ambient temperature for 12 hours. The suspension was filtered through celite (celite covers and requires scraping). The filtrate was slightly cloudy and was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 3,3-dicyclopropylpropanal (76.8 g, 100%),

1H 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

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To a suspension of lithium aluminum hydride (10.4 g, 266.9 mmol) in tetrahydrofuran (500 ml), a solution of 3,3-dicyclopropylpropanal (76 g, 549.9 mmol) in tetrahydrofuran (150 ml) was added dropwise, allowing gentle heating with reflux condenser. The mixture was stirred at ambient temperature for 2 hours. The reaction was cooled in an ice bath and quenched by slowly adding water (10.4 mL, 577.3 mmol), then aqueous sodium hydroxide (10.4 mL, 4 M, 41.60 mmol ), then water (31.2 ml, 1.732 mol). The suspension was filtered through celite, washed with tetrahydrofuran and concentrated in vacuo to give 3,3-dicyclopropylpropan-1-ol (112 g, 73%),

1H NMR (400 MHz, chloroform-d). δ 3.81 (t, J=6.9 Hz, 2H), 1.76 (k, 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

A ⁰ । A η

A. ^пн ii L · - Α/χΑχΝ R

T ’ ---- T Y >4 / λ Ad λ D / ° y

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). DIAD (43.0 mL, 218.4 mmol) was added dropwise to the mixture, allowing the mixture to gradually warm to 45°C. After addition, the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with hexane (450 ml) and approximately 50% of the solvent was removed in vacuo to obtain a suspension. The suspension was filtered using a medium frit and the solid was washed with hexane (3x50 ml). The filtrate was concentrated in vacuo to give an amber oil. The crude oil was diluted with dichloromethane and chromatographed on a 750 g silica gel column, eluting with a gradient of 0% to 40% ethyl acetate in hexane. Two main fractions were collected, the second fraction being the pure product. The first fraction contained triphenylphosphine and was rechromatographed on a 750 g silica gel column, eluting with a gradient of 0% to 25% ethyl acetate in hexane. The product from the second column combined with the product from the first column gave tert-butyl 3-(3,3-dicyclopropylpropoxy)pyrazole-1-carboxylate (39.0 g, 64%) as a clear oil. MS-ESI m/z calc. 306.19434, detected 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 hours. Volatiles were removed in vacuo to give 3-(3,3-dicyclopropylpropoxy)-1H-pyrazole (trifluoroacetate salt) (266 mg, 100%) as a colorless oil, which was used directly in the next reaction. MS-ESI m/z calc. 206.1419, detected 207.2 (M+1) ⁺ ; Retention time: 0.59 min (LC method A).

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

Mixture of tert-butyl 2,6-dichloropyridine-3-carboxylate (220.0 mg, 0.8867 mmol), 3-(3,3dicyclopropylpropoxy)-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) were stirred at room temperature for 15 hours. The reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography using a gradient of 100% hexanes to 20% ethyl acetate in hexanes to give tert-butyl-2-chloro-6[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridin- 3-carboxylate (245 mg, 71%) as a colorless oil. MS-ESI 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

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A solution of tert-butyl-2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridine-3carboxylate (245.0 mg, 0.5862 mmol) in trifluoroacetic acid (500.0 µl, 6.490 mmol) and dichloromethane (1.5 ml) were stirred for 4 hours at room temperature. The solvent was evaporated, the residue was dissolved twice in tetrahydrofuran and concentrated in vacuo to give 2-chloro-6-[3-(3,3dicyclopropylpropoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (204 mg, 96%) as white solid, which was used directly in the next reaction.

1H 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 (k, 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). MS-ESI m/z calc. 361.11932, detected 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]pyridin-3carbonyl]sulfamoyl]-2-pyridyl ]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

Carbonyldiimidazole (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 , then 1,8-diazabicyclo[5.4.0]undec-7-ene (280.4 mg, 275.4 µl, 1.842 mmol) and the reaction mixture was heated at 50°C for 16 hours. The reaction mixture was diluted with ethyl acetate and washed a small amount of 1:1 saturated aqueous ammonium chloride/saline solution. The organic phases were separated, dried over sodium sulfate, filtered and evaporated. The resulting brown residue was purified by silica gel chromatography using a shallow gradient from 100% dichloromethane to 20% methanol in dichloromethane to give tert-butyl 4-[3-[[6-[[2-chloro-6-[3-(3,3dicyclopropylpropoxy )pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2dimethylpyrrolidine-1-carboxylate (356 mg, 51%) as a white solid.

1H 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 (k, 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). MS-ESI m/z calc. 755.3232, detected 756.5 (M+1) ⁺ ; Retention time: 0.6 min (LC method L).

Step-11: 8-[3-(3,3-dicyclopropylpropoxy)-1 H-pyrazol-1 -yl]-12,12-dimethyl-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[17.3. 1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 43)

Solution of tert-butyl 4-[3-[[6-[[2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridin-3carbonyl]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 hours. Solvents were removed in vacuo and the residue was dissolved in ethyl acetate. Wash with 2 ml saturated aqueous sodium bicarbonate solution, the organic layers are collected and the solvent is removed in vacuo. The material was dissolved in dimethyl sulfoxide (17.50 ml) and 3A molecular sieves were added, 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 for nights. Reactionary

- 148 044967 The mixture was filtered through a Whatman filter disc (Puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS using a dual gradient from 20% to 80% mobile phase B over 15.0 min (mobile phase A=water (0.05% hydrochloric acid), mobile phase B=acetonitrile) to give 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]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4trione (compound 43) (158 mg, 55%) as an off-white solid.

1H 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 (k, 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). MS-ESI m/z calc. 619.29407, detected 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-pyrazol1-yl)-18-oxa-2λ ⁶ -thia-3,9,11 ,23-tetraazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (enantiomer 1) (compound 48) and 12 ,12-dimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-18-oxa-2Х ⁶ -thia-3,9,11,23tetraazatetracyclo[ 17.3.1.111,14.05,10]tetracose-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

Sodium hydride was added portionwise to tert-butyl-4-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate (257 mg, 0.9986 mmol) with stirring under nitrogen atmosphere b K,H-dimethylformamide (2.056 ml) (79.87 mg, 1.997 mmol) (caution: evolution of gas) and the mixture was stirred at room temperature for 20 minutes. 6-Fluoropyridine-2-sulfonamide (175.9 mg, 0.9986 mmol) was then added and the resulting mixture was stirred at room temperature for 2 hours and 20 minutes, then sodium hydride (23.96 mg, 0.9984 mmol) was added. (caution: gas evolution) and the resulting mixture was stirred for 20 minutes, then poured into 1 N. citric acid and extracted with ethyl acetate (2X). The combined organic fractions were dried (sodium sulfate), filtered and concentrated to a clear oil, which was purified by silica gel chromatography using a shallow gradient of 100% hexanes to 100% ethyl acetate to give tert-butyl 2,2-dimethyl-4-[3-[ (6-sulfamoyl-2pyridyl)oxy]propyl]pyrrolidine-1-carboxylate (275.2 mg, 67%). MS-ESI 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-1yl]pyridin-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-1yl]pyridine-3-carboxylic acid (96.86 mg, 0.2578 mmol) and carbonyl diimidazole (45.81 mg, 0.2825

- 149 044967 mmol) were combined in tetrahydrofuran (1.53 ml) and stirred for 120 min at 50°C with the lid ajar. Then tert-butyl-2,2-dimethyl-4-[3-[(6-sulfamoyl-2pyridyl)oxy]propyl]pyrrolidine-1-carboxylate (193.8 mg, 0.2578 mmol) in tetrahydrofuran (2, 04 ml) followed by the addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (80.81 mg, 79.38 µl, 0.5308 mmol) and the reaction mixture was heated at 50°C for 16 h. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution, and then with saline solution. The organic phases 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. The product elutes together with some impurities. Fractions containing product were combined and purified again by silica gel chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate to give tert-butyl 4-[3-[[6-[[2-chloro-6-[3-[ 2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]oxy]propyl]-2,2-dimethylpyrrolidine-1carboxylate (64.7 mg, 33 %). MS-ESI m/z calc. 770.2476, found 771.2 (M+1)+; Retention time: 0.94 min (LC method A).

Step 3: 2-chloro-^[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propoxy]-2-pyridyl]sulfonyl]-6-[3-[2[ 1 -(trifluoromethyl)cyclopropyl ]ethoxy]pyrazol-1 -yl]pyridin-3-carboxamide

tert-Butyl 4-[3-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin3-carbonyl]sulfamoyl]-2 -pyridyl]oxy]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (132.5 mg, 0.1718 mmol) was dissolved in dichloromethane (578.2 μl) and trifluoroacetic acid (898.7 mg, 607 .2 µl, 7.882 mmol), and the mixture was stirred at room temperature for 60 minutes. The mixture was concentrated to dryness under reduced pressure, treated with saturated aqueous sodium bicarbonate and ethyl acetate, and the layers were separated. The organic layer was washed 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]pyridin-3-carboxamide (110 mg, 95%). MSIE m/z calc. 670.1952, detected 671.2 (M+1) ⁺ ; Retention time: 0.64 min (LC method A).

Step 4: 12,12-dimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-18oxa-2λ ⁶ -thia-3,9,11 ,23-tetraazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene2,2,4-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]pyridin-3-carboxamide (126.6 mg, 0.1886 mmol) in dimethyl sulfoxide (5.063 ml), potassium carbonate (130.3 mg, 0.9430 mmol), cesium fluoride (34, 38 mg, 0.2263 mmol) and a small amount of 3 A molecular sieves. The resulting mixture was capped and heated to 150°C for 6.5 hours, 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 NH4C1/1 M 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 eluted once 100% ethyl acetate was reached) to give 12,12-dimethyl-8 -(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-18-oxa2λ ⁶ -thia-3,9,11,23-tetraazatetracyclo[17.3.1.111,14.05 ,10]tetracose-1(22),5,7,9,19(23),20-hexαene-2,2,4trione (compound 40) (58.2 mg, 48%) as a white solid. MS-ESI 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}-1 H-pyrazol-1 -yl)-18oxa-2λ ⁶ -thia-3,9,11 ,23-tetraazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene2,2,4-trione (enantiomer 1) (compound 48) and 12 ,12-dimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-18-oxα-2λ ⁶ -thia-3,9,11,23tetraazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (enantiomer 2) (compound 49)

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Racemic 12,12-dimethyl-8-(3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-18oxa-2λ ⁶ -thia-3,9,11,23 -tetraazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene2,2,4-trione (compound 40) (45.3 mg, 0. 07052 mmol) was subjected to chiral resolution using

SLC chromatography using ChiralPak AS-H (250x10 mm column, 5 µm particle size) with a mobile phase of 25% acetonitrile/methanol (90:10)/75% carbon dioxide at 10 ml/min for 8.0 min (vol. injection=70 µl of a 24 mg/ml solution in acetonitrile/methanol (90:10)) as the first enantiomer to elute. 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-18-oxa-2Х ⁶ -thia-3,9,11,23-tetraazatetracyclo [17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (enantiomer 1) (compound 48) (22.20 mg, 97%) as a white solid; MS-ESI m/z calc. 634.2185, detected 635.0 (M+1)+; Retention time: 2.30 min (LC method B) and as the second enantiomer eluted 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl )-18-oxa-2λ ⁶ -tiα-3,9,11,23-tetraazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2 ,2,4-trione (enantiomer 2) (compound 49) (22.33 mg, 100%) as a white solid;

1H NMR (400 MHz, DMSO-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), MS-ESI m/z calc. 634.2185, found 635.1 (M+1) ⁺ ; Retention time: 2.29 min (LC method B).

Example 13: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-2λ ⁶ -thia-3,9,11-triazatetracyclo[17.3 .1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4trione (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-dimethylpyrrolidine-1-carboxylate (5.20 g, 20.20 mmol) in anhydrous CH ₂ Cl ₂ (40 ml) at 0°C (ice bath) under a nitrogen atmosphere. After 15 minutes, the reaction mixture was allowed to warm to ambient temperature and stirring was continued for another 2 hours. The reaction mixture was diluted with ether (200 ml) and saturated aqueous sodium bicarbonate (100 ml) was added slowly (to reduce the evolution of carbon dioxide gas). 10% sodium thiosulfate (50 ml) was then added and stirred at ambient temperature for 30 min. The layers were separated and the aqueous layer was extracted with ether (2x100 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude material. The crude product was purified by medium pressure silica gel chromatography (330 g silica gel column, 5-35% ethyl acetate in hexane for 35 min) to give the desired tert-butyl-2,2-dimethyl-4-(3-oxopropyl)pyrrolidine-1- carboxylate (3.96 g, 77%) as a clear viscous substance, tert-butyl 2,2-dimethyl-4-(3oxopropyl)pyrrolidine-1-carboxylate (3.96 g, 77%).

¹ H NMR (400 MHz, Methanol-d4) δ 4.48 (t, J=5.4 Hz, 1H), 3.66 (dd, J=11.2, 6.9 Hz, 1H), 2.87 (k, J=10.7

- 151 044967

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 (k, 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). MS-ESI m/z calc.

255.18344, detected 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

Potassium carbonate (1.62 g, 11.72 mmol) followed by dropwise addition of (1-dimethoxyphosphoryl-2-oxopropylidene)iminoammonium (12.5 mL 10% w/v, 6.473 mmol). After addition was complete, the mixture was warmed to room temperature and stirred for 4 hours. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate (1X). The aqueous layer was 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 of 100% hexanes to 50% ethyl acetate to hexanes, yielding tertiary as a clear oil. butyl 4-but-3-ynyl-2,2dimethylpyrrolidine-1-carboxylate (1.15 g, 88%). MS-ESI m/z calc. 251.18852, found 252.2 (M+1) ⁺ ; Hold time: 1.96 min.

1H 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 stirred mixture of 3-iodobenzenesulfonamide (308.0 mg, 1.088 mmol), tert-butyl-4-but-3-ynyl-2,2-dimethylpyrrolidine-1-carboxylate (156.3 mg, 0.6218 mmol) , Pd(PPh ₃ ) ₂ Cl ₂ (26.19 mg, 0.03731 mmol), copper iodide (11.84 mg, 0.06218 mmol) and N,N-dimethylformamide (1.563 ml) in a vial for 5 minutes , then X-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 hours, then cooled to room temperature and stirred during the night. Cool to room temperature and pour into water (200 ml) and extract with dichloromethane (2x100 ml), combine organic layers, wash with water (2x100 ml), dry (magnesium sulfate), filter and concentrate to an orange oil, which is purified by silica gel chromatography with using a gradient from 100% hexanes to 100% ethyl acetate to give tert-butyl 2,2-dimethyl-4-[4-(3-sulfamoylphenyl)but-3ynyl]pyrrolidine-1-carboxylate (307.9 mg, 92%) in the form of a yellow oil. MS-ESI 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

Platinum oxide (65.20 mg, 0.2871 mmol) followed by the addition of EtOH (2.188 mL) and nitrogen was bubbled through the mixture for 1 min, followed by hydrogen bubbled through the mixture for 5 min. Then the mixture was capped with a balloon of hydrogen and stirred for 3 hours. It was purged with nitrogen, celite was added, stirred for 1 minute, then filtered through a layer of celite. The filtrate was concentrated to tert-butyl 2,2-dimethyl-4-[4-(3-sulfamoylphenyl)butyl]pyrrolidine-1-carboxylate (320.4 mg, 82%), an orange oil, which was directly transferred to the next step of ISEER 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-1yl]pyridin-3-carbonyl]sulfamoyl] phenyl]butyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

- 152 044967

In a 20 ml vial, 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridine-3-carboxylic acid (95.96 mg, 0.2554 mmol) and carbonyl Diimidazole (41.41 mg, 0.2554 mmol) was combined in tetrahydrofuran (1.00 ml) and stirred for 120 min at 50 °C with the lid ajar. 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 1,8diazabicyclo [5.4.0]undec-7-ene (50.93 μL, 0.3406 mmol), and the reaction mixture was heated at 50°C for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with a small amount of 1:1 saturated aqueous chloride solution ammonium/saline solution. The organic phases were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a shallow gradient of 100% dichloromethane to 20% methanol/dichloromethane to give tert-butyl 4-[4-[3-[[2-chloro -6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]phenyl]butyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (110.5 mg , 84%) as a white solid. MS-ESI m/z calc. 767.27313, detected 768.2 (M+1)+; retention time: 0.95 min (LC method A).

Step 6: 2-chloro-N-[3-[4-(5,5-dimethylpyrrolidin-3-yl)butyl]phenyl]sulfonyl-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazole -1-yl]pyridin-3-carboxamide (trifluoroacetic acid salt)

tert-Butyl 4-[4-[3-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]phenyl]butyl ]-2,2-dimethyl-pyrrolidine-1-carboxylate (110.5 mg, 0.1438 mmol) was dissolved in dichloromethane (482.2 µl) and trifluoroacetic acid (508.3 µl, 6.598 mmol) was added to the mixture and stirred at room temperature for 40 minutes. The mixture was concentrated to dryness under reduced pressure, dissolved in sat. aq. sodium bicarbonate and ethyl acetate and the layers were separated. The aqueous layer was neutralized with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic fraction was dried (sodium sulfate), filtered and concentrated to an orange oil, which was filtered and purified using reverse phase HPLC-MS using a Luna C ₁₈ (2) column (75x30 mm, 5 µm particle size) from Phenomenex (art. .: 00C4252-U0-AX) and a dual gradient run from 1-99% mobile phase B in 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 obtain 2-chloro-N-[3-[4-(5,5-dimethylpyrrolidin3-yl)butyl]phenyl]sulfonyl-6-[3- [2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carboxamide (trifluoroacetic acid salt) (104.5 mg, 93%). MS-ESI m/z calc. 667.2207, detected 668.2 (M+1) ⁺ ; retention time: 0.67 min (LC method A).

Step 7: 12,12-dimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-2X ⁶ -thia3,9,11-triazatetracyclo[17.3 .1.111,14.05,10]tetracose-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]pyrazole- 1-yl]pyridin-3-carboxamide salt of trifluoroacetic acid (112.5 mg, 0.1438 mmol) in dimethyl sulfoxide (4.499 ml), potassium carbonate (119.2 mg, 0.8625 mmol), cesium fluoride (26.22 mg, 0.1726 mmol) and a small amount of 3 A molecular sieves. The resulting mixture was sealed and heated to 165°C for 6 hours. 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 of 100% hexanes to 100% ethyl acetate to give 12,12-dimethyl-8-(3-{2-[ 1-(trifluoromethyl)- 153 044967 cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-2Х ⁶ -thia-3,9,11 -triazatetracyclo [17.3.1.111,14.05,10]tetracose1(22),5 ,7,9,19(23),20-hexaene-2,2,4-trione (compound 53) (46.5 mg, 51%) as a yellow solid.

1H NMR (400 MHz, DMSOC) δ 12.44 (s, 1H), 8.21 (d, J=2.8 Hz, 1H), 7.84 (s, 1H), 7.81 (s, 1H), 7.787.74 (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) . MS-ESI 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-pyrazol1-yl)-2X ⁶ -thia-3,9,11-triazatetracyclo[17.2 .2.111,14.05,10]tetracose-1(21),5,7,9,19,22-hexaene-2,2,4trione (enantiomer 1) (compound 54) and 12,12-dimethyl-8-(3 -{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}1 H-pyrazol-1 -yl)-2Х ⁶ -thia-3,9,11 -triazatetracyclo[17.2.2.111,14.05,10]tetracose-1(21 ),5,7,9,19,22hexaene-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 stirred mixture of 4-bromobenzenesulfonamide (256.9 mg, 1.088 mmol), tert-butyl-4-but-3-ynyl-2,2-dimethylpyrrolidine-1-carboxylate (156.3 mg, 0.6218 mmol) , Pd(PPh ₃ ) ₂ Cl ₂ (26.19 mg, 0.03731 mmol), copper iodide (11.84 mg, 0.06218 mmol) and N,N-dimethylformamide (1.563 ml) in a vial for 5 minutes , 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 during the night. Cool to room temperature and pour into water (200 ml) and extract with dichloromethane (2 x 100 ml), combine organic layers, wash with water (2 x 100 ml), dry (magnesium sulfate), filter and concentrate to an orange oil, which is purified by silica gel chromatography with using a gradient from 100% hexanes to 100% ethyl acetate to give tert-butyl 2,2-dimethyl-4-[4-(4-sulfamoylphenyl)but-3ynyl]pyrrolidine-1-carboxylate (192.5 mg, 76%) as a white solid. MS-ESI 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

Palladium oxide (53.75 mg, 0.2367 mmol) followed by EtOH (1.804 mL) and nitrogen was bubbled through the mixture for 1 min, then hydrogen was bubbled through the mixture for 5 min. Then the mixture was capped with a balloon of hydrogen and stirred for 3 hours. It was purged with nitrogen, celite was added, stirred for 1 minute, then filtered through a layer of celite. Concentrate the filtrate to tert-butyl 2,2-dimethyl-4-[4-(4-sulfamoylphenyl)butyl]pyrrolidine-1-carboxylate (179.5 mg, 92%), an off-white solid. MS-ESI m/z calc. 410.22394, found 411.2 (M+1)+; Hold Time:

0.75 min (LC method A).

Step 3: tert-butyl 4-[4-[4-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-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-1yl]pyridine-3-carboxylic acid (164.3 mg, 0.4372 mmol) and carbonyl Diimidazole (77.70 mg, 0.4792 mmol) was combined in tetrahydrofuran (2.576 ml) and stirred for 120 min at 50 °C with the lid ajar. 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 1,8diazabicyclo[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 hours. 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 reverse phase HPLC-MS using a Luna C ₁₈ (2) column (75x30 mm, 5 µm particle size) sold by Phenomenex (pn: 00C-4252-U0- AX) and a double gradient 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). The target product fractions were combined and acetonitrile was removed under reduced pressure. The material was then diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate (1X) and brine (1X), dried (sodium sulfate), filtered and concentrated to give tert-butyl-4[4-[4-[[2-chloro-6- [3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]phenyl]butyl]-2,2-dimethylpyrrolidine-1-carboxylate (132.8 mg, 40% ), clear oil. MS-ESI 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]pyrazole -1 -yl]pyridin-3-carboxamide

tert-Butyl 4-[4-[4-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]phenyl]butyl ]-2,2-dimethylpyrrolidine-1-carboxylate (132.8 mg, 0.1729 mmol) was dissolved in dichloromethane (579.5 μl) and trifluoroacetic acid (904.5 mg, 611.1 μl, 7.933 mmol) was added to the mixture ) and the mixture was stirred at room temperature for 60 minutes. The mixture was concentrated to dryness under reduced pressure, treated with saturated aqueous sodium bicarbonate and ethyl acetate, and the layers were separated. The organic layer (sodium sulfate) was dried, 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]pyridin-3-carboxamide (99.8 mg, 86%). MSIE 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} -1 H-pyrazol-1 -yl)-2λ ⁶ -tua3,9,11 -triazatetracyclo[17.2 .2.111,14.05,10]tetracose-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]pyrazole- 1-yl]pyridin-3-carboxamide (99.8 mg, 0.1494 mmol) in dimethyl sulfoxide (3.991 ml), potassium carbonate (103.2 mg, 0.7470 mmol), cesium fluoride (27.24 mg, 0 .1793 mmol) and a small amount of 3 A molecular sieves. The resulting mixture was sealed and heated to 155°C overnight. Cool to room temperature, dilute with ethyl acetate and wash with saturated aqueous ammonium chloride and saline. 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}-1 H-pyrazol-1 -yl)-2λ ⁶ -thia-3,9,11 triazatetracyclo[17.2.2.111 ,14.05,10]tetracose-1(21),5,7,9,19,22-hexaene-2,2,4-trione (compound 51) (25 mg, 26%) as a white solid.

Ή NMR (400 MHz, DMSO-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 (k , J=11.6 Hz, 1H), 0.36 (s, 1H). MS-ESI 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} -1 H-pyrazol-1 -yl)-2X ⁶ -thia3,9,11 -triazatetracyclo[17.2 .2.111,14.05,10]tetracose-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)cyclononyl]ethoxy}-1H-nirazol-1-yl)2Х ⁶ -thia-3,9,11-triazatetracyclo[17.2.2.111,14.05,10]tetracose-1 ( 21 ),5,7,9,19,22-hexaene-2,2,4-trione (enantiomer 2) (compound 55) enantiomer enantiomer 2

Racemic 12,12-dimethyl-8-(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)2Х ⁶ -thia-3,9,11 -triazatetracyclo[17.2. 2.111,14.05,10]tetracose-1(21),5,7,9,19,22-hexaene-2,2,4-trione (21.9 mg, 0.03411 mmol) was subjected to chiral resolution using SKZ- chromatography using ChiralPak AS-H (250x10 mm column, 5 µm particle size) with a mobile phase of 25% acetonitrile/methanol (90:10)/75% carbon dioxide at 10 ml/min for 6.0 min (injection volume= 70 µl of a 24 mg/ml solution in 85% acetonitrile/methanol (90:10)/15% dimethyl sulfoxide) to give 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl) as the first enantiomer eluted )cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ ⁶ -thia-3,9,11-triazatetracyclo[17.2.2.111,14.05,10]tetracose1(21),5,7,9,19,22 -hexaene-2,2,4-trione (enantiomer 1) (compound 54) (10.01 mg, 92%) as a white solid; MS-ESI m/z calc. 631.244, detected 632.2 (M+1) ⁺ ; Retention time: 2.44 min (LC method B) and as the second enantiomer eluted 12,12-dimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl )-2Х ⁶ -thia-3,9,11 triazatetracyclo[17.2.2.111,14.05,10]tetracose-1(21),5,7,9,19,22-hexaene-2,2,4-trione (enantiomer 2) (compound 55) (8.59 mg, 80%) as a white solid;

1H NMR (400 MHz, DMSO-de) 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 (k, J= 10.7 Hz, 1H), 0.36 (s, 1H), MS-ESI m/z calc. 631.244, found 632.2 (M+1) ⁺ ; Retention time: 2.44 min (LC method B).

Example 15: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-2X ⁶ -thia-3,9,11-triazatetracyclo[17.3 .1.111,14.05,10] tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4trione (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]tetracose-1 (22),5,7,9,19(23),20hexaene-2,2,4-trione (enantiomer 2) (compound 57) enantiomer enantiomer 2

Step 1: 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclononyl]ethoxy}-1H-pyrazol-1-yl)-2λ ⁶ -thia3,9,11-triazatetracyclo[17.3. 1.111,14.05,10]tetracose-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-pyrazol1-yl)-2λ ⁶ -thia-3,9,11-triazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4trione (enantiomer 2) (compound 57)

- 156 044967

Racemic 12,12-dimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)2Х ⁶ -thia-3,9,11 -triazatetracyclo[17.3. 1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (41.7 mg, 0.06575 mmol) was subjected to chiral resolution with by SLC chromatography using ChiralPak AS-H (250 x 10 mm column, 5 µm particle size) with a mobile phase of 25% acetonitrile/methanol (90:10)/75% carbon dioxide at 10 ml/min for 8.0 min (injection volume = 70 µl of 24 mg/ml solution in 85% acetonitrile/methanol (90:10)/15% dimethyl sulfoxide) yielding 12,12-dimethyl-8-(3-{2-[) as the first enantiomer eluted 1-(trifluoromethyl)cyclopropyl]ethoxy}1 H-pyrazol-1 -yl)-2Х ⁶ -thia-3,9,11 -triazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7 ,9,19(23),20hexaene-2,2,4-trione (enantiomer 1) (compound 56) (20.2 mg, 97%); MS-ESI m/z calc. 631.244, detected 632.2 (M+1)+; Retention time: 2.44 min (LC method B) and as the second enantiomer eluted 12,12-dimethyl-8-(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazole-1 - yl)-2Х ⁶ -thia-3,9,11triazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4- trione (enantiomer 2) (compound 57) (15.9 mg, 75%);

1H NMR (400 MHz, DMSO-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) . MS-ESI m/z calc. 631.244, detected 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-nirazol1 -yl)-2X ⁶ -thia-3,9,11,20,25 -pentaazatetracyclo[19.3.1.111,14.05,10]hexakose-1 (24),5,7,9,21 (25),22-hexaene2,2,4-trione (enantiomer 1) (compound 63) and 12,12 -dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy }-1 H-pyrazol-1 -yl)-2Х ⁶ -thia-3,9,11,20,25-pentaazatetracyclo [19.3 .1.111,14.05,10]hexakose1(24),5,7,9,21(25),22-hexaene-2,2,4-trione (enantiomer 2) (compound 64)

Step 1: Ethyl 1-(bromomethyl)-2-oxocyclohexanecarboxylate

To a suspension of 60% sodium hydride (25.7 g, 641 mmol) and hexamethylphosphoramide (112 ml, 641 mmol) in tetrahydrofuran (850 ml), a solution of ethyl 2-cyclohexanone carboxylate (84.0 g, 493 mmol) in tetrahydrofuran was added dropwise (350 ml) for four hours, and the resulting mixture was stirred at room temperature for one hour. Dibromomethane (173 ml, 2470 mmol) was then added dropwise over one hour and the mixture was refluxed at 70°C for 16 hours. The reaction mixture was diluted with diethyl ether (6 L), the organic layer was washed with water (5x850 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 give ethyl 1-(bromomethyl)-2-oxocyclohexanecarboxylate (68 g, 52%) as a clear oil. Purity was determined to be approx. 80% by ^1H NMR.

- 157 044967 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-methylene heptanedioate

A suspension of ethyl 1-(bromomethyl)-2-oxocyclohexanecarboxylate (68 g, 258 mmol) and potassium carbonate (71.4 g, 517 mmol) in ethanol (600 ml) was stirred for 16 hours 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% hexane/ethyl acetate gradient to give diethyl 2-methylene heptanedioate (45.2 g, 77%) as a clear oil.

^1H 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). MS-ESI 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-nitropropyl)heptanedioate

A mixture of diethyl 2-methylene heptanedioate (48.6 g, 213 mmol), 2-nitropropane (58 mL, 639 mmol) and 1,8diazabicyclo[5.4.0]undec-7-ene (3.2 mL, 21 mmol) was heated at 85°C for five hours. The mixture was concentrated and purified by silica gel chromatography using a 0-15% hexane/ethyl acetate gradient to give diethyl 2-(2-methyl-2-nitropropyl)heptanedioate (58 g, 85%) as a clear oil. MSIE 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-oxopyrrolidin-3-yl)pentanoate

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

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

Lithium aluminum hydride (6.2 g, 164, 1 mmol), then the resulting suspension was refluxed under a nitrogen atmosphere for 17 hours. The mixture was carefully quenched with saturated aqueous sodium sulfate (50 ml) and filtered. The solids were removed and the aqueous phase was separated and discarded. The organic phase was concentrated to give 5-(5,5dimethylpyrrolidin-3-yl)pentan-1-ol (8.8 g) as a pale yellow oil. MS-ESI m/z calc. 185.31, found 186.3 (M+1) ⁺ . Retention time: 1.98 min (LC method Q). The crude product was used for 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 by the addition of di-tert-butyl dicarbonate (31.8 g, 145.7 mmol). The resulting heterogeneous mixture was stirred at room temperature for two hours. The phases were separated and the aqueous phase was discarded. The organic phase was concentrated in vacuo and purified by silica gel chromatography using a 0-45% hexanes/ethyl acetate gradient to give tert-butyl 4-(5-hydroxypentyl)-2,2-dimethylpyrrolidine-1-carboxylate (32.0 g, 77%) in the form of a clear oil.

- 158 044967 ^1H NMR (250 MHz, CDCI3) 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). MS-ESI 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-dimethylpyrrolidine-1-carboxylate (10.5 g, 36.8 mmol) and triethylamine (10.3 ml, 73.6 mmol) in dichloromethane (100 ml) was cooled in an ice water bath. Methanesulfonyl chloride (3.2 mL, 40.5 mmol) was then added dropwise over 15 minutes and the resulting mixture was stirred for one hour in an 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 give tert-butyl 2,2-dimethyl-4-(5-methylsulfonyloxypentyl)pyrrolidine-1-carboxylate (13.3 g, 99%) as a yellow oil. MS-ESI m/z calc. 363.16, found 364.3 (M+1) ⁺ . Hold 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) stirred at 50°C for 24 hours. Tetrahydrofuran and ammonia were removed under vacuum and the remaining aqueous phase was extracted with dichloromethane (3x100 ml), the combined organic layers were concentrated to an oil and purified by silica gel chromatography using a 0-15% dichloromethane/methanol gradient ( 0.25% ammonium hydroxide) to give tert-butyl 4-(5-aminopentyl)-2,2-dimethylpyrrolidine-1-carboxylate (5.4 g, 52%) as a pale oil.

1H NMR (250 MHz, CDCl3) δ 3.53 (q, 1H), 2.75 (q, 1H), 2.05 (s, 2H), 1.86 (m, 1H), 1.43-1.10 (m, 23H). MS-ESI 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

A 100 mL round bottom flask was charged with tert-butyl 4-(5-aminopentyl)-2,2dimethylpyrrolidine-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 was stirred at 100°C for 20 hours. After cooling, the reaction mixture 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 hexane. The pure fractions were collected and the solvents were evaporated to give tert-butyl 2,2-dimethyl4-[5-[(6-sulfamoyl-2-pyridyl)amino]pentyl]pyrrolidine-1-carboxylate (1.184 g, 74%) as a solid. white foam. MS-ESI 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-1yl]pyridin-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-1yl]pyridine-3-carboxylic acid (19.8 mg, 0.8511 mmol) and carbonyl Diimidazole (138.0 mg, 0.8511 mmol) was combined in tetrahydrofuran (3.588 ml) and stirred for 120 min at 50 °C with the lid ajar. Then tert-butyl-2,2-dimethyl-4-[5-[(6-sulfamoyl-2pyridyl)amino]pentyl]pyrrolidine-1-carboxylate (250 mg, 0.5674 mmol) in tetrahydrofuran (4.785 ml) was added with followed by the addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (169.7 µl, 1.135 mmol) and the reaction mixture was heated at 50°C for 16 hours. The reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride, and then with saline solution. The organic layers 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 to give tert-butyl 4-[5-[[6-[[2-chloro- 6-[3[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]pentyl]-2,2-dimethylpyrrolidine-1-carboxylate (416 .8 mg, 92%). MS-ESI 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 o O O OOO

tert-Butyl 4-[5-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin3-carbonyl]sulfamoyl]-2 -pyridyl]amino]pentyl]-2,2-dimethylpyrrolidine-1-carboxylate (416.8 mg, 0.5221 mmol) was dissolved in dichloromethane (1.189 ml) and trifluoroacetic acid (1.845 ml, 23.95 mmol) was added to the mixture. and stirred the mixture at room temperature for 60 minutes. The mixture was concentrated to dryness under reduced pressure, treated with saturated aqueous sodium bicarbonate and ethyl acetate, and the layers were separated. The organic layer was dried (sodium sulfate), filtered and concentrated to a white solid, 2-chloro-N-[[6-[5-(5,5-dimethylpyrrolidin-3yl)pentylamino]-2-pyridyl]sulfonyl]-6- [3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carboxamide (361 mg, 91%). MS-ESI 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}-1 H-pyrazol-1 -yl)-2λ ⁶ thia-3,9,11,20, 25-pentaazatetracyclo[19.3.1.111,14.05,10]hexakose-1 (24),5,7,9,21 (25),22-hexaene-2,2,4trione (enantiomer 1) (compound 63) and 12, 12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}1H-nurazol-1-ul)-2λ ⁶ -thia-3,9,11,20,25-pentaazatetracyclo[19.3. 1.111,14.05,10]hexakose1(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]pyridin-3-carboxamide (361 mg, 0.4736 mmol) in dimethyl sulfoxide (13.22 ml), potassium carbonate (392.6 mg, 2.841 mmol), cesium fluoride (86.33 mg, 0.5683 mmol) and a small amount of 3 A molecular sieves. The resulting mixture was capped and heated to 165°C for 16 hours. 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 SLC chromatography using LUX 3 (250 x 1 mm column, 5 µm particle size) with a mobile phase of 60% methanol (20 mM addition of NH ₃ )) / 40% carbon dioxide at 30 ml/min, obtaining 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazole as the first eluted enantiomer -1-yl)-2λ ⁶ -thia-3,9,11,20,25-pentaazatetracyclo[19.3.1.111,14.05,10]hexacose1(24),5,7,9,21(25),22-hexaene -2,2,4-trione (enantiomer 1) (compound 63) (74.4 mg, 47%) as a white solid;

1H NMR (400 MHz, DMSO-a 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), MS-ESI m/z calc. 661.2658, detected 662.2 (M+1) ⁺ ; Retention time: 2.29 min (LC method B), and the second enantiomer eluted was 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazole-1- yl)-2λ ⁶ -thia-3,9,11,20,25-pentaazatetracyclo[19.3.1.111,14.05,10]hexacose1(24),5,7,9,21(25),22-hexaene-2, 2,4-trione (enantiomer 2) (compound 64) (79.2 mg, 50%) as a white solid;

1H NMR (400 MHz, DMSO-f,) 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,

- 160 044967

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), 0.980.95 (m, 2H), 0.95-0.87 (m, 3H), MS-ESI m/z calc. 661.2658, found 662.2 (M+1)+; Hold Time:

2.29 min (LC method B).

Example 17: Preparation of (14S)-8-[3-(3,3-Dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo [17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4trione (compound 66)

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

Racemic tert-butyl-2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine 1-carboxylate (7 g, 16.97 mmol) was subjected to chiral resolution using SLC chromatography using ChiralPak IG (250x21.2 mm column, 5 µm particle size) with a mobile phase of 40% methanol/60% carbon dioxide at 70 ml/min for 11.0 min (injection volume = 500 µl of 32 mg/ml solution in methanol) giving the first elution peak, tert-butyl (4S)-2,2-dimethyl-4-[3-[(6-sulfamoyl2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (3.4481 g, 99%). MS-ESI 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-1yl]pyridin-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) slowly carbonyldiimidazole (4.4 g, 27.14 mmol) was added. The mixture was stirred at ambient temperature for 1 hour.

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) add 2,3,4,6,7,8,9,10octahydropyrimido[1,2-a]azepine (11.0 ml, 73.56 mmol), then the activated ester from part A and the mixture was stirred at ambient temperature for 16 hours. The reaction was quenched with 50 ml of water and most of the tetrahydrofuran was removed in vacuo. The remaining mixture was diluted with water (250 ml) containing hydrochloric acid (26 ml 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 in vacuo to give 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 give tert-butyl (4S)-4[3-[[6-[[2-chloro-6-[3- (3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (11.2 g, 60%). MS-ESI 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)-5,5dimethylpyrrolidin-3-yl]propylamino] -2-pyridyl]sulfonyl]pyridine-3-carboxamide (trifluoroacetic acid salt)

K tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-(3,3-dicyclononylpropoxy)pyrazol-1-yl]pyridin-3carbonyl]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 hours. The solvent was removed by rotary evaporation at 35° C. to obtain a thick yellow oil. The oil was diluted with dichloromethane (80 ml) and toluene (120 ml), and the solvent was removed by rotary evaporation at 55°C. The process was repeated with dichloromethane and toluene, yielding 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 a thick oil.

¹ H NMR (400 MHz, DMSO-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 (dk, J=12.0, 5.3 Hz, 1H), 3.24 (hept, J=6.7 Hz, 2H), 2.80 (td, J=l 1.8, 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). MS-ESI 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-nirazol-1-yl]-12,12-dimethyl-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-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-[(3 S)-5,5dimethylpyrrolidin-3-yl]propylamino] Potassium carbonate (15.3 g, 110.7 mmol) was added to NMP (300 mL) and then cesium fluoride (3.8 g, 25.02 mmol). The mixture was purged with nitrogen for 5 minutes. The mixture was heated at 150°C for 20 hours. The reaction mixture was cooled to room temperature, added to water (1200 ml) (using a 5-liter flask cooled in an ice bath) and acidified by careful addition of hydrochloric acid (20 ml 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 hour. The solid was collected by filtration using a medium frit (slow filtration), the wet filter cake was dissolved in ethyl acetate (1000 ml) and washed with 500 ml of brine. The aqueous phase was separated and the organic phase was dried over magnesium sulfate, filtered through celite and concentrated in vacuo to give a light yellow foam. The crude product was diluted with acetonitrile, divided into 3 equal volumes (15 ml) and chromatographed on a reverse phase C ₁₈ 415g column, eluting with 50-100% acetonitrile/water to give (14S)-8-[3-(3,3 dicyclopropylpropoxy )-1H-pyrazol-1-yl]-12,12-dimethyl2Х ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7 ,9,19(23),20-hexaene-2,2,4trione (compound 66) (8.91 g, 63%).

^1H NMR (400 MHz, DMSO-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

- 162 044967

Hz, 1H), 0.20 (dd, J=9.7, 4.4 Hz, 2H), 0.04 (d, J=8.3 Hz, 2H). MS-ESI m/z calc. 619.29407, found 620.3 (M+1)+; Retention time: 10.3 min (LC method F).

Example 18: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-III-pyrazol1-yl)-2X ⁶ -thia-3,9,11,18,20 -pentaazatetracyclo[17.2.2.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (enantiomer 1) (compound 72) and 12,12 -dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-2Х ⁶ -thia-3,9,11,18,20-pentaazatetracyclo[17.2 .2.111,14.05,10]tetracose-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-1carboxylate

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) potassium carbonate (219.9 mg, 1.591 mmol) was added and the mixture was stirred at 100°C for 20 hours. Then allowed to cool to room temperature. Dilute with ethyl acetate and pour into saturated aqueous ammonium chloride. The layers were separated, then the organic layer was washed 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 to give tert-butyl 2,2 -dimethyl-4-[3-[(5-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1carboxylate (347 mg, 54%) as a white solid. MS-ESI 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-1yl]pyridin-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-1yl]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 the lid ajar. Then tert-butyl-2,2-dimethyl-4-[3-[(5-sulfamoyl-2pyridyl)amino]propyl]pyrrolidine-1-carboxylate (347 mg, 0.8411 mmol) in tetrahydrofuran (6.642 ml) was added with followed by the addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (251.6 µl, 1.682 mmol) and the reaction mixture was heated at 50°C for 16 hours. The reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride, and after - saline solution. The organic layers were separated and dried over

- 163 044967 sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate to obtain pure product as well as mixed fractions. The mixed fractions were concentrated and re-purified using a reverse phase HPLC-MS method using a Luna C ₁₈ (2) column (75x30 mm, 5 µm particle size) sold by Phenomenex (part number: 00C-4252-U0-AX) and double gradient 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 prepurification were pooled 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]pyridin-3carbonyl]sulfamoyl]-2-pyridyl]amino]propyl] -2.2 -dimethylpyrrolidine-1-carboxylate (539.2 mg, 83%) as a white solid. MS-ESI m/z calc. 769.2636, found 770.2 (M+1)+; Retention time: 0.84 min (LC method A).

Step 3: 2-chloro-X-[[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]pyridin3-carbonyl]sulfamoyl]-2 -pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (539.2 mg, 0.7000 mmol) was dissolved in dichloromethane (2.353 ml) and trifluoroacetic acid (2.474 ml, 32.11 mmol) was added to the mixture. , and the mixture was stirred at room temperature for 60 minutes. The mixture was concentrated to dryness under reduced pressure, dissolved in saturated aqueous sodium bicarbonate and ethyl acetate and separated into layers (the solubility of the product in ethyl acetate under these conditions is low, the addition of some methanol helps to evaporate the organic layer without the use of a solid drying agent). The organic layer was concentrated by rotary evaporation followed by drying in vacuo to give 2-chloro-X-[[6-[3-(5,5dimethylpyrrolidin-3-yl)propylamino]-3-pyridyl]sulfonyl]-6-[3-[ 2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (423.3 mg, 90%) as an off-white solid. MS-ESI 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}-1 H-pyrazol-1-yl)-2λ ⁶ -thia3,9,11,18,20 -pentaazatetracyclo[17.2.2.111,14.05,10]tetracose-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]pyridin-3-carboxamide (423.3 mg, 0.6317 mmol) in dimethyl sulfoxide (16.93 ml), potassium carbonate (523.8 mg, 3.790 mmol), cesium fluoride (115 .1 mg, 0.7577 mmol) and a small amount of 3 A molecular sieves. The resulting mixture was sealed and heated to 165°C for 16 hours. The temperature was raised to 175°C and stirred for 3 hours, then cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and saline. The organic phase was dried (sodium sulfate), filtered and concentrated to 500 mg of a tan amorphous solid, which was filtered and purified using reverse phase HPLC-MS using a Luna C ₁₈ (2) column (75x30 mm, particle size 5 µm), sold by Phenomenex (pn: 00C-4252-U0-AX), and a double gradient of 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 give 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]tetracose1(22),5,7,9,19(23) .20 hexaene-2,2,4-trione (compound 62) (24.2 mg, 6%) as a white solid.

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1H NMR (400 MHz, DMSO-de) 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 (k, J= 13.8, 11.4 Hz,

4H), 0.98-0.92 (m, 2H), 0.92-0.85 (m, 3H). MS-ESI m/z calc. 633.2345, found 634.2 (M+1)+; Retention time: 2.03 min (LC method B).

Step 5: 12,12-dimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-2λ ⁶ -thia3,9,11,18,20 -pentaazatetracyclo[17.2.2.111,14.05,10]tetracose-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}-1Hpyrazol-1-yl)-2λ ⁶ -thia-3,9,11,18,20-pentaazatetracyclo[17.2. 2.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (enantiomer 2) (compound 73)

Racemic 12,12-dimethyl-8-(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)2λ ⁶ -thia-3,9,11,18,20- pentaazatetracyclo[17.2.2.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4trione (17 mg, 0.02565 mmol) was subjected to chiral resolution by SLC chromatography using ChiralPak AS-H (250x 10 mm column, 5 µm particle size) with a mobile phase of 18% methanol (20 mM NH ₃ additive)/82% carbon dioxide at 10 ml/min for 8.0 min (injection volume = 70 µl of 24 mg/ml solution in 90% methanol/10% dimethyl sulfoxide to give 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy as the first eluted enantiomer }-1H-pyrazol-1yl)-2λ ⁶ -thia-3,9,11,18,20-pentaazatetracyclo[17.2.2.111,14.05,10]tetracose-1(22),5,7,9,19(23 ),20-hexaene2,2,4-trione (enantiomer 1) (compound 72) (6.34 mg, 78%) as a white solid; ESI-MS m/z calculated 633.2345, found 634.4 (M+1) ⁺ ; retention time: 2.08 min (LC method B) and as the second eluted enantiomer 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}- 1Hpyrazol-1-yl)-2λ ⁶ -thia-3,9,11,18,20-pentaazatetracyclo[17.2.2.111,14.05,10]tetracose1(22),5,7,9,19(23),20- hexaene-2,2,4-trione (enantiomer 2) (compound 73) (5.54 mg, 68%) as a white solid.

1H NMR (400 MHz, DMSO-de) 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). MS-ESI 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}-1Hpyrazol-1 -yl)-18-oxa-2λ ⁶ -thia-3 ,9,11-triazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (compound 77)

From: (3 S)-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 SLC chromatography using a ChiralPak AD-H (2x25 cm column) with a mobile phase of 30% methanol /carbon dioxide at 60 ml/min (injection volume = 1 ml of a 20 mg/ml solution in methanol to obtain the first eluted enantiomer (3S)-3-(3-hydroxypropyl)-5,5-dimethyl-pyrrolidin2-one (47 g , 48%) as an off-white solid.

- 165 044967

1H NMR (400 MHz, DMSO) 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). MS-ESI 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 three-neck round bottom flask was equipped with a mechanical stirrer, heating hood, dropping funnel, J-Kem temperature sensor/controller, and nitrogen inlet/outlet. Lithium aluminum hydride granules (46.53 g, 1.226 mol) were loaded into a vessel under a nitrogen atmosphere. Tetrahydrofuran (500 ml, 20 ml/g) was then charged into the vessel. Stirring was started and the temperature in the vessel was recorded at 20°C. The mixture was left stirring at room temperature for 0.5 h to allow the granules to dissolve. The reactor temperature of the resulting sulfur suspension was 24°C. A solution of (38)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (60 g, 350.4 mmol) in tetrahydrofuran (600 ml) was loaded into a dropping funnel and the clear pale yellow solution was added dropwise within 90 min. A little heat was required to dissolve. After addition was completed, the reservoir temperature of the resulting grayish slurry was recorded at 24°C. The mixture was then heated to a kettle temperature of 65°C and conditions were maintained for 72 hours. Analysis of the reaction mixture at this point indicated that some residual starting material still remained and no change in product formation. The reaction was subsequently stopped at this stage. The heating mantle was removed and the vessel was provided with a cooling bath. The suspension was cooled to 0°C using a crushed ice/water cooling bath and then quenched by very slowly adding water (46.53 ml) dropwise, then 15 wt% sodium hydroxide solution (46.53 ml) and then water again (139.59 ml). The temperature of the resulting white suspension was 5°C. The cooling bath was removed and the vessel was again fitted with a heating mantle. The suspension was heated to 60°C and kept for 30 minutes. The warm suspension was filtered under vacuum through a Buchner funnel fitted with a glass frit containing a 25 mm layer of celite. The filter cake was then washed with tetrahydrofuran displacement at 60°C (2 x 350 ml) and then stretched for 30 min. The clear filtrate was concentrated under reduced pressure to give (55 g, 0.349 mol, 99% yield) a clear light yellow viscous oil as the desired product, 3-[(3s)-5,5-dimethylpyrrolidin-3-yl]propan-1ol (55 g, 100%).

1H NMR (400 MHz, DMSO-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 (48)-4-(3-hydroxypropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate he he

A 1 L three-neck round bottom flask was equipped with a mechanical stirrer, cooling bath, dropping funnel, J-Kem temperature probe, and nitrogen inlet/outlet. 3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propan-1-ol (25 g, 159.0 mmol) and dichloromethane (250 ml) were charged into a vessel under a nitrogen atmosphere, which gave a clear light yellow solution. Stirring was started and the temperature in the vessel was recorded at 19°C. Crushed ice/water was loaded into the cooling bath and the temperature in the container was lowered to 0°C. The addition funnel was charged with triethylamine (22.16 mL, 159.0 mmol), which was then added neat dropwise over 5 min. No exotherm was observed. Di-tert-butyl dicarbonate (31.32 g, 143.5 mmol) dissolved in dichloromethane (150 ml) was then charged into the addition funnel. A clear, pale yellow solution was then added dropwise over 30 minutes, causing a gentle evolution of gas. No exotherm was observed. The cooling bath was removed and the resulting clear light yellow solution was allowed to warm to room temperature and stirring was continued at room temperature for 3 hours. The reaction mixture was transferred to a separatory funnel and partitioned with water (75 ml). The organic layer was removed and washed with brine (75 ml), dried over sodium sulfate (150 g) and then filtered through a Buchner funnel with a glass frit. The filtrate was concentrated under reduced pressure to obtain (45 g) a clear light yellow oil as the desired crude product. The material was purified by flash chromatography on a silica gel column (liquid loading 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 give tert-butyl (48)-4-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate (39 g, 95%).

1H NMR (400 MHz, DMSO-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 (k, J=10.2 Hz, 1H), 1.47 (s, 3H), 1.44-1.28 (m, 18H), 1.24 (s, 3H). MS-ESI m/z calc. 257.1991,

- 166 044967 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 three-neck round bottom flask was equipped with a mechanical stirrer, cooling bath, dropping funnel, J-Kem temperature probe, and nitrogen inlet/outlet. Tert-butyl (4S)-4-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1carboxylate (25 g, 97.14 mmol) and dichloromethane (250 ml) were charged into the vessel under a nitrogen atmosphere, resulting in a clear, colorless solution. Stirring was started and the temperature in the vessel was recorded at 19°C. Crushed ice/water was loaded into the cooling bath and the temperature in the container 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, resulting in a light yellow suspension and an exothermic reaction at 4°C. The mixture was continued to stir at <5°C for 1 hour when LC/MS analysis 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 two-phase mixture was then transferred to a separatory funnel. The organic layer was removed, washed with saturated ammonium chloride solution (150 ml), dried over sodium sulfate (150 g) and then filtered through a Buchner funnel with a glass frit. The filtrate was concentrated under reduced pressure to give tert-butyl (4S)-2,2-dimethyl-4-(3-methylsulfonyloxypropyl)n-pyrrolidine 1-carboxylate (29 g, 89%) as a clear amber oil.

1H NMR (400 MHz, DMSO-d6) δ 4.19 (t, J=6.4 Hz, 2H), 3.16 (s, 3H), 2.79 (k, 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). MS-ESI 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)nropyl]pyrrolidine-1carboxylate

3-Hydroxybenzenesulfonamide (750 mg, 4.331 mmol) and N,Ndimethylformamide (15 mL) were added to a 100 mL flask. Potassium carbonate (1.8 g, 13.02 mmol) and tert-butyl (4S)-2,2dimethyl-4-(3-methylsulfonyloxypropyl)pyrrolidine-1-carboxylate (1.5 g, 4.471 mmol) were added to the mixture at room temperature. The resulting mixture was stirred at room temperature for 48 hours, then heated to 50°C for 5 hours. Then the mixture was poured into 1 N. citric acid and extracted with ethyl acetate (2X). The combined organic fractions were dried (sodium sulfate), filtered and concentrated to a yellow oil, which was purified by silica gel column chromatography (80 g column) using a gradient of 100% hexanes to 65% ethyl acetate in hexanes to give tert-butyl(48)- 2,2-dimethyl-4-[3-(3-sulfamoylphenoxy)propyl]pyrrolidine-1-carboxylate (868 mg, 49%) as a light yellow foam.

1H NMR (400 MHz, DMSO-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 (k, 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, 3Н).MS-ESI 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]pyrazol1 -yl]pyridin-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 hour at 50°C. Then tert-butyl (48)-2,2-dimethyl-4-[3-(3sulfamoylphenoxy)propyl]pyrrolidine-1-carboxylate (250 mg, 0.6060 mmol) was added, followed by 1,8diazabicyclo[5.4.0] undec-7-ene (230 μl, 1.538 mmol), and the reaction mixture was heated at 50°C for 18 hours. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution, followed by saline. The organic phase was separated, dried over sodium sulfate, filtered and evaporated, and then purified by column chromatography on silica gel (40 g) using a gradient of 100% hexanes to 75% ethyl acetate in hexanes to give tert-butyl( 4S)-4-[3-[3-[[2chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]phenoxy]propyl ]-2,2-dimethylpyrrolidine-1-carboxylate (368 mg, 79%) as an off-white solid. MS-ESI 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}-1 H-pyrazol-1 -yl)18-oxa-2λ ⁶ -thia- 3,9,11-triazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23),5(10),6,8,19,21-hexaene-2,2,4trione (compound 77)

Part A: tert-butyl (4S)-4-[3-[3-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclononyl]ethoxy]nirazol-1yl]pyridin-3- carbonyl]sulfamoyl]phenoxy]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (368 mg, 0.4778 mmol) was dissolved in dichloromethane (7.6 ml) and hydrochloric acid (4M in dioxane) was added to the mixture (4, 0 ml 4 M, 16.00 mmol) and stirred at room temperature for 30 min. The mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate, then 2M aqueous sodium carbonate (5 ml) was added to give a pH of ~10. Extracted the organic layer with ethyl acetate (2x10 ml), washed with brine, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure.

Part B: Combine materials from Part A and potassium carbonate (345 mg, 2.496 mmol), cesium fluoride (115 mg, 0.7571 mmol), 3 A molecular sieves and dimethyl sulfoxide (7.6 ml) in a vial, purged with nitrogen, stopper , heated to 150°C and stirred for 20 hours. Cooled to room temperature. The mixture was filtered then purified by preparative reverse phase HPLC using a C ₁₈ column and Method 30-99 A1-B1 (acetonitrile-water + 5 mM hydrochloric acid) to give (14S)-12,12-dimethyl-8-(3 -{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-18-oxa-2λ ⁶ -thia3,9,11 -triazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23),5(10),6,8,19,21-hexaene-2,2,4-trione (compound 77) (62.1 mg, 20%) as an off-white solid.

1H 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). MS-ESI m/z calc. 633.22327, detected 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]tetracose-1(23),5,7,9,19,21-hexaene-2,2,4-trione (compound 79)

Step 1: 3-(3,3-dimethylbutyl)pyrrolidin-2-one o o

To a solution of 2-pyrrolidone (32.0 g, 0.376 mol) in anhydrous tetrahydrofuran (900 ml) was added n-168 044967 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 hour. A solution of 1-chloro-3,3dimethylbutane (45.3 g, 0.376 mol) in anhydrous tetrahydrofuran (100 ml) was added dropwise to the reaction mixture at -78°C. The reaction mixture was stirred for 10 minutes at -78°C and then slowly raised to room temperature. The reaction was quenched with a 20% aqueous solution of ammonium chloride (500 ml). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2x250 ml). The combined organic layers were washed with brine (300 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with hexane (50 ml) to give 3-(3,3-dimethylbutyl)pyrrolidin-2-one (9.091 g, 14%) as a white crystalline solid.

1H 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). MS-ESI m/z: calc. 169.1, found 169.9 (M+1)+.

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

A 250 mL round bottom flask was charged with 2,6-dichloropyridine-3-carboxylic acid (1.14 g, 5.937 mmol) and anhydrous tetrahydrofuran (20 mL) under nitrogen atmosphere. Carbonyldiimidazole (964 mg, 5.945 mmol) was added and the mixture was stirred under nitrogen at room temperature for 2 hours. In a separate 100 mL flask, tert-butyl (4S)-2,2-dimethyl-4-[3-[( 6-sulfamoyl-2pyridyl)amino]propyl]pyrrolidine-1-carboxylate (1.529 g, 3.706 mmol) in anhydrous tetrahydrofuran (10 ml) was prepared under nitrogen and then added via syringe to the activated ester solution. 1,8-Diazabicyclo[5.4.0]undec-7-ene (1.2 mL, 8.024 mmol) was added via syringe and the reaction mixture was stirred at room temperature under nitrogen for 16 hours. Solvents were removed under reduced pressure to obtain a thick the oil was treated with ethyl acetate (50 ml) and water (30 ml). Hydrochloric acid (4 mL 6 M, 24.00 mmol) was added and the two phases were separated. The aqueous phase was washed with saline (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 hexane. Evaporation of the solvents gives tert-butyl (4S)-4-[3-[[6-[(2,6-dichloropyridin-3-carbonyl)sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1 -carboxylate (1.934 g, 89%) as a white foamy solid.

1H NMR (400 MHz, DMSO-a 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). MS-ESI m/z calc. 585.15796, found 586.1 (M+1)+; Retention time: 2.02 min (LC method B). The product was used in the next step without further purification.

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

In a 100 mL round bottom flask, tert-butyl (4S)-4-[3-[[6-[(2,6-dichloropyridine-3carbonyl)sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine -1-carboxylate (1.923 g, 3.279 mmol) was stirred at room temperature in dichloromethane (10 ml) and hydrochloric acid (3 ml of 4M dioxane solution, 12.00 mmol). A white sticky precipitate quickly formed. More dichloromethane (10 ml) was added and the mixture was stirred at room temperature for another 2.5 hours. Another 2 ml of hydrochloric acid was added and the mixture was stirred for another 2 hours. Volatiles were removed by evaporation and the residue was evaporated in the presence of tetrahydrofuran/ethyl acetate/dichloromethane/methanol/hexane to obtain a foamy solid. Drying under high vacuum over a weekend yielded 2,6-dichloro-N-[[6-[3-[(3S)-5,5-dimethylpyrrolidin-3yl]propylamino]-2-pyridyl]sulfonyl]pyridine-3-carboxamide (dihydrochloride salt) (1.933 g,

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105%) as an off-white foamy solid (approximately 90% purity according to

LCMS).

^1H NMR (400 MHz, DMSO-de) 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 (dk, J=7.1 Hz, 1H), 6.77 (dd, J=8.5, 0.8 Hz, 1H), 3.34 (dk, J=11.2, 5.6 Hz, 1H), 3.24 (k, 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). MS-ESI 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]tetracose-1(23),5 ,7,9,19,21-hexaene-2,2,4-trione (compound D)

2,6-Dichloro-N-[[6-[3-[(3S)-5,5dimethylpyrrolidin-3-yl]propylamino]-2-pyridyl]sulfonyl]pyridin- 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 A molecular sieves, and cesium fluoride ( 285 mg, 1.876 mmol). The vessel was sealed under a nitrogen atmosphere and the mixture was vigorously stirred in an oil bath at 150°C for 22 hours. The mixture was poured into cooled water (85 ml) and acidified by adding hydrochloric acid (2.1 ml, 6 M, 12.60 mmol) (mild foaming). The resulting suspension was filtered through a ceramic funnel using a filter paper, 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 silica gel chromatography using a gradient of ethyl acetate (0 to 100% over 30 min) in hexanes. The product was eluted with 55-65% ethyl acetate in hexanes. Evaporation of the solvents and further concentration gave (14S)-8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23), 5,7,9,19,21-hexaene-2,2,4-trione (320 mg, 54%).

^1H 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). MS-ESI m/z calc. 449.12885, found 450.4 (M+1) ⁺ ; Retention time: 1.76 min (LC method E).

Step 5: (14S)-8-[3-(3,3-dimethylbutyl)-2-oxopyrrolidin-1-yl]-12,12-dimethyl-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1 (23),5,7,9,19,21-hexaene-2,2,4-trione (compound 79)

(148)-8-chloro-12,12-dimethyl-2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23) was loaded into a 4 ml ampoule. 5,7,9,19,21-hexaen-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), xanthos (5 mg, 0.008641 mmol), cesium carbonate (99 mg, 0.3038 mmol) and anhydrous dioxane (400 μl). The mixture was purged with nitrogen for 1-2 minutes, capped and stirred at 120°C for 21 hours. The reaction mixture 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% in 15 min) and hydrochloric acid as a modifier. The pure fractions were collected and the solvents were evaporated to give 4.3 mg of an off-white solid. The product was further purified by flash silica gel chromatography (4 g column) using a gradient of methanol (0 to 5% over 30 min) in dichloromethane. The pure fractions were collected and the solvents were evaporated, yielding (14S)8-[3-(3,3-dimethylbutyl)-2-oxopyrrolidin-1-yl]-12,12-dimethyl- ^2X6 -thia-3,9,11, 18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,2,4-trione (compound 79) (2 mg, 6%) in as an off-white solid (a mixture of diastereomers).

Ή NMR (400 MHz, DMSO-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 (broad s, 1H), 2.94 (d, J=13.3 Hz, 1H ), 2.74-2.54 (m, 2H), 2.29-2.17 (m, 1H), 2.10 (broad s, 1H), 1.87-1.43 (m, 11H), 1.37-1.12 (m, 6H), 0.88 (d , J=3.6 Hz, 9H). MS-ESI m/z calc. 582.2988, found 583.4 (M+1) ⁺ ; retention time: 2.25 min (LC method B).

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Example 21: Preparation of 12,12-dimethyl-8-(4-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1 -yl)-2X ⁶ -thia-3,9,11,19,24 -pentaazatetracyclo[18.3.1.111,14.05,10]pentacose-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)-2Х ⁶ -thia-3,9,11,19,24pentaazatetracyclo[18.3.1.111, 14.05,10]pentacose-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 30% w/v, 408.0 mmol). The reaction mixture was stirred at 0°C for 10 min, then at room temperature for 45 min. The reaction mixture 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 with a small amount of dichloromethane and the solid was vacuum filtered, washed well with more dichloromethane and dried under reduced pressure to give tert-butyl 4hydroxypyrazole-1-carboxylate (19.904 g, 53%) as a white solid.

¹ H NMR (300 MHz, DMSO-δ) 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). MS-ESI 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-4hydroxypyrazole-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 added slowly at 0°C and the reaction mixture was stirred at 0°C for 10 minutes. The reaction mixture was then heated at 70°C overnight. The reaction mixture was cooled to room temperature and the reaction mixture was diluted with dichloromethane (300 ml) and quenched by adding 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 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 yellow oil). The residue was purified by silica gel chromatography using a gradient of 0% to 20% ethyl acetate in heptanes to give tert-butyl 4-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-1-carboxylate (27.31 g, 66%) as a white solid.

¹ H NMR (300 MHz, DMSO-d6) 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, dimethylsulfoxide- _d6 ): δ -68.6 (s, 3F). MSIER 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)

Hydrogen chloride (80 mL 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 the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain 4-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]-1H-pyrazole (hydrochloric acid salt) (8.71 g, 100%) as an off-white solid.

Ή NMR (300 MHz, DMSO-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 ). MS-ESI 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 mixture was cooled to 0°C and sodium hydride (1.87 g, 60% w/w, 46.754 mmol) was added in portions and allowed to stir for 10 minutes. 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 mixture was heated at 75° C. and left stirring overnight. After cooling to room temperature, the reaction was quenched with brine (100 ml) and extracted with ethyl acetate (3x50 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 of 0% to 10% ethyl acetate in heptane to give tert-butyl 2-chloro-6-[4-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl ]pyridine-3-carboxylate (7.68 g, 46%) as a white solid.

Ή 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). ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ -69.9 (broad s, 3F).MS-ESI 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-3carboxylic acid

Trifluoroacetic acid (46.620 g, 31.5 mL, 408.86 mmol) was added to the tert-butyl-2chloro-6-[4-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine solution -3-carboxylate (17.59 g, 40.733 mmol) in dichloromethane (150 ml), and the reaction mixture was stirred at room temperature for 4 hours. 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 (2x100 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain 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.

Ή NMR (300 MHz, DMSO-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). MS-ESI m/z calc. 375.0598, found 376.1 (M+1) ⁺ ; Retention time: 3.14 min (LC method H).

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

2-chloro-6-[4-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridine-3-carboxylic acid (97 mg, 0.2582 mmol), carbonyl diimidazole (45 mg, 0.2775 mmol) and tetrahydrofuran (3.0 ml). The reaction mixture was heated at 40°C for 90 minutes. A solution of tert-butyl 2,2-dimethyl-4-[4-[(6-sulfamoyl-2-pyridyl)amino]butyl]pyrrolidine-1carboxylate (95 mg, 0.2227 mmol) in tetrahydrofuran (2 ml) was added dropwise ), followed by 2,3,4,6,7,8,9,10octahydropyrimido[1,2-a]azepine (120 µl, 0.8024 mmol). The reaction was stirred overnight at room temperature. The reaction was quenched with 1 N. citric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude reaction mixture was purified by HPLC (20-99% acetonitrile:water with 0.1% hydrochloric acid modifier) to give tert-butyl 4-[4-[[6-[[2-chloro-6-[4-[ 2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]butyl]-2,2dimethylpyrrolidine-1-carboxylate (82.7 mg, 49 %) as a white solid.

1H NMR (400 MHz, DMSO^ 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 (k, 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). MS-ESI m/z calc. 783.27924, found 784.3 (M+1)+; Retention time: 2.28 min (LC method B).

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

Into a round bottom flask containing tert-butyl-4-[4-[[6-[[2-chloro-6-[4-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3 -carbonyl]sulfamoyl]-2pyridyl]amino]butyl]-2,2-dimethylpyrrolidine-1-carboxylate (118 mg, 0.1505 mmol) dichloromethane (5 ml) and trifluoroacetic acid (650 μl, 8.437 mmol) were added. The reaction was left under stirring at room temperature for 1 hour. The reaction was evaporated to dryness. A solution of saturated sodium bicarbonate was added followed by ethyl acetate. The reaction mixture was extracted 3 times with ethyl acetate, dried over sodium sulfate, filtered and evaporated to give 2-chloro-X-[[6-[4-(5,5dimethylpyrrolidin-3-yl)butylamino]-2-pyridyl]sulfonyl]-6 -[4-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (102 mg, 99%), which was used without further purification. MS-ESI m/z calc. 683.2268, found 684.4 (M+1) ⁺ ; Retention time: 1.51 min (LC method B).

Step 8: 12,12-dimethyl-8-(4-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-2λ ⁶ -tua3,9,11,19,24 -pentaazatetracyclo[18.3.1.111,14.05,10]pentacose-1 (23),5,7,9,20(24),21-hexaene-2,2,4-trione (compound 70)

Potassium carbonate (92 mg, 0.6657 mmol), cesium fluoride (45 mg, 0.2962 mmol), five 3 A molecular sieves, and a solution of 2-chloro-X-[[6-[4- (5,5-dimethylpyrrolidin-3yl)butylamino]-2-pyridyl]sulfonyl]-6-[4-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carboxamide (90 mg, 0.1315 mmol) in dimethyl sulfoxide (0.8 ml). Reaction mixture

- 173 044967 were hermetically sealed and placed in an oil bath preheated to 150°C overnight. The reaction mixture was cooled to room temperature, filtered and purified by HPLC (10% 99% acetonitrile:water modified with 0.1% hydrochloric acid) to give 12,12-dimethyl-8(4-{2-[1-(trifluoromethyl )cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-2λ ⁶ -thiα-3,9,11,19,24pentaazatetracyclo[18.3.1.111,14.05,10]pentacose-1(23),5,7, 9,20(24),21-hexaene-2,2,4-trione (compound 70) (20.8 mg, 24%) as a white solid. MS-ESI m/z calc. 647.2502, detected 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 -thia3,9,11,19,24- pentaazatetracyclo[18.3.1.111,14.05,10]pentacose-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}-1Hpyrazol-1-yl)-2λ ⁶ -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.111 ,14.05,10]pentacose1(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} -1 H-pyrazol-1 -yl)2λ ⁶ -thia-3,9,11,19,24- pentaazatetracyclo[18.3.1.111,14.05,10]pentacose-1(23),5,7,9,20(24),21-hexaene-2,2,4trione (17 mg, 0.02625 mmol) was subjected to chiral SLC chromatography using ChiralPak

AS-H (250 x 21.2 mm column, 5 µm particle size) with a mobile phase of 20-25% methanol (NH ₃ modifier)/carbon dioxide at 50 ml/min to produce 12,12-dimethyl as the first enantiomer eluted -8-(4- {2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-2λ ⁶ -thia-3,9,11,19,24pentaazatetracyclo[18.3.1.111,14.05 ,10]pentacose-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (enantiomer 1) (compound 82) (7.7 mg, 90%); MS-ESI m/z calc. 647.2502, detected 648.2 (M+1) ⁺ ; Retention time: 3.18 min (LC method D) and 12,12-dimethyl-8-(4-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl) as the second enantiomer eluted -2λ ⁶ -thiα-3,9,11,19,24pentaazatetracyclo[18.3.1.111,14.05,10]pentacose-1(23),5,7,9,20(24),21-hexaene-2,2, 4-trione (enantiomer 2) (compound 83) (7.6 mg, 89%);

Ή NMR (400 MHz, DMSO-Y6) 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), MS-ESI 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}-1Hpyrazol-1-yl)-10λ ⁶ -thia-1,3,9 ,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene8,10,10-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-pentαazatetracyclo[16.2.1.111, 14.02,7]docose-2,4,6,11(22),12pentaene-8,10,10-trione (compound 85)

Step 1: tert-butyl 2,2-dimethyl-4-[3-(3-sulfamoylpyrazol-1-yl)propyl]pyrrolidine-1 carboxylate

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Part A: Add triethylamine (8, 3 ml, 59.55 mmol). The reaction mixture was cooled to 0°C over 10 min and methanesulfonyl chloride (3.7 mL, 47.80 mmol) was added dropwise (exothermic, a white suspension formed) and the reaction mixture 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 give 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 hours. The reaction mixture was cooled to room temperature and poured onto crushed ice and extracted with ethyl acetate (3x100 ml), combined organic layers, washed with water (2 = x 100 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The brown residue was purified by silica gel chromatography (330 g column) using a gradient of 100% hexanes to 100% ethyl acetate to give tert-butyl-2,2dimethyl-4-[3-(3-sulfamoylpyrazol-1-yl)propyl]pyrrolidine -1-carboxylate (7.6 g, 51%) as a white solid. MS-ESI 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-1yl]pyridin-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) was combined in tetrahydrofuran (5 ml) and stirred for 120 min at 50°C. Tert-butyl 2,2-dimethyl-4-[3(3-sulfamoylpyrazol-1-yl)propyl]pyrrolidine-1-carboxylate (388 mg, 1.004 mmol) was then added followed by 1,8diazabicyclo[5.4.0] undec-7-ene (300 μl, 2.006 mmol), and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution, followed by brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexanes to 90% ethyl acetate in hexanes to give tert-butyl-4-[3-[3-[[2- chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]pyrazol-1-yl]propyl]-2,2-dimethyl-pyrrolidine-1 -carboxylate (247 mg, 33%) as a white solid.

Ή 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). MS-ESI 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]docose-2,4,6,11(22),12-pentaene-8,10,10-trione

Part A: tert-butyl 4-[3-[3-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl solution ]sulfamoyl]pyrazol-1-yl]propyl]-2,2-dimethyl-pyrrolidine-1carboxylate (247 mg, 0.3319 mmol) in dichloromethane (1 ml) and trifluoroacetic acid (260 μl, 3.398

- 175 044967 mmol) was stirred at room temperature for 4 hours. Then the solvents were evaporated. The residue was dissolved in ethyl acetate, washed with 2 ml of saturated sodium bicarbonate solution, the solvent was removed and dried under high vacuum.

Part B: The residue from Part A was dissolved in dimethyl sulfoxide (6 ml), 3 A molecular sieves were added and the reaction mixture was stirred for 10 minutes. Cesium fluoride (153 mg, 1.007 mmol) and potassium carbonate (142 mg, 1.027 mmol) were then added and the reaction mixture was heated at 130°C overnight. The reaction mixture was filtered through a Whatman disk filter (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS using a double gradient run of 50-90% mobile phase B for 15.0 min (mobile phase A = water (0. 05% hydrochloric acid), mobile phase B=acetonitrile) to obtain 20,20-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-III-pyrazol-1-yl)-10λ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose2(7),3,5,11(22),12-pentaene-8,10,10-trione (80 mg, 40%) as a white solid. MS-ESI 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]docose-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}-1 H-pyrazol-1 yl)-10λ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2 .1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10trione (compound 85)

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]docose-2(7),3,5,11(22),12-pentaene-8,10,10trione (80 mg) was subjected to chiral separation by SLC chromatography using Chiral Pak AS-H (250x10 mm), column, particle size 5 µm) with mobile phase 27% acetonitrile: methanol, 73% carbon dioxide at 10 ml/min for 8.0 min (injection volume=70 µl ~ 24 mg/ml to acetonitrile:methanol (90:10)) to give (18R)-20,20dimethyl-4-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazole-1) as the first enantiomer eluted -yl)-10λ ⁶ -thia-1,3,9,14,22pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10- trione (compound 84) (27 mg, 27%);

1H 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), MS-ESI m/z calc. 607.2189, found 608.1 (M+1) ⁺ ; Retention time: 2.07 min (LC method B), and as the second enantiomer eluted (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]docose-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), MS-ESI m/z calc. 607.2189, found 608.1 (M+1) ⁺ ; Retention time: 2.07 min (LC method B).

Example 23: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-19-oxa-2λ ⁶ -thia-3,9,11 -triazatetracyclo[18.2.2.111,14.05,10]pentacose-1(22),5,7,9,20,23-hexaene2,2,4-trione (enantiomer 1) (compound 95) and 12,12-dimethyl- 8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-19-oxa-2λ ⁶ -thia-3,9,11 triazatetracyclo[18.2.2.111,14.05,10 ]pentacose-1(22),5,7,9,20,23-hexaene-2,2,4-trione (enantiomer 2) (compound 96)

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

4-Hydroxybenzenesulfonamide (319 mg, 1.842 mmol) and N,Ndimethylformamide (12.88 mL) were added to a 50 mL flask. Tert-butyl-2,2-dimethyl-4-(4methylsulfonyloxybutyl)pyrrolidine-1-carboxylate (643.8 mg, 1.842 mmol) and potassium carbonate (891 mg, 6.447 mmol) were added to the mixture at room temperature and stirred at 50° C during the night. Cool to room temperature and pour into water (100 ml) and extract with ethyl acetate (2x100 ml), combine the organic layers, wash with water (2x100 ml), dry (sodium sulfate), filter and concentrate to a brown residue, which is purified by silica gel chromatography with using a gradient from 100% hexanes to 100% ethyl acetate to obtain tert-butyl-2,2-dimethyl-4-[4-(4sulfamoylphenoxy)butyl]pyrrolidine-1-carboxylate (416.1 mg, 53%) as a light oil -orange color.

¹ H NMR (400 MHz, DMSO-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). MS-ESI 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-1yl]pyridin-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-1yl]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 the lid ajar. 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 ,8diazabicyclo[5.4.0]undec-7-ene (297.0 mg, 291.7 μL, 1.951 mmol), and the reaction mixture was heated at 50°C for 16 hours. The reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride, and then with saline solution. The organic layers 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, which gave very poor separation. Fractions containing product were combined and concentrated, then purified again by silica gel chromatography using a shallow gradient from 100% dichloromethane to 20% methanol/dichloromethane to give tert-butyl 4-[4-[4-[[2-chloro-6- [3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]phenoxy]butyl]-2,2-dimethylpyrrolidine-1-carboxylate (596 mg, 78%) in as a light yellow solid. MS-ESI m/z calc. 783.268, detected 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]pyrazole -1-yl]pyridin-3-carboxamide

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tert-Butyl 4-[4-[4-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]phenoxy]butyl ]-2,2-dimethylpyrrolidine-1-carboxylate (596 mg, 0.7599 mmol) was dissolved in dichloromethane (2.600 ml), and trifluoroacetic acid (3.975 g, 2.686 ml, 34.86 mmol) was added to the mixture and stirred at room temperature 60 min. The mixture was concentrated to dryness under reduced pressure, dissolved in saturated aqueous sodium bicarbonate and ethyl acetate containing a small amount of methanol to ensure solubility, and the layers were separated. The organic layer was concentrated by rotary evaporation followed by high vacuum pump to give 2-chloro-K-[4-[4-(5,5-dimethylpyrrolidin-3-yl)butoxy]phenyl]sulfonyl-6-[3-[2-[ 1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (403.3 mg, 78%) as an off-white solid. MS-ESI 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}-1 H-pyrazol-1 -yl)-19oxa-2λ ⁶ -thia-3,9,11 -triazatetracyclo[18.2.2.111,14.05,10]pentacose-1 (22),5,7,9,20,23-hexaene-2,2,4-trione (compound 89)

To a solution of 2-chloro-I-[4-[4-(5,5-dimethylpyrrolidin-3-yl)butoxy]phenyl]sulfonyl-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazole- 1-yl]pyridin-3-carboxamide (403.3 mg, 0.5895 mmol) in dimethyl sulfoxide (16.13 ml), potassium carbonate (488.7 mg, 3.536 mmol), cesium fluoride (107.5 mg, 0 .7077 mmol) and a small amount of 3 A molecular sieves. The resulting mixture was sealed and heated to 165°C for 18 hours. 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 of 100% hexanes to 100% ethyl acetate to give 12,12-dimethyl-8-(3-{ 2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-19-oxa-2Х ⁶ -thia-3,9,11 triazatetracyclo[18.2.2.111,14.05,10]pentacose-1(22 ),5,7,9,20,23-hexaene-2,2,4-trione (compound 89) (80 mg, 21%).

1H NMR (400 MHz, DMSO-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 (k, J=4.7, 4.0 Hz, 2H), 0.88 (s, 2H), 0.67 (s, 1H). MS-ESI 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}-1 H-pyrazol-1 -yl)-19oxa-2X ⁶ -thia-3,9,11 -triazatetracyclo[18.2.2.111,14.05,10]pentacose-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}-1Hpyrazol-1-yl)-19-oxa-2Х ⁶ -thia-3,9,11-triazatetracyclo[18.2.2.111,14.05 ,10]pentacose-1(22),5,7,9,20,23hexaene-2,2,4-trione (enantiomer 2) (compound 96)

Racemic 12,12-dimethyl-8-(3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-19oxa-2λ ⁶ -thia-3,9,11-triazatetracyclo [18.2.2.111,14.05,10]pentacose-1(22),5,7,9,20,23-hexaene-2,2,4-trione (compound 89) (72.1 mg, 0.1101 mmol) subjected to chiral separation by SLC chromatography using ChiralCel OD-H (250x10 mm column, 5 μm particle size) with a mobile phase of 35% acetonitrile/methanol (90:10)/65% carbon dioxide at 10 ml/min for 8. 0 min (injection volume = 70 µl of a 24 mg/ml solution in acetonitrile/methanol (90:10) to give 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl) as the first enantiomer eluted ]ethoxy}-1Hpyrazol-1-yl)-19-oxa-2Х ⁶ -thia-3,9,11-triazatetracyclo[18.2.2.111,14.05,10]pentacose-1(22),5,7,9,20 ,23hexaene-2,2,4-trione (enantiomer 1) (compound 95) (21.9 mg, 61%);

- 178 044967 ¹ H NMR (400 MHz, DMSO-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), MS-ESI m/z calc. 647.23895, detected 648.2 (M+1)+; Retention time: 2.34 min (LC method B), and the second enantiomer eluted was 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazole-1- yl)-19-oxa-2λ ⁶ -thia-3,9,11-triazatetracyclo[18.2.2.111,14.05,10]pentacose-1(22),5,7,9,20,23-hexaene-2,2 ,4-trione (enantiomer 2) (compound 96) (18.75 mg, 52%); MS-ESI m/z calc. 647.23895, detected 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]-12,12dimethyl-2λ ⁶ -thia-3,9,11 ,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (hydrochloric acid salt) (compound 98 )

Step 1: 1-benzyl-4,4-dimethylpyrrolidin-2-one

To a 100 mL round bottom flask loaded with 4,4-dimethylpyrrolidin-2-one (524 mg, 4.631 mmol), tetrahydrofuran (25 mL) was added followed by sodium 2-methylpropan-2-olate (590 mg, 6.139 mmol) , and the mixture was stirred at room temperature for 30 minutes. Bromomethylbenzene (1000 µl, 8.408 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water (~15 ml) and the crude mixture was extracted with ethyl acetate (3x30 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%-60% ethyl acetate in hexanes) to give a gradient of 1-benzyl-4,4-dimethyl-pyrrolidin-2-one (834 mg, 89%) as a clear oil. MS-ESI 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-dimethylpyrrolidin-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, butyllithium (2.1 mL, 2.5 M, 5.250 mmol) in hexane was added dropwise, and the mixture was stirred at -78°C for 1 hour. 1-bromo- 3,3-dimethylbutane (700 μl, 4.970 mmol), and the reaction mixture was stirred and slowly warmed to room temperature over 18 hours. The reaction was quenched with water (10 ml) and brine (10 ml) and extracted with ethyl acetate (3x40 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) to give 1-benzyl-3-(3,3-dimethylbutyl)-4,4-dimethylpyrrolidin-2-one (107 mg, 9%) in in the form of a clear oil. MS-ESI 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

Propan-1-amine (3 mL) was added to a 50 mL nitrogen-flushed flask charged with 1-benzyl-3-(3,3-dimethylbutyl)-4,4dimethylpyrrolidin-2-one (107 mg, 0.3723 mmol) 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 washed with hexane to remove excess oil) was added. The flask was supplied again

- 179 044967 partition, and the reaction mixture was vigorously stirred while warming slightly to -20°C. Eventually a blue color developed around the lithium wire, which briefly went into solution, and the reaction mixture was allowed to stir until the solution turned dark blue (~20 min). Water (~15 ml) was added, larger pieces of lithium were removed, the mixture was warmed to room temperature and stirred for 10 min. The crude mixture was extracted with ethyl acetate (3x20 ml), the combined organic extracts were washed with water (15 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give crude 3(3,3-dimethylbutyl)-4,4-dimethylpyrrolidin-2-one (115 mg, 157% (crude containing impurities)) as a yellow oil, which was used without further purification. MS-ESI 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]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4trione (hydrochloric acid salt) (compound 98 )

HCI

Crude 3-(3,3-dimethylbutyl)-4,4-dimethylpyrrolidin-2-one (45 mg, 0.2281 mmol) was added to a 4 ml vial, (14S)-8-chloro-12,12-dimethyl was added -2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-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)diphenylphosphane (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 tube was capped, and the reaction mixture was stirred at 120°C for 18 hours. After cooling to room temperature, the crude mixture was diluted with ethyl acetate (~30 mL) and washed with 1.0 M aqueous citric acid (5 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was dissolved in a minimal amount of dimethyl sulfoxide (0.4-1 ml) and purified by HPLC (reverse phase _C18 , 99:1-1:99 water:acetonitrile, hydrochloric acid modifier). The fractions were then concentrated in vacuo and the residue was purified by chromatography on silica gel (0%-70%) gradient of ethyl acetate in hexanes to give (14S)-8-[3-(3,3-dimethylbutyl)-4,4dimethyl-2-oxopyrrolidine-1 -yl]-12,12-dimethyl-2Х ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-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, DMSO-a ₆ ) δ 12.42 (s, 1H), 7.66 (dd, J=8.3, 3.2 Hz, 1H), 7.52 (dd, 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), 1.901.68 (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) . MS-ESI 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-pyrazol1-yl)-18-oxa-2X ⁶ -thia-3,9,11 -triazatetracyclo[17.2.2.111,14.05,10]tetracose-1(21),5,7,9,19,22-hexaene2,2,4-trione (enantiomer 1) (compound 99) and 12,12-dimethyl- 8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-18-oxa-2λ ⁶ -thia-3,9,11 triazatetracyclo[17.2.2.111,14.05,10 ]tetracose-1(21),5,7,9,19,22-hexaene-2,2,4-trione (enantiomer 2) (compound 100)

- 180 044967

Step 1: tert-butyl 2,2-dimethyl-4-[3-(4-sulfamoylphenoxy)propyl]pyrrolidine-1-carboxylate

4-Hydroxybenzenesulfonamide (471.1 mg, 2.720 mmol) and N,Ndimethylformamide (13.69 mL) were added to a 50 mL flask. 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) were added to the mixture at room temperature and stirred at room temperature for 3 hours, then heated to 50°C overnight. Cool to room temperature and pour into water (100 ml) and extract with ethyl acetate (2x100 ml), combine the organic layers, wash with water (2x100 ml), dry (sodium sulfate), filter and concentrate to a brown residue, which is purified by silica gel chromatography with using a gradient from 100% hexanes to 100% ethyl acetate to give tert-butyl 2,2-dimethyl-4-[3-(4-sulfamoylphenoxy)propyl]pyrrolidine-1-carboxylate (578.3 mg, 52%) as oils are light orange in color.

¹ H NMR (400 MHz, DMSO-d6) 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). MS-ESI 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-1yl]pyridin-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-1yl]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 the lid ajar. 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]undec7-ene (426.9 mg, 419.4 μl, 2.804 mmol), and the reaction mixture was heated at 50°C for 16 hours. The reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride, and then with saline solution. The organic layers 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, which gave very poor separation. Fractions containing product were combined and concentrated, then purified again by silica gel chromatography using a shallow gradient of 100% dichloromethane to 20% methanol/dichloromethane to give tert-butyl 4-[3-[4-[[2-chloro-6- [3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]phenoxy]propyl]2,2-dimethylpyrrolidine-1-carboxylate (953.1 mg, 88% ) as a light yellow solid. MS- 181 044967

ESI 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]pyrazole -1 -yl]pyridin-3-carboxamide

tert-Butyl 4-[3-[4-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]phenoxy]propyl ]-2,2-dimethylpyrrolidine-1-carboxylate (953.1 mg, 1.237 mmol) was dissolved in dichloromethane (4.158 ml) and trifluoroacetic acid (6.471 g, 4.372 ml, 56.75 mmol) was added to the mixture and the mixture was stirred at room temperature 60 min. The mixture was concentrated to dryness under reduced pressure, dissolved in saturated aqueous sodium bicarbonate and ethyl acetate containing a small amount of methanol to ensure solubility, and the layers were separated. The organic layer was concentrated on a rotary evaporator followed by drying in vacuo to give 2-chloroN-[4-[3-(5,5-dimethylpyrrolidin-3-yl)propoxy]phenyl]sulfonyl-6-[3-[2-[1 -(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (738.1 mg, 89%) as an off-white solid. MS-ESI m/z calc. 669.19995, detected 670.3 (M+1) ⁺ ; retention time: 0.65 min (LC method A).

Step 4: 12,12-dimethyl-8-(3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-18oxa-2λ ⁶ -thia-3,9,11 -triazatetracyclo[17.2.2.111,14.05,10]tetracose-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]pyrazole- 1-yl]pyridin-3-carboxamide (738.1 mg, 1.101 mmol) in dimethyl sulfoxide (29.52 ml) added potassium carbonate (912.8 mg, 6.605 mmol), cesium fluoride (200.7 mg, 1.321 mmol) and a small amount of 3 A molecular sieves. The resulting mixture was capped and heated to 130°C for 16 hours. Continued heating at 150°C for 16 hours. Heated to 170°C and stirred for 3 hours, then cooled to room temperature, diluted 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 of 100% hexanes to 100% ethyl acetate to give 12,12-dimethyl-8-(3-{ 2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1 -yl)18-oxa-2Х ⁶ -thia-3,9,11-triazatetracyclo[17.2.2.111,14.05,10]tetracose-1 ( 21), 5,7,9,19,22-hexaene-2,2,4trione (30 mg, 4%) as a white solid.

1H NMR (400 MHz, DMSO-de) 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). MS-ESI 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}-1 H-pyrazol-1 -yl)-18oxa-2λ ⁶ -thia-3,9,11 -triazatetracyclo[17.2.2.111,14.05,10]tetracose-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}-1Hpyrazol-1-yl)-18-oxa-2Х ⁶ -thia-3,9,11-triazatetracyclo[17.2.2.111,14.05 ,10]tetracose-1(21),5,7,9,19,22hexaene-2,2,4-trione (enantiomer 2) (compound 100)

Racemic 12,12-dimethyl-8-(3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-18oxa-2λ ⁶ -thia-3,9,11-triazatetracyclo [17.2.2.111,14.05,10]tetracose-1 (21), 5,7,9,19,22-hexaene-2,2,4-trione (27.2 mg, 0.04292 mmol) was subjected to chiral resolution with using SLC chromatography using ChiralCel OD-H (250x10 mm column, 5 µm particle size) with a mobile phase of 42% acetonitrile/methanol (90:10)/58% carbon dioxide at 10 ml/min for 8 .0 min (injection volume = 70 μl of a 24 mg/ml solution in acetonitrile/methanol (90:10) to obtain 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)) as the first eluting enantiomer cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-18-oxa-2Х ⁶ thia-3,9,11-triazatetracyclo[17.2.2.111,14.05,10]tetracose-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, DMSO-b6) 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), MS-ESI m/z calc. 633.22327, detected 634.1 (M+1)+; Retention time: 2.25 min (LC method B), and the second enantiomer eluted was 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazole-1- yl)-18-oxa-2Х ⁶ -thia-3,9,11-triazatetracyclo[17.2.2.111,14.05,10]tetracose-1(21),5,7,9,19,22-hexaene-2,2 ,4-trione (enantiomer 2) (compound 100) (9.72 mg, 71%) as a white solid; MS-ESI m/z calc. 633.22327, detected 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]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4trione (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 dropwise a 2.5 M solution of n-butyllithium in hexane (43.6 ml, 0.109 mol ), and the reaction solution was stirred at this temperature for 1 hour. A solution of 1-chloro-4,4dimethylpentane (7.34 g, 54.52 mmol) in anhydrous tetrahydrofuran (20 ml) was slowly added. After addition was complete, the solution was stirred at -78°C for 20 minutes before it was gradually warmed to ambient temperature. A 20% aqueous ammonium chloride solution (100 ml) was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3x150 ml) and the combined organic layer was washed with brine, dried over sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography using a gradient of 0-100% ethyl acetate in hexane to give 3-(4,4-dimethylpentyl)pyrrolidin-2-one (3.86 g, 39%) as a white solid.

'11 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). MS-ESI m/z calc. 183.16, found 184.2 (M+1) ⁺ . Retention time: 4.66 min (LC method Q).

Step 2: (148)-8-[3-(4,4-dimethylpentyl)-2-oxopyrrolidin-1-yl]-12,12-dimethyl-2X ⁶ -thia3,9,11,18,23-pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 102)

(14S)-8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23) was loaded into a 4 ml ampoule. 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), xanthos (6 mg, 0.01037 mmol), cesium carbonate (87.52 mg, 0.2686 mmol) and anhydrous dioxane (0.4 ml). The mixture was purged with nitrogen for 1-2 min, closed

- 183 044967 with a lid and stirred at 120°C for 21 hours. The reaction mixture was diluted with dimethyl sulfoxide (700 μl), microfiltered and subjected to reverse-phase preparative HPLC (C ₁₈ ) using a gradient of acetonitrile in water (from 1 to 99% in 15 min) and hydrochloric acid as a modifier. The pure fractions were collected, a little 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 gives 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. Pure fractions were collected and solvents were evaporated to give (14S)-8-[3-(4,4dimethylpentyl)-2-oxopyrrolidin-1-yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18 ,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 102) (5.5 mg, 17%) in the form of a white solid mixture of diastereomers.

¹ H NMR (400 MHz, DMSO-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 (broad 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 (broad 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). MS-ESI m/z calc. 596.31445, found 597.4 (M+1)+; Retention time: 2.29 min (LC method B).

Example 27: Synthesis of 8-[3-({dispiro[2.0.2.1]heptan-7-yl}methoxy)-1H-pyrazol-1-yl]-12,12-dimethyl2λ ⁶ -thia-3,9,11, 18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4trione (enantiomer 1) (compound 106) and 8-[3-({dispiro[2.0.2.1]heptan-7-yl}methoxy)-1H-pyrazol-1yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23- pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (enantiomer 2) (compound 107)

Step 1: 1-cyclopropylcyclopropanol

To a solution of methylcyclopropanecarboxylate (75 g, 749.1 mmol) in ether (450 ml) was added titanium (IV) isopropoxide (55.3 ml, 187.4 mmol). Ethyl magnesium bromide (1.6 L 1 M, 1.60 mol) was slowly added to the mixture over 2 hours. The addition is exothermic and is controlled by controlling the rate of addition and the use of a cooling bath. During addition, the reaction temperature was maintained between 21-26°C. After addition, the mixture was stirred for another 2 hours at ambient temperature. The mixture was then cooled to -5°C using an acetone/dry ice bath and quenched slowly with sulfuric acid (970 g 10% w/w, 990 mmol). The reaction mixture was cooled in a dry ice/acetone bath to maintain the temperature in the reaction vessel below 0°C during quenching. During the quenching process, a gray-purple solid formed. After complete addition of aqueous sulfuric acid, the mixture was stirred at 0° C. for 1 hour. The precipitate was filtered through celite using a medium frit, and the precipitate was 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 through celite, and the solvent was evaporated on a rotary evaporator at 100 torr and the water bath was 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 approximately 50% solvent (tetrahydrofuran and iPrOH) and was used as such in the next step.

1H NMR(400 MHz, chloroform-d) δ 1.32 (tm, 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 mixture was stirred at -10°C for an additional 15 minutes. The reaction mixture 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, maintaining the temperature from -15°C to 20°C. After 30 minutes, the addition was completed and the reaction mixture was allowed to gradually warm to room temperature. The reaction mixture was then allowed to stir at 40°C overnight. The reaction mixture was then cooled to room temperature and quenched with water (100 ml). The reaction mixture was then stirred for 10 min and the phases were separated. The organic phase was washed successively with 1 M hydrochloric acid (102 ml), then saturated sodium bicarbonate (50 ml), dried over sodium sulfate, filtered and concentrated (30°C/in situ vacuum ~ 300 torr) to remove most of the dichloromethane. The crude reaction mixture was subjected to rapid distillation (40°C/20 Torr) to remove additional dichloromethane. The solid residue (Ph ₃ PO and product) was reheated and distilled (50-60°C/20 Torr) to obtain 21.5 g (65% yield) of 1-bromo-1-cyclopropylcyclopropane as a cloudy, colorless liquid.

1H NMR (400 MHz, chloroform-d) δ 1.61 (tm, 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).

Stage 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 250 ml three-neck round bottom flask. 1-Bromo-1cyclopropylcyclopropane (20.0 g, 124.2 mmol) was added dropwise and the reaction immediately turned dark and then brown. The reaction was moderately exothermic (temperature maintained between 18°C and 22°C using an ice water bath). After 10 minutes the addition was completed. The ice water bath was removed and the reaction mixture was allowed to stir at room temperature. After 90 minutes, the reaction mixture was distilled in vacuo using flask-to-flask distillation. Distillation occurred from 60°C to 80°C, from 40 to 100 torr. The distillate collected slowly in the receiver to give 18.2 g (7.3 g of product as a 42 wt.% solution in t-BuOH) colorless liquid. The distillate was further washed with water (5x10 ml). Dichloromethane (4 g) was added and the mixture was dried over magnesium sulfate, filtered (washing with two additional portions of 3 g of dichloromethane each) to obtain 17.30 g (6.9 g of product as a 39.6 wt.% solution in dichloromethane; yield 69%) in the form of a colorless liquid.

1H NMR (400 MHz, chloroform-d) δ 1.19 (s, 8H). 1H NMR confirms the presence of dichloromethane and a small amount of tert-buthaiol.

Step 4: ethyl dispiro[2.0.2.1]heptane-7-carboxylate

Rhodium (II) acetate (4.2 g, 9.503 mmol) was added to a solution of cyclopropylidenecyclopropane (49.5 g, 617.8 mmol) in dichloromethane (110 ml) at 0° C. under nitrogen atmosphere. Ethyl 2diazoacetate (106.8 mL, 1.016 mol) was added to the mixture at 0° C. using a syringe pump kit at an addition rate of 0.02 mL/min (1.2 mL/h). The addition was continuous for 89 hours. The crude reaction mixture was filtered through a pad of silica, washing three times with 150 ml of dichloromethane. Volatile materials were removed in vacuo to yield 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)-bum-2-enedioamα as contaminants), which was used directly in the next step.

1H NMR(400 MHz, chloroform-d) δ 4.13 (k, 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

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Ethyl dispiro[2.0.2.1]heptane-7-carboxylate (10.77 g, 64 .79 mmol). The mixture was allowed to reach a gentle reflux during addition and continued to stir at ambient temperature for 1 hour. The reaction mixture was cooled in an ice water bath and slowly quenched by adding water (8.0 mL, 440 mmol), then sodium hydroxide (8.0 ml of 2 M, 16 mmol) and then water (24.0 ml, 1.33 mol). The light yellow suspension was filtered through celite and washed 3 times with 150 ml of methyl tert-butyl ether. The filtrate was concentrated in vacuo to give 8.87 g of a clear oil, dispiro[2.0.2.1]heptan-7-ylmethanol (8.87 g, quantitative yield).

1H 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 (k, 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-ylmethanol (1.36 g, 11.0 mmol), tert-butyl-3-hydroxypyrazole-1carboxylate (2.3 g, 12 mmol) and triphenylphosphine (3.2 g, 12 mmol) into tetrahydrofuran (28 mL) was cooled in an ice bath and diisopropyl azodicarboxylate (2.4 mL, 12 mmol) was added slowly. The cooling bath was removed and the reaction mixture was stirred for 15 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of 0-20% ethyl acetate in hexane to give tert-butyl-3-(dispiro[2.0.2.1]heptan-7-yl methoxy)-1H-pyrazole-1-carboxylate (1, 57 g, yield 49%) as a colorless oil. MS-ESI 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 hours. The volatiles were removed in vacuo and the residue was made basic 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 a pale yellow oil. MS-ESI 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

3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)-1H-pyrazole (0.94 g, 4.9 mmol),

A mixture of ethyl 2,6 dichloropyridine 3-carboxylate (1.15 g, 5.23 mmol), potassium carbonate (0.83 g, 6.0 mmol) and 1,4diazabicyclo[2.2.2]octane (0.12 g, 1.1 mmol) in dimethyl sulfoxide (16 ml) was stirred for 24 hours. 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 in vacuo. The residue was purified by silica gel column chromatography, eluting with a gradient of 0 to 20% ethyl acetate in hexane 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.

1H 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 (k, 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). MS-ESI 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

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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 a 1 M solution, 7.5 mmol) in tetrahydrofuran (6 ml) and ethanol (3 ml) was stirred for 90 min. Volatiles were removed under vacuum and water was added. The reaction mixture was cooled in an ice bath and hydrochloric acid (7.5 mL of 1 M solution, 7.5 mmol) was added slowly. 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.

1H NMR (400 MHz, DMSO-d6) 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). MS-ESI m/z calc. 345.088, detected 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-1yl]pyridin-3-carbonyl]sulfamoyl ]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

2-chloro-6-[3-(dispiro[2.0.2.1]heptan-7ylmethoxy)pyrazol-1-yl]pyridin-3-carboxylic acid (300 mg, 0.8676 mmol) was added to a 100 ml vial under a nitrogen atmosphere. 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 hours. In a separate 20 mL vessel maintained under nitrogen, a solution of tert-butyl-2,2-dimethyl-4-[ 3-[(6-sulfamoyl-2pyridyl)amino]propyl]pyrrolidine-1-carboxylate (358 mg 0.8678 mmol) in anhydrous tetrahydrofuran (2 ml) and added via syringe to the activated ester solution. 1,8Diazabicyclo[5.4.0]undec-7-ene (0.29 ml, 1.939 mmol) was added and the mixture was stirred at room temperature for 19 hours. The solvent was evaporated and the residue was treated with water (50 ml), ethyl acetate (50 ml) and hydrochloric acid (1 ml, 6 M, 6,000 mmol). The two phases were separated. The aqueous phase was further extracted with ethyl acetate (25 ml). The combined organic phases 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 hexane. The pure fractions were collected and the solvents were evaporated to give 408 mg of product as a solid foam. LCMS showed that the material contained 6% of the original 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]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (364 mg, 57%) as a colorless resin. MS-ESI m/z calc. 739.2919, detected 740.3 (M+1) ^+; Retention time: 2.45 min (LC method B).

Step 11: 2-chloro-N-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propylαamino]-2-pyridyl]sulfonyl]-6[3-(dispiro[2.0.2.1]heptane- 7-ylmethoxy)pyrazol-1-yl]pyridin-3-carboxamide (dihydrochloride salt)

LLC 000

Tert-butyl 4-[3-[[6-[[2-chloro-6-[3(dispiro[2.0.2.1]heptan-7-ylmethoxy)pyrazol-1-yl]pyridin- 3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (364 mg, 0.4917 mmol), dichloromethane (5 ml) and hydrochloric acid (0.5 ml 4 M , 2,000 mmol) (4M in dioxane). The vial was capped and stirred at room temperature for 5 hours. Additional hydrochloric acid (0.5 ml 4 M, 2,000 mmol) was added and the mixture was stirred for another hour. Volatiles were removed using a rotary evaporator in vacuum at room temperature. The residue was triturated with dichloromethane/hexanes and the solvents were evaporated. The operation was repeated until a white solid was obtained. Drying in vacuum gives 2-chloro-N-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propylamino]-2-187 044967 pyridyl]sulfonyl]-6-[3-(dispiro[2.0. 2.1 ]heptan-7-ylmethoxy)pyrazol-1 -yl] pyridin-3-carboxamide (dihydrochloride salt) (325 mg, 93%) as a white solid. MS-ESI m/z calc. 639.23944, detected 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- ^2λ6 -thia3,9,11, 18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-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]-12,12dimethyl-2λ ⁶ -thia-3,9,11,18, 23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20hexaene-2,2,4-trione (enantiomer 2) (compound 107)

2-chloro-N-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propylamino]-2-pyridyl]sulfonyl]-6 was charged into a 100 ml round-bottom flask equipped with a magnetic stirrer under a nitrogen atmosphere. -[3(dispiro[2.0.2.1]heptan-7-ylmethoxy)pyrazol-1-yl]pyridin-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 stirred vigorously at 140°C under nitrogen for 15 hours. The mixture was diluted with water (20 ml) and acidified by slowly adding hydrochloric acid (500 µl 6 M, 3,000 mmol, final pH 4-5). The resulting solid was filtered and air dried briefly. The solid was dissolved in dichloromethane/ethyl acetate (total volume 75 ml), dried over sodium sulfate, filtered and concentrated to give a solution which was purified by flash silica gel chromatography using a methanol gradient (0 to 5% over 30 min) in dichloromethane. Evaporation of the solvents gives racemic 8-[3-({dispiro[2.0.2.1]heptan-7yl}methoxy)-1H-pyrazol-1-yl]-12,12-dimethyl- ^2λ6 -thia-3,9,11 ,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound

105) (102 mg, 36%) as a white solid.

Ή NMR (400 MHz, DMSO-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 (broadened 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 (lat. s, 1H), 2.95 (lat. d, J =13.3 Hz, 1H), 2.75-2.65 (m, 1H), 2.12 (b. 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). MS-ESI m/z calc. 603.26276, detected 604.2 (M+1) ⁺ ; Retention time: 2.26 min (LC method B).

This racemic material (97 mg) was subjected to chiral SLC separation (ChiralPak AS-H column (250x10 mm), 5 μm, 35°C, mobile phase 38% acetonitrile:methanol (90:10 unmodified), 62% carbon dioxide, 10 ml/min, 24 mg/ml in acetonitrile:methanol (90:10 without modifier), injection volume 70 µl, 100 bar). The first enantiomer to elute was collected, the solvents were evaporated, and the residue was triturated in dichloromethane/hexane. Evaporation gives 8-[3-({dispiro[2.0.2.1]heptan-7yl}methoxy)-1H-pyrazol-1-yl]-12,12-dimethyl- ^2λ6- thia-3,9,11,18 ,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-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, DMSO-th 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 (broadened 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 (b. d, J=13.4 Hz, 1H), 2.80-2.62 (m, 1H), 2.12 (b. 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). MS-ESI m/z calc. 603.26276, detected 604.3 (M+1) ⁺ ; Retention time: 2.27 min (LC method E). The second enantiomer to be eluted was collected, the solvents were evaporated and the residue was triturated in dichloromethane/hexanes. Evaporation gives 8-[3-({dispiro[2.0.2.1]gentan-7-yl}methoxy)-1H-nirazol-1-yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11, 18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (enantiomer 2) (compound 107) ( 43 mg, 31%).

1H 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 (broadened 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

- 188 044967 (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). MS-ESI m/z calc. 603.26276, detected 604.3 (M+1)+; Retention time: 2.27 min (LC method B).

Example 28: Preparation of 12,12,20-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1 -yl)-2X ⁶ -thia-3,9,11,18 ,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(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} -1 H-pyrazol-1 -yl)-2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1 (23),5(10),6,8,19,21-hexaene-2,2,4-trione (enantiomer 2) (compound 115)

Step 1: 2-chloro-6-iod-3-methylpyridine

A solution of 2-(dimethylamino)ethanol (13.02 g, 14.7 ml, 146.1 mmol) in hexane (120 ml) was cooled to 5°C and treated with butyllithium (132 ml of 2.5 M in hexane, 330.0 mmol) for a period of 45 min. The flask was kept at a temperature of -5 to 0°C for 1 hour, then cooled to -78°C. A solution of 2-chloro-3-methylpyridine (7 g, 54.87 mmol) in hexane (70 ml + 10 ml rinse) was added dropwise over 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 over approximately 1 hour and the reaction mixture was allowed to gradually warm to room temperature overnight. The mixture was cooled in an ice bath and slowly quenched with water (250 ml). Transfer to a 1000 mL separatory funnel and the layers were separated. The aqueous layer was extracted with ethyl acetate (2x250 ml) and the organic layers were combined, washed with water containing 10% aqueous sodium thiosulfate (organic layer became 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 with 0% to 15% ethyl acetate in heptanes to obtain pure and mixed fractions. The mixed fractions were further purified by silica gel chromatography on a 120 g column, eluting with 0% to 15% ethyl acetate in heptanes, then triturated in heptane, dried and combined with the previous pure fractions from the first silica gel column to give 2-chloro-6-iodo- 3-Methylpyridine (9.7 g, 68%) as a pale yellow solid.

1H 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). MS-ESI m/z calc. 252.9155, detected 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

- 189 044967

A solution of 2-chloro-6-iodo-3-methylpyridine (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 within 10 min. Tris(dibenzylideneacetone)dipalladium(0) (1.7 g, 1.856 mmol), xanthos (2.1 g, 3.629 mmol) and 2ethylhexyl-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 with 0% to 20% ethyl acetate in heptanes to give 2-ethylhexyl-3-[(6chloro-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). MS-ESI m/z calc. 343.912, detected 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 hours. 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 (2x250 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 with 0% to 40% ethyl acetate in heptanes, to give 2-ethylhexyl3-[(6-chloro-5-methyl-2-pyridyl)sulfonyl]propanoate (12.36 g , 72%) in the form of a clear oil.

1H 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). MS-ESI m/z calc. 375.911, detected 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-2pyridyl)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 hours, then the mixture was concentrated under reduced pressure to obtain a white solid intermediate. To this intermediate were 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 and then extracted with ethyl acetate (2x300 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 with 20% to 80% ethyl acetate in heptanes, to give 6-chloro-5-methylpyridin-2-sulfonamide (5.9 g, 86%) as a white solid. .

1H NMR (300 MHz, DMSO-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). MS-ESI m/z calc. 206.65, found 207.1 (M+1) ⁺ ; Retention time: 1.44 min (LC method I).

Step 5: tert-butyl pyrrolidine-1-carboxylate:

2,2-dimethyl-4-[3-[(3-methyl-6-sulfamoyl-2-pyridyl)amino]propyl]-

In 5 ml microwave vial 6-chloro-5-methylpyridine-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 vessel was sealed and stirred at 160°C overnight. The mixture was filtered and directly purified by preparative reverse phase HPLC (C ₁₈ ): gradient 1-99% acetonitrile in water/hydrochloric acid modifier (15 min) to give tert-butyl-2,2-dimethyl-4-[3-[( 3-methyl-6-sulfamoyl-2pyridyl)amino]propyl]pyrrolidine-1-carboxylate (130 mg, 21%). MS-ESI m/z calc. 426.23007, detected 427.36 (M+1)+; Retention time: 1.36 min (LC method B).

Step 6: tert-butyl 4-[3-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-190 044967 yl]pyridin-3 -carbonyl]sulfamoyl]-3-methyl-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1 carboxylate:

In a 20 mL microwave-safe vial, 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (345 mg, 0.9182 mmol ) and carbonyl diimidazole (150 mg, 0.9251 mmol) were evacuated/filled with nitrogen (3 times). Dry tetrahydrofuran (4 ml) was added and the mixture was stirred for 90 minutes at 50°C. Then a solution of tert-butyl 2,2-dimethyl-4-[3-[(3-methyl-6sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (260 mg, 0.6095 mmol) and added 1 ,8-diazabicyclo[5.4.0]undec-7-ene (228 μl, 1.525 mmol) in tetrahydrofuran (4 ml) and the mixture was stirred at 50°C overnight. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution, and then with saline solution. The organic extract was dried, evaporated and purified by preparative reverse phase HPLC ( _C18 ): gradient of acetonitrile in water/hydrochloric acid modifier 1-99% (15 min) to obtain tert-butyl-4-[3-[[6-[[ 2-chloro-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-3-methyl-2pyridyl]amino]propyl]-2,2 -dimethylpyrrolidine-1-carboxylate (290 mg, 61%) ESI-MS m/z calc. 783.27924, detected 784.31 (M+1)+; Retention time: 2.42 min (LC method B).

Step 7: 2-chloro-I-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propylamino]-5-methyl-2pyridyl]sulfonyl]-6-[3-[2-[1- (trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carboxamide (hydrochloride salt):

A solution of tert-butyl-4-[3-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl] -3-methyl-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1 carboxylate (290 mg, 0.3698 mmol) in dichloromethane (6 ml) was treated with hydrochloric acid (4 M in dioxane) (3 ml 4 M , 12.00 mmol) and stirred at room temperature for 30 min. The mixture was evaporated to dryness under reduced pressure to give 2-chloro-X-[[6-[3-(5,5dimethylpyrrolidin-3-yl)propylamino]-5-methyl-2-pyridyl]sulfonyl]-6-[3-[ 2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (hydrochloride salt) (265 mg, 99%). The product was used in the next step without further purification.

Step 8: 12,12,20-trimethyl-8-(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-2λ ⁶ thia-3,9,11, 18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4trione:

In a 5 ml microwave vial, a mixture of 2-chloro-X-[[6-[3-(5,5-dimethylpyrrolidin-3 yl)propylamino]-5-methyl-2-pyridyl]sulfonyl]-6-[3- [2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (hydrochloride salt) (265 mg), potassium carbonate (260 mg, 1.881 mmol), cesium fluoride (87 mg 0. 5727 mmol) and 4 A MS (300 mg) was evacuated/refilled with nitrogen (3 times). Dimethyl sulfoxide (6 ml) was added and the mixture was stirred at 140°C for 16 hours. The reaction mixture was filtered and purified by preparative reverse phase HPLC (Cig): gradient 1-99% acetonitrile in water/hydrochloric acid modifier (15 min) with producing 12,12,20trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (100 mg,

42%). ESI-MS m/z calc. 647.2502, found 648.31 (M+1) ⁺ .

Step 9: 12,12,20-trimethyl-8-(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-2λ ⁶ thia-3,9,11, 18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4trione (enantiomer 1) (compound 114) and 12,12,20-trimethyl-8-(3-{2-[1- 191 044967 (trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-2λ ⁶ -thia-3,9,11, 18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23),5(10),6,8,19,21-hexaene-2,2,4-trione (enantiomer

2) (connection 115)

Racemic 12,12,20-trimethyl-8-(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 yl)-2λ ⁶ -thia-3,9,11,18, 23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene2,2,4-trione (100 mg, 0.07052 mmol) was subjected to chiral separation by SLC chromatography using ChiralPak AS-H (250x10 mm, 5 µm particle size) with a mobile phase of 18% methanol (20 mM NH ₃ )/82% carbon dioxide at 10 ml/min for 8.0 min (injection volume =70 µl of a 24 mg/ml solution in methanol/dimethyl sulfoxide (90:10)) yielding 12,12,20-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy as the first eluting enantiomer }-1 H-pyrazol-1 yl)-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6, 8,19,21-hexaene2,2,4-trione (enantiomer 1) (compound 114) (25.8 mg, 10%);

¹ H NMR (400 MHz, chloroform-d) δ 8.19 (d, J=2.8 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.51 (d, J=7.3 Hz, 1H), 7.42 ( d, J=7.3 Hz, 1H), 7.24-7.27 (m, 1H), 5.90 (d, J=2.8 Hz, 1H), 4.56 (s, 1H), 4.39 (t, J=7.2 Hz, 2H), 3.93 (s, 1H), 3.44-3.32 (m, 1H), 3.23 (d, J=19.8 Hz, 1H), 3.06 (t, J=9.3 Hz, 1H), 2.72-2.53 (m, 1H), 2.14 (s, 3H), 2.09 (t, J=7.2 Hz, 3H), 1.25 (s, 2H), 1.05-0.99 (m, 2H), 0.81 (dd, J=12.6, 6.6 Hz, 1H), 0.74 ( t, J=3.1 Hz, 2H), two methyl groups and one CH are overlapped by residual water; MS-ESI m/z calc. 647.2502, detected 648.34 (M+1)+; Retention time: 2.25 min (LC method A), and as the second enantiomer eluted 12,12,20-trimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol- 1 -yl)-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23),5(10),6,8,19,21 -hexaene- 2,2,4-trione (enantiomer 2) (compound 115) (24.7 mg, 25%);

1H NMR (400 MHz, chloroform-d) δ 8.19 (d, J=2.8 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.52 (d, J=7.3 Hz, 1H), 7.43 (d , J=7.4 Hz, 1H), 7.28 (s, 1H), 5.91 (d, J=2.8 Hz, 1H), 4.58 (d, J=8.1 Hz, 1H), 4.39 (t, J=7.2 Hz, 2H ), 3.97 (d, J=5.8 Hz, 1H), 3.43-3.31 (m, 1H), 3.28-3.15 (m, 1H), 3.06 (t, J=9.8 Hz, 1H), 2.65 (d, J= 3.6 Hz, 1H), 2.14 (s, 3H), 2.09 (t, J=7.2 Hz, 3H), 1.25 (s, 2H), 1.04-1.00 (m, 2H), 0.82 (d, J=8.2 Hz, 2H), 0.74 (t, J=3.2 Hz, 2H). Two Me-groups and one C-H are overlapped by residual water; MS-ESI m/z calc. 647.2502, detected 648.31 (M+1) ⁺ ; Retention time: 0.85 min (LC method A).

Example 29: preparation of 8-[3-({dispiro[2.0.2.1]heptan-7-yl}methoxy)-1H-pyrazol-1-yl]-12,12dimethyl-2λ ⁶ -thia-3,9,11, 19,21-pentaazatetracyclo[18.2.2.111,14.05,10]pentacose-1(23),5,7,9,20(24),21hexaene-2,2,4-trione (enantiomer 1) (compound 120) and 8-[3-({dispiro[2.0.2.1]heptan-7-yl}methoxy)-1Hpyrazol-1-yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11,19,21- pentaazatetracyclo[18.2.2.111,14.05,10]pentacose1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (enantiomer 2) (compound 121)

tert-butyl-2,2-dimethyl-4-[4-[(5-sulfamoyl-2-pyridyl)amino]butyl]pyrrolidine-1 Step 1: carboxylate

- 192 044967

A 100 mL round bottom flask was charged under a nitrogen atmosphere with tert-butyl 4-(4-aminobutyl)2,2-dimethylpyrrolidine-1-carboxylate (1.33 g, 4.918 mmol), 6-chloropyridine-3-sulfonamide (945 mg , 4.906 mmol), anhydrous dimethyl sulfoxide (15 ml) and potassium carbonate (695 mg, 5.029 mmol) (freshly ground in a mortar), and the mixture was stirred at 100°C for 20 hours. After cooling, the reaction mixture was diluted with ethyl acetate (50 ml ) and poured into a saturated aqueous solution of 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 (80 g column) using a gradient of ethyl acetate (0 to 100% over 30 min) in hexane. Evaporation of the solvents gave tert-butyl 2,2-dimethyl-4-[4-[(5sulfamoyl-2-pyridyl)amino]butyl]pyrrolidine-1-carboxylate (1.165 g, 56%) as an off-white solid foam. MS-ESI m/z calc. 426.23007, detected 427.3 (M+1)+; Retention time: 1.4 min (LC method B).

Step 2: tert-butyl 4-[4-[[5-[[2-chloro-6-[3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl ]-2-pyridyl]amino]butyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

2-chloro-6-[3-(dispiro[2.0.2.1]heptan-7ylmethoxy)pyrazol-1-yl]pyridin-3-carboxylic acid (355 mg, 1.027 mmol) and anhydrous tetrahydrofuran (5 ml). Carbonyl diimidazole (183 mg, 1.129 mmol) was added and the mixture was stirred under nitrogen at room temperature for 3.5 hours. In a separate 20 mL vessel maintained under nitrogen, a solution of tert-butyl-2,2-dimethyl-4 -[4-[(5-sulfamoyl-2-pyridyl)amino]butyl]pyrrolidine-1-carboxylate (438 mg, 1.027 mmol) in anhydrous tetrahydrofuran (2.5 ml) was prepared and added via syringe to the activated ester solution. 1,8Diazabicyclo[5.4.0]undec-7-ene (0.35 ml, 2.340 mmol) was added and the mixture was stirred at room temperature for 19 hours. The solvent was evaporated and the residue was treated with water (50 ml), ethyl acetate (50 ml) and hydrochloric acid (1 ml, 6 M, 6,000 mmol). The two phases were separated. The aqueous phase was further extracted with ethyl acetate (25 ml). The combined organic phases 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 (40 g gold column) using a gradient of ethyl acetate (0 to 100% over 30 min) in hexane. Pure product fractions were collected and the solvents were evaporated to give tert-butyl-4-[4-[[5-[[2-chloro-6-[3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)pyrazol-1 yl ]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]butyl]-2,2-dimethylpyrrolidine-1-carboxylate (467 mg, 60%) as a white solid. MS-ESI m/z calc. 753.30756, detected 754.3 (M+1) ⁺ ; Retention time: 2.34 min (LC method B).

Step 3: 2-chloro-N-[[6-[4-(5,5-dimethylpyrrolidin-3-yl)butylamino]-3-pyridyl]sulfonyl]-6-[3(dispiro[2.0.2.1]heptane- 7-ylmethoxy)pyrazol-1-yl]pyridin-3-carboxamide (dihydrochloride salt).

Tert-butyl-4-[4-[[5-[[2-chloro-6-[3(dispiro[2.0.2.1] heptan-7-ylmethoxy)pyrazol-1-yl]pyridine was loaded into a 100 ml round bottom flask -3-carbonyl]sulfamoyl]-2-pyridyl]amino]butyl]-2,2-dimethylpyrrolidine-1-carboxylate (467 mg, 0.6191 mmol), dichloromethane (6 ml) and hydrochloric acid (0.63 ml 4 M , 2.520 mmol) (4M in dioxane). The reaction was stirred at room temperature for 3 hours. Additional hydrochloric acid (0.5 ml 4 M, 2,000 mmol) was added and the mixture was stirred for another hour. Volatiles were removed by evaporation under vacuum. The residue was triturated with dichloromethane/hexanes and the solvents were evaporated. This operation was repeated until a white solid was obtained. Drying in vacuum gives 2-χλορ-Ν-[[6-[4-(5,5-193 044967 dimethylpyrrolidin-3-yl)butylamino]-3-pyridyl]sulfonyl]-6-[3-(dispiro[2.0. 2.1]heptan-7 ylmethoxy)pyrazol-1-yl]pyridin-3-carboxamide (dihydrochloride salt) (420 mg, 93%) as a white solid. The product was used in the next step without further purification. MS-ESI m/z calc. 653.2551, detected 654.3 (M+1)+; Retention time: 1.58 min (LC method B).

Step 4: 8-[3-({dispiro[2.0.2.1]heptαn-7-yl}methoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ ⁶ -thia3,9,11,19 ,21-pentaazatetracyclo[18.2.2.111,14.05,10]pentacose-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (enantiomer 1) (compound 120) and 8-[3-({dispiro[2.0.2.1]heptan-7-yl}methoxy)-1H-pyrazol-1-yl]-12,12dimethyl-2λ ⁶ -thia-3,9,11,19,21 -pentaazatetracyclo[18.2.2.111,14.05,10]pentacose-1 (23),5,7,9,20(24),21 hexaene-2,2,4-trione (enantiomer 2) (compound 121)

LLC n

<7 λ N 'N CI fl Λ 2HCI HN-/—

enantiomer 1 enantiomer 2

2-chloro-N-[[6-[4-(5,5-dimethylpyrrolidin-3-yl)butylamino]-3-pyridyl]sulfonyl]-6 was charged into a 100 ml round-bottom flask equipped with a magnetic stirrer under a nitrogen atmosphere. -[3(dispiro[2.0.2.1] heptan-7-ylmethoxy)pyrazol-1 -yl]pyridin-3-carboxamide (dihydrochloride salt) (420 mg, 0.5776 mmol), anhydrous NMP (5 ml), potassium carbonate (343 mg, 2.482 mmol) (freshly ground in a mortar) and cesium fluoride (89 mg, 0.5859 mmol). The mixture was vigorously stirred in a dry bath at 145°C under a nitrogen atmosphere for 13 hours, then at 165°C for 8 hours. After cooling to room temperature, the mixture was diluted with water (30 ml) and acidified by slowly adding hydrochloric acid (600 μl 6 M, 3,600 mmol) (final pH 4-5). The resulting solid was filtered and air dried briefly. The solid was dissolved in dichloromethane/ethyl acetate (total volume 50 ml), dried over sodium sulfate, filtered and concentrated to give a solution which was purified by flash chromatography on silica gel (24 g gold column) using a methanol gradient (0 to 5% for 30 min) in dichloromethane. Evaporation of the solvents, trituration with dichloromethane/hexanes and evaporation of the solvents again gave the racemic product (79 mg, 22%) as a white solid. This racemic material was subjected to chiral SLC chromatography (ChiralPak AS-H (250x10 mm), 5 µM column; mobile phase 38% acetonitrile/methanol (90:10, unmodified), 62% carbon dioxide, 10 ml/min; concentration 24 mg/ml in acetonitrile/methanol/dimethyl sulfoxide (80:10:10; no modifier; injection volume=70 µl, 100 bar). The first enantiomer eluted was 8-[3-({dispiro[2.0.2.1]heptan-7-yl}methoxy)-1H-pyrazol-1-yl]12,12-dimethyl-2X ⁶ -thia-3,9,11 ,19,21-pentaazatetracyclo[18.2.2.111,14.05,10]pentacose1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (enantiomer 1) (compound 120) (25 mg, 14%), white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.13 (broad s, 1H, exchangeable by D2O), 8.50 (broad s, 1H), 8.17 (d, J=2.7 Hz, 1H), 7.88-7.70 (m , 2H), 7.34 (broad s, 1H. exch.), 6.90 (d, J=8.3 Hz, 1H), 6.57 (d, J=9.1 Hz, 1H), 6.10 (d, J=2.8 Hz, 1H ), 4.23 (d, J=7.0 Hz, 2H), 2.54 (s, 4H), 2.08 (broad s, 2H), 1.91 (t, J=7.0 Hz, 1H), 1.73 (d, J=10.4 Hz , 1H), 1.57-1.53 (m, 9H), 1.34-1.15 (m, 1H), 1.05 (broad s, 2H), 0.95-0.83 (m, 4H), 0.75-0.64 (m, 2H), 0.59 (d, J=9.0 Hz, 2H). MS-ESI m/z calc. 617.27844, detected 618.4 (M+1) ⁺ ; Retention time: 2.15 min (LC method B).

The second enantiomer eluted was 8-[3-({dispiro[2.0.2.1]heptan-7-yl}methoxy)-1Hpyrazol-1-yl]-12,12-dimethyl-2X ⁶ -thia-3,9,11, 19,21-pentaazatetracyclo[18.2.2.111,14.05,10]pentacose1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (enantiomer 2) (compound 121) ( 24 mg, 13%), white solid.

1H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 12.11 (s, 1H), 8.51 (broadened s, 1H), 8.17 (d, J=2.8 Hz, 1H), 7.80 (d, J=8.3 Hz, overlapped by broad s, 2H), 7.33 (broad s, 1H), 6.90 (d, J=8.3 Hz, 1H), 6.57 (d, J=8.9 Hz, 1H), 6.10 (d, J=2.7 Hz, 1H), 4.23 (d, J=7.0 Hz, 2H), 2.62-2.49 ( m, overlaps with solvent signal, probably 4H), 2.08 (b.s, 2H), 1.91 (t, J=7.0 Hz, 1H), 1.72 (b.s, 1H), 1.54 (m, 9H), 1.24 (b. s, 1H), 1.05 (b. s, 2H), 0.92-0.82 (m, 4H), 0.75-0, 64 (m, 2H), 0.59 (d, J=9.1 Hz, 2H). MS-ESI m/z calc. 617.27844, detected 618.5 (M+1) ⁺ ; Retention time: 2.15 min (LC method B).

Example 30: Preparation of 8-[3-({dispiro[2.0.2.1]heptan-7-yl}methoxy)-1H-pyrazol-1-yl]-12,12dimethyl-2λ ⁶ -thia-3,9,11, 19,24-pentaazatetracyclo[18.3.1.05,10.011.15]tetracose-1(23),5(10),6,8,20(24),21hexaene-2,2,4-trione (enantiomer 1) (compound 124) and 8-[3-({dispiro[2.0.2.1]heptan-7-yl}methoxy)-1H- 194 044967 pyrazol-1-yl]-12,12-dimethyl-2λ ⁶ -thia-3,9 ,11,19,24-pentaazatetracyclo[18.3.1.05,10.011,15]tetracose1(23),5(10),6,8,20(24),21-hexaene-2,2,4-trione (enantiomer 2 ) (connection 125)

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

6-Fluoropyridine-2-sulfonamide (343 , 1.950 mmol), followed by potassium carbonate (808 mg, 5.850 mmol). The flask was sealed and heated at 70°C in a nitrogen cylinder in an oil bath for 18 hours. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate and washed with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography (80 g column) using a gradient of 100% hexanes to 100% ethyl acetate to give tert-butyl-2,2-dimethyl-5- [3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1carboxylate (428 mg, 53%) as a white foamy solid.

¹ H NMR (400 MHz, chloroform-d) δ 7.51 (t, J=7.9 Hz, 1H), 7.19 (d, J=7.3 Hz, 1H), 6.55 (d, J=8.5 Hz, 1H), 5.51 ( s, 1H), 5.05 (s, 2H), 3.90 (s, 1H), 3.57-3.42 (m, 1H), 3.32 (d, J=9.8 Hz, 2H), 1.91 (s, 2H), 1.77 (d , J=30.5 Hz, 1H), 1.62 (d, J=2.9 Hz, 3H), 1.48 (s, 10H), 1.27 (t, J=3.6 Hz, 3H). MS-ESI m/z calc. 412.21442, detected 413.25 (M+1)+; Retention time: 0.65 min (LC method B).

Step 2: tert-butyl 5-[3-[[6-[[2-chloro-6-[3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl ]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

2-chloro-6-[3-(dispiro[2.0.2.1]heptan-7ylmethoxy)pyrazol-1-yl]pyridin-3-carboxylic acid (327 mg, 0.9457 mmol) was added to a 100 ml vial under a nitrogen atmosphere. and anhydrous tetrahydrofuran (5 ml). Carbonyldiimidazole (168 mg, 1.036 mmol) was added and the mixture was stirred under nitrogen at room temperature for 2 hours (complete activation with LCMS aliquots in sec-butylamine). In a separate 20 ml vessel, maintained under nitrogen, a solution of tert-butyl 2,2-dimethyl-5-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (390 mg, 0 .9453 mmol) in anhydrous tetrahydrofuran (2.5 ml) and added via syringe to the activated ester solution. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.32 ml, 2.140 mmol) was added and the mixture was stirred at room temperature for 13 hours. The solvent was evaporated and the residue was treated with water (50 ml), ethyl acetate ( 50 ml) and hydrochloric acid (1 ml, 6 M, 6,000 mmol). Two phases

- 195 044967 shared. The aqueous phase was further extracted with ethyl acetate (25 ml). The combined organic phases 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 (40 g gold column) using a gradient of ethyl acetate (0 to 100% over 30 min) in hexane. The pure fractions were collected and the solvents were evaporated to give tert-butyl 5-[3-[[6-[[2-chloro-6-[3-(dispiro[2.0.2.1]heptan-7ylmethoxy)pyrazol-1-yl]pyridin- 3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (435 mg, 62%) as a white solid. MS-ESI m/z calc. 739.2919, detected 740.3 (M+1)+; Retention time: 2.47 min (LC method B).

Step 3: 2-chloro-N-[[6-[3-(5,5-dimethylnirrolidin-2-yl)propylamino]-2-niridyl]sulfonyl]-6-[3(dispiro[2.0.2.1]heptane- 7-ylmethoxy)pyrazol-1-yl]pyridin-3-carboxamide (dihydrochloride salt).

Tert-butyl-5-[3-[[6-[[2-chloro-6-[3(dispiro[2.0.2.1]heptan-7-ylmethoxy)pyrazol-1-yl]pyridine was loaded into a 100 ml round bottom flask -3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (435 mg, 0.5876 mmol), dichloromethane (6 ml) and hydrochloric acid (0.6 ml 4 M, 2.400 mmol) (4M in dioxane). The reaction was stirred at room temperature for 3 hours. Additional hydrochloric acid (500 μl of 4 M, 2,000 mmol) was added and the mixture was stirred for another hour. Volatiles were removed by evaporation under vacuum. The residue was triturated with dichloromethane/hexanes and the solvents were evaporated. The operation was repeated until a white solid was obtained. Drying in vacuum gives 2-chloro-C[[6-[3-(5,5dimethylpyrrolidin-2-yl)propylamino]-2-pyridyl]sulfonyl]-6-[3-(dispiro[2.0.2.1] heptane-7 ylmethoxy)pyrazol-1-yl]pyridin-3-carboxamide (dihydrochloride salt) (439 mg, 105%) as a white solid. The product was used in the next step without further purification. MS-ESI m/z calc. 639.23944, detected 640.3 (M+1) ⁺ ; Retention time: 1.7 min (LC method B).

Step 4: 8-[3-({dispiro[2.0.2.1] heptan-7-yl}methoxy)-1H-pyrazol-1-yl]-12,12-dimethyl- ^2λ6 -thia3,9,11, 19,24-pentaazatetracyclo[18.3.1.05,10.011.15]tetracose-1(23),5(10),6,8,20(24),21-hexaene-2,2,4trione (enantiomer 1) (compound 124) 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, 19,24-pentaazatetracyclo[18.3.1.05,10.011.15]tetracose1(23),5(10),6,8,20(24),21-hexaene-2,2,4-trione (enantiomer 2) (compound 125)

2-chloro-X[[6-[3-(5,5-dimethylpyrrolidin-2-yl)propylamino]-2-pyridyl]sulfonyl]-6- was charged into a 100 ml round-bottom flask equipped with a magnetic stirrer under a nitrogen atmosphere. [3(dispiro[2.0.2.1]heptan-7-ylmethoxy)pyrazol-1-yl]pyridin-3-carboxamide (dihydrochloride salt) (439 mg, 0.6156 mmol), anhydrous NMP (5 ml), potassium carbonate ( 410 mg, 2.967 mmol) (freshly ground in a mortar) and cesium fluoride (94.82 mg, 23.04 μl, 0.6242 mmol). The mixture was vigorously stirred in a dry bath at 145°C under a nitrogen atmosphere for 46 hours, then at 155°C for 14 hours. After cooling to room temperature, the mixture was diluted with water (30 ml) and acidified by slowly adding hydrochloric acid (500 μl 6 M, 3,000 mmol) (final pH 4-5). The resulting solid was filtered and air dried briefly. The solid was dissolved in dichloromethane (total volume 50 ml), dried over sodium sulfate, filtered and concentrated, then purified by flash chromatography on silica gel (4 g column) using a methanol gradient (0 to 5% over 30 min) in dichloromethane.

Evaporation of the solvents, trituration with dichloromethane/hexanes and evaporation of the solvents again gave the expected racemic product as an off-white solid (154 mg, 41%). The racemic material was subjected to chiral SLC chromatography (ChiralPak IG column (250x21.2

- 196 044967 mm), 5 µm, mobile phase 38% acetonitrile:methanol (90:10 without modifier), 62% carbon dioxide, 70 ml/min, 30 mg/ml in acetonitrile:methanol (90:10 without modifier), injection volume 500 µl, 100 bar). After evaporation of the solvents, the residue was triturated in dichloromethane/hexanes and the solvents were removed. The first enantiomer eluted was 8-[3-({dispiro[2.0.2.1]heptan-7-yl}methoxy)-1Hpyrazol-1-yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11. 19,24-pentaazatetracyclo[18.3.1.05,10.011.15]tetracose1(23),5(10),6,8,20(24),21-hexaene-2,2,4-trione (enantiomer 1) (compound 124) (62 mg, 33%), isolated as a white solid.

Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.70 (broad s, 1H), 8.21 (d, J=2.8 Hz, 1H), 8.00 (broadened d, J=8.0 Hz, 1H), 7.58 (dd, J =8.5, 7.2 Hz, 1H), 7.28 (broad s, 1H), 7.08 (broad s, 1H), 7.03 (d, J=7.2 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H) , 6.12 (d, J=2.8 Hz, 1H), 4.24 (d, J=7.0 Hz, 2H), 3.71 (broad s, 2H), 3.11 (broad s, 1H), 2.00-1.80 (m, 3 ), 1.73 (broad s, 2H), 1.63-1.43 (m, 5H), 1.42-1.31 (m, 4H), 1.09-0.88 (m, 1H), 0.94-0.80 (m, 4H), 0.760.64 (m, 2H), 0.66-0.53 (m, 2H). MS-ESI m/z calc. 603.26276, detected 604.3 (M+1)+; Retention time: 1.95 min (LC method B).

The second enantiomer eluted was 8-[3-({dispiro[2.0.2.1]heptan-7-yl}methoxy)-1H-pyrazol1-yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11, 19,24-nentaazatetracyclo[18.3.1.05,10.011,15]tetracose1(23),5(10),6,8,20(24),21-hexaene-2,2,4-trione (enantiomer 2) (compound 125) (54 mg, 28%), isolated as a white solid.

1H NMR (400 MHz, dimethylsulfoxide-d ₆ ) δ 12.67 (broadened s, 1H), 8.21 (d, J=2.8 Hz, 1H), 8.00 (broadened d, J=7.1 Hz, 1H), 7.58 ( t, J=7.8 Hz, 1H), 7.37-7.21 (m, 1H), 7.08 (b. s, 1H), 7.03 (d, J=7.1 Hz, 1H), 6.62 (d, J=8.5 Hz, 1H ), 6.12 (d, J=2.8 Hz, 1H), 4.24 (d, J=7.1 Hz, 2H), 3.71 (broad s, 2H), 3.10 (broad s, 1H), 2.02-1.79 (m, 3H), 1.73 (s, 2H), 1.64-1.45 (m, 5H), 1.42-1.28 (m, 4H), 0.99 (broad s, 1H), 0.94-0.77 (m, 4H), 0.77-0.65 ( m, 2H), 0.64-0.54 (m, 2H). MS-ESI m/z calc. 603.26276, detected 604.3 (M+1) ⁺ ; Retention time: 1.96 min (LC method B).

Example 31: Preparation of (14S)-8-[3-(3,3-dimethylbutyl)-2-oxonirrolidin-1-yl]-12,12-dimethyl2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo [17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,2,4trione (diastereomer 1) (compound 126) and (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]tetracose- 1(23),5,7,9,19,21hexaene-2,2,4-trione (diastereomer 2) (compound 127)

diastereomer 1 diastereomer 2

Step 1: (14S)-8-[3-(3,3-dimethylbutyl)-2-oxopyrrolidin-1-yl]-12,12-dimethyl-2λ ⁶ -tiα3,9,11,18,23-pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,2,4-trione (diastereomer 1) (compound 126) and (148)-8-[ 3-(3,3-dimethylbutyl)-2-oxopyrrolidin-1-yl]-12,12-dimethyl2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose- 1 (23),5,7,9,19,21-hexaene-2,2,4trione (diastereomer 2) (compound 127)

diastereomer 1 diastereomer 2 (14S)-8-[3-(3,3-dimethylbutyl)-2-oxopyrrolidin-1-yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo [17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,2,4-trione was subjected to chiral SCLC separation (separation (ChiralCel OJ-H (250x 10 mm), 5 µM column, mobile phase 25% acetonitrile/methanol (90:10, unmodified), 75% carbon dioxide, 10 ml/min, concentration 24 mg/ml in acetonitrile/methanol (90:10); injection volume 70 µl, 100 bar).

For pure collected fractions, the solvents were evaporated and the residue triturated in dichloromethane/hexane. The first diastereomer to elute was (14S)-8-[3-(3,3-dimethylbutyl)-2-oxonirrolidin1 -yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo [17.3.1.111,14.05,10]tetracose1(23),5,7,9,19,21-hexaene-2,2,4-trione (diastereomer 1) (compound 126) (19 mg, 36%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.42 (s, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.62-7.46 (m, 2H), 7.03 (d, J=7.0 Hz, 1H), 6.97 (broad s, 1H), 6.70 (d, J=8.6 Hz, 1H), 4.04 (t, J=9.3 Hz, 1H), 3.99-3.83 (m, 1H), 3.74 (k, J= 10.3, 9.7 Hz, 1H), 3.10 (broad s, 1H), 2.94 (d, J=13.5 Hz, 1H), 2.76-2.63 (m, 1H), 2.24 (dd, J=17.4, 7.7 Hz, 1H ), 2.10 (broad s, 1H), 1.88-1.64 (m, 4H), 1.65-1.40 (m, 9H), 1.40-1.13 (m, 4H), 0.88 (s, 9H). MS-ESI m/z calc. 582.2988, detected 583.4 (M+1) ⁺ ; retention time: 2.13 min (LC method B).

The second diastereomer eluted was (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]tetracose-1(23),5,7,9,19,21hexaene-2,2,4-trione (diastereomer 2) (compound 127) (17 mg, 32%).

¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 12.42 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.61-7.49 (m, 2H), 7.04 (d, J=7.1 Hz, 1H), 6.97 (broadened d, J=7.0 Hz, 1H), 6.70 (d, J=8.4 Hz, 1H), 3.96-3.79 (m, 3H), 3.09

- 197 044967 (broad s, 1H), 2.93 (broad d, J=13.3 Hz, 1H), 2.75-2.55 (m, 2H), 2.30-2.18 (m, 1H), 2.09 (broad s, 1H ), 1.881.69 (m, 3H), 1.69-1.41 (m, 10H), 1.34-1.15 (m, 4H), 0.88 (s, 9H). MS-ESI m/z calc. 582.2988, found

583.4 (M+1)+; Retention time: 2.14 min (LC method B).

Example 32: Preparation of 12,12,22-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1 -yl)-2λ ⁶ -thia-3,9,11,18 ,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (compound 129)

Step 1: 2-benzylsulfanyl-6-chloro-3-methyl-pyridine

2,6-Dichloro-3-methylpyridine (5.05 g, 31.17 mmol) and phenylmethanethiol (3.871 g, 3.659 ml, 31.17 mmol) were dissolved in tetrahydrofuran (50.50 ml) and sodium tert-butoxide (31 .17 ml 2 M, 62.34 mmol). The reaction mixture was stirred for 16 hours and partitioned between water and ethyl acetate. The organic phases were separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The crude material was used without further purification: 2-benzylsulfanyl-6chloro-3-methylpyridine (7.15 g, 92%). MS-ESI m/z calc. 249.0379, detected 250.0 (M+1) ⁺ ; Retention time: 0.81 min (LC method A).

Step 2: 6-chloro-3-methyl-pyridine-2-sulfonamide

A biphasic mixture of 2-benzylsulfanyl-6-chloro-3-methylpyridine (7.15 g, 28.63 mmol) in dichloromethane (42.90 ml), water (14.30 ml) and hydrochloric acid (2.863 ml, 1 M, 2.863 mmol) was cooled in an ice-salt water bath (hydrochloric acid was added to avoid delayed exothermic effect when adding Cl ₂ ). Cl ₂ (8.119 g, 114.5 mmol) was bubbled through the solution (3 times at 2 min intervals) for an hour. The reaction was stirred at 0°C. After 1.5 h, the reaction mixture was added dropwise to an ice bath cooled NH4OH solution (43.01 mL, 28% w/v, 343.6 mmol). The reaction mixture was warmed to room temperature and stirred for 15 minutes. The reaction mixture was partitioned between ethyl acetate (60 ml) and water (20 ml). The organic phases were separated and the aqueous layer was extracted with ethyl acetate (2x60 ml). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered and evaporated. The resulting solid was triturated with dichloromethane (30 ml) and filtered. The solid was washed with a minimal amount of dichloromethane to obtain an off-white solid, 6-chloro-3methylpyridin-2-sulfonamide (2.95 g, 50%).

¹ H NMR (400 MHz, DMSO-Y6) δ 7.94 (d, J=8.1, 0.9 Hz, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.63 (s, 2H), 2.55 (s, 3H ). MS-ESI m/z calc. 205.99167, detected 207.1 (M+1) ⁺ ; Retention time: 0.3 min (LC method A).

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

- 198 044967

6-chloro-3-methylpyridine-2sulfonamide (1.12 g, 5.420 mmol), tert-butyl 4-(3-aminopropyl)-2,2-dimethylpyrrolidine-1carboxylate (1 g, 3.900 mmol)), diisopropylethylamine (2.520 g, 3.396 ml, 19.50 mmol) and n-butanol (11 ml). The vessel was sealed and left to stir at 125°C for 20 hours. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and washed with water. The organic extract was dried over sodium sulfate, evaporated and purified by silica gel chromatography (0% to 85% ethyl acetate in hexane gradient) to give tert-butyl-2,2-dimethyl-4-[3-[(5-methyl-6- sulfamoyl-2pyridyl)amino]propyl]pyrrolidine-1-carboxylate (360 mg, 22%). MS-ESI m/z calc. 426.23007, detected 427.29 (M+1)+; retention time: 0.67 min (LC method A).

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

2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (317.1 mg, 0.8439 mmol) and carbonyl diimidazole (136 .8 mg, 0.8439 mmol) were combined in anhydrous tetrahydrofuran (8.5 ml) and stirred for 90 min at 50°C. Tert-butyl 2,2dimethyl-4-[3-[(5-methyl-6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (360 mg, 0.8439 mmol) was then added followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (128.5 mg, 126.2 µl, 0.8439 mmol), and the reaction mixture was heated at 50°C for 15 hours. The reaction was diluted with ethyl acetate and washed 1M citric acid solution, and then saline solution. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified on silica gel using a gradient of 100% hexanes to 75% ethyl acetate in hexanes to give tert-butyl-4-[3-[ as an off-white solid. [6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl]-5-methyl-2-pyridyl]amino] propyl]-2,2-dimethylpyrrolidine-1carboxylate (326 mg, 49%). MS-ESI m/z calc. 783.27924, detected 784.42 (M+1) ⁺ ; Retention time: 0.89 min (LC method A).

Step 5: 12,12,22-trimethyl-8-(3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-2λ ⁶ thia-3,9,11, 18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4trione (compound 129)

Part A: tert-butyl 4-[3-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl ]-5-methyl-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1carboxylate (186 mg, 0.2372 mmol) was dissolved in dichloromethane (3 ml) and hydrochloric acid (4 M in dioxane) was added to the mixture ( 2.2 ml, 4 M, 8,800 mmol) and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated to dryness under reduced pressure and transferred directly to the next step.

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Part B: Combination material from Part A and potassium carbonate (197 mg, 1.425 mmol), cesium fluoride (60 mg, 0.3950 mmol), 3 A molecular sieves and dimethyl sulfoxide (3 ml) in a nitrogen purged vial, capped, heated to 140°C and stirred for 16 hours. The reaction mixture was allowed to cool to room temperature, filtered and then purified by reverse-phase preparative HPLC chromatography using a C ₁₈ column and a gradient of 30-99 A1-B1 (acetonitrile water + 5 mM hydrochloride acid 30 min, X 2 injections) to obtain 12,12,22-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl) as a white solid -2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2, 4-trione (compound 129) (53 mg, 34%). MS-ESI m/z calc. 647.2502, detected 648.31 (M+1) ⁺ ; Retention time: 2.29 min (LC method B).

Example 33: Preparation of 8-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ ⁶ -thia3,9,11,19,21-pentaazatetracyclo[18.2.2.111 ,14.05,10]pentacose-1(22),5,7,9,20,23-hexaene-2,2,4-trione (compound 130)

Step 1: tert-butyl 4-[4-[[5-[[2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl] amino]butyl]-2,2-dimethyl-pyrrolidine-1-carboxylate o p

2-Chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridin-3-carboxylic acid (356.3 mg, 0.9846 mmol) and carbonyl diimidazole (159.7 mg, 0.9846 mmol ) were combined in tetrahydrofuran (5 ml) and stirred at room temperature for 16 hours. Then tert-butyl-2,2-dimethyl-4-[4[(5-sulfamoyl-2-pyridyl)amino]butyl]pyrrolidine- 1-carboxylate (350 mg, 0.8205 mmol) and 1,8diazabicyclo[5.4.0]undec-7-ene (187.4 mg, 184.1 μL, 1.231 mmol) and the reaction mixture was stirred at room temperature for 6 h. The reaction was diluted with ethyl acetate and washed with a saturated aqueous solution of ammonium chloride, and then with saline. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a gradient of 100% dichloromethane to 20% methanol in dichloromethane to give tert-butyl-4-[4-[[5-[[2-chloro- 6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl]amino]butyl]-2,2-dimethylpyrrolidine-1-carboxylate (423 mg, 67%) as a white solid.

1H NMR (400 MHz, chloroform-d) δ 8.70 (s, 1H), 8.27 (d, J=2.9 Hz, 1H), 8.19 (d, J=8.5 Hz, 1H), 8.08 (d, J=8.9 Hz , 1H), 7.70 (d, J=8.5 Hz, 1H), 6.41 (d, J=8.9 Hz, 1H), 5.95 (d, J=2.9 Hz, 1H), 5.48 (brs, 1H), 4.41 (t , J=6.8 Hz, 2H), 3.64 (dt, J=40.0, 9.2 Hz, 1H), 3.34 (s, 2H), 2.85 (k, J=11.1 Hz, 1H), 2.06 (d, J=14.5 Hz , 1H), 1.96 (k, J=6.8 Hz, 2H), 1.86 (t, J=9.4 Hz, 1H), 1.63 (s, 2H), 1.44 (d, J=6.4 Hz, 10H), 1.36 (d , J=5.8 Hz, 7H), 1.27 (d, J=18.6 Hz, 3H), 0.65 (tq, J=8.3, 5.0, 4.1 Hz, 2H), 0.51-0.36 (m, 4H), 0.35-0.26 ( m, 1H), 0.24-0.14 (m, 2H), 0.130.04 (m, 2H). MS-ESI m/z calc. 769.3388, detected 770.45 (M+1) ⁺ ; Retention time: 0.91 min (LC method A).

Step 2: 8-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11,19,21pentaazatetracyclo[18.2.2.111 ,14.05,10]pentacose-1(22),5,7,9,20,23-hexaene-2,2,4-trione (compound 130)

- 200 044967

Solution of tert-butyl 4-[4-[[5-[[2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl]amino] butyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (415 mg, 0.5387 mmol) in dichloromethane (2 ml) and trifluoroacetic acid (614.2 mg, 412.2 μl, 5.387 mmol) was stirred at room temperature for 4 hours. Then the solvents evaporated. The residue was dissolved in ethyl acetate, washed with 2 ml of saturated sodium bicarbonate solution and the solvent was evaporated to leave a residue which was dissolved in dimethyl sulfoxide (5 ml). 3 A molecular sieves were added and the mixture was stirred for 10 minutes. Cesium fluoride (245.5 mg, 1.616 mmol) and potassium carbonate (223.3 mg, 1.616 mmol) were then added and the reaction mixture was heated at 160°C for 24 hours. The reaction mixture was filtered through a Whatman disc filter (puradisc 25 TF ), and the filtrate was purified by reverse phase HPLC-MS using a double 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 give 8-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2X ⁶ thia-3,9,11,19,21-pentaazatetracyclo[18.2 .2.111,14.05,10]pentacose-1(22),5,7,9,20,23-hexaene-2,2,4-trione (compound 130) (52 mg, 15%) as a white solid.

1H NMR (400 MHz, chloroform-d) δ 8.65 (s, 1H), 8.18 (d, J=2.8 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.3 Hz , 1H), 6.52 (d, J=9.1 Hz, 1H), 5.89 (d, J=2.8 Hz, 1H), 5.24 (s, 1H), 4.41 (t, J=6.8 Hz, 2H), 3.36 (s , 1H), 2.69 (s, 1H), 2.23 (s, 1H), 2.06 (brs, 1H), 1.97 (k, J=6.8 Hz, 2H), 1.78-1.71 (m, 3H), 1.66 (brs, 1H), 1.63 (brs, 1H), 1.60 (s, 3H), 1.58 (s, 3H), 1.20 (brs, 2H), 1.00 (brs, 2H), 0.66 (tq, J=8.7, 5.0, 4.3 Hz , 2H), 0.50-0.38 (m, 4H), 0.32 (dd, J=9.0, 6.9 Hz, 1H), 0.23-0.17 (m, 2H), 0.11 (m, 2H). MS-ESI m/z calc. 633.30975, detected 634.22 (M+1)+; Retention time: 1.66 min (LC method B).

Example 34: Preparation of 8-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2X ⁶ -thia3,9,11,19,24-pentaazatetracyclo[18.3.1.05 ,10.011,15]tetracose-1(23),5(10),6,8,20(24),21-hexaene-2,2,4trione (compound 131)

Step 1: tert-butyl 5-[3-[[6-[[2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl] amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

2-Chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (300 mg, 0.8291 mmol) and di(imidazol-1-yl)methanone (117.9 mg , 0.7272 mmol) were combined in tetrahydrofuran (2.5 ml) and stirred at room temperature for 16 hours. Tert-butyl-2,2dimethyl-5-[3-[(6-sulfamoyl-2-pyridyl)amino] was then added propyl]pyrrolidine-1-carboxylate (250.0 mg, 0.6060 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (138.4 mg, 136.0 μL, 0.9090 mmol) and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and then with brine. The organic phases were separated, dried over sodium sulfate, filtered and evaporated. The resulting brown residue was purified by silica gel chromatography using a gradient of 100% dichloromethane to 20% methanol in

- 201 044967 dichloromethane, to obtain tert-butyl 5-[3-[[6-[[2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl] - 2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (356 mg, 78%) as a white solid. MS-ESI m/z calc. 755.3232, detected 756.5 (M+1)+;

Retention time: 0.63 min (LC method A).

Step 2: 8-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11,19,24pentaazatetracyclo[18.3.1.05 ,10.011,15]tetracose-1 (23),5(10),6,8,20(24),21-hexaene-2,2,4-trione (compound 131)

Solution of tert-butyl 5-[3-[[6-[[2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl]amino] propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (356 mg,

0.4707 mmol) in dichloromethane (2 ml) and trifluoroacetic acid (536.7 mg, 360.2 μl, 4.707 mmol) were stirred at room temperature for 4 hours. The solvents were then evaporated. The residue was dissolved in ethyl acetate, washed with 2 ml of saturated aqueous sodium bicarbonate, the solvent was evaporated and dried under high vacuum. The resulting residue was dissolved in dimethyl sulfoxide (5 ml), 3 A molecular sieves were added and the reaction mixture was stirred for 10 minutes. Cesium fluoride (214.5 mg, 1.412 mmol) and potassium carbonate (195.1 mg, 1.412 mmol) were then added and the reaction mixture was heated at 150°C overnight. The reaction mixture was filtered through a Whatman disc filter (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS using a double gradient run of 50-90% mobile phase B for 15.0 min (mobile phase A = water (0. 05% hydrochloric acid), mobile phase B = acetonitrile) to obtain 8-[3-(3,3dicyclopropylpropoxy)-1 H-pyrazol-1 -yl]-12,12-dimethyl-2λ ⁶ -thia-3,9, 11,19,24pentaazatetracyclo[18.3.1.05,10.011,15]tetracose-1 (23),5(10),6,8,20(24),21-hexaene-2,2,4-trione (compound 131) (115 mg, 39%) as a white solid.

1H NMR (400 MHz, chloroform-d) δ (s, 1H), 8.47 (d, J=8.6 Hz, 1H), 8.26-8.06 (m, 1H), 7.66 (d, J=15.1 Hz, 1H), 7.51-7.40 (m, 2H), 6.45 (d, J=7.8 Hz, 1H), 5.95 (d, J=2.8 Hz, 1H), 4.82 (s, 1H), 4.43 (t, J=6.8 Hz, 2H ), 4.16 (d, J=72.4 Hz, 1H), 3.34 (s, 1H), 3.09 (s, 1H), 2.38 (d, J=8.4 Hz, 2H), 1.97 (k, J=6.8 Hz, 2H ), 1.65 (d, J=42.4 Hz, 8H), 1.15 (s, 2H), 0.95 (s, 1H), 0.66 (qt, J=8.3, 5.0 Hz, 2H), 0.53-0.37 (m, 4H) , 0.32 (tt, J=9.0, 6.8 Hz, 1H), 0.23-0.16 (m, 2H), 0.09 (dtd, J=9.0, 4.9, 3.4 Hz, 2H). MS-ESI m/z calc. 619.29407, found 620.17 (M+1) ⁺ ; Retention time: 1.61 min (LC method B).

Example 35: Preparation of 12,12,19-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-2λ ⁶ -thia-3,9,11,19 ,21-pentaazatetracyclo[18.2.2.111,14.05,10]pentacose1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (compound 132)

Step 1: tert-butyl 2,2-dimethyl-4-[4-(methylamino)butyl]pyrrolidine-1-carboxylate

To a 50 mL round bottom flask charged with tert-butyl 4-(4-aminobutyl)-2,2dimethylpyrrolidine-1-carboxylate (850 mg, 3.143 mmol) in dichloromethane (15 mL), add acetic anhydride (400 μL, 4.239 mmol ), followed by triethylamine (1000 µl, 7.175 mmol). The vessel was closed and the reaction

- 202 044967 tion mixture was stirred at room temperature for 45 minutes. The reaction was quenched with saturated aqueous sodium carbonate (~10 ml) and extracted with dichloromethane (3x ~ 15 ml). The combined organic extracts were washed with saturated aqueous sodium carbonate (2x ~ 10 ml), dried over sodium sulfate, filtered and concentrated in vacuo to obtain a clear oil, which was charged into a 100 ml round bottom flask and N,N-dimethylformamide (15 ml) was added. and then sodium hydride (200 mg 60% w/w, 5,000 mmol) and the reaction mixture was stirred for 30 min at room temperature. Iodomethane (800 µl, 12.85 mmol) was added, the vessel was sealed and the reaction mixture was stirred at 50°C for 48 hours. After cooling to room temperature, the reaction was quenched with water (~15 ml). The crude mixture was extracted with dichloromethane (3x25 ml) and the combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude reaction mixture was purified by silica gel column chromatography (0-30% ethyl acetate in hexanes gradient) to give a yellow oil, which was charged to a 100 mL round bottom flask and added methanol (30 mL) and potassium hydroxide (1.5 g, 26. 74 mmol). The flask was equipped with a reflux condenser and the reaction mixture was stirred at 80°C for 96 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate (~70 ml) and water (~30 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (3x20 ml). The combined organic extracts were washed with water (2 x 25 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give crude tert-butyl 2,2-dimethyl-4-[4-(methylamino)butyl]pyrrolidine-1-carboxylate (873 mg, 98%) as an orange/yellow oil, which was used without further purification. MS-ESI m/z calc. 284.24637, detected 285.2 (M+1)+; Retention time: 1.19 min (LC method B).

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

6-chloropyridine-3-sulfonamide (249 mg, 1.293 mmol), potassium carbonate (250 mg, 1.809 mmol) and dimethyl sulfoxide (4 ml). The headspace was purged with nitrogen, the tube was capped, and the reaction mixture was stirred at 120°C for 18 hours. After 18 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (~40 ml). The crude mixture was washed with water (10 ml) and brine (5 ml), and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude reaction mixture was purified by silica gel column chromatography (0-100% ethyl acetate in hexanes gradient) to give tert-butyl-2,2-dimethyl-4-[4-[methyl-(5-sulfamoyl-2pyridyl)amino]butyl ]pyrrolidine-1-carboxylate (143 mg, 26%) as an off-white solid. MS-ESI m/z calc. 440.24573, detected 441.2 (M+1) ⁺ ; Retention time: 1.6 min (LC method B).

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

Into a 20 ml vial filled with 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (136 mg, 0.3620 mmol) carbonyldiimidazole (59 mg, 0.3639 mmol) and tetrahydrofuran (2 ml) were added. The vessel was sealed and the reaction mixture was stirred at room temperature for 2 hours. At this point, tert-butyl-2,2dimethyl-4-[4-[methyl-(5-sulfamoyl-2-pyridyl)amino]butyl]pyrrolidine-1 was added -carboxylate (143 mg, 0.3246 mmol) in tetrahydrofuran (2 ml), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (75 μl, 0.5015 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction was then quenched with water (~4 ml) and 1 M aqueous citric acid (~4 ml), and the crude mixture was extracted with ethyl acetate (3x10 ml). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-100% ethyl acetate in hexanes gradient) to give tert-butyl-4-[4-[[5-[[2-chloro-6-[3-[2-[1( trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2-203 044967 pyridyl]methylamino]butyl]-2,2-dimethylpyrrolidin-1-carboxylate (167 mg, 64%) as off-white solid. MS-ESI m/z calc. 797.2949, detected 798.4 (M+1)+; Retention time: 2.35 min (LC method B).

Stage

4:

2-chloro-N-[[6-[4-(5,5-dimethylpyrrolidin-3-yl)butyl-methyl-amino]-3pyridyl]sulfonyl]-6-[3-[2-[1 -(trifluoromethyl) cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3 carboxamide (dihydrochloride salt)

In a 20 ml bottle filled with tert-butyl-4-[4-[[5-[[2-chloro-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine CH ₂ Cl ₂ (5 ml) and hydrochloric acid (1 ml 4, 0 M, 4,000 mmol) in dioxane. The vessel was sealed and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo to give crude 2-chloro-N-[[6-[4-(5,5-dimethylpyrrolidin-3yl)butylmethylamino]-3- pyridyl]sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1 yl]pyridine-3-carboxamide (dihydrochloride salt) (147 mg, 91%) as a pale yellow solid substances that were used without further purification. MS-ESI m/z calc. 697.2425, detected 698.4 (M+1) ⁺ ; Retention time: 1.69 min (LC method B).

Step 5: 12,12,19-trimethyl-8-(3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-2λ ⁶ thia-3,9,11, 19,21-pentaazatetracyclo[18.2.2.111,14.05,10]pentacose-1(23),5,7,9,20(24),21-hexaene-2,2,4trione (compound 132)

In a 20 ml bottle filled with 2-chloro-N-[[6-[4-(5,5-dimethyln-pyrrolidin-3yl)butylmethylamino]-3-pyridyl]sulfonyl]-6-[3-[2-[1 - (trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1 yl]pyridine-3-carboxamide (dihydrochloride salt) (147 mg, 0.2105 mmol) added potassium carbonate (152 mg, 1.100 mmol), CsF (96 mg, 0.6320 mmol ) and dimethyl sulfoxide (5 ml). The headspace was purged with nitrogen, the tube was capped, and the reaction mixture was stirred at 150°C for 18 hours. After cooling to room temperature, the solids were filtered off with ethyl acetate eluent, the crude mixture was diluted with ethyl acetate (~35 ml), washed with 1.0 M aqueous citric acid. acid (2x5 ml), saline (5 ml), the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica, gradient from 0% to 5% methanol in dichloromethane) gave 12,12,19-trimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazole-1 -yl)-2λ ⁶ -thia-3,9,11,19,21 pentaazatetracyclo[18.2.2.111,14.05,10]pentacose-1(23),5,7,9,20(24),21-hexaene- 2,2,4-trione (dihydrochloride salt) (compound 132) (64 mg, 39%) as an off-white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.19 (s, 1H), 8.18 (d, J=2.8 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 6.90 (d, J=8.3 Hz, 1H), 6.81 (s, 1H), 6.10 (d, J=2.7 Hz, 1H), 4.31 (t, J=7.0 Hz, 2H), 2.98 (d, J=7.8 Hz, 3H), 2.37 ( s, 1H), 2.07 (t, J=7.1 Hz, 4H), 1.78-1.68 (m, 1H), 1.52 (s, 8H), 1.39 (d, J=51.3 Hz, 2H), 1.27-1.05 (m , 2H), 1.04-0.75 (m, 6H). MS-ESI m/z calc. 661.2658, detected 662.4 (M+1) ⁺ ; Retention time: 1.84 min (LC method B).

Example 36: Preparation of 12,12,18-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclononyl]ethoxy}-1Hπyrazol-1-yl)-2λ ⁶ -thia-3,9,11,18 ,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (compound 133)

- 204 044967

Step 1: tert-butyl 2,2-dimethyl-4-[3-(methylamino)propyl]pyrrolidine-1-carboxylate

To a 50 mL flask charged with tert-butyl 4-(3-aminopropyl)-2,2-dimethylpyrrolidine-1carboxylate (869 mg, 3.389 mmol) in dichloromethane (15 mL), add acetic anhydride (527.3 mg, 487 .3 µl, 5.165 mmol), then Et ₃ N (884.8 mg, 1.219 ml, 8.744 mmol). The vessel was sealed and the reaction mixture was stirred at room temperature for 45 min, then quenched with saturated aqueous sodium carbonate (~10 ml) and extracted with dichloromethane (3x ~ 15 ml). The combined organic extracts were washed with saturated aqueous sodium carbonate (2x ~ 10 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give the crude acetate, which was combined with N,N-dimethylformamide (15 ml), followed by the addition of NaH (225 mg 60% wt., 5.626 mmol) and the reaction mixture was stirred for 30 ml at room temperature. Iodomethane (1000 µl, 16.06 mmol) was added, the vessel was sealed and the reaction mixture was stirred at 50°C for 48 hours. After cooling to room temperature, the reaction was quenched with water (~15 ml) and the crude mixture was extracted with dichloromethane (3x25 ml). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 0% to 30% ethyl acetate in hexanes) provided the methylated acetate intermediate to which methanol (30 mL) and KOH (1.5 g, 26.74 mmol) were added. The flask was equipped with a reflux condenser and the reaction mixture was stirred at 80°C for 96 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate (~70 ml) and water (~30 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (3x20 ml). The combined organic extracts were washed with water (2 x 25 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give tert-butyl 2,2-dimethyl-4-[3-(methylamino)propyl]pyrrolidine-1-carboxylate (889 mg, 97 %) as an orange/yellow oil, which was used without further purification. MS-ESI m/z calc. 270.23074, detected 271.2 (M+1)+; Retention time: 1.1 min (LC method B).

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

To a solution of tert-butyl-2,2-dimethyl-4-[3-(methylamino)propyl]pyrrolidine-1-carboxylate (154 mg, 0.5695 mmol) in dimethyl sulfoxide (2 ml) was added 6-fluoropyridine-2-sulfonamide (103 mg, 0.5847 mmol) and then diisopropylethylamine (500 μl, 2.871 mmol). The flask was sealed and heated at 90°C under nitrogen in an oil bath for 14 hours. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate and washed with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by chromatography on silica gel (80 g column) using a gradient system from 100% hexanes to 100%

- 205 044967 ethyl acetate to obtain tert-butyl 2,2-dimethyl-4-[3-[methyl-(6-sulfamoyl-2pyridyl)amino]propyl]pyrrolidine-1-carboxylate (141 mg, 58%) as a white solid substances.

^1H NMR (400 MHz, DMSO-de) δ 7.65 (dd, J=8.6, 7.2 Hz, 1H), 7.12 (s, 2H), 7.01 (d, J=7.2 Hz, 1H), 6.78 (d, J =8.7 Hz, 1H), 3.53 (k, J=7.8, 7.4 Hz, 3H), 3.17 (d, J=3.6 Hz, 1H), 3.04 (s, 3H), 2.84-2.72 (m, 1H), 2.09 (d, J=9.5 Hz, 1H), 1.88 (td, J=12.8, 5.7 Hz, 1H), 1.53 (dt, J=14.6, 7.4 Hz, 2H), 1.36 (dd, J=15.0, 10.6 Hz, 14H), 1.23 (s, 3H). MS-ESI m/z calc. 426.23007, detected 427.3 (M+1)+; retention time: 0.47 min (LC method A).

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

In a 20 ml scintillation vial, 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (264 mg, 0.7026 mmol) and carbonyl diimidazole (114 mg, 0.7031 mmol) was combined in tetrahydrofuran (2.2 ml) and stirred for 120 min at 50 °C without lid. Tert-butyl 2,2-dimethyl-4-[3-[methyl-(6-sulfamoyl-2pyridyl)amino]propyl]pyrrolidine-1-carboxylate (130 mg, 0.3048 mmol) in tetrahydrofuran (3 ml) was then added ), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (92.80 mg, 91.16 μL, 0.6096 mmol). The reaction was heated at 50°C for 16 hours. The reaction was diluted with ethyl acetate (25 ml) and washed with saturated aqueous ammonium chloride (25 ml) followed by saline (25 ml). The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The crude material was then purified by silica gel chromatography using a shallow gradient from 100% dichloromethane to 20% methanol in dichloromethane. The product (still contaminated with 7% SM) was dissolved in ethyl acetate (50 ml) and washed with saturated aqueous sodium bicarbonate (2x50 ml), dried over sodium sulfate, filtered and concentrated to give tert-butyl-4-[3-[[6- [[2-chloro-6-[3-[2-[1 -(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]methyl-amino]propyl] -2 ,2-dimethylpyrrolidine-1 carboxylate (141 mg, 55%, 93% purity) as a light yellow solid.

1H NMR (400 MHz, DMSO-de) δ 8.40 (k, J=4.2, 3.6 Hz, 1H), 8.16-8.06 (m, 1H), 7.79-7.67 (m, 2H), 7.22 (d, J=7.3 Hz, 1H), 6.92 (d, J=8.7 Hz, 1H), 6.22-6.14 (m, 1H), 4.35 (t, J=7.0 Hz, 2H), 3.49 (dd, J=32.6, 9.1 Hz, 3H ), 3.03 (s, 3H), 2.71 (t, J=10.5 Hz, 1H), 2.10 (k, J=7.3 Hz, 3H), 2.00 (s, 2H), 1.85-1.66 (m, 1H), 1.50 (k, J=7.7 Hz, 1H), 1.43-1.31 (m, 9H), 1.27 (t, J=10.5 Hz, 4H), 1.05-0.82 (m, 5H). MS-ESI m/z calc. 783.27924, detected 784.42 (M+1) ⁺ ; Retention time: 2.52 min (LC method B).

Step 4: 2-chloro-N-[[e-[3-(5,5-dimethylpyrrolidin-3-yl)propyl-methyl-amino]-2pyridyl]sulfonyl]-6-[3-[2-[ 1 - (trifluoromethyl)cyclopropyl] ethoxy] pyrazol-1 -yl] pyridin-3 carboxamide

To a solution of tert-butyl 4-[3-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl] -2-pyridyl]-methyl-amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (141 mg, 0.168 mmol, 93% purity) in dichloromethane (2 ml) was added trifluoroacetic acid (1.390 g, 939.2 μl , 12.19 mmol). The reaction mixture was stirred at room temperature for 2 hours, and then the mixture was concentrated to dryness. The crude product was treated with saturated sodium bicarbonate and then extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-chloro-N-[[e-[3-(5,5dimethylpyrrolidin-3-yl)propyl-methyl-amino]-2-pyridyl]sulfonyl] -6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (100 mg, 48%). MS-ESI m/z calc. 683.2268, detected 684.32 (M+1) ⁺ ; Retention time: 1.72 min (LC method B).

Step 5: 12,12,18-trimethyl-8-(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-2λ ^e thia-3,9,11, 18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4trione (compound 133)

- 206 044967

A mixture of 2-ΧΛορ-Ν-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propyl-methyl-amino]-2-pyridyl]sulfonyl] 6-[3-[2-[1-( trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (83 mg, 0.1213 mmol), potassium carbonate (100 mg, 0.7236 mmol), cesium fluoride (22 mg, 0.1448 mmol) and a small amount of 3 A molecular sieves in dimethyl sulfoxide (4 ml) were sealed and heated to 165°C for 4 hours. 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 fine gradient silica gel chromatography from 100% dichloromethane to 20% methanol in dichloromethane to give 12,12,18trimethyl-8-(3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1 -yl)-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5 (10),6,8,19,21-hexaene-2,2,4-trione (compound 133) (32.9 mg, 42%) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.22 (d, J=2.8 Hz, 1H), 7.78 (dd, J=12.5, 8.0 Hz, 2H), 7.19 (d, J=7.3 Hz, 1H), 6.91 (t, J=8.2 Hz, 2H), 6.12 (d, J=2.7 Hz, 1H), 4.52 (s, 1H), 4.32 (t, J=7.0 Hz, 2H), 3.14 (m, 1H), 2.92 (m, 4H), 2.70 (d, J=17.7 Hz, 1H), 2.08 (m, J=7.1 Hz, 3H), 1.94-1.75 (m, 1H), 1.61 (s, 3H), 1.49(m , J=13.1 Hz, 5H), 1.34 (m, 1H), 1.15-0.77 (m, 5H). MS-ESI m/z calc. 647.2502, detected 648.1 (M+1)+; Retention time: 2.29 min (LC method B).

Example 37: Preparation of 8-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ ⁶ -thia3,9,11,19,24-pentaazatetracyclo[18.3.1.05 ,10.011,15]tetracose-1(23),5(10),6,8,20(24),21-hexaene-2,2,4trione (enantiomer 1) (compound 136) and 8-[3-( 3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12dimethyl-2λ ⁶ -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.05,10.011.15]tetracose-1(23 ),5(10),6,8,20(24),21hexaene-2,2,4-trione (enantiomer 2) (compound 137)

Step 1: 8-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11,19,24pentaazatetracyclo[18.3.1.05, 10.011,15]tetracose-1(23),5(10),6,8,20(24),21-hexaene-2,2,4-trione (enantiomer 1) (compound 136) and 8-[3- (3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ ⁶ -thia3,9,11,19,24-pentaazatetracyclo[18.3.1.05,10.011,15]tetracose-1( 23),5(10),6,8,20(24),21-hexaene-2,2,4trione (enantiomer 2) (compound 137)

Racemic 8-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ ⁶ -thia3,9,11,19,24-pentaazatetracyclo[18.3.1.05,10.011 ,15]tetracose-1(23),5(10),6,8,20(24), 21-hexaene-2,2,4trione (115 mg) was subjected to chiral separation by SCLC chromatography using Phenomenex LUX - 4 (250x21.2 mm), particle size 5 µm, with mobile phase 60% methanol, 40% carbon dioxide at 70 ml/min for 8.0 min (injection volume = 500 µl ~ 30 mg/ml in methanol mixture: acetonitrile: dimethyl sulfoxide (40:40:20)) to obtain 8[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ ⁶ - as the first eluted enantiomer thia-3,9,11,19,24pentaazatetracyclo[18.3.1.05,10.011,15]tetracose-1(23),5(10),6,8,20 (24),21-hexaene-2,2,4 -trione (enantiomer 1) (compound 136) (34.1 mg, 29%) as a white solid;

1H NMR (400 MHz, chloroform-d) δ 14.55 (s, 1H), 8.47 (d, J=8.6 Hz, 1H), 8.16 (d, J=33.0 Hz, 1H), 7.68 (s, 1H), 7.53 -7.39 (m, 2H), 6.45 (d, J=7.9 Hz, 1H), 5.96 (d, J=2.8 Hz, 1H), 4.77 (s, 1H), 4.44 (t, J=6.8 Hz, 2H) , 4.16 (d, J=64.7 Hz, 1H), 3.36 (s, 1H), 3.20-2.90 (m, 1H), 2.38 (d, J=8.1 Hz, 2H), 1.97 (k, J=6.8 Hz, 3H), 1.72 (s, 1H), 1.57 (broad s, 4H), 1.36-1.02 (m, 3H), 1.01-0.82 (m, 2H), 0.66 (ddt, J=13.4, 8.8, 4.2 Hz, 2H), 0.52-0.38 (m, 4H), 0.37-0.29 (m, 1H), 0.23-0.16 (m, 2H), 0.10 (dt, J=9.4, 4.5 Hz, 2H), MS-ESI m/z calc. 619.29407, detected 620.17 (M+1) ⁺ ; Retention time: 1.82 min (LC method B), and as the second enantiomer eluted, 8-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]12,12-dimethyl-2λ ⁶ -thia -3,9,11,19,24-pentaazatetracyclo[18.3.1.05,10.011,15]tetracose-1(23),5(10),6,8,20 (24), 21-hexaene-2,2, 4-trione (enantiomer 2) (compound 137) (24.5 mg, 17%) as a white solid

- 207 044967 society;

1H NMR (400 MHz, chloroform-d) δ 14.55 (s, 1H), 8.47 (d, J=8.6 Hz, 1H), 8.16 (d, J=32.4 Hz, 1H), 7.68 (s, 1H), 7.52 -7.40 (m, 2H), 6.45 (d, J=8.0 Hz, 1H), 5.96 (d, J=2.8 Hz, 1H), 4.77 (s, 1H), 4.44 (t, J=6.8 Hz, 2H) , 4.16 (d, J=70.4 Hz, 1H), 3.49 (s, 1H), 3.03 (d, J=51.3 Hz, 1H), 1.97 (k, J=6.8 Hz, 2H), 1.72 (s, 2H) , 1.56 (s, 4H), 1.27 (d, J=15.3 Hz, 5H), 1.02-0.85 (m, 2H), 0.66 (ddt, J=13.4, 8.6, 4.2 Hz, 2H), 0.51-0.38 (m , 4H), 0.36-0.27 (m, 1H), 0.25-0.15 (m, 2H), 0.15-0.05 (m, 2H), MS-ESI m/z calc. 619.29407, found 620.17 (M+1)+; Retention time: 1.82 min (LC method B).

Example 38: Preparation of (14S)-8-[3-(4,4-dimethylnentyl)-2-oxopyrrolidin-1-yl]-12,12-dimethyl-2λ ⁶ thia-3,9,11,18,23- pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4trione (diastereomer 1) (compound 145) and (14S)- 8-[3-(4,4-dimethylpentyl)-2-oxonirrolidin-1-yl]12,12-dimethyl-2X ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05, 10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 2) (compound 146)

LLC 000

diastereomer 1 diastereomer 2

Step 1: (14S)-8-[3-(4,4-dimethylpentyl)-2-oxopyrrolidin-1-yl]-12,12-dimethyl-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 1) (compound 145) and (14S)- 8-[3-(4,4-dimethylpentyl)-2-oxonirrolidin-1-yl]-12,12dimethyl-2Х ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10 ]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (diastereomer 2) (compound 146) o o o

diastereomer 1 diastereomer 2

(14S)-8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23) was loaded into a 4-ml ampoule. 5,7,9,19,21-hexaene-2,2,4-trione (148 mg, 0.3181 mmol), 3-(4,4-dimethylpentyl)pyrrolidin-2-one (86 mg, 0.4692 mmol), Pd ₂ (dba) ₃ (92 mg, 0.1005 mmol), xanthos (58 mg, 0.1002 mmol), cesium carbonate (623 mg, 1.912 mmol) and anhydrous dioxane (3 ml). The mixture was purged with nitrogen for 2 minutes, capped and stirred at 120°C for 21 hours. After cooling to room temperature, the solids were filtered and washed with ethyl acetate, and the resulting filtrate was concentrated in vacuo. The crude reaction mixture was purified by silica gel column chromatography (0-5% methanol in dichloromethane gradient) to obtain 54 mg of product as a mixture of diastereomers, an off-white solid. The mixture of diastereomers was purified by chiral SCLC using ChiralCel OJ-H (250 x 10 mm column, 5 μm particle size) with a mobile phase of 18% acetonitrile/methanol (90:10; no modifier)/82% carbon dioxide at 10 mL/min for 10.0 min (injection volume = 70 μl of a 24 mg/ml solution in methanol:dimethyl sulfoxide (90:10)) yielding (14S)-8-[3-(4,4-dimethylpentyl)-2oxopyrrolidine as the first diastereomer eluted -1 -yl]-12,12-dimethyl-2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19( 23),20-hexaene-2,2,4-trione (diastereomer 1) (compound 145) (19 mg, 10%);

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.38 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.04 (d, J=7.2 Hz, 1H), 6.96 (broadened d, J=8.0 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 4.05 (t, J=9.4 Hz , 1H), 3.91 (broadened d, J=10.7 Hz, 1H), 3.75 (k, J=9.3, 8.7 Hz, 1H), 3.11 (broadened s, 1H), 2.94 (broadened d, J=13.3 Hz , 1H), 2.82-2.56 (m, 2H), 2.30-2.17 (m, 1H), 2.10 (broad s, 1H), 1.87-1.67 (m, 4H), 1.64-1.41 (m, 9H), 1.41 -1.27 (m, 4H), 1.25-1.13 (m, 2H), 0.87 (s, 9H). MS-ESI m/z calc. 596.31445, detected 597.3 (M+1) ⁺ ;

- 208 044967

Retention time: 2.32 min (LC method B), and as the second diastereomer eluted (14S)-8-[3-(4,4-dimethylnentyl)-2-oxopyrrolidin1 -yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4- trion (diastereomer 2) (compound 146), ¹ H NMR δ 12.38 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.52 (d, J =8.4 Hz, 1H), 7.04 (d, J=7.2 Hz, 1H), 6.96 (broadened d, J=8.0 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 4.05 (t, J= 9.4 Hz, 1H), 3.91 (broadened d, J=10.7 Hz, 1H), 3.75 (broadened, J=9.3, 8.7 Hz, 1H), 3.11 (broadened s, 1H), 2.94 (broadened d, J= 13.3 Hz, 1H), 2.822.56 (m, 2H), 2.30-2.17 (m, 1H), 2.10 (broad s, 1H), 1.87-1.67 (m, 4H), 1.64-1.41 (m, 9H) , 1.41-1.27 (m, 4H), 1.25-1.13 (m, 2H), 0.87 (s, 9H). MS-ESI m/z calc. 596.31445, found 597.3 (M+1)+; Retention time: 2.32 min (LC method B), and as the second diastereomer eluted, (148)-8-[3-(4,4-dimethylpentyl)-2-oxopyrrolidin1 -yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diatereomer 2) (compound 146) (15 mg, 8%);

1H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 12.41 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.61-7.50 (m, 2H), 7.03 (d, J=7.2 Hz, 1H), 6.92 (d, J=27.7 Hz, 1H), 6.69 (d, J=8.5 Hz, 1H), 3, 94 (t, J=9.4 Hz, 2H), 3.82 (kv, J=9.1 Hz, 1H), 3.09 (s, 1H), 2.93 (d, J=13.3 Hz, 1H), 2.68 (t, J=10.9 Hz, 2H), 2.25 (kv, J=8.8 Hz, 1H), 2.08 (d, J=8.3 Hz, 1H), 1.86-1.63 (m, 4H), 1.57 (s, 4H), 1.52 (d, J=4.2 Hz, 1H), 1.46 (s, 3H), 1.41-1.08 (m, 7H) 0.86 (s, 9H); MS-ESI m/z calc. 596.31445, detected 597.3 (M+1) ⁺ ; Retention time: 2.33 min (LC method B).

Example 39: Preparation of 12,12,22-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-2λ ⁶ -thia-3,9,11,18 ,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (enantiomer 1) (compound 148) and 12 ,12,22-trimethyl-8-(3-{2[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3 .1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (enantiomer 2) (compound 149)

Step 1: 12,12,22-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclononyl]ethoxy}-1H-pyrazol-1-yl)-2λ ⁶ thia-3,9,11,18 ,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4trione (enantiomer 1) (compound 148) and 12 ,12,22-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]tetracose1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (enantiomer 2) (compound 149)

Racemic 12,12,22-trimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 yl)-2λ ⁶ -thia-3,9,11,18, 23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene2,2,4-trione (85 mg, 0.1299 mmol) was exposed to chiral SLC chromatography. The following LCLC protocol was used: ChiralPak AS-3 (150x2.1 mm), 3 µm; Mobile phase 35°C: 30% acetonitrile:methanol (90:10), 70% carbon dioxide. The first enantiomer eluted was 12,12,22-trimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ ⁶ -thia3,9,11,18 ,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (enantiomer 1) (compound 148) (34 mg, 40%). MS-ESI m/z calc. 647.2502, detected 648.34 (M+1) ⁺ ; retention time: 2.24 min (LC method B).

The second enantiomer eluted was 12,12,22-trimethyl-8-(3-{2-[1(trifluoromethyl)cyclononyl]ethoxy}-1H-pyrazol-1-yl)-2λ ⁶ -thia-3,9,11, 18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (enantiomer 2) (compound 149) ( 35 mg, 41%).

1H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.23 (d, J=2.8 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.41 (d, J=8.5 Hz , 1H), 6.93 (d, J=8.2 Hz, 1H), 6.65 (d, J=8.6 Hz, 2H), 6.12 (d, J=2.7 Hz, 1H), 4.32 (t, J=7.0 Hz, 2H ), 4.00-3.79 (m, 1H), 3.27-3.14 (m, 1H), 2.93 (d, J=13.2 Hz, 1H), 2.84 (t, J=10.5 Hz, 1H), 2.36 (s, 3H) , 2.08 (t, J=7.1 Hz, 2H), 1.87 (dd, J=11.6, 5.2 Hz, 1H), 1.77 (m, 1H), 1.57 (d, J=35.9 Hz, 8H), 1.44-1.29 ( m, 1H), 0.96 (d, J=4.4 Hz, 2H), 0.91 (d, J=13.2 Hz, 3H). MS-ESI m/z calc. 647.2502, detected 648.34 (M+1) ⁺ ; retention time: 2.25 min (LC method B).

Example 40: Preparation of 4-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-20,20-dimethyl10λ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111 ,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (enantiomer 1) (compound 153) and 4-[3-(3,3-dicyclopropylpropoxy) -1H-pyrazol-1-yl]-20,20-dimethyl- 209 044967

10λ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11 (22), 12-pentaene-8,10,10-trione ( enantiomer 2) (compound 154)

Step 1: tert-butyl 4-[3-[3-[[2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]pyrazol-1-yl] propyl] -2, 2-dimethyl-pyrrolidine-1-carboxylate o?

2-Chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridin-3-carboxylic acid (521 mg, 1.440 mmol) and carbonyldiimidazole (237 mg, 1.462 mmol) were combined in tetrahydrofuran (5, 0 ml) and stirred for 2 hours at room temperature. Tert-butyl 2,2-dimethyl-4-[3(3-sulfamoylpyrazol-1-yl)propyl]pyrrolidine-1-carboxylate (460 mg, 1,190 mmol) was then added followed by 1,8diazabicyclo[5.4.0] undec-7-ene (280 μl, 1.872 mmol), and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and then with brine. The organic phases were separated, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient of 100% dichloromethane to 20% methanol in dichloromethane to give tert-butyl-4-[3-[3[[2-chloro-6-[3-(3,3-dicyclopropylpropoxy) pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]pyrazol-1yl]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (270 mg, 31%) as a white solid.

Ή NMR (400 MHz, chloroform-d) δ 9.61 (d, J=95.1 Hz, 1H), 8.30 (d, J=2.9 Hz, 1H), 8.24 (t, J=8.9 Hz, 1H), 7.75 (d , J=8.4 Hz, 1H), 7.47 (d, J=2.6 Hz, 1H), 7.05 (d, J=2.3 Hz, 1H), 5.97 (d, J=2.9 Hz, 1H), 4.43 (t, J =6.8 Hz, 2H), 4.20 (t, J=7.1 Hz, 2H), 3.78-3.54 (m, 1H), 2.84 (t, J=10.1 Hz, 1H), 2.07 (s, 1H), 1.97 (k , J=6.8 Hz, 2H), 1.93-1.81 (m, 1H), 1.63 (s, 5H), 1.43 (d, J=4.7 Hz, 9H), 1.37-1.23 (m, 6H), 0.72-0.61 ( m, 2H), 0.50-0.38 (m, 4H), 0.33 (tt, J=9.0, 6.8 Hz, 1H), 0.20 (dtd, J=8.2, 4.9, 3.5 Hz, 2H), 0.10 (ddd, J= 9.3, 4.8, 3.5 Hz, 2H). MSIE m/z calc. 729.30756, detected 730.4 (M+1)+; retention time: 0.92 min (LC method A).

Step 2: 4-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-20,20-dimethyl- ^10X6 -thia-1,3,9,14,22pentaazatetracyclo[16.2.1.111 ,14.02,7]docose-2,4,6,11 (22),12-pentaene-8,10,10-trione

Tert-butyl-4-[3-[3-[[2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]pyrazol-1-yl]propyl solution ]-2,2-dimethylpyrrolidine-1-carboxylate (270 mg, 0.3697 mmol) in dichloromethane (1.862 ml) and trifluoroacetic acid (300 μl, 3.920 mmol) was stirred at room temperature for 4 hours. The solvents were then removed in vacuo . The residue was dissolved in ethyl acetate, washed with 2 ml of saturated sodium bicarbonate solution and the solvent was evaporated. The resulting residue was dissolved in dimethyl sulfoxide (5.586 ml), 3 A molecular sieves were added and the reaction mixture was stirred for 10 minutes. Cesium fluoride (171 mg, 1.126 mmol) and potassium carbonate (158 mg, 1.143 mmol) were then added and the reaction mixture was heated at 150°C overnight. The reaction mixture was filtered through a Whatman disc filter (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS using a double gradient run of 50-99% mobile phase B over 15.0 min (mobile phase A = water (0. 05% hydrochloric acid), mobile phase B = acetonitrile) to obtain racemic 4-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]20,20-dimethyl-10λ ⁶ -thia-1,3 ,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene8,10,10-trione (50 mg, 23%) as a white solid substances. MS-ESI m/z calc. 593.27844, detected 594.4 (M+1) ⁺ ; retention time: 2.36 min (LC method B).

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Step 3: 4-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-20,20-dimethyl-10λ ⁶ -thia-1,3,9,14,22pentaazatetracyclo[16.2.1.111, 14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (enantiomer

1)(compound 153) and 4-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-20,20-dimethyl-10λ ⁶ -thia1,3,9,14,22-pentaazatetracyclo[ 16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (enantiomer 2) (compound 154)

Racemic 4-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-20,20-dimethyl-10λ ⁶ -thia1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02, 7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (50 mg) was subjected to chiral separation by SLC chromatography using a ChiralPak AS-H column (250x10 mm), Particle size 5 µm) with a mobile phase of 28% acetonitrile/methanol (90:10)/72% carbon dioxide at 10 ml/min for 8.0 min (injection volume = 70 µl solution of ~ 24 mg/ml in acetonitrile/methanol /dimethyl sulfoxide (82:8:10)) to obtain 4-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-20,20-dimethyl-10λ ⁶ -thia1 as the first eluted enantiomer, 3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11 (22),12-pentaene-8,10,10-trione (enantiomer 1) (compound 153) (20 mg, 18%);

¹ H NMR (400 MHz, chloroform-d) δ 8.63 (s, 1H), 8.17 (d, J=2.7 Hz, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.47 (d, J=2.3 Hz, 1H), 7.07 (d, J=2.3 Hz, 1H), 7.02 (d, J=8.2 Hz, 1H), 5.87 (d, J=2.7 Hz, 1H), 4.42 (t, J=6.8 Hz, 2H), 4.33 (dt, J=13.3, 3.4 Hz, 1H), 4.00-3.85 (m, 1H), 2.74 (t, J=8.1 Hz, 1H), 2.12 (ttd, J=14.6, 10.0, 8.8, 4.7 Hz, 2H), 2.01-1.94 (m, 2H), 1.81-1.70 (m, 1H), 1.58 (s, 3H), 1.55 (s, 3H), 1.47 (t, J=12.2 Hz, 1H), 0.87-0.71 (m, 0H), 0.71-0.61 (m, 2H), 0.53-0.39 (m, 4H), 0.37-0.30 (m, 1H), 0.24-0.15 (m, 2H), 0.15-0.07 (m , 2H), MS-ESI m/z calc. 593.27844, detected 594.4 (M+1)+; Retention time: 2.39 min (LC method B) and as the second enantiomer eluted 4-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]20,20-dimethyl-10λ ⁶ -thia- 1,3,9,14,22 pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene8,10,10-trione (enantiomer 2) (compound 154) ( 23.6 mg, 47%) as a white solid;

1H NMR (400 MHz, chloroform-d) δ 8.16 (d, J=2.7 Hz, 1H), 7.65 (d, J=8.3 Hz, 1H), 7.46 (d, J=2.4 Hz, 1H), 7.06 (d , J=2.3 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H), 5.87 (d, J=2.7 Hz, 1H), 4.42 (t, J=6.8 Hz, 2H), 4.32 (d, J =13.5 Hz, 1H), 4.00-3.83 (m, 1H), 2.73 (t, J=8.1 Hz, 1H), 2.23-2.09 (m, 2H), 1.97 (k, J=6.9 Hz, 3H), 1.74 (dd, J=11.9, 5.2 Hz, 1H), 1.58 (s, 4H), 1.54 (s, 3H), 1.51-1.41 (m, 2H), 0.86-0.72 (m, 1H), 0.71-0.61 (m , 2H), 0.45 (dddd, J=15.6, 8.1, 4.9, 3.7 Hz, 4H), 0.38-0.30 (m, 1H), 0.25-0.18 (m, 2H), 0.12 (ddtd, J=11.4, 5.2, 3.7, 3.1, 1.9 Hz, 2H). MS-ESI m/z calc. 593.27844, detected 594.4 (M+1)+; Retention time: 2.39 min (LC method B).

Example 41: Preparation of 12,12-dimethyl-8-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1Hpyrazol-1-yl)-15-oxa-2λ ⁶ -thia-3,9,11 ,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5,7,9,19,21-hexaene-2,2,4-trione (enantiomer 1) (compound 159) and 12, 12-dimethyl-8-(3-{3-[1(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1-yl)-15-oxa-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,2,4-trione (enantiomer 2) (compound 160)

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Step 1: 2-[1-(trifluoromethyl)cyclopropyl]ethyl methanesulfonate I 0=5=0 ----* F ₃ C^\^O

A 1000 mL three-neck round bottom flask was equipped with a mechanical stirrer, cooling bath, J-Kem temperature probe, addition funnel, and nitrogen inlet/outlet. 2-[1-(trifluoromethyl)cyclopropyl]ethanol (125 g, 811.0 mmol) and 2methyltetrahydrofuran (625 ml) were charged into a vessel under a nitrogen atmosphere to give a clear, colorless solution. Stirring was started and the temperature in the vessel was recorded at 19°C. The vessel was then charged with triethylamine (124.3 mL, 891.8 mmol), added neat in one portion. Then crushed ice/water was loaded into the cooling bath and the temperature in the container was lowered to 0°C. A solution of methanesulfonyl chloride (62.77 ml, 811.0 mmol) in 2-methyltetrahydrofuran (125 ml, 2 ml/g) was loaded into the addition funnel, which was then added dropwise over 90 min, resulting in the formation of a white suspension and an exothermic reaction up to 1°C. The mixture was allowed to slowly warm to room temperature and stirring continued at room temperature for 1 hour, after which the mixture was poured into ice water (250 ml) and then transferred to a separatory funnel. The organic layer was removed and washed with 20 wt.% potassium bicarbonate solution (250 ml), dried over sodium sulfate (200 g) and then filtered through a Buchner funnel with a glass frit. The clear filtrate was concentrated under reduced pressure to give 2-[1-(trifluoromethyl)cyclopropyl]ethylmethanesulfonate (185 g, 98%) as a clear pale yellow oil.

¹ H NMR (400 MHz, chloroform-d) δ 4.36 (ddt, J=7,l, 6.4, 0.7 Hz, 2H), 3.02 (s, 3H), 2.03 (t , J=7.1 Hz, 2H), 1.11-0.98 (m, 2H), 0.81-0.66 (m, 2H).

Step 2: 3-[1-(trifluoromethyl)cyclopropyl]propanenitrile

A 1000 mL three-neck round bottom flask was equipped with a mechanical stirrer, heating hood, J-Kem temperature sensor/controller, water-cooled reflux condenser, and nitrogen inlet/outlet. 2-[1(trifluoromethyl)cyclopropyl]ethylmethanesulfonate (50 g, 215.3 mmol) and dimethyl sulfoxide (250 ml) were charged into a vessel under a nitrogen atmosphere to give a clear, pale yellow solution. Stirring was started and the temperature in the vessel was recorded at 19°C. The vessel was charged with sodium cyanide (13.19 g, 269.1 mmol), added as a solid in one portion. The mixture was heated to a temperature of 70°C and the conditions were maintained for 24 hours. Upon heating, all the sodium cyanide dissolved and the reaction mixture turned into a light amber suspension. After cooling to room temperature, the reaction mixture was poured into water (500 ml) and then transferred to a separatory funnel and partitioned with methyl tert-butyl ether (500 ml). The organic layer was removed and the residual aqueous layer was extracted with methyl tert-butyl ether (3x250 ml). The combined organic layers were washed with water (2x250 ml), dried over sodium sulfate (200 g) and then filtered through a Buchner funnel with a glass frit. The clear filtrate was concentrated under reduced pressure to give 3-[1(trifluoromethyl)cyclopropyl]propanenitrile (30 g, 85%) as a clear amber oil.

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1H NMR (400 MHz, chloroform-d) δ 2.55 (t, J=7.6 Hz, 2H), 1.93 (t, J=7.7 Hz, 2H), 1.11-1.04 (m, 2H),

0.78-0.70 (m, 2H).

Stage 3: 3-[1-(trifluoromethyl)cyclopropyl]propionic acid O _______ I ₃ C ,.··^ D Δ ^₽ /C

A 1000 mL three-neck round bottom flask was equipped with a mechanical stirrer, heating hood, J-Kem temperature sensor/controller, water-cooled reflux condenser, and nitrogen inlet/outlet. 3-[1(trifluoromethyl)cyclopropyl]propanenitrile (25 g, 153.2 mmol) and ethyl alcohol (375 ml) were then charged into the vessel under a nitrogen atmosphere to give a clear amber solution. Stirring was started and the temperature in the vessel was recorded at 19°C. The vessel was then charged with sodium hydroxide (102.1 mL 6 M, 612.6 mmol) added in one portion. The resulting clear amber solution was heated to a temperature of 70°C and kept for 24 hours. After cooling to room temperature, the reaction mixture was concentrated to remove ethyl alcohol. The residual aqueous solution was diluted with water (150 ml) and then transferred to a separatory funnel and separated with methyl tert-butyl ether (50 ml). The aqueous layer was removed and the pH was adjusted to pH ~ 1 using 6 M hydrochloric acid solution.

The resulting aqueous solution was transferred to a separatory funnel and separated with methyl tert-butyl ether (250 ml). The organic layer was removed and the residual aqueous layer was extracted with methyl tert-butyl ether (2x150 ml). The combined organic compounds were dried over sodium sulfate (150 g) and then filtered through a Buchner funnel fitted with a glass frit. The clear filtrate was concentrated under reduced pressure to give 3-[1(trifluoromethyl)cyclopropyl]propanoic acid (26 g, 93%) as a clear amber oil.

1H NMR (400 MHz, chloroform-d) δ 2.63-2.50 (m, 2H), 1.96-1.84 (m, 2H), 1.03-0.95 (m, 2H), 0.66-0.58 (m, J=1.7 Hz, 2H).

Step 4: 3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol O

A 1000 mL three-neck round bottom flask was equipped with a mechanical stirrer, cooling bath, dropping funnel, J-Kem temperature probe, and nitrogen inlet/outlet. Lithium aluminum hydride granules (6.775 g, 178.5 mmol) were loaded into the vessel under a nitrogen atmosphere. Tetrahydrofuran (250 ml) was then charged into the vessel under a nitrogen atmosphere. Stirring was started and the temperature in the vessel was recorded at 20°C. The mixture was left stirring at room temperature for 0.5 h to allow the granules to dissolve. The reactor temperature of the resulting sulfur suspension was 24°C. Then crushed ice/water was loaded into the cooling bath and the temperature in the container was lowered to 0°C. A solution of 3-[1-(trifluoromethyl)cyclopropyl]propanoic acid (25 g, 137.3 mmol) in tetrahydrofuran (75 ml, 3 ml/g) was loaded into a dropping funnel, and the clear pale yellow solution was added dropwise over 1 h. After addition was completed, the reservoir temperature of the resulting grayish-brown slurry was recorded at 5°C. The mixture was allowed to warm slowly to room temperature and continued to stir at room temperature for 24 hours. The suspension was cooled to 0°C using a crushed ice/water cooling bath and then quenched by very slowly adding water (6.775 ml) dropwise, then 15 wt.% sodium hydroxide solution (6.775 ml) and then again water (20.32 ml). The temperature of the resulting white suspension was 5°C. The suspension was continued to stir at ~5°C for 30 min and then filtered through a Buchner funnel fitted with a 20 mm Celite glass frit. The filter cake was washed with tetrahydrofuran (2 x 150 ml) and then dried under vacuum for 15 min. The filtrate was dried over sodium sulfate (250 g) and then filtered through a Buchner funnel fitted with a glass frit. The filtrate was concentrated under reduced pressure to obtain a clear pale amber oil as the desired product, 3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol (21.2 g, 92%).

1H NMR (400 MHz, chloroform-d) δ 3.65 (t, J=6.0 Hz, 2H), 1.78-1.59 (m, 4H), 0.99-0.91 (m, 2H), 0.59 (dp, J=4.7, 1.7 Hz, 2H).

Step 5: tert-butyl 3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazole-1-carboxylate

A 5000 mL three-neck round bottom flask was equipped with a mechanical stirrer, heating hood, J-Kem temperature sensor/controller, dropping funnel, water-cooled reflux condenser, and nitrogen inlet/outlet. Tert-butyl 5-oxo-1H-pyrazole-2-carboxylate (175 g, 950.1 mmol) and tetrahydrofuran (2100 ml) were charged into a vessel under a nitrogen atmosphere to give a clear, pale yellow solution. Stirring was started and the temperature in the vessel was recorded at

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19°C. The vessel was then charged with 3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol (175.7 g, 1.045 mol) neat in one portion, followed by the addition of triphenylphosphine (274.1 g, 1.045 mol) as a solid one serving. The resulting clear, pale yellow solution was then treated with diisopropyl azodicarboxylate (205.7 mL, 1.045 mol) added dropwise neat over 2 hours, resulting in a gradual exotherm to 40° C. to produce a clear, light amber solution. The reaction mixture was then heated to a temperature of 50°C and the conditions were maintained for 2 hours. The clear amber reaction mixture was concentrated under reduced pressure, and the resulting clear dark amber oil was suspended in toluene (1400 ml) and stirred at room temperature for 1 h, during which solid triphenylphosphine oxide precipitated. The thick suspension was filtered through a Buchner funnel fitted with a glass frit and the filter cake was washed with toluene (2x500 ml). The clear amber filtrate was concentrated under reduced pressure to give a clear, pale amber oil (320 g). The material was purified by flash silica gel column chromatography (solid on celite), eluting with a gradient of 100% hexanes to 20% ethyl acetate in hexanes. The desired fractions were combined and concentrated under reduced pressure to give tert-butyl 3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazole-1-carboxylate (280 g, 88%) as a clear, pale yellow oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.07 (d, J=3.0 Hz, 1H), 6.09 (d, J=2.9 Hz, 1H), 4.15 (t, J=6.2 Hz, 2H), 1.91 -1.75 (m, 2H), 1.76-1.63 (m, 2H), 1.55 (s, 9H), 0.98-0.84 (m, 2H), 0.74 (dt, J=3.3, 1.9 Hz, 2H).

Step 6: 3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]-1H-pyrazole

A 5000 mL three-neck round bottom flask was equipped with a mechanical stirrer, heating hood, J-Kem temperature sensor/controller, water reflux condenser, addition funnel, and nitrogen inlet/outlet. Tert-butyl-3[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazole-1-carboxylate (280 g, 837.5 mmol), dichloromethane (840 ml) and methyl alcohol (840 ml) were charged into the vessel under a nitrogen atmosphere ), which gave a clear, pale yellow solution. Stirring was started and the temperature in the vessel was recorded at 19°C. The addition funnel was charged with hydrogen chloride in 1,4-dioxane (628 ml 4 M, 2.512 mol), which was then added dropwise over 2 hours, resulting in a gradual exotherm to 30°C. The resulting clear, pale yellow solution was heated to 45° C. and the conditions were maintained for 1 hour. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The remaining residue was dissolved in methyl tert-butyl ether (2.24 L), then transferred to a separatory funnel and partitioned with ice-cold sodium hydroxide (1.256 L 2 M, 2.512 mol). The organic layer was removed and the residual aqueous layer was extracted with tert-butyl methyl ether (2x500 ml). The combined organics were washed with brine (2 x 500 ml), dried over sodium sulfate (500 g) and then filtered through a Buchner funnel fitted with a glass frit. The clear pale yellow filtrate was concentrated under reduced pressure to give 3-[3-[1(trifluoromethyl)cyclopropyl]propoxy]-1H-pyrazole (190 g, 97%) as a clear light yellow oil. MS-ESI m/z calc. 234.09799, detected 235.1 (M+1)+; retention time: 1.37 min (LC method B).

Step 7: tert-butyl 2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1yl]pyridine-3-carboxylate

A 5000 mL three-neck round bottom flask was equipped with a mechanical stirrer, a cooling bath used as a secondary containment, a J-Kem temperature probe, a water reflux condenser, a dropping funnel, and a nitrogen inlet/outlet. 3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]-1H-pyrazole (188.8 g, 806.1 mmol) and K,X-dimethylformamide (2.40 l) were loaded into a vessel under a nitrogen atmosphere, which gave a clear pale yellow solution. Stirring was started and the temperature in the vessel was recorded at 17°C. The vessel was then charged with tert-butyl 2,6-dichloropyridine-3-carboxylate (200 g, 806.1 mmol), added as a solid in one portion. The resulting clear pale yellow solution was then treated with potassium carbonate (144.8 g, 1.048 mol) added as a solid in one portion, followed by 1,4diazabicyclo[2.2.2]octane (13.56 g, 120.9 mmol) , added as a solid in one portion. The resulting pale yellow suspension was left stirring at room temperature for 24 hours. The reaction mixture was cooled to 10° C. using a crushed ice/water cooling bath. The addition funnel was filled with water (2.40 L), which was added dropwise over 2 hours, resulting in the formation of a thick suspension and an exothermic reaction up to 15°C. The resulting sus

- 214 044967 the mixture was continued to be stirred at 15° C. for 30 minutes and then filtered through a Buchner funnel fitted with a glass frit. The filter cake was washed by displacement with water (3x500 ml) and then dried under vacuum on a Buchner funnel for 2 hours. The material was then allowed to air dry overnight to give tert-butyl-2-chloro-6-[3- [3-[1(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridine-3-carboxylate (305 g, 85%) as a white granular solid. The material was used in the next stage of synthesis without additional purification. MS-ESI m/z calc. 445.138, detected 446.2 (M+1)+; Retention time: 2.54 min (LC method B).

Step 8: 2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridine-3carboxylic acid

A 1000 mL three-neck round bottom flask was equipped with a mechanical stirrer, heating hood, J-Kem temperature sensor/controller, dropping funnel, water-cooled reflux condenser, and nitrogen inlet/outlet. Tert-butyl 2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3-carboxylate (50 g, 112.1 mmol) and 2-propanol (250 ml) to obtain an off-white suspension. Stirring was started and the temperature in the vessel was recorded at 19°C. The addition funnel was charged with hydrochloric acid (93.42 mL 6 M, 560.5 mmol), which was added dropwise over 30 min, resulting in an exothermic reaction at 30°C. The resulting suspension was then heated under reflux (vessel temperature ~ 82°C). When heated, the suspension turns into a transparent pale yellow solution (temperature in the vessel at the moment is ~ 75 ° C). After stirring at reflux for ~30 min, a solid began to precipitate. The suspension continued to be stirred at reflux for an additional 30 minutes, after which water (150 ml) was added dropwise over 45 minutes. The heat was then removed and the suspension continued to be stirred and allowed to cool slowly to room temperature. The material was collected by vacuum filtration in a Buchner funnel with a glass frit and the filter cake was washed by displacement with 1:1 water/2-propanol (250 ml), then water (2x250 ml), and then dried under vacuum in a Buchner funnel for 30 min. The material was further dried in a vacuum oven at 45°C for 24 hours to obtain 2-chloro-6[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridine-3-carboxylic acid ( 41.5 g, 95%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 13.59 (s, 1H), 8.50-8.28 (m, 2H), 7.72 (d, J=8.4 Hz, 1H), 6.20 (d, J=3.0 Hz, 1H) , 4.23 (t, J=6.2 Hz, 2H), 1.86 (dk, J=10.8, 6.3 Hz, 2H), 1.78-1.66 (m, 2H), 0.98-0.87 (m, 2H), 0.76 (dt, J =4.9, 1.7 Hz, 2H).

Step 9: tert-butyl 2,2-dimethyl-4-oxo-pyrrolidine-1-carboxylate

Di-tert-butyl dicarbonate (22.9 g, 24.11 ml, 104.9 mmol) was added to a solution of 5,5dimethylpyrrolidin-3-one (hydrochloride) (13.08 g, 87.42 mmol), triethylamine (17, 71 g, 24.4 ml, 175.0 mmol) and DMAP (1.1 g, 9.004 mmol) in dichloromethane (325 ml), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with 1 N. hydrochloric acid (300 ml) and the aqueous layer was extracted with dichloromethane (2x250 ml). The organic layers were combined, washed with 5% sodium bicarbonate (250 ml) and brine (150 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 2,2-dimethyl4-oxopyrrolidine-1-carboxylate ( 18.5 g, 99%) as a white solid.

1H NMR (300 MHz, CDCl ₃ ) ppm 1.33-1.66 (m, 15H), 2.51 (s, 2H), 3.85 (br. s., 2H). MS-ESI m/z calc. 213.27, found 158.2 (M-C ₄ H ₈ ) ⁺ ; retention time: 1.91 min (LC method I).

Step 10: tert-butyl 4-hydroxy-2,2-dimethyl-pyrrolidine-1-carboxylate

Vos Vos / / - Η tert-Butyl-2,2-dimethyl-4-oxopyrrolidine-1-carboxylate (150 mg, 0.7033 mmol) was dissolved in dry methanol (2.5 ml) and cooled in an ice bath. NaBH ₄ (30 mg, 0.7930 mmol) was added carefully and the reaction mixture was stirred at 0° C. for 1.5 hours. The reaction mixture was diluted with water (25 ml) and 1 M aqueous hydrochloric acid (0.5 ml). The aqueous layer was extracted with ethyl acetate (2x25 ml) and the organic layers were combined, washed with brine (10 ml), dried with sodium sulfate, filtered and concentrated in vacuo to give tert-butyl 4-hydroxy-2,2dimethylpyrrolidine-1-carboxylate (150 mg, 99%), which was used directly at the next stage. MS-ESI m/z calc. 215.15215, detected 216.2 (M+1) ⁺ ; holding time: 0.48 min (method

LC A).

Step 11: tert-butyl 4-(2-hydroxyethoxy)-2,2-dimethyl-pyrrolidine-1-carboxylate:

In a 250 ml flask, dissolve tert-butyl 4-hydroxy-2,2-dimethylpyrrolidine-1-carboxylate (3 g, 13.93 mmol) in N,N-dimethylformamide (15 ml) at 0°C and carefully add the hydride sodium (1.8 g 60% w/w in mineral oil, 45.00 mmol). The mixture was stirred at 0°C for 15 minutes and then 2-bromoethoxy-tert-butyldimethylsilane (9 ml, 41.95 mmol) was added dropwise at 0°C and the mixture was allowed to warm to room temperature. The mixture was stirred for 16 hours. Then the mixture was cooled to 0°C, quenched with water and extracted with ether. The organic extract was washed with water, dried (sodium sulfate), filtered and concentrated in vacuo. The resulting orange oil was purified by chromatography on silica gel, eluting with a gradient of 0 to 30% ethyl acetate in hexanes to give a tert-butyl(dimethyl)silyl protected intermediate, which was dissolved in tetrahydrofuran (20 ml), treated with a solution of TBAF in tetrahydrofuran (28 ml 1 M, 28.00 mmol) and stirred for 2 hours at room temperature. The mixture was concentrated and the residue was dissolved in dichloromethane, washed with water, dried over sodium sulfate, filtered and evaporated in vacuo. The resulting crude material was purified by silica gel chromatography, eluting with a gradient of 0 to 20% methanol in dichloromethane to give tert-butyl 4-(2-hydroxyethoxy)-2,2-dimethylpyrrolidine-1-carboxylate (1.6 g, 44% yield ).

Ή NMR (400 MHz, chloroform-d) δ 3.97 (d, J=4.0 Hz, 1H), 3.80-3.34 (m, 6H), 2.05 (t, J=6.1 Hz, 1H), 1.97 (d, J= 16.4 Hz, 2H), 1.52-1.30 (m, 15H). MS-ESI m/z calc. 259.17834, found 260.17 (M+1)+; Retention time: 0.55 min (LC method A).

Step 12: tert-butyl 4-(2-azidoethoxy)-2,2-dimethyl-pyrrolidine-1-carboxylate

To a solution of tert-butyl 4-(2-hydroxyethoxy)-2,2-dimethylpyrrolidine-1-carboxylate (1.6 g, 6.169 mmol) in dichloromethane (20 ml) was added triethylamine (5.2 ml, 37.31 mmol ), followed by methanesulfonyl chloride (1.4 ml, 18.09 mmol) at 0°C. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was quenched with ice water and dichloromethane and the resulting layers were separated, and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the crude mesylate, which was combined with sodium azide (1,2 g, 18.46 mmol) in N,Ndimethylformamide (10 ml), and the mixture was stirred at 50°C for 2 hours. The reaction was quenched with water and extracted with ether. The organic extract was dried over sodium sulfate, evaporated in vacuo and the residue was purified by chromatography on silica gel, eluting with a gradient of 0 to 50% ethyl acetate in hexane to give tert-butyl-4-(2-azidoethoxy)-2,2-dimethylpyrrolidine-1- carboxylate (1.33 g, 76%).

¹ H NMR (400 MHz, chloroform-d) δ 3.96 (k, J=4.6 Hz, 1H), 3.69-3.31 (m, 6H), 2.06-1.91 (m, 2H), 1.531.32 (m, 15H) .

Step 13: tert-butyl 4-(2-aminoethoxy)-2,2-dimethyl-pyrrolidine-1-carboxylate:

To a solution of tert-butyl 4-(2-azidoethoxy)-2,2-dimethylpyrrolidine-1-carboxylate (1.33 g, 4.677 mmol) in methanol (20 ml) was added palladium on carbon (500 mg 10% wt./ wt., 0.4698 mmol). The mixture was saturated with hydrogen gas and stirred at room temperature, purging hydrogen through the reaction mixture for 2 hours. The mixture was filtered and evaporated in vacuo to give tert-butyl 4(2-aminoethoxy)-2,2-dimethylpyrrolidine-1-carboxylate (1.188 g, 98%).

^1H NMR (400 MHz, chloroform-d) δ 4.00-3.87 (m, 1H), 3.69-3.35 (m, 4H), 2.94-2.71 (m, 2H), 2.07-1.83 (m, 2H), 1.47 ( k, J=9.4, 8.4 Hz, 15H).

Step 14: tert-butyl 2,2-dimethyl-4-[2-[(6-sulfamoyl-2-pyridyl)amino]ethoxy]pyrrolidine-1-carboxylate

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In a sealed 20 mL microwave-safe vial, a solution of tert-butyl 4-(2aminoethoxy)-2,2-dimethylpyrrolidine-1-carboxylate (1.188 mg, 4.598 mmol), 6-fluoropyridine-2sulfonamide (810 mg, 4.598 mmol), and diisopropylethylamine (4 ml, 22.96 mmol) in n-BuOH (10 ml) was stirred at 150°C for 16 hours. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and washed with water. The organic extract was dried over sodium sulfate, evaporated and purified by silica gel chromatography, eluting with a gradient of 0 to 40% ethyl acetate in hexane to give tert-butyl-2,2-dimethyl-4-[2-[(6-sulfamoyl-2- pyridyl)amino]ethoxy]pyrrolidine-1-carboxylate (1.500 g, 66%). MS-ESI m/z calc. 414.1937, detected 415.3 (M+1)+; retention time: 0.61 min (LC method A).

Step 15: tert-butyl 4-[2-[[6-[[2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl ]-2-pyridyl]amino]ethoxy]-2,2-dimethyl-pyrrolidine-1-carboxylate

From a 50 mL flask loaded with carbonyldiimidazole (208 mg, 1.283 mmol) and 2-chloro-6-[3-[3-[1(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridine-3-carboxylic acid ( 500 mg, 1.283 mmol) nitrogen was pumped out and filled again (3X). Tetrahydrofuran (8 ml) was added and the mixture was stirred at 50°C for 1 hour. Then a solution of tert-butyl-2,2-dimethyl-4-[2-[(6-sulfamoyl-2pyridyl)amino]ethoxy]pyrrolidine- 1-carboxylate (483 mg, 1.165 mmol) and 1,8diazabicyclo[5.4.0]undec-7-ene (450 mg, 2.956 mmol) in tetrahydrofuran (6 ml) and the mixture was stirred overnight at 50°C. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, evaporated in vacuo and purified by chromatography on silica gel, eluting with a gradient of 0 to 50% ethyl acetate in hexanes to obtain some pure fractions. The mixed fractions were purified by preparative reverse phase HPLC (C ₁₈ ): 1-99% gradient of acetonitrile in water/hydrochloric acid modifier. The pure fractions from both purifications were combined to give tert-butyl-4-[2-[[6-[[2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1yl]pyridine -3-carbonyl]sulfamoyl]-2-pyridyl]amino]ethoxy]-2,2-dimethylpyrrolidine-1-carboxylate (483 mg, 53%). MS-ESI m/z calc. 785.25854, detected 786.33 (M+1) ⁺ ; Retention time: 0.88 min (LC method A).

Step 16: 2-chloro-N-[[6-[2-(5,5-dimethylpyrrolidin-3-yl)oxyethylamino]-2-pyridyl]sulfonyl]-6[3-[3-[1-(trifluoromethyl) cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3-carboxamide

A solution of tert-butyl-4-[2-[[6-[[2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl] -2-pyridyl]amino]ethoxy]-2,2-dimethylpyrrolidine-1-carboxylate (483 mg, 0.61 mmol) in dioxane (5 ml) was treated with hydrochloric acid in dioxane (6 ml 6 M, 36.00 mmol) and stirred at room temperature for 2 hours. The mixture was evaporated in vacuo and the residue was quenched with aqueous sodium bicarbonate. The resulting white precipitate was filtered off and washed with ethyl acetate. The aqueous phase was further extracted with ethyl acetate, the combined organic extracts were dried over sodium sulfate, filtered and evaporated to yield additional solid, which was combined with the previously precipitated solid and dried in vacuo to yield 2-chloro-I-[[6-[2-( 5,5-dimethylpyrrolidin-3-yl)oxyethylamino]-2-pyridyl]sulfonyl]-6-[3[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3-carboxamide (350 mg, 83%). MSIE m/z calc. 685.2061, detected 686.3 (M+1) ⁺ ; retention time: 0.64 min (LC method A).

Step 17: 12,12-dimethyl-8-(3-{3-[1 -(trifluoromethyl)cyclopropyl]propoxy}-1 H-pyrazol-1 -yl)-15oxa-2λ ⁶ -thia-3,9,11 ,18,23-πpentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene2,2,4-trione

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Cesium fluoride (162 mg, 1.066 mmol), potassium carbonate (367 mg, 2.655 mmol), and 4 A molecular sieves (300 mg) were combined in a 5 mL microwave-safe vial and the vial was evacuated and re-pumped with nitrogen. Then a solution of 2-chloro-N-[[6-[2-(5,5-dimethylpyrrolidin-3yl)oxyethylamino]-2-pyridyl]sulfonyl]-6-[3-[3-[1-(trifluoromethyl)cyclopropyl] was added ]propoxy]pyrazol-1yl]pyridin-3-carboxamide (360 mg, 0.5247 mmol) in dimethyl sulfoxide (5 ml) and the mixture was stirred at 150°C overnight. The mixture was filtered and purified by preparative reverse phase HPLC (Cis): gradient from 1-99% acetonitrile in water/hydrochloric acid modifier (15 min) to give 12,12-dimethyl-8-(3-{3-[1-( trifluoromethyl)cyclopropyl] propoxy }-1 H-pyrazol-1 -yl)-15-oxa2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23) ,5,7,9,19,21-hexaene-2,2,4trione (118.2 mg, 34%).

¹ H NMR (400 MHz, chloroform-d) δ 9.51 (s, 1H), 8.16 (d, J=2.7 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.15 (d, J=8.2 Hz, 1H), 6.65 (d, J=7.3 Hz, 1H), 5.90 (d, J=2.7 Hz, 1H), 4.82 (s, 1H), 4.33 (d, J=7.1 Hz, 1H), 4.24 (t, J=6.1 Hz, 2H), 4.06 (s, 1H), 3.82 (t, J=9.5 Hz, 1H), 3.58 (d, J=12.1 Hz, 1H), 3.43-3.28 (m, 2H), 3.15-3.03 (m, 1H), 2.23-2.14 (m, 1H), 1.95 (dk, J=11.0, 6.3 Hz, 3H), 1.75 (dd, J=10.0, 6.2 Hz, 2H), 1.64 (s, 3H), 1.60 (s, 3H), 0.99-0.95 (m, 2H), 0.60 (d, J=4.8 Hz, 2H). MS-ESI m/z calc. 649.22943, detected 650.29 (M+1)+; retention time: 2.12 min (LC method B).

Step 18: 12,12-dimethyl-8-(3-{3-[1 -(trifluoromethyl)cyclopropyl]propoxy}-1 H-pyrazol-1 -yl)-15oxa-2λ ⁶ -thia-3,9,11 ,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23),5,7,9,19,21-hexaene2,2,4-trione (enantiomer 1) (compound 159) and 12, 12-dimethyl-8-(3-{3-[1(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1-yl)-15-oxa-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,2,4-trione (enantiomer 2) (compound 160)

Racemic 12,12-dimethyl-8-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1-yl)15-oxa-2λ ⁶ -thia-3,9,11,18 ,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23),5,7,9,19,21-hexaene2,2,4-trione (116 mg, 0.18 mmol) was subjected to chiral resolution by SLC chromatography using ChiralPak AS-H (250x21.2 mm, 5 µm particle size) with a mobile phase of 28% acetonitrile/methanol (90:10)/72% carbon dioxide at 70 ml/min for 8.0 min ( injection volume = 500 µl of 32 mg/ml solution in acetonitrile/methanol (90:10)) giving 12,12-dimethyl-8-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy as the first eluting enantiomer }-1H-pyrazol-1-yl)-15-oxa2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23),5,7,9 ,19,21-hexaene-2,2,4trione (enantiomer 1) (compound 159) (48.3 mg, 28%); MS-ESI m/z calc. 649.22943, detected 650.32 (M+1) ⁺ ; Retention time: 2.12 min (LC method B) and as the second enantiomer eluted 12,12-dimethyl-8-(3-{3-[1(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1-yl) -15-oxa-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21 -hexaene-2,2 ,4-trione (enantiomer 2) (compound 160) (56.0 mg, 48%);

¹ H NMR (400 MHz, DMSO-de) δ 12.57 (s, 1H), 8.19 (d, J=2.8 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.58 (t, J=7.7 Hz, 1H), 7.09 (d, J=7.3 Hz, 2H), 6.93 (d, J=8.1 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 6.11 (d, J=2.7 Hz, 1H), 4.19 (t, J=6.2 Hz, 2H), 4.17-3.99 (m, 2H), 3.88 (t, J=11.7 Hz, 1H), 3.60 (d, J=12.9 Hz, 1H), 3.27- 2.75 (m, 3H), 2.07 (dd, J=11.7, 6.0 Hz, 1H), 1.89-1.70 (m, 5H), 1.57 (d, J=9.3 Hz, 6H), 0.93-0.85 (m, 2H) , 0.75 (s, 2H). MSIE m/z calc. 649.22943, detected 650.43 (M+1) ⁺ ; Retention time: 2.12 min (LC method B).

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Example 42: Preparation of (14S)-12,12-dimethyl-8-(3-{3-[1-(trifluoromethyl)cyclopropyl]nponoxy}-1Hpyrazol-1-yl)-2λ ⁶ -thia-3,9,11 ,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 161)

Step 1: tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]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-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridine-3carboxylic acid (10 g, 25.66 mmol) in tetrahydrofuran (100 ml) was added carbonyldiimidazole (4.7 g, 27.71 mmol) and the mixture was stirred at ambient temperature for 90 minutes. To this mixture was then added tert-butyl (4S)-2,2-dimethyl-4-[3-[(6-sulfamoyl-2pyridyl)amino]propyl]pyrrolidine-1-carboxylate (12.0 g, 29.09 mmol ) in tetrahydrofuran (50 ml), then 1,8-diazabicyclo[5.4.0]undec-7-ene (11.5 ml, 76.90 mmol), and the mixture was stirred at ambient temperature for 18 hours. The reaction mixture diluted with water (250 ml) and the mixture was slowly acidified with aqueous hydrochloric acid (23 ml, 6 M, 138.0 mmol). The mixture was extracted with ethyl acetate (500 ml) and the organic phase was separated. The organic phase was washed with 300 ml brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was divided into 3 equal parts, acetonitrile was added and chromatographed on a 415 C ₁₈ reverse phase column, eluting with a gradient of 50% to 100% acetonitrile in water to give the product, tert-butyl (4S)-4-[3-[[6- [[2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2 -dimethylpyrrolidine-1-carboxylate (13.63 g, 68%) as a waxy solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.75 (s, 1H), 8.39 (t, J=2.2 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.62 (dd, J=8.5, 7.2 Hz, 1H), 7.24-7.14 (m, 2H), 6.74 (d, J=8.5 Hz, 1H), 6.20 (dd, J=8.6, 2.9 Hz , 1H), 4.23 (t, J=6.2 Hz, 2H), 3.51 (dt, J=18.4, 9.2 Hz, 1H), 3.24 (s, 2H), 2.74 (t, J=10.5 Hz, 1H), 2.05 -1.96 (m, 1H), 1.91-1.69 (m, 5H), 1.51 (dt, J=15.6, 7.1 Hz, 2H), 1.40-1.27 (m, 15H), 1.18 (s, 3H), 0.97-0.88 (m, 2H), 0.800.71 (m, 2H). MS-ESI m/z calc. 783.27924, detected 784.3 (M+1)+; retention time: 2.38 min (LC method B).

Step 2: 2-chloro-N-[[6-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2-pyridyl]sulfonyl]6-[3-[3-[1 -(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridine-3-carboxamide (dihydrochloride salt)

To a solution of tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-[3-[l-(trifluoromethyl)cyclopropyl]nponokCi]pyrazol-1 -yl]pyridin- 3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1 carboxylate (13.5 g, 17.21 mmol) in dichloromethane (100 ml) and toluene (50 ml) were added hydrochloric acid in dioxane (20 ml 4 M, 80.00 mmol). The mixture was stirred at ambient temperature for 16 hours. The solvent was removed in vacuo and the residue was further evaporated from 200 ml of toluene, obtaining 2-χλορ-Ν-[[6-[3-[(3 8)-5,5-dimethylpyrrolidine- 3-yl] propylamino]-2pyridyl]sulfonyl] -6-[3-[3-[1 -(trifluoromethyl)cyclopropyl] propoxy] pyrazol-1 -yl] pyridin-3 - 219 044967 carboxamide (dihydrochloride salt) (12, 7 g, 97%), which was used without further purification.

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.80 (s, 1H), 9.31 (s, 1H), 9.14 (s, 1H), 8.41 (d, J=2.9 Hz, 1H), 8.11 (d, J =8.3 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.63 (dd, J=8.5, 7.2 Hz, 1H), 7.19-7.15 (m, 3H), 6.78 (dd, J=8.6, 0.7 Hz, 1H), 6.21 (d, J=2.9 Hz, 1H), 4.24 (t, J=6.2 Hz, 2H), 3.28 (dh, J=27.2, 6.6, 6.1 Hz, 3H), 2.82 (tq, J=11.8, 7.2, 5.9 Hz, 1H), 2.43-2.32 (m, 1H), 1.95-1.81 (m, 3H), 1.77-1.68 (m, 2H), 1.61-1.31 (m, 8H), 1.25 ( s, 3H), 0.96-0.88 (m, 2H), 0.81-0.70 (m, 2H). MS-ESI m/z calc. 683.2268, detected 684.3 (M+1)+; retention time: 2.47 min (LC method D).

Step 3: (14S)-12,12-dimethyl-8-(3-{3-[1-(trifluoromethyl)cyclononyl]propoxy}-1H-pyrazol-1yl)-2λ ⁶ -thia-3,9,11, 18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene2,2,4-trione (compound 161)

To a solution of 2-chloro-N-[[6-[3-[(3S)-5,5-dimethylnyrrolidin-3-yl]propylamino]-2pyridyl]sulfonyl]-6-[3-[3-[1 -( trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3 carboxamide (dihydrochloride salt) (12.7 g, 16.77 mmol) in NMP (200 ml) was added potassium carbonate (11.47 g, 82.99 mmol ) followed by the addition of cesium fluoride (2.75 g, 18.10 mmol). The mixture was purged with nitrogen for 5 minutes. The mixture was heated at 150°C for 22 hours. The reaction mixture was then cooled to room temperature and added to cooled water (600 ml). The mixture was carefully acidified with aqueous hydrochloric acid (26 ml 6 M, 156.0 mmol) to obtain a cream-colored foamy suspension. The suspension was stirred at ambient temperature for 1 hour. The solid was collected by filtration using a medium frit Buchner funnel. The wet filter cake was diluted with acetonitrile and chromatographed on a reverse phase C ₁₈ column, eluting with a gradient system of 50%-100% acetonitrile in water, yielding an off-white foam, which was then dried in vacuum at 45°C for 3 days, yielding ( 148)-12,12-dimethyl-8-(3-{3-[1(trifluoromethyl)cyclopropyl]propoxy} -1 H-pyrazol-1 -yl)-2λ ⁶ -thia-3,9,11,18, 23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 161) (6.0 g, 55 %).

Ή NMR (400 MHz, DMSO-dg) δ 12.48 (s, 1H), 8.21 (d, J=2.7 Hz, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.57 (dd, J=8.5, 7.2 Hz, 1H), 7.05 (d, J=7.1 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.5 Hz , 1H), 6.12 (d, J=2.8 Hz, 1H), 4.20 (t, J=6.2 Hz, 2H), 3.92 (d, J=12.5 Hz, 1H), 3.16 (s, 1H), 2.95 (d , J=13.3 Hz, 1H), 2.71 (t, J=11.1 Hz, 1H), 2.12 (s, 1H), 1.84 (k, J=7.8, 6.3 Hz, 3H), 1.80-1.67 (m, 3H) , 1.60 (s, 6H), 1.51 (s, 3H), 1.31 (k, J=12.0 Hz, 1H), 0.97-0.87 (m, 2H), 0.76 (k, J=3.0, 1.7 Hz, 2H). MS-ESI m/z calc. 647.2502, detected 648.3 (M+1)+; retention time: 9.64 min (LC method F).

Example 43: Preparation of 8-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-15-oxa2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo [17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,2,4trione (enantiomer 1) (compound 162) and 8-[3-(3, 3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12dimethyl-15-oxa-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23),5,7,9,19,21hexaene-2,2,4-trione (enantiomer 2) (compound 163)

Step 1: 2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]-N-[[6-[2-(5,5dimethylpyrrolidin-3-yl)oxyethylamino]-2-pyridyl ]sulfonyl]pyridine-3-carboxamide

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From a 50 mL flask with 2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (400 mg, 1.106 mmol) and carbonyldiimidazole (270 mg, 1.665 mmol) pumped out and added nitrogen again (3X). Dry tetrahydrofuran (10 ml) was added and the reaction mixture was stirred for 90 minutes at 50°C. A solution of tert-butyl 2,2-dimethyl-4-[2-[(6-sulfamoyl-2pyridyl)amino]ethoxy]pyrrolidine-1-carboxylate (158 mg, 0.3812 mmol) and 1,8diazabicyclo[5.4] was then added .0]undec-7-ene (430 mg, 2.825 mmol) in tetrahydrofuran (4 ml). The reaction was heated at 50°C overnight. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, evaporated in vacuo and purified by chromatography on silica gel, eluting with a gradient of 0 to 50% ethyl acetate in hexanes, to give an intermediate which was dissolved in dichloromethane (5 ml) and treated with trifluoroacetic acid (1000 μl, 12. 98 mmol) and stirred for 2 hours at room temperature. The solvent was removed in vacuo and the residue was quenched with aqueous sodium bicarbonate and ethyl acetate. A white solid precipitate formed. The biphasic mixture was filtered and the solid was washed with ethyl acetate. The organic extract was separated from the aqueous extract and dried over sodium sulfate, filtered and evaporated in vacuo. The filter solids and evaporation residues were combined and dried in vacuo to give 2-chloro-6-[3-(3,3dicyclopropylpropoxy)pyrazol-1-yl]-N-[[6-[2-(5,5- dimethylpyrrolidin-3-yl)oxyethylamino]-2pyridyl]sulfonyl]pyridine-3-carboxamide (310 mg, 43%). MS-ESI m/z calc. 657.25, detected 658.32 (M+1)+; retention time: 0.68 min (LC method B).

Step 2: 8-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-15-oxa- ^2λ6 -tiα3,9,11,18,23-pentaazatetracyclo [17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,2,4-trione (compound 156)

2-Chloro-6-[3 -(3,3-dicyclopropylpropoxy)pyrazol-1 -yl]-N-[[6-[2-(5,5-dimethylpyrrolidin-3 yl)oxyethylamino]-2-pyridyl]sulfonyl ]pyridine-3-carboxamide (320 mg, 0.4862 mmol), potassium carbonate (340 mg, 2.460 mmol), cesium fluoride (150 mg, 0.9875 mmol) and 3 A molecular sieves (300 mg) were combined, sealed and purged with nitrogen.

Dimethyl sulfoxide (4 ml) was added and the mixture was stirred at 150°C overnight. The mixture was filtered and purified by preparative reverse phase HPLC ( _C18 ): 1-99% acetonitrile in water/hydrochloric acid modifier gradient to give 8-[3-(3,3-dicyclopropylpropoxy)-1Hpyrazol-1-yl]-12, 12-dimethyl-15-oxa-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21- hexaene-2,2,4-trione (compound 156) (92.5 mg, 30%). MS-ESI m/z calc. 621.2733, detected 622.31 (M+1) ⁺ ; retention time: 2.26 min (LC method B).

Step 3: 8-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-15-oxa- ^2λ6 -thia3,9,11,18,23-pentaazatetracyclo [17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,2,4-trione (enantiomer 1) (compound 162) and 8-[3-( 3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl15-oxa-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose -1(23),5,7,9,19,21-hexaene2,2,4-trione (enantiomer 2) (compound 163)

Racemic 8-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-15-oxa-2λ ⁶ -thiα3,9,11,18,23-pentaazatetracyclo[17.3 .1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,2,4-trione (compound 156) (90 mg, 0.145 mmol) was subjected to chiral resolution using SLC - chromatography using ChiralPak AS-H (250x10 mm, particle size 5 µm) with a mobile phase of 40% acetonitrile/methanol (90:10)/60% carbon dioxide at 10 ml/min for 8.0 min (injection volume = 70 μl of a solution of 24 mg/ml in acetonitrile/methanol (90:10)) to obtain 8-[3-(3,3-dicyclopropylpropoxy)-1 H-pyrazol-1-yl] as the first eluted enan-thiomer. -12,12-dimethyl-15-oxa-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21 -hexaene-2,2,4-trione (enantiomer 1) (compound 162) (28.4 mg, 19%); MS-ESI m/z calc. 621.2733, detected 622.38 (M+1)+;

Retention time: 2.26 min (LC method B) and as the second enantiomer eluted 8-[3-(3,3-dicyclopropylpnoxy)-1H-pyrazol-1-yl]12,12-dimethyl-15-oxa-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5,7,9,19,21-hexaene-2,2,4-trione (compound 163) (enantiomer 2) (35.4 mg, 39%);

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.58 (s, 1H), 8.19 (d, J=2.7 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.62-7.55 (m, 1H ), 7.11 (dd, J=16.4, 5.9 Hz, 2H), 6.94 (d, J=8.2 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 6.10 (d, J=2.7 Hz, 1H ), 4.36 (t, J=6.8 Hz, 2H), 4.19-4.00 (m, 2H), 3.88 (t, J=11.3 Hz, 1H), 3.60 (d, J=13.0 Hz, 1H), 3.22 (s , 1H), 2.86 (d, J=9.5 Hz, 1H), 2.07 (dd, J=11.8, 5.9 Hz, 1H), 1.89 (k, J=6.8 Hz, 2H), 1.78 (t, J=10.9 Hz , 1H), 1.57 (d, J=10.0 Hz, 6H), 0.68 (qt, J=8.4, 5.0 Hz, 2H), 0.39 (k, J=5.9 Hz, 4H), 0.34-0.24 (m, 1H) , 0.20 (dt, J=10.4, 5.2 Hz, 2H), 0.03 (dt, J=8.0, 4.0 Hz, 2H), MS-ESI m/z calc. 621.2733, detected 622.42 (M+1) ⁺ ; Retention time: 2.25 min (LC method B).

Example 44: Preparation of 20,20-dimethyl-4-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1Hpyrazol-1-yl)-10λ ⁶ -thia-1,3,9,14,22 -pentaazatetracyclo[16.2.1.111,14.02,7]docose-2(7),3,5,11(22),12pentaene-8,10,10-trione (enantiomer 1) (compound 165) and 20,20-dimethyl -4-(3-{3-[1(trifluoromethyl)cyclopropyl]propoxy} -1 H-pyrazol-1 -yl)-10λ ⁶ -thia-1,3,9,14,22pentaazatetracyclo[16.2.1.111,14.02, 7]docose-2(7),3,5,11(22),12-pentaene-8,10,10-trione (enantiomer 2) (compound 166)

Step 1: tert-butyl 4-[3-[3-[[2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl] pyrazol-1-yl]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate o q _w p

2-Chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (275 mg, 0.7056 mmol) and carbonyldiimidazole (130 mg, 0 .8017 mmol) were combined in anhydrous tetrahydrofuran (5 ml) and stirred for 60 min at 50°C. A tetrahydrofuran solution (7 ml) of tert-butyl 2,2-dimethyl-4-[3-(3-sulfamoylpyrazol-1-yl)propyl]pyrrolidine-1-carboxylate (206 mg, 0.5330 mmol) and 1.8 -diazabicyclo[5.4.0]undec-7-ene (200 µl, 1.337 mmol). The reaction was heated at 50°C for 4 hours. The reaction was diluted with ethyl acetate and washed with 1M citric acid solution, and then with saline solution. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexanes to 75% ethyl acetate in hexanes to give an off-white solid, t-butyl-4-[3-[3 -[[2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]pyrazol-1-yl]propyl]-2,2- dimethylpyrrolidine-1-carboxylate (226 mg, 56%). MSIE m/z calc. 757.2636, detected 758.32 (M+1) ⁺ ; retention time: 0.88 min (LC method A).

Step 2: 20,20-dimethyl-4-(3 -{3-[1 -(trifluoromethyl)cyclopropyl]propoxy} -1 H-pyrazol-1 -yl)-10λ ⁶ thia-1,3,9,14, 22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2(7),3,5,11(22),12-pentaene-8,10,10-trione (compound 155)

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tert-Butyl 4-[3-[3-[[2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl]pyrazol-1 -yl]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (226 mg, 0.2981 mmol) was dissolved in dichloromethane (5 ml) and hydrochloric acid in dioxane (2 ml 4 M, 8.000 mmol) was added to the mixture and stirred at room temperature 30 min. The mixture was concentrated to dryness under reduced pressure and the residue was combined with potassium carbonate (250 mg, 1.809 mmol), cesium fluoride (73 mg, 0.4806 mmol), 3 A molecular sieves and dimethyl sulfoxide (6 ml) in a vial, which was purged with nitrogen, capped , heated to 140°C and stirred for 16 hours. The reaction mixture was allowed to cool to room temperature, filtered and then purified by preparative reverse phase chromatography (C ₁₈ column, 30% to 99% acetonitrile (no modifier) in water (5 mM hydrochloric acid) for 30 min) to give a white solid characterized as 20,20-dimethyl-4-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1Hpyrazol-1-yl)-10λ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2(7),3,5,11(22), 12pentaene-8,10,10-trione ( compound 155) (96 mg, 51%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.69 (s, 1H), 8.18 (d, J=2.8 Hz, 1H), 8.00 (d, J=2.3 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.04-6.80 (m, 2H), 6.10 (d, J=2.8 Hz, 1H), 4.30-4.05 (m, 4H), 2.07 (s, 3H), 1.99-1.66 (m, 6H) , 1.55 (s, 3H), 1.47 (s, 3H), 1.33 (t, J=12.3 Hz, 1H), 0.98-0.87 (m, 2H), 0.75 (s, 2H), 0.64 (s, 1H). MS-ESI m/z calc. 621.2345, detected 622.24 (M+1)+; retention time: 2.22 min (LC method B).

Step 3: 20,20-dimethyl-4-(3 -{3-[1 -(trifluoromethyl)cyclopropyl]propoxy} -1 H-pyrazol-1 -yl)-10λ ⁶ thia-1,3,9,14, 22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2(7),3,5,11(22),12-pentaene-8,10,10-trione (enantiomer 1) (compound 165) and 20, 20-dimethyl-4-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1Hpyrazol-1-yl)-10λ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111 ,14.02,7]docose-2(7),3,5,11(22),12pentaene-8,10,10-trione (enantiomer 2) (compound 166)

Racemic 20,20-dimethyl-4-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1-yl)10λ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo [16.2.1.111,14.02.7]docose-2(7),3,5,11(22),12-pentaene-8,10,10trione (compound 155) (88 mg, 0.1401 mmol) was subjected to chiral SQL chromatography. The following SGC protocol was used: ChiralPak AS-3 (150x2.1 mm), 3 µm; 35°C. Mobile phase: 28% acetonitrile:methanol (90:10), 72% carbon dioxide at a flow rate of 0.5 ml/min. The first enantiomer eluted was 20,20-dimethyl-4-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1 H-pyrazol-1 yl)-10λ ⁶ -thia-1,3,9,14 ,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2(7),3,5,11(22),12-pentaene-8,10,10trione (enantiomer 1) (compound 165) (36 mg, 82%). MS-ESI m/z calc. 621.2345, detected 622.24 (M+1) ⁺ ; retention time: 2.21 min (LC method B).

The second enantiomer eluted was 20,20-dimethyl-4-(3-{3-[1(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1-yl)-10λ ⁶ -thia-1,3,9,14 ,22pentaazatetracyclo[16.2.1.111,14.02,7]docose-2(7),3,5,11 (22), 12-pentaene-8,10,10-trione (enantiomer 2) (compound 166) (34 mg, 77%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.69 (s, 1H), 8.18 (d, J=2.8 Hz, 1H), 8.00 (d, J=2.3 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.04-6.80 (m, 2H), 6.10 (d, J=2.8 Hz, 1H), 4.30-4.05 (m, 4H), 2.74-2.63 (m, 1H), 2.07 (s, 3H) , 1.99-1.66 (m, 7H), 1.55 (s, 3H), 1.47 (s, 3H), 1.33 (t, J=12.3 Hz, 1H), 0.98-0.87 (m, 2H), 0.75 (s, 2H ), 0.64 (s, 1H). MS-ESI m/z calc. 621.2345, detected 622.35 (M+1) ⁺ ; retention time: 2.21 min (LC method B).

Example 45: Preparation of (14S)-12,12-dimethyl-8-(2-oxo-3-{3-[1-(trifluoromethyl)cyclopropyl]propyl}pyrrolidin-1 -yl)-2λ ⁶ -thia-3, 9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 1) ( compound 174) and (14S)-12,12-dimethyl-8-(2oxo-3-{3-[1-(trifluoromethyl)cyclopropyl]propyl}pyrrolidin-1-yl)-2λ ⁶ -thia-3,9, 11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 2) (compound 175 )

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Step 1: 1-(3-bromopropyl)-1-(trifluoromethyl)cyclopropane

To a stirred solution of triphenylphosphine (655 mg, 2.497 mmol) in anhydrous dichloromethane (10 ml) under a nitrogen atmosphere at -15°C, a solution of molecular bromine (130 μl, 2.524 mmol) in dichloromethane (2 ml) was added dropwise over 8 min and Once the addition was complete (pale yellow solution), the mixture was stirred for a further 15 minutes at -15°C. The mixture was then cooled to -30°C and a solution of 3-[1(trifluoromethyl)cyclopropyl]propan-1-ol (500 mg, 2.379 mmol) and pyridine (202 μL, 2.498 mmol) in dichloromethane (3 mL) was added dropwise to for 5 minutes, and upon completion of addition, the mixture was heated to -5°C and stirred for 1 hour. The reaction mixture was then poured into pentane (250 ml), resulting in the formation of a mass of white precipitate. This suspension was filtered through celite and the filtrate was evaporated on a rotary evaporator (250 mbar and 30° C. water bath) to obtain a white solid. Pentane was added to this solid and the mixture was briefly sonicated and filtered. Concentration of this filtrate gave a white solid, which was again briefly sonicated with pentane and filtered to give crude 1-(3-bromopropyl)-1(trifluoromethyl)cyclopropane (500 mg, 64%) as a clear oil.

¹ H NMR (400 MHz, chloroform-d) δ, 3.42 (t, J=6.4 Hz, 2H), 2.09-1.95 (m, 2H), 1.71 (d, J= 5.8 Hz, 2H), 1.36-1.20 (m, 2H), 1.02-0.93 (m, 2H), 0.61-0.58 (m, 2H). NMR showed ~70% purity. The product was used in the next step without further purification.

Step 2: 1-benzyl-3-[3-[1-(trifluoromethyl)cyclopropyl]propyl]pyrrolidin-2-one

A 100 mL three-neck flask was dried using a heat gun under vacuum and filled with nitrogen. The flask was charged with 1-benzylpyrrolidin-2-one (0.21 ml, 1.312 mmol) and anhydrous tetrahydrofuran (2 ml). After cooling to -78°C, a solution of n-butyllithium (0.59 mL, 2.5 M, 1.475 mmol) (2.5 M in hexane) was added dropwise, causing the formation of a pink solution. After stirring at -78°C for 20 minutes (the solution turned pale yellow), a solution of 1-(3-bromopropyl)-1-(trifluoromethyl)cyclopropane (500 mg, 1.515 mmol) in tetrahydrofuran (0.5 ml) was added at drops (the color became dark yellow). The mixture was stirred in a cooling bath, which was allowed to slowly warm to room temperature. After 14 hours, the mixture was quenched by adding saturated aqueous ammonium chloride (50 ml). The product was extracted with ethyl acetate (2x30 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using a gradient of ethyl acetate (0 to 100% over 30 min) in hexane to give 1-benzyl-3-[3-[1-(trifluoromethyl)cyclopropyl]propyl]pyrrolidin-2-one (227 mg, 53%) as a colorless oil.

1H NMR (400 MHz, chloroform-d) δ 7.37-7.16 (m, 5H), 4.49 (d, J=14.7 Hz, 1H), 4.41 (d, J=14.7 Hz, 1H), 3.22-3.14 (m, 2H), 2.45 (qd, J=8.9, 4.3 Hz, 1H), 2.23-2.10 (m, 1H), 1.94-1.80 (m, 1H), 1.72-1.32 (m, 6H), 0.990.88 (m, 2H), 0.61-0.51 (m, 2H). MS-ESI m/z calc. 325.16534, found 326.3 (M+1)+; Retention time: 1.9 min (LC method B).

Step 3: 3-[3-[1-(trifluoromethyl)cyclopropyl]propyl]pyrrolidin-2-one

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A 100 ml flask was charged under a nitrogen atmosphere with 1-benzyl-3-[3-[1(trifluoromethyl)cyclopropyl]propyl]pyrrolidin-2-one (227 mg, 0.6977 mmol), propylamine (3 ml) and 1, 2ethanediamine (0.3 ml, 4.488 mmol). The mixture was cooled to -20°C (external temperature of the cooling bath) and lithium (47 mg, 6.771 mmol) was added (wire briefly rinsed with hexane, then freshly cut into small pieces). A blue color appeared around the small pieces of lithium, which then quickly disappeared in cycles. After 20 minutes at -20°C, the blue color became permanent. The reaction was quenched by adding methanol (400 μl) and water (10 ml) at -10°C. The product was extracted with ethyl acetate (2x25 ml). The combined organic extracts were dried over sodium sulfate and the solvents were evaporated to yield crude material, which was purified by flash silica gel chromatography using a gradient of methanol (0-15% over 30 min) in dichloromethane to yield 192 mg of crude material. This material was dissolved in ethyl acetate (30 ml) and the organic phase was washed with 0.1 N. hydrochloric acid (2x20 ml) and 1 N. hydrochloric acid (2x20 ml). The organic phase was then dried over sodium sulfate, filtered and the solvents were evaporated to give 3-[3-[1(trifluoromethyl)cyclopropyl]propyl]pyrrolidin-2-one (108 mg, 66%) as a white solid.

¹ H NMR(400 MHz, chloroform-d) δ 5.76 (broadened s, 1H), 3.41-3.28 (m, 2H), 2.40-2.23 (m, 2H), 1.881, 73 (m, 2H), 1.67-1.44 (m, 4H), 1.42-1.30 (m, 1H), 0.97-0.90 (m, 2H), 0.61- 0.47 (m, 2H).

MS-ESI m/z calc. 235.1184, detected 236.2 (M+1)+; retention time: 1.43 min (LC method B).

Step 4: (14S)-12,12-dimethyl-8-(2-oxo-3-{3-[1-(trifluoromethyl)cyclopropyl]propyl}pyrrolidin1-yl)-2λ ⁶ -thia-3,9,11 ,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (diastereomer 1) (compound 174) and (14S)-12,12-dimethyl-8-(2-oxo-3-{3-[1(trifluoromethyl)cyclopropyl]propyl}pyrrolidin-1-yl)-2λ ⁶ -thia-3,9,11, 18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 2) (compound 175) diastereomer 1 diastereomer 2

(14S)-8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23) was loaded into a 4 ml ampoule. 5,7,9,19,21-hexaene-2,2,4-trione (100 mg, 0.2222 mmol), 3-[3-[1-(trifluoromethyl)cyclopropyl]propyl]pyrrolidin-2-one ( 54 mg, 0.2295 mmol), Pd ₂ (dba) ₃ (33 mg, 0.03604 mmol), xanthos (21 mg, 0.03629 mmol), cesium carbonate (430 mg, 1.320 mmol) and anhydrous dioxane (1 .5 ml). The mixture was bubbled with nitrogen for approximately 5 minutes (turned into a gel), capped and stirred at 120°C for 14 hours. The organic solvent was evaporated by purging the ampoule with nitrogen. The reaction mixture was then diluted with dimethyl sulfoxide (3 ml), microfiltrated and subjected to reverse phase preparative HPLC (C ₁₈ ) using a gradient of acetonitrile in water (1% to 99% in 15 min) and hydrochloric acid as modifier (4x950 µl for injection, 400 µl). Pure fractions were collected and organic solvents were evaporated. The resulting aqueous solution was extracted with dichloromethane and the organic phase was dried over sodium sulfate. Filtration followed by evaporation of the solvent of the filtrate resulted in 74 mg of solid. The product was then purified by flash chromatography on silica gel using a gradient of methanol (0% to 5% over 30 min) in dichloromethane to obtain a mixture of diastereomers, which was subjected to chiral separation by RPLC (ChiralCel OJ-H (250x10 mm), 5 µM column; moving phase 22% acetonitrile/methanol (90:10, no modifier), 78% carbon dioxide, 10 ml/min; concentration 24 mg/ml in acetonitrile/methanol/dimethyl sulfoxide (85:9:6); injection volume 70 µl, 100 bar). The first diastereomer to elute was (14S)-12,12-dimethyl-8-(2-oxo-3-{3-[1(trifluoromethyl)cyclopropyl]propyl}pyrrolidin-1-yl)-2λ ⁶ -thia-3,9 ,11,18,23 pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 1) ( compound 174) (12.4 mg, 17%).

1H NMR (400 MHz, DMSO-de) δ 12.39 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.56 (t, J=7.9 Hz, 1H), 7.51 (d, J=8.5 Hz , 1H), 7.04 (d, J=7.1 Hz, 1H), 6.96 (broadened d, J=5.3 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 4.04 (t, J=9.1 Hz, 1H), 3.91 (br q, J=12.6 Hz, 1H), 3.80-3.67 (m, 1H), 3.11 (bt s, 1H), 2.94 (bd, J=13.3 Hz, 1H), 2.77-2.57 (m, 2H), 2.31-2.19 (m, 1H), 2.10 (broad s, 1H), 1.87-1.66 (m, 4H), 1.64-1.22 (m, 15H), 0.92-0.83 (m, 2H) , 0.760.68 (m, 2H). MS-ESI m/z calc. 648.27057, detected 649.5 (M+1) ⁺ ; retention time: 2.14 min (LC method B).

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The second diastereomer eluted was (14S)-12,12-dimethyl-8-(2-oxo-3-{3-[1(trifluoromethyl)cyclopropyl]propyl}pyrrolidin-1-yl)-2X ⁶ -thia-3,9 ,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer

2) (compound 175) (12.2 mg, 17%).

1H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 12.39 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.63-7.48 (m, 2H), 7.04 (d, J=7.1 Hz, 1H ), 6.95 (broad d, J=5.1 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 4.04-3.87 (m, 2H), 3.82 (k, J=9.9, 9.0 Hz, 1H) , 3.09 (broad s, 1H), 2.94 (d, J=13.4 Hz, 1H), 2.75-2.61 (m, 2H), 2.24 (k, J=8.7, 7.9 Hz, 1H), 2.171.96 (br m , 1H), 1.87-1.64 (m, 4H), 1.64-1.41 (m, 12H), 1.41-1.15 (m, 3H), 0.92-0.84 (m, 2H), 0.71 (s, 2H). MSIE m/z calc. 648.27057, detected 649.4 (M+1)+; Retention time: 2.12 min (LC method B).

Example 46: preparation of 4-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-20,20dimethyl-10X ⁶ -thia-1,3, 9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene8,10,10-trione (compound 176)

OH step ^CN step 3 step 6

Ό step step 10

Step 1: 7-(bromomethyl)dispiro[2.0.2.1]heptane

A 1000 mL three-neck round bottom flask was equipped with a mechanical stirrer, cooling bath, dropping funnel, J-Kem temperature probe, and nitrogen inlet/outlet. Triphenylphosphine (102.7 mL, 443.2 mmol) and dichloromethane (1 L) were charged into a vessel under a nitrogen atmosphere to give a clear, colorless solution. Stirring is started and acetone is added to the cooling bath. Dry ice was added to the cooling bath in portions until the container temperature reached 15°C. A solution of bromine (22.82 mL, 443.0 mmol) in dichloromethane (220 mL, 10 mL/g) was charged into the addition funnel and then added dropwise over 1 hour. Dry ice was added in portions to the cooling bath during addition to maintaining the container temperature at -15°C. After the addition of bromine was completed, the pale yellow suspension was continued to stir at -15°C for 15 minutes, after which the suspension was cooled to -30°C. A solution of dispiro[2.0.2.1]heptan-7-ylmethanol (50 g, 402.6 mmol), pyridine (35.82 mL, 442.9 mmol) and dichloromethane (250 mL, 5 mL/g) was charged into a dropping funnel. A clear, pale yellow solution was then added dropwise over 1.5 hours, maintaining the container temperature at -30°C. The resulting clear, light yellow reaction mixture was allowed to gradually warm to the container temperature of -5°C, and then stirring was continued at -5°C for 1 hour. The reaction mixture was then poured into hexane (2000 ml), which resulted in the formation of a precipitate. The suspension was stirred at room temperature for 30 min and then filtered through a Buchner funnel fitted with a 20 mm Celite glass frit. The clear filtrate was concentrated under reduced pressure (20°C water bath) to give a yellow oil with some precipitate present. The oil was diluted with a small amount of hexane, kept at room temperature for 15 min and then filtered through a glass Buchner funnel with a 20 mm layer of celite. The clear filtrate was concentrated under reduced pressure (water bath temperature at 20°C) to give 7-(bromomethyl)dispiro[2.0.2.1]heptane (70 g, 93%) as a clear yellow oil.

1H NMR (400 MHz, chloroform-d) δ 3.49 (d, J=7.5 Hz, 2H), 1.90 (t, J=7.5 Hz, 1H), 1.06-0.84 (m, 4H), 0.71 (ddd, J= 9.1, 5.1, 4.0 Hz, 2H), 0.54 (dddd, J=8.6, 4.8,3.8, 1.0 Hz, 2H).

Step 2: 2-dispiro[2.0.2.1]heptan-7-ylacetonitrile

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A 1000 mL three-neck round bottom flask was equipped with a mechanical stirrer, a cooling bath used as a secondary containment, a J-Kem temperature sensor, and a nitrogen inlet/outlet valve. 7-(bromomethyl)dispiro[2.0.2.1]heptane (35 g, 187.1 mmol) and dimethyl sulfoxide (245 ml) were charged into a vessel under a nitrogen atmosphere to give a clear amber solution. Stirring was started and the temperature in the vessel was recorded at 19°C. The vessel was then charged with sodium cyanide (11.46 g, 233.8 mmol) added as a solid in one portion, resulting in a dark solution and a gradual exotherm to 49°C over 15 min. After a few minutes, the temperature in the container began to decrease and the mixture continued to be stirred at room temperature overnight (about 15 hours). The dark reaction mixture was quenched with ice-cold saturated sodium carbonate solution (500 ml) and then transferred to a separatory funnel and partitioned with diethyl ether (500 ml). The organic layer was removed and the residual aqueous layer was extracted with diethyl ether (2x250 ml). The combined organic layers were washed with water (500 ml), dried over sodium sulfate (200 g) and then filtered through a Buchner funnel fitted with a glass frit. The clear amber filtrate was concentrated under reduced pressure (water bath temperature 20°C) to give 2-dispiro[2.0.2.1]heptan-7-ylacetonitrile (21 g, 84%) as a clear dark amber oil.

1H NMR (400 MHz, chloroform-d) δ 2.42 (d, J=6.6 Hz, 2H), 1.69 (t, J=6.6 Hz, 1H), 1.02-0.88 (m, 4H), 0.79-0.70 (m, 2H), 0.66-0.55 (m, 2H).

Step 3: 2-dispiro[2.0.2.1]heptan-7-ylacetic acid

To a solution of 2-dispiro[2.0.2.1]heptan-7-ylacetonitrile (2.1 g, 14.19 mmol) in EtOH (32 mL) was added sodium hydroxide (5.12 g, 128.0 mmol), then water ( 13 ml) and the resulting solution was stirred and heated to 70°C overnight. The mixture was then cooled to room temperature, diluted with water and extracted with diethyl ether. The aqueous phase was brought to pH 1 by adding 6 N. hydrochloric acid (which led to a cloudy precipitate) and extracted with diethyl ether (3x). The organic phases were dried (magnesium sulfate), filtered and concentrated to give 2dispiro[2.0.2.1]heptan-7-ylacetic acid (2.19 g, 99% yield, 98% purity) as an orange solid, which was used in the next step without additional cleaning.

1H NMR (400 MHz, chloroform-d) δ 2.44 (d, J=6.9 Hz, 2H), 1.67 (t, J=6.9 Hz, 1H), 0.91 (ddd, J=9.0, 5.2, 3.9 Hz, 2H) , 0.81 (dddd, J=8.9, 5.2, 3.9, 0.5 Hz, 2H), 0.69 (dddd, J=8.9, 5.2, 3.9 Hz, 2H), 0.56-0.44 (m, 2H).

Step 4: 2-dispiro[2.0.2.1]heptan-7-ylethanol

To lithium aluminum hydride (827.4 mg, 902.3 μL, 21.80 mmol) dissolved in tetrahydrofuran (33.71 mL), cooled in an ice/water bath, was added 2-dispiro[2.0.2.1]heptane-7- ylacetic acid (2.552 g, 16.77 mmol) in tetrahydrofuran (7.470 ml) dropwise over 15 min, maintaining the reaction temperature <20°C. The mixture was allowed to stir for a total of 18 hours, gradually warming to ambient temperature. The mixture was cooled in an ice/water bath and quenched sequentially by slowly adding water (838.4 mg, 838.4 μL, 46.54 mmol), then sodium hydroxide (1.006 mL 5 M, 5.031 mmol), then water (2.493 g, 2.493 ml, 138.4 mmol) to obtain a white granular suspension, which was filtered through celite. The filtered solid was washed with diethyl ether. The filtrate was concentrated in vacuo at ~300 mbar and a 30°C water bath. The residue was diluted with diethyl ether, dried (magnesium sulfate), filtered and concentrated in vacuo at -300 mbar and a 30°C water bath, and then ~30 seconds under vacuum, yielding 2-dispiro[2.0.2.1]heptane-7-ylethanol ( 2.318 g, 100%), which was used directly in the next step without further purification.

1H NMR (400 MHz, chloroform-d) δ 3.64 (s, 2H), 1.68 (d, J=6.7 Hz, 2H), 1.39 (s, 1H), 1.31 (s, 1H), 0.82 (d, J= 14.0 Hz, 4H), 0.65 (s, 2H), 0.50 (d, J=3.6 Hz, 2H).

Step 5: tert-butyl 3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazole-1-carboxylate

To a solution of tert-butyl-5-oxo-1H-pyrazole-2-carboxylate (2.942 g, 15.97 mmol) and 2dispiro[2.0.2.1]heptan-7-ylethanol (2.318 g, 16.77 mmol) in tetrahydrofuran ( 36.78 mL) triphenylphosphine (4.399 g, 16.77 mmol) was added. Diisopropyl azodicarboxylate (3.391 g, 3.302 mL, 16.77 mmol) was added slowly dropwise over 10 minutes (moderately exothermic). The reaction mixture was stirred at room temperature for 30 min, then at

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50°C for 30 min. Tetrahydrofuran was removed in vacuo. Toluene (23.54 ml) was added to the crude residue and the mixture was stirred overnight as the precipitate gradually crystallized. After the celite was suspended, the precipitate was filtered and washed with toluene (8.705 ml) and again with toluene (8.705 ml). The filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate to give tert-butyl-3(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazole-1-carboxylate (3.449 g, 71 %). MS-ESI m/z calc. 304.17868, detected 305.1 (M+1)+; retention time: 0.82 min (LC method A).

Step 6: 3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)-1H-pyrazole

tert-Butyl-3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazole-1-carboxylate (5.304 g, 17.43 mmol) was dissolved in dichloromethane (53.04 ml) with trifluoroacetic acid (29, 81 g, 20.14 ml, 261.4 mmol), and the reaction mixture was stirred at room temperature for 120 minutes. The reaction mixture was evaporated, the resulting oil was partitioned between ethyl acetate and saturated sodium bicarbonate solution, and the layers were separated. The aqueous portion was extracted two more times with ethyl acetate, then the organic layers were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give an oil, 3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)-1H-pyrazole (3.56 g, 100%). MS-ESI m/z calc. 204.12627, detected 205.1 (M+1) ⁺ ; retention time: 0.59 min (LC method A).

Step 7: tert-butyl 2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridine-3carboxylate

tert-Butyl 2,6-dichloropyridine-3-carboxylate (4.322 g, 17.42 mmol), 3-(2-dispiro[2.0.2.1]heptan-7ylethoxy)-1H-pyrazole (3.559 g, 17.42 mmol) and potassium carbonate (2.891 g, 20.92 mmol) were combined in anhydrous dimethyl sulfoxide (71.18 ml). 1,4-Diazabicyclo[2.2.2]octane (391.1 mg, 3.487 mmol) was added and the mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was diluted with water (136.9 ml) and stirred for 15 min. The resulting white solid was filtered and washed with water. The solid was dissolved in dichloromethane and dried over magnesium sulfate. The mixture was filtered and evaporated to give tert-butyl-2-chloro-6-[3-(2dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3-carboxylate (5.69 g, 79 %) as a white solid.

Ή NMR (400 MHz, chloroform-d) δ 8.35 (d, J=2.9 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 5.94 (d , J=2.9 Hz, 1H), 4.25 (s, 2H), 1.90 (d, J=6.8 Hz, 2H), 1.62 (s, 9H), 1.49 (t, J=6.6 Hz, 1H), 0.85 (d , J=1.5 Hz, 4H), 0.65 (d, J=1.5 Hz, 2H), 0.52 (d, J=1.1 Hz, 2H). MS-ESI m/z calc. 415.16626, found 360.0 (M-tBu)+; Retention time: 2.09 min (LC method B).

Step 8: 2-chloro-6-[3-(2-dispiro[2.0.2.1] heptan-7-ylethoxy)pyrazol-1 -yl]pyridin-3-carboxylic acid

tert-Butyl 2-chloro-6-[3-(2-d ispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3-carboxylate (5.85 g, 14.07 mmol) dissolved in dichloromethane (58.5 ml) with trifluoroacetic acid (16.26 ml, 211.1 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated and ether was added to the resulting solid, then the ether was removed at reduced pressure. This evaporation from ether was repeated twice more to give a white solid, 2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridine-3-carboxylic acid . (5.06 g, 100%).

¹ H NMR (400 MHz, chloroform-d) δ 8.41 (d, J=8.5 Hz, 1H), 8.37 (d, J=2.9 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 5.97 ( d, J=2.9 Hz, 1H), 4.27 (s, 2H), 1.91 (d, J=6.7 Hz, 2H), 1.50 (s, 1H), 0.85 (d, J=1.5 Hz, 4H), 0.71- 0.62 (m, 2H), 0.52 (d, J=1.1 Hz, 2H). MS-ESI m/z calc. 359.10367, found 360.2 (M+1) ⁺ ; Retention time: 2.16 min (LC method B).

Step 9: tert-butyl 4-[3-[3-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1yl]pyridin-3-carbonyl] sulfamoyl]pyrazol-1-yl]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

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2-Chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (400 mg, 1.112 mmol) and carbonyldiimidazole (273.5 mg , 1.687 mmol) were combined in tetrahydrofuran (2 ml) and stirred for 90 min at room temperature. Tert-butyl 2,2-dimethyl-4[3-(3-sulfamoylpyrazol-1-yl)propyl]pyrrolidine-1-carboxylate (429.5 mg, 1.111 mmol) was then added followed by 1,8diazabicyclo[5.4. 0]undec-7-ene (430.8 mg, 2.830 mmol) and the reaction mixture was stirred at room temperature for 1 hour, then heated to 50°C and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and then with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexanes to 100% ethyl acetate to give tert-butyl-4-[3-[3-[[2-chloro -6-[3-(2-dispiro[2.0.2.1]heptan-7ylethoxy)pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]pyrazol-1-yl]propyl]-2,2-dimethylpyrrolidine- 1-carboxylate (350 mg, 43%) as an off-white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.34 (s, 1H), 8.08 (d, J=8.2 Hz, 1H), 7.77 (s, 1H), 7.62 (d, J=8.3 Hz, 1H),

6.71-6.49 (m, 1H), 6.10 (d, J=2.8 Hz, 1H), 4.23 (s, 2H), 4.13 (s, 2H), 3.52 (s, 1H), 2.73 (d, J=6.0 Hz , 1H), 2.08 (d, J=6.7 Hz, 1H), 1.81 (k, J=6.6 Hz, 5H), 1.47 (t, J=6.5 Hz, 1H), 1.40-1.21 (m, 18H), 0.83 (d, J=2.0 Hz, 4H), 0.66-0.60 (m, 2H), 0.52-0.46 (m, 2H). MS-ESI m/z calc. 727.2919, detected 728.1 (M+1)+; retention time: 0.92 min (LC method A).

Step 10: 2-χλορ-Ν-[1-[3-(5,5-dimethylpyrrolidin-3-yl)propyl]pyrazol-3-yl]sulfonyl-6-[3-(2dispiro[2.0.2.1]heptan- 7-ylethoxy)pyrazol-1 -yl]pyridin-3-carboxamide

tert-Butyl 4-[3-[3-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]pyrazole -1-yl]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (350 mg, 0.4806 mmol) was dissolved in dichloromethane (1.527 ml) and trifluoroacetic acid (2.192 g, 1.481 ml, 19.22 mmol) was added to the mixture ), and the resulting mixture was stirred at room temperature for 60 minutes. The mixture was concentrated to dryness under reduced pressure, dissolved in saturated aqueous sodium bicarbonate and ethyl acetate containing a small amount of methanol to ensure solubility, and the layers were separated. The organic layer was concentrated by rotary evaporation followed by high vacuum pump to give 2-chloro-N-[1-[3-(5,5-dimethylpyrrolidin-3yl)propyl]pyrazol-3-yl]sulfonyl-6-[3(2- dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3carboxamide (301.9 mg, 100%) as an off-white solid.

1H NMR (400 MHz, CDCl ₃ ) δ 8.28 (d, J=2.8 Hz, 1H), 8.21 (d, J=8.3 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.44 (s, 1H), 6.67 (s, 1H), 5.88 (d, J=2.8 Hz, 1H), 4.22 (t, J=6.8 Hz, 2H), 4.17 (s, 2H), 3.55 (s, 1H), 3.03 ( s, 1H), 2.23 (s, 1H), 1.88 (d, J=6.7 Hz, 2H), 1.83 (s, 3H), 1.48 (s, 1H), 1.46-1.35 (m, 5H), 1.35-1.24 (m, 4H), 0.84 (t, J=1.9 Hz, 4H), 0.63 (d, J=1.6 Hz, 2H), 0.51 (d, J=1.1 Hz, 2H).

Step 11: 4-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-20,20-dimethyl-10λ ⁶ -thia1,3,9 ,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (compound 176)

2-χλορ-Ν-[1-[3-(5,5-dimethylpyrrolidin-3-yl)propyl]pyrazol-3-yl]sulfonyl-6-[3-(2dispiro[2.0.2.1]heptane-7- ylethoxy)pyrazol-1-yl]pyridin-3-carboxamide (310 mg, 0.4935 mmol), potassium carbonate (341.1 mg, 2.468 mmol), cesium fluoride (112.8 mg, 0.7426 mmol), molecular 3 A sieves and dimethyl sulfoxide (9.3 ml) in a vial, which was purged with nitrogen, capped, heated to 155 ° C

- 229 044967 and stirred for 20 hours. Cooled to room temperature, then the mixture was filtered, diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate and then with saline. The organic layers were separated, dried over sodium sulfate, evaporated and then purified by silica gel chromatography using a gradient of 100% hexanes to 100% ethyl acetate to give 4-[3-(2-{dispiro[2.0.2.1]heptane) as a white solid -7-yl}ethoxy)-1H-pyrazol-1yl]-20,20-dimethyl-10X ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2, 4,6,11 (22), 12pentaene-8,10,10-trione (compound 176) (117 mg, 40%).

1H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 8.16 (d, J=2.8 Hz, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.48 (d, J=2.3 Hz, 1H), 7.26 (s, 1H), 7.07 (d, J=2.3 Hz, 1H), 7.02 (d, J=8.3 Hz, 1H), 5.86 (d, J=2.8 Hz, 1H), 4.36 (d, J=13.5 Hz, 1H), 4.24 (s, 2H), 3.95 (d, J=12.4 Hz, 1H), 2.74 (t, J=8.1 Hz, 1H), 2.15 (d, J=4.2 Hz, 2H) , 2.08-1.93 (m, 3H), 1.89 (d, J=6.7 Hz, 2H), 1.76 (dd, J=11.9, 5.3 Hz, 1H), 1.59 (s, 3H), 1.55 (s, 5H), 0.85 (k, J=2.0 Hz, 4H), 0.64 (d, J=1.7 Hz, 2H), 0.51 (d, J=1.2 Hz, 2H). MS-ESI m/z calc. 591.26276, detected 592.4 (M+1)+; Retention time: 2.37 min (LC method B).

Example 47: Preparation of (14S)-8-[3-(2-{dispiro[2.0.2.1]heptαn-7-yl}ethyl)-2-oxopyrrolidin-1-yl]12,12-dimethyl-2X ⁶ -thia -3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 1) (compound 177) and (14S)-8-[3-(2{dispiro[2.0.2.1]heptan-7-yl}ethyl)-2-oxopyrrolidin-1 -yl]-12,12-dimethyl-2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4- trione (diastereomer 2) (compound 178)

Step 1: 7-(2-bromoethyl)dispiro[2.0.2.1]heptane

To a stirred solution of triphenylphosphine (1.07 g, 4.080 mmol) in anhydrous dichloromethane (15 ml) under a nitrogen atmosphere at -15°, a solution of molecular bromine (0.22 ml, 4.271 mmol) in dichloromethane (3 ml) was added dropwise over 10 min. and upon completion of addition (pale orange solution), the mixture was stirred for a further 15 minutes at -15°C. The mixture was then cooled to -30°C and a solution of 2dispiro[2.0.2.1]heptan-7-ylethanol (537 mg, 3.885 mmol) and pyridine (330 μL, 4.080 mmol) in dichloromethane (4 mL) was added dropwise over 5 min , and upon completion of the addition, the mixture was heated to 5°C and stirred for 2 hours. The reaction mixture was then poured into pentane (350 ml), resulting in the formation of a mass of yellow precipitate. This suspension was filtered and the filtrate was evaporated on a rotary evaporator (250 mbar and 30° C. water bath) to obtain a white solid. Pentane was added to this solid and the mixture was briefly sonicated and filtered. Concentration of this filtrate gave 7-(2-bromoethyl) dispiro[2.0.2.1]heptane (634 mg, 81%) as a pale yellow oil, which was used in the next step without any further purification.

1H NMR (400 MHz, chloroform-d) δ 3.37 (t, J=7.1 Hz, 2H), 2.02-1.96 (m, 2H), 1.46 (t, J=6.4 Hz, 1H), 0.91-0.78 (m, 4H), 0.66 (dddd, J=8.1, 4.8, 3.6 Hz, 2H), 0.50 (dddd, J=9.0, 4.9, 3.7, 0.9 Hz, 2H).

Step 2: 1-benzyl-3-(2-dispiro[2.0.2.1]heptan-7-ylethyl)pyrrolidin-2-one

A 100 mL three-neck flask was dried using a heat gun under vacuum and filled with nitrogen. The flask was charged with 1-benzylpyrrolidin-2-one (0.46 ml, 2.875 mmol) and anhydrous tetrahydrofuran (5 ml). After cooling to -78°C, a solution of n-butyllithium (1.3 mL, 2.5 M, 3.250 mmol) (2.5 M in hexane) was added dropwise, causing the formation of an orange solution. After stirring at -78°C for 20 minutes, a solution of 7-(2-bromoethyl)dispiro[2.0.2.1]heptane (611 mg, 3.038 mmol) in tetrahydrofuran (1 ml) was added dropwise. The mixture was stirred in a cooling bath, which was allowed to slowly

- 230 044967 but warm up to room temperature. After 17 hours, the mixture was quenched by adding saturated aqueous ammonium chloride (50 ml). The product was extracted with ethyl acetate (2 x 30 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography using a gradient of ethyl acetate (0 to 100% over 30 min) in hexane. Evaporation of the solvents gave 1-benzyl-3-(2-dispiro[2.0.2.1]heptan-7ylethyl)pyrrolidin-2-one (352 mg, 41%) as a colorless oil.

1H NMR (400 MHz, chloroform-d) δ 7.38-7.17 (m, 5H), 4.45 (k, J=14.7 Hz, 2H), 3.22-3.10 (m, 2H), 2.42 (qd, J=8.8, 4.1 Hz, 1H), 2.21-2.07 (m, 1H), 2.00-1.85 (m, 1H), 1.62 (dk, J=12.7, 8.4 Hz, 1H), 1.51-1.42 (m, 2H), 1.42-1.25 ( m, 2H), 0.88-0.71 (m, 4H), 0.68-0.55 (m, 2H), 0.51-0.39 (m, 2H). MS-ESI m/z calc. 295.1936, found 296.3 (M+1)+; Retention time: 2.08 min (LC method B).

Step 3: 3-(2-dispiro[2.0.2.1]heptan-7-ylethyl)pyrrolidin-2-one

A 100 ml flask was charged under a nitrogen atmosphere with 1-benzyl-3-(2-dispiro[2.0.2.1]heptan-7ylethyl)pyrrolidin-2-one (350 mg, 1.185 mmol), propylamine (4 ml) and 1,2 -ethanediamine (510 µl, 7.629 mmol). The mixture was cooled to -20°C (external cooling bath temperature) and lithium (72 mg, 10.37 mmol) was added (wire briefly rinsed with hexane, then freshly cut into small pieces). A blue color appeared around the small pieces of lithium, which then quickly disappeared. After 2 hours at -20°C the blue color became permanent. The reaction was quenched by adding methanol (400 μl) at -20°C and water (40 ml). After warming to room temperature, the white solid in suspension was filtered, washed with water and air dried briefly (200 mg). The material was purified by flash chromatography on silica gel using a gradient of methanol (0 to 15% over 30 min) in dichloromethane to give 3-(2-dispiro[2.0.2.1]heptan-7-ylethyl)pyrrolidin-2-one (173 mg, 71 %) as a white solid.

1H NMR (400 MHz, chloroform-d) δ 5.69 (broad s, 1H), 3.41-3.24 (m, 2H), 2.37-2.20 (m, 2H), 1.88 (dddd, J=13.4, 9.1, 7.4, 3.8 Hz, 1H), 1.83-1.67 (m, 1H), 1.53-1.41 (m, 2H), 1.41-1.29 (m, 2H), 0.86-0.74 (m, 4H), 0.670.59 (m, 2H), 0.51-0.39 (m, 2H). MS-ESI m/z calc. 205.14667, found 206.2 (M+1) ⁺ ; Retention time: 1.61 min (LC method B).

Step 4: (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethyl)-2-oxopyrrolidin-1-yl]-12,12-dimethyl2λ ⁶ -thia-3 ,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4trione (diastereomer 1) (compound 177) and (148)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethyl)-2oxopyrrolidin-1 -yl]-12,12-dimethyl-2λ ⁶ -thia -3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 2) (connection 178)

(14S)-8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23) was loaded into a 4 ml ampoule. 5,7,9,19,21-hexaene-2,2,4-trione (100 mg, 0.2222 mmol), 3-(2-dispiro[2.0.2.1]heptan-7-ylethyl)pyrrolidine-2- he (47 mg, 0.2289 mmol), Pd ₂ (dba) ₃ (32 mg, 0.03495 mmol), xanthos (19 mg, 0.03284 mmol), cesium carbonate (365 mg, 1.120 mmol) and anhydrous dioxane (1.5 ml). The mixture was purged with nitrogen for approximately 5 minutes, capped and stirred at 120°C for 16 hours. The organic solvent was evaporated by purging the vial with nitrogen. The reaction mixture was diluted with dimethyl sulfoxide (3 ml), microfiltered and subjected to reverse phase preparative HPLC (C ₁₈ ) using a gradient of acetonitrile in water (1 to 99% in 15 min) and hydrochloric acid as a modifier. Pure fractions were collected and organic solvents were evaporated. The resulting aqueous solution was extracted with dichloromethane and the organic phase was dried over sodium sulfate. Evaporation of the solvents gave a residue, which was purified by flash chromatography on silica gel using a gradient of methanol (0 to 5% over 30 min) in dichloromethane. The resulting product was dissolved in dimethyl sulfoxide (2 ml) and further purified by preparative HPLC using a gradient of acetonitrile in water from 50 to 99% over 15 min (hydrochloric acid as modifier). Pure fractions were collected and organic solvents were evaporated. The resulting aqueous solution was extracted with dichloromethane and the organic phase

- 231 044967 dried over sodium sulfate. Evaporation of the solvents gave a diastereomeric mixture, which was subjected to SLC separation (ChiralCel OJ-H (250x10 mm), 5 µM column; mobile phase 24% acetonitrile/methanol (90:10, unmodified), 76% carbon dioxide, 10 ml/min; concentration 24 mg/ml in a mixture of acetonitrile/methanol/dimethyl sulfoxide (72:8:20); injection volume 70 µl, 100 bar). The pure product fractions were combined, the solvents were evaporated and the residue was triturated in dichloromethane/hexane. The first diastereomer to elute was (14S)-8-[3-(2-{dispiro[2.0.24.13]heptan-7-yl}ethyl)-2oxopyrrolidin-1-yl]-12,12-dimethyl-2λ ⁶ -thia- 3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4 trione (diastereomer 1) (compound 177) (6.3 mg, 9%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.38 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.62-7.45 (m, 2H), 7.03 (d, J=7.2 Hz, 1H ), 6.95 (broad s, 1H), 6.70 (d, J=8.7 Hz, 1H), 4.04 (t, J=8.9 Hz, 1H), 3.91 (broad d, J=25.4, 13.2 Hz, 1H) , 3.74 (k, J=9.0, 8.4 Hz, 1H), 3.11 (broad s, 1H), 2.94 (broad d, J=13.5 Hz, 1H), 2.76-2.63 (m, 1H), 2.642.54 (m, 1H), 2.22 (k, J=9.0, 8.2 Hz, 1H), 2.10 (broad s, 1H), 1.92-1.63 (m, 4H), 1.64-1.18 (m, 14H), 0.89-0.70 (m, 4H), 0.68-0.57 (m, 2H), 0.53-0.39 (m, 2H). MS-ESI m/z calc. 618.2988, detected 619.5 (M+1)+; Retention time: 2.37 min (LC method B).

The second diastereomer eluted was (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethyl)-2oxopyrrolidin-1-yl]-12,12-dimethyl-2λ ⁶ -thia- 3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 2 ) (compound 178) (5.2 mg, 7%).

Ή NMR (400 MHz, dimethyl sulfoxide-d6) δ 12.38 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.62-7.45 (m, 2H), 7.03 (d, J=7.0 Hz, 1H) , 6.95 (broad s, 1H), 6.70 (d, J=8.6 Hz, 1H), 3.93 (t, J=9.3 Hz, 2H), 3.82 (k, J=9.9, 8.9 Hz, 1H), 3.10 (broad .s, 1H), 2.93 (br.d, J=13.0 Hz, 1H), 2.76-2.55 (m, 2H), 2.31-2.17 (m, 1H), 2.09 (b.s, 1H), 1.86-1.63 (m, 4H), 1.61-1.29 (m, 14H), 0.86-0.73 (m, 4H), 0.67-0.58 (m, 2H), 0.51-0.40 (m, 2H). MS-ESI m/z calc. 618.2988, detected 619.5 (M+1)+; Retention time: 2.37 min (LC method B).

Example 48: Preparation of (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-2-oxopyrrolidin-1-yl]12,12-dimethyl-2λ ⁶ -thia -3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 1) (compound 179) and (14S)-8-[3-(2{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-2-oxopyrrolidin-1-yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4- trione (diastereomer 2) (compound 180)

Step 1: 3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrrolidin-2-one

A 100 mL flask was charged under nitrogen atmosphere with 2-dispiro[2.0.2.1]heptan-7-ylethanol (502 mg, 65 wt%, 2.361 mmol) (contains 35% w/w residual tetrahydrofuran), 3-bromopyrrolidine -2-one (390 mg, 2.378 mmol) and anhydrous tetrahydrofuran (12 ml). The mixture was cooled to -50°C, then [bis(trimethylsilyl)amino]potassium (10 ml 0.5 M in toluene, 5,000 mmol) was added dropwise and the mixture was stirred at -50°C for 15-20 min, then ice bath at 0°C for 3 hours. The reaction mixture was allowed to slowly warm to room temperature (pinkish reaction mixture). After 14 h, the mixture was cooled to 0°C, then glacial acetic acid (210 μL, 3.693 mmol) was added to the reaction mixture to obtain an orange suspension. Saline (75 ml) and ethyl acetate (75 ml) were added and the two phases were separated. The aqueous phase was further extracted with ethyl acetate (2x25 ml). The combined organic extracts were dried over sodium sulfate, filtered and the solvents were evaporated. The crude residue was purified by silica gel chromatography (0-15% methanol in dichloromethane gradient over 30 min) to give the desired 3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrrolidin-2-one (399 mg, 76 %) as a pale orange resin that hardened slowly.

1H NMR (400 MHz, DMSO-d6) δ 7.74 (broad s, 1H), 3.84 (dd, J=7.7, 7.1 Hz, 1H), 3.71 (dt, J=9.2, 6.7 Hz, 1H), 3.44 (dt , J=9.3, 6.8 Hz, 1H), 3.22-3.01 (m, 2H), 2.27 (dtd, J=12.8, 7.4, 3.7 Hz, 1H), 1.78 (ddt, J=12.8, 8.4, 7.1 Hz, 1H ), 1.57 (k, J=6.7 Hz, 2H), 1.35 (t, J=6.6 Hz, 1H), 0.87-0.70 (m, 4H), 0.67-0.55 (m, 2H), 0.54-0.36 (m, 2H). MS-ESI m/z calc. 221.14159, detected 222.2 (M+1)+; retention time: 1.35 min (LC method B).

Step 2: tert-butyl 2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)-2-oxo-pyrrolidin-1yl]pyridine-3-carboxylate

0% N N CI

SG N CI

Tert-butyl 2,6-dichloropyridine-3carboxylate (424 mg, 1.709 mmol) and 3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrrolidin-2-one ( 376 mg, 1.699 mmol) in anhydrous N,N-dimethylformamide (4 ml). Potassium carbonate (724 mg, 5.239 mmol) (325 mesh) was added followed by 1,4-diazabicyclo[2.2.2]octane (62 mg, 0.5527 mmol). The mixture was stirred at ambient temperature under a nitrogen atmosphere. After 16 h, the reaction was quenched by adding water (50 ml) and then extracted with ethyl acetate (3x40 ml). The organic phase was dried over sodium sulfate, filtered and the volatiles were evaporated. The product was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0 to 50% over 30 min) in hexane. The pure fractions were collected and the solvents were evaporated to give tert-butyl 2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)-2oxopyrrolidin-1-yl]pyridine-3-carboxylate (555 mg , 75%) in the form of a colorless resin.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.33 (d, J=8.6 Hz, 1H), 8.24 (d, J=8.6 Hz, 1H), 4.32 (dd, J=8.8, 7.9 Hz, 1H), 4.07-3.94 (m, 1H), 3.86-3.64 (m, 2H), 3.56 (dt, J=9.2, 6.8 Hz, 1H), 2.49-2.38 (m, 1H), 1.89 (dk, J=12.5, 8.8 Hz, 1H), 1.62 (k, J=6.7 Hz, 2H), 1.55 (s, 9H), 1.39 (t, J=6.6 Hz, 1H), 0.88-0.71 (m, 4H), 0.69-0.57 (m , 2H), 0.46 (d, J=8.8 Hz, 2H). MS-ESI m/z calc. 432.18158, detected 433.3 (M+1) ⁺ ; retention time: 2.43 min (LC method B).

Step 3: 2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)-2-oxo-pyrrolidin-1 -yl]pyridine-3carboxylic acid

N N CI

N N CI

Tert-butyl 2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)2-oxo-pyrrolidin-1-yl]pyridin-3-carboxylate (533) was added to a 100 ml bottle mg, 1.231 mmol), dichloromethane (5 ml) and trifluoroacetic acid (1.4 ml, 18.17 mmol) (color quickly changed to brown). The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane and hexanes, and the volatiles were evaporated under reduced pressure. The residue was triturated with dichloromethane/hexanes and the volatiles were evaporated (the cycle was repeated 3 times) to give 2-chloro-6-[3-(2dispiro[2.0.2.1]heptan-7-ylethoxy)-2-oxo-pyrrolidin-1-yl ]pyridine-3-carboxylic acid (479 mg, 103% yield, 93% purity) as a pale gray solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 13.51 (s, 1H), 8.34 (d, J=8.6 Hz, 1H), 8.31 (d, J=8.5 Hz, 1H), 4.32 (t, J=8.3 Hz, 1H), 4.01 (ddd, J=11.2, 8.8, 2.8 Hz, 1H), 3.88-3.63 (m, 2H), 3.56 (dt, J=9.3, 6.7 Hz, 1H), 2.47-2.37 (m, 1H), 1.89 (dk, J=12.2, 8.6 Hz, 1H), 1.62 (k, J=6.7 Hz, 2H), 1.39 (t, J=6.5 Hz, 1H), 0.93-0.69 (m, 4H), 0.69-0.56 (m, 2H), 0.46 (d, J=8.6 Hz, 2H). MS-ESI m/z calc. 376.119, detected 377.1 (M+1) ⁺ ; retention time: 1.83 min (LC method B).

Step 4: tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)-2-oxopyrrolidine- 1-yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine 1-carboxylate

- 233 044967

2-chloro-6-[3-(2dispiro[2.0.2.1]heptan-7-ylethoxy)-2-oxopyrrolidin-1-yl]pyridine-3-carboxylic acid (475 mg) was charged into a 100 ml round bottom flask under nitrogen atmosphere , 1.261 mmol) and anhydrous tetrahydrofuran (8 ml). Carbonyldiimidazole (225 mg, 1.388 mmol) (freshly recrystallized from tetrahydrofuran) was added and the mixture was stirred under nitrogen at room temperature for 2. Another 150 mg of carbonyldiimidazole was added and the mixture was stirred at room temperature for 2 hours. In a separate 20 ml flask, the solution tert-butyl (4S)2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (520 mg, 1.260 mmol) in anhydrous tetrahydrofuran (4 ml) prepared under a nitrogen atmosphere and subsequently added via syringe to the activated ester solution. 1,8Diazabicyclo[5.4.0]undec-7-ene (0.95 mL, 6.353 mmol) was added via syringe and the reaction mixture was stirred at room temperature under nitrogen overnight. After 18 hours, the solvents were removed under reduced pressure and the resulting thick oil was treated with ethyl acetate (30 ml) and water (30 ml). Aqueous hydrochloric acid (1.4 mL 6 M, 8,400 mmol) was added slowly (final pH 5) and the two phases were separated. The aqueous phase was again extracted with ethyl acetate (30 ml). The combined organic extracts were washed with brine (30 ml) and dried over sodium sulfate. After filtration and evaporation of the solvents, the residue (1.34 g) was dissolved in dichloromethane and purified by flash silica gel chromatography using a gradient of ethyl acetate (0 to 100% over 30 min) in hexane to give the still crude product. This material was further purified by flash silica gel chromatography using a gradient of ethyl acetate (0 to 100% over 30 min) in hexanes to give tert-butyl(4S)-4-[3-[[6-[[2-chloro- 6-[3-(2-disniro[2.0.2.1]heptan-7-ylethoxy)-2-oxopyrrolidin-1yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine -1-carboxylate (449 mg, 46%) as a white foamy solid. MS-ESI m/z calc. 770.3229, detected 771.5 (M+1)+; retention time: 2.43 min (LC method B).

Step 5: 2-chloro-N-[[6-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]nponylamino]-2-pyridyl]sulfonyl]6-[3-(2-dispiro[ 2.0.2.1]heptan-7-ylethoxy)-2-oxo-pyrrolidin-1-yl]pyridin-3-carboxamide (dihydrochloride salt)

Tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]gentan-7-ylethoxy)-2oxopyrrolidine-1 was loaded into 100 ml -yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2dimethylpyrrolidine-1-carboxylate (440 mg, 0.5704 mmol), dichloromethane (5 ml) and hydrochloric acid (800 µl 4M in dioxane, 3,200 mmol). The reaction was stirred at room temperature for almost 3 hours. Volatiles were removed by evaporation under vacuum. The residue was triturated with dichloromethane/hexanes and the solvents were evaporated. The operation was repeated until a white solid was obtained. Drying in vacuo gives 2-chloro-N-[[6-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2pyridyl]sulfonyl]-6-[3-(2-dispiro[ 2.0.2.1] heptan-7-ylethoxy)-2-oxopyrrolidin-1 -yl] pyridin-3 carboxamide (dihydrochloride salt) (453 mg, 107%) as a white solid. The product was used in the next step without further purification.

¹ H NMR (400 MHz, DMSO-a ₆ ) δ 12.75 (broad s, 1H), 9.12 (broad s, 1H), 8.99 (broad s, 1H), 8.32 (d, J=8.5 Hz, 1H) , 8.02 (dd, J=8.5, 0.8 Hz, 1H), 7.61 (dd, J=8.5, 7.2 Hz, 1H), 7.26 (broad s, 1H) 7.19-7.11 (m, 1H), 6.75 (dd, J=8.5, 0.7 Hz, 1H), 4.32 (t, J=8.3 Hz, 1H), 3.97 (td, J=8.8, 8.3, 4.7 Hz, 1H), 3.84-3.65 (m, 2H), 3.56 (dt , J=9.2, 6.7 Hz, 1H), 3.35-3.28 (m, 1H) 3.29-3.15 (m, 2H), 2.88-2.73 (m, 1H), 2.49-2.25 (m, 2H), 1.98-1.81 ( m, 2H), 1.62 (k, J=6.7 Hz, 2H), 1.56-1.44 (m, 3H), 1.44-1.33 (m, 6H), 1.28-1.26 (m, 3H), 0.82-0.76 (m, 4H), 0.680.57 (m, 2H), 0.53-0.39 (m, 2H). MS-ESI m/z calc. 670.27045, detected 671.4 (M+1) ⁺ ; retention time: 1.65 min (LC method B).

Step 6: (14S)-8-[3-(2-{dispiro[2.0.2.1]heptαn-7-yl}ethoxy)-2-oxopyrrolidin-1-yl]-12,12dimethyl-2λ ⁶ -thia-3 ,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione

- 234 044967

A 50 ml round bottom flask equipped with a magnetic stirrer was charged under a nitrogen atmosphere.

2-chloro-N-[[6-[3-[(3S)-5,5-dimethyln-pyrrolidin-3-yl]pronylαamino]-2-pyridyl]sulfonyl]-6-[3-(2 dispiro[2.0.2.1 ] heptan-7-ylethoxy)-2-oxopyrrolidin-1-yl]pyridin-3-carboxamide (dihydrochloride salt) (446 mg, 0.5993 mmol), anhydrous NMP (25 ml), anhydrous potassium carbonate (615 mg, 4.450 mmol) (325 mesh). The mixture was vigorously stirred in a dry bath at 150°C under a nitrogen atmosphere for 14 hours, then at 155°C for 3 hours, then at 160°C for 3.5 hours. After cooling to room temperature, the mixture was poured into cold water (200 ml) and acidified by adding aqueous hydrochloric acid (1.5 ml 6 M, 9,000 mmol) (slight foaming). The resulting solid was filtered and air dried briefly. The solid was dissolved in dichloromethane and the resulting opaque solution was decanted to remove the remaining water and dried over sodium sulfate. After concentration, the residue 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 followed by trituration in dichloromethane/hexanes and evaporation of the solvents gives (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)2-oxopyrrolidin-1-yl]-12 ,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20- hexaene-2,2,4-trione (198 mg, 52%) as a white solid. MS-ESI m/z calc. 634.29376, detected 635.4 (M+1)+; retention time: 2.17 min (LC method B).

Step 7: (148)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-2-oxopyrrolidin-1-yl]-12,12dimethyl-2X ⁶ -thia-3 ,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (diastereomer 1) (compound 179) and (148)-8-[3-(2-{dispiro[2.0.2.1]heptan-7yl}ethoxy)-2-oxopyrrolidin-1 -yl]-12,12-dimethyl-2X ⁶ -thia -3,9,11,18,23-pentaazatetracyclo

[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 2) (compound 180) diastereomer 1 diastereomer 2 (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-2-oxopyrrolidin-1-yl]-12,12-dimethyl-2λ ⁶ -thia3,9, 11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (200 mg, 0 .3088 mmol) was subjected to chiral separation by SLC chromatography using a ChiralPak OJ-H (250x10 mm) column (particle size 5 μm) with a mobile phase of 20% acetonitrile/methanol (90:10)/80% carbon dioxide at 10 ml /min for 8.0 min [injection volume = 70 μl of a 24 mg/ml solution in acetonitrile/methanol/dimethyl sulfoxide (85:9:6)], giving as the first diastereomer (14S)-8-[3-( 2-{dispiro[2.0.2.1]heptαn-7-yl}ethoxy)-2-oxopyrrolidin-1-yl]-12,12dimethyl-2X ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3. 1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (diastereomer 1) (compound 179) (86 mg, 43%, >98 % ee) as a white solid, ¹ H NMR (400 MHz, DMSO-06) δ 12.43 (s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.57 (dd, J=8.5, 7.2 Hz , 1H), 7.51 (d, J=8.4 Hz, 1H), 7.04 (d, J=7.1 Hz, 1H), 6.96 (d, J=9.0 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H ), 4.22 (t, J=7.9 Hz, 1H), 4.02 (ddd, J=10.9, 8.6, 3.2 Hz, 1H), 3.91 (k, J=11.4 Hz, 1H), 3.79 (dt, J=9.2, 6.7 Hz, 1H), 3.70 (dt, J=10.5, 7.5 Hz, 1H), 3.55 (dt, J=9.2, 6.7 Hz, 1H), 3.18-3.06 (m, 1H), 2.94 (d, J=13.2 Hz, 1H), 2.76-2.62 (m, 1H), 2.40 (dtd, J=12.3, 7.2, 2.9 Hz, 1H), 2.18-2.01 (m, 1H), 1.97-1.86 (m, 1H), 1.82 ( dd, J=12.1, 5.4 Hz, 1H), 1.79-1.68 (m, 1H), 1.62 (k, J=6.7 Hz, 4H) (actually two triplets, 2 X 2H), 1.57 (s, 3H), 1.55 -1.49 (m, 1H), 1.46 (s, 3H), 1.38 (t, J=6.5 Hz, 1H), 1.30-1.23 (m, 1H), 0.84-0.77 (m, 4H), 0.67-0.57 (m , 2H), 0.50-0.41 (m, 2H); MS-ESI m/z calc. 634.29376, detected 635.4 (M+1)+; Retention time: 2.19 min (LC method B); and as the second eluting diastereomer (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)2-oxopyrrolidin-1 -yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 2) (compound 180) (76 mg, 38%, >98% ee) as a white solid;

1H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 12.41 (s, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.57 (t, J=7.9 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.04 (d, J=7.2 Hz, 1H), 6.96 (s, 1H), 6.70 (d, J=8.5 Hz, 1H), 4.27 (t, J=8.2 Hz, 1H), 3.91 ( t, J=9.9 Hz, 2H), 3.78 (t, J=8.2 Hz, 2H), 3.54 (k, J=8.2 Hz, 1H), 3.14-3.04 (m, 1H), 2.98-2.89 (m, 1H ),

- 235 044967

2.72-2.63 (m, 1H), 2.16-2.03 (m, 1H), 1.89-1.72 (m, 3H), 1.61 (two triplets, 2 X 2H), 1.57 (s, 3H), 1.53-1.48 (m,

1H), 1.46 (s, 3H), 1.41-1.35 (m, 1H), 1.35-1.19 (m, 2H), 0.83-0.76 (m, 4H), 0.62 (d, J=8.9 Hz, 2H), 0.46 (d,

J=8.8 Hz, 2H); MS-ESI m/z calc. 634.29376, detected 635.4 (M+1)+; Retention time: 2.18 min (LC method B).

Example 49: preparation of (14S)-12,12-dimethyl-8-{3-[2-(2,2,3,3-tetramethylcyclopropyl)ethoxy]-1Hpyrazol-1-yl}-2X ⁶ -thia-3, 9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (compound 185)

Step 1: 1-chloro-2,2,3,3-tetramethyl-1-(1,2,2-trichlorovinyl)cyclopropane

2,3-Dimethylbut-2-ene (20.5 mL, 172.5 mmol) and 1,2,3,3tetrachlorocyclopropene (29.1 g, 163.6 mmol) were added to a microwave-safe vessel. The reaction vial was sealed and heated at 155°C for 16 hours. The reaction mixture was cooled to room temperature and transferred to a flask. The crude reaction mixture was flask-to-flask distilled in vacuo at 195°C to give 1-chloro-2,2,3,3-tetramethyl-1-(1,2,2-trichlorovinyl)cyclopropane (37.49 g, 87 %) in the form of an orange liquid.

¹ H NMR (400 MHz, chloroform-d) δ 1.25 (s, 3H), 1.22 (s, 3H), 1.20 (s, 3H), 1.18 (s, 3H).

Step 2: 3-ethynyl-1,1,2,2-tetramethylcyclopropane

1-Chloro-2,2,3,3-tetramethyl-1-(1,2,2trichlorovinyl)cyclopropane (17.4 g, 66.41 mmol) and diethyl ether (300 mL) were added to a 500 mL round bottom flask. The reaction mixture was cooled to -78°C and stirred for 15 minutes. n-Butyllithium solution (118 mL 2.5 M, 295.0 mmol) was added dropwise over 30 min and the mixture was allowed to warm to room temperature over 2 h and stirred at room temperature for an additional 1 h. The reaction mixture was cooled to -10°C and water (35 ml, 1.943 mol) was added dropwise and the mixture was allowed to stir and warm to room temperature over 30 minutes. The reaction mixture was extracted with ether, dried over sodium sulfate, filtered and evaporated. The crude reaction mixture was purified by distillation at 80°C in vacuo to give 3-ethynyl-1,1,2,2-tetramethylcyclopropane (6.059 g, 75%).

1H NMR (400 MHz, chloroform-d) δ 1.96 (d, J=2.2 Hz, 1H), 1.11 (d, J=3.8 Hz, 12H), 0.86 (d, J =0.9 Hz, 1H).

Step 3: 2-(2,2,3,3-tetramethylcyclopropyl)ethanol

Add 3-ethynyl-1,1,2,2-tetramethylcyclopropane (4.1 g, 33.55

- 236 044967 mmol) and tetrahydrofuran (25 ml). The reaction mixture was cooled in a -30°C bath for 5 minutes. A solution of borane in tetrahydrofuran (33.6 mL of 1 M, 33.60 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature over 30 minutes. The reaction mixture was cooled to -10°C and sodium hydroxide (28.5 ml, 6 M, 171.0 mmol) followed by hydrogen peroxide (38 ml, 30% w/v, 335.1 mmol) was carefully added. The reaction mixture was allowed to stir for 30 minutes while warming to room temperature. The reaction mixture was extracted with ether, dried over sodium sulfate, filtered and evaporated to give the crude aldehyde intermediate. Methanol (40 ml) was added to the crude aldehyde. The reaction mixture was cooled to 0°C and sodium borohydride (2.54 g, 67.14 mmol) was added in portions. The reaction mixture was allowed to stir for 1 hour while warming to room temperature. The reaction was quenched with a solution of saturated ammonium chloride and brine and extracted with ether. The organic layer was dried over sodium sulfate, filtered and evaporated to give 2-(2,2,3,3-tetramethylcyclopropanol (1.800 g, 38%) as an oil.

1H NMR (400 MHz, chloroform-d) δ 3.64 (t, J=6.9 Hz, 2H), 1.54 (k, J=7.0 Hz, 2H), 1.06 (s, 6H), 0.93 (s, 6H), 0.13 (t, J=7.1 Hz, 1H). MS-ESI m/z calc. 142.13577, found 143.1 (M+1)+; Retention time: 1.49 min (LC method B).

Step 4: tert-butyl 3-[2-(2,2,3,3-tetramethylcyclopropyl)ethoxy]pyrazole-1-carboxylate

To a solution of tert-butyl-5-oxo-1H-pyrazole-2-carboxylateα (884 mg, 4.799 mmol) and 2-(2,2,3,3tetramethylcyclopropyl)ethanol (650 mg, 4.570 mmol) in tetrahydrofuran (10 ml) triphenylphosphine (1.26 g, 4.804 mmol) was added. Diisopropyl azodicarboxylate (970 mg, 4.797 mmol) was slowly added dropwise to the mixture over 2 min at room temperature (exothermic effect noted). The reaction mixture was stirred at room temperature for 30 minutes. Tetrahydrofuran was removed in vacuo, toluene (30 ml) was added and the mixture was stirred overnight. No precipitate was observed and the mixture was evaporated and purified by silica gel chromatography (0 to 50% ethyl acetate in hexane gradient) to give tert-butyl-3-[2-(2,2,3,3-tetramethylcyclopropyl)ethoxy]pyrazole-1 -carboxylate (700 mg, 50%).

1H NMR (400 MHz, chloroform-d) δ 7.82 (d, J=2.9 Hz, 1H), 5.86 (d, J=2.9 Hz, 1H), 4.27 (t, J=7.2 Hz, 2H), 1.72 (k , J=7.2 Hz, 2H), 1.61 (s, 10H), 1.05 (s, 6H), 0.95 (s, 6H), 0.22 (t, J=7.2 Hz, 1H). MS-ESI m/z calc. 308.21, found 309.24 (M+1) ⁺ ; Retention time: 0.89 min (LC method A).

Step 5: 3-[2-(2,2,3,3-tetramethylcyclopropyl)ethoxy]-1H-pyrazole

Sodium hydroxide (2, 35 ml 2M, 4.700 mmol) and the mixture was stirred at ambient temperature for 30 minutes. Most of the methanol was removed in vacuo and the residue was diluted with water (14 ml) and aqueous hydrochloric acid (4.5 ml of 1 M, 4,500 mmol). The mixture was extracted with ethyl acetate and the organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a pale yellow oil, 3[2-(2,2,3,3-tetramethylcyclopropyl)ethoxy]-1H-pyrazole ( 471 mg, 100%), which was used directly in the next step. MS-ESI m/z calc. 208.15756, detected 209.2 (M+1) ⁺ ; Retention time: 1.77 min (LC method E).

Step 6: Ethyl 2-chloro-6-[3-[2-(2,2,3,3-tetramethylcyclopropyl)ethoxy]pyrazol-1-yl]pyridine-3carboxylate o

Ethyl 2,6-dichloropyridine-3-carboxylate (494 mg, 2.245 mmol), 3-[2-(2,2,3,3tetramethylcyclopropyl)ethoxy]-1H-pyrazole (471 mg, 2.261 mmol) and potassium carbonate (373 mg, 2.699 mmol) were combined in anhydrous dimethyl sulfoxide (10 ml). 1,4-Diazabicyclo[2.2.2]octane (50.5 mg, 0.4502 mmol) was added and the mixture was stirred at room temperature under nitrogen for 20 hours. The reaction mixture was diluted with water (16 ml) and stirred for 15 min. The resulting white

- 237 044967 the solid was collected by filtration and washed with water. The solid was dissolved in dichloromethane and dried over sodium sulfate. The mixture was filtered and evaporated to give ethyl 2-chloro-6-[3-[2-(2,2,3,3-tetramethylcyclopropyl)ethoxy]pyrazol-1-yl]pyridine-3-carboxylate as an off-white solid. 800 mg, 91%).

1H NMR (400 MHz, chloroform-d) δ 8.36 (d, J=2.9 Hz, 1H), 8.27 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 5.97 (d , J=2.9 Hz, 1H), 4.41 (k, J=7.2 Hz, 2H), 4.25 (t, J=7.2 Hz, 2H), 1.77 (k, J=7.2 Hz, 2H), 1.42 (t, J =7.2 Hz, 3H), 1.08 (s, 6H), 0.97 (s, 6H), 0.25 (t, J=7.2 Hz, 1H). MS-ESI m/z calc. 391.16626, detected 392.2 (M+1)+; retention time: 2.25 min (LC method E).

Step 7: 2-chloro-6-[3-[2-(2,2,3,3-tetramethylcyclopropyl)ethoxy]pyrazol-1-yl]pyridine-3carboxylic acid

Ethyl 2-chloro-6-[3-[2-(2,2,3,3-tetramethylcyclopropyl)ethoxy]pyrazol-1-yl]pyridine-3-carboxylate (800 mg, 2.041 mmol) in tetrahydrofuran (4,000 ml ) and ethanol (1600 ml) were treated with sodium hydroxide (2.0 ml 2 M, 4,000 mmol) and the solution was stirred at room temperature for 1 hour. Most of the solvent was removed under reduced pressure and the solution was acidified by slow addition of citric acid (8.0 ml, 10% w/v, 4.164 mmol) with ice cooling. The resulting thick suspension (~ pH 3) was stirred in an ice bath for 1 hour, filtered and washed with excess water. The collected solid was completely dissolved in dichloromethane, dried over sodium sulfate, filtered and concentrated to dryness using toluene as an azeotrope, and then dried in vacuo for 21 hours to give 2-chloro-6-[3-[2-(2. 2,3,3tetramethylcyclopropyl)ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (710 mg, 96%) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 13.56 (s, 1H), 8.52-8.29 (m, 2H), 7.72 (d, J=8.4 Hz, 1H), 6.18 (d, J=2.8 Hz, 1H ), 4.23 (t, J=6.8 Hz, 2H), 1.72 (k, J=7.0 Hz, 2H), 1.04 (s, 6H), 0.95 (s, 6H), 0.27 (t, J=7.2 Hz, 1H ).MSIE m/z calc. 363.13498, detected 364.2 (M+1) ⁺ ; retention time: 2.35 min (LC method G).

Step 8: tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-[2-(2,2,3,3-tetramethylcyclopropyl)ethoxy]pyrazol1-yl] pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1carboxylate

2-Chloro-6-[3-[2-(2,2,3,3-tetramethylcyclopropyl)ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (255 mg, 0.7009 mmol) and carbonyl diimidazole ( 125 mg, 0.7709 mmol) were combined in tetrahydrofuran (5.738 ml) and stirred for 90 min at room temperature. Tert-butyl (4S)-2,2dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (350 mg, 0.8484 mmol) was added followed by anhydrous 1,8 -diazabicyclo[5.4.0]undec-7-ene (275 μl, 1.839 mmol) and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and then with brine. The organic phase was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure, then purified by silica gel chromatography using a gradient of 100% hexanes to 80% ethyl acetate in hexanes to give tert-butyl (4S)-4-[3- [[6-[[2-chloro-6-[3-[2(2,2,3,3-tetramethylcyclopropyl)ethoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl ]-2,2-dimethylpyrrolidine-1-carboxylate (261 mg, 49%) as a white solid. MS-ESI m/z calc. 757.3388, detected 758.5 (M+1) ⁺ ; retention time: 2.43 min (LC method G).

Step 9: (14S)-12,12-dimethyl-8-{3-[2-(2,2,3,3-tetramethylcyclopropyl)ethoxy]-1H-pyrazol-1-yl}2λ ⁶ -thia-3, 9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4trione (compound 185)

- 238 044967

tert-Butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-[2-(2,2,3,3-tetramethylcyclopropyl)ethoxy]pyrazol-1yl]pyridin-3 -carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (115 mg, 0.1516 mmol), potassium carbonate (125 mg, 0.9045 mmol), 3 A molecular sieves and dimethyl sulfoxide (4 ml) were combined in a vial, purged with nitrogen, capped, heated to 160°C and stirred for 72 hours. Cooled to room temperature. The mixture was filtered and the filtrate was diluted with ethyl acetate and washed with sat. aqueous sodium bicarbonate solution and then saline solution. The organic layers were separated, dried over sodium sulfate and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexanes to 70% ethyl acetate in hexanes to give (14B)-12,12-dimethyl - as an off-white solid. 8-{3-[2-(2,2,3,3tetramethylcyclopropyl)ethoxy]-1H-pyrazol-1-yl}-2λ ^b -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05, 10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (compound 185) (18.14 mg, 19%).

1H NMR (400 MHz, chloroform-d) δ 9.96 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.607.49 (m, 2H) , 7.36-7.23 (m, 2H), 6.56 (d, J=8.0 Hz, 1H), 5.92 (d, J=2.9 Hz, 1H), 4.82-4.58 (m, 1H), 4.25 (t, J=7.2 Hz, 2H), 4.00-3.76 (m, 1H), 3.35 (t, J=8.8 Hz, 1H), 3.17 (d, J=14.3 Hz, 1H), 3.07 (t, J=9.8 Hz, 1H), 2.73-2.50 (m, 1H), 2.09 (dd, J=12.3, 7.9 Hz, 1H), 1.76 (k, J=7.1 Hz, 2H), 1.65-1.59 (m, 6H), 1.53-1.41 (m, 2H), 1.08 (s, 6H), 0.97 (s, 6H), 0.90-0.81 (m, 2H), 0.25 (t, J=7.2 Hz, 1H). MS-ESI m/z calc. 621.30975, detected 622.2 (M+1)+; retention time: 2.22 min (LC method B).

Example 50: Preparation of (18S)-4-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-20,20dimethyl-10X ^b -thia- 1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene8,10,10-trione (compound 187)

Step 1: tert-butyl (4S)-2,2-dimethyl-4-[3-(3-sulfamoylpyrazol-1-yl)propyl]pyrrolidine-1-carboxylate

AR AR

V % an- V4 ^HiN ' ΤΛ

N-Μ ⁿ N

Racemic tert-butyl 2,2-dimethyl-4-[3-(3-sulfamoylpyrazol-1yl)propyl]pyrrolidine-1-carboxylate (3.24 g, 8.383 mmol) was chirally separated by SLC chromatography using ChiralPak IG (250x21 column, 2 mm, particle size 5 μm) with 28% methanol/72% carbon dioxide as mobile phase at 70 ml/min for 14.0 min (injection volume = 500 μl of a 32 mg/ml solution in methanol to obtain the second enantiomer eluted , tert-butyl (48)-2,2-dimethyl-4-[3-(3-sulfamoylpyrazol-1-yl)propyl]pyrrolidine-1-carboxylate (1.45 g, 90%).

1H NMR (400 MHz, CDCI3) δ 7.42 (d, J=2.4 Hz, 1H), 6.72 (d, J=2.5 Hz, 1H), 5.08 (s, 2H), 4.22-4.12 (m, 2H), 3.64 (t, J=9.1 Hz, 1H), 2.80 (t, J=10.8 Hz, 1H), 2.05 (s, 1H), 1.99-1.80 (m, 3H), 1.58 (s, 1H), 1.45 (d, J=2.3 Hz, 9H), 1.40 (d, J=11.4 Hz, 4H), 1.27 (s, 4H). MS-ESI m/z calc. 386.19876, detected 387.1 (M+1) ⁺ ; retention time: 239 044967 1.52 min (LC method B).

Step 2: tert-butyl (4S)-4-[3-[3-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1yl]pyridin- 3-carbonyl]sulfamoyl]pyrazol-1-yl]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

2-Chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3-carboxylic acid (1.35 g, 3.752 mmol) and carbonyl diimidazole (761.1 mg, 4.694 mmol) (freshly recrystallized from tetrahydrofuran, washed with cold ether and dried under high vacuum) were combined in tetrahydrofuran (17.55 ml) and stirred for 50 min at room temperature. Then tert-butyl (48)-2,2-dimethyl-4-[3-(3-sulfamoylpyrazol-1-yl)propyl]pyrrolidine-1-carboxylate (1.45 g, 3.752 mmol) in tetrahydrofuran (6, 75 ml), then 1,8-diazabicyclo[5.4.0]undec-7-ene (2.857 g, 18.77 mmol) and the reaction mixture was stirred at room temperature for 16 hours. Tetrahydrofuran was removed using a rotary evaporator, dissolved in ethyl acetate and washed with saturated aqueous ammonium chloride (1X), then with brine (1X), dried (sodium sulfate), filtered and concentrated to a white solid, which was chromatographed on a 275 g C ₁₈ reverse phase column, eluting with a gradient of 50 to 100 % acetonitrile/water. The product was eluted in both pure fractions and mixed fractions with the starting acid. Pure fractions were pooled, concentrated, then partitioned between 6 N. hydrochloric acid and ethyl acetate. The layers were separated, the aqueous layer was washed again with ethyl acetate, then the organic phases were combined, dried (sodium sulfate), filtered and concentrated to a white solid. The mixed fractions from the reverse phase column were combined and concentrated under reduced pressure. The residue was distributed between 6 n. hydrochloric acid and ethyl acetate. The layers were separated, the aqueous layer was washed again with ethyl acetate, then the organic phases were combined, dried (sodium sulfate), filtered and concentrated to a white solid, which was chromatographed on a 275 g C ₁₈ reverse phase column, eluting with a 50 to 100% gradient. acetonitrile/water. The pure fractions were combined, concentrated and added to the purified material from the first column to give tert-butyl (4S)-4-[3-[3-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptane- 7-ylethoxy)pyrazol-1-yl]pyridin-3 carbonyl]sulfamoyl]pyrazol-1-yl]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (1.96 g, 72%).

¹ H NMR (400 MHz, CDCl3) δ 9.50 (s, 1H), 8.30 (d, J=2.9 Hz, 1H), 8.26 (d, J=8.5 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.47 (d, J=2.4 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 5.96 (d, J=2.9 Hz, 1H), 4.25 (t, J=6.8 Hz, 2H) , 4.20 (t, J=7.1 Hz, 2H), 3.66 (s, 1H), 2.83 (t, J=10.6 Hz, 1H), 2.06 (d, J=9.7 Hz, 1H), 1.90 (p, J= 7.2 Hz, 5H), 1.48 (t, J=6.7 Hz, 2H), 1.44 (s, 9H), 1.37 (s, 3H), 1.35-1.29 (m, 2H), 1.26 (s, 3H), 0.87- 0.82 (m, 4H), 0.69-0.64 (m, 2H), 0.51 (d, J=8.8 Hz, 2H).

MS-ESI m/z calc. 727.2919, detected 728.1 (M+1)+; retention time: 0.91 min (LC method A).

Step 3: 2-χλορ-Ν-[1-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propyl]pyrazol-3-yl]sulfonyl-6-[3(2-dispiro[2.0 .2.1] heptan-7-ylethoxy)pyrazol-1 -yl] pyridin-3-carboxamide

tert-Butyl (4S)-4-[3-[3-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin3-carbonyl ]sulfamoyl]pyrazol-1-yl]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (1.96 g, 2.691 mmol) was dissolved in dichloromethane (8.553 ml) and trifluoroacetic acid (8.291 ml, 107.6 mmol), and the mixture was stirred at room temperature for 60 minutes. The mixture was concentrated to dryness under reduced pressure, treated with saturated aqueous sodium bicarbonate and ethyl acetate containing a little methanol to ensure solubility, and the layers were separated. The organic layer was concentrated on a rotary evaporator followed by high vacuum pump to obtain 2-chloro-N-[1-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propyl]pyrazol-3yl]sulfonyl-6- [3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3-carboxamide (1.84 g, 109%) as a yellow solid. MS-ESI m/z calc. 627.23944, detected 628.1 (M+1) ⁺ ; retention time: 0.65 min (LC method A).

Step 4: (18S)-4-[3-(2-{dispiro[2.O.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-2O,20-dimethyl-1Oλ ⁶ - 240 044967 thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.P1,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10- trion (compound 187)

Combined 2-chloro-N-[1-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propyl]pyrazol-3-yl]sulfonyl-6[3-(2-dispiro[2.0.2.1 ]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3-carboxamide (1.69 g, 2.690 mmol), potassium carbonate (1.859 g, 13.45 mmol), cesium fluoride (614.9 mg, 4.048 mmol ), 3 A molecular sieves and dimethyl sulfoxide (102.5 ml) in a vial, purged with nitrogen, capped, heated to 155°C and stirred for 18 hours. Cooled to room temperature and the mixture was filtered, diluted with ethyl acetate and washed with saturated aqueous solution sodium bicarbonate and then saline. The organic layers were separated, dried over sodium sulfate, evaporated and then purified by silica gel chromatography using a gradient of 100% hexanes to 100% ethyl acetate to give (18S)-4-[3-(2-{dispiro[2.0) as a white solid .2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1yl]-20,20-dimethyl-10λ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02.7] docose-2,4,6,11(22),12pentaene-8,10,10-trione (compound 187) (1.14 g, 72%).

1H NMR (400 MHz, DMSO-de) δ 12.69 (s, 1H), 8.17 (d, J=2.8 Hz, 1H), 8.00 (d, J=2.3 Hz, 1H), 7.71 (d, J=8.2 Hz , 1H), 6.91-6.84 (m, 2H), 6.06 (d, J=2.7 Hz, 1H), 4.21 (qd, J=7.2, 6.6, 2.7 Hz, 3H), 4.13 (dd, J=13.7, 11.3 Hz, 1H), 2.72-2.62 (m, 1H), 2.09 (d, J=12.0 Hz, 2H), 1.94-1.84 (m, 1H), 1.84-1.75 (m, 5H), 1.55 (s, 3H) , 1.47 (s, 3H), 1.47-1.43 (m, 1H), 1.33 (t, J=12.3 Hz, 1H), 0.82 (k, J=2.6 Hz, 4H), 0.68-0.58 (m, 3H), 0.49 (dd, J=7.8, 4.2 Hz, 2H). MS-ESI m/z calc. 591.26276, detected 592.1 (M+1) ⁺ ; retention time: 2.34 min (LC method B).

Example 51: Preparation of 8-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12,18-trimethyl-2λ ⁶ thia-3,9,11,18,23-pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4trione (compound 189)

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

Dess-Martin periodinane (2.0 g, 4.715 mmol) at 0°C in a nitrogen atmosphere. The resulting heterogeneous reaction mixture was slowly warmed to room temperature and stirred for another 2 hours. The reaction mixture was diluted with diethyl ether and filtered through a pad of celite.

The filtrate was concentrated and the residue was purified with a silica gel short plug using a 1:1 mixture of hexanes and ether to give tert-butyl 2,2-dimethyl-4-(3-oxopropyl)pyrrolidine-1-carboxylate (992 mg, 100% ) in the form of a colorless viscous oil. MS-ESI m/z calc. 255.18344, detected 256.2 (M+1)+; Retention time: 0.64 min (LC method A).

Step 2: tert-butyl 2,2-dimethyl-4-[3-(methylamino)propyl]pyrrolidine-1-carboxylate

- 241 044967

To a solution of tert-butyl-2,2-dimethyl-4-(3-oxopropyl)pyrrolidine-1-carboxylate (500 mg, 1.958 mmol) in dichloromethane (10 ml) was added sodium acetate (241 mg, 2.938 mmol), and then methylamine (1.2 ml 2 M, 2,400 mmol). The reaction mixture was stirred at room temperature for 1 hour, cooled to 0°C and sodium cyanoborohydride (372 mg, 5.920 mmol) was added under a nitrogen atmosphere. The heterogeneous reaction mixture was slowly warmed to room temperature and stirred for an additional 16 hours. The reaction mixture was quenched with water and slowly extracted with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The reaction mixture was purified by reverse phase HPLC-MS using a dual gradient of 20-80% mobile phase B over 15.0 min (mobile phase A=water (5 mM hydrochloric acid), mobile phase B=acetonitrile) to obtain tert -butyl-2,2-dimethyl-4-[3(methylamino)propyl]pyrrolidine-1-carboxylate (154 mg, 29%) as a viscous oil.

¹ H NMR (400 MHz, chloroform-d) δ 3.80-3.53 (m, 1H), 3.04-2.81 (m, 3H), 2.69 (k, J=4.8 Hz, 3H), 2.13 (s, 1H), 1.89 (s, 3H), 1.80 (s, 2H), 1.45 (d, J=10.5 Hz, 12H), 1.38 (s, 2H), 1.29 (s, 3H). MS-ESI m/z calc. 270.23074, found 271.3 (M+1)+; Retention time: 0.47 min (LC method A).

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

To a solution of tert-butyl-2,2-dimethyl-4-[3-(methylamino)propyl]pyrrolidine-1-carboxylate (154 mg, 0.5695 mmol) in dimethyl sulfoxide (2 ml) was added 6-fluoropyridine-2-sulfonamide (103 mg, 0.5847 mmol) and then diisopropylethylamine (500 μl, 2.871 mmol). The flask was sealed and heated at 90°C under a nitrogen atmosphere (balloon) in an oil bath for 14 hours. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate and washed with brine, dried over sodium sulfate, filtered and evaporated. The resulting residue was purified by silica gel chromatography using a gradient of 100% hexanes to 100% ethyl acetate to give tert-butyl-2,2dimethyl-4-[3-[methyl-(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine -1-carboxylate (141 mg, 58%) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.65 (dd, J=8.6, 7.2 Hz, 1H), 7.12 (s, 2H), 7.01 (d, J=7.2 Hz, 1H), 6.78 (d, J =8.7 Hz, 1H), 3.53 (k, J=7.8, 7.4 Hz, 3H), 3.17 (d, J=3.6 Hz, 1H), 3.04 (s, 3H), 2.84-2.72 (m, 1H), 2.09 (d, J=9.5 Hz, 1H), 1.88 (td, J=12.8, 5.7 Hz, 1H), 1.53 (dt, J=14.6, 7.4 Hz, 2H), 1.36 (dd, J=15.0, 10.6 Hz, 14H), 1.23 (s, 3H). MS-ESI m/z calc. 426.23007, detected 427.3 (M+1) ⁺ ; retention time: 0.47 min (LC method A).

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

In a 20 ml scintillation vial, 2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1yl]pyridine-3-carboxylic acid (141 mg, 0.3858 mmol) and carbonyldiimidazole (65 mg, 0.4009 mmol) were combined in tetrahydrofuran (2 ml) and stirred for 2 hours at room temperature. Tert-butyl 2,2-dimethyl-4-[3-[methyl-(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (134 mg, 0.3141 mmol) was then added followed by 1. 8 diazabicyclo[5.4.0]undec-7-ene (100 µl, 0.6687 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with a small amount of 1:1 saturated aqueous ammonium chloride /saline solution. The organic phases were separated, dried over sodium sulfate, filtered and evaporated. The resulting brown residue was purified by silica gel chromatography using a shallow gradient from 100% dichloromethane to 20% methanol in dichloromethane to give tert-butyl 4-[3-[[6-[[2-chloro-6-[3-(3,3 -dicyclopropylpropoxy)pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl]methylamino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (158 mg, 65%) as a white solid.

- 242 044967

1H NMR (400 MHz, chloroform-d) δ 8.29 (d, J=2.8 Hz, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.77-7.60 (m, 2H), 7.52 (d, J= 7.2 Hz, 1H), 6.64 (d, J=8.6 Hz, 1H), 5.98-5.91 (m, 1H), 4.42 (dt, J=8.3, 6.8 Hz, 2H), 4.14-4.04 (m, 1H), 3.91 (d, J=13.9 Hz, 1H), 3.32-3.21 (m, 1H), 3.01 (s, 3H), 2.91 (t, J=10.7 Hz, 1H), 2.18 (d, J=12.8 Hz, 1H ), 2.02-1.93 (m, 2H), 1.79 (td, J=16.6, 14.4, 6.6 Hz, 2H), 1.65-1.48 (m, 2H), 1.37 (s, 9H), 1.30 (s, 3H), 1.25 (s, 3H), 1.22-1.14 (m, 2H), 0.67 (tdd, J=13.3, 6.7, 3.6 Hz, 2H), 0.49-0.39 (m, 4H), 0.37-0.30 (m, 1H), 0.23-0.17 (m, 2H), 0.10 (dtd, J=9.4, 5.1, 4.5, 2.3 Hz, 2H). MS-ESI m/z calc. 769.3388, detected 770.45 (M+1)+; retention time: 0.67 min (LC method A).

Step 5: 8-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12,18-trimethyl-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[17.3 .1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 189)

Solution of tert-butyl 4-[3-[[6-[[2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl]-methyl -amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (153 mg, 0.1986 mmol) in dichloromethane (1.2 ml) and trifluoroacetic acid (150.0 μl, 1.960 mmol) was stirred at room temperature for 4 hours. Then the solvents were removed under vacuum. The residue was dissolved in ethyl acetate, washed with 2 ml of saturated sodium bicarbonate solution, the solvent was removed and dried under high vacuum. The resulting residue was dissolved in dimethyl sulfoxide (8 ml), 4A molecular sieves were added and the reaction mixture was stirred for 10 minutes. Cesium fluoride (98 mg, 0.6451 mmol) and potassium carbonate (91 mg, 0.6584 mmol) were then added and the reaction mixture was heated at 130°C overnight. The reaction mixture was filtered through a Whatman disk filter (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS using a dual gradient of 20-80% mobile phase B over 15.0 min (mobile phase A = water (0.05 % hydrochloric acid), mobile phase B = acetonitrile) to obtain 8-[3-(3,3dicyclopropylpropoxy)-1 H-pyrazol-1 -yl]-12,12,18-trimethyl-2λ ⁶ -tua-3,9 ,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 189) (76 mg, 60%) as an off-white solid.

1H NMR (400 MHz, chloroform-d) δ 10.54 (s, 1H), 8.19 (d, J=2.8 Hz, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.67 (dd, J=8.6, 7.3 Hz, 1H), 7.60-7.54 (m, 1H), 7.37 (d, J=8.4 Hz, 1H), 6.69 (dd, J=8.7, 0.8 Hz, 1H), 5.92 (d, J=2.8 Hz, 1H), 4.43 (t, J=6.8 Hz, 2H), 4.37 (s, 1H), 3.37 (dd, J=9.8, 7.2 Hz, 1H), 3.13-3.05 (m, 1H), 3.01 (s, 3H ), 2.87 (d, J=26.3 Hz, 1H), 2.24 (dd, J=12.5, 9.1 Hz, 1H), 1.97 (k, J=6.8 Hz, 2H), 1.70 (s, 1H), 1.65 (s , 3H), 1.61 (s, 3H), 1.55 (dd, J=12.5, 8.5 Hz, 1H), 1.50-1.40 (m, 4H), 0.72-0.59 (m, 2H), 0.50-0.39 (m, 4H ), 0.34 (ddd, J=15.9, 9.0, 6.9 Hz, 1H), 0.23-0.16 (m, 2H), 0.15-0.07 (m, 2H). MS-ESI m/z calc. 633.30975, detected 634.22 (M+1) ⁺ ; retention time: 1.55 min (LC method J).

Example 52: Preparation of (14R)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12dumethyl-2λ ⁶ -thia- 3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (compound 194 )

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

Racemic tert-butyl-2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine 1-carboxylate (7 g, 16.97 mmol) was subjected to chiral resolution using SLC chromatography With

- 243 044967 using ChiralPak IG (250x21.2 mm column, 5 µm particle size) with a mobile phase of 40% methanol/60% carbon dioxide at 70 ml/min for 11.0 min (injection volume = 500 µl of 32 mg/ solution) ml in methanol as the second enantiomer eluting tert-butyl (4R)-2,2-dimethyl-4-[3-[(6sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (3.167 g, 90%) ESI-MS m/z calculated 412.21442, detected 413.2 (M+1)+, retention time: 0.63 min (LC method).

Step 2: tert-butyl (4R)-4-[3-[[6-[[2-chloro-6-[3-(2-dispiro[2.0.2.1 ]heptan-7-ylethoxy)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-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3-carboxylic acid (1.95 g, 5.420 mmol) in tetrahydrofuran ( 20 ml) carbonyldiimidazole (1.03 g, 6.073 mmol) was added and the mixture was stirred at ambient temperature for 1 hour. To this mixture was added tert-butyl (4R)-2,2-dimethyl-4-[3-[ (6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1 carboxylate (1.95 g, 4.301 mmol) into tetrahydrofuran (9 ml), then 1,8-diazabicyclo[5.4.0]undec-7-ene ( 2.0 ml, 13.37 mmol), and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with water (50 ml) and the mixture was acidified with hydrochloric acid (5 ml 6 M, 30.00 mmol). The mixture was extracted with ethyl acetate (200 ml) and the organic phase was separated. The organic phase was washed with brine and the combined aqueous phases were back-extracted with 50 ml ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting crude product was chromatographed on a 275 g C ₁₈ reverse phase column, eluting with 50-100% acetonitrile/water. Product fractions were collected and concentrated in vacuo to give tert-butyl (4R)-4-[3-[[6-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy )pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (2.73 g, 65%).

1H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 8.38 (t, J=2.3 Hz, 1H), 8.11 (d, J=8.3 Hz, 1H), 7.70 (d, J=8.3 Hz , 1H), 7.62 (dd, J=8.5, 7.2 Hz, 1H), 7.18 (dd, J=12.6, 6.3 Hz, 2H), 6.74 (d, J=8.5 Hz, 1H), 6.16 (dd, J= 2.9, 1.4 Hz, 1H), 4.24 (t, J=6.6 Hz, 2H), 3.57-3.44 (m, 1H), 3.24 (t, J=6.0 Hz, 2H), 2.74 (t, J=10.5 Hz, 1H), 2.01 (tt, J=11.9, 6.5 Hz, 1H), 1.82 (k, J=6.6 Hz, 3H), 1.49 (dt, J=13.0, 6.9 Hz, 3H), 1.36 (d, J=11.6 Hz, 10H), 1.33-1.24 (m, 6H), 1.17 (s, 3H), 0.89-0.75 (m, 4H), 0.71-0.60 (m, 2H), 0.54-0.44 (m, 2H). MS-ESI m/z calc. 753.30756, detected 754.4 (M+1) ⁺ ; retention time: 3.69 min (LC method D).

Step 3: 2-chloro-N-[[6-[3-[(3R)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2pyridyl]sulfonyl]-6-[3-(2-dispiro[2.0 .2.1 ]heptan-7-ylethoxy)pyrazol-1 -yl] pyridin-3-carboxamide (trifluoroacetate salt)

To a solution of tert-butyl (4R)-4-[3-[[6-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1yl]pyridin- 3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1 carboxylate (2.73 g, 3.619 mmol) in dichloromethane (15 ml) and toluene (5 ml) was added trifluoroacetic acid (3 ml, 38.94 mmol) and the mixture was stirred at ambient temperature for 48 hours. The solvent was removed in vacuo with a bath temperature set at 45°C to obtain a thick yellow oil. The oil was diluted with toluene (20 ml) and the solvent was removed in vacuo with a bath temperature set at 45°C to give 2-chloro-N-[[6-[3-[(3R)-5,5-dimethylpyrrolidin-3yl] propylamino]-2-pyridyl]sulfonyl]-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1yl]pyridin-3-carboxamide (trifluoroacetate salt) (2.78 g, 100%) in the form of oil, which was used without further purification.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.78 (s, 1H), 8.61 (s, 2H), 8.39 (d, J=2.9 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H) , 7.71 (d, J=8.3 Hz, 1H), 7.63 (dd, J=8.5, 7.2 Hz, 1H), 7.34-7.11 (m, 5H), 6.75 (dd, J=8.6, 0.7 Hz, 1H), 6.18 (d, J=2.9 Hz, 1H), 4.24 (t, J=6.7 Hz, 2H), 3.36 (dt, J=11.6, 6.1 Hz, 1H), 3.25 (k, J=6.6 Hz, 2H), 2.89-2.71 (m, 1H), 2.30 (s, 2H), 1.93 (dd, J=12.9, 7.6 Hz, 1H), 1.89-1.71 (m, 2H), 1.48 (k, J=7.2, 6.3 Hz, 4H), 1.34 (s, 5H), 1.24 (d, J=6.0 Hz, 4H), 0.89-0.75 (m, 4H), 0.70-0.62 (m, 2H), 0.55-0.46 (m, 2H). MS-ESI m/z calc. 653.2551, detected 654.3 (M+1) ⁺ ; retention time: 2.49 min (LC method D).

Step 4: (14R)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ ⁶ - 244 044967 thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4trione (connection 194)

To a solution of 2-chloro-N-[[6-[3-[(3R)-5,5-dimethylpyrrolidin-3-yl]pronulamino]-2pyridyl]sulfonyl]-6-[3-(2-dispiro[2.0. 2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3-carboxamide (trifluoroacetate salt) (2.78 g, 3.619 mmol) in NMP (50 ml) was added potassium carbonate (2.5 g, 18.09 mmol). The mixture was purged with nitrogen for 5 minutes. The mixture was heated at 135°C for 22 hours. The reaction mixture was cooled to room temperature and added to water (150 ml). The mixture was carefully acidified with hydrochloric acid (7 ml 6 M, 42.00 mmol) to obtain a foamy suspension. The solid was collected by filtration using a medium frit. The wet filter cake was dissolved in ethyl acetate (200 ml), washed with 100 ml brine, then concentrated in vacuo. The crude product was diluted with acetonitrile and chromatographed on a C ₁₈ 250 g reverse phase column, eluting with 50-100% water/acetonitrile to give a foam which was dried in a vacuum oven at 45°C for 48 hours to give (14R)-8 -[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1Hpyrazol-1-yl]-12,12-dimethyl-2X ⁶ -thia-3,9,11,18,23 -pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 194) (1.3 g, 57% ).

1H NMR (400 MHz, DMSO-b ₆ ) δ 12.51 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.58 (dd, J=8.5 , 7.2 Hz, 1H), 7.05 (d, J=7.2 Hz, 1H), 6.99 (d, J=8.9 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 6.09 (d, J=2.7 Hz, 1H), 4.21 (td, J=6.6, 1.4 Hz, 2H), 3.92 (d, J=11.8 Hz, 1H), 3.15 (s, 1H), 2.95 (d, J=13.2 Hz, 1H), 2.78-2.64 (m, 1H), 2.12 (s, 1H), 1.90-1.70 (m, 4H), 1.60 (s, 6H), 1.51 (s, 3H) , 1.47 (t, J=6.5 Hz, 1H), 1.31 (k, J=12.0 Hz, 1H), 0.89-0.78 (m, 4H), 0.70-0.61 (m, 2H), 0.55-0.44 (m, 2H ). MS-ESI m/z calc. 617.27844, detected 618.4 (M+1)+; retention time: 3.38 min (LC method D).

Example 53: preparation of (14S)-8-[3-(2-{disπuro[2.0.2.1]heπtan-7-yl}ethoxy)-1H-πyrazol-1-yl]-12,12dimethyl-2Х ⁶ -thia- 3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (compound 195 )

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

To a solution of 2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (5.2 g, 14.45 mmol) in tetrahydrofuran (100 ml), carbonyl diimidazole (2.8 g, 16.51 mmol) was added and the mixture was stirred at ambient temperature for 1 hour. To this mixture was added tert-butyl (45)-2,2-dimethyl-4- [3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1carboxylate (6.0 g, 14.54 mmol) in tetrahydrofuran (15 ml), then 1,8-diazabicyclo[5.4.0]undec -7-ene (6.5 ml, 43.47 mmol) and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with water (150 ml) and the mixture was acidified with aqueous hydrochloric acid (15 ml, 6 M, 90 .00 mmol). The mixture was extracted with ethyl acetate (300 ml) and the organic phase was separated. The organic phase was washed with brine, dried over magnesium sulfate, filtered through celite and concentrated in vacuo to give a white precipitate. The precipitate was suspended in acetonitrile, the solid was collected by filtration using a medium glass frit and washed with acetonitrile. The filtrate was concentrated in vacuo to give a yellow oil. Unrefined oil

- 245 044967 was diluted with acetonitrile and some N-methyl-2-pyrrolidone and chromatographed on a C ₁₈ 415 g reverse phase column, eluting with 50-100% acetonitrile in water to give tert-butyl (4S)4-[3-[[ 6-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]- 2,2-dimethylpyrrolidine-1-carboxylate (4.5 g, 41%).

MS-ESI m/z calc. 753.30756, detected 754.4 (M+1)+; retention time: 3.79 min (LC method D).

Step 2: 2-chloro-N-[[6-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2-pyridyl]sulfonyl]6-[3-(2-dispiro[ 2.0.2.1 ]heptan-7 -ylethoxy)pyrazol-1 -yl]pyridin-3-carboxamide (trifluoroacetate salt)

To a solution of tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)nurazol-1yl]pyridin- 3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1 carboxylate (5.9 g, 7.821 mmol) in dichloromethane (30 ml) and toluene (15 ml) added trifluoroacetic acid (6.0 mL, 77.88 mmol) and the mixture was stirred at ambient temperature for 18 hours. The solvent was removed in vacuo with a bath temperature set at 45° C. to obtain a thick yellow oil. The oil was diluted with toluene (125 ml) and the solvent was removed in vacuo with the bath temperature set at 45°C. The oil was diluted with toluene and the solvent was removed in vacuo to give a thick, viscous yellow oil, 2-chloro-N-[[6-[3-[(3S)-5,5-dimethylnirrolidin-3-yl]propylamino]-2pyridyl]sulfonyl ]-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3-carboxamide (trifluoroacetate salt) (6.0 g, 100%), which was used for next stage without additional cleaning. MS-ESI m/z calc. 653.2551, detected 654.3 (M+1) ⁺ ; retention time: 2.6 min (LC method B).

Step 3: (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ ⁶ thia- 3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4trione (compound 195 )

OOO OOO

To a solution of 2-chloro-N-[[6-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propulamino]-2pyridyl]sulfonyl]-6-[3-(2-dispiro[2.0. 2.1 ]heptan-7-ylethoxy)pyrazol-1 -yl]pyridin-3-carboxamide (trifluoroacetate salt) (6.0 g, 7.810 mmol) in NMP (140 ml) was added potassium carbonate (5.3 g, 38.35 mmol). The mixture was purged with nitrogen for 5 minutes. The mixture was then heated at 150°C for 22 hours. The reaction mixture was cooled to room temperature and added to water (300 ml) to obtain an off-white solid. The mixture was carefully acidified with aqueous hydrochloric acid (12 ml 6 M, 72.00 mmol) to obtain a foamy suspension. The solid was collected by filtration using a medium glass frit. The wet filter cake was dissolved in ethyl acetate (500 ml) and washed with 200 ml of saline solution. The aqueous phase was slightly cloudy, so it was acidified with a small amount of 6 N. hydrochloric acid and returned to the organic phase. The aqueous phase was separated and the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give a light yellow oil. This crude product was diluted with acetonitrile and chromatographed on a 415 g C ₁₈ reverse phase column, eluting with a mixture of 50-100% acetonitrile in water. The product was isolated in the form of a cream-colored foam. The foam was dried in vacuum at 45°C for 48 hours, obtaining (14S)-8-[3-(2{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-nirazol-1-yl]- 12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene -2,2,4-trione (compound 195) (3.32 g, 68%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.48 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.57 (dd, J= 8.5, 7.2 Hz, 1H), 7.05 (d, J=7.1 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.71 (d, J= 8.5 Hz, 1H), 6.08 (d, J=2.7 Hz, 1H), 4.21 (td, J=6.7, 1.3 Hz, 2H), 3.92 (d, J=12.0 Hz, 1H), 3.16 (s, 1H) , 2.95 (d, J=13.3 Hz, 1H), 2.78-2.66 (m, 1H), 2.07 (s, 1H), 1.92-1.72 (m, 4H), 1.60 (s, 6H), 1.51 (s, 3H ), 1.47 (t, J=6.5 Hz, 1H), 1.31 (k, J=12.2 Hz, 1H), 0.89-0.77 (m, 4H), 0.69-0.61 (m, 2H), 0.53-0.45 (m, 2H). MS-ESI m/z calc. 617.27844, detected 618.4 (M+1)+; retention time: 10.29 min (LC method F).

The Ca ²⁺ , Na ⁺ and K+ salts of compound 195 were prepared by mixing compound 195 with Ca(OCH ₃ ) ₂ , Na(OCH ₃ ) and KOH, respectively: mixing compound 195 (1 g) and Ca(OCH ₃ ) ₂ (83 mg) in methanol (65 ml) at room temperature for 30 minutes and then at 65°C for 30 minutes; mixing

- 246 044967

Compound 195 (0.6 g (1 mmol)) in MeOH (40 ml) with 25 wt.% Na(OCH3) in MeOH (250 ml (1 molar equivalent)) at 60°C for 20 min; and mixing compounds 195 (0.6 g) in acetone (11 ml) with 1 N. KOH (1 molar equivalent) at 50°C for 1 h. After filtering the resulting hot solutions, the filtrates were evaporated to dryness to obtain the desired amorphous salts, respectively (PXRD data not shown).

Example 54: Preparation of 8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12dimethyl-15-oxa-2λ ⁶ -thia- 3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (enantiomer 1 ) (compound 196) and 8-[3-(2{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-15-oxa-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23),5(10),6,8,19,21 -hexaene-2,2,4-trione (enantiomer

2) (connection 197)

Step 1: tert-butyl 4-[2-[[6-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1yl]pyridin-3-carbonyl ]sulfamoyl]-2-pyridyl]amino]ethoxy]-2,2-dimethyl-pyrrolidine-1-carboxylate

2-Chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (412 mg, 1.145 mmol) and carbonyldiimidazole (185.7 mg , 1.145 mmol) were combined in anhydrous tetrahydrofuran (10.47 ml) and stirred for 60 min at 50°C. A tetrahydrofuran solution (7 ml) of tert-butyl 2,2-dimethyl-4-[2-[(6-sulfamoyl-2-pyridyl)amino]ethoxy]pyrrolidine-1-carboxylate (431.5 mg, 1.041 mmol) was then added and 1,8-diazabicyclo[5.4.0]undec-7-ene (400.7 mg, 393.6 µl, 2.632 mmol). The reaction was heated at 50°C for 4 hours. The reaction was diluted with ethyl acetate and washed with 1 M aqueous citric acid followed by a wash with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified on silica gel using a gradient of 100% hexanes to 75% ethyl acetate in hexanes to give tert-butyl-4-[2- [[6-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]ethoxy ]-2,2-dimethylpyrrolidine-1-carboxylate (452 mg, 57%). MS-ESI m/z calc. 755.2868, detected 756.41 (M+1)+; Retention time: 0.92 min (LC method A).

Step 2: 8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-15-oxa2λ ⁶ -thia-3 ,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,1O]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4trione (compound 188)

tert-Butyl 4-[2-[[6-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3- 247 044967 carbonyl]sulfamoyl]-2-pyridyl]amino]ethoxy]-2,2-dimethylpyrrolidine-1-carboxylate (410 mg, 0.5421 mmol) was dissolved in dichloromethane (6 ml) and trifluoroacetic acid (800 μl, 10 .38 mmol). The reaction solution was stirred at room temperature for 30 minutes. The reaction solution was concentrated to dryness in vacuo under reduced pressure to obtain a residue. Combine this residue and potassium carbonate (450 mg, 3.256 mmol), cesium fluoride (105 mg, 0.6912 mmol), 3 A molecular sieves and dimethyl sulfoxide (5 ml) in a vial, purged with nitrogen, capped, heated to 140 ° C and stirred for 20 hours. The reaction mixture was allowed to cool to room temperature, filtered and then purified by preparative reverse phase chromatography (C ₁₈ column, 30% to 99% acetonitrile (no modifier) in water (5 mM hydrochloric acid) for 30 min) to give a white solid, 8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12dimethyl-15-oxa- 2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5(10),6,8,19,21-hexaene-2,2,4 -trione (compound 188) (330 mg, 97%).

1H NMR (400 MHz, DMSO-dg) δ 12.55 (s, 1H), 8.19 (d, J=2.8 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.59 (t, J=7.9 Hz , 1H), 7.09 (m, 2H), 6.93 (d, J=8.1 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 6.08 (d, J=2.8 Hz, 1H), 4.21 (t , J=6.6 Hz, 2H), 4.10 (s, 2H), 3.88 (t, J=11.8 Hz, 1H), 3.60 (d, J=12.4 Hz, 1H), 2.86 (s, 1H), 2.07 (dd , J=11.9, 6.0 Hz, 1H), 1.81 (k, J=6.6 Hz, 3H), 1.57 (d, J=9.2 Hz, 6H), 1.47 (t, J=6.5 Hz, 1H), 1.23 (s , 2H), 0.94-0.75 (m, 4H), 0.64 (dd, J=8.4, 4.5 Hz, 2H), 0.50 (dd, J=7.8, 4.3 Hz, 2H). MS-ESI m/z calc. 619.2577, detected 620.33 (M+1)+; retention time: 2.25 min (LC method B).

Step 3: 8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-15-oxa2λ ⁶ -thia-3 ,9,11,18,23-pentaazαtetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4trione (enantiomer 1) (compound 196) and 8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]12,12-dimethyl-15-oxa-2λ ⁶ - thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5(10),6,8,19,21-hexaene-2,2,4-trione ( enantiomer 2) (compound 197) enantiomer enantiomer 2

Racemic compound 8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12dimethyl-15-oxa-2λ ⁶ -thia-3, 9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (compound 188) ( 320 mg, 0.5112 mmol) was subjected to chiral SLC chromatography. The following LCLC protocol was used: ChiralPak AS-3 (150x2.1 mm), 3 µm; Mobile phase 35°C: 30% acetonitrile:methanol (90:10), 70% carbon dioxide. The first enantiomer eluted was 8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl15-oxa-2λ ⁶ -thia- 3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21hexaene-2,2,4 trione (enantiomer 1) (compound 196) (63 mg, 39%). MS-ESI m/z calc. 619.2577, detected 620.33 (M+1) ⁺ ; retention time: 2.18 min (LC method B).

The second enantiomer eluted was 8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol1-yl]-12,12-dimethyl-15-oxa-2λ ⁶ -thia- 3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (enantiomer 2 ) (compound 197) (62 mg, 39%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.56 (s, 1H), 8.19 (d, J=2.8 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.09 (d, J=7.2 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 6.08 (d, J=2.8 Hz, 1H), 4.21 (t, J=6.7 Hz, 2H), 3.88 (t, J=11.9 Hz, 1H), 3.60 (d, J=13.0 Hz, 1H), 3.17 (d, J=4.3 Hz, 3H) , 2.86 (s, 1H), 2.08 (dd, J=11.8, 5.9 Hz, 1H), 1.81 (k, J=6.5 Hz, 3H), 1.57 (d, J=9.4 Hz, 6H), 1.47 (t, J=6.5 Hz, 1H), 1.42-1.33 (m, 1H), 1.24 (s, 1H), 0.96-0.78 (m, 4H), 0.72-0.57 (m, 2H), 0.57-0.42 (m, 2H) . MS-ESI m/z calc. 619.2577, found 620.33 (M+1) ⁺ ; Retention time: 2.18 min (LC method B).

Example 55: Preparation of 20,20-dimethyl-4-{3-[2-(2,2,3,3-tetramethylcyclopropyl)ethoxy]-1H-pyrazol1 -yl}-10λ ⁶ -thia-1,3,9 ,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2(7),3,5,11 (22), 12-pentaene8,10,10-trione (enantiomer 1) (compound 206) and 20 ,20-dimethyl-4-{3-[2-(2,2,3,3-tetramethylcyclopropyl)ethoxy]-1 H-pyrazol-1 -yl} -10λ ⁶ -thia-1,3,9,14 ,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose2(7),3,5,11(22),12-pentaene-8,10,10-trione (enantiomer 2) (compound 207)

- 248 044967

Step 1: tert-butyl 4-[3-[3-[[2-chloro-6-[3-[2-(2,2,3,3-tetramethylcyclopropyl)ethoxy]pyrazol-1yl]pyridin-3-carbonyl ]sulfamoyl]pyrazol-1-yl]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

2-Chloro-6-[3-[2-(2,2,3,3-tetramethylcyclopropyl)ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (350 mg, 0.9620 mmol) and carbonyl diimidazole ( 188 mg, 1.159 mmol) were combined in tetrahydrofuran (8.0 ml) and stirred for 90 min at room temperature. Tert-butyl 2,2dimethyl-4-[3-(3-sulfamoylpyrazol-1-yl)propyl]pyrrolidine-1-carboxylate (446 mg, 1.154 mmol) was then added followed by anhydrous 1,8-diazabicyclo[5.4. 0]undec-7-ene (360 µl, 2.407 mmol), and the reaction mixture was stirred at room temperature for 30 minutes followed by heating to 40°C for 20 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, and then saline solution. The organic layers were separated, dried over sodium sulfate, evaporated and then purified by silica gel chromatography using a gradient of 100% hexanes to 80% ethyl acetate in hexanes and then on a second silica gel column using a gradient of 100% dichloromethane to 15% methanol in dichloromethane to give tert-butyl-4-[3-[3-[[2-chloro-6-[3-[2(2,2,3,3-tetramethylcyclopropyl)ethoxy]pyrazol-1-yl]pyridin- 3-carbonyl]sulfamoyl]pyrazol-1yl]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (360 mg, 51%) as a white solid. MSIE m/z calc. 731.3232, detected 732.5 (M+1)+; retention time: 2.14 min (LC method G).

Step 2: 20,20-dimethyl-4-{3-[2-(2,2,3,3-tetramethylcyclopropyl)ethoxy]-1H-pyrazol-1-yl}-10X ⁶ thia-1,3,9, 14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2(7),3,5,11(22),12-pentaene-8,10,10-trione (compound 198)

tert-Butyl 4-[3-[3-[[2-chloro-6-[3-[2-(2,2,3,3-tetramethylcyclopropyl)ethoxy]pyrazol-1-yl]pyridin3-carbonyl]sulfamoyl] pyrazol-1-yl]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (360 mg, 0.4916 mmol), potassium carbonate (400 mg, 2.894 mmol), 3 A molecular sieves and NMP (10 ml) were added to A 20 ml microwave vial was purged with nitrogen, capped, heated to 160°C and stirred for 96 hours. The reaction vessel was cooled to room temperature, filtered and the filtrate was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate followed by brine. The organic layers were separated, dried over sodium sulfate, evaporated and then purified by silica gel chromatography using a gradient of 100% hexanes to 90% ethyl acetate in hexanes to give 20,20-dimethyl-4-{3-[2-(2,2, 3,3-tetramethylcyclopropyl)ethoxy]1H-pyrazol-1-yl}-10Х ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2(7),3 ,5,11(22),12pentaene-8,10,10-trione (compound 198) (59.7 mg, 20%) as a white solid.

1H NMR (400 MHz, chloroform-d) δ 8.42 (s, 1H), 8.17 (d, J=2.8 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), 7.03 (d, J=8.3 Hz, 1H), 5.88 (d, J=2.7 Hz, 1H), 4.43-4.29 (m, 1H), 4.24 (t, J=7.2 Hz, 2H), 4.00-3.87 (m, 1H), 2.75 (t, J=8.3 Hz, 1H), 2.16-2.12 (m, 1H), 2.03-1.94 (m, 2H), 1.76 (k, J=7.1 Hz, 3H), 1.57 (d, J=15.2 Hz, 6H), 1.47 (t, J=12.3 Hz, 2H), 1.10-1.05 (m, 6H), 0.97 (s, 6H ), 0.91-0.75 (m, 2H), 0.25 (t, J=7.2 Hz, 1H). MS-ESI m/z calc. 595.29407, detected 596.2 (M+1) ⁺ ; retention time: 1.94

- 249 044967 min (LC method E).

Step 3: 20,20-dimethyl-4-{3-[2-(2,2,3,3-tetramethylcyclopropyl)ethoxy]-1 H-pyrazol-1 -yl} -10λ ⁶ thia-1,3,9 ,14,22-pentaazatetracyclo[16.2.1.Ш,14.02,7]docose-2(7),3,5,11(22),12-pentaene-8,10,10-trione (enantiomer 1) (compound 206) and 20,20-dimethyl-4-{3-[2-(2,2,3,3-tetramethylcyclopropyl)ethoxy]-1Hpyrazol-1 -yl} -10λ ⁶ -thia-1,3,9,14 ,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2(7),3,5,11 (22), 12pentaene-8,10,10-trione (enantiomer 2) (compound 207)

Racemic 20,20-dimethyl-4-{3-[2-(2,2,3,3-tetramethylcyclopropyl)ethoxy]-1H-pyrazol-1-yl}10λ ⁶ -thia-1,3,9,14, 22-pentaazatetracyclo[16.2.1.111,14.02.7]docose-2(7),3,5,11 (22), 12-pentaene-8,10,10trione (compound 198) (45.4 mg, 0.07544 mmol) was separated by chiral SLC chromatography using ChiralPak AS-H (250 x 21.2 mm column, 5 μm particle size) with 32% acetonitrile:methanol (90:10; no modifier) / 68% carbon dioxide mobile phase at 0.5 ml/min., 20,20-dimethyl-4-{3-[2-(2,2,3,3tetramethylcyclopropyl)ethoxy]-1H-pyrazol-1-yl} was obtained as the first enantiomer eluted -10Х ⁶ -thia-1,3,9,14,22pentaazatetracyclo[16.2.1.111,14.02,7]docose-2(7),3,5,11(22),12-pentaene-8,10,10- trione (enantiomer 1) (compound 206) (18.9 mg, 84%) as a white solid. MS-ESI m/z calc. 595.29407, detected 596.2 (M+1) ⁺ ; retention time: 1.94 min (LC method E).

The second enantiomer eluted was

20,20-dimethyl-4-{3-[2-(2,2,3,3tetramethylcyclopropyl)ethoxy] -1 H-pyrazol-1 -yl} -10Х ⁶ -thia-1,3,9,14,22pentaazatetracyclo [16.2.1.111,14.02.7]docose-2(7),3,5,11(22),12-pentaene-8,10,10-trione (enantiomer 2) (compound 207) (19.2 mg, 85% ) as a white solid.

1H NMR (400 MHz, chloroform-d) δ 8.38 (s, 1H), 8.17 (d, J=2.8 Hz, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.48 (d, J=2.3 Hz , 1H), 7.12-6.99 (m, 2H), 5.88 (d, J=2.7 Hz, 1H), 4.43-4.30 (m, 1H), 4.24 (t, J=7.2 Hz, 2H), 3.93 (t, J=12.1 Hz, 1H), 2.74 (t, J=8.2 Hz, 1H), 2.17-2.11 (m, 1H), 2.04-1.96 (m, 2H), 1.76 (k, J=7.2 Hz, 3H), 1.59 (s, 6H), 1.47 (t, J=12.1 Hz, 2H), 1.08 (s, 6H), 0.97 (s, 6H), 0.92-0.71 (m, 2H), 0.25 (t, J=7.2 Hz , 1H). MS-ESI m/z calc. 595.29407, detected 596.2 (M+1)+; retention time: 1.94 min (LC method E).

Example 56: Preparation of (14S)-12,12-dimethyl-8-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol1-yl]-2λ ⁶ -thia-3,9 ,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (compound 208)

Step 1: 3,3,3-trifluoro-2,2-dimethyl-propan-1-ol

A 1 L three-neck round bottom flask was equipped with a mechanical stirrer, a cooling bath, a dropping funnel, and a J-Kem temperature probe. Lithium aluminum hydride granules (6.3 g, 0.1665 mol) were loaded into the vessel under a nitrogen atmosphere. Tetrahydrofuran (200 ml) was then charged into the vessel under a nitrogen atmosphere. The mixture was left stirring at room temperature for 0.5 h to allow the granules to dissolve. Then crushed ice in water was loaded into the cooling bath and the reaction temperature was reduced to 0°C. A solution of 3,3,3-trifluoro-2,2-dimethylpropane was loaded into a dropping funnel.

- 250 044967 acid (20 g, 0.1281 mol) in tetrahydrofuran (60 ml), and a clear pale yellow solution was added dropwise over 1 hour. Once addition was complete, the mixture was allowed to warm slowly to room temperature and stirring was continued for 24 h. The suspension was cooled to 0°C using an ice bath and then quenched very slowly, dropwise, by adding water (6.3 ml), then sodium hydroxide solution (15 wt.%; 6.3 ml) and finally water (18.9 ml). The reaction temperature of the resulting white suspension was 5°C. The suspension was stirred at ~5°C for 30 min and then filtered through a 20 mm thick layer of celite. The filter cake was washed with tetrahydrofuran (2x100 ml). The filtrate was dried over sodium sulfate (150 g) and then filtered. The filtrate was concentrated under reduced pressure to obtain a clear, colorless oil (15 g) containing a mixture of product 3,3,3-trifluoro-2,2-dimethylpropan-1-ol in tetrahydrofuran (73% wt., product (10.95 g) and 27 wt.% tetrahydrofuran, as determined by 1H-NMR). The distillate from the rotary evaporator was distilled at atmospheric pressure using a 30 cm Vigreux column to obtain 8.75 g of a residue containing 60 wt% tetrahydrofuran and 40 wt% product (3.5 g). These product mixtures in tetrahydrofuran were combined to give 3,3,3-trifluoro-2,2-dimethylpropan-1-ol (14.45 g, 61 wt% in tetrahydrofuran, 79% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 4.99 (t, J=5.7 Hz, 1H), 3.38 (dd, J=5.8, 0.9 Hz, 2H), 1.04 (d, J=0.9 Hz, 6H).

Step 2: tert-butyl 3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazole-1-carboxylate |_| . | OH NN + ₀₌ / NBoc _____ I _O % ^NBoc

F ₃ C / - ⁷

F ₃ C

Mixture of 3,3,3-trifluoro-2,2-dimethylpropan-1-ol (10 g, 70.36 mmol) and tert-butyl-3-hydroxypyrazole 1-carboxylate (12.96 g, 70.36 mmol) in toluene (130 ml) was treated with triphenylphosphine (20.30 g, 77.40 mmol), then isopropyl-N-isopropoxycarbonyliminocarbamate (14.99 ml, 77.40 mmol), and the mixture was stirred at 110°C for 16 hours. Yellow solution concentrated under reduced pressure, diluted with heptane (100 ml) and the precipitated triphenylphosphine oxide was removed by filtration and washed with a mixture of heptane/toluene 4:1 (100 ml). The yellow filtrate was evaporated and the residue was purified by silica gel chromatography with a linear gradient of ethyl acetate in hexane (0-40%), yielding tert-butyl-3-(3,3,3-trifluoro-2,2-dimethyl-methyl-propoxy)pyrazole-1- carboxylate (12.3 g, 57%) as an off-white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.10 (d, J=3.0 Hz, 1H), 6.15 (d, J=3.0 Hz, 1H), 4.18 (s, 2H), 1.55 (s, 9H), 1.21 (s, 6H). MS-ESI m/z calc. 308.13477, detected 309.0 (M+1) ⁺ ; retention time: 1.92 min (LC method B).

Step 3: 3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazole

F ₃ CF ₃ C tert-Butyl-3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazole-1-carboxylate (13.5 g, 43.79 mmol) was treated with 4 M hydrogen chloride in dioxane ( 54.75 ml, 219.0 mmol) and the mixture was stirred at 45°C for 1 hour. The reaction mixture was evaporated to dryness and the residue was extracted with 1 M aqueous sodium hydroxide (100 ml) and methyl tert-butyl ether (100 ml), washed with saline (50 ml) and extracted with methyl tert-butyl ether (50 ml). The combined organic phases were dried over sodium sulfate, filtered and evaporated to give 3-(3,3,3-trifluoro-2,2-dimethylpropoxy)N-pyrazole (9.0 g, 96%) as an off-white waxy solid. .

1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 7.52 (d, J=2.2 Hz, 1H), 5.69 (t, J=2.3 Hz, 1H), 4.06 (s, 2H), 1.19 (s, 6H). MS-ESI m/z calc. 208.08235, detected 209.0 (M+1) ⁺ ; retention time: 1.22 min (LC method B).

Step 4: tert-butyl 2-chloro-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl]pyridine-3carboxylate

To a solution of tert-butyl-2,6-dichloropyridine-3-carboxylate (10.4 g, 41.9 mmol) and 3-(3,3,3-trifluoro2,2-dimethylpropoxy)-1H-pyrazole (9.0 g, 41.93 mmol) in N,N-dimethylformamide (110 ml) was added potassium carbonate (7.53 g, 54.5 mmol) and 1,4-diazabicyclo[2.2.2]octane (706 mg, 6.29 mmol) and the mixture was stirred at room temperature for 16 hours. The creamy suspension was cooled in a cold water bath and cold water (130 ml) was slowly added. The thick suspension was stirred at room temperature for 1 hour, filtered and washed with water to obtain tert-butyl-2-chloro6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl]pyridine -3-carboxylate (17.6 g, 99%) as

- 251 044967 off-white solid after vacuum drying.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.44 (d, J=2.9 Hz, 1H), 8.31 (d, J=8.4 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 6.26 ( d, J=2.9 Hz, 1H), 4.27 (s, 2H), 1.57 (s, 9H), 1.24 (s, 6H). MS-ESI m/z calc. 419.12234, detected 420.0 (M+1)+; retention time: 2.36 min (LC method B).

Step 5: 2-chloro-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl]pyridin-3-carboxylic acid

F ₃ CF ₃ C tert-Butyl-2-chloro-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl]pyridine-3-carboxylate (17.6 g, 40.25 mmol) suspended in isopropanol (85 ml), treated with hydrochloric acid (34 ml 6 M, 201 mmol) and refluxed for 3 hours (almost completely went into solution upon reflux and began to precipitate again sediment). The suspension was diluted with water (51 ml) at reflux and allowed to cool to room temperature with stirring over 2.5 hours. The solid was collected by filtration, washed with 1:1 isopropanol/water (50 ml), additional water and dried in a drying oven under vacuum at 45-50°C with nitrogen purging overnight to obtain 2-chloro-6[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl]pyridin- 3-carboxylic acid (13.7 g, 91%) as an off-white solid.

1H NMR (400 MHz, DMSO-b ₆ ) δ 13.61 (s, 1H), 8.44 (d, J=2.9 Hz, 1H), 8.39 (d, J=8.4 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 6.25 (d, J=2.9 Hz, 1H), 4.28 (s, 2H), 1.24 (s, 6H). MS-ESI m/z calc. 363.05975, detected 364.0 (M+1) ⁺ ; Retention time: 1.79 min (LC method B).

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

2-Chloro-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (174.5 mg, 0.4702 mmol) and carbonyl diimidazole (95.31 mg, 0.5878 mmol) was combined in tetrahydrofuran (2.223 ml) and stirred for 90 min at room temperature. Then tert-butyl (4S)-2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (194 mg, 0.4702 mmol) was added as solution in tetrahydrofuran (855 μl) followed by the addition of 1,8diazabicyclo[5.4.0]undec-7-ene (357.9 mg, 2.351 mmol) and the reaction mixture was stirred at 50°C for 2.5 hours. Stirring was continued at room temperature for 4 days. The reaction mixture was then diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and then with brine. The organic layers were separated, dried over sodium sulfate, evaporated and then purified by silica gel chromatography using a shallow gradient of 100% hexanes to 100% ethyl acetate to obtain pure product and acid-mixed starting material fractions. The mixed starting acid fractions were combined, evaporated and purified using reverse phase HPLC-MS using a Luna C ₁₈ (2) column (75x30 mm, 5 µm particle size) sold by Phenomenex (art. no.: 00C-4252-U0 - ACh) and a double gradient 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) and the pure product fractions were combined with the pure material from the original silica column to give tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[ 3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (110.4 mg, 31%) as a white solid. MS-ESI m/z calc. 757.2636, detected 758.4 (M+1) ⁺ ; retention time: 0.9 min (LC method A).

Step 7: 2-chloro-N-[[6-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2-pyridyl]sulfonyl]6-[3-(3,3, 3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl]pyridin-3-carboxamide

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Into a round bottom flask containing tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-(3,3,3-trifluoro-2,2dimethylpropoxy)pyrazol-1-yl ]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2dimethylpyrrolidine-1-carboxylate (110.4 mg, 0.1456 mmol) dichloromethane (2 ml) and trifluoroacetic acid (450 μl, 5.841 mmol). After 1 hour at room temperature, the reaction mixture was evaporated to dryness. The crude reaction mixture was neutralized with saturated sodium bicarbonate and extracted with ethyl acetate. The product flew out and some methanol was used for extraction. The organic layer was separated and evaporated to give 2-chloro-N-[[6-[3-[(3S)-5,5-dimethylpyrrolidin-3yl]propylamino]-2-pyridyl]sulfonyl]-6-[3-(3 ,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1yl]pyridine-3-carboxamide (95 mg, 99%) as a white solid. MS-ESI m/z calc. 657.2112, detected 658.4 (M+1)+; retention time: 1.62 min (LC method B).

Step 8: (14S)-12,12-dimethyl-8-[3 -(3,3,3-trifluoro-2,2-dimethylpropoxy)-1 H-pyrazol-1 -yl]-2λ ⁶ thia-3, 9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4trione (compound 208)

Cesium fluoride (33.5 mg, 0.2205 mmol), potassium carbonate (100 mg, 0.7236 mmol), 3 A molecular sieves, and 2-chloro-N-[[6-[3-[ solution were added to the vial (3S)-5,5-dimethylpyrrolidin-3yl]propylamino]-2-pyridyl]sulfonyl]-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1yl]pyridin-3- carboxamide (95 mg, 0.1443 mmol) in dimethyl sulfoxide (2.5 ml). The reaction mixture was sealed and placed in an oil bath preheated to 150°C overnight. The reaction mixture was cooled to room temperature, filtered and purified by HPLC (30-99% acetonitrile:water with 0.1% hydrochloric acid modifier to give (14S)-12,12-dimethyl-8-[3(3,3, 3-trifluoro-2,2-dimethylpropoxy)-1 H-pyrazol-1 -yl]-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22) ,5,7,9,19(23),20-hexaene-2,2,4-trione (compound 208) (45.5 mg, 51%) as a tan solid.

1H NMR (400 MHz, DMSO) δ 12.49 (s, 1H), 8.23 (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=7.1 Hz, 1H), 6.95 (d, J=8.2 Hz, 2H), 6.71 (d, J=8.5 Hz, 1H), 6.18 (d,

J=2.7 Hz, 1H), 4.27-4.19 (m, 2H), 3.92 (d, J=12.4 Hz, 1H), 3.16 (s, 1H), 2.95 (d, J=13.5 Hz, 1H), 2.71 ( t, J=10.8 Hz, 1H), 2.13 (s, 1H), 1.86 (dd, J=11.8, 5.2 Hz, 1H), 1.77 (s, 1H), 1.65-1.48 (m, 9H), 1.35 (dd , J=25.8, 14.3 Hz, 1H), 1.24 (s, 6H). MS-ESI m/z calc. 621.2345, detected 622.3 (M+1) ⁺ ; retention time: 2.24 min (LC method B).

Example 57: Preparation of (14S)-12,12-dimethyl-8-[3-(4,4,4-trifluoro-3,3-dimethylbutoxy)-1H-pyrazol-1yl]-2λ ⁶ -thia-3,9 ,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene2,2,4-trione (compound 212)

О./ _F \/-OH step ξ _F θ' Step 2 F__ * ^F Y^ ' ^F /T he P ^H Hub _F Step 4 F. /— ^/ step 5 /1 F 1 ^F Y F 0 Λ P ih ' ⁰ FW + IT ^Ste₽7 N Λ A \ / II J ------* _o ^{NN Cl F} / S- сг'ш ci .—' ^{F 1} F ₃ c^/ A °'/ O—A'C ^{N Cl} step 9 _o 2% Stage 1: (3,3,3-trifluoro-2,2-dimethylpropyl)methanesulfonate F Y\ /—OH ^F %K ---- \ / ⁰ ' — N step 3 - О I NAA ° steps 0 0 J< ₊ step 8 ⁺ ' II nYo —%/T nh

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Triethylamine (45.0 mL, 322.9 mmol) was added to a solution of 3,3,3-trifluoro-2,2-dimethylpropan-1-ol (17 g, 104.1 mmol) in dry dichloromethane (150 mL). The reaction mixture was cooled to 0°C and methanesulfonyl chloride (10 ml, 129.2 mmol) was added slowly dropwise under nitrogen atmosphere. The resulting heterogeneous mixture was stirred for 1 hour while heating to ambient 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 (bath temperature 20°C at 300 mbar) to obtain 3,3,3-trifluoro-2,2-dimethylpropylmethanesulfonate (18.4 g, 80%) as a clear yellowish liquid .

Ή NMR (400 MHz, chloroform-d) δ 4.13 (d, J=2.4 Hz, 2H), 3.03 (d, J=2.4 Hz, 3H), 1.21 (d, J =2.4 Hz, 6H).

Step 2: 4, 4, 4-trifluoro-3,3-dimethylbutanenitrile

To a solution of (3,3,3-trifluoro-2,2-dimethylpropyl)methanesulfonate (30.00 g, 136.2 mmol) in dimethyl sulfoxide (150 ml) was added cyanosodium (20.05 g, 409.1 mmol). The reaction mixture was refluxed and heated at 120°C for 3 days. The reaction mixture was then cooled to 0°C and ice water was added, followed by brine. The reaction mixture was then extracted twice with ether, the organic layers were combined and dried over sodium sulfate, filtered and evaporated to give 4,4,4-trifluoro-3,3-dimethylbutanenitrile (18.43 g, 90%) as an orange liquid.

1H NMR (400 MHz, chloroform-d) δ 2.56 (s, 2H), 1.33 (s, 6H).

Step 3: 4, 4, 4-trifluoro-3,3-dimethylbutanoic acid

To a solution of 4,4,4-trifluoro-3,3-dimethylbutanenitrile (12 g, 39.70 mmol) in ethanol (100 ml) was added sodium hydroxide (35 ml 6 M, 210.0 mmol). The resulting clear amber solution was heated to 70°C overnight. The reaction mixture was cooled to ambient temperature, water (30 ml) was added to the reaction mixture and extracted with ether. The ether layer was washed with 6 M sodium hydroxide. The aqueous layers were combined, and the aqueous solution was carefully adjusted to pH 1 with concentrated hydrochloric acid at 0°C. The mixture was then extracted with ether (3x100 ml). The organic extracts were combined and dried over sodium sulfate, filtered and concentrated (bath temperature 20°C at 300 mbar) to give 4,4,4-trifluoro-3,3-dimethylbutanoic acid (3.8 g, 28%).

1H NMR (400 MHz, chloroform-d) δ 2.48 (s, 2H), 1.27-1.26 (s, 6H).

Step 4: 4,4,4-trifluoro-3,3-dimethyl-butan-1-ol

HE is \<4. \ N ^F /—H θ—K

F IF ।

To a suspension of lithium aluminum hydride (438 mg, 11.24 mmol) in ether (30 ml) was added dropwise through a dropping funnel a solution of 4,4,4-trifluoro-3,3-dimethylbutanoic acid (3.8 g, 11.17 mmol ) in ether (30 ml) at 0°C in a nitrogen atmosphere. The resulting suspension was stirred at ambient temperature for 24 hours. The reaction mixture was cooled in an ice bath and quenched successively with water (450 µl, 24.98 mmol) (slow), then sodium hydroxide (450 µl 6 M, 2,700 mmol), then water (1.35 ml, 74.94 mmol) to obtain a white granular suspension, which was further stirred with anhydrous magnesium sulfate for 30 minutes, then filtered through celite. The precipitate was washed with ether and the filtrate was concentrated (at ~400 mbar and 20°C in a water bath) to give 4,4,4-trifluoro-3,3-dimethyl-butan-1-ol (1.5 g, 86%) in form of a colorless liquid.

1H NMR (400 MHz, chloroform-d) δ 3.77 (td, J=7.3, 0.8 Hz, 2H), 1.79 (t, J=7.4 Hz, 2H), 1.15 (d, J=0.8 Hz, 6H).

Step 5: tert-butyl 3-(4,4,4-trifluoro-3,3-dimethylbutoxy)pyrazole-1-carboxylate

Solution of 4,4,4-trifluoro-3,3-dimethylbutan-1-ol (1.0 g, 6.404 mmol), tert-butyl-3-hydroxypyrazole 1-carboxylate (1.2 g, 6.515 mmol), triphenylphosphine (1.9 g, 7.244 mmol) in dry tetrahydrofuran (10 ml) was cooled in an ice bath and DIAD (1.5 ml, 7.618 mmol) was added slowly under a nitrogen atmosphere. The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, then with brine and dried over sodium sulfate, filtered and evaporated in vacuum.

The residue was purified by silica gel column chromatography using a gradient from 100% hexanes to

50% ethyl acetate in hexanes to give tert-butyl 3-(4,4,4-trifluoro-3,3-dimethylbutoxy)pyrazole-1carboxylate (650 mg, 31%) as a colorless oil.

Ή NMR (400 MHz, chloroform-d) δ 7.83 (d, J=2.9 Hz, 1H), 5.84 (d, J=3.1 Hz, 1H), 4.38 (t, J=7.2 Hz, 2H), 1.98 (t , J=7.1 Hz, 2H), 1.61 (s, 9H), 1.18 (s, 6H). MS-ESI m/z calc. 322.15042, found 323.18 (M+1)+; Retention time: 0.74 min (LC method A).

Step 6: 3-(4,4,4-trifluoro-3,3-dimethyl-butoxy)-1H-pyrazole

A solution of tert-butyl 3-(4,4,4-trifluoro-3,3-dimethyl-butoxy)pyrazole-1-carboxylate (650 mg, 2.017 mmol) and trifluoroacetic acid (1 ml, 12.98 mmol) in dichloromethane (4 ml ) was stirred for 4 hours at room temperature. The volatiles were removed in vacuo and the residue was made basic with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and evaporated to give 3-(4,4,4-trifluoro-3,3-dimethylbutoxy)-1H-pyrazole (448 mg, 100%) as a colorless oil. MS-ESI m/z calc. 222.09799, detected 223.09 (M+1) ⁺ ; retention time: 0.53 min (LC method A).

Step 7: tert-butyl 2-chloro-6-[3-(4,4,4-trifluoro-3,3-dimethyl-butoxy)pyrazol-1-yl]pyridine-3-carboxylate

A mixture of 3-(4,4,4-trifluoro-3,3-gimethyl-butoxy)-1H-pyrazole (448 mg, 2.016 mmol), tert-butyl 2,6-dichloropyridine-3-carboxylate (501 mg, 2.019 mmol), Potassium carbonate (336 mg, 2.431 mmol) and 1,4diazabicyclo[2.2.2]octane (46 mg, 0.4101 mmol) in dimethyl sulfoxide (5 ml) were stirred at room temperature for 15 hours. The reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography using a gradient of 100% hexanes to 20% ethyl acetate in hexanes to give tert-butyl-2-chloro-6-[3-(4,4,4-trifluoro-3,3dimethylbutoxy)pyrazole -1-yl]pyridin-3-carboxylate (471 mg, 54%) as a white solid.

¹ H NMR (400 MHz, chloroform-d) δ 8.36 (d, J=2.8 Hz, 1H), 8.19 (dd, J=8.2, 1.8 Hz, 1H), 7.69 (dd, J=8.2, 1.8 Hz, 1H ), 5.94 (d, J=2.8 Hz, 1H), 4.38 (t, J=7.2 Hz, 2H), 2.03 (t, J=7.2 Hz, 2H), 1.62 (d, J=2.1 Hz, 9H), 1.22 (s, 6H). MS-ESI m/z calc. 433.138, detected 434.2 (M+1) ⁺ ; retention time: 0.91 min (LC method A).

Step 8: tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-(4,4,4-trifluoro-3,3-dimethylbutoxy)pyrazol-1yl ]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

A solution of tert-butyl-2-chloro-6-[3-(4,4,4-trifluoro-3,3-dimethyl-butoxy)pyrazol-1-yl]pyridin-3carboxylate (150 mg, 0.3457 mmol) in trifluoroacetic acid (150 µl, 1.947 mmol) and dichloromethane (1 ml) were stirred at room temperature for 2 hours. The solvent was removed and the residue was dried under high vacuum to obtain a white solid. To a solution of this solid in tetrahydrofuran (2 ml) was added carbonyldiimidazole (68 mg, 0.4194 mmol) and the reaction mixture was stirred for 4 hours at room temperature. Then tert-butyl (4S)-2,2-dimethyl-4-[3-[(6sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (146 mg, 0.3539 mmol) in tetrahydrofuran (2 ml), then 1,8-diazabicyclo[5.4.0]undec-7-ene (110 µl, 0.7356 mmol), and the reaction mixture was stirred for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with a mixture of saturated ammonium chloride and saline solution (1:1). The organic phases were separated, dried over sodium sulfate, filtered and evaporated. The resulting brown residue was purified by silica gel chromatography using a shallow gradient from 100% dichloromethane to 20% methanol/dichloromethane to give tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3 -(4,4,4-trifluoro-3,3-dimethyl-butoxy)pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1 carboxylate (82 mg, 31%) as a white solid. MS-ESI m/z calc. 771.27924, detected 772.36 (M+1) ⁺ ; retention time: 0.89 min (LC method A).

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Step 9: (14S)-12,12-dimethyl-8-[3-(4,4,4-trifluoro-3,3-dimethylbutoxy)-1H-pyrazol-1-yl] ^-2λ6 -thia3,9 ,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 212)

Tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-(4,4,4-trifluoro-3,3-dimethylbutoxy)pyrazol-1yl]pyridine solution -3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1 carboxylate (82 mg, 0.1062 mmol) in dichloromethane (500 µl) and trifluoroacetic acid (100 µl, 1.307 mmol) was stirred at room temperature for 4 hours. Then the solvents were removed and the residue was dried in vacuum. This residue was dissolved in dimethyl sulfoxide (5 ml), oven-dried 3 A molecular sieves were added and the reaction mixture was stirred for 10 minutes. Cesium fluoride (51 mg, 0.3357 mmol) and potassium carbonate (48 mg, 0.3473 mmol) were then added and the reaction mixture was heated at 130°C overnight. The reaction mixture was filtered through a Whatman disc filter (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS using a double gradient run of 50-99% mobile phase B over 15.0 min (mobile phase A = water (0. 05% hydrochloric acid) Mobile phase B = acetonitrile) to obtain (14S)-12,12-dimethyl-8-[3-(4,4,4-trifluoro3,3-dimethylbutoxy)-1 H-pyrazole-1 - yl] -2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2, 2,4-trione (compound 212) (34.5 mg, 51%) as a white solid.

1H NMR (400 MHz, chloroform-d) δ 9.84 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.54 (dt, J=15.1, 7.2 Hz, 2H), 7.27 (d, J=8.3 Hz, 1H), 6.57 (d, J=8.1 Hz, 1H), 5.91 (d, J=2.8 Hz, 1H), 4.38 (t, J=7.2 Hz , 2H), 3.91 (s, 1H), 3.41-3.31 (m, 1H), 3.17 (d, J=14.5 Hz, 1H), 3.06 (t, J=9.7 Hz, 1H), 2.62 (s, 1H) , 2.09 (dd, J=12.3, 7.9 Hz, 1H), 2.03 (t, J=7.2 Hz, 2H), 1.62 (d, J=3.6 Hz, 11H), 1.22 (d, J=0.8 Hz, 6H) . MS-ESI m/z calc. 635.2502, detected 636.2 (M+1)+; retention time: 1.14 min (LC method J).

Example 58: Preparation of 8-[3-(3,3-dimethylbutyl)-2-okCOimidazolidin-1-yl]-12,12,17-trimethyl-2λ ⁶ thia-3,9,11,18,23-pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4trione (diastereomer pair 1) (compound 209), 8-[3- (3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl]12,12,17-trimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer pair 2) (compound 210), 8-[3-(3,3dimethylbutyl)-2-oxoimidazolidine -1 -yl] -12,12,17 -trimethyl-2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9, 19(23),20-hexaene-2,2,4-trione (diastereomer pair 1, enantiomer 1) (compound 215), 8-[3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl] 12,12,17-trimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20 -hexaene-2,2,4-trione (pair of diastereomers 1, enantiomer 2) (compound 216), 8-[3(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl]-12,12,17- trimethyl-2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2 ,4-trione (pair of diastereomers 2, enantiomer 1) (compound 218) and 8-[3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl]12,12,17-trimethyl-2λ ⁶ -thia -3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (para diastereomers 2, enantiomer 2) (compound 219)

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Step 1: tert-butyl N-[2-(3,3-dimethylbutylamino)ethyl]carbamate

To a solution of tert-butyl N-(2-aminoethyl)carbamate (25 g, 156.04 mmol) in methanol (400 ml) was added 3,3-dimethylbutanal (20 ml, 159.35 mmol). The mixture was stirred at room temperature for 1 hour. Cool to 0°C and add sodium borohydride (6.2 g, 163.88 mmol) slowly. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated, then the residue was redissolved in ethyl acetate (500 ml). The resulting solution was washed twice with saturated aqueous sodium bicarbonate (2x300 ml) and saline (1x500 ml), then dried over sodium sulfate. The solution was filtered and concentrated to give tert-butyl-N-[2-(3,3dimethylbutylamino)ethyl]carbamate (37.5 g, 96%) as an oil. ESI-MS m/z: 244.37, found 245.5 (M+1)+; retention time: 2.25 min (LC method P).

Step 2: 1-(3,3-dimethylbutyl)imidazolidin-2-one

To tert-butyl N-[2-(3,3-dimethylbutylamino)ethyl]carbamate (15.8 g, 64.65 mmol) was added tetrahydrofuran (200 ml) in a 1000 ml vial. Solid potassium t-butoxide (21.77 g, 194.0 mmol) was added and the resulting yellow solution was heated to 60°C for 3 hours. The mixture was cooled to ambient temperature and acidified to pH 1-2 with aqueous hydrochloric acid ( 1 M) and concentrated under reduced pressure. The aqueous residue was extracted with ethyl acetate (2x200 ml), the organic phase was washed twice with brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a beige solid, which was purified by flash column chromatography on silica gel (from 0 % to 10% methanol in ethyl acetate) gives 1-(3,3-dimethylbutyl)imidazolidin-2-one (8.3 g, 72%) as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) ppm 0.89 (s, 9H), 1.26-1.37 (m, 2H), 2.97-3.09 (m, 2H), 3.14-3.22 (m, 2H), 3.24-3.32 ( m, 2H), 6.12-6.32 (m, 1H). MS-ESI m/z calc. 170.252, detected 171.2 (M+1) ⁺ ; retention time: 2.17 min (LC method H).

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

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A nitrogen-purged 100 mL round bottom flask was charged under a nitrogen atmosphere with 2,6dichloropyridine-3-carboxylic acid (220 mg, 1.146 mmol), carbonyldiimidazole (185 mg, 1.141 mmol) and anhydrous tetrahydrofuran (7 mL). The mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. In a separate 100 ml flask, a solution of tert-butyl-2,2-dimethyl-4-[3-[(6-sulfamoyl-2pyridyl)amino]butyl]pyrrolidine-1 α-carboxylate (485 mg, 1.137 mmol) in anhydrous tetrahydrofuran (3 ml) was prepared under nitrogen and was subsequently added by syringe to the activated ester solution. 1,8-Diazabicyclo[5.4.0]undec-7-ene (373 μL, 2.494 mmol) was added via syringe and the reaction mixture was stirred at room temperature under nitrogen for 6 hours. Solvents were removed under reduced pressure and the resulting thick oil was worked up. aqueous citric acid. The two phases were separated. The aqueous phase was extracted with ethyl acetate (30 ml). The combined organic extracts were washed with brine (30 ml) and dried over sodium sulfate. After filtration and evaporation of the solvents, the residue was dissolved in dichloromethane and purified by silica gel chromatography using a gradient of ethyl acetate (0% to 100% over 30 min) in hexanes to give tert-butyl 4-[3-[[6-[(2. 6-dichloropyridine-3-carbonyl)sulfamoyl]-2-pyridyl]amino]butyl]-2,2dimethylpyrrolidine-1-carboxylate (412 mg, 60%) as a white foamy solid mixture of diastereomers. MS-ESI m/z calc. 599.1736, detected 600.21 (M+1)+; retention time: 0.77 min (LC method A).

Step 4: 8-chloro-12,12,17-trimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7 ,9,19(23),20-hexaene-2,2,4-trione

A solution of tert-butyl 4-[3-[[6-[(2,6-dichloropyridine-3-carbonyl)sulfamoyl]-2-pyridyl]amino]butyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (412 mg, 0.6860 mmol) in dichloromethane (4 ml) and trifluoroacetic acid (0.55 ml, 7.187 mmol) were stirred at room temperature for 4 hours. Solvents were removed and the residue was dissolved in ethyl acetate (100 ml). This solution was then washed with saturated sodium bicarbonate solution and water. The organic extract was concentrated and dried under vacuum. The resulting residue was dissolved in dimethyl sulfoxide (3 ml), 3 A molecular sieves were added and the reaction mixture was stirred for 10 minutes. Cesium fluoride (312.5 mg, 2.057 mmol) and potassium carbonate (288.4 mg, 2.087 mmol) were then added and the reaction mixture was heated at 140°C overnight. The reaction mixture was filtered and water was added to the filtrate. This solution was extracted with ethyl acetate, and the organic extract was washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting brown residue was purified by silica gel column chromatography using a gradient from 100% dichloromethane to 50% dichloromethane/methanol to give 8-chloro-12,12,17-trimethyl-2λ ⁶ -thia-3,9,11,18. 23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (98 mg, 31%). MS-ESI m/z calc. 463.1445, detected 464.19 (M+1) ⁺ ; retention time: 0.74 min (LC method A).

Step 5: 8-[3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl]-12,12,17-trimethyl-2X ⁶ -thia3,9,11,18,23-pentaazatetracyclo[17.3. 1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer pair 1) (compound 209) and 8-[3- (3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl]-12,12,17trimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose- 1 (22),5,7,9,19(23),20hexaene-2,2,4-trione (diastereomer pair 2) (compound 210)

- 258 044967

diastereomer pair 1 diastereomer pair 2

8-chloro-12,12,17-trimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5 was loaded into a 4 ml bottle. 7,9,19(23),20-hexaene-2,2,4-trione (89 mg, 0.1918 mmol), 1-(3,3-dimethylbutyl)imidazolidin-2-one (46 mg, 0. 2702 mmol), Pd ₂ (dba) ₃ (46 mg, 0.05023 mmol), xanthos (29 mg, 0.05012 mmol), cesium carbonate (314 mg, 0.9637 mmol) and anhydrous dioxane (3 ml). The mixture was purged with nitrogen for 1-2 minutes, capped and stirred at 120°C for 14 hours. The solvent was evaporated, the reaction mixture was diluted with dimethyl sulfoxide (900 mg), microfiltered and subjected to reverse phase preparative HPLC (C ₁₈ ) using a gradient of acetonitrile in water (from 1 to 99% in 15 min) and hydrochloric acid as a modifier to obtain as of the first pair of eluting diastereomers, 8-[3-(3,3-dimethylbutyl)-2oxoimidazolidin-1-yl]-12,12,17-trimethyl-2λ ⁶ -tiα-3,9,11,18,23-pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione(diastereomer pair 1) (compound 209) (34 mg, 59%); MS-ESI m/z calc. 597.30975, detected 598.36 (M+1)+; Retention time: 2.04 min (LC method B); and as the second pair of eluting diastereomers 8-[3-(3,3-dimethylbutyl)2-oxoimidazolidin-1-yl]-12,12,17-trimethyl-2λ ⁶ -thia-3,9,11,18,23 -pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer pair 2) (compound 210) ( 63.5 mg, quantitative); MS-ESI m/z calc. 597.30975, detected 598.36 (M+1) ⁺ ; Retention time: 2.07 min (LC method B).

Step 6: 8-[3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl]-12,12,17-trimethyl-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[17.3. 1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (pair of diastereomers 1, enantiomer 1) (compound 215) and 8- [3-(3,3-dimethylbutyl)-2-oxoimidazolidin1 -yl]-12,12,17-trimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo [17.3.1.111,14.05,10 ]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (pair of diastereomers 1, enantiomer 2) (compound 216)

diastereomer pair 1 diastereomer pair 1, enantiomer 1 diastereomer pair 1, enantiomer 2

8-[3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl]-12,12,17-trimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05 ,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer pair 1) (compound 209) (31 mg, 0.05134 mmol) was subjected to chiral SLC chromatography. The following LCLC protocol was used: ChiralPak AS-3 (150x2.1 mm), 3 µm; Mobile phase 35°C: 30% acetonitrile:methanol (90:10), 70% carbon dioxide. The first enantiomer eluted was 8-[3-(3,3-dimethylbutyl)-2-oxoimid azolide in-1-yl]-12,12,17-trimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo [17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer pair 1, enantiomer 1) (compound 215) (8.1 mg, 52%). MS-ESI m/z calc. 597.30975, detected 598.1 (M+1) ⁺ ; retention time: 2.06 min (LC method B).

The second enantiomer eluted was 8-[3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl]12,12,17-trimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer pair 1, enantiomer 2) (compound 216) (9.1 mg , 58%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.39 (s, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.38 (s, 1H), 7.10-6.82 (m, 2H), 6.68 (d , J=30.7 Hz, 1H), 4.17 (s, 1H), 4.03-3.79 (m, 2H), 3.46 (p, J=8.5, 7.9 Hz, 2H), 3.21 (dd, J=10.3, 6.1 Hz, 2H), 3.00 (s, 2H), 2.10 (s, 1H), 1.79 (d, J=10.2 Hz, 1H), 1.52 (d, J=50.3 Hz, 9H), 1.40 (t, J=8.1 Hz, 2H), 1.28 (d, J=40.1 Hz, 3H), 1.03 (d, J=6.3 Hz, 3H), 0.92 (s, 9H). MS-ESI m/z calc. 597.30975, detected 598.2 (M+1) ⁺ ; retention time: 2.06 min (LC method B).

Step 7: 8-[3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl]-12,12,17-trimethyl-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[17.3. 1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione

- 259 044967 (pair of diastereomers 2, enantiomer 1) (compound 218) and 8-[3-(3,3-dimethylbutyl)-2-oxoimidazolidin1 -yl] -12,12,17 -trimethyl-2λ ⁶ -thia-3 ,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer pair 2 , enantiomer 2) (compound 219)

diastereomer pair 2 diastereomer pair 2, enantiomer 1 diastereomer pair 2, enantiomer 2

8-[3-(3,3-dimethylbutyl)-2-oxoimide azolide in-1-yl]-12,12,17-trimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111 ,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer pair 2) (compound 210) (60 mg) was subjected to chiral SCLC chromatography. The following LCLC protocol was used: Phenomenex LUX-4 AS-H (250x10 mm), 5 µm; mobile phase: 42% methanol (no modifier), 58% carbon dioxide; injection of 70 µl with a concentration of 24 mg/ml in methanol at a rate of 10 ml/min. The first enantiomer eluted was 8-[3-(3,3-dimethylbutyl)-2oxoimidazolidin-1-yl]-12,12,17-trimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111 ,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer pair 2, enantiomer 1) (compound 218) (9 mg, thirty%).

1H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.51-7.31 (m, 2H), 7.15 (d, J=7.3 Hz, 2H) , 6.68 (d, J=8.5 Hz, 1H), 4.03-3.80 (m, 1H), 3.45 (t, J=8.3 Hz, 2H), 3.25-3.16 (m, 2H), 3.08 (s, 2H), 2.25 (d, J=21.1 Hz, 1H), 1.84 (dd, J=11.9, 5.8 Hz, 1H), 1.71 (s, 1H), 1.57 (s, 3H), 1.49 (s, 4H), 1.47-1.33 (m, 3H), 1.29-1.17 (m, 7H), 0.92 (s, 9H). MS-ESI m/z calc. 597.30975, detected 598.36 (M+1)+; retention time: 0.82 min (LC method A).

The second enantiomer eluted was 8-[3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl]12,12,17-trimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[ 17.3.1.111,14.O5,10]tetracoseα1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (pair of diastereomers 2, enantiomer 2) (compound 219) ( 14 mg, 46%). MS-ESI m/z calc. 597.30975, detected 598.33 (M+1) ⁺ ; retention time: 2.11 min (LC method B).

Example 59: Preparation of (14S)-8-{3-[(4,4-dimethylcyclohexyl)methyl]-2-oxoimidazolidin-1-yl}12,12-dimethyl-2λ ⁶ -thia-3,9,11,18 ,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 217)

Step 1: tert-butyl N-[2-[(4,4-dimethylcyclohexyl)methylamino]ethyl]carbamate

To a stirred solution of 4,4-dimethylcyclohexanecarbaldehyde (250 mg, 1.783 mmol) in anhydrous methanol (10 ml) was added a solution of tert-butyl-N-(2-aminoethyl)carbamate (286 mg, 1.785 mmol) and anhydrous methanol (1 ml) in a nitrogen atmosphere. After the yellow solution was stirred at ambient temperature for 1 hour, it was cooled to 0°C (ice bath). Sodium borohydride (142 mg, 3.753 mmol) was then added slowly in two portions, the mixture was allowed to warm to ambient temperature and stirring was continued for 15 hours. Volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (30 ml) and washed with saturated aqueous sodium bicarbonate (2x15 ml) and brine (15 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl N-[2-[( 4,4dimethylcyclohexyl)methylamino]ethyl]carbamate (481 mg, 95%) as yellow gum. The crude material was used in the next step without further purification. MS-ESI m/z calc. 284.24637, detected 285.3 (M+1) ⁺ ; retention time: 1.04 min (LC method B).

Step 2: 1-[(4,4-dimethylcyclohexyl)methyl]imidazolidin-2-one

- 260 044967

Solid potassium tert-butoxide (300 mg, 2.674 mmol) was added to a solution of tert-butyl N-[2-[(4,4dimethylcyclohexyl)methylamino]ethyl]carbamate (240 mg, 0.8438 mmol) in anhydrous tetrahydrofuran (12 ml) under a nitrogen atmosphere, and the reaction mixture was heated at 70°C for 13 hours. The heterogeneous mixture was allowed to cool to ambient temperature and acidified with hydrochloric acid (3.5 ml of 1.0 M, 3,500 mmol). Volatiles were removed under reduced pressure (not to dryness). The aqueous residue was extracted with ethyl acetate (3x10 ml), and the organic layers were combined, washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% methanol in dichloromethane gradient over 30 min) to give 1-[(4,4-dimethylcyclohexyl)methyl]imidazolidin-2-one (62 mg, 35%) as dirty white solid.

¹ H NMR (400 MHz, Benzene-d ₆ ) δ 5.42 (s, 1H), 3.10 (d, J=7.3 Hz, 2H), 2.84-2.77 (m, 2H), 2.77-2.71 (m, 2H), 1.58-1.52 (m, 2H), 1.46-1.42 (m, 2H), 1.38 (dk, J=10.7, 3.5 Hz, 1H), 1.27-1.20 (m, 2H), 1.19-1.12 (m, 2H), 1.00 (s, 3H), 0.92 (s, 3H). MS-ESI m/z calc. 210.17322, detected 211.2 (M+1)+; retention time: 1.17 min (LC method B).

Step 3: (14S)-8-{3-[(4,4-dimethylcyclohexyl)methyl]-2-oxoimidazolidin-1 -yl}-12,12-dimethyl2λ ⁶ -thia-3,9,11,18,23 -pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4trione (compound 217)

(14S)-8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23) was loaded into a 4 ml bottle. 5,7,9,19,21-hexaene-2,2,4-trione (50 mg, 0.1111 mmol), 1-[(4,4-dimethylcyclohexyl)methyl]imidazolidin-2-one (26 mg, 0.1236 mmol), cesium carbonate (130 mg, 0.3990 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg, 0.01728 mmol) (Xanphos) and anhydrous dioxane (1, 5 ml) in the order indicated. Nitrogen was purged through the heterogeneous mixture for 2 min. Tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01092 mmol) was then added under nitrogen and the mixture was purged with nitrogen for a further 2 min and the vessel was capped under nitrogen. The mixture was stirred at 115°C overnight. The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (60 μL, 1.055 mmol). Volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.5 mL) and filtered through a 0.45 μm Whatman PTFE syringe disk filter. The sample was purified using preparative reverse phase HPLC-MS (Luna C ₁₈ (2) column (75x30 mm, 5 µm particle size) sold by Phenomenex (P/N: 00C-4252-U0-AX), dual gradient run 30-99 % acetonitrile in water for 15 minutes (hydrochloric acid as a modifier)). The desired product fractions were combined and concentrated under reduced pressure, the residue was dissolved in ethyl acetate (25 ml) and washed with brine (10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (14S)-8-{3-[(4,4dimethylcyclohexyl)methyl]-2-oxoimidazolidin-1-yl}-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4- trione (compound 217) (7.5 mg, 11%) as a light yellowish solid.

1H NMR (400 MHz, Methanol-d ₄ ) δ 7.70 (d, J=8.6 Hz, 1H), 7.52 (dd, J=8.5, 7.2 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.15 (dd, J=7.2, 0.8 Hz, 1H), 6.65 (dd, J=8.5, 0.8 Hz, 1H), 4.10-4.07 (m, 1H), 4.07-4.02 (m, 1H), 4.02-3.95 ( m, 1H), 3.56-3.52 (m, 1H), 3.51-3.47 (m, 1H), 3.23 (dd, J=10.2, 6.7 Hz, 1H), 3.18-3.09 (m, 2H), 3.07-2.98 ( m, 1H), 2.86 (t, J=10.4 Hz, 1H), 2.21-2.07 (m, 1H), 1.83 (dd, J=11.7, 5.4 Hz, 2H), 1.64 (s, 3H), 1.63-1.55 (m, 5H), 1.55 (s, 3H), 1.48-1.35 (m, 3H), 1.31-1.27 (m, 2H), 1.22-1.16 (m, 3H), 0.91 (s, 6H). MS-ESI m/z calc. 623.3254, detected 624.4 (M+1) ⁺ ; retention time: 2.13 min (LC method B).

Example 60: Preparation of 12,12-dimethyl-8-{3-[3-methyl-2-(propan-2-yl)butoxy]-1H-nirazol-1-yl}-2λ ⁶ thia-3,9,11 ,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4trione (compound 220)

- 261 044967

Step 1: tert-butyl 3-(2-isopropyl-3-methyl-butoxy)pyrazole-1-carboxylate

A solution of 2-isopropyl-3-methylbutan-1-ol (500 mg, 3.839 mmol), tert-butyl-3-hydroxypyrazole-1-carboxylate (705 mg, 3.828 mmol) and triphenylphosphine (1.16 g, 4.423 mmol) in dry tetrahydrofuran (20 mL) was cooled in an ice bath and DIAD (830 μL, 4.216 mmol) was added slowly under nitrogen. The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography with a gradient of 0-50% ethyl acetate in hexanes to give tert-butyl 3-(2-isopropyl-3-methylbutoxy)pyrazole-1-carboxylate (980 mg, 86%) as a clear oil.

¹ H NMR (400 MHz, chloroform-d) δ 7.82 (d, J=3.0 Hz, 1H), 5.84 (d, J=2.9 Hz, 1H), 4.29 (d, J=4.8 Hz, 2H), 1.91 ( pd, J=6.9, 5.6 Hz, 2H), 1.61 (s, 9H), 1.44-1.24 (m, 1H), 0.98 (d, J=6.8 Hz, 6H), 0.92 (d, J=6.9 Hz, 6H ). MS-ESI m/z calc. 296.21, found 297.21 (M+1)+; Retention time: 0.84 min (LC method A).

Step 2: 3-(2-isopropyl-3-methyl-butoxy)-1H-pyrazole

Tert-butyl 3-(2-isopropyl-3-methylbutoxy)pyrazole-1-carboxylate (980 mg, 3.306 mmol), dichloromethane (10 mL), and methyl alcohol (10 mL) were placed in a 250 mL round bottom flask. To this clear solution was added hydrogen chloride in 1,4-dioxane (4.1 mL 4 M, 16.40 mmol) using a syringe. The homogeneous solution was stirred at 45°C for 19 hours. Two additional equivalents of 4 M hydrogen chloride in 1,4-dioxane were added and stirred for another hour. Volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (50 ml) and washed with aqueous 1 N. sodium hydroxide. The layers were separated and the aqueous phase was extracted with ethyl acetate (20 ml). The combined organic extracts were washed with brine, dried over sodium sulfate and the solvents were evaporated to give 3-(2-isopropyl-3-methylbutoxy)-1H-pyrazole (490 mg, 76%) as a colorless oil. MSIE m/z calc. 196.15756, detected 197.1 (M+1) ⁺ ; Retention time: 0.72 min (LC method A).

Step 3: Ethyl 2-chloro-6-[3-(2-isopropyl-3-methyl-butoxy)pyrazol-1-yl]pyridine-3-carboxylate o

Ethyl 2,6-dichloropyridine-3-carboxylate (547 mg, 2.486 mmol), 3-(2-isopropyl-3-methylbutoxy)-1Hpyrazole (488 mg, 2.486 mmol) and potassium carbonate (412 mg, 2.981 mmol) were combined to anhydrous dimethyl sulfoxide (6 ml). 1,4-Diazabicyclo[2.2.2]octane (56 mg, 0.4992 mmol) was added and the mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was diluted with water (80 ml) and stirred for 15 minutes. The resulting white solid was collected by filtration and washed with water. The solid was dissolved in dichloromethane and dried over magnesium sulfate. The mixture was filtered and the filtrate was evaporated to give ethyl 2-chloro-6-[3-(2-isopropyl-3-methylbutoxy)pyrazol-1yl]pyridine-3-carboxylate (900 mg, 95%).

1H NMR (400 MHz, DMSO-b ₆ ) δ 8.42 (d, J=2.9 Hz, 1H), 8.39 (d, J=8.5 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 6.20 ( d, J=2.9 Hz, 1H), 4.34 (k, J=7.1 Hz, 2H), 4.26 (d, J=4.8 Hz, 2H), 2.02-1.76 (m, 2H), 1.45-1.29 (m, 4H ), 0.98 (d, J=6.8 Hz, 6H), 0.92 (d, J=6.8 Hz, 6H). MS-ESI m/z calc. 379.16626, detected 380.21 (M+1) ⁺ ;

- 262 044967 retention time: 2.56 min (LC method B).

Step 4: 2-chloro-6-[3-(2-isopropyl-3-methyl-butoxy)pyrazol-1-yl]pyridine-3-carboxylic acid o o

Ethyl 2-chloro-6-[3-(2-isopropyl-3-methylbutoxy)pyrazol-1yl]pyridine-3-carboxylate (900 mg, 2.369 mmol), tetrahydrofuran (6 mL) and aqueous sodium hydroxide ( 1.4 ml 5 M, 7,000 mmol). The reaction solution was allowed to stir for 4 hours at room temperature. The reaction solution was diluted with ethyl acetate (100 ml) and aqueous hydrochloric acid (12 ml, 1 M, 12.00 mmol) was added. The phases were separated and the aqueous layer was extracted with ethyl acetate (2x30 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give 2-chloro-6-[3-(2-isopropyl-3-methylbutoxy)pyrazol-1yl]pyridine-3-carboxylic acid (655 mg, 79%) , which was used without further purification. MS-ESI m/z calc. 351.13498, detected 352.19 (M+1)+; retention time: 0.87 min (LC method A).

Step 5: tert-butyl 5-[3-[[6-[[2-chloro-6-[3-(2-isopropyl-3-methyl-butoxy)pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl] - 2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

2-Chloro-6-[3-(2-isopropyl-3-methylbutoxy)pyrazol-1-yl]pyridin-3-carboxylic acid (170 mg, 0.4832 mmol) and carbonyldiimidazole (81 mg, 0.4995 mmol) combined in anhydrous tetrahydrofuran (4 ml) and stirred for 75 minutes at 40°C. A tetrahydrofuran solution (7 ml) of tert-butyl 2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (165 mg, 0.400 mmol) was then added and 1,8-diazabicyclo[5.4.0]undec-7-ene (152 µl, 1.016 mmol). The reaction was heated at 50°C for 4 hours. The reaction was diluted with ethyl acetate and washed with 1 M aqueous citric acid followed by a wash with brine. The organic layer was dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexanes to 75% ethyl acetate in hexanes to give tert-butyl 5-[3-[[ as an off-white solid. 6-[[2-chloro-6-[3 -(2-isopropyl-3-methylbutoxy)pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine -1-carboxylate (200 mg, 67%). MS-ESI m/z calc. 745.3388, detected 746.3 (M+1) ⁺ ; retention time: 0.87 min (LC method K).

Step 6: 12,12-dimethyl-8-{3-[3-methyl-2-(propan-2-yl)butoxy]-1 H-pyrazol-1 -yl}-2Х ⁶ -thia3,9,11, 18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (compound 220)

tert-Butyl 5-[3-[[6-[[2-chloro-6-[3-(2-isopropyl-3-methylbutoxy)pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl]amino ]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (200 mg, 0.2680 mmol) was dissolved in dichloromethane (3.5 ml) and hydrochloric acid (4 ml of 4 M in dioxane, 16.00 mmol) was added to the mixture. . The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure to obtain a precipitate. Combine this residue and potassium carbonate (223 mg, 1.614 mmol), cesium fluoride (66 mg, 0.4345 mmol), 3 Aq molecular sieves and dimethyl sulfoxide (3.2 ml) in a nitrogen purged vial, capped, heated to 140 °C. and stirred for 16 hours. The reaction mixture was allowed to cool to room temperature, filtered and then purified by preparative reverse phase chromatography (C ₁₈ column, 30% to 99% acetonitrile (no modifier) in water (5 mM hydrochloric acid) for 30 min) with a gradient to obtain 12,12-dimethyl-8-{3-[3-methyl-2-(propan-2-263 044967 yl)butoxy]-1 H-pyrazol-1 -yl as a white solid } -2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5(10),6,8,19,21-hexaene-2,2 ,4-trione (compound 220) (65 mg, 39%). MS-ESI m/z calc. 609.30975, detected 610.47 (M+1) ⁺ ; retention time: 2.52 min (LC method B).

Example 61: Preparation of (18S)-20,20-dimethyl-4-[3-(4,4,4-trifluoro-3,3-dimethylbutoxy)-1H-pyrazol-1yl]-10λ ⁶ -thia-1,3 ,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10trione (compound 221)

Step 1: tert-butyl (4S)-4-[3-[3-[[2-chloro-6-[3-(4,4,4-trifluoro-3,3-dimethylbutoxy)pyrazol-1yl] pyridin-3-carbonyl]sulfamoyl]pyrazol-1-yl]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

tert-Butyl 2-chloro-6-[3-(4,4,4-trifluoro-3,3-dimethylbutoxy)pyrazol-1-yl]pyridine-3-carboxylate (150 mg, 0.3457 mmol) in trifluoroacetic acid solution acid (150 µl, 1.947 mmol) in dichloromethane (400 µl) was stirred at room temperature for 2 hours. The solvent was removed and the residue was dried in vacuum. This material was dissolved in tetrahydrofuran (2 ml) and carbonyldiimidazole (69 mg, 0.4255 mmol) was added and the reaction mixture was stirred for 4 hours at room temperature. Then tert-butyl (4S)-2,2-dimethyl-4-[3-(3-sulfamoylpyrazol-1-yl)propyl]pyrrolidine-1 carboxylate (136 mg, 0.3519 mmol) in tetrahydrofuran (2 ml) was added followed by 1,8-diazabicyclo[5.4.0]undec-7ene (110 μL, 0.7356 mmol), and the reaction mixture was stirred for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride/saline (1 :1). The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The resulting brown residue was purified by silica gel chromatography using a fine gradient from 100% dichloromethane to 20% methanol/dichloromethane to give tert-butyl (4S)-4-[3-[3-[[2-chloro-6-[3- (4,4,4-trifluoro3,3-dimethylbutoxy)pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]pyrazol-1-yl]propyl]-2,2dimethylpyrrolidin-1-carboxylate (82 mg, 32%) as a white solid. MS-ESI m/z calc. 745.2636, detected 746.14 (M+1)+; retention time: 0.87 min (LC method A).

Step 2: (18 S)-20,20-dimethyl-4-[3 -(4,4,4-trifluoro-3,3-dimethylbutoxy)-1 H-pyrazol-1 -yl]-10λ ⁶ -thia1, 3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (compound 221)

A solution of tert-butyl (4S)-4-[3-[3-[[2-chloro-6-[3-(4,4,4-trifluoro-3,3-dimethyl-butoxy)pyrazol-1yl]pyridin- 3-carbonyl]sulfamoyl]pyrazol-1-yl]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (82 mg, 0.1099 mmol) in dichloromethane (400 μl) and trifluoroacetic acid (100 μl, 1.307 mmol) was stirred at room temperature for 2 hours. After completion of the reaction, the solvents were evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution (2 ml), the organic layer was collected and the solvent was evaporated. The resulting residue was dissolved in dimethyl sulfoxide (5 ml), 3 A molecular sieves were added and the reaction mixture was stirred for 10 minutes. Cesium fluoride (54 mg, 0.3555 mmol) and potassium carbonate (48 mg, 0.3473 mmol) were then added and the reaction mixture was heated at 130°C overnight. The reaction mixture was filtered through a Whatman disc filter (puradisc 25 TF) and the filtrate was purified by reverse phase HPLCMS using a dual gradient run of 50-99% mobile phase B over 15.0 min (mobile phase A=water(0. 05% hydrochloric acid), mobile phase B = acetonitrile) to obtain (18 S)-20,20-dimethyl-4-[3 -(4,4,4-trifluoro-3,3-dimethylbutoxy)-1 H-pyrazole -1 -yl] -10λ ⁶ -thia1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10, 10-trione (compound 221) (14.3 mg, 21%) as a white solid.

1H NMR (400 MHz, chloroform-d) δ 8.40 (s, 1H), 8.18 (d, J=2.8 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), 7.02 (d, J=8.3 Hz, 1H), 5.87 (d, J=2.7 Hz, 1H), 4.36 (k, J=7.0 Hz, 3H ), 3.94 (t, J=12.0 Hz, 1H), 2.74 (t, J=8.2 Hz, 1H), 2.14 (s, 2H), 2.02 (t, J=7.2 Hz, 3H), 1.76 (dd, J =11.8, 5.2 Hz, 1H), 1.59 (s, 5H), 1.55 (s, 3H), 1.47 (t, J=12.1 Hz, 1H), 1.24-1.21 (m, 6H), 0.90-0.73 (m, 1H). MS-ESI m/z calc. 609.2345, found 610.07 (M+1)+; Retention time: 2.17 min (LC method B).

Example 62: preparation of (14S)-12,12-dimethyl-8-[2-oxo-3-(4,4,4-trifluoro-3,3dimethylbutyl)imidazolidin-1-yl]-2λ ⁶ -thia-3, 9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound

223)

Step 1: tert-butyl N-[2-[(4,4,4-trifluoro-3,3-dimethylbutyl)amino]ethyl]carbamate

Dess-Martin periodinan (660 mg, 1.556 mmol) was added to a stirred solution of 4,4,4trifluoro-3,3-dimethylbutan-1-ol (210 mg, 1.345 mmol) in anhydrous methylene chloride (7 ml) at 0°C (bath with ice) in a nitrogen atmosphere. After 15 minutes, the bath was removed, the reaction mixture was allowed to warm to ambient temperature, and stirring was continued for another 2 hours. The reaction mixture was diluted with ether (60 ml) and saturated aqueous sodium bicarbonate (20 ml) was added slowly (carbon dioxide gas was observed to evolve). Sodium thiosulfate (10 ml) was then added and stirred at ambient temperature for 30 minutes. The layers were separated and the aqueous layer was extracted with ether (2x20 ml). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and partially concentrated under reduced pressure (to approximately 2 mL volume) to give the aldehyde intermediate as a crude solution. The previously prepared ethereal solution of the aldehyde intermediate in anhydrous methanol (1 mL) was then added to a stirred solution of tert-butyl N-(2-aminoethyl)carbamate (216 mg, 1.348 mmol) in anhydrous methanol (7 mL) under a nitrogen atmosphere. After the yellow solution was stirred at ambient temperature for 1 hour, it was cooled to 0°C (ice bath). Sodium borohydride (110 mg, 2.908 mmol) was then added slowly in two portions, the mixture was allowed to warm to ambient temperature and stirring was continued for 15 hours. Volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (30 ml) and washed with saturated aqueous sodium bicarbonate (2x15 ml) and brine (15 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl N-[2-[( 4,4,4-trifluoro-3,3dimethylbutyl)amino]ethyl]carbamate (380 mg, 95%) as a clear viscous oil. MS-ESI m/z calc. 298.1868, detected 299.2 (M+1)+; retention time: 0.82 min (LC method B).

Step 2: 1-(4,4,4-trifluoro-3,3-dimethylbutyl)imidazolidin-2-one

Solid potassium tert-butoxide (440 mg, 3.921 mmol) was added to a stirred solution of tert-butyl-N.-[2-[(4,4,4-trifluoro-3,3-dimethyl-butyl)amino]ethyl]carbamate (380 mg , 1.274 mmol) in anhydrous tetrahydrofuran (12 ml) under a nitrogen atmosphere, and the reaction mixture was heated at 70°C for 13 hours. The heterogeneous mixture was allowed to cool to ambient temperature and acidified with aqueous hydrochloric acid (5.0 ml, 1.0 M, 5,000 mmol), and volatiles were removed under reduced pressure. The aqueous residue was extracted with ethyl acetate (3x10 ml), and the combined organic layers were washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% methanol in dichloromethane gradient over 30 min) to give 1-(4,4,4-trifluoro-3,3-dimethylbutyl)imidazolidin-2-one (172 mg, 60%) as an off-white solid.

¹ H NMR (400 MHz, Benzene-d6) δ 5.50 (s, 1H), 3.23-3.12 (m, 2H), 2.71-2.66 (m, 2H), 2.65-2.59 (m, 2H), 1.64-1.53 ( m, 2H), 1.01 (s, 6H). ¹⁹ F NMR (376 MHz, methanol-d4) δ -79.87. MS-ESI m/z calc. 224.11365, detected 225.1 (M+1)+; retention time: 1.08 min (LC method B).

Step 3: (14S)-12,12-dimethyl-8-[2-oxo-3-(4,4,4-trifluoro-3,3-dimethylbutyl)imidazolidin-1-yl]2λ ⁶ -thia-3, 9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4trione (compound 223)

(14S)-8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23) was added to a 4 ml vial. 5,7,9,19,21-hexaene-2,2,4-trione (51 mg, 0.1133 mmol), 1-(4,4,4-trifluoro-3,3-dimethylbutyl)imidazolidine- 2-one (31 mg, 0.1383 mmol), cesium carbonate (130 mg, 0.3990 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg, 0.01728 mmol) and anhydrous dioxane (1.5 ml) in this order. Nitrogen was bubbled through the heterogeneous mixture for 2 min. Tris(benzylideneacetone)dipalladium(0) (10 mg, 0.01092 mmol) was then added under nitrogen and nitrogen was bubbled for an additional 2 min and the reaction was capped under nitrogen. The mixture was stirred at 115°C overnight. The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (50 μL, 0.8792 mmol). Volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.2 ml), filtered through a Whatman 0.45 μm PTFE syringe disk filter. The sample was purified using preparative reverse phase HPLC (Luna C ₁₈ (2) column (75x30 mm, 5 µm particle size) sold by Phenomenex (P/N: 00C-4252-U0-AX), dual gradient run 30-99% acetonitrile in water for 15 minutes (hydrochloric acid as a modifier)). The desired product fractions were combined and concentrated under reduced pressure, the residue was dissolved in ethyl acetate (25 ml) and washed with brine (10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (14S)-12,12-dimethyl-8-[2-oxo-3-(4,4,4-trifluoro-3,3dimethylbutyl)imidazolidine- 1 -yl] -2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20- hexaene-2,2,4-trione (compound 223) (37 mg, 51%) as a yellowish solid.

1H NMR (400 MHz, Methanol-d ₄ ) δ 7.70 (d, J=8.6 Hz, 1H), 7.52 (dd, J=8.5, 7.2 Hz, 1H), 7.44 (d, J=8.6 Hz, 1H), 7.15 (dd, J=7.2, 0.8 Hz, 1H), 6.65 (dd, J=8.5, 0.8 Hz, 1H), 4.10-4.07 (m, 1H), 4.07-4.01 (m, 1H), 4.01-3.95 ( m, 1H), 3.58-3.46 (m, 2H), 3.42-3.34 (m, 2H), 3.23 (t, J=8.6 Hz, 1H), 3.08-2.97 (m, 1H), 2.85 (t, J= 10.4 Hz, 1H), 2.22-2.07 (m, 1H), 1.89-1.73 (m, 4H), 1.71-1.64 (m, 1H), 1.63 (s, 3H), 1.62-1.55 (m, 2H), 1.54 (s, 3H), 1.47-1.35 (m, 1H), 1.19 (s, 6H). MS-ESI m/z calc. 637.2658, detected 638.5 (M+1) ⁺ ; retention time: 1.9 min (LC method B).

Example 63: Preparation of (14S)-8-[3-fluoro-5-(2-methylpropoxy)phenyl]-12,12-dimethyl-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[17.3.1.111, 14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 224)

- 266 044967

Step 1: tert-butyl 2-chloro-6-(3-fluoro-5-isobutoxyphenyl)pyridine-3-carboxylate

tert-Butyl 2,6-dichloropyridine-3-carboxylate (15.0 g, 60.5 mmol) and (3-fluoro-5-isobutoxyphenyl)boronic acid (13.46 g, 63.48 mmol) were combined and completely dissolved in ethanol (150 ml) and toluene (150 ml). A suspension of sodium carbonate (19.23 g, 181.4 mmol) in water (30 ml) was added. Tetrakis(triphenylphosphine)palladium(0) (2.096 g, 1.814 mmol) was added under nitrogen. The reaction mixture was left under stirring at 60°C for 16 hours. Volatiles were removed under reduced pressure. The remaining solids were partitioned between water (100 ml) and ethyl acetate (100 ml). The organic layer was washed with brine (1x100 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The material was subjected to silica gel column chromatography (0% to 20% ethyl acetate in a hexane gradient). The material was purified again by chromatography on silica gel (isocratic 100% hexane for 10 min, then a gradient of 0 to 5% ethyl acetate in hexane) to give tert-butyl-2-chloro-6-(3-fluoro-5-isobutoxyphenyl)pyridine- 3-carboxylate (18.87 g, 49.68 mmol, 82%), obtained as a colorless oil.

¹ H NMR (400 MHz, DMSOL) δ 8.24 (d, J=8.0 Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 7.48 (dd, J=9.4, 2.0 Hz, 2H), 6.99 ( dt, J=10.8, 2.2 Hz, 1H), 3.86 (d, J=6.5 Hz, 2H), 2.05 (dt, J=13.3, 6.6 Hz, 1H), 1.57 (d, J=9.3 Hz, 9H), 1.00 (t, J=5.5 Hz, 6H). MS-ESI m/z calc. 379.13504, detected 380.2 (M+1)+; retention time: 2.57 min.

(LC method B).

Step 2: 2-chloro-6-(3-fluoro-5-isobutoxyphenyl)pyridine-3-carboxylic acid

tert-Butyl 2-chloro-6-(3-fluoro-5-isobutoxyphenyl)pyridine-3-carboxylate (18.57 g, 48.89 mmol) was dissolved in dichloromethane (200 ml). Trifluoroacetic acid (60 ml, 780 mmol) was added and the reaction mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was stirred at 40°C for 2 hours. The reaction mixture was concentrated under reduced pressure and dissolved in ethyl acetate (100 ml) . This solution was washed with saturated aqueous sodium bicarbonate (1x100 ml) and brine (1x100 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was suspended in ethyl acetate (75 ml) and washed with aqueous hydrochloric acid (1N, 1x75 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid (17.7 g) was stirred as a suspension in dichloromethane (35 ml) at 40° C. for 30 minutes. After cooling to room temperature, the suspension was filtered and then washed with cold dichloromethane to give 2-chloro-6-(3-fluoro-5-isobutoxyphenyl)pyridine-3-carboxylic acid (11.35 g, 35.06 mmol, 72%) in as a white solid.

1H NMR (400 MHz, DMSO-a ₆ ) δ 13.76 (s, 1H), 8.31 (d, J=8.0 Hz, 1H), 8.17 (d, J=8.1 Hz, 1H), 7.54-7.47

- 267 044967 (m, 2H), 7.00 (dt, J=10.8, 2.3 Hz, 1H), 3.87 (d, J=6.5 Hz, 2H), 2.05 (dt, J=13.3, 6.6 Hz, 1H), 1.01 (d, J=6.7 Hz,

6H). MS-ESI m/z calc. 323.1, found 324.1 (M+1)+; Retention time: 1.96 min (LC method B).

Step 3: tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-(3-fluoro-5-isobutoxyphenyl)pyridine-3carbonyl]sulfamoyl]-2-pyridyl]amino ]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

In a 20 ml scintillation tube, mix 2-chloro-6-(3-fluoro-5-isobutoxyphenyl)pyridine-3carboxylic acid (156 mg, 0.3751 mmol) and carbonyldiimidazole (61 mg, 0.3762 mmol) in tetrahydrofuran (2 ml) and stirred at room temperature for 2 hours. Then tert-butyl (4S)-2,2-dimethyl-4-[3-[(6-sulfamoyl-2-niridyl)amino]propyl]pyrrolidine-1- carboxylate (100 mg, 0.2424 mmol) in tetrahydrofuran (2 ml), then 1,8-diazabicyclo[5.4.0]undec-7-ene (110 μl, 0.7356 mmol), and the reaction mixture was stirred for 16 h. The reaction mixture was diluted with ethyl acetate and washed with a small amount of 1:1 saturated aqueous ammonium chloride/saline solution. The organic phases were separated, dried over sodium sulfate, filtered and evaporated. The resulting brown residue was purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate to give tert-butyl (48)-4-[3-[[6-[[2-chloro-6-(3-fluoro- 5-isobutoxyphenyl)pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine 1-carboxylate (116 mg, 67%). MS-ESI m/z calc. 717.2763, detected 718.38 (M+1) ⁺ ; retention time: 0.95 min (LC method A).

Step 4: (148)-8-[3-fluoro-5-(2-methylpropoxy)phenyl]-12,12-dimethyl-2X ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05 ,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 224)

A solution of tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-(3-fluoro-5-isobutoxyphenyl)pyridine-3carbonyl]sulfamoyl]-2-pyridyl]amino]propyl ]-2,2-dimethyl-pyrrolidine-1-carboxylate (110 mg, 0.1531 mmol) in dichloromethane (1 ml) and trifluoroacetic acid (200 μl, 2.614 mmol) was stirred at room temperature for 4 hours. The solvents were then evaporated . The residue was dissolved in ethyl acetate, washed with 2 ml of saturated sodium bicarbonate solution, the solvent was evaporated and dried in vacuum. The resulting residue was dissolved in dimethyl sulfoxide (5 ml), 3 A molecular sieves were added and the reaction mixture was stirred for 10 minutes. Cesium fluoride (76 mg, 0.5003 mmol) and potassium carbonate (64 mg, 0.4631 mmol) were then added and the reaction mixture was heated at 150°C for 16 hours. The reaction mixture was filtered through a Whatman disc filter (puradisc 25 TF ), and the filtrate was purified by reverse phase HPLC-MS using a dual gradient run of 20-80% mobile phase B over 15.0 min (mobile phase A = water (0.05% hydrochloric acid), mobile phase B = acetonitrile) to give (148)-8-[3-fluoro-5-(2-methylpropoxy)enyl]-12,12-dimethyl-2X ⁶ -thia3,9,11,18,23-pentaazatetracyclo[17.3.1.111, 14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 224) (12.5 mg, 14%) as dirty white solid.

1H NMR (400 MHz, chloroform-d) δ 10.39 (s, 1H), 8.08 (d, J=8.1 Hz, 1H), 7.60-7.46 (m, 2H), 7.36 (t, J=1.9 Hz, 1H) , 7.33-7.21 (m, 2H), 6.68 (dt, J=10.4, 2.3 Hz, 1H), 6.57 (dd, J=7.8, 1.4 Hz, 1H), 4.75 (s, 1H), 3.90 (s, 1H ), 3.77 (d, J=6.6 Hz, 2H), 3.36 (t, J=8.7 Hz, 1H), 3.17 (d, J=12.6 Hz, 1H), 3.08 (t, J=9.6 Hz, 1H), 2.69 (d, J=10.1 Hz, 1H), 2.12 (dt, J=13.3, 6.7 Hz, 2H), 1.68 (d, J=2.6 Hz, 6H), 1.65-1.54 (m, 5H), 1.04 (d , J=6.7 Hz, 6H). MS-ESI m/z calc. 581.2472, found 582.34 (M+1) ⁺ ; Retention time: 1.24 min (LC method J).

Example 64: Preparation of (18S)-4-[3-Fluoro-5-(2-methylpropoxy)phenyl]-20,20-dimethyl-10λ ⁶ -thia1,3,9,14,22-pentaazatetracyclo[16.2.1.111, 14.02,7]docose-2,4,6,11 (22), 12-pentaene-8,10,10-trione

- 268 044967

Step 1: tert-butyl (4S)-4-[3-[3-[[2-chloro-6-(3-fluoro-5-isobutoxyphenyl)pyridin-3carbonyl]sulfamoyl]pyrazol-1-yl]propyl ]-2,2-dimethyl-pyrrolidine-1-carboxylate

In a 20 ml scintillation tube, mix 2-chloro-6-(3-fluoro-5-isobutoxyphenyl)pyridine-3carboxylic acid (71 mg, 0.1707 mmol) and carbonyldiimidazole (27 mg, 0.1665 mmol) in tetrahydrofuran (2 ml) and stirred for 6 hours at room temperature. Then tert-butyl (4S)2,2-dimethyl-4-[3-(3-sulfamoylpyrazol-1-yl)propyl]pyrrolidine-1-carboxylate (50 mg, 0.1294 mmol) in tetrahydrofuran (2 ml) was added , and then 1,8-diazabicyclo[5.4.0]undec-7-ene (42 µl, 0.2809 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with a small amount of 1: 1 saturated aqueous ammonium chloride/saline solution. The organic phases were separated, dried over sodium sulfate, filtered and evaporated. The resulting brown residue was purified by silica gel chromatography using a fine gradient from 100% dichloromethane to 20% methanol/dichloromethane to give tert-butyl (4S)-4-[3[3-[[2-chloro-6-(3-fluoro -5-isobutoxyphenyl)pyridine-3-carbonyl]sulfamoyl]pyrazol-1-yl]propyl]-2,2dimethylpyrrolidine-1-carboxylate (52 mg, 58%) as a white solid. MS-ESI m/z calc. 691.2607, detected 692.0 (M+1)+; Retention time: 0.92 min (LC method A).

Step 2: (18S)-4-[3-fluoro-5-(2-methylpropoxy)phenyl]-20,20-dimethyl-10λ ⁶ -thia-1,3,9,14,22pentaazatetracyclo[16.2.1.111,14.02 ,7]docose-2,4,6,11 (22), 12-pentaene-8,10,10-trione

tert-butyl (4S)-4-[3-[3-[[2-chloro-6-(3-fluoro-5-isobutoxy-phenyl)pyridine-3Solution carbonyl]sulfamoyl]pyrazol-1-yl]propyl]- 2,2-dimethyl-pyrrolidine-1-carboxylate (52 mg, 0.07512 mmol) in dichloromethane (500 µl) and trifluoroacetic acid (100 µl, 1.307 mmol) was stirred at room temperature for 4 hours. The solvents were then evaporated. The residue was dissolved in ethyl acetate, washed with 2 ml of saturated sodium bicarbonate solution, the solvent was removed and dried under high vacuum to give a residue, which was dissolved in dimethyl sulfoxide (5 ml), 3 A molecular sieves were added and the reaction mixture was stirred for 10 minutes. Cesium fluoride (38 mg, 0.2502 mmol) and potassium carbonate (34 mg, 0.2460 mmol) were then added and the reaction mixture was heated at 150°C for 16 hours. The reaction mixture was filtered through a Whatman disk filter (puradisc 25 TF ), and the filtrate was purified by reverse phase HPLC-MS using a dual gradient run of 50-99% mobile phase B over 15.0 min (mobile phase A = water (0.05% hydrochloric acid), mobile phase B = acetonitrile) to give (18S)-4-[3-fluoro-5-(2-methylpropoxy)phenyl]-20,20-dimethyl-10λ ⁶ -thia1,3,9,14,22-pentaazatetracyclo[16.2.1.111, 14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (14.0 mg, 34%) off-white solid.

1H NMR (400 MHz, chloroform-d) δ 7.65 (d, J=7.9 Hz, 1H), 7.47 (d, J=2.3 Hz, 1H), 7.35-7.32 (m, 1H), 7.28-7.23 (m, 1H), 7.08 (s, 1H), 6.95 (d, J=7.9 Hz, 1H), 6.64 (dt, J=10.4, 2.3 Hz, 1H), 4.33 (d, J=13.3 Hz, 1H), 3.92 ( dd, J=13.9, 11.2 Hz, 1H), 3.75 (d, J=6.6 Hz, 2H), 2.75 (s, 1H), 2.21-2.07 (m, 3H), 1.98 (dd, J=19.3, 10.6

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Hz, 1H), 1.80-1.72 (m, 1H), 1.63 (s, 3H), 1.61 (s, 3H), 1.48 (t, J=12.2 Hz, 1H), 1.38-1.21 (m, 1H), 1.03 (s, 3H),

1.02 (s, 3H), 0.93-0.70 (m, 2H). MS-ESI m/z calc. 555.23157, detected 556.14 (M+1)+; retention time: 1.09 min (LC method J).

Example 65: preparation of (14S)-12,12-dimethyl-8-{3-[3-methyl-2-(propan-2-yl)butoxy]-1H-nirazol-1yl}-2λ ⁶ -thia-3, 9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene2,2,4-trione (compound 227)

Step 1: tert-butyl (48)-4-[3-[[6-[[2-chloro-6-[3-(2-isopropyl-3-methyl-butoxy)pyrazol-1yl]pyridin-3-carbonyl ]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

From a 50 mL flask loaded with carbonyldiimidazole (76 mg, 0.4687 mmol) and 2-chloro-6-[3-(2isopropyl-3-methylbutoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (164 mg, 0.4661 mmol) nitrogen was pumped out and filled again (3X). Tetrahydrofuran (5 ml) was added and the mixture was stirred at 50°C for 1 hour. Then a solution of tert-butyl (48)-2,2-dimethyl-4-[3-[(6-sulfamoyl-2pyridyl)amino] was added propyl]pyrrolidine-1-carboxylate (160 mg, 0.3878 mmol) and 1,8diazabicyclo[5.4.0]undec-7-ene (150 mg, 0.9853 mmol) in tetrahydrofuran (5 ml), and the mixture was stirred at 50°C overnight. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, evaporated in vacuo and purified by preparative reverse phase HPLC (( _C18 ): 1-99% acetonitrile in water/modifier hydrochloric acid (15 min)) to give tert-butyl (4S)4-[ 3-[[6-[[2-chloro-6-[3-(2-isopropyl-3-methylbutoxy)pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2, 2-dimethylpyrrolidine-1-carboxylate (90 mg, 31%). MS-ESI m/z calc. 745.3388, detected 746.47 (M+1) ⁺ ; retention time: 1.96 min (LC method B).

Step 2: 2-chloro-N-[[6-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2-pyridyl]sulfonyl]6-[3-(2-isopropyl- 3-methyl-butoxy)pyrazol-1-yl]pyridin-3-carboxamide (hydrochloride salt)

A solution of tert-butyl (4 S)-4-[3-[[6-[[2-chloro-6-[3-(2-isopropyl-3-methylbutoxy)pyrazol-1-yl]pyridin3-carbonyl]sulfamoyl] -2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (90 mg, 0.12 mmol) in dioxane (5 ml) was treated with 6 M dioxane hydrochloric acid solution (1.3 ml, 7,800 mmol) and stirred at room temperature for 3 hours. The mixture was evaporated in vacuo to give 2-chloro-N-[[6-[3-[(3 S)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2- pyridyl]sulfonyl]-6-[3(2-isopropyl-3-methylbutoxy)pyrazol-1-yl]pyridin-3-carboxamide (hydrochloride salt) (100 mg, 38%). MS-ESI m/z calc. 645.2864, detected 646.36 (M+1) ⁺ ; retention time: 0.27 min (LC method A).

Step 3: (14S)-12,12-dimethyl-8-{3-[3-methyl-2-(propan-2-yl)butoxy]-1H-nirazol-1-yl}-2λ ⁶ -thia3,9 ,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (compound 227)

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In a 5 mL vial, potassium carbonate (102 mg, 0.7380 mmol), cesium fluoride (45 mg, 0.2962 mmol) and 4A molecular sieves (300 mg) were sealed and purged with nitrogen. A solution of 2-chloroN-[[6-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2-pyridyl]sulfonyl]-6-[3-(2-isopropyl-3 methylbutoxy) was added )pyrazol-1-yl]pyridin-3-carboxamide (hydrochloride salt) (100 mg, 0.1465 mmol) in dimethyl sulfoxide (2 ml) and the mixture was stirred at 150°C overnight. The mixture was filtered and purified by preparative reverse phase HPLC ((Cis): 50-99% acetonitrile in water/hydrochloric acid modifier (15 min)) to give (14S)-12,12-dimethyl-8-{3-[3- methyl-2-(propan-2-yl)butoxy]-1Hpyrazol-1-yl} -2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23) ,5(10),6,8,19,21-hexaene-2,2,4-trione (compound 227) (18.0 mg, 20%).

Ή NMR (400 MHz, chloroform-d) δ 9.99 (s, 1H), 8.19 (d, J=2.8 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.607.48 (m, 2H) , 7.30 (d, J=8.4 Hz, 1H), 6.61-6.52 (m, 1H), 5.91 (d, J=2.8 Hz, 1H), 4.6-4.9 (br. s, 1H), 4.28 (d, J =4.9 Hz, 2H), 3.89 (s, 1H), 3.35 (dd, J=9.9, 7.6 Hz, 1H), 3.17 (dd, J=10.7, 6.7 Hz, 1H), 3.06 (t, J=9.7 Hz , 1H), 2.62 (s, 1H), 2.09 (dd, J=12.3, 8.0 Hz, 1H), 1.99-1.87 (m, 2H), 1.62 (d, J=2.9 Hz, 11H), 1.39 (p, J=5.2 Hz, 1H), 1.01 (d, J=6.9 Hz, 6H), 0.96 (d, J=6.9 Hz, 6H). MS-ESI m/z calc. 609.30975, found 610.39 (M+1)+; Retention time: 1.59 min (LC method J).

Example 66: Preparation of (148)-8-{3-[2-(adamantan-1-yl)ethyl]-2-oxoimidazolidin-1-yl}-12,12dimethyl-2λ ⁶ -thia-3,9,11, 18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20hexaene-2,2,4-trione (compound 228)

Step 1: 2-(1-adamantyl)acetaldehyde

Solid Dess-Martin periodinane (825 mg, 1.945 mmol) was added to a stirred solution of 2-(1-adamantyl)ethanol (300 mg, 1.664 mmol) in anhydrous dichloromethane (10 mL) at 0°C (ice-water bath) in nitrogen atmosphere. After 15 minutes, the bath was removed, the reaction mixture was allowed to warm to ambient temperature, and stirring was continued for another 2 hours. The reaction mixture was diluted with ether (60 ml) and saturated aqueous sodium bicarbonate (20 ml) was added slowly (to reduce the evolution of carbon dioxide gas). Sodium thiosulfate (10 ml) was then added and stirred at ambient temperature for 30 minutes. The layers were separated and the aqueous layer was extracted with ether (2x20 ml). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(1-adamantyl)acetaldehyde (149 mg, 50%) as a colorless semi-solid. It was used in a subsequent stage without further drying or purification.

¹ H NMR(400 MHz, benzene-de) δ 9.70 (t, J=3.1 Hz, 1H), 1.95-1.93 (m, 1H), 1.89-1.87 (m , 2H), 1.85 (d, J=3.1 Hz, 2H), 1.68 (d, J=3.0 Hz, 3H), 1.59 (dk, J=4.0, 2, 0 Hz, 2H), 1.56 (d, J=2.2 Hz, 1H), 1.49 (d, J=2.8 Hz, 6H).

Step 2: tert-butyl N-[2-[2-(1-adamantyl)ethylamino]ethyl]carbamate

To a stirred solution of 2-(1-adamantyl)acetaldehyde (130.0 mg, 0.7292 mmol) in anhydrous methylene chloride (10 ml) was added a solution of tert-butyl-N-(2-aminoethyl)carbamate (117 mg, 0.7303 mmol) in anhydrous methylene chloride (1 mL) followed by the addition of glacial acetic acid (50 μL, 0.8792 mmol) at ambient temperature under nitrogen. The cloudy reaction mixture was stirred for 30 minutes, then sodium triacetoxyborohydride (242 mg, 1.142 mmol) was added in one portion at ambient temperature and stirring was continued overnight (13 hours).

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Volatiles were removed under reduced pressure. The residue was taken up in ethyl acetate (30 ml) and washed with saturated aqueous sodium bicarbonate (2x15 ml) and brine (15 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl-N-[2- [2-(1-adamantyl)ethylamino]ethyl]carbamate (209 mg, 89%) as a yellow resinous substance. The crude material was used in the next step without further purification. MS-ESI m/z calc. 322.26202, detected 323.4 (M+1)+; retention time: 1.19 min (LC method B).

Step 3: 1-[2-(1-adamantyl)ethyl]imidazolidin-2-one

Solid potassium tert-butoxide (212 mg, 1.889 mmol) was added to a stirred solution of tert-butyl-N-[2-[2-(1-adamantyl)ethylamino]ethyl]carbamate (200 mg, 0.6202 mmol) in anhydrous tetrahydrofuran. (12 ml) under a nitrogen atmosphere, and the reaction mixture was heated at 70°C for 13 hours. The heterogeneous mixture was allowed to cool to ambient temperature, it was acidified with aqueous hydrochloric acid (3.0 ml, 1.0 M, 3000 mmol) and volatiles were removed under reduced pressure. The aqueous residue was extracted with ethyl acetate (3x10 ml) and the combined organic layers were washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% methanol in dichloromethane gradient over 30 min) to give 1-[2-(1-adamantyl)ethyl]imidazolidin-2-one (53 mg, 34%) as off-white solid matter.

¹ H NMR (400 MHz, Benzene-d ₆ ) δ 4.92 (s, 1H), 3.35-3.25 (m, 2H), 2.85-2.76 (m, 2H), 2.74-2.66 (m, 2H), 1.99 (p , J=3.0 Hz, 3H), 1.80-1.73 (m, 3H), 1.69 (dk, J=12.3, 2.3 Hz, 3H), 1.55 (d, J=2.8 Hz, 6H), 1.32-1.21 (m, 2H). MS-ESI m/z calc. 248.18886, detected 249.3 (M+1) ⁺ ; retention time: 1.67 min (LC method B).

Step 4: (14S)-8-{3-[2-(adamantan-1 -yl)ethyl]-2-oxoimidazolidin-1 -yl}-12,12-dimethyl-2λ ⁶ -thia3,9,11,18 ,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 228)

(14S)-8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23) was added to a 4 ml bottle. 5,7,9,19,21-hexaene-2,2,4-trione (20 mg, 0.04298 mmol), 1-[2-(1-adamantyl)ethyl]imidazolidin-2-one (13 mg, 0.05234 mmol), cesium carbonate (52 mg, 0.1596 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4 mg, 0.006913 mmol) and anhydrous dioxane (1.0 ml) in the order listed. Nitrogen was bubbled through the heterogeneous mixture for 2 min. Tris(dibenzylideneacetone)dipalladium(0) (4 mg, 0.004368 mmol) was then added under nitrogen and nitrogen was bubbled for an additional 2 min and the reaction was capped under nitrogen. The mixture was stirred at 115°C overnight. The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (20 μL, 0.3517 mmol). Volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.0 mL) and filtered through a 0.45 μm Whatman PTFE syringe disk filter. The sample was purified using preparative reverse phase HPLC-MS

[Luna C ₁₈ (2) column (75x30 mm, 5 µm particle size), sold by Phenomenex (P/N: 00C-4252-U0-AX), (dual gradient run of 30-99% acetonitrile in water for 15 min ( hydrochloric acid as a modifier)] to obtain (14S)-8-{3-[2-(adamantan-1 -yl)ethyl]-2-oxoimidazolidin-1 -yl}-12,12dimethyl-2λ ⁶ -thia-3 ,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (compound 228) (13.0 mg, 44%) as a yellowish solid.

¹ H NMR (400 MHz, DMSO-de) δ 12.29 (s, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.57-7.53 (m, 1H), 7.41 (d, J=8.5 Hz, 1H ), 7.03 (d, J=7.2 Hz, 1H), 6.96 (d, J=6.7 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 4.00-3.82 (m, 3H), 3.49-3.42 (m, 2H), 3.26-3.16 (m, 2H), 3.13-3.03 (m, 1H), 2.93 (d, J=13.3 Hz, 1H), 2.73-2.64 (m, 1H), 2.18-2.01 (m , 2H), 1.93 (s, 3H), 1.80 (dd, J=12.1, 5.6 Hz, 2H), 1.71-1.59 (m, 7H), 1.58 (s, 3H), 1.55-1.53 (m, 1H), 1.51 (two s, 6H), 1.46 (s, 3H), 1.31-1.22 (m, 3H). MS-ESI m/z calc. 661.341, detected 662.5 (M+1) ⁺ ; retention time: 1.92 min (LC method G).

Example 67: Preparation of (14S)-8-[3-(adamantan-1-yl)-2-oxoimidazolidin-1-yl]-12,12-dimethyl-2λ ⁶ thia-3,9,11,18,23- pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4trione (compound 230)

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HCl

Step 1: tert-butyl N-[2-(1-adamantylamino)ethyl]carbamate

To a stirred solution of tert-butyl-N-(2-oxoethyl) carbamate (505 mg, 3.172 mmol) in anhydrous methylene chloride (20 mL) was added solid adamantane-1-amine (hydrochloride salt) (475 mg, 3.141 mmol), followed by triethylamine (500 µl, 3.587 mmol) and glacial acetic acid (200 µl, 3.517 mmol) in that order and the reaction mixture was stirred at ambient temperature under nitrogen atmosphere. The heterogeneous (white suspension) reaction mixture was stirred for 30 min, then sodium triacetoxyborohydride (1.0 g, 4.718 mmol) was added in one portion at ambient temperature and stirring was continued overnight. Volatiles were removed under reduced pressure. The residue was taken up in ethyl acetate (30 ml) and washed with saturated aqueous sodium bicarbonate (2x15 ml) and brine (15 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butylN-[2-( 1-adamantylamino)ethyl]carbamate (731 mg, 79%) as a yellow resinous substance. The crude material was used in the next step without further purification. MS-ESI m/z calc. 294.23074, detected 295.4 (M+1) ⁺ ; retention time: 0.91 min (LC method B).

Step 2: 1-(1-adamantyl)imidazolidin-2-one

Solid potassium tert-butoxide (465 mg, 4.144 mmol) was added to a stirred solution of tert-butyl N-[2-(1-adamantylamino)ethyl]carbamate (400 mg, 1.359 mmol) in anhydrous tetrahydrofuran (12 ml) under a nitrogen atmosphere, and the reaction the mixture was heated at 70°C for 13 hours. The heterogeneous mixture was allowed to cool to ambient temperature and acidified with aqueous hydrochloric acid (5.5 ml, 1.0 M, 5,500 mmol) to pH 4-5, and volatiles were removed under reduced pressure. pressure. The aqueous residue was extracted with ethyl acetate (3x10 ml), and the combined organic layers were washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% methanol in dichloromethane gradient over 30 min) to give 1-(1-adamantyl)imidazolidin-2-one (69 mg, 23%) as an off-white solid.

1H NMR (400 MHz, Benzene-d ₆ ) δ 4.91 (s, 1H), 2.90 (dd, J=8.5, 6.7 Hz, 2H), 2.64 (dd, J=8.5, 6.7, 1.2 Hz, 2H), 2.21 (d, J=2.9 Hz, 6H), 2.06 (dd, J=5.9, 3.0 Hz, 3H), 1.75-1.68 (m, 3H), 1.67-1.60 (m, 3H). MS-ESI m/z calc. 220.15756, detected 221.2 (M+1) ⁺ ; retention time: 1.36 min (LC method B).

Step 3: (14S)-8-[3-(adamantan-1 -yl)-2-oxoimidazolidin-1 -yl]-12,12-dimethyl-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 230)

(14S)-8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23) was added to a 4 ml vial. 5,7,9,19,21-hexaene-2,2,4-trione (20 mg, 0.04298 mmol), 1-(1-adamantyl) imidazolidin-2-one (13 mg, 0.05901 mmol) , cesium carbonate (52 mg, 0.1596 mmol), 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (4 mg, 0.006913 mmol) and anhydrous dioxane (1.0 ml) in that order. Nitrogen was bubbled through the heterogeneous mixture for 2 min. Tris(dibenzylideneacetone)dipalladium(0) (4 mg, 0.004368 mmol) was then added under nitrogen, nitrogen was bubbled for an additional 2 min, and the vessel was sealed under nitrogen. The mixture was stirred at 115°C overnight. The mixture was allowed to cool to ambient temperature and neutralized with ice-cold vinegar

- 273 044967 acid (20 µl, 0.3517 mmol). Volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.0 mL), filtered through a Whatman 0.45 μm PTFE syringe disk filter. The sample was purified using preparative reverse phase HPLC-MS [Luna C ₁₈ (2) column (75 x 30 mm, 5 µm particle size), sold by Phenomenex (P/N: 00C-4252-U0-AX), (dual gradient run 30-99% acetonitrile in water for 15 min (hydrochloric acid as a modifier)] to obtain (14S)-8-[3-(adamantan-1 -yl)-2-oxoimidazolidin-1 -yl]-12, 12-dimethyl-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2 ,2,4-trione (compound 230) (9 mg, 33%) as a yellowish solid.

¹ H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 7.61-7.57 (m, 1H), 7.57-7.52 (m, 1H), 7.38 (d, J=8.6 Hz, 1H), 7.03 (d, J=7.1 Hz, 1H), 6.96 (d, J=7.3 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 3.96-3.74 (m, 3H), 3.53-3.46 (m, 2H), 3.12-3.03 (m, 1H), 2.93 (d, J=13.4 Hz, 1H), 2.73-2.65 (m, 1H), 2.12-2.02 (m, 8H), 1.83-1.71 (m, 2H) , 1.65 (s, 5H), 1.62-1.59 (m, 1H), 1.57 (s, 3H), 1.55-1.48 (m, 3H), 1.46 (s, 3H), 1.36-1.22 (m, 3H). MS-ESI m/z calc. 633.30975, detected 634.5 (M+1)+; retention time: 1.66 min (LC method G).

Example 68: Preparation of (14S)-8-[3-(3,3-Dicyclobutylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo [17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4trione (compound 231)

Step 1: 2,2-di(cyclobutyl)ethyl methanesulfonate

Triethylamine (2.72 mL, 19.51 mmol) was added to a 100 mL round bottom flask containing 2,2-di(cyclobutyl)ethanol (1.0 g, 6.483 mmol) in dichloromethane (11.0 mL). The reaction mixture was cooled to 0°C in an ice bath. Methanesulfonyl chloride (891 mg, 7.778 mmol) was added dropwise (exothermic, a slight yellowish suspension formed) and the reaction mixture was stirred for 1 hour while warming to room temperature. After stirring for 1 hour, the reaction was then quenched with cold water (15 ml) (the mixture became a clear pale yellow solution) and extracted twice with dichloromethane (20 ml), the organic layer was washed with brine. The organic layer was dried over sodium sulfate, filtered and evaporated to obtain crude 2,2di(cyclobutyl)ethylmethanesulfonate (1.5 g, 100%) as a clear, colorless to pale yellowish liquid. This product was used in the next reaction without further purification.

1H NMR (400 MHz, chloroform-d) δ 4.03 (d, J=4.6 Hz, 2H), 2.97 (s, 3H), 2.37-2.12 (m, 2H), 2 .09-1.47 (m, 13H).

Step 2: 3,3-di(cyclobutyl)propanenitrile

To a solution of 2,2-di(cyclobutyl)ethylmethanesulfonate (1.75 g, 7.532 mmol) in dimethyl sulfoxide (23 mL) was added solid cyanosodium (290 μL, 9.468 mmol) under a nitrogen atmosphere. The mixture was stirred at 70°C. The reaction turned to a light yellow suspension when heated, and then to a light yellow

- 274 044967 suspension over time. The reaction was left with stirring for 17 hours at 70°C. The reaction mixture was then poured into cold water (25 ml) and extracted with diethyl ether (3x25 ml). The combined organic layers were washed with water (2x25 ml), dried over sodium sulfate, filtered and concentrated to give the crude product, 3,3-di(cyclobutyl)propanenitrile (1.2 g, 98%) as a clear pale amber liquid, which was used without further purification.

¹ H NMR (400 MHz, chloroform-d) δ 3.48 (k, J=7.0 Hz, 1H), 2.38-2.21 (m, 2H), 2.10-1.92 (m, 2H), 1.921.64 (m, 8H) , 1.63-1.48 (m, 2H), 1.21 (t, J=7.0 Hz, 2H).

Step 3: 3,3-di(cyclobutyl)propionic acid o

To a solution of 3,3-di(cyclobutyl)propanenitrile (1.2 g, 7.350 mmol) in ethanol (18 mL) was added sodium hydroxide (12.5 mL, 6 M, 75.00 mmol). The resulting light amber solution was heated to 70°C for 3 days. Solid sodium hydroxide (3 g, 75.01 mmol) was added and the reaction was stirred for an additional 3 days at 100°C. The ethanol was evaporated and the pH of the aqueous layer was adjusted to 1 by adding 5 M hydrochloric acid. The mixture was then extracted with diethyl ether (3x20 ml). The organic extract was dried over sodium sulfate, filtered and concentrated to give 3,3-di(cyclobutyl)propanoic acid (1 g, 75%) as a light orange thick oil.

¹ H NMR (400 MHz, chloroform-d) δ 2.16 (dddd, J=13.0, 9.0, 5.4, 2.5 Hz, 2H), 2.10 (d, J=6, 3 Hz, 2H), 1.99-1.87 (m, 5H), 1.86-1.60 (m, 8H).

Step 4: 3,3-di(cyclobutyl)propan-1-ol

Lithium aluminum hydride (300 mg, 8.844 mmol) (beads) was suspended in tetrahydrofuran (15 ml) and stirred at room temperature for 30 min, after which the beads formed a suspension. The mixture was then cooled in an ice/water bath and 3,3di(cyclobutyl)propanoic acid (988 mg, 5.421 mmol) in tetrahydrofuran (7.2 mL) was added dropwise over 15 min, maintaining the reaction temperature <20°C. The mixture was allowed to stir for a total of 72 hours, gradually warming to ambient temperature. The mixture was cooled in an ice bath and quenched slowly successively with water (830 µL, 46.07 mmol), then sodium hydroxide (830 µL 6 M, 4.980 mmol) and then water (2.5 ml, 138.8 mmol). The mixture was stirred until the gray suspension was completely converted into a white granular suspension, which was filtered through celite. The solid was washed with ether. The filtrate was concentrated in vacuo at ~90 mbar and a 30°C water bath, diluted with diethyl ether, dried (magnesium sulfate), filtered and concentrated in vacuo to give 3,3-di(cyclobutyl)propan-1-ol (868 mg, 95 %) in the form of a colorless liquid.

¹ H NMR (400 MHz, chloroform-d) δ 3.64-3.54 (m, 2H), 2.11 (m, J=13.9, 9.8, 7.4, 6.0, 2.0 Hz, 2H), 2.011.84 (m, 4H), 1.83-1.59 (m, 8H), 1.50-1.37 (m, 2H).

Step 5: tert-butyl 3-[3,3-di(cyclobutyl)propoxy]pyrazole-1-carboxylate II ⁰ \ o * °=ο ^Λ °<—' dS

To a solution of tert-butyl-5-oxo-1H-pyrazole-2-carboxylate (530 mg, 2.877 mmol) and 3,3di(cyclobutyl)propan-1-ol (536 mg, 3.185 mmol) in tetrahydrofuran (8 ml) triphenylphosphine (830 mg, 3.164 mmol). Diisopropyl azodicarboxylate (680 μL, 3.454 mmol) was added slowly dropwise to this mixture over 10 min. The reaction mixture was stirred at 50°C for 16 hours. Tetrahydrofuran was removed in vacuo. Toluene was added to the crude mixture to precipitate triphenylphosphine oxide. The mixture did not form a precipitate. The clear solution was then concentrated to dryness. The thick yellow oil was dissolved in dichloromethane and purified by chromatography on silica gel with a gradient of 0% to 20% ethyl acetate in hexanes. The pure fractions were combined and concentrated to dryness to give the desired product, tert-butyl 3-[3,3-di(cyclobutyl)propoxy]pyrazole-1-carboxylate (560 mg, 58%), as a white solid.

¹ H NMR (400 MHz, chloroform-d) δ 7.82 (d, J=2.9 Hz, 1H), 5.85 (d, J=2.9 Hz, 1H), 4.21 (t, J=7.4 Hz, 2H), 2.24- 2.11 (m, 2H), 2.02-1.86 (m, 3H), 1.84-1.64 (m, 4H), 1.61 (s, 11H), 1.51-1.29 (m, 1H). MS-ESI m/z calc. 334.22565, detected 335.24 (M+1)+; retention time: 2.47 min (LC method B).

Step 6: 3-[3,3-di(cyclobutyl)propoxy]-1H-pyrazole

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Trifluoroacetic acid (700 μL, 9.086 mmol) was added to a solution of tert-butyl 3-[3,3-di(cyclobutyl)propoxy]pyrazole-1-carboxylate (200 mg, 0.5980 mmol) in dichloromethane (2 ml). The mixture was stirred at room temperature for 2 hours. Trifluoroacetic acid was removed under reduced pressure and the resulting crude product was diluted with ethyl acetate. The organic solution was washed with aqueous sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2x). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness to give 3-[3,3-di(cyclobutyl)propoxy]-1H-nirazole (140 mg, 100%). MS-ESI m/z calc. 234.17322, detected 235.15 (M+1)+; retention time: 1.9 min (LC method B).

Step 7: tert-butyl 2-chloro-6-[3-[3,3-di(cyclobutyl)propoxy]pyrazol-1-yl]pyridine-3-carboxylate

tert-Butyl 2,6-dichloropyridine-3-carboxylate (275 mg, 1.108 mmol), 3-[3,3di(cyclobutyl)propoxy]-1H-pyrazole (260 mg, 1.110 mmol) and potassium carbonate (185 mg, 1.339 mmol) were combined in anhydrous dimethyl sulfoxide (5.2 ml), 1,4-diazabicyclo[2.2.2]octane (25 mg, 0.2229 mmol) was added and the mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture diluted with water (10 ml) and stirred for 15 minutes. The resulting white solid was collected and washed with water. The solid was dissolved in dichloromethane and dried over magnesium sulfate. The mixture was filtered and evaporated to give the product as a colorless oil, tert-butyl 2-chloro-6-[3-[3,3-di(cyclobutyl)propoxy]pyrazol-1-yl]pyridin-3-carboxylate (367 mg, 74 %).

¹ H NMR (400 MHz, chloroform-d) δ 8.35 (d, J=2.9 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 5.95 ( d, J=2.8 Hz, 1H), 4.20 (t, J=7.5 Hz, 2H), 2.18 (tt, J=9.6, 4.4 Hz, 2H), 2.07-1.86 (m, 4H), 1.87-1.35 (m , 20H). MS-ESI m/z calc. 445.21323, found 446.29 (M+1) ⁺ ; Retention time: 0.88 min (LC method L).

Step 8: 2-chloro-6-[3-[3,3-di(cyclobutyl)propoxy]pyrazol-1-yl]pyridine-3-carboxylic acid

tert-Butyl 2-chloro-6-[3-[3,3-di(cyclobutyl)propoxy]pyrazol-1-yl]pyridin-3-carboxylate (367 mg, 0.8229 mmol) was dissolved in dichloromethane (4 ml) and trifluoroacetic acid acid (1.5 ml, 19.47 mmol) was added. The reaction was stirred at room temperature for 16 hours. The reaction mixture was evaporated, the resulting solid was suspended in ether, and then the ether was removed under reduced pressure. This ether evaporation procedure was repeated twice to obtain a white solid, 2chloro-6-[3-[3,3-di(cyclobutyl)propoxy]pyrazol-1-yl]pyridin-3-carboxylic acid (300 mg, 94%). MS-ESI m/z calc. 389.1506, detected 390.22 (M+1) ⁺ ; retention time: 1.45 min (LC method J).

Step 9: tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-[3,3-di(cyclobutyl)propoxy]pyrazol-1yl]pyridin-3-carbonyl ]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

In a 20 ml scintillation vial, 2-chloro-6-[3-[3,3-di(cyclobutyl)propoxy]pyrazol-1yl]pyridine-3-carboxylic acid (71 mg, 0.1821 mmol) and carbonyldiimidazole (30 mg , 0.1850 mmol) were combined in tetrahydrofuran (550 μl) and stirred for 60 min at 50°C without a lid. Thereafter, tert-butyl (4S)-2,2-dimethyl-4-[3-[(6-sulfamoyl-2pyridyl)amino]propyl]pyrrolidine-1-carboxylate (50 mg, 0.1212 mmol) in tetrahydrofuran ( 850 µl), and then 1,8-diazabicyclo[5.4.0]undec-7-ene (36 µl, 0.2407 mmol) was added and the reaction was heated at 50°C for 16 hours. The reaction mixture was allowed to cool to room temperature , then concentrated to an oily residue, which was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride and then with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a shallow gradient of 100% dichloromethane to 20% methanol in dichloromethane to give tert-butyl (4S)-4-[3-[[6- [[2chloro-6-[3-[3,3-di(cyclobutyl)propoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1- carboxylate (64.5 mg, 66%) as light yellow

- 276 044967 thick oil. MS-ESI m/z calc. 783.3545, detected 784.46 (M+1)+; retention time: 2.21 min (LC method J).

Step 10: 2-chloro-6-[3-[3,3-di(cyclobutyl)propoxy]pyrazol-1-yl]-N-[[6-[3-[(3S)-5,5dimethylpyrrolidin-3 - yl]propylamino]-2-pyridyl]sulfonyl]pyridine-3-carboxamide (trifluoroacetate salt)

tert-Butyl (48)-4-[3-[[6-[[2-chloro-6-[3-[3,3-di(cyclobutyl)propoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl] -2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (64.5 mg, 0.082 mmol) was dissolved in dichloromethane (1.5 ml). Trifluoroacetic acid (235 μL, 3.050 mmol) was added and the resulting reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and the resulting crude product was dried further under high vacuum to give 2-chloro-6-[3-[ 3,3-di(cyclobutyl)propoxy]pyrazol-1-yl]-X[[6-[3-[(3 8)-5,5-dimethylpyrrolidin-3 -yl]propylamino]-2-pyridyl]sulfonyl] pyridine-3-carboxamide (trifluoroacetate salt) (53 mg, 52%, purity 97%) ES-MS m/z cal. 683.30206, detected 684.39 (M+1) ⁺ ; Retention time: 0.86 min (LC method J).

Step 11: (14S)-8-[3-(3,3-Dicyclobutylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ ⁶ -tiα3,9,11,18,23-pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 231)

n

Mixture of 2-chloro-6-[3-[3,3-di(cyclobutyl)propoxy]pyrazol-1-yl]-N-[[6-[3-[(3S)-5,5dimethylpyrrolidin-3 -yl] propylamino]-2-pyridyl] sulfonal] pyridine-3-carboxamide (trifluoroacetate salt) (52 mg, 0.07599 mmol), potassium carbonate (55 mg, 0.3980 mmol), cesium fluoride (25 mg, 0.1646 mmol ), 3 A molecular sieves and dimethyl sulfoxide (3.6 ml) were placed in a vial, purged with nitrogen, capped, heated to 165°C and stirred for 16 hours. The reaction mixture was cooled to room temperature and the mixture was filtered. The filtrate was purified by reverse phase HPLC-MS using a Luna C ₁₈ (2) column (75x30 mm, 5 µm particle size) sold by Phenomenex (P/N: 00C-4252-U0-AX), dual gradient run 30-99% mobile phase B in 15.0 min (mobile phase A=water (5 mM hydrochloric acid), mobile phase B=acetonitrile, flow rate=50 ml/min, injection volume=1300 µl and column temperature=25°C) to s by obtaining (14S)-8-[3-(3,3-dicyclobutylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18 as a white solid ,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 231) (15.5 mg, 32%).

1H NMR (400 MHz, chloroform-d) δ 9.96 (s, 1H), 8.19 (d, J=2.8 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.607.48 (m, 2H) , 7.28 (d, J=8.3 Hz, 1H), 6.56 (dd, J=8.1, 1.1 Hz, 1H), 5.91 (d, J=2.8 Hz, 1H), 4.70 (d, J=7.0 Hz, 1H) , 4.20 (t, J=7.4 Hz, 2H), 3.90 (s, 1H), 3.35 (dd, J=10.1, 7.5 Hz, 1H), 3.17 (d, J=14.1 Hz, 1H), 3.06 (t, J=9.8 Hz, 1H), 2.26-2.11 (m, 2H), 2.09 (dd, J=12.3, 7.9 Hz, 1H), 2.03 -1.86 (m, 3H), 1.80 (s, 1H), 1.82-1.72 (m, 2H), 1.76-1.62 (m, 3H), 1.62 (d, J=3.3 Hz, 7H), 1.46 (ddd, J=14.2, 9.0, 5.2 Hz, 1H), 1.26 (s, 1H), several aliphatic protons are hidden by the water peak. MS-ESI m/z calc. 647.3254, detected 648.38 (M+1) ⁺ ; retention time: 1.89 min (LC method J).

Example 69: Preparation of 7,7-dimethyl-11-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1Hpyrazol-1-yl)-17λ ⁶ -thia-2,8,1O,16,22 -pentaazatetracyclo[16.3.1.15,8.09,14]tricoseα-1(22),9,11,13,18,2Ohexaene-15,17,17-trione (enantiomer 1) (compound 234) and 7,7-dimethyl- 11-(3-{3-[1(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1-yl)-17λ ⁶ -thia-2,8,10,16,22pentaazatetracyclo[16.3.1.15,8.09,14] tricose-1(22),9,11,13,18,20-hexaene-15,17,17-trione (enantiomer 2) (compound 235)

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Step 1: 3-(2-methyl-2-nitropropyl)dihydrofuran-2-one

To a mixture of 2-nitropropane (49 ml, 2.2 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.1 ml, 0.1 mol) under nitrogen atmosphere was added 3-methylenedihydrofuran-2 (3H)-one (75 g, 776 mmol) dropwise over 45 min. The addition is exothermic: the temperature was maintained below 90°C by controlling the rate of addition as the reaction progressed. The mixture was stirred for another 4 hours at 85°C, cooled to room temperature and diluted with ethyl acetate (500 ml) and 1 M hydrochloric acid (60 ml). The organic phase was separated, dried over sodium sulfate, filtered and concentrated in vacuo to give a dark oil. Trituration with a small amount of methyl tert-butyl ether gave a copious amount of white precipitate, which was collected by filtration to give 3-(2-methyl-2nitropropyl)dihydrofuran-2-one (75.6 g, 73% yield) as a white solid. . The material was used in the next step without further purification. MS-ESI m/z calc. 187.2, detected 188.0 (M+1)+. Retention time: 2.34 min (LC method Q).

Step 2: 3-(2-hydroxyethyl)-5,5-dimethylpyrrolidin-2-one

A 1.5 L Parr reactor was charged with a suspension of Raney nickel (10 g), 3-(2-methyl-2nitropropyl) dihydrofuran-2-one (75.6 g, 0.86 mol) and ethanol (1.2 L) . The reactor was sealed and heated to 60°C under a hydrogen pressure of 2 bar for 16 hours and then cooled to room temperature. Approximately 100 g of celite was added to the reactor. The resulting suspension was filtered through a thin layer of silica gel and washed with ethanol (200 ml). The combined filtrates were concentrated in vacuo to give 3-(2-hydroxyethyl)-5,5-dimethylpyrrolidin-2-one (64.5 g, quantitative yield) as a white solid. The crude material was used in the next step without further purification. MS-ESI m/z calc. 157.2, detected 158.1 (M+1) ⁺ . Retention time: 1.38 min (LC method M).

Step 3: tert-butyl ester (4-(2-hydroxyethyl)-2,2-dimethylpyrrolidine-1carboxylic acid

Lithium aluminum hydride (53.9 g, 1.4 mol) was added to a mixture of 3-(2-hydroxyethyl)-5,5dimethylpyrrolidin-2-one (55.8 g, 0.36 mol) and tetrahydrofuran (710 ml). The addition was made in small portions over 45 min to avoid excessive hydrogen evolution. The mixture was refluxed under nitrogen for 22 hours. The mixture was allowed to cool to room temperature and carefully quenched by adding sodium sulfate decahydrate (300 g). The resulting gray suspension was filtered and the solids were washed with tetrahydrofuran (500 ml). Di-tert-butyl dicarbonate (52.3 g, 225 mmol) was added to the combined filtrates (1.2 L). The resulting mixture was stirred for 24 hours at room temperature. The reaction mixture was concentrated and purified by silica gel chromatography using a gradient of 0-100% ethyl acetate in hexanes to give (4-(2-hydroxyethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester as an oil light color (40.8 g, 74% yield), ESI-MS m/z calculated 243.3, found 244.1 (M+1)+, retention time: 4.01 min (LC method M).

Step 4: 4-(2-methanesulfonyloxyethyl)-2,2-dimethylpyrrolidine-1carboxylic acid tert-butyl ester

4-(2-hydroxyethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (32.1 g, 132 mmol) and triethylamine (36.8 ml, 264 mmol) were dissolved in dichloromethane (400 ml) and the resulting mixture was cooled in an ice water bath for 15 minutes. Methanesulfonyl chloride (11.3 mL, 145 mmol) was added dropwise and the reaction mixture was stirred for 30 minutes. The reaction was quenched by adding saturated aqueous sodium bicarbonate (100 ml). The organic layer was separated, washed with water (100 ml), dried over sodium sulfate, filtered and concentrated to give 4-(2-methanesulfonyloxyethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester as an orange oil. (41.6 g, 98% yield). The material was used in the next step without further purification. MS-ESI m/z calc. 321.4, detected 322.2 (M+1) ⁺ . Retention time: 4.88 min (LC method M).

Step 5: 4-(2-aminoethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester

A 1.5 L Parr reactor was charged with 4-(2methanesulfonyloxyethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (32.4 g, 101 mmol), dioxane (640 ml) and 30% ammonium hydroxide (640 ml). The solution was then sealed and heated to 50°C for 18 hours. The reaction mixture was concentrated under reduced pressure until most of the dioxane was removed, and then dichloromethane (1 L) was added. The resulting mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted with dichloromethane (2x250 ml) and discarded. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography using a gradient of 0-15% methanol in dichloromethane containing 5 ml/liter 30% ammonium hydroxide to give 4-(2aminoethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (20.6 g, 66% yield) as a light-colored oil.

1H NMR (500 MHz, CDCl3) δ (ppm): 3.66 (dt, 1H), 2.88 (p, 1H), 2.69 (m, 2H), 2.15 (m, 1H), 1.88 (m, 1H), 1.48- 1.14 (m, 20H). MS-ESI m/z calc. 242.3, detected 243.0 (M+1) ⁺ . Retention time: 3.06 min (LC method M).

Step 6: tert-butyl 2,2-dimethyl-4-[2-[(6-sulfamoyl-2-pyridyl)amino]ethyl]pyrrolidine-1-carboxylate

6-Fluoropyridine-2-sulfonamide (2.089 g, 11.86 mmol) and dimethyl sulfoxide (24 ml) were added to a 20 ml microwavable vessel. Potassium carbonate (8.60 g, 62.23 mmol) and tert-butyl 4(2-aminoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (3.00 g, 12.38 mmol) were added and the vial was capped and heated to 100°C on a hot plate for 4 hours. The reaction mixture was filtered, then diluted with ethyl acetate and washed with a 1M solution of citric acid, and then with saline. The organic layer was separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a gradient of 100% hexanes to 80% ethyl acetate in hexanes to give tert-butyl-2,2-dimethyl-4 as a white solid -[2-[(6-sulfamoyl-2-pyridyl)amino]ethyl]pyrrolidine-1-carboxylate (1.475 g, 31%). MS-ESI m/z calc. 398.19876, detected 399.2 (M+1) ⁺ ; retention time: 1.55 min (LC method B).

Step 7: tert-butyl 4-[2-[[6-[[2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl ]-2-pyridyl]amino]ethyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

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2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (361 mg, 0.9262 mmol) and freshly recrystallized carbonyldiimidazole were added to the round bottom flask (188 mg, 1.159 mmol). Tetrahydrofuran (5.5 ml) was added and the reaction mixture was heated at 40°C for 2 hours. A solution of tert-butyl-2,2-dimethyl-4-[2-[(6-sulfamoyl2-pyridyl)amino]ethyl] was added pyrrolidine-1-carboxylate (370 mg, 0.9284 mmol) in tetrahydrofuran (2 ml), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (450 μl, 3.009 mmol). The reaction mixture turned pale yellow and was left to stir overnight at room temperature. The reaction was quenched with saturated sodium bicarbonate and brine and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude residue was then purified by silica gel chromatography using a gradient of 0%-100% ethyl acetate in hexane to give tert-butyl-4-[2-[[6-[[2-chloro-6-[3-[3-[ 1 -(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl]amino]ethyl]-2,2-dimethylpyrrolidine-1-carboxylate (400 mg, 56%) as white foam. MS-ESI m/z calc. 769.2636, detected 770.4 (M+1)+; retention time: 2.01 min (LC method G).

Step 8: 2-chloro-N-[[6-[2-(5,5-dimethylpyrrolidin-3-yl)ethylamino]-2-pyridyl]sulfonyl]-6-[3-[3[ 1 -(trifluoromethyl) cyclopropyl] propoxy] pyrazol-1 -yl] pyridin-3-carboxamide

Into a round bottom flask containing tert-butyl-4-[2-[[6-[[2-chloro-6-[3-[3-[1(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3 -carbonyl]sulfamoyl]-2pyridyl]amino]ethyl]-2,2-dimethylpyrrolidine-1-carboxylate (400 mg, 0.5193 mmol), dichloromethane (10 ml) and trifluoroacetic acid (2.0 ml, 25.96) were added mmol). The reaction was stirred for 90 min at room temperature. Then the reaction mixture was evaporated to dryness. The crude reaction mixture was neutralized with saturated sodium bicarbonate and extracted with ethyl acetate. The product flew out and some methanol was used for extraction. The organic layer was separated (not dried over sodium sulfate) and evaporated to give 2-chloro-N-[[6-[2-(5,5-dimethylpyrrolidin-3yl)ethylamino]-2-pyridyl]sulfonyl]-6-[3 -[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1yl]pyridin-3-carboxamide (344 mg, 99%) as a white solid. MS-ESI m/z calc. 669.2112, detected 670.5 (M+1) ⁺ ; retention time: 0.94 min (LC method G).

Step 9: 7,7-dimethyl-11-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1-yl)-17λ ⁶ thia-2,8,10,16,22 -pentaazatetracyclo[16.3.1.15,8.09,14]tricose-1(22),9,11,13,18,20-hexaene-15,17,17-trione (compound 233)

Potassium carbonate (355 mg, 2.569 mmol), cesium fluoride (156 mg, 1.027 mmol), several 3 A molecular sieves, and a solution of 2-chloro-N-[[6-[2-(5,5dimethylpyrrolidine) were added to a microwave-safe vessel -3-yl)ethylamino]-2-pyridyl]sulfonyl]-6-[3-[3-[1(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3-carboxamide (344 mg, 0.5133 mmol) in dimethyl sulfoxide (4 ml). The reaction mixture was capped and placed in an oil bath preheated to 150°C overnight. The reaction mixture was cooled to room temperature, filtered and purified by HPLC with a gradient of 50%-99% acetonitrile in water (0.1% hydrochloric acid modifier) to give 7,7-dimethyl-11-(3-{3-[1 -(trifluoromethyl)cyclopropyl]propoxy}-1Hpyrazol-1-yl)-17λ ⁶ -thia-2,8,10,16,22-pentaazatetracyclo[16.3.1.15,8.09,14]tricose-1(22),9, 11,13,18,20hexaene-15,17,17-trione (compound 233) (138.6 mg, 43%) as a white powder. MS-ESI m/z calc. 633.2345, detected 634.3 (M+1) ⁺ ; retention time: 2.22 min (LC method B).

Step 10: 7,7-dimethyl-11-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1-yl)-17λ ⁶ thia-2,8,10,16,22 -pentaazatetracyclo[16.3.1.15,8.09,14]tricose-1(22),9,11,13,18,20-hexaene-15,17,17-trione (enantiomer 1) (compound 234) and 7,7- dimethyl-11-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1Hpyrazol-1-yl)-17λ ⁶ -thia-2,8,10,16,22-pentaazatetracyclo[16.3.1.15,8.09 ,14]tricose-1(22),9,11,13,18,20hexaene-15,17,17-trione (enantiomer 2) (compound 235)

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Racemic 7,7-dimethyl-11-(3-{3-[1 -(trifluoromethyl)cyclopropyl]propoxy} -1 H-pyrazol-1 -yl)17λ ⁶ -thia-2,8,10,16,22- pentaazatetracyclo[16.3.1.15,8.09,14]tricose-1(22),9,11,13,18,20-hexaene-15,17,17trione (compound 233) (138.6 mg, 0.2187 mmol) was separated chiral SLC chromatography using ChiralPak AS-H (250 x 21.2 mm column, 5 µm particle size) with 28% acetonitrile:methanol (90:10, no modifier) / 72% carbon dioxide mobile phase at 70 ml/min , which gives as the first eluted enantiomer 7,7-dimethyl-11-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1Hpyrazol-1-yl)-17λ ⁶ -thia-2,8,10 ,16,22-pentaazatetracyclo[16.3.1.15,8.09,14]tricose-1(22),9,11,13,18,20hexaene-15,17,17-trione (enantiomer 1) (compound 234) (68, 1 mg, 98%). MS-ESI m/z calc. 633.2345, detected 634.4 (M+1)+; retention time: 2.22 min (LC method B).

The second enantiomer eluted was

7,7-dimethyl-11-(3-{3-[1(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1 -yl)- 17λ ⁶ -thia-2,8,10,16,22pentaazatetracyclo[16.3. 1.15,8.09,14]tricose-1(22),9,11,13,18,20-hexaene-15,17,17-trione (enantiomer 2) (compound 235) (59.3 mg, 86%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.46 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.75 (d, J=33.8 Hz, 2H), 7.18 (s, 1H) , 6.90 (d, J=8.2 Hz, 1H), 6.82 (s, 1H), 6.11 (d, J=2.8 Hz, 1H), 4.20 (t, J=6.2 Hz, 2H), 3.72-3.46 (m, 1H), 2.26 (s, 1H), 1.99-1.65 (m, 6H), 1.55 (s, 6H), 1.49-1.15 (m, 2H), 0.95-0.87 (m, 2H), 0.79-0.70 (m, 2H), some protons are hidden by the solvent peak. MS-ESI m/z calc. 633.2345, found 634.3 (M+1) ⁺ ; Retention time: 2.22 min (LC method B).

Example 70: Preparation of (14S)-12,12-dimethyl-8-[2-oxo-3-(4,4,4-trifluoro-3,3-dimethylbutoxy)pyrrolidin-1-ul]-2λ ⁶ -thia- 3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetrakose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (compound 237 )

Step 1: 3-(4,4,4-trifluoro-3,3-dimethyl-butoxy)pyrrolidin-2-one

To a stirred solution of 4,4,4-trifluoro-3,3-dimethylbutan-1-ol (280 mg, 1.793 mmol, contains 29 mol% residual diethyl ether) and 3-bromopyrrolidin-2-one (275 mg 1.677 mmol) in anhydrous tetrahydrofuran (12 ml) add [bis(trimethylsilyl)amino]potassium (7.1 ml 0.5 M in toluene, 3.550 mmol) dropwise at -50 to -60°C for 2 min under nitrogen atmosphere . After stirring for 15 minutes at this temperature, the cooling bath was removed and the flask was immediately placed in an ice water bath at 0°C. The reaction mixture was then allowed to warm to ambient temperature and stirring was continued overnight under a nitrogen atmosphere. Glacial acetic acid (200 μL, 3.517 mmol) was added to the reaction mixture and volatiles were removed under reduced pressure. The residue was purified by silica gel chromatography (0%-10% gradient of methanol in dichloromethane over 25 min) to give 3-(4,4,4-trifluoro-3,3-dimethylbutoxy)pyrrolidin-2-one (238 mg, 59% ) as an off-white solid.

1H NMR (400 MHz, Benzene-d6) δ 5.87 (s, 1H), 4.13 (dt, J=9.6, 7.0 Hz, 1H), 3.42 (dt, J=9.6, 6.8 Hz, 1H), 3.39-3.33 ( m, 1H), 2.52-2.41 (m, 1H), 2.25 (dt, J=9.6, 7.0 Hz, 1H), 1.72 (td, J=6.9, 1.5 Hz, 2H), 1.57-1.43 (m, 2H) , 0.94 (d, J=3.6 Hz, 6H). ^19F NMR (376 MHz, benzene- _d6 ) δ -78.62. MS-ESI m/z calc. 239.11331, detected 240.2 (M+1) ⁺ ; retention time: 1.16 min (LC method B).

Step 2: (148)-12,12-dimethyl-8-[2-oxo-3-(4,4,4-trifluoro-3,3-dimethylbutoxy)pyrrolidin-1-yl]2λ ⁶ -thia-3, 9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4trione (compound 237)

- 281 044967

(14S)-8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23) was added to a 4 ml bottle. 5,7,9,19,21-hexaene-2,2,4-trione (20 mg, 0.04445 mmol), 3-(4,4,4-trifluoro-3,3-dimethylbutoxy)pyrrolidine- 2-one (13 mg, 0.05434 mmol), cesium carbonate (52 mg, 0.1596 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4 mg, 0.006913 mmol) and anhydrous dioxane (0.7 ml) in this order. Nitrogen was purged through the heterogeneous mixture for 3 min. Tris(benzylideneacetone)dipalladium(0) (4 mg, 0.004368 mmol) was then added under nitrogen and the mixture was purged with nitrogen for an additional 2 min and capped under nitrogen. The mixture was stirred at 108°C overnight. The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (20 μL, 0.3517 mmol). Volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.5 ml) and filtered through a 0.45 μm Whatman PTFE syringe disk filter. The sample was purified using preparative reverse phase HPLC-MS [Luna C ₁₈ (2) column (75x30 mm, 5 µm particle size) sold by Phenomenex (P/N: 00C4252-U0-AX), dual gradient run 30-99% acetonitrile in water for 15 min (hydrochloric acid as a modifier)] to form (14S)-12,12-dimethyl-8-[2-oxo-3-(4,4,4trifluoro-3,3-dimethylbutoxy)pyrrolidine- 1 -yl] -2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene- 2,2,4-trione (compound 237) (8 mg, 27%) as a yellowish solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.42 (s, 1H), 7.71 (dd, J=8.4, 1.9 Hz, 1H), 7.57 (dd, J=8.5, 7.2 Hz, 1H), 7.52 (dd , J=8.4, 6.3 Hz, 1H), 7.04 (dt, J=7.3, 0.9 Hz, 1H), 6.96 (d, J=8.8 Hz, 1H), 6.70 (dd, J=8.5, 0.8 Hz, 1H) , 4.31 (two t, J=8.3 Hz, 1H), 4.08-3.87 (m, 3H), 3.81-3.64 (m, 2H), 3.17-3.04 (m, 1H), 2.94 (d, J=13.2 Hz, 1H), 2.73-2.63 (m, 1H), 2.47-2.38 (m, 1H), 2.15-2.02 (m, 1H), 1.98-1.86 (m, 1H), 1.82 (dd, J=11.7, 5.1 Hz, 1H), 1.76 (td, J=7.0, 1.8 Hz, 3H), 1.69-1.57 (m, 2H), 1.57 (s, 3H), 1.50 (t, J=12.4 Hz, 1H), 1.46 (s, 3H ), 1.29 (dd, J=13.6, 12.8 Hz, 1H), 1.14 (t, J=1.9 Hz, 6H). ^19F NMR (376 MHz, dimethyl sulfoxide-d ₆ ) δ -77.59. MS-ESI m/z calc. 652.2655, detected 653.4 (M+1)+; retention time: 2.1 min (LC method B).

Example 71: preparation of 12,12-dimethyl-8-{3-[3-methyl-2-(propan-2-yl)butoxy]-1H-pyrazol-1-yl}-15oxa-2X ⁶ -thia-3, 9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene2,2,4-trione (compound 238)

Step 1: tert-butyl 4-[2-[[6-[[2-chloro-6-[3-(2-isopropyl-3-methyl-butoxy)pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]- 2-pyridyl]amino]ethoxy]-2,2-dimethyl-pyrrolidine-1-carboxylate

2-Chloro-6-[3-(2-isopropyl-3-methyl-butoxy)pyrazol-1-yl]pyridin-3-carboxylic acid (225 mg, 0.6395 mmol) and carbonyl diimidazole (111 mg, 0.6846 mmol ) were combined in anhydrous tetrahydrofuran (8 ml) and stirred for 75 min at 40°C. A tetrahydrofuran solution (7 ml) of tert-butyl 2,2-dimethyl-4-[2-[(6-sulfamoyl-2-pyridyl)amino]ethoxy]pyrrolidine-1-carboxylate (265 mg, 0.6393 mmol) was then added ) and 1,8-diazabicyclo[5.4.0]undec-7-ene (200 µl, 1.337 mmol). The reaction was heated at 50°C for 4 hours. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution, and then with saline solution. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexanes to 75% ethyl acetate in hexanes to give tert-butyl-4-[2 as an off-white solid. -[[6-[[2- 282 044967 chloro-6-[3-(2-isopropyl-3-methylbutoxy)pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]ethoxy]-2 ,2-dimethylpyrrolidine-1-carboxylate (176 mg, 37%). MS-ESI m/z calc.

747.3181, detected 748.41 (M+1)+; retention time: 0.67 min (LC method A).

Step 2: 12,12-dimethyl-8-{3-[3-methyl-2-(propan-2-yl)butoxy]-1H-pyrazol-1-yl}-15-oxa-2λ ⁶ -thia3,9 ,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (compound 238)

4-[2-[[6-[[2-chloro-6-[3-(2-isopropyl-3-methyl-butoxy)pyrazol-1-yl]pyridin-3tert-Butyl carbonyl]sulfamoyl]-2-pyridyl ]amino]ethoxy]-2,2-dimethyl-pyrrolidine-1-carboxylate (176 mg, 0.2352 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (550 μl, 7.14 mmol) was added to the mixture. The reaction solution was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was combined with potassium carbonate (195 mg, 1.41 mmol), cesium fluoride (53.6 mg, 0.353 mmol), 3 A molecular sieves and dimethyl sulfoxide (3 ml) in a vial and purged with nitrogen. The vial was closed, heated to 140°C and stirred for 20 hours. The mixture was cooled to room temperature. The reaction mixture was filtered and then purified by preparative reverse phase chromatography (C ₁₈ column, 30% to 99% acetonitrile (no modifier) in water (5 mM hydrochloric acid) for 30 min) to obtain 12 as a white solid. 12-dimethyl-8-{3-[3-methyl-2-(propan-2-yl)butoxy]-1H-pyrazol-1yl}-15-oxa-2λ ⁶ -thia-3,9,11,18, 23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21hexaene-2,2,4-trione (compound 238) (64 mg, 44%) .

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.59 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.59 (dd, J=8.5 , 7.2 Hz, 1H), 7.13 (d, J=9.1 Hz, 1H), 7.10 (d, J=7.2 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 6.11 (d, J=2.8 Hz, 1H), 4.23 (d, J=4.8 Hz, 2H), 4.10 (d, J=8.7 Hz, 2H), 3.88 (t, J=11.9 Hz, 1H), 3.61 (d, J=12.7 Hz, 1H), 3.22 (s, 1H), 2.87 (d, J=9.4 Hz, 1H), 2.08 (dd, J=11.4, 6.0 Hz, 1H), 1.89 ( dk, J=13.2, 6.6 Hz, 2H), 1.79 (t, J=10.9 Hz, 1H), 1.58 (d, J=9.7 Hz, 6H), 1.42-1.30 (m, 2H), 0.98 (d, J =6.8 Hz, 6H), 0.92 (d, J=6.8 Hz, 6H). MS-ESI m/z calc. 611.289, found 612.2 (M+1) ⁺ ; Retention time: 2.29 min (LC method B).

Example 72: Preparation of (14S)-8-{3-[2-(adamantan-1-yl)ethoxy]-2-oxopyrrolidin-1-yl}-12,12dimethyl-2λ ⁶ -thia-3,9,11, 18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (diastereomer 1) (compound 240) and (14S)-8-{3-[2-(adamantan-1-yl)ethoxy]-2oxopyrrolidin-1 -yl}-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 2) (compound 241)

Step 1: 3-[2-(1-adamantyl)ethoxy]pyrrolidin-2-one

To a solution of 1-adamantanethanol (1.099 g, 6.098 mmol) and 3-bromopyrrolidin-2-one (1.00 g, 6.098 mmol) in anhydrous tetrahydrofuran (50 ml) was added potassium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran , 12.8 ml, 12.8 mmol) at -50°C dropwise. The reaction mixture was stirred at the same temperature for 20 minutes, then in an ice bath for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride (50 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was triturated with hexane and the resulting solid was collected by filtration to give 3-(2-adamantan-1-ylethoxy)pyrrolidin-2-one (1.192 g, 74%) as an off-white solid.

¹ H NMR (250 MHz, dimethyl sulfoxide-d ₆ ) d (ppm): 7.78 (s, sh, 1H), 3.81 (m, 2H), 3.51 (sq, t=8, 8 Hz, 1H), 3.11 (m, 2H), 2.27 (m, 1H), 1.90-1.40 (m, 16H), 1.30 (t, J=7.3 Hz, 2H). MS-ESI m/z: calc. 263.19, detected 263.8 (M+1)+. Retention time: 5.24 min (LC method Q).

Step 2: (14S)-8-{3-[2-(adamantan-1-yl)ethoxy]-2-oxopyrrolidin-1-yl}-12,12-dimethyl-2λ ⁶ -thia3,9,11,18 ,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 1) (compound 240) and (14S)-8-{3-[2-(adamantan-1-yl)ethoxy]-2-oxopyrrolidin-1-yl}12,12-dimethyl-2λ ⁶ -thia-3,9,11,18, 23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 2) (compound 241) o

(14S)-8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23) was added to a 4 ml bottle. 5,7,9,19,21-hexaene-2,2,4-trione (35 mg, 0.07779 mmol), 3-[2-(1-adamantyl)ethoxy]pyrrolidin-2-one (29 mg, 0.1101 mmol), Pd ₂ (dba) ₃ (11 mg, 0.01201 mmol), xanthos (9 mg, 0.01555 mmol), cesium carbonate (129 mg, 0.3959 mmol) and anhydrous doxane (0. 5 ml). The mixture was purged with nitrogen for approximately 3 minutes, capped and stirred at 120°C for 14 hours. The organic solvent was concentrated by purging the ampoule with nitrogen. The residue was diluted with dimethyl sulfoxide (900 mg), microfiltered and subjected to reverse phase preparative HPLC (C ₁₈ ) using a gradient of acetonitrile in water (from 30 to 99% in 15 min) and hydrochloric acid as a modifier. Pure fractions were collected and organic solvents were evaporated. The resulting aqueous solution was extracted with dichloromethane (1X) and ethyl acetate (2X) and the organic phases were combined and dried over sodium sulfate. Filtration and then evaporation of the solvents yielded a solid, which was further purified by flash silica gel chromatography using a gradient of methanol (0% to 5% over 30 min) in dichloromethane. Pure fractions were combined and the solvents were evaporated. The residue was triturated with dichloromethane/hexanes and the solvents were evaporated to give a mixture of diastereomers, which were separated by chiral LCLC (chiralCel OJ-H (250x10 mm), 5 µM column; mobile phase: 24% acetonitrile/methanol (90:10, 20 mM NH3 ), 76% carbon dioxide, 10 ml/min; 14 mg/ml in acetonitrile:methanol:dimethyl sulfoxide (81:9:10); injection volume 70 µl, 100 bar).

The first diastereomer eluted was (14S)-8-{3-[2-(adamantan-1-yl)ethoxy]-2oxopyrrolidin-1-yl}-12,12-dimethyl-2λ ⁶ -thia-3,9,11. 18,23-pentaazatetracyclo[17.3.1.111,14.O5,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 1) ( compound 240) (6.1 mg, 22%, 98% ee).

¹ H NMR (400 MHz, DMSO-d6) δ 12.45 (broad s, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.60-7.44 (m, 2H), 7.03 (d, J=7.2 Hz, 1H), 6.94 (br.s, 1H), 6.68 (b.d, J=8.5 Hz, 1H), 4.21 (t, J=8.0 Hz, 1H), 4.02 (t, J=9.5 Hz, 1H), 3.97-3.82 (m, 2H), 3.74-3.65 (m, 1H), 3.64-3.53 (m, 1H), 3.12 (b s, 1H), 2.93 (d, J=13.3 Hz, 1H), 2.77- 2.64 (m, 1H), 2.45-2.34 (m, 1H), 2.17-2.03 (m, 1H), 2.00-1.71 (m, 6H), 1.70-1.39 (m, 19H), 1.40-1.13 (m, 5H ). MSIE m/z calc. 676.3407, detected 677.4 (M+1) ⁺ ; retention time: 2.42 min (LC method B).

The second diastereomer eluted was (14S)-8-{3-[2-(pyrazol-1-yl)ethoxy]-2oxopyrrolidin-1-yl}-12,12-dimethyl-2λ ⁶ -thia-3,9,11, 18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 2) (compound 241) ( 5.1 mg, 17%, 93% ee).

¹ H NMR (400 MHz, dimethyl sulfoxide-d6) δ 12.44 (broad s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.61-7.49 (m, 2H), 7.04 (d, J=7.2 Hz, 1H), 7.00-6.89 (br m, 1H), 6.70 (d, J=8.5 Hz, 1H), 4.26 (t, J=8.2 Hz, 1H), 3.98-3.82 (m, 3H), 3.76 ( k, J=8.5 Hz, 1H), 3.58 (k, J=7.7 Hz, 1H), 3.10 (br. s, 1H), 2.94 (b. d, J=13.3 Hz, 1H), 2.74-2.63 (m , 1H), 2.47-2.34 (m, 1H), 2.10 (broad s, 1H), 1.95-1.69 (m, 6H), 1.68-1.39 (m, 19H), 1.37-1.18 (m, 5H). MS-ESI m/z calc. 676.3407, detected 677.4 (M+1) ⁺ ; Retention time: 2.41 min (LC method B).

- 284 044967

Example 73: preparation of (14S)-12,12-dimethyl-8-(2-oxo-3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}pyrrolidin-1 -yl)-2X ⁶ -thia-3, 9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 1) ( compound 242) and (14S)-12,12-dimethyl-8-(2oxo-3 - {3-[1 -(trifluoromethyl)cyclopropyl]propoxy}pyrrolidin-1 -yl)-2Х ⁶ -thia-3,9, 11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 2) (compound 243 )

Step 1: 3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrrolidin-2-one

A 100 mL flask was charged under a nitrogen atmosphere with 3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol (450 mg, 2.676 mmol), 3-bromopyrrolidin-2-one (442 mg, 2.695 mmol) and anhydrous tetrahydrofuran ( 12 ml). The mixture was cooled to -50°C. [Bis(trimethylsilyl)amino]potassium (11.3 mL 0.5 M in toluene, 5.650 mmol) was added dropwise over 5 min and the yellow mixture was stirred at -50°C for 15-20 min, then in an ice bath at 0°C for at least 3 hours. The reaction mixture was stirred in an ice bath, which was allowed to slowly warm to room temperature. After 16 h, the mixture was cooled to 0°C, then glacial acetic acid (250 μL, 4.396 mmol) was added to the reaction mixture to obtain a pale brown suspension. Saline (75 ml) and ethyl acetate (75 ml) were added and the two phases were separated. The aqueous phase was further extracted with ethyl acetate (2x25 ml). The combined organic extracts were dried over sodium sulfate, filtered and the solvents were evaporated. The crude residue was purified by silica gel chromatography (0%-15% gradient methanol in dichloromethane over 30 min) to give the desired 3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrrolidin-2-one (555 mg, 83% ) as an off-white solid.

1H NMR (400 MHz, chloroform-d) δ 6.65 (broad s, 1H), 3.95 (dd, J=7.7, 7.0 Hz, 1H), 3.84 (dt, J=9.2, 6.2 Hz, 1H), 3.54 (dt , J=9.2, 6.3 Hz, 1H), 3.41 dddd, J=9.7, 8.5, 3.7, 1.1 Hz, 1H), 3.33-3.23 (m, 1H), 2.40 (dtd, J=13.1, 7.6, 3.7 Hz, 1H), 2.09-1.96 (m, 1H), 1.80-1.69 (m, 2H), 1.69-1.52 (m, 2H), 0.98-0.85 (m, 2H), 0.64-0.47 (m, 2H). MS-ESI m/z calc. 251.11331, detected 252.1 (M+1)+; retention time: 1.32 min (LC method B).

Step 2: (14S)-12,12-dimethyl-8-(2-oxo-3-{3-[1 -(trifluoromethyl)cyclopropyl]propoxy}pyrrolidin-1-yl)-2X ⁶ -thia-3,9 ,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 1) (compound 242) and (14S)-12,12-dimethyl-8-(2oxo-3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}pyrrolidin-1-yl)-2Х ⁶ -thia-3,9,11 ,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 2) (compound 243)

diastereomer 1 diastereomer 2

(14S)-8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23) was added to a 4 ml bottle. 5,7,9,19,21-hexaene-2,2,4-trione (32 mg, 0.07112 mmol), 3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrrolidin-2-one (25 mg , 0.09950 mmol), Pd ₂ (dba) ₃ (11 mg, 0.01201 mmol), xanthos (11 mg, 0.01901 mmol), cesium carbonate (110 mg, 0.3376 mmol) and anhydrous dioxane (0.6 ml). The mixture was purged with nitrogen for approximately 3 minutes, capped and stirred at 120°C for 16 hours. The organic solvent was concentrated by purging the vial with nitrogen. The reaction mixture was diluted with dimethyl sulfoxide (900 μl), microfiltered and

- 285 044967 was subjected to reverse phase preparative HPLC (C ₁₈ ) using a gradient of acetonitrile in water (from 30% to 99% in 15 min) and hydrochloric acid as a modifier. Pure fractions were collected and organic solvents were evaporated. The resulting aqueous solution was extracted with ethyl acetate (3x) and the combined organic phases were dried over sodium sulfate. Filtration and evaporation of the solvents gave a solid, which was purified by flash chromatography on silica gel using a gradient of methanol (0% to 5% over 30 min) in dichloromethane. Pure fractions were combined and the solvents were evaporated. The residue was triturated with dichloromethane/hexanes and the solvents were evaporated to give a mixture of diastereomers, which were separated by chiral LCLC (ChiralCel OJ-H (250x10 mm), 5 µM column; mobile phase: 24% acetonitrile/methanol (90:10; 20 mM NH3 ), 76% carbon dioxide, 10 ml/min; concentration: 23 mg/ml: in acetonitrile/methanol (90:10; 20 mM NH3); injection volume 70 µl, 100 bar). The first diastereomer eluted was (14S)-12,12dimethyl-8-(2-oxo-3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}pyrrolidin-1-yl) ^-2λ6 -thia3,9,11. 18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 1) (compound 242 ) (6.3 mg, 26%). MS-ESI m/z calc. 664.2655, detected 665.4 (M+1)+; retention time: 2.05 min (LC method B).

The second diastereomer eluted was (14S)-12,12-dimethyl-8-(2-oxo-3-{3-[1(trifluoromethyl)cyclopropyl]propoxy}pyrrolidin-1-yl)-2X ⁶ -thia-3,9 ,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 2) (compound 243) (5.2 mg, 22%).

Ή NMR (400 MHz, DMSO-de) δ 12.45 (broad s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.61-7.47 (m, 2H), 7.04 (d, J=7.2 Hz, 1H ), 6.96 (s, 1H), 6.69 (d, J=8.5 Hz, 1H), 4.30 (t, J=8.4 Hz, 1H), 3.92 (t, J=9.8 Hz, 2H), 3.82-3.70 (m , 2H), 3.60-3.49 (m, 1H), 3.10 (broad s, 1H), 2.93 (d, J=13.3 Hz, 1H), 2.74-2.64 (m, 1H), 2.48-2.36 (m, 1H ), 2.10 (broad s, 1H), 1.93-1.68 (m, 3H), 1.68-1.40 (m, 12H), 1.38-1.20 (m, 2H), 0.93-0.83 (m, 2H), 0.77-0.66 (m, 2H). MS-ESI m/z calc. 664.2655, detected 665.4 (M+1) ⁺ ; retention time: 2.06 min (LC method B).

Example 74: preparation of (14S)-8-{3-[(adamantan-1-yl)methoxy]-2-oxopyrrolidin-1-yl}-12,12dimethyl-2X ⁶ -thia-3,9,11,18, 23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (diastereomer 1) (compound 244) and (14S )-8-{3-[(adamantan-1-yl)methoxy]-2oxopyrrolidin-1 -yl}-12,12-dimethyl-2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111, 14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 2) (compound 245)

diastereomer 1 diastereomer 2

Step 1: 3-(1-adamantylmethoxy)pyrrolidin-2-one

To a solution of 1-adamantanemethanol (0.500 g, 3.007 mmol) and 3-bromopyrrolidin-2-one (0.493 g, 3.007 mmol) in anhydrous tetrahydrofuran (20 ml) was added a 1 M solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran. (6.3 ml, 6.30 mmol) at -60°C. The reaction mixture was stirred at this temperature for 20 minutes, then raised to 0°C and stirred for another 2 hours. The reaction was quenched with saturated aqueous ammonium chloride (20 ml) and extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was triturated with hexane (30 ml) and the resulting solid was collected by filtration to give 3-(adamantan-1-ylethoxy)pyrrolidin-2-one (0.594 g, 79%) as a white solid.

Ή NMR (250 MHz, dimethyl sulfoxide-d ₆ ) d (ppm): 7.77 (s, br, 1H), 3.82 (t, J=7.3 Hz, 1H), 3.31 (m, 1H), 3.11 (m , 2H), 3.30 (d, J=9 Hz, 1H), 2.26 (m, 1H), 1.92-1.48 (m, 16H). MS-ESI m/z: calc. 249.17, found 250.2 (M+1) ⁺ . Retention time: 4.97 min (LC method Q).

Step 2: (14S)-8-{3-[(adamantan-1 -yl)methoxy]-2-oxopyrrolidin-1 -yl}-12,12-dimethyl-2λ ⁶ -thia3,9,11,18,23 -pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 1) (compound 244) and ( 14S)-S-{3-[(adamantan-1-yl)methoxy]-2-oxopyrrolidin-1-yl}12,12-dimethyl-2X ⁶ -thia-3,9,11,18,23-pentaazatetracyclo [ 17.3.1.111,14.05,10]tetracose- 286 044967

1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 2) (compound 245)

diastereomer 1 diastereomer 2

(148)-8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23) was added to a 4 ml bottle. 5,7,9,19,21-hexaene-2,2,4-trione (35 mg, 0.07779 mmol), 3-(1-adamantylmethoxy)pyrrolidin-2-one (30 mg, 0.1203 mmol) , Pd ₂ (dba) ₃ (10 mg, 0.01092 mmol), xanthos (12 mg, 0.02074 mmol), cesium carbonate (130 mg, 0.3990 mmol) and anhydrous dioxane (0.6 ml). The mixture was purged with nitrogen for approximately 3 minutes, capped and stirred at 120°C for 22 hours. The organic solvent was concentrated by purging the vial with nitrogen. The reaction mixture was diluted with dimethyl sulfoxide (900 μl), microfiltered and subjected to reverse phase preparative HPLC (C ₁₈ ) using a gradient of acetonitrile in water (from 30% to 99% in 15 min) and hydrochloric acid as a modifier (950 μl injection). Pure fractions were collected and organic solvents were evaporated. The solid was extracted with ethyl acetate (2X) and the organic phase was dried over sodium sulfate. Filtration and then evaporation of the solvents gave a solid, which was purified by flash chromatography on silica gel using a gradient of methanol (0% to 5% over 30 min) in dichloromethane. Pure fractions were collected and the solvents were evaporated. The residue was triturated with dichloromethane/hexanes and the solvents were evaporated, yielding a mixture of diastereomers, which were separated by chiral LCLC (ChiralCel OJ-H (250x10 mm), 5 μM column; mobile phase 31% acetonitrile/methanol (90:10, 20 mM NH ₃ ), 69% carbon dioxide, 10 ml/min; concentration 23 mg/ml in acetonitrile/methanol (90:10; 20 mM NH3); injection volume 70 µl, 100 bar). The first diastereomer eluted was (148)-8 -{3-[(adamantan-1-yl)methoxy]-2oxopyrrolidin-1 -yl} -12,12-dimethyl-2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10 ]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 1) (compound 244) (6.3 mg, 23%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.46 (broad s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.56 (t, J=7.9 Hz, 1H), 7.50 (d, J= 8.4 Hz, 1H), 7.03 (d, J=7.2 Hz, 1H), 6.95 (broad s, 1H), 6.69 (d, J=8.4 Hz, 1H), 4.19 (t, J=8.1 Hz, 1H) , 4.02 (t, J=9.3 Hz, 1H), 3.98-3.84 (m, 1H), 3.69 (dt, J=10.4, 7.5 Hz, 1H), 3.41 (d, J=9.0 Hz, 2H), 3.11 ( d, J=9.0 Hz, 2H), 2.93 (d, J=13.2Hz, 1H), 2.76-2.64 (m, 1H), 2.45-2.36 (m, 1H), 2.10 (broad s, 1H), 1.98 -1.85 (m, 4H), 1.85-1.41 (m, 22H), 1.34-1.26 (m, 1H). MS-ESI m/z calc. 662.325, detected 663.5 (M+1)+; retention time: 2.41 min (LC method B).

The second diastereomer eluted was (148)-8-{3-[(adamantan-1-yl)methoxy]-2oxopyrrolidin-1-yl}-12,12-dimethyl-2X ⁶ -thia-3,9,11,18, 23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 2) (compound 245) (5, 6 mg, 20%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.45 (broad s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.61-7.48 (m, 2H), 7.04 (d, J=7.2 Hz, 1H), 6.95 (b, s, 1H), 6.69 (d, J=8.5 Hz, 1H), 4.24 (t, J=8.3 Hz, 1H), 3.92 (t, J=9.5 Hz, 2H), 3.77 ( k, J=9.4, 8.8 Hz, 1H), 3.41 (d, J=8.9 Hz, 2H), 3.10 (d, J=9.0 Hz, 2H), 2.93 (d, J=13.3 Hz, 1H), 2.77- 2.64 (m, 1H), 2.46-2.38 (m, 1H), 2.10 (broad s, 1H), 1.96-1.72 (m, 6H), 1.72-1.42 (m, 20H), 1.38-1.25 (m, 1H ).

MS-ESI m/z calc. 662.325, detected 663.5 (M+1) ⁺ ; retention time: 2.41 min (LC method B).

Example 75: Preparation of (148)-8-{3-[(4,4-dimethylpentyl)oxy]-2-oxopyrrolidin-1-yl}-12,12dimethyl-2X ⁶ -thia-3,9,11,18, 23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (diastereomer 1) (compound 246) and (148 )-8-{3-[(4,4-dimethylpentyl)oxy]-2oxopyrrolidin-1-yl}-12,12-dimethyl-2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111, 14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 2) (compound 247)

- 287 044967

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

A 100 mL flask was charged with 4,4-dimethylpentan-1-ol (0.97 g, 8.348 mmol), 3-bromopyrrolidin-2-one (1.41 g, 8.598 mmol) and anhydrous tetrahydrofuran (5 mL) under nitrogen atmosphere. The mixture was cooled in an ice water bath and a KHMDS solution (17 mL of 1 M, 17.00 mmol) was added over 10 min (the solution quickly turned brown). The mixture was stirred in a cooling bath, which was allowed to warm to room temperature overnight. After 24 hours, the reaction mixture was cooled in an ice water bath and treated with acetic acid (1 ml, 17.58 mmol) and brine (50 ml). The product was extracted with ethyl acetate (2x40 ml). The combined organic extracts were washed with sodium sulfate, filtered and the solvents were evaporated to give crude material (430 mg). The residue was flash chromatographed on silica gel using a gradient of methanol (0% to 15% over 20 min) in dichloromethane to give 3-(4,4-dimethylpentoxy)pyrrolidin-2-one (239 mg, 14%) as beige solid.

¹ H NMR (400 MHz, chloroform-d) δ 5.85 (broad s, 1H), 3.97 (dd, J=7.7, 6.9 Hz, 1H), 3.83 (dd, J=8.9, 7.4, 6.6 Hz, 1H), 3.52 (dt, J=9.0, 7.1 Hz, 1H), 3.43 (dddd, J=9.6, 8.4, 3.8, 1.2 Hz, 1H), 3.29 (dddd, J=9.6, 7.5, 6.7, 0.8 Hz, 1H), 2.42 (dtd, J=13.1, 7.6, 3.9 Hz, 1H), 2.09 (ddt, J=13.0, 8.4, 6.8 Hz, 1H), 1.68-1.49 (m, 2H overlapped with residual solvent), 1.28-1.12 (m , 2H), 0.88 (s, 9H). MC-ESI m/z calc. 199.15723, found 200.2 (M+1)+; Retention time: 1.3 min (LC method B).

Step 2: Ethyl 2-chloro-6-[3-(4,4-dimethylpentoxy)-2-oxo-pyrrolidin-1-yl]pyridine-3-carboxylate o

A 100 mL flask was charged under a nitrogen atmosphere with ethyl 2,6-dichloropyridine-3-carboxylate (336 mg, 1.527 mmol) and 3-(4,4-dimethylpentoxy)pyrrolidin-2-one (287 mg, 1.440 mmol) in anhydrous N,Ndimethylformamide (6 ml). Potassium carbonate (271 mg, 1.961 mmol) (325 mesh) was added followed by 1,4diazabicyclo[2.2.2]octane (25 mg, 0.2229 mmol). The mixture was stirred at ambient temperature under a nitrogen atmosphere. After 2 days, the reaction was quenched by adding water (50 ml), then extracted with ethyl acetate (2x25 ml). The organic phase was dried over sodium sulfate, filtered and the solvents were evaporated. The product was purified by flash silica gel chromatography using a gradient of ethyl acetate (0% to 50% over 20 min) in hexane. The pure fractions were collected and the solvents were evaporated to give ethyl 2-chloro-6-[3-(4,4-dimethylpentoxy)-2-oxopyrrolidin-1-yl]pyridin-3-carboxylate (358 mg, 65%) as a colorless gum , which slowly hardened.

1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J=8.6 Hz, 1H), 8.32 (d, J=8.6 Hz, 1H), 4.38-4.26 (m, 3H), 4.02

- 288 044967 (ddd, J=11.1, 8.9, 2.6 Hz, 1H), 3.81-3.67 (m, 2H), 3.54 (dt, J=9.3, 6.6 Hz, 1H), 2.49-2.39 (m, 1H), 1.92 (dk,

J=12.4, 8.8 Hz, 1H), 1.58-1.44 (m, 2H), 1.32 (t, J=7.1 Hz, 3H), 1.25-1.16 (m, 2H), 0.87 (s, 9H). MS-ESI m/z calc. 382.16592, detected 383.3 (M+1)+; Retention time: 2.26 min (LC method B).

Step 3: 6-[[3-carboxy-3-(4,4-dimethylpentoxy)propyl]amino]-2-chloro-pyridine-3-carboxylic acid

In a 100 mL flask, ethyl 2-chloro-6-[3-(4,4-dimethylpentoxy)-2-oxopyrrolidin-1-yl]pyridine-3-carboxylate (335 mg, 0.8749 mmol) in methanol (5 mL) and tetrahydrofuran (5 ml) was stirred until homogeneous. Sodium hydroxide (1 ml 2 M, 2,000 mmol) (2 M aq) was added to the mixture and the cloudy mixture was stirred at ambient temperature for 9 hours. More sodium hydroxide (1 ml 6 N) was added and the mixture was stirred overnight . The reaction was diluted with water (40 ml). The solution was acidified by slow addition of 6 N. hydrochloric acid to pH 2. The solid was extracted with ethyl acetate (2x50 ml, 1x25 ml) and the combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with dichloromethane/hexanes and the solvents were evaporated to give 6-[[3-carboxy-3-(4,4-dimethylpentoxy)propyl]amino]-2chloropyridine-3-carboxylic acid (333 mg, quantitative yield) as crude white solid.

1H NMR (400 MHz, DMSO-a ₆ ) δ 12.60 (s, 2H), 7.87 (d, J=8.6 Hz, 1H), 7.61 (t, J=5.6 Hz, 1H), 6.44 (d, J=8.7 Hz, 1H), 3.83 (dd, J=8.9, 3.8 Hz, 1H), 3.50 (dt, J=8.9, 6.6 Hz, 1H), 3.42-3.36 (m, 1H), 3.34 (broad s, partially overlapped with water signal, 1H), 3.25 (dt, J=8.9, 6.7 Hz, 1H), 2.00-1.85 (m, 1H), 1.85-1.73 (m, 1H), 1.52-1.39 (m, 2H), 1.20-1.12 (m, 2H), 0.84 (s, 9H). MS-ESI m/z calc. 372.1452, detected 373.2 (M+1) ⁺ ; retention time: 1.47 min (LC method B).

Step 4: 2-chloro-6-[3-(4,4-dimethylpentoxy)-2-oxo-pyrrolidin-1-yl]pyridine-3-carboxylic acid o

6-[[3-Carboxy-3-(4,4-dimethylpentoxy)propyl]amino]-2-chloropyridine-3-carboxylic acid (281 mg, 0.7537 mmol), HATU was charged into a 100 mL flask under nitrogen atmosphere. (292 mg, 0.7680 mmol) and anhydrous tetrahydrofuran (6 ml) (partial suspension). Triethylamine (0.34 mL, 2.439 mmol) was added (rapidly converted to a yellow homogeneous solution) and the mixture was stirred at room temperature for 2 days. Water (30 ml) was added followed by hydrochloric acid (200 µl 6 M, 1,200 mmol) (6 N aq, final pH 4). The resulting white solid was filtered and washed with water to obtain pure 2-chloro-6-[3-(4,4-dimethylpentoxy)-2-oxopyrrolidin-1yl]pyridine-3-carboxylic acid (196 mg, 73%) as white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 13.51 (s, 1H), 8.34 (d, J=8.6 Hz, 1H), 8.31 (d, J=8.6 Hz, 1H), 4.33 (dd, J=8.9 , 7.9 Hz, 1H), 4.01 (ddd, J=11.2, 8.8, 2.6 Hz, 1H), 3.82-3.67 (m, 2H), 3.54 (dt, J=9.2, 6.6 Hz, 1H), 2.482.37 ( m, 1H), 1.91 (dk, J=12.4, 8.9 Hz, 1H), 1.58-1.44 (m, 2H), 1.27-1.14 (m, 2H), 0.87 (s, 9H). MS-ESI m/z calc. 354.13464, detected 355.3 (M+1) ⁺ ; retention time: 1.91 min (LC method B).

Step 5: tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-(4,4-dimethylpentoxy)-2-oxo-pyrrolidin-1yl]pyridin-3- carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

A 100 mL round bottom flask was charged under a nitrogen atmosphere with 2-chloro-6-[3-(4,4-dimethylpentoxy)2-oxopyrrolidin-1-yl]pyridine-3-carboxylic acid (182 mg, 0.5129 mmol) and anhydrous tetrahydrofuran (3 ml). Carbonyl diimidazole (102 mg, 0.6291 mmol) (freshly recrystallized from tetrahydrofuran) was added and the mixture was stirred under nitrogen at room temperature for 3 hours. An additional 35 mg of carbonyldiimidazole was added and the mixture was stirred at room temperature for 2 hours. In a separate 20-volume flask ml solution of tert-butyl (48)-2,2-dimethyl-4-[3-[(6-sulfamoyl-2pyridyl)amino]propyl]pyrrolidine-1-carboxylate (211 mg, 0.5115 mmol) in anhydrous tetrahydrofuran ( 1.5 ml) was obtained under nitrogen atmosphere and subsequently it was added using a syringe to the solution

- 289 044967 activated ester. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.38 mL, 2.541 mmol) was added via syringe and the reaction mixture was stirred at room temperature under nitrogen atmosphere overnight. After 2 days, the solvents were removed under reduced pressure and the resulting thick oil was treated with ethyl acetate (20 ml) and water (20 ml). Hydrochloric acid (600 μl 6 M, 3,600 mmol) was added slowly (final pH 5) and the two phases were separated. The aqueous phase was extracted with ethyl acetate (30 ml). The combined extracts were washed with saline (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 using a gradient of ethyl acetate (0% to 100% over 30 min) in hexanes to give tert-butyl (4S)-4-[3-[[6-[[ 2-chloro-6-[3-(4,4-dimethylpentoxy)-2-oxopyrrolidin-1yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (138 mg, 36%, 90% purity) as a colorless resin. MS-ESI m/z calc. 748.3385, detected 749.5 (M+1)+; retention time: 2.42 min (LC method B).

Step 6: 2-chloro-6-[3-(4,4-dimethylpentoxy)-2-oxo-pyrrolidin-1-yl]-N-[[6-[3-[(3S)-5,5dimethylpyrrolidin-3 -yl]propylamino]-2-pyridyl]sulfonyl]pyridine-3-carboxamide (dihydrochloride salt).

Tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-(4,4-dimethylpentoxy)-2oxopyrrolidin-1-yl]pyridin-3 was loaded into a 100 ml flask -carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2dimethylpyrrolidine-1-carboxylate (138 mg, 0.1842 mmol), dichloromethane (2 ml) and hydrochloric acid (300 µl 4M in dioxane, 1,200 mmol) . The reaction mixture was stirred at room temperature for 3.5 hours (60% conversion). Additional hydrochloric acid (300 μl 4 M, 1,200 mmol) was added and the reaction mixture was stirred for an additional 2 hours. Volatiles were removed by evaporation under vacuum. The residue was triturated with dichloromethane/hexanes and the solvents were evaporated. The operation was repeated until a white solid was obtained. Drying in vacuum gives 2chloro-6-[3-(4,4-dimethylpentoxy)-2-oxopyrrolidin-1-yl]-N-[[6-[3-[(3S)-5,5-dimethylpyrrolidin-3yl] propylamino]-2-pyridyl]sulfonyl]pyridine-3-carboxamide (dihydrochloride salt) (125 mg, 94%) as a white solid. The product was used in the next step without further purification. MS-ESI m/z calc. 648.2861, detected 649.4 (M+1) ⁺ ; retention time: 1.62 min (LC method B).

Step 7: (14S)-8-{3-[(4,4-dimethylpentyl)oxy]-2-oxopyrrolidin-1-yl}-12,12-dimethyl-2λ ⁶ -thia3,9,11,18,23 -pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 1) (compound 246) and ( 14S)-8-{3-[(4,4-dimethylpentyl)oxy]-2-oxopyrrolidin-1-yl}12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 2) (compound 247)

diastereomer 1 diastereomer 2

2-chloro-6-[3-(4,4-dimethylpentoxy)-2-oxopyrrolidin-1-yl]-N-[[6-[3- [(3S)-5,5-dimethylpyrrolidin-3yl]propylamino]-2-pyridyl]sulfonyl]pyridine-3-carboxamide (dihydrochloride salt) (125 mg, 0.1731 mmol), anhydrous NMP (7 ml) and potassium carbonate (465 mg, 3.365 mmol) (325 mesh). The mixture was vigorously stirred in a dry bath at 155°C under a nitrogen atmosphere for 20 hours. After cooling to room temperature, the mixture was poured into chilled water (50 ml) and acidified by adding hydrochloric acid (1 ml 6 M, 6,000 mmol) (slight foaming ). The resulting solid was filtered and air dried briefly. The solid was dissolved in dichloromethane and purified by flash silica gel chromatography using a gradient of methanol (0% to 5% over 30 min) in dichloromethane to give a mixture of diastereomers, which were subjected to chiral separation by ultrifuge chromatography.

- 290 044967 (ChiralCel OJ-H (250x10 mm), 5 µM column; mobile phase 24% acetonitrile/methanol (90:10, 20 mM NH ₃ ), 76% carbon dioxide, 10 ml/min; concentration 23 mg/ml in acetonitrile/methanol (90:10; 20 mM NH ₃ ; injection volume 70 μl, 100 bar), which gives as the first eluted diastereomer (14S)-8{3-[(4,4-dimethylpentyl)oxy]- 2-oxopyrrolidin-1-yl}-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9 ,19(23),20-hexaene-2,2,4-trione (diastereomer 1) (compound 246) (22 mg, 20%).

Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.43 (s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.04 (d, J=7.2 Hz, 1H), 6.96 (broad s, 1H), 6.70 (d, J=8.5 Hz, 1H), 4.24 (t, J=8.2 Hz, 1H), 4.03 (t, J=8.7 Hz, 1H), 3.95-3.87 (br m, 1H), 3.81-3.64 (m, 2H), 3.52 (dt, J=9.2, 6.6 Hz, 1H), 3.12 (br. s, 1H), 2.94 (d, J=13.5 Hz, 1H), 2.78-2.61 (m, 1H), 2.42 (dk, J=13.0, 7.9, 6.3 Hz, 1H), 2.11 (broad s, 1H), 1.92 ( dk, J=12.3, 8.6 Hz, 1H), 1.85-1.68 (m, 2H), 1.64-1.41 (m, 10H), 1.36-1.13 (m, 4H), 0.87 (s, 9H). MS-ESI m/z calc. 612.3094, detected 613.4 (M+1)+; retention time: 2.17 min (LC method B).

The second diastereomer eluted was (14S)-8-{3-[(4,4-dimethylnentyl)oxy]-2oxopyrrolidin-1-yl}-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18, 23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 2) (compound 247) (21 mg , 19%).

1H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 12.41 (s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.59-7.51 (m, 2H), 7.04 (d, J=7.2 Hz, 1H ), 6.96 (broad s, 1H), 6.70 (d, J=8.5 Hz, 1H), 4.28 (t, J=8.4 Hz, 1H), 3.92 (t, J=9.8 Hz, 2H), 3.83-3.68 ( m, 2H), 3.52 (dt, J=9.2, 6.6 Hz, 1H), 3.10 (br. s, 1H), 2.94 (br. d, J=13.4 Hz, 1H), 2.80-2.59 (m, 1H) , 2.48-2.37 (m, 1H), 2.10 (broad s, 1H), 1.95-1.68 (m, 3H), 1.64-1.42 (m, 10H), 1.36-1.14 (m, 4H), 0.87 (s, 9H). MS-ESI m/z calc. 612.3094, detected 613.4 (M+1) ⁺ ; Retention time: 2.17 min (LC method B).

Example 76: Preparation of 12,12-dimethyl-8-{3-[3-methyl-2-(propan-2-yl)butoxy]-1H-pyrazol-1-yl}-15oxa-2λ ⁶ -thia-3, 9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene2,2,4-trione (enantiomer 1) ( compound 248) and 12,12-dimethyl-8-{3-[3-methyl-2-(propan-2-yl)butoxy]1H-nirazol-1-yl}-15-oxa-2λ ⁶ -thia-3 ,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (enantiomer 2) (connection 249)

Step 1: 12,12-dimethyl-8-{3-[3-methyl-2-(propan-2-yl)butoxy]-1 H-pyrazol-1 -yl}-15-oxa-2X ⁶ -thia3, 9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (enantiomer 1 ) (compound 248) and 12,12-dimethyl-8-{3-[3-methyl-2-(propan-2-yl)butoxy]-1H-pyrazol-1yl}-15-oxa-2Х ⁶ -thia- 3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21hexaene-2,2,4-trione (enantiomer 2 ) (connection 249)

Racemic 12,12-dimethyl-8-{3-[3-methyl-2-(propan-2-yl)butoxy]-1H-pyrazol-1-yl}-15-oxa2X ⁶ -thia-3,9,11 ,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4trione (60 mg, 0.09612 mmol ) were subjected to chiral SLC chromatography. The following LCLC protocol was used: ChiralPak AS-3 (150x 2.1 mm), 3 µm; Mobile phase 35°C: 30% acetonitrile:methanol (90:10), 70% carbon dioxide. The first enantiomer eluted was 12,12-dimethyl8-{3-[3-methyl-2-(propan-2-yl)butoxy]-1H-pyrazol-1 -yl}-15-oxa-2X ⁶ -thia-3, 9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (enantiomer 1) ( compound 248) (21 mg, 71%). MS-ESI m/z calc. 611.289, detected 612.2 (M+1) ⁺ ; retention time: 2.30 min (LC method B).

The second enantiomer eluted was 12,12-dimethyl-8-{3-[3-methyl-2-(propan-2-yl)butoxy]1H-πyrazol-1-yl}-15-oxa-2λ ⁶ -thia-3 ,9,11,18,23-πpentaazatetracyclo[17.3.1.111,14.O5,10]tetracose1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (enantiomer 2) (compound 249) (22 mg, 74%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.56 (s, 1H), 8.19 (d, J=2.8 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.59 (dd, J=8.5 , 7.2 Hz, 1H), 7.10 (t, J=7.4 Hz, 2H), 6.95 (d, J=8.2 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 6.11 (d, J=2.7 Hz,

1H), 4.23 (d, J=4.8 Hz, 2H), 4.11 (t, J=8.3 Hz, 2H), 3.88 (t, J=12.0 Hz, 1H), 3.60 (d, J=12.9 Hz, 1H) , 3.23 (s,

1H), 3.07 (s, 1H), 2.87 (d, J=9.4 Hz, 1H), 2.08 (dd, J=11.7, 5.9 Hz, 1H), 1.96-1.85 (m, 2H), 1.79 (t, J =10.9 Hz,

1H), 1.58 (d, J=9.2 Hz, 6H), 1.35 (p, J=5.2 Hz, 1H), 0.98 (d, J=6.8 Hz, 6H), 0.92 (d, J=6.8 Hz, 6H) . MS-ESI m/z calc. 611.289, found 612.2 (M+1) ⁺ ; Retention time: 2.29 min (LC method B).

Example 77: preparation of 11-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-7,7-dimethyl-17X ⁶ -thia- 291 044967

2,8,10,16,22-pentaazatetracyclo[16.3.1.15,8.09,14]tricose-1(22),9,11,13,18,20-hexaene-15,17,17-trione (enantiomer 1) (connection 251)

Step 1: tert-butyl 2,2-dimethyl-4-[2-[(6-sulfamoyl-2-pyridyl)amino]ethyl]pyrrolidine-1-carboxylate

Racemic tert-butyl-2,2-dimethyl-4-[2-[(6-sulfamoyl-2-pyridyl)amino]ethyl]pyrrolidine-1carboxylate (1.475 g, 3.701 mmol) was separated by chiral RPLC using ChiralPak IG (250x21 column .2 mm, particle size 5 µm) with a mobile phase of 32% methanol (no modifier) / 68% carbon dioxide at 70 ml/min, giving tert-butyl 2,2-dimethyl4-[2-[ as the first eluting enantiomer (6-sulfamoyl-2-pyridyl)amino]ethyl]pyrrolidine-1-carboxylate (enantiomer 1) (670 mg, 91%) as a white foam. MS-ESI m/z calc. 398.19876, detected 399.3 (M+1)+; retention time: 1.59 min (LC method B).

Step 2: tert-butyl 4-[2-[[6-[[2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl] amino]ethyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (enantiomer 1)

enantiomer 1 enantiomer 1

2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (147.7 mg, 0.4082 mmol), recrystallized carbonyldiimidazole (66.2 mg) was added to the flask , 0.4083 mmol) and tetrahydrofuran (4 ml). The reaction mixture was stirred at 40°C for 90 minutes. Tert-butyl 2,2-dimethyl-4-[2-[(6-sulfamoyl-2-pyridyl)amino]ethyl]pyrrolidine-1-carboxylate (enantiomer 1) (130 mg, 0.3262 mmol) was then added with followed by the addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (150 µl, 1.003 mmol). The reaction mixture was stirred for 2 days. The reaction was filtered and purified by HPLC (30-99% acetonitrile:water gradient modified with 0.1% hydrochloric acid) to give tert-butyl 4-[2-[[6-[[2-chloro-6-[3-( 3,3-Dicyclopropylpropoxy)pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]ethyl]-2,2-dimethylpyrrolidine-1-carboxylate (enantiomer 1) (30.4 mg, 13%) . MS-ESI m/z calc. 741.30756, detected 742.4 (M+1) ⁺ ; retention time: 2.2 min (LC method G).

Step 3: 2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]-N-[[6-[2-(5,5dimethylpyrrolidin-3-yl)ethylamino]-2-pyridyl ]sulfonyl]pyridine-3-carboxamide (enantiomer 1)

- 292 044967

Into a flask containing tert-butyl 4-[2-[[6-[[2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl ]amino]ethyl]-2,2-dimethylpyrrolidine-1-carboxylate (enantiomer 1) (30.4 mg, 0.04095 mmol), dichloromethane (3 mL) and trifluoroacetic acid (125 μL, 1.622 mmol) were added. The reaction mixture was allowed to stir at room temperature for 30 minutes. The reaction mixture was evaporated to dryness and washed with saturated aqueous sodium bicarbonate. The reaction mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered and evaporated to give 2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]-N-[[6[2-(5.5 -dimethylpyrrolidin-3-yl)ethylamino]-2-pyridyl]sulfonyl]pyridine-3-carboxamide (enantiomer 1) (24 mg, 91%). MS-ESI m/z calc. 641.2551, detected 642.3 (M+1)+; retention time: 1.76 min (LC method B).

Step 4: 11-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-7,7-dimethyl-17λ ⁶ -thia-2,8,10,16,22pentaazatetracyclo[16.3.1.15, 8.09,14]tricose-1(22),9,11,13,18,20-hexaene-15,17,17-trione (enantiomer 1) (compound 251)

Potassium carbonate (35 mg, 0.2532 mmol), cesium fluoride (12 mg, 0.07900 mmol), 3 A molecular sieves, and 2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazole solution were added to the vial -1-yl]-N-[[6-[2-(5,5dimethylpyrrolidin-3-yl)ethylamino]-2-pyridyl]sulfonyl]pyridine-3-carboxamide (enantiomer 1) (24 mg, 0.03737 mmol ) in dimethyl sulfoxide (1.5 ml). The reaction mixture was placed in an oil bath at 150°C and left to stir overnight. The reaction mixture was cooled to room temperature, filtered and purified by HPLC (10-99% acetonitrile:water gradient modified with 0.1% hydrochloric acid) to give 11-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol- 1yl]-7,7-dimethyl-17λ ⁶ -thia-2,8,10,16,22-pentaazatetracyclo[16.3.1.15,8.09,14]tricose-1(22),9,11,13,18,20hexaene -15,17,17-trione (enantiomer 1) (compound 251) (9.3 mg, 41%).

1H NMR (400 MHz, DMSO-de) δ 12.45 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.74 (d, J=33.0 Hz, 2H), 7.17 (s, 1H), 6.90 (d, J=8.2 Hz, 1H), 6.82 (s, 1H), 6.10 (d, J=2.8 Hz, 1H), 4.37 (t, J=6.8 Hz, 2H), 2.25 (s, 3H), 1.90 (k, J=6.8 Hz, 4H), 1.56 (s, 6H), 1.49 (s, 2H), 0.68 (dtd, J=13.4, 8.6, 5.0 Hz, 2H), 0.46-0.34 (m, 5H), 0.30 (ddd, J=15.8, 8.9, 6.7 Hz, 1H), 0.25-0.15 (m, 2H), 0.09-0.02 (m, 2H). Two protons are hidden by the solvent. MS-ESI m/z calc. 605.27844, detected 606.2 (M+1) ⁺ ; retention time: 2.3 min (LC method B).

Example 78: Preparation of (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}-2,2-dideuteroethoxy)-1Hpyrazol-1-yl]-12,12- dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2 ,4-trione (compound 252)

- 293 044967

Step 1: dideutero(dispiro[2.0.2.1]heptan-7-yl)methanol xYi d D

A solution of ethyl dispiro[2.0.2.1]heptane-7-carboxylate (2.8 g, 16.84 mmol) in tetrahydrofuran (35 ml) was cooled in an ice-water bath. Lithium aluminum deuteride (678 mg, 16.14 mmol) was added in small portions over 3 minutes and the reaction mixture was stirred under nitrogen at ambient temperature for 5 hours. The reaction mixture was cooled in an ice-water bath, and the reaction mixture was diluted with ether (40 ml) and slowly quenched by adding saturated aqueous Rochelle salt solution (~30 ml) until the layers were clearly separated. The lower aqueous layer was extracted with diethyl ether (2x30 ml). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated to give dideutero(dispiro[2.0.2.1]heptan-7-yl)methanol (2.5 g, 98%) as a light yellow oils

^1H NMR (400 MHz, chloroform-d) δ 4.82 (br. C, 1H), 1.62 (s, 1H), 0.87 (m, 4 H), 0.65-0.48 ( m, 4 N).

Step 2: 7-[bromo(dideutero)methyl]dispiro[2.0.2.1]heptane ^br

D D

To a solution of triphenylphosphine (5.3 g, 20.1 mmol) in dichloromethane (74 ml) under a nitrogen atmosphere at 15°C was added a solution of bromine (1.1 ml, 21.3 mmol) in dichloromethane (9 ml) over 15 min. The reaction mixture was stirred for another 15 minutes at -15°C and then cooled to -30°C. A solution of dideutero(dispiro[2.0.2.1]heptan-7-yl)methanol (2.5 g, 16.6 mmol) and pyridine (1.65 mL, 20.5 mmol) in dichloromethane (18 mL) was added dropwise. The mixture was heated to -5°C, stirred for 1 hour and poured into pentane (1 L). The resulting precipitate was filtered off and the filtrate was concentrated. Pentane (300 ml) was added to the residue, and the mixture was sonicated and filtered. The filtrate was concentrated to give a white solid, which was again treated with pentane (300 ml) and filtered. The filtrate was concentrated and the residue was purified by chromatography on silica gel using a gradient of 0-5% diethyl ether in pentane. Fractions containing product were combined and concentrated at 300 mbar in a 30° C. water bath to give 7-[bromo(dideutero)methyl]dispiro[2.0.2.1]heptane (2 g, 58%) as a white solid.

^1H NMR (250 MHz, chloroform-d) δ 1.88 (s, 1H), 0.8-1.0 (m, 4H), 0.63-0.72 (m, 2H), 0. 48-0.6 (m, 2H).

Step 3: 2,2-dideutero-2-dispiro[2.0.2.1]heptan-7-ylacetonitrile

To a solution of 7-[bromo(dideutero)methyl]dispiro[2.0.2.1]heptane (2.3 g, 22.02 mmol) in dimethyl sulfoxide (30 ml) was added sodium cyanide (753 mg, 27.53 mmol) and the reaction mixture stirred at room temperature for 2 hours. The mixture was diluted with saline (40 ml) and extracted with pentane (2x50 ml). The combined pentane layers were dried over magnesium sulfate, filtered and concentrated to give 2,2-dideutero-2-dispiro[2.0.2.1]heptan-7-ylacetonitrile (1.8 g, 77%) as colorless

- 294 044967 oil.

Ή NMR (250 MHz, chloroform-d) δ 1.68 (s, 1H), 0.8-1.05 (m, 4 H), 0.65-0.8 (m, 2H), 0.54-0.62 (m, 2H).

Step 4: 2,2-dideutero-2-dispiro[2.0.2.1]heptan-7-ylacetic acid.

2,2-dideutero-2-dispiro[2.0.2.1]heptan-7-ylacetonitrile (7.7 g, 56.951 mmol) was dissolved in CH ₃ CwaterD (105 ml) at room temperature. Sodium deuteroxide (52.2 g, 40% wt., 509.23 mmol) was added followed by CH ₃ CwaterD (105 ml). The mixture was heated at 72°C in an oil bath under a nitrogen atmosphere (balloon) for 16 hours. The mixture was cooled in an ice water bath for 15 minutes. D ₂ O (~20 ml) was added. Ether (2x50 ml) was used to extract the aqueous mixture. The aqueous layer was saved and treated with hydrochloric acid (6N) to pH ~ 2. The mixture was extracted with ether (3x50 ml). The combined ether layers were dried over anhydrous magnesium sulfate, filtered and concentrated to give 2,2-dideutero-2-dispiro[2.0.2.1]heptan-7-ylacetic acid (6 g, 65%) as a pale yellow solid.

1H NMR (250 MHz, chloroform-d) δ 1.64 (s, 1H), 1.01-0.73 (m, 4H), 0.67 (ddd, J=8.3, 4.9, 3 .5 Hz, 2H), 0.58-0.35 (m, 2H).

Step 5: 2,2-dideutero-2-dispiro[2.0.2.1]heptan-7-ylethanol

Lithium aluminum hydride (2.84 g, 74.827 mmol) was weighed into a round bottom flask and cooled in an ice water bath under nitrogen (balloon). Tetrahydrofuran (150 ml) was added and the mixture was stirred at 0°C for 10 minutes. 2,2-dideutero-2dispiro[2.0.2.1]heptan-7-ylacetic acid (8.1 g, 52.528 mmol) in tetrahydrofuran solution (20 mL, 10 mL for rinse) was then added dropwise over 20 min. The mixture was slowly warmed to room temperature and stirred for 15 hours. It was then cooled in an ice water bath and slowly quenched with Rochelle's saline solution. Ether (200 ml) was added, the layers were separated and the aqueous layer was extracted with additional ether (2x150 ml). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to give 2,2-dideutero-2-dispiro[2.0.2.1]heptan-7-ylethanol (7.5 g, 89%) as a pale yellow oil.

^1H NMR (250 MHz, chloroform-d) δ 3.62 (s, 2H), 1.69 (s, 1H), 0.73-1.0 (m, 4H), 0.60-0, 75 (m, 2H), 0.450.59 (m, 2H).

Step 6: tert-butyl 3-(2,2-dideutero-2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazole-1-carboxylate

To a solution of tert-butyl 5-oxo-1H-pyrazol-2-carboxylate (10.25 g, 55.65 mmol) and 2,2-dideutero-2dispiro[2.0.2.1]heptan-7-yl-ethanol (8.193 g , 58.43 mmol) in tetrahydrofuran (128.1 ml), triphenylphosphine (15.33 g, 58.45 mmol) was added. Diisopropyl azodicarboxylate (11.82 g, 58.45 mmol) was added slowly dropwise to the mixture over 10 min. The reaction mixture was stirred at room temperature for 2 hours. Tetrahydrofuran was removed under reduced pressure and the residue was purified by silica gel chromatography using a shallow gradient from 100% hexane to 100% ethyl acetate to give tert-butyl-3-(2,2-dideutero-2 -dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazole-1-carboxylate (11.57 g, 68%) as a clear syrup. MS-ESI m/z calc. 306.19125, detected 307.2 (M+1) ⁺ ; retention time: 0.8 min (LC method A).

Step 7: 3-(2,2-dideutero-2-dispiro[2.0.2.1] heptan-7-ylethoxy)-1H-pyrazole

tert-Butyl-3-(2,2-dideutero-2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazole-1-carboxylate (11.57 g, 37.76 mmol) was dissolved in dichloromethane (115.7 ml) with trifluoroacetic acid (43.64 ml, 566.4 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the resulting oil was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous portion was extracted two more times with ethyl acetate, then the organic layers were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give 3-(2,2dideutero-2-dispiro[2.0.2.1]heptan-7-ylethoxy)-1H -pyrazole (7.789 g, 100%) as an oil. MS-ESI m/z calc. 206.13881, detected 207.1 (M+1)+; retention time: 0.59 min (LC method A).

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Step 8: tert-butyl-2-chloro-6-[3-(2,2-dideutero-2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1yl]pyridine-3-carboxylate

tert-butyl 2,6-dichloropyridin-3-carboxylate (9.368 g, 37.76 mmol), 3-(2,2-dideutero-2dispiro[2.0.2.1]heptan-7-ylethoxy)-1H-pyrazole (7.789 g , 37.76 mmol) and potassium carbonate (6.268 g, 45.35 mmol) were combined in anhydrous dimethyl sulfoxide (155.8 ml). 1,4Diazabicyclo[2.2.2]octane (848 mg, 7.560 mmol) was added and the mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was diluted with water (300 ml) and stirred for 15 minutes. The solid was filtered and washed with water. The solid was dissolved in dichloromethane, dried over magnesium sulfate, filtered and concentrated to give tert-butyl-2chloro-6-[3-(2,2-dideutero-2-dispiro[2.0.2.1]heptan-7-yl-ethoxy) pyrazol-1-yl]pyridin-3-carboxylate (15.54 g, 98%) as a white solid. MS-ESI m/z calc. 417.17883, detected 418.1 (M+1)+; retention time: 0.97 min (LC method A).

Step 9: 2-chloro-6-[3-(2,2-dideutero-2-dispiro[2.0.2.1]heptan-7-yl-ethoxy)pyrazol-1-yl]pyridine3-carboxylic acid

tert-Butyl-2-chloro-6-[3-(2,2-dideutero-2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridine 3-carboxylate (15.54 g, 37 .18 g mmol) was dissolved in dichloromethane (155.4 ml) with trifluoroacetic acid (42.97 ml, 557.7 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated, and ether was added to the resulting solid. , and then the ether was removed under reduced pressure. This was repeated twice more to obtain a white solid, which was recrystallized from dichloromethane to give the pure product as a solid. The product remained in the filtrate, which was evaporated to leave an off-white solid, which was dissolved in ethyl acetate and washed with 5N. sodium hydroxide (2x), then 1 N. hydrochloric acid (1x), then dried (sodium sulfate), filtered and concentrated to a white solid, purified by reverse phase HPLC-MS using a Luna C ₁₈ (2) column (75x30 mm, 5 µm particle size), sold Phenomenex (Item: 00C-4252-U0-AX), and a double gradient run with mobile phase B 20% to 80% 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 obtain pure product, which was combined with the originally crystallized material to obtain 2-chloro-6-[3-(2,2 -dideutero2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (10.43 g, 78%) as a white solid. MS-ESI m/z calc. 361.1162, detected 362.1 (M+1) ⁺ ; retention time: 0.78 min (LC method A).

Step 10: tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-(2,2-dideutero-2-dispyro[2.0.2.1]hetan-7-ylethoxy )pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate

To a solution of 2-chloro-6-[3-(2,2-dideutero-2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridine3-carboxylic acid (2 g, 5.528 mmol) in tetrahydrofuran (13.66 ml), carbonyldiimidazole (1.12 g, 6.907 mmol) (freshly recrystallized from tetrahydrofuran) was added and the mixture was stirred at room temperature for 3 hours. Then tert-butyl (4S)-2,2-dimethyl- 4-[3-[(6-sulfamoyl2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (2.383 g, 5.776 mmol) as a solution in tetrahydrofuran (5 ml), followed by 1,8-diazabicyclo [5.4.0]undec-7-ene (2.594 mL, 17.35 mmol) and the resulting mixture was stirred for 3 hours at room temperature. The reaction mixture was diluted with water and ethyl acetate, and then hydrochloric acid (6.178 mL, 6 M, 37.07 mmol) (pH 1) was added to the aqueous layer. The layers were separated and the organic layer was washed with water (1X) and brine (1X), then dried over sodium sulfate, filtered and concentrated to a white foam, which was purified on a 275 g C ₁₈ reverse phase column eluting with a 50%-100% gradient. acetonitrile/water to give tert-butyl-(4S)-4-[3-[[6-[[2-chloro-6-[3-(2,2-dideutero-2-dispiro[2.0.2.1]heptane- 7-ylethoxy)pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (3.0854 g, 74%) as a white solid. MS-ESI m/z calc. 755.32007, detected 756.1 (M+1)+; retention time: 0.93 min (LC method A).

Step 11: 2-chloro-6-[3-(2,2-dideutero-2-dispiro[2.0.2.1]heptan-7-yl-ethoxy)pyrazol-1-yl]-N-[[6-[3 [(3S)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2-pyridyl]sulfonyl]pyridine-3-carboxamide

tert-Butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-(2,2-dideutero-2-disniro[2.0.2.1]heptαn-7-ylethoxy)pyrazole1 - yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1 carboxylate (3.0854 g, 4.079 mmol) was dissolved in dichloromethane (13.46 ml) and trifluoroacetic acid was added (12.57 mL, 163.2 mmol) and the mixture was stirred at room temperature for 90 minutes. The mixture was concentrated to dryness under reduced pressure. Toluene (50 ml) was added and the mixture was evaporated on a rotary evaporator (water bath at 45°C). Toluene (50 ml) was added again and removed by rotary evaporation (45°C water bath), then dried in vacuo to give 2-chloro-6-[3-(2,2-dideutero-2dispiro[2.0.2.1]heptane- 7-ylethoxy)pyrazol-1-yl]-N-[[6-[3-[(3S)-5,5-dimethylpyrrolidin-3yl]propylamino]-2-pyridyl]sulfonyl]pyridine-3-carboxamide (trifluoroacetate salt ) (3.142 g, 100%) as a white solid. MS-ESI m/z calc. 655.26764, detected 656.2 (M+1) ⁺ ; retention time: 0.65 min (LC method A).

Step 12: (14S)-8-[3-(2-{disniro[2.0.2.1]heptan-7-yl}-2,2-dideuteroethoxy)-1H-nirazol-1-yl]12,12- dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2 ,4-trione (compound 252)

To a solution of 2-chloro-6-[3-(2,2-dideutero-2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]-N-[[6-[3[(3S )-5,5-dimethylpyrrolidin-3-yl]propylamino]-2-pyridyl]sulfonyl]pyridine-3-carboxamide (trifluoroacetate salt) (3.142 g, 4.079 mmol) in NMP (188.5 ml) was added potassium carbonate (3.946 g, 28.55 mmol). The mixture was purged with nitrogen for 5 minutes. The mixture was heated at 150°C for 24 hours. The reaction mixture was cooled to room temperature and added to water (~200 ml) to obtain an off-white solid. The mixture was carefully acidified with hydrochloric acid (6.798 ml 6 M, 40.79 mmol) to obtain a foamy suspension. The solid was collected by filtration and the wet filter cake was dissolved in ethyl acetate and washed with brine (1x) and a small amount of 6N. hydrochloric acid to preserve the transparency of the layers. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give a light yellow oil, which was chromatographed on a 275 g C ₁₈ reverse phase column, eluting with 50-100% acetonitrile/water to give (14S)-8-[ 3-(2-{disπro[2.0.2.1]heptan-7-yl}-2,2-dideuteroethoxy)-1H-πyrazol1 -yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11, 18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 252) (2.16 g , 85%) as a white solid.

1H NMR (400 MHz, DMSO-a ₆ ) δ 12.50 (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 (d, J=7.1 Hz, 1H), 6.98 (d, J=8.7 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 6.08 (d, J=2.7 Hz, 1H), 4.20 (d, J=1.4 Hz, 2H), 3.92 (d, J=12.9 Hz, 1H), 3.17 (d, J=5.0 Hz, 1H), 2.95 (d, J=13.1 Hz, 1H), 2.69 (d, J=13.8 Hz, 1H), 2.13 (s, 1H), 1.86 (dd, J=11.6, 5.2 Hz, 1H), 1.77 ( s, 1H), 1.59 (d, J=7.7 Hz, 6H), 1.51 (s, 3H), 1.46 (s, 1H), 1.38-1.24 (m, 1H), 0.83 (s, 4H), 0.69-0.60 (m, 2H), 0.55-0.44 (m, 2H). MS- 297 044967

ESI m/z calc. 619.29095, detected 620.2 (M+1)+; Retention time: 2.37 min (LC method B).

Example 79: Preparation of (14S)-8-(3-{2-[(7-deuterio)dispiro[2.0.2.1]heptan-7-yl]ethoxy}-1H-pyrazol1 -yl)-12,12-dimethyl- 2Х ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4 -trione (compound 253)

Step 1: ethyl 7-deuterodispiro[2.0.2.1]heptane-7-carboxylate

-y ^D o

A solution of cyclopropylidenecyclopropane (5.3 g, 66.1 mmol) in dichloromethane (15 ml) was cooled in an ice water bath. Rhodium(II) acetate dimer (600 mg, 5.2038 mmol) was added in one portion. The mixture was stirred under a nitrogen atmosphere at 0-5°C for 5 minutes. Ethyl 2-deutero-2-diazoacetate (20 mL, 152 mmol), prepared according to JACS 1993, 115, 2239, was then added using a syringe pump at a rate of 0.11 mL/h. The addition lasted 26 hours. After addition was complete, the mixture was stirred for an additional 10 minutes. The mixture was concentrated to a volume of 50 ml and filtered through a pad of silica gel. The pad was washed with dichloromethane (200 ml) and the combined filtrate was concentrated to 50 ml, filtered again and washed with dichloromethane (300 ml). The filtrate was concentrated to give ethyl 7-deuterodispiro[2.0.2.1]heptane-7-carboxylate (9 g, 66.25%) as a light yellow oil.

1H NMR (250 MHz, chloroform-d) δ 4.13 (kv, J=7.1 Hz, 2H), 1.39-1.14 (m, 4H), 1.11-0.92 (m, 3H), 0.910.67 (m, 4H).

Step 2: (7-deuterodispiro[2.0.2.1]heptan-7-yl)methanol —- L ° ^no

A solution of ethyl 7-deuterodispiro[2.0.2.1]heptane-7-carboxylate (9 g, 53.82 mmol) in tetrahydrofuran (100 ml) was cooled in an ice water bath. Lithium aluminum hydride (2.5 g, 65.78 mmol) was added in small portions over 5 minutes and the mixture was stirred under nitrogen at ambient temperature for 5 hours. The reaction mixture was cooled in an ice-water bath for 5 minutes, diluted with ether (200 ml) and slowly quenched by adding saturated aqueous Rochelle salt solution (approximately 30 ml) until the layers were clearly separated. The aqueous layer was extracted with diethyl ether (2x50 ml). The combined ether layers were washed with brine (50 mL), dried over magnesium sulfate and concentrated to give (7-deuterodispiro[2.0.2.1]heptan7-yl)methanol (4.7 g, 98%) as a light yellow oil.

1H NMR (250 MHz, chloroform-d) δ 3.72 (s, 2H), 1.00-0.75 (m, 4H), 0.74-0.44 (m, 4H).

Step 3: 7-(bromomethyl)-7-deuterodispiro[2.0.2.1]heptane xLc° ⁿ —- 298 044967

A solution of triphenylphosphine (9.38 g, 35.65 mmol) in dichloromethane (130 ml) under nitrogen was cooled to -15°C using an acetone dry ice bath. A solution of bromine (1.85 ml, 35.65 mmol) in dichloromethane (17 ml) was added over 15 minutes and the reaction mixture was stirred for a further 15 minutes at 15°C. The mixture was cooled to -30°C and a solution of (7-deuterodispiro[2.0.2.1]heptan-7-yl)methanol (4.5 g, 35.95 mmol) and pyridine (2.9 ml, 36 mmol) in dichloromethane ( 34 ml) was added dropwise. The mixture was then heated to -5°C and stirred for 1 hour. The reaction mixture was poured into pentane (1 L), resulting in the formation of a white precipitate. The solid was filtered through celite and the filtrate was concentrated (250 mbar with approximately 30° C. water bath) to give a white solid. Pentane (300 ml) was added and the mixture was sonicated and filtered. The filtrate was concentrated to give a white solid, which was again treated with pentane (300 ml) and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography using 05% diethyl ether in pentane. Fractions containing product were concentrated at 300 mbar in a 30° C. water bath to give 7-(bromomethyl)-7-deuterodispiro[2.0.2.1]heptane (6.4 g, 95%) as a clear oil.

1H NMR (250 MHz, chloroform-d) δ 3.49 (s, 2H), 1.42-1.17 (m, 2H), 1.12-0.81 (m, 2H), 0.79- 0.64 (m, 2H), 0.62-0.43 (m, 2H).

Step 4: 2-(7-deuterodispiro[2.0.2.1]heptan-7-yl)acetonitrile

To a solution of 7-(bromomethyl)-7-deuterodispiro[2.0.2.1]heptane (2.3 g, 22.02 mmol) in dimethyl sulfoxide (30 ml) was added sodium cyanide (753 mg, 27.53 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with brine (40 ml) and extracted with pentane (2x50 ml).

The combined pentane layer was dried over magnesium sulfate, filtered and concentrated to give 2-(7-deuterodispiro[2.0.2.1]heptan-7-yl)acetonitrile (4 g, 87%) as a clear oil.

1H NMR (250 MHz, chloroform-d) δ 2.42 (s, 2H), 1.04-0.79 (m, 4H), 0.79-0.65 (m, 2H), 0.65- 0.44 (m, 2H).

Step 5: 2-(7-deuterodispiro[2.0.2.1]heptan-7-yl)acetic acid

To a solution of 2-(7-deuterodispiro[2.0.2.1]heptan-7-yl)acetonitrile (4 g, 29.8 mmol) in ethanol (60 ml) was added a solution of sodium hydroxide (12 g, 300 mmol) in water (25 ml), and the resulting solution was stirred at 73°C for 15 hours. The mixture was cooled to room temperature, diluted with water (~40 ml) and extracted with diethyl ether (2x25 ml). The aqueous phase was adjusted to pH 1 by adding 6 M hydrochloric acid and then extracted with diethyl ether (2x40 ml). The combined ether layers were dried over magnesium sulfate, filtered and concentrated to give 2-(7deuterodispiro[2.0.2.1]heptan-7-yl)acetic acid (2.6 g, 57%) as a slightly yellow solid.

1H NMR (250 MHz, chloroform-d) δ 2.44 (s, 2H), 1.03-0.73 (m, 4H), 0.75-0.61 (m, 2H), 0.59- 0.38 (m, 2H).

Step 6: 2-(7-deuterodispiro[2.0.2.1]heptan-7-yl)ethanol

A suspension of lithium aluminum hydride (836 mg, 22 mmol) in tetrahydrofuran (35 ml) was cooled in an ice water bath. 2-(7-deuterodispiro[2.0.2.1]heptan-7yl)acetic acid (2.59 g, 16.9 mmol) in tetrahydrofuran (15 ml) was added dropwise over 10 min. The mixture was allowed to warm to ambient temperature and stirred under nitrogen for 15 hours. The reaction mixture was cooled in an ice-water bath for 5 minutes, then diluted with diethyl ether (60 ml) and slowly quenched by adding saturated aqueous Rochelle's salt (~ 40 ml) until the layers are clearly separated. The lower aqueous layer was extracted with diethyl ether (2x50 ml). The combined ethereal layers were washed with brine (40 mL), dried over magnesium sulfate, filtered and concentrated to give 2-(7-deuterodispiro[2.0.2.1]heptan-7-yl)ethanol (2.4 g, quantitative yield) as light yellow oil.

1H NMR (250 MHz, chloroform-d) δ 3.63 (t, J=6.9 Hz, 2H), 1.68 (t, J=6.8 Hz, 2H), 0.94-0.72 (m, 4H), 0.72-0.57 (m, 2H), 0.57-0.38 (m, 2H).

Step 7: tert-butyl-3-[2-(7-deuterodispiro[2.0.2.1]heptan-7-yl)ethoxy]pyrazole-1-carboxylate

- 299 044967

To a solution of tert-butyl-5-oxo-III-pyrazol-2-carboxylate (1.26 g, 6.84 mmol) and 2-(7deuterodispiro[2.0.2.1]heptan-7-yl)ethanol (1 g, 6 .48 mmol), triphenylphosphine (1.78 g, 6.8 mmol) in tetrahydrofuran (10 ml), diisopropyl azodicarboxylate (1.34 ml, 7.18 mmol) was added dropwise and the reaction mixture was stirred at 50°C for 12 h The mixture was concentrated and the residue was purified by silica gel column chromatography using a gradient of 100% hexane to 10% ethyl acetate in hexane to give tert-butyl-3-[(7-deuterodispiro[2.0.2.1]heptan-7-yl)methoxy ]pyrazole-1carboxylate (1.75 g, 80%) as a white solid.

¹ H NMR (250 MHz, chloroform-d) δ 7.82 (d, J=2.9 Hz, 1H), 5.84 (d, J=3.0 Hz, 1H), 4.26 (s, 2H), 1.58 (s, 9H), 1.44 (d, J=6.2 Hz, 2H), 0.93-0.73 (m, 4H), 0.65 (d, J=9.2 Hz, 2H), 0.49 (d, J=8.8 Hz, 2H). MS-ESI m/z calc. 306.2, found 307.3 (M+1)+; Retention time: 4.85 min (LC method P).

Step 8: 3-[2-(7-deuterodispyro[2.0.2.1]heptan-7-yl)ethoxy]-1H-pyrazole

To a solution of tert-butyl-3-[(7-deuterodispiro[2.0.2.1]heptan-7-yl)methoxy]pyrazol-1-carboxylate (1.75 g, 5.72 mmol) in dichloromethane (20 ml) was added trifluoroacetic acid acid (10 ml) and the resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated and the residue was partitioned between ethyl acetate (50 ml) and saturated aqueous sodium bicarbonate (25 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2x25 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give 3-[(7-deuterodispiro[2.0.2.1]heptan-7-yl)methoxy]-1H-pyrazoleα (1.2 g, quantitative yield) , as a white solid.

1H NMR (250 MHz, chloroform-d) δ 7.35 (d, J=1.3 Hz, 1H), 5.71 (d, J=1.4 Hz, 1H), 4.12 (t, J=7.8 Hz, 2H), 1.87 (t , J=6.7 Hz, 2H), 0.96-0.73 (m, 4H), 0.70-0.58 (m, 2H), 0.56-0.39 (m, 2H). MS-ESI m/z calc. 205.1, found 206.4 (M+1) ⁺ ; Retention time: 2.95 min (LC method R).

Step 9: tert-butyl 2-chloro-6-[3-[2-(7-deuterodispiro[2.0.2.1]heptan-7-yl)ethoxy]pyrazol-1yl]pyridine-3-carboxylate

To a mixture of tert-butyl-2,6-dichloropyridin-3-carboxylate (1.44 g, 5.8 mmol) and 3-[(7deuterodispiro[2.0.2.1]heptan-7-yl)methoxy]-1H-pyrazole ( 1.2 g, 3.93 mmol) in anhydrous dimethyl sulfoxide (24 ml) added potassium carbonate (965 mg, 6.97 mmol) and 1,4-diazabicyclo[2.2.2]octane (130 mg, 1.16 mmol) . The resulting mixture was stirred under nitrogen atmosphere at room temperature for 16 hours. The mixture was then diluted with water (45 ml) and stirred for 15 minutes. The resulting white solid was collected by filtration and washed with water (2x20 ml). The solid was dried and purified by silica gel column chromatography using a gradient of 100% hexanes to 60% ethyl acetate in hexanes to give tert-butyl-2-chloro-6-[3-[(7-deuterodispiro[2.0.2.1]heptane -7-yl)methoxy]pyrazol-1yl]pyridine-3-carboxylate (1.8 g, quantitative yield) as a white solid.

1H NMR (250 MHz, chloroform-d) δ 8.34 (dd, J=2.9, 1.1 Hz, 1H), 8.18 (dd, J=8.4, 1.1 Hz, 1H), 7.69 (dd, J=8.4, 1.0 Hz, 1H), 5.93 (dd, J=2.9, 1.1 Hz, 1H), 4.24 (s, 2H), 1.74-1.52 (m, 10H), 1.48 (s,lH), 0.93-0.77 (m, 4H), 0.71 -0.60 (m, 2H), 0.55-0.44 (m, 2H). MS-ESI m/z calc. 416.2, found 417.5 (M+1) ⁺ ; Retention time: 4.87 min (LC method R).

Step 10: 2-chloro-6-[3-[2-(7-deuterodispiro[2.0.2.1]heptan-7-yl)ethoxy]pyrazol-1-yl]pyridin-3 carboxylic acid

To a solution of tert-butyl-2-chloro-6-[3-[(7-deuterodispiro[2.0.2.1]heptan-7-yl)methoxy]pyrazol-1yl]pyridine-3-carboxylate (1.8 g, 4 .32 mmol) in dichloromethane (20 ml), trifluoroacetic acid (5 ml) was added and the reaction mixture was stirred at room temperature for 15 hours. The mixture was concentrated and the residue was triturated with diethyl ether/pentane (20 ml each). The precipitated solid was collected by filtration to give 2-chloro-6-[3-[(7-deuterodispiro[2.0.2.1]heptane-300 044967

7-yl)methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (1.19 g, 76% yield) as a white solid.

1H NMR (250 MHz, DMSO-d ₆ ) δ 8.46-8.34 (m, 2H), 7.72 (dd, J=8.4, 0.8 Hz, 1H), 6.17 (dd, J=2.9, 0.8 Hz, 1H), 4.23 (s, 2H), 1.46 (s, 2H), 0.92-0.74 (m, 4H), 0.64 (dd, J=7.6, 4.3 Hz, 2H), 0.50 (dd, J=7.1, 4.2 Hz, 2H). MS-ESI m/z calc. 361.1, detected 361.3 (M+1)+; retention time: 3.85 min (LC method R).

Step 11: tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-[2-(7-deuterodispiro[2.0.2.1]heptan-7yl)ethoxy]pyrazol- 1-yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate

To a solution of 2-chloro-6-[3-[2-(7-deuterodispiro[2.0.2.1]heptan-7-yl)ethoxy]pyrazol-1-yl]pyridin-3carboxylic acid (100 mg, 0.2772 mmol) in tetrahydrofuran (2 ml), carbonyldiimidazole (54 mg, 0.3330 mmol) was added and the mixture was stirred under a nitrogen atmosphere (balloon) at room temperature for 2 hours. Then tert-butyl (4S)-2,2-dimethyl-4 was added -[3-[(6-sulfamoyl-2pyridyl)amino]propyl]pyrrolidine-1-carboxylate (121 mg, 0.2933 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (130 µl, 0.8693 mmol) and the reaction mixture was stirred for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride/saline 1:1. The organic phases were separated, dried over sodium sulfate, filtered and evaporated. The resulting brown residue was purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate to give tert-butyl (4S)-4-[3-[[6[[2-chloro-6-[3-[2 -(7-deuterodispiro[2.0.2.1]heptan-7-yl)ethoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate ( 77 mg, 31%) as a white solid. MS-ESI m/z calc. 754.3138, detected 755.46 (M+1) ⁺ ; retention time: 0.67 min (LC method G).

Step 12: (14S)-8-(3-{2-[(7-deutero)dispiro[2.0.2.1]heptan-7-yl]ethoxy}-1H-pyrazol-1-yl)-12,12dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4- trione (compound 253) tert-butyl

Solution of (4S)-4-[3-[[6-[[2-chloro-6-[3-[2-(7-deuterodispiro[2.0.2.1]heptan-7 yl)ethoxy]pyrazol-1-yl] pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2dimethylpyrrolidine-1-carboxylate (77 mg, 0.1019 mmol) in dichloromethane (400 µl) and trifluoroacetic acid (100 µl, 1.307 mmol) stirred at room temperature for 4 hours. Solvents were removed by evaporation and the resulting residue was dissolved in ethyl acetate. Wash with 2 ml saturated sodium bicarbonate solution, the organic layer is collected and the solvent is evaporated. The resulting thick oil was additionally dried in vacuum. The resulting residue was dissolved in dimethyl sulfoxide (5 ml), 3 A molecular sieves were added and the reaction mixture was stirred for 10 minutes. Cesium fluoride (49 mg, 0.3226 mmol) and potassium carbonate (47 mg, 0.3401 mmol) were then added and the reaction mixture was heated at 150°C for 16 hours. The reaction mixture was filtered through a Whatman disk filter (puradisc 25 TF ), and the filtrate was purified by reverse phase HPLC-MS using a dual gradient from 50-99% mobile phase B over 15.0 min (mobile phase A=water (0.05% hydrochloric acid), mobile phase B=acetonitrile ) to give (14S)-8-(3-{2-[(7deutero)dispiro[2.0.2.1]heptan-7-yl]ethoxy}-1H-pyrazol-1-yl)-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4- trione (compound 253) (26.9 mg, 43%) as a white solid.

1H NMR (400 MHz, chloroform-d) δ 8.18 (d, J=2.8 Hz, 1H), 8.05 (d, J=8.3 Hz, 1H), 7.58-7.47 (m, 2H), 7.26 (s, 1H) , 6.56 (d, J=8.2 Hz, 1H), 5.89 (d, J=2.8 Hz, 1H), 4.71 (s, 1H), 4.24 (t, J=6.8 Hz, 2H), 3.85 (d, J= 37.1 Hz, 1H), 3.32 (s, 1H), 3.15 (d, J=13.6 Hz, 1H), 3.02 (d, J=27.8 Hz, 1H), 2.56 (s, 1H), 2.06 (t, J= 10.0 Hz, 1H), 1.89 (t, J=6.8 Hz, 2H), 1.74-1.37 (m, 10H), 0.85 (k, J=2.4 Hz, 4H), 0.75-0.58 (m, 2H), 0.55- 0.42 (m, 2H). MSIE m/z calc. 618.2847, found 619.15 (M+1) ⁺ ; Retention time: 1.96 min (LC method G).

- 301 044967

Example 80: Preparation of (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-20hydroxy-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5,7,9,19,21-hexaene-2,2,4-trione (compound 254)

Step 1: 3-benzyloxy-6-bromo-2-nitropyridine

A solution of 6-bromo-2-nitropyridin-3-ol (12 g, 54.796 mmol) in dry N,N-dimethylformamide (100 ml) under nitrogen was cooled in an ice water bath. Sodium hydride (2.49 g, 62.256 mmol, 60% in mineral oil) was added in one portion and the reaction mixture was stirred for 10 minutes. Benzyl chloride (7.5900 g, 6.9 mL, 59.961 mmol) was then added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at 60°C for two days. The reaction mixture was allowed to cool to room temperature, quenched with water (200 ml) and extracted with ethyl acetate (5x100 ml). The combined organic layers were washed with brine (3x70 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated in a mixture of heptanes/ethyl acetate 4:1 (50 ml). The resulting solid was filtered, washed with heptanes and dried under reduced pressure to obtain 3-benzyloxy-6-bromo-2-nitropyridine (13.643 g, 81%) as a yellow solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 5.23 (s, 2H), 7.33-7.43 (m, 6H), 7.60 (d, J=8.7 Hz, 1H). MS-ESI m/z calc. 307.9797, detected 309.0 (M+1)+; Retention time: 2.155 min (LC method I).

Step 2: 2-ethylhexyl 3-[(5-benzyloxy-6-nitro-2-pyridyl)sulfanyl]propanoate

Xantphos (1.49 g, 2.5751 mmol), tris(dibenzylideneacetone)dipalladium (0) (1.155 g, 1.2613 mmol) and diisopropylethylamine (11.130 g, 15 ml, 86.117 mmol). The reaction mixture was refluxed and stirred overnight at 110°C. The reaction mixture was cooled to room temperature, filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography. The companion was loaded with heptane (gradient from 100% heptane to 30% ethyl acetate in heptane) to give 2-ethylhexyl-3-[(5-benzyloxy-6-nitro-2pyridyl)sulfanyl]propanoate (18.977 g, 95%). MS-ESI m/z calc. 446.1875, detected 447.2 (M+1)+; retention time: 2.262 min (LC method I).

Step 3: 2-ethylhexyl 3-[(5-benzyloxy-6-nitro-2-pyridyl)sulfonyl]propanoate

M-chloroperbenzoic acid (19.795 g, 88.326 mmol) was added portionwise to a solution of 2ethylhexyl-3-[(5-benzyloxy-6-nitro-2-pyridyl)sulfanyl]propanoate (19.65 g, 44.003 mmol) in dichloromethane (170 ml ). The reaction was exothermic and the substance became cloudy. The reaction was stirred overnight at room temperature. Ethyl acetate (200 ml) was added and the reaction mixture was washed successively with aqueous 5% sodium bicarbonate (200 ml) and 0.5 M aqueous sodium hydroxide (2x 200 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-ethylhexyl-3-[(5-benzyloxy-6-nitro-2pyridyl)sulfonyl]propanoate (20.905 g, 99%) as a yellow oil.

¹ H NMR (300 MHz, CDCl ₃ ) δ 0.83-0.94 (m, 6H), 1.22-1.32 (m, 6H), 1.50-1.64 (m, 2H), 2.87 (t, J=7.6 Hz, 2H), 3.70 (t, J=7.6 Hz, 2H), 4.01 (dd, J=6.0, 2.2 Hz, 2H), 5.37 (s, 2H), 7.35-7.48 (m, 5H), 7.69 (d, J=8.5 Hz , 1H), 8.22 (d, J=8.5 Hz, 1H). MS-ESI m/z calc. 478.1774, found 367.1 (MC ₈ H ₁₆ +1) ⁺ ; Retention time: 2.419 min (LC method I).

Step 4: 2-ethylhexyl 3-[(6-amino-5-benzyloxy-2-pyridyl)sulfonyl]propanoate

Iron (2.525 g, 45.214 mmol) and ammonium chloride (2.021 g, 37.782 mmol). The reaction mixture was stirred at 100°C for 1.5 hours, cooled to room temperature, filtered through celite and washed with dichloromethane (200 ml). The filtrate was concentrated under reduced pressure, diluted with dichloromethane (100 ml) and washed with water (2x50 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-ethylhexyl-3-[(6-amino-5-benzyloxy-2pyridyl)sulfonyl]propanoate (6.25 g, quantitative yield) as a yellow oil colors. MS-ESI m/z calc. 448.2032, detected 449.3 (M+1)+; retention time: 2.565 min (LC method N).

Step 5: 2-ethylhexyl 3-[(5-benzyloxy-6-fluoro-2-pyridyl)sulfonyl]propanoate

A solution of 2-ethylhexyl-3-[(6-amino-5-benzyloxy-2-pyridyl)sulfonyl]propanoate (6.25 g, 13.933 mmol) in hydrogen fluoride in pyridine (71.500 g, 65 ml, 721.45 mmol) cooled to -40°C. The resulting red solution was treated with sodium nitrite (1.92 g, 27.828 mmol) and allowed to warm to room temperature. Gas evolution was observed and the reaction became orange and cloudy. The reaction mixture was stirred overnight at room temperature and poured slowly onto ice and water (400 ml). The mixture was neutralized by careful addition of aqueous sodium bicarbonate and extracted with ethyl acetate (4x150 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel loaded with heptane (gradient from 100% heptane to 40% ethyl acetate in heptane) to give 2-ethylhexyl-3-[(5-benzyloxy-6-fluoro-2-pyridyl)sulfonyl]propanoate (3.691 g, 59%) as a yellow oil. MS-ESI m/z calc. 451.1829, detected 452.2 (M+1)+; retention time: 2.648 min (LC O method).

Step 6: 5-benzyloxy-6-fluoropyridine-2-sulfonamide

- 303 044967

1,8-Diazabicyclo (5 ,4.0) undec-7-ene (2.0200 g, 2 ml, 13.269 mmol). The reaction mixture was stirred for 1 hour at room temperature and a solution of hydroxylamine-O-sulfonic acid (3.873 g, 34.246 mmol) and sodium acetate (2.246 g, 27.379 mmol) in water (12 ml) was added. The reaction mixture was stirred for 1 hour at room temperature, diluted with water (50 ml) and extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel loaded with heptane (100:0 to 50:50 heptane/ethyl acetate gradient) to give 5benzyloxy-6-fluoropyridine-2-sulfonamide (1.58 g, 80%) as a white solid substances.

¹ H NMR (300 MHz, DMSO-y6) δ 5.33 (s, 2H), 7.34-7.52 (m, 7H), 7.79-7.95 (m, 2H). ¹⁹ F NMR (282 MHz, dimethyl sulfoxide-d6) δ -83.6 (d, J=12.2 Hz, 1F). MS-ESI m/z calc. 282.0474, detected 283.1 (M+1)+; retention time: 2.33 min (LC method H).

Step 7: tert-butyl (4S)-4-[3-[(3-benzyloxy-6-sulfamoyl-2-pyridyl)amino]propyl]-2,2dimethyl-pyrrolidine-1-carboxylate

tert-butyl (4S)-4-(3-aminopropyl)-2,2-dimethylpyrrolidine-1 To a stirred solution of the carboxylate (200 mg, 0.7801 mmol) in anhydrous dimethyl sulfoxide (2.5 ml) was added 5-benzyloxy6-fluoropyridine- 2-sulfonamide (221 mg, 0.7829 mmol) and N,N-diisopropylethylamine (200 µl, 1.148 mmol) in that order under nitrogen. The resulting yellow solution was stirred at 85°C for 9 hours, then at 40°C for 13 hours. The reaction mixture was allowed to cool to ambient temperature and ethyl acetate (60 ml) and water (50 ml) were added. The solution was then acidified with 10% citric acid (10 ml) and the layers were separated. The organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a yellow viscous material. The crude reaction mixture was purified by silica gel chromatography (40 g silica gel, eluting with a gradient of 10-60% ethyl acetate in hexane over 30 min) to give the desired tert-butyl (4S)-4-[3-[(3-benzyloxy -6-sulfamoyl-2pyridyl)amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (370 mg, 91%) as a white foam. MSIE m/z calc. 518.2563, detected 519.4 (M+1) ⁺ ; retention time: 1.75 min (LC method B).

Step 8: tert-butyl (4S)-4-[3-[[3-benzyloxy-6-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7ylethoxy)pyrazole-1 -yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate

To a stirred solution of 2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1yl]pyridine-3-carboxylic acid (150 mg, 0.4169 mmol) in anhydrous tetrahydrofuran ( 3 ml) carbonyldiimidazole (75 mg, 0.4625 mmol) was added and stirring was continued at ambient temperature under nitrogen atmosphere for 2 hours. A solution of tert-butyl (4S)-4-[3-[(3benzyloxy-6) was added to the reaction -sulfamoyl-2-pyridyl)amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (196 mg, 0.3779 mmol) in anhydrous tetrahydrofuran (1 ml), then 1,8-diazabicyclo[5.4.0]undec -7-ene (220 µl, 1.471 mmol) and the mixture was stirred at ambient temperature for 15 hours. Volatiles were removed under reduced pressure, the residue was dissolved in ethyl acetate (20 ml) and water (10 ml), and the mixture was slowly acidified with hydrochloric acid acid (1.6 ml 1.0 M, 1,600 mmol) to approximately pH 4.0. The layers were separated and the aqueous layer was extracted with ethyl acetate (10 ml). Combined organic phases

- 304 044967 washed with saline (15 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via silica gel chromatography (24 g silica gel column, 0-70% ethyl acetate in hexane gradient over 35 min) to give tert-butyl (4S)-4-[3-[[3-benzyloxy-6- [[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7ylethoxy)pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl] -2, 2dimethylpyrrolidine-1-carboxylate (171 mg, 37%) as a white solid. MS-ESI m/z calc. 859.34937, detected 860.5 (M+1)+; retention time: 2.49 min (LC method G).

Step 9: N-[[5-Benzyloxy-6-[3-[(3 8)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2pyridyl]sulfonyl]-2-chloro-6-[3-( 2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3carboxamide (trifluoroacetate salt)

To a stirred solution of tert-butyl (4S)-4-[3-[[3-benzyloxy-6-[[2-chloro-6-[3-(2dispiro[2.0.2.1 ]heptan-7-ylethoxy)pyrazole-1 -yl]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (75 mg, 0.08716 mmol) in anhydrous methylene chloride (3 ml) was added trifluoroacetic acid (350 μl , 4.543 mmol) at ambient temperature in a nitrogen atmosphere. The orange solution was stirred for 1 hour, then the volatiles were removed under reduced pressure. Toluene (20 ml) was added to the residue and concentrated to dryness under reduced pressure. The process was repeated once more to remove residual trifluoroacetic acid and finally dried under vacuum for 2 hours to obtain crude N-[[5-benzyloxy6-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl] propylamino]-2-pyridyl]sulfonyl]-2-chloro-6-[3-(2dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3-carboxamide (trifluoroacetate salt) (66 mg , 87%). The material was transferred directly to the next stage without further purification. MSIE m/z calc. 759.29694, detected 760.5 (M+1) ⁺ ; retention time: 1.43 min (LC method B).

Step 10: (14S)-20-(benzyloxy)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]12,12-dimethyl -2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21hexaene-2,2,4-trione

N-[[5-benzyloxy-6-[3-[(3S)-5,5-dimethylpyrrolidin-3yl]propylamino]-2-pyridyl]sulfonyl]-2-chloro-6-[3 was loaded into a 20 ml bottle -(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1yl]pyridin-3-carboxamide (trifluoroacetate salt) (60 mg, 0.06862 mmol), potassium carbonate (60 mg, 0.4341 mmol) , cesium fluoride (21 mg, 0.1382 mmol) and anhydrous dimethyl sulfoxide (4 ml) in that order. The vessel was purged with a stream of nitrogen for 2 minutes, capped and stirred at 160°C for 15 hours. The reaction mixture was allowed to cool to ambient temperature and the heterogeneous mixture was diluted with ethyl acetate (30 ml) and water (20 ml) and acidified with hydrochloric acid (1.0 ml, 1.0 M, 1,000 mmol). The layers were separated and the aqueous layer was extracted with additional ethyl acetate (20 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by silica gel chromatography (0%-10% methanol in dichloromethane for 30 min) to give (14S)-20-(benzyloxy)-8-[3-(2-{dispiro[2.0.2.1] heptan-7-yl}ethoxy)-1Hpyrazol-1-yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23 ),5,7,9,19,21-hexaene-2,2,4-trione (41 mg, 83%) as a white solid. MS-ESI m/z calc. 723.3203, detected 724.5 (M+1) ⁺ ; retention time: 2.27 min (LC method G).

Step 11: (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-20-hydroxy-12,12dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene2,2,4-trione (compound 254 )

- 305 044967

To a stirred solution of (14S)-2O-(benzyloxy)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)1H-nurazol-1-yl]-12,12-dimethyl -2λ ⁶ -tua-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5,7,9,19,21-hexaene-2,2,4-trione (30 mg, 0.04144 mmol) in anhydrous methanol (6 ml) was added 10% Pd on carbon (wet, Degussa) (16 mg, 0.01503 mmol) under nitrogen atmosphere. The heterogeneous mixture was stirred in a hydrogen atmosphere (from a balloon) for 2.5 hours at ambient temperature. The hydrogen balloon was removed, the flask was purged with nitrogen, and the black heterogeneous reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure, the residue was dissolved in dimethyl sulfoxide (1.5 ml) and filtered through a 0.45 μm Whatman PTFE syringe disc filter. The sample was purified using a preparative reverse phase HPLC-MS [Luna C ₁₈ (2) column (75x30 mm, 5 µm particle size) sold by Phenomenex (P/N: 00C-4252-U0-AX), (double gradient run from 30% to 99% acetonitrile in water for 15 min (no modifier)] to give (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazole -1-yl]-20-hydroxy-12,12-dimethyl-2λ ⁶ thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7 ,9,19,21-hexaene-2,2,4-trione (compound 254) (20 mg, 75%) as a pale blue-green solid.

¹ H NMR (400 MHz, Methanol-d4) δ 8.24 (d, J=2.8 Hz, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 6.97 ( d, J=8.3 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 5.94 (d, J=2.7 Hz, 1H), 4.24 (t, J=6.6 Hz, 2H), 4.04 (t, J=13.2 Hz, 1H), 3.37-3.32 (m, 1H), 3.14 (dt, J=13.6, 4.4 Hz, 1H), 2.86 (t, J=10.4 Hz, 1H), 2.30-2.13 (m, 1H ), 1.88 (k, J=6.7 Hz, 4H), 1.78-1.66 (m, 2H), 1.66 (s, 3H), 1.63-1.60 (m, 1H), 1.60 (s, 3H), 1.48 (t, J=6.6 Hz, 1H), 1.44-1.33 (m, 1H), 0.92-0.78 (m, 4H), 0.66 (ddd, J=8.7, 4.6, 3.3 Hz, 2H), 0.56-0.47 (m, 2H) . MS-ESI m/z calc. 633.2733, detected 634.4 (M+1)+; retention time: 1.9 min (LC method G).

Example 81: Preparation of (148)-20-hydroxy-12,12-dimethyl-8-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1-yl)-2λ ⁶ -tua -3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 255)

Step 1: tert-butyl (48)-4-[3-[[3-benzyloxy-6-[[2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazole-1 -yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate

To a stirred solution of 2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1yl]pyridine-3-carboxylic acid (150 mg, 0.3849 mmol) in anhydrous tetrahydrofuran (3 ml ) carbonyldiimidazole (68 mg, 0.4194 mmol) was added and stirring was continued at ambient temperature under nitrogen for 2 hours. A solution of tert-butyl (4S)-4-[3[(3-benzyloxy-6) was added to this reaction -sulfamoyl-2-pyridyl)amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (180 mg, 0.3470 mmol) in anhydrous tetrahydrofuran (1 ml), then 1,8-diazabicyclo[5.4.0]undec -7-ene (200 µl, 1.337 mmol) and the mixture was stirred at ambient temperature for 15 hours. Volatiles were removed under reduced pressure, the residue was dissolved in ethyl acetate (20 ml) and water (10 ml), and

- 306 044967 the mixture was slowly acidified with hydrochloric acid (1.5 ml, 1.0 M, 1,500 mmol) to approximately pH 4.0. The layers were separated and the aqueous layer was extracted with ethyl acetate (10 ml). The combined organic phases were washed with brine (15 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (0% to 70% ethyl acetate in hexane gradient over 35 min) to give tert-butyl (4S)4-[3-[[3-benzyloxy-6-[[2-chloro-6 -[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidin-1-carboxylate (170 mg, 22%) as a white solid. MS-ESI m/z calc. 889.3211, detected 890.5 (M+1)+; retention time: 2.32 min (LC method G).

Step 2: N-[[5-benzyloxy-6-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2pyridyl]sulfonyl]-2-chloro-6-[3-[3 -[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3 carboxamide (trifluoroacetate salt)

To a stirred solution of tert-butyl (4S)-4-[3-[[3-benzyloxy-6-[[2-chloro-6-[3-[3-[1(trifluoromethyl)cyclopropyl]propoxy]pyrazole-1- yl]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (80 mg, 0.08985 mmol) in anhydrous methylene chloride (2.0 ml) and trifluoroacetic acid was added ( 350 µl, 4.543 mmol) at ambient temperature under nitrogen atmosphere. The orange solution was stirred for 1 hour and then the volatiles were removed under reduced pressure. Toluene (20 ml) was added to the residue and then concentrated to dryness under reduced pressure. The process was repeated once more to remove residual trifluoroacetic acid and finally dried in vacuo for 2 hours to obtain crude N-[[5benzyloxy-6-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propylamino ]-2-nurudyl]sulfonyl]-2-chloro-6-[3-[3[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3-carboxamide (trifluoroacetate salt) (81 mg, 100 %). The material was carried directly to the next stage without any purification. MS-ESI m/z calc. 789.2687, detected 790.5 (M+1) ⁺ ; retention time: 1.9 min (LC method B).

Step 3: (14S)-20-(benzyloxy)-12,12-dimethyl-8-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}1H-nurazol-1-ul)-2λ ⁶ -thia -3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione

N-[[5-benzyloxy-6-[3-(5,5-dimethylpyrrolidin-3-yl)propylamino]2-pyridyl]sulfonyl]-2-chloro-6-[3-[3] was loaded into a 20 ml bottle -[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridine3-carboxamide (trifluoroacetate salt) (80 mg, 0.08846 mmol), potassium carbonate (75 mg, 0.5427 mmol), cesium fluoride (27 mg, 0.1777 mmol) and anhydrous dimethyl sulfoxide (5 ml) in that order. The vessel was purged with a stream of nitrogen for 2 minutes, capped and stirred at 160°C for 15 hours. The reaction mixture was allowed to cool to ambient temperature and the heterogeneous mixture was diluted with ethyl acetate (30 ml) and water (20 ml) and acidified with hydrochloric acid (1.5 ml, 1.0 M, 1,500 mmol). The layers were separated and the aqueous layer was extracted with ethyl acetate (20 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (0%-10% methanol in dichloromethane gradient over 30 min) to give (14S)-20-(benzyloxy)12,12-dimethyl-8-(3-{3-[1-( trifluoromethyl)cyclopropyl]pronoxy}-1H-pyrazol-1-yl)-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7, 9,19(23),20-hexaene-2,2,4-trione (55 mg, 82%) as a white solid. MS-ESI m/z calc. 753.29205, detected 754.5 (M+1) ⁺ ; retention time: 2.11 min (LC method G).

Step 4: (148)-20-hydroxy-12,12-dimethyl-8-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1Hπyrazol-1-yl)-2λ ⁶ -thia-3, 9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 255)

To a stirred solution of (14S)-20-(benzyloxy)-12,12-dimethyl-8-(3-{3-[1- 307 044967 (trifluoromethyl)cyclopropyl]propoxy} -1 H-pyrazol-1 -yl)- 2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4 -trione (42 mg,

0.05572 mmol) in anhydrous methanol (5 ml) was added 10% Pd on carbon (wet, Degussa) (8 mg, 0.007517 mmol) under nitrogen atmosphere. The heterogeneous mixture was stirred in a hydrogen atmosphere (from a balloon) for 2.5 hours at ambient temperature. The hydrogen balloon was removed, the flask was purged with nitrogen, and the black heterogeneous reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure, the residue was dissolved in dimethyl sulfoxide (1.5 ml) and filtered through a 0.45 μm Whatman PTFE syringe disc filter. The sample was purified using a preparative reverse phase HPLC-MS [Luna C ₁₈ (2) column (75x30 mm, 5 µm particle size) sold by Phenomenex (P/N: 00C-4252-U0-AX), (double gradient run from 30% to 99% acetonitrile in water for 15 min (no modifier)] to give (14S)-20-hydroxy-12,12-dimethyl-8(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy} -1H-pyrazol-1-yl)-2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23) ,20-hexaene-2,2,4-trione (compound 255) (27 mg, 72%) as a pale blue-green solid.

¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.25 (d, J=2.8 Hz, 1H), 7.82 (d, J=8.1 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 6.98 (d, J=8.3 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 5.97 (d, J=2.9 Hz, 1H), 4.24 (t, J=6.1 Hz, 2H), 4.03 (t , J=12.8 Hz, 1H), 3.42-3.32 (m, 1H), 3.14 (dt, J=13.9, 4.4 Hz, 1H), 2.85 (s, 1H), 2.32-2.09 (m, 1H), 1.99- 1.83 (m, 4H), 1.80-1.74 (m, 2H), 1.74-1.66 (m, 2H), 1.66 (s, 3H), 1.63-1.60 (m, 1H), 1.59 (s, 3H), 1.40 ( dd, J=13.3, 10.1 Hz, 1H), 0.98-0.92 (m, 2H), 0.69 (ddd, J=6.0, 4.2, 3.0 Hz, 2H). MS-ESI m/z calc. 663.24506, detected 664.4 (M+1)+; retention time: 1.7 min (LC method G).

Example 82: Preparation of (14S)-8-(3-hydroxy-1H-pyrazol-1-yl)-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05 ,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 256)

Step 1: tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol1-yl]pyridin- 3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1carboxylate

2-Chloro-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (200 mg, 0.5717 mmol) and carbonyldiimidazole (116 mg, 0.7154 mmol) (freshly recrystallized from tetrahydrofuran, washed with cold ether and dried in high vacuum) were combined in tetrahydrofuran (2 ml) and stirred for 2 hours at room temperature. Then tert-butyl (4S)-2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (275 mg, 0.6666 mmol) was added, followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (500 μL, 3.343 mmol) was added and the reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate), filtered and concentrated. The resulting brown residue was purified by silica gel column chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate to give tert-butyl(4S)-4-[3-[[6-[[2-chloro-6-[3- [(2,2,3,3tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (172 mg, 40%) as an off-white solid. MS-ESI m/z calc. 743.3232, detected 744.45 (M+1) ⁺ ; retention time: 0.97 min (LC method A).

Step 2: (14S)-8-(3-hydroxy-1H-πyrazol-1-yl)-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05, 10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 256)

A solution of tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-[(2,2,3,3-tetramethylcyclononyl)methoxy]nirazol-1yl]pyridin-3- carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate

- 308 044967 (172 mg, 0.2311 mmol) in dichloromethane (1.5 ml) and trifluoroacetic acid (500 μl, 6.534 mmol) were stirred at room temperature for 4 hours. The solvents were removed and the residue was dissolved in ethyl acetate. Wash with 2 ml saturated aqueous sodium bicarbonate solution, the organic layer is collected and the solvent is removed in vacuo. The residue was dissolved in dimethyl sulfoxide (10 ml), 3 A molecular sieves were added and the reaction mixture was stirred for 10 minutes. Cesium fluoride (115 mg, 0.7571 mmol) and potassium carbonate (107 mg, 0.7742 mmol) were then added and the reaction mixture was heated at 150°C for 16 hours. The reaction mixture was cooled to room temperature and filtered through celite. and a saturated ammonium chloride solution was added to the filtrate. The mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting brown residue was purified by reverse phase HPLC-MS using a Luna C _i8 (2) column (75x30 mm, 5 µm particle size) sold by Phenomenex (art. no.: 00C-4252-U0-AX) and a double gradient of 30 % to 99% of mobile phase B within 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 obtain (14S)8-(3-hydroxy-1H-pyrazol-1-yl)-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111, 14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 256) (19.5 mg, 17%) as dirty white solid.

1H NMR (400 MHz, DMSO-yb) δ 12.58 (s, 1H), 10.63 (s, 1H), 8.22 (d, J=2.7 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.65 (s, 1H), 7.13 (d, J=6.9 Hz, 1H), 6.94 (d, J=8.2 Hz, 1H), 6.79 (s, 1H), 6.00 (d, J=2.7 Hz, 1H), 4.02 (d, J=12.8 Hz, 1H), 3.27 (d, J=5.2 Hz, 1H), 3.04 (d, J=13.3 Hz, 1H), 2.90-2.73 (m, 0H), 2.18 (d, J= 4.1 Hz, 1H), 1.95 (dd, J=11.7, 5.2 Hz, 1H), 1.86 (s, 0H), 1.70 (s, 3H), 1.66 (d, J=13.3 Hz, 5H), 1.61 (s, 3H), 1.49-1.36 (m, 1H). MS-ESI m/z calc. 497.1845, detected 498.33 (M+1)+; retention time: 1.47 min (LC method B).

Example 83: Preparation of (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}-2-hydroxyethoxy)-1H-pyrazol1-yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (connection 257)

Step 1: tert-butyl-3-(2-dispiro[2.0.2.1]heptan-7-yl-2-oxoethoxy)pyrazole-1-carboxylate o I

A solution of n-BuLi (16 ml of 2.5 M in hexane, 40,000 mmol) was added to a solution of diisopropylamine (4.0432 g, 5.6 ml, 39,957 mmol) in tetrahydrofuran (50 ml), which was pre-cooled to 30°C ( flask 1). The mixture was stirred for 20 minutes in an ice water bath before cooling to 78°C. In a separate flask, ethyldispiro[2.0.2.1]heptane-7-carboxylate (1.66 g, 9.9869 mmol) was dissolved in 100 ml of tetrahydrofuran. Chloro(iodo)methane (8.8112 g, 3.7 mL, 48.956 mmol) was added and the solution was cooled to -78°C in a nitrogen cylinder (flask 2). The contents of flask 1 were transferred through the cannula over ~15 min (very quickly dropwise) into flask 2. The resulting mixture was further stirred at -78°C for 1 hour. A mixture of acetic acid/tetrahydrofuran (15 ml/15 ml) was added dropwise. . The dry ice bath was removed and the mixture was allowed to warm to ~0°C. It was then partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was washed again with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated

- 309 044967 triaged. The residue was dissolved in N,N-dimethylformamide (15 ml) at room temperature. Tert-butyl 3-hydroxypyrazole-1-carboxylate (810 mg, 4.3976 mmol) was added, followed by potassium carbonate (1.25 g, 9.0445 mmol) and potassium iodide (62 mg, 0.3735 mmol). The mixture was stirred at 60°C for 48 hours. It was then cooled to room temperature and diluted with ethyl acetate/water (30 ml each). The layers were separated, and the aqueous layer was extracted again with ethyl acetate (20 ml). The combined organic layers were washed with water (20 ml), brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography using a gradient of 5% to 40% ethyl acetate in hexane. The desired product (less polar isomer) tert-butyl 3-(2dispiro[2.0.2.1]heptan-7-yl-2-oxoethoxy)pyrazole-1-carboxylate (620 mg, 47%) was obtained as a white solid.

¹ H NMR (250 MHz, chloroform-d) δ 7.85 (s, 1H), 5.96 (s, 1H), 4.95 (s, 2H), 2.62 (s, 1H), 1.60 (s 9H), 1.34-1.16 ( m, 2H), 1.14-0.63 (m, 6H). MS-ESI m/z calc. 318.158, found 319.5 (M+1)+; Retention time: 3.59 min (LC method R).

Step 2: tert-butyl 3-(2-dispiro[2.0.2.1]heptan-7-yl-2-hydroxyethoxy)pyrazole-1-carboxylate

tert-butyl-3-(2-dispiro[2.0.2.1]heptan-7-yl-2-oxoethoxy)pyrazole-1-carboxylate (620 mg, 1.7527 mmol) was dissolved in ethanol (10 ml) and the mixture was cooled in ice water bath. Sodium borohydride (66.309 mg, 0.0702 mL, 1.7176 mmol) was added. After 5 min, methanol (0.5 ml) was added. The mixture was stirred at room temperature for 1 hour. Then quenched with saturated aqueous ammonium chloride and partitioned between ethyl acetate and water (20 ml each). The layers were separated and the organic layer was filtered through a pad of anhydrous sodium sulfate and concentrated. The crude material was used in the next step without further purification, tert-butyl 3-(2dispiro[2.0.2.1]heptan-7-yl-2-hydroxyethoxy)pyrazole-1-carboxylate (600 mg, 91%). MS-ESI m/z calc. 320.1736, detected 321.3 (M+1) ⁺ ; retention time: 3.44 min (LC method P).

Step 3: tert-butyl-[1-disiro[2.0.2.1]heptan-7-yl-2-(1H-nurazol-3-uloxy)ethoxy]dimethylsilane

tert-butyl-3-(2-dispiro[2.0.2.1]heptan-7-yl-2-hydroxyethoxy)pyrazole-1-carboxylate (300 mg, 0.8896 mmol) was dissolved in dichloromethane (10 ml) and the mixture was stirred in ice water bath under a nitrogen cylinder. 2,6-lutidine (686.96 mg, 0.75 mL, 6.3469 mmol) was added followed by TBDMCOTf (1.2408 g, 1.1 mL, 4.6001 mmol). The mixture was stirred for 30 minutes. More 2,6-lutidine (551 mg, 0.6 mL, 5 mmol) was added, followed by TVDMSOTG (1.2408 g, 1.1 mL, 4.6001 mmol). The mixture was stirred for 12 hours. It was then diluted with dichloromethane (40 ml) and treated with saturated aqueous sodium bicarbonate (30 ml). The layers were separated and the dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0% to 30% ethyl acetate in hexane to give tert-butyl-[1-dispiro[2.0.2.1]heptane-7-ul-2-(1H-nirazol-3yloxy)ethoxy] dimethylsilane (300 mg, 81%) as a colorless oil. MS-ESI m/z calc. 334.2077, detected 335.6 (M+1) ⁺ ; retention time: 4.55 min (LC method R).

Step 4: tert-butyl-6-[3-[2-[tert-butyl(dimethyl)silyl]oxy-2-dispiro[2.0.2.1]heptan-7ylethoxy]pyrazol-1 -yl]-2-chloro-pyridine -3-carboxylate

tert-Butyl-[1-dispiro[2.0.2.1]heptan-7-yl-2-(1H-pyrazol-3-yloxy)ethoxy]dimethylsilane (300 mg, 0.8071 mmol) was dissolved in dimethyl sulfoxide (8 ml) at room temperature. Tert-butyl 2,6-dichloropyridine-3-carboxylate (210 mg, 0.8464 mmol) was added, followed by potassium carbonate (138 mg, 0.9985 mmol) and 1,4-diazabicyclo[2.2.2]octane (18 mg, 0 ,1605 mmol). The mixture was stirred at room temperature for 24 hours. Ethyl acetate (~25 ml) was added followed by water (~20 ml). The layers were separated and the aqueous layer was extracted again (~20 ml) with ethyl acetate. The combined organic layers were concentrated and the residue was purified by silica gel chromatography using a gradient of 0-10% ethyl acetate in hexane to give tert-butyl-6-[3-[2-[tert-butyl(dimethyl)silyl]oxy-2-dispiro [2.0.2.1]heptane-7- 310 044967 ylethoxy]pyrazol-1-yl]-2-chloropyridine-3-carboxylate (490 mg, 100%) as a white solid.

^1H NMR (250 MHz, chloroform-d) δ 8.35 (dd, J=2.8, 0.9 Hz, 1H), 8.19 (dd, J=8.4, 0.9 Hz, 1H ), 7.68 (dd, J=8.4, 0.9 Hz, 1H), 5.93 (dd, J=2.9, 0.9 Hz, 1H), 4.17 (dd, J= 5.5, 0.9 Hz, 2H), 4.01-3.80 (m, 1H), 1.78-1.43 (m, 13H), 1.38-1.16 (m, 4H) , 1.15-0.45 (m, 22H), 0.20-0.01 (m, 6H).

Step 5: 6-[3-[2-[tert-Butyl(dimethyl)silyl]oxy-2-dispiro[2.0.2.1]heptan-7-ylethoxy]pyrazol-1yl]-2-chloropyridine-3-carboxylic acid

tert-Butyl 6-[3-[2-[tert-butyl(dimethyl)silyl]oxy-2-dispiro[2.0.2.1]heptan-7-ylethoxy]pyrazol-1yl]-2-chloropyridine-3-carboxylate (200 mg, 0.3296 mmol) was dissolved in dichloromethane (4 ml) and cooled in an ice water bath. Triethylamine (200.11 mg, 0.2756 mL, 1.9776 mmol) was added followed by TBDMCOTf (609.88 mg, 2.3072 mmol). The mixture was stirred at room temperature for 5 hours and diluted with dichloromethane (10 ml). Water (~10 ml) was added and the layers were separated. The dichloromethane layer was concentrated and the residue was purified by silica gel chromatography using a 0%-10% methanol/dichloromethane gradient to give 6-[3-[2-[tert-butyl(dimethyl)silyl]oxy-2-dispiro[2.0.2.1 ]heptan-7ylethoxy]pyrazol-1-yl]-2-chloropyridine-3-carboxylic acid (50 mg, 22%).

Ή NMR (250 MHz, chloroform-d) δ 8.49-8.17 (m, 2H), 7.70 (d, J=8.4 Hz, 1H), 5.94 (d, J=2.9 Hz, 1H), 4.16 (d, J= 5.4 Hz, 2H), 3.89 (dt, J=8.6, 5.4 Hz, 1H), 1.65 (t, J=7.6 Hz, 1H), 1.12-0.41 (m, 19H), 0.06 (d, J=2.2 Hz, 6H). MS-ESI m/z calc. 489.1851, detected 490.7 (M+1)+; retention time: 4.53 min (LC method P).

Step 6: tert-butyl-(4S)-4-[3-[[6-[[6-[3-[2-[tert-butyl(dimethyl)silyl]oxy-2dispiro[2.0.2.1]heptane-7 -ylethoxy]pyrazol-1-yl]-2-chloropyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate

6-[3-[2-[tert-Butyl(dimethyl)silyl]oxy-2-dispiro[2.0.2.1]heptan-7-ylethoxy]pyrazol-1-yl]-2chloropyridin-3-carboxylic acid (750 mg, 1.5304 mmol) was dissolved in tetrahydrofuran (5 ml) at room temperature under a nitrogen balloon. Carbonyldiimidazole (345 mg, 2.0851 mmol) was added in one portion. The reaction mixture was stirred for 4 hours. Tert-butyl (4S)-2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1carboxylate was added to a separate flask. 695 mg, 1.6847 mmol) and tetrahydrofuran (5 ml), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (249.90 mg, 0.25 ml, 1.6087 mmol). The activated acid mixture was then transferred into a solution of 1,8diazabicyclo[5.4.0]undec-7-ene using a pipette. The resulting mixture was stirred at room temperature for 14 hours. The mixture was then concentrated, taken up in ethyl acetate (~30 ml) and washed with brine. The organic fraction was dried (sodium sulfate), filtered and concentrated. Purify by chromatography on silica gel using a gradient of 25-80% ethyl acetate in hexanes to give tert-butyl (4S)-4-[3-[[6-[[6-[3-[2-[tert-butyl(dimethyl) silyl]oxy-2dispiro[2.0.2.1]heptan-7-ylethoxy]pyrazol-1-yl]-2-chloropyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (500 mg, 35%) as an oil. MS-ESI m/z calc. 883.3889, detected 884.8 (M+1) ⁺ ; retention time: 5.39 min (LC method P).

Step 7: 6-[3-[2-[tert-Butyl(dimethyl)silyl]oxy-2-dispiro[2.0.2.1]heptan-7-ylethoxy]pyrazol-1yl]-2-chloro-N-[[6 -[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2-pyridyl]sulfonyl]pyridine-3carboxamide

tert-Butyl (4S)-4-[3-[[6-[[6-[3-[2-[tert-butyl(dimethyl)silyl]oxy-2-dispiro[2.0.2.1]heptan-7ylethoxy]pyrazole -1-yl]-2-chloropyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2dimethylpyrrolidine-1-carboxylate (500 mg, 0.5370 mmol) was dissolved in dichloromethane (15 ml) and cooled in an ice water bath. Triethylamine (232.32 mg, 0.3200 mL, 2.2500 mmol) was added, followed by

- 311 044967 drops were added TVDMCOTf (1.1510 g, 1.0000 ml, 4.2672 mmol). The mixture was then stirred at room temperature for 15 h and then diluted with dichloromethane (~20 ml) and quenched with saturated aqueous sodium bicarbonate (20 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0-5% methanol in dichloromethane to give 6-[3-[2-[tert-butyl(dimethyl)silyl]oxy-2-dispiro[2.0.2.1]heptan-7-ylethoxy]pyrazol- 1-yl]-2-chloro-N-[[6-[3-[(3S)-5,5dimethylpyrrolidin-3-yl]propylamino]-2-pyridyl]sulfonyl]pyridine-3-carboxamide (310 mg, 70 %). MS-ESI m/z calc. 783.3365, detected 785.0 (M+1)+; retention time: 3.29 min (LC method P).

Step 8: (14S)-8-(3-{2-[(tert-butyldimethylsilyl)oxy]-2-{disniro[2.0.2.1]gentan-7-yl}ethoxy}1H-pyrazol-1-yl)- 12,12-dimethyl-2λ ⁶ -thiα-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracoseα1 (23),5,7,9,19,21-hexaene-2, 2,4-trione

6-[3-[2-[tert-butyl(dimethyl)silyl]oxy-2-dispiro[2.0.2.1]heptan-7-ylethoxy]pyrazol-1-yl]-2-chloroN-[[6-[3 -[(3S)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2-pyridyl]sulfonyl]pyridine-3 carboxamide (310 mg, 0.3952 mmol) was dissolved in dimethyl sulfoxide (40 ml). Potassium carbonate (329 mg, 2.3805 mmol) was added followed by molecular sieves (0.3952 mmol). The mixture was degassed and protected under a nitrogen cylinder. It was then heated in an oil bath at 140°C for 12 hours. After cooling to room temperature, the mixture was diluted with brine (20 ml) and extracted with dichloromethane (2x20 ml). The solvent was removed and the residue was purified with a short pad of silica gel, eluting with ethyl acetate, to give (14S)-8-(3-{2-[(tert-butyldimethylsilyl)oxy]-2-{dispyro[2.0.2.1]hetan-7yl} ethoxy}-1 H-pyrazol-1 -yl)-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23) ,5,7,9,19,21-hexaene-2,2,4-trione (170 mg, 55%) (170 mg, 55%).

Ή NMR (250 MHz, chloroform-d) δ 8.20 (d, J=2.8 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.67-7.42 (m,2R), 7.33 -7.19 (s, 1H), 6.57 (d, J=7.7 Hz, 1H), 5.90 (d, 1H), 4.69 (s, 1H), 4.17 (d, J=5.4 Hz, 2H), 4.02-3.73 (m, 2H), 3.54 -2.88 (m, 3H), 2.61 (m, 1H), 2.05 (m, 1H), 1.77 -1.40 (m, 8H), 1.26 (s, 6H), 1.11-0.45 (m, 17H), 0.08 ( 2s, 6H). MS-ESI m/z calc. 747.3598, found 748.8 (M+1) ⁺ ; Retention time: 4.9 min (LC method R).

Step 9: (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}-2-hydroxyethoxy)-1H-pyrazol-1-yl]-12,12dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (connection 257)

(14S)-8-(3-{2-[(tert-butyldimethylsilyl)oxy]-2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy}-1H-pyrazol1 -yl)-12,12- dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5,7,9,19,21-hexaene-2,2,4- trione (170 mg, 0.2273 mmol) was dissolved in tetrahydrofuran (5 ml) in a plastic bottle and cooled in an ice water bath. 70% hydrogen fluoride-pyridine (0.5 ml) was added. The mixture was stirred for 10 min at room temperature and cooled again in an ice water bath. Another portion of 70% hydrogen fluoride-pyridine (~0.5 ml) was added and the mixture was stirred for 10 min, removing the ice water bath. A third portion of 70% w/w was added. hydrogen fluoride with pyridine (~0.5 ml) and the mixture was stirred for 10 minutes. It was then diluted with ethyl acetate (30 ml) and saline (20 ml). The layers were separated and the organic layers were concentrated in vacuo. Toward the end of solvent removal, a white precipitate was observed. The residue was treated with a mixture of ethyl acetate and water (30 ml each) and left at room temperature for ~2 hours. The layers were separated, the organic layer was concentrated, and the residue was purified by silica gel chromatography using a gradient of 0-5% methanol in dichloromethane to give (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl }-2hydroxyethoxy)-1 H-pyrazol-1 -yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22) ,5,7,9,19(23),20-hexaene-2,2,4-trione (compound 257) (63 mg, 44%).

¹ H NMR (250 MHz, CDCl ₃ ) δ 8.20 (d, J=2.8 Hz, 1H), 8.03 (d, J=8.2 Hz, 1H), 7.65-7.36 (m, 2H), 7.18 (d, J= 8.3 Hz, 1H), 6.55 (d, J=8.0 Hz, 1H), 5.94 (d, J=2.8 Hz, 1H), 4.71 (s,lH),4.38-4.03 (m, 3H), 4.03-3.70 ( m, 2H), 3.33 (t, J=8.8 Hz, 1H), 3.25-2.89 (m, 2H), 2.56 (s, 2H),2.05 (s, 2H), 1.62 (m, 6H, overlapping with water peak ), 1.38 -1.16 (m, 4H), 1.08 (dd, J=8.6, 4.1 Hz, 1H), 1.04-0.76 (m, 5H), 0.67 (d, J=12.8 Hz, 4H). MS-ESI m/z calc. 633.2733, detected 634.4 (M+1) ⁺ ; retention time: 2.87 min (LC method R).

- 312 044967

Example 84: Preparation of (14S)-8-(3-{2-hydroxy-3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1Hpyrazol-1-yl)-12,12-dimethyl-2λ ⁶ -thia-3 ,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5(10),6,8,19(23),20-hexaene-2,2,4-trione ( connection 259)

Step 1: Dimethyl {2-oxo-3-[1-(trifluoromethyl)cyclopropyl]propylidene}-λ ⁶ -sulfanone

2-[1-(trifluoromethyl)cyclopropyl]acetic acid (3.0 g, 17.85 mmol) was added to the reaction vessel and dissolved in dichloromethane (30 ml). The mixture was cooled to 0°C and N, Ndimethylformamide (50 μl, 0.6457 mmol) and oxalyl chloride (1.9 ml, 21.78 mmol) were added. The resulting reaction mixture was first stirred for 2 hours at 0°C, allowing it to warm to room temperature during this period. The volatiles were then removed using a rotary evaporator (vacuum set at 100 mbar, water bath at 20° C.) to obtain the desired pure acid chloride. The acid chloride solution was used directly without further purification. In a separate vessel, trimethylsulfoxonium iodide (12.2 g, 55.44 mmol) was added and dissolved in tetrahydrofuran (30 ml). Potassium tert-butoxide (6.2 g, 55.25 mmol) was added as a 1 M solution in tetrahydrofuran and the resulting mixture was refluxed for 2 hours. The mixture was cooled to 0° C. and the acid chloride obtained above was added to as a solution in tetrahydrofuran (30 ml), maintaining the temperature below 5°C. The mixture was stirred at 0°C for 1 hour. Celite was added to the mixture, then filtered through celite (washing solids with ethyl acetate and concentrating volatiles by rotary evaporation). The resulting mixture was washed with water in a separatory funnel and extracted with ethyl acetate (2x100 ml). The combined ethyl acetate layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give dimethyl ({2-oxo-3-[1(trifluoromethyl)cyclopropyl]propylidene})-λ ⁶ -sulfanone (1.9 g, 44 %) in the form of oil.

Ή NMR (400 MHz, chloroform-d) δ 3.39 (s, 6H), 2.99 (s, 1H), 2.40 (s, 2H), 1.01 (d, J=2.0 Hz, 2H), 0.940.81 (m, 2H). MS-ESI m/z calc. 242.05884, found 243.2 (M+1)+; Retention time: 0.72 min (LC method E).

Step 2: 1-chloro-3-[1-(trifluoromethyl)cyclopropyl]propan-2-one

Dimethyl({2-oxo-3-[1(trifluoromethyl)cyclopropyl]propylidene})-λ ⁶ -sulfanone (1.9 g, 7.843 mmol) dissolved in dry tetrahydrofuran (16) was added to a 100 mL round bottom flask under nitrogen atmosphere. .0 ml), and then hydrochloric acid (4M in dioxane) (2.5 ml 4M, 10.00 mmol) was added. The resulting mixture was heated to 60° C. and stirred for 3 hours. The solvent was evaporated in vacuo (130 mbar and water bath at 20° C.) and the resulting residue was partitioned between ethyl acetate and water, then a little brine was added and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo (100 mbar, water bath at 30°C) to give 1-chloro-3-[1-(trifluoromethyl)cyclopropyl]propan2-one (1.57 g, 100%) as orange oil.

1H NMR (400 MHz, chloroform-d) δ 3.70 (s, 2H), 2.04 (s, 2H), 1.17-1.05 (m, 2H), 0.85 (tm, J= 3.8, 2.8, 2.2 Hz, 2H).

Step 3: tert-butyl 3-[2-oxo-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazole-1-carboxylate

- 313 044967

To a 100 mL flask filled with nitrogen, add tert-butyl 3-hydroxypyrazole-1-carboxylate (1.20 g, 6.515 mmol), potassium carbonate (1.81 g, 13.10 mmol) and sodium iodide (11 mg , 0.07339 mmol), dissolved in N,N-dimethylformamide (15 ml). The mixture was stirred for 5 min and then 1-chloro-3-[1-(trifluoromethyl)cyclopropyl]propan-2-one (1.57 g, 7.827 mmol) was added as a solution in N,Ndimethylformamide (10 ml). The resulting mixture was heated at 65°C for 16 hours. The reaction mixture was poured into saturated saline solution. The material was extracted with ethyl acetate (2x150 ml), the organic layers were combined, washed with water (2x150 ml), dried over sodium sulfate, filtered and concentrated. The orange residue was purified by silica gel chromatography using a gradient of 100% hexanes to 60% ethyl acetate in hexanes to give tert-butyl-3-[2-oxo-3-[1(trifluoromethyl)cyclopropyl]propoxy]pyrazole-1-carboxylate ( 700 mg, 31%) as a light yellow oil.

¹ H NMR (400 MHz, chloroform-d) δ 7.86 (d, J=2.8 Hz, 1H), 5.96 (d, J=2.8 Hz, 1H), 4.93 (s, 2H), 2.77 (s, 2H), 1.60 (s, 9H), 1.15-1.07 (m, 2H), 0.91-0.86 (m, 2H). MS-ESI m/z calc. 348.1297, found 349.2 (M+1) ⁺ ; Retention time: 1.73 min (LC method E).

Step 4: 1-(1H-pyrazol-3-yloxy)-3-[1-(trifluoromethyl)cyclopropyl]propan-2-one

tert-butyl-3-[2-oxo-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazole-1 to a solution of carboxylate (700 mg, 2.010 mmol) in dichloromethane (14 ml) was added trifluoroacetic acid (3.1 ml, 40 .24 mmol) and the mixture was stirred for 1 hour. The solvent was removed and the resulting oil was evaporated and dried in vacuo to give a light yellow solid. The solid was dissolved in ethyl acetate, saturated aqueous sodium bicarbonate was added and the layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1-(1Hpyrazol-3-yloxy)-3-[1-(trifluoromethyl)cyclopropyl]propan-2-one (498 mg, 100%). MS-ESI m/z calc. 248.07726, detected 249.2 (M+1)+; Retention time: 1.11 min (LC method E).

Step 5: tert-butyl 2-chloro-6-[3-[2-oxo-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1yl]pyridine-3-carboxylate

tert-Butyl 2,6-dichloropyridine-3-carboxylate (497 mg, 2.003 mmol), 1-(1H-pyrazol-3-yloxy)-3-[1(trifluoromethyl)cyclopropyl]propan-2-one (498 mg 2.006 mmol) and potassium carbonate (625 mg, 4.522 mmol) were combined in anhydrous dimethyl sulfoxide (14 ml). 1,4-Diazabicyclo[2.2.2]octane (45 mg, 0.4012 mmol) was added and the mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was diluted with water (16 ml) and stirred for 15 minutes. The resulting mixture was diluted with ethyl acetate and washed with water (3x50 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The orange residue was purified by silica gel chromatography using a gradient of 100% hexanes to 60% ethyl acetate in hexanes to give a light yellow oil, which was then dried in vacuo to give tert-butyl-2-chloro-6-[3-[2- oxo-3-[1(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridine-3-carboxylate (500 mg, 54%).

¹ H NMR (400 MHz, chloroform-d) δ 8.38 (d, J=2.8 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 6.04 ( d, J=2.8 Hz, 1H), 4.87 (s, 2H), 2.79 (s, 2H), 1.62 (s, 10H), 1.14-1.09 (m, 2H), 0.85 (dd, J=3.0, 1.7 Hz , 2H). MS-ESI m/z calc. 459.11728, found 460.2 (M+1) ⁺ ; Retention time: 2.21 min (LC method E).

Step 6: 2-chloro-6-[3-[2-oxo-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridine-3-carboxylic acid

tert-Butyl-2-chloro-6-[3-[2-oxo-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridine 3-carboxylate (500 mg, 1.087 mmol) was dissolved in dichloromethane. (11 ml) and cooled to 0°C in an ice bath. Hydrochloric acid (1.5 ml 4M in dioxane, 6,000 mmol) was slowly added to the mixture and the mixture was stirred at 0°C for 1 hour. Additional hydrochloric acid (5.5

- 314 044967 ml 4M in dioxane, 22.00 mmol) and stirred for 30 minutes at 0°C, then 2 hours at room temperature. Additional hydrochloric acid (5.435 mL 4M in dioxane, 21.74 mmol) was added and stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure to a white solid, which was then suspended in diethyl ether, filtered and resuspended in diethyl ether. The solid was collected by vacuum filtration and dried under vacuum for 20 hours to give 2-chloro6-[3-[2-oxo-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3- carboxylic acid (237.5 mg, 54%) as a white solid. MS-ESI m/z calc. 403.05466, detected 404.2 (M+1)+; Retention time: 1.59 min (LC method E).

Step 7: tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-[2-oxo-3-[1-(trifluoromethyl)cyclonronyl]propoxy]pyrazole-1 -yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate

2-Chloro-6-[3-[2-oxo-3 - [1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3 carboxylic acid (166 mg, 0.4112 mmol) and carbonyldiimidazole (75 mg, 0.4625 mmol) were combined in tetrahydrofuran (4.0 ml) and stirred for 110 min at room temperature. Then tert-butyl (4S)-2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1 carboxylate (187 mg, 0.4533 mmol) was added followed by anhydrous 1,8diazabicyclo[5.4.0]undec-7-ene (160 μL, 1.070 mmol), and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and then with brine . The organic layer was dried over sodium sulfate, filtered, evaporated and then purified by silica gel chromatography using a gradient of 100% hexanes to 100% ethyl acetate, followed by a second silica gel column using a gradient of 100% dichloromethane to 15% methanol in dichloromethane to prepare tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-[2-oxo-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl ]pyridine-3carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (173.7 mg, 53%) as a white solid. MS-ESI m/z calc. 797.25854, detected 798.2 (M+1) ⁺ ; Retention time: 2.21 min (LC method E).

Step 8: tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-[2-hydroxy-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazole-1 -yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate

To a stirred solution of tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-[2-oxo-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazole-1 -yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2dimethylpyrrolidine-1-carboxylate (80 mg, 0.1002 mmol) in methanol (1.25 ml) under nitrogen and added sodium borohydride (10 mg, 0.2643 mmol), in portions to control significant boiling. Once the addition is complete (which took 1 min), the reaction mixture is a solution. The reaction mixture was concentrated on a rotary evaporator, then diluted with ethyl acetate and washed with water (2x20 ml) and then brine (1x). The organic layer was then separated, dried over sodium sulfate, filtered and concentrated. The residue was dried in vacuo to give tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-[2-hydroxy-3-[1-(trifluoromethyl)cyclopropyl]propoxy] pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (80 mg, 100%) as a white solid. MS-ESI m/z calc. 799.2742, detected 800.3 (M+1) ⁺ ;

Retention time: 2.15 min (LC method E).

Step 9: (14S)-8-(3- {2-hydroxy-3-[ 1 -(trifluoromethyl)cyclopropyl]propoxy}-1 H-pyrazol-1 -yl)12,12-dimethyl-2λ ⁶ -thia- 3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5(10),6,8,19(23),20-hexaene-2,2,4-trione (connection 259)

- 315 044967

Into a flask containing tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-[2-hydroxy-3-[1(trifluoromethyl)cyclopropyl]propoxy]pyrazole-1 -yl]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (80 mg, 0.09996 mmol), dichloromethane (2.5 ml) and hydrochloric acid ( 500 µl 4M in dioxane, 2,000 mmol). After stirring for 90 min, the mixture was evaporated to dryness, then diluted with ether (5 ml) and re-concentrated on a rotary evaporator. The residue was then diluted with ether (5 ml) and concentrated again on a rotary evaporator. Dry in vacuo overnight to a residue, which is combined with potassium carbonate (139 mg, 1.006 mmol), 3 A molecular sieves and dimethyl sulfoxide (3.5 ml) in a vial, purged with nitrogen, capped, heated to 155°C and stirred for 4 hours. Cool to room temperature and the mixture was filtered, diluted with ethyl acetate and washed with water (2x20 ml) and then with brine. The organic layer was further washed with water, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient of 100% hexanes to 100% ethyl acetate to give (14S)-8-(3-{2-hydroxy-3-[1(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol- 1 -yl)-12,12-dimethyl-2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5(10),6,8, 19(23),20-hexaene-2,2,4-trione (compound 259) (27.91 mg, 42%) as an off-white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.49 (s, 1H), 8.22 (d, J=2.8 Hz, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.58 (dd, J=8.5 , 7.2 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), 6.13 (d, J=2.8 Hz, 1H), 5.03 (s, 1H), 4.10 (dd, J=4.9, 2.4 Hz, 2H), 3.97 (d, J=4.7 Hz, 2H), 3.16 (s, 1H ), 2.95 (d, J=13.4 Hz, 1H), 2.73-2.65 (m, 1H), 2.47-2.29 (m, 1H), 2.13 (s, 1H), 1.98 (dd, J=13.7, 3.4 Hz, 1H), 1.86 (dd, J=11.6, 3.6 Hz, 1H), 1.77 (s, 1H), 1.70-1.63 (m, 1H), 1.61 (s, 3H), 1.57 (d, J=12.4 Hz, 2H ), 1.52 (s, 3H), 1.37-1.27 (m, 1H), 1.01-0.90 (m, 2H), 0.90-0.78 (m, 2H). MS-ESI m/z calc. 663.24506, detected 664.4 (M+1)+; retention time: 1.88 min (LC method E).

Example 85: Preparation of (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-22hydroxy-12,12-dimethyl-2X ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4- Trion (compound 260)

Step 1: 2-bromo-6-nitropyridin-3-ol

To a solution of 2-bromopyridin-3-ol (46 g, 264.38 mmol) in sulfuric acid (230 ml) was added nitric acid (24.989 g, 17.685 ml, 277.60 mmol) (70%) at 0°C. The reaction mixture was stirred at 0°C for 30 min, then at room temperature for 48 h, then poured into cold water (200 ml) and extracted with ethyl acetate (2x100 ml). The combined organic layers were washed with water (150 ml) and brine (150 ml), dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (silica gel, 0% to 20% ethyl acetate in heptane) with

- 316 044967 obtaining 2-bromo-6-nitropyridin-3-ol (9.2 g, 16%) as a yellow solid.

1H NMR (300 MHz, CDClз)δ 8.24 (d, J=8.5 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 6.37 (br.s., 1H). MS-ESI m/z calc. 217.9327, detected 221.0 (M+1)+; retention time: 1.492 min (LC method N).

Step 2: 3-benzyloxy-2-bromo-6-nitropyridine

A solution of 2-bromo-6-nitropyridin-3-ol (9 g, 41.097 mmol) in dimethylformamide (60 ml) was added dropwise to a solution of sodium hydride (2 g, 50.005 mmol) at 0°C in dimethylformamide (30 ml). After 30 minutes, benzyl bromide (7.4776 g, 5.2 ml, 43.720 mmol) was added, the cooling bath was removed and the reaction mixture was stirred at room temperature for 16 hours. The crude mixture was diluted with water (75 ml) and extracted with ethyl acetate (3x75 ml) . The combined organic layers were washed with water (2x75 ml), brine (100 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The solid residue was triturated in ethyl acetate/heptane (9/1) (50 ml), then filtered and washed with more ethyl acetate/heptane (9/1) (50 ml) to give 3-benzyloxy-2-bromo-6-nitropyridine ( 8.7 g, 68%) as a yellow solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.42 (d, J=8.5 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.30-7.59 (m, 5H), 5.43 (s, 2H ). MS-ESI m/z calc. 307.9797, detected 311.0 (M+1)+; retention time: 1.956 min (LC method S).

Step 3: 2-ethylhexyl 3-[(3-benzyloxy-6-nitro-2-pyridyl)sulfanyl]propanoate

To a solution of 3-benzyloxy-2-bromo-6-nitropyridine (14.5 g, 46.908 mmol), xanthos (1.7 g, 2.9380 mmol), Pd ₂ (dba) ₃ (1.35 g, 1. 4743 mmol) in toluene (300 ml), 2-ethylhexyl-3sulfanylpropanoate (11.5 g, 52.666 mmol) was added followed by N,N-diisopropylethylamine (12.614 g, 17 ml, 97.599 mmol). The resulting solution was evacuated and refilled with nitrogen three times and then refluxed at 110°C overnight. After cooling to room temperature, the reaction mixture was filtered through a pad of celite and washed with ethyl acetate (75 ml). The combined filtrates were concentrated and the resulting residue was purified by silica gel chromatography (0% to 15% ethyl acetate in heptanes gradient) to give 2-ethylhexyl-3-[(3-benzyloxy-6nitro-2-pyridyl)sulfanyl]propanoate (20 g, 95 %).

1H NMR (300 MHz, CDCl ₃ ) δ 7.94 (d, J=8.5 Hz, 1H), 7.32-7.51 (m, 5H), 7.09-7.17 (m, 1H), 5.25 (s, 2H), 3.97-4.12 (m, 2H), 3.51 (t, J=6.9 Hz, 2H), 2.89 (t, J=6.8 Hz, 2H), 1.51-1.67 (m, 1H), 1.20-1.43 (m, 8H), 0.810. 96 (m, 6H). MS-ESI m/z calc. 446.1875, detected 447.2 (M+1)+; retention time: 4.181 min (LC T method).

Step 4: 2-ethylhexyl 3-[(3-benzyloxy-6-nitro-2-pyridyl)sulfonyl]propanoate

M-chloroperbenzoic acid (21 g, 77% w/w in tetrahydrofuran, 93.703 mmol) was slowly added to a solution of 2-ethylhexyl-3-[(3-benzyloxy-6-nitro-2-pyridyl)sulfanyl]propanoate (20 g, 44.787 mmol) in dichloromethane (400 ml) at room temperature. The mixture was stirred at this temperature overnight. The solid was filtered and the mixture was washed with 10% sodium thiosulfate solution (150 ml), 5% sodium bicarbonate solution (2x100 ml), water (100 ml) and saline (100 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 2-ethylhexyl-3-[(3-benzyloxy-6-nitro-2pyridyl)sulfonyl]propanoate (20.5 g, 96%) as a solid. yellow color.

1H NMR (300 MHz, CDCl ₃ ) δ 8.39 (d, J=9.1 Hz, 1H), 7.64 (d, J=9.1 Hz, 1H), 7.31-7.52 (m, 5H), 5.45 (s, 2H), 4.03 (dd, J=5.7, 2.5 Hz, 2H), 3.89-4.00 (m, 2H), 3.04 (t, J=7.5 Hz, 2H), 1.50-1.66 (m, 1H), 1.22-1.41 (m, 8H), 0.83-0.95 (m, 6H).

Step 5: 2-ethylhexyl 3-[(6-amino-3-benzyloxy-2-pyridyl)sulfonyl]propanoate

- 317 044967

Iron (2.4 g, 42.976 mmol) and ammonium chloride (1.7 g, 31.781 mmol). The reaction mixture was stirred at 100°C for 1.5 hours. The dark solution was allowed to cool to room temperature, filtered through celite and washed with dichloromethane (150 ml). The filtrate was concentrated under reduced pressure. The crude product was diluted with water (100 ml) and extracted with dichloromethane (2x75 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by trituration with tert-butyl methyl ether (50 ml), the suspension was filtered and washed with tert-butyl methyl ether (50 ml). The resulting off-white solid was dried in vacuo overnight to give 2-ethylhexyl-3-[(6-amino-3-benzyloxy-2pyridyl)sulfonyl]propanoate (4.5 g, 96%). MS-ESI m/z calc. 448.2032, detected 449.2 (M+1)+; retention time: 2.35 min (LC method I).

Step 6: 2-ethylhexyl 3-[(3-benzyloxy-6-fluoro-2-pyridyl)sulfonyl]propanoate

ORP ------* ^{0Vp 0 0} y)

_H2NF

A solution of 2-ethylhexyl-3-[(6-amino-3-benzyloxy-2-pyridyl)sulfonyl]propanoate (4.5 g, 10.032 mmol) in hydrogen fluoride with pyridine (55.0 g, 50 ml, 554.96 mmol) was cooled to -52°C. The resulting red solution was treated with sodium nitrite (1.4 g, 20.291 mmol) and allowed to warm to room temperature. Gas evolution was observed and the reaction became orange and cloudy. The reaction mixture was stirred overnight at room temperature and poured slowly onto ice and water (50 ml). The mixture was neutralized by careful addition of aqueous sodium bicarbonate and extracted with ethyl acetate (3x50 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude 2-ethylhexyl-3-[(3-benzyloxy-6-fluoro-2-pyridyl)sulfonyl]propanoate (4 g, 88%). MS-ESI m/z calc. 451.1829, detected 452.2 (M+1) ⁺ ; retention time: 2.46 min (LC method I).

Step 7: 3-benzyloxy-6-fluoropyridine-2-sulfonamide

1,8-Diazabicyclo (5,4,0 ) undec-7-ene (5.5550 g, 5.5 ml, 36.489 mmol). The reaction mixture was stirred for 1 hour at room temperature and a solution of hydroxylamine-O-sulfonic acid (10.1 g, 89.307 mmol) and sodium acetate (6 g, 73.141 mmol) in water (32 ml) was added. The reaction mixture was stirred for 1 hour at room temperature, diluted with water (100 ml) and extracted with ethyl acetate (3x75 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (10% to 40% ethyl acetate in heptane gradient) to give 3-benzyloxy-6-fluoropyridine-2-sulfonamide (4.1 g, 82%) as an off-white solid.

¹ H NMR (300 MHz, DMSO-d6) δ 5.38 (s, 2H), 7.25-7.48 (m, 4H), 7.49-7.57 (m, 4H), 7.96 (dd, J=9.0, 6.0 Hz, 1H) ; ¹⁹ F NMR (282 MHz, DMSO-d6) δ -78.5-78.2 (m, 1F). MS-ESI m/z calc. 282.0474, detected 283.1 (M+1) ⁺ ; retention time: 2.14 min (LC method H).

Step 8: tert-butyl (4S)-4-[3-[(5-benzyloxy-6-sulfamoyl-2-pyridyl)amino]propyl]-2,2dimethyl-pyrrolidine-1-carboxylate

VPO

Tert-butyl (4S)-4-(3-aminopropyl)-2,2dimethylpyrrolidine-1-carboxylate (291 mg, 1.135 mmol), 3-benzyloxy-6-fluoro-pyridine-2 was loaded into a 20 ml ampoule under nitrogen atmosphere. -sulfonamide (321 mg, 1.137 mmol), anhydrous dimethyl sulfoxide (3 ml) and N,N-diisopropylethylamine (0.3 ml, 1.722 mmol). The vessel was capped and stirred at 85°C for 3 hours, then at 110°C for 16 hours, then at 120°C for 29 hours. The mixture was diluted with ethyl acetate (50 ml), water (50 ml) and 10% citric acid (10 ml). The two phases were separated. The organic phase was washed with brine (30 ml), dried over sodium sulfate and the solvents were evaporated. The product was purified by flash chromatography

- 318 044967 on silica gel using a gradient of ethyl acetate (0% to 60% over 30 min) in hexanes to give tert-butyl (4S)-4-[3-[(5-benzyloxy-6-sulfamoyl-2-pyridyl )amino]nronyl]-2,2-dimethylpyrrolidine-1carboxylate (342 mg, 58% yield, 92% purity) as a foamy solid.

1H NMR (400 MHz, DMSO-d6) δ 7.54-7.47 (m, 2H), 7.44 (d, J=9.0 Hz, 1H), 7.41-7.33 (m, 2H), 7.33-7.22 (m, 1H), 6.94 (s, 2H), 6.60 (d, J=8.9 Hz, 1H), 6.49 (t, J=5.5 Hz, 1H), 5.11 (s, 2H), 3.55 (k, J=8.7 Hz, 1H), 3.273.16 (m, 2H), 2.79 (k, J=10.1 Hz, 1H), 2.10 (broad s, 1H), 1.93-1.85 (m, 1H), 1.54-1.43 (m, 2H), 1.43-1.37 (m, 15H), 1.24 (s, 3H). MS-ESI m/z calc. 518.2563, detected 519.4 (M+1)+; retention time: 1.88 min (LC method B).

Step 9: tert-butyl (48)-4-[3-[[5-benzyloxy-6-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7ylethoxy)pyrazole-1 -yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate

2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7ylethoxy)pyrazol-1-yl]pyridin-3-carboxylic acid (100 mg, 0.2779) was loaded into a 20 ml ampoule under a nitrogen atmosphere mmol) and anhydrous tetrahydrofuran (2 ml). Carbonyldiimidazole (45 mg, 0.2775 mmol) was added and the mixture was stirred under nitrogen at room temperature for 4 hours. A second amount of carbonyldiimidazole (45 mg, 0.2775 mmol) was added and the mixture was stirred at room temperature for 3 hours. in a separate 20 ml flask a solution of tert-butyl (4S)-4-[3-[(5-benzyloxy-6-sulfamoyl-2-pyridyl)amino]propyl]-2,2dimethylpyrrolidine-1-carboxylate (121 mg, 0. 2333 mmol) in anhydrous tetrahydrofuran (1 ml) was prepared under nitrogen atmosphere and subsequently added via syringe to the activated ether solution. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.18 mL, 1.204 mmol) was added via syringe and the reaction mixture was stirred at room temperature under nitrogen. After 17 hours, the solvents were removed under reduced pressure and the resulting thick oil was treated with ethyl acetate (25 ml) and water (25 ml). Aqueous hydrochloric acid (250 μl 6 M, 1500 mmol) was added slowly (final pH 5) and the two phases were separated. The aqueous phase was extracted with ethyl acetate (30 ml). The combined organic extracts were washed with brine (30 ml) and dried over sodium sulfate. After filtration and evaporation of the solvents, the residue 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 to give tert-butyl (4S)-4-[3-[[5- benzyloxy-6-[[2-chloro-6-[3-(2-dispiro[2.0.2.1] heptan-7 ylethoxy)pyrazol-1 -yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl] amino] propyl]-2,2dimethylpyrrolidine-1-carboxylate (99 mg, 49% yield, 93% purity) as a colorless film. MS-ESI m/z calc. 859.34937, detected 860.5 (M+1) ⁺ ; retention time: 1.82 min (LC method B).

Step 10: N-[[3-Benzyloxy-6-[3-[(3 S)-5,5-dimethylpyrrolidin-3 -yl]propylamino]-2pyridyl]sulfonyl]-2-chloro-6-[3 -( 2-dispiro[2.0.2.1] heptan-7-ylethoxy)pyrazol-1 -yl]pyridin-3 carboxamide (trifluoroacetate salt).

VPO VPO

To a solution of tert-butyl (48)-4-[3-[[5-benzyloxy-6-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7ylethoxy)pyrazol-1- yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2dimethylpyrrolidine-1-carboxylate (99 mg, 0.1151 mmol) in dichloromethane (0.5 ml) and toluene (0.2 ml) trifluoroacetic acid (100 µl, 1.298 mmol) was added and the mixture was stirred at ambient temperature for 23 hours. The solvent was removed in vacuo with the bath temperature set at 40°C to form a thick yellow oil. The oil was diluted with toluene (5 ml) and the solvent was removed in vacuo at 40°C, providing N-[[3-benzyloxy-6-[3-[(3S)-5,5-dimethylpyrrolidin-3yl]propylamino]-2-pyridyl ]sulfonyl]-2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1yl]pyride in-3-carboxamide (trifluoroacetate salt) (100 mg, 99%) in in the form of a yellow resin. MS-ESI m/z calc. 759.29694, detected 760.4 (M+1) ⁺ ; retention time: 1.9 min (LC method B).

Step 11: (14S)-22-(benzyloxy)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]12,12-dimethyl -2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2, 4-trione

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To a solution of N-[[3-benzyloxy-6-[3-[(3 S)-5,5-dimethylpyrrolidin-3 -yl]propylamino]-2pyridyl]sulfonyl]-2-chloro-6-[3 -(2 -dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1 -yl]pyridin-3 carboxamide (trifluoroacetate salt) (100 mg, 0.1144 mmol) in NMP (2 ml) was added potassium carbonate (180 mg, 1.302 mmol). The mixture was purged with nitrogen for 5 minutes. The mixture was heated at 150°C for 20 hours. The reaction mixture was cooled to room temperature and added to water (8 ml). The mixture was carefully acidified with aqueous hydrochloric acid (500 μl of 6 M, 3,000 mmol) to pH 1, obtaining a foamy suspension. The solid was collected by paper filtration. The wet solid was dissolved in ethyl acetate and the solution was dried over sodium sulfate, then filtered. Solvents were removed and the residue was purified by flash chromatography on silica gel using a gradient of methanol (0% to 5% over 30 min) in dichloromethane to give (148)-22-(benzyloxy)-8-[3-(2-{dispiro[ 2.0.2.1]heptan-7-yl}ethoxy)1H-pyrazol-1-yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05, 10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4trione (31 mg, 37%) as an off-white solid. MS-ESI m/z calc. 723.3203, detected 724.5 (M+1)+; retention time: 2.19 min (LC method B).

Step 12: (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-22-hydroxy-12,12dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (connection 260)

(14S)-22-(benzyloxy)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)1H-pyrazol-1-yl]-12 was loaded into a 100 ml flask. 12-dimethyl-2λ ⁶ -thiα-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2 ,2,4-trione (31 mg, 0.04282 mmol) and methanol (6 ml). The solution was purged with nitrogen. 10% palladium on carbon (wet, Degussa, 21 mg, 0.01973 mmol) was added and the mixture was stirred under a hydrogen atmosphere (balloon) for 3 hours. The solution was purged with nitrogen, diluted with methanol and filtered through celite. After evaporation of the solvents, the residue was dissolved in dimethyl sulfoxide (1 ml). The solution was microfiltered and purified by preparative reverse phase HPLC (C ₁₈ ) using a gradient of acetonitrile in water (30% to 99% over 15 min, 950 μl injection, no modifier). Pure fractions were collected and solvents were removed by evaporation. The residue was treated with dichloromethane/hexanes and the solvents were evaporated to give (148)-8-[3-(2-{dispiro[2.0.2.1]heptan7-yl}ethoxy)-1H-pyrazol-1-yl]-22-hydroxy-12 ,12-dimethyl-2λ ⁶ -tiα-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene- 2,2,4-trione (compound 260) (10 mg, 36%) as an off-white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.39 (b. s, 1H), 9.07 (b. s, 1H, exch.), 8.21 (d, J=2.8 Hz, 1H), 7.80 (b. d , J=8.0 Hz, 1H), 7.20 (br. s, 1H), 6.91 (br. d, J=8.2 Hz, 1H), 6.69 (br. d, J=8.8 Hz, 1H), 6.28 (br. s, 1H, exch.), 6.08 (d, J=2.6 Hz, 1H), 4.21 (t, J=6.7 Hz, 2H), 3.77 (br. s, 1H), 3.20 (b. s, 1H), 2.96-2.79 (m, 2H), 2.12 (broad s, 1H), 1.91-1.50 (m, 13H), 1.47 (t, J=6.5 Hz, 1H), 1.42-1.29 (m, 1H), 0.890. 78 (m, 4H), 0.68-0.60 (m, 2H), 0.53-0.44 (m, 2H). MS-ESI m/z calc. 633.2733, detected 634.3 (M+1) ⁺ ; retention time: 2.39 min (LC method B).

Example 86: Preparation of (14S)-22-hydroxy-12,12-dimethyl-8-(3-{3-[1(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1-yl)-2λ ⁶ -thia -3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 261)

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BnO

Step 1: tert-butyl (4S)-4-[3-[[5-benzyloxy-6-[[2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclonronyl]propoxy]pyrazole-1 -yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate

VPO VPO

2-chloro-6-[3-[3-[1(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3-carboxylic acid (188 mg, 0.4824 mmol) was loaded into a 20 ml ampoule under nitrogen atmosphere ) and anhydrous tetrahydrofuran (3 ml). Carbonyldiimidazole (75 mg, 0.4625 mmol) was added and the mixture was stirred under nitrogen at room temperature for 4 hours. A second amount of carbonyldiimidazole (75 mg, 0.4625 mmol) was added and the mixture was stirred at room temperature for 2 hours. in a separate 20 ml flask a solution of tert-butyl (48)-4-[3-[(5-benzyloxy-6-sulfamoyl-2pyridyl)amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (204 mg, 0. 3933 mmol) in anhydrous tetrahydrofuran (2 ml) was prepared under nitrogen atmosphere and subsequently added via syringe to the activated ester solution. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.31 mL, 2.073 mmol) was added via syringe and the reaction mixture was stirred at room temperature under nitrogen for 5 days. The solvents were removed under reduced pressure and the resulting thick oil was treated with ethyl acetate (50 ml) and water (50 ml). Hydrochloric acid (450 μl 6 M, 2,700 mmol) was added slowly (final pH 5) and the two phases were separated. The aqueous phase was extracted with ethyl acetate (30 ml). The combined organic extracts were washed with brine (30 ml) and dried over sodium sulfate. After filtration and evaporation of the solvents, the residue 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 product was eluted together with an impurity, which was removed by a second purification by chromatography on silica gel under the same conditions as on the first column. Fractions containing the expected material were combined and the solvents were evaporated, yielding tert-butyl (4S)-4-[3-[[5benzyloxy-6-[[2-chloro-6-[3-[3-[1-(trifluoromethyl )cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (109 mg, 31% yield, 86% purity) as off-white film. MS-ESI m/z calc. 889.3211, detected 890.4 (M+1)+; Retention time: 2.49 min (LC method B).

Step 2: N-[[3-benzyloxy-6-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2pyridyl]sulfonyl]-2-chloro-6-[3-[ 3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3 carboxamide (ditrifluoroacetate salt)

To a solution of tert-butyl (4S)-4-[3-[[5-benzyloxy-6-[[2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclononyl]propoxy]pyrazole-1- yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2dimethylpyrrolidine-1-carboxylate (109 mg, 0.1224 mmol) in dichloromethane (0.5 ml) and toluene (0.2 ml) trifluoroacetic acid (100 μl 1.298 mmol) was added and the mixture was stirred at ambient temperature for 23 hours. Solvents were removed in vacuo at a bath temperature of 40°C. The residue was diluted with toluene (5 ml) and the solvent was removed in vacuo at a bath temperature of 40°C. The residue was treated with dichloromethane/hexanes and the solvents were evaporated to give N-[[3-benzyloxy-6-[3-[(3S)5,5-dimethylpyrrolidin-3-yl]propylamino]-2-pyridyl]sulfonyl] -2-chloro-6-[3-[3-[1(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3-carboxamide (ditrifluoroacetate salt) (130 mg, quantitative yield) as an off-white solid substances. MS-ESI m/z calc. 789.2687, detected 790.5 (M+1)+; retention time: 1.85 min (LC method B).

Step 3: (14S)-22-(benzyloxy)-12,12-dimethyl-8-(3-{3-[1 -(trifluoromethyl)cyclopropyl]propoxy} 1 H-pyrazol-1 -yl)-2X ⁶ - thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione

To a solution of N-[[3-benzyloxy-6-[3-[(3 S)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2pyridyl]sulfonyl]-2-chloro-6-[3-[3 -[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3-carboxamide (ditrifluoroacetate salt) (130 mg, 0.1277 mmol) to NMP (3 ml) was added potassium carbonate (230 mg, 1.664 mmol). The mixture was purged with nitrogen for 5 minutes. The mixture was heated at 150°C for 22 hours. The reaction mixture was cooled to room temperature and added to water (10 ml). The mixture was carefully acidified with aqueous hydrochloric acid (500 μl of 6 M, 3,000 mmol) to pH 1, obtaining a foamy suspension. The solid was collected by paper filtration. The wet solid was dissolved in ethyl acetate, the solution was dried over sodium sulfate and filtered. The solvents were evaporated and the residue was purified by flash chromatography on silica gel using a gradient of methanol (0% to 5% over 30 min) in dichloromethane to give (14S)-22-(benzyloxy)-12,12-dimethyl-8-(3- {3-[1(trifluoromethyl)cyclopropyl]propoxy}-1 H-pyrazol-1 -yl)-2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1( 22),5,7,9,19(23),20-hexaene-2,2,4 trione (38 mg, 39%) as a white solid. MS-ESI m/z calc. 753.29205, detected 754.5 (M+1) ⁺ ; retention time: 2.38 min (LC method B).

Step 4: (14S)-22-hydroxy-12,12-dimethyl-8-(3-{3-[ 1 -(trifluoromethyl)cyclopropyl]propoxy} -1Hpyrazol-1 -yl)-2X ⁶ -thia-3, 9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 261)

(148)-22-(benzyloxy)-12,12-dimethyl-8-(3-{3-[1(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1-yl)- was loaded into a 100 ml flask 2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4 -trione (39 mg,

0.05174 mmol) and methanol (8 ml). The solution was purged with nitrogen. 10% palladium on carbon (wet, Degussa, 27 mg, 0.02537 mmol) was added and the mixture was stirred under a hydrogen atmosphere (balloon) for 4 hours. The solution was purged with nitrogen, diluted with methanol and filtered through celite. After evaporation of the solvents, the residue was dissolved in dimethyl sulfoxide (1 ml). The solution was microfiltered and purified by preparative reverse phase HPLC (C ₁₈ ) using a gradient of acetonitrile in water (30% to 99% over 15 min, 950 μl injection, no modifier). Pure fractions were collected and solvents were removed by evaporation. The residue was treated with dichloromethane/hexanes and the solvents were evaporated to give (148)-22-hydroxy-12,12-dimethyl-8-(3-{3-[1 -(trifluoromethyl)cyclopropyl]propoxy} 1 H-pyrazol-1 -yl )-2Х ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2 ,4-trione (compound 261) (22 mg, 63%) as an off-white solid.

1H NMR (400 MHz, DMSO-d6) δ 12.38 (broad s, 1H), 9.07 (broad s, 1H), 8.21 (d, J=2.7 Hz, 1H), 7.79 (broad s, 1H), 7.20 (broad s, 1H), 6.90 (broad s, 1H), 6.68 (broad s, 1H), 6.28 (broad s, 1H), 6.10 (broad s, 1H), 4.20 (t, J= 6.2 Hz, 2H), 3.76 (b.s., 1H), 3.21 (b.s., 1H), 2.98-2.75 (m, 2H), 2.12 (b.s., 1H), 1.93-1.77 (m, 3H) , 1.78-1.66 (m, 3H), 1.68-1.46 (m, 8H), 1.37 (br m, 2H), 0.95-0.88 (m, 2H), 0.79-0.68 (m, 2H). MS-ESI m/z calc. 663.24506, detected 664.3 (M+1) ⁺ ; retention time: 2.24 min (LC method B).

Example 87: Preparation of 2-imino-12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-2X ⁶ -thia-3,9,11 ,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23), 5,7,9,19,21hexaene-2,4-dione (diastereomer pair 1) (compound 262) and 2-imino -12,12-dimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1 -yl)-2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3 .1.111,14.05,10]tetracose-1 (23), 5,7,9,19,21-hexaene-2,4-dione (diastereomer pair 2) (compound 263)

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Step 1: tert-butyl 2,6-difluoropyridine-3-carboxylate

To a solution of 2,6-difluoropyridine-3-carboxylic acid (10 g, 62.858 mmol) and BF ₃ -Et ₂ O (0.4 ml, 3.2 mmol, 0.05 eq.) in dry tetrahydrofuran (60 ml) At 0°C, tert-butyl 2,2,2trichloroethanimidate (10 g, 45.8 mmol) was added slowly over 10 min. The reaction solution was stirred at room temperature for 2 hours under a nitrogen atmosphere. More tert-butyl-2,2,2-trichloroethanimidate (20 g, 91.5 mmol) and BF ₃ -Et ₂ O (0.4 ml) were added at room temperature. The reaction mixture was stirred for 1 hour. It was then allowed to stand over the weekend and then quenched with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (2x60 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0% to 20% ethyl acetate in heptanes to give tert-butyl 2,6-difluoropyridine-3-carboxylate (12 g, 89%) as a white solid. MS-ESI m/z calc. 215.0758, detected 216.1 (M+1)+; retention time: 2.13 min (LC method I).

Step 2: tert-butyl 2-fluoro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine 3-carboxylate

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1,4-Diazabicyclo[2.2.2]octane (125 mg, 1.1144 mmol) was added to a solution of tert-butyl 2,6-difluoropyridine-3-carboxylate (1.2 g, 5.5763 mmol) and 3-[2- [1-(trifluoromethyl)cyclopropyl]ethoxy]-1Hpyrazole (1.29 g, 5.8585 mmol). The mixture was stirred for 10 min and potassium carbonate (1.2 g, 8.6827 mmol) was added. The mixture was stirred at 20°C under nitrogen atmosphere for 16 hours. The reaction mixture was diluted with ethyl acetate (100 ml), washed with water (3x30 ml), brine (30 ml), dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a gradient of ethyl acetate in heptanes (0-15%), to give tert-butyl-2-fluoro-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl ]pyridine-3-carboxylate (1.46 g, 63% yield) as a white solid.

1H NMR (300 MHz, CDCl ₃ ) δ 0.71-0.78 (m, 2H), 1.01-1.05 (m, 2H), 1.60 (s, 9H), 2.10 (t, J=7.1 Hz, 2H), 4.41 (t , J=7.1 Hz, 2H), 5.95 (d, J=2.9Hz, 1H), 7.63 (dd, J=8.2, 1.2Hz, 1H), 8.29 (d, J=2.8 Hz, 1H), 8.32-8.38 (m, 1H). ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ -69.9 (s, 3F), -62.4 (d, J=9.2 Hz, 1F). MS-ESI m/z calc. 415.1519, detected 416.2 (M+1)+; retention time: 2.69 min (LC method U).

Step 3: 2-fluoro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3 carboxylic acid

Trifluoroacetic acid (3 ml) was added to a solution of tert-butyl-2-fluoro-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylate (1.46 g , 3.5148 mmol) in dichloromethane (12 ml). The mixture was stirred at 40°C for 4 hours. The mixture was then concentrated under reduced pressure and dried under vacuum to give 2-fluoro-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl] pyridine-3-carboxylic acid (1.26 g, 100%) as a white solid.

1H NMR (300 MHz, CDCl ₃ ) δ 0.84-.091 (m, 2H), 0.93-0.99 (m, 2H), 2.09 (t, J=7.0 Hz, 2H), 4.35 (t, J=7.0 Hz, 2H), 6.21 (d, J=2.7 Hz, 1H), 7.67 (d, J=9.3 Hz, 1H), 8.42 (d, J=3.1 Hz, 1H), 8.50 (dd, J=9.3, 8.5 Hz, 1H), 13.48 (br.s., 1H). ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ -68.38 (s, 3F), -63.25 (d, J=9.5 Hz, 1F). MC-ESI m/z calc. 359.0893, detected 360.1 (M+1)+; retention time: 2.19 min (LC method I).

Step 4: 2-fluoro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carboxamide

To a suspension of 2-fluoro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3carboxylic acid (1.26 g, 3.5071 mmol) in dichloromethane (20 ml ) one drop of N,Ndimethylformamide (0.015 mL) was added followed by dropwise addition of oxalyl chloride (625.65 mg, 0.43 mL, 4.9293 mmol). The reaction mixture was stirred at room temperature for 2 hours until the formation of bubbles stopped. The solvent was removed under reduced pressure. The resulting white solid was dissolved in anhydrous tetrahydrofuran (10 ml) and added to a mixture of 28% aqueous ammonium hydroxide (10 ml) and tetrahydrofuran (5 ml), which was cooled in an ice water bath. The reaction mixture was then stirred at room temperature for 1 hour and then diluted with ethyl acetate (100 ml), washed with water (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-fluoro-6-[3 -[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (1.3 g, quantitative yield) as a white solid.

1H NMR (300 MHz, CDCl ₃ ) δ 0.70-0.79 (m, 2H), 0.99-1.08 (m, 2H), 2.10 (t, J=7.2 Hz, 2H), 4.42 (t, J=7.1 Hz, 2H ), 5.80 (br.s, 1H), 5.97 (d, J=2.9 Hz, 1H), 6.61-6.71 (m, 1H), 7.74 (dd, J=8.3, 2.0 Hz, 1H), 8.28 (d, J=2.8 Hz, 1H), 8.62 (dd, J=9.8, 8.3 Hz, 1H). ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ -69.86 (s, 3F), -65.44 (t, J=8.8 Hz, 1F).

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MS-ESI m/z calc. 358.1053, detected 359.1 (M+1)+; retention time: 2.08 min (LC method I).

Step 5: 2-tert-butylsulfanyl-6-fluoropyridine

2-Methylpropane-2-thiol (9.0400 g, 11.3 mL, 100.24 mmol) was added to a suspension of sodium hydride (4.8 g, 120 mmol, 60% in oil, washed with 20 mL anhydrous ether) in anhydrous tetrahydrofuran (200 ml) at 0°C. The gray suspension was stirred at room temperature for 30 min, then 2,6-difluoropyridine (10 ml, 110.3 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was then cooled in an ice water bath and then quenched with water. The resulting mixture was diluted with ethyl acetate (60 ml), washed with water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2t-butylsulfanyl-6-fluoro-pyridine (22 g, yield 96%, purity 81%) as a pale yellow oil, which was used directly in the next step.

1H NMR (300 MHz, CDCl ₃ ) δ 1.55 (s, 9 H), 6.64 (ddd, J=8.1, 2.9, 0.5 Hz, 1H), 7.12 (dd, J=7.6, 2.2, 0.5 Hz, 1H), 7.57 (k, J=8.0 Hz, 1H). MS-ESI m/z calc. 185.0674, detected 186.1 (M+1)+; Retention time: 2.21 min (LC method I).

Step 6: 6-fluoropyridine-2-thiol

At room temperature (about 20°C), 100 ml (100 mmol) of a 1 M solution of boron tribromide in dichloromethane was added dropwise to a solution of 2-tert-butylsulfanyl-6-fluoropyridine (22 g, purity 81%., 96.188 mmol) in 150 ml dichloromethane. The reaction mixture was stirred at room temperature for 2.5 hours. Boron tribromide (50.00 ml of 1M in dichloromethane, 50 mmol) was also added. After 10 min, the reaction mixture was diluted with 100 ml dichloromethane, washed with water (2x100 ml), shaken vigorously to obtain two clear phases, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give crude 6-fluoropyridine-2-thiol (28 g, yield 100%, purity 45%) as a yellow oil.

1H NMR (300 MHz, CDCl3) δ 6.65 (dd, J=8.1, 2.5 Hz, 1H), 7.07 (dd, J=7.6, 2.2Hz, 1H), 7.60 (k, J=7.9 Hz, 1H). 19F NMR (282 MHz, CDCl ₃ ) δ -66.78 (s, 1F).

Step 7: 2-fluoro-6-[(6-fluoro-2-pyridyl)disulfanyl]pyridine

Bromine (17.063 g, 5.5 mL, 106.77 mmol) was slowly added to a solution of 6-fluoropyridine-2-thiol (28 g, 45% purity, 97.557 mmol) in ethyl ether (160 mL) at room temperature until pure orange color. The addition was stopped and the reaction mixture was diluted with ethyl acetate (100 ml), washed with a 1:1 mixture of saturated sodium bicarbonate and 10% sodium thiosulfate solution, brine and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with a gradient of ethyl acetate in heptanes (0-20%), to give 2-fluoro-6-[(6-fluoro-2pyridyl)disulfanyl]pyridine (10.5 g, 84%) as a brown solid substances.

1H NMR (300 MHz, CDCl3) δ 6.75 (dd, J=8.0, 2.6 Hz, 1H), 7.49 (dd, J=7.7, 2.1 Hz, 1H), 7.72 (k, J=7.7 Hz, 1H). 19F NMR (282 MHz, CDCl3) δ -66.37 (d, J=6.8 Hz, 1F). MS-ESI m/z calc. 255.994, detected 257.1 (M+1)+; retention time: 2.12 min (LC method I).

Step 8: 2-fluoro-N-[(6-fluoro-2-pyridyl)sulfanyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3- carboxamide

Bromine (310.25 mg, 0.1000 mL, 1.9414 mmol) was slowly added to a solution of 2-fluoro-6-[(6-fluoro-2pyridyl)disulfanyl]pyridine (520 mg, 2.0289 mmol) in anhydrous acetonitrile (4 ml) at 0°C. After stirring for 2 min at the same temperature, the red solution was added to the solution of 2-fluoro6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (720 mg, 2.0095 mmol) in anhydrous acetonitrile (4 ml) and pyridine (6 ml) at 0°C. The resulting dark mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was evaporated with toluene and purified by silica gel chromatography using a gradient of 0% to 30% ethyl acetate in heptanes to give 2-fluoro-X-[(6-fluoro-2-pyridyl)sulfanyl]-6-[3-[ 2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (700 mg, 72%) as white

- 325 044967 solid matter. MS-ESI m/z calc. 485.0945, detected 486.1 (M+1)+; retention time: 2.36 min (LC method I).

Step 9: 2-fluoro-N-[(6-fluoro-2-pyridyl)sulfinyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1 -yl]pyridin-3 - carboxamide

Meta-chloroperoxybenzoic acid (355 mg, 77% purity, 1.58 mmol) was added to a solution of 2fluoro-N-[(6-fluoro-2-pyridyl)sulfanyl]-6-[3-[2-[1-(trifluoromethyl )cyclopropyl]ethoxy]pyrazol-1yl]pyridine-3-carboxamide (700 mg, 1.4420 mmol) in dichloromethane (20 ml) at 0°C, and the reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted dichloromethane (70 ml), washed successively with 10% w/v. aqueous sodium thiosulfate, 5% w/v. aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with a gradient of 0% to 40% ethyl acetate in heptanes to give racemic 2-fluoro-N-[(6-fluoro-2-pyridyl)sulfinyl]-6-[3-[2[1- (trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (700 mg, 97%) as a white solid. MS-ESI m/z calc. 501.0894, detected 502.1 (M+1) ⁺ ; retention time: 2.25 min (LC method I).

Step 10: 4-(3-azidopropyl)-2,2-dimethylpyrrolidine (hydrochloride salt)

Hydrochloric acid (2 mL 4 M in 1,4-dioxane, 8.0 mmol) was added to a solution of tert-butyl 4-(3-azidopropyl)-2,2-dimethylpyrrolidine-1-carboxylate (1.2 g, 4.2496 mmol ) in dichloromethane (10 ml) cooled in an ice water bath. The mixture was left stirring at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was evaporated twice with toluene (40 ml) to obtain crude 4-(3-azidopropyl)-2,2-dimethylpyrrolidine (hydrochloride salt) (930 mg, 100%) as a light yellow oil.

1H NMR (300 MHz, CDC13) δ 1.29 (s, 3H), 1.38-1.54 (m, 8H), 1.99 (dd, J=12.7, 7.7Hz, 1H), 2.31-2.42 (m, 1H), 2.76- 2.89 (m, 1H), 3.32-3.36 (m, 3H), 9.00 (br.s., 1H), 9.11 (br.s., 1H). MS-ESI m/z calc. 182.1531, detected 183.2 (M+1)+; Retention time: 0.94 min (LC method I).

Step 11: 2-[4-(3-azidopropyl)-2,2-dimethylpyrrolidin-1-yl]-N-[(6-fluoro-2-pyridyl)sulfinyl]6-[3-[2-[1- (trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide

Sodium hydride (193 mg, 60% w/w dispersion in mineral oil, 2.6 mmol) was added to a solution of 4-(3-azidopropyl)-2,2-dimethylpyrrolidine hydrochloride salt (528 mg, 2.4 mmol) in anhydrous N,N-dimethylformamide (10 ml) was cooled in an ice water bath. The mixture was stirred for 5 min and 2-fluorine-containing N-[(6-fluoro-2-pyridyl)sulfinyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3 -carboxamide (930 mg, 1.85 mmol) was added. The mixture was stirred at room temperature for 30 minutes and then placed in an oil bath (50°C) and stirred for 4 hours. The mixture was then allowed to cool and stand overnight. The mixture was diluted with ethyl acetate (100 ml). The resulting mixture was washed with water (3x30 ml), brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0% to 70% ethyl acetate in heptanes to give 2-[4-(3-azidopropyl)-2,2-dimethylpyrrolidin-1-yl]-N-[(6-fluoro-2 -pyridyl)sulfinyl]-6-[3[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (600 mg, 49%) as a white solid. MS-ESI m/z calc. 663.2363, detected 664.3 (M+1) ⁺ ; retention time: 2.61 min (LC method I).

Step 12: 2-[4-(3-azidopropyl)-2,2-dimethylpyrrolidin-1-yl]-N-[(6-fluoro-2pyridyl)sulfonimidoyl]-6-[3-[2-[ 1 -( trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3 carboxamide

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Ammonia (10 ml of a 0.5 M solution in 1,4-dioxane, 5 mmol) was added to a solution of 2-[4-(3-azidopropyl)2,2-dimethylpyrrolidin-1-yl]-N-[(6-fluoro -2-pyridyl)sulfinyl]-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (580 mg, 0.87 mmol) in anhydrous acetonitrile (5 ml) at 0°C. N-chlorosuccinimide (140 mg, 1.05 mmol) was added in one portion (the mixture turned orange) and the reaction mixture was stirred at 0°C for 1 hour. Additional N-chlorosuccinimide (100 mg, 0 .75 mmol) and the reaction mixture was stirred at the same temperature for 30 minutes. The reaction was then quenched with 10% aqueous sodium thiosulfate (w/v) and extracted with ethyl acetate (50 ml). The organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with a gradient of 0% to 55% ethyl acetate in heptanes to give 2-[4-(3-azidopropyl)-2,2-dimethylpyrrolidin-1-yl]-N-[(6-fluoro-2pyridyl )sulfonimidoyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (400 mg, 67%) as a yellow sticky solid.

Step 13: 2-[4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl]-N-[(6-fluoro-2pyridyl)sulfonimidoyl]-6-[3-[2-[1-( trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3carboxamide

Mixture of 2-[4-(3-azidononyl)-2,2-dimethylpyrrolidin-1-yl]-N-[(6-fluoro-2pyridyl)sulfonimidoyl]-6-[3-[2-[1-(trifluoromethyl) cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carboxamide (360 mg, 0.5304 mmol), ammonia in methanol (7 N, 1 ml) and 10% palladium on carbon (wet, Degussa, 200 mg, 0.094 mmol) in methanol (10 ml) was hydrogenated at 1 atm H ₂ (balloon) at room temperature for 3 hours. The flask was evacuated and again filled with nitrogen. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give crude 2-[4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl]-N-[(6-fluoro-2-pyridyl)sulfonimidoyl]-6[3-[ 2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (380 mg, 81% yield, 74% purity) as a yellow solid. The crude product was directly used in the next step without purification. MS-ESI m/z calc. 652.2567, detected 653.3 (M+1)+; retention time: 1.70 min (LC method I).

Step 14: 2-imino-12,12-dimethyl-8-(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 yl)-2λ ⁶ -thia-3,9, 11,18,23-πpentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,4dione (pair of diastereomers 1) (compound 262) and 2- imino-12,12-dimethyl-8-(3-{2-[1(trifluoromethyl)cyclonronyl]ethoxy}-1H-pyrazol-1-yl)-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,4-dione (diastereomer pair 2) (compound 263)

Mixture of 2-[4-(3-aminonronyl)-2,2-dimethylpyrrolidin-1-yl]-N-[(6-fluoro-2pyridyl)sulfonimidoyl]-6-[3-[2-[ 1 -(trifluoromethyl) cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3 carboxamide (380 mg, 0.5822 mmol), triethylamine (239.58 mg, 0.33 ml, 2.3676 mmol) and dry dimethyl sulfoxide (25 ml) were stirred in sealed tube at 100°C for 4 hours. The mixture was allowed to cool to room temperature, then diluted with water (100 ml) and extracted with ethyl acetate (3x40 ml). The combined organic layers were washed with water (2x30 ml), brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0% to 60% ethyl acetate in heptanes to give 2-imino-12,12dimethyl-8-(3-{2-[1-(trifluoromethyl) as the first diastereomeric pair of enantiomers to elute cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9, 19,21-hexaene-2,4-dione (diastereomer pair 1) (compound 262) (88.76 mg, 23% yield) as a white solid,

Ή NMR (300 MHz, CDCl ₃ ) ppm 0.72-0.80 (m, 2H), 0.96-1.05 (m, 2H), 1.13-1.23 (m, 1H), 1.29-1.44 (m,

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1H), 1.59 (s, 3H), 1.67-1.71 (m, 1H), 1.75 (s, 3H), 1.82-1.94 (m, 2H), 2.00-2.31 (m, 4H), 3.09-3.34 (m, 2H), 3.60 (t, J=11.0 Hz, 1H), 3.75-3.94 (m, 1H), 4.39 (t, J=7.0 Hz, 2H), 4.70-4.80 (m, 1H), 5.86 (d, J =2.6 Hz, 1H), 6.47 (d,

J=8.5 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 7.02 (br. s., 2H), 7.30 (d, J=7.0 Hz, 1H), 7.47 (dd, J=8.2, 7.3 Hz, 1H),

8.17 (d, J=8.2 Hz, 1H), 8.24 (d, J=2.6 Hz, 1H). ¹⁹ F NMR (282 MHz, CDCl ₃ ) ppm -70.0 (br.s, 3F). MS-ESI m/z calc. 632.2505, detected 633.3 (M+1) ⁺ ; Retention time: 3.98 min (LC method H), and as the second diastereomeric pair of eluted enantiomers, 2-imino-12,12-dimethyl-8-(3{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H -pyrazol-1-yl)-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21 -hexaene- 2,4-Dione (diastereomer pair 2) (compound 263) (97.02 mg, 25% yield) as a white solid.

1H NMR (300 MHz, CDCl ₃ ) δ 0.70-0.78 (m, 2H), 0.97-1.05 (m, 2H), 1.34-1.46 (m, 2H), 1.58-1.63 (m, 7H), 1.64-1.74 ( m, 2H), 1.82 (dd, J=11.3, 5.4 Hz, 1H), 2.08-2.12 (m, 3H), 2.96-3.11 (m, 2H), 3.29-3.42 (m, 1H), 4.164.25 ( m, 1H), 4.32-4.41 (m, 3H), 5.09 (br. s., 2H), 5.84 (d, J=2.6 Hz, 1H), 6.53 (d, J=8.5 Hz, 1H), 6.96 ( d, J=8.2 Hz, 1H), 7.35 (d, J=7.0 Hz, 1H), 7.53 (dd, J=8.5, 7.3 Hz, 1H), 8.07 (d, J=8.2 Hz, 1H), 8.20 ( d, J=2.6 Hz, 1H). ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ -70.0 (s, 3F). MS-ESI m/z calc. 632.2505, detected 633.3 (M+l) ⁺ ; Retention time: 3.77 min (LC method H).

Example 88: Preparation of (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-21hydroxy-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5,7,9,19,21-hexaene-2,2,4-trione (compound 264)

Step 1: 4-benzyloxy-2-chloro-6-fluoropyridine

To a solution of 2-chloro-6-fluoropyridin-4-ol (4.62 g, 31.315 mmol) in acetonitrile (90 ml) was added cesium carbonate (15.3 g, 46.959 mmol) and benzyl bromide (5.8958 g, 4. 1 ml, 34.472 mmol). The reaction mixture was stirred at room temperature overnight. The solution was dissolved in ethyl acetate (350 ml) and water (100 ml). The aqueous phase was removed and the organic phase was washed with water (100 ml) and brine (75 ml). The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of 0% to 10% ethyl acetate in heptanes to give 4-benzyloxy-2-chloro-6-fluoropyridine (7.01 g, 94%) as a white solid. MS-ESI m/z calc. 237.0357, detected 238.1 (M+1)+; retention time: 2.38 min (LC method N).

Step 2: 2-ethylhexyl 3-[(4-benzyloxy-6-fluoro-2-pyridyl)sulfanyl]propanoate

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A solution of 4-benzyloxy-2-chloro-6-fluoropyridine (6.77 g, 28.486 mmol) and diisopropylethylamine (7.4200 g, 10 mL, 57.411 mmol) in toluene (250 mL) was degassed by bubbling nitrogen for 5 min. Tris(dibenzylideneacetone)dipalladium(0) (783 mg, 0.8551 mmol), xantphos (990 mg, 1.7110 mmol) and 2-ethylhexyl-3-sulfanylpropanoate (6.5280 g, 6.8 ml, 29.896 mmol) were added ) and the mixture was heated at 125°C overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0% to 10% ethyl acetate in heptane to give 2ethylhexyl-3-[(4-benzyloxy-6-fluoro-2-pyridyl)sulfanyl]propanoate (12.06 g, quantitative yield) in the form of orange oil.

1H NMR (300 MHz, CDCl3) δ 0.80-0.95 (m, 6H), 1.19-1.43 (m, 8H), 1.51-1.63 (m, 1H), 2.77 (t, J=7.0 Hz, 2H), 3.37 ( t, J=6.9 Hz, 2H), 4.02 (dd, J=5.9, 1.2 Hz, 2H), 5.07 (s, 2H), 6.18 (d, J=1.8 Hz, 1H), 6.65 (d, J=1.2 Hz, 1H), 7.28-7.49 (m, 5H). ¹⁹ F NMR (282 MHz, CDC^) δ -65.7 (s, 1F). MS-ESI m/z calc. 419.193, detected 420.2 (M+1)+; retention time: 2.8 min (LC method I).

Step 3: 2-ethylhexyl 3-[(4-benzyloxy-6-fluoro-2-pyridyl)sulfonyl]propanoate

M-chloroperbenzoic acid (12.9 g, 57.561 mmol) was added slowly at 0°C to a solution of 2-ethylhexyl-3-[(4-benzyloxy-6-fluoro-2-pyridyl)sulfanyl]propanoate (12.06 g, 28.745 mmol ) in dichloromethane (150 ml). The mixture was stirred at this temperature overnight. Ethyl acetate (150 ml) was added and washed with saturated sodium bicarbonate (100 ml) and 0.5 M sodium hydroxide (2x100 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-ethylhexyl-3-[(4-benzyloxy-6-fluoro-2pyridyl)sulfonyl]propanoate (12.05 g, 93%) as a colorless oil . MS-ESI m/z calc. 451.1829, detected 452.2 (M+1)+; retention time: 2.54 min (LC method I).

Step 4: 4-benzyloxy-6-fluoropyridine-2-sulfonamide

To a solution of 2-ethylhexyl-3-[(4-benzyloxy-6-fluoro-2-pyridyl)sulfonal]propanoate (10.69 g, 23.674 mmol) in dimethyl sulfoxide (60 ml) was added 1,8-diazabicyclo[5.4.0 ]undec-7-ene (7.0700 g, 7 ml, 46.441 mmol). The reaction mixture was stirred for 1 hour at room temperature and a solution of hydroxylamine-O-sulfonic acid (13.3 g, 117.60 mmol) and sodium acetate (7.7 g, 93.864 mmol) in water (40 ml) was added at 10 °C. The reaction mixture was stirred for 1 hour at room temperature, diluted with water (300 ml) and extracted with ethyl acetate (2 x 300 ml). The combined organic layers were washed with brine (300 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was triturated overnight with heptane:ethyl acetate 9:1 (100 ml). The product was isolated by filtration. The product was redissolved in ethyl acetate and filtered through a pad of silica gel, eluting with ethyl acetate (500 ml) and concentrated to give 4-benzyloxy-6-fluoropyridine-2-sulfonamide (5.56 g, 83%).

1H NMR (300 MHz, DMSO-d6) δ 5.34 (s, 2H), 7.15 (d, J=2.1 Hz, 1H), 7.30-7.54 (m, 6H), 7.62 (s, 2H). ^19F NMR (282 MHz, dimethyl sulfoxide-d6) δ -66.0 (s, 1F). MS-ESI m/z calc. 282.0474, detected 283.1 (M+1)+; retention time: 1.75 min (LC method I).

Step 5: tert-butyl (48)-4-[3-[(4-benzyloxy-6-sulfamoyl-2-pyridyl)amino]propyl]-2,2dimethyl-pyrrolidine-1-carboxylate

Tert-butyl (4S)-4-(3-aminopropyl)-2,2dimethylpyrrolidine-1-carboxylate (312 mg, 1.217 mmol), 4-benzyloxy-6-fluoro-pyridine-2 was loaded into a 20 ml ampoule under nitrogen atmosphere -sulfonamide (344 mg, 1.219 mmol), anhydrous dimethyl sulfoxide (3.5 ml) and diisopropylethylamine (0.32 ml, 1.837

- 329 044967 mmol). The vial was sealed and stirred at 85°C for 16 hours. The mixture was diluted with ethyl acetate (50 ml), water (50 ml) and 10% citric acid (10 ml). The two phases were separated. The organic phase was washed with brine (30 ml), dried over sodium sulfate, filtered and the solvents were evaporated. The product was purified by silica gel chromatography using a gradient of ethyl acetate (0% to 70% over 30 min) in hexane to give tert-butyl (4S)-4-[3-[(4-benzyloxy-6-sulfamoyl-2pyridyl)amino ]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (427 mg, 68%) as a white foamy solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.47-7.29 (m, 5H), 7.07 (s, 2H), 6.83 (t, J=5.4 Hz, 1H), 6.66 (d, J=2.0 Hz, 1H ), 6.15 (d, J=1.8 Hz, 1H), 5.14 (s, 2H), 3.55 (k, J=9.5 Hz, 1H), 3.25 (broad q, J=6.4 Hz, 2H), 2.78 (k, J=9.9 Hz, 1H), 2.10 (broad s, 1H), 1.94-1.81 (m, 1H), 1.57-1.43 (m, 2H), 1.45-1.29 (m, 15H), 1.24 (s, 3H) . MSIE m/z calc. 518.2563, detected 519.4 (M+1)+; retention time: 1.92 min (LC method B).

Step 6: tert-butyl (48)-4-[3-[[4-benzyloxy-6-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7ylethoxy)pyrazole-1 -yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate

Boc'N

To a stirred solution of 2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1yl]pyridine-3-carboxylic acid (130 mg, 0.3613 mmol) in anhydrous tetrahydrofuran ( 2 ml) carbonyldiimidazole (60 mg, 0.3700 mmol) was added and stirring was continued at ambient temperature under nitrogen atmosphere for 2 hours. A solution of tert-butyl (4S)-4-[3-[(4benzyloxy-6) was added to the reaction -sulfamoyl-2-pyridyl)amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (160 mg, 0.3085 mmol) in anhydrous tetrahydrofuran (1 ml), then 1,8-diazabicyclo[5.4.0]undec -7-ene (200 µl, 1.337 mmol) and the mixture was stirred at ambient temperature for 15 hours. Volatiles were removed under reduced pressure and the residue was diluted with ethyl acetate (20 ml) and water (20 ml), and the mixture was slowly acidified 4 M aqueous hydrochloric acid (350 µl 4 M, 1,400 mmol) to approximately pH 4.0. The layers were separated and the aqueous layer was extracted with ethyl acetate (15 ml). The combined organic phases were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (0% to 70% ethyl acetate in hexane gradient over 35 min) to give tert-butyl (48)-4-[3-[[4-benzyloxy-6-[[2 -chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7ylethoxy)pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2dimethylpyrrolidine-1 -carboxylate (72 mg, 27%) as a white solid. MS-ESI m/z calc. 859.34937, detected 860.6 (M+1) ⁺ ; retention time: 2.41 min (LC method G).

Step 7: N-[[4-Benzyloxy-6-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2pyridyl]sulfonyl]-2-chloro-6-[3-(2 -dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3carboxamide (trifluoroacetate salt)

Boc'N

To a stirred solution of tert-butyl (4S)-4-[3-[[4-benzyloxy-6-[[2-chloro-6-[3-(2dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazole-1 -yl]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (70 mg, 0.08135 mmol) in anhydrous methylene chloride (2 ml) was added trifluoroacetic acid (300 μl , 3.894 mmol) at ambient temperature in a nitrogen atmosphere. The orange solution was stirred for 1 hour, then the volatiles were removed under reduced pressure. Toluene (20 ml) was added to the residue and concentrated to dryness under reduced pressure. The process was repeated once more to remove residual trifluoroacetic acid and finally dried under vacuum for 2 hours to obtain crude N-[[4-benzyloxy6-[3-[(38)-5,5-dimethylpyrrolidin-3-yl]propylamino ]-2-pyridyl]sulfonyl]-2-chloro-6-[3-(2dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3-carboxamide (trifluoroacetate salt) (71 mg, 100%). MS-ESI m/z calc. 759.29694, detected 760.5 (M+1) ⁺ ; retention time: 2.01 min (LC method

IN).

Step 8: (14S)-21-(benzuloxy)-8-[3-(2-{dispiro[2.0.2.1]heptαn-7-yl}ethoxy)-1H-pyrazol-1-yl]12,12-dimethyl -2λ ⁶ -thia-3,9,11,18,23-πpentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21- 330 044967 hexaene-2,2 ,4-trione

N-[[4-benzyloxy-6-[3-[(3S)-5,5-dimethylpyrrolidin-3yl]propylamino]-2-pyridyl]sulfonyl]-2-chloro-6-[3 was loaded into a 20 ml bottle -(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1yl]pyridin-3-carboxamide (trifluoroacetate salt) (67 mg, 0.07663 mmol), potassium carbonate (65 mg, 0.4703 mmol) , cesium fluoride (24 mg, 0.1580 mmol) and anhydrous dimethyl sulfoxide (5 ml) in that order. The vessel was purged with a stream of nitrogen for 2 minutes, capped and stirred at 160°C for 15 hours. The reaction mixture was allowed to cool to ambient temperature and the heterogeneous mixture was diluted with ethyl acetate (30 ml) and water (20 ml) and acidified with hydrochloric acid (1.0 ml, 1.0 M, 1,000 mmol). The layers were separated and the aqueous layer was re-extracted with ethyl acetate (20 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0%-10% methanol in dichloromethane for 30 min) to give (14S)-21(benzyloxy)-8-[3-(2-{dispiro[2.0.2.1]heptane-7- yl} ethoxy)-1 H-pyrazol-1 -yl]-12,12-dimethyl-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23) ,5,7,9,19,21-hexaene-2,2,4-trione (34 mg, 61%) as a white solid. MS-ESI m/z calc. 723.3203, detected 724.5 (M+1)+; retention time: 2.22 min (LC method G).

Step 9: (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-21-hydroxy-12,12dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene2,2,4-trione (compound 264 )

To a stirred solution of (14S)-21-(benzyloxy)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)1H-pyrazol-1-yl]-12,12-dimethyl -2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5,7,9,19,21-hexaene-2,2,4-trione (25 mg, 0.03454 mmol) in anhydrous methanol (5 ml) was added 10% palladium on carbon (wet, Degussa, 12 mg, 0.01128 mmol) under nitrogen atmosphere. The heterogeneous mixture was stirred in a hydrogen atmosphere (balloon) for 3 hours at ambient temperature. The hydrogen balloon was removed, the flask was purged with nitrogen, and the black heterogeneous reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure, the residue was dissolved in dimethyl sulfoxide (1.5 ml) and filtered through a 0.45 μm Whatman PTFE syringe filter. The sample was purified using preparative reverse phase HPLC-MS [Luna C ₁₈ (2) column (75 x 30 mm, 5 µm particle size), sold by Phenomenex (P/N: 00C-4252-U0-AX), (dual gradient run 30%-99% acetonitrile in water for 15 min (without modifier)] to give (14S)-8-[3(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol- 1-yl]-21-hydroxy-12,12-dimethyl-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23),5,7,9 ,19,21-hexaene-2,2,4-trione (compound 264) (8 mg, 36%) as an off-white solid.

1H NMR (400 MHz, Methanol-d ₄ ) δ 8.24 (d, J=2.8 Hz, 1H), 7.85 (d, J=8.2 Hz, 1H), 6.97 (d, J=8.2 Hz, 1H), 6.75 ( d, J=1.9 Hz, 1H), 6.00 (d, J=1.9 Hz, 1H), 5.94 (d, J=2.7 Hz, 1H), 4.24 (t, J=6.6 Hz, 2H), 4.02 (t, J=13.1 Hz, 1H), 3.38-3.32 (m, 2H), 3.08-2.97 (m, 1H), 2.92 (t, J=10.5 Hz, 1H), 2.24-2.09 (m, 1H), 1.88 (k , J=6.6 Hz, 3H), 1.85-1.76 (m, 1H), 1.66 (s, 3H), 1.63 (d, J=5.7 Hz, 2H), 1.60 (s, 3H), 1.49 (d, J= 6.5 Hz, 1H), 1.47-1.39 (m, 1H), 0.91-0.79 (m, 4H), 0.66 (ddd, J=8.8, 4.7, 3.4 Hz, 2H), 0.58-0.48 (m, 2H). MS-ESI m/z calc. 633.2733, detected 634.5 (M+1) ⁺ ; retention time: 2.27 min (LC method B).

Example 89: Preparation of (14S)-21-hydroxy-12,12-dimethyl-8-(3-{3-[1(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1-yl)-2λ ⁶ -thia -3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 265)

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Step 1: tert-butyl (4S)-4-[3-[[4-benzyloxy-6-[[2-chloro-6-[3-[3-[1(trifluoromethyl)cyclopropyl]propoxy]pyrazole-1 - yl]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

To a stirred solution of 2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1yl]pyridine-3-carboxylic acid (130 mg, 0.3335 mmol) in anhydrous tetrahydrofuran (2 ml ) carbonyldiimidazole (55 mg, 0.3392 mmol) was added and stirring was continued at ambient temperature under nitrogen atmosphere for 2 hours. A solution of tert-butyl (4S)-4-[3-[(4benzyloxy-6-sulfamoyl) was added to the reaction -2-pyridyl)amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (150 mg, 0.2892 mmol) in anhydrous tetrahydrofuran (1 ml), then 1,8-diazabicyclo[5.4.0]undec-7 -ene (200 µl, 1.337 mmol) and the mixture was stirred at ambient temperature for 15 hours. Volatiles were removed under reduced pressure and the residue was diluted with ethyl acetate (20 ml) and water (20 ml), and the mixture was slowly acidified with 4 M aqueous hydrochloric acid (350 µl 4 M, 1,400 mmol) to approximately pH 4.0. The layers were separated and the aqueous layer was extracted with ethyl acetate (15 ml). The combined organic phases were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (gradient from 0% to 70% ethyl acetate in hexanes over 35 min) to give tert-butyl (4S)-4-[3-[[4-benzyloxy-6-[[2-chloro -6-[3-[3-[1(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate ( 128 mg, 50%) as a white solid. MS-ESI m/z calc. 889.3211, detected 890.6 (M+1)+; retention time: 2.25 min (LC method G).

Step 2: N-[[4-benzyloxy-6-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2pyridyl]sulfonyl]-2-chloro-6-[3-[3 -[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3carboxamide (trifluoroacetate salt)

To a stirred solution of tert-butyl 4-[3-[[4-benzyloxy-6-[[2-chloro-6-[3-[3-[1(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin- 3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (121 mg, 0.1359 mmol) in anhydrous methylene chloride (3 ml) was added trifluoroacetic acid (500 μl, 6.490 mmol) at ambient temperature in a nitrogen atmosphere. The orange solution was stirred for 1 hour and then the volatiles were removed under reduced pressure. Toluene (20 ml) was added to the residue and concentrated to dryness under reduced pressure. The process was repeated once more to remove residual trifluoroacetic acid and finally dried under vacuum for 2 h to obtain crude N-[[4-benzyloxy-6-[3[(3S)-5,5-dimethylpyrrolidin-3-yl] propylamino]-2-pyridyl]sulfonyl]-2-chloro-6-[3-[3-[1 (trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3-carboxamide (trifluoroacetate salt) (122 mg, 99%). The material was carried directly to the next stage without any purification.

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MS-ESI m/z calc. 789.2687, detected 790.5 (M+1)+; retention time: 1.9 min (LC method B).

Step 3: (14S)-21 -(benzyloxy)-12,12-dimethyl-8-(3-{3-[ 1 -(trifluoromethyl)cyclopropyl]propoxy} 1 H-pyrazol-1 -yl)-2λ ⁶ - thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione

N-[[4-Benzyloxy-6-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2-pyridyl]sulfonyl]-2-chloro-6- was loaded into a 20 ml bottle. [3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1yl]pyridine-3-carboxamide (trifluoroacetate salt) (115 mg, 0.1272 mmol), potassium carbonate (110 mg, 0.7959 mmol) , cesium fluoride (39 mg, 0.2567 mmol) and anhydrous dimethyl sulfoxide (9 ml), in that order. The vessel was purged with a stream of nitrogen for 2 minutes, capped and stirred at 160°C for 15 hours. The reaction mixture was allowed to cool to ambient temperature and the heterogeneous mixture was diluted with ethyl acetate (40 ml) and water (30 ml) and acidified with hydrochloric acid (1.6 ml 1.0 M, 1.600 mmol). The layers were separated and the aqueous layer was re-extracted with ethyl acetate (20 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0% to 10% methanol in dichloromethane gradient over 30 min) to give (14S)-21-(benzyloxy)-12,12-dimethyl-8-(3-{3-[ 1-(trifluoromethyl)cyclononyl]propoxy}-1H-pyrazol-1-yl)-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5 ,7,9,19(23),20-hexaene-2,2,4 trione (54 mg, 56%) as a white solid. MS-ESI m/z calc. 753.29205, detected 754.5 (M+1) ⁺ ; retention time: 1.51 min (LC method J).

Step 4: (14S)-21-hydroxy-12,12-dimethyl-8-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1Hpyrazol-1-yl)-2λ ⁶ -thia-3, 9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 265)

To a stirred solution of (14S)-21-(benzyloxy)-12,12-dimethyl-8-(3-{3-[1(trifluoromethyl)cyclopropyl]propoxy} -1 H-pyrazol-1 -yl)-2λ ⁶ - thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4 trione (40 mg, 0.05306 mmol) in anhydrous methanol (5 ml) was added 10% palladium on carbon (wet, Degussa, 19 mg, 0.01785 mmol) under nitrogen atmosphere. The heterogeneous mixture was stirred in a hydrogen atmosphere (balloon) for 2.5 hours at ambient temperature. The hydrogen balloon was removed, the flask was purged with nitrogen, and the black heterogeneous reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure, the residue was dissolved in dimethyl sulfoxide (1.5 ml) and filtered through a 0.45 μm Whatman PTFE syringe disc filter. The sample was purified using preparative reverse phase HPLC-MS [Luna C ₁₈ (2) column (75x30 mm, 5 µm particle size) sold by Phenomenex (P/N: 00C-4252-U0-AX), (double gradient run 30 -99% acetonitrile in water for 15 min (without modifier)] to give (14S)-21-hydroxy-12,12-dimethyl-8-(3-{3-[1(trifluoromethyl)cyclopropyl]propoxy}-1 N-pyrazol-1 -yl)-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23), 20-hexaene-2,2,4-trione (compound 265) (16 mg, 45%) as a pale blue-green solid.

¹ H NMR (400 MHz, Methanol-d4) δ 8.25 (d, J=2.8 Hz, 1H), 7.85 (d, J=8.2 Hz, 1H), 6.97 (d, J=8.2 Hz, 1H), 6.76 ( d, J=1.9 Hz, 1H), 6.00 (d, J=1.9 Hz, 1H), 5.97 (d, J=2.8 Hz, 1H), 4.24 (t, J=6.1 Hz, 2H), 4.01 (t, J=12.8 Hz, 1H), 3.36-3.32 (m, 1H), 3.02 (d, J=13.6 Hz, 1H), 2.94 (t, J=10.5 Hz, 1H), 2.24-2.08 (m, 1H), 1.94 (dk, J=11.0, 6.3 Hz, 2H), 1.90-1.79 (m, 2H), 1.78 (d, J=4.6 Hz, 1H), 1.77-1.74 (m, 1H), 1.66 (s, 3H) , 1.63 (d, J=7.0 Hz, 2H), 1.60 (s, 3H), 1.58 (d, J=7.9 Hz, 1H), 1.51-1.36 (m, 1H), 0.98-0.92 (m, 2H), 0.73-0.65 (m, 2H). ¹⁹ F NMR (376 MHz, methanol-d4) δ -70.92. MS-ESI m/z calc. 663.24506, detected 665.5 (M+1) ⁺ ; retention time: 2.13 min (LC method B).

Example 90: Preparation of 2-imino-12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-2λ ⁶ -thia-3,9,11 ,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23), 5,7,9,19,21 hexaene-2,4-dione (diastereomer pair 1, enantiomer 1) (compound 266) , 2-imino-12,12-dimethyl-8-(3{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-2Х ⁶ -thia-3,9,11, 18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23), 5,7,9,19,21-hexaene-2,4-dione (pair of diastereomers 1, enantiomer 2) (compound 267), 2 -imino-12,12-dimethyl-8-(3-{2-[1- 333 044967 (trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-2λ ⁶ -tua-3,9,11 ,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23), 5,7,9,19,21-hexaene-2,4-dione (pair of diastereomers 2, enantiomer 1) (compound 271) and 2-imino-12,12-dimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ ⁶ -thua-3,9,11,18, 23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23), 5,7,9,19,21-hexaene-2,4-dione (diastereomer pair 2, enantiomer 2) (compound 272)

Step 1: 2-imino-12,12-dimethyl-8-(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 yl)-2λ ⁶ -thia-3,9, 11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,4dione (pair of diastereomers 1, enantiomer 1)(compound 266) and 2-imino-12,12-dimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ ⁶ -thia-3,9,11,18 ,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,4-dione (pair of diastereomers 1, enantiomer 2)(compound 267)

Racemic 2-imino-12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-2λ ⁶ -thia-3,9,11,18, 23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,4dione (81 mg, 0.1248 mmol) (diastereomer pair 1) (81 mg) were subjected to chiral SCLC (ChiralPak AD-H (250x10 mm), 5 µM column; mobile phase 34% acetonitrile/methanol (50:50, 20 mM NH ₃ ), 66% carbon dioxide, 10 ml/min; concentration 12 mg/ml in acetonitrile/methanol (50:50 20 mM NH3); injection volume 70 µl, 100 bar) to give 2-imino12,12-dimethyl-8-(3-{2-[1-) as the first eluting enantiomer (trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7 ,9,19,21-hexaene-2,4-dione (diastereomer pair 1, enantiomer 1) (compound 266) (15.2 mg, 38%), ^1H NMR (400 MHz, DMSO-06) δ 8.14 ( d, J=2.7 Hz, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.54-7.43 (m, 1H), 7.03 (t, J=6.8 Hz, 2H), 6.77 (d, J=8.1 Hz, 1H), 6.54 (d, J=8.4 Hz, 1H), 6.00 (d, J=2.6 Hz, 1H), 4.24 (t, J=7.0 Hz, 2H), 3.17 (dd, J=10.8, 7.3 Hz, 1H), 2.12 (s, 1H), 2.05-1.99 (m, 2H), 1.82 (s, 2H), 1.53 (d, J=26.0 Hz, 9H), 1.23 (d, J=51.9 Hz, 4H ), 0.85 (d, J=28.0 Hz, 4H); MS-ESI m/z calc. 632.2505, detected 633.0 (M+1)+; Retention time: 3.16 min (LC method D); and as the second eluting enantiomer, 2-imino-12,12-dimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ ⁶ -tua-3, 9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,4-dione (pair of diastereomers 1, enantiomer 2) (compound 267) (15 mg, 38%).

¹ H NMR (400 MHz, dimethyl sulfoxide-b6) δ 8.21 (s, 1H), 7.82 (d, J=8.1 Hz, 1H), 7.53 (s, 1H), 7.09 (s, 2H), 6.83 (d, J =8.1 Hz, 1H), 6.60 (d, J=8.3 Hz, 1H), 6.07 (s, 1H), 4.30 (s, 2H), 3.48 (s, 1H), 3.24 (s, 1H), 2.20 (s , 1H), 2.07 (d, J=14.1 Hz, 2H), 1.87 (s, 2H), 1.59 (d, J=25.3 Hz, 8H), 1.35 (s, 1H), 1.23 (s, 2H), 0.92 (d, J=27.7 Hz, 4H). MS-ESI m/z calc. 632.2505, detected 633.0 (M+1) ⁺ ; Retention time: 3.18 min (LC method D).

Step 2: 2-imino-12,12-dimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1 yl)-2λ ⁶ -thia-3,9,11 ,18,23-πpentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,4dione (pair of diastereomers 2, enantiomer 1)(compound 271) and 2-imino-12,12-dimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ ⁶ -thua-3,9,11,18, 23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,4-dione (pair of diastereomers 2, enantiomer 2) (compound 272)

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Racemic 2-imino-12,12-dimethyl-8-(3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol1-yl)-2λ ⁶ -tua-3,9,11,18 ,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,4dione (diastereomer pair 2) (91 mg) was subjected to chiral SCLC (Phenomenex LUX -4 (250x21.2 mm), 5 µM column; mobile phase 40% acetonitrile/methanol (90:10, 20 mM NH3), 60% carbon dioxide, 70 ml/min; concentration 15 mg/ml in acetonitrile/methanol ( 90:10; 20 mM NH3); injection volume 700 µl, 100 bar). The first enantiomer was further eluted by preparative reverse phase chromatography using a C column for ₁₈ and 15 minutes. eluent gradient from 50% to 99% acetonitrile in water containing 10 mM ammonium formate to give 2-imino-12,12-dimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1H -pyrazol-1-yl)-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene- 2,4-dione (diastereomer pair 2, enantiomer 1) (compound 271) (22.4 mg, 50%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.19 (d, J=2.7 Hz, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.59-7.53 (m, 1H), 7.41 (s, 2H ), 7.05 (d, J=7.2 Hz, 1H), 6.86 (t, J=9.5 Hz, 2H), 6.65 (d, J=8.4 Hz, 1H), 4.31 (t, J=7.0 Hz, 2H), 4.08-3.92 (m, 1H), 3.20 (s, 1H), 2.89 (t, J=10.8 Hz, 2H), 2.08 (k, J=7.0, 6.0 Hz, 3H), 1.86-1.72 (m, 2H) , 1.55 (d, J=27.1 Hz, 10H), 1.31 (d, J=11.4 Hz, 1H), 0.92 (d, J=28.7 Hz, 5H). MS-ESI m/z calc. 632.2505, detected 633.0 (M+1)+; retention time: 3.02 min (LC method D).

The second enantiomer eluted after SCLC separation was 2-imino-12,12-dimethyl-8-(3-{2[ 1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -ul)-2λ ⁶ - thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,4-dione (para 2 diastereomer, enantiomer 2) (compound 272) (29.8 mg, 67%).

¹ H NMR (400 MHz, dimethyl sulfoxide-a ₆ ) δ 8.19 (d, J=2.6 Hz, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.60-7.52 (m, 1H), 7.41 (s, 2H), 7.05 (d, J=7.2 Hz, 1H), 6.85 (dd, J=12.7, 8.7 Hz, 2H), 6.64 (d, J=8.4 Hz, 1H), 6.06 (d, J=2.6 Hz, 1H), 4.31 (s, 2H), 3.99 (d, J=11.5 Hz, 1H), 3.20 (s, 1H), 2.91 (d, J=10.9 Hz, 2H), 2.08 (t, J=7.0 Hz, 3H), 1.88-1.71 (m, 2H), 1.55 (d, J=27.0 Hz, 9H), 1.31 (d, J=11.2 Hz, 1H), 0.92 (d, J=29.2 Hz, 4H). MS-ESI m/z calc. 632.2505, detected 633.0 (M+1) ⁺ ; Retention time: 3.07 min (LC method D).

Example 91: preparation of (14S)-12,12-dimethyl-8-(3-{3-[1-(trifluoromethyl)cyclopropyl]-3,3-dideuteropropoxy}-1H-pyrazol-1 -yl)-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5(10),6,8,19(23),20-hexaene-2,2, 4-trione (compound 269)

Step 1: dideutero-[1-(trifluoromethyl)cyclopropyl]methanol

To a suspension of lithium aluminum deuteride (2.86 g, 71.563 mmol) in anhydrous tetrahydrofuran (100 ml), a solution of 1-(trifluoromethyl)cyclopropanecarboxylic acid (10 g, 64.898 mmol) in anhydrous tetrahydrofuran (50 ml) was added dropwise at 0° WITH. The reaction mixture was stirred at room temperature for 16 hours. The reaction was diluted with diethyl ether (100 ml) and quenched with water (2.9 ml), 15% sodium hydroxide (2.9 ml) and water (8.7 ml) successively at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. The white solid was filtered through a pad of celite.

The filtrate was concentrated in vacuo to give dideutero[1(trifluoromethyl)cyclopropyl]methanol (10.855 g, 86%) as a clear liquid.

1H NMR (250 MHz, CDCl ₃ ) δ 1.72 (s, 1H), 1.03 (m, 2H), 0.79 (m, 2H).

Step 2: [dideutero-[1-(trifluoromethyl)cyclopropyl]methyl]methanesulfonate

D D D D

To a solution of dideutero-[1-(trifluoromethyl)cyclopropyl]methanol (8.537 g, 54.064 mmol) and triethylamine (10.942 g, 15.072 ml, 108.13 mmol) in dichloromethane (100 ml) was added methanesulfonyl chloride (7.4318 g, 5. 0215 ml, 64.877 mmol) dropwise at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with 10% citric acid (50 ml), saturated sodium bicarbonate (50 ml) and brine (50 ml). The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0% to 70% diethyl ether in hexane to give [dideutero-[1-(trifluoromethyl)cyclopropyl]methyl]methanesulfonate (11.203 g, 88%) as a clear liquid.

¹ H NMR (250 MHz, CDCl ₃ ) 5 3.06 (s, 3H), 1.21 (m, 2H), 1.02-0.81 (m, 2H).

Step 3: 2,2-dideutero-2-[1-(trifluoromethyl)cyclopropyl]acetonitrile.

D D D D

To a solution of [dideutero-[1-(trifluoromethyl)cyclopropyl]methyl]methanesulfonate (11.203 g, 47.823 mmol) in dimethyl sulfoxide (55 ml) was added sodium cyanide (2.9296 g, 59.779 mmol). The reaction mixture was stirred at 70°C for 24 hours. After cooling to room temperature, water (50 ml) and diethyl ether (50 ml) were added to the reaction mixture. The two layers were separated. The aqueous layer was extracted with diethyl ether (2 x 70 ml). The combined organic layers were washed with water (2x50 ml) and brine (50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 2,2-dideutero-2-[1-(trifluoromethyl)cyclopropyl]acetonitrile (6.828 g , 84%) in the form of a yellow liquid.

¹ H NMR (250 MHz, CDCl ₃ ) δ 1.18 (m, 2H), 0.93 (s, 2H).

Step 4: 2,2-dideutero-2-[1-(trifluoromethyl)cyclopropyl]acetic acid

D D D D

To a solution of 2,2-dideutero-2-[1-(trifluoromethyl)cyclopropyl]acetonitrile (6.828 g, 40.211 mmol) in _CH3CwaterD (70 ml) was added a solution of sodium deuteroxide (16.487 g, 40% w/w 160.84 mmol) in deuterium oxide (16 ml). The reaction mixture was stirred at 70°C for 24 hours. After cooling to room temperature, CH ₃ CwaterD was removed under reduced pressure. The solvent was diluted with water (70 ml) and washed with diethyl ether (2x50 ml). The aqueous layer was acidified with 6 N. hydrochloric acid to pH 1 and then extracted with diethyl ether (3x70 ml). The combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 2,2-dideutero-2-[1(trifluoromethyl)cyclopropyl]acetic acid (6.387 g, 83%) in in the form of a yellow liquid.

1H NMR (250 MHz, CDCl3) δ 1.18-1.05 (m, 2H), 0.93-0.79 (m, 2H).

Step 5: 2,2-dideutero-2-[1-(trifluoromethyl)cyclopropyl]ethanol.

D D D D

F ₃ CX<.OH -----> F ₃ cX<^OH

ΔΔ _o ΔΔ

A solution of 2,2-dideutero-2-[1-(trifluoromethyl)cyclopropyl]acetic acid (3, 35 g, 19.297 mmol) in anhydrous tetrahydrofuran (50 ml) at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with diethyl ether (50 ml) and cooled to 0°C. Water (1 ml), 15% aqueous sodium hydroxide (1 ml) and water (3 ml) were added successively and the resulting mixture was stirred at room temperature for 15 minutes. Anhydrous magnesium sulfate was added and the reaction mixture was stirred at room temperature for an additional 15 minutes. The solids were filtered off and the filtrate was concentrated in vacuo to give 2,2-dideutero-2-[1-(trifluoromethyl)cyclopropyl]ethanol (3.154 g, 84%) as a clear liquid.

1H NMR (250 MHz, CDCl3) δ 3.79 (s, 2H), 1.05-0.78 (m, 2H), 0.78-0.41 (m, 2H).

Step 6: [2,2-dideutero-2-[1-(trifluoromethyl)cyclopropyl]ethyl]methanesulfonate

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To a solution of 2,2-dideutero-2-[1-(trifluoromethyl)cyclopropyl]ethanol (3.154 g, 16.160 mmol) in dichloromethane (32 mL) was added triethylamine (4.9057 g, 6.7572 mL, 48.480 mmol). The reaction mixture was cooled to 0°C and methanesulfonyl chloride (2.2214 g, 1.5009 ml, 19.392 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with dichloromethane (50 ml) and washed with 10% aqueous citric acid (50 ml), saturated sodium bicarbonate (50 ml) and brine (50 ml). The solution was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 0% to 50% diethyl ether in hexane to give [2,2dideutero-2-[1-(trifluoromethyl)cyclopropyl]ethyl]methanesulfonate (3.28 g, 82%) as clear liquid.

¹ H NMR (250 MHz, CDCl3) δ 4.36 (s, 2H), 3.20-2.87 (s, 3H), 1.15-0.94 (m, 2H), 0.79-0.59 (m, 2H).

Step 7: 3,3-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propanenitrile

Sodium cyanide (858 mg, 16.6 mmol) was added to a solution of [2,2-dideutero-2-[1-(trifluoromethyl)cyclopropyl]ethyl]methanesulfonate (3.28 g, 13.303 mmol) in dimethyl sulfoxide (17 mL). The reaction mixture was stirred at 70°C for 16 hours. After cooling to room temperature, the reaction mixture was poured into water (30 ml). The mixture was extracted with diethyl ether (3x50 ml). The combined organic layers were washed with water (2x30 ml) and brine (50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 3,3-dideutero3-[1-(trifluoromethyl)cyclopropyl]propanenitrile (2.267 g, 99%) in the form of a clear liquid.

Ή NMR (250 MHz, CDCl3) δ 2.54 (s, 2H), 1.14-1.00 (m, 2H), 0.80-0.66 (m, 2H).

Step 8: 3,3-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propanoic acid.

To a solution of 3,3-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propanenitrile (2.267 g, 13.178 mmol) in ethanol (34 ml) was added a solution of sodium hydroxide (2.1083 g, 52.712 mmol) in water (9 ml ). The reaction mixture was stirred at 70°C for 20 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo, then diluted with water (30 ml). The aqueous solution was washed with diethyl ether (2x30 ml) and then acidified with 6N. hydrochloric acid (aqueous) to pH 1. The aqueous solution was extracted with diethyl ether (3x50 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 3,3-dideutero-3-[1(trifluoromethyl)cyclopropyl]propanoic acid (2.652 g, 92%) in in the form of a light yellow liquid.

¹ H NMR (250 MHz, CDCl ₃ ) δ 2.55 (s, 2H), 1.07-0.82 (m, 2H), 0.61 (m, 2H).

Step 9: 3,3-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propan-1-o l

To a suspension of lithium aluminum hydride (628 mg, 14.940 mmol) in anhydrous tetrahydrofuran (20 ml) was added a solution of 3,3-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propanoic acid (2.652 g, 12.097 mmol) in anhydrous tetrahydrofuran (20 ml) at 0°C drop by drop. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with diethyl ether (20 ml) and cooled to 0°C. Water (0.63 ml), 15% aqueous sodium hydroxide (0.63 ml) and water (1.9 ml) were sequentially added to the reaction mixture. The reaction mixture was stirred at room temperature for 15 minutes, then magnesium sulfate was added and the reaction mixture was stirred for another 15 minutes at room temperature. The white precipitate was filtered off. The filtrate was concentrated under reduced pressure to give 3,3-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol (1.78 g, 82%) as a clear liquid.

¹ H NMR (250 MHz, DMSO-de) δ 4.45 (t, J=5.1 Hz, 1H), 3.46-3.36 (m, 2H), 1.50 (t, J=6.2 Hz, 2H), 0.86 (m, 2H ), 0.69 (m, 2H).

10: tert-butyl

Carboxylate stage

3-[3,3-dideutero-3 - [1 -(trifluoromethyl)cyclopropyl]propoxy]pyrazole-1 -

- 337 044967

To a solution of tert-butyl-5-oxo-1H-pyrazole-2-carboxylate (910 mg, 4.940 mmol) and 3,3-dideutero-3[1-(trifluoromethyl)cyclopropyl]propan-1-ol (880 mg, 5.171 mmol) in tetrahydrofuran (11.25 ml), triphenylphosphine (1.36 g, 5.185 mmol) was added. Diisopropyl azodicarboxylate (1.05 g, 5.193 mmol) was added slowly dropwise to the mixture over 5 min. The reaction mixture was stirred at room temperature for 30 minutes. Tetrahydrofuran was removed in vacuo. The crude product was purified by silica gel chromatography using a shallow gradient from 100% hexane to 20% ethyl acetate in hexane to give tert-butyl-3-[3,3-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazole-1 -carboxylate (1.1 g, 66%) as a colorless oil.

1H NMR (400 MHz, chloroform-d) δ 7.83 (d, J=3.0 Hz, 1H), 5.85 (d, J=3.0 Hz, 1H), 4.27 (t, J=6.2 Hz, 2H), 1.90 (t , J=6.4 Hz, 2H), 1.61 (s, 9H), 1.00-0.91 (m, 2H), 0.64-0.50 (m, J=1.6 Hz, 2H). MS-ESI m/z calc. 336.163, found 337.2 (M+1)+; Retention time: 2.03 min (LC method E).

Step 11: 3-[3,3-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]-1H-pyrazole

To a flask containing tert-butyl 3-[3,3-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazole-1-carboxylate (1.1 g, 3.270 mmol) was added dichloromethane (22 ml) and trifluoroacetic acid (6.3 ml, 81.77 mmol). After 30 minutes, the mixture was evaporated to dryness and neutralized with saturated aqueous sodium bicarbonate. The reaction mixture was extracted with ethyl acetate and the organic layer was dried over sodium sulfate, filtered and evaporated to give 3-[3,3-dideutero-3-[1(trifluoromethyl)cyclopropyl]propoxy]-1H-pyrazole (762 mg, 99%) in in the form of a colorless oil. MS-ESI m/z calc. 236.11055, detected 237.2 (M+1) ⁺ ; Retention time: 1.43 min (LC method E).

Step 12: tert-butyl 2-chloro-6-[3-[3,3-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridine-3-carboxylate

tert-Butyl 2,6-dichloropyridine-3-carboxylate (800 mg, 3.224 mmol), 3-[3,3-dideutero-3-[1(trifluoromethyl)cyclopropyl]propoxy]-1H-pyrazole (762 mg, 3.226 mmol ) and potassium carbonate (1.1 g, 7.959 mmol) were combined in anhydrous dimethyl sulfoxide (22.0 ml). 1,4-Diazabicyclo[2.2.2]octane (72.5 mg, 0.6463 mmol) was added and the mixture was stirred at room temperature under nitrogen for 18 hours. The reaction mixture was diluted with water (16 ml) and stirred for 15 min. The resulting solid was filtered, collected and dried under high vacuum. The remaining filtrate was diluted with ethyl acetate and washed with water (3x20 ml). The organic layers were combined and washed with brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 100% hexanes to 60% ethyl acetate in hexanes to give a light yellow oil, which was then dried in vacuo to give a pale yellow solid. This purified solid and the solid after initial filtration were combined to give tert-butyl-2-chloro-6-[3-[3,3-dideutero-3[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl] pyridine-3-carboxylate (1.36 g, 94%).

1H NMR (400 MHz, chloroform-d) δ 8.35 (d, J=2.8 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 5.95 (d , J=2.8 Hz, 1H), 4.26 (t, J=6.2 Hz, 2H), 1.95 (t, J=6.2 Hz, 2H), 1.62 (s, 9H), 1.02-0.94 (m, 2H), 0.660 .55 (m, J=1.8 Hz, 2H). MS-ESI m/z calc. 447.15054, found 448.2 (M+1) ⁺ ; Retention time: 2.49 min (LC method E).

Step 13: 2-chloro-6-[3-[3,3-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1yl]pyridine-3-carboxylic acid

tert-Butyl-2-chloro-6-[3-[3,3-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1yl]pyridine-3-carboxylate (1.36 g, 3.037 mmol) dissolved in dichloromethane (30 ml). Trifluoroacetic acid (5.0 mL, 64.90 mmol) was slowly added to the mixture and the mixture continued to stir at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to a solid, which was then suspended in diethyl ether and filtered, then the solid

- 338 044967 the material was resuspended in diethyl ether and filtered to give a solid, which was recrystallized from dichloromethane, then dried in vacuo for 20 hours to give 2-chloro-6-[3[3,3-dideutero-3 -[ 1 -(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3-carboxylic acid (1.055 g, 89%) as a white solid. MS-ESI m/z calc. 391.08795, detected 392.2 (M+1)+; Retention time: 1.35 min (LC method E).

Step 14: tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-[3,3-dideutero-3-[1(trifluoromethyl)cyclopropyl]propoxy]pyrazol- 1 -yl]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

2-Chloro-6-[3-[3,3-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (250 mg, 0.6381 mmol) and freshly recrystallized carbonyldiimidazole (120 mg, 0.7401 mmol) were combined in tetrahydrofuran (6.0 ml) and stirred for 2 hours at room temperature. Then tert-butyl (4S)-2,2-dimethyl-4-[3-[(6-sulfamoyl-2pyridyl)amino]propyl]pyrrolidine-1-carboxylate (303 mg, 0.7345 mmol) was added followed by anhydrous 1,8-diazabicyclo[5.4.0]undec-7-ene (240 µl, 1.605 mmol), and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and then saline solution. The organic layer was separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate to give tert-butyl (4S)-4[3-[[6-[[2 -chloro-6-[3-[3,3-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2 ,2-dimethylpyrrolide in-1-carboxylate (259 mg, 52%) as a white solid. MS-ESI m/z calc. 785.2918, detected 786.2 (M+1) ⁺ ; Retention time: 2.06 min (LC method E).

Step 15: (14S)-12,12-dimethyl-8-(3-{3-[1-(trifluoromethyl)cyclopropyl]-3,3-dideuteropropoxy}1H-pyrazol-1-yl)-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5(10),6,8,19(23),20-hexaene-2,2, 4-trione (compound 269)

tert-Butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-[3,3-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazole-1 - yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1 carboxylate (228 mg, 0.2900 mmol) was dissolved in dichloromethane (7 ml) and trifluoroacetic acid was added to the mixture (900 µl, 11.68 mmol) and stirred at room temperature for 15 min. The mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate and then aqueous saturated sodium bicarbonate (10 ml) was added. The layers were separated and the aqueous layer was further extracted with ethyl acetate (2x10 ml). The combined organic layers were washed with brine, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. Combine the resulting material and potassium carbonate (205 mg, 1.483 mmol), 3 A molecular sieves and dimethyl sulfoxide (9.5 ml) in a vial, purged with nitrogen, cap, heat to 150 ° C and stir for 16 hours. Cool to room temperature and the mixture was filtered, diluted with ethyl acetate and washed with water (2x20 ml), followed by saline. The organic layer was further washed with water (1x), then dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient of 100% hexanes to 100% ethyl acetate followed by a second silica gel column chromatography using a gradient of 100% dichloromethane to 10% methanol in dichloromethane to give (14S)-12,12-dimethyl- 8-(3-{3-[1(trifluoromethyl)cyclopropyl]-3,3-dideuteropropoxy}-1H-pyrazol-1-yl)-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111 ,14.05,10]tetracose-1(22),5 (10), 6,8,19(23),20-hexaene-2,2,4-trione (compound 269) (44.8 mg, 24%) as a white solid.

1H NMR (400 MHz, DMSO-46) δ 12.51 (s, 1H), 8.21 (d, J=2.8 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.57 (t, J=7.9 Hz , 1H), 7.05 (d, J=7.2 Hz, 1H), 6.98 (s, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.6 Hz, 1H), 6.12 (d , J=2.8 Hz, 1H), 4.20 (t, J=6.3 Hz, 2H), 3.92 (d, J=12.0 Hz, 1H), 3.17 (d, J=5.2 Hz, 1H), 2.95 (d, J =13.3 Hz, 1H), 2.69 (d, J=15.6 Hz, 1H), 2.10 (d, J=18.7 Hz, 1H), 1.83 (t, J=6.2 Hz, 3H), 1.79-1.69 (m, 1H ), 1.60 (s, 4H), 1.57 (d, J=12.5 Hz, 2H), 1.51 (s, 3H), 1.37-1.22 (m, 2H), 0.93-0.89 (m, 2H), 0.75 (t, J=1.6 Hz, 2H). MS-ESI m/z calc.

- 339 044967

649.2627, detected 650.2 (M+1)+; retention time: 2.27 min (LC method E).

Example 92: Preparation of (14S)-12,12-dimethyl-8-(3-{3-[1-(trifluoromethyl)cyclopropyl]-2,2-dideuteropropoxy}-1H-pyrazol-1-yl)-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (connection 270)

Step 1: 1,1-dideutero-2-[1-(trifluoromethyl)cyclopropyl]ethanol.

To a suspension of lithium aluminum deuteride (1.0265 g, 25.684 mmol) in anhydrous tetrahydrofuran (50 ml) was added a solution of 2-[1-(trifluoromethyl)cyclopropyl]acetic acid (3.954 g, 19.757 mmol) in anhydrous tetrahydrofuran (50 ml) drop by drop at 0°C. The reaction mixture was stirred at room temperature for an additional 16 hours. The reaction mixture was diluted with diethyl ether (50 ml) and cooled to 0°C. Water (1 ml), 15% sodium hydroxide (aq) (1 ml) and water (3 ml) were added to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 15 minutes. Anhydrous magnesium sulfate was added to the reaction mixture. The reaction mixture was stirred for another 15 minutes. The white precipitate was removed by suction filtration and the solvent was removed under reduced pressure to give 1,1-dideutero-2-[1-(trifluoromethyl)cyclopropyl]ethanol (3.629 g, 82%) as a light yellow oil.

^1H NMR (250 MHz, chloroform-d) δ 1.83 (s, 2H), 1.43 (s, 1H), 1.04-0.91 (m, 2H), 0.72-0.62 (m, 2H).

Step 2: [1,1-dideutero-2-[1-(trifluoromethyl)cyclopropyl]ethyl]methanesulfonate

To a solution of 1,1-dideutero-2-[1-(trifluoromethyl)cyclopropyl]ethanol (3.629 g, 16.269 mmol) in dichloromethane (36 mL) was added triethylamine (4.9388 g, 6.8028 mL, 48.807 mmol). The mixture was cooled to 0°C. Methanesulfonyl chloride (2.2364 g, 1.5111 mL, 19.523 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane (100 ml) and washed with 10% aqueous citric acid (30 ml), saturated aqueous sodium bicarbonate (30 ml) and brine (30 ml). The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using a gradient of 0% to 70% diethyl ether in hexane to give [1,1-dideutero-2-[1-(trifluoromethyl)cyclopropyl]ethyl]methanesulfonate (3.413 g, 90%) as clear liquid.

1H NMR (250 MHz, chloroform-d) δ 3.02 (s, 3H), 2.02 (s, 2H), 1.14-0.95 (m, 2H), 0.81-0.63 ( m, 2H).

Step 3: 2,2-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propanenitrile

To a solution of [1,1-dideutero-2-[1-(trifluoromethyl)cyclopropyl]ethyl]methanesulfonate (3.413 g, 14.571

- 340 044967 mmol) in dimethyl sulfoxide (17 ml) sodium cyanide (892.62 mg, 18.214 mmol) was added. The reaction mixture was stirred at 70°C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water (30 ml) and extracted with diethyl ether (3x30 ml). The combined organic layers were washed with water (2x30 ml) and brine (30 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 0% to 50% diethyl ether in pentane to give 2,2dideutero-3-[1-(trifluoromethyl)cyclopropyl]propanenitrile (2.181 g, 81%) as a clear liquid.

1H NMR (250 MHz, chloroform-d) δ 1.92 (s, 2H), 1.14-1.01 (m, 2H), 0.74 (m, 2H).

Step 4: 2,2-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propanoic acid.

To a solution of 2,2-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propanenitrile (2.181 g, 11.753 mmol) in CH ₃ CwaterD (30 ml) was added D2O (4 ml) and sodium deuteroxide in D2O (4.8191 g , 40% by weight, 47.012 mmol). The reaction mixture was stirred at 70°C for 20 hours. CH ₃ CwaterD was removed under reduced pressure. The resulting solution was diluted with D2O (20 ml) and washed with diethyl ether (2x20 ml). Then the aqueous solution was acidified with 6 N. hydrochloric acid to pH 1 and then extracted with diethyl ether (3x20 ml). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 2,2-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propanoic acid (1.945 g, 89%) in the form of an amber liquid.

^1H NMR (250 MHz, chloroform-d) δ 1.89 (s, 2H), 1.10-0.88 (m, 2H), 0.75-0.52 (m, 2H).

Step 5: 2,2-dideutero-3-G 1 -(trifluoromethyl)cyclopropyl]propan-1-ol

To a suspension of lithium aluminum hydride (521.15 mg, 0.5683 ml, 13.731 mmol) in anhydrous tetrahydrofuran (20 ml), a solution of 2,2-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propanoic acid (1.945 g) was added dropwise , 10.562 mmol) in tetrahydrofuran (20 ml) at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The reaction was diluted with diethyl ether (30 ml) and quenched with water (0.53 ml), 15% aqueous sodium hydroxide (0.53 ml) and water (1.59 ml) at 0°C. The reaction mixture was stirred at room temperature for 30 minutes, and then anhydrous magnesium sulfate was added and stirred for another 15 minutes. The solid was filtered off and the filtrate was concentrated in vacuo to give 2,2-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol (1.423 g, 75%) as a clear liquid.

1H NMR (250 MHz, DMSO-d6) δ 4.44 (t, J=5.1 Hz, 1H), 3.38 (s, 2H), 1.57 (s, 2H), 0.87 (t, J=5.8 Hz, 2H), 0.69 (s, 2H).

Step 6: tert-butyl 3-[2,2-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazole-1carboxylate

To a solution of tert-butyl 5-oxo-1H-pyrazole-2-carboxylate (775 mg, 4.208 mmol) and 2,2-dideutero-3[1-(trifluoromethyl)cyclopropyl]propan-1-ol (750 mg, 4.407 mmol ) in tetrahydrofuran (10 ml), triphenylphosphine (1.156 g, 4.407 mmol) was added. Diisopropyl azodicarboxylate (870 μL, 4.419 mmol) was added slowly dropwise to the mixture over 10 min. The reaction mixture was stirred at room temperature for 30 minutes, then at 50°C for 30 minutes. Tetrahydrofuran was removed and the residue was purified by silica gel chromatography using a shallow gradient of 100% hexanes to 20% ethyl acetate in hexanes to give tert-butyl-3-[2,2-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazole -1-carboxylate (0.998 g, 71%) as a colorless oil.

1H NMR (400 MHz, chloroform-d) δ 7.83 (d, J=2.9 Hz, 1H), 5.85 (d, J=2.9 Hz, 1H), 4.26 (s, 2H), 1.70 (s, 2H), 1.61 (s, 9H), 0.99-0.93 (m, 2H), 0.62-0.56 (m, 2H). MS-ESI m/z calc. 336.163, detected 337.2 (M+1)+; retention time: 1.96 min (LC method B).

Step 7: 3-[2,2-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]-1H-pyrazole

- 341 044967

To a round bottom flask containing tert-butyl 3-[2,2-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazole-1-carboxylate (998 mg, 2.967 mmol), add dichloromethane (20 mL) and trifluoroacetic acid (5.7 ml, 73.98 mmol). After 5 min, the reaction mixture was evaporated to dryness and neutralized with saturated sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate, the organic layer was dried over sodium sulfate, filtered and evaporated to obtain 3-[2,2dideutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]-1H-pyrazole (700 mg, 100%) as colorless oils

¹ H NMR (400 MHz, chloroform-d) δ 7.36 (d, J=2.6 Hz, 1H), 5.73 (d, J=2.5 Hz, 1H), 4.13 (d, J=1.6 Hz, 2H), 1.72 ( s, 2H), 0.99-0.93 (m, 2H), 0.63-0.56 (m, 2H). MS-ESI m/z calc. 236.11055, found 237.1 (M+1)+; Retention time: 1.41 min (LC method B).

Step 8: tert-butyl 2-chloro-6-[3-[2,2-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3-carboxylate

A mixture of 3-[2,2-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]-1H-pyrazole (700 mg, 2.963 mmol), tert-butyl 2,6-dichloropyridine-3-carboxylate (742 mg, 2.991 mmol), potassium carbonate (501 mg, 3.625 mmol) and 1,4-diazabicyclo[2.2.2]octane (71 mg, 0.6330 mmol) in dimethyl sulfoxide (5 ml) were stirred at room temperature for 15 hours. The reaction diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. The resulting residue was purified by silica gel column chromatography with a gradient of 100% hexane to 20% ethyl acetate in hexane to give tert-butyl 2-chloro-6-[3-[2,2dideutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy] pyrazol-1-yl]pyridin-3-carboxylate (472 mg, 36%) as a white solid.

1H NMR (400 MHz, chloroform-d) δ 8.35 (d, J=2.8 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 5.95 (d , J=2.8 Hz, 1H), 4.25 (s, 2H), 1.74 (s, 2H), 1.61 (s, 9H), 1.02-0.94 (m, 2H), 0.63-0.57 (m, 2H). MSIE m/z calc. 447.15054, found 448.23 (M+1) ⁺ ; Retention time: 0.95 min (LC method A).

Step 9: tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-[2,2-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazole -1-yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate

Tert-Butyl 2-chloro-6-[3-[2,2-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3-carboxylate solution (250 mg, 0.5582 mmol) in dichloromethane (1.5 ml) and trifluoroacetic acid (500 μl, 6.490 mmol) were stirred at room temperature for 4 hours. The solvents were then removed and the residue was dried in vacuo. The resulting residue was dissolved in tetrahydrofuran (2 ml) and carbonyldiimidazole (102 mg, 0.6291 mmol) was added and the mixture was stirred for 2 hours at room temperature. Tert-butyl (4S)-2,2-dimethyl-4-[3-[(6-sulfamoyl-2pyridyl)amino]propyl]pyrrolidine-1-carboxylate (255 mg, 0.6181 mmol) was then added followed by 1 ,8-diazabicyclo[5.4.0]undec-7-ene (130 μL, 0.8693 mmol) and the reaction mixture was stirred for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with a small amount of 1:1 saturated aqueous ammonium chloride/saline solution solution. The organic phases were separated, dried over sodium sulfate, filtered and evaporated. The resulting brown residue was purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate to give tert-butyl (4S)-4-[3-[[6-[ [2-chloro-6-[3-[ 2,2-dideutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2dimethylpyrrolidine-1-carboxylate ( 172 mg, 39%) as a white solid. MS-ESI m/z calc. 785.2918, detected 786.4 (M+1) ⁺ ; retention time: 0.93 min (LC method A).

Step 10: (14S)-12,12-dimethyl-8-(3-{3-[1-(trifluoromethyl)cyclopropyl]-2,2-dideuteropropoxy}1 H-pyrazol-1 -yl)-2λ ⁶ -thiα-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (connection 270)

- 342 044967

tert-butyl (48)-4-[3-[[6-[[2-chloro-6-[3-[2,2-dideutero-3-[1Solution of (trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl ]pyridine-3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (170 mg, 0.2162 mmol) in dichloromethane (1.2 ml) and trifluoroacetic acid (400 μl, 5.227 mmol) was stirred at room temperature for 4 hours. The solvents were then removed and the residue was dissolved in ethyl acetate. The mixture was washed with 2 ml saturated sodium bicarbonate solution, the organic layer was collected and the solvent was removed in vacuo. The resulting residue was dissolved in dimethyl sulfoxide (8 ml), 3 A molecular sieves were added and the reaction mixture was stirred for 10 minutes. Cesium fluoride (101 mg, 0.6649 mmol) and potassium carbonate (96 mg, 0.6946 mmol) were then added and the reaction mixture was heated at 150°C for 16 hours. The reaction mixture was filtered through a Whatman filter disc (puradisc 25 TF), and the filtrate was purified by reverse phase HPLC-MS using a dual gradient from 30% to 99% mobile phase B over 15.0 min (mobile phase A = water (0.05% hydrochloric acid), mobile phase B =acetonitrile) to give (14S)-12,12-dimethyl-8-(3-{3-[1-(trifluoromethyl)cyclopropyl]-2,2dideuteropropoxy} -1 H-pyrazol-1 -yl)-2λ ⁶ - thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23),5(10),6,8,19,21-hexaene-2,2,4-trione ( compound 270) (62.4 mg, 44%) as an off-white solid.

1H NMR (400 MHz, chloroform-d) δ 9.87 (s, 1H), 8.19 (d, J=2.8 Hz, 1H), 8.04 (d, J=8.3 Hz, 1H), 7.567.44 (m, 2H) , 7.23 (d, J=8.4 Hz, 1H), 6.55 (dd, J=8.2, 1.0 Hz, 1H), 5.91 (d, J=2.8 Hz, 1H), 4.71 (dd, J=8.6, 3.4 Hz, 1H), 4.24 (s, 2H), 3.89 (s, 1H), 3.33 (dd, J=10.1, 7.4 Hz, 1H), 3.15 (dd, J=14.0, 3.6 Hz, 1H), 3.05 (t, J =9.8 Hz, 1H), 2.56 (s, 1H), 2.06 (dd, J=12.2, 7.7 Hz, 1H), 1.74 (s, 2H), 1.61 (t, J=4.0 Hz, 10H), 1.01-0.93 (m, 2H), 0.64-0.57 (m, 2H). MS-ESI m/z calc. 649.2627, found 650.12 (M+1)+; Retention time: 1.75 min (LC method G).

Example 93: Preparation of (148)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12di(trideutero)methyl-2X ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5,7,9,19,21-hexaene-2,2,4-trione (compound 274)

Step 1: 3-[3,3,3-trideutero-2-nitro-2-(trideuteromethyl)propyl]tetrahydropyran-2-one

1,8-Diazabicyclo[5.4.0]undec-7-ene (7.7 ml, 51.3 mmol) was added to a mixture of 1,1,1,3,3,3-hexadeutero2-nitropropane (CDN Isotopes, Quebec, Canada) (23.4 g, 246.2 mmol) and 3-methylenetetrahydropyran-2-one (23.0 g, 205.2 mmol). The reaction was exothermic: after the initial heat had dissipated, the mixture was heated in an oil bath at 80°C for 18 hours, then cooled to room temperature and diluted with 1M hydrochloric acid (100 ml) and dichloromethane (500 ml). The phases were separated. The aqueous phase was discarded and the organic phase was dried over sodium sulfate, filtered and

- 343 044967 concentrated, in vacuo, to give 3-[3,3,3-trideutero-2-nitro-2-(trideuteromethyl)propyl]tetrahydropyran-2-one (41.8 g, 98%) as a yellow oil . The material was used in the next step without further purification. MS-ESI m/z calc. 207.22, found 208.10 (M+1)+; Retention time: 3.29 min (LC method Q).

Step 2: 3-(3-hydroxypropyl)-5,5-bis(trideuteromethyl)pyrrolidin-2-one

A suspension of Raney nickel (5 g, 85 mmol) in water (10 ml) was added to a solution of 3-[3,3,3-trideutero-2nitro-2-(trideuteromethyl)propyl]tetrahydropyran-2-one (41.8 g, 201.8 mmol) in ethanol (600 ml). The resulting suspension was hydrogenated under 60 psi H ₂ pressure. inch at 80°C for 22 hours, cooled to room temperature, filtered through celite and then concentrated in vacuo to give an orange oil. The orange oil was purified by silica gel chromatography (0-50% ethyl acetate in hexane gradient) to give pure 3-(3-hydroxypropyl)-5,5bis(trideuteromethyl)pyrrolidin-2-one (7 g, 20%) as off-white solid matter.

¹ H NMR (250 MHz, DMSO-de) δ 7.62 (s, 1H), 4.39 (t, 1H), 3.81 (m, 2H), 2.37 (m, 2H), 2.01 (dd, 1H), 1.73 (m , 1H), 1.43 (m, 3H), 1.17 (m, 1H). MS-ESI m/z calc. 177.20, found 178.00 (M+1) ⁺ ; Retention time: 1.91 min (LC method Q).

Step 3: (3S)-3-(3-hydroxypropyl)-5,5-bis(trideuteromethyl)pyrrolidin-2-one

Racemic 3-(3-hydroxypropyl)-5,5-bis(trideuteromethyl)pyrrolidin-2-one (6.78 g) was chirally separated by SLC chromatography using ChiralPak IA (250 x 21.2 mm column, particle size 5 µm) with a mobile phase of 10% methanol (unmodified)/90% carbon dioxide at 70 ml/min for 7.0 min (injection volume = 500 µl of 32 mg/ml methanol solution), yielding ( 3S)-3-(3-hydroxypropyl)-5,5bis(trideuteromethyl)pyrrolidin-2-one (2.4 g, 70.7%) as an off-white solid. MS-ESI m/z calc. 177.20, found 178.00 (M+1) ⁺ ; retention time: 1.91 min (LC method B).

Step 4: 3-[(3S)-5,5-bis(trideuteromethyl)pyrrolidin-3-yl]propan-1-ol

To a suspension of lithium aluminum hydride (1.37 g, 35.16 mmol) (2 granules) in tetrahydrofuran (22 ml) was added solid (3S)-3-(3-hydroxypropyl)-5,5bis(trideuteromethyl )pyrrolidin-2-one (2.4 g, 13.54 mmol) in portions over 20 minutes. During addition, the internal temperature was maintained below 32°C. The reaction mixture was then refluxed and stirred under a nitrogen atmosphere. After 19 hours, the reaction mixture thickened and was no longer stirred. The reaction mixture was cooled to room temperature. Tetrahydrofuran (10 ml) and methyl tert-butyl ether (10 ml) were added to the mixture, followed by the addition of saturated sodium sulfate (aq.) dropwise until no more bubbles formed. Another 10 ml of saturated sodium sulfate solution was added to the cloudy solution. The mixture was filtered through celite and washed with methyl tert-butyl ether. The filtrate was concentrated to give 3-[(3S)-5,5bis(trideuteromethyl)pyrrolidin-3-yl]propan-1-ol (1.85 g, 83%) as a clear oil.

¹ H NMR (400 MHz, DMSO-d6) δ 4.32 (t, J=5.2 Hz, 1H), 3.36 (k, J=6.2 Hz, 3H), 2.95 (dd, J=10.6, 7.5 Hz, 1H), 2.40 (dd, J=10.6, 7.6 Hz, 1H), 2.03 (hept, J=7.7 Hz, 1H), 1.86 (m, 1H), 1.68 (dd, J=12.1, 8.2 Hz, 1H), 1.471.22 (m, 5H), 1.01 (dd, J=12.1, 8.8 Hz, 1H).

Step 5: tert-butyl-(4S)-4-(3-hydroxypropyl)-2,2-bis(trideuteromethyl)pyrrolidine-1 carboxylate

To a solution of 3-[(3S)-5,5-bis(trudeuteromethyl)pyrrolidin-3-yl]propan-1-ol (1.85 g, 11.33 mmol) (1.85 g) in methyl tert- butyl ether (11.5 ml) tert-butoxycarbonyl tert-butyl carbonate (2.60 g, 11.91 mmol) was added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere. After 17 hours, the reaction mixture was diluted with water and extracted. The aqueous layer was again extracted with methyl tert-butyl ether. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give a clear oil (2.94 g). The clear oil was purified by flash chromatography (silica, 30% ethyl acetate in hexanes) to give tert-butyl (4S)-4-(3hydroxypropyl)-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate (2.41 g, 81% ) in the form of transparent

- 344 044967 oil.

1H NMR (400 MHz, DMSO-d ₆ ) δ 4.36 (t, J=5.2 Hz, 1H), 3.61-3.48 (m, 1H), 3.37 (k, J=6.0 Hz, 2H), 2.76 (k, J =10.1 Hz, 1H), 2.14-1.96 (m, 1H), 1.95-1.77 (m, 1H), 1.48-1.24 (m, 14H).

Step 6: tert-butyl-(4S)-4-(3-methylsulfonyloxypropyl)-2,2-bis(trideuteromethyl)pyrrolidine 1-carboxylate o=( o=(

D ₃ C^/ ^N X d ₃ c^ ⁿ %

D ₃ cA>X^-^OH b'Ъ

Triethylamine was added to a solution of tert-butyl (4S)-4-(3-hydroxypropyl)-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate (2.41 g, 9.149 mmol) in methyl tert-butyl ether (15 ml). (1.111 g, 1.530 mL, 10.98 mmol) followed by methanesulfonyl chloride (781 μL, 10.09 mmol) in an ice water bath for 5 min. A white precipitate immediately formed. The temperature of the reaction mixture was brought to room temperature. The reaction mixture was then diluted with methyl tert-butyl ether, filtered, washed with water, dried over sodium sulfate, filtered and concentrated. After standing overnight, tert-butyl (4S)-4-(3-methylsulfonyloxypropyl)-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate (2.64 g, 81%) solidified to a white solid.

1H NMR (400 MHz, DMSO-a ₆ ) δ 4.19 (t, J=6.4 Hz, 2H), 3.63-3.50 (m, 1H), 3.16 (s, 3H), 2.79 (k, J=10.3 Hz, 1H ), 2.17-2.02 (m, 1H), 1.97-1.80 (m, 1H), 1.73-1.58 (m, 2H), 1.47-1.26 (m, 12H).

Step 7: tert-butyl-(4S)-4-(3-azidopropyl)-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate

To a solution of tert-butyl (48)-4-(3-methylsulfonyloxypropyl)-2,2bis(trideuteromethyl)pyrrolidine-1-carboxylate (2.64 g, 7.576 mmol) in N,N-dimethylformamide (26 ml) at room temperature sodium azide (1.07 g, 16.46 mmol) was added. The reaction mixture was heated to 50°C and stirred under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, extracted with ethyl acetate (200 ml) and washed with water (50 ml). The organic layer was dried over sodium sulfate, filtered and concentrated. Heptane was added and concentrated to remove excess N,N-dimethylformamide to give tert-butyl (4S)-4-(3-azidopropyl)-2,2bis(trideuteromethyl)pyrrolidine-1-carboxylate (1.77 g, 80.2% ).

1H NMR (400 MHz, DMSO-d ₆ ) δ 3.55 (dt, J=10.7, 7.1 Hz, 1H), 3.32 (t, 2H), 2.85-2.70 (m, 1H), 2.20-2.01 (m, 1H) , 1.88 (td, J=14.0, 13.5, 6.1 Hz, 1H), 1.61-1.28 (m, 14H).

Step 8: tert-butyl-(4S)-4-(3-aminopropyl)-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate

Platinum oxide (50 .68 mg, 0.2232 mmol). The reaction mixture was hydrogenated using a Buchiglasuster hydrogenation apparatus. The mixture was purged three times from vacuum with nitrogen, then three times from vacuum with hydrogen (0.4 l). The reaction mixture was stirred under a hydrogen atmosphere at 930 rpm at a hydrogen pressure of about 2.18 bar at 25° C. for 18 hours. 337 ml of hydrogen gas was consumed. The reaction mixture was filtered through celite and washed with water (25 ml). The organic layer was washed with brine (25 ml), dried with sodium sulfate, filtered and concentrated to give tert-butyl (4S)-4-(3-aminopropyl)-2,2bis(trideuteromethyl)pyrrolidine-1-carboxylate (1.66 g , quantitative yield) as a dark oil.

1H NMR (400 MHz, DMSO-d ₆ ) δ 3.53 (dt, J=12.2, 6.5 Hz, 1H), 2.76 (k, J=10.2 Hz, 1H), 2.18-1.99 (m, 1H), 1.86 (td , J=15.8, 14.2, 6.1 Hz, 1H), 1.55-1.21 (m, 16H).

Step 9: tert-butyl-(4S)-4-[3-[(6-sulfamoyl-2-niridyl)amino]propyl]-2,2bis(trideuteromethyl)pyrrolidine-1-carboxylate.

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To a solution of tert-butyl (4S)-4-(3-aminopropyl)-2,2-bis(trideuteromethyl)pyrrolidine-1carboxylate (1.61 g, 6.135 mmol) in dimethyl sulfoxide (30 ml) was added diisopropylethylamine (1.28 ml , 7.349 mmol), followed by 6-fluoropyridine-2-sulfonamide (1.31 g, 7.436 mmol). The reaction mixture was placed under a nitrogen atmosphere and stirred at 85°C for 18 hours. The reaction mixture was diluted with methyl tert-butyl ether (50 ml) and extracted with water (20 ml). The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in dichloromethane and purified by chromatography on silica gel (60% ethyl acetate in hexane). For the pooled fractions containing product, a second purification was completed by chromatography on silica gel (gradient from

0% to 5% methanol in dichloromethane) to give tert-butyl (4S)-4-[3-[(6-sulfamoyl-2pyridyl)amino]propyl]-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate ( 1.72 g, 67%) as a white sticky solid.

¹ H NMR (400 MHz, DMSO-b ₆ ) δ 7.51 (t, J=8.5, 7.2 Hz, 1H), 7.06 (s, 2H), 7.01-6.88 (m, 2H), 6.61 (d, J=8.4 Hz, 1H), 3.55 (k, J=9.2 Hz, 1H), 3.30-3.21 (m, 2H), 2.88-2.71 (m, 1H), 2.19-2.00 (m, 1H), 2.01-1.78 (m, 1H), 1.66-1.27 (m, 14H).

Step 10: tert-butyl(4S)-4-[3-[[6-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1yl]pyridine -3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-bis(trideuteromethyl)pyrrolidine 1-carboxylate

To a solution of 2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3-carboxylic acid (250 mg, 0.6892 mmol) in tetrahydrofuran ( 2.058 ml) carbonyldiimidazole (134 mg, 0.8264 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. Carbonyldiimidazole (11.8 mg, 0.07277 mmol) was added and stirred for another 30 minutes. Add a solution of tert-butyl (4S)-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]-2,2-bis(trideuteromethyl)pyrrolidine-1carboxylate (307 mg, 0.7334 mmol) in tetrahydrofuran (420 µl) dropwise, followed by 1,8diazabicyclo[5.4.0]undec-7-ene (310 µl, 2.073 mmol). The reaction continued to stir at room temperature under a nitrogen atmosphere. After 18 hours, water (8.2 mL), ethyl acetate (25 mL) and hydrochloric acid (710 μL 6 M, 4.260 mmol) were added to give the aqueous layer a pH of 3. The reaction mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated. Purification was carried out by flash chromatography (50% ethyl acetate in hexanes) to give tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-(2-dispiro[2.0. 2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate (308 mg, 59%) . MS-ESI m/z calc. 759.35, detected 760.4 (M+1)+; retention time: 2.20 min (LC method G).

Step 11: N-[[6-[3-[(3S)-5,5-bis(trideuteromethyl)pyrrolidin-3-yl]propylamino]-2pyridyl]sulfonyl]-2-chloro-6-[3-(2 -dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3carboxamide

To a solution of tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1yl]pyridin- 3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-bis(trideuteromethyl)pyrrolidine 1-carboxylate (308 mg, 0.3565 mmol) in dichloromethane (1.26 ml) and toluene (624 µl) trifluoroacetic acid (411 µl, 5.335 mmol) was added and the mixture was stirred at ambient temperature for 2.5 hours. The reaction mixture was concentrated, diluted with toluene (4.989 ml) and concentrated at 45°C to give N-[[6-[ 3-[(3S)-5,5-bis(trideuteromethyl)pyrrolidin-3-yl]propylamino]-2- 346 044967 pyridyl]sulfonyl]-2-chloro-6-[3 -(2-dispiro [2.0.2.1 ]heptan-7-ylethoxy)pyrazol-1 -yl] pyridin-3 carboxamide (trifluoroacetate salt) (276 mg, 100%). MS-ESI m/z calc. 659.2928, detected 660.4 (M+1)+; retention time: 1.11 min (LC method G).

Stage

12:

(14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12di(trideutero)methyl-2λ ⁶ -thia- 3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5,7,9,19,21-hexaene-2,2,4-trione (compound 274)

^[[6-[3-[(38)-5,5-bis(trideuteromethyl)pyrrolidin-3-yl]propylamino]-2-pyridyl]sulfonyl]-2-chloro-6-[3 -(2-dispiro[ 2.0.2.1 ]heptan-7-ylethoxy)pyrazol-1 -yl]pyridin-3 carboxamide (trifluoroacetate salt) (356 mg, 0.4598 mmol) to NMP (8.6 ml) was added potassium carbonate (322 mg, 2.330 mmol ). The mixture was purged with nitrogen 3 times and heated at 150°C overnight. The reaction mixture was cooled to room temperature and added to water (18 ml). The mixture was carefully acidified with hydrochloric acid (5 ml 1 M, 5,000 mmol) to obtain a foamy suspension. The solid was collected by filtration using a medium frit. The filtrate contained no product and was discarded. The wet filter cake was dissolved in ethyl acetate (21 ml) and washed with 10 ml of saline solution. The aqueous phase was separated and the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give a light yellow oil. The crude product was diluted with acetonitrile and chromatographed on a 30 g C ₁₈ reverse phase column, eluting with a gradient of 60% to 100% acetonitrile in water to give (14S)-8-[3-(2-{dispiro[2.0.2.1]heptane -7-yl}ethoxy)-1Hpyrazol-1 -yl]-12,12-di(trideutero)methyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose- 1(23),5,7,9,19,21-hexaene-2,2,4-trione (compound 274) (135 mg, 47%) as a cream foam.

¹ H NMR (400 MHz, DMSO-46) 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), 7.19-6.81 (m, 3H), 6.71 (d, J=8.5 Hz, 1H), 6.08 (d, J=2.8 Hz, 1H), 4.21 (t, J=6.7, 1.4 Hz, 2H ), 4.08-3.81 (m, 1H), 3.24-3.03 (m, 1H), 2.95 (d, J=13.3 Hz, 1H), 2.80-2.57 (m, 1H), 2.18 (d, J=50.0 Hz, 1H), 1.971.68 (m, 4H), 1.68-1.42 (m, 4H), 1.42-1.11 (m, 1H), 0.95-0.72 (m, 4H), 0.72-0.56 (m, 2H), 0.56- 0.33 (m, 2H). MS-ESI m/z calc. 623.32, detected 624.3 (M+1) ⁺ ; retention time: 1.98 min (LC method G).

Example 94: Preparation of 20,20,22-trimethyl-4-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1yl]-10λ ⁶ -thia-1,3,9 ,13,14-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10trione (racemic atropisomer 1) (compound 280), 12.20 ,20-trimethyl-4-[3-(3,3,3-trifluoro-2,2dimethylpropoxy)-1H-pyrazol-1-yl]-10λ ⁶ -thia-1,3,9,13,14-pentaazatetracyclo[ 16.2.1.111,14.02,7]docose2,4,6,11(22),12-pentaene-8,10,10-trione (compound 281) and 20,20,22-trimethyl-4-[3-(3 ,3,3-trifluoro-2,2dimethylpropoxy)-1 H-pyrazol-1 -yl] -10λ ⁶ -thia-1,3,9,13,14-pentaazatetracyclo [16,2.1.111,14.02,7]docose2 ,4,6,11(22),12-pentaene-8,10,10-trione (racemic atropisomer 2) (compound 282)

- 347 044967

Step 1: tert-butyl 2,2-dimethyl-4-[3-(5-methyl-4-sulfamoylpyrazol-1-yl)propyl]pyrrolidine-1-carboxylate and tert-butyl 2,2-dimethyl-4-[ 3-(3-methyl-4-sulfamoyl-pyrazol-1-yl)propyl]pyrrolidine-1carboxylate (2:1 mixture of inseparable regioisomers)

To a round bottom flask containing tert-butyl 2,2-dimethyl-4-(3-methylsulfonyloxypropyl)pyrrolidine-1-carboxylate (1.97 g, 5.873 mmol), add N,N-dimethylformamide (20 ml), potassium carbonate (2.44 g, 17.65 mmol) and 5-methyl-1H-pyrazole-4-sulfonamide (947 mg, 5.875 mmol). The reaction was heated at 65°C for 24 hours. The reaction mixture was filtered, and the flask and filter cake were further washed with ethyl acetate. The filtrate was evaporated and purified by HPLC (20-80% acetonitrile in an aqueous gradient with 0.1% hydrochloric acid modifier). The purified fractions were evaporated together until a white foam was obtained. Inseparable regioisomeric products, tert-butyl-2,2dimethyl-4-[3-(5-methyl-4-sulfamoylpyrazol-1-yl)propyl]pyrrolidine-1-carboxylate and tert-butyl-2,2dimethyl-4-[3 -(3-methyl-4-sulfamoylpyrazol-1-yl)propyl]pyrrolidine-1-carboxylate (total yield 972 mg, 41%), ESI-MS m/z cal. 400.21442, detected 345.2 (M+1)+; Retention time: 1.51 min (LC method B). The presence of products in the mixture in a 2:1 ratio was confirmed by 1H NMR analysis.

Step 2: tert-butyl-4-[3-[4-[[2-chloro-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1yl]pyridin-3-carbonyl ]sulfamoyl]-5-methylpyrazol-1-yl]propyl]-2,2-dimethylpyrrolidine-1carboxylate and tert-butyl-4-[3-[4-[[2-chloro-6-[3-(3,3 ,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl]-3-methylpyrazol-1-yl]propyl]-2,2-dimethylpyrrolidine-1carboxylate (mixture of inseparable regioisomers 2:1)

2-chloro-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-348 044967 yl]pyridine-3-carboxylic acid (952 mg, 2.565 mmol) was added to the round bottom flask. carbonyldiimidazole (469 mg, 2.892 mmol) and tetrahydrofuran (10 ml). The reaction was heated at 35°C and stirred for 2 hours. The mixture was added

2:1 tert-butyl-2,2-dimethyl-4-[3-(5-methyl-4-sulfamoylpyrazol-1-yl)propyl]pyrrolidine-1 carboxylate and tert-butyl-2,2-dimethyl-4- [3-(3-methyl-4-sulfamoylpyrazol-1-yl)propyl]pyrrolidine-1carboxylate (965 mg, 2.409 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.10 ml, 7.356 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified directly by silica gel chromatography using a gradient of 20% to 100% ethyl acetate in hexane. Inseparable regioisomeric products, tert-butyl 4-[3-[4-[[2-chloro-6-[3-(3,3,3trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl]pyridin-3-carbonyl ]sulfamoyl]-5-methylpyrazol-1yl]propyl]-2,2-dimethylpyrrolidine-1-carboxylate and tert-butyl 4-[3-[4-[[2-chloro-6-[3-(3,3, 3-trifluoro-2,2dimethylpropoxy)pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-3-methylpyrazol-1-yl]propyl]-2,2dimethylpyrrolidine-1-carboxylate (total yield 1.073 g, 60%) was isolated in the form of white foam. MS-ESI m/z calc. 745.2636, detected 746.4 (M+1)+; retention time: 1.85 min (LC method G). The regiochemical ratio of the mixture (2:1) was confirmed by 1H NMR.

Step 3: 2-χλορ-Ν -[1-[3-(5,5-dimethylpyrrolidin-3-yl)propyl]-5-methylpyrazol-4-yl]sulfonyl-6[3-(3,3,3- trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl]pyridin-3-carboxamide and 2-χλορ-Ν-[1-[3-(5,5dimethylpyrrolidin-3-yl)propyl]-3-methylpyrazol-4- yl]sulfonyl-6-[3-(3,3,3-trifluoro-2,2dimethylpropoxy)pyrazol-1-yl]pyridin-3-carboxamide (2:1 mixture of inseparable regioisomers)

Into a round bottom flask containing a 2:1 mixture of tert-butyl 4-[3-[4-[[2-chloro-6-[3-(3,3,3-trifluoro-2,2dimethylpropoxy)pyrazol-1-yl] pyridine-3-carbonyl]sulfamoyl]-5-methylpyrazol-1-yl]propyl]-2,2dimethylpyrrolidine-1-carboxylate and tert-butyl 4-[3-[4-[[2-chloro-6-[3- (3,3,3-trifluoro-2,2dimethylpropoxy)pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-3-methylpyrazol-1-yl]propyl]-2,2dimethylpyrrolidine-1-carboxylate (1.068 g, 1.431 mmol) dichloromethane (15 ml) and trifluoroacetic acid (4.4 ml, 57.11 mmol) were added. The reaction mixture was allowed to stir for 1 hour at room temperature. The reaction was evaporated to dryness. Saturated sodium bicarbonate and brine were added and the reaction mixture was extracted with ethyl acetate. The organic layer was evaporated to obtain the product, however a significant amount of product still remained in the aqueous layer after two more extractions with ethyl acetate. Therefore, the aqueous layer was evaporated to dryness, dry acetone was added to the solid and filtered. The dissolved acetone was evaporated and combined with the organic layers to give 2-chloro-N-[1-[3-(5,5-dimethylpyrrolidin-3-yl)propyl]-5methylpyrazol-4-yl]sulfonyl-6-[3-( 3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl]pyridin-3carboxamide and 2-χλορ-Ν-[1-[3-(5,5-dimethylpyrrolidin-3-yl)propyl]- 3-methylpyrazol-4-yl]sulfonyl6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl]pyridin-3-carboxamide (2:1 mixture of inseparable regioisomers) (920 mg , 100%). MS-ESI m/z calc. 645.2112, detected 646.3 (M+1) ⁺ ; retention time: 1.45 min (LC method B).

Step 4: 20,20,22-trimethyl-4-[3-(3,3,3-trifluoro-2,2-dimethylpronoxy)-1H-pyrazol-1-yl]-10λ ⁶ -thia1,3,9, 13,14-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (racemic atropisomer 1) (compound 280), 12, 20,20-trimethyl-4-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)1H-nirazol-1-yl]-10λ ⁶ -thia-1,3,9,13,14- pentααzatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12pentaene-8,10,10-trione (compound 281) and 20,20,22-trimethyl-4-[3- (3,3,3-trifluoro-2,2-dimethylpropoxy)1H-pyrazol-1-yl]-10λ ⁶ -thia-1,3,9,13,14-pentααzatetracyclo[16.2.1.111.14.02.7 ]docose-2,4,6,11(22),12pentaene-8,10,10-trione (racemic atropoisomer 2) (compound 282)

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To a 250 mL round bottom flask, add cesium fluoride (432 mg, 2.844 mmol), potassium carbonate (984 mg, 7.120 mmol), 3 A molecular sieves, and a solution of the regioisomer mixture, 2-chloro-N-[1-[3-(5 ,5dimethylpyrrolidin-3-yl)propyl]-5-methylpyrazol-4-yl]sulfonyl-6-[3 -(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1 -yl]pyridin-3 - carboxamide and 2-chloro-N-[1-[3-(5,5-dimethylpyrrolidin-3yl)propyl]-3-methylpyrazol-4-yl]sulfonyl-6-[3-(3,3,3-trifluoro -2,2-dimethylpropoxy)pyrazol-1yl]pyridin-3-carboxamide (2:1 mixture of inseparable regioisomers) (920 mg, 1.424 mmol) in dimethyl sulfoxide (55 ml). The reaction mixture was purged with nitrogen and heated at 150°C overnight. The reaction mixture was cooled to room temperature, filtered, washed with brine and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and purified by HPLC (10%-70% acetonitrile in water with 0.1% hydrochloric acid modifier) to give 20,20,22-trimethyl as the first atropoisomer/regioisomer to elute

4-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1 H-pyrazol-1-yl]-10λ ⁶ -thia-1,3,9,13,14pentaazatetracyclo[16.2.1.111, 14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione atropisomer 1) (compound 280) (45 mg, 10%).

(racemic

1H NMR (400 MHz, DMSO-Y6) δ 12.41 (s, 1H), 8.19 (d, J=2.8 Hz, 1H), 7.86 (s, 1H), 7.77 (d, J=8.2 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 6.16 (d, J=2.8 Hz, 1H), 4.38 (d, J=14.2 Hz, 1H), 4.23 (s, 2H), 4.01 (t, J=13.7 Hz , 1H), 2.05 (s, 3H), 1.89-1.70 (m, 3H), 1.55 (s, 3H), 1.48 (s, 3H), 1.44-1.28 (m, 2H), 1.23 (s, 6H), 1.08 (d, J=11.1 Hz, 1H). MS-ESI m/z calc. 609.2345, detected 610.4 (M+1) ⁺ ; Retention time: 3.01 min (LC method D).

The second atropoisomer/regioisomer eluted was 12,20,20-trimethyl-4-[3-(3,3,3-trifluoro2,2-dimethylpropoxy)-1 H-pyrazol-1 -yl]-10λ ⁶ -thia-1, 3,9,13,14-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (compound 281) (73 mg, 17%). MS-ESI m/z calc. 609.2345, detected 610.4 (M+1) ⁺ ; retention time: 3.07 min (LC method D). The third eluent was an atropoisomer/regioisomer soluble

20,20,22-trimethyl-4-[3 -(3,3,3-trifluoro-2,2 dimethylpropoxy)-1H-pyrazol-1-yl]-10λ ⁶ -thia-1,3,9,13, 14-pentaazatetracyclo[16.2.1.111,14.02.7]docose2,4,6,11(22),12-pentaene-8,10,10-trione (racemic atropisomer 2) (compound 282) (19 mg, 4%) . MSIE m/z calc. 609.2345, detected 610.4 (M+1)+; retention time: 3.14 min (LC method D).

Example 95: Preparation of (14S)-8-(3-{2-hydroxy-3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1Hpyrazol-1-yl)-12,12-dimethyl-2λ ⁶ -thia-3 ,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5(10),6,8,19(23),20-hexaene-2,2,4-trione ( diastereomer 1) (compound 284) and of (14S)-8-(3-{2hydroxy-3-[1 -(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1-yl)-12,12-dimethyl- 2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5(10),6,8,19(23),20-hexaene-2, 2,4trione (diastereomer 2) (compound 283)

Step 1: (148)-8-(3-{2-hydroxy-3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1-yl)12,12-dimethyl-2λ ⁶ -thia-3 ,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose- 350 044967

1(22),5(10),6,8,19(23),20-hexaene-2,2,4-trione (diastereomer 1) (compound 284) and (14S)-8-(3-{2 -hydroxy3-[1 -(trifluoromethyl)cyclopropyl]propoxy }-1 H-pyrazol-1 -yl)-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05 ,10]tetracose-1(22),5(10),6,8,19(23),20-hexaene-2,2,4-trione (diastereomer 2) (compound 283)

(14S)-8-(3-{2-hydroxy-3-[1-(trifluoromethyl)cyclopropyl]nроnoxy}-1Н-pyrazol-1-yl)-12,12dimethyl-2Х ⁶ -thia-3,9,11 ,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5 (10),6,8,19 (23),20-hexaene-2,2,4-trione (3, 24 g, 8.383 mmol) were subjected to chiral separation by SLC chromatography using a ChiralPak IG column (250 x 10 mm, 5 μm particle size) with a mobile phase of 44% acetonitrile/methanol (90:10)/56% carbon dioxide at 10 ml/min for 12.0 min (injection volume = 70 μl of a 22 mg/ml solution in acetonitrile/methanol (90:10)) to obtain (14S)-8-(3-{2-hydroxy-3-) as the first diastereomer eluted [1-(trifluoromethyl)cyclopropyl]propoxy} -1 H-pyrazol-1 -yl)-12,12-dimethyl-2Х ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05, 10]tetracose-1(22),5(10), 6,8,19(23),20-hexaene-2,2,4-trione (diastereomer 1) (compound 284) (6.8 mg, 49% ) as a white solid;

Ή NMR (400 MHz, DMSO-Y6) δ 12.52 (s, 1H), 8.22 (d, J=2.8 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.57 (t, J=7.9 Hz , 1H), 7.05 (d, J=7.2 Hz, 1H), 6.98 (s, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 6.13 (d , J=2.8 Hz, 1H), 5.07 (d, J=5.7 Hz, 1H), 4.10 (d, J=5.2 Hz, 2H), 4.00-3.72 (m, 2H), 3.16 (s, 1H), 2.95 (d, J=13.5 Hz, 1H), 2.71 (s, 1H), 2.35 (d, J=17.2 Hz, 1H), 2.18-2.07 (m, 1H), 1.98 (dd, J=14.9, 4.0 Hz, 1H), 1.86 (dd, J=11.5, 5.2 Hz, 1H), 1.76 (s, 1H), 1.68 (s, 1H), 1.67-1.60 (m, 3H), 1.57 (d, J=12.6 Hz, 2H ), 1.52 (s, 3H), 1.33 (t, J=12.0 Hz, 1H), 1.05-0.90 (m, 2H), 0.90-0.70 (m, 2H); MS-ESI m/z calc. 663.24506, found 664.4 (M+1)+; Retention time: 1.9 min (LC method E), and as the second diastereomer eluted (14S)-8-(3-{2-hydroxy-3-[1(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazole-1- yl)-12,12-dimethyl-2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5(10),6,8,19( 23),20-hexaene-2,2,4-trione (diastereomer 2) (compound 283) (7.62 mg, 54%) as a white solid;

1H 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 (t, J=7.9 Hz, 1H), 7.06 (d, J=7.2 Hz, 1H), 7.04-6.94 (m, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 6.14 (d, J=2.7 Hz, 1H), 4.14-4.06 (m, 2H), 3.96 (dp, J=15.9, 6.0, 5.0 Hz, 2H), 3.16 (s, 1H), 2.95 (d, J= 13.3 Hz, 1H), 2.70 (d, J=11.1 Hz, 1H), 2.50-2.36 (m, 1H), 2.13 (s, 1H), 1.98 (dd, J=15.0, 4.0 Hz, 1H), 1.86 ( dd, J=11.8, 5.2 Hz, 1H), 1.77 (s, 1H), 1.71-1.65 (m, 1H), 1.63 (s, 1H), 1.61 (s, 3H), 1.57 (d, J=12.3 Hz , 2H), 1.52 (s, 3H), 1.31 (k, J=13.6, 12.7 Hz, 1H), 1.04-0.91 (m, 2H), 0.90-0.77 (m, 2H); MS-ESI m/z calc. 663.24506, detected 664.4 (M+1) ⁺ ; Retention time: 1.9 min (LC method).

Example 96: Preparation of (14S)-12,12-dimethyl-8-(3-{3-[1-(trifluoromethyl)cyclopropyl]-2,2,3,3tetradeuteropropoxy}-1H-pyrazol-1-yl) -2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2, 4-trione (compound 287)

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Step 1: 1,1,2,2-tetradeutero-2-[1-(trifluoromethyl)cyclopropyl]ethanol

To a suspension of lithium aluminum deuteride (1.0872 g, 27.204 mmol) in anhydrous tetrahydrofuran (50 ml) was added a solution of 2,2-dideutero-2-[1-(trifluoromethyl)cyclopropyl]acetic acid (4 g, 20.926 mmol) in anhydrous tetrahydrofuran (50 ml) dropwise at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with diethyl ether (50 ml) and cooled to 0°C, and then it was quenched sequentially with water (1.1 ml), 15% sodium hydroxide (aq, 1.1 ml) and water (3.3 ml). The reaction mixture was stirred at room temperature for 30 minutes, and then it was filtered through a pad of celite and dried over anhydrous magnesium sulfate. Filtered and the filtrate was concentrated under reduced pressure to give 1,1,2,2tetradeutero-2-[1-(trifluoromethyl)cyclopropyl]ethanol (3.288 g, 92%) as a clear liquid.

¹ H NMR (250 MHz, CDCl ₃ ) δ 1.42 (s, 1H), 1.03-0.89 (m, 2H), 0.67 (m, 2H).

Step 2: [1,1,2,2-tetradeutero-2-[1-(trifluoromethyl)cyclopropyl]ethyl]methanesulfonate

In a solution of 1,1,2,2-tetradeutero-2-[1-(trifluoromethyl)cyclopropyl]ethanol (3.288 g, 19.334 mmol) and triethylamine (5.8692 g, 8.0843 ml, 58.002 mmol) in dichloromethane (35 ml). methanesulfonyl chloride (2.6577 g, 1.7957 ml, 23.201 mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 1 hour and then diluted with dichloromethane (50 ml) and 10% citric acid (50 ml). The two layers were separated, and the organic layer was washed with saturated sodium bicarbonate (50 ml) and brine (50 ml). The organic solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 0% to 70% diethyl ether in hexane to give [1,1,2,2-tetradeutero-2-[1(trifluoromethyl)cyclopropyl]ethyl]methanesulfonate (3.982 g, 83% ) in the form of a clear liquid.

1H NMR (250 MHz, CDCl3) δ 3.01 (s, 3H), 1.03 (m, 2H), 0.71 (m, 2H).

Step 3: 2,2,3,3-tetradeutero-3-[1-(trifluoromethyl)cyclopropyl]propanenitrile

To a solution of [1,1,2,2-tetradeutero-2-[1-(trifluoromethyl)cyclopropyl]ethyl]methanesulfonate (3.982 g, 16.013 mmol) in dimethyl sulfoxide (20 ml) was added sodium cyanide (980.93 mg, 20.016 mmol ). The reaction mixture was stirred at 70°C for 2 days. After cooling to room temperature, the reaction mixture was poured into water (50 ml). The aqueous solution was extracted with diethyl ether (3x50 ml). The combined organic layers were washed with water (2x50 ml) and brine (50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 2,2,3,3tetradeutero-3-[1-(trifluoromethyl)cyclopropyl]propanenitrile ( 2.769 g, 96%) as a light yellow oil.

1H NMR (250 MHz, CDCl ₃ ) δ 1.12-1.00 (m, 2H), 0.78-0.66 (m, 2H).

Step 4: 2,2,3,3-tetradeutero-3-[1-(trifluoromethyl)cyclopropyl]propanoic acid.

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To a solution of 2,2,3,3-tetradeutero-3-[1-(trifluoromethyl)cyclopropyl]propanenitrile (2.769 g, 15.405 mmol) in CH ₃ CwaterD (30 ml) was added sodium deuteroxide (6.3166 g, 40% wt ./wt. 61.620 mmol) and deuterium oxide (6 ml). The reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The aqueous solution was diluted with water (50 ml) and washed with diethyl ether (2x50 ml). The aqueous phase was then acidified to pH ~ 1 and extracted with diethyl ether (3x50 ml). These combined ether layers were washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2,2,3,3-tetradeutero-3-[1-(trifluoromethyl)cyclopropyl]propanoic acid (2.737 g , 91%) in the form of a yellow liquid.

1H NMR (250 MHz, CDCl3) δ 1.08-0.83 (m, 2H), 0.72-0.49 (m, 2H).

Step 5: 2,2,3,3-tetradeutero-3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol

A solution of 2,2,3,3-tetradeutero-3-[1-(trifluoromethyl)cyclopropyl]propanoic acid ( 2.737 g, 13.967 mmol) in anhydrous tetrahydrofuran (20 ml) dropwise at 0°C. The reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with diethyl ether (20 ml) and cooled to 0°C. Water (0.7 ml), 15% sodium hydroxide (aq) (0.7 ml) and water (2.1 ml) were added sequentially. The reaction mixture was stirred at room temperature for 30 minutes and filtered through a pad of celite. The filtrate was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 2,2,3,3-tetradeutero-3-[1(trifluoromethyl)cyclopropyl]propan-1-ol (2.04 g, 84%) as pure liquids.

¹ H NMR (250 MHz, DMSO-de) δ 4.44 (t, J=5.1 Hz, 1H), 3.38 (s, 2H), 0.95-0.79 (m, 2H), 0.68 (dd, J=2.2, 1.2 Hz , 2H).

Step 6: tert-butyl 3-[2,2,3,3-tetradeutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazole 1-carboxylate

To a solution of tert-butyl 5-oxo-1H-pyrazole-2-carboxylate (2.08 g, 11.29 mmol) and 2,2,3,3tetradeutero-3-[1-(trifluoromethyl)cyclopropyl]propane-1- ol (2.04 g, 11.85 mmol) in tetrahydrofuran (26 ml) was added triphenylphosphine (3.108 g, 11.85 mmol). Diisopropyl azodicarboxylate (2.396 g, 11.85 mmol) was added dropwise slowly over 10 min (exothermic effect noted). The reaction mixture was stirred at room temperature for 2 hours. Tetrahydrofuran was removed in vacuo. Toluene (16.64 ml) was added to the crude reaction mixture and the mixture was stirred overnight. The solution was concentrated in vacuo. The crude product was purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate to give tert-butyl-3[2,2,3,3-tetradeutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazole- 1-Carboxylate (2.43 g, 64%) as a clear syrup. MS-ESI m/z calc. 338.17554, detected 339.0 (M+1)+; Retention time: 0.75 min (LC method A).

Step 7: 3-[2,2,3,3-tetradeutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]-1H-pyrazole

tert-Butyl-3-[2,2,3,3-tetradeutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazole-1carboxylate (2.43 g, 7.182 mmol) was dissolved in dichloromethane (24.3 ml) with trifluoroacetic acid. (8.297 ml, 107.7 mmol) and the reaction mixture was stirred at room temperature for 120 minutes. The reaction mixture was evaporated and the resulting oil was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous portion was extracted two more times with ethyl acetate, then the organic layers were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give 3-[2,2,3,3-tetradeutero-3-[1(trifluoromethyl) as an oil. cyclopropyl]propoxy]-1H-pyrazole (1.711 g, 100%). MS-ESI m/z calc. 238.12311, detected 239.1 (M+1) ⁺ ; retention time: 0.54 min (LC method A).

Step 8: tert-butyl 2-chloro-6-[3-[2,2,3,3-tetradeutero-3-[1-(trifluoromethyl)cyclopropyl]-353 044967 propoxy]pyrazol-1-yl]pyridin-3 -carboxylate

2,6-Dichloropyridine-3-carboxylic acid tert-Butyl ester (1.782 g, 7.182 mmol), 3[2,2,3,3-tetradeutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]-1H- pyrazole (1.711 g, 7.182 mmol) and potassium carbonate (1.192 g, 8.625 mmol) were combined in anhydrous dimethyl sulfoxide (34.22 ml). 1,4-Diazabicyclo[2.2.2]octane (161.3 mg, 1.438 mmol) was added and the mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was diluted with water (65.81 ml) and stirred for 15 min. The resulting white solid was filtered and washed with water. The solid was dissolved in dichloromethane and dried over magnesium sulfate. The mixture was filtered and the filtrate was evaporated to give tert-butyl 2-chloro-6-[3-[2,2,3,3-tetradeutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin- 3-carboxylate (2.58 g, 80%) as a white solid. MS-ESI m/z calc. 449.16312, detected 450.0 (M+1)+; retention time: 0.91 min (LC method A).

Step 9: 2-chloro-6-[3-(2,2-dideutero-2-dispiro[2.0.2.1]heptan-7-yl-ethoxy)pyrazol-1-yl]pyridine3-carboxylic acid

tert-Butyl-2-chloro-6-[3-[2,2,3,3-tetradeutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol1-yl]pyridine-3-carboxylate (2.58 g , 5.735 mmol) was dissolved in dichloromethane (25.8 ml) with trifluoroacetic acid (6.627 ml, 86.02 mmol), and the reaction mixture was stirred at room temperature for 16 hours. Trifluoroacetic acid (2.209 ml, 28.67 mmol) was added. and continued stirring for 30 minutes. The reaction mixture was evaporated and ether was added to the resulting solid, and then the ether was removed under reduced pressure. This was repeated twice more to give a white solid, which was recrystallized from dichloromethane to give the pure product as a solid (Collection 1). The product remained in the filtrate, which was evaporated to leave an off-white solid, which was dissolved in ethyl acetate and washed with 5N. sodium hydroxide (2x), then 1 N. hydrochloric acid (1x), then dried (sodium sulfate), filtered and concentrated to a white solid, which was purified by silica gel chromatography using a shallow gradient from 100% dichloromethane to 20% methanol in dichloromethane, resulting in poor separation. Fractions containing the product were pooled, concentrated, filtered and purified using a reverse phase HPLC-MS method using a Luna C ₁₈ (2) column (75 x 30 mm, 5 µm particle size) sold by Phenomenex (item: 00C-4252 -U0-AX), and a dual gradient run from 20% to 80% 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 obtain the pure product, which was combined with the initially crystallized solid material to obtain 2-chloro-6-[3-[2,2,3,3-tetradeutero -3-[1(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (1.75 g, 78%) as a white solid. MS-ESI m/z calc. 393.10052, detected 394.0 (M+1) ⁺ ; Retention time: 0.72 min (LC method A).

Step 10: tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-[2,2,3,3-tetradeutero-3-[1(trifluoromethyl)cyclopropyl] propoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

To a solution of 2-chloro-6-[3-[2,2,3,3-tetradeutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol1-yl]pyridine-3-carboxylic acid (1 g, 2.539 mmol ) in tetrahydrofuran (6.832 ml), carbonyldiimidazole (514.7 mg, 3.174 mmol) (recrystallized from tetrahydrofuran) was added and the mixture was stirred at room temperature for 3 hours, then tert-butyl (4S)-2,2-dimethyl- 4-[3-[(6sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (1.047 g, 2.538 mmol) as a solution in tetrahydrofuran (2.5 ml) followed by 1,8-diazabicyclo[5.4 .0]undec-7-ene (1.192 ml, 7.971 mmol), and semi

- 354 044967 the mixture was stirred for 6 hours at room temperature. The reaction mixture was diluted with water and ethyl acetate, then hydrochloric acid (1.418 ml, 12 M, 17.02 mmol) was added, the pH of the aqueous layer was 1. The layers were separated and the organic layer was washed with water (1X) and brine. (1X) was then dried over sodium sulfate, filtered and concentrated to a white foam, which was purified on a 275 g _C18 reverse phase column, eluting with a gradient of 50% to 100% acetonitrile in water to give tert-butyl (4S)-4- [3-[[6-[[2-chloro-6-[3-[2,2,3,3-tetradeutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1 -yl]pyridin-3 -carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2dimethylpyrrolidine-1-carboxylato (1.261 g, 63%) as a white solid. MS-ESI m/z calc. 787.3044, detected 788.2 (M+1)+; retention time: 0.89 min (LC method A).

Step 11: 2-chloro-N-[[6-[3-[(3S)-5,5-dimethyln-pyrrolidin-3-yl]propylamino]-2pyridyl]sulfonyl]-6-[3-[2,2,3 ,3-tetradeutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1 yl]pyridine-3-carboxamide (trifluoroacetate salt)

Ooh Ooh

tert-Butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-[2,2,3,3-tetradeutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy] pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2dimethylpyrrolidine-1-carboxylate (1.409 g, 1.787 mmol) was dissolved in dichloromethane (6.147 ml) and trifluoroacetic acid was added to the mixture (5.509 ml, 71.51 mmol) and the mixture was stirred at room temperature for 90 minutes. The mixture was concentrated to dryness under reduced pressure, 50 ml of toluene was added and removed by rotary evaporation (45°C water bath). 50 ml of toluene were added again and removed by rotary evaporation (water bath 45°C), then dried in vacuo to obtain 2-χλορ-Ν-[[6-[3[(3S)-5,5-dimethylpyrrolidin-3-yl] propylamino]-2-pyridyl]sulfonyl]-6-[3-[2,2,3,3-tetradeutero-3-[1(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3-carboxamide (trifluoroacetate salt) (1.434 g, 100%) as a white solid. MS-ESI m/z calc. 687.25195, detected 688.2 (M+1) ⁺ ; retention time: 0.62 min (LC method A).

Step 12: (14S)-12,12-dimethyl-8-(3-{3-[1-(trifluoromethyl)cyclopropyl]-2,2,3,3-tetradeuteropropoxy}-1H-pyrazol-1-yl) -2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2, 4-trione (compound 287)

To a solution of 2-chloro-N-[[6-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2pyridyl]sulfonyl]-6-[3-[2,2,3, 3-tetradeutero-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1yl]pyridine-3-carboxamide (trifluoroacetate salt) (1.434 g, 1.788 mmol) in NMP (86.04 ml) was added potassium carbonate (1, 73 g, 12.52 mmol). The mixture was purged with nitrogen for 5 minutes. The mixture was then heated at 155°C for 18 hours. The reaction mixture was cooled to room temperature and added to water (~200 ml) to obtain an off-white solid. The mixture was carefully acidified with hydrochloric acid (2.235 ml 12 M, 26.82 mmol) to obtain a foamy suspension. The solid was collected by filtration and washed with water. The filtrate was discarded. The wet filter cake was dissolved in ethyl acetate and dried over magnesium sulfate, filtered and concentrated in vacuo to give a light yellow oil, which was chromatographed on a 275 g reverse phase C ₁₈ column, eluting with a gradient of 50% to 100% acetonitrile in water to give (148)-12,12-dimethyl-8-(3-{3-[1(trifluoromethyl)cyclopropyl]-2,2,3,3-tetradeuteropropoxy}-1 H-pyrazol-1 -yl)-2λ ⁶ - thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione ( compound 287) (845.2 mg, 73%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.50 (s, 1H), 8.21 (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 (d, J=7.1 Hz, 1H), 6.99 (s, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H) , 6.12 (d, J=2.8 Hz, 1H), 4.19 (s, 2H), 3.92 (d, J=12.2 Hz, 1H), 3.15 (s, 1H), 2.95 (d, J=13.5 Hz, 1H) , 2.71 (s, 1H), 2.12 (s, 1H), 1.86 (dd, J=11.9, 5.3 Hz, 1H), 1.77 (s, 1H), 1.60 (s, 4H), 1.57 (d, J=13.9 Hz, 2H), 1.51 (s, 3H), 1.37-1.23 (m, 1H), 0.93-0.86 (m, 2H), 0.75 (s, 2H). MS-ESI m/z calc. 651.27527, detected 652.4 (M+1) ⁺ ; retention time: 2.25 min (LC method B).

Example 97: Preparation of 20,20,22-trimethyl-4-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1yl]-10λ ⁶ -thia-1,3,9 ,13,14-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10trione (atropisomer 1, enantiomer 1) (compound 288) and 20 ,20,22-trimethyl-4-[3-(3,3,3-trifluoro-2,2- 355 044967 dimethylpropoxy)-1H-pyrazol-1-yl]-10λ ⁶ -thia-1,3,9, 13,14-pentaazatetracyclo[16.2.1.111,14.02,7]docose2,4,6,11(22),12-pentaene-8,10,10-trione (atropoisomer 1, enantiomer 2) (compound 289)

Step 1: 20,20,22-trimethyl-4-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl]-10λ ⁶ -thia1,3,9, 13,14-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (atropisomer 1, enantiomer 1) (compound 288) and 20,20,22-trimethyl-4-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)1H-pyrazol-1-yl]-10λ ⁶ -thia-1,3,9,13, 14-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12pentaene-8,10,10-trione (atropisomer 1, enantiomer 2) (compound 289)

Racemic 20,20,22-trimethyl-4-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl]-10λ ⁶ thia-1,3,9,13 ,14-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (45 mg, 0.07381 mmol) (racemic atropisomer 1 ) were separated by chiral SLC chromatography using ChiralPak AS-H (250x21.2 mm column, 5 µm particle size) with a mobile phase of 24% acetonitrile:methanol (90:10, 20 mM NH3)/76% carbon dioxide at 70 ml/min, yielding 20,20,22-trimethyl-4-[3-(3,3,3-trifluoro-2,2dimethylpropoxy)-1H-pyrazol-1-yl]-10λ ⁶ - as the first eluted enantiomer thia-1,3,9,13,14-pentaazatetracyclo[16.2.1.111,14.02,7]docose2,4,6,11(22),12-pentaene-8,10,10-trione (atropoisomer 1, enantiomer 1 ) (compound 288) (18.6 mg, 83%). MS-ESI m/z calc. 609.2345, detected 610.4 (M+1)+; retention time: 3.0 min (LC method D).

The second enantiomer eluted was 20,20,22-trimethyl-4-[3-(3,3,3-trifluoro-2,2dimethylpropoxy)-1H-pyrazol-1-yl]-10λ ⁶ -thia-1,3,9 ,13,14-pentaazatetracyclo[16.2.1.111,14.02,7]docose2,4,6,11(22),12-pentaene-8,10,10-trione (atropisomer 1, enantiomer 2) (compound 289) (15 .5 mg, 69%).

1H NMR (500 MHz, DMSO-b ₆ ) δ 12.16 (bs, 1H), 8.19 (d, J=2.8 Hz, 1H), 7.82 (s, 1H), 7.81 (d, J=7.9 Hz, 1H), 6.92 (d, J=7.9 Hz, 1H), 6.10 (d, J=2.8 Hz, 1H), 4.35 (m, 1H), 4.22 (bs, 2H), 4.02 (m, 1H), 2.53 (s, 3H ), 2.02 (m, 3H), 1.83 (m, 2H), 1.75 (dd, J=12.1 Hz, 5.6 Hz, 1H), 1.54 (s, 3H), 1.47 (s, 3H), 1.36 (k, J =15.6 Hz, 12.4 Hz, 2H), 1.22 (s, 6H), 1.12 (m, 1H). MS-ESI m/z calc. 609.2345, detected 610.4 (M+1) ⁺ ; retention time: 3.0 min (LC method D).

Example 98: Preparation of (148)-12,12-di(trideutero)methyl-8-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1-yl)-2λ ⁶ -thia -3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 292)

- 356 044967

tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]Step 1:

pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2bis(trideuteromethyl)pyrrolidine-1-carboxylate

To a solution of 2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridine-3carboxylic acid (175 mg, 0.4490 mmol) in tetrahydrofuran (1.5 ml ) carbonyldiimidazole (86 mg, 0.5070 mmol) was added and the mixture was stirred at ambient temperature for 90 minutes. To this solution was added tert-butyl (4S)-4-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]-2,2bis(trideuteromethyl)pyrrolidine-1-carboxylate (140 mg, 0.3345 mmol ) in tetrahydrofuran (1 ml), then 1,8-diazabicyclo[5.4.0]undec-7-ene (135 µl, 0.9027 mmol), and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with water (5 ml) and the mixture was slowly acidified with hydrochloric acid (1.7 ml 1 M, 1,700 mmol). The mixture was extracted with ethyl acetate (10 ml) and the organic phase was separated.

The organic phase was concentrated in vacuo. The crude product was chromatographed on a 30 gram reverse phase column, eluting with 50-100% acetonitrile in water to give tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-[3- [1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-bis(trideuteromethyl)pyrrolidine-1-carboxylate (200 mg, 76 %). MS-ESI m/z calc. 789.31696, detected 790.4 (M+1)+; retention time: 3.47 min (LC method D).

Step 2: N-[[6-[3-[(3S)-5,5-bis(trideuteromethyl)nirrolidin-3-yl]propylamino]-2pyridyl]sulfonyl]-2-chloro-6-[3-[3 -[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3 carboxamide (trifluoroacetate salt)

To tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]nirazol1 -yl]pyridin-3-carbonyl ]sulfamoyl]-2-pyridyl]amino]propyl]-2,2bis(trideuteromethyl)pyrrolidine-1-carboxylate (200 mg, 0.2531 mmol) in dichloromethane (3 ml) and toluene (1 ml) was added trifluoroacetic acid (200 µl, 2.596 mmol). The mixture was stirred at ambient temperature for 18 hours. The solvent was removed in vacuo and the residue was treated with 10 ml of toluene and concentrated in vacuo to give N-[[6-[3-[(3S)-5,5-bis(trideuteromethyl) pyrrolidin3 -yl]propylamino]-2-pyridyl]sulfonyl]-2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3-carboxamide (trifluoroacetate salt ) (204 mg, 100%). MS-ESI m/z calc. 689.2645, detected 690.3 (M+1) ⁺ ; retention time: 2.23 min (LC method D).

Step 3: (14S)-12,12-di(trideutero)methyl-8-(3-{3-[ 1 -(trifluoromethyl)cyclopropyl]propoxy}-1Hpyrazol-1-yl)-2λ ⁶ -thia-3, 9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 292)

- 357 044967

CD ₃

To a solution of N-[[6-[3-[(3S)-5,5-bis(trideuteromethyl)nirrolidin-3-yl]nropylamino]-2pyridyl]sulfonyl]-2-chloro-6-[3-[3- [1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3-carboxamide (trifluoroacetate salt) (200 mg, 0.2487 mmol) to NMP (6 ml) was added potassium carbonate (180 mg, 1.302 mmol). The mixture was purged with nitrogen for 5 minutes and then heated at 135°C for 22 hours. The reaction mixture was cooled to ambient temperature and diluted with water (10 ml). The mixture was carefully acidified with hydrochloric acid (500 μl 6 M, 3,000 mmol). The suspension was extracted with ethyl acetate (15 ml) and the organic phase was washed with brine. The organic phase was concentrated in vacuo. The crude product was chromatographed on a 30 g reverse phase column, eluting with a gradient of 50% to 100% acetonitrile in water to give a foam, which was dried in a vacuum oven at 45°C for 48 h to give (148)-12,12- di(trideutero)methyl-8-(3-{3-[1(trifluoromethyl)cyclopropyl]propoxy} -1 H-pyrazol-1 -yl)-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17 ,3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 292) (45.2 mg, 27% ).

1H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 8.21 (d, J=2.7 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.63-7.51 (m, 1H) , 7.05 (d, J=7.2 Hz, 1H), 6.99 (s, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 6.12 (d, J= 2.7 Hz, 1H), 4.20 (t, J=6.2 Hz, 2H), 3.92 (s, 1H), 3.15 (s, 1H), 2.95 (d, J=13.4 Hz, 1H), 2.75-2.65 (m, 1H), 2.10 (d, J=18.4 Hz, 1H), 1.85 (dd, J=11.1, 5.2 Hz, 3H), 1.79-1.67 (m, 3H), 1.54 (t, J=12.5 Hz, 3H), 1.39-1.25 (m, 1H), 0.91 (t, J=3.3 Hz, 2H), 0.75 (s, 2H). MS-ESI m/z calc. 653.28784, found 654.4 (M+1)+; Retention time: 2.21 min (LC method B).

Example 99: Preparation of (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}-2-hydroxyethoxy)-1H-pyrazol1 -yl]-12,12-dimethyl-2X ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 1) (compound 294) and (14S)-8-[3-(2{dispiro[2.0.2.1]heptan-7-yl}-2-hydroxyethoxy)-1H-nirazol-1-yl]-12, 12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2 ,2,4-trione (diastereomer 2) (compound 293)

Step 1: (14S)-S-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}-2-hydroxyethoxy)-1 H-pyrazol-1 -yl]-12,12dimethyl-2X ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (diastereomer 1) (compound 294) and (14S)-8-[3-(2-{dispiro[2.0.2.1]gentan-7-yl}-2hydroxyethoxy)-1H-pyrazol-1-yl]-12,12 -dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2, 2,4-trione (diastereomer 2) (compound 293)

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(14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}-2-hydroxyethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl2λ ⁶ -thia-3 ,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4trione (62 mg, 0.09030 mmol) was subjected to chiral separation by SLC chromatography using ChiralCel AS-H (250x10 mm column, 5 μm particle size) with a mobile phase of 38% acetonitrile/methanol (90:10)/62% carbon dioxide at 10 ml /min for 28.0 min (injection volume = 70 μl of a 23 mg/ml solution in acetonitrile/methanol (90:10) to obtain (14S)-8-[3-(2-{dispiro[) as the first diastereomer eluted 2,0.2.1]heptan-7-yl}-2-hydroxyethoxy)-1H-pyrazol-1-yl]12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo [17.3 .1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 1) (compound 294) (16.4 mg, 55% ) as a white solid;

1H NMR (400 MHz, DMSO) δ 12.51 (s, 1H), 8.20 (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=7.2 Hz, 1H), 6.99 (d, J=9.1 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 6.09 (d, J=2.7 Hz, 1H), 4.87 (dd, J=5.2, 1.3 Hz, 1H), 4.09 (d, J=5.5 Hz, 2H), 3.92 (d, J=12.6 Hz, 1H), 3.57 (dt, J=9.2, 5.3 Hz, 1H), 3.16 (d, J=10.0 Hz, 1H), 2.95 (d, J=13.3 Hz, 1H), 2.69 (d, J=9.6 Hz, 1H), 2.12 (s, 1H), 1.86 (dd, J=11.9, 5.2 Hz, 1H), 1.76 (s, 1H), 1.60 (s, 3H), 1.59-1.53 (m, 3H), 1.52 (s, 3H) , 1.31 (k, J=9.4, 7.1 Hz, 1H), 1.08 (ddd, J=8.9, 5.3, 3.6 Hz, 1H), 0.95-0.88 (m, 1H), 0.84 (ddd, J=8.8, 5.2, 3.7 Hz, 1H), 0.73 (ddd, J=8.0, 4.8, 3.3 Hz, 1H), 0.63 (ddd, J=8.7, 5.2, 3.6 Hz, 2H), 0.60-0.54 (m, 2H), 0.52 (dt , J=8.4, 3.8 Hz, 1H); ESI-MS m/z calc. 633.2733, found 634.2 (M+1)+; Retention time: 1.95 min (LC method B) and as the second diastereomer eluted (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}-2hydroxyethoxy)-1H- pyrazol-1-yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19 (23),20-hexaene-2,2,4-trione (diastereomer 2) (compound 293) (17.3 mg, 60%) as a white solid;

1H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 12.52 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.05 (d, J=7.2 Hz, 1H), 6.99 (d, J=8.9 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 6.09 (d, J=2.7 Hz, 1H), 4.88 (d, J=5.2 Hz, 1H), 4.15-4.05 (m, 2H), 3.92 (d, J=11.8 Hz, 1H), 3.57 ( ddd, J=9.2, 4.8, 1.8 Hz, 1H), 3.16 (d, J=9.6 Hz, 1H), 2.95 (d, J=13.2 Hz, 1H), 2.70 (s, 1H), 2.12 (s, 1H ), 1.85 (t, J=6.1 Hz, 1H), 1.76 (s, 1H), 1.61 (s, 3H), 1.59-1.53 (m, 3H), 1.51 (d, J=2.2 Hz, 3H), 1.31 (d, J=12.4 Hz, 1H), 1.08 (ddt, J=8.9, 5.3, 3.6 Hz, 1H), 0.92 (dd, J=8.6, 4.2 Hz, 1H), 0.84 (ddt, J=7.4, 5.2 , 3.5 Hz, 2H), 0.74-0.70 (m, 1H), 0.63 (ddd, J=8.9, 5.3, 3.8 Hz, 1H), 0.59-0.54 (m, 2H), 0.54-0.48 (m, 1H); MS-ESI m/z calc. 633.2733, detected 634.2 (M+1)+; Retention time: 1.95 min (LC method B).

Example 100: Preparation of (14S)-8-(3-{3-hydroxy-3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1Hpyrazol-1-yl)-12,12-dimethyl-2λ ⁶ -thia- 3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 295 )

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Step 1: Ethyl 3-oxo-3-[1-(trifluoromethyl)cyclopropyl]propanoate

To a suspension of (3-ethoxy-3-oxopropanoyl)oxypotassium (23.197 g, 136.29 mmol) in acetonitrile (200 ml) was added triethylamine (21.014 g, 28.945 ml, 207.67 mmol) and dichloromagnesium (15.448 g, 162.25 mmol). The mixture was stirred at room temperature for 2 hours. A mixture of carbonyldiimidazole (12.628 g, 77.878 mmol) and 1-(trifluoromethyl)cyclopropanecarboxylic acid (10 g, 64.898 mmol) in acetonitrile (40 ml) was added to the mixture, and the combined mixture was stirred for nights. The mixture was diluted with ethyl acetate (250 ml) and washed with water (500 ml) and brine (500 ml) before drying over sodium sulfate and then filtered. After concentrating the filtrate in vacuo, the organic residue was purified by silica gel chromatography, eluting with 30% hexanes-ethyl acetate to give ethyl 3-oxo-3-[1-(trifluoromethyl)cyclopropyl]propanoate (3.875 g, 25%).

1H NMR (250 MHz, CDCl3) δ 4.17 (qd, J=7.1, 0.6 Hz, 2H), 3.73 (s, 2H), 1.41-1.32 (m, 3H), 1.24 (td, J=7.1, 0.6 Hz, 4H).

Step 2: Ethyl 3-hydroxy-3-[1-(trifluoromethyl)cyclopropyl]propanoate

To a solution of ethyl 3-oxo-3-[1-(trifluoromethyl)cyclopropyl]propanoate (3.513 g, 15.671 mmol) in EtOH (35.130 ml) was added NaBH ₄ (652.16 mg, 0.6901 ml, 17.238 mmol) at - 78°C. The mixture was stirred at 0°C and then quenched with 1 M aqueous hydrochloric acid (35 ml). The organic layer was extracted with ethyl acetate (3x100 ml), then washed with brine (100 ml) and dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated in vacuo to give ethyl 3-hydroxy-3-[1(trifluoromethyl)cyclopropyl]propanoate (3.31 g, 63%).

¹ H NMR (250 MHz, CDCl ₃ ) δ 4.09 (d, J=7.1 Hz, 2H), 3.89 (s, 1H), 2.70 (d, J=3.1 Hz, 2H), 1.26-1.21 (m, 3H) , 0.96 (d, J=6.9 Hz, 4H).

Step 3: Ethyl 3-[tert-butyl(dimethyl)silyl]oxy-3-[1-(trifluoromethyl)cyclopropyl]propanoate

To a solution of ethyl 3-hydroxy-3-[1-(trifluoromethyl)cyclopropyl]propanoate (3.19 g, 14.103 mmol) in dichloromethane (63.800 ml) was added 2,6-lutidine (3.1734 g, 3.4300 ml, 29.616 mmol) and [tert-butyl(dimethyl)silyl]trifluoromethanesulfonate (5.5918 g, 4.8624 ml, 21.154 mmol) at 0°C. The reaction was stirred at room temperature for 3 hours. The solution was diluted with diethyl ether (60 ml) and washed with 1 M hydrochloric acid (60 ml), saturated sodium bicarbonate (60 ml) and brine (60 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give ethyl 3-[tert-butyl(dimethyl)silyl]oxy-3-[1(trifluoromethyl)cyclopropyl]propanoate (3.51 g, 72%) as a clear liquids.

1H NMR (250 MHz, CDCl ₃ ) δ 4.12 (k, J=7.2 Hz, 2H), 3.95 (ddd, J=8.5, 3.9, 1.1 Hz, 1H), 2.71-2.59 (m, 2H), 1.33-1.19 (m, 3H), 0.89-0.87 (m, 3H), 0.88-0.82 (m, 6H), 0.11-0.05 (m, 4H), 0.04-0.01 (m, 6H).

Step 4: 1-[1-(trifluoromethyl)cyclopropyl]propane-1,3-diol

Lithium aluminum hydride (469.57 mg, 0.5121 ml, 12.372 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with diethyl ether (50 ml) and then quenched with water (0.5 ml), 15% sodium hydroxide (0.5 ml) and water (1.5 ml ) at 0°C and stirred for 30 min. Magnesium sulfate was added and the solid was removed by filtration. The filtrate was concentrated in vacuo and purified by silica gel chromatography using a gradient of 100% hexanes to 100% ethyl acetate to give 1-[1(trifluoromethyl)cyclopropyl]propane-1,3-diol (1.493 g, 73%). in the form of a clear liquid.

¹ H NMR (250 MHz, chloroform-d) δ 4.03-3.67 (m, 3H), 2.83 (d, J=4.2 Hz, 1H), 2.16 (s, 1H), 1.96-1.74 (m, 2H), 1.13-0.93 (m, 2H), 0.93-0.69 (m, 2H).

Step 5: tert-butyl 3-[3-hydroxy-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazole-1carboxylate

To a solution of 1-[1-(trifluoromethyl)cyclopropyl]propane-1,3-diol (1.493 g, 7.5397 mmol), tert-butyl3-hydroxypyrazole-1-carboxylate (1.4582 g, 7.9167 mmol) and triphenylphosphine (3.9550 g, 15.079 mmol) in anhydrous tetrahydrofuran (30 ml) was added dropwise with DIAD (3.0491 g, 15.079 mmol) at 0°C. The reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched with water (30 ml) and tetrahydrofuran was removed under reduced pressure. The product was extracted with ethyl acetate (3x30 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 0% to 50% ethyl acetate in hexanes to give tert-butyl 3-[3hydroxy-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazole-1-carboxylate (1.04 g, 37%) in the form of a clear liquid.

¹ H NMR (250 MHz, chloroform-d) δ 7.84 (d, J=2.9 Hz, 1H), 5.85 (d, J=2.9 Hz, 1H), 4.58 (ddd, J=10.9, 9.4, 3.8 Hz, 1H ), 4.37 (dt, J=10.6, 4.6 Hz, 1H), 3.79 (d, J=10.6 Hz, 1H), 3.70 (s, 1H), 2.31-2.07 (m, 1H), 1.971.75 (m, 1H), 1.60 (s, 9H), 1.06-0.68 (m, 4H). MS-ESI m/z calc. 350.1453, found 351.1 (M+1)+; Retention time: 4.97 min (LC method Q).

Step 6: tert-butyldimethyl-[3-(1H-pyrazol-3-yloxy)-1-[1-(trifluoromethyl)cyclopropyl]propoxy]silane

To a solution of tert-butyl-3-[3-hydroxy-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazole-1 carboxylate (1.04 g, 2.9686 mmol) and 2,6-lutidine (1.5905 g, 1.7191 ml, 14.843 mmol) in anhydrous dichloromethane (50 ml) was added dropwise [tert-butyl(dimethyl)silyl]trifluoromethanesulfonate (3.1387 g, 2.7269 ml, 11.874 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 days, then quenched with 1 N. hydrochloric acid (50 ml). The two layers were separated. The aqueous layer was extracted with dichloromethane (2x50 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 0% to 30% acetone in hexanes to give tert-butyldimethyl-[3-(1Hpyrazol-3-yloxy)-1-[1-(trifluoromethyl)cyclopropyl]propoxy]silane (895 .1 mg, 82%) as a light yellow oil.

1H NMR (250 MHz, DMSO-d ₆ ) δ 11.84 (s, 1H), 7.49 (s, 1H), 5.62 (s, 1H), 4.16-3.98 (m, 2H), 3.64-3.55

- 361 044967 (m, 1H), 2.12-1.85 (m, 2H), 1.07-0.94 (m, 2H), 0.85 (s, 9H), 0.79-0.62 (m, 2H), 0.06 (s, 3H), -0.02 (s, 3H). MSIE m/z calc. 364.1794, detected 365.1 (M+1)+; Retention time: 6.52 min (LC method Q).

Step 7: tert-butyl-6-[3-[3-[tert-butyl(dimethyl)silyl]oxy-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]-2-chloropyridin-3 -carboxylate

To a solution of tert-butyl 2,6-dichloropyridin-3-carboxylate (378 mg, 1.524 mmol) and tert-butyl and methyl-[3-(1H-pyrazol-3-yloxy)-1-[1-(trifluoromethyl)cyclopropyl ]propoxy]silane (500 mg, 1.372 mmol) in dimethyl sulfoxide (10 ml), potassium carbonate (234 mg, 1.693 mmol) was added, followed by 1,4diazabicyclo[2.2.2]octane (37 mg, 0.3298 mmol). The heterogeneous mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was quenched with ice and stirred for 15 minutes. The resulting white solid was collected by filtration and washed with water. The solid was dissolved in dichloromethane and dried over magnesium sulfate. The mixture was filtered and the filtrate was evaporated, and the resulting brown residue was purified by silica gel column chromatography using a shallow gradient of 100% hexane to 100% ethyl acetate to give tert-butyl 6-[3-[3-[tert-butyl(dimethyl)silyl]oxy -3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]-2-chloropyridine-3carboxylate (640 mg, 81%) as a white solid. MS-ESI m/z calc. 575.2194, detected 576.36 (M+1) ⁺ ; retention time: 0.85 min (LC method L).

Step 8: 6-[3-[3-[tert-Butyl(dimethyl)silyl]oxy-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1 -yl]-2-chloropyridine-3-carboxylic acid

tert-Butyl 6-[3-[3-[tert-butyl(dimethyl)silyl]oxy-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]-2-chloropyridine-3-carboxylate (640 mg, 1.111 mmol) was dissolved in a premixed mixture of dichloromethane (2 mL) and trifluoroacetic acid (500 μL, 6.490 mmol), and the reaction mixture was stirred at room temperature for 60 min. The reaction mixture was evaporated and the resulting oil was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous portion was extracted two more times with ethyl acetate, then the organic layers were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give 6-[3-[3-[tert-butyl(dimethyl)silyl]oxy-3-[1-( trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]-2-chloropyridine-3carboxylic acid (540 mg, 93%). MS-ESI m/z calc. 519.1568, detected 520.3 (M+1) ⁺ ; Retention time: 0.6 min (LC method L).

Step 9: tert-butyl-(4S)-4-[3-[[6-[[6-[3-[3-[tert-butyl(dimethyl)silyl]oxy-3-[1(trifluoromethyl)cyclopropyl] propoxy]pyrazol-1-yl]-2-chloropyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate

6-[3-[3-[tert-Butyl(dimethyl)silyl]oxy-3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]2-chloropyridin-3-carboxylic acid (540 mg, 1.038 mmol) and carbonyldiimidazole (204 mg, 1.258 mmol) (freshly recrystallized from tetrahydrofuran, washed with cold ether and dried in vacuo) were combined in tetrahydrofuran (5 ml) and stirred for 2 hours at room temperature. After this, tert-butyl (48)-2,2-dimethyl-4-[3-[(6-sulfamoyl-2-pyridyl) amino]propyl]pyrrolidine-1-carboxylate (431 mg, 1.045 mmol) was added, followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (800 μl, 5.350 mmol) and the reaction was stirred at room temperature for 14 hours. The reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to a light brown oil, which was purified by silica gel chromatography using a shallow gradient of 100% hexanes to 100% ethyl acetate to give tert-butyl (4S) -4-[3[[6-[[6-[3-[3-[tert-butyl(dimethyl)silyl]oxy-3-[1 -(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1 -yl] 2- chloropyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1 carboxylate (572 mg, 60%) as a white solid. MS-ESI m/z calc. 913.36066, detected 914.5 (M+1)+; retention time: 0.79 min (LC method L).

Step 10: (14S)-8-(3-{3-hydroxy-3-[1 -(trifluoromethyl)cyclopropyl]propoxy}-1 H-pyrazol-1 -yl)12,12-dimethyl-2λ ⁶ -thua- 3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 295 )

Solution of tert-butyl (4S)-4-[3-[[6-[[6-[3-[3-[tert-butyl(dimethyl)silyl]oxy-3-[1(trifluoromethyl)cyclopropyl]propoxy]pyrazole -1-yl]-2-chloropyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (572 mg, 0.6254 mmol) in dichloromethane (4.8 ml) and trifluoroacetic acid (1.2 ml, 15.68 mmol) were stirred at room temperature for 4 hours. Solvents were evaporated, the residue was dissolved in ethyl acetate, washed with 2 ml saturated sodium bicarbonate solution, the solvent was removed and dried in vacuum. The resulting residue was dissolved in dimethyl sulfoxide (15 ml), 3 A molecular sieves were added and the reaction mixture was stirred for 10 minutes. Cesium fluoride (301 mg, 1.982 mmol) and potassium carbonate (284 mg, 2.055 mmol) were then added and the reaction mixture was heated at 150°C for 16 hours. The reaction mixture was cooled to room temperature and filtered through celite, and the filtrate was added saturated ammonium chloride solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated.

The resulting brown residue was purified by silica gel column chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate to give (14S)-8-(3-{3-hydroxy-3-[1(trifluoromethyl)cyclopropyl]propoxy}-1 N-pyrazol-1-yl)-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9 ,19(23),20-hexaene-2,2,4-trione (compound 295) (192 mg, 46%) as an off-white solid.

1H NMR (400 MHz, chloroform-d) δ 9.77 (s, 1H), 8.20 (dd, J=2.7, 1.1 Hz, 1H), 8.02 (dd, J=8.4, 0.9 Hz, 1H), 7.54 (d, J=7.5 Hz, 1H), 7.47 (dt, J=7.4, 1.1 Hz, 1H), 7.15 (d, J=8.3 Hz, 1H), 6.54 (d, J=8.2 Hz, 1H), 5.92 (d, J=2.7 Hz, 1H), 4.70 (s, 1H), 4.57 (dddd, J=11.1, 9.1, 4.0, 2.1 Hz, 1H), 4.40 (dt, J=10.5, 5.1 Hz, 1H), 3.90 (s , 1H), 3.80 (dd, J=10.0, 2.5 Hz, 1H), 3.32 (dd, J=10.1, 7.4 Hz, 1H), 3.16 (d, J=13.7 Hz, 1H), 3.08-2.94 (m, 1H), 2.53 (d, J=11.2 Hz, 1H), 2.28-2.16 (m, 1H), 2.11-1.89 (m, 2H), 1.70-1.49 (m, 10H), 1.09-0.93 (m, 2H) , 0.92-0.80 (m, 2H). MS-ESI m/z calc. 663.24506, detected 664.17 (M+1) ⁺ ; retention time: 1.93 min (LC method B).

Example 101: Preparation of (14S)-8-(3-{3-hydroxy-3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1Hπyrazol-1-yl)-12,12-dimethyl-2λ ⁶ -thia- 3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 1 ) (compound 296) and (14S)-8-(3-{3-hydroxy-3[ 1 -(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1 -yl)-12,12-dimethyl-2λ ⁶ - thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione ( diastereomer 2) (compound 297)

Step 1: (148)-8-(3-{3-hydroxy-3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1-yl)- 363 044967

12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene -2,2,4-trione (diastereomer 1) (compound 296) and (14S)-8-(3-{3-hydroxy-3[ 1 -(trifluoromethyl)cyclopropyl] propoxy} -1 H-pyrazole-1 - yl)-12,12-dimethyl-2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23), 20-hexaene-2,2,4-trione (diastereomer

2) (connection 297)

(14S)-8-(3-{3-hydroxy-3-[1-(trifluoromethyl)cyclopropyl]nроnoxy}-1Н-pyrazol-1-yl)-12,12dimethyl-2Х ⁶ -thia-3,9,11 ,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (187 mg) was subjected to chiral resolution with by SLC chromatography using a Chiral Pak IG column (250x21.2 mm) (particle size 5 µm) with a mobile phase of 38% methanol, 62% carbon dioxide at 70 ml/min for 8.0 min (injection volume = 500 µl ~ 31 mg/ml in a mixture of acetonitrile:methanol (90:10)) to obtain (14S)8-(3-{3-hydroxy-3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1 as the first eluted diastereomer N-pyrazol-1 -yl)-12,12-dimethyl-2Х ⁶ -thia3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9 ,19(23),20-hexaene-2,2,4-trione (diastereomer 1) (compound 296) (59.2 mg, 32%) as a white solid;

Ή NMR (400 MHz, DMSO-06) δ 12.50 (s, 1H), 8.21 (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=7.1 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.5 Hz , 1H), 6.13 (d, J=2.7 Hz, 1H), 5.23 (d, J=5.7 Hz, 1H), 4.31 (dd, J=8.2, 5.6 Hz, 2H), 3.92 (d, J=12.8 Hz , 1H), 3.69 (t, J=7.0 Hz, 1H), 3.17 (d, J=4.7 Hz, 1H), 2.95 (d, J=13.2 Hz, 1H), 2.76-2.66 (m, 1H), 2.08 (dd, J=12.4, 7.7 Hz, 2H), 1.82 (dtd, J=16.6, 11.7, 6.2 Hz, 3H), 1.61 (s, 3H), 1.60-1.53 (m, 2H), 1.52 (s, 3H ), 1.30 (dt, J=24.6, 12.0 Hz, 1H), 0.93-0.81 (m, 4H); MS-ESI m/z calc. 663.24506, detected 664.11 (M+1)+; Retention time: 1.94 min (LC method B), and as the second diastereomer eluted (14S)-8-(3-{3-hydroxy-3-[1(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol- 1-yl)-12,12-dimethyl-2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23 )20-hexaene-2,2,4-trione (diastereomer 2) (compound 297) (57.8 mg, 31%) as a white solid;

¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 12.51 (s, 1H), 8.21 (d, J=2.7 Hz, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.63-7.54 (m, 1H), 7.05 (d, J=7.1 Hz, 1H), 6.98 (s, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 6.12 (d, J=2.7 Hz, 1H), 5.24 (d, J=5.7 Hz, 1H), 4.31 (dd, J=7.6, 5.0 Hz, 2H), 3.92 (d, J=13.3 Hz, 1H), 3.69 (t, J=7.4 Hz, 1H), 3.17 (d, J=5.0 Hz, 1H), 2.95 (d, J=13.4 Hz, 1H), 2.69 (d, J=16.0 Hz, 1H), 2.20-2.01 (m, 2H), 1.83 (ddd, J=25.2, 11.4, 6.3 Hz, 3H), 1.61 (s, 3H), 1.57 (d, J=12.7 Hz, 2H), 1.52 (s, 3H), 1.31 (k, J =12.5, 12.1 Hz, 1H), 0.87 (d, J=8.1 Hz, 4H); MS-ESI m/z calc. 663.24506, found 664.11 (M+1) ⁺ ; Retention time: 1.94 min (LC method B).

Example 102: Preparation of (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}-1,1,2,2-tetradeuteroethoxy)1H-pyrazol-1-yl] -12,12-dimethyl-2X ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5(10),6,8,19(23) ,20-hexaene-2,2,4-trione (compound 299)

- 364 044967

Step 1: 1,1,2,2-tetradeutero-2-dispiro[2.0.2.1]heptan-7-ylethanol

Lithium aluminum deuteride (2.8120 g, 68.955 mmol) was weighed into a reaction flask placed in an ice water bath under a nitrogen cylinder. Tetrahydrofuran (160 ml) was added slowly. The mixtures were left stirring in an ice water bath for 10 min. 2,2-dideutero-2-dispiro[2.0.2.1]heptan-7-yl-acetic acid (10.85 g, 63.326 mmol), separately dissolved in tetrahydrofuran (40 ml), was quickly added dropwise through a syringe. The mixture was allowed to warm to room temperature and stirred for 15 hours at room temperature. It was then re-cooled in an ice water bath. A Rochelle salt solution was added in small portions to quench the unreacted lithium aluminum deuteride. After quenching was completed, more Rochelle solution (200 ml) was added. The mixture was stirred at room temperature for 10 minutes and the layers were separated. The aqueous layer was extracted with ether (3x60 ml). The combined organic layers were then washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated at 30°C, 100 mbar to give 1,1,2,2-tetradeutero-2-dispiro[2.0.2.1]heptan-7-ylethanol ( 9.72 g, 97%, 90% purity) as a slightly yellow liquid.

Ή NMR (250 MHz, DMSO-a ₆ ) δ 1.34 (s, 1H), 0.76 (k, J=8.6, 7.1 Hz, 4H), 0.67-0.53 (m, 2H), 0.53-0.33 (m, 2H) .

Step 2: tert-butyl-3-(1,1,2,2-tetradeutero-2-dispiro[2.0.2.1] heptan-7-ylethoxy)pyrazole-1 carboxylate

To a solution of tert-butyl-5-oxo-1H-pyrazole-2-carboxylate (6.235 g, 33.85 mmol) and 1,1,2,2tetradeutero-2-dispiro[2.0.2.1]heptan-7-yl-ethanol (5.0 g, 35.15 mmol) in tetrahydrofuran (80 ml) was added triphenylphosphine (9.37 g, 35.72 mmol). Diisopropyl azodicarboxylate (7.0 mL, 35.55 mmol) was added dropwise slowly over 10 min (exothermic). The reaction mixture was stirred at room temperature for 2 hours. Tetrahydrofuran was removed in vacuo. The crude product was purified by silica gel chromatography using a shallow gradient of 100% hexanes to 20% ethyl acetate in hexanes to give tert-butyl-3-(1,1,2,2-tetradeutero-2-365 044967 dispiro[2.0.2.1]heptane -7-ylethoxy)pyrazole-1-carboxylate (7.4 g, 71%) as a clear syrup.

1H NMR (400 MHz, chloroform-d) δ 7.82 (d, J=2.9 Hz, 1H), 5.84 (d, J=2.9 Hz, 1H), 1.61 (s, 9H), 1.44 (s, 1H), 0.83 (k, J=1.9 Hz, 4H), 0.68-0.61 (m, 2H), 0.52-0.45 (m, 2H). MS-ESI m/z calc. 308.2038, found 309.2 (M+1)+; Retention time: 2.08 min (LC method E).

Step 3: 3-(1,1,2,2-tetradeutero-2-dispiro[2.0.2.1]heptan-7-ylethoxy)-1H-pyrazole

To the flask containing tert-butyl 3-(1,1,2,2-tetradeutero-2-dispiro[2.0.2.1]heptan-7ylethoxy)pyrazole-1-carboxylate (7.4 g, 23.99 mmol) dichloromethane (125 ml) and trifluoroacetic acid (45 ml, 584.1 mmol). After 30 minutes, the mixture was evaporated to dryness and neutralized with saturated sodium bicarbonate. The reaction mixture was extracted with ethyl acetate and the organic layer was dried over sodium sulfate, filtered and evaporated to give a colorless oil, 3-(1,1,2,2-tetradeutero-2dispiro[2.0.2.1]heptan-7-ylethoxy)-1H-nirazole (4.95 g, 99%). MS-ESI m/z calc. 208.15137, detected 209.2 (M+1) ⁺ ; Retention time: 1.46 min (LC method E).

Step 4: tert-butyl-2-chloro-6-[3 -(1,1,2,2-tetradeutero-2-dispiro[2.0.2.1]heptan-7ylethoxy)pyrazol-1 -yl]pyridin-3-carboxylate

tert-Butyl 2,6-dichloropyridine-3-carboxylate (6.05 g, 24.38 mmol), 3-(1,1,2,2-tetradeutero-2dispiro[2.0.2.1]heptan-7-ylethoxy)- 1H-pyrazole (5.04 g, 24.20 mmol) and potassium carbonate (7.4 g, 53.54 mmol) were combined in anhydrous dimethyl sulfoxide (125 ml). 1,4-Diazabicyclo[2.2.2]octane (545 mg, 4.859 mmol) was added and the mixture was stirred at room temperature under nitrogen for 18 hours. The reaction mixture was diluted with water (75 ml) and stirred for 15 minutes. The resulting solid was filtered, collected and dried in vacuo overnight. The remaining filtrate was diluted with ethyl acetate and washed with water (3x50 ml). The organic layers were combined and washed with brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 100% hexanes to 60% ethyl acetate in hexanes to give a light yellow oil, which was dried in vacuo to give a pale yellow solid, which was combined with the pre-filtered solid to give tert-butyl 2-chloro-6-[3-(1,1,2,2-tetradeutero-2dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3-carboxylate (9.95 g, 98 %).

¹ H NMR (400 MHz, chloroform-d) δ 8.35 (d, J=2.9 Hz, 1H), 8.19 (d, J=8.5 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 5.94 ( d, J=2.8 Hz, 1H), 1.62 (s, 9H), 1.48 (s, 1H), 0.88-0.81 (m, 4H), 0.70-0.62 (m, 2H), 0.51 (dt, J=10.7, 1.5 Hz, 2H). MS-ESI m/z calc. 419.19138, found 420.2 (M+1) ⁺ ; Retention time: 2.58 min (LC method E).

Step 5: 2-chloro-6-[3-(1,1,2,2-tetradeutero-2-dispiro[2.0.2.1]heptan-7-yl-ethoxy)pyrazol-1yl]pyridine-3-carboxylic acid

tert-butyl 2-chloro-6-[3-(1,1,2,2-tetradeutero-2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1yl]pyridine-3-carboxylate (13.15 g, 31.31 mmol) was dissolved in dichloromethane (250 ml). Trifluoroacetic acid (50 mL, 649.0 mmol) was slowly added to the mixture and the mixture continued to stir at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to a solid, which was then suspended in diethyl ether and filtered (2X), to resulting in a solid which was recrystallized from dichloromethane and collected by filtration to give a white solid (collection 1). The product remained in the dichloromethane filtrate, which was evaporated to leave an off-white solid, which was dissolved in ethyl acetate and washed with 5N. sodium hydroxide (2x), then 1 N. hydrochloric acid (1x), then dried

- 366 044967 (sodium sulfate), filtered and concentrated to a white solid, which was chromatographed on a 150 g reverse phase C ₁₈ column loading dimethyl sulfoxide and eluting with a gradient from

50% to 100% acetonitrile in water to give (after combining with filtered solid of cut 1) 2-chloro-6-[3-(1,1,2,2-tetradeutero-2-dispiro[2.0.2.1]heptane -7-ylethoxy)pyrazol-1yl]pyridine-3-carboxylic acid (9.05 g, 79%) as a white solid.

1H NMR (400 MHz, DMSO-4 ₆ ) δ 13.61 (s, 1H), 8.53-8.28 (m, 2H), 7.72 (d, J=8.4 Hz, 1H), 6.17 (d, J=2.9 Hz, 1H ), 1.46(s, 1H), 0.87-0.79 (m, 4H), 0.68-0.61 (m, 2H), 0.53-0.45 (m, 2H). MS-ESI m/z calc. 363.12878, detected 364.3 (M+1)+; retention time: 1.45 min (LC method G).

Step 6: tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-(1,1,2,2-tetradeutero-2-dispiro[2.0.2.1]heptane -7yl-ethoxy)pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate

To a solution of 2-chloro-6-[3-(1,1,2,2-tetradeutero-2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1yl]pyridine-3-carboxylic acid (200 mg, 0.5497 mmol) in tetrahydrofuran (1.5 ml), carbonyldiimidazole (110 mg, 0.6784 mmol) (recrystallized from tetrahydrofuran) was added and the mixture was stirred at room temperature for 3 hours, then tert-butyl (4S)- 2,2-dimethyl-4-[3[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (240 mg, 0.5818 mmol) as a solution in tetrahydrofuran (500 µl) followed by addition 1,8-diazabicyclo[5.4.0]undec-7-ene (250 µl, 1.672 mmol) and the resulting mixture was stirred for 18 hours at room temperature. The reaction mixture was diluted with water and ethyl acetate, then hydrochloric acid (600 μl of 6 M, 3,600 mmol) was added (the aqueous layer was then pH 1). The layers were separated and the organic layer was washed with water (1X) and brine (1X), then dried over sodium sulfate, filtered and concentrated to a white foam, which was purified on a reverse phase C ₁₈ column eluting with a gradient of 50%-100% acetonitrile in water to form tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-(1,1,2,2tetradeutero-2-dispiro[2.0.2.1]heptane-7 -ylethoxy)pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (190 mg, 46%) as an off-white solid. MS-ESI m/z calc. 757.33264, detected 758.3 (M+1) ⁺ ; retention time: 2.14 min (LC method G).

Step 7: (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}-1,1,2,2-tetradeuteroethoxy)-1H-pyrazol-1yl]-12 ,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5(10),6,8,19(23),20 -hexaene-2,2,4-trione (compound 299)

tert-Butyl (48)-4-[3-[[6-[[2-chloro-6-[3-(1,1,2,2-tetradeutero-2-dispiro[2.0.2.1]heptan-7ylethoxy) pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2dimethylpyrrolidine-1-carboxylate (160 mg, 0.2110 mmol) was dissolved in dichloromethane (5 ml), and Trifluoroacetic acid (525 μL, 6.814 mmol) was added to the mixture, and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was concentrated to dryness under reduced pressure, 25 ml of toluene was added and removed by rotary evaporation. 25 mL of toluene was added again and removed by rotary evaporation, then dried in vacuo overnight to leave a residue which was combined with potassium carbonate (205 mg, 1.483 mmol), 3 A molecular sieves and NMP (9.5 mL) in a purged vial nitrogen, capped, heated to 155°C and stirred for 5 hours. Cooled to room temperature and the mixture was filtered, diluted with ethyl acetate and washed with water (2x20 ml), and then with brine. The organic layer was further washed with water, dried over sodium sulfate, filtered and evaporated. The residue was purified on a C ₁₈ reverse phase column, eluting with a gradient of 50% to 100% acetonitrile in water to give material, which was then subjected to silica gel column chromatography using a shallow gradient of 100% dichloromethane to 10% methanol in dichloromethane to give as an off-white solid, (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7yl}-1,1,2,2-tetradeuteroethoxy)-1H-pyrazol-1-yl] -12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5(10),6,8,19(23) ,20-hexaene-2,2,4-trione (compound 299) (79.04 mg, 60%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.51 (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=7.1 Hz, 1H), 6.99 (s, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.6 Hz, 1H) , 6.08 (d,

J=2.8 Hz, 1H), 3.92 (d, J=12.7 Hz, 1H), 3.15 (s, 1H), 2.95 (d, J=13.3 Hz, 1H), 2.78-2.63 (m, 1H), 2.12 ( s, 1H),

1.85 (dd, J=11.8, 5.2 Hz, 1H), 1.77 (s, 1H), 1.60 (s, 5H), 1.55 (s, 1H), 1.51 (s, 3H), 1.45 (s, 1H), 1.30 (dt,

J=23.8, 11.4 Hz, 1H), 0.87-0.79 (m, 4H), 0.69-0.60 (m, 2H), 0.53-0.46 (m, 2H). MS-ESI m/z calc. 621.3035, detected 622.3 (M+1)+; retention time: 1.87 min (LC method G).

Example 103: Preparation of (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}-2,2-dideuteroethoxy)-1Hpyrazol-1 -yl]-12,12- dimethyl(20-deutero)-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2 ,2,4-trione (compound 298)

Step 1: tert-butyl (4S)-4-[3-[[3-benzyloxy-6-[[2-chloro-6-[3-(2,2-dideutero-2dispiro[2.0.2.1]heptane-7 -yl-ethoxy)pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

2-Chloro-6-[3-(2,2-dideutero-2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3-carboxylic acid (1.5 g, 4.146 mmol) and carbonyldiimidazole (831 mg, 5.125 mmol) (freshly recrystallized from tetrahydrofuran, washed with cold ether and dried in high vacuum) was combined in tetrahydrofuran (10 ml) and stirred for 2 hours at room temperature. Then tert-butyl (4S)-4-[3-[(3-benzyloxy-6-sulfamoyl-2-pyridyl)amino]propyl]-2,2dimethylpyrrolidine-1-carboxylate (1.5 g, 2.892 mmol) was added. and then 1,8-diazabicyclo[5.4.0]undec-7-ene (3.2 ml, 21.40 mmol), and the reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was quenched with saturated ammonium chloride solution and extracted ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting brown residue was purified by silica gel column chromatography using a fine gradient from 100% hexanes to 100% ethyl acetate to give tert-butyl (4S)-4-[3-[[3benzyloxy-6-[[2-chloro-6-[ 3-(2,2-dideutero-2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine -1-carboxylate (2.2 g, 62%) as an off-white solid. MS-ESI m/z calc. 861.36194, detected 862.3 (M+1)+; retention time: 0.76 min (LC method L).

Step 2: (14S)-20-(benzyloxy)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}(2,2-dideutero)ethoxy)-1H- 368 044967 pyrazol- 1-yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23 ),20-hexaene-2,2,4-trione

Solution of tert-butyl (4S)-4-[3-[[3-benzuloxy-6-[[2-chloro-6-[3-(2,2-dideutero-2-dispiro[2.0.2.1]heptane-7 -ylethoxy)pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2dimethylpyrrolidine-1-carboxylate (2.2 g, 2.551 mmol) in dichloromethane (16 ml) and trifluoroacetic acid (4 mL, 52.27 mmol) was stirred at room temperature for 2 hours. Reaction solvents were removed by evaporation. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate (2 ml), the organic layer was collected and the solvent was removed. The resulting residue was dissolved in dimethyl sulfoxide (50 ml) and oven-dried 4 A MS was added and the mixture was stirred for 10 minutes. Cesium fluoride (1.2 g, 7.900 mmol) and potassium carbonate (1.1 g, 7.959 mmol) were then added and the reaction mixture was heated at 150°C for 16 hours. The reaction mixture was cooled to room temperature and filtered through celite. washed with ethyl acetate and added saturated ammonium chloride solution. The mixture was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting brown residue was purified by silica gel column chromatography using a fine gradient from 100% hexanes to 100% ethyl acetate to give (14S)-20(benzyloxy)-8-[3-(2-{dispiro[2.0.2.1]heptane- 7-yl}(2,2-dideutero)ethoxy)-1H-pyrazol-1-yl]-12,12dimethyl-2λ ⁶ -thua-3,9,11,18,23-pentaαzatetracyclo[17.3.1.111.14, 05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (1.26 g, 68%) as an off-white solid.

1H NMR (400 MHz, chloroform-d) δ 9.99 (s, 1H), 8.19 (d, J=2.7 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H), 7.53 (d, J=8.0 Hz , 1H), 7.47-7.36 (m, 5H), 7.27-7.23 (m, 1H), 6.98 (d, J=8.1 Hz, 1H), 5.89 (d, J=2.7 Hz, 1H), 5.30 (d, J=8.4 Hz, 1H), 5.10 (s, 2H), 4.23 (s, 2H), 3.92 (s, 1H), 3.35 (dd, J=10.1, 7.4 Hz, 1H), 3.19 (d, J=14.1 Hz, 1H), 3.05 (t, J=9.9 Hz, 1H), 2.63 (s, 1H), 2.14-2.05 (m, 1H), 1.62 (t, J=3.2 Hz, 11H), 1.48 (s, 1H ), 0.85 (k, J=2.5 Hz, 4H), 0.71-0.60 (m, 2H), 0.55-0.43 (m, 2H). MS-ESI m/z calc. 725.3328, found 726.45 (M+1)+; Retention time: 0.7 min (LC method L).

Step 3: (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}(2,2-dideutero)ethoxy)-1H-pyrazol-1-yl]-20hydroxy-12 ,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1 (23),5,7,9,19,21-hexaene-2,2 ,4-trione

To a stirred solution of (14S)-20-(benzuloxy)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}(2,2dideutero)ethoxy)-1 H-pyrazol-1 -yl ] -12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20 -hexaene-2,2,4-trione (500 mg,

0.6888 mmol) in EtOH (10 ml) was added 10% palladium on carbon (wet, Degussa, 155 mg, 0.1456 mmol) under nitrogen atmosphere. The heterogeneous mixture was stirred in a hydrogen cylinder for 2 hours at ambient temperature and the black heterogeneous reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give (14S)-8-[3-(2{dispiro[2.0.2.1]heptan-7-yl} (2,2-dideutero)ethoxy)-1H-pyrazol-1-yl] -20-hydroxy-12,12-dimethyl-2λ ⁶ thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23),5,7,9,19, 21-hexaene-2,2,4-trione (156 mg, 36%) as a light brown solid.

1H NMR (400 MHz, DMSO-a ₆ ) δ 12.31 (s, 1H), 10.84 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.07 (d, J=7.7 Hz, 1H), 6.91 (dd, J=9.6, 7.9 Hz, 2H), 6.17 (s, 1H), 6.07 (d, J=2.7 Hz, 1H), 4.20 (d, J =1.5 Hz, 2H), 3.92 (s, 1H), 3.18 (s, 1H), 2.99 (d, J=13.1 Hz, 1H), 2.68 (s, 1H), 2.11 (d, J=6.6 Hz, 1H ), 1.97-1.81 (m, 2H), 1.66-1.48 (m, 9H), 1.45 (s, 1H), 1.24 (k, J=11.7 Hz, 1H), 0.87-0.79 (m, 4H), 0.69- 0.59 (m, 2H), 0.56-0.43 (m, 2H). MS-ESI m/z calc. 635.2859, detected 636.39 (M+1) ⁺ ; Retention time: 0.54 min (LC method L).

Step 4: (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}(2,2-dideutero)ethoxy)-1H-pyrazol-1-ul]-

12,12-dimethyl-2,2,4-trioxo-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1 (23),5,7,9, 19,21-hexaen-20-yl 4-methylbenzene-1-sulfonate

- 369 044967

To a stirred solution of (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}(2,2-dideutero)ethoxy)1 H-pyrazol-1 -yl]-20-hydroxy -12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23), 5,7,9,19,21-hexaene-2 ,2,4-trione (50 mg, 0.07864 mmol) in anhydrous dichloromethane (2 ml) was added 4-methylbenzenesulfonyl chloride (17.8 mg, 0.09337 mmol), triethylamine (30 μl, 0.2152 mmol) and catalytic amount of N,N-dimethylpyridin-4-amine (2.7 mg, 0.02210 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The resulting brown residue was purified by silica gel column chromatography using a fine gradient from 100% hexanes to 100% ethyl acetate to give (14S)-8[3-(2-{dispiro[2.0.2.1]heptan-7-yl} (2 ,2-dideutero)ethoxy)-1 H-pyrazol-1-yl]-12,12-dimethyl-2,2,4trioxo-2Х ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17,3.1 .111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaen20-yl 4-methylbenzene-1-sulfonate (36 mg, 58%) as a white solid.

¹ H NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.80 (d, J=8.3 Hz, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.12 (d, J=8.1 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.76 (s, 1H), 6.08 (d, J=2.7 Hz, 1H), 4.20 (d, J=1.1 Hz, 2H), 3.77 (d, J=13.2 Hz, 1H), 3.34 (m, 1H), 3.03 (s, 1H), 2.79 (d, J=13.2 Hz, 1H), 2.50 (p, J=1.8 Hz, 1H), 2.42 (s, 3H), 2.03 (s, 1H), 1.83 ( dd, J=11.8, 5.3 Hz, 2H), 1.58 (s, 3H), 1.51 (s, 3H), 1.48-1.32 (m, 4H), 0.88-0.76 (m, 4H), 0.68-0.59 (m, 2H), 0.54-0.40 (m, 2H). MS-ESI m/z calc. 789.29474, detected 690.18 (M+1)+; Retention time: 0.67 min (LC method L).

Step 5: (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}-2,2-dideuteroethoxy)-1H-pyrazol-1-yl] 12.12 -dimethyl(20-deutero)-2X ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5,7,9,19,21-hexaene- 2,2,4-trione (compound 298)

Solution of (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}(2,2-dideutero)ethoxy)-1H-pyrazol-1-yl]-12,12dimethyl-2 ,2,4-trioxo-2Х ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5,7,9,19,21-hexaene-20 -yl-4-methylbenzene-1-sulfonate (70 mg, 0.088 mmol) in dry N,Ndimethylformamide (2 ml) was purged with nitrogen for 5 min using a balloon. Dichloronickel, triphenylphosphane (15 mg, 0.023 mmol) and tricyclohexylphosphane (18 mg, 0.064 mmol) were then added. The resulting green solution was stirred for 5 min under a nitrogen atmosphere and tetradeuteroboranuide (sodium salt) (50 mg, 1.195 mmol) was added in one portion. The resulting dark reddish brown mixture was stirred at room temperature for 1 hour. Additionally, dichloronickel, triphenylphosphane (15 mg, 0.023 mmol), tricyclohexylphosphane (18 mg, 0.064 mmol) and tetradeuteroboranuide (sodium salt) (50 mg, 1.195 mmol) were added, and the mixture was stirred at room temperature under nitrogen atmosphere overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, filtered and evaporated. The resulting residue was dissolved in dimethyl sulfoxide and filtered through a Whatman disk filter (puradisc 25 TF), and the filtrate was purified by reverse phase HPLC-MS using a dual gradient from 50% to 99% mobile phase B over 15.0 min (mobile phase A=water (5 mM hydrochloric acid), mobile phase B=acetonitrile) to give (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}2,2-dideuteroethoxy )-1 H-pyrazol-1 -yl]-12,12-dimethyl(20-deutero)-2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1( 23),5,7,9,19,21-hexaene-2,2,4-trione (compound 298) (22.8 mg, 41%) as a white solid.

¹ H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.57 (d,

J=7.3 Hz, 1H), 7.05 (d, J=7.2 Hz, 1H), 7.00 (s, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.08 (d, J=2.7 Hz, 1H) , 4.20(d,

J=1.4 Hz, 2H), 3.92 (d, J=12.4 Hz, 1H), 3.16 (s, 1H), 2.95 (d, J=13.2 Hz, 1H), 2.71 (t, J=10.8 Hz, 1H) , 2.13(s,

1H), 1.86 (dd, J=11.8, 5.3 Hz, 1H), 1.77 (s, 1H), 1.60 (s, 5H), 1.51 (s, 3H), 1.46 (s, 1H), 1.31 (k, J =12.6, 12.2 Hz, 1H), 0.90-0.78 (m, 5H), 0.68-0.62 (m, 2H), 0.53-0.46 (m, 2H). MS-ESI m/z calc. 620.29, detected 621.24 (M+1)+; retention time: 1.3 min (LC method J).

Example 104: Preparation of (148)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-370 044967 dimethyl(20 -deutero)-2Х ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5,7,9,19,21-hexaene-2,2, 4-trione (compound 300)

Step 1: (14S)-8-[3-(2-{dispo[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl2,2,4- trioxo-2Х ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21hexaen-20-yl 4-methylbenzene -1-sulfonate

To a stirred solution of (14S)-8-[3-(2-{disniro[2.0.2.1]heptan-7-yl}ethokCi)-1H-pyrazol-1yl]-20-hydroxy-12,12-dimethyl-2Х ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5,7,9,19,21-hexaene-2,2,4-trione (150 mg , 0.2367 mmol) in anhydrous dichloromethane (3.000 ml) was added 4-methylbenzenesulfonyl chloride (58 mg, 0.3042 mmol), triethylamine (80 μl, 0.5740 mmol) and a catalytic amount of N,N-dimethylpyridin-4-amine ( 10 mg, 0.08185 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The resulting brown residue was purified by silica gel column chromatography using a fine gradient from 100% hexanes to 100% ethyl acetate to give (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy) -1H-nirazol-1-yl]-12,12dimethyl-2,2,4-trioxo-2Х ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23 ),5,7,9,19,21-hexaen-20-yl-4-methylbenzene-1-sulfonate (120 mg, 51%) as a white solid. MS-ESI m/z calc. 787.28217, detected 788.42 (M+1)+; retention time: 1.39 min (LC method J).

Step 2: (148)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl(20deutero)-2X ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene2,2,4-trione (compound 300)

Solution (148)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2,2,4trioxo- 2Х ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23),5,7,9,19,21-hexaen20-yl 4-methylbenzene-1 β-sulfonate (120 mg, 0.1523 mmol) in dry N,N-dimethylformamide (1 ml) was purged with nitrogen for 5 min using a balloon. Dichloronickel, triphenylphosphane (30 mg, 0.04586 mmol) and tricyclohexylphosphane (34 mg, 0.1212 mmol) were then added. The resulting green solution was stirred for 5 min under a nitrogen atmosphere and tetradeuteroboranuide (sodium salt) (87 mg, 2.079 mmol) was added in one portion. The resulting dark reddish brown mixture was stirred at room temperature for 1 hour. Additionally, dichloronickel, triphenylphosphane (30 mg, 0.04586 mmol), tricyclohexylphosphane (34 mg, 0.1212 mmol) and tetradeuteroboranuide (sodium salt) (87 mg) were added , 2.079 mmol), and the mixture was stirred at room temperature under nitrogen atmosphere overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated. The resulting residue was dissolved in dimethyl sulfoxide and filtered through a Whatman disk filter (puradisc 25 TF), and the filtrate was purified by reverse phase HPLC-MS using a dual gradient from 50% to 99% of liquid phase B over 15.0 min (mobile phase A=water (5 mM hydrochloric acid), mobile phase B=acetonitrile) to give (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)- 1Hpyrazol-1 -yl]-12,12-dimethyl(20-deutero)-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23),5, 7,9,19,21-hexaene-2,2,4-trione (compound 300) (35 mg, 37%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.52 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.56 (d, J= 7.1 Hz, 1H), 7.04 (d, J=7.2 Hz, 1H), 6.98 (s, 1H), 6.90 (d, J=8.1 Hz, 1H), 6.08 (d, J=2.7 Hz, 1H), 4.25 -4.17 (m, 2H), 3.92 (d, J=12.5 Hz, 1H), 3.17 (s, 1H), 2.94 (d, J=13.2 Hz, 1H), 2.72 (s, 1H), 2.20-2.06 ( m, 1H), 1.81 (k, J=6.6 Hz, 4H), 1.60 (s, 3H), 1.56 (d, J=13.5 Hz, 2H), 1.51 (s, 3H), 1.46 (d, J=6.5 Hz, 1H), 1.36-1.26 (m, 1H), 1.23 (s, 1H), 0.87-0.76 (m, 4H), 0.70-0.59 (m, 2H), 0.50 (dd, J=8.0, 4.3 Hz, 2H). MS-ESI m/z calc. 618.2847, detected 619.25 (M+1)+; retention time: 1.28 min (LC method J).

Example 105: Preparation of (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-ul}-1,1,2,2-tetradeuteroethoxy)1H-pyrazol-1-yl ] -12,12-dimethyl(20-deutero)-2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23),5,7,9,19 ,21-hexaene-2,2,4-trione (compound 301)

Step 1: tert-butyl (4S)-4-[3-[[3-benzyloxy-6-[[2-chloro-6-[3-(1,1,2,2-tetradeutero-2dispiro[2.0.2.1 ]heptan-7-yl-ethoxy)pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

To a solution of 2-chloro-6-[3-(1,1,2,2-tetradeutero-2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1yl]pyridine-3-carboxylic acid (500 mg, 1.374 mmol) in dry tetrahydrofuran (5 ml), carbonyldiimidazole (207 mg, 1.277 mmol) was added and the mixture was stirred for 2 hours at room temperature. Then tert-butyl (4S)-4-[3-[(3-benzyloxy-6-sulfamoyl-2-pyridyl)amino]propyl]-2,2dimethylpyrrolidine-1-carboxylate (410 mg, 0.7905 mmol) was added. and then 1,8-diazabicyclo[5.4.0]undec-7-ene (600 µl, 4.012 mmol), and the reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate), filtered and concentrated. The resulting brown residue was purified by silica gel column chromatography using a fine gradient from 100% hexanes to 100% ethyl acetate to give tert-butyl(4S)-4-[3[[3-benzyloxy-6-[[2-chloro-6- [3-(1,1,2,2-tetradeutero-2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]- 2,2-dimethylpyrrolidine-1-carboxylate (436 mg, 37%) as an off-white foamy solid. MS-ESI m/z calc. 863.3745, detected 864.47 (M+1) ⁺ ; retention time: 1.74 min (LC method L).

Step 2: (14S)-20-(benzyloxy)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}-1,1,2,2-tetradeuteroethoxy)1H-pyrazole -1-yl]-12,12-dimethyl-2Х ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19( 23),20-hexaene-2,2,4-trione

- 372 044967

A solution of tert-butyl (4S)-4-[3-[[3-benzyloxy-6-[[2-chloro-6-[3-(1,1,2,2-tetradeutero-2dispiro[2,0.2. 1 ]heptan-7-ylethoxy)pyrazol-1 -yl]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (436 mg, 0.5043 mmol) in trifluoroacetic acid (400 µl, 5.192 mmol) and dichloromethane (1.6 ml) were stirred at room temperature for 2 hours. The solvents were evaporated and the resulting residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate (2 ml), the organic layer was collected and the solvent deleted. The resulting residue was dissolved in dimethyl sulfoxide (5 ml) and oven-dried 4 A MS was added and the resulting mixture was stirred for 10 minutes. Potassium carbonate (231 mg, 1.671 mmol) was then added and the reaction mixture was heated at 140° C. for 16 hours. The reaction mixture was filtered through a Whatman disc filter (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS using double gradient from 50% to 99% mobile phase B over 15.0 min (mobile phase A=water (5 mM hydrochloric acid), mobile phase B=acetonitrile) to give (14S)-20-(benzyloxy)-8- [3-(2-{dispiro[2.0.2.1]heptan-7-yl}-1,1,2,2-tetradeuteroethoxy)-1H-pyrazol-1yl]-12,12-dimethyl-2λ ⁶ -thia-3 ,9,11,18,23-pentaazatetracyclo[17.3.1.111,14,05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (184 mg, 44%) as an off-white solid.

1H NMR (400 MHz, chloroform-d) δ 9.96 (s, 1H), 8.19 (d, J=2.8 Hz, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.0 Hz , 1H), 7.46-7.36 (m, 5H), 7.27 (d, J=8.5 Hz, 1H), 7.00 (d, J=8.1 Hz, 1H), 5.90 (d, J=2.8 Hz, 1H), 5.32 (d, J=6.3 Hz, 1H), 5.11 (s, 2H), 3.91 (s, 1H), 3.42-3.31 (m, 1H), 3.19 (d, J=14.1 Hz, 1H), 3.05 (t, J=9.7 Hz, 1H), 2.67 (s, 1H), 2.10 (dd, J=12.2, 8.2 Hz, 1H), 1.62 (s, 3H), 1.61 (s, 3H), 1.58 (broad s, 4H ), 1.25 (s, 1H), 0.85 (k, J=2.5 Hz, 4H), 0.69-0.61 (m, 2H), 0.54-0.46 (m, 2H). MS-ESI m/z calc. 727.3454, detected 728.47 (M+1)+; retention time: 1.43 min (LC method J).

Step 3: (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}-1,1,2,2-tetradeuteroethoxy)-1H-pyrazol-1 yl] -20-hydroxy-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1 (23),5,7,9,19,21 -hexaene-2,2,4-trione

To a stirred solution of (14S)-20-(benzyloxy)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}-1,1,2,2tetradeuteroethoxy)-1 H-pyrazole-1 -yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23) ,20-hexaene-2,2,4-trione (184 mg,

0.2528 mmol) in EtOH (5 ml) was added 10% palladium on carbon (wet, Degussa, 27 mg, 0.02537 mmol) under nitrogen atmosphere. The heterogeneous mixture was stirred under a hydrogen atmosphere (from a balloon) for approximately 2 hours at ambient temperature and the black heterogeneous reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give (14S)-8[3-(2-{dispiro[2.0.2.1]heptan-7-yl}-1,1,2,2-tetradeuteroethoxy)-1H-pyrazol-1-yl ]-20-hydroxy-12,12dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19, 21-hexaene2,2,4-trione (160 mg, 83%) as a light brown solid.

1H NMR (400 MHz, DMSO-dg) δ 12.42 (s, 1H), 11.02 (s, 1H), 8.30 (d, J=2.7 Hz, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.17 (d, J=7.7 Hz, 1H), 7.06 (d, J=7.8 Hz, 1H), 7.00 (d, J=8.2 Hz, 1H), 6.27 (s, 1H), 6.18 (d, J=2.8 Hz , 1H), 4.01 (s, 1H), 3.28 (s, 1H), 3.09 (d, J=12.9 Hz, 1H), 2.86-2.69 (m, 1H), 2.22 (s, 1H), 2.01 (s, 1H), 1.99-1.90 (m, 1H), 1.65 (d, J=34.6 Hz, 9H), 1.55 (s, 1H), 1.40-1.28 (m, 1H), 0.97-0.89 (m, 4H), 0.77 -0.70 (m, 2H), 0.62-0.53 (m, 2H). MS-ESI m/z calc. 637.29846, detected 638.33 (M+1) ⁺ ; retention time: 0.91 min (LC method J).

Step 4: (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}-1,1,2,2-tetradeuteroethoxy)-1H-pyrazol-1 yl] -12,12-dimethyl-2,2,4-trioxo-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5,7,9 ,19,21-hexaen-20-yl 4-methylbenzene-1-sulfonate

- 373 044967

To a stirred solution of (14S)-8-[3-(2-{disniro[2.0.2.1]gentan-7-yl}-1,1,2,2tetradeuteroethoxy)-1H-pyrazol-1-yl]-20-hydroxy -12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2 ,2,4-trione (160 mg, 0.2107 mmol) in anhydrous dichloromethane (2 ml) was added 4-methylbenzenesulfonyl chloride (45 mg, 0.2360 mmol), triethylamine (60 μl, 0.4305 mmol) and a catalytic amount of N ,N-dimethylpyridin-4-amine (6 mg, 0.04911 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The resulting brown residue was purified by silica gel column chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate to give (14S)-8-[3-(2{dispiro[2.0.2.1]heptan-7-yl}-1, 1,2,2-tetradeuteroethoxy)-1 H-pyrazol-1 -yl]-12,12-dimethyl-2,2,4trioxo-2X ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3. 1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaen20-yl 4-methylbenzene-1-sulfonate (147 mg, 88%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.51 (s, 1H), 8.14 (s, 1H), 7.85 (d, J=8.2 Hz, 2H), 7.73 (d, J=8.2 Hz, 1H) , 7.59 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.2 Hz, 2H), 7.05 (d, J=8.0 Hz, 1H), 6.84 (d, J=8.2 Hz, 1H), 6.70 (s, 1H), 6.02 (d, J=2.7 Hz, 1H), 3.76-3.64 (m, 1H), 3.24 (d, J=7.0 Hz, 1H), 2.96 (tt, J=11.8, 5.3 Hz, 1H), 2.73 (d, J=13.2 Hz, 1H), 2.35 (s, 3H), 2.02-1.92 (m, 1H), 1.79 (t, J=11.9 Hz, 2H), 1.52 (s, 4H), 1.45 (s, 3H), 1.39 (s, 1H), 1.34 (d, J=12.1 Hz, 2H), 1.19 (d, J=12.7 Hz, 1H), 0.76 (t, J=3.5 Hz, 4H), 0.57 (dd, J=8.1, 4.4 Hz, 2H), 0.43 (d, J=9.2 Hz, 2H).MS-ESI m/z calc. 791.3073, detected 792.17 (M+1)+; Retention time: 0.65 min (LC method L).

Step 5: (148)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}-1,1,2,2-tetradeuteroethoxy)-1H-pyrazol-1yl]-12 ,12-dimethyl(20-deutero)-2λ ⁶ -thiα-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5,7,9,19,21- hexaene-2,2,4-trione (compound 301)

Solution (148)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}-1,1,2,2-tetradeuteroethoxy)-1H-pyrazol-1-yl]12,12- dimethyl-2,2,4-trioxo-2Х ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5,7,9,19,21- hexaen-20-yl-4-methylbenzene-1-sulfonate (145 mg, 0.1831 mmol) in dry N,Ndimethylformamide (2 ml) was purged with nitrogen for 5 min using a balloon. Dichloronickel, triphenylphosphane (42 mg, 0.06420 mmol) and tricyclohexylphosphane (46 mg, 0.1640 mmol) were then added. The resulting green solution was stirred for 5 min under a nitrogen atmosphere and tetradeuteroboranuide (sodium salt) (108 mg, 2.580 mmol) was added in one portion. The resulting dark reddish brown mixture was stirred at room temperature for 1 hour. Additional dichloronickel was added; triphenylphosphane (42 mg, 0.06420 mmol), tricyclohexylphosphane (46 mg, 0.1640 mmol) and tetradeuteroboranuide (sodium salt) (108 mg, 2.580 mmol), and the mixture was stirred at room temperature under nitrogen atmosphere overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated. The resulting residue was dissolved in dimethyl sulfoxide and filtered through a Whatman disk filter (puradisc 25 TF), and the filtrate was purified by reverse phase HPLC-MS using a dual gradient from 50% to 99% mobile phase B over 15.0 min (mobile phase A=water (5 mM hydrochloric acid), mobile phase B=acetonitrile) to give (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}-1,1,2, 2tetradeuteroethoxy)-1 H-pyrazol-1 -yl]-12,12-dimethyl(20-deutero)-2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23),5,7,9,19,21-hexaene-2,2,4-trione (compound 301) (26.9 mg, 24%) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.60 (s, 1H), 8.30 (d, J=2.8 Hz, 1H), 7.91 (d, J=8.2 Hz, 1H), 7.70-7.66 (m, 1H ), 7.15 (d, J=7.2 Hz, 1H), 7.08 (d, J=8.9 Hz, 1H), 7.01 (d, J=8.2 Hz, 1H), 6.18 (d, J=2.7 Hz, 1H), 4.02 (d, J=12.1 Hz, 1H), 3.26 (d, J=6.9 Hz, 1H), 3.05 (d, J=13.2 Hz, 1H), 2.83-2.76 (m, 1H), 2.20 (d, J =19.9 Hz, 1H), 1.99-1.93 (m, 1H), 1.87 (s, 1H), 1.70 (s, 6H), 1.61 (s, 3H), 1.55 (s, 1H), 1.46-1.37 (m, 1H), 0.97-0.90 (m, 4H), 0.76-0.72 (m, 2H), 0.63-0.57 (m, 2H). MS-ESI m/z calc. 622.3098, detected 623.26 (M+1) ⁺ ; retention time: 1.3 min (LC method J).

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Example 106: Preparation of 11-[3-(2,2-dimethylpropoxy)-1H-pyrazol-1-yl]-7,7-dimethyl-17λ ⁶ -thia2,8,10,16,22-pentaazatetracyclo[16.3.1.15 ,8.09,14]tricose-1(21),9(14),10,12,18(22),19-hexaene-15,17,17trione (compound 1)

Step 1: 1-benzyl-5,5-dimethylpyrrolidin-2-one o o

ΗΝ'φ ____Впы'Э

Ά sp

5,5-Dimethylpyrrolidin-2-one (19.6 g, 0.174 mol) was dissolved in N,N-dimethylformamide (100 ml) and cooled to 0°C, followed by slow addition of NaH (10.4 g, 0.261 mol). The reaction mixture was stirred for 10 minutes, after which benzyl chloride (22 ml, 0.19 mol) was added. The reaction mixture was allowed to warm to 21°C for 16 hours. The reaction was quenched by adding saturated aqueous NH ₄ Cl followed by the addition of ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash filtration through a pad of silica (20% ethyl acetate in heptanes) to give pure 1-benzyl-5,5dimethylpyrrolidin-2-one (30 g, 85%) as a colorless oil.

1H NMR (300 MHz, CDCl ₃ ): δ 7.3 (m, 5H); 4.4 (s, 2H); 2.42 (t, 2H); 1.9 (t, 2H); 1.1 (s, 6H).

Step 2: 1-benzyl-5,5-dimethyl-2-oxopyrrolidine-3-carboxylate ⁰ O o

ΙΒπΝ·>

Diisopropylamine (27.6 ml, 197 mmol) was dissolved in tetrahydrofuran (200 ml) under nitrogen and cooled to -78°C. n-BuLi (79 ml, 197 mmol, 2.5 M solution in hexane) was added dropwise and stirring was continued for another 90 min, allowing the mixture to warm to -20°C. The reaction mixture was again cooled to -78°C and 1-benzyl-5,5-dimethylpyrrolidin-2-one (20 g, 98.4 mmol) dissolved in tetrahydrofuran (20 ml) was added, maintaining the temperature below -78°C. Stirring was continued for another 1 hour, after which the temperature was adjusted to -80°C and dimethyl carbonate (17.4 ml, 206.6 mmol) was added. The reaction mixture was allowed to warm to -20°C. Water (20 ml) was slowly added followed by 4N. aqueous hydrochloric acid (20 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2x20 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. Pure methyl 1-benzyl-5,5-dimethyl-2oxopyrrolidine-3-carboxylate (7.8 g, 30%) was obtained as a yellow oil after chromatographic purification on silica gel (40% ethyl acetate in heptanes).

1H NMR (300 MHz, CDCl ₃ ): d 7.3 (m, 5H); 4.4 (dd, 2H); 3.8 (s, 3H); 3.6 (t, 1H); 2.2 (m, 2H); 1.2 (s, 3H); 1.1 (s, 3H).

Step 3: 2-(1-benzyl-5,5-dimethylpyrrolidin-3-yl)acetonitrile

Lithium aluminum hydride (4.2 g, 110.4 mmol) was suspended in tetrahydrofuran (100 ml) and cooled to 0° C., followed by dropwise addition of methyl 1-benzyl-5,5-dimethyl-2-oxopyrrolidine- 3-carboxylate (7.8 g, 29.8 mmol) dissolved in tetrahydrofuran (20 ml). The reaction mixture was allowed to warm to 20°C for 16 hours, quenched with water and extracted with ethyl acetate (3x30 ml). The combined organic layers were dried over sodium sulfate and concentrated. Crude (1-benzyl-5,5dimethylpyrrolidin-3-yl) methanol (6.6 g, quant.) was used without further purification in the next step.

1H NMR (300 MHz, CDCl ₃ ): d 7.3 (m, 5H); 3.8 (d, 1H); 3.5 (m, 2H); 3.2 (d, 1H); 2.8 (bs, 1H); 2.6 (m, 2H); 2.2 (m, 1H); 1.9 (m, 1H); 1.6 (m, 1H); 1.3 (s, 3H); 1.03 (s, 3H).

Step 4: 2-(1-benzyl-5,5-dimethylpyrrolidin-3-yl)acetonitrile

(1-Benzyl-5,5-dimethylpyrrolidin-3-yl)methanol (5 g, 22.8 mmol) was dissolved in tetrahydrofuran (60 ml) and cooled to -23°C followed by the addition of Et ₃ N (4.74 ml , 34.2 mmol) and MsCl (2.1 ml, 27.4 mmol). The reaction mixture was stirred at this temperature for 15 minutes, then the cooling bath was removed and stirring was continued for another 30 minutes. Water was added followed by ethyl acetate. The layers were separated and the aqueous layer was washed with ethyl acetate (2x30 ml). The combined organic layers were dried over sodium sulfate and concentrated. The crude material was further dissolved in dimethyl sulfoxide (40 mL) and sodium cyanide (1.7 g, 34.2 mmol) was added. The residue was stirred at 60°C for 5 hours, after which another amount of sodium cyanide (770 mg) was added and stirring was continued for another 5 hours. The reaction mixture was cooled, water was added, and then ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2x20 ml). The combined organic layers were dried over sodium sulfate and concentrated. Pure 2-(1-benzyl-5,5-dimethylpyrrolidin-3-yl)acetonitrile (3 g, 58%) was obtained as a yellow oil after purification by silica gel chromatography (30% ethyl acetate in heptanes).

1H NMR (300 MHz, CDCl ₃ ): d 7.3 (m, 5H); 3.7 (d, 1H); 3.4 (d, 1H); 2.78 (t, 1H); 2.4 (m, 2H); 2.0 (m, 1H); 1.6 (m, 2H); 1.2 (s, 3H); 1.05 (s, 3H).

Step 5: 2-(1-benzyl-5,5-dimethylpyrrolidin-3-yl)ethan-1-amine hydrochloride

Lithium aluminum hydride (1.25 g, 32.8 mmol) was suspended in tetrahydrofuran (30 ml) and cooled to 0°C followed by slow addition of 2-(1-benzyl-5,5-dimethylpyrrolidin-3-yl)acetonitrile (3 g , 13.1 mmol) dissolved in tetrahydrofuran (5 ml). The reaction mixture was allowed to warm to 20°C for 15 hours. The reaction was quenched with water (20 ml) and 15% aqueous sodium hydroxide (10 ml). The resulting precipitate was filtered through a layer of celite. The filter cake was washed with ethyl acetate and the layers were separated. The organic layer containing the crude amine was concentrated and the residue was treated with 4N. hydrochloric acid in dioxane, then evaporated to give pure 2-(1-benzyl5,5-dimethylpyrrolidin-3-yl)ethan-1-amine hydrochloride (3.8 g, 98%) as a yellowish solid.

1H NMR (300 MHz, D2O): d 7.4 (m, 5H); 4.4 (m, 1H); 3.9 (m, 1H); 3.6 (m, 1H); 3.4 and 3.0 (m, 1H); 2.8 (m, 2H); 2.6 (m, 1H); 2.2 (m, 1H); 1.6 (m, 1H); 1.42 (s, 3H); 1.3 (s, 3H).

Step 6: 2-(5,5-dimethylpyrrolidin-3-yl)ethan-1-amine dihydrochloride

Palladium hydroxide (653.0 mg, 0.9300 mmol) and hydrochloric acid (155.0 μl 6 M, 0.9300 mmol). The reaction flask was evacuated and washed with H2 _; using a balloon with a three-way adapter and repeated 3 times. Stir under H ₂ atmosphere at room temperature for 48 hours. The reaction mixture was filtered through a pad of celite and the layer was washed with methanol. The filtrate was evaporated to give 2-(5,5-dimethylpyrrolidin-3-yl)ethanamine dihydrochloride (557 mg, 70%). MS-ESI m/z calc. 142.147, detected 143.2 (M+1)+; Retention time: 0.09 min (LC method A).

Step 7: tert-butyl 3-(2,2-dimethylpropoxy)pyrazole-1-carboxylate

To tert-butyl-3-hydroxypyrazole-1-carboxylate (40 g, 217.2 mmol) in tetrahydrofuran (480.0 ml) under nitrogen was added 2,2-dimethylpropan-1-ol (21.06 g, 238. 9 mmol) and triphenylphosphine (62.66 g, 55.35 ml, 238.9 mmol). DIAD (48.31 g, 47.04 mL, 238.9 mmol) was added dropwise to the mixture, allowing the mixture to gradually warm to 45°C. After addition, the mixture was heated at 50°C for 5 hours. The mixture was allowed to cool to ambient temperature. The reaction mixture was diluted with 200 ml of ethyl acetate and the organic phase was washed with 500 ml of 1 N. sodium hydroxide, 500 ml saline solution, dried over

- 376 044967 magnesium sulfate, filtered through celite and concentrated in vacuo to a volume of approximately 300 ml. Triphenylphosphine oxide began to crystallize and the light red suspension was left overnight. The suspension was filtered using a medium frit and washed three times with 100 ml of 50% ethyl acetate/hexanes. The filtrate was concentrated in vacuo. The crude rose oil was diluted with dichloromethane and chromatographed on a 750 g silica gel column, eluting with a 0-25% ethyl acetate/hexanes gradient. The collected crude fractions were re-chromatographed on a 330 g silica gel column, eluting with 0-25% ethyl acetate/hexanes. The pure fractions from both columns were combined and concentrated to give tert-butyl 3-(2,2-dimethylpropoxy)pyrazole-1-carboxylate (45.8 g, 83%).

1H NMR (400 MHz, chloroform-d) δ 7.83 (d, J=3.2 Hz, 1H), 5.88 (d, J=3.2 Hz, 1H), 3.95 (s, 2H), 1.62 (d, J=2.2 Hz , 9H), 1.01 (d, J=2.7 Hz, 9H). MS-ESI m/z calc. 254.16304, found 199.1 (M+UBu) ⁺ ; Retention time: 1.89 min (LC method B).

Step 8: 3-(2,2-dimethylpropoxy)-1H-pyrazole

To tert-butyl-3-(2,2-dimethylpropoxy)pyrazole-1-carboxylate (111 g, 436.4 mmol) in dichloromethane (450 ml) and methanol (450 ml) was added hydrochloric acid (330 ml 4 M in dioxane . mole). The aqueous phase was extracted with 500 ml MTBE and the combined organic phases were washed with 800 ml brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give 3-(2,2-dimethylpropoxy)-1H-pyrazole as an off-white solid ( 65 g, 97%).

1H NMR (400 MHz, DMSO) δ 11.81 (s, 1H), 7.48 (d, J=2.5 Hz, 1H), 5.65 (t, J=1.9 Hz, 1H), 3.70 (s, 2H), 0.96 (s , 9H). MS-ESI m/z calc. 154.11061, detected 155.1 (M+1) ⁺ ; retention time: 1.48 min (LC method D).

Step 9: tert-butyl 2-chloro-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]pyridine-3-carboxylate

To tert-butyl-2,6-dichloropyridine-3-carboxylate (12.75 g, 51.39 mmol) and 3-(2,2-dimethylpropoxy)1H-pyrazole (7.925 g, 51.39 mmol) in N, To N-dimethylformamide (95.10 mL), potassium carbonate (9.232 g, 66.80 mmol) and 1,4-diazabicyclo[2.2.2]octane (864.6 mg, 7.708 mmol) were added under nitrogen and the reaction mixture was stirred at room temperature for 18 hours. The fine suspension was diluted with water (95.10 ml), which resulted in the precipitation of a tar-like substance, which began to harden. The mixture was allowed to settle and the clear solution was decanted from the resinous solid. The solid was diluted with 200 ml of water and 25 ml of isopropyl alcohol. The mixture was heated until a homogeneous solution. The mixture was allowed to cool and then placed in an ice bath, resulting in a cream-colored semi-solid. The solid was collected using a medium frit and washed three times with 10 ml water. The solid was air-dried for 18 hours to give tert-butyl-2chloro-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]pyridine-3-carboxylate (18 g, 95%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.41 (d, J=2.9 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 6.22 ( d, J=2.9 Hz, 1H), 3.92 (s, 2H), 1.57 (s, 9H), 1.01 (s, 9H). MS-ESI m/z calc. 365.1506, detected 366.2 (M+1) ⁺ ; retention time: 3.53 min (LC method D).

Step 10: 2-chloro-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]pyridine-3-carboxylic acid

To tert-butyl 2-chloro-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]pyridin-3-carboxylate (18 g, 49.20 mmol) in isopropyl alcohol (90.00 ml) aqueous hydrochloric acid solution (41.00 ml 6 M, 246.0 mmol), and the mixture was refluxed for 90 minutes (oil bath temperature=100°C). The mixture was allowed to cool to ambient temperature and then diluted with water (90.00 ml). The suspension was cooled slightly in an ice water bath and the precipitate was collected using a medium frit. The precipitate was washed 3 times with 10 ml of water and dried in vacuum at 45°C for 2 days, obtaining 2-chloro-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]pyridine-3-carboxylic acid ( 12.72 g, 83%).

1H NMR (400 MHz, DMSO-a ₆ ) δ 13.62 (s, 1H), 8.42 (d, J=2.9 Hz, 1H), 8.38 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 6.22 (d, J=2.9 Hz, 1H), 3.93 (s, 2H), 1.01 (s, 9H). MS-ESI m/z calc. 309,088, discovered

- 377 044967

310.2 (M+1)+; retention time: 2.61 min (LC method D).

Step 11: 2-chloro-6-[3-(2,2-dimethylpropoxy)nirazol-1-yl]-N-[(6-fluoro-2pyridyl)sulfonyl]pyridine-3-carboxamide

A 40 ml ampoule was loaded under a nitrogen atmosphere with 2-chloro-6-[3-(2,2-dimethylpropoxy)pyrazol-1yl]pyridine-3-carboxylic acid (1.0 g, 3.228 mmol) and carbonyldiimidazole (785.1 mg, 4.842 mmol). N,N-dimethylformamide (9.615 ml) was added and the mixture was stirred at 45°C under nitrogen for 1 hour. In a separate 40 ml vial, a solution of 6-fluoro-2-pyridine sulfonamide (682.5 mg, 3.874 mmol) was dissolved in anhydrous N,N-dimethylformamide (9.615 ml) under nitrogen. Sodium hydride (154.9 mg, 3.874 mmol) (60% oil suspension) was added portionwise and the mixture was stirred under nitrogen until gas evolution ceased. The vessel was closed with a lid and stirred at 45°C for 45 minutes. The two mixtures were combined and stirred at room temperature for 2 hours. Water and ice were added. Concentrated hydrochloric acid was added dropwise until a white precipitate appeared, then washed with ethyl acetate (2X), the organic layers were combined, dried (sodium sulfate), filtered and concentrated to a yellow residue. The residue was dissolved in ethyl acetate and washed with 1:1 saturated aqueous sodium bicarbonate/1N. sodium hydroxide (3x), dried over sodium sulfate, filtered and concentrated. The material was further purified by silica gel chromatography using a gradient from 100% hexanes to 100% ethyl acetate to isolate 2chloro-6-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-N-[ as a pale yellow foam (6-fluoro-2-pyridyl)sulfonyl]pyridine-3carboxamide (1.01 g, 67%).

¹ H NMR (400 MHz, DMSO-th ₆ ) δ 8.36 (d, J=2.8 Hz, 1H), 8.21-8.10 (m, 2H), 7.89 (d, J=5.7 Hz, 1H), 7.65 (d, J=8.3 Hz, 1H), 7.30 (d, J=7.1 Hz, 1H), 6.15 (d, J=2.8 Hz, 1H), 3.92 (s, 2H), 1.00 (s, 9H) MS-ESM m/ z calc. 467.08304, found 468.2 (M+1) ⁺ ; Retention time: 1.92 min (LC method E).

Step 12: 11-[3-(2,2-dimethylpropoxy)-1H-nirazol-1-yl]-7,7-dimethyl-17λ ⁶ -thia-2,8,10,16,22pentaazatetracyclo[16.3.1.15, 8.09,14]tricose-1(21),9(14),10,12,18(22),19-hexaene-15,17,17-trione (compound 1)

2-chloro-6-[3-(2,2-dimethylnpronoxy)pyrazol-1-yl]-N-[(6-fluoro2-pyridyl)sulfonyl]pyridine-3-carboxamide (330 mg, 0.6065 mmol) in dimethyl sulfoxide (2.980 ml), potassium carbonate (419.2 mg, 3.033 mmol) and 2-(5,5-dimethylpyrrolidin-3-yl)ethanamine dihydrochloride (108.4 mg, 0.504 mmol). The vessel was capped and heated to 120°C on a hot plate for 20 hours. Additional 2-(5,5-dimethylpyrrolidin-3-yl)ethanamine dihydrochloride (108.4 mg, 0.504 mmol) was added and heated to 125°C for hot plate for 24 hours. The reaction mixture was filtered and then purified directly by preparative reverse phase chromatography using a C ₁₈ column (10-99 acetonitrile-water + 5 mM hydrochloric acid) to obtain an off-white solid, to which excess was added potassium carbonate (419.2 mg, 3.033 mmol) and dimethyl sulfoxide (2.980 ml), and the mixture was heated for 18 hours at 155°C. The reaction mixture was filtered and then purified directly by preparative reverse phase chromatography using a C ₁₈ column (10-99 acetonitrile-water + 5 mM hydrochloric acid) to give 11-[3-(2,2- dimethylpropoxy)-1H-pyrazol-1-yl]-7,7-dimethyl17λ ⁶ -thia-2,8,10,16,22-pentaazatetracyclo[16.3.1.15,8.09,14]tricose-1(21),9( 14),10,12,18(22),19-hexaene15,17,17-trione (compound 1) (34.5 mg, 10%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-a ₆ ) δ 12.45 (s, 1H), 8.27-8.16 (m, 1H), 7.74 (d, J=30.7 Hz, 2H), 7.17 (d, J=6.1 Hz, 1H ), 6.96-6.88 (m, 1H), 6.88-6.74 (m, 1H), 6.17-6.10 (m, 1H), 3.89 (s, 2H), 3.61 (dd, J=15.1, 8.4 Hz, 1H), 3.35 (s, 1H), 2.48-2.29 (m, 1H), 2.25 (s, 1H), 1.91 (dd, J=10.8, 5.3 Hz, 2H), 1.56 (s, 6H), 1.50 (s, 1H) , 1.43-1.28 (m, 1H), 1.19 (dd, J=30.9, 7.8 Hz, 1H), 1.00 (s, 9H).MS-ESI m/z calc. 553.24713, detected 554.2 (M+1) ⁺ ; Retention time: 2.14 min (LC method E).

Example 107: Preparation of 11-[3-(2,2-dimethylpropoxy)-1H-nirazol-1-yl]-7,7-dimethyl-17λ ⁶ -thia2,8,10,16,22-pentaazatetracyclo[16.3.1.15 ,8.09,14]tricose-1(21),9(14),10,12,18(22),19-hexaene-15,17,17trione (enantiomer 1) (compound 2) and 11-[3-( 2,2-dimethylpropoxy)-1H-pyrazol-1-yl]-7,7-dimethyl17λ ⁶ -thia-2,8,10,16,22-pentaazatetracyclo[16.3.1.15.8.09.14]tricose-1(21 ),9(14),10,12,18(22),19-hexaene15,17,17-trione (enantiomer 2) (compound 3)

- 378 044967

Step 1: 11-[3-(2,2-dimethylpropoxy)-1H-pyrazol-1-yl]-7,7-dimethyl-17λ ⁶ -thua-2,8,10,16,22pentaazatetracyclo[16.3.1.15, 8.09,14]tricose-1(21),9(14),10,12,18(22),19-hexaene-15,17,17-trione (enantiomer 1) (compound 2) and 11-[3- (2,2-dimethylpronoxy)-1H-nirazol-1-ul]-7,7-dimethyl-17λ ⁶ -tua2,8,10,16,22-pentaazatetracyclo[16.3.1.15,8.09,14]tricose-1( 21),9(14),10,12,18(22),19-hexaene-15,17,17trione (enantiomer 2) (compound 3)

Racemic 11-[3-(2,2-dimethylpropoxy)-1H-pyrazol-1-yl]-7,7-dimethyl-17λ ⁶ -thua-2,8,10,16,22pentaazatetracyclo[16.3.1.15,8.09, 14]tricose-1(21),9(14),10,12,18(22),19-hexaene-15,17,17-trione (28.4 mg) was chirally purified by SCLC using ChiralPak AS-H (250x10 mm column, 5 µm particle size) with a mobile phase of 28% methanol/72% carbon dioxide at 10 ml/min, yielding 11-[3-(2,2-dimethylpropoxy)-1H-pyrazole as the first enantiomer to elute -1-yl]-7,7-dimethyl17λ ⁶ -thia-2,8,1O,16,22-pentaazatetracyclo[16.3.1.15,8.O9,14]tricose-1(21),9(14),10 ,12,18(22),19-hexaene15,17,17-trione (enantiomer 1) (compound 2) (4.4 mg, 32%), ESI-MS m/z calc. 553.24713, detected 554.2 (M+1)+; Retention time: 2.14 min (LC method E); and as the second eluting enantiomer 11 -[3-(2,2-dimethylpropoxy)-1H-pyrazol-1-yl]-7,7-dimethyl-17λ ⁶ -thia-2,8,10,16,22pentaazatetracyclo[16.3 .1.15,8.09,14]tricose-1(21),9(14),10,12,18(22),19-hexaene-15,17,17-trione (enantiomer 2) (compound 3) (5, 6 mg, 41%), MS-ESI m/z calc. 553.24713, detected 554.2 (M+1) ⁺ ; Retention time: 2.15 min (LC method E).

Example 108: Preparation of 7,7-dimethyl-11-(3-{[1 -(trifluoromethyl)cyclopropyl]methoxy }-1 H-pyrazol1-yl)-17λ ⁶ -thia-2,8,1O,16,22- npentaazatetracyclo[16.3.1.1(5,8).0(9,14)]tricose-1(21),9(14),1O,12,18(22),19hexaene-15,17,17-trione (compound 4)

F ₃ s

Step 1: 2-chloro-N-[(6-fluoro-2-pyridyl)sulfonyl]-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1 -yl]pyridin-3-carboxamide

A solution of 2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (3.5 g, 9.386 mmol) and carbonyldiimidazole (2.283 g, 14. 08 mmol) in dimethylformamide (32.64 ml) was stirred at 60°C for 60 min and a separate solution of 6-fluoro-2-pyridine sulfonamide (1.984 g, 11.26 mmol) and sodium hydride (450.4 mg, 11. 26 mmol) in dimethylformamide (32.64 ml) was stirred at 45°C for 45 minutes. The two solutions were combined and stirred at 60°C for 1 hour. Cooled to room temperature and poured into water. Add concentrated hydrochloric acid dropwise until a white precipitate remains, then wash with ethyl acetate (2X), combine the organic layers, dry (sodium sulfate), filter and concentrate to a white solid. Dissolve in ethyl acetate and wash with 1:1 saturated aqueous sodium bicarbonate/1N.

sodium hydroxide (3x), dried (sodium sulfate), filtered and concentrated to an off-white foam. Stir in ether and remove the ether under reduced pressure. The residue was dissolved in a minimal amount of warm dichloromethane, left for 5 minutes, then cooled to 4°C overnight. A mass of white solid was filtered and washed with dichloromethane. The filtrate was converted to a yellow solid, dissolved in a minimum amount of warm dichloromethane and slowly cooled to 4°C overnight. The resulting mass of white solid was filtered and washed with dichloromethane to give 2-chloro-N-[(6-fluoro-2-pyridyl)sulfonyl]-6-[3-[[1(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl ]pyridine-3-carboxamide (3.339 g, 62%). MS-ESI m/z calc. 519.86, detected 520.2 (M+1)+; retention time: 1.75 min (LC method B).

Step 2: 7,7-dimethyl-11-(3-{[1-(trifluoromethyl)cyclopropyl]methoxy}-1H-pyrazol-1-yl)-17λ ⁶ -thia2,8,10,16,22-pentaazatetracyclo[ 16.3.1.1(5,8).0(9,14)]tricose-1(21),9(14),10,12,18(22),19-hexaene15,17,17-trione (compound 4)

2-chloro-N-[(6-fluoro-2-pyridyl)sulfonyl]-6-[3-[[1(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridin-3- was combined in a 5 ml vial. carboxamide (400 mg, 0.7310 mmol) in dimethyl sulfoxide (3.040 ml), followed by potassium carbonate (505.1 mg, 3.655 mmol) and 2-(5,5dimethylpyrrolidin-3-yl)ethanamine dihydrochloride (137.2 mg, 0 .64 mmol). The vial was capped and heated to 75°C on a hot plate for 92 hours, then at 125°C for 20 hours. The reaction mixture was filtered and then purified directly by preparative reverse phase chromatography using a C ₁₈ column (10-99 acetonitrile-water + 5 mM hydrochloric acid) to give the product isolated as a tan solid, 7,7- dimethyl-11-(3-{[1(trifluoromethyl)cyclopropyl]methoxy}-1H-pyrazol-1 -yl)- 17λ ⁶ -thia-2,8,10,16,22pentaazatetracyclo[16.3.1.1(5,8) .0(9,14)]tricose-1(21),9(14),10,12,18(22),19-hexaene-15,17,17-trione (compound 4) (35.2 mg, 9%).

1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.43-8.41 (m, 1H), 8.21 (d, J=2.8 Hz, 1H), 7.74 (d, J=33.4 Hz, 2H) , 7.17 (d, J=7.0 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.82 (s, 1H), 6.15 (d, J=2.7 Hz, 1H), 4.37 (k, J= 11.9 Hz, 2H), 3.61 (d, J=9.1 Hz, 1H), 3.41 (d, J=3.9 Hz, 1H), 3.19 (d, J=26.6 Hz, 2H), 2.26 (d, J=5.9 Hz , 1H), 1.91 (d, J=3.5 Hz, 1H), 1.55 (s, 6H), 1.48 (d, J=11.0 Hz, 1H), 1.34 (d, J=12.7 Hz, 1H), 1.18 (d , J=11.8 Hz, 1H), 1.11-1.06 (m, 4H). MS-ESI m/z calc. 605.2032, detected 606.2 (M+1) ⁺ ; retention time: 2.02 min (LC method E).

Example 109: Preparation of 7,7-dimethyl-11-(3-{[1-(trifluoromethyl)cyclopropyl]methoxy}-1H-pyrazol1-yl)-17λ ⁶ -thia-2,8,1O,16,22-pentaazatetracyclo [16.3.1.1(5,8).0(9,14)]tricose-1(21),9(14),1O,12,18(22),19hexaene-15,17,17-trione (enantiomer 1 ) (compound 5) and 7,7-dimethyl-11-(3-{[1(trifluoromethyl)cyclopropyl]methoxy }-1 H-pyrazol-1-yl)-17 λ ⁶ -thia-2,8,10, 16,22pentaazatetracyclo[16.3.1.1(5.8).0(9.14)]tricose-1(21),9(14),10,12,18(22),19-hexaene-15,17,17 -trione (enantiomer 2) (compound 6)

enantiomer 1 enantiomer 2

Step 1: 7,7-dimethyl-11-(3-{[1-(trifluoromethyl)cyclopropyl]methoxy}-1H-pyrazol-1-yl)-17λ ⁶ -thia2,8,10,16,22-pentaazatetracyclo[ 16.3.1.1(5,8).0(9,14)]tricose-1(21),9(14),10,12,18(22),19-hexaene15,17,17-trione (enantiomer 1) (compound 5) and 7,7-dimethyl-11-(3-{[1-(trifluoromethyl)cyclopropyl]methoxy}-1 H-pyrazol-1-yl)-17λ ⁶ -thia-2,8,10,16 ,22-pentaazatetracyclo[16.3.1.1 (5.8).0(9.14)]tricose1(21),9(14),10,12,18(22),19-hexaene-15,17,17- trione (enantiomer 2) (compound 6)

enantiomer 1 enantiomer 2

Racemic 7,7-dimethyl-11-(3-{[1 -(trifluoromethyl)cyclopropyl]methoxy} -1 H-pyrazol-1 -yl)17λ ⁶ -thia-2,8,10,16,22-pentaazatetracyclo[ 16.3.1.1(5,8).0(9,14)]tricose-1(21),9(14),10,12,18(22),19hexaene-15,17,17-trione (31 mg, 0.05119 mmol) was subjected to chiral LCLC purification using a ChiralPak AS-H (250 x 10 mm column, 5 μm particle size) with a 20% methanol/80% carbon dioxide mobile phase at 10 mL/min, yielding 7 as the first enantiomer eluted. 7-dimethyl-11-(3{[ 1 -(trifluoromethyl)cyclopropyl]methoxy}-1H-pyrazol-1-yl)- 17λ ⁶ -thia-2,8,10,16,22pentaazatetracyclo[16.3.1.1(5, 8).0(9,14)]tricose-1(21),9(14),10,12,18(22),19-hexaene-15,17,17-trione (enantiomer 1) (compound 5) (11.5 mg, 74%); MS-ESI m/z calc. 605.2032, detected 606.2 (M+1) ⁺ ; Retention time: 2.02 min (LC method E), and as the second enantiomer eluted 7,7-dimethyl11-(3-{[1 -(trifluoromethyl)cyclopropyl]methoxy}-1H-pyrazol-1-yl)- 17 λ ⁶ -thia-2,8,10,16,22pentaazatetracyclo[16.3.1.1(5.8).0(9.14)]tricose-1(21),9(14),10,12,18( 22),19-hexaene-15,17,17-trione

- 380 044967 (enantiomer 2) (compound 6) (11.4 mg, 72%); MS-ESI m/z calc. 605.2032, detected 606.2 (M+1)+;

Retention time: 2.02 min (LC method E).

Example 110: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-19-oxa-2λ ⁶ -thia-3,9,11 -triazatetracyclo[18.3.1.05,10.011.15]tetracose-1(24),5(10),6,8,20,22hexaene-2,2,4-trione (enantiomer 1) (compound 7) and 12,12 -dimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-19-oxa-2λ ⁶ -thia-3,9,11triazatetracyclo[18.3.1.05, 10.011,15]tetracose-1(24),5(10),6,8,20,22-hexaene-2,2,4-trione (enantiomer 2) (compound 8)

enantiomer 1 enantiomer 2

Step 1: tert-butyl 2,2-dimethyl-5-[3-(3-sulfamoylphenoxy)propyl]pyrrolidine-1-carboxylate

3-Hydroxybenzenesulfonamide (510 mg, 2.945 mmol) and N,N-dimethylformamide (10.20 mL) were added to a 50 mL round bottom flask. Potassium carbonate (1.425 g, 10.31 mmol) and tert-butyl 2,2-dimethyl-5-(3-methylsulfonyloxypropyl)pyrrolidine-1-carboxylate (1.017 g, 3.033 mmol) were added to the mixture at room temperature and stirred at room temperature. for 3 hours, then heated to 50°C overnight. Cool to room temperature and pour into water (100 ml) and extract with ethyl acetate (2x100 ml), combine organic layers, wash with water (2x100 ml), dry (sodium sulfate), filter and concentrate. The brown residue was purified by silica gel chromatography using a gradient of 100% hexanes to 100% ethyl acetate to give tert-butyl 2,2-dimethyl-5-[3-(3-sulfamoylphenoxy)propyl]pyrrolidine-1-carboxylate as a light orange oil. (770 mg, 63%).

¹ H NMR (400 MHz, DMSO-b 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). MS-ESI m/z calc. 412.2032, detected 413.2 (M+1) ⁺ ; retention time: 1.81 min (LC method E).

Step 2: tert-butyl 5-[3-[3-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl] phenoxy]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

A 100 ml flask was charged under a nitrogen atmosphere with 2-chloro-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (650 mg, 1.730 mmol) and carbonyldiimidazole (345 mg, 2.128 mmol). N,N-dimethylformamide (5.850 ml) was added and the mixture was stirred at 40°C under nitrogen atmosphere for 1 hour. In a separate 100 ml flask, tert-381 044967 butyl-2,2-dimethyl-5-[3- (3-sulfamoylphenoxy)propyl]pyrrolidine-1-carboxylate (750 mg, 1.818 mmol) under nitrogen in anhydrous N,N-dimethylformamide (5.850 ml). NaH (77.0 mg, 1.925 mmol) (60% oil suspension) was added portionwise and the mixture was stirred under nitrogen until gas evolution ceased. The vessel was closed with a lid and stirred at room temperature for 45 minutes. The two mixtures were combined and stirred at room temperature for 20 hours. Heated to 55°C for another 4 hours. Water and ice were added, followed by concentrated hydrochloric acid dropwise until a white precipitate remained. The mixture was then washed with ethyl acetate and the combined organic layers were washed with brine, then washed with 1:1 saturated aqueous sodium bicarbonate/1N. sodium hydroxide (3X), dried over sodium sulfate, filtered in vacuo and concentrated. The residue was then dissolved in 10 ml dichloromethane and purified by silica gel chromatography using a shallow gradient of 100% hexanes to 65% ethyl acetate in hexanes to give tert-butyl 5-[3-[3-[[2-chloro as a white solid -6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1 yl]pyridin-3-carbonyl]sulfamoyl]phenoxy]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (450 mg, 34%).

¹ H NMR (400 MHz, DMSO-d ₆ ) ¹ H NMR (400 MHz, DMSO) δ 8.39 (d, J=2.9 Hz, 1H), 8.11 (d, J=8.3 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.62-7.51 (m, 2H), 7.46 (d, J=1.9 Hz, 1H), 7.30 (d, J=6.9 Hz, 1H), 6.18 (d, J=2.9 Hz, 1H), 4.48-4.25 (m, 2H), 4.06 (s, 2H), 3.74 (s, 1H), 2.08 (dd, J=9.0, 5.1 Hz, 2H), 1.88 (s, 2H), 1.71 (dd , J=25.9, 15.0 Hz, 4H), 1.55 (d, J=5.7 Hz, 2H), 1.36 (s, 12H), 1.23 (s, 3H), 0.96 (dd, J=7.7, 3.8 Hz, 2H) , 0.88 (s, 2H). MSIE m/z calc. 769.2524, detected 770.5 (M+1)+; retention time: 2.11 min (LC method G).

Step 3: 12,12-dimethyl-8-(3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-19oxa-2λ ⁶ -thia-3,9,11 -triazatetracyclo[18.3.1.05,1O.011,15]tetracose-1(24),5(1O),6,8,20,22-hexaene-2,2,4trione

tert-Butyl 5-[3-[3-[[2-chloro-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3 was combined in a 50 ml round bottom flask -carbonyl]sulfamoyl]phenoxy]propyl]2,2-dimethylpyrrolidine-1-carboxylate (445 mg, 0.5777 mmol), dissolved in dichloromethane (2.225 ml), followed by the addition of hydrochloric acid (4 M in dioxane) (1.589 ml 4 M, 6.355 mmol) and the mixture was stirred for 2 hours. The material was then concentrated under reduced pressure to dryness to obtain the material, which was dissolved in dimethyl sulfoxide (9 ml) followed by the addition of excess potassium carbonate (1.0 g, 7.236 mmol). The vessel was capped and heated to 150°C on a hot plate for 20 hours. Cesium fluoride (131.6 mg, 31.98 μL, 0.8666 mmol) was added and the reaction mixture was heated to 170°C for an additional 4 hours The reaction mixture was filtered and then purified by preparative reverse phase chromatography using a C ₁₈ column (40-70 acetonitrile water + 5 mM trifluoroacetic acid) to give 12,12dimethyl-8-(3-{2-[) as an off-white solid 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-19-oxa-2λ ⁶ -thia-3,9,11triazatetracyclo[18.3.1.05,10.011.15]tetracose-1(24), 5(10),6,8,20,22-hexaene-2,2,4-trione (15.3 mg, 4%). MS-ESI m/z calc. 633.22327, detected 634.2 (M+1) ⁺ ; Retention time: 1.83 min (LC method E).

Step 4: 12,12-dimethyl-8-(3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-19oxa-2λ ⁶ -thia-3,9,11 -triazatetracyclo[18.3.1.05,10.011,15]tetracose-1 (24),5(10),6,8,20,22-hexaene-2,2,4trione (enantiomer 1) (compound 7) and 12,12 -dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}1 H-pyrazol-1 -yl)-19-oxa-2X ⁶ -thia-3,9,11-triazatetracyclo[18.3. 1.05,10.011,15]tetracose1(24),5(10),6,8,20,22-hexaene-2,2,4-trione (enantiomer 2) (compound 8)

enantiomer 1 enantiomer 2

Racemic 12,12-dimethyl-8-(3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-19oxa-2λ ⁶ -thia-3,9,11-triazatetracyclo [18.3.1.05,1O.011.15]tetracose-1(24),5(10),6,8,20,22-hexaene-2,2,4trione (15.3 mg, 0.02414 mmol) was subjected to chiral LCLC purification using ChiralPak AS-H (250 x 10 mm column, 5 µm particle size) with a mobile phase of 18% methanol/82% carbon dioxide at 10 ml/min, yielding the first enantiomer, eluting as an off-white solid substances, 12,12-dimethyl-8-(3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-19oxa-2λ ⁶ -thia-3,9,11- triazatetracyclo[18.3.1.05,1O.011.15]tetracose-1(24),5(1O),6,8,20,22-hexaene-2,2,4trione (enantiomer 1) (compound 7) (3.4 mg , 44%), MS-ESI m/z calc. 633.22327, discovered 634.2

- 382 044967 (M+1)+; Retention time: 1.84 min (LC method E), and 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy} as the second enantiomer eluting as an off-white solid -1Hpyrazol-1-yl)-19-oxa-2λ ⁶ -thia-3,9,11-triazatetracyclo[18.3.1.05,10.011.15]tetracose1(24),5(10),6,8,20,22 -hexaene-2,2,4-trione (enantiomer 2) (compound 8) (3.4 mg, 44%), ESI-MS m/z calc.

633.22327, detected 634.2 (M+1) ⁺ ; Retention time: 1.84 min (LC method E).

Example 111: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-2λ ⁶ -thia-3,9,11,19,24 -pentaazatetracyclo[18.3.1.05,10.011,15]tetracose-1(23),5,7,9,20(24),21hexaene-2,2,4-trione (compound 16)

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

Potassium carbonate (495 mg, 3.582 mmol), tert-butyl 5-(3-aminopropyl)-2,2 dimethylpyrrolidine-1-carboxylate (304 mg, 1.19 mmol), 6-fluoropyridine-2-sulfonamide ( 208.9 mg, 1.186 mmol) and dimethyl sulfoxide (3 ml). The reaction mixture was stirred at 80°C overnight. The reaction was filtered and purified by HPLC (1%-99% acetonitrile/water gradient, modifier 0.1% hydrochloric acid) to give tert-butyl-2,2-dimethyl-5-[3-[(6-sulfamoyl-2pyridyl)amino ]propyl]pyrrolidine-1-carboxylate (224.7 mg, 46%) as a white foam. MS-ESI m/z calc. 412.21442, detected 413.8 (M+1) ⁺ ; retention time: 0.94 min (LC method B).

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

Add 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridine-3-carboxylic acid (204 mg, 0.5429 mmol), carbonyldiimidazole (93 mg) to the round bottom flask , 0.5735 mmol) and tetrahydrofuran (3 ml). The reaction mixture was purged with nitrogen and placed in an oil bath preheated to 45°C for 90 minutes. Tert-butyl 2,2-dimethyl-5-[3-[(6-sulfamoyl-2pyridyl)amino]propyl]pyrrolidine-1-carboxylate (224 mg, 0.5430 mmol) was added followed by 1,8diazabicyclo[5.4 .0]undec-7-ene (250 µl, 1.672 mmol), and the reaction mixture was left to stir overnight at room temperature. The reaction mixture was filtered and purified by HPLC (30-99% acetonitrile/water gradient with 0.1% hydrochloric acid modifier) to give tert-butyl 5-[3-[[6-[[2-chloro-6-[3 -[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (196.5 mg , 47%) as a white solid. MS-ESI m/z calc. 769.2636, detected 770.5 (M+1) ⁺ ;

- 383 044967 retention time: 1.98 min (LC method B).

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

Tert-butyl-5-[3-[[6-[[2-chloro-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3- was added to the round bottom flask. carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (195 mg, 0.2532 mmol) and dichloromethane (5 ml). Hydrochloric acid (1.3 ml 4M in dioxane, 5.200 mmol) was added dropwise and the reaction mixture was allowed to stir at room temperature for 1 hour. The reaction was evaporated to dryness. The reaction mixture was diluted with 3 M potassium carbonate to pH 10 and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and evaporated to give 2-chloro-N-[[6-[3-(5,5-dimethylpyrrolidin-2-yl)propylamino]-2pyridyl]sulfonyl]-6-[3- [2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3 carboxamide (169 mg, 100%). MS-ESI m/z calc. 669.2112, detected 670.5 (M+1)+; retention time: 0.78 min (LC method B).

Step 4: 12,12-dimethyl-8-(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy }-1 H-pyrazol-1 -yl)-2λ ⁶ -thia3,9,11,19,24 -pentaazatetracyclo[18.3.1.05,10.011,15]tetracose-1 (23),5,7,9,20(24),21 -hexaene-2,2,4-trione (compound 16)

OOO

Potassium carbonate (175 mg, 1.266 mmol), cesium fluoride (58 mg, 0.3818 mmol) and a solution of 2-chloro-N-[[6-[3-(5,5-dimethylpyrrolidin-2-yl) were added to the ampoule. propylamino]-2-pyridyl]sulfonyl]-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (169 mg, 0.2522 mmol) in dimethyl sulfoxide ( 3.0 ml). The reaction mixture was heated in a sealed tube overnight at 150°C. The reaction mixture was quenched with brine and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude reaction mixture was purified by silica gel chromatography (0-50% ethyl acetate in dichloromethane gradient) to give 12,12dimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl )-2λ ⁶ -thia-3,9,11,19,24pentaazatetracyclo[18.3.1.05,10.011,15]tetracose-1 (23),5,7,9,20(24),21-hexaene-2,2 ,4-trione (compound 16) (93 mg, 58%) as a white solid.

Ή NMR (400 MHz, DMSO-de) δ 12.75 (s, 1H), 8.23 (d, J=2.7 Hz, 1H), 8.01 (d, J=8.2 Hz, 1H), 7.58 (t, J=7.8 Hz , 1H), 7.29 (s, 1H), 7.03 (d, J=7.2 Hz, 2H), 6.63 (d, J=8.4 Hz, 1H), 6.13 (d, J=2.7 Hz, 1H), 4.32 (t , J=7.1 Hz, 2H), 3.72 (s, 2H), 3.10 (s, 1H), 2.08 (t, J=7.0 Hz, 2H), 1.86 (s, 2H), 1.73 (s, 2H), 1.51 (s, 4H), 1.35 (s, 3H), 1.24 (s, 2H), 1.02-0.93 (m, 3H), 0.90-0.85 (m, 2H). MS-ESI m/z calc. 633.2345, detected 634.2 (M+1) ⁺ ; retention time: 1.85 min (LC method B).

Example 112: Preparation of 20,20,22-trimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-10λ ⁶ -thia-1,3,9,13 ,14-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene8,10,10-trione (compound 18) and 12,20,20-trimethyl-4- (3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-10λ ⁶ -thia-1,3,9,13,14-pentaazatetracyclo[16.2.1.111,14.02,7]docose -2,4,6,11(22),12-pentaene8,10,10-trione (compound 19)

- 384 044967

Step 1: 2-chloro-H-[(5-methyl-1H-pyrazol-4-yl)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]pyridine3-carboxylic acid (100 mg, 0.2661 mmol), carbonyldiimidazole (48 mg, 0.30 mmol) and tetrahydrofuran (1 ml). The reaction mixture was stirred at 45°C for 1 hour. 5-Methyl-1H-pyrazol-4sulfonamide (43 mg, 0.2668 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (125 μl) were added , 0.836 mmol) and left the reaction mixture to stir overnight at 45°C. The crude reaction mixture was filtered and purified by HPLC (10-99% acetonitrile/water gradient modified with 0.1% hydrochloric acid to give 2-chloro-K-[(5-methyl-1H-pyrazol-4-yl)sulfonyl] -6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (80.0 mg, 58%) ESI-MS m/z calculated 518.0751 , detected 519.1 (M+1)+; Retention time: 1.7 min (LC method B).

Step 2: tert-butyl 4-[3-[4-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl] -3-methylpyrazol-1-yl]propyl]-2,2-dimethylpyrrolidine-1-carboxylate and tert-butyl 4-[3-[4-[[2-chloro-6-[3-[2-[1-(trifluoromethyl )cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl]-5-methylpyrazol-1-yl]propyl]-2,2-dimethylpyrrolidine-1 carboxylate (mixture of regioisomers)

Into a round bottom flask containing 2-chloro-K-[(5-methyl-N-pyrazol-4-yl)sulfonyl]-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl ]pyridine-3-carboxamide (80 mg, 0.1542 mmol) was added H,H-dimethylformamide (2 ml), potassium carbonate (65 mg, 0.47 mmol) and tert-butyl-2,2-dimethyl-4- (3

- 385 044967 methylsulfonyloxypropyl)pyrrolidine-1-carboxylate (68 mg, 0.20 mmol) in N,N-dimethylformamide (2 ml). The reaction mixture was heated at 60°C and stirred for 4 days. The reaction mixture was filtered and purified by HPLC (30-99% acetonitrile/water gradient with 0.1% hydrochloric acid modifier) to give tert-butyl 4-[3-[4-[[2-chloro-6-[3- [2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-3-methylpyrazol-1 yl]propyl]-2,2-dimethylpyrrolidin-1-carboxylate and tert-butyl 4-[3-[4-[[2-chloro-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-5-methylpyrazol- 1 yl]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (mixture of regioisomers) (49.9 mg, 43%) as a white foam. MS-ESI m/z calc. 757.2636, detected 758.4 (M+1)+; retention time: 1.82 min (LC method G).

Step 3: 2-chloro-X -[1-[3 -(5,5-dimethylpyrrolidin-3-yl)propyl]-3-methylpyrazol-4-yl]sulfonyl-6[3-[2-[1-( trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide and 2-chloro-X-[1-[3-(5,5dimethylpyrrolidin-3-yl)propyl]-5-methyl-pyrazol-4- yl]sulfonyl-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (mixture of regioisomers)

mixture of regioisomers

Tert-butyl-4-[3-[4-[[2-chloro-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl was added to the round bottom flask ]sulfamoyl]-3-methylpyrazol-1yl]propyl]-2,2-dimethylpyrrolidine-1-carboxylate and tert-butyl-4-[3-[4-[[2-chloro-6-[3-[2-[ 1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-5-methylpyrazol-1yl]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (mixture of regioisomers) (49, 9 mg, 0.0658 mmol), dioxane (1 ml) and hydrochloric acid (165 µl 4M in dioxane, 0.660 mmol). The reaction was heated at 35°C overnight. The reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated to give 2-χλορ-Ν[1-[3-(5,5-dimethylpyrrolidin-3-yl)propyl]-3-methylpyrazol-4-yl]sulfonyl-6-[ 3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide and 2-χλορ-Ν -[1-[3-(5,5dimethylpyrrolidin-3-yl)propyl] - 5-methylpyrazol-4-yl]sulfonyl-6-[3-[2-[1 (trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (mixture of regioisomers) (42 mg, 97%) in as a white solid. MS-ESI m/z calc. 657.2112, detected 658.4 (M+1) ⁺ ; retention time: 0.74 min (LC method B).

Step 4: 20,20,22-trimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)10λ ⁶ -thia-1,3,9,13 ,14-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (compound 18) and 12,20,20-trimethyl- 4-(3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)10λ ⁶ -thia-1,3,9,13,14-pentaazatetracyclo[16.2.1.111,14.02 ,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (compound 19)

- 386 044967

Into a round bottom flask containing 2-chloro-N-[1-[3-(5,5-dimethylpyrrolidin-3-yl)propyl]-3methylpyrazol-4-yl]sulfonyl-6-[3-[2-[1- (trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide and 2-chloro-N[1-[3-(5,5-dimethylpyrrolidin-3-yl)propyl]-5-methylpyrazol-4-yl] sulfonyl6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (mixture of regioisomers) (42 mg, 0.06382 mmol) added potassium carbonate (44 mg, 0 .32 mmol), cesium fluoride (50 mg, 0.33 mmol), dimethyl sulfoxide (2 ml) and four 3 A molecular sieves. The reaction was heated at 150°C overnight. The reaction mixture was cooled to room temperature, filtered and purified by HPLC (10-99% acetonitrile/water gradient modified with 0.1% hydrochloric acid), yielding 20,20,22-trimethyl-4-(3) as the first eluting isomer -{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-10Х ⁶ -thia-1,3,9,13,14pentaazatetracyclo[16.2.1.111,14.02,7]docose-2 ,4,6,11(22),12-pentaene-8,10,10-trione (compound 18) (2.8 mg, 7%) as an orange solid;

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.39 (s, 1H), 8.18 (d, J=2.8 Hz, 1H), 7.86 (s, 1H), 7.77 (d, J=8.3 Hz, 1H), 6.90 (d, J=8.2 Hz, 1H), 6.09 (d, J=2.7 Hz, 1H), 4.43-4.34 (m, 1H), 4.30 (t, J=7.0 Hz, 2H), 4.08-3.96 (m , 1H), 2.06 (k, J=7.4 Hz, 6H), 1.95-1.69 (m, 4H), 1.55 (s, 3H), 1.47 (s, 3H), 1.40-1.08 (m, 4H), 0.96 ( td, J=4.9, 4.4, 3.1 Hz, 2H), 0.90-0.85 (m, 2H), MS-ESI m/z calc. 621.2345, found 622.6 (M+1) ⁺ ; Retention time: 1.48 min (LC method B), as the second eluting isomer,

12,20,20-trimethyl-4-(3-{2-[1 (trifluorophenyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-10λ ⁶ -thia-1,3,9,13,14pentaazatetracyclo [16.2.1.111,14.02.7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (compound 19) (3.7 mg, 9%) as an orange solid substances;

Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.18 (s, 1H), 8.41 (s, 1H), 8.18 (d, J=2.8 Hz, 1H), 7.75 (d, J=8.2 Hz, 1H), 6.89 (d, J=8.2 Hz, 1H), 6.10 (d, J=2.8 Hz, 1H), 4.31 (t, J=7.0 Hz, 2H), 4.22 (dt, J=13.6, 3.8 Hz, 1H), 3.97 (t, J=12.4 Hz, 1H), 2.40 (s, 3H), 2.20 (s, 1H), 2.07 (t, J=7.1 Hz, 4H), 2.02-1.68 (m, 4H), 1.51 (d , J=13.0 Hz, 6H), 1.38 (t, J=12.3 Hz, 1H), 1.03 (s, 1H), 0.96 (td, J=5.0, 4.5, 3.2 Hz, 2H), 0.93-0.84 (m, 2H), MS-ESI m/z calc. 621.2345, found 622.4 (M+1)+; Retention time: 1.54 min (LC method B).

Example 113: Preparation of 7,7-dimethyl-11-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-17λ ⁶ -thia-2,8,10,16,22 -pentaazatetracyclo[16.3.1.15,8.09,14]tricose-1(21),9,11,13,18(22),19-hexaene15,17,17-trione (compound 20)

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

- 387 044967

2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine3-carboxylic acid (615 mg, 1.64 mmol), carbonyldiimidazole (279 mg, 1.72 mmol) and tetrahydrofuran (3 ml). The reaction mixture was stirred at 45°C for 2 hours. Tert-butyl-2,2dimethyl-4-[2-[(6-sulfamoyl-2-pyridyl)amino]ethyl]pyrrolidine-1-carboxylate (654 mg, 1.641 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (750 μL, 5.02 mmol) and the reaction mixture was left stirring at 45°C overnight. The reaction was quenched with 1 N. citric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude reaction mixture was purified by silica gel chromatography (10%-100% ethyl acetate in hexane gradient) to give tert-butyl-4-[2-[[6-[[2-chloro-6-[3-[2-[1 -(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin3-carbonyl]sulfamoyl]-2-pyridyl]amino]ethyl]-2,2-dimethylpyrrolidine-1-carboxylate (830 mg, 67%) as a white solid substances. MS-ESI m/z calc. 755.248, detected 756.5 (M+1)+; retention time: 1.8 min (LC method G).

Step 2: 2-chloro-N-[[6-[2-(5,5-dimethylpyrrolidin-3-yl)ethylamino]-2-pyridyl]sulfonyl]-6-[3-[2[ 1 -(trifluoromethyl) cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide

Into a round bottom flask containing tert-butyl-4-[2-[[6-[[2-chloro-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3 -carbonyl]sulfamoyl]-2pyridyl]amino]ethyl]-2,2-dimethylpyrrolidine-1-carboxylate (830 mg, 1.098 mmol) added dichloromethane (2 ml) and hydrochloric acid (2.75 ml 4M in dioxane, 11.00 mmol). After 40 min, the reaction was quenched with saturated sodium bicarbonate and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and evaporated to give 2-chloro-N-[[6-[2-(5,5dimethylpyrrolidin-3-yl)ethylamino]-2-pyridyl]sulfonyl]-6-[3- [2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (715 mg, 99%) as a white solid.

¹ H NMR (400 MHz, DMSS-Y6) δ 8.35 (d, J=2.8 Hz, 1H), 8.11 (d, J=8.3 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.44 ( dd, J=8.3, 7.3 Hz, 1H), 6.98 (dd, J=7.2, 0.8 Hz, 1H), 6.84 (t, J=5.8 Hz, 1H), 6.47 (dd, J=8.3, 0.8 Hz, 1H ), 6.12 (d, J=2.8 Hz, 1H), 4.33 (t, J=7.0 Hz, 2H), 3.81-3.69 (m, 1H), 3.17 (dk, J=12.3, 5.8 Hz, 1H), 3.09 -2.97 (m, 1H), 2.39 (p, J=8.0 Hz, 1H), 2.08 (t, J=7.1 Hz, 2H), 1.95 (dd, J=12.8, 7.7 Hz, 1H), 1.62 (dp, J=19.9, 6.4 Hz, 2H), 1.35 (dd, J=12.8, 10.2 Hz, 1H), 1.26 (d, J=32.0 Hz, 6H), 1.01-0.84 (m, 4H). MS-ESI m/z calc. 655.19556, detected 656.6 (M+1) ⁺ ; retention time: 0.78 min (LC method B).

Step 3: 7,7-dimethyl-11-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-17λ ⁶ -tiα2,8,10,16,22- pentaazatetracyclo[16.3.1.15,8.09,14]tricose-1(21),9,11,13,18(22),19-hexaene-15,17,17-trione (compound 20)

Potassium carbonate (263 mg, 1.90 mmol), cesium fluoride (133 mg, 0.876 mmol), four 3 A molecular sieves, 2-chloro-N-[[6-[2-(5.5- dimethylpyrrolidin-3-yl)ethylamino]-2pyridyl]sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carboxamide (250 mg, 0.381 mmol) and dimethyl sulfoxide (7 ml). The reaction mixture was capped and placed in a preheated 155°C oil bath overnight. The reaction was diluted with ethyl acetate and quenched with 1 N. citric acid, and then with saline solution. The reaction mixture was extracted twice with ethyl acetate, dried over sodium sulfate, filtered and evaporated. Crude reaction mixture

- 388 044967 purify by silica gel chromatography (0%-100% ethyl acetate in hexane gradient) to provide 7,7-dimethyl-11-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H -pyrazol-1 -yl)- 17λ ⁶ -tiα2,8,10,16,22-pentaazatetracyclo[16.3.1.15,8.09,14]tricose-1(21),9,11,13,18(22),19 -hexaene-15,17,17-trione (compound 20) (101 mg, 43%). MS-ESI m/z calc. 619.2189, detected 620.2 (M+1)+; Hold Time:

2.07 min (LC method B).

Example 114: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-2λ ⁶ -thia-3,9,11,18,22 -nentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21hexaene-2,2,4-trione (hydrochloride salt) (compound 23) o o

U A

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

4-Aminopyridine-2-sulfonamide ( 310 mg, 1.79 mmol) and cesium carbonate (900 mg, 2.76 mmol). The reaction mixture was stirred at 70°C for 4 hours. The reaction mixture was cooled to room temperature and poured into water (100 ml) and extracted with ethyl acetate (2x 100 ml), the organic layers were combined, washed with brine, dried (sodium sulfate), filtered and concentrated to give tert-butyl 2,2-dimethyl-4-[3[(2-sulfamoyl-4-pyridyl)amino]propyl]pyrrolidine-1-carboxylate, which was used directly in the next step (369 mg, quant.) .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (brs, 2H), 8.12 (dd, J=6.6, 1.6 Hz, 1H), 7.24 (dd, J=6.3, 2.4 Hz, 1H), 6.87 ( dt, J=6.7, 2.0 Hz, 1H), 3.50 (k, J=9.0 Hz, 2H), 3.40-3.28 (m, 1H), 2.96 (p, J=7.0, 6.4 Hz, 2H), 2.83-2.68 (m, 1H), 2.07-1.96 (m, 1H), 1.89-1.74 (m, 2H), 1.45-1.26 (m, 14H), 1.23 (s, 3H). MS-ESI m/z calc. 412.21442, detected 413.5 (M+1) ⁺ ; retention time: 0.52 min (LC method A).

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

A solution of 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (300 mg, 0.798 mmol) and carbonyldiimidazole (130 mg, 0.802 mmol) in tetrahydrofuran (5 ml) was stirred for 45 minutes. Then tert-butyl 2,2-dimethyl-4-[3-[(2-sulfamoyl-4pyridyl)amino]propyl]pyrrolidine-1-carboxylate (330 mg, 0.800 mmol) and 1,8diazabicyclo[5.4.0] were added undec-7-ene (150 μl, 1.00 mmol) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to give an oily material, which was purified by reverse phase HPLC-MS using a Luna C ₁₈ (2) column (75 x 30 mm, 5 µm particle size). sold by Phenomenex (art. no.: 00C-4252-U0-AX), and dual gradient from 1% to 99% mobile phase B in

- 389 044967 for 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 the desired product tert-butyl 4-[3-[[2-[[2-chloro-6-[ 3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-4pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (23 mg, 4 %) in the form of an off-white sticky material.

1H NMR (400 MHz, DMSOC) δ 8.40 (d, J=2.8 Hz, 1H), 8.15 (d, J=5.6 Hz, 1H), 7.96 (d, J=8.3 Hz, 1H), 7.66 (d, J =8.3 Hz, 1H), 7.00 (d, J=2.2 Hz, 1H), 6.80 (s, 2H), 6.69 (dd, J=5.7, 2.2 Hz, 1H), 6.18 (d, J=2.8 Hz, 1H ), 4.34 (t, J=7.1 Hz, 2H), 3.81-3.71 (m, 1H), 3.54 (k, J=8.3 Hz, 1H), 2.77 (k, J=10.0 Hz, 1H), 2.18-2.02 (m, 4H), 1.90-1.77 (m, 1H), 1.74-1.65 (m, 1H), 1.43-1.32 (m, 14H), 1.22 (s, 3H), 1.01-0.94 (m, 2H), 0.91 -0.87 (m, 2H). MS-ESI m/z calc. 769.2636, detected 770.7 (M+1)+; Retention time: 0.87 min (LC method A).

Step 3: 12,12-dimethyl-8-(3 - {2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-2λ ⁶ -thia3,9,11,18,22 -pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21 -hexaene-2,2,4-trione (hydrochloride salt) (compound 23)

tert-Butyl 4-[3-[[2-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin3-carbonyl]sulfamoyl]-4 -pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (20 mg, 0.026 mmol) was dissolved in dioxane (1.0 ml) and hydrochloric acid (4 M in dioxane) (250 μl 4 M, 1.0 mmol), and the resulting mixture was stirred at room temperature for 3 hours. The mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate, then aqueous 2 M sodium carbonate (5 ml), pH ~ 10 was added. The organic layer was extracted with ethyl acetate (2 x 10 ml), washed with brine, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure, yielding material which was combined with potassium carbonate (20 mg, 0.14 mmol), cesium fluoride (10 mg, 0.066 mmol) and dimethyl sulfoxide (2.0 ml) in a vial. The vial was purged with nitrogen, capped, heated to 150°C and stirred for 16 hours. Cooled to room temperature and the reaction mixture was filtered through a Whatman disk filter (puradysc 25 TF), and the filtrate was purified by reverse phase HPLC-MS using a column Luna C ₁₈ (2) (75x30 mm, 5 µm particle size), sold by Phenomenex (art. no.: 00C-4252-U0-AX), and a dual gradient from 50% to 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 obtain 12,12-dimethyl-8-( 3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-2λ ⁶ -thia-3,9,11,18,22pentaazatetracyclo[17.3.1.111,14.05,10]tetracose- 1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (hydrochloride salt) (compound 23) (1.6 mg, 9%) as a white solid. MS-ESI m/z calc. 633.2345, detected 634.6 (M+1) ⁺ ; Retention time: 2.15 min (LC method B).

Example 115: Preparation of 6,6-dimethyl-10-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-16X ⁶ -thia-2,7,9,15,21 -pentaazatetracyclo[15.3.1.14,7.08,13]docose-1(20),8,10,12,17(21),18-hexaene14,16,16-trione (compound 17)

Step 1: tert-butyl 4-(hydroxymethyl)-2,2-dimethylpyrrolidine-1-carboxylate

- 390 044967

(1-Benzyl-5,5-dimethylpyrrolidin-3-yl)methanol (1 g, 4.56 mmol) was dissolved in EtOH (40 ml), 20% Pd(OH) ₂ on carbon (400 mg) was added and the reaction mixture stirred in a hydrogen atmosphere at 20°C for 24 hours. The catalyst was filtered through celite. The filter cake was washed with ethyl acetate and the filtrate was concentrated. The crude intermediate was dissolved in tetrahydrofuran/water (50 ml/50 ml) and potassium carbonate (3.1 g, 22.8 mmol) was added followed by Boc ₂ O (1.22 g, 4.56 mmol) at 0 °C. The reaction mixture was allowed to warm to 20°C for 16 hours, then poured into water and extracted with ethyl acetate (3x20 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness. Pure tert-butyl 4-(hydroxymethyl)-2,2dimethylpyrrolidine-1-carboxylate (1.04 g, quant) was obtained as a colorless oil after purification on silica gel (eluted with 30% ethyl acetate in heptanes).

¹ H NMR (300 MHz, CDCl ₃ ): d 3.6 (m, 4H); 3.1 (m, 1H); 2.4 (m, 1H); 1.9 (m, 1H); 1.4 (m, 15H).

Step 2: tert-butyl-4-(aminomethyl)-2,2-dimethylpyrrolidine-1-carboxylate Boc N _ Boc N p^ he p^ nh ₂

MsCl (0.57 mL, 7.3 mmol) was slowly added to a solution of tert-butyl 4-(hydroxymethyl)-2,2dimethylpyrrolidine-1-carboxylate (1.4 g, 6.1 mmol) and DIPEA (1.6 ml, 9.15 mmol) in dichloromethane (30 ml) at 0°C. The reaction mixture was stirred for 1 hour, water was added, the layers were separated and the aqueous layer was extracted with dichloromethane (2x10 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude mesylate was dissolved in N,N-dimethylformamide (20 ml), NaN ₃ (600 mg, 9.15 mmol) was added and the reaction mixture was stirred in a closed vessel at 100°C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude azide was dissolved in tetrahydrofuran/water (18/2 ml), PPh ₃ (2.4 g, 9.15 mmol) was added and the reaction mixture was stirred at 50°C for 3 hours. The reaction mixture was cooled, carefully acidified to pH 3 using 4 n. aqueous hydrochloric acid and washed quickly with ethyl acetate (2x20 ml). The aqueous layer was made alkaline to pH 10 and extracted with ethyl acetate (3x10 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give tert-butyl-4-(aminomethyl)-2,2dimethylpyrrolidine-1-carboxylate (600 mg, 43%) as a yellow oil after purification on silica gel (eluted with 5% methanol in dichloromethane).

¹ H NMR (300 MHz, CDCl ₃ ): d 3.7 (m, 1H); 3.0 (m, 1H); 2.7 (m, 2H); 2.2 (m, 1H); 1.9 (m, 1H); 1.4 (m, 15H).

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

In a 20 ml vial, combine 6-fluoropyridine-2-sulfonamide (340 mg, 1.9 mmol) in dimethyl sulfoxide (4.0 ml), followed by potassium carbonate (1.3 g, 9.4 mmol) and tert-butyl- 4-(aminomethyl)-2,2dimethylpyrrolidine-1-carboxylate (460 mg, 2.0 mmol). The vessel was capped and heated to 100°C on a hot plate for 16 hours. The reaction mixture was cooled to room temperature, then filtered, diluted with ethyl acetate and washed with 1 M citric acid solution and then with saline. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexanes to 80% ethyl acetate in hexanes to give tert-butyl-2,2-dimethyl-4-[[( 6-sulfamoyl-2-pyridyl)amino]methyl]pyrrolidine 1-carboxylate (222 mg, 30%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.53 (dd, J=8.4, 7.3 Hz, 1H), 7.10 (s, 2H), 7.06 (d, J=5.5 Hz, 1H), 6.97 (d, J=6.9 Hz, 1H), 6.64 (d, J=8.1 Hz, 1H), 3.65-3.54 (m, 1H), 3.17 (d, J=5.2 Hz, 2H), 2.95 (t, J=10.1 Hz, 1H), 2.47-2.35 (m, 1H), 2.00-1.86 (m, 1H), 1.55 (dt, J=32.7, 12.1 Hz, 1H), 1.42-1.36(m, 12H), 1.25 (s, 3H) . MC-ESI m/z calculated 384.18314, found 385.2 (M+1)+; retention time: 1.46 min (LC method E).

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

- 391 044967

2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (202 mg, 0.538 mmol) and carbonyl diimidazole (87.5 mg, 0.540 mmol) were combined in tetrahydrofuran (3.0 ml) and stirred for 2 hours at 45°C. Tert-butyl 2,2-dimethyl-4-[[(6sulfamoyl-2-pyridyl)amino]methyl]pyrrolidine-1-carboxylate (207 mg, 0.538 mmol) was then added followed by 1,8diazabicyclo[5.4.0] undec-7-ene (175 μl, 1.17 mmol), and the reaction mixture was heated at 50°C for 16 hours. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution, followed by saline. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a gradient of 100% hexanes to 70% ethyl acetate in hexanes to give tert-butyl-4-[[[6-[[2-chloro- 6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2 pyridyl]amino]methyl]-2,2-dimethylpyrrolidine-1-carboxylate ( 234 mg, 59%) as a light yellow solid.

Ή NMR (400 MHz, DMSOA) δ 12.79 (s, 1H), 8.40 (m, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.70 (t, J=7.0 Hz, 1H), 7.63 (m , 1H), 7.28 (s, 1H), 7.19 (d, J=7.2 Hz, 1H), 6.77 (d, J=8.6 Hz, 1H), 6.19 (dd, J=4.4, 2.9 Hz, 1H), 4.34 (t, J=7.1 Hz, 2H), 3.55 (m, 1H), 3.26 (m, 2H), 2.91 (t, J=10.4 Hz, 1H), 2.41 (m, 1H), 2.09 (t, J= 7.1 Hz, 3H), 1.86 (m, 1H), 1.50 (m, 1H), 1.35 (t, J=13.2 Hz, 12H), 1.18 (s, 3H), 0.95 (m, 2H), 0.89 (s, 2H). MS-ESI m/z calc. 741.2323, detected 742.2 (M+1)+; retention time: 2.25 min (LC method E).

Step 5: 6,6-dimethyl-10-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1-yl)-16λ ⁶ -thia2,7,9,15,21 -pentaazatetracyclo[15.3.1.14,7.08,13]docose-1(20),8,10,12,17 (21),18-hexaene-14,16,16-trione (compound 17)

tert-Butyl 4-[[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl ]amino]methyl]-2,2-dimethylpyrrolidine-1-carboxylate (234 mg, 0.315 mmol) was dissolved in dichloromethane (5.0 ml) and hydrochloric acid (3.0 ml 4 M in dioxane, 12.0 mmol) and stirred at room temperature for 2 hours. The mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate, then aqueous 2M sodium carbonate (2 ml), pH ~ 10 was added. The organic layer was extracted with ethyl acetate (2x5 ml), washed with saline solution, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. Combine this material and potassium carbonate (220 mg, 1.59 mmol), cesium fluoride (72.0 mg, 0.474 mmol), 3 A molecular sieves, and dimethyl sulfoxide (7.0 mL) in a vial, purged with nitrogen, capped, heated up to 155°C. and stirred for 16 hours. Cooled to room temperature, and the reaction mixture was diluted with ethyl acetate and washed with 1 M citric acid solution and then with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a gradient of 100% hexanes to 80% ethyl acetate in hexanes to give 6,6-dimethyl-10-(3-{2-[1( trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-16λ ⁶ -thia-2,7,9,15,21pentaazatetracyclo[15.3.1.14,7.08,13]docose-1(20),8,10, 12,17(21),18-hexaene-14,16,16-trione (compound 17) (111 mg, 57%) as a white solid.

1H NMR (400 MHz, DMSO-de) δ 12.52 (s, 1H), 8.19 (d, J=2.7 Hz, 1H), 7.67-7.50 (m, 2H), 7.47 (d, J=8.1 Hz, 1H) , 7.16 (d, J=7.2 Hz, 1H), 6.82 (d, J=8.1 Hz, 1H), 6.73 (d, J=8.5 Hz, 1H), 6.09 (d, J=2.7 Hz, 1H), 4.52 (t, J=9.8 Hz, 1H), 4.30 (t, J=7.0 Hz, 2H), 3.54-3.42 (m, 1H), 3.27-3.16 (m, 1H), 3.02 (t, J=8.7 Hz, 1H), 2.32 (dt, J=12.3, 5.7 Hz, 1H), 2.07 (dd, J=8.7, 5.4 Hz, 2H), 1.97 (dd, J=11.4, 5.8 Hz, 1H), 1.68 (s, 3H ), 1.64 (d, J=12.2 Hz, 1H), 1.45 (s, 3H), 0.95 (t, J=5.8 Hz, 2H), 0.87 (s, 2H). MS-ESI m/z calc. 605.2032, detected 606.4 (M+1) ⁺ ; retention time: 2.02 min (LC method E).

Example 116: Preparation of 6,6-dimethyl-10-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-16λ ⁶ -thia-2,7,9,15,21 -pentaazatetracyclo[15.3.1.14,7.08,13]docose-1(20),8,10,12,17(21),18-hexaene14,16,16-trione (enantiomer 1) (compound 24) and 6,6 -dimethyl-10-(3-{2-[1- 392 044967 (trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-16λ ⁶ -thia-2,7,9,15,21 pentaazatetracyclo[ 15.3.1.14,7.08,13]docose-1(20),8,10,12,17(21),18-hexaene-14,16,16-trione (enantiomer

2) (connection 25)

Step 1: 6,6-dimethyl-10-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-16X ⁶ -thia2,7,9,15,21- pentaazatetracyclo[15.3.1.14,7.08,13]docose-1(20),8,10,12,17(21),18-hexaene-14,16,16-trione (enantiomer 1) (compound 24) and 6, 6-dimethyl-10-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-16λ ⁶ -thia-2,7,9,15,21-pentaazatetracyclo[15.3.1.14 ,7.08,13]docose-1(20),8,10,12,17(21),18hexaene-14,16,16-trione (enantiomer 2) (compound 25)

Racemic 6,6-dimethyl-10-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)16λ ⁶ -thia-2,7,9,15,21-pentaazatetracyclo [15.3.1.14,7.08,13]docose-1(20),8,10,12,17(21),18-hexaene14,16,16-trione (131 mg) was subjected to chiral SLC chromatography using ChiralPak AS- H (250 x 21.2 mm column, 5 µm particle size) with a mobile phase of 15% acetonitrile:methanol (90:10)/85% carbon dioxide at 10 ml/min, giving 6,6-dimethyl10- as the first enantiomer eluted (3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-16λ ⁶ -thia-2,7,9,15,21pentaazatetracyclo[15.3.1.14,7.08,13] docose-1(20),8,10,12,17(21),18-hexaene-14,16,16-trione (enantiomer 1) (compound 24) (29.04 mg, 69%) as not quite white solid;

1H NMR (400 MHz, DMSO-de) δ 12.52 (s, 1H), 8.19 (d, J=2.7 Hz, 1H), 7.61 (dd, J=10.5, 5.2 Hz, 2H), 7.47 (d, J= 8.1 Hz, 1H), 7.16 (d, J=7.2 Hz, 1H), 6.82 (d, J=8.1 Hz, 1H), 6.73 (d, J=8.5 Hz, 1H), 6.09 (d, J=2.7 Hz , 1H), 4.51 (t, J=10.0 Hz, 1H), 4.30 (t, J=7.0 Hz, 2H), 3.58-3.38 (m, 1H), 3.22 (d, J=5.6 Hz, 1H), 3.09 -2.95 (m, 1H), 2.40-2.20 (m, 1H), 2.07 (t, J=7.0 Hz, 2H), 1.97 (dd, J=12.2, 6.2 Hz, 1H), 1.74-1.60 (m, 4H ), 1.45 (s, 3H), 0.95 (t, J=5.7 Hz, 2H), 0.89 (d, J=11.5 Hz, 2H), MS-ESM m/z calc. 605.2032, found 606.2 (M+1)+; Retention time: 2.03 min (method E), and the second enantiomer eluted was 6,6-dimethyl-10-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl )-16Х ⁶ -thia-2,7,9,15,21pentaazatetracyclo[15.3.1.14,7.08,13]docose-1(20),8,10,12,17(21),18-hexaene-14,16 ,16-trione (enantiomer 2) (compound 25) (28.84 mg, 68%) as an off-white solid;

1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 12.52 (s, 1H), 8.19 (d, J=2.7 Hz, 1H), 7.61 (dd, J=10.3, 5.4 Hz, 2H), 7.47 (d, J= 8.1 Hz, 1H), 7.16 (d, J=7.2 Hz, 1H), 6.82 (d, J=8.1 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 6.09 (d, J=2.7 Hz , 1H), 4.51 (t, J=9.9 Hz, 1H), 4.30 (t, J=7.0 Hz, 2H), 3.58-3.41 (m, 1H), 3.22 (dd, J=12.0, 5.7 Hz, 1H) , 3.02 (t, J=8.6 Hz, 1H), 2.31 (dd, J=15.2, 6.3 Hz, 1H), 2.07 (t, J=7.0 Hz, 2H), 1.97 (dd, J=12.1, 6.3 Hz, 1H), 1.71-1.59 (m, 4H), 1.45 (s, 3H), 0.95 (t, J=5.7 Hz, 2H), 0.89 (d, J=11.5 Hz, 2H), MS-ESI m/z calculated . 605.2032, found 606.2 (M+1) ⁺ ; Retention time: 2.03 min (LC method E).

Example 117: Preparation of 7,7-dimethyl-11-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-17λ ⁶ -thia-2,8,10,16,22 -pentaazatetracyclo[16.3.1.15,8.09,14]tricose-1(21),9,11,13,18(22),19-hexaene15,17,17-trione (enantiomer 1) (compound 26) and 7,7 -dimethyl-11-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1H-pyrazol-1 -yl)- 17Х ⁶ -thia-2,8,10,16,22pentaazatetracyclo[16.3.1.15,8.09 ,14]tricose-1(21),9,11,13,18(22),19-hexaene-15,17,17-trione (enantiomer 2) (compound 27)

Step 1: 7,7-dimethyl-11 -(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1 -yl)-17X ⁶ -thia2,8,10,16,22- pentaazatetracyclo[16.3.1.15,8.09,14]tricose-1(21),9,11,13,18(22),19-hexaene-15,17,17-trione (enantiomer 1) (compound 26) and 7, 7-dimethyl-11-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-17λ ⁶ -thia-2,8,10,16,22-pentaazatetracyclo[16.3.1.15 ,8.09,14]tricose-1(21),9,11,13,18(22),19hexaene-15,17,17-trione (enantiomer 2) (compound 27)

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Racemic 7,7-dimethyl-11-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)17λ ⁶ -thia-2,8,10,16,22- pentaazatetracyclo[16.3.1.15,8.09,14]tricose-1(21),9,11,13,18(22),19-hexaene15,17,17-trione (85 mg, 0.1372 mmol) was exposed to chiral SLC - chromatography using ChiralPak AS-H (column 250x21.2 mm, particle size 5 μm) with a mobile phase of 20% methanol (without modifier) / 80% carbon dioxide at 10 ml/min, obtaining enantiomer 7 as the first eluted one, 7-dimethyl-11-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1-yl)-17λ ⁶ thia-2,8,10,16,22-pentaazatetracyclo[16.3 .1.15,8.09,14]tricose-1(21),9,11,13,18(22),19-hexaene-15,17,17trione (enantiomer 1) (compound 26) (24.1 mg, 28% ); MS-ESI m/z calc. 619.2189, detected 620.2 (M+1) ⁺ ; Retention time: 2.07 min (LC method B) and as the second eluted enantiomer 7,7dimethyl-11-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)- 17λ ⁶ -thia-2,8,10,16,22pentaazatetracyclo[16.3.1.15,8.09,14]tricose-1(21),9,11,13,18(22),19-hexaene-15,17,17 -trione (enantiomer 2) (compound 27) (26 mg, 31%); MS-ESI m/z calc. 619.2189, detected 620.2 (M+1) ⁺ ; Retention time: 2.06 min (LC method B).

Example 118: Preparation of 4-chloro-20,20-dimethyl-10λ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22 ), 12-pentaene-8,10,10-trione (compound A) and 4-chloro-21,21-dimethyl10λ ⁶ -thia-1,3,9,14,15-pentaazatetracyclo[17.2.1.02,7.011.15 ]docose-2,4,6,11,13-pentaene-8,10,10-trione (compound B)

Step 1: 2,6-dichloro-N-(1H-pyrazol-3-ylsulfonyl)pyridin-3-carboxamide

2,6-Dichloropyridine-3-carboxylic acid (1 g, 5.208 mmol) and carbonyldiimidazole (1.690 g, 10.42 mmol) in N,N-dimethylformamide (10.00 ml) were stirred at 50°C for 1 hour. A suspension of sodium hydride (312.5 mg, 7.812 mmol) in N,N-dimethylformamide was added to a solution of 1H-pyrazole-5sulfonyl chloride (194.5 mg, 1.16 mmol, 1.5 eq.) in N,N-dimethylformamide and stirred for 30 min at room temperature in a separate flask. The two mixtures were combined and stirred at room temperature for 1 hour. The reaction mixture was poured onto ice and acidified to pH 2 by adding aqueous 4 M hydrochloric acid. The resulting mixture was extracted with ethyl acetate, the organic layer was dried over sodium sulfate, filtered and volatiles were removed by rotary evaporation. The crude material was purified by silica gel chromatography eluting with 10% methanol in dichloromethane to give 2,6-dichloro-N-(1H-pyrazol-3-ylsulfonyl)pyridin-3-carboxamide (1.341 g, 68%). MS-ESI m/z calc. 319.95377, detected 321.0 (M+1)+; retention time: 0.34 min (LC method A).

Step 2: tert-butyl 4-[3-[3-[(2,6-dichloropyridine-3-carbonyl)sulfamoyl]pyrazol-1-yl]propyl]2,2-dimethyl-pyrrolidine-1-carboxylate

2,6-Dichloro- N-(1H-pyrazol-3-394 044967 ylsulfonyl)pyridine-3-carboxamide (300 mg, 0.934 mmol), then cesium carbonate (875 mg, 2.69 mmol), and the reaction mixture was stirred at 60°C for 16 h. The reaction mixture was cooled to room temperature, poured into water (100 ml) and extracted with ethyl acetate (2x100 ml). Combine the organic layers, wash with water (2x100 ml), dry (sodium sulfate), filter and concentrate. The resulting brown residue was purified by silica gel column chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate to give tert-butyl-4-[3-[3-[(2,6-dichloropyridine-3-[(2,6-dichloropyridine-3-) as the first regioisomer eluted carbonyl)sulfamoyl]pyrazol-1-yl]propyl]2,2-dimethylpyrrolidine-1-carboxylate (327 mg, 65%) as a white solid;

¹ H NMR (400 MHz, DMSO-de) δ 7.92 (d, J=8.0 Hz, 1H), 7.70 (d, J=2.2 Hz, 1H), 7.51-7.46 (m, 1H), 6.48 (d, J =2.3 Hz, 1H), 4.14-4.05 (m, 2H), 3.53 (dt, J=14.7, 10.3 Hz, 1H), 2.78-2.67 (m, 1H), 2.08 (dk, J=11.7, 5.9, 5.3 Hz, 1H), 1.39 (s, 4H), 1.34 (k, J=11.5, 8.4 Hz, 12H), 1.22 (s, 3H), MS-ESM m/z calc. 559.1423, found 560.5 (M+1)+; Retention time: 0.71 min (LC method A), and as the second regioisomer eluted, tert-butyl 4-[3-[5-[(2,6-dichloropyridin-3carbonyl)sulfamoyl]pyrazol-1-yl]propyl]-2 ,2-dimethyl-pyrrolidine-1-carboxylate (126 mg, 25%) as a viscous, colorless oil;

1H NMR (400 MHz, DMSO-de) δ 8.01 (dd, J=8.0, 5.0 Hz, 1H), 7.95 (s, 1H), 7.50 (dd, J=7.9, 1.5 Hz, 1H), 7.37 (d, J=1.9 Hz, 1H), 6.50 (d, J=1.9 Hz, 1H), 4.34 (t, J=7.3 Hz, 2H), 3.46 (dt, J=14.4, 9.9 Hz, 1H), 2.66 (td, J=10.4, 4.7 Hz, 1H), 1.99 (s, 0H), 1.76 (dt, J=17.9, 8.3 Hz, 3H), 1.38 (d, J=12.7 Hz, 9H), 1.30 (d, J=10.5 Hz, 3H), 1.17 (d, J=2.3 Hz, 3H), MS-ESI m/z calc. 559.1423, found 560.5 (M+1) ⁺ ; Retention time: 0.74 min (LC method A).

Step 3: 4-chloro-20,20-dimethyl-10λ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose2,4,6,11(22),12 -pentaene-8,10,10-trione (compound A)

Solution of tert-butyl 4-[3-[5-[(2,6-dichloropyridine-3-carbonyl)sulfamoyl]pyrazol-1-yl]propyl]-2,2dimethylpyrrolidine-1-carboxylate (100 mg, 0.1784 mmol) in dichloromethane (2 ml) and trifluoroacetic acid (150 µl, 1.960 mmol) were stirred at room temperature for 4 hours. Solvents were removed by evaporation and 2 M NH3 in methanol (10 ml) was added, the reaction mixture was stirred for 30 minutes, then concentrated and dried in vacuum. The above residue was dissolved in dimethyl sulfoxide (2 ml) and 3 A molecular sieves were added and the reaction mixture was stirred for 10 minutes. Cesium fluoride (85 mg, 0.5596 mmol) and potassium carbonate (78 mg, 0.5644 mmol) were then added and the reaction mixture was heated at 140°C overnight. The reaction mixture was filtered through a Whatman disk filter (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS (Luna C ₁₈ (2) column (75x30 mm, 5 µm particle size) sold by Phenomenex (pn: 00C-4252-U0 -AX) and a double gradient from 50% to 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 obtain 4-chloro-2O,20-dimethyl-1Oλ ⁶ -thia1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2, 4,6,11(22),12-pentaene-8,10,10-trione (28 mg, 12%) as a white solid.

1H NMR (400 MHz, chloroform-d) δ 8.77 (s, 1H), 7.54-7.44 (m, 2H), 7.07 (d, J=2.3 Hz, 1H), 6.48 (d, J=7.9 Hz, 1H) , 4.36-4.24 (m, 1H), 4.06-3.85 (m, 1H), 2.67 (t, J=8.3 Hz, 1H), 2.14 (ddt, J=17.7, 12.1, 6.2 Hz, 2H), 2.07-2.01 (m, 1H), 1.98-1.84 (m, 2H), 1.73 (ddd, J=12.1, 5.5, 1.5 Hz, 1H), 1.55 (s, 3H), 1.50 (s, 3H), 1.44 (t, J =12.3 Hz, 1H), 0.86-0.69 (m, 1H). MS-ESI m/z calc. 423.1132, found 424.4 (M+1) ⁺ ; Retention time: 1.76 min (LC method B).

Step 4: 4-chloro-21,21-dimethyl-10λ ⁶ -thia-1,3,9,14,15-pentaazatetracyclo[17.2.1.02,7.011,15]docose2,4,6,11,13-pentaene- 8,10,10-trione (compound B)

Solution of tert-butyl 4-[3-[3-[(2,6-dichloropyridine-3-carbonyl)sulfamoyl]pyrazol-1-yl]propyl]-2,2dimethylpyrrolidine-1-carboxylate (100 mg, 0.1784 mmol) in dichloromethane (2 ml) and trifluoroacetic acid

- 395 044967 acid (150 µl, 1.960 mmol) was stirred at room temperature for 4 hours. After completion of the reaction, the solvents were removed by evaporation and 2 M NH ₃ in methanol (10 ml) was added and the reaction mixture was stirred for 30 minutes, concentrated, then dried under vacuum. The residue was dissolved in dimethyl sulfoxide (2 ml), 3 A molecular sieves were added and the reaction mixture was stirred for 10 minutes. Cesium fluoride (85 mg, 0.5596 mmol) and potassium carbonate (78 mg, 0.5644 mmol) were then added and the reaction mixture was heated at 140°C overnight. The reaction mixture was filtered through a Whatman disc filter (puradisc 25 TF) and the filtrate was purified by reverse phase HPLCMS (Luna C ₁₈ (2) column (75x30 mm, 5 µm particle size) sold by Phenomenex (pn: 00C-4252-U0AX) and double gradient from 50% to 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 obtain 4-chloro-21,21-dimethyl-10λ ⁶ -thia1,3,9,14,15-pentaazatetracyclo[17.2.1.02,7.011,15]docose-2,4,6, 11,13-pentaene-8,10,10-trione (10.2 mg, 4%) as an off-white solid.

1H NMR (400 MHz, chloroform-d) δ 9.16 (s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.57 (d, J=2.1 Hz, 1H), 7.35 (d, J=2.1 Hz , 1H), 6.82 (d, J=8.0 Hz, 1H), 4.78 (dt, J=13.8, 4.0 Hz, 1H), 4.41-4.29 (m, 1H), 3.20 (t, J=9.7 Hz, 1H) , 2.62-2.56 (m, 1H), 2.52 (s, 1H), 2.21-2.06 (m, 1H), 1.91 (s, 1H), 1.81-1.69 (m, 3H), 1.63 (s, 4H), 1.45 (s, 3H). MS-ESI m/z calc. 423.1132, found 424.4 (M+1)+; Retention time: 1.9 min (LC method B).

Example 119: Preparation of 20,20-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-10λ ⁶ -thia-1,3,9,14,22 -pentaazatetracyclo[16.2.1.111,14.02,7]docose-2(7),3,5,11(22),12-pentaene8,10,10-trione (compound 32)

Step 1: 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]docose-2(7),3,5,11(22),12-pentaene-8,10,10-trione (compound 32)

Solution of 4-chloro-20,20-dimethyl-10λ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose2,4,6,11(22),12-pentaene -8,10,10-trione (20 mg, 0.04718 mmol), scandium triflate, 3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]-1H-pyrazole (31.16 mg, 0.1415 mmol) and NaH (9.435 mg 60% wt, 0.2359 mmol) in dimethyl sulfoxide (2.0 ml) were stirred at 140°C for 16 hours. The reaction mixture was quenched with a few drops of water and filtered through a Whatman disk filter (puradysc 25 TF), and the filtrate was purified using a reverse phase HPLC-MS method using a Luna C ₁₈ (2) column (75x30 mm, 5 μm particle size) sold by Phenomenex (Item No.: 00C-4252-U0-AX), double gradient run from 1-99% mobile phase B for 15.0 min (mobile phase A=water (5 mM hydrochloric acid), mobile phase B=acetonitrile. Flow rate=50 ml/min, column temperature=25°C) to obtain 20 ,20-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-10λ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2. 1.111,14.02,7]docose-2(7),3,5,11(22),12pentaene-8,10,10-trione (compound 32) (2.4 mg, 8%) as a white solid.

1H NMR (400 MHz, chloroform-d) δ 8.49 (s, 1H), 8.17 (d, J=2.7 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.49 (s, 1H), 7.08 (d, J=2.1 Hz, 1H), 7.01 (d, J=8.2 Hz, 1H), 5.87 (d, J=2.7 Hz, 1H), 4.39 (t, J=7.1 Hz, 2H), 4.35 (s , 1H), 3.94 (t, J=12.9 Hz, 1H), 2.78-2.72 (m, 1H), 2.20-2.13 (m, 2H), 2.10 (d, J=7.0 Hz, 2H), 1.99 (t, J=10.3 Hz, 3H), 1.79-1.74 (m, 1H), 1.59 (s, 3H), 1.55 (s, 3H), 1.47 (t, J=12.0 Hz, 2H), 1.04-1.00 (m, 2H ), 0.77-0.73 (m, 2H). MSIE m/z calc. 607.2189, found 608.6 (M+1) ⁺ ; Retention time: 2.18 min (LC method E).

Example 120: Preparation of (15S)-12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-2λ ⁶ -thia-3,9,11 ,19,24-pentaazatetracyclo[18.3.1.05,10.011,15]tetracose1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (compound 33) and (15R) -12,12-dimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1-yl)-2λ ⁶ -thia-3,9,11,19,24pentaazatetracyclo[ 18.3.1.05,10.011,15]tetracose-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (compound 34)

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Step 1: (15S)-12,12-dimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)2λ ⁶ -thia-3,9, 11,19,24-pentaazatetracyclo[18.3.1.05,10.011.15]tetracose-1(23),5,7,9,20(24),21-hexaene-2,2,4trione (compound 33) and (15R )-12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-2λ ⁶ -thia-3,9,11,19,24-pentaazatetracyclo [18.3.1.05,10.011,15]tetracose1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (compound 34)

Racemic 12,12-dimethyl-8-(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)2λ ⁶ -thia-3,9,11,19,24- pentaazatetracyclo[18.3.1.05,10.011.15]tetracose-1(23),5,7,9,20(24),21-hexaene-2,2,4trione (90 mg, 0.1420 mmol) was subjected to chiral SLC chromatography using ChiralPak ASH (250x10 mm column, 5 µm particle size) with 18% acetonitrile:methanol (90:10; no modifier)/82% carbon dioxide mobile phase at 10 ml/min to produce the first enantiomer for elution, (15S)-12,12-dimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 yl)-2λ ⁶ -thia-3,9,11,19 ,24-pentaazatetracyclo[18.3.1.05,10.011.15]tetracose-1(23),5,7,9,20(24),21-hexaene2,2,4-trione (compound 33) (28.6 mg, 64%);

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.73 (s, 1H), 8.23 (d, J=2.8 Hz, 1H), 8.01 (d, J=8.3 Hz, 1H), 7.58 (t, J= 7.8 Hz, 1H), 7.29 (t, J=6.2 Hz, 1H), 7.03 (d, J=7.2 Hz, 2H), 6.63 (d, J=8.4 Hz, 1H), 6.13 (d, J=2.8 Hz , 1H), 4.32 (t, J=6.9 Hz, 2H), 3.72 (s, 2H), 3.10 (s, 1H), 2.11-2.05 (m, 2H), 1.85 (s, 2H), 1.74 (d, J=8.9 Hz, 2H), 1.43 (d, J=65.6 Hz, 9H), 1.01-0.85 (m, 5H), ESI-MS m/z calc. 633.2345, found 634.2 (M+1)+; Retention time: 1.85 min (LC method B), and as the first enantiomer to elute, (15R)-12,12-dimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1H- pyrazol-1 -yl)-2λ ⁶ -thia-3,9,11,19,24pentaazatetracyclo[18.3.1.05,10.011,15]tetracose-1(23),5,7,9,20(24),21 - hexaene-2,2,4-trione (compound 34) (29.1 mg, 65%);

¹ H NMR (400 MHz, DMSO-06) δ 12.73 (s, 1H), 8.23 (d, J=2.8 Hz, 1H), 8.01 (d, J=8.2 Hz, 1H), 7.58 (dd, J=8.4 , 7.2 Hz, 1H), 7.29 (d, J=6.9 Hz, 1H), 7.03 (d, J=7.2 Hz, 2H), 6.63 (d, J=8.4 Hz, 1H), 6.13 (d, J=2.8 Hz, 1H), 4.38-4.28 (m, 2H), 3.72 (s, 2H), 3.10 (s, 1H), 2.08 (t, J=7.0 Hz, 2H), 1.96-1.68 (m, 4H), 1.51 (s, 5H), 1.35 (s, 4H), 0.99-0.85 (m, 5H), ESI-MS m/z calc. 633.2345, found 634.2 (M+1) ⁺ ; Retention time: 1.85 min (LC method B).

Example 121: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-2λ ⁶ -thia-3,9,11,20,25 -pentaazatetracyclo[19.3.1.05,10.011,15]pentacose-1(24),5,7,9,21(25),22hexaene-2,2,4-trione (compound 37)

Step 1: tert-butyl 5-(3-cyanopropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

Add tert-butyl 2,2-dimethyl-5-(3-methylsulfonyloxypropyl)pyrrolidine-1-carboxylate (650 mg, 1.938 mmol), dimethyl sulfoxide (2 mL), and sodium cyanide (100 mg,

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2.041 mmol). The reaction was heated at 80°C overnight. The reaction mixture was filtered and purified by HPLC (1-99% acetonitrile in water with 0.1% hydrochloric acid modifier) to give tert-butyl 5-(3-cyanopropyl)-2,2-dimethylpyrrolidine-1-carboxylate (272 mg , 53%). MS-ESI m/z calc. 266.19943, detected 211.2 (M+1)+; retention time: 1.67 min (LC method B).

Step 2: tert-butyl 5-(4-aminobutyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

Add tert-butyl 5-(3-cyanopropyl)-2,2-dimethylpyrrolidine-1-carboxylate (271 mg, 1.017 mmol), methanol (1.50 mL), Raney nickel (100 mg 50% w/v) to a round bottom flask .) and ammonia (2.80 ml 7 M, 19.60 mmol). The reaction mixture was purged with nitrogen, a balloon of hydrogen (2.050 mg, 1.017 mmol) was added and the mixture was stirred overnight at room temperature. Additional Raney nickel (100 mg, 50% w/v) and ammonia (2.80 mL 7 M, 19.60 mmol) were added and the reaction mixture was stirred for 4 hours. The reaction mixture was filtered and the filter cake was washed with additional methanol and dichloromethane. The filtrate solution was evaporated to dryness to obtain tert-butyl 5-(4-aminobutyl)-2,2-dimethylpyrrolidine-1-carboxylate (270 mg, 98%) as a clear, colorless oil. MS-ESI m/z calc. 270.23074, detected 271.3 (M+1) ⁺ ; Retention time: 1.1 min (LC method B).

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

Potassium carbonate (415 mg, 3.003 mmol), 6-fluoropyridine-2-sulfonamide (170 mg, 0.9650 mmol) and a solution of tert-butyl-5-(4-aminobutyl)-2,2-dimethyl- pyrrolidine-1-carboxylate (270 mg, 0.9985 mmol) in dimethyl sulfoxide (3 ml). The reaction mixture was placed in an oil bath preheated to 80°C and left to stir overnight. The reaction mixture was filtered and purified by HPLC (1-99% acetonitrile in water with 0.1% hydrochloric acid modifier) to give tert-butyl-2,2-dimethyl-5-[4-[(6-sulfamoyl-2- pyridyl)amino]butyl]pyrrolidine-1-carboxylate (155.2 mg, 38%). MS-ESI m/z calc. 426.23007, detected 427.3 (M+1) ⁺ ; retention time: 1.71 min (LC method B).

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

2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridine-3-carboxylic acid (166.0 mg, 0.4418 mmol), carbonyldiimidazole ( 71 mg, 0.4379 mmol) and tetrahydrofuran (2.0 ml). The reaction mixture was heated to 45°C for 2 hours, then a solution of tert-butyl-2,2-dimethyl-5-[4-[(6-sulfamoyl-2-pyridyl)amino]butyl]pyrrolidine-1-carboxylate was added ( 155.2 mg, 0.3638 mmol) in tetrahydrofuran (2.0 mL), then 1,8-diazabicyclo[5.4.0]undec-7-ene (165 μL, 1.103 mmol) and the reaction mixture was allowed to stir at room temperature during the night. The reaction mixture was filtered and purified by HPLC (30-99% acetonitrile in water with 0.1% hydrochloric acid modifier) to give tert-butyl-5-[4-[[6-[[2-chloro-6-[3 -[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]butyl]-2,2-dimethylpyrrolidine-1-carboxylate (126 mg, 44% ) is isolated as a white solid. MS-ESI m/z calc. 783.27924, detected 784.5 (M+1) ⁺ ; retention time: 1.9 min (LC method G).

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

- 398 044967

Tert-butyl 5-[4-[[6-[[2-chloro-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl was added to the round bottom flask ]sulfamoyl]-2pyridyl]amino]butyl]-2,2-dimethylpyrrolidine-1-carboxylate (126 mg, 0.1607 mmol), dichloromethane (2 ml) and hydrochloric acid (400 μl 4M in dioxane, 1.600 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated to give 2-chloro-N-[[6-[4-(5,5-dimethylpyrrolidin-2-yl)butylamino]-2-pyridyl]sulfonyl]-6-[3 -[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (105 mg, 96%). MS-ESI m/z calc. 683.2268, detected 684.5 (M+1)+; retention time: 0.79 min (LC method B).

Step 6: 12,12-dimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1-yl)-2λ ⁶ -thia3,9,11,20,25 -pentaazatetracyclo[19.3.1.05,10.011.15]pentacose-1 (24),5,7,9,21 (25),22-hexaene-2,2,4-trione (compound 37)

Potassium carbonate (107 mg, 0.7742 mmol), cesium fluoride (35 mg, 0.2304 mmol) and a solution of 2-chloro-N-[[6-[4-(5,5-dimethylpyrrolidine-2- yl)butylamino]-2-pyridyl]sulfonyl]-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (105 mg, 0.1535 mmol) in dimethyl sulfoxide (1.8 ml). The reaction mixture was heated in a sealed tube overnight at 150°C. The reaction mixture was quenched with brine and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude product was purified by HPLC (30-99% acetonitrile in water with 0.1% hydrochloric acid modifier) to give 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}- 1H-pyrazol-1-yl)-2λ ⁶ -thia3,9,11,20,25-pentaazatetracyclo[19.3.1.05,10.011,15]pentacose-1(24),5,7,9,21(25), 22-hexaene-2,2,4-trione (compound 37) (27 mg, 25%). MS-ESI m/z calc. 647.2502, detected 648.2 (M+1) ⁺ ; retention time: 1.97 min (LC method B).

Example 122: Preparation of 8-(3-hydroxy-1H-pyrazol-1-yl)-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose -1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (hydrochloride salt) (compound 38)

Step 1: tert-butyl 4-[3-[[6-[[2-chloro-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1yl]pyridin-3-carbonyl] sulfamoyl]-2-pyridyl] amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

- 399 044967

2-Chloro-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (200 mg, 0.5431 mmol) and carbonyldiimidazole (88.06 mg, 0.5431 mmol) were combined in tetrahydrofuran (2 ml) and stirred for 90 min at 50°C. Then tert-butyl 2,2-dimethyl-4-[3-[(6sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (179.3 mg, 0.4345 mmol) was added, followed by 1. 8diazabicyclo[5.4.0]undec-7-ene (124.0 mg, 121.8 μL, 0.8147 mmol), and the reaction mixture was heated at 50°C for 18 hours. The reaction was diluted with ethyl acetate and washed with saturated ammonium chloride solution , followed by rinsing with saline solution. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a gradient of 100% hexanes to 70% ethyl acetate in hexanes to give tert-butyl-4-[3-[[ as a white solid. 6-[[2-chloro-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2 ,2-dimethylpyrrolidine-1-carboxylate (206 mg, 51%). MS-ESI m/z calc. 743.3232, detected 744.7 (M+1)+; retention time: 0.95 min (LC method A).

Step 2: 2-chloro-N-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propylamino]-2-pyridyl]sulfonyl]-6-(3hydroxypyrazol-1 -yl)pyridin-3 - carboxamide

To a solution of tert-butyl-4-[3-[[6-[[2-chloro-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1yl]pyridin-3-carbonyl] sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (25 mg, 0.03359 mmol) in dichloromethane (1 ml) and trifluoroacetic acid (19.16 mg, 12.95 μl) was added , 0.1680 mmol) at 0°C and the mixture was stirred for 30 min (reaction mixture 1). Separately to a solution of tert-butyl-4-[3-[[6-[[2-chloro-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1yl]pyridine-3-carbonyl ]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (25 mg, 0.03359 mmol) in dioxane (1 ml) was added hydrochloric acid (42.00 μl 4 M, 0. 1680 mmol) at 0°C, and the mixture was stirred for 30 min (reaction mixture 2). Separately, a solution of tert-butyl-4-[3-[[6-[[2-chloro-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl] -2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (25 mg, 0.03359 mmol) in 2,2,2-trifluoroethanol (1.680 g, 1.224 ml, 16.79 mmol) containing 1% trifluoroacetic acid, stirred for 30 min (reaction mixture 3). Separately to a solution of tert-butyl-4-[3-[[6-[[2-chloro-6[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1 -yl]pyridine-3- carbonyl]sulfamoyl]-2pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (25 mg, 0.03359 mmol) in toluene (1 ml) was added silica gel (100 mg) and the mixture was heated at 90°C in for 24 hours (reaction mixture 4). All four reaction mixtures were combined and purified by reverse phase HPLC-MS using a Luna C ₁₈ (2) column (75x30 mm, 5 µm particle size) sold by Phenomenex (pn: 00C-4252U0-AX) and a double gradient from 20% to 80% 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 obtain 2-chloro-X[[6-[3-(5,5dimethylpyrrolidin-3-yl)propylamino]-2-pyridyl]sulfonyl]-6-(3-hydroxypyrazol-1 -yl)pyridin-3 carboxamide (42 mg, 47%).

1H NMR (400 MHz, Methanol-d4) δ 8.31 (d, J=2.9 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.72-7.63 (m, 2H), 7.30 (dd, J= 7.2, 0.8 Hz, 1H), 6.84 (dd, J=8.6, 0.8 Hz, 1H), 5.97 (d, J=2.8 Hz, 1H), 3.50 (dd, J=l 1.8, 8.4 Hz, 21H), 3.41 (dp, J=20.3, 6.7 Hz, 2H), 2.93 (dd, J=11.8, 9.1 Hz, 1H), 2.54 (dt, J=16.6, 8.3 Hz, 1H), 2.09 (dd, J=13.1, 7.5 Hz, 1H), 1.70-1.59 (m, 2H), 1.59-1.48 (m, 2H), 1.45 (s, 3H), 1.37 (s, 3H). MS-ESI m/z calc. 533.1612, detected 534.5 (M+1)+; retention time: 0.45 min (LC method A).

Step 3. 8-(3-hydroxy-1H-pyrazol-1-yl)-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose- 1 (22),5,7,9,19(23),20-hexaene-2,2,4trione (hydrochloride salt) (compound 38)

To a solution of 2-chloro-K-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propylamino]-2-pyridyl]sulfonyl]-6(3-hydroxypyrazol-1-yl)pyridine -3- carboxamide (42 mg, 0.07865 mmol) in dimethyl sulfoxide (2.0

- 400 044967 ml) was added through 3 A molecular sieves and the mixture was stirred at room temperature for 15 minutes. Cesium fluoride (11.95 mg, 0.07865 mmol) and potassium carbonate (10.87 mg, 0.07865 mmol) were then added and the reaction mixture was heated at 140°C overnight. The reaction mixture was filtered through a Whatman disc filter (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS using a Luna C ₁₈ (2) column (75x30 mm, 5 µm particle size) sold by Phenomenex (pn: 00C- 4252-U0-AX) and a dual gradient from 30% to 80% 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 obtain 8-(3hydroxy-1H-pyrazol-1-yl)-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18, 23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (hydrochloride salt) (compound 38) (2, 5 mg, 17%) as a white solid.

¹ H NMR (400 MHz, Methanol-d4) δ 8.21 (d, J=2.7 Hz, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.57-7.51 (m, 1H), 7.16 (d, J =7.2 Hz, 1H), 6.92 (d, J=8.3 Hz, 1H), 6.67 (d, J=8.5 Hz, 1H), 5.87 (d, J=2.7 Hz, 1H), 4.10-4.00 (m, 1H ), 3.66-3.49 (m, 1H), 3.09-3.00 (m, 1H), 2.90-2.82 (m, 1H), 2.66 (d, J=11.1 Hz, 1H), 2.24-2.12 (m, 1H), 1.92-1.82 (m, 1H), 1.66 (s, 3H), 1.59 (s, 3H), 1.49-1.39 (m, 2H), 0.95-0.83 (m, 2H). MS-ESI m/z calc. 497.1845, detected 498.5 (M+1)+; retention time: 1.48 min (LC method E).

Example 123: Preparation of 21,21-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-10λ ⁶ -thia-1,3,9,14,23 -pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4,6,11(23),12-pentaene-8,10,10trione (compound 39)

Opp

Step 1: tert-butyl 2,2-dimethyl-4-[4-(3-sulfamoylpyrazol-1-yl)butyl]pyrrolidine-1-carboxylate

tert-Butyl 2,2-dimethyl-4-(4-methylsulfonyloxybutyl)pyrrolidine-1-carboxylate (848 mg, 2.426 mmol) and 1H-pyrazole-3-sulfonamide (361.5 mg, 2.457 mmol) followed by carbonate potassium (1.2 g, 8.683 mmol) was dissolved in N,N-dimethylformamide (9.0 ml) and stirred at 60°C in a sealed 20 ml vial for 20 hours (UPLC indicates conversion to the intended product plus a minor less polar second peak with the same mass as the by-product of the minor regioisomer). Cool to room temperature, pour into water (100 ml) and extract with ethyl acetate (2x100 ml), combine organic layers, wash with water (2x100 ml), dry (sodium sulfate), filter and concentrate. The brown residue was purified by silica gel chromatography using a gradient of 100% hexanes to 100% ethyl acetate to give tert-butyl-2,2-dimethyl4-[4-(3-sulfamoylpyrazole) as a colorless oil which converted to a white solid in vacuo -1-yl)butyl]pyrrolidine-1-carboxylate (427 mg, 44%).

1H NMR (400 MHz, DMSOChD) δ 7.87 (d, J=2.3 Hz, 1H), 7.37 (s, 2H), 6.56 (d, J=2.3 Hz, 1H), 4.15 (t, J=7.1 Hz, 2H ), 3.53 (dd, J=11.2, 5.4 Hz, 1H), 2.76 (dd, J=22.3, 10.8 Hz, 1H), 2.05 (s, 1H), 1.94-1.83 (m, 1H), 1.82-1.73 ( m, 2H), 1.40-1.35 (m, 12H), 1.33 (s, 3H), 1.30 (d, J=2.5 Hz, 1H), 1.23 (s, 4H). MS-ESI m/z calc. 400.21442, detected 401.2 (M+1) ⁺ ; Retention time: 1.64 min (LC method E).

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

2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid

- 401 044967 (500 mg, 1.331 mmol) and carbonyldiimidazole (215 mg, 1.326 mmol) were combined in tetrahydrofuran (8.0 ml) and stirred for 120 min at 50°C. Tert-butyl 2,2-dimethyl-4-[4-(3sulfamoylpyrazol-1-yl)butyl]pyrrolidine-1-carboxylate (423 mg, 1.056 mmol) was then added followed by 1,8diazabicyclo[5.4.0]undec -7-ene (350 μl, 2.340 mmol), and the reaction mixture was heated at 50°C for 20 hours. The reaction mixture was diluted with ethyl acetate and washed with 1 M citric acid solution, followed by saline. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexanes to 90% ethyl acetate in hexanes to give tert-butyl-4-[4-[ as a white solid. 3-[[2-chloro-6[3-[2-[1 -(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1 -yl]pyridin-3-carbonyl]sulfamoyl]pyrazol-1 yl]butyl]-2,2 -dimethylpyrrolidine-1-carboxylate (587 mg, 73%). MS-ESI m/z calc. 757.2636, detected 758.2 (M+1)+; Retention time: 2.37 min (LC method E).

Step 3. 21,21-dimethyl-4-(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-10λ ⁶ thia-1,3,9,14, 23-pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4,6,11(23),12-pentaene-8,10,10-trione (compound 39)

tert-Butyl 4-[4-[3-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]pyrazol-1 -yl]butyl]-2,2-dimethylpyrrolidine-1-carboxylate (580 mg, 0.7649 mmol) was dissolved in dichloromethane (12 ml) and hydrochloric acid (6.0 ml 4M in dioxane, 24.00 mmol) was added to the mixture ) and stirred at room temperature for 1 hour. The mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate and then aqueous 2M sodium carbonate (5 ml) was added to give a pH of ~10. The organic layer was removed and the aqueous layer was further washed with ethyl acetate (2x10 ml), the organic layers were combined, washed with brine, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. Combine this material and potassium carbonate (550 mg, 3.980 mmol), cesium fluoride (185 mg, 1.218 mmol), 3 A molecular sieves and dimethyl sulfoxide (12 ml) in a nitrogen purged, capped vial heated to 150°C. and stirred for 18 hours. Cooled to room temperature, and the reaction mixture was diluted with ethyl acetate and washed with 1M citric acid solution and then with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a gradient of 100% hexanes to 80% ethyl acetate in hexanes to give 21,21-dimethyl-4-(3-) as a white solid. {2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-10Х ⁶ -thia-1,3,9,14,23pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2, 4,6,11 (23), 12-pentaene-8,10,10-trione (compound 39) (176.9 mg, 37%).

1H NMR (400 MHz, DMSO-de) δ 12.59 (s, 1H), 8.21 (d, J=2.8 Hz, 1H), 7.99 (d, J=2.1 Hz, 1H), 7.77 (d, J=8.3 Hz , 1H), 6.97-6.81 (m, 2H), 6.12 (d, J=2.7 Hz, 1H), 4.30 (dd, J=15.9, 9.0 Hz, 4H), 2.73 (dt, J=22.6, 11.0 Hz, 2H), 2.31-2.18 (m, 1H), 2.18-2.03 (m, 3H), 2.02-1.92 (m, 1H), 1.89 (dd, J=11.9, 5.5 Hz, 1H), 1.67 (s, 1H) , 1.61 (s, 3H), 1.60-1.54 (m, 1H), 1.52 (s, 3H), 1.48 (d, J=12.4 Hz, 1H), 1.16-1.03 (m, 1H), 0.99-0.93 (m , 2H), 0.90 (d, J=10.9 Hz, 2H), 0.77 (s, 1H). MS-ESI m/z calc. 621.2345, detected 622.4 (M+1) ⁺ ; retention time: 2.2 min (LC method E).

Example 124: Preparation of 7,7-dimethyl-11-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-17λ ⁶ -thia-2,8,10,16,22 -pentaazatetracyclo[16.3.1.04,8.09,14]docose-1(22),9,11,13,18,20-hexaene15,17,17-trione (compound 41)

- 402 044967

Step 1: 5,5-dimethyl-1-trimethylsilyloxypyrrolidine-2-carbonitrile

Trimethylsilylformonitrile (30.93 g, 39 mL, 311.8 mmol) was added to 2,2-dimethyl-1-oxido-3,4dihydropyrrol-1-ium (23.31 g, 206.0 mmol) in dichloromethane (920 mL ) and the mixture was left to stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure under safe conditions to obtain the desired product 5,5-dimethyl-1trimethylsilyloxypyrrolidine-2-carbonitrile (44.04 g, 101%) as a crude amber oil, which was used directly in the next step. MS-ESI m/z calc. 212.13, detected 213.2 (M+1) ⁺ ; retention time: 2.325 min (LC method I).

Step 2: 1-hydroxy-5,5-dimethylpyrrolidine-2-carboxamide

5,5-Dimethyl-1-trimethylsilyloxypyrrolidine-2-carbonitrile (13 g, 61.22 mmol) was added slowly to sulfuric acid (160.1 g, 87 mL, 1.632 mol), cooled in an ice bath and left to stir at room temperature 3 hours. The reaction mixture was diluted with ice (400 ml) and the resulting mixture was slowly neutralized with solid sodium hydroxide (125 g, 3.125 mol) divided into 3 portions (the last two portions were dissolved in water (75 ml)), and the pH was tested to be weak basic to neutral. The mixture was extracted with ethyl acetate (3x500 ml). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure, then dried in vacuo to give the desired product, 1-hydroxy-5,5dimethylpyrrolidine-2-carboxamide (8.51 g, 88%). pale yellow powder.

¹ H NMR (300 MHz, DMSO-a ₆ ) ppm 0.92 (s, 3H), 1.07 (s, 3H), 1.38-1.59 (m, 3H), 1.91-2.09 (m, 1H), 3.133.22 (m , 1H), 6.92 (br. s., 1H), 7.08 (br. s., 1H), 7.62 (s, 1H). MS-ESI m/z calc. 158.198, detected 159.2 (M+1)+; retention time: 1.561 min (LC method I).

Step 3: 5,5-dimethylpyrrolidine-2-carboxamide

1-Hydroxy-5,5-dimethylpyrrolidine-2-carboxamide (8.51 g, 53.79 mmol), dissolved in methanol (200 ml), stirred overnight with Raney nickel (8.7 g, 148.2 mmol ) and hydrogen gas from an inflated cylinder having a capacity of 8 liters of gas. After 5 hours, more Raney nickel (8 g, 136.3 mmol) was added and the mixture was stirred overnight. Additional Raney nickel (9.69 g, 165.1 mmol) was added to the mixture and the mixture was stirred for an additional 3 days. More Raney nickel (9.5 g, 161.9 mmol) was added to the reaction mixture and the mixture was stirred for 4 hours. The reaction mixture was decanted, the solid nickel was washed with methanol (3x250 ml), some celite was added to the combined methanol fraction, then filtered through celite and the precipitate was washed with methanol. Combined

- 403 044967 the filtrate was concentrated under reduced pressure to obtain the desired product, 5,5dimethylpyrrolidine-2-carboxamide (7.29 g, 95%) as a beige solid.

1H NMR (300 MHz, CDCl3) ppm 1.16 (s, 3H), 1.19 (s, 3H), 1.45-1.72 (m, 2H), 1.81 (br. s., 1H), 1.92-2.09 (m, 1H) , 2.18-2.40 (m, 1H), 3.78 (dd, J=9.4, 6.2 Hz, 1H), 5.70 (br. s., 1H), 7.45 (br. s., 1H). MS-ESI m/z calc.

142.1106, detected 143.2 (M+1) ⁺ ; retention time: 0.31 min (LC method I).

Step 4: tert-butyl 5-carbamoyl-2,2-dimethyl-pyrrolidine-1-carboxylate

Di-tert-butyl dicarbonate (21 g, 96.22 mmol) was added to 5,5-dimethylpyrrolidine-2-carboxamide (7.25 g, 50.98 mmol) dissolved in dioxane (140 ml) and water was added to the mixture (50 ml), the mixture was then left to stir at room temperature overnight. Sodium hydroxide (1.84 g, 46.00 mmol) dissolved in water (100 ml) was added to the mixture and the mixture was left stirring for 2 minutes, then ethyl acetate (200 ml) was added and the aqueous phase was discarded. The organic fraction was dried over anhydrous magnesium sulfate, filtered, then concentrated under reduced pressure. The resulting oil partially hardens when kept in a vacuum. The solid was triturated in heptane (50 ml), filtered and washed with more heptane (3 x 100 ml), then dried in vacuo to give tert-butyl 5-carbamoyl-2,2-dimethyl-pyrrolidine-1-carboxylate (10.95 g, 89%) in the form of a white powder.

1H NMR (300 MHz, CDCl ₃ ) ppm 1.33 (br. s., 3H), 1.48 (br. s., 12H), 1.70-2.34 (m, 4H), 4.16-4.48 (m, 1H), 5.30- 5.58 (m, 1H), 5.71-7.03 (m, 1H). MS-ESI m/z calc. 242.163, detected 143.2 (M+1) ⁺ ; retention time: 1.67 min (LC method I).

Step 5: tert-butyl 5-(aminomethyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

tert-Butyl-5-carbamoyl-2,2-dimethyl-pyrrolidine-1-carboxylate (5.3 g, 21.87 mmol) was added to borane-tetrahydrofuran (102 ml of 1 M in tetrahydrofuran, 102.0 mmol) and then To stop the evolution of hydrogen, the reaction mixture was heated to 70°C overnight. The reaction mixture was slowly quenched with concentrated ammonium chloride (1 ml). This mixture was then transferred to a 1 L round bottom flask containing deionized water (110 mL). Iodine (100 mg, 0.020 mL, 0.394 mmol) was added with vigorous stirring and the mixture was allowed to stir in air for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified on silica gel using a gradient from 10% to 100% methanol in dichloromethane. Additional material was recovered by applying ammonium hydroxide (2 mL) to the top of the column, followed by elution with pure methanol (done 3 times). This gave tert-butyl 5-(aminomethyl)-2,2-dimethylpyrrolidine-1-carboxylate (1.19 g, 24%) as an amber oil.

1H NMR (300 MHz, CDCl ₃ ) ppm 1.27 (br. s., 3H), 1.33-1.51 (m, 14H), 1.62-1.76 (m, 2H), 1.78-2.03 (m, 2H), 2.53 (dd , J=12.6, 8.2 Hz, 1H), 2.73-3.00 (m, 1H), 3.61-3.99 (m, 1H). MS-ESI m/z calc. 228.331, detected 229.3 (M+1) ⁺ ; retention time: 1.33 min (LC method I).

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

To tert-butyl-5-(aminomethyl)-2,2-dimethylpyrrolidine-1-carboxylate (140 mg, 0.6131 mmol) and 6fluoropyridine-2-sulfonamide (108.0 mg, 0.6131 mmol) in dimethyl sulfoxide (1.179 ml) potassium carbonate (86.43 mg, 0.6254 mmol) was added and the mixture was stirred at 100°C for 20 hours, then allowed to cool to room temperature. Dilute with ethyl acetate and pour into 1 M citric acid. The layers were separated, then the organic layer was washed with saturated aqueous brine, dried (sodium sulfate), filtered and concentrated to a yellow foam, which was purified by silica gel chromatography using a fine gradient from 100% hexanes to 100% ethyl acetate to give tert-butyl 2,2 -dimethyl-5-[[(6-sulfamoyl-2-pyridyl)amino]methyl]pyrrolidine-1-carboxylate (115.6 mg, 49%) as a white solid. MS-ESI m/z calc. 384.18314, detected 385.4 (M+1)+; retention time: 0.62 min (LC method A).

- 404 044967

Step 7: tert-butyl 5-[[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl] - 2-pyridyl]amino]methyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

In a 20 ml vial, 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine3-carboxylic acid (113.0 mg, 0.3007 mmol) and carbonyldiimidazole . (53.44 mg, 0.3296 mmol) were combined in tetrahydrofuran (1.659 ml) and stirred for 120 min at 50 °C without lid. Then tert-butyl 2,2-dimethyl-5-[[(6-sulfamoyl-2-pyridyl)amino]methyl]pyrrolidine-1-carboxylate (115.6 mg, 0.3007 mmol) in tetrahydrofuran (2.213 ml) was added ) followed by the addition of 1,8diazabicyclo[5.4.0]undec-7-ene (94.25 mg, 92.58 μL, 0.6191 mmol), and the reaction mixture was heated at 50°C for 16 hours. The reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride, and then with saline. Organics were separated, dried over sodium sulfate, filtered and evaporated, then purified using reverse phase HPLC-MS using a Luna C ₁₈ (2) column (75x30mm, 5µm particle size) sold by Phenomenex (pn: 00C - 4252-U0-AX) and a dual gradient from 30% to 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 obtain tert-butyl 5-[[[6-[[2-chloro-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazole -1-yl]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]amino]methyl]-2,2-dimethylpyrrolidine-1-carboxylate (119.2 mg, 53%). MS-ESI m/z calc. 741.2323, detected 742.2 (M+1)+; retention time: 0.88 min (LC method A).

Step 8: 2-χλορ-Ν-[[6-[(5,5-dimethylpyrrolidin-2-yl)methylamino]-2-pyridyl]sulfonyl]-6-[3-[2[1-(trifluoromethyl)cyclopropyl] ethoxy]pyrazol-1-yl]pyridin-3-carboxamide

tert-Butyl 5-[[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl ]amino]methyl]-2,2-dimethylpyrrolidine-1-carboxylate (119.2 mg, 0.1606 mmol) was dissolved in dichloromethane (520.2 μl) and trifluoroacetic acid (840.1 mg, 567.6 µl, 7.368 mmol) and stirred the resulting mixture at room temperature for 60 minutes. The mixture was concentrated to dryness under reduced pressure, redissolved in dichloromethane and hexane (1:1), and then the material was evaporated to dryness under reduced pressure and placed under vacuum overnight to give 2-chloro-N-[[6-[(5, 5-dimethylpyrrolidin-2-yl)methylamino]-2pyridyl]sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carboxamide (92.9 mg, 90 %). MS-ESI m/z calc. 641.1799, detected 642.2 (M+1) ⁺ ; Retention time: 0.63 min (LC method A).

Step 9: 7,7-dimethyl-11 -(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)- 17λ ⁶ -thiα2,8,10,16,22 -pentaazatetracyclo[16.3.1.04,8.09,14]docose-1(22),9,11,13,18,20-hexaene-15,17,17-trione (compound 41)

To a solution of 2-chloro-N-[[6-[(5,5-dimethylpyrrolidin-2-yl)methylamino]-2-pyridyl]sulfonyl]-6-[3[2-[1-(trifluoromethyl)cyclopropyl]ethoxy ]pyrazol-1-yl]pyridin-3-carboxamide (92.9 mg, 0.1447 mmol) in dimethyl sulfoxide (3.716 ml), potassium carbonate (99.99 mg, 0.7235 mmol), CsF (26.37) was added mg, 0.1736 mmol) and a small amount of 3 A molecular sieves. The resulting mixture was capped, heated to 150°C and stirred overnight. Cool to room temperature, filter and purify using reverse phase HPLC-MS using a Luna C ₁₈ column (2)

- 405 044967 (75x30 mm, particle size 5 µm), sold by Phenomenex (pn: 00C-4252-U0-AX) and a double gradient from 30% to 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). The combined fractions containing product were removed by rotary evaporation of acetonitrile, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate (1X), dried (sodium sulfate), filtered and concentrated to give 7,7-dimethyl-11-(3-{2- [1(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1-yl)- 17λ ⁶ -thia-2,8,10,16,22pentaazatetracyclo[16.3.1.04,8.09,14]docose-1(22), 9,11,13,18,20-hexaene-15,17,17-trione (compound 41) (27.6 mg, 31%) as a white solid. MS-ESI m/z calc. 605.2032, detected 606.0 (M+1)+; retention time: 1.89 min (LC method B).

Example 125: Preparation of 21,21-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-10λ ⁶ -thia-1,3,9,14,23 -pentaazatetracyclo[17.2.1.111,14.02,7]tricoseα-2,4,6,11(23),12-pentaene-8,10,10trione (enantiomer 1) (compound 44) and 21,21-dimethyl-4- (3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}1 H-pyrazol-1-yl)-10λ ⁶ -thia-1,3,9,14,23-pentaazatetracyclo[17.2.1.111,14.02.7 ]tricose-2,4,6,11 (23), 12pentaene-8,10,10-trione (enantiomer 2) (compound 45)

Step 1: 21,21 -dimethyl-4-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-10λ ⁶ thia-1,3,9,14, 23-pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4,6,11(23),12-pentaene-8,10,10-trione (enantiomer 1) (compound 44) and 21,21-dimethyl -4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-10λ ⁶ -thia-1,3,9,14,23-pentaazatetracyclo[17.2.1.111,14.02, 7]tricose-2,4,6,11(23),12pentaene-8,10,10-trione (enantiomer 2) (compound 45)

Racemic 21,21 -dimethyl-4-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1 -yl)10λ ⁶ -thia-1,3,9,14,23-pentaazatetracyclo [17.2.1.111,14.02,7]tricose-2,4,6,11 (23), 12-pentaene-8,10,10-trione (160 mg, 0.2548 mmol) was subjected to chiral SLC chromatography using ChiralPak AS-H (250x21.2 mm column, 5 µm particle size) with a mobile phase of 25% acetonitrile:methanol (90:10)/75% carbon dioxide at 70 ml/min, producing 21,21dimethyl- as the first enantiomer eluted 4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-10λ ⁶ -thia-1,3,9,14,23pentaazatetracyclo[17.2.1.111,14.02.7 ]tricose-2,4,6,11(23),12-pentaene-8,10,10-trione (enantiomer 1) (compound 44) (65.8 mg, 82%) as a white solid; MS-ESI m/z calc. 621.2345, detected 622.4 (M+1) ⁺ ; Retention time: 2.2 min (LC method E) and as the second enantiomer eluted 21,21-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl )-10λ ⁶ -thia-1,3,9,14,23pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4,6,11(23),12-pentaene-8,10,10-trione ( enantiomer 2) (compound 45) (70.8 mg, 89%) as a white solid;

¹ H NMR (400 MHz, DMSO-Y6) δ 12.59 (s, 1H), 8.21 (d, J=2.8 Hz, 1H), 7.99 (s, 1H), 7.77 (d, J=7.2 Hz, 1H), 7.02-6.80 (m, 2H), 6.12 (d, J=2.7 Hz, 1H), 4.44-4.19 (m, 4H), 2.70 (d, J=21.3 Hz, 2H), 2.20 (s, 1H), 2.08 (t, J=7.1 Hz, 2H), 2.00 (d, J=6.6 Hz, 1H), 1.89 (dd, J=11.9, 5.6 Hz, 1H), 1.67 (d, J=5.7 Hz, 1H), 1.61 (s, 3H), 1.611.53 (m, 2H), 1.52 (s, 3H), 1.48 (d, J=12.2 Hz, 1H), 1.18-1.04 (m, 1H), 1.00-0.93 (m, 2H ), 0.89 (s, 2H), 0.77 (s, 1H). MS-ESI m/z calc. 621.2345, detected 622.4 (M+1) ⁺ ; Retention time: 2.2 min (LC method E).

Example 126: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-2λ ⁶ -thia-3,9,11,20,25 -pentaazatetracyclo[19.3.1.05,10.011.15]pentacose-1(24),5,7,9,21(25),22hexaene-2,2,4-trione (enantiomer 1) (compound 46) and 12,12 -dimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ ⁶ -thia-3,9,11,20,25pentaazatetracyclo[19.3.1.05,10.011 ,15]pentacose-1(24),5,7,9,21(25),22-hexaene-2,2,4-trione (enantiomer 2) (compound 47)

Step 1: 12,12-dimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1-yl)-2λ ⁶ -thia3,9,11,20,25 -pentaazatetracyclo[19.3.1.05,10.011.15]pentacose-1(24),5,7,9,21(25),22-hexaene-2,2,4-trione (enantiomer 1) (compound 46) and 12 ,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-2λ ⁶ -thia-3,9,11,20,25-pentaazatetracyclo[19.3. 1.05,10.011,15]pentacose- 406 044967

1(24),5,7,9,21(25),22-hexaene-2,2,4-trione (enantiomer 2) (compound 47)

12,12-dimethyl-8-(3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1 -yl)-2 //'-sha3,9,11,20,25-pentaazatetracyclo [19.3.1.05,10.011,15]pentacose-1 (24),5,7,9,21 (25),22-hexaene-2,2,4-trione (23 mg, 0.03320 mmol) was subjected to chiral SLC - chromatography using ChiralPak AS-H (column 250x10 mm, particle size 5 μm) with a mobile phase of 18% acetonitrile:methanol (90:10; no modifier) / 82% carbon dioxide at 10 ml/min, which gives as the first eluted enantiomer, 12,12-dimethyl-8-(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-2λ ⁶ -τthia3,9,11,20, 25-pentaazatetracyclo[19.3.1.05,10.011.15]pentacose-1 (24),5,7,9,21 (25),22-hexaene-2,2,4-trione (enantiomer 1) (compound 46) ( 6.9 mg, 64%); MS-ESI m/z calc. 647.2502, detected 648.3 (M+1)+; Retention time: 1.97 min (LC method B) and as the second eluted enantiomer 12,12dimethyl-8-(3-{2-[1-(τtrifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)- 2λ ⁶ -τia-3,9,11,20,25pentaazatetracyclo[19.3.1.05,10.011,15]pentacose-1(24),5,7,9,21(25),22-hexaene-2,2,4 -trione (enantiomer 2) (compound 47) (6.8 mg, 63%); MS-ESI m/z calc. 647.2502, detected 648.3 (M+1) ⁺ ; Retention time: 1.97 min (LC method B).

Example 127: Preparation of 7,7-dimethyl-11-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-17λ ⁶ -τia-2,8,10,16,22 -pentaazatetracyclo[16.3.1.04,8.09,14]docose-1(22),9,11,13,18,20-hexaene15,17,17-trione (enantiomer 1) (compound 50) and 7,7-dimethyl- 11-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-17 λ ⁶ -τthia-2,8,10,16,22pentaazatetracyclo[16.3.1.04,8.09, 14]docose-1(22),9,11,13,18,20-hexaene-15,17,17-trione (enantiomer 2) (compound 51) o o ,p O o ,p o q _w o

N ITC! ^Step1 Ν ΙΤΤΟ ⁺ Ν ΐττΟ oX'N Ν N-yxy ---► _ο 2% Ν NC\fo^f'N /— ⁷ —I—/ NH /—' —I—/ NH /—' —I— /NH

F ₃ CZ I । ^F ₃ C % ।

Y' enantiomer 1 enantiomer 2

Step 1: 7,7-dimethyl-11-(3-{2-[1-(τtrifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-17λ ⁶ -thia2,8,10,16,22- pentaazatetracyclo[16.3.1.04,8.09,14]docose-1(22),9,11,13,18,20-hexaene-15,17,17-trione (enantiomer 1) (compound 50) and 7,7-dimethyl -11-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-17λ ⁶ -thia-2,8,1O,16,22-pentaazatetetracyclo[16.3.1.O4, 8.09,14]docose-1(22),9,11,13,18,2Ohexaene-15,17,17-trione (enantiomer 2) (compound 51)

Racemic 7,7-dimethyl-11-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)17λ ⁶ -thia-2,8,10,16,22-pentaazatetetracyclo [16.3.1.04,8.09,14]docose-1(22),9,11,13,18,20-hexaene-15,17,17trione (26 mg, 0.04246 mmol) was chirally separated by SLC chromatography with using ChiralPak AS-H (250 x 10 mm column, 5 µm particle size) with a mobile phase of 32% acetonitrile/methanol (90:10; no modifier)/68% carbon dioxide at 10 ml/min (injection volume = 70 µl 24 mg/ml solution in acetonitrile/methanol (90:10)) to obtain 7,7-dimethyl-11-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol- 1-yl)17λ ⁶ -τthia-2,8,10,16,22-pentaazatetracyclo[16.3.1.04,8.09,14]docose-1(22),9,11,13,18,20-hexaene-15, 17,17trione (enantiomer 1) (compound 50) (11.8 mg, 92%) as a white solid; MS-ESI m/z calc. 605.2032, detected 606.3 (M+1) ⁺ ; Retention time: 1.93 min (LC method B) and as the second eluted enantiomer 7,7-dimethyl-11-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1yl)- 17λ ⁶ -thia-2,8,10,16,22-pentaazatetracyclo[16.3.1.04,8.09,14]docose-1(22),9,11,13,18,20-hexaene15,17,17-trione ( enantiomer 2) (compound 51) (12.8 mg, 100%) as a white solid; MSIE m/z calc. 605.2032, detected 606.3 (M+1) ⁺ ; Retention time: 1.93 min (LC method B).

Example 128: Preparation of (14R)-8-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12-dimethyl2λ ⁶ -thia-3,9,11,18,23-pentaazatetetracyclo [17.3.1.111,14.O5,1O]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4trione (compound 65)

- 407 044967

Step 1: (14R)-8-[3-(3,3-dicyclopropylpropoxy)-1H-nirazol-1-yl]-12,12-dimethyl-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 65)

Racemic 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]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4trione chiral separation by SLC chromatography using ChiralPak AS-H (250x21.2 mm column, particle size 5 μm) with a mobile phase of 38% acetonitrile:methanol (90:10))/62% carbon dioxide at 70 ml/min, yielding (14R)-8-[3-(3) as the first enantiomer eluted ,3-dicyclopropylpropoxy)-1H-nirazol-1-yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22) ,5,7,9,19(23),20-hexaene-2,2,4-trione (compound 65) (51.2 mg, 36%) as a white solid.

Ή NMR (400 MHz, chloroform-d) δ 10.10 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 8.06 (d, J=8.2 Hz, 1H), 7.55 (s, 1H), 7.50 (d, J=6.8 Hz, 1H), 7.28 (s, 1H), 6.57 (s, 1H), 5.91 (d, J=2.7 Hz, 1H), 4.69 (s, 1H), 4.43 (t, J= 6.8 Hz, 2H), 3.92 (s, 1H), 3.34 (t, J=8.4 Hz, 1H), 3.17 (s, 1H), 3.06 (s, 1H), 2.07 (dd, J=12.1, 7.5 Hz, 1H), 1.97 (k, J=6.8 Hz, 2H), 1.62 (d, J=4.7 Hz, 10H), 0.67 (ddt, J=13.3, 8.5, 4.2 Hz, 2H), 0.44 (tdd, J=8.1 , 5.0, 3.7 Hz, 4H), 0.370.29 (m, 1H), 0.20 (dk, J=6.5, 4.2, 3.6 Hz, 2H), 0.11 (dp, J=9.7, 4.7 Hz, 2H). MS-ESI m/z calc. 619.29407, detected 620.23 (M+1)+; retention time: 1.94 min (LC method G).

Example 129: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-2λ ⁶ -thia-3,9,11,19,21 -pentaazatetracyclo[18.2.2.111,14.05,10]pentacose-1(23),5,7,9,20(24),21hexaene-2,2,4-trione (enantiomer 1) (compound 67) and 12,12 -dimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-2λ ⁶ -thia-3,9,11,19,21pentaazatetracyclo[18.2.2.111, 14.05,10]pentacose-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (enantiomer 2) (compound 68)

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

In a 20 ml vial, 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine3-carboxylic acid (353.0 mg, 0.9396 mmol) and carbonyldiimidazole (152.4 mg, 0.9396 mmol) were combined in tetrahydrofuran (3.834 ml) and stirred for 120 minutes at 50°C without a lid. Then tert-butyl 2,2-dimethyl-4-[4-[(5-sulfamoyl-2-pyridyl)amino]butyl]pyrrolidine-1carboxylate (267.2 mg, 0.6264 mmol) in tetrahydrofuran (5.114 ml) was added ) followed by the addition of 1,8diazabicyclo[5.4.0]undec-7-ene (187.4 µl, 1.253 mmol), and the reaction mixture was heated at 50°C for 16 hours. The reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride, and then with saline solution. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a shallow gradient of 100% hexanes to 100% ethyl acetate to give tert-butyl 4-[4-[[5-[[2-chloro- 6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]2pyridyl]amino]butyl]-2,2-dimethylpyrrolidine-1-carboxylate (422, 4 mg, 86%) as a white solid. MS-ESI m/z calc. 783.27924, detected 784.2 (M+1)+; retention time: 0.86 min (LC method A).

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

tert-Butyl-4-[4-[[5-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin3-carbonyl]sulfamoyl]2 -pyridyl]amino]butyl]-2,2-dimethylpyrrolidine-1-carboxylate (422.4 mg, 0.5386 mmol) was dissolved in dichloromethane (1.843 ml) and trifluoroacetic acid (1.904 ml, 24.71 mmol) was added to the mixture. . and the mixture was stirred at room temperature for 60 minutes. The mixture was concentrated to dryness under reduced pressure, treated with saturated aqueous sodium bicarbonate and ethyl acetate, and the layers were separated. (Attention, the solubility of the product in ethyl acetate under these conditions is low; the addition of some methanol necessary to evaporate the organic layer without the use of a solid drying agent helps). The organic layer was concentrated on a rotary evaporator followed by drying in vacuo to give 2-chloro-N-[[6-[4-(5,5dimethylpyrrolidin-3-yl)butylamino]-3-pyridyl]sulfonyl]-6-[3- [2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (323.6 mg, 88%) as an off-white solid. MS-ESI m/z calc. 683.2268, detected 684.2 (M+1) ⁺ ; retention time: 0.58 min (LC method A).

Step 3: 12,12-dimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1H-πyrazol-1-yl)-2λ ⁶ -thia3,9,11,19,21- pentaazatetracyclo[18.2.2.111,14.05,10]pentacose-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (enantiomer 1) (compound 67) and 12, 12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hπyrazol-1-yl)-2λ ⁶ -thia-3,9,11,19,21-pentaazatetracyclo[18.2.2.111 ,14.05,10]pentacose1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (enantiomer 2) (compound 68)

To a solution of 2-chloro-X - [[6-[4-(5,5-dimethylpyrrolidin-3-yl)propoxy]-3-pyridyl]sulfonyl]-6-[3-[2[1-(trifluoromethyl)cyclopropyl ]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (323.6 mg, 0.4730 mmol) in dimethyl sulfoxide (12.94 ml), potassium carbonate (392.2 mg, 2.838 mmol), cesium fluoride (86 .22 mg, 0.5676 mmol) and a small amount of 3 A molecular sieves. The resulting mixture was capped and heated to 165°C for 16 hours. The mixture was then cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous NH4C1 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 SLC chromatography using a ChiralPak OD3 column, eluting with isocratic 30% methanol (20 mM NH ₃ modifier)/70% mobile phase carbon dioxide for 2 minutes to produce a single enantiomer of the expected product (first elution, peak 1), which still contained some impurities, and another single enantiomer of the expected product (second elution, peak 2), which still contained some impurities, impurities as white solid particles.

The first elution peak of 1 from the chiral SLC separation (50.2 mg) was filtered and purified using a reverse phase HPLC-MS method using a Luna C _i8 column (2) (75x30 mm, 5 µm particle size) sold by Phenomenex (pn : 00C-4252-U0-AX) and double gradient from 1% to

- 409 044967

99% mobile phase B for 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-1yl)-2λ ⁶ -thia-3,9,11,19,21 -pentaazatetracyclo[18.2.2.111,14.05,10]pentacose-1 (23),5,7,9,20(24),21-hexaene2,2,4-trione (enantiomer 1) (compound 67) (27.7 mg, 18%) as a white solid.

¹ H NMR (400 MHz, DMSO-b ₆ ) δ 12.15 (s, 1H), 8.47 (s, 1H), 8.19 (d, J=2.7 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H) , 7.30 (s, 1H), 6.89 (d, J=8.3 Hz, 1H), 6.56 (d, J=8.9 Hz, 1H), 6.10 (d, J=2.7 Hz, 1H), 4.31 (t, J= 7.0 Hz, 2H), 2.45 (s, 1H), 2.07 (t, J=7.1 Hz, 3H), 1.99 (s, 1H), 1.72 (s, 1H), 1.54 (s, 10H), 1.25 (d, J=9.7 Hz, 2H), 1.05 (s, 2H), 0.99-0.92 (m, 2H), 0.92-0.84 (m, 2H). MS-ESI m/z calc. 647.2502, detected 648.2 (M+1)+; retention time: 2.12 min (LC method B).

The second elution peak 2 from the RSLC chiral separation (46.5 mg) was filtered and purified using a reverse phase HPLC-MS method using a Luna C ₁₈ (2) column (75x0 mm, 5 µm particle size) sold by Phenomenex (pn: OOC-4252-UO-AX) and a dual gradient from 1% to 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), which gives 12,12-dimethyl-8-(3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazole-1 yl)-2λ ⁶ -thia-3,9,11,19,21-nentaazatetracyclo[18.2.2.111,14.05,10]pentacose-1(23),5,7,9,20(24),21-hexaene2, 2,4-trione (enantiomer 2) (compound 68) (29.4 mg, 19%) as a white solid.

¹ H NMR (400 MHz, DMSO-a ₆ ) δ 12.15 (s, 1H), 8.46 (s, 1H), 8.19 (d, J=2.8 Hz, 1H), 7.80 (d, J=8.5 Hz, 1H) , 7.28 (s, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.55 (d, J=8.9 Hz, 1H), 6.10 (d, J=2.7 Hz, 1H), 4.31 (t, J= 7.0 Hz, 2H), 2.07 (t, J=7.1 Hz, 3H), 1.99 (s, 1H), 1.72 (d, J=10.9 Hz, 1H), 1.54 (d, J=1.3 Hz, 10H), 1.29 -1.14 (m, 2H), 1.04 (s, 2H), 0.97-0.94 (m, 2H), 0.91-0.86 (m, 2H). MS-ESI m/z calc. 647.2502, detected 648.2 (M+1) ⁺ ; retention time: 2.11 min (LC method B).

Example 130: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1 -yl)-15-oxa-2λ ⁶ -thia-3,9,11 ,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5(10),6,8,19(23),20-hexaene-2,2,4-trione (compound 69)

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

2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxylic acid (154 mg, 0.4099 mmol) and carbonyldiimidazole (66 mg, 0 .4070 mmol) were combined in tetrahydrofuran (2.0 ml) and stirred for 90 min at 50°C. Tert-butyl 2,2-dimethyl-4-[2-[(6sulfamoyl-2-pyridyl)amino]ethoxy]pyrrolidine-1-carboxylate (94 mg, 0.2268 mmol) was then added followed by 1,8diazabicyclo[ 5.4.0]undec-7-ene (85.0 μl, 0.5684 mmol), and the reaction mixture was heated at 50°C for 36 hours. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution, followed by saline. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by preparative reverse phase chromatography using a C ₁₈ column (30-99% acetonitrile in water (5 mM hydrochloric acid) to give tert-butyl as a white solid 4-[2-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl]2-pyridyl]amino ]ethoxy]-2,2-dimethylpyrrolidine-1-carboxylate (77 mg, 44%) ESI-MS m/z calculated 771.24286, found 772.2 (M+1) ⁺ ;Retention time: 2.28 min (LC method E).

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Step 2: 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-15oxa-2λ ⁶ -thia-3,9,11, 18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5(10),6,8,19(23),20hexaene-2,2,4-trione (compound 69)

tert-Butyl 4-[2-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin3-carbonyl]sulfamoyl]-2 -pyridyl]amino]ethoxy]-2,2-dimethylpyrrolidine-1-carboxylate (77 mg, 0.09971 mmol) was dissolved in dichloromethane (1.6 ml) and hydrochloric acid (800 μl 4M in dioxane, 3.200 mmol) was added to the mixture ), and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate and then aqueous 2M sodium carbonate (5 ml) was added to give a pH of ~10. The organic layer was extracted with ethyl acetate (2x10 ml), washed with brine, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. Combine the resulting material of potassium carbonate (72 mg, 0.5210 mmol), cesium fluoride (25.0 mg, 0.1646 mmol), 3 A molecular sieves and dimethyl sulfoxide (1.6 ml) in a nitrogen purged vial, capped , heated to 150°C and stirred for 20 hours. Cool to room temperature, filter and then purify by preparative reverse phase chromatography using a C ₁₈ column (30-99% acetonitrile in water (5 mM hydrochloric acid) to obtain as white solid 12,12-dimethyl-8-(3-{2[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-15-oxa-2λ ⁶ -thia-3,9,11 ,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5(10),6,8,19(23),20-hexaene-2,2,4-trione (compound 69) ( 38.8 mg, 61%).

1H NMR (400 MHz, DMSO-06) δ 12.59 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.59 (dd, J=8.5, 7.3 Hz, 1H), 7.13 (d, J=7.7 Hz, 1H), 7.10 (d, J=7.0 Hz, 1H), 6.94 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.2 Hz , 1H), 6.11 (d, J=2.7 Hz, 1H), 4.31 (t, J=7.0 Hz, 2H), 4.11 (td, J=12.8, 5.9 Hz, 2H), 3.88 (t, J=11.6 Hz , 1H), 3.61 (dd, J=8.7, 4.2 Hz, 1H), 3.32-3.20 (m, 1H), 3.06 (dd, J=10.6, 5.0 Hz, 1H), 2.92-2.77 (m, 1H), 2.08 (t, J=7.1 Hz, 3H), 1.79 (t, J=10.9 Hz, 1H), 1.57 (d, J=9.8 Hz, 6H), 1.00-0.93 (m, 2H), 0.88 (s, 2H ). MS-ESI m/z calc. 635.21375, detected 636.2 (M+1)+; Retention time: 2.0 min (LC method E).

Example 131: Preparation of 21,21,23-trimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-10 ⁶ -thia-1,3,9,13 ,14-pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4,6,11(23),12-pentaene8,10,10-trione (compound 76) and 12,21,21-trimethyl-4- (3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1 -yl)-10λ ⁶ -thia-1,3,9,13,14-pentaazatetracyclo[17.2.1.111,14.02,7]tricose -2,4,6,11 (23), 12pentaene-8,10,10-trione (compound 71)

Step 1: tert-butyl 4-[4-[4-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl] -3-methylpyrazol-1 -yl]butyl]-2,2-dimethylpyrrolidine-1 - 411 044967 carboxylate and tert-butyl 4-[4-[4-[[2-chloro-6-[3-[2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1 yl]pyridin-3-carbonyl]sulfamoyl]-5-methylpyrazol-1-yl]butyl]-2,2-dimethylpyrrolidine-1carboxylate (mixture of regioisomers)

2-chloro-N-[(5-methyl-1H-pyrazol-4-yl)sulfonyl]-6-[3-[2-[1 added ampoule of (trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3 -carboxamide (454 mg, 0.8749 mmol), N,Ndimethylformamide (4 ml) and potassium carbonate (424 mg, 3.068 mmol). The reaction mixture was stirred for 5 min at room temperature, and then tert-butyl 2,2-dimethyl-4-(4methylsulfonyloxybutyl)pyrrolidine-1-carboxylate (410 mg, 1.173 mmol) in N,N-dimethylformamide (2 ml) , added drop by drop. The reaction mixture was placed in an oil bath at 80°C overnight. The reaction mixture was cooled to room temperature, filtered and purified by HPLC (10-99% acetonitrile/water gradient modified with 0.1% hydrochloric acid to give tert-butyl-4-[4-[4-[[2-chloro-6- [3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-3-methylpyrazol-1-yl]butyl]-2,2-dimethyl-pyrrolidine-1- carboxylate and tert-butyl

4-[4-[4-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3 carbonyl]sulfamoyl]-5-methylpyrazol- 1-yl]butyl]-2,2-dimethylpyrrolidine-1-carboxylate (mixture of regioisomers) (184.3 mg, 27%). MS-ESI m/z calc. 771.27924, detected 772.7 (M+1)+; retention time: 1.85 min (LC method G).

Step 2: 2-chloro-N-[1-[4-(5,5-dimethylpyrrolidin-3-yl)butyl]-3-methylpyrazol-4-yl]sulfonyl-6[3-[2-[1-( trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide and 2-chloro-I-[1-[4-(5,5dimethylpyrrolidin-3-yl)butyl]-5-methyl-pyrazol-4- yl]sulfonyl-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (mixture of regioisomers)

Tert-butyl-4-[4-[4-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1 -yl]pyridin-3-carbonyl was added to the flask ]sulfamoyl]-3-methylpyrazol-1-yl]butyl]-2,2-dimethylpyrrolidine-1 carboxylate and tert-butyl 4-[4-[4-[[2-chloro-6-[3-[2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1 yl]pyridin-3-carbonyl]sulfamoyl]-5-methylpyrazol-1-yl]butyl]-2,2-dimethylpyrrolidine-1 carboxylate (mixture of regioisomers) (81 mg, 0.1049 mmol), dichloromethane (3 ml) and trifluoroacetic acid (450 μl, 5.841 mmol). The reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was evaporated. The residue was washed with 2 M potassium carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated to give 2-chloro-X-[1-[4-(5,5-dimethylpyrrolidin-3-yl)butyl]-3-methylpyrazol-4-yl]sulfonyl-6 -[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide and 2-χλορ-Ν-[1-[4-(5,5- 412 044967 dimethylpyrrolidine-3 -yl)butyl]-5-methylpyrazol-4-yl]sulfonyl-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (mixture of regioisomers) (70 mg,

99%). MS-ESI m/z calc. 671.2268, detected 672.2 (M+1)+; retention time: 1.64 min (LC method B).

Step 3: 21,21,23-trimethyl-4-(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)10λ ⁶ -thia-1,3,9, 13,14-pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4,6,11(23),12-pentaene-8,10,10-trione (compound 76) and 12,21,21-trimethyl -4-(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)10λ ⁶ -thia-1,3,9,13,14-pentaazatetracyclo[17.2.1.111, 14.02,7]tricose-2,4,6,11 (23), 12-pentaene-8,10,10-trione (compound 71)

mixture of regioisomers

K 2-chloro-N-[1-[4-(5,5-dimethylpyrrolidin-3-yl)butyl]-3-methylpyrazol-4-yl]sulfonyl-6-[3-[2-[1(trifluoromethyl) cyclopropyl] ethoxy] pyrazol-1 -yl] pyridin-3-carboxamide and 2-χλορ-Ν-[1-[4-(5,5dimethylpyrrolidin-3-yl)butyl]-5-methylpyrazol-4-yl]sulfonyl- Potassium carbonate (72 mg, 0 .5210 mmol), cesium fluoride (36 mg, 0.2370 mmol) and dimethyl sulfoxide (800 µl). The reaction was heated at 150°C overnight. The reaction mixture was cooled to room temperature, filtered and purified by HPLC (20-80% acetonitrile in water modified with 0.1% hydrochloric acid), yielding 12,21,21trimethyl-4-(3-{2) as the first eluting peak -[ 1 -(trifluoromethyl)cyclopropyl]ethoxy }-1 H-pyrazol-1 -yl)-10λ ⁶ -thia-1,3,9,13,14pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4 ,6,11 (23),12-pentaene-8,10,10-trione (compound 71) (16.6 mg, 50%);

¹ H NMR (400 MHz, DMSO-f,) δ 12.25 (s, 1H), 8.63 (s, 1H), 8.21 (dd, J=4.5, 2.8 Hz, 1H), 7.85-7.74 (m, 1H), 6.92 (dd, J=8.3, 4.4 Hz, 1H), 6.11 (dd, J=2.7, 1.5 Hz, 1H), 4.31 (k, J=6.4, 5.9 Hz, 3H), 4.10 (dd, J=11.9, 6.8 Hz, 1H), 2.85 (t, J=10.1 Hz, 1H), 2.67 (bs, 1H), 2.39 (s, 3H), 2.15-2.02 (m, 4H), 1.83 (dd, J=11.8, 5.6 Hz, 1H), 1.58 (d, J=6.7 Hz, 4H), 1.51 (d, J=5.9 Hz, 5H), 1.19 (d, J=8.8 Hz, 2H), 1.02-0.93 (m, 2H), 0.93-0.85 (m, 2H), 0.13 (s, 1H), ESI-MS m/z calc. 635.2502, found 636.4 (M+1) ⁺ ; Retention time: 2.14 min (LC method B), and as the second eluting peak, 21,21,23-trimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H- pyrazol-1-yl)-10λ ⁶ -thia-1,3,9,13,14-pentasateracyclo[17.2.1.111,14.02,7]tricose2,4,6,11(23),12-pentaene-8,10 ,10-trione (compound 76) (4.2 mg, 13%);MS-ESI m/z calc. 635.2502, detected 636.3 (M+1) ⁺ ; Retention time: 2.08 min (LC method B).

Example 132: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1 -yl)-15-oxa-2λ ⁶ -thia-3,9,11 ,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5(10),6,8,19(23),20-hexaene-2,2,4-trione (enantiomer 1) ( compound 74) and 12,12-dimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-15-oxa-2λ ⁶ -thia-3,9 ,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5(10),6,8,19(23),20-hexaene-2,2,4-trione (enantiomer 2 ) (connection 75)

Step 1: 12,12-dimethyl-8-(3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-15oxa-2λ ⁶ -thia-3,9,11 ,18,23-pentaazatetracyclo[17.3.1.111,14.O5,1O]tetracose-1(22),5(1O),6,8,19(23),20hexaene-2,2,4-trione (enantiomer 1 ) (compound 74) and 12,12-dimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-15-oxa-2λ ⁶ -thia-3 ,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5(10),6,8,19(23),20-hexaene-2,2,4-trione ( enantiomer 2) (compound 75)

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Racemic 12,12-dimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-15-oxa-2λ ⁶ -thia-3,9,11,18 was subjected to ,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5(10),6,8,19(23),20-hexaene-2,2,4-trione (36 mg 0.05607 mmol ) chiral separation using

SLC chromatography using ChiralPak AS-H (column 250x21.2 mm, particle size 5 μm) with a mobile phase gradient from 5% to 60% methanol (20 mM NH3) in carbon dioxide at 50 ml/min with obtaining as the first eluted enantiomer 12,12-dimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-15-oxa-2λ ⁶ -thia-3,9,11 ,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5(10),6,8,19(23),20-hexaene-2,2,4-trione (enantiomer 1) ( compound 74) (9.76 mg, 54%) as an off-white solid; MS-ESI m/z calc. 635.21375, detected 636.2 (M+1); Retention time: 2.0 min (LC method E) and as the second enantiomer eluted 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1yl)- 15-oxa-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5(10),6,8,19(23),20- hexaene-2,2,4-trione (enantiomer 2) (compound 75) (11.29 mg, 63%) as an off-white solid; MS-ESI m/z calc. 635.21375, detected 636.2 (M+1) ⁺ ; Retention time: 2.0 min (LC method E).

Example 133: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-2λ ⁶ -thia-3,9,11,23-tetraazatetracyclo [17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,2,4trione (compound 78)

Step 1: tert-butyl 2,2-dimethyl-4-[4-(6-sulfamoyl-2-pyridyl)but-3-ynyl]pyrrolidine-1-carboxylate

6-bromopyridine-2-sulfonamide (840 mg, 3.543 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (125 mg, 0.1781 mmol) and copper iodide (34 mg, 0.1785 mmol) were added sequentially to a round bottom flask ). Anhydrous N,N-dimethylformamide (11 mL) was then added to the vessel, sealed with a rubber septum under a nitrogen atmosphere, followed by the addition of diisopropylamine (1000 μL, 7.135 mmol). Then tert-butyl-4-but-3-ynyl-2,2-dimethylpyrrolidine-1-carboxylate (1.15 g, 4.575 mmol) in 3 ml N,N-dimethylformamide was added and the reaction mixture was heated to 100°C in oil bath under nitrogen atmosphere for 2 hours. The residue was diluted with ethyl acetate and washed with water (2x50 ml), then with saline (50 ml). The organic layers were combined, dried (sodium sulfate), filtered and concentrated to an orange residue, which was purified by silica gel chromatography using a gradient of 100% hexanes to 90% ethyl acetate in hexanes to give tert-butyl-2 as a light yellow foam. 2-dimethyl-4-[4-(6-sulfamoyl-2-pyridyl)but-3-ynyl]pyrrolidine-1-carboxylate (1.4 g, 97%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.04 (t, J=7.8 Hz, 1H), 7.85 (dd, J=7.9, 0.8 Hz, 1H), 7.67 (dd, J=7.7, 3.5 Hz, 1H ), 7.53 (s, 2H), 3.63 (dd, J=18.0, 9.0 Hz, 1H), 2.88 (k, J=10.5 Hz, 1H), 2.58-2.52 (m, 1H), 2.24 (s, 1H) , 1.94 (dd, J=20.1, 6.4 Hz, 1H), 1.64 (dd, J=14.1, 7.0 Hz, 2H), 1.50 (dd, J=22.0, 9.7 Hz, 1H), 1.39 (dd, J=18.3 , 9.6 Hz, 13H), 1.26 (s, 3H). MS-ESI m/z calc. 407.18787, detected 408.2 (M+1) ⁺ ; retention time: 1.77 min (LC method E).

Step 2: tert-butyl 2,2-dimethyl-4-[4-(6-sulfamoyl-2-pyridyl)butyl]pyrrolidine-1-carboxylate

- 414 044967

Platinum oxide (61 .29 mg, 0.2699 mmol) then methanol (11.00 ml) and the mixture was purged with nitrogen, then hydrogen, then capped with a hydrogen balloon and stirred for 4 hours. Additional platinum oxide (61.29 mg, 0.2699 mmol) was added ) and stirred for 1 hour. The reaction mixture was filtered through celite and washed with excess methanol, and then the filtrate was concentrated. The residue was then purified by silica gel chromatography using a gradient of 100% hexanes to 100% ethyl acetate to give tert-butyl-2,2-dimethyl-4-[4-(6-sulfamoyl-2pyridyl)butyl]pyrrolidine- 1-carboxylate (1.10 g, 99%), which was contaminated with a small amount of intermediate olefin and was used directly in the next step. MS-ESI m/z calc. 411.21918, detected 412.2 (M+1)+; Retention time: 1.85 min (LC method E).

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

2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxylic acid (685 mg, 1.823 mmol) and carbonyldiimidazole (296 mg, 1.825 mmol) combined in tetrahydrofuran (11 ml) and stirred for 90 min at 50°C. Tert-butyl 2,2-dimethyl-4-[4-(6sulfamoyl-2-pyridyl)butyl]pyrrolidine-1-carboxylate (500 mg, 1.215 mmol) was then added followed by 1,8diazabicyclo[5.4.0]undec -7-ene (455 μl, 3.043 mmol), and the reaction mixture was heated at 50°C for 18 hours. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution, followed by saline. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexanes to 75% ethyl acetate in hexanes to give, as an off-white solid, tert-butyl 4-[4- [6-[[2chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-2pyridyl]butyl]-2,2-dimethylpyrrolidine -1-carboxylate (165 mg, 35%). MS-ESI m/z calc. 768.2684, detected 769.2 (M+1) ⁺ ; retention time: 2.13 min (LC method G).

Step 4: 12,12-dimethyl-8-(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy }-1 H-pyrazol-1 -yl)-2λ ⁶ -thia3,9,11,23-tetraazatetracyclo [17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,2,4-trione (compound 78)

tert-Butyl 4-[4-[6-[[2-chloro-6-[3-[2-[1 -(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1 -yl]pyridin-3 carbonyl]sulfamoyl]-2 -pyridyl]butyl]-2,2-dimethylpyrrolidine-1-carboxylate (125 mg, 0.1625 mmol) was dissolved in dichloromethane (2.5 ml) and hydrochloric acid (1.5 ml 4 M in dioxane, 6.000 mmol) and stirred at room temperature for 30 min. The mixture was concentrated to dryness under reduced pressure and combined with potassium carbonate (135 mg, 0.9768 mmol), cesium fluoride (40 mg, 0.2633 mmol), 3 A molecular sieves and dimethyl sulfoxide (2.5 ml) in a vial purged with nitrogen , the vial was sealed, heated to 150°C and stirred for 20 hours. Cooled to room temperature and the mixture was filtered and then purified by reverse phase preparative chromatography using a C _i8 column (30-99% acetonitrile in water (5 mM hydrochloride acid) to obtain 12,12-dimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-2λ ⁶ -thia-3 as a white solid. 9,11,23tetraazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,2,4-trione (compound 78)

- 415 044967 (37.67 mg, 37%). MS-ESI m/z calc. 632.23926, detected 633.2 (M+1)+; retention time: 1.92 min (LC method G).

Example 134: Preparation of 21,21,23-trimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-10λ ⁶ -thia-1,3,9,13 ,14-pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4,6,11(23),12pentaene-8,10,10-trione (enantiomer 1) (compound 80) and 21,21,23- trimethyl-4-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-10Х ⁶ -thia-1,3,9,13,14pentaazatetracyclo[17.2.1.111,14.02 ,7]tricose-2,4,6,11 (23),12-pentaene-8,10,10-trione (enantiomer 2) (compound 81)

Step 1: 21,21,23-trimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)10λ ⁶ -thia-1,3,9,13 ,14-pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4,6,11 (23), 12-pentaene-8,10,10-trione (enantiomer 1) (compound 80) and 21,21, 23-trimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-10λ ⁶ -thia-1,3,9,13,14-pentaazatetracyclo[17.2.1.111 ,14.02,7]tricose-2,4,6,11(23),12pentaene-8,10,10-trione (enantiomer 2) (compound 81)

21,21,23-trimethyl-4-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1H-pyrazol-1-yl)-10Х ⁶ -thia1,3,9,13,14-pentaazatetracyclo [17.2.1.111,14.02,7]tricose-2,4,6,11(23),12-pentaene-8,10,10-trione (12 mg, 0.01888 mmol) was chirally resolved by SLC chromatography using

ChiralPak AS-H (250x21 mm column, 5 µm particle size) with a mobile phase of 20-25% methanol (20 mM NH3) in carbon dioxide at 50 ml/min (injection volume = 950 µl 4 mg/ml solution in 50% methanol in dimethyl sulfoxide) to obtain 21,21,23-trimethyl-4-(3{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-10λ ⁶ -thia as the first eluted enantiomer -1,3,9,13,14pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4,6,11 (23),12-pentaene-8,10,10-trione (enantiomer 1) (compound 80 ) (3.3 mg, 55%); MS-ESI m/z calc. 635.2502, detected 636.3 (M+1) ⁺ ; Retention time: 2.95 min (LC method D) and as the second enantiomer eluted 21,21,23-trimethyl-4-(3-{2[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazole-1 -yl)-10Х ⁶ -thia-1,3,9,13,14pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4,6,11 (23),12-pentaene-8,10,10- trione (enantiomer 2) (compound 81) (3.8 mg, 63%); MS-ESI m/z calc. 635.2502, detected 636.3 (M+1) ⁺ ; Retention time: 2.95 min (LC method D).

Example 135: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-2λ ⁶ -thia-3,9,11,23-tetraazatetracyclo [17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,2,4trione (enantiomer 1) (compound 86) and 12,12-dimethyl-8- (3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}1H-pyrazol-1-yl)-2λ ⁶ -thia-3,9,11,23-tetraazatetracyclo[17.3.1.111,14.05,1O]tetracose- 1(23),5,7,9,19,21hexaene-2,2,4-trione (enantiomer 2) (compound 87)

Step 1: 12,12-dimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-2λ ⁶ -thia3,9,11,23-tetraazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene-2,2,4-trione (enantiomer 1) (compound 86) and 12,12-dimethyl-8 -(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-2λ ⁶ -thia-3,9,11,23-tetraazatetracyclo[17.3.1.111,14.05,10]tetracose- 1(23),5,7,9,19,21-hexaene-2,2,4trione (enantiomer 2) (compound 87)

Racemic 12,12-dimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-2X6-thia-3,9,11,23-tetraazatetracyclo[17.3. 1.111,14.05,10]tetracose-1(23),5,7,9,19,21hexaene-2,2,4-trione (34.9 mg, 0.05516 mmol) to chiral resolution by SLC chromatography using Chiral Pak AS-H (250x10 mm column, 5 µm particle size) with a mobile phase of 25% acetonitrile:methanol (90:10; no modifier), 75% carbon dioxide at 10 ml/min (injection volume - 416 044967 ska=70 µl ~ 24 mg/ml in a mixture of acetonitrile: methanol (90:10)) to obtain 12,12-dimethyl-8-(3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 as the first eluted enantiomer N-pyrazol-1-yl)-2λ ⁶ thia-3,9,11,23-tetraazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5,7,9,19,21-hexaene- 2,2,4-trione (enantiomer 1) (compound 86) (13.11 mg, 74%) as a white solid;

¹ H NMR (400 MHz, DMSO-06) δ 12.74 (s, 1H), 8.21 (d, J=2.7 Hz, 1H), 8.08 (t, J=7.7 Hz, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.12 (d, J=2.7 Hz, 1H), 4.32 (t, J=7.0 Hz, 2H), 2.87 (s, 2H), 2.84-2.77 (m, 1H), 2.67 (t, J=12.6 Hz, 1H), 2.16 (dd, J=11.5 , 5.3 Hz, 1H), 2.08 (t, J=7.0 Hz, 2H), 1.98-1.85 (m, 2H), 1.61 (s, 1H), 1.53 (t, J=24.3 Hz, 8H), 1.45 (s , 1H), 1.03 (dd, J=12.9, 7.3 Hz, 1H), 0.96 (t, J=5.7 Hz, 2H), 0.92 (d, J=8.6 Hz, 1H), 0.89 (s, 2H), MS -IER m/z calc. 632.23926, found 633.2 (M+1)+; Retention time: 1.88 min (LC method G), and the second enantiomer eluted was 12,12-dimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)- 2Х ⁶ -thia-3,9,11,23tetraazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23),5,7,9,19,21 -hexaene-2,2,4-trione (enantiomer 2 ) (compound 87) (12.96 mg, 74%) as a white solid; MS-ESI m/z calc. 632.23926, found 633.2 (M+1) ⁺ ; Retention time: 1.92 min (LC method G).

Example 136: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-18-oxa-2X ⁶ -thia-3,9,11 ,20-tetraazatetracyclo[17.2.2.111,14.05,10]tetracose-1(21),5(10),6,8,19,22hexaene-2,2,4-trione (compound 90)

1: tert-butyl 2,2-dimethyl-4-[3-[(5-sulfamoyl-2-pyridyl)oxy]propyl]pyrrolidine-1 Step carboxylate

To tert-butyl-4-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate (400 mg, 1.554 mmol), NaH ( 125 mg, 3.125 mmol) (caution: evolution of gas) and the mixture was stirred at room temperature for 20 minutes. 6-chloropyridine-3-sulfonamide (296 mg, 1.537 mmol) was then added and the resulting mixture was stirred at room temperature for 140 min, then NaH (62 mg, 1.550 mmol) was added (caution: gas evolution) and the resulting mixture was heated to 100 °C after refluxing for 20 hours. Add more 6-chloropyridine-3-sulfonamide (145 mg, 0.750 mmol, NaH (62 mg, 1.55 mmol) and heat to 105 °C for 20 hours. Then the mixture poured into 1N citric acid and extracted with ethyl acetate (2X).The combined organic fractions were dried (sodium sulfate), filtered and concentrated to a yellow oil, which was purified by silica gel chromatography using a gradient of 100% hexanes to 65% ethyl acetate in hexanes to obtain tert-butyl-2,2dimethyl-4-[3-[(5-sulfamoyl-2-pyridyl)oxy]propyl]pyrrolidine-1-carboxylate (50.36 mg, 8%). ISEER m/z calc 413 ,19846, detected 414.2 (M+1) ⁺ ; Retention time: 1.81 min (LC method E).

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

2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (69 mg, 0.1836 mmol) and carbonyldiimidazole (30 mg, 0 .1850 mmol) were combined in tetrahydrofuran (1.108 ml) and stirred for 90 min at room temperature. Then tert-butyl-417 044967

2,2-dimethyl-4-[3-[(5-sulfamoyl-2-pyridyl)oxy]propyl]pyrrolidine-1-carboxylate (50.36 mg, 0.1218 mmol) followed by 1,8-diazabicyclo[ 5.4.0]undec-7-ene (50 μl, 0.3343 mmol), and the reaction mixture was heated at 50°C for 18 hours. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution, followed by saline. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a gradient of 100% hexanes to 75% ethyl acetate in hexanes to give tert-butyl-4-[3-[[ as an off-white solid. 5-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl]oxy]propyl]-2, 2-dimethylpyrrolidine-1-carboxylate (71 mg, 76%). MS-ESI m/z calc. 770.2476, detected 771.2 (M+1)+; Retention time: 2.11 min (LC method E).

Step 3: 12,12-dimethyl-8-(3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-18oxa-2λ ⁶ -thia-3,9,11 ,20-tetraazatetracyclo[17.2.2.111,14.05,10]tetracose-1(21),5(10),6,8,19,22-hexaene2,2,4-trione (compound 90)

tert-Butyl 4-[3-[[5-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin3-carbonyl]sulfamoyl]-2 -pyridyl]oxy]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (71 mg, 0.09206 mmol) was dissolved in dichloromethane (1.5 ml) and hydrochloric acid (4 M in dioxane) (800 μl 4 M, 3,200 mmol), and the mixture was stirred at room temperature for 30 min. The mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate and then aqueous 2M sodium carbonate (5 ml) was added to give a pH of ~10. The organic layer was extracted with ethyl acetate (2x10 ml), washed with brine, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. Combine the resulting material and potassium carbonate (69 mg, 0.4993 mmol), cesium fluoride (23 mg, 0.1514 mmol), 3 A molecular sieves and dimethyl sulfoxide (1.5 ml) in a vial, purged with nitrogen, capped, heated to 155°C and stirred for 24 hours. Cool to room temperature, filter and then purify by preparative reverse phase chromatography using a C ₁₈ column (30-99% acetonitrile in water (5 mM hydrochloric acid) to obtain dirty white solid 12,12-dimethyl-8-(3{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-18-oxa-2X ⁶ -thia-3,9, 11,20tetraazatetracyclo[17.2.2,111,14,05,10]tetracose-1(21),5(10),6,8,19,22-hexaene-2,2,4-trione (compound 90) (3, 95 mg, 7%). ESI-MS m/z calculated 634.2185, found 635.2 (M+1) ⁺ ; Retention time: 2.27 min (LC method E).

Example 137: Preparation of 12,21,21-trimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hπyrazol-1-yl)-10λ ⁶ -thia-1,3,9,13 ,14-πpentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4,6,11(23),12pentaene-8,10,10-trione (enantiomer 1) (compound 91) and 12,21,21- trimethyl-4-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-10Х ⁶ -thia-1,3,9,13,14pentaazatetracyclo[17.2.1.111,14.02 ,7]tricose-2,4,6,11 (23),12-pentaene-8,10,10-trione (enantiomer 2) (compound 92)

Step 1: 12,21,21-trimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)10λ ⁶ -thia-1,3,9,13 ,14-pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4,6,11 (23), 12-pentaene-8,10,10-trione (enantiomer 1) (compound 91) and 12,21, 21-trimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-10λ ⁶ -thia-1,3,9,13,14-pentaazatetracyclo[17.2.1.111 ,14.02,7]tricose-2,4,6,11(23),12pentaene-8,10,10-trione (enantiomer 2) (compound 92)

Racemic 12,21,21 -trimethyl-4-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 yl)-10λ ⁶ -thia-1,3,9,13, 14-pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4,6,11(23),12-pentaene-8,10,10trione (35 mg, 0.05506 mmol) was subjected to chiral separation by SLC chromatography with using a Chiral Pak AS-H column (250x10 mm, 5 µm particle size) with 20-30% methanol (20 mM NH3) in a carbon dioxide mobile phase, giving as the first enantiomer eluted, 12,21,21-trimethyl4-( 3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-10Х ⁶ -thia-1,3,9,13,14pentaazatetracyclo[17.2.1.111,14.02,7]tricose -2,4,6,11(23),12-pentaene-8,10,10-trione (enantiomer 1) (compound 91) (12.1 mg, 69%); MS-ESI m/z calc. 635.2502, detected 636.3 (M+1) ⁺ ; Retention time: 3.04 min (LC method G) and as the second enantiomer eluted 12,21,21-trimethyl-4-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazole-1 -yl)-10Х ⁶ -thia-1,3,9,13,14- 418 044967 pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4,6,11 (23), 12-pentaene-8, 10,10-trione (enantiomer 2) (compound 92) (8.9 mg, 51%); MS-ESI m/z calc. 635.2502, detected 636.3 (M+1)+; Hold Time:

3.03 min (LC method G).

Example 138: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-2λ ⁶ -thia-3,9,11,18,20 -pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (compound 93)

1: tert-butyl

2,2-dimethyl-4-[3-[(4-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1 Carboxylate step

A solution of 2-chloropyridine-4-sulfonamide (300 mg, 1.557 mmol), tert-butyl 4-(3-aminopropyl)-2,2dimethylpyrrolidine-1-carboxylate (399.2 mg, 1.557 mmol), sodium tert-butoxide ( 224.4 mg, 2.335 mmol) and chloro(2-di-tert-butylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium (II) (202.8 mg, 0.3114 mmol) in dioxane (5.000 ml) was degassed with a nitrogen purge and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The resulting brown residue was purified by silica gel column chromatography using a gradient of 100% dichloromethane to 20% methanol in dichloromethane to give tert-butyl-2,2-dimethyl-4-[3-[(4-sulfamoyl-2-pyridyl) amino]propyl]pyrrolidine-1-carboxylate (175 mg, 27%, 1:1 mixture with tert-butyl-4-[3-[bis(4-sulfamoyl-2-pyridyl)amino]propyl]-2,2dimethylpyrrolidine- 1-carboxylate) as a light brown sticky solid, which was used directly in the next step. MS-ESI m/z calc. 412.21442, detected 413.6 (M+1) ⁺ ; retention time: 0.5 min (LC method A).

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

2-Chloro-6-[3-[2-[1 -(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxylic acid (154.8 mg, 0.4120 mmol) and carbonyldiimidazole (66, 81 mg, 0.4120 mmol) were combined in tetrahydrofuran (2.0 ml) and stirred for 90 min at 50°C. Tert-butyl 2,2-dimethyl-4-[3[(4-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1-carboxylate (85 mg, 0.2060 mmol) was then added followed by 1,8diazabicyclo [5.4.0]undec-7-ene (47.04 mg, 46.21 µl, 0.3090 mmol), and the reaction mixture was heated at 50°C for 18 hours. The reaction was diluted with ethyl acetate and washed with saturated ammonium chloride solution, followed by rinsing with saline solution. The organic phases were separated, dried over sodium sulfate, filtered and evaporated. The resulting brown residue was purified by reverse phase HPLC-MS using a dual gradient from 20% to 99% mobile phase B over 15.0 min (mobile phase A=water (5 mM hydrochloric acid), mobile phase B=acetonitrile, speed flow=50 ml/min, injection volume=950 µl and column temperature=25°C) with

- 419 044967 by obtaining tert-butyl-4-[3-[[4-[[2-chloro-6-[3-[2-[1 -(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1 yl]pyridin-3 - carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (45.6 mg, 29%) as an off-white solid.

¹ H NMR (400 MHz, chloroform-d) δ 8.33-8.28 (m, 1H), 8.28-8.12 (m, 2H), 7.70 (dd, J=8.2, 4.3 Hz, 1H), 7.28 (d, J= 6.1 Hz, 1H), 7.21 (d, J=16.4 Hz, 1H), 5.95 (t, J=2.7 Hz, 1H), 4.39 (t, J=7.1 Hz, 2H), 3.77-3.68 (m, 1H) , 3.68-3.52 (m, 1H), 3.38 (s, 2H), 2.85 (t, J=11.7 Hz, 1H), 2.23-2.11 (m, 1H), 2.09 (t, J=7.2 Hz, 2H), 1.941.79 (m, 1H), 1.75-1.56 (m, 2H), 1.43 (s, 12H), 1.35 (s, 2H), 1.26 (s, 3H), 1.07-0.97 (m, 2H), 0.73 ( s, 2H). MSIE m/z calc. 769.2636, found 770.4 (M+1)+; Retention time: 0.77 min (LC method A).

Step 3: 12,12-dimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1-yl)-2λ ⁶ -thia3,9,11,18,20 -pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 93)

A solution of tert-butyl-4-[3-[[4-[[2-chloro-6-[3-[2-[1 -(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl ]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (50 mg, 0.06491 mmol) in dichloromethane (416.7 μl) and trifluoroacetic acid (74.01 mg, 49.67 μl , 0.6491 mmol) was stirred at room temperature for 4 hours. The solvents were removed and the residue was dissolved in ethyl acetate. Washed with 2 ml saturated sodium bicarbonate solution, the organic layer was collected, the solvent was removed, then dried in vacuo. The resulting residue was dissolved in dimethyl sulfoxide (2,500 ml), 3 A molecular sieves were added and the reaction mixture was stirred for 10 minutes. Cesium fluoride (29.58 mg, 0.1947 mmol) and potassium carbonate (26.91 mg, 0.1947 mmol) were then added and the reaction mixture was heated at 130°C overnight. The reaction mixture was filtered through a Whatman disk filter (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS using a dual gradient from 20% to 80% mobile phase B over 15.0 min (mobile phase A = water (0 .05% hydrochloric acid), mobile phase B=acetonitrile) to obtain 12,12-dimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)- 2λ ⁶ -thia3,9,11,18,20-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4 -trione (compound 93) (12.3 mg, 30%) as a light yellow solid.

1H NMR (400 MHz, chloroform-d) δ 8.39-8.22 (m, 1H), 8.16 (s, 1H), 7.94 (s, 2H), 7.61 (s, 1H), 7.20 (s, 1H), 6.98 ( s, 1H), 5.91 (s, 1H), 4.37 (s, 2H), 3.47 (d, J=13.7 Hz, 2H), 3.01 (d, J=43.7 Hz, 2H), 2.20 (s, 1H), 2.08 (t, J=7.1 Hz, 3H), 1.86 (s, 2H), 1.71 (s, 2H), 1.65 (s, 3H), 1.61 (s, 3H), 1.30 (d, J=39.7 Hz, 2H ), 1.05-0.98 (m, 2H), 0.74 (s, 2H). MS-ESI m/z calc. 633.2345, found 634.4 (M+1) ⁺ ; Retention time: 1.75 min (LC method B).

Example 139: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-19-oxa-2λ ⁶ -thia-3,9,11 ,21-tetraazatetracyclo[18.2.2.111,14.05,10]pentacose-1(23),5,7,9,20(24),21hexaene-2,2,4-trione (compound 94)

1: tert-butyl 2,2-dimethyl-4-[4-[(5-sulfamoyl-2-pyridyl)oxy]butyl]pyrrolidine-1 Step carboxylate

To tert-butyl 4-(4-hydroxybutyl)-2,2-dimethylpyrrolidine-1-carboxylate (800 mg, 2.948 mmol)

- 420 044967 While stirring under nitrogen, NaH (240 mg, 6.001 mmol) was added portionwise to N,N-dimethylformamide (8 mL) (caution: gas evolution) in a 20 mL vial and the mixture was stirred at room temperature for 20 min. . 6-chloropyridine-3-sulfonamide (570 mg, 2.959 mmol) was then added and the resulting mixture was stirred at room temperature for 1 hour, then NaH (120 mg, 3,000 mmol) was added (caution: gas evolution), the vial was capped and the resulting mixture heated to 100°C for 20 hours. Added additional 6-chloropyridine-3-sulfonamide (145 mg, 0.750 mmol and NaH (62 mg, 1.55 mmol) and heated to 105°C for 48 hours. The mixture was then poured in 1 N citric acid and extracted with ethyl acetate (2X).The combined organic fractions were dried (sodium sulfate), filtered and concentrated to a yellow oil, which was purified by silica gel chromatography using a gradient of 100% hexanes to 65% ethyl acetate in hexanes followed by a second purification on silica gel using a gradient from 100% dichloromethane to 15% methanol in dichloromethane to obtain tert-butyl-2,2-dimethyl-4-[4-[(5sulfamoyl-2-pyridyl)oxy]butyl] as a clear viscous oil pyrrolidine-1-carboxylate (335 mg, 27%).

1H NMR (400 MHz, DMSO-66) δ 8.54 (d, J=2.1 Hz, 1H), 8.10-7.95 (m, 1H), 7.44 (d, J=6.2 Hz, 2H), 6.98 (d, J= 8.8 Hz, 1H), 4.32 (t, J=6.6 Hz, 2H), 3.55 (dd, J=17.1, 6.9 Hz, 1H), 2.78 (k, J=10.5 Hz, 1H), 2.19-2.01 (m, 1H), 1.95-1.80 (m, 1H), 1.76-1.68 (m, 2H), 1.44 (d, J=12.1 Hz, 2H), 1.40-1.36 (m, 12H), 1.32 (d, J=17.3 Hz , 3H), 1.24 (s, 3H). MS-ESI m/z calc. 427.21408, detected 428.2 (M+1)+; retention time: 1.87 min (LC method E).

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

2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (437.0 mg, 1.163 mmol) and carbonyldiimidazole (190.0 mg , 1.172 mmol) were combined in tetrahydrofuran (7.260 ml) and stirred for 90 min at 50°C. Then tert-butyl 2,2-dimethyl-4-[4[(5-sulfamoyl-2-pyridyl)oxy]butyl]pyrrolidine-1-carboxylate (330 mg, 0.7718 mmol) was added followed by 1,8diazabicyclo [5.4.0]undec-7-ene (322.6 mg, 316.9 μL, 2.119 mmol), and the reaction mixture was heated at 50°C for 20 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, and then saline solution. The organic layer was separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexanes to 55% ethyl acetate in hexanes, followed by a second purification on silica gel using a gradient of 100% dichloromethane to 15% methanol. dichloromethane to give a light yellow solid, tert-butyl 4-[4-[[5-[[2-chloro-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl] pyridine 3-carbonyl]sulfamoyl]-2pyridyl]oxy]butyl]-2,2-dimethylpyrrolidine-1-carboxylate (350 mg, 58%). MS-ESI m/z calc. 784.2633, detected 785.2 (M+1) ⁺ ; retention time: 2.19 min (LC method G).

Step 3: 12,12-dimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-19oxa-2λ ⁶ -thua-3,9,11 ,21-tetraazatetracyclo[18.2.2.111,14.O5,1O]pentacose-1(23),5,7,9,20(24),21-hexaene2,2,4-trione (compound 94)

tert-Butyl 4-[4-[[5-[[2-chloro-6-[3-[2-[1 -(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1 -yl]pyridin3-carbonyl]sulfamoyl]2- pyridyl]oxy]butyl]-2,2-dimethylpyrrolidine-1-carboxylate (350 mg, 0.4457 mmol) was dissolved in dichloromethane (7.5 ml) and hydrochloric acid (4.0 ml 4 M in dioxane, 16.00 mmol) and stirred at room temperature for 30 minutes. The mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate and then aqueous 2M sodium carbonate (5 ml) was added to give a pH of ~10. Extracted with ethyl acetate (2x10 ml), combined organic layers, washed with brine, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. Combine the resulting material and potassium carbonate (310 mg, 2.243 mmol), cesium fluoride (105 mg, 0.6912 mmol), 3 A molecular sieves and dimethyl sulfoxide (7.5 ml) in a vial purged with nitrogen, capped, heated to 150 °C and stirred for 20

- 421 044967

h. Cooled to room temperature and the mixture was filtered, diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate and then with saline. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexanes to 55% ethyl acetate in hexanes to give 12,12-dimethyl-8-( as an off-white solid 3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}1H-nirazol-1-yl)-19-oxα-2λ ⁶ -thiα-3,9,11,21-tetraazatetracyclo[18.2.2.111,14.05,10 ]ntacose1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (compound 94) (76.3 mg, 26%). MS-ESI m/z calc. 648.2342, detected 649.2 (M+1)+; Retention time: 2.41 min (LC method E).

Example 140: Preparation of (14S)-8-[3-(3,3-dimethylbutyl)-4-methyl-2-oxonirrolidin-1-yl]-12,12dimethyl-2λ ⁶ -thia-3,9,11,18 ,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (hydrochloride salt)(compound 97)

Step 1: 1-benzyl-4-methylpyrrolidin-2-one

A 100 mL flask was charged with 4-methylpyrrolidin-2-one (1.52 g, 15.33 mmol) and anhydrous tetrahydrofuran (30 mL) under nitrogen atmosphere. The mixture was cooled in an ice bath and NaH (811.9 mg 60 wt%, 20.30 mmol) was added in small portions. Significant foaming was observed and the reaction became a difficult to stir suspension. Mixing was facilitated by adding additional tetrahydrofuran (10 ml). The mixture was stirred in a cooling bath for 1.5 hours. Benzyl bromide (2.2 mL, 18.50 mmol) was added dropwise through a syringe. The mixture was stirred in a cooling bath, which was allowed to warm slowly to room temperature overnight. After 29 h, the reaction mixture was poured into ice/water. The product was extracted with ethyl acetate (2x75 ml), the organic phase was dried over sodium sulfate, filtered and the solvents were evaporated. The residue was dissolved in dichloromethane and purified by silica gel chromatography using a gradient of ethyl acetate (0% to 100%) in hexane to give 1-benzyl-4-methylpyrrolidin-2-one (2.52 g, 87%) as a slightly brown oils

¹ H NMR (400 MHz, chloroform-d) δ 7.37-7.17 (m, 5H), 4.44 (s, 2H), 3.36 (dd, J=9.6, 7.7 Hz, 1H), 2.82 (dd, J=9.6, 6.0 Hz, 1H), 2.61 (dd, J=16.6, 8.6 Hz, 1H), 2.40 (ddtd, J=8.6, 7.8, 6.9, 6.0 Hz, 1H), 2.08 (dd, J=16.6, 6.9 Hz, 1H ), 1.07 (d, J=6.8 Hz, 3H). MS-ESI m/z calc. 189.11537, found 190.1 (M+1) ⁺ ; Retention time: 1.16 min (LC method B).

Step 2: 1-benzyl-3-(3,3-dimethylbutyl)-4-methyl-pyrrolidin-2-one

A 100 mL round bottom flask was dried using a heat gun under vacuum and filled with nitrogen. The flask was charged with 1-benzyl-4-methylpyrrolidin-2-one (542 mg, 2.864 mmol) and anhydrous tetrahydrofuran (8 ml). After cooling to -78°C, a solution of n-butyllithium (1.3 mL, 2.5 M in hexane, 3.250 mmol) was added dropwise, causing the formation of a red solution. After stirring at -78°C for 30 minutes, 1-bromo-3,3-dimethylbutane (450 μL, 3.195 mmol) was added dropwise. The mixture was stirred in a cooling bath, which was then allowed to slowly warm to room temperature. After 22 hours, the mixture was quenched by adding saturated aqueous ammonium chloride (50 ml). The product was extracted with ethyl acetate (3x20 ml) and the combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography on silica gel using a gradient of 0% to 40% ethyl acetate in hexanes gave 1-benzyl-3-(3,3-dimethylbutyl)-4-methylpyrrolidin-2-one (342 mg, 44%) as a colorless oil. MS-ESI m/z calc. 273.20926, detected 274.2 (M+1) ⁺ ; retention time: 2.03 min (LC method B).

Step 3: 3-(3,3-dimethylbutyl)-4-methyl-pyrrolidin-2-one

- 422 044967

To a 50 mL nitrogen-flushed flask charged with 1-benzyl-3-(3,3-dimethylbutyl)-4methylpyrrolidin-2-one (342 mg, 1.251 mmol), propan-1-amine (6 mL) and ethane-1 ,2-diamine (500 µl, 7.479 mmol). The solution was cooled to -30°C and a strip of lithium wire (6 cm, cut into 6 smaller pieces and washed with hexane to remove excess oil) was added. The flask was again fitted with a septum and the reaction mixture was vigorously stirred while warming slightly to 20°C. Ultimately, a blue color formed around the lithium wire, which briefly went into solution, and the reaction mixture was allowed to stir until the solution turned completely dark blue (~20 min). Water (~15 ml) was added, large pieces of lithium were removed, the mixture was warmed to room temperature and stirred for 10 min. The crude mixture was extracted with ethyl acetate (3x25 ml). The combined organic extracts were washed with water (15 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give crude 3-(3,3-dimethylbutyl)-4-methylpyrrolidin-2-one (388 mg, 169%) as yellow oil that was used without further purification. MS-ESI m/z calc. 183.16231, detected 184.1 (M+1) ⁺ ; retention time: 1.43 min (LC method B).

Step 4: (14S)-8-[3-(3,3-dimethylbutyl)-4-methyl-2-oxopyrrolidin-1-yl]-12,12-dimethyl-2λ ⁶ -tiα3,9,11,18, 23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (hydrochloride salt) (compound 97)

To a vial filled with crude 3-(3,3-dimethylbutyl)-4-methylpyrrolidin-2-one (22 mg, mmol) was added

0.1200 (14S)-8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23 pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5, 7,9,19,21-hexaen-2,2,4-trione (25 mg, 0.05373 mmol), (5-diphenylphosphanyl-9,9-dimethylxanthen-4-yl)diphenylphosphane (8 mg, 0 ,01383 mmol), (1E,4E)1,5-diphenylpenta-1,4-dien-3-one; palladium (13 mg, 0.01420 mmol), Cs ₂ CO ₃ (23 mg, 0.07059 mmol) and dioxane (1 ml). The headspace was purged with nitrogen, the tube was capped, and the reaction mixture was stirred at 120°C for 18 hours. After cooling to room temperature, the crude mixture was diluted with ethyl acetate (~30 mL) and washed with 1.0 M aqueous citric acid (5 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was dissolved in a minimal amount of dimethyl sulfoxide (0.4-1 ml) and purified by HPLC (C ₁₈ reverse phase, 1% to 99% acetonitrile in water with hydrochloric acid modifier). The pure fractions were then concentrated in vacuo and the residue was further purified by silica gel chromatography (0% to 70% ethyl acetate in hexanes) to give (14S)-8[3-(3,3-dimethylbutyl)-4-methyl-2-oxonirrolidine- 1-yl]-12,12-dimethyl-2λ ⁶ -thua-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23 ),20-hexaene-2,2,4 trione (hydrochloride salt) (compound 97) (2 mg, 6%) as an off-white solid. MS-ESI m/z calc. 596.31445, detected 597.2 (M+1)+; retention time: 2.32 min (LC method B).

Example 141: Preparation of (14S)-12,12-dimethyl-8-{3-[(1-methylcyclohexyl)methyl]-2-oxopyrrolidin1-yl}-2λ ⁶ -thia-3,9,11,18,23- pentaαzatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (compound 101)

Step 1: 1-benzyl-3-diethoxyphosphorylpyrrolidin-2-one

In a 250 mL flask, a solution of 1-benzylpyrrolidin-2-one (5.000 g, 28.53 mmol) in dry tetrahydrofuran (5 ml) dropwise over 5 minutes. Orange solution changes

- 423 044967 was stirred for 1 hour and a solution of 1[chloro(ethoxy)phosphoryl]oxyethane (5.170 g, 29.96 mmol) in dry tetrahydrofuran (5 ml) was added dropwise over 5 minutes. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 hours. The reaction was quenched with cold ice water (50 ml) and acidified to approximately pH 2.0 by the addition of aqueous 1.0 M hydrochloric acid. The aqueous layer was separated and extracted with ethyl acetate (3x50 ml). The combined organic extracts were dried (sodium sulfate), filtered and concentrated under reduced pressure to give crude product (8.74 g). Purification by silica gel flash column chromatography (first attempted with 10% to 100% ethyl acetate in hexane for 40 min but no material recovered, then 0 to 10% methanol in CH ₂ Cl ₂ used to elute product ) gave the desired 1-benzyl-3-diethoxyphosphorylpyrrolidin-2-one (3.31 g, 37%) as an orange viscous oil.

¹ H NMR (400 MHz, DMSO-d6) δ 7.38-7.31 (m, 2H), 7.31-7.25 (m, 1H), 7.25-7.21 (m, 2H), 4.49 (dd, J=15.1, 1.4 Hz, 1H), 4.30 (d, J=15.1 Hz, 1H), 4.15-3.98 (m, 4H), 3.31-3.14 (m, 3H), 2.34-2.19 (m, 1H), 2.19-2.04 (m, 1H) , 1.22 (two sets of t, J=7.2 Hz, 6H). MS-ESI m/z calc. 311.12863, detected 312.2 (M+1)+; retention time: 0.93 min (LC method B).

Step 2: 1-benzyl-3-[(1-methylcyclohexyl)methylene]pyrrolidin-2-one

In a 50 mL flask, sodium hydride (42.40 mg, 47.11 μL, 1.060 mmol, 60% dispersion in mineral oil) in three portions (to reduce gas evolution) at 5°C (ice water bath) under nitrogen atmosphere. After stirring for 10 min, a solution of 1-methylcyclohexanecarbaldehyde (182.5 mg, 1.446 mmol) in dry tetrahydrofuran (2 ml) was added dropwise over 3 min. Then stirred at this temperature for 3 hours and quenched with a saturated solution of NH ₄ Cl (15 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (3x20 ml). The combined organic layers were washed successively with water (15 ml) and brine (15 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude olefin product. The crude material was purified by silica gel column chromatography, eluting with 5-60% ethyl acetate in hexane.

Isomers E and Z eluted together. Removal of volatiles gives 1-benzyl-3-[(1methylcyclohexyl)methylene]pyrrolidin-2-one (265 mg, 97%) as a yellow viscous oil and a mixture of E and Z isomers. ES-MS m/z calc. 283.1936, detected 284.2 (M+1) ⁺ ; retention time: 1.98 min (LC method B).

Step 3: 1-benzyl-3-[(1-methylcyclohexyl)methyl]pyrrolidin-2-one

1-Benzyl-3-[(1methylcyclohexyl)methylene]pyrrolidin-2-one (260 mg, 0.9174 mmol) as a mixture of isomers E and Z and anhydrous methanol (15 ml) was charged into a 50 ml three-neck flask under a nitrogen atmosphere. . The flask was purged with nitrogen, then palladium (100 mg, 0.09397 mmol, 10% on activated carbon) was added under nitrogen and stirred under hydrogen (balloon) at 50°C for 2 days. The reaction mixture was allowed to cool to ambient temperature and the flask was purged with hydrogen, then filtered through a pad of celite. The filtrate was concentrated to give crude 1-benzyl-3-[(1-methylcyclohexyl)methyl]pyrrolidin-2-one (138 mg, 53%) as a brown gum, which was used in the next step without further purification.

MS-ESI m/z calc. 285.20926, detected 286.3 (M+1) ⁺ ; retention time: 1.98 min (LC method B).

Step 4: 3-[(1-methylcyclohexyl)methyl]pyrrolidin-2-one

A 50 ml flask was charged under a nitrogen atmosphere with 1-benzyl-3-[(1-methylcyclohexyl) methyl]pyrrolidin-2-one (164 mg, 0.5746 mmol), propan-1-amine (5 ml) and ethanol. 1,2-diamine (250 µl, 3.740 mmol) in the order listed at ambient temperature. The solution was cooled to -35°C (dry ice-acetone bath, to which 1 or 2 trays of dry ice were periodically added to maintain a constant temperature) and lithium (40 mg, 5.763 mmol, wire briefly rinsed with hexane, then freshly cut into small pieces) was added immediately pieces). A blue color began to develop around the small pieces of lithium, and the final dark blue color occurred after 1 hour. The reaction was quenched with saturated ammonium chloride (5 ml) at -35°C and the reaction mixture was allowed to warm to ambient temperature. Volatiles were removed under reduced pressure and the aqueous residue was extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous sodium sulfate and volatiles were removed under reduced pressure. After vacuum drying, crude 3-[(1-methylcyclohexyl)methyl]pyrrolidin-2-one (78 mg, 70%) was obtained as a white semi-solid and used without further purification. MS-ESI m/z calc. 195.16231, detected 196.1 (M+1)+; retention time: 1.47 min (LC method B).

Step 5: (14S)-12,12-dimethyl-8-{3-[(1-methylcyclohexyl)methyl]-2-oxopyrrolidin-1-yl} ^-2λ6- thia3,9,11,18,23-pentaazatetracyclo [17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 101)

(148)-8-chloro-12,12-dimethyl-2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23) was loaded into a 4 ml ampoule. 5,7,9,19,21-hexaene-2,2,4-trione (25 mg, 0.05373 mmol), 3-[(1-methylcyclohexyl)methyl]pyrrolidin-2-one (10 mg, 0. 05120 mmol), Pd ₂ (dba) ₃ (8 mg, 0.008736 mmol), xanthos (5 mg, 0.008641 mmol), cesium carbonate (87.52 mg, 0.2686 mmol) and anhydrous dioxane (0. 4 ml). The mixture was purged with nitrogen for 1-2 min, capped and stirred at 120°C for 15 h. The reaction mixture was diluted with dimethyl sulfoxide (1000 μl), microfiltered and subjected to reverse-phase preparative HPLC (C ₁₈ ) using a gradient of acetonitrile in water (from 1% to 99% in 15 minutes) and hydrochloric acid as a modifier. The pure fractions were collected and combined, a little brine was added, and the organic solvents were evaporated. The product was extracted with dichloromethane and the organic phase was dried over sodium sulfate then filtered. Evaporation of the filtrate gave 10 mg of solid. The product was further purified by flash silica gel chromatography using a gradient of methanol (0% to 5% over 30 min) in dichloromethane to give (14S)-12,12-dimethyl-8-{3-[(1-methylcyclohexyl)methyl] -2oxopyrrolidin-1-yl} -2Х ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20 -hexaene-2,2,4-trione (compound 101) (6.4 mg, 19%) as an off-white solid.

¹ H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 7.68 (dd, J=8.5, 1.4 Hz, 1H), 7.61-7.47 (m, 2H), 7.04 (d, J=7.1 Hz , 1H), 6.97 (broadened d, J=9.0 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 4.11-3.65 (m, 3H), 3.10 (broadened s, 1H), 2.94 (d , J=13.3 Hz, 1H), 2.75-2.57 (m, 2H), 2.43-2.28 (m, 1H), 2.10 (broad s, 1H), 2.02-1.93 (m, 1H), 1.891.64 (m , 3H), 1.64-1.37 (m, 13H), 1.35-1.10 (m, 8H), 0.89 (d, J=1.7 Hz, 3H). MS-ESI m/z calc. 608.31445, detected 609.3 (M+1) ⁺ ; retention time: 2.34 min (LC method B).

Example 142: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-19-oxa-2X ⁶ -thia-3,9,11 ,21-tetraazatetracyclo[18.2.2.111,14.05,10]pentacose-1(23),5,7,9,20(24),21 hexaene-2,2,4-trione (enantiomer 1) (compound 103) and 12,12-dimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-19-oxa-2Х ⁶ -thia-3,9,11,21tetraazatetracyclo [18.2.2.111,14.05,10]pentacose-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (enantiomer

2) (connection 104)

Step 1: 12,12-dimethyl-8-(3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-19oxa-2λ ⁶ -thia-3,9,11 ,21-tetraazatetracyclo[18.2.2.111,14.05,10]pentacose-1(23),5,7,9,20(24),21-hexaene2,2,4-trione (enantiomer 1) (compound 103) and 12 ,12-dimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-19-oxa-2λ ⁶ -thia-3,9,11,21tetraazatetracyclo[ 18.2.2.111,14.05,10]pentacose-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (enantiomer 2) (compound 104)

Racemic 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-19oxa-2λ ⁶ -thia-3,9,11,21- tetraazatetracyclo[18.2.2.111,14.05,10]pentacose-1(23),5,7,9,20(24),21-hexaene2,2,4-trione (71 mg, 0.1095 mmol) was subjected to chiral resolution using SKZH-425 044967 chromatography using ChiralCel OD-H (column 250x10 mm, particle size 5 μm) with a mobile phase of 42% acetonitrile/methanol (90:10)/58% carbon dioxide at 10 ml/min for 8, 0 min (injection volume = 70 μl of a 24 mg/ml solution in acetonitrile/methanol (90:10) to obtain 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl) as the first eluted enantiomer ]ethoxu}-1Hpyrazol-1-yl)-19-oxa-2λ ⁶ -thia-3,9,11,21-tetraazatetracyclo[18.2.2.111,14.O5,10]pentacose1(23),5,7,9 ,20(24),21-hexaene-2,2,4-trione (enantiomer 1) (compound 103) (19.77 mg, 56%) as a white solid, ESI-MS m/z calc 648, 2342, found 649.2 (M+1)+; Retention time: 2.38 min (LC method E) and as the second eluted enantiomer 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl ) cyclopropyl]toxy}-1 H-pyrazol-1 -yl)-19-oxa-2λ ⁶ -thia-3,9,11,21tetraazatetracyclo[18.2.2.111,14.05,10]pentacose-1(23),5, 7,9,20(24),21-hexaene-2,2,4-trione (enantiomer 2) (compound 104) (20.25 mg, 57%) as a white solid.

Ή NMR (400 MHz, DMSO-66) δ 12.46 (s, 1H), 8.77 (s, 1H), 8.19 (d, J=2.8 Hz, 2H), 7.88 (d, J=8.3 Hz, 1H), 7.03 (d, J=8.7 Hz, 1H), 6.92 (d, J=8.3 Hz, 1H), 6.11 (d, J=2.7 Hz, 1H), 4.31 (t, J=7.0 Hz, 2H), 2.41 (dd , J=8.3, 5.3 Hz, 1H), 2.07 (t, J=7.0 Hz, 3H), 2.04-1.98 (m, 1H), 1.73 (d, J=6.4 Hz, 2H), 1.67 (dd, J= 7.9, 4.9 Hz, 1H), 1.64-1.55 (m, 1H), 1.51 (d, J=11.5 Hz, 9H), 1.16 (dd, J=9.6, 1.7 Hz, 1H), 1.06-0.97 (m, 1H ), 0.95 (d, J=4.3 Hz, 2H), 0.88 (s, 2H), 0.86-0.77 (m, 1H). MS-ESI m/z calc. 648.2342, detected 649.2 (M+1) ⁺ ; retention time: 2.38 min (LC method E).

Example 143: Preparation of 8,8-dimethyl-12-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-18λ ⁶ -thia-2,9,11,17,23 -pentaazatetracyclo[17.3.1.O5,9.O1O,15]tricose-1(23),10(15),11,13,19,21hexaene-16,18,18-trione (compound 108), 8,8 -dimethyl-12-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}1H-nurazol-1-ul)-18λ ⁶ -thia-2,9,11,17,23-pentaazatetracyclo[17,3.1 .05,9.O1O,15]tricose1(23),10(15),11,13,19,21-hexaene-16,18,18-trione (enantiomer 1) (compound 116) and 8,8-dimethyl -12-(3-{2[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-18λ ⁶ -thia-2,9,11,17,23pentaazatetracyclo[17.3.1.05,9.010, 15]tricose-1(23),10(15),11,13,19,21-hexaene-16,18,18-trione (enantiomer 2) (compound 117)

Step 1: 2-(1-hydroxy-5,5-dimethyl-pyrrolidin-2-yl)acetonitrile

N-butyllithium (127 ml 2.5 M, 317.5 mmol) was added dropwise to dry tetrahydrofuran (270 ml) cooled to -78°C. During addition, the internal temperature was maintained below -65°C. Acetonitrile (13.13 g, 16.7 mL, 319.8 mmol) was then added slowly while maintaining the internal temperature below -70°C. A white precipitate of lithiated acetonitrile was observed after adding half of the acetonitrile. After 30 min at -78°C, a solution of 2,2-dimethyl-1-oxido-3,4-dihydropyrrol-1ium (11.20 g, 99 mmol) in dry tetrahydrofuran (15 ml) was added at a rate such that the internal temperature did not rise above -70°C. The yellow suspension was stirred at -78°C for 1 hour, then quenched with saturated ammonium chloride solution (150 ml). After warming to room temperature for two

- 426 044967 layers were separated. The aqueous layer was extracted with ethyl acetate (2x150 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude 2-(1-hydroxy-5,5-dimethylpyrrolidin-2yl)acetonitrile (17 g, ~80%). % purity by 1H NMR, 89% yield) as a brown oil, which was directly used in the next step without further purification.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.04 (s, 3H), 1.18 (s, 3H), 1.48-1.67 (m, 3H), 1.99-2.06 (m, 1H), 2.59 (d, J=5.2 Hz, 2H), 3.17-3.26 (m, 1H), 4.59 (br. s., 1H).

Step 2: 2-(5,5-dimethylpyrrolidin-2-yl)acetonitrile

Zinc (4.9 g, 0.6869 mL, 74.935 mmol) was added in several portions to a solution of 2-(1-hydroxy5,5-dimethylpyrrolidin-2-yl)acetonitrile (1.8 g, 8.1707 mmol) in acetic acid (21 ml) in an ice-water bath and allowed the mixture to warm to room temperature, stirred vigorously and heated to 30°C for 6 hours. The crude mixture was filtered and concentrated under reduced pressure to give the crude product, which was neutralized with 5% bicarbonate sodium (100 ml) and extracted with dichloromethane (2x100 ml). The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product 2-(5,5-dimethylpyrrolidin-2-yl)acetonitrile (0.9 g, 70%) as a pale yellow semi-solid. MS-ESI m/z calc. 138.1157, detected 139.2 (M+1)+; retention time: 0.312 min (LC method I).

Step 3: tert-butyl 5-(cyanomethyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

Di-tert-butyl dicarbonate (17.4 g, 18.32 mL, 79.73 mmol) was added to a solution of 2-(5,5dimethylpyrrolidin-2-yl)acetonitrile (12 g, 51% purity, 44.28 mmol) and triethylamine (8.712 g, 12 ml, 86.10 mmol) in tetrahydrofuran (100 ml). The reaction mixture was stirred at room temperature over the weekend. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. The residue was purified by silica gel chromatography using a gradient of 0% to 20% ethyl acetate in heptanes to give tert-butyl 5-(cyanomethyl)-2,2-dimethylpyrrolidine-1carboxylate (9.5 g, 63%) as light yellow oil. MS-ESI m/z calc. 238.326, detected 261.2 (M+Na)+; retention time: 2.12 min (LC method I).

Step 4: tert-butyl 5-(2-aminoethyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

BocN7 VoSM'7

Ύ Ύ

A 250 ml round bottom flask was charged with tert-butyl 5-(cyanomethyl)-2,2-dimethylpyrrolidine-1carboxylate (9.1 g, 38.2 mmol), ammonia (10 ml of a 7 M solution in methanol, 70 mmol), methanol (70 ml) and Raney nickel (suspension in water, approximately 4 g, taken with a spatula without precise weighing). The mixture was vigorously stirred at room temperature to 1 atmosphere of H ₂ (balloon) for three days. Additionally, Raney nickel (suspension in water, approximately 6 g, taken with a spatula without precise weighing) and ammonia (10 ml of a 7 M solution in methanol, 70 mmol) were added. The reaction mixture was stirred overnight. The mixture was filtered through a pad of celite, washing with ethyl acetate. The filtrate was concentrated under reduced pressure to give a yellow oil, which was tert-butyl 5-(2aminoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (8.16 g, 83% yield).

¹ H NMR (300 MHz, CDCl3) ppm 1.16-1.34 (m, 3H), 1.34-1.59 (m, 16H), 1.63-2.00 (m, 4H), 2.60-2.75 (m, 2H), 3.73-3.90 ( m, 0.3H), 3.90-4.05 (m, 0.6H). Two rotamers were observed. MS-ESI m/z calc. 242.358, detected 243.2 (M+1) ⁺ ; retention time: 1.74 min (LC method H).

Step 5: tert-butyl 2,2-dimethyl-5-[2-[(6-sulfamoyl-2-pyridyl)amino]ethyl]pyrrolidine-1-carboxylate

- 427 044967

6-fluoropyridine-2 was added to a solution of tert-butyl 5-(2-aminoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (500.0 mg, 2.063 mmol) in N,N-dimethylformamide (5 mL). -sulfonamide (302.8 mg, 1.719 mmol), followed by potassium carbonate (712.9 mg, 5.158 mmol). The flask was sealed and heated at 90°C under nitrogen in an oil bath for 14 hours. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate and washed with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexanes to 100% ethyl acetate to give tert-butyl2,2-dimethyl-5-[2-[(6-sulfamoyl -2-pyridyl)amino]ethyl]pyrrolidine-1-carboxylate (428 mg, 62%) as a white solid.

¹ H NMR (400 MHz, chloroform-d) δ 7.48 (t, J=7.9 Hz, 1H), 7.18 (dd, J=7.2, 3.3 Hz, 1H), 6.53 (d, J=8.4 Hz, 1H), 5.68 (d, J=5.8 Hz, 1H), 5.50 (s, 2H), 4.00 (k, J=6.6 Hz, 1H), 3.48 (dk, J=13.0, 6.9 Hz, 1H), 3.20-3.06 (m , 1H), 2.03-1.86 (m, 1H), 1.77 (t, J=5.3 Hz, 1H), 1.59 (dk, J=14.4, 7.1 Hz, 1H), 1.46 (s, 9H), 1.39 (s, 3H), 1.28 (s, 3H). MS-ESI m/z calc. 398.19876, found 399.24 (M+1)+; Retention time: 0.63 min (LC method A).

Step 6: tert-butyl 5-[2-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl ]-2-pyridyl]amino]ethyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

2-Chloro-6-[3-[2-[1 -(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxylic acid (237.6 mg, 0.6323 mmol) and carbonyldiimidazole (102, 5 mg, 0.6323 mmol) were combined in tetrahydrofuran (3.0 ml) and stirred for 90 min at 50°C. Tert-butyl 2,2-dimethyl-5-[2[(6-sulfamoyl-2-pyridyl)amino]ethyl]pyrrolidine-1-carboxylate (210 mg, 0.5269 mmol) was then added followed by 1,8diazabicycloid [5.4.0]undec-7-ene (120.3 mg, 118.2 μL, 0.7904 mmol), and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution, and then saline solution. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a gradient of 100% dichloromethane to 20% methanol in dichloromethane to give tert-butyl 5-[2-[[6-[[2-chloro -6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl]amino]ethyl]-2,2-dimethyl-pyrrolidine-1 -carboxylate (321 mg, 81%) as a white solid.

¹ H NMR (400 MHz, chloroform-d) δ 8.22 (s, 1H), 8.14 (d, J=8.1 Hz, 1H), 7.54 (d, J=14.9 Hz, 2H), 7.39 (d, J=19.1 Hz, 1H), 6.54 (s, 1H), 6.06 (s, 1H), 5.89 (d, J=2.8 Hz, 1H), 4.36 (t, J=7.2 Hz, 2H), 3.90 (s, 1H), 3.29 (s, 1H), 3.09 (s, 1H), 2.08 (t, J=7.3 Hz, 2H), 1.86 (s, 4H), 1.69 (s, 1H), 1.52 (s, 1H), 1.37 (d , J=37.2 Hz, 12H), 1.22 (s, 3H), 1.06-0.99 (m, 2H), 0.78-0.70 (m, 2H). MS-ESI m/z calc. 755.248, detected 756.2 (M+1) ⁺ ; Retention time: 0.87 min (LC method A).

Step 7: 8,8-dimethyl-12-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-18λ ⁶ -tiα2,9,11,17,23 -pentaazatetracyclo[17.3.1.05,9.010,15]tricose-1(23),10(15),11,13,19,21-hexaene-16,18,18trione (compound 108)

A solution of tert-butyl-5-[2-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl] -2-pyridyl]amino]ethyl]-2,2-dimethylpyrrolidine-1-carboxylate (320 mg, 0.4231 mmol) in dichloromethane (2.667 ml) and trifluoroacetic acid (482.4 mg, 323.8 μl, 4.231

- 428 044967 mmol) was stirred at room temperature for 4 hours. The solvents were removed and the residue was dissolved in ethyl acetate. Wash with 2 ml saturated sodium bicarbonate solution, the organic layer is collected, the solvent is removed and the residue is dried in vacuo. The above residue was dissolved in dimethyl sulfoxide (5 ml), 3 A molecular sieves were added and the reaction mixture was stirred for 10 minutes. Cesium fluoride (192.8 mg, 1.269 mmol) and potassium carbonate (175.4 mg, 1.269 mmol) were then added and the reaction mixture was heated at 130°C for 24 hours. The reaction mixture was filtered through celite and the celite layer was washed with ethyl acetate . The filtrate was washed again with brine and the solvent was removed. The resulting brown residue was purified by silica gel column chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate to give 8,8-dimethyl12-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazole -1-yl)-18λ ⁶ -thia-2,9,11,17,23pentaazatetracyclo[17.3.1.05,9.010,15]tricose-1(23),10(15),11,13,19,21-hexaene -16,18,18-trione (compound 108) (145 mg, 55%) as a light yellow solid.

1H NMR (400 MHz, chloroform-d) δ 13.95 (s, 1H), 8.50 (s, 1H), 8.24 (d, J=2.8 Hz, 1H), 7.63 (s, 1H), 7.52 (dd, J= 8.3, 7.3 Hz, 1H), 7.28 (d, J=7.3 Hz, 1H), 6.49 (d, J=8.3 Hz, 1H), 5.96 (d, J=2.8 Hz, 1H), 4.85 (s, 1H) , 4.42 (t, J=7.1 Hz, 2H), 4.24 (s, 1H), 3.01 (s, 2H), 2.59 (d, J=19.1 Hz, 1H), 2.32 (s, 1H), 2.10 (t, J=7.1 Hz, 2H), 1.91 (s, 2H), 1.60 (s, 3H), 1.13 (s, 3H), 1.06-1.00 (m, 2H), 0.77-0.70 (m, 2H). MS-ESI m/z calc. 619.2189, found 620.06 (M+1)+; Retention time: 1.87 min (LC method B).

Step 8: 8,8-dimethyl-12-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-18X ⁶ -thia2,9,11,17,23- pentaazatetracyclo[17.3.1.05,9.010.15]tricose-1(23),10(15),11,13,19,21-hexaene-16,18,18trione (enantiomer 1) (compound 116) and 8,8- dimethyl-12-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}1H-pyrazol-1-yl)-18Х ⁶ -thia-2,9,11,17,23-pentaazatetracyclo[17.3.1.05, 9.010,15]tricose1(23),10(15),11,13,19,21-hexaene-16,18,18-trione (enantiomer 2) (compound 117)

Racemic 8,8-dimethyl-12-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)18λ ⁶ -thia-2,9,11,17,23- pentaazatetracyclo[17.3.1.05,9.010.15]tricose-1(23),10(15),11,13,19,21-hexaene16,18,18-trione (compound 108) (145 mg) was subjected to chiral separation by SLC chromatography using ChiralPak AS-H (250x21.2 mm column, 5 µm particle size) with a mobile phase of 25% acetonitrile/methanol (90:10)/75% carbon dioxide at 70 ml/min (injection volume = 500 µl of 32 mg solution /ml in acetonitrile/methanol (90:10)) to obtain 8,8-dimethyl-12-(3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazole-1 as the first eluted enantiomer -yl)18Х ⁶ -thia-2,9,11,17,23-pentaazatetracyclo[17.3.1.05,9.010,15]tricose-1(23),10(15),11,13,19,21-hexaene16, 18,18-trione (enantiomer 1) (compound 116) (46.5 mg, 34%);

1H NMR (400 MHz, chloroform-d) δ 13.88 (s, 1H), 8.50 (s, 1H), 8.24 (d, J=2.8 Hz, 1H), 7.64 (s, 1H), 7.52 (dd, J= 8.4, 7.3 Hz, 1H), 7.28 (s, 1H), 6.50 (d, J=8.3 Hz, 1H), 5.96 (d, J=2.8 Hz, 1H), 4.89 (s, 1H), 4.48-4.38 ( m, 2H), 4.24 (s, 1H), 3.01 (s, 2H), 2.59 (d, J=23.4 Hz, 1H), 2.32 (s, 1H), 2.11 (t, J=7.1 Hz, 2H), 1.92 (brs, 2H), 1.61 (d, J=6.7 Hz, 6H), 1.14 (brs, 2H), 1.07-1.00 (m, 2H), 0.79-0.71 (m, 2H), MS-ESI m/z calc. 619.2189, found 620.1 (M+1) ⁺ ; Retention time: 1.86 min (LC method B), and the second enantiomer eluted was 8,8-dimethyl-12-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl ) -18Х ⁶ -thia-2,9,11,17,23pentaazatetracyclo[17.3.1.05,9.010,15]tricose-1(23),10(15),11,13,19,21 hexaene-16,18, 18-trione (enantiomer 2) (compound 117) (66.1 mg, 50%);

^1H NMR (400 MHz, chloroform-d) δ 13.87 (s, 1H), 8.50 (s, 1H), 8.25 (s, 1H), 7.63 (s, 1H), 7.54 (s, 1H), 7.28 (s , 1H), 6.52 (s, 1H), 5.96 (s, 1H), 4.81 (s, 1H), 4.42 (s, 2H), 4.25 (s, 1H), 3.04 (s, 2H), 2.58 (s, 2H), 1H), 2.33 (s, 1H), 2.11 (t, J=5.0 Hz, 2H), 1.92 (s, 2H), 1.60 (s, 6H), 1.14 (s, 2H), 1.03 (d, J=5.6 Hz, 2H), 0.75 (s, 2H). MSIE m/z calc. 619.2189, found 620.1 (M+1) ⁺ ; Retention time: 1.86 min (LC method B).

Example 144: Preparation of (14S)-12,12,20-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}1 H-pyrazol-1 -yl)-18-oxa-2X ⁶ -thia-3,9,11,23-tetraazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (compound 109)

- 429 044967

Step 1: tert-butyl (48)-2,2-dimethyl-4-[3-[(3-methyl-6-sulfamoyl-2pyridyl)oxy]propyl]pyrrolidine-1-carboxylate

NaH was added portionwise to tert-butyl (48)-4-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate (496 mg, 1.927 mmol) with stirring under nitrogen in N,N-dimethylformamide (6 mL). (154.1 mg, 171.2 µl, 3.854 mmol), and the mixture was stirred at room temperature for 15 minutes. 6-chloro-5-methylpyridin-2-sulfonamide (398.2 mg, 1.927 mmol) was then added and the resulting mixture was stirred at room temperature for 80 minutes. Additional NaH (77.07 mg, 85.63 μL, 1.927 mmol) was added to the stirred solution at room temperature and the reaction tube was capped. The resulting mixture was stirred at 100°C for 14 hours. The cooled reaction mixture was poured into 1 N. citric acid and extracted with ethyl acetate (2X). The organic fractions were combined, dried (sodium sulfate), filtered and concentrated in vacuo to a clear oil, which was purified by silica gel chromatography using a mobile phase gradient from 100% hexanes to 100% ethyl acetate to give tert-butyl (48)-2,2- dimethyl 4-[3-[(3-methyl-6sulfamoyl-2-pyridyl)oxy]propyl]pyrrolidine-1-carboxylate (336 mg, 41%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.74 (dd, J=7.4, 1.0 Hz, 1H), 7.39 (d, J=7.4 Hz, 1H), 7.29 (s, 2H), 4.36 (s, 2H ), 3.58 (k, J=8.4, 7.9 Hz, 1H), 2.81 (k, J=10.1 Hz, 1H), 2.20 (t, J=1.8 Hz, 4H), 1.96 (d, J=26.1 Hz, 1H ), 1.75 (dt, J=14.2, 6.9 Hz, 2H), 1.46 (k, J=7.6, 7.1 Hz, 2H), 1.37 (t, J=10.7 Hz, 13H), 1.25 (s, 3H). MS-ESI m/z calc. 427.21408, detected 428.21 (M+1)+; retention time: 0.72 min (LC method A).

Step 2: tert-butyl (48)-4-[3-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol1-yl]pyridin-3 -carbonyl]sulfamoyl]-3-methyl-2-pyridyl]oxy]propyl]-2,2-dimethyl-pyrrolidine-1carboxylate

2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxylic acid (175.8 mg, 0.4678 mmol) and carbonyl diimidazole (75 .85 mg, 0.4678 mmol) were combined in tetrahydrofuran (4.678 ml) and stirred for 60 min at 50°C. Then tert-butyl (48)-2,2dimethyl-4-[3-[(3-methyl-6-sulfamoyl-2-pyridyl)oxy]propyl]pyrrolidine-1-carboxylate (200 mg, 0.4678 mmol) was added , followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (71.22 mg, 69.96 μL, 0.4678 mmol), and the reaction mixture was heated at 50°C for 15 hours. The reaction was diluted ethyl acetate and washed with 1 M citric acid solution, and then with saline solution. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexanes to 75% ethyl acetate in hexanes to give, as an off-white solid, tert-butyl (48)-4 -[3-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1 -yl]pyridin-3-carbonyl]sulfamoyl]-3-methyl -2-pyridyl]hydroxy]propyl]-2,2dimethylpyrrolidine-1-carboxylate (296 mg, 81%). MS-ESI m/z calc. 784.2633, detected 785.1 (M+1) ⁺ ; Retention time: 0.84 min (LC method A).

- 430 044967

Step 3: (14S)-12,12,20-trimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 yl)-18-oxa-2λ ⁶ - thia-3,9,11,23-tetraazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21hexaene-2,2,4-trione (compound 109 )

tert-Butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carbonyl] sulfamoyl]-3-methyl-2-pyridyl]oxy]propyl]-2,2-dimethylpyrrolidine-1 carboxylate (296 mg, 0.3769 mmol) was dissolved in dichloromethane (5 ml) and hydrochloric acid (3.5 ml 4M in dioxane, 14.00 mmol) and stirred at room temperature for 30 min. The reaction solution was concentrated to dryness in vacuo. Combine the resulting material with potassium carbonate (313 mg, 2.265 mmol), cesium fluoride (93 mg, 0.6122 mmol), 3 A molecular sieves and dimethyl sulfoxide (6 ml) in a vial, purged with nitrogen, capped, heated to 140 ° C and stirred for 16 hours. Cool to room temperature and the reaction mixture was filtered and then purified by preparative reverse phase chromatography using a C18 column (20-99% acetonitrile-water + 5 mM hydrochloric acid) to obtain as a white solid (14S)-12,12,20-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-18-oxa-2λ ⁶ -thia-3,9 ,11,23-tetraazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (compound 109) (78 mg, 32%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.73 (s, 1H), 8.21 (d, J=2.8 Hz, 1H), 7.86 (dd, J=8.3, 7.0 Hz, 2H), 7.58 (d, J =7.4 Hz, 1H), 6.94 (d, J=8.2 Hz, 1H), 6.12 (d, J=2.7 Hz, 1H), 5.18 (t, J=12.2 Hz, 1H), 4.32 (t, J=7.0 Hz, 2H), 3.96 (d, J=ll.l Hz, 1H), 3.14 (t, J=8.4 Hz, 1H), 2.56 (d, J=10.8 Hz, 1H), 2.18 (s, 3H), 2.11-2.01 (m, 3H), 1.85 (dd, J=11.9, 5.3 Hz, 1H), 1.70 (t, J=12.9 Hz, 2H), 1.55 (d, J=39.3 Hz, 8H), 1.22 (k , J=12.6, 12.2 Hz, 1H), 1.03-0.92 (m, 2H), 0.92-0.84 (m, 2H). MS-ESI m/z calc. 648.2342, detected 649.41 (M+1) ⁺ ; retention time: 2.38 min (LC method B).

Example 145: Preparation of 20,20-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-10λ ⁶ -thia-1,3,9,13,14 -pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10trione (compound 110)

Step 1: tert-butyl 2,2-dimethyl-4-[3-(4-sulfamoylpyrazol-1-yl)propyl]pyrrolidine-1-carboxylate

tert-Butyl-2,2-dimethyl-4-(3-methylsulfonyloxypropyl)pyrrolidine-1-carboxylate (490 mg, 1.461 mmol) and 1H-pyrazole-4-sulfonamide (215 mg, 1.461 mmol) followed by potassium carbonate ( 710 mg, 5.137 mmol) was dissolved in N,N-dimethylformamide (15 ml) and stirred at 50°C in a 150 ml sealed vessel for 48 hours.

Cool to room temperature, then pour into water (100 ml) and extract with ethyl acetate (2x100 ml), combine organic layers, wash with water (2x100 ml), dry (sodium sulfate), filter and concentrate. The orange residue was purified by silica gel chromatography using a gradient of 100% hexanes to 100% ethyl acetate to give tert-butyl-2,2-dimethyl-4 as a colorless oil which became a white solid after vacuum drying. -[3-(4sulfamoylpyrazol-1-yl)propyl]pyrrolidine-1-carboxylate (400 mg, 71%).

1H NMR (400 MHz, DMSO-de) δ 8.20 (s, 1H), 7.71 (s, 1H), 7.23 (s, 2H), 4.14 (t, J=6.7 Hz, 2H), 3.54 (dd, J= 18.0, 10.3 Hz, 1H), 2.74 (k, J=10.2 Hz, 1H), 2.10 (dt, J=10.1, 6.4 Hz, 1H), 1.87 (td, J=13.0, 6.1 Hz, 1H), 1.811. 69 (m, 2H), 1.38 (d, J=10.5 Hz, 10H), 1.34 (d, J=10.7 Hz, 3H), 1.24 (s, 5H). MS-ESI m/z calc. 386.19876, detected 387.2 (M+1)+; retention time: 1.49 min (LC method E).

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

2-Chloro-6-[3-[2-[1-(tetramethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (335 mg, 0.8916 mmol) and carbonyl diimidazole (143 mg, 0.8819 mmol) were combined in tetrahydrofuran (4.5 ml) and stirred for 60 min at room temperature. Then tert-butyl 2,2dimethyl-4-[3-(4-sulfamoylpyrazol-1-yl)propyl]pyrrolidine-1-carboxylate (200 mg, 0.5175 mmol) was added followed by 1,8-diazabicyclo[5.4 .0]undec-7-ene (225 μl, 1.505 mmol), and the reaction mixture was heated at 50°C for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and then with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexanes to 100% ethyl acetate to give, as an off-white solid, tert-butyl 4-[3-[4 - [[2-chloro-6-[3-[2-[1 -(trifluoromethyl)cyclopropyl] ethoxy] pyrazol-1 yl] pyridin-3-carbonyl] sulfamoyl] pyrazol-1 -yl] propyl] -2.2 -dimethylpyrrolidine-1-carboxylate (201 mg, 52%). MS-ESI m/z calc. 743.248, detected 744.2 (M+1) ⁺ ; Retention time: 1.84 min (LC method E).

Step 3: 20,2O-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-1Oλ ⁶ thia-1,3,9,13,14 -pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (compound 110)

tert-Butyl 4-[3-[4-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]pyrazol-1 -yl]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (200 mg, 0.2687 mmol) was dissolved in dichloromethane (5.0 ml) and hydrochloric acid (2.5 ml 4M in dioxane, 10.00 mmol) was added to the mixture ) and stirred at room temperature for 30 min. The mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate and then aqueous 2M sodium carbonate (5 ml) was added to give a pH of ~10. The solution was extracted with ethyl acetate (2x10 ml), washed with brine, then dried over sodium sulfate, filtered and evaporated dry under reduced pressure. Combine the resulting material and potassium carbonate (190 mg, 1.375 mmol), cesium fluoride (65 mg, 0.4279 mmol), 3 A molecular sieves and dimethyl sulfoxide (6 ml) in a nitrogen purged, capped vial heated to 155°C and stirred for 20 hours. Cooled to room temperature and filtered, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and then with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexanes to 80% ethyl acetate in hexanes followed by a second column gradient of 100% dichloromethane to 10% methanol in dichloromethane to give as a white solid

20,20-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-III-pyrazol-1-yl)-10λ ⁶ -thia

1,3,9,13,14-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (compound 110) (59 .6 mg, 36%).

¹ H NMR (400 MHz, DMSO-de) δ 12.24 (s, 1H), 8.55 (s, 1H), 8.18 (d, J=2.8 Hz, 1H), 7.88 (s, 1H), 7.74 (d, J =8.2 Hz, 1H), 6.89 (d, J=8.2 Hz, 1H), 6.10 (d, J=2.7 Hz, 1H), 4.31 (t, J=7.0 Hz, 3H), 4.07 (t, J=11.5 Hz, 1H), 2.17 (dd, J=7.3, 5.2 Hz, 1H), 2.07 (t, J=7.1 Hz, 4H), 1.93 (t, J=9.3 Hz, 1H), 1.87-1.69 (m, 2H ), 1.60 (d, J=12.4 Hz, 1H), 1.49 (s, 6H), 1.37 (t, J=12.1 Hz, 1H), 1.09-0.99 (m, 1H), 0.98-0.93 (m, 2H) , 0.89 (d, J=11.2 Hz, 2H). MS-ESI m/z calc. 607.2189, detected 608.2 (M+1) ⁺ ; Retention time: 2.07 min (LC method E).

- 432 044967

Example 146. Preparation of (18S)-20,20,22-trimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}1H-pyrazol-1-yl)-10λ ⁶ -thia.-1 ,3,9,13,14-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12pentaene-8,10,10-trione (atropoisomer 1) (compound 111), (18S)-12,20,20-trimethyl-4-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-10λ ⁶ -thia-1,3,9 ,13,14pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (compound 112) and (18S)-20,20, 22-trimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-10λ ⁶ -thia1,3,9,13,14-pentaazatetracyclo[16.2.1.111 ,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (atropoisomer 2) (compound 113)

Step 1: tert-butyl-(4S)-4-[3-[4-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol1 -yl]pyridin-3 -carbonyl]sulfamoyl]-3-methylpyrazol-1-yl]propyl]-2,2-dimethylpyrrolidine-1 carboxylate and tert-butyl(4S)-4-[3-[4-[[2-chloro-6-[ 3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl]-5-methylpyrazol-1-yl]propyl]-2,2-dimethylpyrrolidine-1 carboxylate (mixture of regioisomers )

mixture of reglolsomers

Into a flask containing 2-chloro-N-[(5-methyl-1H-pyrazol-4-yl)sulfonyl]-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl] pyridine-3-carboxamide (900 mg, 1.734 mmol), potassium carbonate (720 mg, 5.210 mmol) and dimethyl sulfoxide (14 ml) was added to a solution of tert-butyl (4S)-2,2dimethyl-4-(3-methylsulfonyloxypropyl)pyrrolidine- 1-carboxylate (699 mg, 2.084 mmol) in dimethyl sulfoxide (2 ml), and the reaction mixture was allowed to stir at 95°C overnight. The reaction mixture was cooled to room temperature, filtered and purified by HPLC (30-99% acetonitrile/water with 0.1% hydrochloric acid modifier to give tert-butyl (4S)4-[3-[4-[[2-chloro -6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-3-methylpyrazol-1-yl]propyl]-2,2-dimethylpyrrolidine-1 -carboxylate and tert-butyl (48)-4-[3-[4-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carbonyl] sulfamoyl]-5-methylpyrazol-1-yl]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (mixture

- 433 044967 regioisomers) (524.1 mg, 40%). MS-ESI m/z calc. 757.2636, detected 758.5 (M+1)+; retention time: 1.93 min (LC method G).

Step 2: 2-chloro-I-[1-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propyl]-3-methylpyrazol-4yl]sulfonyl-6-[3-[2-[ 1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide and 2chloro-N-[1-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propyl]-5 -methylpyrazol-4-yl]sulfonyl-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (mixture of regioisomers)

mixture of regloisomers

mixture of regloisomers

Tert-butyl (4S)-4-[3-[4-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin- 3-carbonyl]sulfamoyl]-3-methylpyrazol-1-yl]propyl]-2,2dimethylpyrrolidine-1-carboxylate and tert-butyl (4S)-4-[3-[4-[[2-chloro-6-[ 3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-5-methylpyrazol-1-yl]propyl]-2,2dimethylpyrrolidine-1-carboxylate (mixture regioisomers) (524 mg, 0.6911 mmol), dichloromethane (10 ml) and trifluoroacetic acid (2.7 ml, 35.05 mmol) were added. The reaction was stirred for 1 hour at room temperature. The reaction mixture was then evaporated to dryness and quenched with saturated sodium bicarbonate. The reaction mixture was extracted 3 times with dichloromethane:methanol (9:1), dried over sodium sulfate and evaporated to give 2-chloromethylene chloride. N-[1-[3-[(3S)-5,5dimethylpyrrolidin-3-yl]propyl]-3-methylpyrazol-4-yl]sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl] ethoxy]pyrazol-1-yl]pyridin-3-carboxamide and 2-chloro-N-[1-[3-[(3S)-5,5-dimethylpyrrolidin-3yl]propyl]-5-methylpyrazol-4-yl] sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1 yl]pyridine-3-carboxamide (mixture of regioisomers) (435 mg, 96%). MS-ESI m/z calc. 657.2112, detected 658.3 (M+1) ⁺ ; Retention time: 1.61 min (LC method E).

Step 3: (188)-20,20,22-trimethyl-4-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 yl)-10λ ⁶ -thia-1, 3,9,13,14-pentaazatetracyclo[16.2.1.111,14.02,7]dokose-2,4,6,11(22),12-pentaene-8,10,10trione (atropoisomer 1) (compound 111), ( 18S)-12,20,20-trimethyl-4-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-10Х ⁶ -thia-1,3,9, 13,14pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11 (22),12-pentaene-8,10,10-trione (compound 112) and (188)-20,20,22 -trimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-10Х ⁶ -thia1,3,9,13,14-pentaazatetracyclo[16.2.1.111, 14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (atropoisomer 2) (compound 113)

mixture of regloisomers

atropisomer 1 atropisomer 2

Potassium carbonate (458 mg, 3.314 mmol), cesium fluoride (302 mg, 1.988 mmol) and a solution of 2-chloro-N-[1-[3-[(3S)-5,5-dimethylpyrrolidine- 3-yl]propyl]-3-methylnirazol-4yl]sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide and 2chloro-N-[ 1-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propyl]-5-methylpyrazol-4-yl]sulfonyl-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy] pyrazol-1-yl]pyridin-3-carboxamide (mixture of regioisomers) (435

- 434 044967 mg, 0.6610 mmol) in dimethyl sulfoxide (17.50 ml). The reaction was heated at 160°C overnight. The reaction mixture was cooled to room temperature, filtered and purified by HPLC (3080% acetonitrile in water with hydrochloric acid modifier) to give (18S)-20,20,22-trimethyl-4-(3-{2) as the first elute -[1-(trifluoromethyl)cyclopropyl]ethoxy}1H-pyrazol-1-yl)-1Oλ ⁶ -thia-1,3,9,13,14-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4 ,6,11(22),12pentaene-8,10,10-trione (atropisomer 1) (compound 111) (32.5 mg, 16%).

Ή NMR (400 MHz, DMSO-de) δ 12.39 (s, 1H), 8.18 (d, J=2.8 Hz, 1H), 7.86 (s, 1H), 7.77 (d, J=8.2 Hz, 1H), 6.90 (d, J=8.2 Hz, 1H), 6.10 (d, J=2.7 Hz, 1H), 4.38 (dt, J=14.1, 3.1 Hz, 1H), 4.31 (t, J=7.0 Hz, 2H), 4.01 (td, J=14.0, 2.8 Hz, 1H), 2.06 (k, J=8.0, 7.6 Hz, 5H), 1.90-1.71 (m, 3H), 1.55 (s, 3H), 1.47 (s, 3H), 1.45-1.30 (m, 2H), 1.10 (s, 1H), 0.99-0.93 (m, 2H), 0.93-0.85 (m, 2H). The residual solvent covers three protons. MS-ESI m/z calc. 621.2345, detected 622.3 (M+1)+; retention time: 2.96 min (LC method D).

The second product eluted was (18S)-12,20,20-trimethyl-4-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-10λ ⁶ -thia-1 ,3,9,13,14pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (compound 112) (53.9 mg , 26%).

¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 12.18 (s, 1H), 8.41 (s, 1H), 8.18 (d, J=2.8 Hz, 1H), 7.75 (d, J=8.2 Hz, 1H) , 6.89 (d, J=8.2 Hz, 1H), 6.10 (d, J=2.7 Hz, 1H), 4.31 (t, J=7.0 Hz, 2H), 4.22 (dt, J=13.6, 3.8 Hz, 1H) , 4.03-3.92 (m, 1H), 2.40 (s, 3H), 2.22 (d, J=11.8 Hz, 1H), 2.11-1.91 (m, 5H), 1.83 (dt, J=15.7, 7.4 Hz, 1H ), 1.75 (dd, J=11.9, 5.0 Hz, 1H), 1.51 (d, J=13.0 Hz, 7H), 1.38 (t, J=12.2 Hz, 1H), 1.03 (s, 1H), 0.99-0.84 (m, 4H). MS-ESI m/z calc. 621.2345, detected 622.3 (M+1) ⁺ ; Retention time: 3.01 min (LC method D).

The third product eluted was (18S)-20,2O,22-trimethyl-4-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl) ^-10λ6 -thia-1 ,3,9,13,14pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (atropoisomer 2) (compound 113) ( 12.4 mg, 6%).

1H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 12.10 (s, 1H), 8.18 (d, J=2.8 Hz, 1H), 7.81-7.70 (m, 2H), 6.88 (d, J=8.3 Hz, 1H ), 6.10 (d, J=2.8 Hz, 1H), 4.40-4.26 (m, 3H), 4.00 (ddd, J=13.5, 10.2, 2.7 Hz, 1H), 2.68 (s, 3H), 2.43-2.32 ( m, 1H), 2.07 (t, J=7.1 Hz, 3H), 1.96-1.57 (m, 5H), 1.57 -1.41 (m, 8H), 1.00-0.84 (m, 4H). (2 are covered with residual solvent). MS-ESI m/z calc. 621.2345, detected 622.4 (M+1) ⁺ ; retention time: 3.08 min (LC method D).

Example 147: Preparation of 20,20-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-1Oλ ⁶ -thia-1,3,9,13, 14-pentaazatetraarcyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12pentaene-8,10,10-trione (enantiomer 1) (compound 118) and 20,20-dimethyl-4 -(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-10λ ⁶ -thia-1,3,9,13,14pentaazatetracyclo[16.2.1.111,14.02.7] docose-2,4,6,11(22),12-pentaene-8,10,10-trione (enantiomer 2) (compound 119)

Step 1: 20,2O-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-1Oλ ⁶ thia-1,3,9,13,14 -pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (enantiomer 1) (compound 118) and 20,20-dimethyl- 4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-10λ ⁶ -thia-1,3,9,13,14-pentaazatetracyclo[16.2.1.111,14.02.7 ]docose-2,4,6,11(22),12-pentaene8,10,10-trione (enantiomer 2) (compound 119)

Racemic 20,20-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)10λ ⁶ -thia-1,3,9,13,14-pentaazatetracyclo [16.2.1.111,14.02.7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (57 mg, 0.09287 mmol) was subjected to chiral resolution using SLC chromatography using ChiralPak AS-H (250x10 mm, 5 µm particle size) with a mobile phase of 26% acetonitrile:methanol (90:10; no modifier)/74% carbon dioxide at 10 mL/min for 8.0 min (vol. injection = 70 μl of 24 mg/ml solution in methanol/dimethyl sulfoxide (90:10)) to obtain 20,20-dimethyl-4-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} - as the first eluted enantiomer 1 H-pyrazol-1 -yl)-10λ ⁶ -thia-1,3,9,13,14pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene- 8,10,10-trione (enantiomer 1) (compound 118) (20.76 mg, 74%) as a white solid.

1H NMR (400 MHz, DMSO-de) δ 12.24 (s, 1H), 8.53 (s, 1H), 8.18 (d, J=2.8 Hz, 1H), 7.87 (s, 1H), 7.73 (d, J= 8.2 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 6.09 (d, J=2.7 Hz, 1H), 4.30 (t, J=7.1 Hz, 3H), 4.06 (t, J=11.7 Hz , 1H),

- 435 044967

2.25-2.10 (m, 1H), 2.05 (dt, J=9.6, 5.0 Hz, 4H), 1.93 (dd, J=16.2, 7.1 Hz, 1H), 1.82 (d, J=12.4 Hz, 1H), 1.76 -1.68 (m, 1H), 1.54 (s, 1H), 1.51 (d, J=15.5 Hz, 6H), 1.37 (t, J=12.0 Hz, 1H), 1.08-0.99 (m, 1H), 0.98- 0.92 (m, 2H),

0.91-0.84 (m, 2H). MS-ESI m/z calc. 607.2189, detected 608.2 (M+1)+; retention time: 2.07 min (LC method E).

The second enantiomer eluted was 20,20-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-III-pyrazol-1-yl)-10λ ⁶ -thia-1,3,9,13 ,14-pentaazatetracyclo[16.2.1.111,14.02,7]docose2,4,6,11(22),12-pentaene-8,10,10-trione (enantiomer 2) (compound 119) (17.84 mg, 63 %) as a white solid. MS-ESI m/z calc. 607.2189, detected 608.3 (M+1) ⁺ ; Retention time: 2.07 min (LC method E).

Example 148: Preparation of 21,21-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-10λ ⁶ -thia-1,3,9,13,14 -pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4,6,11(23),12-pentaene-8,10,10trione (compound 122)

Step 1: tert-butyl 2,2-dimethyl-4-[4-(4-sulfamoylpyrazol-1-yl)butyl]pyrrolidine-1-carboxylate

tert-Butyl-2,2-dimethyl-4-(4-methylsulfonyloxybutyl)pyrrolidine-1-carboxylate (600 mg, 1.717 mmol), N-pyrazole-4-sulfonamide (256 mg, 1.740 mmol) and potassium carbonate (850 mg , 6.150 mmol) were combined in N,N-dimethylformamide (15 ml) and stirred at 50°C in a 150 ml sealed vessel for 22 hours. The mixture was cooled to room temperature, poured into water (100 ml) and extracted with ethyl acetate (2x100 ml), combine the organic layers, wash with water (2x100 ml), dry (sodium sulfate), filter and concentrate. The orange residue was purified by silica gel chromatography using a gradient of 100% dichloromethane to 15% methanol in dichloromethane to give tert-butyl-2,2-dimethyl-4-[4-(4-sulfamoylpyrazol-1 -yl) as a colorless oil. butyl]pyrrolidine-1 carboxylate (499 mg, 73%).

Ή NMR (400 MHz, DMSO-de) δ 8.19 (s, 1H), 7.71 (s, 1H), 7.23 (s, 2H), 4.13 (t, J=7.0 Hz, 2H), 3.52 (dd, J= 13.9, 8.6 Hz, 1H), 2.06 (d, J=12.0 Hz, 1H), 1.85 (dd, J=16.8, 10.1 Hz, 1H), 1.80-1.71 (m, 2H), 1.42-1.34 (m, 13H ), 1.32 (d, J=7.2 Hz, 3H), 1.29 (d, J=5.6 Hz, 1H), 1.23 (s, 4H). MS-ESI m/z calc. 400.21442, detected 401.2 (M+1) ⁺ ; retention time: 1.61 min (LC method E).

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

2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (410 mg, 1.091 mmol) and carbonyldiimidazole (177 mg, 1.092 mmol) combined in tetrahydrofuran (6.0 ml) and stirred for 90 min at 50°C. Tert-butyl 2,2-dimethyl-4-[4-(4sulfamoylpyrazol-1-yl)butyl]pyrrolidine-1-carboxylate (257 mg, 0.6416 mmol) was then added followed by 1,8diazabicyclo[5.4.0 ]undec-7-ene (240 μl, 1.605 mmol), and the reaction mixture was heated at 50°C for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and then with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% dichloromethane to 10% methanol in dichloromethane to give tert-butyl 4-[4- as an off-white solid. [4-[[2-chloro-6-[3-[2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1 - 436 044967 yl]pyridin-3-carbonyl]sulfamoyl]pyrazol-1-yl]butyl ]-2,2-dimethylpyrrolidine-1-carboxylate (345 mg, 71%). MS-ESI m/z calc. 757.2636, detected 758.2 (M+1)+; Retention time: 1.93 min (LC method

E).

Step 3: 21,21 -dimethyl-4-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-10λ ⁶ thia-1,3,9,13, 14-pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4,6,11(23),12-pentaene-8,10,10-trione (compound 122)

tert-Butyl 4-[4-[4-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]pyrazol-1 -yl]butyl]-2,2-dimethylpyrrolidine-1-carboxylate (315 mg, 0.4154 mmol) was dissolved in dichloromethane (8.5 ml) and hydrochloric acid (3.25 ml 4 M in dioxane, 13.00) was added to the mixture mmol), and the mixture was stirred at room temperature for 30 minutes. Concentrate the mixture to dryness under reduced pressure, redissolve in ethyl acetate and then add aqueous 2 M sodium carbonate (5 ml), giving a pH of ~ 10. The solution was extracted with ethyl acetate (2x10 ml), washed with brine, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. Combine the resulting material with potassium carbonate (290 mg, 2.098 mmol), cesium fluoride (95 mg, 0.6254 mmol), 3 A molecular sieves and dimethyl sulfoxide (10.0 ml) in a vial, purged with nitrogen, capped, heated to 155° C and stirred for 20 hours. Cooled to room temperature and filtered, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and then with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% dichloromethane to 10% methanol in dichloromethane, followed by a second column gradient of 100% hexanes to 80% ethyl acetate in hexanes to obtain 21,21-dimethyl-4-(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 yl)-10λ ⁶ -thia-1,3 as a white solid 9,13,14-pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4,6,11(23),12-pentaene-8,10,10trione (compound 122) (131 mg, 50%).

1H NMR (400 MHz, DMSO-th ₆ ) δ 12.34 (s, 1H), 8.83 (s, 1H), 8.21 (d, J=2.7 Hz, 1H), 7.94 (s, 1H), 7.81 (d, J =8.4 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.12 (d, J=2.6 Hz, 1H), 4.44 (td, J=11.3, 3.3 Hz, 1H), 4.31 (t, J =7.0 Hz, 2H), 4.19 (dd, J=19.3, 5.9 Hz, 1H), 2.97 (t, J=9.5 Hz, 1H), 2.33 (dd, J=12.1, 8.3 Hz, 1H), 2.08 (t , J=6.9 Hz, 4H), 1.85 (dd, J=11.6, 5.2 Hz, 1H), 1.59 (s, 4H), 1.54 (d, J=9.8 Hz, 4H), 1.48 (d, J=9.2 Hz , 1H), 1.27 (dd, J=21.2, 8.7 Hz, 2H), 0.95 (k, J=7.1 Hz, 2H), 0.90 (d, J=10.6 Hz, 2H), 0.02 - -0.08 (m, 1H ). MS-ESI m/z calc. 621.2345, detected 622.3 (M+1) ⁺ ; retention time: 2.16 min (LC method E).

Example 149: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-2λ ⁶ -thia-3,9,11,19,22 -pentaazatetracyclo[18.2.2.111,14.05,10]pentacose-1(22),5(10),6,8,20,23hexaene-2,2,4-trione (compound 123)

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

In a sealed 5 ml vial, a solution of tert-butyl 4-(4-aminobutyl)-2,2 dimethylpyrrolidine-1-carboxylate (507 mg, 1.875 mmol), 5-fluoropyridine-2-sulfonamide (300 mg, 1.703 mmol) and diisopropylethylamine (1.5 ml, 8.612 mmol) in n-BuOH (3 ml) was stirred at 160°C for

- 437 044967 16 h. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and washed with water. The organic extract was dried over sodium sulfate, filtered, evaporated and purified by silica gel chromatography (0% to 40% ethyl acetate in hexanes) to give tert-butyl-2,2-dimethyl-4-[4-[(6sulfamoyl-3-pyridyl )amino]butyl]pyrrolidine-1-carboxylate (210 mg, 29%). MS-ESI m/z calc. 426.23007, detected 427.26 (M+1)+; Retention time: 1.73 min (LC method c).

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

2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxylic acid (278 mg, 0.7399 mmol) and carbonyldiimidazole (120 mg, 0 .7401 mmol) were combined in tetrahydrofuran (6 ml) and stirred for 90 min at 50°C. Then a solution of tert-butyl-2,2-dimethyl-4[4-[(6-sulfamoyl-3-pyridyl)amino]butyl]pyrrolidine-1-carboxylate (210 mg, 0.4923 mmol) and 1,8diazabicyclo[ 5.4.0]undec-7-ene (190 mg, 1.248 mmol) in tetrahydrofuran (3 ml). The reaction was heated at 50°C overnight. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered and evaporated, then purified by preparative reverse phase HPLC ( _C18 , 1% to 99% acetonitrile in water modified with hydrochloric acid to give tert-butyl 4-[4-[[6-[ [2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl]-3-pyridyl]amino]butyl]-2,2-dimethylpyrrolidine -1-carboxylate (264.4 mg, 68%) ESI-MS m/z calculated 783.27924, found 784.39 (M+1)+, retention time: 0.91 min (LC method A).

Step 3: 12,12-dimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-nirazol-1-yl)-2λ ⁶ -thia3,9,11,19,22 -pentaazatetracyclo[18.2.2.111,14.05,10]pentacose-1(22),5(10),6,8,20,23-hexaene-2,2,4-trione (compound 123)

tert-Butyl 4-[4-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin3-carbonyl]sulfamoyl]3- pyridyl]amino]butyl]-2,2-dimethylpyrrolidine-1-carboxylate (260 mg, 0.3315 mmol) was dissolved in dichloromethane (5 ml), and hydrochloric acid (2.5 ml 4 M in dioxane, 10 .00 mmol), and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was concentrated to dryness under reduced pressure and the resulting intermediate was combined with potassium carbonate (230 mg, 1.664 mmol), cesium fluoride (80 mg, 0.5266 mmol), 3 A molecular sieves (300 mg) and dimethyl sulfoxide (3 ml) in a vial volume of 5 ml, which was purged with nitrogen and stirred at 150°C overnight. The mixture was cooled to room temperature, filtered and purified by preparative reverse phase HPLC ( _C18 , 1% to 99% acetonitrile in water modified with hydrochloric acid to give 12,12-dimethyl-8-(3-{2-[1( trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-2λ ⁶ -thia-3,9,11,19,22pentaazatetracyclo[18.2.2.111,14.05,10]pentacose-1(22),5 (10 ), 6,8,20,23-hexaene-2,2,4-trione (compound 123) (8.7 mg, 4%). ESI-MS m/z calculated 647.2502, found 648.34 ( M+1) ⁺ ; retention time: 2.2 min (LC method B).

Example 150: Preparation of 21,21-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-10λ ⁶ -thia-1,3,9,13,14 -pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4,6,11(23),12-pentaene-8,10,10trione (enantiomer 1) (compound 134) and 21,21-dimethyl-4- (3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-10λ ⁶ -thia-1,3,9,13,14-pentaazatetracyclo[17.2.1.111,14.02, 7]tricose2,4,6,11(23),12-pentaene-8,10,10-trione (enantiomer 2) (compound 135)

Step 1: 21,21 -dimethyl-4-(3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-10λ ⁶ - 438 044967 thia-1,3,9 ,13,14-pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4,6,11(23),12-pentaene-8,10,10-trione (enantiomer 1) (compound 134) and 21, 21-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-10λ ⁶ -thia-1,3,9,13,14-pentaazatetracyclo[17.2.1.111 ,14.02,7]tricose-2,4,6,11(23),12pentaene-8,10,10-trione (enantiomer 2) (compound 135)

Racemic 21,21 -dimethyl-4-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)10Х ⁶ -thia-1,3,9,13,14- pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4,6,11(23),12-pentaene-8,10,10-trione (100 mg, 0.1592 mmol) was subjected to chiral SLC chromatography (ChiralPak AS-H (250x10 mm), 5 µM column; mobile phase=34% acetonitrile/methanol (90:10, unmodified), 66% carbon dioxide, 10 ml/min; concentration 24 mg/ml in acetonitrile/methanol/dimethyl sulfoxide (80:10:10; no modifier); injection volume 70 µl, 100 bar). The first enantiomer eluted was 21,21dimethyl-4-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-10X ⁶ -thia-1,3,9,13, 14pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4,6,11(23),12-pentaene-8,10,10-trione (enantiomer 1) (compound 134) (24.1 mg, 49% ) as a white solid. MS-ESI m/z calc. 621.2345, detected 622.3 (M+1)+; Retention time: 2.16 min (LC method E).

The second enantiomer eluted was 21,21-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-10λ ⁶ -thia-1,3,9,13 ,14-pentaazatetracyclo[17.2.1.111,14.02,7]tricose2,4,6,11(23),12-pentaene-8,10,10-trione (enantiomer 2) (compound 135) (25.4 mg, 51 %) as a white solid. MS-ESI m/z calc. 621.2345, detected 622.3 (M+1) ⁺ ; Retention time: 2.16 min (LC method E).

Example 151: preparation of 12,12,18-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hπpyrazol-1-yl)-2λ ⁶ -thia-3,9,11, 18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (enantiomer 1) (compound 138) and 12,12,18-trimethyl-8-(3-{2[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo [17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (enantiomer 2) (compound 139)

Step 1: 12,12,18-trimethyl-8-(3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-2X ⁶ thia-3,9,11, 18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4trione (enantiomer 1) (compound 138) and 12,12,18-trimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1 -yl)-2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (enantiomer 2) (compound 139)

Racemic 12,12,18-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-7H-pyrazol-1yl)-2λ ⁶ -thia-3,9,11,18,23- pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene2,2,4-trione (29 mg) was subjected to chiral resolution using SLC chromatography using a Phenomenex LUX-4 column (250x10 mm), 5 µm particle size with a mobile phase of 22% methanol (0.1% trifluoroacetic acid), 78% carbon dioxide at 10 ml/min for 6.0 min (injection volume= 70 µl ~ 24 mg/ml in a mixture of methanol:dimethyl sulfoxide (85:15)) obtaining 12,12,18-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy as the first eluted enantiomer }1H-nirazol-1-yl)-2λ ⁶ -thia-3,9,11,18,23-nentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5(10),6,8,19 ,21-hexaene-2,2,4-trione (enantiomer 1) (compound 138) (7.1 mg, 49%); MS-ESI m/z calc. 647.2502, detected 648.34 (M+1) ⁺ ; Retention time: 2.38 min (LC method B) and as the second enantiomer eluted 12,12,18-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl )-2Х ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5(10),6,8,19,21-hexaene-2,2 ,4-trione (enantiomer 2) (compound 139) (9.4 mg, 55%); MS-ESI m/z calc. 647.2502, detected 648.42 (M+1) ⁺ ; Retention time: 2.38 min (LC method B).

Example 152: preparation of 12,12,18-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H- 439 044967 pyrαzol-1-yl)-2λ ⁶ -thia-3, 9,11,18,20-pentaazatetracyclo[17.2.2.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 140)

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

6-chloropyridine-3-sulfonamide (261 mg, 1.355 mmol) was added to a 20 mL vial filled with tert-butyl-2,2-dimethyl-4-[3-(methylamino)propyl]pyrrolidine-1-carboxylate (350 mg, 1.294 mmol). ), potassium carbonate (256 mg, 1.852 mmol) and dimethyl sulfoxide (4 ml). The headspace was purged with nitrogen, the tube was capped and the reaction mixture was stirred at 120°C for 18 hours. Cooled to room temperature, diluted with ethyl acetate (~40 ml) and the crude mixture was washed with water (10 ml), saline (5 ml) and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica, shallow gradient from 100% hexanes to 100% ethyl acetate) gave tert-butyl-2,2-dimethyl-4-[3-[methyl-(5-sulfamoyl-2pyridyl)amino]propyl]pyrrolidine-1 -carboxylate (109 mg, 20%) as an off-white solid. MS-ESI m/z calc. 426.23007, detected 427.2 (M+1)+; retention time: 1.49 min (LC method B).

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

Into a 20 ml vial filled with 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (106 mg, 0.2821 mmol) carbonyldiimidazole (47 mg, 0.2899 mmol) and tetrahydrofuran (2 ml) were added. The vessel was sealed and the reaction mixture was stirred at room temperature for 2 hours. At this point, tert-butyl-2,2-dimethyl-4-[3[methyl-(5-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine- 1-carboxylate (109 mg, 0.2555 mmol) in tetrahydrofuran (2 ml), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (60 µl, 0.4012 mmol). The reaction mixture was stirred at room temperature for 18 h and quenched with water (~4 ml). Aqueous citric acid (~4 ml, 1 M) was added and the crude mixture was extracted with ethyl acetate (3x10 ml). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. Column chromatography (silica, gradient from 100% hexanes to 100% ethyl acetate) gave tert-butyl 4-[3-[[5-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl ]ethoxy]pyrazol-1-yl]pyridin3-carbonyl]sulfamoyl]-2-pyridyl]methylamino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (87 mg, 43%) as an off-white solid. MS-ESI m/z calc. 783.27924, detected 784.4 (M+1) ⁺ ; retention time: 2.42 min (LC method B).

- 440 044967

Step 3: 2-chloro-N-[[6-[3-(5,5-dimethyln-pyrrolidin-3-yl)propyl-methyl-amino]-3pyridyl]sulfonyl]-6-[3-[2-[ 1 - (trifluoromethyl)cyclopropyl] ethoxy] pyrazol-1 -yl] pyridin-3 carboxamide

Into a bottle with tert-butyl 4-[3-[[5-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl ]-2-pyridyl]-methylamino]propyl]-2,2-dimethyl-pyrrolidine-1carboxylate (87 mg, 0.1109 mmol) was added dichloromethane (5 ml) followed by hydrochloric acid (1 ml 4 M, 4.000 mmol) in dioxane. The vessel was sealed and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo to give crude 2-chloro-N-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propylmethylamino] -3-pyridyl]sulfonyl]-6[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (75 mg, 99%) as a pale yellow solid , which was used without further purification. MS-ESI m/z calc. 683.2268, detected 684.1 (M+1)+; retention time: 1.61 min (LC method B).

Step 4: 12,12,18-trimethyl-8-(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-2λ ⁶ thia-3,9,11, 18,20-pentaazatetracyclo[17.2.2.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4trione (compound 140)

Potassium carbonate (140 mg, 1.013 mmol) and CsF (131 mg, 0.8624 mmol) were loaded into a vial with a stirrer. A solution of 2-chloro-N-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propylmethylamino]-3pyridyl]sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl] was added ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (70 mg, 0.1023 mmol) in dimethyl sulfoxide (10 ml), the vessel was sealed and the reaction mixture was stirred at 200°C for 1.5 hours in a microwave reactor. After cooling to room temperature, the solids were filtered off using ethyl acetate as eluent. The filtrate was diluted with ethyl acetate (~60 ml), washed with 1.0 M aqueous citric acid (10 ml) and brine (5 ml), and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica, 0% to 5% methanol in dichloromethane gradient) gave 12,12,18-trimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol- 1 -yl)-2λ ⁶ -thia3,9,11,18,20-pentaazatetracyclo[17.2.2.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene- 2,2,4 trione (compound 140) (9 mg, 12%) as an off-white solid. MS-ESI m/z calc. 647.2502, detected 648.2 (M+1) ⁺ ; retention time: 2.21 min (LC method B).

Example 153: preparation of 4-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-20,20-dimethyl-10λ ⁶ thia-1,3,9,14,22-pentaazatetracyclo[16.2. 1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (compound 141)

Step 1: tert-butyl 4-[3-[3-[[2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]pyrazol-1-yl] propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

- 441 044967

2-Chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (107.6 mg, 0.2975 mmol) and carbonyldiimidazole (57.89 mg, 0.3570 mmol) were combined in tetrahydrofuran (2 ml) and stirred for 90 min at 50°C. Tert-butyl 2,2-dimethyl-4-[3-(3-sulfamoylpyrazol-1yl)propyl]pyrrolidine-1-carboxylate (115 mg, 0.2975 mmol) was then added followed by 1,8-diazabicyclo[5.4 .0]undec-7-ene (67.94 mg, 66.74 μL, 0.4463 mmol), and the reaction mixture was stirred at room temperature for 18 hours. The reaction was diluted with ethyl acetate and washed with saturated ammonium chloride solution, followed by washing saline solution. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a gradient of 100% hexanes to 100% ethyl acetate to give tert-butyl-4-[3-[3-[[2-chloro- 6-[3-(3,3dicyclopropylpropoxy)pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]pyrazol-1-yl]propyl]-2,2dimethylpyrrolidine-1-carboxylate (145 mg, 67%) as white solid matter.

¹ H NMR (400 MHz, chloroform-d) δ 9.75 (s, 1H), 8.30 (d, J=2.9 Hz, 1H), 8.27-8.20 (m, 1H), 7.75 (d, J=8.4 Hz, 1H ), 7.48 (t, J=3.1 Hz, 1H), 7.05 (d, J=2.5 Hz, 1H), 5.97 (d, J=2.9 Hz, 1H), 4.43 (t, J=6.8 Hz, 2H), 4.20 (t, J=7.0 Hz, 2H), 3.64 (dt, J=42.1, 9.1 Hz, 1H), 2.91-2.75 (m, 1H), 2.07 (s, 1H), 1.97 (k, J=6.8 Hz , 2H), 1.91 (t, J=7.7 Hz, 1H), 1.84 (dd, J=12.1, 5.9 Hz, 1H), 1.69-1.54 (m, 4H), 1.43 (d, J=4.6 Hz, 11H) , 1.37-1.22 (m, 6H), 0.67 (qt, J=8.4, 5.1 Hz, 2H), 0.50-0.38 (m, 4H), 0.32 (tt, J=9.0, 6.8 Hz, 1H), 0.20 (dtd , J=9.5, 4.9, 3.6 Hz, 2H), 0.14-0.06 (m, 2H).

MS-ESI m/z calc. 729.30756, detected 730.37 (M+1)+; Retention time: 0.91 min (LC method A).

Step 2: 4-[3-(3,3-diciclopropylpropoxy)-1H-pyrazol-1-yl]-20,20-dimethyl-10λ ⁶ -thua-1,3,9,14,22pentaazatetracyclo[16.2.1.111, 14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (compound 141)

Tert-butyl-4-[3-[3-[[2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]pyrazol-1-yl]propyl solution ]-2,2-dimethylpyrrolidine-1-carboxylate (145 mg, 0.1985 mmol) in dichloromethane (1 ml) and trifluoroacetic acid (150 μl, 1.960 mmol) was stirred at room temperature for 4 hours. Solvents were removed and the residue was dissolved in ethyl acetate. Washed with 2 ml saturated sodium bicarbonate solution, the organic layer was collected and the solvent was removed, followed by drying the residue in vacuo. The above residue was dissolved in dimethyl sulfoxide (3 ml), 3 A molecular sieves were added and the reaction mixture was stirred for 10 minutes. Cesium fluoride (94 mg, 0.6188 mmol) and potassium carbonate (86 mg, 0.6223 mmol) were then added and the reaction mixture was heated at 150°C overnight. The reaction mixture was filtered through a Whatman disc filter (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS using a dual gradient from 50% to 99% mobile phase B over 15.0 min (mobile phase A = water (0 .05% hydrochloric acid), mobile phase B = acetonitrile) to obtain 4-[3-(3,3dicyclopropylpropoxy)-1 H-pyrazol-1 -yl]-20,20-dimethyl-10λ ⁶ -thia-1,3 ,9,14,22pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11 (22),12-pentaene-8,10,10-trione (compound 141) (26 mg, 22%) as a white solid.

1H NMR (400 MHz, chloroform-d) δ 8.62 (s, 1H), 8.17 (d, J=2.8 Hz, 1H), 7.67 (d, J=8.2 Hz, 1H), 7.48 (d, J=2.3 Hz , 1H), 7.07 (d, J=2.3 Hz, 1H), 7.02 (d, J=8.3 Hz, 1H), 5.87 (d, J=2.8 Hz, 1H), 4.41 (t, J=6.8 Hz, 2H ), 4.35 (dt, J=13.3, 3.4 Hz, 1H), 4.00-3.87 (m, 1H), 2.75 (t, J=8.2 Hz, 1H), 2.25-1.87 (m, 3H), 1.80-1.71 ( m, 1H), 1.62 (s, 4H), 1.59 (s, 3H), 1.55 (s, 3H), 1.47 (t, J=12.3 Hz, 1H), 0.80 (dd, J=12.5, 6.7 Hz, 1H ), 0.73-0.60 (m, 2H), 0.52-0.38 (m, 4H), 0.38-0.28 (m, 1H), 0.24-0.15 (m, 2H), 0.11 (dddd, J=8.6, 7.2, 3.9, 2.6 Hz, 2H). MS-ESI m/z calc. 593.27844, detected 594.2 (M+1) ⁺ ; retention time: 1.82 min (LC method G).

Example 154: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-2λ ⁶ -thia-3,9,11,21-tetraazatetracyclo [18.2.2.111,14.05,10]pentacose-1(23),5,7,9,20(24),21-hexaene2,2,4-trione (compound 142)

- 442 044967

Step 1: tert-butyl 2,2-dimethyl-4-(4-oxobutyl)pyrrolidine-1-carboxylate

Dess-Martin periodinane (9.59 g, 22.61 mmol) was added to a stirred solution of tert-butyl 4-(4-hydroxybutyl)-2,2-dimethylpyrrolidine-1-carboxylate (5.2 g, 19.16 mmol) in anhydrous CH ₂ Cl ₂ (35 ml) at 0°C (ice bath) under a nitrogen atmosphere. After 15 minutes, the reaction mixture was allowed to warm to ambient temperature and stirring was continued for another 3 hours. The reaction mixture was diluted with ether (200 ml) and saturated aqueous sodium bicarbonate (100 ml) was added slowly (to reduce the evolution of carbon dioxide gas). 10% sodium thiosulfate (50 ml) was then added and the mixture was stirred at ambient temperature for 30 minutes. The layers were not clearly separated, so the mixture was filtered through a fritted filter funnel. The layers were separated from the filtrate and the aqueous layer was extracted with ether (2x100 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude material. The crude product was purified by silica gel chromatography (5-40% ethyl acetate in hexanes gradient) to give the desired tert-butyl 2,2-dimethyl-4-(4-oxobutyl)pyrrolidine-1-carboxylate (4.39 g, 85%) in the form of a transparent viscous material.

¹ H NMR (400 MHz, Methanol-d4) δ 4.48 (t, J=5.5 Hz, 1H), 3.64 (h, J=4.8 Hz, 1H), 2.86 (td, J=10.6, 5.2 Hz, 1H), 2.30 (t, J=7.3 Hz, 1H), 2.22-2.06 (m, 1H), 1.95 (ddt, J=17.2, 11.6, 5.8 Hz, 1H), 1.67-1.53 (m, 2H), 1.531.48 ( m, 2H), 1.47 (s, 4H), 1.43 (s, 5H), 1.40 (s, 3H), 1.39-1.34 (m, 2H), 1.31 (s, 3H). MS-ESI m/z calc. 269.1991, detected 270.2 (M+1)+; Retention time: 1.7 min (LC method B).

Step 2: tert-butyl 2,2-dimethyl-4-pent-4-ynyl-pyrrolidine-1-carboxylate

To a stirred solution of tert-butyl 2,2-dimethyl-4-(4-oxobutyl)pyrrolidine-1-carboxylate (3.0 g, 11.14 mmol) in anhydrous methanol (40 ml) at 0°C (bath ice) potassium carbonate (3.39 g, 24.53 mmol) was added followed by dropwise addition of 1-diazo-1-dimethoxyphosphorylpropan-2-one (2.1 mL, 13.99 mmol). Once addition was complete, the mixture was allowed to warm to room temperature and stirred for 16 hours (the reaction was complete within 4 hours). The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate (50 ml) and washed with brine (20 ml). The aqueous layer was again extracted (2x20 ml) with ethyl acetate and the organic layers were combined, washed with brine (20 ml), dried (over anhydrous sodium sulfate), filtered and concentrated to a clear oil, which was purified by silica gel chromatography (0-20 gradient). % ethyl acetate in hexanes) gave the desired tert-butyl-2,2-dimethyl-4-pent-4-ynylpyrrolidine-1-carboxylate (2.29 g, 77%) as a clear oil.

¹ H NMR (400 MHz, Methanol-d4) δ 3.72-3.57 (m, 1H), 2.86 (t, J=10.7 Hz, 1H), 2.27-2.07 (m, 4H), 1.95 (ddd, J=16.7, 12.2, 6.1 Hz, 1H), 1.58-1.48 (m, 4H), 1.47 (s, 5H), 1.43 (s, 5H), 1.41 (s, 2H), 1.31 (s, 3H). MSIE m/z calc. 265.2042, detected 266.2 (M+1) ⁺ ; retention time: 1.77 min (LC method B).

Step 3: tert-butyl 2,2-dimethyl-4-[5-(5-sulfamoyl-2-pyridyl)pent-4-ynyl]pyrrolidine-1-carboxylate

- 443 044967

A dry 20 ml bottle was loaded with tert-butyl-2,2-dimethyl-4-pent-4-inylpyrrolidine-1-carboxylate (700 mg, 2.638 mmol), 6-chloropyridine-3-sulfonamide (900 mg, 4.672 mmol), copper iodide (51 mg, 0.2678 mmol), bis(triphenylphosphine) palladium chloride (112 mg, 0.1596 mmol) and anhydrous N,Ndimethylformamide (6 ml) in that order. Nitrogen was then bubbled through the stirred dark mixture for 3 minutes, diisopropylamine (700 μL, 4.995 mmol) was added and the vessel was sealed under nitrogen. The reaction mixture was stirred at 52°C for 11 hours, then cooled to ambient temperature, poured into water (100 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed successively with water (2x50 ml) and brine (30 ml), dried (over anhydrous sodium sulfate), filtered and concentrated under reduced pressure to an orange oil, which was purified by silica gel chromatography using a gradient of 15-50% ethyl acetate in hexanes to obtain the desired tert-butyl 2,2-dimethyl-4-[5-(5-sulfamoyl-2pyridyl)pent-4-ynyl]pyrrolidine-1-carboxylate (699 mg, 63%) as a white solid .

Ή NMR (400 MHz, Methanol-d4) δ 8.91 (dd, J=2.4, 0.9 Hz, 1H), 8.20 (dd, J=8.3, 2.4 Hz, 1H), 7.60 (dd, J=8.2, 0.9 Hz, 1H), 3.71-3.63 (m, 1H), 2.90 (t, J=10.7 Hz, 1H), 2.53 (t, J=6.8 Hz, 2H), 2.28-2.14 (m, 1H), 2.031.92 (m , 1H), 1.74-1.62 (m, 2H), 1.62-1.50 (m, 3H), 1.47 (s, 5H), 1.43 (s, 5H), 1.42 (s, 2H), 1.32 (s, 3H). MS-ESI m/z calc. 421.20352, detected 422.3 (M+1)+; retention time: 1.74 min (LC method B).

Step 4: tert-butyl 2,2-dimethyl-4-[5-(5-sulfamoyl-2-pyridyl)pentyl]pyrrolidine-1carboxylate nh ₂ PR ¹ S Λ ^{= O} Η ₂ Ν Ίι Ί

ΓΥ ό I J

Vos. VosΝ]

Nitrogen was bubbled through a stirred solution of tert-butyl 2,2-dimethyl-4-[5-(5-sulfamoyl-2pyridyl)pent-4-ynyl]pyrrolidine-1-carboxylate (698 mg, 1.656 mmol) in ethanol (20 ml ). Platinum oxide (76 mg, 0.3347 mmol) was then added under a nitrogen atmosphere and the reaction mixture was stirred under a hydrogen atmosphere (balloon) at ambient temperature. After 2 hours, more platinum oxide (110 mg, 0.4844 mmol) was added and the reaction mixture was stirred for another 3 hours. The reaction mixture was then purged with nitrogen, 5 g of celite was added and stirred for 20 minutes. The heterogeneous mixture was filtered through a layer of celite. The filtrate was concentrated under reduced pressure to give the crude material, which was purified by silica gel chromatography (5-50% ethyl acetate in hexanes gradient) to give tert-butyl-2,2-dimethyl-4-[5-(5-sulfamoyl-2-pyridyl )pentyl]pyrrolidine-1-carboxylate (655 mg, 93%) as a white solid.

¹ H NMR (400 MHz, Methanol-d4) δ 8.90 (dd, J=2.4, 0.8 Hz, 1H), 8.17 (dd, J=8.2, 2.4 Hz, 1H), 7.47 (dd, J=8.2, 0.8 Hz , 1H), 3.66-3.58 (m, 1H), 2.91-2.80 (m, 3H), 2.19-2.05 (m, 1H), 1.98-1.86 (m, 1H), 1.75 (p, J=7.4 Hz, 2H ), 1.47 (s, 5H), 1.43 (s, 4H), 1.42 (s, 2H), 1.40 (s, 2H), 1.36 (s, 6H), 1.30 (s, 3H). MS-ESI m/z calc. 425.23483, detected 426.3 (M+1) ⁺ ; retention time: 1.73 min (LC method B).

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

To a solution of 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]irazol-1-yl]pyridin-3-carboxylic acid (440 mg, 1.171 mmol) in dry tetrahydrofuran (6 ml) was added carbonyldiimidazole (195 mg, 1.203 mmol) at ambient temperature under nitrogen atmosphere. The mixture was stirred at this temperature for 3 hours to form an activated acid. A solution of tert-butyl-2,2-dimethyl-4-[5-(5-sulfamoyl-2-pyridyl) pentyl]pyrrolidine-1-carboxylate (500 mg, 1.175 mmol) in dry tetrahydrofuran (4 ml) was added to the activated acid solution ), then 1,8diazabicyclo[5.4.0]undec-7-ene (400 μL, 2.675 mmol), and the mixture was stirred at ambient temperature for 15 h. Volatiles were removed under reduced pressure and the thick residue was partitioned between water (15 ml) and ethyl acetate (30 ml). The mixture was acidified with aqueous 4 M hydrochloride

- 444 044967 native acid to pH ~ 3-4 and the layers were separated. The organic phase was washed with brine (20 ml) and the combined aqueous layers were re-extracted with ethyl acetate (30 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude material. The crude product was chromatographed (silica gel column, eluting with a gradient of 0-80% ethyl acetate in hexanes) to give tert-butyl-4-[5-[5[[2-chloro-6-[3-[2-[1-(trifluoromethyl )cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]2-pyridyl]pentyl]-2,2-dimethylpyrrolidine-1-carboxylate (750 mg, 82%) as a white foam.

¹ H NMR (400 MHz, Methanol-d4) δ 9.02 (dd, J=2.3, 0.8 Hz, 1H), 8.69 (s, 1H), 8.32 (d, J=1.0 Hz, 1H), 8.32-8.29 (m , 1H), 7.98 (d, J=8.3 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.49 (d, J=1.3 Hz, 1H), 7.45 (dd, J=8.2, 0.8 Hz , 1H), 5.97 (d, J=2.8 Hz, 1H), 4.43-4.33 (m, 2H), 3.67-3.56 (m, 1H), 2.86 (t, J=7.7 Hz, 2H), 2.83 (d, J=11.1 Hz, 1H), 2.10 (t, J=7.0 Hz, 2H), 1.92 (td, J=13.9, 13.4, 6.0 Hz, 1H), 1.80-1.69 (m, 2H), 1.46 (s, 5H ), 1.42 (s, 4H), 1.41 (s, 2H), 1.39 (s, 3H), 1.36 (s, 6H), 1.29 (s, 3H), 1.03-0.96 (m, 2H), 0.82 (tt, J=5.4, 2.9 Hz, 2H). MS-ESI m/z calc. 782.284, detected 783.4 (M+1)+; retention time: 2.42 min (LC method B).

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

To a solution of tert-butyl 4-[5-[5-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl]- 2-pyridyl]pentyl]-2,2-dimethylpyrrolidine-1-carboxylate (750 mg, 0.9575 mmol) in anhydrous CH ₂ Cl ₂ (15 ml) was added hydrochloric acid (6.0 ml, 4.0 M in dioxane , 24.00 mmol) at 0°C (ice bath) under nitrogen atmosphere. After 5 minutes, the bath was removed and stirring was continued at room temperature for another 20 minutes. The reaction mixture was concentrated to dryness under reduced pressure. The residue was taken into ethyl acetate (30 ml) and the pH was adjusted to ~5 by adding saturated aqueous sodium bicarbonate. The layers were separated and the aqueous portion was re-extracted with ethyl acetate (2x20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to dryness to give 2-chloro-N-[[6-[5-(5,5-dimethylpyrroligin-3-yl)pentyl]-3 -pyrigyl]sulfonyl]-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (dihydrochloride salt) (720 mg, 99%) as a white solid . MS-ESI m/z calc. 682.23157, detected 683.4 (M+1) ⁺ ; retention time: 1.65 min (LC method B).

Step 7: 12,12-dimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1-yl)-2λ ⁶ -thia3,9,11,21-tetraazatetracyclo [18.2.2.111,14.05,10]pentacose-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (compound 142)

OOO

A 20 ml bottle was loaded with 2-chloro-N-[[6-[5-(5,5-dimethylpyrroligin-3-yl)pentyl]-3pyridyl]sulfonyl]-6-[3-[2-[1-(trifluoromethyl )cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (dihydrochloride salt) (715 mg, 0.9456 mmol), potassium carbonate (650 mg, 4.703 mmol), cesium fluoride (215 mg, 1.415 mmol) and anhydrous dimethyl sulfoxide (15 ml). The vessel was purged with nitrogen for 2 minutes, capped and stirred at 165°C for 24 hours. The reaction mixture was allowed to cool to ambient temperature and then diluted with ethyl acetate (50 ml) and ice water (50 ml). The layers were separated and the organic phase was washed with saturated aqueous sodium bicarbonate (20 ml). The aqueous layers were extracted with ethyl acetate (50 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to dryness. The crude product was purified by silica gel chromatography (0%-55% ethyl acetate in hexanes gradient) followed by a second silica gel column (0%-10% methanol in dichloromethane) to give 12,12-dimethyl-8-(3-{2-[ 1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-2λ ⁶ -thia-3,9,11,21tetraazatetracyclo[18.2.2.111,14.05,10]pentacose-1(23),5,7 ,9,20(24),21-hexaene-2,2,4-trione (compound 142) (221 mg, 36%) as a white solid.

- 445 044967

1H NMR (400 MHz, DMSO^b) δ 12.56 (s, 1H), 9.02 (s, 1H), 8.31 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.93 (d, J= 8.2 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 6.95 (d, J=8.3 Hz, 1H), 6.12 (d, J=2.7 Hz, 1H), 4.32 (t, J=7.0 Hz , 2H), 3.08-2.93 (m, 1H), 2.91-2.78 (m, 1H), 2.49-2.41 (m, 1H), 2.08 (t, J=7.0 Hz, 2H), 2.02-1.87 (m, 3H ), 1.85-1.66 (m, 2H), 1.55 (s, 4H), 1.49 (s, 3H), 1.43 (t, J=11.9 Hz, 1H), 1.33-1.22 (m, 2H), 0.96 (k, J=4.8, 4.2 Hz, 2H), 0.92-0.87 (m, 2H), 0.85 (s, 1H), 0.62 (s, 1H), -0.31 (s, 1H). MS-ESI m/z calc. 646.2549, detected 647.5 (M+1)+; retention time: 1.94 min (LC method B).

Example 155: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-2λ ⁶ -thia-3,9,11,22-tetraazatetracyclo [18.2.2.111,14.05,10]pentacose-1(23),5,7,9,20(24),21-hexaene2,2,4-trione (compound 143)

1: tert-butyl 2,2-dimethyl-4-[5-(6-sulfamoyl-3-pyridyl)pent-4-ynyl]pyrrolidine-1 Carboxylate step

A dry 20 ml bottle was loaded with tert-butyl-2,2-dimethyl-4-pent-4-inylpyrrolidine-1-carboxylate (600 mg, 2.261 mmol), 5-bromopyridine-2-sulfonamide (640 mg, 2.700 mmol), copper(I) iodide (44 mg, 0.2310 mmol), bis(triphenylphosphine)palladium(II) dichloride (96 mg, 0.1368 mmol) and anhydrous N,Ndimethylformamide (6 ml) in that order. Nitrogen was then bubbled through the stirred dark mixture for 3 min, diisopropylamine (450 μL, 3.211 mmol) was added and the vessel was sealed under nitrogen. The reaction mixture was stirred at 52°C for 12 hours, then cooled to ambient temperature, poured into water (80 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed successively with water (2x50 ml) and brine (30 ml), dried (over anhydrous sodium sulfate), filtered and concentrated under reduced pressure to an orange oil, which was purified by silica gel chromatography using a gradient of 15%-50% ethyl acetate in hexanes to obtain the desired tert-butyl 2,2-dimethyl-4-[5-(6-sulfamoyl-3pyridyl)pent-4-ynyl]pyrrolidine-1-carboxylate (889 mg, 93%) as a white solid substances. MSIE m/z calc. 421.20352, detected 422.3 (M+1) ⁺ ; Retention time: 0.72 min (LC method A).

Step 2: tert-butyl 2,2-dimethyl-4-[5-(6-sulfamoyl-3-pyridyl)pentyl]pyrrolidine-1-carboxylate

Nitrogen gas was bubbled through a stirred solution of tert-butyl 2,2-dimethyl-4-[5-(6sulfamoyl-3-pyridyl)pent-4-ynyl]pyrrolidine-1-carboxylate (883 mg, 2.095 mmol) in ethanol (20 ml). Platinum(IV) oxide (240 mg, 1.057 mmol) was then added under a nitrogen atmosphere and the reaction mixture was stirred under a hydrogen atmosphere (balloon) at ambient temperature. After stirring for 2.5 hours, the reaction mixture was purged with nitrogen, 5 g of celite was added and stirred for 20 minutes. The heterogeneous mixture was filtered through a layer of celite. The dark filtrate was concentrated under reduced pressure, the residue was dissolved in methylene chloride and filtered again through a pad of silica gel

- 446 044967 for removing residual platinum black material. After concentration under reduced pressure, the crude product was purified by silica gel chromatography (5-50% ethyl acetate in hexanes) to obtain the desired tert-butyl-2,2-dimethyl-4-[5-(6-sulfamoyl-3-pyridyl)pentyl]pyrrolidine -1 carboxylate (882 mg, 99%) as a white solid. MS-ESI m/z calc. 425.23483, detected

426.3 (M+1)+; retention time: 1.67 min (LC method B).

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

Carbonyldiimidazole was added to a solution of 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3carboxylic acid (773 mg, 2.057 mmol) in anhydrous tetrahydrofuran (8 ml) (340 mg, 2.097 mmol) at ambient temperature under nitrogen atmosphere. The mixture was stirred at 45°C for 3 hours to form activated acid. A solution of tert-butyl-2,2-dimethyl-4-[5-(6-sulfamoyl-3-pyridyl) pentyl]pyrrolidine 1-carboxylate (875 mg, 2.056 mmol) in anhydrous tetrahydrofuran (3 ml) was added to the activated acid solution. then 1,8diazabicyclo[5.4.0]undec-7-ene (650 µl, 4.347 mmol), and the mixture was stirred at ambient temperature for 48 hours. Volatiles were removed under reduced pressure and the thick residue was partitioned between water (15 ml) and ethyl acetate (30 ml). The mixture was acidified with aqueous 4 M hydrochloric acid to pH ~ 3-4 and the layers were separated. The organic layer phase was washed with brine (20 ml) and the combined aqueous layers were re-extracted with ethyl acetate (30 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude material. The crude product was chromatographed (silica gel column, eluting with a gradient of 0-80% ethyl acetate in hexanes) to give tert-butyl 4[5-[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl) cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-3-pyridyl]pentyl]-2,2-dimethylpyrrolidine-1-carboxylate (854 mg, 53%) as a white foam. MS-ESI m/z calc. 782.284, detected 783.5 (M+1) ⁺ ; retention time: 2.2 min (LC method B).

Step 4: 2-chloro-X-[[5-[5-(5,5-dimethylpyrrolidin-3-yl)pentyl]-2-pyridyl]sulfonyl]-6-[3-[2-[1(trifluoromethyl) cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (hydrochloride salt)

To a stirred solution of tert-butyl 4-[5-[6-[[2-chloro-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl ]-3pyridyl]pentyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (850 mg, 1.085 mmol) in anhydrous methylene chloride (10 ml) was added hydrochloric acid in dioxane (6.8 ml, 4.0 M, 27. 20 mmol) at 0°C (ice bath) in a nitrogen atmosphere. After 10 minutes, the bath was removed and stirring continued at room temperature for 30 minutes. The volatiles were then removed under reduced pressure and the residue was dissolved in ethyl acetate (30 ml) and washed with saturated aqueous sodium bicarbonate (20 ml). The aqueous layer was re-extracted with ethyl acetate (25 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give crude 2-chloroform-X-[[5-[5-(5,5dimethylpyrrolidin-3-yl)pentyl]-2- pyridyl]sulfonyl]-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (hydrochloride salt) (781 mg, 100%) as a pale yellow foam . MS-ESI m/z calc. 682.23157, detected 683.4 (M+1) ⁺ ; retention time: 1.71 min (LC method B).

Step 5: 12,12-dimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl) ^-2λ6- thia3,9,11,22-tetraazatetracyclo [18.2.2.111,14.05,10]pentacose-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (compound 143)

- 447 044967

2-chloro-N-[[5-[5-(5,5-dimethylpyrrolidin-3-yl)pentyl]-2 A 20 ml bottle was loaded with pyridyl]sulfonyl]-6-[3-[2-[ 1 -(trifluoromethyl )cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3 carboxamide (hydrochloride salt) (0.812 g, 1.128 mmol), potassium carbonate (1.11 g, 8.032 mmol), cesium fluoride (0.258 g, 1.698 mmol) and anhydrous dimethyl sulfoxide (25 ml). The vessel was purged with a stream of nitrogen for 2 minutes, capped and stirred at 165°C for 17 hours. The reaction mixture was allowed to cool to ambient temperature, the mixture was diluted with ethyl acetate (30 ml) and washed with saturated aqueous sodium bicarbonate and then with brine . The organic layers were separated, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. Then silica gel chromatography (0-55% ethyl acetate in hexanes gradient) followed by another silica gel column (0%-10% methanol in dichloromethane) gave 12,12-dimethyl-8-(3-{2-[1(trifluoromethyl) cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-2λ ⁶ -thia-3,9,11,22tetraazatetracyclo[18.2.2.111,14.05,10]pentacose-1(23),5,7,9,20 (24),21-hexaene-2,2,4-trione (compound 143) (80 mg, 11%) as a white solid.

¹ H NMR (400 MHz, DMSO-ph) δ 12.59 (s, 1H), 8.69 (s, 1H), 8.19 (d, J=2.8 Hz, 1H), 8.14 (d, J=7.9 Hz, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.91 (d, J=8.3 Hz, 1H), 6.91 (d, J=8.3 Hz, 1H), 6.10 (d, J=2.7 Hz, 1H), 4.32 ( t, J=7.0 Hz, 2H), 3.01-2.87 (m, 1H), 2.74-2.62 (m, 1H), 2.47-2.36 (m, 1H), 2.08 (t, J=7.0 Hz, 2H), 2.03 -1.82 (m, 3H), 1.80-1.64 (m, 2H), 1.53 (s, 3H), 1.50 (s, 3H), 1.40 (t, J=12.2 Hz, 1H), 1.33-1.27 (m, 1H ), 1.23 (s, 2H), 0.980.92 (m, 2H), 0.92-0.86 (m, 2H), 0.82 (d, J=12.6 Hz, 1H), 0.73-0.59 (m, 1H), 0.08 - -0.03 (m, 1H). MS-ESI m/z calc. 646.2549, detected 647.5 (M+1)+; retention time: 1.96 min (LC method B).

Example 156. Preparation of 13,20,20-trimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-10λ ⁶ -thia-1,3,9,14 ,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene8,10,10-trione (compound 144)

Step 1: 1-[(4-methoxyphenyl)methyl]-5-methyl-3-nitropyrazole

A 100 mL round bottom flask attached to a reflux condenser was charged with 1(bromomethyl)-4-methoxybenzene (2.7 g, 13.43 mmol), acetonitrile (20 mL), 5-methyl-3-nitro-1H-pyrazole (1.55 g, 12.20 mmol) and potassium carbonate (2.53 g, 18.31 mmol). The mixture was stirred at 80°C for 6 hours, then at room temperature for 3 days before concentration under reduced pressure. The residue was suspended in dichloromethane (80 ml). After stirring for 10 minutes, the mixture was filtered and the filtrate was mixed with silica gel before concentration. The residue was purified by silica gel chromatography using a gradient of 0% to 30% ethyl acetate in heptanes to give 1-[(4methoxyphenyl)methyl]-5-methyl-3-nitropyrazole (2.4 g, 80%). as a yellow solid.

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1H NMR (300 MHz, CDCl ₃ ) δ 2.25 (s, 3H), 3.79 (s, 3H), 5.28 (s, 2H), 6.67 (s, 1H), 6.87 (d, J=8.7 Hz, 2H),

7.14 (d, J=8.7 Hz, 2H). ESI-MS m/z 270.1 (M+Na) ⁺ ; Retention time: 1.88 min (LC method I).

Step 2: 1-[(4-methoxyphenyl)methyl]-5-methylpyrazol-3-amine

A mixture of 1-[(4-methoxyphenyl) methyl]-5-methyl-3-nitropyrazole (2.4 g, 9.707 mmol), NH ₄ Cl (5 g, 3.268 ml, 93.47 mmol), iron (5 g, 89.53 mmol), EtOH (20 ml) and water (4 ml) were stirred at 80°C overnight. After cooling to room temperature, the reaction mixture was filtered through a pad of celite, washing with methanol. The filtrate was concentrated, the residue was suspended in water (50 ml) and extracted with ethyl acetate (80 ml). The organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-[(4methoxyphenyl)methyl]-5-methylpyrazol-3-amine as a red oil (2 g, 91% purity by LCMS , yield 86%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.13 (s, 3H), 3.78 (s, 3H), 5.01 (s, 2H), 5.44 (s, 1H), 6.83 (d, J=8.7 Hz, 2H) , 7.04 (d, J=8.7 Hz, 2H). MS-ESI m/z calc. 217.1215, detected 218.2 (M+1) ⁺ ; Retention time: 1.21 min (LC method I).

Step 3: 1-[(4-methoxyphenyl)methyl]-5-methylpyrazole-3-sulfonyl chloride

1-[(4-Methoxyphenyl)methyl]-5-methylpyrazol-3-amine (20 g, 92 mmol) was dissolved in AcOH (60 ml) and formic acid (20 ml). The mixture was cooled in an ice-methanol bath. Hydrochloric acid (15.2 ml 12 M, 182 mmol) was then added. After the internal temperature reached about -8°C, a solution of sodium nitrite (6.6 g, 96 mmol) in water (10 ml) was slowly added, maintaining the internal temperature between -5°C and -10°C. The mixture was stirred at the same temperature for 5 minutes, then this mixture was added by pipette in parts to a mixture of CuCl (2.74 g, 28 mmol), SO ₂ (44 g, 343 mmol) and AcOH (60 ml) at room temperature ( SO ₂ solution in AcOH was prepared by passing the gas through AcOH at 0°C). The resulting mixture was allowed to warm to room temperature over 1 hour. The mixture was concentrated under reduced pressure. The residue was mixed with diethyl ether (200 ml) and ice water (50 ml). There was a lot of black oil that did not dissolve in any of the phases. After the mixture was vigorously stirred for 20 minutes, the two layers were separated. The organic layer was washed with water (2x50 ml), brine (30 ml) and concentrated under reduced pressure and finally co-evaporated with toluene (60 ml) to give 1-[(4-methoxyphenyl) methyl]-5-methylpyrazole-3 α-sulfonyl chloride (9 g, 33%) as a brown oil, which was used directly in the next step. MS-ESI m/z calc. 300.0335, detected 323.0 (M+Na)+; retention time: 2.05 min (LC method I).

Step 4: 1-[(4-methoxyphenyl)methyl]-5-methylpyrazole-3-sulfonamide

A solution of 1-[(4-methoxyphenyl)methyl]-5-methylpyrazole-3-sulfonyl chloride (586 mg, 1.9484 mmol) in dichloromethane (4 ml) was added to a solution of ammonia (15 ml of 0.5 M in 1,4- dioxane, 7.5000 mmol), cooled with ice water (partially frozen). After 30 minutes, the cooling bath was removed and the reaction mixture was stirred at room temperature for 2 hours before concentration under reduced pressure. The residue was purified by silica gel chromatography using 0%-70% ethyl acetate in heptanes to give 1-[(4-methoxyphenyl)methyl]-5-methylpyrazole-3-sulfonamide (200 mg, 36% yield) as a white solid. MS-ESI m/z calc. 281.0834, detected 282.1 (M+1) ⁺ ; retention time: 1.49 min (LC method I).

Step 5: 5-methyl-1H-pyrazole-3-sulfonamide

A solution of 1-[(4-methoxyphenyl)methyl]-5-methylpyrazole-3-sulfonamide (16.3 g, 57.9 mmol) in trifluoroacetic acid (80 ml) was stirred at 80° C. (oil bath) overnight. The mixture was concentrated and the residue was purified by silica gel chromatography using 0-100% ethyl acetate in heptanes. Fractions containing the desired product were combined and concentrated. The residue was triturated with dichloromethane (30 ml) to give 5-methyl-1H-pyrazole-3-sulfonamide as a light yellow solid (6741 mg, 69% yield).

¹ H NMR (300 MHz, DMSO-de) ppm 2.25 (s, 3H), 6.32 (s, 1H), 7.28 (s, 2H), 13.11 (br. s., 1H).

Step 6: tert-butyl 2,2-dimethyl-4-[3-(5-methyl-3-sulfamoyl-pyrazol-1-yl)propyl]pyrrolidine-1-carboxylate

tert-Butyl-2,2-dimethyl-4-(3-methylsulfonyloxypropyl)pyrrolidine-1-carboxylate (1.35 g, 4.024 mmol) and 5-methyl-1H-pyrazole-3-sulfonamide (638 mg, 3.958 mmol) , and then potassium carbonate (1.95 g, 14.11 mmol) was dissolved in N, N-dimethylformamide (41.32 ml) and stirred at 80 ° C in a sealed vessel with a volume of 150 ml for 20 hours. Cooled, poured into water (100 ml) and extracted with ethyl acetate (2x100 ml), combined the organic layers, washed with water (2x100 ml), dried (sodium sulfate), filtered and concentrated. The orange residue was purified by silica gel chromatography using a gradient of 100% hexanes to 100% ethyl acetate to give tert-butyl 2,2-dimethyl-4-[3- (5-methyl-3sulfamoylpyrazol-1-yl)propyl]pyrrolidine-1-carboxylate (419 mg, 52%).

Ή NMR (400 MHz, DMSO-de) δ 7.31 (s, 2H), 6.36 (s, 1H), 4.05 (t, J=6.4 Hz, 2H), 3.54 (dd, J=18.2, 8.1 Hz, 1H) , 2.77 (k, J=10.2 Hz, 1H), 2.31 (d, J=15.4 Hz, 3H), 2.12 (d, J=19.6 Hz, 1H), 1.87 (td, J=14.0, 6.4 Hz, 1H) , 1.78-1.65 (m, 2H), 1.41-1.28 (m, 15H), 1.24 (s, 3H). MS-ESI m/z calc. 400.21442, detected 401.2 (M+1)+; retention time: 1.54 min (LC method E).

Step 7: tert-butyl 4-[3-[3-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl] -5-methyl-pyrazol-1-yl]propyl]-2,2-dimethyl-pyrrolidine-1carboxylate

2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (485 mg, 1.291 mmol) and carbonyldiimidazole (210 mg, 1.295 mmol) combined in tetrahydrofuran (8.0 ml) and stirred for 90 min at room temperature. Tert-butyl 2,2dimethyl-4-[3-(5-methyl-3-sulfamoylpyrazol-1-yl)propyl]pyrrolidine-1-carboxylate (342 mg, 0.8539 mmol) was then added followed by 1.8 -diazabicyclo[5.4.0]undec-7-ene (325 μl, 2.173 mmol), and the reaction mixture was heated at 50°C for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and then with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexanes to 100% ethyl acetate to give, as an off-white solid, tert-butyl 4-[3-[3 -[[2-chloro-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]-5-methylpyrazol-1 yl]propyl]-2 ,2-dimethylpyrrolidine-1-carboxylate (451 mg, 70%). MS-ESI m/z calc. 757.2636, detected 758.2 (M+1) ⁺ ; Retention time: 2.32 min (LCC method).

Step 8: 13,20,20-trimethyl-4-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)10λ ⁶ -thia-1,3,9, 14,22-pentaazαtetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (compound 144)

tert-Butyl 4-[3-[3-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-5- Methylpyrazol-1-yl]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (451 mg, 0.5948 mmol) was dissolved in dichloromethane (11 ml) and hydrochloric acid (4.5

- 450 044967 ml 4 M in dioxane, 18.00 mmol) and stirred at room temperature for 45 minutes. Concentrate the mixture to dryness under reduced pressure, redissolve in ethyl acetate and then add aqueous 2 M sodium carbonate (5 ml), giving a pH of ~ 10. The solution was extracted with ethyl acetate (2x10 ml), washed with brine, then dried over sodium sulfate, filtered and evaporated to dryness at reduced pressure. Combine the resulting material and potassium carbonate (411 mg, 2.974 mmol), cesium fluoride (136 mg, 0.8953 mmol), 3 A molecular sieves and dimethyl sulfoxide (13.5 ml) in a vial, purged with nitrogen, capped, heated to 155 °C and stirred for 20 hours. Cooled to room temperature and filtered, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and then with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexanes to 80% ethyl acetate in hexanes to give 13,20,20-trimethyl-4-( as a white solid 3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1-yl)-10λ ⁶ thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02.7] docose-2,4,6,11(22),12-pentaene-8,10,10-trione (compound 144) (141 mg, 38%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.68 (s, 1H), 8.19 (d, J=2.8 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 6.69 (s, 1H), 6.09 (d, J=2.7 Hz, 1H), 4.30 (t, J=7.0 Hz, 2H), 4.10-3.94 (m, 2H), 2.82-2.71 (m , 1H), 2.34 (d, J=8.9 Hz, 3H), 2.13 (dd, J=8.7, 4.0 Hz, 1H), 2.09-2.02 (m, 3H), 1.96-1.80 (m, 3H), 1.77 ( dd, J=11.9, 5.2 Hz, 1H), 1.54 (s, 3H), 1.48 (s, 3H), 1.35 (t, J=12.3 Hz, 1H), 0.99-0.92 (m, 2H), 0.89 (d , J=11.6 Hz, 2H), 0.590.39 (m, 1H). MS-ESI m/z calc. 621.2345, detected 622.2 (M+1)+; retention time: 2.14 min (LC method E).

Example 157: Preparation of 12,12-dimethyl-8-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-yl)-19-oxa-2λ ⁶ -thia-3,9,11 ,24-tetraαzatetracyclo[18.3.1.05,10.011,15]tetracose-1(24),5(10),6,8,20,22hexaene-2,2,4-trione (compound 147)

Step 1: tert-butyl 2,2-dimethyl-5-[3-[(6-sulfamoyl-2-pyridyl)oxy]propyl]pyrrolidine-1-carboxylate

Tert-butyl 5-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1carboxylate (631 mg, 2.452 mmol) and anhydrous N,N-dimethylformamide (8 mL) were added to a 20 mL vial. 60% NaH (196 mg, 4,900 mmol) was added portionwise to the solution (caution: gas evolution) and the mixture was stirred at room temperature for 15 minutes. 6-fluoropyridine-2-sulfonamide (432 mg, 2.452 mmol) was then added and the resulting mixture was stirred at room temperature for 30 minutes. Additional NaH (98 mg, 2.450 mmol) was added to the stirred solution at room temperature and the reaction vessel was sealed. The resulting mixture was stirred at 100°C for 14 hours. The reaction solution was diluted with ethyl acetate, then poured into aqueous 1 N. citric acid and extracted with ethyl acetate (2X). The combined organic fractions were dried (sodium sulfate), filtered and concentrated to a clear oil, which was purified by silica gel chromatography using a mobile phase gradient of 100% hexanes to 100% ethyl acetate to give tert-butyl-2,2dimethyl-5-[3-[ (6-sulfamoyl-2-pyridyl)oxy]propyl]pyrrolidine-1-carboxylate (350 mg, 35%). MSIE m/z calc. 413.19846, found 414.31 (M+1) ⁺ ; Retention time: 0.69 min (LC method A).

Step 2: tert-butyl 5-[3-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl ]-2-pyridyl]oxy]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

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2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (387 mg, 1.030 mmol) and carbonyldiimidazole (193 mg, 1.190 mmol) combined in anhydrous tetrahydrofuran (8 ml) and stirred for 75 minutes at 50°C. A tetrahydrofuran solution (7 ml) of tert-butyl 2,2-dimethyl-5-[3-[(6-sulfamoyl-2-pyridyl)oxy]propyl]pyrrolidine-1-carboxylate (328 mg, 0.7932 mmol) was then added and 1,8-diazabicyclo[5.4.0]undec-7-ene (300 µl, 2.006 mmol). The reaction was heated at 50°C for 4 hours. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution, and then with saline solution. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexanes to 75% ethyl acetate in hexanes to give tert-butyl 5-[3- [[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl]oxy]propyl]- 2,2-dimethylpyrrolidine-1-carboxylate (409 mg, 67%). MS-ESI m/z calc. 770.2476, detected 771.37 (M+1)+; Retention time: 0.92 min (LC method A).

Step 3: 12,12-dimethyl-8-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-19oxa-2λ ⁶ -thia-3,9,11 ,24-tetraazatetracyclo[18.3.1.05,10.011,15]tetracose-1(24),5(10),6,8,20,22-hexaene2,2,4-trione (compound 147)

tert-Butyl-5-[3-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin3-carbonyl]sulfamoyl]- 2-pyridyl]oxy]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (408 mg, 0.5290 mmol) was dissolved in dichloromethane (7 ml) and hydrochloric acid (4 ml of 4 M solution in dioxane, 16 .00 mmol) and stirred at room temperature for 30 min. The mixture was concentrated to dryness under reduced pressure and the resulting material was combined with potassium carbonate (440 mg, 3.184 mmol), cesium fluoride (130 mg, 0.8558 mmol), 3 A molecular sieves and dimethyl sulfoxide (8 ml) in a nitrogen purged vial, capped , heated to 140°C and stirred for 16 hours. Cooled to room temperature, filtered and then purified by reverse phase preparative chromatography using a C ₁₈ column (30-99% acetonitrile in water + 5 mM hydrochloric acid) to obtain as white solid 12,12-dimethyl-8-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-19-oxa-2λ ⁶ -thia-3,9, 11,24tetraazatetracyclo[18.3.1.05,10.011.15]tetracose-1(24),5(10),6,8,20,22-hexaene-2,2,4-trione (compound 147) (17 mg, 5 %). MS-ESI m/z calc. 634.2185, detected 635.29 (M+1) ⁺ ; retention time: 2.0 min (LC method B).

Example 158: Preparation of 13,20,20-trimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hπyrazol-1-yl)-10λ ⁶ -thia-1,3,9, 14,22-πpentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-πpentaene8,10,10-trione (enantiomer 1) (compound 150) and 13,20,20 -trimethyl-4-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-10λ ⁶ -thia-1,3,9,14,22pentaazatetracyclo[16.2.1.111, 14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (enantiomer 2) (compound 151)

Step 1: 13,20,20-trimethyl-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]docose-2,4,6,11 (22), 12-pentaene-8,10,10-trione (enantiomer 1) (compound 150) and 13,20, 20-trimethyl-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]docose-2,4,6,11(22),12pentaene-8,10,10-trione (enantiomer 2) (compound 151)

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Racemic 13,20,20-trimethyl-4-(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy }-1 H-pyrazol-1 yl)-1Oλ ⁶ -thia-1,3,9,14, 22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,1O,1Otrione (114 mg, 0.1815 mmol) was subjected to chiral SLC chromatography. The following SGC protocol was used: ChiralPak AS-H (150x21.2 mm), 5 µm; Mobile phase 35°C: 25% acetonitrile:methanol (90:10; no modifier), 75% carbon dioxide at 70 ml/min for 8.0 min (injection volume = 70 µl ~ 32 mg/ml in a mixture of acetonitrile: methanol (90:10) to obtain 13,20,20-trimethyl-4-(3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)- as the first eluted enantiomer 10λ ⁶ thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11 (22),12-pentaene-8,10,10-trione (enantiomer 1) (compound 150) (51.27 mg, 91%) as a white solid.

¹ H NMR (400 MHz, DMSO-66) δ 12.66 (s, 1H), 8.19 (d, J=2.8 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 6.69 (s, 1H), 6.09 (d, J=2.7 Hz, 1H), 4.31 (t, J=7.0 Hz, 2H), 4.10-3.93 (m, 2H), 2.85-2.70 (m , 1H), 2.35 (s, 3H), 2.12 (d, J=5.6 Hz, 1H), 2.07 (t, J=7.1 Hz, 3H), 1.97-1.81 (m, 3H), 1.77 (dd, J= 11.8, 5.4 Hz, 1H), 1.54 (s, 3H), 1.48 (s, 3H), 1.35 (t, J=12.3 Hz, 1H), 0.99-0.92 (m, 2H), 0.89 (d, J=11.9 Hz, 2H), 0.52 (dd, J=15.5, 8.4 Hz, 1H). MS-ESI m/z calc. 621.2345, detected 622.5 (M+1)+; retention time: 2.19 min (LC method E).

The second enantiomer eluted was 13,20,20-trimethyl-4-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-10λ ⁶ -thia-1,3,9 ,14,22pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (enantiomer 2) (compound 151) (31.08 mg , 55%) as a white solid. MS-ESI m/z calc. 621.2345, detected 622.5 (M+1) ⁺ ; Retention time: 2.19 min (LC method E).

Example 159: Preparation of 21,21-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol1-ul)-18-oxa-10λ ⁶ -thia-1,3,9 ,14,15-pentaazatetracyclo[17.2.1.02,7.011,15]docose-2(7),3,5,11,13-pentaene8,10,10-trione (compound 152)

Step 1: tert-butyl 2,2-dimethyl-4-[2-(3-sulfamoylpyrazol-1-yl)ethoxy]pyrrolidine-1-carboxylate

Dichloromethane (70 mL) was added to a round bottom flask under nitrogen bubbling containing tert-butyl 4-(2-hydroxyethoxy)2,2-dimethylpyrrolidine-1-carboxylate (1.94 g, 7.480 mmol). The solution was cooled to 0°C before adding Et ₃ N (6 ml, 43.05 mmol) and methanesulfonyl chloride (1.7 ml, 21.96 mmol). The reaction mixture was stirred for 20 hours, allowing it to warm to room temperature after 1 hour (the clear solution turned cloudy orange after 10 minutes). The reaction mixture was quenched by adding water. Dichloromethane was added, then the brine and the organic layer was separated. The aqueous layer was further extracted with dichloromethane (2x20 ml) and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was dried in vacuo for 1 hour to give a yellow oil, which was combined with 1H-pyrazole-3-sulfonamide (1.1 g, 7.475 mmol) in a round bottom flask followed by the addition of

- 453 044967 potassium carbonate (2.23 g, 16.14 mmol) and the mixture was dissolved in N,N-dimethylformamide (13 ml). The reaction mixture was stirred at 50°C in a sealed 150 ml vessel for 48 hours. The mixture was cooled to room temperature, poured into water (100 ml) and extracted with ethyl acetate (2x100 ml), the organic layers were combined, washed with water (2x100 ml), dried (sodium sulfate), filtered and concentrated. The orange residue was purified by silica gel chromatography using a gradient of 100% hexanes to 100% ethyl acetate to give the less polar regioisomer tert-butyl-2,2-dimethyl-4-[2-(5-sulfamoylpyrazol-1-yl) as the first elute. ethoxy]pyrrolidine-1carboxylate (550 mg, 38%). MS-ESI m/z calc. 388.17804, detected 389.1 (M+1)+; Retention time: 0.56 min (LC method A).

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

2-Chloro-6-[3-[2-[1 -(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxylic acid (183.5 mg, 0.4884 mmol) and carbonyldiimidazole (91, 40 mg, 0.5637 mmol) were combined in anhydrous tetrahydrofuran (4 ml) and stirred for 90 min at 50°C. A tetrahydrofuran solution (7 ml) of tert-butyl 2,2-dimethyl-4-[2-(3-sulfamoylpyrazol-1-yl)ethoxy]pyrrolidine-1-carboxylate (146 mg, 0.3758 mmol) and 1.8 -diazabicyclo[5.4.0]undec-7-ene (142.1 µl, 0.9502 mmol). The reaction was heated at 50°C for 4 hours. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution, and then with saline solution. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexanes to 75% ethyl acetate in hexanes to give tert-butyl 4-[2-[3-[[2-chloro -6[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]pyrazol-1yl]ethoxy]-2,2-dimethylpyrrolidine-1-carboxylate (162 mg, 58%) as an off-white solid. MS-ESI m/z calc. 745.22723, detected 746.22 (M+1) ⁺ ; retention time: 0.87 min (LC method A).

Step 3: 21,21 -dimethyl-4-(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-18oxa-10λ ⁶ -thia-1,3,9 ,14,15-pentaazatetracyclo[17.2.1.02,7.011,15]docose-2(7),3,5,11,13-pentaene-8,10,10trione (compound 152)

tert-Butyl 4-[2-[3-[[2-chloro-6-[3-[2-[1 -(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3 carbonyl]sulfamoyl]pyrazol- 1-yl]ethoxy]-2,2-dimethylpyrrolidine-1-carboxylate (162 mg, 0.2171 mmol) was dissolved in dichloromethane (3 ml) and hydrochloric acid (1.6 ml 4 M in dioxane, 6.400 mmol) was added to the mixture ) and stirred at room temperature for 30 min. The mixture was concentrated to dryness under reduced pressure and combined with potassium carbonate (180 mg, 1.302 mmol), cesium fluoride (55 mg, 0.3621 mmol), 3 A molecular sieves and dimethyl sulfoxide (3.5 ml) in a vial, purged with nitrogen, capped , heated to 140°C and stirred for 10 hours. Cooled to room temperature, filtered and then purified by preparative reverse phase chromatography using a C ₁₈ column (30-99% acetonitrile/water + 5 mM hydrochloric acid) to obtain as white solid 21,21-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-18-oxa-10λ ⁶ -thia-1,3, 9,14,15-pentaazatetracyclo[17.2.1.02,7.011,15]docose2(7),3,5,11,13-pentaene-8,10,10-trione (compound 152) (45 mg, 34%).

1H NMR (400 MHz, DMSO-Y6) δ 13.14 (s, 1H), 8.28 (d, J=2.8 Hz, 1H), 7.96 (d, J=8.3 Hz, 1H), 7.71 (d, J=2.0 Hz , 1H), 7.25 (d, J=8.2 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 6.14 (d, J=2.8 Hz, 1H), 4.79-4.63 (m, 1H), 4.614 .46 (m, 1H), 4.32 (t, J=7.0 Hz, 2H), 4.17-3.98 (m, 2H), 3.89 (ddd, J=11.1, 6.4, 2.7 Hz, 1H), 3.39 (dd, J =11.0, 4.4 Hz, 1H), 3.00 (d, J=10.9 Hz, 1H), 2.06 (dt, J=13.1, 6.6 Hz, 3H), 1.91 (dd, J=13.4, 2.7 Hz, 1H), 1.48 (s, 3H), 1.38 (s, 3H), 1.02-0.92 (m, 2H), 0.92-0.82 (m, 2H). MS-ESI m/z calc. 609.1981, detected 610.25 (M+1) ⁺ ; retention time: 2.04 min (LC method B).

Example 160: Preparation of (14S)-12,12-dimethyl-8-(2-oxo-3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}pyrrolidin-1-yl)-2λ ⁶ -thia-3, 9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose- 454 044967

1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 158)

Step 1: 3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrrolidin-2-one

To a stirred solution of 3-bromopyrrolidin-2-one (600 mg, 3.659 mmol) and 2-[1(trifluoromethyl)cyclopropyl]ethanol (665 mg, 4.315 mmol) in anhydrous tetrahydrofuran (15 ml) was added potassium hexamethyldisilazide (16.0 ml 0.5 M in toluene, 8,000 mmol) at 0°C (ice bath) for 2 min under nitrogen. The reaction mixture was allowed to gradually warm to ambient temperature overnight (14 h). The reaction mixture was acidified with glacial acetic acid (300 μl, 5.275 mmol) and volatiles were removed at 20°C under reduced pressure. The aqueous residue was dissolved in ethyl acetate (50 ml) and washed with brine (20 ml). The organic layer was dried (anhydrous sodium sulfate), filtered and concentrated under reduced pressure to obtain a brownish crude material. The crude product was purified by silica gel chromatography (0%-10% methanol/methylene chloride gradient) to give 3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrrolidin-2-one (285 mg, 33%) as a white solid substances.

¹ H NMR (400 MHz, Benzene-d ₆ ) δ 6.76 (s, 1H), 4.21 (dt, J=9.4, 6.7 Hz, 1H), 3.73-3.64 (m, 1H), 3.55 (t, J=7.3 Hz, 1H), 2.67 (dddd, J=9.3, 7.6, 4.6, 1.2 Hz, 1H), 2.46 (dt, J=9.6, 7.1 Hz, 1H), 1.95 (dt, J=14.3, 7.1 Hz, 1H) , 1.90-1.81 (m, 1H), 1.74-1.58 (m, 2H), 0.86-0.77 (m, 2H), 0.54-0.43 (m, 2H). MS-ESI m/z calc. 237.09766, detected 238.1 (M+1)+; retention time: 0.9 min (LC method B).

Step 2: (14S)-12,12-dimethyl-8-(2-oxo-3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}pyrrolidin1-yl)-2λ ⁶ -thia-3,9,11 ,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (compound 158)

(14S)-8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23) was added to a 5 ml bottle. 5,7,9,19,21-hexaene-2,2,4-trione (100 mg, 0.2222 mmol), 3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrrolidin-2-one ( 63 mg, 0.2656 mmol), cesium carbonate (275 mg, 0.8440 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20 mg, 0.03457 mmol) (xanthos) and dry dioxane (2 ml) in this sequence. Nitrogen was bubbled through the heterogeneous mixture for 3 min. Pd ₂ (dba) ₃ (20 mg, 0.02184 mmol) was then added under nitrogen and nitrogen was bubbled for a further 2 min and capped under nitrogen. The mixture was stirred at 115°C for 15 hours. The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (150 μl, 2.638 mmol). Volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (3.0 mL) and filtered through a 0.45 μm Whatman PTFE syringe disk filter. The sample was purified by preparative reverse phase HPLC-MS (30-99% acetonitrile in water for 15 min (hydrochloric acid as modifier)). The desired product fractions were combined and concentrated under reduced pressure and the residue was dissolved in ethyl acetate (25 ml) and washed successively with saturated aqueous sodium bicarbonate (2x10 ml) and brine (10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (14S)-12,12-dimethyl-8-(2-oxo-3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}pyrrolidine-1 -yl)-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2 ,2,4-trione (compound 158) (31 mg, 19%) as an off-white solid.

1H NMR (400 MHz, Methanol-d4) δ 7.78 (dd, J=8.4, 2.0 Hz, 1H), 7.59 (dd, J=8.4, 4.4 Hz, 1H), 7.53 (dd, J=8.5, 7.1 Hz, 1H), 7.16 (d, J=7.3 Hz, 1H), 6.65 (d, J=8.5 Hz, 1H), 4.26 (dt, J=12.5, 8.0 Hz, 1H), 4.22-4.00 (m, 2H), 3.97 (dt, J=9.1, 6.8 Hz, 1H), 3.92-3.71 (m, 2H), 3.29-3.21 (m, 1H), 3.03 (d, J=13.9 Hz, 1H), 2.86 (t, J= 10.2 Hz, 1H), 2.49 (dqd, J=12.8, 7.7, 3.0 Hz, 1H), 2.24-2.07 (m, 1H), 2.04-1.90 (m, 3H), 1.84 (dd, J=11.5, 5.4 Hz ,

- 455 044967

2H), 1.71-1.63 (m, 2H), 1.62 (s, 3H), 1.60 (d, J=12.0 Hz, 1H), 1.54 (s, 3H), 1.47-1.36 (m, 1H), 0.96-0.91 (m, 2H),

0.84-0.77 (m, 2H). MS-ESI m/z calc. 650.2498, detected 651.4 (M+1)+; retention time: 2.04 min (LC method B).

Example 161. Preparation of 20,20-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-17-oxa-10λ ⁶ -thia-1,3,9 ,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose2(7),3,5,11(22),12-pentaene-8,10,10-trione (compound 164), 20,20-dimethyl -4-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)- 17-oxa-10λ ⁶ thia-1,3,9,14,22pentaazatetracyclo[16.2.1.111 ,14.02,7]docose-2(7),3,5,11 (22), 12-pentaene-8,10,10-trione (enantiomer 1) (compound 302) and 20,20-dimethyl-4-( 3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-17oxa-10λ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02, 7]docose-2(7),3,5,11(22),12-pentaene8,10,10-trione (enantiomer 2) (compound 167)

Step 1: tert-butyl 2,2-dimethyl-4-[2-(3-sulfamoylpyrazol-1-yl)ethoxy]pyrrolidine-1-carboxylate

Dichloromethane (70 mL) was added to a round bottom flask under nitrogen bubbling containing tert-butyl 4-(2-hydroxyethoxy)2,2-dimethylpyrrolidine-1-carboxylate (1.94 g, 7.480 mmol). The solution was cooled to 0°C before adding Et ₃ N (6 ml, 43.05 mmol) and methanesulfonyl chloride (1.7 ml, 21.96 mmol). The reaction mixture was stirred for 20 hours, allowing it to warm to room temperature after 1 hour (the clear solution turned cloudy orange after 10 minutes). The reaction mixture was quenched by adding water. Dichloromethane was added, then the brine and the organic layer was separated. The aqueous layer was further extracted with dichloromethane (2x20 ml) and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was dried in vacuo for 1 hour to give a yellow oil, which was combined with 1H-pyrazole-3-sulfonamide (1.1 g, 7.475 mmol) in a round bottom flask followed by the addition of potassium carbonate (2.23 g, 16.14 mmol) and the mixture was dissolved in N,N-dimethylformamide (13 ml). The reaction mixture was stirred at 50°C in a sealed 150 ml vessel for 48 hours. The mixture was cooled to room temperature, poured into water (100 ml) and extracted with ethyl acetate (2x100 ml), the organic layers were combined, washed with water (2x100 ml), dried (sodium sulfate), filtered and concentrated. The orange residue was purified by silica gel chromatography using a gradient of 100% hexanes to 100% ethyl acetate to yield the more polar regioisomer, tert-butyl-2,2-dimethyl-4-[2-(3-sulfamoylpyrazol-1-yl) as the second elute )ethoxy]pyrrolidine-1carboxylate (475 mg, 33%). MS-ESI m/z calc. 388.17804, detected 389.1 (M+1) ⁺ ; Retention time: 0.52 min (LC method A).

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

2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (691.7 mg, 1.841 mmol) and carbonyldiimidazole (310.0 mg , 1.912 mmol) were combined in anhydrous tetrahydrofuran (15 ml) and stirred for 60 min at 40°C. Then a tetrahydrofuran solution (7 ml) of tert-butyl 2,2-dimethyl-4-[2-(3-sulfamoylpyrazol-1-yl)ethoxy]pyrrolidin-1-456 044967 carboxylate (550 mg, 1.416 mmol) and 1 ,8-diazabicyclo[5.4.0]undec-7-ene (538.9 mg, 529.4 µl, 3.540 mmol). The reaction was heated at 40°C for 14 hours. The reaction was diluted with ethyl acetate and washed with 1 M citric acid solution, and then with saline solution. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexanes to 75% ethyl acetate in hexanes to give tert-butyl 4-[2- as an off-white solid. [3-[[2-chloro-6-[3-[2-[1 -(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1 yl]pyridin-3-carbonyl]sulfamoyl]pyrazol-1-yl]ethoxy]-2 ,2-dimethylpyrrolidine-1-carboxylate (493 mg, 47%). MS-ESI m/z calc. 745.22723, detected 746.29 (M+1)+; Retention time: 0.83 min (LC method A).

Step 3: 20,20-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-17oxa-10λ ^6- thia-1,3,9 ,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2(7),3,5,11(22),12-pentaene8,10,10-trione (compound 164)

tert-Butyl 4-[2-[3-[[2-chloro-6-[3-[2-[1 -(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3 carbonyl]sulfamoyl]pyrazol- 1-yl]ethoxy]-2,2-dimethyl-pyrrolidine-1-carboxylate (467 mg, 0.6258 mmol) was dissolved in dichloromethane (10 ml) and hydrochloric acid (4.5 ml 4M in dioxane, 18.00) was added to the mixture mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated to dryness under reduced pressure and combined with potassium carbonate (520 mg, 3.763 mmol), cesium fluoride (154 mg, 1.014 mmol), 3 A molecular sieves and dimethyl sulfoxide (10 ml) in a vial, purged with nitrogen, capped, heated to 140 °C and stirred for 16 hours. The reaction mixture was allowed to cool to room temperature, filtered and then purified by preparative reverse phase chromatography using a C ₁₈ column (30%-99% acetonitrile-water + 5 mM hydrochloric acid) to obtain as white solid 20,20-dimethyl-4-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-17-oxa-10λ ⁶ -thia-1,3, 9,14,22pentaazatetracyclo[16.2.1.111,14.02,7]docose-2(7),3,5,11(22),12-pentaene-8,10,10-trione (compound 164) (115 mg, 30 %).

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.74 (s, 1H), 8.17 (d, J=2.8 Hz, 1H), 7.96 (s, 1H), 7.69 (d, J=8.2 Hz, 1H), 6.89 (d, J=8.2 Hz, 2H), 6.08 (d, J=2.8 Hz, 1H), 4.42 (t, J=13.0 Hz, 1H), 4.38-4.07 (m, 5H), 3.88 (t, J =11.4 Hz, 1H), 2.88 (s, 1H), 2.18-2.03 (m, 2H), 2.01 (dd, J=11.5, 6.0 Hz, 1H), 1.78 (t, J=9.1 Hz, 1H), 1.61 (t, J=11.5 Hz, 1H), 1.54 (s, 3H), 1.50 (s, 3H), 1.01-0.92 (m, 2H), 0.92-0.84 (m, 2H). MS-ESI m/z calc. 609.1981, found 610.36 (M+1) ⁺ ; Retention time: 2.03 min (LC method B).

Step 4: 20,20-dimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-17oxa-10λ ⁶ -thia-1,3,9, 14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2(7),3,5,11(22),12-pentaene8,10,10-trione (enantiomer 1) (compound 302) and 20, 20-dimethyl-4-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)- 17-oxa-10λ ⁶ -thia-1,3,9,14,22pentaazatetracyclo [16.2.1.111,14.02,7]docose-2(7),3,5,11 (22), 12-pentaene-8,10,10-trione (enantiomer 2) (compound 167)

Racemic compound, 20,20-dimethyl-4-(3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy} -1Hpyrazol-1 -yl)-17-oxa-10λ ⁶ -thia-1,3,9, 14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose2(7),3,5,11(22),12-pentaene-8,10,10-trione (compound 164) (98 mg, 0.1591 mmol) were subjected to chiral preparative LCLC to separate the enantiomers. The following LCLC protocol was used: ChiralPak AS-3 (150 x 2.1 mm), 3 µm; Mobile phase 35°C: 30% acetonitrile:methanol (90:10), 70% carbon dioxide. The first enantiomer eluted was 20,20-dimethyl-4-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-17-oxa-10λ ⁶ -thia-1,3 ,9,14,22pentaazatetracyclo[16.2.1.111,14.02,7]docose-2(7),3,5,11(22),12-pentaene-8,10,10-trione (enantiomer 1) (compound 302) (31 mg, 63%); MS-ESI m/z calc. 609.1981, found 610.32 (M+1) ⁺ ; Retention time: 2.01 min (LC method B).

The second enantiomer eluted was 20,20-dimethyl-4-(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-17-oxa- ^10λ6 -thia-1,3 ,9,14,22pentaazatetracyclo[16.2.1.111,14.02,7]docose-2(7),3,5,11 (22), 12-pentaene-8,10,10-trione (enantiomer 2) (compound 167) (31 mg, 63%); MS-ESI m/z calc. 609.1981, detected 610.28 (M+1)+; Hold time

- 457 044967 nia: 2.0 min (LC method B).

Example 162: preparation of 4-chloro-2O,2O-dimethyl-10λ ⁶ -thia-1,3,9,14,22pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22), 12-pentaene-8,10,10-trione (enantiomer 1) and 4chloro-20,20-dimethyl-10λ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose -2,4,6,11 (22), 12pentaene-8,10,10-trione (enantiomer 2)

Step 1: 4-chloro-20,2O-dimethyl-1Oλ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.O2,7]docose2,4,6,11(22) ,12-pentaene-8,10,10-trione (enantiomer 1) (compound E) and 4-chloro-2O,20-dimethyl-1Oλ ⁶ -thia1,3,9,14,22-pentaazatetracyclo[16.2.1.111, 14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (enantiomer 2) (compound F)

Racemic 4-chloro-20,20-dimethyl-10λ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12 -pentaene-8,10,10-trione (498 mg) was subjected to chiral SCLC chromatography. The following LCLC protocol was used: ChiralPak AS-H (250x21.2 mm), 5 µm; 35°C, mobile phase: 18% acetonitrile:methanol (90:10), 82% carbon dioxide at a flow rate of 70 ml/min. The first enantiomer eluted was 4-chloro-20,20-dimethyl-10λ ⁶ -thia-1,3,9,14,22pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22), 12-pentaene-8,10,10-trione (enantiomer 1) (162 mg, 13%).

Ή NMR (400 MHz, chloroform-d) δ 8.73 (s, 1H), 7.57-7.45 (m, 2H), 7.06 (d, J=2.3 Hz, 1H), 6.49 (d, J=7.8 Hz, 1H) , 4.28 (dt, J=13.4, 3.3 Hz, 1H), 4.02-3.85 (m, 1H), 2.67 (s, 1H), 2.13 (dt, J=11.4, 5.3 Hz, 2H), 2.08-1.98 (m , 1H), 1.92 (dt, J=15.4, 10.2 Hz, 2H), 1.77-1.70 (m, 1H), 1.54 (s, 3H), 1.49 (s, 3H), 1.44 (t, J=12.3 Hz, 1H), 0.83-0.71 (m, 1H). MS-ESI m/z calc. 423.1132, found 424.04 (M+1)+; Retention time: 1.66 min (LC method B).

The second enantiomer eluted 4-chloro-20,2O-dimethyl-10λ ⁶ -thia-1,3,9,14,22pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12 -pentaene-8,10,10-trione (enantiomer 2) (163 mg, 13%).

Ή NMR (400 MHz, chloroform-d) δ 8.82 (s, 1H), 7.57-7.45 (m, 2H), 7.06 (d, J=2.3 Hz, 1H), 6.49 (d, J=7.8 Hz, 1H) , 4.27 (dt, J=13.3, 3.4 Hz, 1H), 4.01-3.87 (m, 1H), 2.67 (s, 1H), 2.24-2.07 (m, 2H), 2.08-1.98 (m, 1H), 2.00 -1.84 (m, 2H), 1.82-1.68 (m, 1H), 1.54 (s, 3H), 1.49 (s, 3H), 1.44 (t, J=12.3 Hz, 1H), 0.77 (dt, J=18.8 , 9.0 Hz, 1H). MS-ESI m/z calc. 423.1132, found 424.04 (M+1) ⁺ ; Retention time: 1.67 min (LC method B).

Example 163: Preparation of 4-[3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl]-2O,2O-dimethyl-10λ ⁶ thia-1,3,9,14,22-pentaazatetracyclo[16.2. 1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (compound 168)

Step 1: 4-[3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl]-20,20-dimethyl-10λ ⁶ -thia-1,3,9,14,22pentaazatetracyclo[16.2.1.111, 14.02,7]docose-2,4,6,11 (22),12-pentaene-8,10,10-trione (compound 168)

Solution of 4-chloro-20,2O-dimethyl-1Oλ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose2,4,6,11(22),12-pentaene -8,10,10-trione (75 mg, 0.1769 mmol), 1-(3,3-dimethylbutyl)imidazolidin-2-one (38 mg, 0.2232 mmol), sodium tert-butoxide (27 mg, 0.2809 mmol) and chloro(2-di-tert-butylphosphino2',4',6'-tri-isopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium (II) (31 mg, 0.04760 mmol) in dioxane (2 ml) in the vial was degassed by purging with nitrogen for 2 min. The mixture was then stirred at room temperature for 1 hour. The reaction mixture was quenched with 0.5 ml acetic acid and filtered through a Whatman disk filter (Puradisc 25 TF) using a small amount of dimethyl sulfoxide, and the filtrate was purified by reverse HPLC-MS. phase using a double gradient from 50% to 99% mobile phase B in 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 obtain 4-[3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-ul]-20,20-dimethyl-10λ ⁶ -thia1,3,9,14, 22-pentaazatetracyclo[16.2.1.111,14.02.7]docose-2,4,6,11 (22), 12-pentaene-8,10,10-trione (compound 168) (24 mg, 24%) as white solid matter.

¹ H NMR (400 MHz, chloroform-d) δ 8.38 (s, 1H), 7.55 (s, 2H), 7.46 (d, J=2.3 Hz, 1H), 7.05 (d, J=2.3 Hz, 1H), 4.35 (d, J=11.7 Hz, 1H), 3.96 (dt, J=36.5, 11.0 Hz, 3H), 3.46 (d, J=8.4 Hz, 2H), 3.39-3.27 (m, 2H), 2.71 (s , 1H), 2.12 (s, 2H), 2.02 (s, 2H), 1.92 (s, 1H), 1.72 (d, J=8.8 Hz, 1H), 1.55 (s, 3H), 1.49 (s, 3H) , 1.45 (dd, J=10.1, 6.6 Hz, 3H), 0.96 (s, 9H), 0.79 (d, J=9.7 Hz, 1H). MS-ESI m/z calc. 557.27844, found 558.17 (M+1)+; Retention time: 1.84 min (LC method B).

Example 164: Preparation of 4-[3-(4,4-dimethylpentyl)-2-oxoimidazolidin-1-yl]-20,20-dimethyl-10λ ⁶ thia-1,3,9,14,22-pentaazatetracyclo[16.2. 1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (compound 169)

Step 1: 4,4-dimethylpentanenitrile

1-Bromo-3,3-dimethylbutane (25 g, 151.45 mmol) was slowly added to a suspension of sodium cyanide (8.17 g, 166.71 mmol) in dimethyl sulfoxide (80 ml) at 60°C, maintaining the internal temperature between 55°C and 65°C. The reaction mixture was heated at 70°C for 90 min, then cooled to room temperature. The reaction mixture was diluted with water (300 ml) and extracted with diethyl ether (3x150 ml). The organic layers were combined, washed with 5 N. hydrochloric acid (75 ml) and water (75 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 4,4-dimethylpentanenitrile (17.82 g, 89%) as a pure oil. The crude material was used directly in the next step without further purification.

¹ H NMR (300 MHz, CDCl ₃ ) ppm 0.93 (s, 9H), 1.56-1.67 (m, 2H), 2.28 (dd, J=8.8, 7.3 Hz, 2H).

Step 2: 4,4-dimethylpentanal

Diisobutylaluminum hydride (226 ml 1M in dichloromethane, 226.00 mmol) was added to a solution of 4,4dimethylpentanenitrile (16.75 g, 150.65 mmol) in dichloromethane (560 ml) at 0°C. The reaction mixture was stirred at 0°C for 90 min, then quenched with 3 M hydrochloric acid. The aqueous layer was separated and extracted with dichloromethane. The combined organic layers were washed with 10% hydrochloric acid, water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 4,4-dimethylpentanal (16.23 g, 94%) as a yellow oil. The crude material was used in the next step without any further purification.

¹ H NMR (300 MHz, CDCl3) ppm 0.90 (s, 9H), 1.46-1.61 (m, 2H), 2.40 (td, J=8.1, 1.9 Hz, 2H), 9.78 (t, J=1.9 Hz, 1H ).

Step 3: tert-butyl-N[2-(4,4-dimethylpentylamino)ethyl]carbamate

4,4-Dimethylpentanal (15.2 g, 133.12 mmol) was added to a solution of tert-butyl N-(2aminoethyl)carbamate (20.948 g, 20.7 mL, 130.75 mmol) in methanol (300 mL), and the reaction mixture was stirred at room temperature for 1 hour. After cooling the reaction mixture to 0°C, sodium borohydride (5.2 g, 137.45 mmol) was slowly added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure . The residue was dissolved in ethyl acetate (300 ml) and washed with saturated aqueous sodium bicarbonate (2x300 ml) and brine (300 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl N-[2-(4 ,4-dimethylpentylamino)ethyl]carbamate (21.83 g, 65%) as a yellow oil. The crude material was used in the next step without any additional purification. MS-ESI m/z calc. 258.2307, detected 259.3 (M+1)+; retention time: 1.39 min (LC method I).

Step 4: 1-(4,4-dimethylpentyl)imidazolidin-2-one

Solid potassium tert-butoxide (28.6 g, 254.87 mmol) was added to a solution of tert-butyl N-[2-(4,4dimethylpentylamino)ethyl]carbamate (21.83 g, 84.481 mmol) in tetrahydrofuran (260 ml) and the reaction mixture was heated at 60°C for 3 hours. After cooling to room temperature, the reaction mixture was acidified to pH 1-2 with aqueous hydrochloric acid (1 M) and concentrated under reduced pressure. The aqueous residue was extracted with ethyl acetate (3x250 ml), the organic layers were combined, washed with brine (2x200 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0% to 10% methanol in ethyl acetate to give 1-(4,4-dimethylpentyl)imidazolidin-2one (7.36 g, 45%) as an off-white solid.

Ή NMR (300 MHz, DMSO-de) ppm 0.84 (s, 9H), 1.02-1.15 (m, 2H), 1.28-1.43 (m, 2H), 2.96 (t, J=7.2 Hz, 2H), 3.14- 3.22 (m, 2H), 3.23-3.31 (m, 2H), 6.20 (br. s., 1H). MS-ESI m/z calc. 184.1576, detected 185.3 (M+1) ⁺ ; retention time: 2.34 min (LC method H).

Step 5: 4-[3-(4,4-dimethylpentyl)-2-oxoimidazolidin-1-yl]-20,20-dimethyl-10λ ⁶ -thia-1,3,9,14,22pentaazatetracyclo[16.2.1.111, 14.02,7]docose-2,4,6,11 (22), 12-pentaene-8,10,10-trione (compound 169)

Solution of 4-chloro-20,20-dimethyl-10λ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose2,4,6,11(22),12-pentaene -8,10,10-trione (30 mg, 0.07077 mmol), 1-(4,4-dimethylpentyl)imidazolidin-2one (16 mg, 0.08683 mmol), sodium tert-butoxide (12 mg, 0. 1249 mmol) and chloro(2-di-tert-butylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium (II) (14 mg, 0.02150 mmol) in dioxane (2 ml) in the vial was degassed by purging with nitrogen for 2 min. The mixture was stirred at room temperature for about 1 hour. The reaction mixture was quenched with 0.5 ml acetic acid and filtered through a Whatman disc filter (puradisc 25 TF) using a small amount of dimethyl sulfoxide, and the filtrate was purified by reverse phase HPLC-MS using a dual gradient from 50% to 99% mobile phase B for 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 obtain 4-[ 3-(4,4-dimethylpentyl)-2-oxoimidazolidin-1-yl]20,20-dimethyl-10λ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose -2,4,6,11(22),12-pentaene8,10,10-trione (compound 169) (6.8 mg, 16%) as an off-white solid.

1H NMR (400 MHz, chloroform-d) δ 8.54 (s, 1H), 7.54 (s, 2H), 7.46 (d, J=2.2 Hz, 1H), 7.05 (d, J=2.1 Hz, 1H), 4.35 (d, J=13.2 Hz, 1H), 4.09-3.85 (m, 3H), 3.46 (d, J=8.7 Hz, 2H), 3.27 (t, J=7.3 Hz, 2H), 2.71 (s, 1H) , 2.11 (s, 3H), 1.99-1.85 (m, 1H), 1.71 (dd, J=11.7, 5.3 Hz, 1H), 1.60 (s, 3H), 1.55 (s, 3H), 1.49 (s, 3H ), 1.48-1.35 (m, 1H), 1.30-1.17 (m, 2H), 0.88 (s, 8H), 0.75 (d, J=19.6 Hz, 2H). MS-ESI m/z calc. 571.29407, found 572.3 (M+1) ⁺ ; Retention time: 2.02 min (LC method B).

Example 165: Preparation of (14S)-8-[3-(3,3-dimethylbutoxy)-2-oxopyrrolidin-1-yl]-12,12-dimethyl2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo [17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4trione (diastereomer 1) (compound 170) and (14S)-8 -[3-(3,3-dimethylbutoxy)-2-oxopyrrolidin-1-yl]12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10 ]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 2) (compound 171)

diastereomer 1 diastereomer 2

Step 1: 3-(3,3-dimethylbutoxy)pyrrolidin-2-one

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To a stirred solution of 3,3-dimethylbutan-1-ol (540 mg, 5.285 mmol) in anhydrous tetrahydrofuran (20 mL) was added [bis(trimethylsilyl)amino]potassium (10.6 mL of 0.5 M in toluene, 5.300 mmol) at ambient temperature in a nitrogen atmosphere. The milky reaction mixture was stirred for 30 min, then a solution of 3-bromopyrrolidin-2-one (830 mg, 4.808 mmol) in anhydrous tetrahydrofuran (3 ml) was added dropwise at 0° C. (ice bath). The reaction mixture was allowed to gradually warm to ambient temperature overnight (18 hours). The reaction mixture was acidified with 1 M aqueous hydrochloric acid (1.5 ml) and volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (30 ml) and washed with brine (15 ml). The organic portion was dried (anhydrous sodium sulfate), filtered and concentrated under reduced pressure to obtain a brownish crude material. The crude product was purified by silica gel chromatography (0%-10% methanol in dichloromethane gradient) to give 3-(3,3dimethylbutoxy)pyrrolidin-2-one (143 mg, 16%) as a white solid. MS-ESI m/z calc. 185.14159, detected 186.2 (M+1)+; retention time: 0.95 min (LC method B).

Step 2: (14S)-8-[3-(3,3-dimethylbutoxy)-2-oxopyrrolidin-1-yl]-12,12-dimethyl-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione

(14S)-8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5 was added to the bottle ,7,9,19,21-hexaen-2,2,4-trione (100 mg, 0.2222 mmol), 3-(3,3dimethylbutoxy)pyrrolidin-2-one (50 mg, 0.2699 mmol), cesium carbonate (290 mg, 0.8901 mmol), 4,5bis(diphenylphosphino)-9,9-dimethylxanthene (20 mg, 0.03457 mmol) (xanthos) and dry dioxane (2 ml) in that order. Nitrogen was purged through the heterogeneous mixture for 3 min. Pd ₂ (dba) ₃ (20 mg, 0.02184 mmol) was then added under nitrogen and the vial was purged with nitrogen for a further 2 min, then sealed under nitrogen. The mixture was stirred at 115°C for 15 hours. The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (130 μl, 2.286 mmol). Volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (3.0 mL) and filtered through a 0.45 μm Whatman PTFE syringe disk filter. The sample was purified by preparative reverse phase HPLC-MS (30-99% gradient of acetonitrile in water over 15 min (hydrochloric acid as modifier). The desired product fractions were combined and concentrated under reduced pressure, the residue was dissolved in ethyl acetate (25 ml) and washed with brine (10 ml).The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (148)-8-[3-(3,3-dimethylbutoxy)-2oxopyrrolidin-1-yl]-12, 12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2 ,2,4-trione (27 mg, 20%) as an off-white solid mixture of diastereomers.

¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.78 (dd, J=8.4, 2.1 Hz, 1H), 7.60 (dd, J=8.4, 4.3 Hz, 1H), 7.53 (dd, J=8.5, 7.2 Hz, 1H), 7.16 (dt, J=7.2, 1.0 Hz, 1H), 6.65 (d, J=8.5 Hz, 1H), 4.25 (dt, J=12.8, 8.0 Hz, 1H), 4.20-3.99 (m , 2H), 3.97-3.76 (m, 2H), 3.74-3.65 (m, 1H), 3.03 (d, J=13.8 Hz, 1H), 2.86 (t, J=9.9 Hz, 1H), 2.56-2.44 ( m, 1H), 2.17 (s, 1H), 2.04-1.93 (m, 1H), 1.84 (dd, J=11.7, 5.7 Hz, 2H), 1.63 (br, 6H), 1.61-1.55 (m, 4H) , 1.54 (s, 2n), 1.44 (t, J=11.6 Hz, 1h), 0.95 (s, 9H). MS-ESI m/z calc. 598.29376, found 651.4 (M+1) ⁺ ; Retention time: 2.04 min (LC method B).

Step 3: (14S)-8-[3-(3,3-dimethylbutoxy)-2-oxopyrrolidin-1-yl]-12,12-dimethyl-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 1) (compound 170) and (14S)- 8-[3-(3,3-dimethylbutoxy)-2-oxopyrrolidin-1-yl]-12,12dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10 ]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (diastereomer 2) (compound 171)

Ooo Ooo Ooo

diastereomer 1 diastereomer 2

Racemic diastereomeric (14S)-8-[3 -(3,3-dimethylbutoxy)-2-oxopyrrolidin-1 -yl]-12,12dimethyl-2λ ⁶ -tua-3,9,11,18,23-pentaazatetracyclo[17.3 .1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20

- 461 044967 hexaene-2,2,4-trione was subjected to chiral SLC chromatography. The following LCLC protocol was used: ChiralCel OJ-H (250x10 mm), 5 µm; mobile phase: 20% acetonitrile:methanol (90:10; no modifier), 80% carbon dioxide at a flow rate of 10 ml/min to provide (14S)-8-[3-(3,3-) as the first diastereomer eluted dimethylbutoxy)-2-oxopyrrolidin-1-yl]-12,12dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5, 7,9,19(23),20hexaene-2,2,4-trione (diastereomer 1) (compound 170) (11 mg, 8%);

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.43 (s, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.51 (d, J= 8.3 Hz, 1H), 7.04 (d, J=7.2 Hz, 1H), 6.96 (s, 1H), 6.70 (d, J=8.5 Hz, 1H), 4.23 (t, J=8.0 Hz, 1H), 4.07 -3.98 (m, 1H), 3.88 (dt, J=8.8, 7.2 Hz, 2H), 3.70 (dt, J=10.5, 7.6 Hz, 1H), 3.60 (dt, J=9.2, 7.2 Hz, 1H), 3.20-3.03 (m, 1H), 2.94 (d, J=13.4 Hz, 1H), 2.77-2.63 (m, 1H), 2.46-2.37 (m, 1H), 2.18-2.04 (m, 1H), 1.91 ( dk, J=12.6, 8.4 Hz, 1H), 1.82 (dd, J=11.8, 5.2 Hz, 1H), 1.80-1.68 (m, 1H), 1.64-1.57 (m, 2H), 1.57 (s, 3H) , 1.52-1.48 (m, 2H), 1.46 (s, 3H), 1.34-1.26 (m, 1H), 1.24 (s, 1H), 0.91 (d, J=0.9 Hz, 9H), MS-ESI m/ z calc. 598.29376, found 599.4 (M+1)+; Retention time: 2.21 min (LC method B), and as the second diastereomer eluted, (14S)-8-[3-(3,3-dimethylbutoxy)-2oxopyrrolidin-1-yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4 -trione (diastereomer 2) (compound 171) (10 mg, 7%);

1H NMR (400 MHz, DMSO-b6) δ 12.41 (s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.57 (t, J=7.9 Hz, 1H), 7.53 (d, J=8.4 Hz , 1H), 7.04 (d, J=7.2 Hz, 1H), 6.96 (s, 1H), 6.70 (d, J=8.5 Hz, 1H), 4.28 (t, J=8.3 Hz, 1H), 3.97-3.92 (m, 1H), 3.92-3.89 (m, 1H), 3.89-3.84 (m, 1H), 3.77 (dt, J=10.2, 7.5 Hz, 1H), 3.59 (ddd, J=9.3, 7.7, 6.7 Hz , 1H), 3.16-3.03 (m, 1H), 2.94 (d, J=13.3 Hz, 1H), 2.74-2.64 (m, 1H), 2.48-2.39 (m, 1H), 2.20-2.02 (m, 1H ), 1.93-1.85 (m, 1H), 1.84-1.79 (m, 1H), 1.79-1.69 (m, 1H), 1.63-1.57 (m, 2H), 1.57 (s, 3H), 1.52-1.47 (m , 2H), 1.46 (s, 3H), 1.29 (d, J=12.4 Hz, 1H), 1.24 (s, 1H), 0.91 (s, 9H). MS-ESI m/z calc. 598.29376, detected 599.4 (M+1) ⁺ ; Retention time: 2.18 min (LC method B).

Example 166: Preparation of (14S)-12,12-dimethyl-8-(2-oxo-3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}pyrrolidin-1-yl)-2λ ⁶ -thia-3, 9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 1) ( compound 172) and (14S)-12,12-dimethyl-8-(2oxo-3-{2-[1-(trifluoromethyl)cyclononyl]ethoxy}pyrrolidin-1-yl)-2λ ⁶ -thia-3,9, 11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 2) (compound 173 )

Step 1: (14S)-12,12-dimethyl-8-(2-oxo-3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}pyrrolidin1-yl)-2λ ⁶ -thia-3,9,11 ,18,23-pentaazatetracyclo[17.3.1.111,14.O5,1O]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (diastereomer 1) (compound 172) and (14S)-12,12-dimethyl-8-(2-oxo-3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} pyrrolidin-1 -yl)-2λ ⁶ -thia-3,9, 11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 2) (compound 173 )

A mixture of diastereomers (14S)-12,12-dimethyl-8-(2-oxo-3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} pyrrolidin-1 -yl)-2λ ⁶ -thia-3,9,11 ,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4 trione (dihydrochloride salt) (31 mg) was subjected to chiral purification of SLC. The LCLC purification method used used a ChiralCel OJ-H column (250x10 mm), 5 µm; mobile phase: 20% acetonitrile:methanol (90:10; no modifier), 80% carbon dioxide; Flow rate: 10 ml/min; Sample concentration: ~ 24 mg/ml in acetonitrile:methanol:dimethyl sulfoxide (85:9:6); injection volume: 70 µl; pressure: 100 bar. The first diastereomer to elute was (14S)-12,12-dimethyl-8-(2-oxo-3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}πpyrrolidin-1-yl)-2λ ⁶ -thia-3,9 ,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 1) (compound 172) (7 mg, 5%). MS-ESI m/z calc. 650.2498, detected 651.4 (M+1) ⁺ ; retention time: 2.09 min (LC method B).

The second diastereomer eluted was (145)-12,12-dimethyl-8-(2-oxo-3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy}pyrrolidin-1-yl)-2λ ⁶ -thia-3,9 ,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (diastereomer 2) (compound 173) (7 mg, 5%). MS-ESI m/z calc. 650.2498, detected 651.4 (M+1) ⁺ ; Hold Time:

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2.09 min (LC method B).

Example 167:

receiving

20,20-dimethyl-4-(2-oxo-3-{3-[ 1 (trifluoromethyl)cyclopropyl]propyl}pyrrolidin-1 -yl)-10λ ⁶ -thia-1,3,9,14,22pentaazatetracyclo[16.2 .1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (diastereomer 1) (compound 181) and 20,20-dimethyl-4-(2 -oxo-3-{3-[1-(trifluoromethyl)cyclopropyl]propyl}pyrrolidin-1yl)-10λ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose- 2,4,6,11(22),12-pentaene-8,10,10trione (diastereomer 2) (compound 182)

Step 1: 20,20-dimethyl-4-(2-oxo-3-{3-[1-(trifluoromethyl)cyclopropyl]propyl}pyrrolidin-1-yl)10λ ⁶ -thia-1,3,9,14, 22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11 (22), 12-pentaene-8,10,10-trione (diastereomer 1) (compound 181) and 20,20-dimethyl -4-(2-oxo-3-{3-[1-(trifluoromethyl)cyclopropyl]propyl} pyrrolidin-1 -yl)-10λ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111 ,14.02,7]docose2,4,6,11(22),12-pentaene-8,10,10-trione (diastereomer 2) (compound 182)

4-chloro-20,20-dimethyl-10λ ⁶ -thia-1,3,9,14,22-pentaazatetracyclofalcon was added

In

[16.2.1.111,14.02.7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (enantiomer 2) (40 mg, 0.09436 mmol), 3[3 -[1-(trifluoromethyl)cyclopropyl]propyl]pyrrolidin-2-one (27 mg, 0.1148 mmol), cesium carbonate (110 mg, 0.3376 mmol), 4,5-bis(diphenylphosphino)-9.9 -dimethylxanthene (9 mg, 0.01555 mmol) (xanthos) and dry dioxane (2 ml) in that order. Nitrogen was bubbled through the heterogeneous mixture for 2 min. Pd ₂ (dba) ₃ (9 mg, 0.009960 mmol) was then added under nitrogen and nitrogen was bubbled through the reaction mixture for an additional 2 minutes and then the mixture was blocked under nitrogen. The mixture was stirred at 115°C for 15 hours. The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (50 μl, 0.8792 mmol). Volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.5 ml) and filtered through a 0.45 μm Whatman PTFE syringe disk filter. The sample was purified by preparative reverse phase HPLC-MS (30-99% acetonitrile in water for 15 min (hydrochloric acid as modifier)). The desired product fractions were combined and concentrated under reduced pressure and the residue was dissolved in ethyl acetate (25 ml) and washed successively with saturated aqueous sodium bicarbonate (2 x 10 ml) and brine (10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 20,20-dimethyl-4-(2-oxo-3-{3-[1-(trifluoromethyl)cyclopropyl]propyl}pyrrolidin-1-yl) -10λ ⁶ -thia1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (41 mg 70%) as an off-white solid mixture of diastereomers, which was subjected to chiral LCLC purification using a ChiralCel OJ-3H column (250x10 mm), 5 μm; mobile phase: 20% acetonitrile: methanol (90:10; no modifier), 80% carbon dioxide; flow: 10 ml/min; concentration: ~24 mg/ml in acetonitrile:methanol:dimethyl sulfoxide (81:9:10); injection volume: 70 µl; pressure: 100 bar; wavelength: 242 nm. The first diastereomer to elute was 20,20-dimethyl-4-(2-oxo-3-{3-[1(trifluoromethyl)cyclopropyl]propyl}pyrrolidin-1-yl)-10λ ⁶ -thia-1,3,9,14 ,22pentaazatetracyclo[16.2.1.111,14.02.7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (diastereomer 1) (compound 181) (11 mg, 18%) . MS-ESI m/z calc. 622.2549, detected 623.4 (M+1)+; retention time: 2.18 min (LC method B).

- 463 044967

The second diastereomer eluted was 20,20-dimethyl-4-(2-oxo-3-{3-[1(trifluoromethyl)cyclopropyl]propyl}pyrrolidin-1-yl)-10λ ⁶ -thia-1,3,9,14 ,22pentaazatetracyclo[16.2.1.111,14.02.7]docose-2,4,6,11 (22),12-pentaene-8,10,10-trione (diastereomer 2) (compound 182) (10 mg, 17%) . MS-ESI m/z calc. 622.2549, detected 623.4 (M+1)+; Hold Time:

2.19 min (LC method B).

Example 168: preparation of 20,20-dimethyl-4-(2-oxo-3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}pyrrolidin-1-yl)-10X ⁶ -thia-1,3,9, 14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12pentaene-8,10,10-trione (compound 183), 20,20-dimethyl-4-( 2-oxo-3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}pyrrolidin-1-yl)-10λ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02.7 ]docose2,4,6,11(22),12-pentaene-8,10,10-trione (diastereomer 1) (compound 191) and 20,20-dimethyl-4-(2-oxo-3{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}pyrrolidin-1 -yl)-10Х ⁶ -thia-1,3,9,14,22pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11 (22 ),12-pentaene-8,10,10-trione (diastereomer 2) (compound 192)

enantiomer 2

dla stereo omer 1 dla stereo omer 2

Step 1: 20,20-dimethyl-4-(2-oxo-3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}pyrrolidin-1-yl)10λ ⁶ -thia-1,3,9,14, 22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11 (22), 12-pentaene-8,10,10-trione (compound 183)

enantiomer 2

4-chloro-20,20-dimethyl-10X ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22) was added to the bottle ,12-pentaene-8,10,10-trione (enantiomer 2) (40 mg, 0.09436 mmol), 3[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrrolidin-2-one (23 mg, 0 .09696 mmol), cesium carbonate (102 mg, 0.3131 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8 mg, 0.01383 mmol) (xanthos) and dry dioxane (1.5 ml) in the order indicated. Nitrogen was bubbled through the heterogeneous mixture for 2 min. Pd ₂ (dba) ₃ (8 mg, 0.008853 mmol) was then added under nitrogen and nitrogen was bubbled through the reaction mixture for a further 2 min, then capped under nitrogen. The mixture was stirred at 115°C for 15 hours. The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (50 μl, 0.8792 mmol). Volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.5 ml) and filtered through a 0.45 μm Whatman PTFE syringe disk filter. The sample was purified by preparative reverse phase HPLC-MS (30-99% acetonitrile in water for 15 min, hydrochloric acid as modifier). The desired product fractions were combined and concentrated under reduced pressure and the residue was dissolved in ethyl acetate (25 ml) and washed successively with saturated aqueous sodium bicarbonate (2x10 ml) and brine (10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 20,20-dimethyl-4-(2oxo-3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}pyrrolidin-1-yl)-10λ ⁶ -thia-1,3,9,14,22pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (compound 183) (41 mg, 74%) as an off-white solid.

¹ H NMR (400 MHz, Methanol-d4) δ 7.79 (d, J=2.3 Hz, 1H), 7.64 (dd, J=8.4, 2.1 Hz, 1H), 7.61-7.54 (m, 1H), 6.91 (dd , J=2.4, 1.1 Hz, 1H), 4.31-4.21 (m, 2H), 4.16 (ddd, J=11.8, 8.8, 3.2 Hz, 1H), 4.12-4.00 (m, 1H), 3.96 (k, J =7.5 Hz, 1H), 3.90-3.72 (m, 2H), 2.83-2.73 (m, 1H), 2.55-2.43 (m, 1H), 2.23-2.08 (m, 2H), 2.02-1.87 (m, 6H ), 1.77 (dd, J=11.9, 5.4 Hz, 1H), 1.57 (s, 3H), 1.50 (s, 3H), 1.39 (t, J=12.2 Hz, 1H), 0.96-0.90 (m, 2H) , 0.840.76 (m, 2H), 0.76-0.68 (m, 1H). MS-ESI m/z calc. 624.2342, found 625.4 (M+1) ⁺ ; Retention time: 2.05 min (LC method B).

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

- 464 044967 (diastereomer 1) (compound 191) and 20,20-dimethyl-4-(2-oxo-3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}pyrrolidin-1-yl)-10λ ⁶ - thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose2,4,6,11 (22), 12-pentaene-8,10,10-trione (diastereomer 2) (compound 192)

diastereomer 1 diastereomer 2

20,20-dimethyl-4-(2-oxo-3-{2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy}pyrrolidin-1 -yl)-10Х ⁶ -thia1,3,9,14,22-pentaazatetracyclo[ 16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (compound 183) was subjected to chiral SCLC using a ChiralPak IG column (250x10 mm), 5 µm; mobile phase: 42% acetonitrile:methanol (90:10; no modifier), 58% carbon dioxide; flow: 70 ml/min; concentration: ~ 24 mg/ml in a mixture of acetonitrile: methanol (90:10, without modifier); injection volume: 70 µl; pressure: 100 bar. The first diastereomer to elute was 20,20-dimethyl-4-(2-oxo-3{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}pyrrolidin-1-yl)-10X ⁶ -thia-1,3,9,14 ,22pentaazatetracyclo[16.2.1.111,14.02.7]docose-2,4,6,11 (22),12-pentaene-8,10,10-trione (diastereomer 1) (compound 191) (13.6 mg, 24 %). MS-ESI m/z calc. 624.2342, detected 625.4 (M+1)+; retention time: 1.87 min (LC method B).

The second diastereomer eluted was 20,20-dimethyl-4-(2-oxo-3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}pyrrolidin-1-yl)-10λ ⁶ -thia-1,3,9, 14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose 2,4,6,11(22),12-pentaene-8,10,10-trione (diastereomer 2) (compound 192) (13.5 mg, 24%). MS-ESI m/z calc. 624.2342, detected 625.4 (M+1) ⁺ ; retention time: 1.88 min (LC method B).

Example 169: Preparation of 4-[3-(3,3-dimethylbutyl)-2-oxopyrrolidin-1-yl]-20,20-dimethyl-10X ⁶ -thia1,3,9,14,22-pentaazatetracyclo[16.2.1.111 ,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (compound 184)

enantiomer 1

Step 1: 4-[3-(3,3-dimethylbutyl)-2-oxopyrrolidin-1-yl]-20,20-dimethyl-10X ⁶ -thia-1,3,9,14,22pentaazatetracyclo[16.2.1.111, 14.02,7]docose-2,4,6,11 (22),12-pentaene-8,10,10-trione (compound 184)

enantiomer 1

4-chloro-20,20-dimethyl-10X ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22) was added to the bottle ,12-pentaene-8,10,10-trione (enantiomer 1) (11 mg, 0.02595 mmol), 3(3,3-dimethylbutyl)pyrrolidin-2-one (8 mg, 0.04726 mmol), carbonate cesium (32 mg, 0.09821 mmol), 4,5bis(diphenylphosphino)-9,9-dimethylxanthene (3 mg, 0.005185 mmol) (xanthos) and dry dioxane (0.8 ml) in that order. Nitrogen was bubbled through the heterogeneous mixture for 2 min. Pd ₂ (dba) ₃ (3 mg, 0.003320 mmol) was then added under nitrogen and nitrogen was bubbled through the mixture for a further 2 minutes and the mixture was capped under nitrogen. The mixture was stirred at 115°C for 13 hours. The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (20 μl, 0.3517 mmol). Volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.0 mL) and filtered through a 0.45 μm Whatman PTFE syringe disk filter. The sample was purified by preparative reverse phase HPLC-MS (30-99% acetonitrile in water for 15 min (hydrochloric acid as modifier)). The desired product fractions were combined and concentrated under reduced pressure to give 4-[3-(3,3-dimethylbutyl)-2oxopyrrolidin-1-yl]-20,20-dimethyl- ^10X6 -thia-1,3,9,14. 22-pentaazatetracyclo[16.2.1.111,14.02.7]docose2,4,6,11(22),12-pentaene-8,10,10-trione (compound 184) (7.5 mg, 51%) as pale -yellow solid

- 465 044967 substances.

1H NMR (400 MHz, Methanol-d4) δ 7.78 (d, J=2.5 Hz, 1H), 7.67-7.60 (m, 1H), 7.56 (dd, J=8.5, 7.0 Hz, 1H), 6.91 (d, J=2.4 Hz, 1H), 4.33-4.22 (m, 1H), 4.20-4.11 (m, 1H), 4.10-3.97 (m, 1H), 3.96-3.78 (m, 1H), 2.832.73 (m, 1H), 2.62 (ddd, J=13.7, 9.4, 5.0 Hz, 1H), 2.31 (k, J=9.0 Hz, 1H), 2.21-2.08 (m, 2H), 2.04-1.84 (m, 4H), 1.81 -1.69 (m, 2H), 1.57 (s, 3H), 1.51 (s, 3H), 1.39 (t, J=12.4 Hz, 2H), 1.33-1.27 (m, 2H), 0.92 (s, 9H), 0.79-0.66 (m, 1H). MS-ESI m/z calc. 556.2832, detected 557.5 (M+1)+; retention time: 2.23 min (LC method B).

Example 170: Preparation of (18R)-4-[3-(2-{disniro[2.0.2.1]heptan-7-yl}ethoxy)-1H-nirazol-1-yl]-20,20dimethyl-10λ ⁶ -thia- 1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene8,10,10-trione (compound 186)

Ooo

Step 1: tert-butyl 4-[3-[3-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1yl]pyridin-3-carbonyl] sulfamoyl]pyrazol-1-yl]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

2-Chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (400 mg, 1.112 mmol) and carbonyldiimidazole (273.5 mg , 1.687 mmol) were combined in tetrahydrofuran (2 ml) and stirred for 90 min at room temperature. Tert-butyl 2,2-dimethyl-4[3-(3-sulfamoylpyrazol-1-yl)propyl]pyrrolidine-1-carboxylate (429.5 mg, 1.111 mmol) was then added followed by 1,8diazabicyclo[5.4. 0]undec-7-ene (430.8 mg, 2.830 mmol) and the reaction mixture was stirred at room temperature for 1 hour, then heated to 50°C and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and then with brine. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexanes to 100% ethyl acetate to give tert-butyl 4-[3-[3 as an off-white solid -[[2-chloro-6[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl]pyrazol-1 yl]propyl]-2, 2-dimethylpyrrolidine-1-carboxylate (350 mg, 43%).

1H NMR (400 MHz, DMSO-de) δ 8.34 (s, 1H), 8.08 (d, J=8.2 Hz, 1H), 7.77 (s, 1H), 7.62 (d, J=8.3 Hz, 1H), 6.71 -6.49 (m, 1H), 6.10 (d, J=2.8 Hz, 1H), 4.23 (s, 2H), 4.13 (s, 2H), 3.52 (s, 1H), 2.73 (d, J=6.0 Hz, 1H), 2.08 (d, J=6.7 Hz, 1H), 1.81 (k, J=6.6 Hz, 5H), 1.47 (t, J=6.5 Hz, 1H), 1.40-1.21 (m, 18H), 0.83 ( d, J=2.0 Hz, 4H), 0.66-0.60 (m, 2H), 0.52-0.46 (m, 2H). MS-ESI m/z calc. 727.2919, detected 728.1 (M+1) ⁺ ; retention time: 0.92 min (LC method A).

Step 2: 2-chloro-N-[1-[3-(5,5-dimethyln-pyrrolidin-3-yl)propyl]pyrazol-3-yl]sulfonyl-6-[3-(2dispiro[2.0.2.1]heptan- 7-ylethoxy)pyrazol-1-yl]pyridin-3-carboxamide

tert-Butyl 4-[3-[3-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]pyrazole -1-yl]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (350 mg, 0.4806

- 466044967 mmol) was dissolved in dichloromethane (1.527 ml) and trifluoroacetic acid (2.192 g, 1.481 ml, 19.22 mmol) was added to the mixture and the resulting mixture was stirred at room temperature for 60 minutes. The mixture was concentrated to dryness under reduced pressure and dissolved in saturated aqueous sodium bicarbonate and ethyl acetate, and the layers were separated. (Attention, the solubility of the product in ethyl acetate under these conditions is low; the addition of some methanol necessary to evaporate the organic layer without the use of a solid drying agent helps). The organic layer was concentrated on a rotary evaporator followed by drying in vacuo to give 2-chloro-I-[1-[3-(5,5dimethylpyrrolidin-3-yl)propyl]pyrazol-3-yl]sulfonyl-6-[3-( 2-dispiro[2.0.2.1]heptan-7ylethoxy)pyrazol-1-yl]pyridin-3-carboxamide (301.9 mg, 100%) as an off-white solid, which was used directly in the next step.

¹ H NMR (400 MHz, chloroform-d) δ 8.28 (d, J=2.8 Hz, 1H), 8.21 (d, J=8.3 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.44 ( s, 1H), 6.67 (s, 1H), 5.88 (d, J=2.8 Hz, 1H), 4.22 (t, J=6.8 Hz, 2H), 4.17 (s, 2H), 3.55 (s, 1H), 3.03 (s, 1H), 2.23 (s, 1H), 1.88 (d, J=6.7 Hz, 2H), 1.83 (s, 3H), 1.48 (s, 1H), 1.46-1.35 (m, 5H), 1.35 -1.24 (m, 4H), 0.84 (t, J=1.9 Hz, 4H), 0.63 (d, J=1.6 Hz, 2H), 0.51 (d, J=1.1 Hz, 2H).

Step 3: 4-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-20,20-dimethyl-10λ ⁶ -thia1,3,9 ,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione

2-chloro-I-[1-[3-(5,5-dimethylpyrrolidin-3-yl)propyl]pyrazol-3-yl]sulfonyl-6-[3-(2dispiro[2.0.2.1]heptane-7- ylethoxy)pyrazol-1-yl]pyridin-3-carboxamide (310 mg, 0.4935 mmol), potassium carbonate (341.1 mg, 2.468 mmol), cesium fluoride (112.8 mg, 0.7426 mmol), molecular 3 A sieve and dimethyl sulfoxide (9.3 ml) in a vial, which was purged with nitrogen, capped, heated to 155°C and stirred for 20 hours. The mixture was then cooled to room temperature and filtered, then diluted with ethyl acetate and washed with saturated aqueous solution sodium bicarbonate and then saline. The organic layers were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexanes to 100% ethyl acetate (product eluted when 100% ethyl acetate was reached) to give 4-[3 as a white solid -(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-20,20-dimethyl-10λ ⁶ thia-1,3,9,14,22-pentaazatetracyclo [16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (117 mg, 40%).

1H NMR (400 MHz, chloroform-d) δ 8.37 (s, 1H), 8.16 (d, J=2.8 Hz, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.48 (d, J=2.3 Hz , 1H), 7.26 (s, 1H), 7.07 (d, J=2.3 Hz, 1H), 7.02 (d, J=8.3 Hz, 1H), 5.86 (d, J=2.8 Hz, 1H), 4.36 (d , J=13.5 Hz, 1H), 4.24 (s, 2H), 3.95 (d, J=12.4 Hz, 1H), 2.74 (t, J=8.1 Hz, 1H), 2.15 (d, J=4.2 Hz, 2H ), 2.08-1.93 (m, 3H), 1.89 (d, J=6.7 Hz, 2H), 1.76 (dd, J=11.9, 5.3 Hz, 1H), 1.59 (s, 3H), 1.55 (s, 5H) , 0.85 (k, J=2.0 Hz, 4H), 0.64 (d, J=1.7 Hz, 2H), 0.51 (d, J=1.2 Hz, 2H). MS-ESI m/z calc. 591.26276, detected 592.4 (M+1)+; Retention time: 2.37 min (LC method B).

Step 4: (18R)-4-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-20,20-dimethyl10λ ⁶ -thia-1 ,3,9,14,22-pentaazαtetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (compound 186)

4-[3-(2-{Dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-20,20-dimethyl-10λ ⁶ -thia-1,3,9, 14,22pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (103 mg 0.1741 mmol) was subjected to chiral resolution using SLC - chromatography using ChiralPak AS-H (250x10 mm, particle size 5 μm) with a mobile phase of 34% acetonitrile/methanol (90:10)/66% carbon dioxide at 10 ml/min for 8.0 min (injection volume = 70 µl of a 24 mg/ml solution in acetonitrile/methanol (90:10)), which gives (18R)-4-[3-(2{dispiro[2.0.2.1]heptan-7-yl}ethoxy) as the first eluted enantiomer -1H-pyrazol-1-yl]-20,20-dimethyl-10λ ⁶ -thia-1,3,9,14,22pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11 (22 ),12-pentaene-8,10,10-trione (compound 186) (40.8 mg, 79%). MS-ESI m/z calc. 591.26276, detected 593.1 (M+1) ⁺ ; retention time: 2.3 min (LC method B).

- 467 044967

Example 171: Preparation of (14R)-12,12-dimethyl-8-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}1 H-pyrazol-1 -yl)-2λ ⁶ -thia-3, 9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5,7,9,19,21-hexaene-2,2,4-trione (compound 190)

Step 1: 2-chloro-N-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propylamino]-2-pyridyl]sulfonyl]-6-[3[3-[1 -(trifluoromethyl) cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3-carboxamide

From a 50 mL flask loaded with carbonyldiimidazole (216 mg, 1.332 mmol) and 2-chloro-6-[3-[3-[1(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridine-3-carboxylic acid ( 520 mg, 1.334 mmol) was pumped out with nitrogen, then filled with nitrogen again. Tetrahydrofuran (8 ml) was added and the mixture was stirred at 50°C for 1 hour. Then a solution of tert-butyl-2,2-dimethyl-4-[3-[(6-sulfamoyl2-pyridyl)amino]propyl]pyrrolidine- 1-carboxylate (500 mg, 1.212 mmol) and 1,8diazabicyclo[5.4.0]undec-7-ene (555 mg, 3.646 mmol) in tetrahydrofuran (3 ml) and the mixture was stirred overnight at 50°C. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, evaporated in vacuo and purified by chromatography on silica gel (0% to 50% ethyl acetate in hexanes) to obtain some pure fractions. The mixed fractions were further purified by preparative reverse phase HPLC (C ₁₈ ): l%-99% acetonitrile in water modified with hydrochloric acid. The neat fractions from the silica gel column and the HPLC preparatory column were combined to give the acyl sulfonamide intermediate, which was dissolved in dioxane (5 mL) and then treated with dioxane hydrochloric acid solution (2 mL 6 M, 12.00 mmol) and then stirred, at room temperature. temperature for 2 hours. The mixture was evaporated in vacuo and the residue was quenched with aqueous sodium bicarbonate. The white precipitate of the product was filtered off and washed with ethyl acetate. The aqueous phase was further extracted with ethyl acetate. The organic extract was dried over sodium sulfate, filtered and evaporated, obtaining after drying in vacuo 2-chloro-N[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propylamino]-2-pyridyl]sulfonyl]-6 -[3-[3-[1(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3-carboxamide (343 mg, 41%). MS-ESI m/z calc. 683.2268, detected 684.32 (M+1)+; retention time: 0.65 min (LC method A).

Step 2: (14R)-12,12-dimethyl-8-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1yl)-2Х ⁶ -thia-3,9,11, 18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (23),5,7,9,19,21-hexaene-2,2,4trione (compound 190)

Cesium fluoride (160 mg, 1.053 mmol), potassium carbonate (360 mg, 2.605 mmol), and 4A molecular sieves (600 mg) were combined in a 5 mL vial and the vial was evacuated and then re-pumped with nitrogen. Next, a solution of 2-chloro-N-[[6-[3-(5,5-dimethylpyrrolidin-3-yl)propulamino]-2pyridyl]sulfonyl]-6-[3-[3-[1-(trifluoromethyl)cyclopropyl] was added ]propoxy]pyrazol-1-yl]pyridin-3carboxamide (350 mg, 0.5116 mmol) in dimethyl sulfoxide (5 ml) and the mixture was stirred at 150°C overnight. The mixture was filtered and purified by preparative reverse phase (C ₁₈ ) HPLC: 1%-99% acetonitrile in water/hydrochloric acid modifier to give the racemic product. The racemate was subjected to chiral resolution by SLC chromatography using ChiralPak AS-H (250x10 mm, 5 μm particle size) with a mobile phase of 28% acetonitrile/methanol (90:10)/72%

- 468 044967 carbon dioxide (injection volume = 500 µl of a 32 mg/ml solution in acetonitrile/methanol (90:10)) to obtain (14R)-12,12-dimethyl-8-(3-{3) as the first enantiomer eluted -[1(trifluoromethyl)cyclopropyl]propoxy} -1 H-pyrazol-1 -yl)-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23) ,5,7,9,19,21-hexaene-2,2,4-trione (compound 190) (82.3 mg, 49%). MS-ESI m/z calc. 647.2502, detected 648.1 (M+1)+; retention time: 2.21 min (LC method B).

Example 172: Preparation of (14S)-8-[3-(4,4-dimethylpentyl)-2-oxoimidazolidin-1-yl]-12,12-dimethyl2X ⁶ -thia-3,9,11,18,23-pentaazatetracyclo [17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4trione (compound 193)

Step 1: (14S)-8-[3-(4,4-dimethylnentyl)-2-oxoimidazolidin-1-yl]-12,12-dimethyl-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 193)

(14S)-8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5 was added to the bottle ,7,9,19,21-hexaen-2,2,4-trione (60 mg, 0.1333 mmol), 1-(4,4dimethylpentyl)imidazolidin-2-one (50 mg, 0.2713 mmol), cesium carbonate (155 mg, 0.4757 mmol), 4,5bis(diphenylphosphino)-9,9-dimethylxanthene (12 mg, 0.02074 mmol) (xanthos) and anhydrous dioxane (2.0 ml) in that order. Nitrogen was bubbled through the heterogeneous mixture for 2 min. Pd ₂ (dba) ₃ (12 mg, 0.01328 mmol) was then added under nitrogen and nitrogen was bubbled through the mixture for a further 2 minutes before the vessel was capped under nitrogen. The mixture was stirred at 115°C for 13 hours. The mixture was allowed to cool to ambient temperature and then neutralized with glacial acetic acid (70 μl, 1.231 mmol). Volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.5 ml) and filtered through a 0.45 μm Whatman PTFE syringe disk filter. The sample was purified by preparative reverse phase HPLC-MS [30-99% acetonitrile in water (hydrochloric acid as modifier)]. The desired product fractions were combined and concentrated under reduced pressure and then dried under high vacuum to give (148)-8-[3-(4,4-dimethylpentyl)-2-oxoimidazolidin-1-yl]-12,12-dimethyl- 2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4 -trione (compound 193) (29 mg, 36%) as a pale yellow solid.

¹ H NMR (400 MHz, Methanol-d4) δ 7.70 (d, J=8.6 Hz, 1H), 7.52 (dd, J=8.5, 7.2 Hz, 1H), 7.44 (d, J=8.6 Hz, 1H), 7.15 (d, J=7.2 Hz, 1H), 6.65 (d, J=8.5 Hz, 1H), 4.14-3.94 (m, 3H), 3.52 (ddd, J=9.8, 7.0, 3.2 Hz, 2H), 3.24 (k, J=7.2 Hz, 3H), 3.09-2.97 (m, 1H), 2.86 (t, J=10.4 Hz, 1H), 2.23-2.08 (m, 1H), 1.83 (dd, J=11.3, 5.1 Hz, 2H), 1.65-1.63 (m, 3H), 1.63-1.55 (m, 4H), 1.55 (s, 3H), 1.42 (k, J=11.5 Hz, 1H), 1.29 (s, 1H), 1.26 -1.19 (m, 2H), 0.92 (s, 9H). MS-ESI m/z calc. 597.30975, detected 598.5 (M+1) ⁺ ; Retention time: 2.08 min (LC method B).

Example 173: Preparation of 12,20,20-trimethyl-4-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-10λ ⁶ -thia-1,3,9,14 ,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2(7),3,5,11(22),12pentaene-8,10,10-trione (compound 199)

- 469 044967

Step 1: 3-iodo-1-[(4-methoxyphenyl)methyl]-4-methylpyrazole and 5-iodo-1-[(4-methoxyphenyl)methyl]-4methylpyrazole (mixture of regioisomers).

N-iodosuccinimide (27.4 g, 121.79 mmol) was added to a solution of 4-methyl-N-pyrazole (10 g, 121.80 mmol) in dimethylformamide (100 ml) at room temperature. The mixture was stirred overnight, then poured into water (700 ml) and extracted with ethyl acetate (4x150 ml). The organic phases were combined and washed with water (3x150 ml) and brine (150 ml), dried with sodium sulfate, filtered and concentrated under reduced pressure to give the crude iodinated intermediate. To a solution of crude iodinated material (2 g, 9.6154 mmol) and potassium carbonate (2 g, 14.471 mmol) in acetonitrile (15 ml) was added 1-(chloromethyl)-4-methoxybenzene (1.5015 g, 1.3 ml , 9.5876 mmol). The mixture was stirred at 80°C overnight before concentration under reduced pressure. The residue was suspended in dichloromethane (80 ml). After stirring for 10 min, the mixture was mixed with silica gel before concentration. The dry residue was added to a silica gel column and eluted with 0-30% ethyl acetate in heptanes to obtain 3-iodo-1-[(4methoxyphenyl)methyl]-4-methylpyrazole and 5-iodo-1-[(4-methoxyphenyl)methyl]- 4-methylpyrazole (mixture of regioisomers) (1.36 g, 43%) as a pale yellow solid. MS-ESI m/z calc. 328.0073, detected 329.0 (M+1)+; retention time: 2.02 min (LC method I).

Step 2: 2-ethylhexyl-3-[1-[(4-methoxyphenyl)methyl]-4-methylpyrazol-3-yl]sulfanylpropanoate and 2-ethylhexyl 3-[2-[(4-methoxyphenyl)methyl]-4- Methyl-pyrazol-3-yl]sulfanylpropanoate (mixture of regioisomers)

mixture of regioisomers

In a hermetically sealed test tube, a solution of 3-iodo-1-[(4-methoxyphenyl)methyl]-4-methylpyrazole and 5iodo-1-[(4-methoxyphenyl)methyl]-4-methylpyrazole (mixture of regioisomers) (1.34 g, 4.0835 mmol) and diisopropylethylamine (1.0685 g, 1.44 mL, 8.2674 mmol) in toluene (25 mL) were degassed by bubbling nitrogen for 5 min. Tris(dibenzylideneacetone)dipalladium (0) (111 mg, 0.1212 mmol), xanthos (142 mg, 0.2454 mmol) and 2-ethylhexyl-3-sulfanylpropanoate (986 mg, 4.5156 mmol) were added and the vial was sealed. and the mixture was heated at 110°C overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0% to 20% ethyl acetate in heptanes to give 2-ethylhexyl-3-[1-[(4-methoxyphenyl)methyl]-4-methylpyrazol3-yl]sulfanylpropanoate and 2-ethylhexyl- 3-[2-[(4-methoxyphenyl)methyl]-4-methylpyrazol-3yl]sulfanylpropanoate (mixture of regioisomers) (1.54 g, 90%) as an orange oil. MS-ESI m/z calc. 418.229, detected 419.3 (M+1) ⁺ ; retention time: 2.58 min (LC method I).

Step 3: [1-[(4-methoxyphenyl)methyl]-4-methylpyrazol-3-yl]sulfinyloxysodium and [2-[(4methoxyphenyl)methyl]-4-methylpyrazol-3-yl]sulfinyloxysodium (mixture of regioisomers)

- 470 044967

Sodium methoxide (750.17 mg, 13.886 mmol) was added to a solution of 2-ethylhexyl-3-[1-[(4methoxyphenyl)methyl]-4-methylpyrazol-3-yl]sulfonylpropanoate and 2-ethylhexyl-3-[2-[ (4methoxyphenyl)methyl]-4-methylpyrazol-3-yl]sulfonylpropanoate (mixture of regioisomers) (1.56 g, 3.4621 mmol) in tetrahydrofuran (4 ml) and methanol (1.4 ml) at room temperature. The reaction mixture was stirred for 2 hours, then the mixture was concentrated under reduced pressure to give [1[(4-methoxyphenyl)methyl]-4-methylpyrazol-3-yl]sulfinyloxysodium and [2-[(4-methoxyphenyl)methyl]-4methylpyrazole -3-yl]sulfinyloxysodium (mixture of regioisomers) (1.04 g, 104%) as a beige solid. MS-ESI m/z calc. 288.0545, detected 289.1 (M+1)+; retention time: 1.5 min (LC method I).

Step 4: 1-[(4-methoxyphenyl)methyl]-4-methylpyrazole-3-sulfonamide and 2-[(4-methoxyphenyl)methyl]4-methylpyrazole-3-sulfonamide (mixture of regioisomers).

Hydroxylamine-O-sulfonic acid (9.7 g, 85.770 mmol) was added to a solution of [1-[(4methoxyphenyl)methyl]-4-methylpyrazol-3-yl]sulfinyloxysodium and [2-[(4-methoxyphenyl)methyl]- 4methylpyrazol-3-yl]sulfinyloxysodium (mixture of regioisomers) (12.4 g, 43.011 mmol) and sodium acetate (10.5 g, 128.00 mmol) in water (400 ml) at 0°C. The mixture was stirred at room temperature overnight and then extracted with ethyl acetate (2x300 ml). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 20% to 60% ethyl acetate in heptanes to give 1-[(4methoxyphenyl)methyl]-4-methylpyrazole-3-sulfonamide and 2-[(4-methoxyphenyl)methyl]-4- Methylpyrazole-3sulfonamide (mixture of regioisomers) (9.72 g, 80%) as an off-white solid. MS-ESI m/z calc. 281.0834, detected 282.1 (M+1) ⁺ ; retention time: 1.51 min (LC method I).

Step 5: 4-methyl-1H-pyrazole-3-sulfonamide

Solution of 1-[(4-methoxyphenyl)methyl]-4-methylpyrazole-3-sulfonamide and 2-[(4-methoxyphenyl)methyl]4-methylpyrazole-3-sulfonamide (mixture of regioisomers) (270 mg, 0.9597 mmol) in trifluoroacetic acid (2 ml) was stirred at 80°C overnight. The mixture was concentrated and the residue was purified by silica gel chromatography using a gradient of 20% to 100% ethyl acetate in heptanes followed by isocratic 10% methanol in ethyl acetate to give 4-methyl-1H-pyrazole-3-sulfonamide (120 mg, 78%) as white solid.

¹ H NMR (300 MHz, DMSO-66) ppm 2.12 (s, 3H), 7.29 (s, 2H), 7.64 (s, 1H), 13.11 (br. s., 1H). MS-ESI m/z calc. 161.0259, detected 162.1 (M+1) ⁺ ; Retention time: 0.46 min (LC method I).

Step 6: tert-butyl 2,2-dimethyl-4-[3-(4-methyl-3-sulfamoyl-pyrazol-1-yl)propyl]pyrrolidine-1-carboxylate

A solution of tert-butyl 2,2-dimethyl-4-(3-methylsulfonyloxypropyl)pyrrolidine-1-carboxylate (750 mg, 2.236 mmol), potassium carbonate (772 mg, 5.586 mmol) and 4-methyl-1H-pyrazole-3 α-sulfonamide (300 mg, 1.861 mmol) in N,N-dimethylformamide (3 ml) was stirred at 80°C for 4 hours. The mixture was filtered and dissolved in diethyl ether. The mixture was washed with water, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography (0% to 30% ethyl acetate in hexane), which resulted in poor separation. The mixed fractions were combined, evaporated and separated by preparative reverse phase HPLC ( _C18 , 1-99% acetonitrile in water/hydrochloric acid modifier) to yield tert-butyl-2,2-dimethyl-4- as the first major regioisomer eluted. [3-(4-methyl-3-sulfamoyl-pyrazol-1-yl)propyl]pyrrolidine-1-carboxylate (200 mg,

27%).

1H NMR (400 MHz, chloroform-d) δ 7.23-7.19 (m, 1H), 5.06 (s, 2H), 4.08 (t, J=7.0 Hz, 2H), 3.65 (dd, J=10.2, 7.6 Hz, 1H), 2.82 (t, J=10.6 Hz, 1H), 2.26 (d, J=0.7 Hz, 3H), 2.11-1.97 (m, 1H), 1.92-1.82 (m, 3H), 1.661.58 (m , 1H), 1.46 (s, 9H), 1.39 (s, 3H), 1.37-1.30 (m, 2H), 1.27 (s, 3H). MS-ESI m/z calc. 400.21442, found 401.26 (M+1)+; Retention time: 0.65 min (LC method A).

Step 7: 2-chloro-K-[1-[3-(5,5-dimethylpyrrolidin-3-yl)propyl]-4-methyl-pyrazol-3-yl]sulfonyl6-[3-[2-[1- (trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (hydrochloride salt)

From a 50 mL flask loaded with carbonyldiimidazole (73 mg, 0.4502 mmol) and 2-chloro-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxylic acid acid (170 mg, 0.4525 mmol), nitrogen was pumped out, then filled with nitrogen again. Tetrahydrofuran (5 ml) was added and the mixture was stirred at 50°C for 1 hour. Then a solution of tert-butyl-2,2-dimethyl-4-[3-(4-methyl-3sulfamoylpyrazol-1-yl)propyl] was added pyrrolidine-1-carboxylate (150 mg, 0.3745 mmol) and 1,8diazabicyclo[5.4.0]undec-7-ene (143 mg, 0.9393 mmol) in tetrahydrofuran (4 ml) and the mixture was stirred overnight at 50°C. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, evaporated in vacuo and purified by preparative reverse phase HPLC ( _C18 , l%-99% acetonitrile in water/hydrochloric acid modifier) to obtain the acyl sulfonamide intermediate, which was dissolved in dioxane (5 ml), treated with hydrochloric acid acid (1.3 ml of 6 M in dioxane, 7,800 mmol) and stirred at room temperature for 3 hours. The mixture was evaporated in vacuo to give 2-chloro-I-[1-[3-(5,5-dimethylpyrrolidin-3-yl )propyl]-4methylpyrazol-3-yl]sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carboxamide (hydrochloride salt) (57 mg, 22%) . MS-ESI m/z calc. 657.2112, detected 658.32 (M+1) ⁺ ; retention time: 0.6 min (LC method A).

Step 8: 12,20,20-trimethyl-4-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)1Oλ ⁶ -thia-1,3,9, 14,22-pentaazatetracyclo[16.2.1.111,14.O2,7]docose-2(7),3,5,11(22),12-pentaene-8,10,1Otrione (compound 199)

The vial was hermetically sealed with 5 ml of 2-chloro-I-[1-[3-(5,5-dimethylpyrrolidin-3-yl)propyl]-4methylpyrazol-3-yl]sulfonyl-6-[3-[2-[1 -(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3carboxamide (hydrochloride salt) (57 mg, 0.08206 mmol), potassium carbonate (58 mg, 0.4197 mmol), cesium fluoride (25 mg, 0 ,1646 mmol) and 3 A molecular sieves (300 mg), and purged with nitrogen. Dimethyl sulfoxide (3 ml) was added and the mixture was stirred at 150°C overnight. The mixture was filtered and purified by preparative reverse phase HPLC ( _C18 , l%-99% acetonitrile in water/hydrochloric acid modifier) to give 12,20,20-trimethyl-4-(3-{2-[1-(trifluoromethyl) cyclopropyl]ethoxy}1H-pyrazol-1-yl)-1Oλ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2(7),3,5,11 (22),12pentaene-8,10,10-trione (compound 199) (6.2 mg, 12%). MS-ESI m/z calc. 621.2345, detected 622.35 (M+1) ⁺ ; retention time: 2.16 min (LC method B).

Example 174: Preparation of (14S)-8-(3-cyclohexyl-2-oxoimidazolidin-1-yl)-12,12-dimethyl-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05 ,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 200)

- 472 044967

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

200)

(14S)-8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23) was loaded into a 5 ml ampoule. 5,7,9,19,21-hexaene-2,2,4-trione (50 mg, 0.1075 mmol), 1-cyclohexylimidazolidin-2-one (26 mg, 0.1545 mmol), Pd ₂ (dba ) ₃ (26 mg, 0.02839 mmol), xanthos (16 mg, 0.02765 mmol), cesium carbonate (180 mg, 0.5525 mmol) and anhydrous dioxane (800 µl). The mixture was purged with nitrogen for 1-2 minutes, capped and stirred at 120°C for 20 hours, and then cooled to room temperature. The solvent was evaporated, the reaction mixture was diluted with dimethyl sulfoxide (900 μl), microfiltered and purified by reverse phase preparative chromatography using a C ₁₈ column (10%-99% acetonitrile in water + 5 mM hydrochloric acid). The product fractions were combined, brine was added, and the organic solvents were evaporated. The product was extracted with dichloromethane, the organic phase was dried over sodium sulfate, filtered and evaporation of the solvents gave a solid. The product was further purified by silica gel chromatography using a gradient of 100% dichloromethane to 5% methanol in dichloromethane to provide an off-white solid (14S)-8-(3-cyclohexyl-2oxoimidazolidin-1-yl)-12,12- dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2 ,4-trione (compound 200) (22.5 mg, 36%).

1H NMR (400 MHz, chloroform-d) δ 10.79 (s, 1H), 8.01 (d, J=8.7 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.55 (k, J=2.9, 2.1 Hz, 2H), 6.54 (dd, J=5.4, 3.7 Hz, 1H), 4.80 (s, 1H), 3.99 (dd, J=9.1, 7.1 Hz, 2H), 3.83 (s, 2H), 3.45 ( t, J=8.1 Hz, 2H), 3.32 (t, J=8.9 Hz, 1H), 3.23-3.10 (m, 1H), 3.04 (t, J=9.4 Hz, 1H), 2.71 (s, 1H), 2.12 (dd, J=12.4, 8.6 Hz, 1H), 1.84-1.76 (m, 4H), 1.69 (d, J=13.2 Hz, 2H), 1.56 (d, J=5.2 Hz, 8H), 1.43-1.36 (m, 4H), 1.15-1.06 (m, 1H), 0.91-0.85 (m, 1H). MS-ESI m/z calc. 581.27844, detected 582.2 (M+1)+; retention time: 1.86 min (LC method E).

Example 175: Preparation of 4-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,20,20-trimethyl10λ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2 .1.111,14.02,7]docose-2(7),3,5,11(22),12-pentaene-8,10,10trione (enantiomer 1) (compound 201) and 4-[3-(3,3 -dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,20,20trimethyl-10λ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02.7]docose-2(7) ,3,5,11(22),12-pentaene8,10,10-trione (enantiomer 2) (compound 202)

Step 1: 2-chloro-6-[3-(3,3-dicyclopropylpropoxy)nirazol-1-yl]-N-[1-[3-(5,5dimethylpyrrolidin-3-yl)propyl]-4-methyl- pyrazol-3-yl]sulfonylpyridin-3-carboxamide (hydrochloride salt)

From a 50 mL flask loaded with carbonyldiimidazole (78 mg, 0.4810 mmol) and 2-chloro-6-[3-(3,3dicyclopropylpropoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (174 mg, 0. 4809 mmol) the nitrogen was pumped out and refilled with it. Tetrahydrofuran (8 ml) was added and the mixture was stirred at 50°C for 1 hour. Then a solution of tert-butyl-2,2-dimethyl-4-[3-(4-methyl-3-sulfamoylpyrazol-1yl)propyl]pyrrolidine was added -1-carboxylate (160 mg, 0.3995 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (160

- 473 044967 mg, 1.051 mmol) in tetrahydrofuran (4 ml) and the mixture was stirred overnight at 50°C. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, evaporated in vacuo and purified by chromatography on silica gel (0% to 50% ethyl acetate in hexanes) to obtain some pure fractions. The mixed fractions were repurified by preparative reverse phase HPLC (C ₁₈ , l%-99% acetonitrile in water/hydrochloric acid modifier) and the resulting pure material was combined with the pure fractions from the original silica gel column to yield the acyl sulfonamide intermediate. A solution of the acyl sulfonamide intermediate in dioxane (5 ml) was treated with hydrochloric acid (1.3 ml, 6 M in dioxane, 7.800 mmol) and stirred at room temperature for 3 hours. The mixture was evaporated in vacuo to give 2-chloro-6-[3 -(3,3dicyclopropylpronoxy)pyrazol-1-yl]-N-[1-[3-(5,5-dimethylpyrrolidin-3-yl)propyl]-4-methylnirazol3-yl]sulfonylpyridin-3-carboxamide (hydrochloride salt) (160 mg, 59%). MS-ESI m/z calc. 643.27075, detected 644.38 (M+1)+; retention time: 0.65 min (LC method A).

Step 2: 4-[3 -(3,3-dicyclopropylpropoxy)-1 H-pyrazol-1 -yl]-12,20,20-trimethyl-10λ ⁶ -thia1,3,9,14,22-pentaazatetracyclo[16.2 .1.111,14.02,7]docose-2(7),3,5,11(22),12-pentaene-8,10,10-trione

The vial was hermetically sealed with 5 ml of 2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]-N[1-[3-(5,5-dimethylpyrrolidin-3-yl)propyl]- 4-methylpyrazol-3-yl]sulfonylpyridin-3-carboxamide (hydrochloride salt) (160 mg, 0.2351 mmol), potassium carbonate (165 mg, 1.194 mmol), cesium fluoride (73 mg, 0.4806 mmol) and molecular 3 A sieve (300 mg) and purged with nitrogen. Dimethyl sulfoxide (4 ml) was added and the mixture was stirred at 150°C overnight. The mixture was filtered and purified by preparative reverse phase HPLC ( _C18 , l%-99% acetonitrile in water/hydrochloric acid modifier) to give 4-[3-(3,3-dicyclopropylpnoxy)-1H-pyrazol-1-yl]- 12,20,20-trimethyl-10λ ⁶ -thia1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2(7),3,5,11(22),12-pentaene -8,10,10-trione (53.7 mg, 38%). MS-ESI m/z calc. 607.29407, detected 608.41 (M+1) ⁺ ; retention time: 2.36 min (LC method B).

Step 3: 4-[3 -(3,3-dicyclopropylpropoxy)-1 H-pyrazol-1 -yl]-12,20,20-trimethyl-10λ ⁶ -thia1,3,9,14,22-pentaazatetracyclo[16.2 .1.111,14.02,7]docose-2(7),3,5,11(22),12-pentaene-8,10,10-trione (enan thiomer 1) (compound 201) and 4-[3-( 3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,20,20-trimethyl10λ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2 (7),3,5,11 (22), 12-pentaene-8,10,10trione (enantiomer 2) (compound 202)

4-[3-(3,3-Dicyclopropylpronoxy)-1H-pyrazol-1-yl]-12,20,20-trimethyl-10λ ⁶ -thia-1,3,9,14,22pentaazatetracyclo[16.2.1.111,14.02 ,7]docose-2(7),3,5,11(22),12-pentaene-8,10,10-trione (53.7 mg) was subjected to chiral separation by SLC chromatography using ChiralPak AS-3 (150x2.1 mm, particle size 3 μm) with a mobile phase of 32% acetonitrile/methanol (90:10)/68% carbon dioxide at 0.5 ml/min for 6.0 min (1.6 mg/ml solution in acetonitrile/methanol (90:10)) to obtain 4-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]12,20,20-trimethyl-10λ ⁶ -thia- as the first eluted enantiomer 1,3,9,14,22-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2(7),3,5,11(22),12pentaene-8,10,10-trione (enantiomer 1) ( compound 201) (3.5 mg, 5%). MS-ESI m/z calc. 607.29407, detected 608.38 (M+1) ⁺ ; retention time: 2.36 min (LC method B).

The second enantiomer eluted was 4-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]12,20,20-trimethyl-10λ ⁶ -thia-1,3,9,14,22-pentaazatetracyclo[ 16.2.1.111,14.02,7]docose-2(7),3,5,11(22),12pentaene-8,10,10-trione (enantiomer 2) (compound 202) (5.0 mg, 7%) . MS-ESI m/z calc. 607.29407, detected 608.3 (M+1) ⁺ ; Retention time: 2.49 min (LC method B).

Example 176: Preparation of 8-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12,18-trimethyl2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3 .1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4trione (enantiomer 1) (compound 203) and 8-[3-(3 ,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12,18trimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 ( 22),5,7,9,19(23),20hexaene-2,2,4-trione (enantiomer 2) (compound 204)

- 474 044967

Step 1: 8-[3-(3,3-dicyclononylpronoxy)-1H-pyrazol-1-yl]-12,12,18-trimethyl-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[17.3. 1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (enantiomer 1) (compound 203) and 8-[3-( 3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12,18trimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20hexaene-2,2,4-trione (enantiomer 2) (compound 204)

Racemic 8-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-12,12,18-trimethyl2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3. 1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4trione (76 mg) by chiral SLC chromatography. The following LCLC protocol was used: ChiralPak

AS-H (250x10 mm), 5 µm; mobile phase: 38% acetonitrile:methanol (90:10), 62% carbon dioxide, injection of 70 µl of a 16 mg/ml solution in acetonitrile:methanol:dimethyl sulfoxide (74:8:18) at a rate of 10 ml/min. The first enantiomer eluted was 8-[3-(3,3-dicyclopropylpropoxy)-1Hpyrazol-1-yl]-12,12,18-trimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3 .1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4 trione (enantiomer 1) (compound 203) (3.5 mg, 6%) as a white solid. MS-ESI m/z calc. 633.30975, detected 634.4 (M+1)+; retention time: 1.54 min (LC method J).

The second enantiomer eluted was 8-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]12,12,18-trimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4 trione (enantiomer 2) (compound 204) (3.5 mg, 6% ) as a white solid. MS-ESI m/z calc. 633.30975, detected 634.4 (M+1) ⁺ ; retention time: 1.54 min (LC method J).

Example 177: Preparation of (14S)-12,12-dimethyl-8-(2-oxo-3-{3-[1-(trifluoromethyl)cyclononyl]πpropyl}imidazolidin-1-yl)-2λ ⁶ -thia-3, 9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 205)

Step 1: 3-[1-(trifluoromethyl)cyclopropyl]propanal o

Dess-Martin periodinan (880 mg, 2.075 mmol) was added to a stirred solution of 3-[1(trifluoromethyl)cyclopropyl]propan-1-ol (350 mg, 1.665 mmol) in anhydrous methylene chloride (10 ml) at 0°C (bath ice) in a nitrogen atmosphere. After 15 minutes, the bath was removed, the reaction mixture was allowed to warm to ambient temperature, and stirring was continued for another 3 hours. The reaction mixture was diluted with ether (60 ml) and saturated aqueous sodium bicarbonate (20 ml) was added slowly (to reduce the evolution of carbon dioxide gas). Sodium thiosulfate (10 ml) was then added and the mixture was stirred at ambient temperature for 30 minutes. The layers were separated and the aqueous layer was extracted with ether (2x20 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure (rotary evaporator, 300 mbar pressure to avoid evaporation of some volatile products) to give 3-[1-(trifluoromethyl)cyclopropyl] propanal (250 mg, 90%) as a yellow oil. This material was used in the subsequent reaction without drying to pure material and without further purification.

1H NMR (400 MHz, Benzene-d6) δ 9.15 (s, 1H), 1.99-1.90 (m, 2H), 1.52-1.44 (m, 2H), 0.68-0.59 (m, 2H), 0.00 (dd, J =2.5, 1.6 Hz, 2H).

Step 2: tert-butyl N-[2-[3-[1-(trifluoromethyl)cyclopropyl]propylamino]ethyl]carbamate

- 475 044967 o

To a stirred solution of tert-butyl N-(2-aminoethyl)carbamate (242 mg, 1.510 mmol) in anhydrous methanol (7 ml) was added a solution of 3-[1-(trifluoromethyl)cyclopropyl]propanal (250 mg, 1.505 mmol) in anhydrous methanol (1 ml) under nitrogen atmosphere. After the yellow solution was stirred at ambient temperature for 1 hour, it was cooled to 0°C (ice bath). Sodium borohydride (125 mg, 3.304 mmol) was then added slowly in two portions and the mixture was allowed to warm to ambient temperature and stirring was continued for 13 hours. Volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (30 ml) and washed with saturated aqueous sodium bicarbonate (2x 15 ml) and brine (15 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product tert-butyl N-[2-[ 3-[1-(trifluoromethyl)cyclopropyl]propylamino]ethyl]carbamate (467 mg, 100%) as a yellow oil contaminated with some bis-adduct. This material was carried directly to the next stage. MS-ESI m/z calc. 310.1868, detected 311.3 (M+1)+; retention time: 1.17 min (LC method B).

Step 3: 1-[3-[1-(trifluoromethyl)cyclopropyl]propyl]imidazolidin-2-one o

Solid potassium tert-butoxide (275 mg, 2.451 mmol) was added to a solution of crude tert-butyl-N-[2-[3-[1-(trifluoromethyl)cyclopropyl]propylamino]ethyl]carbamate (250 mg, 0.8055 mmol, contaminated with some bis-adducts from the previous step) in anhydrous tetrahydrofuran (10 ml) under a nitrogen atmosphere and the reaction mixture was heated to 70°C for 13 hours. The reaction mixture was allowed to cool to ambient temperature and the reaction mixture was acidified to pH 4-5 with aqueous hydrochloric acid (2.5 ml 1 M, 2,500 mmol). After removal of volatiles under reduced pressure, the aqueous residue was extracted with ethyl acetate (3x25 ml). The combined organic layers were washed with brine (2x20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0%-10% methanol methylene chloride gradient) to give 1-[3-[1-(trifluoromethyl)cyclopropyl]propyl]imidazolidin-2-one (72 mg, 38%) as off-white solid matter.

¹ H NMR (400 MHz, Benzene-d ₆ ) δ 5.35 (s, 1H), 2.84 (t, J=6.8 Hz, 2H), 2.54-2.41 (m, 4H), 1.33-1.25 (m, 2H), 1.23-1.17 (m, 2H), 0.63-0.54 (m, 2H), 0.05- -0.06 (m, 2H). MS-ESI m/z calc. 236.11365, detected 237.1 (M+1) ⁺ ; retention time: 0.93 min (LC method B).

Step 4: (14S)-12,12-dimethyl-8-(2-oxo-3-{3-[1-(trifluoromethyl)cyclopropyl]propyl}imidαzolidin-1-yl)-2λ ⁶ -thiα-3,9 ,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 205)

(14S)-8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23) was added to a 4 ml bottle. 5,7,9,19,21-hexaene-2,2,4-trione (50 mg, 0.1111 mmol), 1-[3-[1-(trifluoromethyl)cyclopropyl]propyl]imidazolidin-2-one ( 32 mg, 0.1355 mmol), cesium carbonate (130 mg, 0.3990 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg, 0.01728 mmol) (xanphos) and dioxane anhydrous (1.1 ml) in this sequence. Nitrogen was bubbled through the heterogeneous mixture for 2 min. Pd ₂ (dba) ₃ (10 mg, 0.01107 mmol) was then added under nitrogen and nitrogen was bubbled through the reaction mixture for an additional 2 minutes and the reaction mixture was capped under nitrogen. The mixture was stirred at 115°C for 14 hours. The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (50 μl, 0.8792 mmol). Volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.5 ml) and filtered through a 0.45 μm Whatman PTFE syringe disk filter. The sample was purified by preparative reverse phase HPLC-MS (30-99% acetonitrile in water (hydrochloric acid as modifier)). The desired product fractions were combined and concentrated under reduced pressure and the residue was dissolved in ethyl acetate (25 ml) and washed successively with saturated aqueous sodium bicarbonate (2x10 ml) and brine (10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (14S)-12,12-dimethyl-8-(2-oxo-3-{3-[1-(trifluoromethyl)cyclopropyl]propyl}imidazolidine- 1-yl)-2λ ⁶ thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene -2,2,4- 476 044967 trione (compound 205) (19.0 mg, 26%) as an off-white solid.

Ή NMR (400 MHz, Methanol-d ₄ ) δ 7.70 (d, J=8.5 Hz, 1H), 7.53 (dd, J=8.5, 7.2 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.15 (dd, J=7.2, 0.8 Hz, 1H), 6.65 (dd, J=8.5, 0.8 Hz, 1H), 4.14-4.07 (m, 1H), 4.07-4.02 (m, 1H), 4.02-3.95 ( m, 1H), 3.56-3.45 (m, 2H), 3.29-3.19 (m, 3H), 3.03 (d, J=13.8 Hz, 1H), 2.86 (t, J=10.4 Hz, 1H), 2.21-2.09 (m, 1H), 1.83 (dd, J=11.7, 5.4 Hz, 2H), 1.78-1.69 (m, 2H), 1.69-1.63 (m, 4H, partially obscured by residual water peak), 1.61 (d, J =5.6 Hz, 2H), 1.60-1.57 (m, 1H), 1.55 (s, 3H), 1.42 (k, J=11.5 Hz, 1H), 1.32-1.26 (m, 1H), 0.960.90 (m, 2H), 0.72-0.66 (m, 2H). MS-ESI m/z calc. 649.2658, detected 650.4 (M+1)+; retention time: 1.92 min (LC method B). Example 178: Preparation of (14S)-12,12-dimethyl-8-(2-oxo-3-{2-[1(trifluoromethyl)cyclopropyl]ethyl}imidazolidin-1-yl)-2λ ⁶ -thia-3,9 ,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 211)

Step 1: 2-[1-(trifluoromethyl)cyclopropyl]acetaldehyde

Dess-Martin periodinane (2.43 g, 5.729 mmol) was added to a stirred solution of 2-[1(trifluoromethyl)cyclopropyl]ethanol (700 mg, 4.542 mmol) in anhydrous methylene chloride (15 ml) at 0°C (ice water bath ) in a nitrogen atmosphere. After 15 minutes, the bath was removed, the reaction mixture was allowed to warm to ambient temperature, and stirring was continued for another 3 hours. The reaction mixture was diluted with ether (60 ml) and saturated aqueous sodium bicarbonate (20 ml) was added slowly (to reduce the evolution of carbon dioxide gas). Sodium thiosulfate (10 ml) was then added and the mixture was stirred at ambient temperature for 30 minutes. The layers were separated and the aqueous layer was extracted with ether (2x20 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure (at 300 mbar to avoid evaporation of some volatile products) to give 2-[1-(trifluoromethyl)cyclopropyl]acetaldehyde (500 mg, 72%) as crude material. Due to its volatility, it was not dried or purified.

1H NMR (400 MHz, Benzene-d ₆ ) δ 9.24 (tt, J=2.3, 1.2 Hz, 1H), 1.77 (d, J=2.4 Hz, 2H), 0.66-0.59 (m, 2H), 0.00 (qd , J=4.4, 2.3 Hz, 2H). ¹⁹ F NMR (376 MHz, benzene-de) δ -70.56.

Step 2: tert-butyl N-[2-[2-[1-(trifluoromethyl)cyclopropyl]ethylamino]ethyl]carbamate

IC 4- H ₂ N NHBoc М NHBoc ^{n s} -d< 7 \__I ------► FiC \__/ /Λ h

To a stirred solution of tert-butyl Na(2-aminoethyl) carbamate (527 mg, 3.289 mmol) in anhydrous methanol (15 ml) was added a solution of 2-[1-(trifluoromethyl)cyclopropyl]acetaldehyde (500 mg, 3.287 mmol) in anhydrous methanol (1 ml) under nitrogen atmosphere. After the yellow solution was stirred at ambient temperature for 1 hour, it was cooled to 0°C (ice bath). Sodium borohydride (260 mg, 6.872 mmol) was then added slowly in two portions, the mixture was allowed to warm to ambient temperature and stirring was continued for 15 hours. Volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (30 ml) and washed with saturated aqueous sodium bicarbonate (2x 15 ml) and brine (15 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl N-[2-[ 2-[1(trifluoromethyl)cyclopropyl]ethylamino]ethyl]carbamate (970 mg, 100%) as a yellow oil. The crude material was used in a further step without any further purification. MSIE m/z calc. 296.17117, detected 297.3 (M+1) ⁺ ; retention time: 0.79 min (LC method B).

Step 3: 1-[2-[1 -(trifluoromethyl)cyclopropyl]ethyl]imidazolidin-2-one <7° pA/^NH NHBoc<7 A

_F3CNH

F ₃ CVA

Solid potassium tert-butoxide (460 mg, 4.099 mmol) was added to a solution of tert-butyl-N-[2-[2-[1(trifluoromethyl)cyclopropyl]ethylamino]ethyl]carbamate (400 mg, 1.350 mmol) in anhydrous tetrahydrofuran ( 20 ml) and the heterogeneous reaction mixture was heated at 70°C for 13 hours. The reaction mixture was allowed to cool to ambient temperature and acidified with glacial acetic acid (250 μl, 4.396 mmol). Volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography (0%-10% methanol methylene chloride gradient) to give 1-[2-[1-477 044967 (trifluoromethyl)cyclopropyl]ethyl]imidazolidin-2-one (127 mg , 42%) as an off-white solid.

¹ H NMR (400 MHz, Benzene-d ₆ ) δ 4.99 (s, 1H), 3.35-3.20 (m, 2H), 2.71-2.56 (m, 4H), 1.70-1.59 (m, 2H), 0.86-0.73 (m, 2H), 0.46-0.33 (m, 2H). MS-ESI m/z calc. 222.09799, detected 223.1 (M+1)+; retention time: 0.78 min (LC method B).

Step 4: (14S)-12,12-dimethyl-8-(2-oxo-3 -{2-[1 -(trifluoromethyl)cyclopropyl]ethyl} imidazolidin1-yl)-2λ ⁶ -thia-3,9,11 ,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (compound 211)

(148)-8-chloro-12,12-dimethyl-2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5 was added to a ml bottle ,7,9,19,21-hexaene-2,2,4-trione (50 mg, 0.1111 mmol), 1-[2-[1-(trifluoromethyl)cyclopropyl]ethyl]imidazolidin-2-one (30 mg, 0.1350 mmol), cesium carbonate (130 mg, 0.3990 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg, 0.01728 mmol) (xanphos) and dioxane anhydrous ( 1 ml) in this sequence. Nitrogen was purged through the heterogeneous mixture for 2 min. Pd ₂ (dba) ₃ (10 mg, 0.01107 mmol) was then added under nitrogen and the mixture was purged with nitrogen for a further 2 minutes, then capped under nitrogen. The mixture was stirred at 115°C for 14 hours. The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (50 μl, 0.8792 mmol). Volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.5 ml) and filtered through a 0.45 μm Whatman PTFE syringe disk filter. The sample was purified by preparative reverse phase HPLC-MS (30-99% acetonitrile in water (hydrochloric acid as modifier). Desired product fractions were combined and concentrated under reduced pressure, the residue was dissolved in ethyl acetate (25 ml) and washed with brine (10 ml) The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a yellowish solid.The solid was further purified by silica gel column chromatography (0%-10% methanol in dichloromethane) to give (148)-12,12- dimethyl-8-(2-oxo-3-{2-[1(trifluoromethyl)cyclopropyl]ethyl}imidazolidin-1 -yl)-2Х ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05 ,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 211) (18 mg, 25%) as an off-white solid .

1H NMR (400 MHz, Methanol-d4) δ 7.71 (d, J=8.6 Hz, 1H), 7.52 (dd, J=8.5, 7.2 Hz, 1H), 7.42 (d, J=8.6 Hz, 1H), 7.15 (dd, J=7.3, 0.8 Hz, 1H), 6.65 (d, J=8.5 Hz, 1H), 4.17-4.03 (m, 2H), 3.99 (td, J=10.2, 9.7, 6.7 Hz, 1H), 3.53 (ddd, J=9.5, 6.9, 2.5 Hz, 2H), 3.45-3.37 (m, 2H), 3.24 (t, J=8.7 Hz, 1H), 3.03 (d, J=13.7 Hz, 1H), 2.87 (t, J=10.5 Hz, 1H), 2.20-2.09 (m, 1H), 1.89-1.80 (m, 4H), 1.63 (s, 3H), 1.59 (t, J=12.2 Hz, 1H), 1.54 ( s, 3H), 1.48-1.38 (m, 1H), 1.29 (s, 2H), 1.02-0.96 (m, 2H), 0.81-0.75 (m, 2H). MS-ESI m/z calc. 635.2502, detected 636.4 (M+1) ⁺ ; retention time: 1.85 min (LC method B).

Example 179: Preparation of (14S)-8-{3-[(4,4-difluorocyclohexyl)methyl]-2-okCOimidazolidin-1-yl}12,12-dimethyl-2X ⁶ -thia-3,9,11,18 ,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 214)

Step 1: tert-butyl K-[2-[(4,4-difluorocyclohexyl)methylamino]ethyl]carbamate

To a stirred solution of tert-butyl N-(2-aminoethyl)carbamate (325 mg, 2.029 mmol) in anhydrous methanol (15 ml) was added a solution of 4,4-difluorocyclohexanecarbaldehyde (300 mg, 2.025 mmol) in anhydrous methanol (1 ml) in nitrogen atmosphere. After the yellow solution was stirred at ambient temperature for 1 hour, it was cooled to 0°C (ice bath). Then slowly add

- 478 044967 sodium borohydride (165 mg, 4.361 mmol) was added in two portions, the mixture was allowed to warm to ambient temperature and stirring was continued for 15 hours. Volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (30 ml) and washed with saturated aqueous sodium bicarbonate (2x15 ml) and brine (15 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl-N-[2- [(4,4difluorocyclohexyl)methylamino]ethyl]carbamate (590 mg, 100%) as a yellow oil. The crude material was used in the next step without any further purification.

Ή NMR (400 MHz, Benzene-d ₆ ) δ 4.76 (s, 1H), 3.16 (k, J=5.8 Hz, 2H), 2.35 (t, J=5.9 Hz, 2H), 2.05 (d, J=6.5 Hz, 2H), 2.03-1.97 (m, 1H), 1.59 (s, 9H), 1.54-1.42 (m, 4H), 1.16-1.03 (m, 2H), 1.02-0.84 (m, 1H), 0.48 ( s, 2H). MS-ESI m/z calc. 292.19623, detected 293.3 (M+1)+; retention time: 0.73 min (LC method B).

Step 2: 1-[(4,4-difluorocyclohexyl)methyl]imidazolidin-2-one

NH NHBoc o

N NH

Solid potassium tert-butoxide (866 mg, 7.718 mmol) was added to a stirred solution of tert-butyl N-[2-[(4,4-difluorocyclohexyl)methylamino]ethyl]carbamate (750 mg, 2.565 mmol) in tetrahydrofuran (12 ml), and the heterogeneous reaction mixture was heated at 70°C for 13 hours. After cooling to room temperature, the reaction mixture was acidified with glacial acetic acid (500 μl, 8.792 mmol) and concentrated under reduced pressure. The residue was partitioned between aqueous sodium bicarbonate (15 ml) and ethyl acetate (25 ml) and the layers were separated. The aqueous portion was further extracted with ethyl acetate (25 ml). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-[(4,4-difluorocyclohexyl)methyl]imidazolidin-2-one (379 mg, 68%). as an off-white solid.

Ή NMR (400 MHz, Methanol-d4) δ 3.51-3.44 (m, 2H), 3.42-3.35 (m, 2H), 3.04 (d, J=7.1 Hz, 2H), 2.09-1.98 (m, 2H), 1.83-1.65 (m, 5H), 1.33-1.20 (m, 2H). MS-ESI m/z calc. 218.12306, detected 219.1 (M+1) ⁺ ; retention time: 0.7 min (LC method B).

Step 3: (14S)-8-{3-[(4,4-difluorocyclohexyl)methyl]-2-oxoimidazolidin-1-yl}-12,12-dimethyl2λ ⁶ -thia-3,9,11,18,23 -pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4trione (compound 214)

(14S)-8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23) was loaded into a 4 ml ampoule. 5,7,9,19,21-hexaene-2,2,4-trione (50 mg, 0.1111 mmol), 1-[(4,4-difluorocyclohexyl)methyl]imidazolidin-2-one (34 mg, 0.1558 mmol), Pd ₂ (dba) ₃ (15 mg, 0.01638 mmol), xanthos (16 mg, 0.02765 mmol), cesium carbonate (213 mg, 0.6537 mmol) and anhydrous dioxane (0. 75 ml). The mixture was purged with nitrogen for approximately 5 minutes, capped and stirred at 120°C for 22 hours. The reaction mixture was concentrated by purging nitrogen into the vial. The reaction mixture was diluted with dimethyl sulfoxide (1.5 ml), microfiltered and subjected to reverse phase preparative HPLC (C ₁₈ ) using a gradient of acetonitrile in water (1% to 99%) and hydrochloric acid as a modifier. Pure fractions were collected and organic solvents were evaporated. The solution was extracted with dichloromethane and the organic phase was dried over sodium sulfate and then filtered. Evaporation of the filtrate gave a solid, which was purified by flash silica gel chromatography using a gradient of methanol (0% to 5%) in dichloromethane. Pure fractions were collected and the solvents were evaporated. The residue was triturated with dichloromethane/hexanes and the solvents were evaporated to give (14S)-8-{3-[(4,4-difluorocyclohexyl)methyl]-2oxoimidazolidin-1-yl}-12,12-dimethyl-2λ ⁶ -thia-3 ,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 214) (20 mg, 27%) as an off-white solid.

¹ H NMR (400 MHz, DMSO-de) δ 12.26 (s, 1H), 7.65-7.51 (m, 2H), 7.40 (d, J=8.6 Hz, 1H), 7.03 (d, J=7.1 Hz, 1H ), 6.94 (broadened d, J=9.1 Hz, 1H), 6.69 (d, J=8.5 Hz, 1H), 4.03-3.85 (m, 3H), 3.56-3.40 (m, 2H), 3.183.03 (m , 3H), 2.94 (d, J=13.3 Hz, 1H), 2.71 (d, J=10.9 Hz, 1H), 2.12-1.96 (m, 3H), 1.86-1.69 (m, 7H), 1.63-1.43 ( m, 9H), 1.36-1.27 (m, 1H), 1.23-1.10 (m, 2H). MS-ESI m/z calc. 631.2752, detected 632.3 (M+1) ⁺ ; retention time: 1.79 min (LC method B).

Example 180: preparation of (14S)-12,12-dimethyl-8-[2-oxo-3-(3,3,3-trifluoro-2,2- 479 044967 dimethylpropyl)imidazolidin-1 -yl]-2λ ⁶ - thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione ( compound

225)

Dess-Martin periodinane (in dichloromethane) (5.4 g, 12.73 mmol) was added to

Step 1: 3,3,3-trifluoro-2,2-dimethylpropanal to stirred solution of 3,3,3-trifluoro-2,2-dimethyl-propan-1-ol (2.0 g 75% wt., 10.55 mmol) in anhydrous dichloromethane (30 ml) at 0°C (ice bath) under nitrogen atmosphere. After 15 minutes, the bath was removed, the reaction mixture was allowed to warm to ambient temperature, and stirring was continued for another 2 hours. The reaction mixture was diluted with ether (80 ml) and saturated aqueous sodium bicarbonate (30 ml) was added slowly (to reduce the evolution of carbon dioxide gas). A solution of 10% sodium thiosulfate (10 ml) was then added and the mixture was stirred at ambient temperature for 30 minutes, during which time all solids had dissolved. The layers were separated and the aqueous layer was extracted with ether (2x30 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered and partially concentrated under reduced pressure to about 3-5 ml to give 3,3,3-trifluoro-2,2-dimethylpropanal (1.37 g , 93%) as a crude solution in ether, which was used directly in the next step. MS-ESI m/z calc. 140.0449, detected 141.2 (M+1)+; Retention time: 0.42 min (LC method E).

Step 2: tert-butyl X-[2-[(3,3,3-trifluoro-2,2-dimethylpropyl)amino]ethyl]carbamate

To a stirred solution of tert-butyl-N-(2-aminoethyl)carbamate (1.2 g, 7.490 mmol) in anhydrous methanol (45 ml) was added a crude ethereal solution of 3,3,3-trifluoro-2,2-dimethylpropanal (1 .37 g, 9.778 mmol) described in the previous step, in anhydrous methanol (8 ml) under nitrogen. After stirring the pale yellow solution at ambient temperature for 1 hour, it was cooled to 0°C (ice water bath). Sodium borohydride (875 mg, 23.13 mmol) was added slowly in two batches and the mixture was allowed to warm to ambient temperature and stirring was continued for 24 hours. Volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and washed with saturated aqueous sodium bicarbonate (2x50 ml) and brine (50 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl K-[2-[( 3,3,3-trifluoro-2,2-dimethylpropyl) amino]ethyl]carbamate (777 mg, 36%) as a clear viscous oil. MS-ESI m/z calc. 284.17117, detected 285.2 (M+1) ⁺ ; Retention time: 0.97 min (LC method E).

Step 3: 1-(3,3,3-trifluoro-2,2-dimethylpropyl)imidazolidin-2-one

Solid potassium tert-butoxide (860 mg, 7.664 mmol) was added to a solution of tert-butyl-N-[2-[(3,3,3trifluoro-2,2-dimethyl-propyl)amino]ethyl]carbamate (777 mg, 2.733 mmol) in anhydrous tetrahydrofuran (40 ml), and the heterogeneous reaction mixture was heated at 70°C for 18 hours. The reaction mixture was allowed to cool to ambient temperature and acidified to pH ~ 5 with aqueous hydrochloric acid (1 M). Volatiles were removed under reduced pressure and the aqueous residue was extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine (2x40 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0%-10% methanol in methylene chloride) to give 1-(3,3,3-trifluoro-2,2-dimethylpropyl)imidazolidin-2-one (19.38 mg, 3%) in as an off-white solid.

1H NMR (400 MHz, chloroform-d) δ 3.57-3.48 (m, 2H), 3.44-3.39 (m, 2H), 3.25 (d, J=2.5 Hz, 2H), 1.16 (d, J=5.9 Hz, 6H). MS-ESI m/z calc. 210.09799, found 211.1 (M+1) ⁺ ; Retention time: 0.94 min (LC method E).

Step 4: (14S)-12,12-dimethyl-8-[2-oxo-3-(3,3,3-trifluoro-2,2-dimethylpropyl)imidazolidin-1-yl]2λ ⁶ -thia-3, 9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4- 480 044967 trione ( connection 225)

ml was loaded with (14S)-8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23 into a 5 ampoule of pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23), 5,7,9,19,21-hexaene-2,2,4-trione (40 mg, 0.08890 mmol), 1-(3,3,3-trifluoro-2,2-dimethylpropyl)imidazolidine-2- he (20.56 mg, 0.09781 mmol), Pd ₂ (dba) ₃ (21.5 mg, 0.02348 mmol), xanthos (13.5 mg, 0.02333 mmol), cesium carbonate (150 mg, 0.4604 mmol) and anhydrous dioxane (800 µl). The mixture was purged with nitrogen for 1-2 minutes, capped and stirred at 120°C for 20 hours, and then cooled to room temperature. The solvent was evaporated, the reaction mixture was diluted with dimethyl sulfoxide (900 μl), microfiltered and purified by reverse phase preparative chromatography using a C ₁₈ column (10-99% acetonitrile in water + 5 mM hydrochloric acid for a 15 min run). The product fractions were combined, brine was added, and the organic solvents were evaporated. The product was extracted with dichloromethane, the organic phase was dried over sodium sulfate and evaporation of the solvents gave a solid. The solid was purified by silica gel chromatography using a gradient of 100% dichloromethane to 5% methanol in dichloromethane. Pure fractions were collected, the solvents were evaporated, but impurities remained. The material was diluted with dimethyl sulfoxide (900 µl) and purified by preparative reverse phase chromatography using a C ₁₈ column (20%-80% acetonitrile in water + 5 mM hydrochloric acid for 30 min) to give an off-white solid (14S)-12 ,12-dimethyl-8-[2-oxo-3-(3,3,3-trifluoro-2,2-dimethylpropyl)imidazolidin-1-yl]-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo [17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4 trione (compound 225) (1.9 mg, 3%) . MS-ESI m/z calc. 623.2502, detected 624.2 (M+1) ⁺ ; Retention time: 1.88 min (LC method E).

Example 181: Preparation of (148)-8-{3-[(adamantan-1-yl)methyl]-2-oxoimidazolidin-1-yl}-12,12dimethyl-2X ⁶ -thia-3,9,11,18, 23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione (compound 229)

Step 1: tert-butyl N-[2-(1-adamantylmethylamino)ethyl]carbamate

To a stirred solution of tert-butyl N-(2-oxoethyl)carbamate (494 mg, 3.103 mmol) in anhydrous methylene chloride (20 ml) was added a solution of 1-adamantylmethanamine (509 mg, 3.080 mmol) in anhydrous methylene chloride (1 ml), followed by glacial acetic acid (200 µl, 3.517 mmol) at ambient temperature under nitrogen atmosphere. The clear reaction mixture was stirred for 30 minutes, then sodium triacetoxyborohydride (1.0 g, 4.718 mmol) was added in one portion at ambient temperature and stirring was continued for 13 hours. Volatiles were removed under reduced pressure. The residue was taken up in ethyl acetate (30 ml) and washed with saturated aqueous sodium bicarbonate (2x15 ml) and brine (15 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butylN-[2-(l -adamantylamino)ethyl]carbamate (901 mg, 95%) as a yellow resinous substance. The crude material was used in the next step without further purification. MS-ESI m/z calc. 308.24637, detected 309.4 (M+1)+; retention time: 1.09 min (LC method B).

Step 2: 1-(1-adamantylmethyl)imidazolidin-2-one

Solid potassium tert-butoxide (520 mg, 4.634 mmol) was added to a stirred solution of tert-butyl N-[2-(1-adamantylmethylamino)ethyl]carbamate (470 mg, 1.524 mmol) in anhydrous tetrahydrofuran (13 ml) under a nitrogen atmosphere, and the reaction the mixture was heated at 70°C for 13 hours. Heterogeneous

- 481 044967 the mixture was allowed to cool to ambient temperature, it was acidified with hydrochloric acid (6.0 ml, 1.0 M, 6,000 mmol), and the volatiles were removed under reduced pressure. The aqueous residue was extracted with ethyl acetate (3x10 ml), and the combined organic layers were washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0%-10% methanol in CH2Cl2) with yielding 1-(1-adamantylmethyl)imidazolidin-2-one (49 mg, 14%) as an off-white solid.

1H NMR (400 MHz, benzene-d6) δ 5.31 (s, 1H), 2.90 (dd, J=8.9, 6.6 Hz, 2H), 2.83 (s, 2H), 2.73 (dd, J=8.7, 6.7 Hz, 2H), 2.06-1.98 (m, 3H), 1.80-1.73 (m, 3H), 1.69 (dk, J=12.4, 2.3 Hz, 3H), 1.61 (d, J=2.8 Hz, 6H). MSIE m/z calc. 234.17322, detected 235.2 (M+1)+; retention time: 1.51 min (LC method B).

Step 3: (14S)-8-{3-[(adamantan-1 -yl)methyl]-2-oxoimidazolidin-1 -yl}-12,12-dimethyl-2λ ⁶ -thia3,9,11,18,23 -pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 229)

In a 4 ml bottle, (148)-8-chloro-12,12-dimethyl-2X ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23), 5,7,9,19,21-hexaene-2,2,4-trione (20 mg, 0.04298 mmol), 1-(1-adamantylmethyl)imidazolidin-2-one (13 mg, 0.05548 mmol) Cesium carbonate (52 mg, 0.1596 mmol), xanthos (4 mg, 0.006913 mmol) and anhydrous dioxane (1.0 ml) were added in that order. Nitrogen was bubbled through the heterogeneous mixture for 2 min. Pd ₂ (dba) ₃ (4 mg, 0.004368 mmol) was then added under nitrogen and nitrogen was bubbled through the reaction mixture for a further 2 minutes and the mixture was capped under nitrogen. The mixture was stirred at 115°C for 15 hours. The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (20 μl, 0.3517 mmol). Volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.0 mL) and filtered through a 0.45 μm Whatman PTFE syringe disk filter. The sample was purified by preparative reverse phase HPLC-MS (30-99% acetonitrile in water (hydrochloric acid as modifier)) to give (14S)-8-{3-[(adamantan-1-yl)methyl]-2oxoimidazolidine- 1 -yl }-12,12-dimethyl-2Х ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19 (23),20-hexaene-2,2,4-trione (compound 229) (12 mg, 43%) as a yellowish solid. MS-ESI m/z calc. 647.3254, detected 648.5 (M+1) ⁺ ; retention time: 1.82 min (LC method G).

Example 182: Preparation of 23,23-dimethyl-11-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1Hpyrazol-1-yl)-17λ ⁶ -thia-2,8,10,16, 22-pentaazatetracyclo[16.3.1.15,8.09,14]tricose-1(22),9,11,13,18,20hexaene-15,17,17-trione (compound 236)

o o ₀ A Step 1 A. step 2 JJ Step3 HNX < he he CR _Λ , _Λ CR Η ₂ Ν' ⁸ χ Vosmu step 6 BocN 'y _w step 7 ' XX · ™ OMs NH ₂ BocN'j' 0 qo stepS О .TnA/ ^N X ' О-/ rr- ^NH BocN4— ο ο _λ ο O—Y NN Ν \ γ /— ^/ JX NH / W Step 1: 4-(1-methyl-1-nitroethyl)tetrahydropyran-2 -He Step 4 ВССГАХ Stepy OH 0 J + steps χΤ ^{Ν n Cl} 0 O'O |f%H step 10 TnAi V - /γ^ΝΗ HN-y

- 482 044967 o o δ — _γ δ

5,6-Dihydropyran-2-one (50 g, 510 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (7.6 ml, 51 mmol) were dissolved in 2-nitropropane (138 ml, 1530 mmol), and the resulting mixture was heated to 100°C for 2.5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated in vacuo to remove excess volatiles. The remaining oil was dissolved in ethyl acetate (1 L) and extracted with 1 M hydrochloric acid (100 ml) and water (100 ml). The aqueous phases were discarded and the organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to give 4-(1-methyl-1-nitroethyl)tetrahydropyran-2-one (85 g, 79%) as an orange solid. MS-ESI m/z calc. 187.00, found 188.00 (M+1)+; retention time: 2.62 min (LC method P).

Step 2: 4-(2-hydroxyethyl)-5,5-dimethylpyrrolidin-2-one

-ή he

4-(1-Methyl-1-nitroethyl)tetrahydropyran-2-one (85 g, 454 mmol) was dissolved in ethanol (1.2 L), then Raney nickel (10 g, 170 mmol) was added and the resulting suspension was hydrogenated at 2 bar H ₂ /80°C for 25 hours. The reaction mixture was filtered, the filter cake was discarded, and the filtrate was returned to the reactor and heated to 120°C for 23 hours. The mixture was concentrated to an oil in vacuo to give 4-(2- hydroxyethyl)-5,5-dimethylpyrrolidin-2-one (63.5 g, 89%) as a pale yellow solid. MS-ESI m/z calc. 157.00, found 158.20 (M+1) ⁺ ; retention time: 1.30 min (LCR method).

Step 3: 2-(2,2-dimethylpyrrolidin-3-yl)-ethanol

4-(2-Hydroxyethyl)-5,5-dimethylpyrrolidin-2-one (63.5 g, 404 mmol) was dissolved in tetrahydrofuran (2 L). Lithium aluminum hydride (61.3 g, 1616 mmol) was added in small portions and the resulting suspension was refluxed under nitrogen for 45 hours, cooled to room temperature and carefully quenched with saturated sodium sulfate solution (300 ml). The mixture was diluted with MTBE (1 L) and filtered. The filter cake was discarded and the filtrate was dried over sodium sulfate, filtered and concentrated in vacuo to give 2-(2,2-dimethylpyrrolidin-3-yl) ethanol (50.8 g, 87%) as a pale yellow oil. MS -IER m/z calc. 143.00, found 144.20 (M+1) ⁺ ; retention time: 0.68 min (LC method P). The crude product was used without further purification.

Step 4: 3-(2-hydroxyethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester.

2-(2,2-Dimethylpyrrolidin-3-yl) ethanol (50.8 g, 355 mmol) was dissolved in a mixture of dichloromethane (350 ml) and water (350 ml). Sodium bicarbonate (59.6 g, 710 mmol) and di-tert-butyl dicarbonate (73.6 g, 337 mmol) were added and the resulting mixture was stirred at room temperature for 19 hours. Sodium hydroxide (14 g, 350 mmol) was then added ) and water (50 ml), and the mixture was stirred at room temperature for 18 hours, then diluted with diethyl ether (1 L). The phases were separated and the aqueous phase was extracted with diethyl ether (2x350 ml). The aqueous phase was discarded and the combined organic phases were dried over sodium sulfate, concentrated in vacuo, then triturated with hexane. The resulting pale yellow solid was collected by vacuum filtration to provide 3-(2-hydroxyethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (60.0 g, 69%) as a pale yellow solid. MS-ESI m/z calc. 243.00, found 244.00 (M+1) ⁺ ; retention time: 4.24 min (LC method P).

Step 5: 3-(2-methanesulfonyloxyethyl)-2,2-dimethylpyrrolidine-1carboxylic acid tert-butyl ester

- 483 044967

3-(2-hydroxyethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (54.5 g, 224 mmol) was dissolved in dichloromethane (545 ml). Triethylamine (62.5 mL, 448 mmol) was added and the resulting solution was cooled in an ice water bath before methanesulfonyl chloride (19.2 mL, 247 mmol) was added dropwise over 1 h. The ice bath was then removed and the reaction mixture was stirred for 1 hour at room temperature and then quenched with saturated aqueous sodium bicarbonate (200 ml). The phases were separated and the organic phase was extracted with water (2x200 ml). The aqueous phases were discarded and the organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to give 3-(2-methanesulfonyloxyethyl)-2,2-dimethylpyrrolidine-1carboxylic acid tert-butyl ester (72.2 g, quant.) as orange oil. MS-ESI m/z calc. 321.00, found 322.20 (M+1) ⁺ ; retention time: 5.24 min (LC method P).

Step 6: 3-(2-aminoethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester

3-(2-methanesulfonyloxyethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (10.0 g, 31.1 mmol) was dissolved in 1,4-dioxane (100 ml). 28% ammonium hydroxide (100 ml) was added and the reaction mixture was heated to 40°C in a Parr reactor for 26 hours. The 1,4-dioxane was removed in vacuo and the remaining material was extracted with dichloromethane (2x100 ml). The phases were separated, the aqueous phase was discarded, and the combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The remaining yellow oil was purified by silica gel chromatography (0%-15% methanol dichloromethane gradient) to give 3-(2-aminoethyl)-2,2-dimethylpyrrolidine 1-carboxylic acid tert-butyl ester. (5.1 g, 68%) as a pale yellow solid. MS-ESI m/z calc. 242.00, found 243.20 (M+1) ⁺ ; retention time: 3.09 min (LC method R).

Step 7: tert-butyl 2,2-dimethyl-3-[2-[(6-sulfamoyl-2-pyridyl)amino]ethyl]pyrrolidine-1-carboxylate

To 3-(2-aminoethyl)-2,2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 2.063 mmol) and 6-fluoropyridine-2-sulfonamide (363.4 mg, 2.063 mmol) in dimethyl sulfoxide (4.21 ml), potassium carbonate (290.8 mg, 2.104 mmol) was added and the mixture was stirred at 100°C for 20 hours, then allowed to cool to room temperature. Dilute with ethyl acetate and pour into saturated aqueous NH ₄ Cl. The layers were separated, then the organic layer was washed with saturated aqueous brine, dried (sodium sulfate), filtered and concentrated to a yellow foam, which was purified by silica gel chromatography using a fine gradient from 100% hexanes to 100% ethyl acetate to give tert-butyl 2,2 -dimethyl-3-[2-[(6-sulfamoyl-2-pyridyl)amino]ethyl]pyrrolidine-1 carboxylate (497.5 mg, 61%) as a white solid. MS-ESI m/z calc. 398.19876, detected 399.1 (M+1)+; retention time: 0.58 min (LC method A).

Step 8: tert-butyl 3-[2-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl ]-2-pyridyl]amino]ethyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (499.7 mg, 1.330 mmol) and carbonyldiimidazole (269.8 mg , 1.664 mmol) (recrystallized from tetrahydrofuran) were combined in tetrahydrofuran (6.89 ml) and stirred for 60 min at room temperature. Then tert-butyl-2,2-dimethyl-3-[2-[(6-sulfamoyl-2pyridyl)amino]ethyl]pyrrolidine-1-carboxylate (530 mg, 1.330 mmol) in tetrahydrofuran (2.65 ml) was added. behind

- 484 044967 then 1,8-diazabicyclo[5.4.0]undec-7-ene (1.013 g, 6.654 mmol), and the reaction mixture was stirred at room temperature for 16 hours. Tetrahydrofuran was removed using a rotary evaporator, the residue was dissolved in ethyl acetate and washed with 6 N. hydrochloric acid (1X), then brine (1X), dried (sodium sulfate), filtered and concentrated to a white solid, which was chromatographed on a 275g C ₁₈ reverse phase column eluting with a gradient of 50% to 100% acetonitrile in water to give tert-butyl-3-[2-[[6-[[2-chloro-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carbonyl]sulfamoyl] -2pyridyl]amino]ethyl]-2,2-dimethylpyrrolidine-1-carboxylate (497.5 mg, 49%) as a white solid.

¹ H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 8.40 (d, J=2.8 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.62 (dd, J=8.5, 7.2 Hz, 1H), 7.21 (s, 1H), 7.18 (d, J=7.2 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.18 (d, J=2.8 Hz, 1H), 4.35 (t, J=7.1 Hz, 2H), 3.25 (s, 2H), 3.02 (d, J=9.1 Hz, 1H), 2.09 (t, J=7.1 Hz, 2H), 1.90-1.57 (m, 4H), 1.41-1.31 (m, 11H), 1.29 (s, 2H), 1.19 (d, J=1.7 Hz, 1H), 0.98 (d, J=5.1 Hz , 2H), 0.96 (t, J=4.2 Hz, 3H), 0.89 (d, J=5.1 Hz, 2H). MS-ESI m/z calc. 755.248, detected 756.1 (M+1)+; retention time: 0.84 min (LC method A).

Step 9: 2-chloro-I-[[6-[2-(2,2-dimethylpyrrolidin-3-yl)ethylamino]-2-pyridyl]sulfonyl]-6-[3-[2[1-(trifluoromethyl) cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide

tert-Butyl 3-[2-[[6-[[2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin3-carbonyl]sulfamoyl]-2 -pyridyl]amino]ethyl]-2,2-dimethylpyrrolidine-1-carboxylate (498.6 mg, 0.6593 mmol) was dissolved in dichloromethane (2.176 ml) and trifluoroacetic acid (2.032 ml, 26.37 mmol) was added to the mixture. , and the mixture was stirred at room temperature for 60 minutes. The mixture was concentrated to dryness under reduced pressure, treated with saturated aqueous sodium bicarbonate and ethyl acetate, and the layers were separated. (The solubility of the product in ethyl acetate under these conditions is very low, the addition of methanol helps). The ethyl acetate layer was washed with 6 N. hydrochloric acid, then dried (sodium sulfate), filtered and concentrated the organic layer by rotary evaporation followed by drying in vacuo to give 2-chloro-N-[[6-[2-(2,2-dimethylpyrrolidin-3yl)ethylamino]- 2-pyridyl]sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridine-3-carboxamide (351.2 mg, 81%) as a white solid. MS-ESI m/z calc. 655.19556, detected 656.1 (M+1) ⁺ ; retention time: 0.58 min (LC method A).

Step 10: 23,23-dimethyl-11-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-17λ ⁶ thia-2,8,10,16,22 -pentaazatetracyclo[16.3.1.15,8.09,14]tricose-1(22),9,11,13,18,20-hexaene-15,17,17-trione (compound 236)

Combined 2-chloro-N-[[6-[2-(2,2-dimethylpyrrolidin-3-yl)ethylamino]-2-pyridyl]sulfonyl]-6-[3-[2-[1-(trifluoromethyl)cyclopropyl ]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (351.2 mg, 0.5353 mmol), potassium carbonate (369.8 mg, 2.676 mmol), 3 A molecular sieves and dimethyl sulfoxide (21.3 ml) in a vial purged with nitrogen, close, heat to 180°C and stir for 18 hours. Cool to room temperature and the mixture is filtered, diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate and then with saline. The organic layers were separated, dried over sodium sulfate and evaporated, then purified by silica gel chromatography using a gradient of 100% hexanes to 100% ethyl acetate (product eluted when 100% ethyl acetate was reached) to give 23,23-dimethyl-11 as a white solid -(3-{2-[1(trifluoromethyl)cyclopropyl]ethoxy} -1 H-pyrazol-1-yl)-17 X ⁶ -thia-2,8,10,16,22pentaazatetracyclo[16.3.1.15,8.09,14 ]tricose-1(22),9,11,13,18,20-hexaene-15,17,17-trione (compound 236) (5.7 mg, 2%). MS-ESI m/z calc. 619.2189, detected 620.1 (M+1) ⁺ ; retention time: 2.08 min (LC method B).

Example 183: Preparation of (14S)-12,12-dimethyl-8-(2-oxo-3-{[4-(trifluoromethyl)cyclohexyl]methyl}imidazolidin-1-yl)-2X ⁶ -thia-3,9, 11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 239)

- 485 044967

Step 1: tert-butyl N-[2-[[4-(trifluoromethyl)cyclohexyl]methylamino]ethyl]carbamate

To a stirred solution of 4-(trifluoromethyl)cyclohexanecarbaldehyde (250 mg, 1.388 mmol) in anhydrous methanol (10 ml) was added a solution of tert-butyl-N-(2-aminoethyl) carbamate (223 mg, 1.392 mmol) in anhydrous methanol (1 ml ) in a nitrogen atmosphere. After the yellow solution was stirred at ambient temperature for 1 hour, it was cooled to 0°C (ice bath). Sodium borohydride (112 mg, 2.960 mmol) was then added slowly in two portions, the mixture was allowed to warm to ambient temperature and stirring was continued for 15 hours. Volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (30 ml) and washed with saturated aqueous sodium bicarbonate (2x15 ml) and brine (15 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl N-[2-[[ 4(trifluoromethyl)cyclohexyl]methylamino]ethyl]carbamate (400 mg, 89%) as yellow gum. The crude material was used in the next step without further purification. MS-ESI m/z calc. 324.20245, detected 325.3 (M+1)+; retention time: 0.9 min (LC method B).

Step 2: 1-[[4-(trifluoromethyl)cyclohexyl]methyl]imidazolidin-2-one (cis/trans isomer 2)

Solid potassium tert-butoxide (270 mg, 2.406 mmol) was added to a stirred solution of tert-butyl-N-[2-[[4-(trifluoromethyl)cyclohexyl]methylamino]ethyl]carbamate (260 mg, 0.8015 mmol) in anhydrous tetrahydrofuran ( 10 ml) under a nitrogen atmosphere, and the reaction mixture was heated at 70°C for 13 hours. The heterogeneous mixture was allowed to cool to ambient temperature and then acidified with aqueous hydrochloric acid (3.0 ml, 1.0 M, 3,000 mmol) and volatiles were removed under reduced pressure. The aqueous residue was extracted with ethyl acetate (3x10 ml). The combined organic phases were washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC-MS (0-70% acetonitrile in water (hydrochloric acid as modifier) to give the second cis/trans isomer to elute, 1-[[4(trifluoromethyl)cyclohexyl]methyl ]imidazolidin-2-one (cis/trans isomer 2) (52 mg, 26%) as an off-white solid.

1H NMR (400 MHz, Benzene-d ₆ ) δ 4.93 (s, 1H), 2.89 (d, J=7.2 Hz, 2H), 2.77-2.63 (m, 4H), 1.80 (dd, J=13.4, 3.6 Hz , 2H), 1.72-1.57 (m, 1H), 1.52 (dd, J=13.4, 3.5 Hz, 2H), 1.22-1.06 (m, 3H), 0.66 (qd, J=13.3, 3.6 Hz, 2H). MS-ESI m/z calc. 250.1293, detected 251.2 (M+1) ⁺ ; retention time: 1.3 min (LC method B).

Step 3: (14S)-12,12-dimethyl-8-(2-oxo-3 - {[4-(trifluoromethyl)cyclohexyl]methyl}imidazolidin-1 yl)-2λ ⁶ -thia-3,9,11, 18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene2,2,4-trione (compound 239)

vial, (14S)-8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo(23),5,7,9,19,21-hexaene-2, 2,4-trione (20 mg, 0.04445 mmol), 1-[[4Bo

[17.3.1.111,14.05,10]tetracose-1

- 486 044967 (trifluoromethyl) cyclohexyl]methyl]imidazolidin-2-one (13 mg, 0.05195 mmol), cesium carbonate (52 mg, 0.1596 mmol), xanthos (4 mg, 0.006913 mmol) and anhydrous dioxane (0.7 ml) were added in the order indicated. Nitrogen was purged through the heterogeneous mixture for 3 min. Pd ₂ (dba) ₃ (4 mg, 0.004368 mmol) was then added under nitrogen and the mixture was purged with nitrogen for a further 2 min, then blocked under nitrogen. The mixture was stirred at 108°C for 15 hours. The mixture was allowed to cool to ambient temperature and neutralized with glacial acetic acid (20 μl, 0.3517 mmol). Volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.5 ml) and filtered through a 0.45 μm Whatman PTFE syringe disk filter. The sample was purified by preparative reverse phase HPLC-MS (30%-99% acetonitrile in water (hydrochloric acid as modifier) to give (14S)-12,12-dimethyl-8-(2-oxo-3-{[4 -(trifluoromethyl)cyclohexyl]methyl} imidazolidin-1 -yl)-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9 ,19(23),20-hexaene-2,2,4-trione (compound 239) (9 mg, 31%) as a yellowish solid.This compound is a single isomer of unknown cis or trans orientation on the cyclohexane ring.

¹ H NMR (400 MHz, DMSO-de) δ 12.26 (s, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.58-7.53 (m, 1H), 7.40 (dd, J=8.6, 2.7 Hz , 1H), 7.06-7.01 (m, 1H), 6.94 (d, J=8.7 Hz, 1H), 6.70 (dd, J=8.5, 0.8 Hz, 1H), 4.01-3.83 (m, 3H), 3.513. 41 (m, 3H), 3.31-3.28 (m, 1H), 3.11-3.04 (m, 2H), 2.94 (d, J=13.4 Hz, 1H), 2.70 (t, J=0.8 Hz, 1H), 2.18 (t, J=8.1 Hz, 1H), 2.13-2.01 (m, 1H), 1.95-1.80 (m, 4H), 1.79-1.74 (m, 2H), 1.58 (s, 3H), 1.57-1.48 (m , 3H), 1.47 (s, 3H), 1.34-1.14 (m, 3H), 1.00 (k, J=12.6 Hz, 2H). ¹⁹ F NMR (376 MHz, dimethyl sulfoxide-d ₆ ) δ -72.24 (d, J=8.9 Hz). MS-ESI m/z calc. 663.28143, detected 664.4 (M+1) ⁺ ; retention time: 2.0 min (LC method B).

Example 184: Preparation of 11-[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-7,7-dimethyl-17λ ⁶ thia-2,8,10,16,22-pentaazatetracyclo[16.3. 1.15,8.09,14]tricose-1(22),9,11,13,18,20-hexaene-15,17,17trione (enantiomer 2) (compound 250)

Step 1: tert-butyl 2,2-dimethyl-4-[2-[(6-sulfamoyl-2-pyridyl)amino]ethyl]pyrrolidine-1carboxylate (enantiomer 2)

Racemic tert-butyl-2,2-dimethyl-4-[2-[(6-sulfamoyl-2-pyridyl)amino]ethyl]pyrrolidine-1carboxylate (1.475 g, 3.701 mmol) was separated by chiral RPLC using ChiralPak IG. (250 x 21.2 mm column, 5 µm particle size) with 32% methanol (no modifier)/68% carbon dioxide mobile phase at 70 ml/min, giving tert-butyl 2,2-dimethyl-4-[ as the second enantiomer for elution 2-[(6-sulfamoyl-2-pyridyl)amino]ethyl]pyrrolidine-1-carboxylate (enantiomer 2) (617 mg, 84%) as a white foam. MS-ESI m/z calc. 398.19876, detected 399.3 (M+1)+; retention time: 1.59 min (LC method B).

Step 2: tert-butyl 4-[2-[[6-[[2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridin-3-487 044967 carbonyl]sulfamoyl] - 2-pyridyl]amino]ethyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (enantiomer 2)

2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (147.7 mg, 0.4082 mmol), recrystallized carbonyldiimidazole (66.2 mg) was added to the flask , 0.4083 mmol) and tetrahydrofuran (4 ml). The reaction mixture was stirred at 40°C for 90 minutes. Tert-butyl 2,2-dimethyl-4-[2-[(6-sulfamoyl-2-pyridyl)amino]ethyl]pyrrolidine-1-carboxylate (enantiomer 2) (130 mg, 0.3262 mmol) was then added with followed by the addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (150 µl, 1.003 mmol). The reaction mixture was stirred overnight. The reaction mixture was filtered and purified by HPLC (30-99% acetonitrile in water with 0.1% hydrochloric acid modifier) to give tert-butyl-4-[2-[[6-[[2-chloro-6-[3 -(3,3-dicyclopropylpropoxy)pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]ethyl]-2,2-dimethylpyrrolidine-1-carboxylate (enantiomer 2) (64 mg, 26%) in the form of white foam. MS-ESI m/z calc. 741.30756, detected 742.4 (M+1)+; retention time: 2.19 min (LC method G).

Step 3: 2-chloro-6-[3-(3,3-dicyclopropylpropoxy)nazol-1-yl]-N-[[6-[2-(5,5dimethylpyrrolidin-3-yl)ethylamino]-2-pyridyl ]sulfonyl]pyridine-3-carboxamide (enantiomer 2)

enantiomer 2 enantiomer 2

Tert-butyl-4-[2-[[6-[[2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl was added to the flask ]amino]ethyl]-2,2-dimethylpyrrolidine-1-carboxylate (enantiomer 2) (64 mg, 0.08622 mmol), dichloromethane (5 ml) and trifluoroacetic acid (250 μl, 3.245 mmol). The reaction mixture was stirred for 30 minutes. The reaction mixture was evaporated to dryness and neutralized with saturated sodium bicarbonate. The reaction mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered and evaporated to give 2-chloro-6-[3-(3,3dicyclonopylnponoxy)nyrazol-1-yl]-N-[[6-[2-(5,5- dimethylpyrrolidin-3-yl)ethylamino]-2pyridyl]sulfonyl]pyridine-3-carboxamide (enantiomer 2) (51 mg, 92%) as a white solid. MS-ESI m/z calc. 641.2551, detected 642.3 (M+1) ⁺ ; retention time: 1.11 min (LC method G).

Step 4: 11 -[3-(3,3-dicyclopropylpropoxy)-1H-pyrazol-1-yl]-7,7-dimethyl-17λ ⁶ -thia-2,8,10,16,22pentaazatetracyclo[16.3.1.15, 8.09,14]tricose-1(22),9,11,13,18,20-hexaene-15,17,17-trione (enantiomer 2) (compound 250)

enantiomer 2

Potassium carbonate (59 mg, 0.4269 mmol), cesium fluoride (25 mg, 0.1646 mmol), 3 A molecular sieves, and a solution of 2-chloro-6-[3-(3,3-dicyclonopylpropoxy) were added to the vial. pyrαzola-1-yl]-N-[[6-[2-(5,5dimethylpyrrolidin-3-yl)ethylamino]-2-pyridyl]sulfonyl]pyridine-3-carboxamide (enantiomer 2) (51 mg, 0.07941 mmol) in dimethyl sulfoxide (3.5 ml). The reaction mixture was placed in an oil bath preheated to 150°C and left to stir overnight. The reaction mixture was cooled to room temperature, filtered and purified by HPLC (10-99% acetonitrile in water modified with 0.1% hydrochloric acid) to give 11-[3-(3,3dicyclopropylnpoxy)-1H-nirazol-1-yl ]-7,7-dimethyl-17λ ⁶ -thia-2,8,10,16,22pentaazatetracyclo[16.3.1.15,8.09,14]tricose-1(22),9,11,13,18,20-hexaene- 15,17,17-trione (enantiomer 2) (compound 250) (14.1 mg, 29%). MS-ESI m/z calc. 605.27844, detected 606.4 (M+1) ⁺ ; retention time: 1.9 min (LC method G).

Example 185: Preparation of (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}-2-oxoethoxy)-1H-pyrazol-1-488 044967 yl]-12,12- dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2 ,4-trione (compound 258)

Step 1: 1-dispiro[2.0.2.1]heptan-7-yl-2-(III-pyrazol-3-yloxy)ethanone.

tert-Butyl-3-(2-dispiro[2.0.2.1]heptan-7-yl-2-oxoethoxy)pyrazole-1-carboxylate (350 mg, 0.7256 mmol) was dissolved in dichloromethane (2.31 ml) with trifluoroacetic acid acid (1.241 g, 10.88 mmol), and the reaction mixture was stirred at room temperature for 60 minutes. The reaction mixture was evaporated and the resulting oil was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous portion was extracted two more times with ethyl acetate, then the organic layers were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give an oil, 1-dispiro[2.0.2.1]heptan-7-yl-2-(1H-pyrazol- 3-yloxy) ethanone (223.7 mg, 93%). MS-ESI m/z calc. 218.10553, detected 219.0 (M+1)+; retention time: 0.43 min (LC method A).

Step 2: tert-butyl 2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-yl-2-oxo-ethoxy)pyrazol-1yl]pyridine-3-carboxylate

tert-Butyl 2,6-dichloropyridin-3-carboxylate (134.3 mg, 0.5413 mmol), 1-dispiro[2.0.2.1]heptan-7yl-2-(1H-pyrazol-3-yloxy) ethanone (179 .1 mg, 0.5416 mmol) and potassium carbonate (89.88 mg, 0.6503 mmol) were combined in anhydrous dimethyl sulfoxide (2.362 ml). 1,4-Diazabicyclo[2.2.2]octane (12.16 mg, 0.1084 mmol) was added and the heterogeneous mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was diluted with water (4.542 ml) and stirred for 15 minutes. The resulting white solid was collected and washed with water. The solid was dissolved in dichloromethane and dried over magnesium sulfate. The mixture was filtered and evaporated to give tert-butyl-2-chloro-6-[3(2-dispiro[2.0.2.1]heptan-7-yl-2-oxoethoxy)pyrazol-1-yl]pyridine-3-carboxylate (148 .7 mg, 64%) as a white solid. MS-ESI m/z calc. 429.14554, detected 430.0 (M+1) ⁺ ; Retention time: 0.83 min (LC method A).

Step 3: 2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-yl-2-oxo-ethoxy)pyrazol-1-yl]pyridine-3carboxylic acid

tert-Butyl 2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-yl-2-oxoethoxy)pyrazol-1-yl]pyridine-3carboxylate (145.7 mg, 0.3389 mmol ) was dissolved in dichloromethane (1.457 ml) with trifluoroacetic acid (391.7 µl, 5.084 mmol), and the reaction mixture was stirred at room temperature for 2.5 hours. Volatiles were removed by rotary evaporation (without heating) followed by 30 minutes of drying under vacuum. The crude material was purified by silica gel chromatography using a shallow

- 489 044967 gradient from 100% dichloromethane to 20% methanol in dichloromethane, which gave 2-chloro-6-[3-(2dispiro[2.0.2.1]heptan-7-yl-2-oxoethoxy)pyrazol-1-yl]pyridine -3-carboxylic acid (89.6 mg, 71%) as a brown solid contaminated with a small amount of starting material, which was immediately sent to the next step. MS-ESI m/z calc. 373.08295, detected 374.0 (M+1)+;

Retention time: 0.61 min (LC method A).

Step 4: tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-yl-2-oxoethoxy)pyrazole -1-yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate

2-Chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-yl-2-oxoethoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (89.6 mg, 0.2397 mmol ) and carbonyldiimidazole (48.63 mg, 0.2999 mmol) (freshly recrystallized from tetrahydrofuran) were combined in tetrahydrofuran (1.165 ml) and stirred for 45 min at room temperature. Then tert-butyl (48)-2,2-dimethyl-4-[3-[(6-sulfamoyl-2pyridyl)amino]propyl]pyrrolidine-1-carboxylate (98.89 mg, 0.2397 mmol) in tetrahydrofuran was added (448 µl), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (179.3 µl, 1.199 mmol), and the reaction mixture was stirred at room temperature for 16 hours. Tetrahydrofuran was removed using a rotary evaporator , then dissolved in ethyl acetate and washed with 1 N. hydrochloric acid (1X) and brine (1X), dried (magnesium sulfate), filtered and concentrated to a light brown oil, which was purified by silica gel chromatography using a fine gradient from 100% dichloromethane to 20% methanol in dichloromethane, resulting in poor separation of the product from the two starting materials. The material was then filtered and purified using a reverse phase HPLC-MS method (Luna C ₁₈ (2) column (75x30 mm, 5 µm particle size) sold by Phenomenex (art. no.: 00°C-4252-U0-AX). and double gradient from 1% to 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 obtain tert-butyl (4S)-4[3-[[6-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-yl -2-oxoethoxy)pyrazol-1-yl]pyridin-3carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (49.5 mg, 27%). MS-ESI m/z calc. 767.2868, detected 768.1 (M+1) ⁺ ; Retention time: 0.83 min (LC method A).

Step 5: 2-chloro-N-[[6-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propylamino]-2-pyridyl]sulfonyl]6-[3-(2-dispiro[ 2.0.2.1 ]heptan-7-yl-2-oxo-ethoxy)pyrazol-1 -yl] pyridin-3-carboxamide (trifluoroacetate salt) tert-Butyl (4S)-4-[3-[[6-[[2 -chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-yl-2-oxoethoxy)pyrazol-1 yl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl] - 2,2-Dimethylpyrrolidine-1-carboxylate (49.5 mg, 0.06443 mmol) was dissolved in dichloromethane (1.5 ml) and cooled to 0°C and trifluoroacetic acid (49.64 µl, 0 ,6443 mmol), and the mixture was stirred at 0°C for 60 minutes. Add trifluoroacetic acid (49.64 µl, 0.6443 mmol) dropwise at 0°C, then warm to room temperature and stir for 30 min, cool again to 0°C, add trifluoroacetic acid (49.64 µl, 0.6443 mmol), warmed to room temperature and stirred for 20 min, then trifluoroacetic acid (49.64 μl, 0.6443 mmol) was added dropwise at room temperature and stirring continued at room temperature for 1 h. The mixture was concentrated to dryness on a rotary evaporator without heating Evaporate with ether (5X), then place under vacuum for 1 hour to give 2-chloro-N-[[6-[3-[(3S)-5,5-dimethylpyrrolidin-3-yl]propylamino]2-pyridyl ] sulfonyl]-6-[3 -(2-dispiro[2.0.2.1] heptan-7-yl-2-oxoethoxy)pyrazol-1 -yl] pyridin-3 carboxamide (trifluoroacetate salt) (50.4 mg, 100% ) as a white solid. MS-ESI m/z calc. 667.2344, detected 668.1 (M+1) ⁺ ; retention time: 0.55 min (LC method A).

Step 6: (14S)-8-[3-(2-{dispiro[2.0.2.1]gentan-7-yl}-2-oxoethoxy)-1H-pyrazol-1-yl]-12,12dimethyl-2λ ⁶ - thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione ( connection 258)

- 490 044967

Combined 2-χΛορ-Ν-[[6-[3-[(3 S)-5,5-dimethylpyrrolidin-3 -yl]propylamino]-2pyridyl]sulfonyl]-6-[3 -(2-dispiro[2.0. 2.1] heptan-7-yl-2-oxoethoxy)pyrazol-1 -yl] pyridin-3 carboxamide (trifluoroacetate salt) (50.4 mg, 0.06443 mmol), potassium carbonate (53.43 mg, 0.3866 mmol ), 3 A molecular sieves and dimethyl sulfoxide (3.057 ml) in a vial purged with nitrogen, capped, heated to 155°C and stirred for 18 hours. Cool to room temperature and the mixture was filtered, diluted with ethyl acetate and 1 N. hydrochloric acid and the layers were separated. The aqueous layer was washed again with ethyl acetate and the organic layers were combined, washed with brine (1x), dried (magnesium sulfate), filtered and concentrated to a brown solid, which was purified by silica gel chromatography using a shallow gradient of 100% hexanes to 100% ethyl acetate to give (14S)-8-[3-(2-{dispyro[2.0.2.1]heptan-7-yl}-2-oxoethoxy)-1Hpyrazol-1-yl]-12,12-dimethyl-2λ ⁶ -thia -3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (11 mg), which was still contaminated with impurities. For subsequent reaction, this material was dissolved in methanol (110 µl) at room temperature and NaBH ₄ (1.646 mg, 0.04351 mmol) was added (strong bubbling was observed) and the resulting solution was stirred for 10 min, then concentrated on a rotary evaporator. The residue was dissolved in dimethyl sulfoxide, filtered and purified using reverse phase HPLC-MS using a Luna Q8 column (2) (75 x 30 mm, 5 µm particle size) sold by Phenomenex (pn: 00°C-4252-U0-AX) and a double gradient from 30% to 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 obtain (14S)-8-[3-(2-{dispyro[2.0.2.1]heptan-7-yl}-2oxoethoxy)-1 H- as the recovered starting material upon reduction pyrazol-1-yl]-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19 (23),20-hexaene-2,2,4-trione (compound 258) (2.20 mg, 20%) as a white solid. MS-ESI m/z calc. 631.2577, detected 632.2 (M+1)+; retention time: 1.99 min (LC method B).

Example 186: preparation of (14S)-12,12-dimethyl-8-(2-οoxo-3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1,2-dihydropyridin-1-yl)-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (connection 268)

Step 1: 3-[tert-butyl(dimethyl)silyl]oxy-1H-pyridin-2-one

- 491 044967

3-Hydroxy-1H-pyridin-2-one (1 g, 9.001 mmol) and imidazole (1.6 g, 23.50 mmol) were suspended in

N,N-dimethylformamide (10 ml) in an inert atmosphere. A solution of tert-butylchlorodimethylsilane (1.5 g, 9.952 mmol) in N,N-dimethylformamide (10 ml) was added dropwise at room temperature over 30 min. The reaction mixture was then allowed to stir overnight.

The resulting solution was then poured into water and the mixture was extracted with tert-butyl methyl ether (3x50 ml). The combined organic layers were washed with water, brine, then dried over sodium sulfate. After filtration, the solvent was removed under reduced pressure to give 3-[tert-butyl(dimethyl)silyl]oxy-1H-pyridin-2-one (1.8 g, 89%) as a light brown solid, which was used directly in the next reaction.

¹ H NMR (400 MHz, chloroform-d) δ 6.97 (dd, J=6.4, 1.8, 0.8 Hz, 1H), 6.89 (dd, J=7.2, 1.8 Hz, 1H), 6.14 (dd, J=7.2, 6.5 Hz, 1H), 1.00 (d, J=1.3 Hz, 9H), 0.26 (s, 6H).

Step 2: tert-butyl 2-chloro-6-(3-hydroxy-2-oxo-1-pyridyl)pyridine-3-carboxylate

Mixture of tert-butyl 2,6-dichloropyridin-3-carboxylate (1 g, 4.031 mmol), 3-[tert-butyl (dimethyl)silyl]oxy-1H-pyridin-2-one (910 mg, 4.038 mmol) potassium carbonate (1.32 g, 9.551 mmol) and 1,4diazabicyclo[2.2.2]octane (112 mg, 0.9985 mmol) in dimethyl sulfoxide (10 ml) were stirred at room temperature for 15 hours. The reaction mixture was poured onto crushed ice, the resulting precipitate was collected by filtration and dried to give tert-butyl-2-chloro-6-(3-hydroxy-2-oxo-1pyridyl)pyridine-3-carboxylate (0.82 g, 63%) as a light brown solid .

1H NMR (400 MHz, chloroform-d) δ 12.57 (s, 1H), 8.15 (d, J=8.6 Hz, 1H), 7.36 (dd, J=7.2, 1.8 Hz, 1H), 7.23 (dd, J= 6.6, 1.8 Hz, 1H), 6.95 (d, J=8.3 Hz, 1H), 6.29 (t, J=6.9 Hz, 1H), 1.59 (s, 9H). MS-ESI m/z calc. 322.07202, detected 323.14 (M+1)+; retention time: 0.55 min (LC method G).

Step 3: 2-chloro-6-[2-oxo-3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]-1-pyridyl]pyridine-3carboxylic acid

Mixture of 2-[1-(trifluoromethyl)cyclopropyl]ethylmethanesulfonate (362 mg, 1.559 mmol), tert-butyl 2chloro-6-(3-hydroxy-2-oxo-1-pyridyl)pyridine-3-carboxylate (500 mg, 1.549 mmol), cesium carbonate (1.1 g, 3.376 mmol) in dimethyl sulfoxide (10 ml) was stirred at room temperature for 15 hours. 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. The residue was purified by silica gel column chromatography (0%-80% ethyl acetate in hexanes) and the second regioisomer was isolated for elution, and trifluoroacetic acid (1.5 mL, 19.47 mmol) and dichloromethane (5 mL) were added to this material at room temperature. temperature with stirring for 2 hours, followed by evaporation of volatile substances to obtain 2-chloro-6-[2-oxo-3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]1-pyridyl]pyridine-3-carboxylic acid (120 mg, 19%).

1H NMR (400 MHz, chloroform-d) δ 8.14 (d, J=8.4 Hz, 1H), 7.28 (td, J=7.2, 1.9 Hz, 2H), 6.95 (d, J=8.4 Hz, 1H), 6.22 (t, J=7.1 Hz, 1H), 4.13 (t, J=7.3 Hz, 2H), 2.01 (t, J=7.2 Hz, 2H), 1.58 (s, 9H), 1.01-0.87 (m, 2H) , 0.69-0.57 (m, 2H). MS-ESI m/z calc. 402.05942, detected 403.13 (M+1) ⁺ ; retention time: 0.56 min (LC method A).

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

In a 20 ml bottle tert-butyl-2-chloro-6-[2-oxo-3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]-1-pyridyl]pyridine-3-carboxylate (100 mg, 0. 2483 mmol) and carbo-492 044967 nyldiimidazole (47 mg, 0.2899 mmol) were combined in tetrahydrofuran (2 ml) and stirred at room temperature for 2 hours. Then tert-butyl (48)-2,2-dimethyl- 4-[3-[(6-sulfamoyl-2pyridyl)amino]propyl]pyrrolidine-1-carboxylate (114 mg, 0.2763 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene ( 50 μl, 0.3343 mmol) and the reaction mixture was stirred for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with a small amount of 1:1 saturated aqueous ammonium chloride/saline solution. The organic phases were separated, dried over sodium sulfate, filtered and evaporated. The resulting brown residue was purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% ethyl acetate to give tert-butyl(4S)-4-[3-[[6-[[2-chloro-6-[2-oxo -3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]-1pyridyl]pyridin-3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1carboxylate (48 mg, 24% ). MS-ESI m/z calc. 796.2633, detected 797.4 (M+1) ⁺ ; Retention time: 0.81 min (LC method A).

Step 5: (14S)-12,12-dimethyl-8-(2-oxo-3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1,2dihydropyridin-1-yl)-2λ ⁶ -thia- 3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (compound 268 )

A solution of tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-[2-oxo-3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]-1pyridyl]pyridin- 3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1carboxylate (48 mg, 0.06020 mmol) in dichloromethane (400 μl) and trifluoroacetic acid (100 μl, 1.307 mmol) was stirred at room temperature for 4 hours. Solvents were removed by evaporation and dissolved in ethyl acetate. This solution was washed with 2 ml of saturated sodium bicarbonate solution and the organic layer was collected, the solvent was removed by evaporation, then dried in vacuo. The resulting residue was dissolved in dimethyl sulfoxide (5 ml), 3 A molecular sieves were added and the reaction mixture was stirred for 10 minutes. Cesium fluoride (36 mg, 0.2370 mmol) and potassium carbonate (31 mg, 0.2243 mmol) were then added and the reaction mixture was heated at 150°C for 16 hours. The reaction mixture was filtered through a Whatman disk filter (puradisc 25 TF ), and the filtrate was purified by reverse phase HPLC-MS using a dual gradient from 30% to 99% mobile phase B over 15.0 min (mobile phase A = water (0.05% hydrochloric acid), mobile phase B = acetonitrile) to give (14S)-12,12-dimethyl-8-(2-oxo-3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1,2-dihydropyridin-1-yl)-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (compound 268) (19.5 mg, 49%) as an off-white solid.

1H NMR (400 MHz, chloroform-d) δ 7.96 (d, J=8.4 Hz, 1H), 7.59 (s, 1H), 7.46 (d, J=6.7 Hz, 1H), 7.21 (t, J=8.4 Hz , 2H), 6.72 (s, 1H), 6.43 (d, J=8.3 Hz, 1H), 6.21 (t, J=7.0 Hz, 1H), 4.06 (s, 2H), 3.86 (brs, 1H), 3.293 .13 (m, 2H), 2.89 (brs, 1H), 2.36 (brs, 1H), 1.95 (t, J=7.8 Hz, 2H), 1.85 (brs, 1H), 1.67-1.54 (m, 3H), 1.46 (t, J=11.4 Hz, 2H), 1.18 (s, 3H), 1.14 (s, 3H), 0.99 (s, 2H), 0.67 (s, 2H). MS-ESI m/z calc. 660.2342, detected 661.4 (M+1)+; retention time: 1.83 min (LC method B).

Example 187: Preparation of 19,19-dimethyl-4-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1Hpyrazol-1-yl)-10λ ⁶ -thia-1,3,9,14,21 -pentaazatetracyclo[15.2.1.111,14.02,7]genicose-2,4,6,11(21),12pentaene-8,10,10-trione (compound 273)

- 493 044967

Step 1: tert-butyl 2,2-dimethyl-4-(2-methylsulfonyloxyethyl)pyrrolidine-1-carboxylate

Tert-butyl 4-(2-hydroxyethyl)-2,2-dimethylpyrrolidine-1-carboxylate (751 mg, 3.086 mmol), dichloromethane (10 mL), and triethylamine (1.75 mL, 12.56 mmol) were added to the flask. . The reaction flask was cooled to 0°C and then methanesulfonyl chloride (290 µl, 3.747 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature and stirred for 45 minutes. The reaction was quenched with ice water. The reaction mixture was extracted twice with dichloromethane, dried over sodium sulfate, filtered and evaporated to give tert-butyl 2,2-dimethyl-4-(2-methylsulfonyloxyethyl)pyrrolidine 1-carboxylate (980 mg, 99%) as a thick yellow oil. MS-ESI m/z calc. 321.16098, detected 322.1 (M+1)+; retention time: 1.22 min (LC method B).

Step 2: tert-butyl 2,2-dimethyl-4-[2-(3-sulfamoylpyrazol-1-yl)ethyl]pyrrolidine-1-carboxylate

Potassium carbonate (1.264 g, 9.146 mmol), 1H-pyrazole-3-sulfonamide (449 mg, 3.051 mmol) and tert-butyl-2,2-dimethyl-4-(2-methylsulfonyloxyethyl)pyrrolidine solution were added to a 20 mL vial -1carboxylate (980 mg, 3.049 mmol) in N,N-dimethylformamide (12 ml). The reaction mixture was capped and placed in an oil bath at 75°C and left stirring for 18 hours. The reaction mixture was quenched with brine and extracted with ethyl acetate 3 times. The organic layers were combined, dried over sodium sulfate, filtered and evaporated. The reaction mixture was purified by column chromatography (0-30% methanol in dichloromethane gradient) to give tert-butyl 2,2-dimethyl-4-[2(3-sulfamoylpyrazol-1-yl)ethyl]pyrrolidine-1-carboxylate ( 259.0 mg, 23%) as a white solid along with a smaller amount of regioisomeric byproduct. MS-ESI m/z calc. 372.18314, detected 373.2 (M+1) ⁺ ; retention time: 1.39 min (LC method B).

Step 3: tert-butyl 4-[2-[3-[[2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl] pyrazol-1-yl]ethyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridine3-carboxylic acid (271 mg, 0.6953 mmol), carbonyldiimidazole (136 mg, 0.8387 mmol) and tetrahydrofuran (3 ml). The reaction mixture was placed in an oil bath preheated to 35°C and left to stir for 2 hours. The reaction mixture was then removed from the oil bath and solid tert-butyl-2,2-dimethyl-4-[2-(3-sulfamoylpyrazol- 1-yl)ethyl]pyrrolidine-1-carboxylate (259 mg, 0.6953 mmol) from the flask, which was washed with tetrahydrofuran (2 ml), into the reaction mixture. 1,8-Diazabicyclo[5.4.0]undec-7-ene (350 μL, 2.340 mmol) was added and the reaction mixture was left to stir at room temperature overnight. The reaction mixture was quenched with brine and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated to obtain a foam. The foamy residue was purified by chromatography on silica gel (0%-20% methanol in a dichloromethane gradient) to give tert-butyl 4-[2-[3-[[2-chloro-6-[3-[3-[1-494 044967 ( trifluoromethyl)cyclopropyl] propoxy] pyrazol-1 -yl] pyridin-3 -carbonyl] sulfamoyl] pyrazol-1 yl] ethyl]-2,2-dimethylpyrrolidine-1-carboxylate (336 mg, 65%) as a white foam.

¹ H NMR (400 MHz, DMSO-de) δ 8.35 (d, J=2.8 Hz, 1H), 8.08 (d, J=8.2 Hz, 1H), 7.79 (s, 1H), 7.62 (d, J=8.3 Hz, 1H), 6.59 (s, 1H), 6.13 (d, J=2.8 Hz, 1H), 4.22 (t, J=6.2 Hz, 2H), 4.13 (t, J=7.2 Hz, 2H), 3.54 ( dt, J=23.2, 9.6 Hz, 1H), 2.82 (t, J=10.5 Hz, 1H), 2.00 (d, J=8.2 Hz, 1H), 1.91-1.78 (m, 5H), 1.77-1.68 (m , 2H), 1.35 (dd, J=18.7, 10.1 Hz, 13H), 1.18 (d, J=1.7 Hz, 3H), 0.95-0.88 (m, 2H), 0.79-0.72 (m, 2H). MS-ESI m/z calc. 743.248, detected 744.4 (M+1)+; retention time: 1.81 min (LC method G).

Step 4: 2-chloro-K-({1-[2-(5,5-dimethylpyrrolidin-3-yl)ethyl]-1 H-pyrazol-3-yl}sulfonyl)-6-(3{3-[ 1 -(trifluoromethyl)cyclopropyl]propoxy} -1 H-pyrazol-1 -yl)pyridin-3-carboxamide

Tert-butyl 4-[2-[3-[[2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3-carbonyl] was added to the flask. sulfamoyl]pyrazol-1-yl]ethyl]-2,2-dimethylpyrrolidine-1carboxylate (330 mg, 0.4434 mmol) and dichloromethane (6 ml). Trifluoroacetic acid (1.5 mL, 19.47 mmol) was added and the reaction mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was evaporated to dryness, neutralized with saturated sodium bicarbonate and extracted with ethyl acetate (poor solubility in ethyl acetate). The organic layer was dried over sodium sulfate and filtered. Most of the desired material was still on the filter cake, so the filter cake (mostly sodium sulfate) was dissolved in water and washed with more ethyl acetate. The organic phase was separated and evaporated without drying over sodium sulfate. The product was dried in vacuo to remove residual water before obtaining 2-chloro-X-({1-[2-(5,5dimethylpyrrolidin-3-yl)ethyl]-1H-pyrazol-3-yl}sulfonyl)-6-( 3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1-yl)pyridin-3-carboxamide (246 mg, 86%) as a white solid. MS-ESI m/z calc. 643.19556, detected 644.3 (M+1) ⁺ ; retention time: 1.52 min (LC method B).

Step 5: 19,19-dimethyl-4-(3 -{3-[1 -(trifluoromethyl)cyclopropyl]propoxy}-1 H-pyrazol-1 -yl)-10λ ⁶ thia-1,3,9,14, 21-pentaazatetracyclo[15.2.1.111,14.02,7]genicose-2,4,6,11(21),12-pentaene-8,10,10-trione (compound 273)

Added 3 A molecular sieves, potassium carbonate (264 mg, 1.910 mmol), cesium fluoride (116 mg, 0.7636 mmol) and 2-chloro-N-({1-[2-(5, 5-dimethylpyrrolidin-3-yl)ethyl]-1Hpyrazol-3-yl}sulfonyl)-6-(3-{3-[1 -(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1-yl)pyridin3- carboxamide (246 mg, 0.3819 mmol) in dimethyl sulfoxide (15 ml). The reaction mixture was capped and placed in a preheated 150°C oil bath and left to stir overnight. The reaction mixture was allowed to cool to room temperature, filtered, and purified by reverse phase HPLC (10-99% acetonitrile in water modified with 0.1% hydrochloric acid) to give 19,19-dimethyl-4-(3-{3-[1 -(trifluoromethyl)cyclopropyl] propoxy} -1 H-pyrazol-1 -yl)-10λ ⁶ -thia1,3,9,14,21 -pentaazatetracyclo[15.2.1.111,14.02,7]genicose-2,4,6, 11(21),12-pentaene-8,10,10-trione (compound 273) (25.5 mg, 11%). MS-ESI m/z calc. 607.2189, detected 608.3 (M+1) ⁺ ; retention time: 2.08 min (LC method B).

Example 188: Preparation of 21,21-dimethyl-4-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1Hpyrazol-1-yl)-10λ ⁶ -thia-1,3,9,14,23 -pentaazatetracyclo[17.2.1.111,14.02,7]tricoseα-2,4,6,11(23),12pentaene-8,10,10-trione (compound 275)

Oh oh

Step 1: tert-butyl 4-[4-[3-[[2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1yl]pyridin-3-carbonyl]sulfamoyl] pyrazol-1-yl]butyl]-2,2-dimethyl-pyrrolidin-1

- 495 044967 o o

2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridine3-carboxylic acid (280 mg, 0.7184 mmol), carbonyldiimidazole (140 mg, 0.8634 mmol) and tetrahydrofuran (3 ml). The reaction mixture was heated at 35°C for 90 minutes. The reaction mixture was removed from the oil bath and a solution of tert-butyl 2,2-dimethyl-4-[4-(3-sulfamoylpyrazol-1yl)butyl]pyrrolidine-1-carboxylate (288 mg, 0.7190 mmol) in tetrahydrofuran was added ( 3 ml), followed by 1,8diazabicyclo[5.4.0]undec-7-ene (350 µl, 2.340 mmol). The reaction mixture was allowed to stir for 18 hours and then quenched with brine and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated to obtain a foam. The residual foam was purified by silica gel chromatography (0%-20% methanol in dichloromethane) to give tert-butyl 4-[4-[3[[2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl] propoxy] pyrazol-1 -yl] pyridin-3 carbonyl] sulfamoyl] pyrazol-1-yl] butyl]-2,2-dimethylpyrrolidine-1-carboxylate (159.1 mg, 29%) as a white foam.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.88 (s, 1H), 8.39 (d, J=2.9 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.00 (d, J= 2.4 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 6.86 (d, J=2.3 Hz, 1H), 6.19 (d, J=2.9 Hz, 1H), 4.23 (t, J=6.3 Hz , 4H), 3.49 (k, J=10.1 Hz, 1H), 2.73 (k, J=10.0 Hz, 1H), 2.07-1.94 (m, 1H), 1.82 (ddt, J=27.6, 14.2, 7.0 Hz, 5H), 1.741.69 (m, 2H), 1.36 (d, J=10.9 Hz, 10H), 1.30 (d, J=11.7 Hz, 5H), 1.18 (s, 4H), 0.95-0.87 (m, 2H ), 0.80-0.70 (m, 2H). MS-ESI m/z calc. 771.27924, detected 772.4 (M+1)+; retention time: 1.99 min (LC method G).

Step 2: 2-chloro N-({1-[4-(5,5-dimethylpyrrolidin-3-yl)butyl]-1H-pyrazol-3-yl}sulfonyl)-6-(3{3-[1 - (trifluoromethyl)cyclopropyl]propoxy}-1 H-pyrazol-1-yl)pyridin-3-carboxamide

Into a flask containing tert-butyl-4-[4-[3-[[2-chloro-6-[3-[3-[1-(trifluoromethyl)cyclopropyl]propoxy]pyrazol-1-yl]pyridin-3- carbonyl]sulfamoyl]pyrazol-1-yl]butyl]-2,2-dimethylpyrrolidine-1carboxylate (156 mg, 0.2020 mmol) dichloromethane (6 ml) and trifluoroacetic acid (600 μl, 7.788 mmol) were added. The reaction was left stirring at room temperature for 1 hour. The reaction mixture was evaporated to dryness and saturated sodium bicarbonate solution was added until the pH of the reaction mixture reached 7. Ethyl acetate was added and the mixture was stirred for 3 minutes. The mixture was separated and the organic layer (not completely dissolved) was evaporated to dryness and dried in vacuo overnight to give 2-chloro-N-({1-[4-(5,5-dimethylpyrrolidin-3-yl)butyl]-1H -pyrazol-3yl}sulfonyl)-6-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1-yl)pyridin-3carboxamide (133 mg, 98%) as a white solid. MS-ESI m/z calc. 671.2268, detected 672.4 (M+1) ⁺ ; retention time: 1.56 min (LC method G).

Step 3: 21,21 -dimethyl-4-(3 -{3-[1 -(trifluoromethyl)cyclopropyl]propoxy} -1 H-pyrazol-1 -yl)-10λ ⁶ thia-1,3,9,14, 23-pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4,6,11 (23),12-pentaene-8,10,10-trione (compound 275)

Potassium carbonate (137 mg, 0.9913 mmol), cesium fluoride (62 mg, 0.4082 mmol), 3 A molecular sieves and a solution of 2-chloro-N-({1-[4-(5.5 -dimethylpyrrolidin-3-yl)butyl]-1H-pyrazol-3yl}sulfonyl)-6-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1-yl)pyridin-3carboxamide ( 133 mg, 0.1979 mmol) in dimethyl sulfoxide (8 ml). The reaction mixture was placed in a preheated 150°C oil bath and left stirring for 18 hours. The reaction mixture was filtered and purified by reverse phase HPLC (30-99% acetonitrile in water with 0.1% hydrochloric acid modifier) to give 21. 21-dimethyl-4-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1 H-pyrazol-1 -yl)-10λ ⁶ -thia-1,3,9,14,23-pentaazatetracyclo[ 17.2.1.111,14.02,7]tricose-2,4,6,11(23),12-pentaene-8,10,10-trione (compound 275) (58.6 mg, 47%) as a white solid . MS-ESI m/z calc. 635.2502, detected 636.4 (M+1) ⁺ ; retention time: 2.22 min (LC method B).

Example 189: preparation of 21,21-dimethyl-4-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1H- 496 044967 pyrazol-1-yl)-10λ ⁶ -thia-1,3,9 ,14,23-pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4,6,11(23),12pentaene-8,10,10-trione (enantiomer 1) (compound 276) and 21,21- dimethyl-4-(3-{3-[1(trifluoromethyl)cyclopropyl]propoxy} -1 H-pyrazol-1 -yl)-10λ ⁶ -thia-1,3,9,14,23pentaazatetracyclo[17.2.1.111,14.02 ,7]tricose-2,4,6,11 (23), 12-pentaene-8,10,10-trione (enantiomer 2) (compound 277)

Step 1: 21,21 -dimethyl-4-(3 -{3-[1 -(trifluoromethyl)cyclopropyl] propoxy }-1 H-pyrazol-1 -yl)-10λ ⁶ thia-1,3,9,14, 23-pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4,6,11(23),12-pentaene-8,10,10-trione (enantiomer 1) (compound 276) and 21,21-dimethyl -4-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1Hpyrazol-1-yl)-10λ ⁶ -thia-1,3,9,14,23-pentaazatetracyclo[17.2.1.111,14.02, 7]tricose-2,4,6,11(23),12pentaene-8,10,10-trione (enantiomer 2) (compound 277)

Racemic 21,21 -dimethyl-4-(3-{3-[1 -(trifluoromethyl)cyclopropyl]propoxy} -1H-pyrazol-1 -yl)10λ ⁶ -thia-1,3,9,14,23-pentaazatetracyclo [17.2.1.111,14.02,7]tricose-2,4,6,11(23),12-pentaene-8,10,10-trione (53 mg, 0.08337 mmol) was separated by chiral FPLC using ChiralPak AS-H (250 x 21.2 mm column, 5 µm particle size) with 25% acetonitrile:methanol (90:10; 20 mM NH ₃ ))/75% carbon dioxide mobile phase at 10 ml/min to obtain as the first eluted enantiomer, 21,21 -dimethyl-4-(3 -{3-[1 -(trifluoromethyl)cyclopropyl]propoxy} -1 H-pyrazol-1 -yl)-10λ ⁶ -thia1,3,9,14 ,23-pentaazatetracyclo[17.2.1.111,14.02.7]tricose-2,4,6,11(23),12-pentaene-8,10,10-trione (enantiomer 1) (compound 276) (19, 6 mg, 74%);

¹ H NMR (400 MHz, DMSO-a ₆ ) δ 12.57 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.98 (s, 1H), 7.75 (s, 1H), 6.89 (d, J=9.1 Hz, 2H), 6.11 (d, J=2.3 Hz, 1H), 4.27 (s, 2H), 4.20 (t, J=6.2 Hz, 2H), 2.72 (d, J=9.3 Hz, 2H) , 2.54 (s, 6H), 1.85 (dd, J=10.3, 5.4 Hz, 3H), 1.75-1.69 (m, 2H), 1.61 (s, 4H), 1.52 (s, 4H), 0.93-0.89 (m , 2Н), 0.77-0.73 (m, 2Н), MS-ESI m/z calc. 635.2502, found 636.4 (M+1)+; Retention time: 2.24 min (LC method B).

The second eluted enantiomer is 21,21-dimethyl-4-(3-{3-[1(trifluoromethyl)cyclopropyl]propoxy}-1 H-pyrazol-1 -yl)-10λ ⁶ -thia-1,3,9,14, 23pentaazatetracyclo[17.2.1.111,14.02,7]tricose-2,4,6,11(23),12-pentaene-8,10,10-trione (enantiomer 2) (compound 277) (16.6 mg, 63% ). MS-ESI m/z calc. 635.2502, detected 636.4 (M+1) ⁺ ; retention time: 2.22 min (LC method B).

Example 190: Preparation of 20,20,22-trimethyl-4-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol1-yl]-10λ ⁶ -thia-1,3,9 ,13,14-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10trione (atropisomer 2, enantiomer 1) (compound 285) and 20 ,20,22-trimethyl-4-[3-(3,3,3-trifluoro-2,2dimethylpropoxy)-1 H-pyrazol-1 -yl]-10λ ⁶ -thia-1,3,9,13,14 -pentaazatetracyclo[16.2.1.111,14.02,7]docose2,4,6,11(22),12-pentaene-8,10,10-trione (atropisomer 2, enantiomer 2) (compound 286)

- 497 044967

Step 1: 2O,20,22-trimethyl-4-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl]-1Oλ ⁶ -thia1,3,9, 13,14-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (atropisomer 2, enantiomer 1) (compound 285) and 20,20,22-trimethyl-4-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)1H-nirazol-1-yl]-1Oλ ⁶ -thia-1,3,9,13, 14-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12pentaene-8,10,10-trione (atropisomer 2, enantiomer 2) (compound 286)

20,20,22-Trimethyl-4-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-nirazol-1-yl]-10λ ⁶ -thia1,3,9,13,14 -pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (17 mg, 0.02788 mmol) (racemic atropisomer 2) was separated by chiral LCLC using ChiralPak AS-H (250x10 mm column, 5 µm particle size) with a mobile phase of 24% acetonitrile:methanol (90:10; 20 mM NH ₃ ))/76% carbon dioxide at 10 ml/min, which gives the first eluting enantiomer, 20,20,22-trimethyl-4-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-nirazol-1-yl]-10λ ⁶ -thia-1, 3,9,13,14pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11 (22),12-pentaene-8,10,10-trione (atropoisomer 2, enantiomer 1) (compound 285 ) (5.4 mg, 64%) as a yellow solid.

Ή NMR (400 MHz, DMSO-a ₆ ) δ 12.16 (bs, 1H), 8.19 (d, J=2.8 Hz, 1H), 7.81 (d, J=7.9 Hz, 1H), 7.71 (s, 1H), 6.92 (d, J=7.9 Hz, 1H), 6.10 (d, J=2.8 Hz, 1H), 4.35 (m, 1H), 4.22 (bs, 2H), 4.02 (m, 1H), 2.66 (s, 3H ), 2.39 (m, 1H), 2.02 (m, 3H), 1.83 (m, 2H), 1.65 (dd, J=12.1 Hz, 5.6 Hz, 1H), 1.50 (k, J=15.6 Hz, 12.4 Hz, 2 N), 1.50 (m, 8H), 1.36 (k, J=15.6 Hz, 12.4 Hz, 2H), 1.22 (s, 6H), 1.12 (m, 1H). MS-ESI m/z calc. 609.2345, detected 610.4 (M+1)+; retention time: 3.14 min (LC method D).

The second enantiomer eluted was 20,20,22-trimethyl-4-[3-(3,3,3-trifluoro-2,2dimethylpropoxy)-1H-pyrazol-1-yl]-10λ ⁶ -thia-1,3,9 ,13,14-pentaazatetracyclo[16.2.1.111,14.02,7]docose2,4,6,11(22),12-pentaene-8,10,10-trione (atropoisomer 2, enantiomer 2) (compound 286) (6 .5 mg, 76%), isolated as a yellow foam. MS-ESI m/z calc. 609.2345, detected 610.4 (M+1) ⁺ ; retention time: 3.14 min (LC method D).

Example 191: Preparation of 12,20,20-trimethyl-4-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol1-yl]-1Oλ ⁶ -thia-1,3,9 ,13,14-pentaazatetracyclo[16.2.1.111,14.O2,7]docose-2,4,6,11(22),12-pentaene-8,1O,10trione (enantiomer 1) (compound 290) and 12, 20,20-trimethyl-4-[3-(3,3,3-trifluoro-2,2dimethylpropoxy)-1H-pyrazol-1-yl]-10λ ⁶ -thia-1,3,9,13,14-pentaazatetracyclo [16.2.1.111,14.02,7]docose2,4,6,11(22),12-pentaene-8,10,10-trione (enantiomer 2) (compound 291)

Step 1: 12,20,2O-trimethyl-4-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl]-1Oλ ⁶ -thia1,3,9, 13,14-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (enantiomer 1) (compound 290) and 12,20 ,20-trimethyl-4-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1yl]-10λ ⁶ -thia-1,3,9,13,14-pentaazatetracyclo[ 16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10- 498 044967 trione (enantiomer 2) (compound 291)

Racemic 12,2O,2O-trimethyl-4-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl]-10λ ⁶ thia-1,3,9,13 ,14-pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (73 mg, 0.1197 mmol) was subjected to chiral SCLC- chromatography using ChiralPak AS-H (250x21.2 mm column, 5 µm particle size) with 20% acetonitrile:methanol (90:10, 20 mM NH ₃ ))/80% carbon dioxide mobile phase at 70 ml/min, giving as the first enantiomer for the eluate, 12,20,20trimethyl-4-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl]-10λ ⁶ -tua-1 ,3,9,13,14pentaazatetracyclo[16.2.1.111,14.02,7]docose-2,4,6,11(22),12-pentaene-8,10,10-trione (enantiomer 1) (compound 290) ( 35.1 mg, 92%). MS-ESI m/z calc. 609.2345, detected 610.4 (M+1)+; retention time: 3.07 min (LC method D).

The second enantiomer eluted was 12,20,20-trimethyl-4-[3-(3,3,3-trifluoro-2,2dimethylpropoxy)-1H-nurazol-1-yl]-10λ ⁶ -tua-1,3,9 ,13,14-pentaazatetracyclo[16.2.1.111,14.02,7]docose2,4,6,11(22),12-pentaene-8,10,10-trione (enantiomer 2) (compound 291) (28.5 mg , 78%).

1H NMR (400 MHz, DMSO-Y6) δ 12.16 (bs, 1H), 8.38 (s, 1H), 8.19 (d, J=2.8 Hz, 1H), 7.81 (d, J=7.9 Hz, 1H), 6.92 (d, J=7.9 Hz, 1H), 6.10 (d, J=2.8 Hz, 1H), 4.35 (m, 1H), 4.22 (bs, 2H), 4.02 (m, 1H), 2.38 (s, 3H) , 2.02 (m, 3H), 1.83 (m, 2H), 1.75 (dd, J=12.1 Hz, 5.6 Hz, 1H), 1.54 (s, 3H), 1.47 (s, 3H), 1.36 (k, J= 15.6 Hz, 12.4 Hz, 2H), 1.22 (s, 6H), 1.12 (m, 1H). MS-ESI m/z calc. 609.2345, detected 610.4 (M+1) ⁺ ; retention time: 3.07 min (LC method D).

Example 192: Preparation of 5,5-dimethyl-9-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1yl)-15λ ⁶ -thia-2,6,8,14,20 -pentaazatetracyclo[14.3.1.13,6.07,12]genicose-1(2O),7,9,11,16,18-hexaene13,15,15-trione (compound 31)

Step 1: 1-benzyl-5,5-dimethylpyrrolidin-3-one

To a stirred solution of 5,5-dimethylpyrrolidin-3-one (1.020 g, 9.014 mmol) in anhydrous acetonitrile (30 mL) was added anhydrous potassium carbonate (5.00 g, 36.18 mmol) under a nitrogen atmosphere at ambient temperature. After stirring for 15 min, benzyl bromide (1.2 mL, 10.09 mmol) was added. After 7 hours the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the crude product which was extracted from water (20 ml) with ethyl acetate (3 x 30 ml). The combined organic extracts were washed with water and dried over anhydrous sodium sulfate, filtered through a pad of silica gel and concentrated in vacuo to give the crude product, 1-benzyl-5,5dimethylpyrrolidin-3-one (1.67 g, 91%) as an orange viscous material , which was used in the subsequent reaction without further purification. MS-ESI m/z calc. 203.13101, detected 204.1 (M+1) ⁺ ; retention time: 0.81 min (LC method B).

Step 2: (E)-N-(1-benzyl-5,5-dimethylpyrrolidin-3-ylidene)-2-methylpropan-2-sulfinamide.

Titanium(IV) ethoxide (IV) was added to a stirred solution of 1-benzyl-5,5-dimethylpyrrolidin-3-one (1.762 g, 8.668 mmol) and 2methylpropane-2-sulfinamide (1.157 g, 9.546 mmol) in anhydrous tetrahydrofuran (70 mL). 7.3 ml, 34.82 mmol) under nitrogen atmosphere at ambient temperature. Reak

- 499 044967 tion mixture was allowed to stir at 80°C for 13 hours, then allowed to cool to ambient temperature. The reaction was slowly quenched with saturated aqueous sodium bicarbonate until some precipitate formed (although titanium salts are white, the color of the product caused the salt to appear brownish) (about 40 ml of sodium bicarbonate was used). The inorganic suspension was filtered through a pad of celite and the filter cake was washed with ethyl acetate (100 ml). After separating the layers from the filtrate, the aqueous portion was extracted with ethyl acetate (2x50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (E)-N-(1-benzyl-5,5-dimethylpyrrolidin-3ylidene)-2-methylpropane-2-sulfinamide (2.602 g, 98%) as a brownish solid, which was used in the subsequent reaction without further purification. MS-ESI m/z calc. 306.17657, detected 307.2 (M+1)+; retention time: 0.8 min (LC method B).

Step 3: N-(1-benzyl-5,5-dimethylpyrrolidin-3-yl)-2-methylpropan-2-sulfinamide

To a stirred solution of (E)-N-(1-benzyl-5,5-dimethylpyrrolidin-3-ylidene)-2-methylpropan-2sulfinamide (770 mg, 2.51 mmol) in anhydrous methanol (3 ml) and tetrahydrofuran (10 ml) at -10°C, sodium borohydride (290 mg, 7.665 mmol) was added in three portions under a nitrogen atmosphere. The reaction mixture was allowed to warm to 0°C and stirred at this temperature for 2 hours. The reaction was quenched with aqueous NH4Cl (5 ml) and then with saturated aqueous sodium bicarbonate (20 ml). The volatiles were removed and the remaining aqueous portion was extracted with ethyl acetate (25 ml). The aqueous layer was further extracted with ethyl acetate (2x15 ml). The combined organic layers were dried (magnesium sulfate), filtered and concentrated to give crude N-(1-benzyl-5,5-dimethylpyrrolidin-3-yl)-2methylpropan-2-sulfinamide (650 mg, 84%) as a brownish solid . MS-ESI m/z calc. 308.19223, detected 309.2 (M+1) ⁺ ; retention time: 0.63 min (LC method B).

Step 4: 1-Benzyl-5,5-dimethylpyrrolidin-3-amine (dihydrochloride salt)

Crude N-(1-benzyl-5,5-dimethyl-pyrrolidin-3-yl)-2-methylpropan-2-sulfinamide (650 mg, 2.107 mmol) was dissolved in methanol (10 ml) and hydrogen chloride (2.2 ml 4.0 M in dioxane, 8.800 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 1 hour. Volatiles were removed under reduced pressure. Trituration with ether was attempted, but the crude product became a sticky material, so the ether was removed under reduced pressure and the resulting material was dried in vacuo to give 1-benzyl-5,5-dimethylpyrrolidin-3-amine (dihydrochloride salt). (580 mg, 99%) in the form of a brownish resinous mass. It was used in the subsequent reaction without further purification. MS-ESI m/z calc. 204.16264, detected 205.1 (M+1) ⁺ ; retention time: 0.3 min (LC method B).

Step 5: 6-[(1-benzyl-5,5-dimethylpyrrolidin-3-yl)amino]pyridin-2-sulfonamide

A 20 ml vial was loaded with 6-fluoropyridine-2-sulfonamide (0.351 g, 1.992 mmol) and anhydrous dimethyl sulfoxide (5 ml), followed by the addition of anhydrous potassium carbonate (1.377 g, 9.963 mmol) and 1-benzyl-5,5-dimethylpyrrolidine -3-amine (dihydrochloride salt) (0.580 g, 2.092 mmol), in that order. The vessel was sealed under nitrogen and stirred to 70°C in an oil bath for 13 hours, then at 90°C for 8 hours, followed by brief heating at 100°C for approximately 30 minutes. The reaction mixture was filtered through a pad of celite, then diluted with ethyl acetate (30 ml) and neutralized with ice-cold AcOH to pH ~ 7. Washed with water (15 ml) and then saline (15 ml). The organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by chromatography on silica gel. Initially, using a gradient from 20% to 100% ethyl acetate in hexane did not give a pure product. A second purification by silica gel chromatography (0-15% methanol in dichloromethane) gave the desired compound, 6-[(1-benzyl-5,5-dimethylpyrrolidin-3-yl)amino]pyridin-2-sulfonamide (125 mg, 17 %) as a light brown solid. MS-ESI m/z calc. 360.162, detected 361.2 (M+1) ⁺ ; time

- 500 044967 retention: 0.59 min (LC method B).

Step 6: 6-[(5,5-dimethylpyrrolidin-3-yl)amino]pyridin-2-sulfonamide

A stirred solution of 6-[(1-benzyl-5,5-dimethylpyrrolidin-3-yl)amino]pyridin-2sulfonamide (125 mg, 0.3468 mmol) in anhydrous methanol (8 ml) was treated with palladium on carbon (40 mg, 0 .03759 mmol) in a nitrogen atmosphere. The reaction mixture was stirred at 52°C under a hydrogen atmosphere (balloon) for 10 hours. The reaction mixture was allowed to cool to ambient temperature, the flask was evacuated, filled with nitrogen, then palladium hydroxide (25 mg, 0.03560 mmol) was added. Again the reaction mixture was stirred at 52°C under a hydrogen atmosphere (balloon) for 7 hours, then allowed to cool to ambient temperature. The catalyst was filtered through a pad of celite and the filtrate was concentrated under reduced pressure and dried in vacuo to give 6-[(5,5dimethylpyrrolidin-3-yl)amino]pyridin-2-sulfonamide (61 mg, 65%) as a light brown solid. substances that were used in the subsequent reaction without further purification. MS-ESI m/z calc. 270.11505, detected 271.1 (M+1)+; retention time: 0.53 min (LC method B).

Step 7: 2-chloro-N-[[6-[(5,5-dimethylpyrrolidin-3-yl)amino]-2-pyridyl]sulfonyl]-6-[3-[2-[1(trifluoromethyl)cyclopropyl] ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (dihydrochloride salt)

6-[(5,5-Dimethylpyrrolidin-3-yl)amino]pyridin-2-sulfonamide (43 mg, 0.1591 mmol) and carbonyldiimidazole (29 mg, 0.1788 mmol) were combined in dry tetrahydrofuran (3 ml) and stirred under nitrogen at 48°C for 1 hour. Then a solution of 2-chloro-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (60 mg, 0.1597 mmol) in dry tetrahydrofuran (1 ml), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (30 µl, 0.2006 mmol). The reaction mixture was removed from the heat and stirred at ambient temperature for 12 hours. Volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.5 ml), filtered through a Whatman 0.45 µm syringe disc filter and purified by preparative reverse -phase HPLC (1-99% acetonitrile in water, hydrochloric acid as modifier) to form 2-chloro-N-[[6-[(5,5-dimethylpyrrolidin-3-yl)amino]-2-pyridyl]sulfonyl ]-6-[3-[2[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridin-3-carboxamide (dihydrochloride salt) (13 mg, 12%) as an off-white solid.

1H NMR (400 MHz, DMSO-de) δ 9.09 (s, 2H), 8.40 (d, J=2.9 Hz, 1H), 8.13 (d, J=8.3 Hz, 1H), 7.77-7.63 (m, 3H) , 7.23 (d, J=7.2 Hz, 1H), 6.81 (d, J=8.4 Hz, 1H), 6.18 (d, J=2.9 Hz, 1H), 4.45-4.36 (m, 1H), 4.34 (t, J=7.1 Hz, 2H), 3.72-3.62 (m, 1H), 3.26-3.14 (m, 1H), 2.24 (dd, J=13.4, 8.3 Hz, 1H), 2.08 (t, J=7.1 Hz, 2H ), 1.89 (dd, J=14.4.0 Hz, 1H), 1.48 (s, 3H), 1.28 (s, 3H), 1.00-0.92 (m, 2H), 0.94-0.85 (m, 2H). MS-ESI m/z calc. 627.16425, detected 628.2 (M+1)+; Retention time: 1.55 min (LC method B).

Step 8: 5,5-dimethyl-9-(3-{2-[1 -(trifluoromethyl)cyclopropyl]ethoxy}-1 H-pyrazol-1 -yl)-15λ ⁶ -thia2,6,8,14,20 -pentaazatetracyclo[14.3.1.13,6.07,12]genicose-1(20),7,9,11,16,18-hexaene-13,15,15-trione (compound 31) ooo ooo

To a solution of 2-chloro-N-[[6-[(5,5-dimethylpyrrolidin-3-yl)amino]-2-pyridyl]sulfonyl]-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy ]pyrazol-1-yl]pyridin-3-carboxamide (dihydrochloride salt) (11 mg, 0.01569 mmol) in anhydrous dimethyl sulfoxide (1.5 ml), added cesium fluoride (3 mg, 0.01975 mmol), potassium carbonate (12 mg, 0.08683 mmol) (ground in a mortar and pestle) and a small amount of 4 A molecular sieve granules (about 500 mg, heated with a heat gun for 5 minutes until dry). The resulting mixture was sealed under nitrogen and heated at 150°C for 17 hours, then allowed to cool to ambient temperature, allowing the solid to settle to the bottom.

- 501 044967

The supernatant was filtered through a 0.45 μm Whatman PTFE syringe disk filter. The filtrate was concentrated and purified using reverse phase HPLC-MS using a Luna C ₁₈ column (2) and a dual gradient from 1% to 99% acetonitrile in water (no modifier) to give 5,5-dimethyl-9-(3 -{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)-15λ ⁶ -tua-2,6,8,14,20pentaazatetracyclo[14.3.1.13,6.07,12]genicose-1 (20), 7,9,11,16,18-hexaene-13,15,15-trione (compound 31) (3.5 mg, 37%). MS-ESI m/z calc. 591.18756, detected 592.3 (M+1)+; retention time: 1.6 min (LC method B).

Example 193: Preparation of (14S)-12,12-dimethyl-8-{3-oxo-octahydroimidazo[1,5-a]pyridin-2-yl}-2λ ⁶ thia-3,9,11,18,23- pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4trione (compound 213)

Step 1: (14S)-12,12-dimethyl-8-{3-oxo-octahydroimidazo[1,5-a]pyridin-2-yl} ^-2λ6- thia3,9,11,18,23-pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene-2,2,4-trione (compound 213)

(14S)-8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23) was loaded into a 5 ml bottle. 5,7,9,19,21-hexaene-2,2,4-trione (100 mg, 0.2222 mmol), 2,5,6,7,8,8a-hexahydro-1H-imidazo[1,5 -a]pyrudin-3-one (45 mg, 0.3210 mmol), Pd ₂ (dba) ₃ (54 mg, 0.05897 mmol), xanthos (33 mg, 0.05703 mmol), cesium carbonate (375 mg , 1.151 mmol) and anhydrous dioxane (1.6 ml). The mixture was purged with nitrogen for 1-2 minutes, capped and stirred at 120°C for 20 hours, and then cooled to room temperature. The solvent was evaporated and the reaction mixture was diluted with dimethyl sulfoxide (900 μl), microfiltered and purified by preparative reverse phase chromatography using a C ₁₈ column (10%-99% acetonitrile in water + 5 mM hydrochloric acid). The product fractions were combined, brine was added, and the organic solvents were evaporated. The product was extracted with dichloromethane, the organic phase was dried over sodium sulfate, filtered and evaporation of the solvents gave a solid. The resulting solid was purified by silica gel chromatography using a gradient of 100% dichloromethane to 5% methanol in dichloromethane to give (14S)-12,12-dimethyl-8-{3-oxooctahydroimidazo[1,5-a]pyridin-2yl}- 2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5(10),6,8,19,21-hexaene2,2,4 -trione (compound 213) (58.6 mg, 47%).

1H NMR (400 MHz, chloroform-d) δ 10.77 (s, 1H), 8.01 (d, J=8.7 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.617.49 (m, 2H) , 6.54 (p, J=3.7 Hz, 1H), 4.79 (d, J=7.9 Hz, 1H), 4.21-4.07 (m, 1H), 4.02 (dd, J=12.5, 3.6 Hz, 1H), 3.83 ( s, 1H), 3.64-3.48 (m, 2H), 3.32 (t, J=8.9 Hz, 1H), 3.15 (d, J=14.0 Hz, 1H), 3.04 (t, J=9.4 Hz, 1H), 2.832.74 (m, 1H), 2.11 (dd, J=12.4, 8.6 Hz, 1H), 2.00-1.85 (m, 2H), 1.71 (d, J=9.8 Hz, 2H), 1.57 (d, J= 2.0 Hz, 6H), 1.55 (d, J=1.2 Hz, 3H), 1.51-1.43 (m, 3H), 1.37 (t, J=12.8 Hz, 2H). MS-ESI m/z calc. 553.24713, detected 554.2 (M+1)+; retention time: 1.62 min (LC method E).

Example 194: Preparation of (14S)-12,12-dimethyl-8-{1-oxo-2-azaspiro[4.5]decan-2-yl}-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[17.3 .1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 222)

Step 1: (14S)-12,12-dimethyl-8-{1-oxo-2-azaspiro[4.5]decan-2-yl}-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3. 1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 222)

(14S)-8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23- 502 044967 pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 was loaded into a 5 ml ampoule (23),5,7,9,19,21-hexaene-2,2,4-trione (50 mg, 0.1111 mmol), 2-azaspiro[4,5]decan-1-one (24 mg, 0.1566 mmol), Pd ₂ (dba) ₃ (26 mg, 0.02839 mmol), xanthos (16 mg, 0.02765 mmol), cesium carbonate (180 mg, 0.5525 mmol) and anhydrous dioxane (800 µl ). The mixture was purged with nitrogen for 1-2 minutes, capped and stirred at 120°C for 20 hours, and then cooled to room temperature. The solvent was evaporated, the reaction mixture was diluted with dimethyl sulfoxide (900 μl), microfiltered and purified by preparative reverse phase chromatography using a C ₁₈ column (10%-99% acetonitrile in water + 5 mM hydrochloric acid). The product fractions were combined, brine was added, and the organic solvents were evaporated. The product was extracted with dichloromethane, the organic phase was dried over sodium sulfate, filtered and evaporation of the solvents gave a solid. The crude material was then purified by silica gel chromatography using a shallow gradient from 100% dichloromethane to 5% methanol in dichloromethane. The pure fractions were collected and the solvents were evaporated to give (14S)-12,12-dimethyl-8-{1-oxo-2-azacniro[4.5]decan-2-yl}-2λ ⁶ thia-3 as an off-white solid ,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4trione (compound 222) (13.01 mg, 20%).

Ή NMR (400 MHz, chloroform-d) δ 10.41 (s, 1H), 8.10-7.95 (m, 2H), 7.62-7.49 (m, 2H), 6.55 (dd, J=6.8, 2.4 Hz, 1H), 4.74 (s, 1H), 3.93 (t, J=7.2 Hz, 2H), 3.90-3.79 (m, 1H), 3.32 (dd, J=10.0, 7.7 Hz, 1H), 3.16 (d, J=14.3 Hz , 1H), 3.07 (s, 1H), 2.68 (dd, J=11.9, 6.4 Hz, 1H), 2.11 (dd, J=12.4, 8.4 Hz, 1H), 2.03 (dd, J=8.0, 6.3 Hz, 2H), 1.78-1.72 (m, 3H), 1.70-1.62 (m, 3H), 1.57 (d, J=5.4 Hz, 8H), 1.38 (k, J=11.0, 9.2 Hz, 4H), 1.24-1.17 (m, 1H), 0.91-0.79 (m, 2H). MS-ESI m/z calc. 566.2675, detected 567.2 (M+1) ⁺ ; retention time: 2.01 min (LC method E).

Example 195: Preparation of 8-[3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl]-12,12-dimethyl-2X ⁶ -thia3,9,11,19,24-pentaazatetracyclo[18.3.1.05 ,10.011,15]tetracose-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (compound 232)

Step 1: 2,6-dichloro-N-[[6-[3-(5,5-dimethyln-pyrrolidin-2-yl)propylamino]-2pyridyl]sulfonyl]pyridine-3-carboxamide (hydrochloride salt)

A 50 mL flask loaded with 2,6-dichloropyridine-3-carboxylic acid (733 mg, 3.818 mmol) and carbonyldiimidazole (620 mg, 3.824 mmol) was evacuated/refilled with nitrogen. Tetrahydrofuran (15 ml) was added and the mixture was stirred at 50°C for 1 hour. Then a solution of tert-butyl2,2-dimethyl-5-[3-[(6-sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine was added -1-carboxylate (1.5 g, 3.636 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1385 mg, 9.098 mmol) in tetrahydrofuran (10 ml) and the mixture was stirred overnight at 50 °C overnight. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered and evaporated in vacuo, then purified by preparative reverse phase chromatography using a C ₁₈ column (5-95% acetonitrile in water) to give the acyl sulfonamide intermediate. A solution of this intermediate in dioxane (5 ml) was treated with hydrochloric acid (6 ml, 6 M in dioxane, 36.00 mmol) and stirred at room temperature for 3 hours. The mixture was evaporated in vacuo to give 2,6-dichloro-N -[[6-[3-(5,5-dimethylπpyrrolidin-2-yl)πpropylamino]-2-πyridyl]sulfonyl]pyridine-3carboxamide (hydrochloride salt) (0.9 g, 47%). MS-ESI m/z calc. 485.10553, detected 486.15 (M+1) ⁺ ; retention time: 0.42 min (LC method A).

Step 2: 8-chloro-12,12-dimethyl-2λ ⁶ thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.05,10.011,15]tetracose-1(23),5,7,9, 20(24),21-hexaene-2,2,4-trione

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A 5 mL vial was sealed and purged with nitrogen with potassium carbonate (133 mg, 0.9623 mmol), cesium fluoride (60 mg, 0.3950 mmol), and 4 A molecular sieves (300 mg). Then a solution of 2,6-dichloroN-[[6-[3-(5,5-dimethylpyrrolidin-2-yl)propylamino]-2-pyridyl]sulfonyl]pyridine-3-carboxamide (hydrochloride salt) (100 mg, 0. 1912 mmol) in dimethyl sulfoxide (3 ml), and the mixture was stirred at 150°C overnight. The mixture was filtered and purified by preparative reverse phase HPLC (C ₁₈ column, 1-99% acetonitrile in water with hydrochloric acid modifier) to give 8chloro-12,12-dimethyl-2X ⁶ -thia-3,9,11,19,24 -pentaazatetracyclo[18.3.1.05,10.011.15]tetracose1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (20.8 mg, 24%). MS-ESI m/z calc. 449.12885, detected 450.18 (M+1)+; retention time: 1.46 min (LC method B).

Step 3: 8-[3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl]-12,12-dimethyl-2X ⁶ -thia-3,9,11,19,24pentaazatetracyclo[18.3.1.05, 10.011,15]tetracose-1(23),5,7,9,20(24),21-hexaene-2,2,4-trione (compound 232)

8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.05,10.011,15] Tetracose-1(23),5,7,9,20 solution (24),21-hexaene-2,2,4-trione (200 mg, 0.4445 mmol), 1-(3,3-dimethylbutyl)imidazolidin-2-one (114 mg, 0.6696 mmol), xantphos (65 mg, 0.1123 mmol), Pd ₂ (dba) ₃ (102 mg, 0.1114 mmol) and cesium carbonate (724 mg, 2.222 mmol) in dioxane (4 ml) were degassed by purging with nitrogen for 2 min. The mixture was stirred at 120°C overnight. The reaction mixture was filtered and purified by preparative reverse phase HPLC (C ₁₈ column, 1-99% acetonitrile in water with hydrochloric acid modifier) to give 8-[3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl] -12,12-dimethyl2X ⁶ -thia-3,9,11,19,24-pentaazatetracyclo[18.3.1.05,10.011,15]tetracose-1(23),5,7,9,20(24),21- hexaene-2,2,4trione (compound 232) (9 mg, 3%). MS-ESI m/z calc. 583.29407, detected 584.39 (M+1) ⁺ ; retention time: 1.71 min (LC method B).

Example 196: Preparation of 19,19-dimethyl-4-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1Hpyrazol-1-yl)-10λ ⁶ -thia-1,3,9,14,21 -pentaazatetracyclo[15.2.1.111,14.02,7]genicose-2,4,6,11(21),12pentaene-8,10,10-trione (enantiomer 1) (compound 279) and 19,19-dimethyl-4- (3-{3-[1(trifluoromethyl)cyclopropyl]propoxy}-1 H-pyrazol-1 -yl)-10Х ⁶ -thia-1,3,9,14,21pentaazatetracyclo[15.2.1.111,14.02,7]genicose -2,4,6,11(21),12-pentaene-8,10,10-trione (enantiomer 2) (compound 278)

Step 1: 19,19-dimethyl-4-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1-yl)-10λ ⁶ thia-1,3,9,14,21 -pentaazatetracyclo[15.2.1.111,14.02,7]genicose-2,4,6,11(21),12-pentaene-8,10,10-trione (enantiomer 1) (compound 279) and 19,19-dimethyl- 4-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1Hpyrazol-1-yl)-10λ ⁶ -thia-1,3,9,14,21-pentaazatetracyclo[15.2.1.111,14.02.7 ]genicose-2,4,6,11(21),12pentaene-8,10,10-trione (enantiomer 2) (compound 278)

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Racemic 19,19-dimethyl-4-(3-{3-[ 1 -(trifluoromethyl)cyclopropyl]propoxy}-1 H-pyrazol-1-yl)10λ ⁶ -thia-1,3,9,14,21- pentaazatetracyclo[15.2.1.111,14.02,7]genicose-2,4,6,11(21),12-pentaene-8,10,10trione (21 mg, 0.03456 mmol) was subjected to chiral SLC chromatography using ChiralPak AS -H (250x21.2 mm column, 5 µm particle size) with 25% acetonitrile:methanol (90:10, 20 mM NH ₃ ))/75% carbon dioxide mobile phase at 10 ml/min, giving as the first eluting enantiomer , 19,19-dimethyl-4-(3-{3-[ 1 -(trifluoromethyl)cyclopropyl]propoxy} -1 H-pyrazol-1-yl)-10λ ⁶ -thia-1,3,9,14,21 pentaazatetracyclo[15.2.1.111,14.02,7]genicose-2,4,6,11(21),12-pentaene-8,10,10-trione (enantiomer 1) (compound 279) (7.3 mg, 70% ).

Ή NMR (400 MHz, DMSO^) δ 12.61 (s, 1H), 8.18 (d, J=2.7 Hz, 1H), 8.01 (s, 1H), 7.65 (d, J=8.2 Hz, 1H), 6.93 ( s, 1H), 6.85 (d, J=8.2 Hz, 1H), 6.09 (d, J=2.7 Hz, 1H), 4.59 (d, J=13.9 Hz, 1H), 4.23-4.08 (m, 3H), 3.06 (s, 1H), 2.17 (d, J=14.9 Hz, 1H), 1.94 (dd, J=11.9, 5.7 Hz, 1H), 1.85 (dk, J=10.7, 6.3 Hz, 2H), 1.77-1.65 (m, 3H), 1.56 (s, 3H), 1.49 (s, 4H), 0.95-0.88 (m, 2H), 0.79-0.70 (m, 2H). MS-ESI m/z calc. 607.2189, detected 608.3 (M+1)+; Retention time: 2.08 min (LC method B).

The second eluted enantiomer was 19,19-dimethyl-4-(3-{3-[1-(trifluoromethyl)cyclopropyl]propoxy}-1H-pyrazol-1-yl)-10λ ⁶ -thia-1,3,9,14, 21-pentaazatetracyclo[15.2.1.111,14.02,7]genicose2,4,6,11(21),12-pentaene-8,10,10-trione (enantiomer 2) (compound 278) (7.8 mg, 70% ). MS-ESI m/z calc. 607.2189, detected 608.4 (M+1) ⁺ ; retention time: 2.08 min (LC method B).

Example 197: Preparation of (14S)-8-[3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl]-12,12-dimethyl2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo [17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4trione (compound 128)

Step 1: (14S)-8-[3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl]-12,12-dimethyl-2λ ⁶ -thia3,9,11,18,23-pentaazatetracyclo[ 17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 128)

(14S)-8-chloro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(23),5 was loaded into the ampoule ,7,9,19,21-hexaen-2,2,4-trione (25 mg, 0.05373 mmol), 1-(3,3dimethylbutyl)imidazolidin-2-one (13 mg, 0.07636 mmol), Pd ₂ (dba) ₃ (13 mg, 0.01420 mmol), xanthos (8 mg, 0.01383 mmol), cesium carbonate (88 mg, 0.2701 mmol) and anhydrous dioxane (400 µl). The mixture was bubbled with nitrogen for 1-2 minutes, capped and stirred at 120°C for 5-14 hours (heating failed during the 14 hour period at an unknown time). The solvent was evaporated, the reaction mixture 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%) and hydrochloric acid as a modifier. LCMS preparatory HPLC showed partial conversion to the expected product (about 20%), which was collected and combined with the product of the second reaction described below.

The second reaction was again carried out with the same amount of reagents and stirred at 120°C for 19 hours. The solvent was evaporated, dimethyl sulfoxide (1 ml) was added and the mixture was purified by preparative reverse phase HPLC (C ₁₈ ) using a gradient of acetonitrile in water (from 1 % up to 99%) and hydrochloric acid as a modifier. Pure fractions were combined with fractions from the first experiment, a little saline solution was added, and the organic solvents were evaporated. The product was extracted with dichloromethane and the organic phase was dried over sodium sulfate. Filtration and then evaporation of the solvents yields a solid. The solid residue was purified by flash chromatography on silica using a gradient of methanol (0% to 5%) in dichloromethane to give (14S)-8-[3-(3,3-dimethylbutyl)-2-oxoimidazolidin-1-yl]-12 ,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23 pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene -2,2,4-trione (compound 128) (17 mg, 27%) as an off-white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.29 (s, 1H), 7.62-7.52 (m, 2H), 7.41 (d, J=8.6 Hz, 1H), 7.03 (d, J=7.2 Hz, 1H), 6.95 (broadened d, J=9.0 Hz, 1H), 6.69 (d, J=8.5 Hz, 1H), 4.01-3.80 (m, 3H), 3.53-3.40 (m, 2H), 3.21 (dd, J=10.1, 6.1 Hz, 2H), 3.12-3.03 (m, 1H), 2.93 (d, J=13.4 Hz, 1H), 2.76-2.62 (m, 1H), 2.08 (broad s, 1H), 1.85 -1.68 (m, 2H), 1.64-1.34 (m, 11H), 1.36-1.25 (m, 1H), 0.92 (s, 9H). MS-ESI m/z calc. 583.29407, detected 584.4 (M+1)+; retention time: 1.88 min (LC method B).

Example 198: Preparation of (14S)-8-(3,4-dihydro-2H-pyran-6-yl)-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111 ,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 303)

Step 1: tert-butyl 2-chloro-6-(3,4-dihydro-2H-pyran-6-yl)pyridin-3-carboxylate

A 50 mL round bottom flask equipped with a magnetic stirrer was charged with tert-butyl 2,6-dichloropyridin-3-carboxylate (10.09 g, 40.668 mmol), 2-(3,4-dihydro-2H-pyran-6-yl)- 4,4,5,5tetramethyl-1,3,2-dioxaborolane (10.55 g, 49.215 mmol) and Pd(PPh3) 2Cl2 (1.42 g, 2.0231 mmol) in EtOH (10 ml), toluene ( 10 ml) and water (2 ml). The mixture was refluxed at 95°C overnight in an oil bath. The cooled reaction mixture was concentrated, then dissolved in ethyl acetate and washed with aqueous brine. The organic layer was dried over sodium sulfate, filtered and evaporated to give a crude oil, which was purified by silica gel chromatography using a gradient of 100% hexanes to 5% ethyl acetate in hexanes to give tert-butyl 2-chloro-6(3,4-dihydro- 2H-pyran-6-yl)pyridin-3-carboxylate (9.2 g, 76%) as a colorless oil.

1H NMR (250 MHz, DMSO-d6) δ 8.17 (d, J=8.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 6.19-6.04 (m, 1H), 4.274.06 (m, 2H), 2.23 (k, J=6.1, 4.4 Hz, 2H), 1.96-1.78 (m, 2H), 1.55 (s, 9H). MS-ESI m/z calc. 295.09753, detected 296.0 (M+1) ⁺ ; Retention time: 6.52 min (LC method Q).

Step 2: 2-chloro-6-(3,4-dihydro-2H-pyran-6-yl)pyridine-3-carboxylic acid

Lithium hydroxide monohydrate (468 mg, 11.153 mmol) was added to a solution of tert-butyl-2-chloro-6(3,4-dihydro-2H-pyran-6-yl)pyridin-3-carboxylate (320 mg, 1.0711 mmol ) in methanol (5 ml), tetrahydrofuran (20 ml) and water (10 ml). The mixture was stirred at 40°C for 16 hours and cooled to room temperature. The mixture was acidified with 5% HCl and extracted with EtOAc (2x20 ml). United authorities

- 506 044967 ical layers were washed with saline and dried over Na2SO4, filtered and evaporated to obtain 2-chloro-6-(3,4-dihydro-2H-pyran-6-yl)pyridin-3-carboxylic acid (248 mg, 94 %) as a white solid.

¹ H NMR (250 MHz, DMSO-d6) δ 8.25 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 6.13 (t, J=4.2 Hz, 1H), 4.21- 4.12 (m, 2H), 2.24 (k, J=6.3, 5.8 Hz, 2H), 1.86 (p, J=5.9 Hz, 2H). MS-ESI m/z calc. 239.0349, detected 240.0 (M+1)+; Retention time: 3.95 min (LC method Q).

Step 3: tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-(3,4-dihydro-2H-pyran-6-yl)pyridin-3carbonyl]sulfamoyl]-2 -pyridyl]amino]propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate

Carbonyldiimidazole (252 mg, 1.554 mmol), and the mixture was stirred at room temperature for 20 hours. Then tert-butyl (4S)-2,2-dimethyl-4-[3-[(6sulfamoyl-2-pyridyl)amino]propyl]pyrrolidine-1 was added -carboxylate (400 mg, 0.9696 mmol) followed by the addition of DBU (475 μl, 3.176 mmol), and the resulting mixture was stirred for 3 hours at room temperature. The reaction was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was further washed with a 10% aqueous citric acid solution and then with brine. The organic layers were separated, dried over sodium sulfate, filtered, evaporated and then purified by silica gel chromatography using a gradient of 100% hexanes to 100% ethyl acetate. The resulting residue was further purified by preparative reverse phase HPLC (C ₁₈ column, 30-99% acetonitrile in water with hydrochloric acid modifier) to obtain tert-butyl(4S)-4-[3-[[6-[[2-chloro- 6-(3,4-dihydro-2H-pyran-6-yl)pyridin3-carbonyl]sulfamoyl]-2-pyridyl]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (140 mg, 23%) in as a white solid. MS-ESI m/z calc. 633.2388, detected 634.2 (M+1) ⁺ ; retention time: 2.11 min (LC method B).

Step 4: 2-chloro-6-(3,4-dihydro-2H-pyran-6-yl)-N-[[6-[3-[(3S)-5,5-dimethylpyrrolidin-3yl]propylamino] -2-pyridyl]sulfonyl]pyridine-3-carboxamide (trifluoroacetate salt)

tert-butyl (4S)-4-[3-[[6-[[2-chloro-6-(3,4-dihydro-2H-pyran-6-yl)pyridin-3-carbonyl]sulfamoyl]2-pyridyl ]amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (140 mg, 0.2208 mmol) was dissolved in dichloromethane (610.8 μl) and trifluoroacetic acid (681.1 μl, 8.841 mmol) was added to the mixture stirred at room temperature for 2 hours. The mixture was concentrated to dryness under reduced pressure, 1 ml of toluene was added and removed by rotary evaporation (45°C water bath). 1 ml of toluene was added again and removed on a rotary evaporator (water bath at 45°C), then dried in vacuum, obtaining 2-chloro-6-(3,4-dihydro-2H-pyran-6-yl)-N- [[6-[3-[(3S)-5,5-dimethylpyrrolidin-3yl]propylamino]-2-pyridyl]sulfonyl]pyridine-3-carboxamide (trifluoroacetate salt) (162.3 mg, 100%) as white solid matter. MS-ESI m/z calc. 533.18634, detected 534.3 (M+1) ⁺ ; Retention time: 0.52 min (LC method A).

Step 5: (14S)-8-(3,4-dihydro-2H-pyran-6-yl)-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111, 14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound 303)

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To a solution of 2-chloro-6-(3,4-dihydro-2H-pyran-6-yl)-N-[[6-[3-[(3S)-5,5-dimethylpyrrolidin-3yl]propylamino]-2 -pyridyl]sulfonal]pyridine-3-carboxamide (trifluoroacetate salt) (162.3 mg, 0.2204 mmol) to NMP (8.591 ml) was added potassium carbonate (213.8 mg, 1.547 mmol). The mixture was purged with nitrogen for 5 minutes, then heated to 180°C and stirred overnight. Cooled to room temperature, diluted with EtOAc, washed with 1 N. HCl, dried (sodium sulfate), filtered and concentrated to a brown oil, which was filtered and purified by reverse phase HPLC (C18 column, 1-99% acetonitrile in water (5 mM HCl)) to form a white solid (148)-8 -(3,4-dihydro2H-pyran-6-yl)-12,12-dimethyl-2Х ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22) ,5,7,9,19(23),20-hexaene-2,2,4-trione (3.31 mg, 3%).

Ή NMR (400 MHz, DMSOC) δ 12.50 (s, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.57 (t, J=7.9 Hz, 1H), 7.04 (d, J=7.1 Hz, 1H ), 6.98 (s, 1H), 6.76 (d, J=8.0 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 5.94 (s, 1H), 4.11 (s, 2H), 3.92 (d , J=11.8 Hz, 1H), 3.11 (s, 1H), 2.93 (d, J=13.1 Hz, 1H), 2.66 (s, 1H), 2.20 (d, J=5.3 Hz, 2H), 2.09 (s , 1H), 1.83 (d, J=5.9 Hz, 3H), 1.73 (s, 1H), 1.61 (s, 1H), 1.57 (s, 3H), 1.52 (s, 1H), 1.49 (s, 3H) , 1.29 (d, J=12.2 Hz, 1H), 1.24 (s, 1H). MS-ESI m/z calc. 497.2097, detected 498.1 (M+1)+; retention time: 1.98 min (LC method B).

Example 199: Preparation of 8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-16,16difluoro-12,12-dimethyl-2X ⁶ - thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione ( enantiomer 1) (compound 305, peak 1 SCLC) and 8-[3-(2{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-16,16-difluoro- 12,12-dimethyl-2Х ⁶ -thia3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene -2,2,4-trione (enantiomer 2) (compound 304, peak 2 SCLC)

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Step 1: 1-[(4-methoxyphenyl)methyl]-5,5-dimethylpyrrolidin-2-one

The reaction was carried out in two batches.

Batch 1: A solution of 5,5-dimethylpyrrolidin-2-one (121 g, 1.0693 mol) in DMF (1.8 L) was cooled to 3°C in an ice water bath, then 60% NaH in mineral oil (64.150 g, 1.6039 mol) was added in portions over approximately thirty minutes. The mixture was stirred in an ice water bath for an additional thirty minutes, then at room temperature for 1.5 hours. The resulting off-white suspension was again cooled to 3°C in an ice water bath, then 1(chloromethyl)-4- was added methoxybenzene (251.19 g, 1.6039 mol). The ice water bath was removed after addition and the mixture was stirred overnight. The reaction mixture was carefully quenched with water (100 ml) and stored in the freezer overnight. The mixture was combined with a second batch of material before processing and purification.

Batch 2: A solution of 5,5-dimethylpyrrolidin-2-one (484 g, 4.2772 mol) in DMF (7.2 L) was cooled to 3°C in a 20 L jacketed reactor, then 60% NaH in mineral oil (256.61 g, 6.4158 mol) was added in portions over a four hour period. The resulting mixture was stirred at 3°C for another hour, then at room temperature for 2 hours. The resulting suspension was again cooled to 3°C, then 1-(chloromethyl)-4-methoxybenzene (1.0048 kg, 6.4158 mol) was added ). The cooling system was turned off after addition was complete and the resulting slurry was stirred overnight while it was allowed to warm to room temperature. The reaction mixture was carefully quenched with water (500 ml), combined with the reaction mixture of batch 1 and divided into two equal parts. Each portion was processed as follows: it was diluted with saturated ammonium chloride (10 L), then extracted with ethyl acetate (4x2 L). The aqueous phase was discarded and then the combined organic phases were diluted with hexane (2 L) and extracted with saturated ammonium chloride (2x2 L), then with water (2 L). The aqueous phases were discarded and the organic phase was dried over sodium sulfate. The combined organic phases from both treatments were concentrated in vacuo to give crude 1-[(4methoxyphenyl)methyl]-5,5-dimethylpyrrolidin-2-one as a brown oil (1.5 kg). One kilogram of crude product was purified by silica gel chromatography (0-100% ethyl acetate:hexane) to give pure 1-[(4-methoxyphenyl)methyl]-5,5-dimethylpyrrolidin-2-one (608 g, 58%) as yellow oils MSIE m/z calc. 233.1416, detected 234.3 (M+1)+; Retention time: 3.97 min (LC method Q).

Step 2: 3-diethoxyphosphoryl-1-[(4-methoxyphenyl)methyl]-5,5-dimethylpyrrolidin-2-one

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A solution of diisopropylamine (529.14 g, 732.88 ml, 5.2292 mol) in tetrahydrofuran (3.5 L) was cooled to -75°C in a dry ice-acetone bath, then N-butyllithium (2.092 L 2.5 M, 5.2292 mol) added in a slow stream. The temperature was kept below -70°C during the addition. The resulting yellow solution was stirred for thirty minutes, then a solution of 1-[(4-methoxyphenyl)methyl]-5,5dimethylpyrrolidin-2-one (488 g, 2.0917 mol) in tetrahydrofuran (1.5 L) was added slowly and then stirred for another hour. During addition, the temperature was not allowed to exceed 70°C. 1-[chloro(ethoxy)phosphoryl]oxyethane (541.38 g, 451.15 mL, 3.1376 mol) was added dropwise to the reaction mixture, ensuring that the temperature remained below -70°C during the addition. The resulting mixture was stirred for 16 hours, allowing it to thaw to room temperature. The reaction was then quenched with 1 M hydrochloric acid (3 L) and extracted with ethyl acetate (2x2.4 L). The aqueous phase was discarded and the combined organic phases were extracted with water (3 x 2.4 L). The aqueous phases were discarded and the organic phase was dried over sodium sulfate and purified by chromatography on silica gel (0100% ethyl acetate/hexane) and then concentrated in vacuo to give 3-diethoxyphosphoryl-1-[(4methoxyphenyl)methyl]-5,5-dimethylpyrrolidine- 2-one (677 g, 81%). MS-ESI m/z calc. 369.1705, detected 370.1 (M+1)+; Retention time: 4.2 min (LC method Q).

Step 3: N-(benzotriazol-1-ylmethyl)-N-benzyl-1-phenylmethanamine

To a solution of benzotriazol-1-ylmethanol (30 g, 201.14 mmol) in EtOH (600 mL) was added N-benzyl-1-phenylmethanamine (39.680 g, 38.674 mL, 201.14 mmol) at room temperature. The solution was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was washed with diethyl ether (3x400 ml) to obtain N-(benzotriazol-1-ylmethyl)-N-benzyl-1-phenylmethanamine (59.83 g, 91%) as a white solid.

¹ H NMR (250 MHz, CDCl ₃ ) δ 7.67-7.23 (m, 14H), 5.47 (s, 2H), 3.79 (s, 4H).

Step 4: Ethyl 3-(dibenzylamino)-2,2-difluoropropanoate

To a suspension of Zn (17.3 g, 2.4253 ml, 264.57 mmol) in THF (175 ml) was added TMS-Cl (28.691 g, 33.4 ml, 264.09 mmol), followed by ethyl-2- bromo-2,2-difluoroacetate (11.850 g, 7.5 ml, 58.380 mmol) at room temperature. The solution was stirred for 15 min, after which N-(benzotriazol-1-ylmethyl)-N-benzyl-1-phenylmethanamine (17.344 g, 52.812 mmol) in THF (100 ml) was added dropwise to the reaction mixture. The combined solution was stirred for 2 hours, then quenched with sodium bicarbonate (350 ml) and extracted with ethyl acetate (3x500 ml). The combined organic layers were washed with water (750 ml) and dried over sodium sulfate before concentration in vacuo. The organic residue was purified by chromatography on silica gel, eluting with 0-15% diethyl ether in hexane to give ethyl 3(dibenzylamino)-2,2-difluoropropanoate (8.98 g, 49%) as a clear liquid.

1H NMR (500 MHz, DMSO-d ₆ ) δ 7.37-7.29 (m, 4H), 7.29-7.22 (m, 6H), 4.13 (k, J=7.1 Hz, 2H), 3.61 (s, 4H), 3.15 (t, J=13.5 Hz, 2H), 1.13 (t, J=7.1 Hz, 3H). MS-ESI m/z calc. 333.154, detected 334.5 (M+1) ⁺ ; retention time: 3.18 min (LC method R).

Step 5: 3-(dibenzylamino)-2,2-difluoropropanal

To a solution of ethyl 3-(dibenzylamino)-2,2-difluoropropanoate (9.01 g, 27.027 mmol) in anhydrous DCM (125 ml) was added dropwise diisobutylaluminum hydride (37.8 ml 1 M, 37.800 mmol) at -78° WITH. The reaction mixture was stirred for 40 min and then quenched with citric acid (100 ml) at -78°C. The solution was extracted with diethyl ether (3x200 ml), washed with brine (200 ml) and dried over sodium sulfate before concentration in vacuo to give 3-(dibenzylamino)-2,2difluoropropanal (9.54 g, 93%). MS-ESI m/z calc. 289.1278, detected 290.2 (M+1) ⁺ ; retention time: 2.39 min (LC method P).

Step 6: 3-[3-(dibenzylamino)-2,2-difluoropropylidene]-1-[(4-methoxyphenyl)methyl]-5,5dimethylpyrrolidin-2-one

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DIEA (5.1 g, 6 .8733 ml, 39.461 mmol) and LiCl (1.7 g, 40.100 mmol) at 0°C. The solution was stirred at this temperature for 30 min before adding 3(dibenzylamino)-2,2-difluoropropanal (9.544 g, 32.988 mmol) in ACN (50 ml) at 0°C. The mixture was warmed to room temperature with stirring overnight. The solution was quenched with saturated ammonium chloride solution (150 ml), then extracted with diethyl ether (3x200 ml) and washed with brine (300 ml), then dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography, eluting with 0-25% ethyl acetate in hexane to give 3-[3(dibenzylamino)-2,2-difluoropropylidene]-1-[(4-methoxyphenyl)methyl]-5,5-dimethylpyrrolidine -2-one (E/Z-isomer mixture) (8.03 g, 48%).

1H NMR (250 MHz, CDCl3) δ 7.36-7.22 (m, 10H), 7.21-7.15 (m, 2H), 6.89-6.72 (m, 2H), 6.67-5.75 (m, 1H), 4.54-4.16 (m , 2H), 3.85-3.60 (m, 7H), 3.60-3.45 (m, 1H), 3.19-2.79 (m, 1H), 2.57-2.33 (m, 2H), 1.22-0.98 (m, 6H). MS-ESI m/z calc. 504.2588, detected 505.2 (M+1)+; retention time: 3.02 min., 3.51 min. (LC method R).

Stage

7:

3-[3 -(dibenzylamino)-2,2-difluoropropyl]-1-[(4-methoxyphenyl)methyl]-5,5 dimethylpyrrolidin-2-one

To a solution of 3-[3-(dibenzylamino)-2,2-difluoropropylidene]-1-[(4-methoxyphenyl)methyl]-5,5dimethylpyrrolidin-2-one (8 g, 15.854 mmol) in ethanol (400 ml) was added Raney nickel (8 g, 136.30 mmol). The resulting solution was hydrogenated in a Parr-Shaker at 65 psi. inch for 24 hours, then filtered through celite and washed with ethanol to obtain the crude product. The crude product was purified by flash chromatography (loaded on CH2Cl2) (220 g SiO2, eluting with 0 to 20% acetone in hexane) to give 3-[3-(dibenzylamino)-2,2-difluoropropyl]-1-[(4- methoxyphenyl)methyl]5,5-dimethylpyrrolidin-2-one (4.97 g, 56%) as a pale yellow liquid.

1H NMR (250 MHz, CDCl ₃ ) δ 7.43-7.29 (m, 10H), 7.22 (d J=8.6 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H), 4.38 (s, 2H), 3.81 (s, 3H), 3.78-3.50 (m, 6H), 2.97-2.74 (m, 3H), 2.61-2.44 (m, 1H), 2.21-2.01 (m, 1H), 1.16 (s, 3H), 0.93 (s, 3H). MS-ESI m/z calc. 506.2745, detected 507.2 (M+1) ⁺ ; Retention time: 5.75 min (LC method Q).

Step 8: 3-[3-(dibenzylamino)-2,2-difluoropropyl]-5,5-dimethylpyrrolidin-2-one

To 3-[3-(dibenzylamino)-2,2-difluoropropyl]-1-[(4-methoxyphenyl)methyl]-5,5-dimethylpyrrolidin-2one (4.97 g, 8.9271 mmol) TFA was added to the vessel (100 ml), then the vessel was closed and heated at 100°C for 11 days. All solvents were removed under reduced pressure. The residue was dissolved in dichloromethane (300 ml), washed with saturated aqueous sodium bicarbonate (3x100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (loaded on CH ₂ Cl ₂ ) (120 g SiO 2, eluting with 0 to 45% ethyl acetate in hexane) to give 3-[3-(dibenzylamino)-2,2-difluoropropyl]-5, 5dimethylpyrrolidin-2-one (2.28 g, 66%) as a pale yellow liquid. MS-ESI m/z calc. 386.217, detected 387.3 (M+1) ⁺ ; Retention time: 3.29 min (LC method Q).

Step 9: N,N-dibenzyl-3-(5,5-dimethylpyrrolidin-3-yl)-2,2-difluoropropan-1-amine

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To a stirred solution of 3-[3-(dibenzylamino)-2,2-difluoropropyl]-5,5-dimethylpyrrolidin-2one (2.23 g, 5.7701 mmol) in anhydrous THF (100 ml) at 0°C in an atmosphere nitrogen, a solution of BH ₃ Me ₂ S (40 ml 2 M, 80,000 mmol) in THF was slowly added. After addition was complete, the reaction mixture was heated to 65°C for 24 hours. The reaction mixture was cooled to 0°C and slowly quenched with 6 M aqueous

HCl (50 ml).

Methanol (50 ml) was added and the reaction mixture was heated to 65°C for 1 hour. After cooling to room temperature, the reaction mixture was made basic with saturated aqueous NaHCO ₃ (300 ml) and volatiles were removed in vacuo. The product was extracted with ethyl acetate (3x150 ml). The combined organic layers were washed with brine (80 ml), dried over anhydrous sodium sulfate and concentrated to give N,N-dibenzyl-3-(5,5-dimethylpyrrolidin-3-yl)-2,2difluoropropan-1-amine (2. 46 g, quantity) in the form of a yellow oil. This product was carried to the next step without further purification. MS-ESI m/z calc. 372.2377, detected 373.4 (M+1)+; Retention time: 3.87 min (LC method Q).

Step 10: tert-butyl 4-[3-(dibenzylamino)-2,2-difluoropropyl]-2,2-dimethyl-pyrrolidine-1carboxylate

To a stirred solution of N,N-dibenzyl-3-(5,5-dimethylpyrrolidin-3-yl)-2,2-difluoropropan-1amine (2.46 g, 5.9437 mmol) in DCM (80 ml) at 0° Triethylamine (1.0164 g, 1.4 mL, 10.044 mmol) was added followed by Boc2O (1.96 g, 8.9807 mmol). The reaction mixture was stirred at this temperature for 1 hour. The reaction was quenched with saline (100 ml) and then warmed to room temperature. The two layers were separated and the aqueous layer was extracted with DCM (2x50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel chromatography using a gradient of 0-15% ethyl acetate in hexanes to give tert-butyl 4-[3-(dibenzylamino)-2,2-difluoropropyl]-2,2-dimethylpyrrolidine-1-carboxylate (2, 79 g, 94%) as a colorless oil. MS-ESI m/z calc. 472.2901, detected 473.5 (M+1) ⁺ ; Retention time: 7.45 min (LC method Q).

Step 11: tert-butyl 4-(3-amino-2,2-difluoropropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

To a stirred solution of tert-butyl 4-[3-(dibenzylamino)-2,2-difluoropropyl]-2,2dimethylpyrrolidine-1-carboxylate (2.68 g, 5.6706 mmol) in anhydrous methanol (60 ml) at room temperature under a nitrogen atmosphere, palladium on carbon (2.1 g, 10% wt., 1.9733 mmol) was added, followed by ammonium formate (3.6 g, 57.092 mmol). The reaction mixture was heated to 65°C for 6 hours. After cooling to room temperature, the reaction mixture was filtered through a pad of celite. The filter cake was washed with methanol (2x30 ml) and the combined filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography using a gradient of 0-10% methanol in dichloromethane to give tert-butyl 4-(3-amino-2,2-difluoropropyl)-2,2-dimethylpyrrolidine-1carboxylate (1.34 g, 77%) as a yellow oil.

¹ H NMR (250 MHz, CDCl3) δ 3.87-3.66 (m, 1H), 3.32 (s, 3H), 3.13-2.86 (m, 3H), 2.52-2.32 (m, 1H), 2.081.79 (m, 3H), 1.57-1.24 (m, 15H). MS-ESI m/z calc. 292.1962, detected 293.5 (M+1) ⁺ ; Retention time: 3.55 min (LC method Q).

Step 12: tert-butyl 4-[2,2-difluoro-3-[(6-sulfamoyl-2-pyridyl)amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate

To a stirred solution of tert-butyl 4-(3-amino-2,2-difluoropropyl)-2,2-dimethylpyrrolidine 1-carboxylate (1.24 g, 4.2413 mmol) and 6-fluoropyridine-2-sulfonamide (1, 12 g, 6.3934 mmol) in anhydrous DMSO (7 mL) was added DIEA (1.7020 g, 2.3 mL, 13.169 mmol) at room temperature under nitrogen. The reaction mixture was heated to 120°C for 30 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 ml) and brine (150 ml), and the product was extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by reverse phase HPLC using the water-acetonitrile gradient method (C ₁₈ Varian column, 50-90% acetonitrile, 60 ml/min) to give tert-butyl-4-[2,2-difluoro-3-[( 6-sulfamoyl-2pyridyl)amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (574 mg, 29%) as a white foam.

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1H NMR (500 MHz, DMSO-d ₆ ) δ 7.58 (dd, J=8.4, 7.2 Hz, 1H), 7.37 (t, J=6.4 Hz, 1H), 7.16 (s, 2H), 7.067.00 (m , 1H), 6.75 (d, J=8.7 Hz, 1H), 3.96-3.81 (m, 2H), 3.64-3.51 (m, 1H), 2.83 (k, J=10.4 Hz, 1H), 2.42-2.29 ( m, 1H), 2.10-1.82 (m, 3H), 1.54-1.42 (m, 1H), 1.41-1.30 (m, 12H), 1.23 (s, 3H). MS-ESI m/z calc. 448.1956, detected 449.2 (M+1)+; retention time: 2.38 min (LC method R).

Step 13: tert-butyl 4-[3-[[6-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1yl]pyridin-3-carbonyl ] sulfamoyl] -2-pyridyl] amino] -2,2-difluoropropyl] -2,2-dimethyl-pyrrolidine-1 carboxylate

OOO

2-chloro-6-[3-(2dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (457 mg, 1.270 mmol) was charged into a 100 mL round bottom flask under nitrogen atmosphere. ) and anhydrous THF (8 ml). CDI (355 mg, 2.189 mmol) was added and the mixture was stirred under nitrogen at room temperature for 15 hours. In a separate 20 mL flask, a solution of tert-butyl-4-[2,2difluoro-3-[(6-sulfamoyl-2 -pyridyl)amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate (570 mg, 1.271 mmol) in anhydrous THF (4 ml) was prepared under nitrogen and then added via syringe to the activated ester solution. DBU (0.78 mL, 5.216 mmol) was added via syringe and the reaction mixture was stirred at room temperature under nitrogen for 5 hours. Solvents were removed under reduced pressure and the resulting thick oil was treated with ethyl acetate (35 mL) and water (35 mL). . HCl (1.5 mL 6 M, 9,000 mmol) was added slowly (final pH 5) and the two phases were separated. The aqueous phase was extracted with EtOAc (30 ml). The combined extracts were washed with saline (30 ml) and dried over sodium sulfate. After evaporation of the solvents, the residue was dissolved in DCM and purified by flash chromatography on silica gel (80 g gold column) using a gradient of ethyl acetate (0 to 100% over 30 min) in hexanes. The product was eluted with 45-65% EtOAc. The pure fractions were combined and the solvents were evaporated to give tert-butyl-4-[3-[[6-[[2-chloro-6-[3-(2dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl ]pyridine-3-carbonyl]sulfamoyl]-2-pyridyl]amino]2,2-difluoropropyl]-2,2-dimethylpyrrolidine-1-carboxylate (667 mg, 66%) as a colorless resin. MSIE m/z calc. 789.2887, detected 790.54 (M+1) ⁺ ; retention time: 2.51 min (LC method B).

Step 14: 2-chloro-N-[[6-[[3-(5,5-dimethylpyrrolidin-3-yl)-2,2-difluoropropyl]amino]-2pyridyl]sulfonyl]-6-[3 - (2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3-carboxamide (dihydrochloride salt)

LLC 000

Tert-butyl-4-[3-[[6-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol1-yl]pyridin-3 was loaded into 100 ml -carbonyl]sulfamoyl]-2-pyridyl]amino]-2,2-difluoropropyl]-2,2-dimethylpyrrolidine-1carboxylate (667 mg, 0.8440 mmol), DCM (8 ml) and HCl (1.25 ml 4M in dioxane, 5,000 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. Volatile substances were removed by evaporation under vacuum. The residue was triturated with dichloromethane/hexanes and the solvents were evaporated. The operation was repeated until a nice white solid was obtained. Drying in vacuum gives 2-chloroN-[[6-[[3-(5,5-dimethylpyrrolidin-3-yl)-2,2-difluoropropyl]amino]-2-pyridyl]sulfonyl]-6-[3-( 2dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3-carboxamide (dihydrochloride salt) (570 mg, 89%) as a white solid. MS-ESI m/z calc. 689.23627, detected 690.3 (M+1)+; retention time: 1.77 min (LC method B).

Step 15: 8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-16,16-difluoro-12,12dimethyl-2λ ⁶ - thia-3,9,11,18,23-nentaαzatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20hexaene-2,2,4-trione ( enantiomer 1) (compound 305, peak 1 SCLC) and 8-[3-(2-{dispiro[2.0.2.1]heptan-7yl}ethoxy)-1H-pyrazol-1-yl]-16,16-difluoro- 12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23),20-hexaene -2,2,4-trione (enantiomer 2) (compound 304, peak 2 SCLC)

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2-χΛορ-Ν-[[6-[[3-(5,5-dimethylpyrrolidin-3-yl)-2,2-difluoropropyl]amino]- was loaded into a 100 ml round-bottom flask equipped with a magnetic stirrer under a nitrogen atmosphere. 2pyridyl]sulfonyl]-6-[3-(2-dispiro[2.0.2.1] heptan-7-ylethoxy)pyrazol-1 -yl]pyridin-3-carboxamide (dihydrochloride salt) (570 mg, 0.7469 mmol), anhydrous NMP (24 ml) and K2CO3 (766 mg, 5.542 mmol) (325 mesh). The mixture was vigorously stirred in a dry bath at 150°C under a nitrogen atmosphere for 18 hours. After cooling to room temperature, the mixture was poured into cooled water (200 ml) and acidified by adding HCl (2 ml, 6 M, 12.00 mmol) ( slight foaming). The resulting solid was filtered on a Buchner funnel and briefly air dried. The solid was dissolved in DCM and a small amount of methanol, and the resulting cloudy solution was evaporated. The product was purified by flash chromatography on silica gel (40 g gold column) using a gradient of methanol (0 to 5% over 30 min) in dichloromethane. The product eluted with about 1% methanol. Evaporation of the solvents followed by trituration in DCM/hexane and evaporation of the solvents gives racemic 8-[3-(2{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-16.16 -difluoro-12,12-dimethyl-2λ ^e -thia3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9,19(23), 20-hexaene-2,2,4-trione (404 mg, 83%) as an off-white solid. MS-ESI m/z calc. 653.2596, detected 654.33 (M+1)+; Retention time: 2.34 min (LC method B).

The two enantiomers were separated by chiral SCLC using ChiralPak AS-3 (250x21.2 mm), 5 µM column at 40°C, mobile phase 24% MeOH (no modifier), 76% CO ₂ , flow: 70 ml/min. , concentration: 31 mg/ml in MeOH, injection volume: 500 µl, pressure: 156 bar, wavelength: 280 nm. After evaporation of the solvents, each enantiomer was purified a second time by flash chromatography on silica gel (24 g column) using a gradient of methanol (0 to 5% over 30 min) in dichloromethane. After evaporation of the solvents, the compounds were triturated in DCM/hexane. Evaporation of the solvents gives the two enantiomers as white solids.

Compound 305, peak 1 SCLC. its >98%. 8-[3-(2-{Disnir[2.0.2.1]gentan-7-yl}ethoxy)-1H-pyrazol1-yl]-1e,16-difluoro-12,12-dimethyl-2λ ^e -thia-3, 9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (enantiomer 1 ) (174 mg, 70%).

1H NMR (500 MHz, DMSO-de) δ 12.54 (s, 1H), 8.22 (d, J=2.8 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.71 (t, J=7.9 Hz , 1H), 7.52 (d, J=10.2 Hz, 1H), 7.22 (d, J=7.2 Hz, 1H), 6.96 (d, J=8.3 Hz, 2H), 6.10 (d, J=2.7 Hz, 1H ), 4.48 (dt, J=37.1, 12.7 Hz, 1H), 4.22 (t, J=6.8 Hz, 2H), 3.30 (broad s, 1H), 3.12 (t, J=8.6 Hz, 1H), 2.77 ( t, J=10.6 Hz, 1H), 2.39 (broad s, 1H), 2.27-2.03 (m, 2H), 1.93 (dd, J=11.7, 5.2 Hz, 1H), 1.82 (k, J=6.6 Hz , 2H), 1.72 (t, J=12.4 Hz, 1H), 1.63 (s, 3H), 1.54 (s, 3H), 1.48 (t, J=6.6 Hz, 1H), 0.90-0.75 (m, 4H) , 0.69-0.60 (m, 2H), 0.550.39 (m, 2H). MS-ESI m/z calc. 653.2596, detected 654.33 (M+1) ⁺ ; retention time: 2.34 min (LC method B).

Compound 304, peak 2 SCLC. Its >98%. 8-[3-(2-{dispyro[2.0.2.1]gentan-7-yl}ethoxy)-1H-pyrazol1-yl]-1e,16-difluoro-12,12-dimethyl-2λ ^e -thia-3, 9,11,18,23-pentaazαtetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (enantiomer 2 ) (178 mg, 71%).

1H NMR (500 MHz, DMSO-de) δ 12.53 (s, 1H), 8.22 (d, J=2.8 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.71 (t, J=7.9 Hz , 1H), 7.52 (d, J=10.1 Hz, 1H), 7.21 (d, J=7.2 Hz, 1H), 6.96 (d, J=8.3 Hz, 2H), 6.10 (d, J=2.7 Hz, 1H ), 4.48 (dt, J=37.3, 12.4 Hz, 1H), 4.22 (t, J=6.7 Hz, 2H), 3.30 (broad s, 1H), 3.12 (t, J=8.6 Hz, 1H), 2.77 ( t, J=10.6 Hz, 1H), 2.39 (b. s, 1H), 2.26-2.05 (m, 2H), 1.93 (dd, J=12.0, 5.2 Hz, 1H), 1.82 (k, J=6.6 Hz , 2H), 1.72 (t, J=12.4 Hz, 1H), 1.64 (s, 3H), 1.54 (s, 3H), 1.48 (t, J=6.6 Hz, 1H), 0.90-0.77 (m, 4H) , 0.72-0.60 (m, 2H), 0.560.45 (m, 2H). MS-ESI m/z calc. 653.2596, detected 654.33 (M+1) ⁺ ; retention time: 2.34 min (LC method B).

Example 200: Preparation of 8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-16-fluoro12,12-dimethyl-2X6-thia-3 ,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (enantiomer 1) (compound 309, peak 1 SCLC), 8-[3-(2{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-16-fluoro-12,12- dimethyl-2Х6-thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2, 4-trione (enantiomer

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2) (compound 308, peak 2 SCLC), 8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-16fluoro-12,12- dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2 ,4-trione (enantiomer 3) (compound 307, peak 3 SCLC) and 8-[3-(2{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-16 -fluoro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23), 20-hexaene-2,2,4-trione (enantiomer 4) (compound 306, SCLC peak 4)

Step 1: 3-allyl-1-[(4-methoxyphenyl)methyl]-5,5-dimethylpyrrolidin-2-one

A solution of diisopropylamine (4.3372 g, 6.0 mL, 42.862 mmol) in tetrahydrofuran (100 mL) was cooled to -78°C and N-butyllithium (17.1 mL, 2.5 M, 42.862 mmol) was added dropwise. The solution was stirred for thirty minutes, then a solution of 1-[(4-methoxyphenyl)methyl]-5,5-dimethylpyrrolidin-2one (10 g, 42.862 mmol) in THF (10 ml) was added dropwise, and then stirred for hours. 3-Bromoprop-1-ene (5.1853 g, 3.71 mL, 42.862 mmol) was added dropwise to the reaction mixture, stirred for one hour at -78°C, and then allowed to warm to 0°C over 30 min. The reaction was then quenched with saturated ammonium chloride (100 ml) and extracted with ethyl acetate (3x50 ml). The combined organic phases were dried over sodium sulfate and purified by silica gel chromatography (0-20% ethyl acetate/hexane) to give 3-allyl-1-[(4-methoxyphenyl)methyl]-5,5-dimethylpyrrolidin-2-one (8, 75 g, 71%). MS-ESI m/z calc. 273.1729, detected 274.0 (M+1)+; retention time: 2.97 min (LC method R).

Step 2: 3-allyl-5,5-dimethyl-pyrrolidin-2-one

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3-Allyl-1-[(4-methoxyphenyl)methyl]-5,5-dimethylpyrrolidin-2-one (7.75 g, 28.350 mmol) was dissolved in acetonitrile (140 ml) and water (16 ml), then in ceric acid acid. Ammonium nitrate (64.559 g, 113.40 mmol) was added in portions at room temperature and the reaction mixture was stirred for 3 hours. It was then quenched with brine (300 ml) and extracted with EtOAc (3x150 ml). The organic fractions were combined, dried over sodium sulfate and evaporated, the residue was purified by silica gel column chromatography using 0-100% hexanes-ethyl acetate to give 3-allyl-5,5dimethylpyrrolidin-2-one (3.77 g, 76%). MS-ESI m/z calc. 153.1154, detected 154.2 (M+1)+; retention time: 1.61 min (LC method P).

Step 3: tert-butyl 4-allyl-2,2-dimethyl-pyrrolidine-1-carboxylate

To a suspension of LiAlH ₄ (2.8016 g, 3.05 ml, 73.815 mmol) in THF (50 ml) was added dropwise a solution of 3allyl-5,5-dimethylpyrrolidin-2-one (3.77 g, 24.605 mmol) in THF (25 ml) at reflux. The mixture was refluxed for 3 hours, cooled to 0°C and then water (2.8 ml) was added very slowly, followed by 15% sodium hydroxide (2.8 ml) and water (8.4 ml) . The mixture was allowed to warm to room temperature and Boc ₂ O (6.4440 g, 6.7832 ml, 29.526 mmol) was added. The mixture was stirred for 16 hours, filtered, and the filter cake was triturated with THF. The organic fractions were combined and evaporated, and the residue was purified by silica gel column chromatography using 0-5% ethyl acetate in hexane to give tert-butyl-4-allyl-2,2-dimethylpyrrolidine-1-carboxylate (5.06 g, 77%) .

Ή NMR (250 MHz, chloroform-d) δ 5.93-5.58 (m, 1H), 5.15-4.89 (m, 2H), 3.82-3.48 (m, 1H), 2.90 (k, J=10.9 Hz, 1H), 2.32-1.97 (m, 3H), 1.94-1.75 (m, 1H), 1.50-1.25 (m, 16H). MS-ESI m/z calc. 239.1885, detected 240.3 (M+1) ⁺ ; retention time: 3.53 min (LC method P).

Step 4: tert-butyl 4-(3-bromo-2-fluoropropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

A solution of tert-butyl-4-allyl-2,2-dimethyl-pyrrolidine-1-carboxylate (500 mg, 1.8801 mmol) and triethylamine trihydrofluoride (710 mg, 1.6296 mmol) in DCM (10 ml) was cooled to 0 °C. and NBS (500 mg, 2.8092 mmol) was added. The mixture was left to warm to room temperature and stirred for 4 hours. The mixture was quenched with saturated sodium bicarbonate (50 ml), the aqueous phase was separated and extracted with DCM (100 ml). The organic fractions were combined, dried over sodium sulfate and evaporated. The residue was purified by silica gel column chromatography using 0-10% ethyl acetate in hexanes to give tert-butyl 4-(3-bromo-2-fluoropropyl)-2,2-dimethylpyrrolidine-1-carboxylate (420 mg, 65% ) in the form of a colorless oil.

^1H NMR (250 MHz, CDCl ₃ ) δ 4.87-4.42 (m, 1H), 3.86-3.54 (m, 1H), 3.55-3.22 (m, 2H), 3.07-2.75 (m, 1H), 2.56-2.18 (m, 1H), 2.12-1.71 (m, 3H), 1.71-1.57 (m, 1H), 1.51-1.38 (m, 12H), 1.35-1.24 (m, 3H). MS-ESI m/z calc. 337.1053, detected 338.5 (M+1) ⁺ ; retention time: 3.59 min (LC method R).

Step 5: tert-butyl 4-(3-amino-2-fluoropropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate

NaN ₃ (0. 6 g, 9.1832 mmol) and the mixture was stirred at 45°C for 18 hours. The mixture was diluted with water (150 ml), then saturated sodium bicarbonate (150 ml), and the mixture was extracted with ethyl acetate (2 x 200 ml). The organic layer was washed with brine (300 ml), dried over sodium sulfate, filtered and concentrated to give the azide intermediate as a brown oil. To a solution of this azide oil intermediate in ethyl acetate (30 ml)

- 516 044967 platinum oxide monohydrate (0.5 g, 2.2018 mmol) was added. The mixture was hydrogenated on a Parr shaker at psi. inch for 1 hour. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated to give tert-butyl 4-(3-amino-2-fluoropropyl)-2,2-dimethylpyrrolidine-1-carboxylate (1.59 g, 87%) as a dark oil. MS-ESI m/z calc. 274.2057, detected 275.6 (M+1)+; Retention time: 3.51 min (LC method Q).

Step 6: tert-butyl 4-[2-fluoro-3-[(6-sulfamoyl-2-pyridyl)amino]propyl]-2,2-dimethylpyrrolidine-1-carboxylate

To a mixture of tert-butyl 4-(3-amino-2-fluoropropyl)-2,2-dimethylpyrrolidine-1-carboxylate (1.59 g, 5.6791 mmol) and 6-fluoropyridine-2-sulfonamide (1.3 g, 7.0103 mmol) to DMSO (10 ml) was added DIEA (2.2260 g, 3 ml, 17.223 mmol). The mixture was stirred at 110°C for 16 hours. The mixture was cooled to room temperature and the mixture was treated with water/saline (100/100 ml) and ethyl acetate (150 ml). The organic layer was dried over sodium sulfate, filtered through a pad of celite and concentrated. The residue (2.1 g, combined with 0.56 g of product from the previous reaction) was dissolved in DMSO (10 ml) and applied to a preparative HPLC column (Varian C ₁₈ 10 μm 5x30 cm; flow rate: 60 ml/min; mobile phase A: water; mobile phase B: acetonitrile; method: 40-90% B in 45 minutes). Pure fractions were combined and concentrated to remove acetonitrile. The resulting aqueous phase was extracted with ethyl acetate (2x 100 ml). The organic layer was washed with brine (200 ml), dried over sodium sulfate and concentrated to give tert-butyl-4-[2-fluoro-3-[(6-sulfamoyl-2pyridyl)amino]propyl]-2,2-dimethylpyrrolidine- 1-Carboxylate (1.5 g, 58%) as a white solid.

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 7.56 (t, J=7.8 Hz, 1H), 7.27 (t, J=5.8 Hz, 1H), 7.12 (s, 2H), 7.00 (d, J= 7.1 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 4.95-4.46 (m, 1H), 3.77-3.40 (m, 3H), 2.95-2.73 (m, 1H), 2.40-2.15 (m , 1H), 2.02-1.85 (m, 1H), 1.83-1.57 (m, 3H), 1.54-1.29 (m, 12H), 1.25 (s, 3H). MS-ESI m/z calc. 430.205, detected 431.5 (M+1) ⁺ ; retention time: 2.35 min (LC method R).

Step 7: tert-butyl 4-[3-[[6-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1yl]pyridin-3-carbonyl ]sulfamoyl]-2-pyridyl]amino]-2-fluoropropyl]-2,2-dimethyl-pyrrolidine-1carboxylate

2-chloro-6-[3-(2dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3-carboxylic acid (573 mg., 1.593) was charged into a 100 ml round bottom flask under nitrogen atmosphere. mmol) and anhydrous THF (10 ml). CDI (315 mg, 1.943 mmol) was added and the mixture was stirred under nitrogen at room temperature for 2 hours. An additional 150 mg of CDI was added and the mixture was stirred at room temperature for 15 hours until complete conversion. In a separate 20 ml flask, a solution of tert-butyl 4-[2-fluoro-3-[(6-sulfamoyl-2-pyridyl)amino]propyl]-2,2-dimethylpyrrolidine-1carboxylate (693 mg, 1.610 mmol) in Anhydrous THF (5 ml) was prepared under nitrogen and then added by syringe to the activated ester solution. DBU (0.96 mL, 6.419 mmol) was added via syringe and the reaction mixture was stirred at room temperature under nitrogen for 5 hours. Solvents were removed under reduced pressure and the resulting thick oil was treated with ethyl acetate (40 mL) and water (40 mL). HCl (1.8 mL 6 M, 10.80 mmol) was added slowly (final pH 5) and the two phases were separated. The aqueous phase was extracted with EtOAc (30 ml). The combined organic extracts were washed with brine (30 ml) and dried over sodium sulfate. After evaporation of the solvents, the residue (1.34 g) was dissolved in DCM and purified by flash chromatography on silica gel (80 g gold column) using a gradient of ethyl acetate (0 to 100% in 30 min) in hexane. The product elutes with 45-65% EtOAc. The pure fractions were combined and the solvents were evaporated to give tert-butyl-4-[3-[[6-[[2chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl ]pyridine-3-carbonyl]sulfamoyl]-2pyridyl]amino]-2-fluoropropyl]-2,2-dimethylpyrrolidine-1-carboxylate (804 mg, 65%) as a white foamy solid. MS-ESI m/z calc. 771.2981, detected 772.39 (M+1) ⁺ ; Retention time: 2 diastereomers visible, 1:1, Rt=2.51 and Rt=2.52 min (LC method B). The product was used in the next step without further purification.

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Step 8: 2-chloro-N-[[6-[[3-(5,5-dimethylpyrrolidin-3-yl)-2-fluoropropyl]amino]-2pyridyl]sulfonyl]-6-[3 -(2 -dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1 -yl]pyridin-3-carboxamide (dihydrochloride salt)

Tert-butyl-4-[3-[[6-[[2-chloro-6-[3-(2-dispiro[2.0.2.1]heptan-7ylethoxy)pyrazol-1-yl]pyridine was loaded into a 100 ml flask -3-carbonyl]sulfamoyl]-2-pyridyl]amino]-2-fluoropropyl]-2,2dimethylpyrrolidine-1-carboxylate (782 mg, 1.013 mmol), DCM (9 ml) and HCl (1.5 ml 4M in dioxane , 6,000 mmol). The reaction was stirred at room temperature for approximately 5 hours. Volatiles were removed by evaporation under vacuum. The residue was triturated with dichloromethane/hexanes and the solvents were evaporated. The operation was repeated until a nice white solid was obtained. Drying in vacuo gives 2-chloro-I-[[6-[[3-(5,5-dimethylpyrrolidin-3-yl)-2-fluoropropyl]amino]-2pyridyl]sulfonyl]-6-[3-(2- dispiro[2.0.2.1]heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3-carboxamide (dihydrochloride salt) (731 mg, 97%) as a white solid. The product was used in the next step without further purification. MS-ESI m/z calc. 671.24567, detected 672.44 (M+1)+; retention time: 1.75 min (LC method B).

Step 9: 8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-16-fluoro-12,12-dimethyl2λ ⁶ -thia-3 ,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2,4trione (enantiomer 1) (compound 309, peak 1 SCLC), 8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1Hpyrazol-1-yl]-16-fluoro-12,12-dimethyl- 2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23),20-hexaene-2,2 ,4-trione (enantiomer 2) (compound 308, SCLC peak 2), 8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]- 16-fluoro-12,12-dimethyl2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1(22),5,7,9,19(23) ,20-hexaene-2,2,4trione (enantiomer 3) (compound 307, peak 3 SCLC) and 8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1Hpyrazole-1 - yl]-16-fluoro-12,12-dimethyl-2λ ⁶ -thia-3,9,11,18,23pentaazatetracyclo[17.3.1.111,14.05,10]tetracose-1 (22),5,7,9, 19(23),20-hexaene-2,2,4-trione (enantiomer 4) (compound 306, peak 4 SCLC)

enantiomer 3 enantiomer 4

2-chloro-N-[[6-[[3-(5,5-dimethylpyrrolidin-3-yl)-2-fluoropropyl]amino]-2- pyridyl]sulfonyl]-6-[3(2-dispiro[2.0.2.1] heptan-7-ylethoxy)pyrazol-1-yl]pyridin-3-carboxamide (dihydrochloride salt) (723 mg, 0.9703 mmol), anhydrous NMP (30 ml) and K2CO3 (996 mg, 7.207 mmol) (325 mesh). The mixture was vigorously stirred in a dry bath at 150°C under a nitrogen atmosphere for 18 hours. After cooling to room temperature, the mixture was poured into chilled water (300 ml) and acidified by adding HCl (2.5 ml, 6 M, 15.00 mmol ) (light foaming). The resulting solid was filtered on a Buchner funnel and briefly air dried. The solid was dissolved in DCM and a small amount of methanol, and the resulting cloudy solution was dried over sodium sulfate. After concentration (910 mg crude solid), the solution was purified by flash chromatography on silica gel (80 g gold column) using a gradient of methanol (0 to 5% over 30 min) in dichloromethane. The product eluted with about 2-3% methanol. Evaporation of the solvents followed by trituration in DCM/hexane and evaporation of the solvents gives 8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-16fluoro-12, 12-dimethyl-2λ ⁶ -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14,05,10]tetracose1(22),5,7,9,19(23),20-hexaene -2,2,4-trione (467 mg, 76%) (mixture of 4 isomers) as an off-white solid.

¹ H NMR (500 MHz, DMSO-d ₆ ) several diastereomers were observed δ 12.57 and 12.50 (two s, total 1H), 8.25-8.19 (m, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.65 ( k, J=8.0 Hz, 1H), 7.37-7.11 (m, 2H), 6.98-6.74 (m, 2H),

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6.10 (dd, J=4.6, 2.7 Hz, 1H), 4.87 (d, J=43.7 Hz, 1H), 4.32-4.04 (m, 3H), 3.29-2.97 (m, 2H), 2.92-2.60 (m, 1H),

2.47-2.23 (m, 1H), 2.18-1.76 (m, 5H), 1.75-1.44 (m, 8H), 0.87-0.77 (m, 4H), 0.70-0.56 (m, 2H), 0.56-0.43 (m ,

2H). MS-ESI m/z calc. 635.269, detected 636.37 (M+1)+; Retention time: two peaks visible, Rt=2.32 and

Rt=2.34 min (LC method B).

The four stereoisomers were separated by chiral SCLC in two steps. The sample was first purified using a normal phase LC-MS method using a LUX-4 column (250 x 21.2 mm, 5 μm particle size) sold by Phenomenex (pn: 00G-4491-P0-AX). Mobile phase: 41% MeOH (without modifier), 59% CO ₂ , 70 ml/min, 31 mg/ml in MeOH, injection volume = 500 μl, column temperature = 40 ° C, pressure 178 bar, wavelength 280 nM. This separated peak 1 and peak 2 from peaks 3 and 4, which eluted together. After evaporation of the solvents, peaks 3 and 4 (216 mg solid) were separated using a chiralPak AS-3 column (250x21.2 mm), 5 µM, mobile phase 28% MeOH (unmodified), 72% CO ₂ , 70 ml/min , 31 mg/ml in MeOH, injection volume 500 µl, pressure 156 bar, wavelength 280 mm. After evaporation of the solvent, each compound was purified by flash chromatography on silica gel (12 g column) using a methanol gradient (0 to 5% over 15 min) in dichloromethane. For each isomer separated, the solvents were evaporated and the residue triturated in DCM/hexane. Evaporation of solvents produces products as off-white solids. Based on the LC retention time, peak 1/2 and peak 3/4 form enantiomeric pairs. This was confirmed by mixing the QC solution from peak 2 with peak 3, resulting in two separate peaks. Superposition of the 1H NMR of the 4 isomers confirms the observation that peaks 1 and 2 have the same 1H NMR spectrum, while peak 3 of the 1H NMR spectrum is identical to peak 4.

Compound 309, peak 1 SCLC. its >98%. 8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol1-yl]-16-fluoro-12,12-dimethyl-2λ ⁶ -thia-3,9, 11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (enantiomer 1) (98 mg , 61%).

1H NMR (500 MHz, DMSO-d6) δ 12.50 (broad s, 1H), 8.22 (s, 1H), 7.82 (b s, 1H), 7.66 (t, J=7.9 Hz, 1H), 7.24 (b .s, 1H), 7.19-7.13 (br m, 1H), 6.95 (d, J=8.2 Hz, 1H), 6.78 (broad s, 1H), 6.10 (d, J=2.9 Hz, 1h), 4.83 (broad d, 1H), 4.22 (broad s, 2H), 4.12 (broad s, 1H), 3.26-3.02 (br m, 2H), 2.82 (broad s, 1H), 2.44 (broad s , 1H), 2.08 (broad s, 1H), 1.98-1.44 (m, 12H), 0.89-0.75 (m, 4H), 0.72-0.60 (m, 2H), 0.55-0.43 (m, 2H). MS-ESI m/z calc. 635.269, detected 636.37 (M+1) ⁺ ; retention time: 2.33 min (LC method B).

Compound 308, peak 2 scLx. its >98%. 8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol1-yl]-16-fluoro-12,12-dimethyl-2λ ⁶ -thia-3,9, 11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (enantiomer 2) (98 mg , 61%).

1H NMR (500 MHz, DMSO-d ₆ ) δ 12.50 (s, 1H), 8.23 (d, J=2.8 Hz, 1H), 7.84 (d, J=7.4 Hz, 1H), 7.66 (t, J=7.9 Hz, 1H), 7.24 (broad s, 1H), 7.17 (d, J=7.2 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H), 6.78 (broad s, 1H), 6.10 (d, J=2.7 Hz, 1H), 4.83 (broad. d, J=44.5 Hz, 1H), 4.23 (tt, J=6.8, 2.7 Hz, 2H), 4.13 (broad. s, 1H), 3.15 (broad. s , 2H), 2.82 (broad s, 1H), 2.44 (broad s, 1H), 2.08 (broad s, 1H), 1.97-1.42 (m, 12H), 0.90-0.76 (m, 4H), 0.730 .57 (m, 2H), 0.56-0.41 (m, 2H). MS-ESI m/z calc. 635.269, detected 636.33 (M+1) ⁺ ; retention time: 2.33 min (LC method B).

Compound 307, peak 3 SCLC. its >98%. 8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol1-yl]-16-fluoro-12,12-dimethyl-2λ ⁶ -thia-3,9, 11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (enantiomer 3) (90 mg , 56%).

1H NMR (500 MHz, DMSO-d6) δ 12.57 (s, 1H), 8.21 (d, J=2.8 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.64 (t, J=7.9 Hz , 1H), 7.33 (broadened d, J=9.8 Hz, 1H), 7.14 (d, J=7.2 Hz, 1H), 6.94 (t, J=9.2 Hz, 2H), 6.09 (d, J=2.8 Hz, 1H), 4.88 (d, J=42.8 Hz, 1H), 4.30-4.09 (m, 3H), 3.36 (m, 1H overlapped with water), 3.01 (t, J=8.9 Hz, 1H), 2.64 (t, J=10.7 Hz, 1H), 2.31 (broad s, 1H), 1.94-1.75 (m, 5H), 1.69-1.57 (m, 4H), 1.52 (s, 3H), 1.48 (t, J=6.5 Hz, 1H), 0.90-0.78 (m, 4H), 0.68-0.59 (m, 2H), 0.55-0.41 (m, 2H). MS-ESI m/z calc. 635.269, detected 636.37 (M+1) ⁺ ; retention time: 2.3 min (LC method B).

Compound 306, peak 4 SCLC. its >98%. 8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol1-yl]-16-fluoro-12,12-dimethyl-2λ ⁶ -thia-3,9, 11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracose1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (enantiomer 4) (74 mg , 46%).

1H NMR (500 MHz, DMSO-d ₆ ) δ 12.57 (s, 1H), 8.21 (d, J=2.8 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.33 (broadened d, J=9.7 Hz, 1H), 7.13 (d, J=7.2 Hz, 1H), 6.94 (dd, J=10.6, 8.4 Hz, 2H), 6.10 (d, J= 2.7 Hz, 1H), 4.88 (d, J=43.5 Hz, 1H), 4.28-4.08 (m, 3H), 3.35-3.24 (m, 1H overlapped with water), 3.042.92 (m, 1H), 2.63 ( t, J=10.9 Hz, 1H), 2.31 (broad. s, 1H), 1.97-1.75 (m, 5H), 1.67-1.59 (m, 4H), 1.52 (s, 3H), 1.48 (t, J= 6.6 Hz, 1H), 0.91-0.76 (m, 4H), 0.67-0.60 (m, 2H), 0.54-0.41 (m, 2H). MS-ESI m/z calc. 635.269, detected 636.33 (M+1) ⁺ ; retention time: 2.3 min (LC method B).

Bioactivity assays.

Solutions.

Basic medium (ADF +++) consisted of Advanced DMEM/Ham's F12, 2 mM glutamax, 10 mM HEPES, 1 μ/ml penicillin/streptomycin.

Intestinal enteroid maintenance medium (IEMM) consisted of ADF+++, 1 B27 supplement, 1 N2 supplement, 1.25 mM N-acetylcysteine, 10 mM nicotinamide, 50 ng/ml hEGF, 10 nM gastrin, 1 μg/ml

- 519 044967 hR-cnoHguH-l, 100 ng/ml hNoggin, TGF-b type 1 receptor inhibitor A-83-01, 100 μg/ml primocin, 10 μM P38 MAPK inhibitor SB202190.

Bath buffer ₁ consisted of 1 mM MgCl2, 160 mM NaCl, 4.5 mM KCl, 10 mM HEPES, 10 mM glucose, 2 mM CaCl2.

The chloride-free buffer consisted of 1 mM magnesium gluconate, 2 mM calcium gluconate, 4.5 mM potassium gluconate, 160 mM sodium gluconate, 10 mM HEPES, 10 mM glucose.

Bath 1 dye solution consisted of Bath 1 buffer, 0.04% Pluronic F127, 20 μM methyloxonol, 30 μM CaCCinh-A01, 30 μM Chicago Sky Blue.

The chloride-free dye solution consisted of chloride-free buffer, 0.04% Pluronic F127, 20 μM Methyl Oxonol, 30 μM CaCCinh-A01, 30 μM Chicago Sky Blue.

The chloride-free dye stimulation solution consisted of a chloride-free dye solution, 100 μM forskolin, 100 μM IBMX, and 300 nM compound III.

Cell culture.

Human intestinal epithelial enteroid cells were obtained from the Institute of Developmental Biology and Stem Cell Research. Hubrecht, Utrecht, the Netherlands, and propagated in Tkolb as described previously (Dekkers JF, Wiegerinck CL, de Jonge HR, Bronsveld I, Janssens HM, de Winterde Groot KM, Brandsma AM, de Jong NWM, Bijvelds MJC, Scholte BJ, Nieuwenhuis EES, van den Brink S, Clevers H, van der Ent CK, Middendorp S and M Beekman JM. Functional analysis of CFTR using intestinal organoids from primary cystic fibrosis. Nat Med. 2013 Jul;19(7):939-45.).

Collection and culture of enteroid cells.

Cells were reconstituted in cell recovery solution, collected by centrifugation at 650 rpm for 5 min at 4°C, resuspended in TryPLE, and incubated for 5 min at 37°C. Cells were then collected by centrifugation at 650 rpm for 5 min at 4°C and resuspended in IEMM containing 10 μM ROCK inhibitor (RI) (trans-4-[(1R)-1-aminoethyl]-N-4pyridinylcyclohexanecarboxamide) . The cell suspension was passed through a 40 μm cell strainer and resuspended at a concentration of 1 x 10 ⁶ cells/ml in IEMM containing 10 μM RI. Cells were seeded at 5000 cells per well in multiwell plates and incubated overnight at 37°C, 95% humidity and 5% CO ₂ until analysis.

Membrane potential dye assay.

Enteroid cells were incubated with test compound in IEMM for 18-24 hours at 37°C, 95% humidity and 5% CO ₂ . Following incubation of the compounds, a dye transmembrane potential assay using FLIPR Tetra was used to directly measure the activity and efficiency of the test compound on CFTR-mediated chloride transport after rapid addition of 10 μM forskolin and 300 nM Compound III. Briefly, cells were washed 5 times in Bath 1 buffer. Bath 1 dye solution was added and cells were incubated for 25 min at room temperature. After incubation with the dye, the cells were washed 3 times with a chloride-free dye solution. Chloride transport was initiated by adding a chloride-free dye stimulation solution and the fluorescence signal was read for 15 min. CFTR-mediated chloride transport for each condition was determined by the AUC of the fluorescent response to acute stimulation with forskolin and 300 nM compound III. Chloride transfer was then expressed as a percentage of chloride transfer after treatment with 3 μM Compound A, 3 μM Compound II, and 300 nM control triple combination.

Compounds III acute action (% activity).

Connection A:

In table 5 shows the results of biological activity assays for typical compounds of the invention (maximum activity: +++ means >60%; ++ means 30-60%; + means <30%. EC50: +++ <1 µM; ++ means 1- 3 µM; +> 3 µM; and BUT - not defined.)

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Table 5

Connection No. Molecule Max, activity EU50 1 OOO N,C ₀ ΑνΑΑνα/'Χ H _a c4ClNH H3C H ₃ C +++ +++ 2 ⁰ 9 9 Н,С о Ν'ίί Н,с-)—' \s=i Н с4—+Γνη ^Н = ^с Н ₃ С +++ ++ 3 ⁰ 9 9 НзС about НзСА-' ^=4 HsC'M'VnH НзС НзС +++ +++ 4 Ooo <1 O L NNN\ 'G ^F 4 ^N ^ ^N +++ +++ 5 LLC ο-^'Ν^Ν^-Χ ^N T _HaC -/V^NH ^f A ^ks +++ +++ 6 O OO ^Η ί ₃ Ο^ ^ΝΗ +++ +++ 7 Ooo _N xYCO o -/ NNN -TV)/r _F lz^ H,C 4-2 0 7> ^СНз ++ +++ 8 LLC _Ν χΥή'ίΟ o ΝΝΝ -Ap >g L n ₃ s-M o KT> SNz + + 9 O 0.0 o/nХХХг ¹ ++ +++ 10 O o o o d ^| '»Ag'mt/-g ^F ₽^< ^H '°^ ^UcH · + + eleven Ooo F _f ^ H ₃ cV and _сНз +++ +++

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12 SyX LL +++ +++ 13 Ooo. .^-4/7 ⁵ 4 <C ^NH + ++ 14 Ooo _N o^· NN Ν-χ Y _Нз с4Л?Н FL> ^CK +++ +++ 15 ° op +++ +++ 16 ^H ' ^C CH _S ++ +++ 17 o o rAP NAA NH _o // nn^n \_j FA /—' H ₃ c4— fT> ^СНз ++ ++ 18 ⁵ ίΑ· O-^k „ °' ^z:c < JA A- i? /LL ++ +++

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19 oh oh? сн ₃ A „RE ^N ' ^S СНз ^Ί ++ ++ 20 oh oh. .о Ά , Ar °“Cj НзС^А ^ ^{νη 3} сн _e +++ +++ 21 LLC ν ΓόΎ A OA NN NA_T F )° +S%Ch/N L ^sn ' ++ + 22 LLC PgAM _F A H.cRA“ % ^sn - +++ +++ 23 O o o o A -NAA A^T NzsA/^nh g> ^snz + + 24 o o _F oY'n^n^n-Aa ^NH F-RA ⁷ H,C-4--/ ^snz + + 25 0 0 ιΆ _F □лЛ'А-у/и FT / ^/ H,C-4-/ ^СНз ++ +++

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26 o 0. .0 ML ΠΧ-Q sn ₃ +++ +++ 27 0 0. .о l, о °~О НзС-М ^{7 Vnh 3} сн ₃ +++ +++ 28 Ooo h ₃ c4V7nh /P> CH ₃ ++ +++ 29 ⁰ 9 9 _f LM H ₃ c4V7 NH |/р> СНз М ++ +++ thirty ⁰ 99 ₀ l-OCvp ¹ _F L+ ls+y NH /p> sn ₃ O +++ +++ 31 9 9 HN ^S ^X F,— ¹ \M \_/ =D / N,S-1—'/P> ^СНз + + 32 /xJ ⁹ s° jTx n and _F V NN^N^n^N У ^Γ \Ζν^Ν JJ \ 1 Λ _f a ο^Μ НзС-MVj ^Г CHj +++ +++

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33 oh oh. 9 gl- xYCP N ₃ C + + 34 ++ .хф ^F n _1С +An n _e s +++ +++ 35 ° 99 _Ν ηόΌ Ο^'Ν Ν ΝΑ γ n ₃ с4^/н ^F Z~b СНз 1 ^F СНз +++ +++ 36 θ 99 RcAX/H ^r Lk sn ₃ ' ^F ch. +++ +++ 37 About 0.0 Dr. rfs'O + +++ 38 LLC ηο-υ/ ^Ν ν ^ν Ίμ-λ ^N t НзС-jjM NH H ₃ C ^L - ¹ ++ +

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39 ⁰ 9 9 \ \=^ n ₃ s-|—'ί) ^P 7~ΐ> CH _e +++ ++ 40 ⁰ 9 9 olHYKYU ¹ fL/ ⁷ n ₃ s^< ⁰ γ|> sn ₃ ++ +++ 41 o op ν rf «00 ο +n ^a n ^a nW _f L/-^ A» ¹ h,c+V ^nh GY ^CHj + + 42 o qp Hc w ₀ Lm-Sf K ³ H ₃ C< XI NH H ₃ C< yg ⁴ / 1—f H ₃ C ^H ° ^c +++ +++ 43 LLC •XCP /к/-' X ¹ НзС^Г M NH h ₃ c ^L - ¹ +++ +++ 44 o qp olHYSR F XJ Η,οφΧ k) ^F <> ^CHa ++ + 45 o qp n A JL d nn o-// n^n^nAA nc\ H ₃ c-|X k) ^CHa +++ +++

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46 °qp + + 47 OOO ίϊΧΟ +++ +++ 48 ⁰ 9.9 ν ХХ*^ νΟ rlА Η,οΑΧθ Z> сн ₃ + + 49 LLC -zhsr q l Ν Ν N T NesA^uo <~ί> sn ₃ +++ +++ 50 LLC ν nVn fL/^ η,Ο'Μ NH /> CH _a + + 51 O OO ν ίΥύϋ n.s+-/ ΝΗ рП> ^СНз + + 52 LLC, oh-Due- ^{Nzs snz} ++ +++

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53 o o o γη> ^sn ' +++ +++ 54 th V To ++ ++ 55 dn ₃ +++ +++ 56 about 9-9 <ί> SK + +++ 57 ⁰ 9-9 , tsH^Y? /b> sn ₃ ++ +++ 58 LLC ^F XT> CH ₃ * ^F CH ₃ + +++ 59 LLC •lСр ^F 7r> ^сн з i F СН ₃ +++ +++

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60 ° 9 9 n 0 J'N ^a n ^a naV _fk + n,s4~Ch/ ^{n f} 7-< сн ₃ I ^F CH ₃ +++ +++ 61 ⁰ 9 9 ₀ /nXXvQ + /^ H,c++<\NH VT> ch ₃ 1 ^F CH ₃ +++ +++ 62 LLC n iWn _O k· NN ΝΆ_, N NH _F S/—' NzsCh-k^ ^- ^ Fl> ^CH = +++ +++ 63 LLC N /YVO o T fM> ^СНз +++ +++ 64 4 ά shB=° И5 ^% ++ +++ 65 LLC n /70¾ Ο^'Ν^Ν^Ν-λ ^Ν ψ . l-x Vk ^Η 3°τΟ.....I HN !>V h ₃ c 1 1 ++ +++ 66 LLC n Λ JL ^H Nx.J O-/7 NV z-^ H,C%k. HN !>V h ₃ c 1 1 +++ +++

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67 OOO _s Ji J and u D o ν/Ν%%-ν?Ν ^Λ ΝΗ el/—' H.cdd 71> CH ₃ +++ +++ 68 OOO ^n^ m L L n L 1 OJ NNN NH units/—' H ₃ C%/ V^/ FL> CH ₃ ++ +++ 69 LLC n Γό'ΙΟ ₽ ^Ν ?ΎοΤ H.C++<NH +++ +++ 70 o 0.9 _l dHds ο kc O ++ +++ 71 o pP CH ₃ F Г> ° V НзСЛСНз + + 72 LLC m Jl J n LI o-D Ν Ν Ν ΝΗ _R d/—' n ₃ s%/ ^Λ — ⁷ ΥΊ> ^СНз + + 73 ο ο.ρ _ы Ji J n id o J^ N^N-'V^N'^NH рД/—' Н _з с4~+ — ⁷ rТ> ^СНз +++ +++

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74 ⁰ °P F + ++ 75 ° Op F f%% h.c4/Vh p νΠ ₃ +++ +++ 76 o op CH, ³ CH, But But 77 Ooo n o ^ ⁿ n^n^nA. _f ^f \h,c fL> ch. +++ +++ 78 O pp ^P r > CH, +++ +++ 79 ns I O ^y , ^ΝΗ Ηαθ ³ ^^γ% ^Λ _Ν ^ι/>— N, C / >4 ⁿ ' ^s Tn, ++ +++ 80 o 0.9 dn, ³ dn, + +

- 531 044967

- 532 044967

87 LLC rt> sn ₃ +++ +++ 88 o 0.0 s 11 J n L C O--Z· NNN^y^^/O fY/— ⁷ n ₃ s4—' ⁴ —'7~b> CH ₃ ++ +++ 89 LLC _y L JL n L k 0 -//Ν Ν ΝΛ+^Ο s _\ / ' n ₃ s t ' ^SНz ++ +++ 90 O O. .O Γ ^! ΥΧ ^Ν ^ΊίΥ О / 0 _f ^f \ /- ⁷ H _: cY ⁴ —' ^f Ci> ^ch · ++ +++ 91 0 0.9 CH ₃ F % ,Ν-Ν^Ν^ΝΎη \ °Λ^ h,cW O' CH ₃ + + 92 o 0.9 sn ₃ F Αν ^Λ Ν ΝΛη \ °V Η,οΉ CH ₃ ++ +++ 93 o o.o +++ +++

- 533 044967

94 LLC _y Ji J and L, 1 0 ^N'^N'^N'XY'N^O FA / H ₃ C 4 ' CH ₃ + + 95 OOO m JI J n L JI _F °Xj ^{n H} ' ^C CH ₃ ++ +++ 96 LLC _s Jl J and L 1 0 γ'Ν Ν ΝΥρ^Ο c \ '— H,C 4-^ CH ₃ + + 97 Ο °ί-Ο ο ρΑϊ ^Ν > H ₃ C Н,сХр ρ ^Н ' ^С Н3С ^НЭС CH3 +++ +++ 98 ⁰ p? ^й ' ^N > Н ₃ С Xn^N^N^X^ Н ₃ SE-ХХ mg< ^Н ' ^{С НзС} bь ^НзС сн ₃ ++ +++ 99 LLC xA'Vii _y XI n L J1 ογ'N^N^NXpO _F XX НзсХ/ ⁴ ^ ^F _f >-$ CH. +++ +++ 100 LLC n 1 Ί n L 1 Ο-^'Ν Ν ^Α ΝΧρο ndH 'ru> ^СНз + +

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101 ο ίΐ “ J ^NH Q ⁿ ' ^s Tn _e ++ +++ 102 O °iDD ο ρΛίί ⁿ⁴ nh /-D Ν ^Λ ν Aj/X-^xx ⁷ η,ο^^ _HC V Η,ΟΟΗ, CH, +++ +++ 103 OOO m 1 L n k O D'M Ν N'XXN^O rD- ⁷ n ₃ s4-U / r> CH, ++ +++ 104 OOO m 1 L n k O l · Ν Ν ΝΛ?Ν Ο N,sD^^ UT> ^sn ' + + 105 o °-8-O 1 DH <n ' ^N D +++ +++ 106 o °--§DD x ⁿ ' D ^{1 N} ' ^S Dn, +++ +++ 107 I SD / О:<д) 1 g А·' P X +++ +++

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108 ° op ³ CH, ++ +++ 109 LLC m to L. n m -JL ₀ Λ N^nA^Y^H, fA-Z^ Η ₃ ο4-/χ° /£> ch, ++ +++ BY OOO _Ν iY^ ^s Z ^N O^N^N'ScXfL/ ^- ^ h ₃ cW Γ> ^CH ' ++ +++ 111 o oP u ^s ^-x \ J> (ΓΎ h 1 ^N f<\ У Λ n zn F N. _n An ^A n4 ^c I °ϋ НзсХУЧ] H ₃ C +++ +++ 112 o o P CH _{3 M} No. ν ^4 ^NN _HC p^ kc ++ +++ 113 OO.9 ch, H ₃ C ++ ++ 114 ⁰ OP _f a_Z^ η ₃ ο4^Τ ^{νη F} rt> ^СНз + +

- 536 044967

115 Ooo DD> ch ₃ +++ +++ 116 ⁰ 9-9 rD SN, ++ +++ 117 and θ° <D S Η, ++ +++ 118 LLC m JL JL ⁿ ^m· n,s4-7 fT> CH, + ++ 119 OOO IiV^'Vn fL> ch, +++ +++ 120 LLC <k _Ν OVtl CH ₃ ++ +++ 121 Ο ο.ο .DU LgLl Ed n ₃ s4Dch-—chD SNz +++ +++

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122 LLC Ο^ ^Ν Ν^ΐΛ1\^ kT> sn ₃ ++ +++ 123 О 0.0 ΑϊΛν- ⁵ υΑ m JL* 1 n m ρΔ/''<L> sn. +++ +++ 124 T ά “о =0 s T\=/ +++ +++ 125 KlAAg LLC? dn ₃ + +++ 126 ο <4^ ^{0 N} NH n ₃ s u II 1 and j H=CH ₌ C / ^НзС Тн ₃ ++ +++ 127 0 HC S rfi r ^H - ^c < +++ +++ 128 v ^Q ^O ° ίΓΎ H ,NH ^H = ^c H,c< Wb +++ +++

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129 LLC СНз ₀ lЛХлР _F \ζ- ⁷ СН ₃ +++ +++ 130 o O o y 1 L n II I οΑ'Ν Ν Ν ΝΗ __/ НзС^^У-х Ί О-/ НзС^ ⁴ +++ +++ 131 ° QP /AL n _a s^ L-nh ++ +++ 132 LLC Ν Ν Ν X Ν N D H,c-p+-v4 ^F |/f> sn _e ++ +++ 133 OOO _Ν ΓίΥΌ oJ% ^N ν _λ X +++ +++ 134 OOO d ν GV V °Л^ h ₃ cV7L>У~[> СНз + +++ 135 LLC d L,-. Ν LAN V ο^'Ν^ν^ν^χ^, Х НзСVtJ fL> ^СНг +++ +++

- 539 044967

136 °QP Δγ- ⁷ L- ^NH +++ +++ 137 °Q.p l Δγ- h.?CJ L™ + + 138 OOO n S^kA^ CH, 7F> ^J CH, + + 139 ⁰ o® _F o^nJOO R N _: S A ^CH> +++ +++ 140 ⁰ O. P ^N^N ^CHa A /—' KsA-A-ALL _F n> ^cNa ++ +++ 141 O QP Ν·μΛ.Α Ji ^Ν ·Ν ° Ν N ^N^y-h \ Δ-ϋ ⁴ ' ⁷ Н _з с4^ i ^сн . +++ +++ 142 o qp y> ^СНз + +++

- 540 044967

143 OOO + ++ 144 OOO l A /s' ίι ΊΓ ΰ +VcH _a ^NS D ++ +++ 145 o Ly ^Ν > НзС / Лд ^зС сн, H ₃ cV +++ +++ 146 I? hg g % I +++ +++ 147 o oo ^F /T> ch. ++ +++ 148 o o o ^сн = ₀ ^·νΑΧΧ|Φ Н,с4~/<>н ^F E~L> ^СНз + + 149 LLC CH, Fy-/ W Η,ο+Ζ^ΝΗ F^fc* ^СНз +++ +++

- 541 044967

150 OOO If Υΰ YVcn, oJ'-AAv? f!/— ⁷ Ηγ-Ρ 7π> ^СНз + ++ 151 ο ο ο Cl [f ^S YYcH, o/AAiV? fL/^n ₃ s4~/ Ct> sn ₃ +++ +++ 152 O OO ^F |/> СНз + + 153 О 0.0 ^ν ·νΑΑ Jij w оу Ν ^Ν \ Δ-/^ НзСА— ⁷ ρί сн ₃ + + 154 Ο 0.0 ΐίΥ^Η^Ά οΑ ^νΑ Ά _ν ^ν НзС-С ⁷ СНз +++ +++ 155 Ο OP rCi^ ^N '^V% o -J ¹ ' NNAN ' 4 <7/^ h ₃ c 4--/ \x CH, ^F F +++ +++ 156 o O O ν 0.4'4'1+% ^Ν % t\/— ^{J ΝΗ} ζγ N ₃ C +++ +++

- 542 044967

157 V ° O O vV n.s/uo nh n ₃ s Cj +++ +++ 158 LLC ^G F An ^A N ^A N ^z VY НзС-УЧ^н CH ₃ ^v +++ +++ 159 F-HH A ^Z ^ ^N ' ^S YA H+ + Vo _NH H ₃ C^ V/ + + 160 V ° O 0 _N xTw ^;s n ^F o/nV WH ₃ c< Vo NH ns^ V; +++ +++ 161 „ ⁰ o. 0 ^F J4 ^Ff 0J4 WCN-? X +++ +++ 162 Ooo ^NzS CHU? ^nh κγ n ₃ s ++ ++ 163 Ooo О-ANN ^X N-\ T K,—/ W Н,сУ>О NH иу H ₃ CV/ ++ +++

- 543 044967

164 ⁰ o..o θ'4 gD/^ Η ₃ θ4-+ γ/ FL> CH ₃ ++ ++ 165 ° qo o/n'COjQ <7 G ⁷ n.sAG/ F СНз ^F F + + 166 ° o. .0 suAgAhu o^nAiAiAna <L/~~' ^/ n ₃ с4А\/ Fy^ CH ₃ ^F F +++ +++ 167 ° OO ^Ζν· ⁵ υ\ ΊΑ? ^F rT> ^СНз ++ +++ 168 A % ° □ Ar nA H ₃ C ts II 1 H ³ hc^AVJ ch ₃ + + 169 ΑΛ ^{ο 0} (T^r ^N Λ_ НзС^/^/ уу ^Ν 7^>\ ^Ν ί НзСси НзС-UAJ ³ СНз ++ +++ 170 LLC ^H3 V ^H4 /hL _m ^ ^H ' ^C VX ΧΤλ yu oA Ν ^Ν Gx T ηρΆΑ / ^ΝΗ СНз ^V ++ +++

- 544 044967

171 LLC n ₃ c sn ₃ ⁿ = ^c < 1 ίχ and O Ν Ν γ Μ ⁷ Η ₃ θ4-Π NH CH ₃ ^v +++ +++ 172 ⁰ 9 9 ο ι+γΥΜί H _s cP7 NH CH ₃ V ++ +++ 173 ⁰ 9. .9 НзС'РМ^ CH ₃ +++ +++ 174 o °iQ ° ρλϊ An Ά n^ _H1 +++ +++ 175 °MQ S fX * j ^NH F^> М _зС ^ _Нз +++ +++ 176 OOO _s 11 J ^H N-hi MM p4>E P<f ³ CH ₃ +++ +++ 177 o °fO 0 fA Ah ^Η Ά, ++ +++

- 545 044967

178 o -O <7 0 η ^Ν JNH ^h ' ^c Vh, +++ +++ 179 r> LLC A 1 AA A :. _with рД CH ₃ ^v ++ +++ 180 G> LLC YL 7 Yfo H ₃ CP4 NH CH ₃ ^V +++ +++ 181 o o o ³ dn ₃ ++ ++ 182 LLC NzS-A^ ⁵ СНz ++ +++ 183 OOO f d A A - f^—Г ⁰ |Υί and ρ ^ζ \__. \ϊ JI JL H Nai ^F ' ₀ Λν ^λ ν ^λ νΑ^ XJ n _e S СНз ++ +++ 184 LLC ___A ,'s' ° Гп N \LA JL ^H N -M ^Z HC rCPTHj h ₃ c/a hc-W H ₃ C СНз + ++

- 546 044967

185 ° ⁰ ° n ₃ s /—' h ₃ c4-/X^nh X) ch, CH, +++ +++ 186 OOO llm U JI JH s ./ [><7 ch ₃ + +++ 187 LLC λΑΛα oJ-n^/nV-n z—7 VJ Н,СХ ^ CXI ™ ₃ +++ +++ 188 LLC NXA ^H NJ O J ^N NNN\ V zV H ₃ c4X ^NH />4 ch ₃ +++ +++ 189 LLC N iXVY) ο Λν-'Χ-'Χ-λ Y . XV ^N ' ^S LH NCH, i>—/ h,c |__1 +++ +++ 190 V ° ° ^{0 F} ++ +++

- 547 044967

191 LLC f to A A- f^—< ° ΙιίΓ And ^NN ”V\ d rc-I СНз ++ +++ 192 OOO f is AA f-)—r ⁰ Γί □ h ₃ cA CH ₃ +++ +++ 193 o qp l«^y? v—J uc -4Ά 7 nh U Г' / ^π : ^{υ 1 3} 5b _С Н СН ₃ НзС = +++ +++ 194 LLC Ν /UyAO _k Η,Ο-Μ^ΝΗ /Ap ^sn ' ++ +++ 195 LLC _N £XV ^S O oJ^'n^'n'^n'A- t _Η3θ γνχ _ΝΗ [><f СНз +++ +++ 196 o qp ο^ΧίνΡ . Z-^ Η ₃ ο4ΑχΝΗ /AP he. ++ ++

- 548 044967

197 ⁰ 9 9 oxnXxXp ZNq ch ₃ +++ +++ 198 o 0.0 ο γ ^Ν ' N^N ^N-¾'N h ₃ c / ' h ₃ c4V >d CH ₃ u^ GSN, CH ₃ But But 199 o 0.0 CH ₃ ογ ^Ν h _: cUV \L сн ₃ Ф ++ +++ 200 o oo ⁰ /—\ ϋ J· Λ HU ( Y Нзс+'-'Тт'И CH ₃ + +++ 201 0 op СНз i^r^N^vK T\/—'Η,ο4> V l/γ сн ₃ + + 202 LLC sn ₃ o _Z/ ^N - NN γΝ' 4 n ₃ с4^\/ Ι/γ СНз ++ +++

- 549 044967

203 O 0.0 n 1 JL ⁿ νΎ qJ'N Ν ^Χ ΙΚ V К /—' \=4 ^Н = ^С ХЦ NCH, ί>—< n,s / 1 +++ +++ 204 LLC ^Ν γ _k ^N %Х N CH, >—< n,s 1 ι + + 205 ί>° Λ ο4-ζ >=ο Ύ +++ +++ 206 ⁰ 9Ρ o/ААу^ n _e s / ' n, сХ\/ XI СНз ^НзС g-сн ₅ сн _e + +++ 207 LLC O V/ ^N ' ΝΧΧν Λγ' ^Ν \ n3s / ⁷ A=J n3s4xx/ XI ch, n, su _sn CH, +++ +++ 208 LLC ν χΥΥη KC^O^NN _c NyX ^F T\ N ₃ C V FF +++ +++ 209 O «.с rfLYr H=C НзС^С ³ CH ₃ ++ +++

- 550 044967

210 „ g H _: CH ₃ C% ³ CH ₃ ++ +++ 211 ⁰ 9.9 _ _y^ Н _: сДЧД ^Н FF CH ₃ ++ +++ 212 ο ο,ρ _N /ΠΤΌ F ,___/ \=XH ₃ CX/.HN rD-D h ₃ c O g gen, ^F n ₃ s +++ +++ 213 o 9 9 S D n ₃ s-D7d ⁿ XX sn ₃ + + 214 And to about g t ++ +++ 215 LLC » χνΧν ^U-/ vJ n.s+x^ ^{n n} = ^s sn _e 1 sn ₃ + +

- 551 044967

216 LLC λ rxYn H ₃ C / n ₃ s4^7mn ⁿ = ^s СНз I СНз +++ +++ 217 OOO 1 lHo γ AND ShchS-P SNz ++ +++ 218 ⁰ 9 9 I ^S O Н ₃ С t ^7- ⁷ vJ nesL^<\ ^мн = ^с сн3 x СНз + + 219 o 9 9 N.C ΐ°Λ^ N.C-M7 NH ⁿ ' ^s СНз to СНз ++ +++ 220 ° 9.9 сн, _N Хл й ⁵ П НзС-/ Q / _z ^N N^N'^N'X”'f^ и _Г Х H,c4-Z^NH ³ d ^CH * СНз +++ +++ 221 О 0.0 oJ' nXX^ ^F /-V VJ Н,сЛ \ ^р Хй ^{Нз НзС} +++ +++

- 552 044967

222 ⁰ 9θ x χχΥχ ΧΛννΛ τ κοΆΑρ СНз ++ +++ 223 ⁰ 9-9 CH YnOCVP Н.С+ХГ ^F K CH ₃ +++ +++ 224 about 9-9 +++ +++ 225 o 9. P is4D, ⁱⁿ Chs ^CH · CH. ++ +++ 226 τ o η o “O J ^Ζ Α ++ +++ 227 ° Or n ₃ s ~Ζ ^Η _Ο p-N'OOxjQ “t +++ +++

- 553 044967

228 o op ++ +++ 229 LLC 1 xWn Н ₃ С йЛ™ V\y сн ₃ ++ +++ 230 ⁰ 9..9 ³ CH ₃ ^ ⁷ + +++ 231 Υ DM Η ₃ ° сн ₃ +++ +++ 232 ° O Р1 n.s I ίΥ^ ^ΝΗ Ηο2χ-Ν ^Λ Ν ^Λ Ν ^Λ Ν V ⁿ ° ^s nxL ks + + 233 „ LLC ^N ' ^S X / 1 ΝΗ N ₃ S BUT BUT 234 __ OOO _Ν xUyo ^F 0¾ ^{Ν Ν Ν} ΎΑ t L=d ΗοΟχΥ^Η N ₃ C ++ +++

- 554 044967

235 „ LLC A/Zhur N ₃ S +++ +++ 236 Ooo n huU K) Ο-ΛαγΊ^Ν^ Y L N ₃ C Y? Z-NH ^F pr> sn ₃ + + 237 SI? Υ™· ί ΐΥ» О ^F oyS ⁿ j CH ₃ ^ν +++ +++ 238 ο ο.ρ ^ΗΛ Ό α CH, +++ +++ 239 OOO o <V^ ^N Ύιΐ h,c+-/7nh ,9 “' FF + +++ 240 Ο (Υίί Άη ογ/Xr^ (hЗ> ^НзС CH _S ++ +++

- 555 044967

241 ₀ ? lit > ⁿ Q И' ⁰ ^ ++ +++ 242 o _F j ^f ? ^N g ³ CH ₃ ++ +++ 243 £ ΛLL +++ +++ 244 ^η ·°Τη. ++ +++ 245 ⁿ ' ^s Tn _e +++ +++ 246 g'Yu ⁰ ΓΪ ^th y X. H _s c ++ +++ 247 ο-Λν^ν^νΧ— h _sC v n ₃ s ¹ +++ +++

- 556 044967

248 ° qp ns D ^CH ο^κτί^^ ns/^ h»c4^nh sn ++ +++ 249 o 9Р ns * ^c ts% ^NH sn +++ +++ 250 OOO _Ν rfCO o JΝ Ν Ν\2γ . /—' \D NzSDD ^yn L>—With ns ++ +++ 251 LLC _Ν ns^E Lnh A sn ++ +++ 252 ⁰ Q r \D NSDD. NH X ns <j +++ +++ 253 oYaL „L O +++ +++ 254 G> LLC % ..-*ХС+~ ^0Ч + n.s+D/n CH ^W ++ +++

- 557 044967

255 LLC <L X ^th H,cPX ^NH CH, ++ +++ 256 LLC "λΥώ ηο/·ν Н ₃ сЧ7 NH сн ₃ ⁴⁷ ++ + 257 .0 „7'ХЗ? )—' \=J Н ₃ суУТ NH £></ сн ₃ ⁴⁷ +++ +++ 258 OOO o Α-V \=4 H ₃ s4—/7 NH UH CH ₃ ⁴⁷ +++ +++ 259 LLC N HO oJ'-N^N^NAjY <1 X h ₃ c4v7, ^nh F-/^ ^CH ° FF +++ +++ 260 0^^---^47 ά A A .о I τ +++ +++

- 558 044967

261 a „g? ++ +++ 262 o O ΝΗ , .DO? FJ Z— ⁷ \=^ H ₃ C-%/<. ΝΗ F^>CH, +++ +++ 263 ° Ο ΝΗ _F o/LYuR fA z— ⁷ \=^ H ₃ C-%/<,NH F CH, ++ +++ 264 r> LLC η ₃ ο4~Πνη sn ₃ ^ ⁷ +++ +++ 265 LLC <L ^Λ'%ν ^ΟΗ 7 h p hG Ν Ίτ ιΓ F-/ '—\ Ν Λ JL D W oL ^{m N n} A_T h,c-PXnh CH, +++ +++ 266 Qin .о/= _o LmХИСЗн HC-H ^V KL> ^НзС ++ +++ 267 Qin.P /= _N oJ^N^N^N^vX^NH ^f _f >^ ^Нз ns +++ +++

- 559 044967

268 ⁰ o.. ° /x o A X 1 ⁿ M N,s<Jahn n ₃ s <4 ++ + 269 LLC n /00¾ oJ'-N^N^N'XjY <1/^ ηδ4α7νη fV^h ch, ² H ^p +++ +++ 270 ° °/ ² N ² N Γϊι ί ΤΡΊ ft w n,c J Χην n ₃ s VJ +++ +++ 271 About Ο.ΝΗ^ _about lying +++ +++ 272 ΟΟ.ΝΗ Ν HUN ⁵ ^ ρΥτ ⁷ Η,οΉ'FL> ^НзС + + 273 F^T ^HsC CH ₃ + +++ 274 o o o 0^λ· Ν Ν N \_ Г /- ⁷ and ₃ с4^х/ ⁿ £Х7 CD:i +++ +++

- 560 044967

275 Ύ ^F H ₃ C sn ₃ ++ ++ 276 J ^F H ₃ C CH ₃ ++ +++ 277 fY4 V ^N ' ) ^F Yf ^lO ^F H ₃ C CH ₃ + + 278 O O GC1 . AY f/; НзС^Нз + + 279 ° Ο GC ^f t+ ^h ' ^Cch · ++ +++ 280 nA F-Ц^ ^N ^y _H ^CH ' F CH, ++ +++ 281 Dol yrО ( _Ρ γΆ ^Ν F СНз + ++

- 561 044967

282 4% —-w FCH, + + 283 oo 0 n /%¾ but OJ n^n^nVy h ₃ c4-a7 NH ^F T< ^ch = FF +++ +++ 284 ⁰ QO HQ ^Ν γ <LJ^ h,cV7nh F-/^ CH, ^ ⁷ ff +++ +++ 285 ⁰ сыСУ _F FCHp^ F CH, + +++ 286 _Ρ γ.°Α ^{Ν N} ---% ^H F CH, + +++ 287 O 0 0 H,c4-/7 NH у+ ⁿ CH. ++ +++ 288 FCH, + ++

- 562 044967

289 ХМ _f ^°a ⁿⁿ -¾ ¹ F CH ₃ ++ +++ 290 F CH ₃ + + 291 F CH ₃ ++ +++ 292 o o o <L schsTsmM nh _F +++ +++ 293 o qp HO _N jTjA iO A JI ο/ν ^λ ν ^λ νλ V Y n ₃ s +++ +++ 294 ° ^qpH ? n _ы jTXm А Λ O^> N^N^N-г НхМЦ r(jH Y h ₃ c <j +++ ++ 295 o o o ν rXa ^;s 'O /Λν ν^ν-. ν oЛм Η,οχχτ Μ; ++ +++

- 563 044967

296 LLC ν rYY) JΝ Ν N N-D V o\d Η,ογγ · A _F HC A ^Η Α +++ +++ 297 OOO before? ODD ^N ' ^S X/ANM A _F N.S Aj ^N A +++ +++ 298 Г>°Qo xК ^! ηΥ |·ν\^ΝΛ *Ύη ^Η “A ks-RAN sn, +++ +++ 299 LLC ν rY ^s -0 _2n ² n οΥνΧνλ ^Ν γ U—6 N-S-DT NH χί ² n ⁿ n ₃ s BUT But 300 G> OOO A Ad °A n.s+>O ⁿ CH ₃ +++ +++ 301 J> ° 0.0 _s χχ ΉΤ-D NDDD Dn and °A n,s4D™ SC, +++ +++

- 564 044967

Other embodiments

The foregoing discussion discloses and describes only exemplary embodiments of the present invention. One skilled in the art will readily understand from such discussion and from the accompanying drawings and claims that various changes, modifications and variations may be made thereto without departing from the spirit and scope of this invention.

Claims (52)

1. A compound of formula (I) a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein ring A is 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 represents O, NH or N(C ₁ -C ₄ -αalkyl); each R ¹ is independently selected from C1- _C2 alkyl groups, C1- _C2 alkoxy groups, C1-C2 haloalkyl groups, C1- _C2 haloalkoxy groups, halogens, a cyano group and a hydroxyl group; m is 0, 1, 2, 3 or 4; each R ² is independently selected from C1- _C2 alkyl groups, C1- _C2 alkoxy groups, C1-C2 haloalkyl groups, C1- _C2 haloalkoxy groups, halogens, a cyano group and a hydroxyl group; n is 0, 1 or 2; each R ³ represents methyl; each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and is independently substituted with one or more groups selected from halogens, C1-C2 alkyl groups, C1- _C2 haloalkyl groups, hydroxyl group, C1- _C2 alkoxy groups and C1- _C2 haloalkoxy groups; where k is 0, 1, 2, 3, 4, 5 or 6; each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo; each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C 1 -C ₂ alkyl groups, C 1 -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C 1 -C ₂ haloalkoxy groups ; and each R ^a is independently selected from hydrogen and C1- _C2 alkyl groups; And R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected 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 bivalent linker of formula (L) _r , where r is 1, 2, 3, 4, 5 or 6; each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C1-C ₂ haloalkyl groups, C1-C2 alkyl groups, hydroxyl group, C1-C ₂ alkoxy groups and C1-C ₂ haloalkoxy groups; and each R ^b is independently selected from hydrogen and C1- _C2 alkyl groups; where each 5-membered heteroaryl or heterocyclyl ring contains 1-4 heteroatoms independently selected from O, N and S; where each 6-membered heteroaryl or heterocyclyl ring contains 1-5 heteroatoms independently selected from O, N and S; and wherein each heterocyclyl ring is a non-aromatic ring. 2. A compound according to claim 1, a pharmaceutically acceptable salt or a deuterated derivative thereof - 566 044967 any of the above, in which 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 above, wherein the carbon marked * has S-stereochemistry or R-stereochemistry; ring A is 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 selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C ₁ -C ₂ haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group; m is 0, 1, 2, 3 or 4; each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C ₁ -C ₂ haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group; n is 0, 1 or 2; each R ³ represents methyl; each R ⁴ is independently selected from halogens, hydroxyl group, oxo group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and is independently substituted with one or more groups selected from halogens, C1- _C2 alkyl groups, _C1 - _C2 haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups, where k is 0, 1, 2, 3, 4, 5 or 6; each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo; each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected 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 bivalent linker of formula (L) _r , where r is 1, 2, 3, 4, 5 or 6; each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C ₁ -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups, hydroxyl group, C ₁ -C ₂ alkoxy groups and C ₁ -C ₂ haloalkoxy groups; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups. - 567 044967 3. A compound according to claim 1, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein the compound of formula I is a compound of formula W-A or W-B: a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein the carbon marked * has S-stereochemistry or R-stereochemistry; ring A is 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 selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group; m is 0, 1, 2, 3 or 4; each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group; n is 0, 1 or 2; each R ³ represents methyl; each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which optionally independently substituted with one or more groups selected from halogens, C1- _C2 alkyl groups, _C1 - _C2 haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups, where k is 0, 1, 2, 3, 4, 5 or 6; each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo; each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups and halogens; q is equal to 1 or 2; Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5; each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C ₁ -C ₂ -alkyl groups, hydroxyl group, C ₁ -C ₂ -alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups. 4. A compound according to claim 1, a pharmaceutically acceptable salt or a deuterated derivative thereof - 568 044967 any of the above, in which 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 above, wherein the carbon marked * 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 selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group; m is 0, 1, 2, 3 or 4; each R ² is independently selected from C ₁ -C ₂ -alkyl groups, C ₁ -C 2 -alkoxy groups, C 1 -C ₂ -haloalkyl groups, C ₁ -C ₂ -haloalkoxy groups, halogens, cyano group and hydroxyl group; n is 0, 1 or 2; each R ³ represents methyl; each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and is independently substituted with one or more groups selected from halogens, C1- _C2 alkyl groups, _C1 - _C2 haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups, where k is 0, 1, 2, 3, 4, 5 or 6; each Y is independently selected from the C(R5)(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo; each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens; q is equal to 1 or 2; Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5; each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C ₁ -C ₂ -alkyl groups, hydroxyl group, C ₁ -C ₂ -alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups. 5. A compound according to claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, 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 above, wherein the carbon marked * 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 selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group; m is 0, 1, 2, 3 or 4; each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group; n is 0, 1 or 2; each R ³ represents methyl; each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and is independently substituted with one or more groups selected from halogens, C1- _C2 alkyl groups, haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups, where k is 0.1 , 2, 3, 4, 5 or 6; each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y) _k - ^R7 is not bonded to another heteroatom in -(Y) ^kR7 , wherein each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo; each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C 1 -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ - haloalkoxy groups; and each R ^a is independently selected from hydrogen and C1- _C2 alkyl groups; And R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C 1 -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens; q is equal to 1 or 2; r is 3 or 4; each R ⁸ and R ⁹ is independently selected from hydrogen, halogens, C1- _C2 alkyl groups, hydroxyl group, C1- _C2 alkoxyl groups and C1- _C2 haloalkoxy groups; and each R ^b is independently selected from hydrogen and C1- _C2 alkyl groups. 6. A compound according to claim 1, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, 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 above, wherein the carbon marked * has S-stereochemistry or R-stereochemistry; each R ¹ is independently selected from C1- _C2 alkyl groups, C1- _C2 alkoxy groups, C1-C2 haloalkyl groups, _C1 - _C2 haloalkoxy groups, halogens, a cyano group and a hydroxyl group; m is 0, 1, 2, 3 or 4; each R ² is independently selected from C1- _C2 alkyl groups, C1- _C2 alkoxy groups, C1-C2 haloalkyl groups, _C1 - _C2 haloalkoxy groups, halogens, a cyano group and a hydroxyl group; n is 0, 1 or 2; each R ³ represents methyl; each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y) _k -R ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and independently substituted - 570 044967 one or more groups selected from halogens, C1-C2 alkyl groups, C1-C2 haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups, where k is equal to 0, 1, 2, 3, 4, 5 or 6; each Y is independently selected from the C(R5)(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y) _k -R ⁷ is not bonded to another heteroatom in -(Y) _k -R ⁷ where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, Ci-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo ; each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens; q is equal to 1 or 2; r is 3 or 4; each R ⁸ and R ⁹ is independently selected from hydrogen, halogens, C ₁ -C ₂ alkyl groups, hydroxyl group, C ₁ -C ₂ alkoxy groups and C ₁ -C ₂ haloalkoxy groups; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups. 7. A compound according to claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein the compound of formula I is a compound of formula VA: a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein the carbon labeled * 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 selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group; m is 0, 1, 2, 3 or 4; each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group; n is 0, 1 or 2; each R ³ represents methyl; each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and is independently substituted with one or more groups selected from halogens, C1- _C2 alkyl groups, _C1 - _C2 haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups, where k is 0, 1, 2, 3, 4, 5 or 6; each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo; each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ -cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ -alkyl groups, Ci-C ₂ - 571 044967 haloalkyl groups and halogens; q is equal to 1 or 2; Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5; each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C ₁ -C ₂ -alkyl groups, hydroxyl group, C ₁ -C ₂ -alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups. 8. A compound according to claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, 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 above, wherein the carbon marked * 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 selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C ₁ -C ₂ haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group; m is 0, 1, 2, 3 or 4; each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C ₁ -C ₂ haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group; n is 0, 1 or 2; each R ³ represents methyl; each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and is independently substituted with one or more groups selected from halogens, C1- _C2 alkyl groups, _C1 - _C2 haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups, where k is 0, 1, 2, 3, 4, 5 or 6; each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo; each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C ₁ -C ₂ alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups and halogens; q is equal to 1 or 2; r is 3, 4 or 5; and each R ⁸ and R ⁹ is independently selected from hydrogen, halogens, C ₁ -C ₂ alkyl groups, hydroxyl group, C ₁ -C ₂ alkoxy groups and C ₁ -C ₂ haloalkoxy groups. 9. A compound according to claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein the compound of formula I is a compound of formula VI-A or VI-B: - 572 044967 (VI-A) or R ³ -^/ with its pharmaceutically acceptable salt or a deuterated derivative of any of the above, where the carbon labeled * 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 selected from Cl-C ₂ alkyl groups, Cl-C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group; m is 0, 1, 2, 3 or 4; each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group; n is 0, 1 or 2; each R ³ represents methyl; each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and is independently substituted with one or more groups selected from halogens, C1- _C2 alkyl groups, _C1 - _C2 haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups, where k is 0, 1, 2, 3, 4, 5 or 6; each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3.5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form C3. ₅ cycloalkyl group or oxo; each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, Ci-C ₂ haloalkyl groups and halogens; q is equal to 1 or 2; Z is a bivalent linker of formula (L) _r , where r is 3, 4 or 5; each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C ₁ -C ₂ -alkyl groups, hydroxyl group, C ₁ -C ₂ -alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups. 10. A compound according to claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein the compound of formula I is a compound of formula VI-C or VI-D: - 573 044967 a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, where the carbon marked * 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 selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C ₂ haloalkyl groups, C 1 -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group; m is 0, 1, 2, 3 or 4; each R ² is independently selected from C1- _C2 alkyl groups, C1- _C2 alkoxy groups, C1- _C2 haloalkyl groups, _C1 - _C2 haloalkoxy groups, halogens, a cyano group and a hydroxyl group; n is 0, 1 or 2; each R ³ represents methyl; each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and is independently substituted with one or more groups selected from halogens, C1-C2 alkyl groups, C1- _C2 haloalkyl groups, hydroxyl group, _{CrC2 alkoxy} groups and _C1 - _C2 haloalkoxy groups, where k is 0, 1, 2, 3, 4, 5 or 6; each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo; each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C 1 -C ₂ alkyl groups, C 1 -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C ₂ alkoxy groups and C 1 -C ₂ - haloalkoxy groups; and each R ^a is independently selected from hydrogen and C1- _C2 alkyl groups; And R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C 1 -C ₂ alkyl groups, C 1 -C ₂ haloalkyl groups and halogens; q is equal to 1 or 2; r is 3 or 4; and each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C1- _C2 alkyl groups, hydroxyl group, C1- _C2 alkoxyl groups and C1- _C2 haloalkoxy groups. 11. A compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein ring A is a phenyl ring, a pyridyl ring or a pyrazolyl ring, wherein ring A is optionally substituted with (R1) _m . 12. A compound according to any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ¹ is independently selected from deuterium, C1C ₂ alkyl groups and a hydroxyl group, and m is 0 or 1. 13. A compound according to any one of claims 1 to 11, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein n is 0. 14. A compound according to any one of claims 1-5 and 7-10, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein ring D is a 5-membered heteroaryl ring substituted with (R4) _q . - 574 044967 15. A compound according to claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein the D ring is a phenyl ring, a pyridinyl ring, a pyrazolyl ring, an imidazolidinone ring, a pyrrolidinone ring, or a pyridinone ring, wherein the D ring is substituted (R ⁴ )q. 16. A compound according to claim 1 or 5, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is a pyrazolyl ring or a pyridinone ring, wherein ring D is substituted with (R ⁴ ) _q . 17. A compound according to any one of claims 3-5 and 7-10, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein ring D is a pyrazolyl ring, wherein ring D is substituted with (R ⁴ ) _q . 18. A compound according to any one of claims 1-5 and 7-10, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein ring D is o where indicates the point of attachment of ring D to ring B. 19. The compound of claim 18, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein ring D is wherein indicates the point of attachment of ring D to ring B. 20. A compound according to any one of claims 1 to 19, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or groups -(Y) _k -R ⁷ , where k is 0, 1, 2, 3, 4, 5 or 6; each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ and where each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group; each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C 1 -C 2 haloalkyl groups and halogens. 21. A compound according to any one of claims 1 to 19, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from an oxo group or groups -O-(Y) _k -R ⁷ where k is 0, 1, 2, 3, 4 or 5; each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ and where each R ⁵ and R ⁶ are independently selected from hydrogen, deuterium, halogens, hydroxyl group, C1C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo; each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And - 575 044967 R ⁷ is selected from hydrogen, halogens, cyano groups and C3-C1o cycloalkyl groups, optionally substituted by one or more groups selected from C ₁ -C ₂ alkyl groups, C1-C2 haloalkyl groups and halogens. 22. A compound according to any one of claims 1 to 21, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein each R ⁴ is independently selected from - 576 044967 - 577 044967 where indicates the point of attachment of R ⁴ to ring D. 23. A compound according to any one of claims 1 to 20 and 22, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein k is 3, 4, 5 or 6. 24. A compound according to any one of claims 1 to 23, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, in which q is equal to 1. 25. A compound according to any one of claims 1-4, 7, 9 and 11-24, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein Z is a divalent linker of formula (L) _r , where r is 3, 4 or 5; each L is independently selected from C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, wherein the heteroatom at Z is not bonded to another heteroatom at Z and wherein R ⁸ and R ⁹ are each independently selected from hydrogen and deuterium; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups. 26. A compound according to any one of claims 1-4, 7, 9 and 11-24, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein Z is a divalent linker of the formula (L)r, where r is 3, 4 or 5; each L is independently selected from C(R ⁸ )(R ⁹ ) groups and -NR ^b groups, where the heteroatom at Z is not bonded to another heteroatom at Z, and: R ⁸ and R ⁹ are each independently selected from hydrogen and deuterium; and each R ^b is independently selected from hydrogen and methyl. 27. A compound according to any one of claims 1-4, 7, 9 and 11-24, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein Z is a divalent linker of the formula (L)r, where r is 3, 4 or 5; each L is independently selected from C(R ⁸ )(R ⁹ ) groups and -NR ^b groups, wherein the heteroatom in Z is not bonded to another heteroatom in Z and wherein each R ⁸ and R ⁹ are independently selected from hydrogen and deuterium; and each R ^b is hydrogen. 28. A compound according to any one of claims 1-4, 7, 9 and 11-24, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein Z is a divalent linker of formula (L) _r , where r is 3, 4 or 5; each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, wherein the heteroatom at Z is not bonded to another heteroatom at Z, wherein each R ⁸ and R ⁹ is hydrogen; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups. 29. A compound according to any one of claims 1 to 28, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above, wherein each R ³ independently represents CD3. 30. A compound according to claim 5 or 6, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein r is 3 or 4; R ⁸ and R ⁹ are each independently selected from hydrogen and deuterium; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups. 31. A compound according to claim 5 or 6, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein r is 3 or 4; R ⁸ and R ⁹ are each independently selected from hydrogen and deuterium; and each R ^b is hydrogen. 32. The compound according to claim 6, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein r is 3 or 4; and each R ⁸ and R ⁹ is independently selected from hydrogen and deuterium. 33. The compound according to claim 6, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein r is 3 or 4; and R ⁸ and R ⁹ are each hydrogen. 34. Connection selected from: - 578 044967 - 579 044967 - 580 044967 - 581 044967 - 582 044967 - 583 044967 - 584 044967 - 585 044967 - 586 044967 o TP ii^ ^N ' ^s YX Ν' A Τ xAk _o -ru ^N WHAT^DA? fp-^ ⁷ ~n 2 Connection 95 9 ο ο ίι μ Αι'Α Ν' А А А \Ач °~Aj ^N 1 ' ^=зС ~^~ ^У Т'/ 2 Connection 96 ° °w° « Г]й X ~y—' [ νη 2 Compound 97 O O O \ ^{h x} / « fi and X _x χΧΧγγγ /—L ^nh 2 Compound 98 9 o o Ar ^N ' ^S X Ν' L A l BH o—ru ^{Ν F} 3 ^C ~^ ^V ~K 2 Compound 99 9 ^.P ίι m Αι^Ί Ν' A A d AJA Ο—ρΝ ^Ν ΝρΧΡ/ Ο ^ν3Ζ ~0^ Τ'/ 2 Connection 100 θ 4,° « f ι n X Д^ l ^NH 2 Connection 101 /9 ο ο D A Α. χ ~Λ - ^ΝΗ 2 Compound 102 o o.p fl N Al Ί Ν' Λ Λ Λ ί Λ ° ~\υ ^Ν Ch D^AA? ~D 2 Connection 103 9 ΡΡ if ν Αι Ν' Λ A l 1A °p_J ^ν Ch^XxAd FsC-^ ⁷ ~K 2 Connection 104 Ρ ο ρ X Ν /D/ xDH AD/ ~Ά ^Ν Ν Ν\ ^Ν \ V '— __[/—\ ΝΗ 2 Compound 105 9 o r g, ν ΆΑ Al mDr ⁿ =( v '— ХХ^Ху ¹⁴¹⁴ 2 Connection 106 - 587 044967 - 588 044967 Connection 120 Connection 119 Connection 121 Connection 122 Connection 123 Connection 124 Connection 125 Connection 126 Connection 127 Connection 128 Connection 129 OOO Connection 130 - 589 044967 ά 5 Connection 131 F ₃ CZ ".u >ω / °' ⁴ γ 2 l Connection 133 Ooo ν qJ'AA U / 'ί — / Ν \>Λ~| ) F ₃ CZ 5 Connection 135 Ο Ο^/Ρ .. U Js. fy ^N \ ι) ^Ν ' _Μ Α|Λ ” ^Ν< Υ Ο—/ ^Ν Ν—pl / —/ XU —J) to ^NH Connection 137 Η /=\ 4V^ ^N ' ^S V/ 1 Η n ν—\ F ₃ cV Connection 139 Oooh ?s Ji Ύ Η 4 __/0--^j ^{N Ν} 5 Connection 141 0 q _w p UA'VX II Ί and || Ί 0—<2' nn F ₃ CZ Connection 132 Jv n JU a Y o-UU x / 'C -1 \vW| ) F ₃ CZ Connection 134 ? 0^./,0 .. U if Uf ^N \ /1 ν,Λ A 0—/ ^N n—C7 —/ XU ~tA/ to ^NH Connection 136 H °*° /=\ LT^' ⁸ V/ 1 II Η Ν \ F ₃ C~Z Connection 138 ο, ,ο ΗΝ || U+U+o %-^Ύ Ο _yz ^N ' Ν 4 F ₃ CZ Connection 140 o o _{c /} r A fl ΊΓ ^Ν η Ί 1 1 η 1 ^{ν Ν} F3C-Z Connection 142 - 590 044967 - 591 044967 Connection 155 Connection 156 o Connection 157 Connection 158 Connection 159 F ₃ C Connection 160 Connection 161 Connection 162 Connection 163 Connection 164 Connection 165 Connection 166 - 592 044967 - 593 044967 - 594 044967 - 595 044967 - 596 044967 - 597 044967 - 598 044967 - 599 044967 - 600 044967 - 601 044967 - 602 044967 - 603 044967 Connection 299 , Connection 300 Connection 301 Connection 302 Connection 303 Connection 304 Connection 306 Compound 308 is a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of these compounds, or a pharmaceutically acceptable salt of any of the deuterated derivatives of these compounds. 35. A compound according to any one of claims 1 to 34, wherein the compound is in the form of a pharmaceutically acceptable salt. 36. A pharmaceutical composition containing at least one compound selected from the compounds according to any one of claims 1 to 35, a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, and a pharmaceutically acceptable carrier. 37. The pharmaceutical composition according to claim 36, where the composition further contains one or more of: (a) compounds II: - 604 044967 a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above; and (b) compound III or compound III-d: a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above. 38. Compound formula: a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above. 39. Compound formula: its pharmaceutically acceptable salt. 40. The compound of claim 38 or 39, wherein the compound is in the form of a pharmaceutically acceptable salt. 41. A compound according to claim 40, wherein the pharmaceutically acceptable salt is a calcium salt. 42. A compound according to claim 40, wherein the pharmaceutically acceptable salt is a sodium salt. 43. A compound according to claim 40, wherein the pharmaceutically acceptable salt is a potassium salt. 44. A pharmaceutical composition comprising a compound, a pharmaceutically acceptable salt or a deuterated derivative according to any one of claims 38 to 43 and a pharmaceutically acceptable carrier. 45. The pharmaceutical composition according to claim 44, where the composition further contains one or more of: (a) compounds II: a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above; and (b) compound III or compound III-d: a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above. 46. A pharmaceutical composition comprising a pharmaceutically acceptable salt according to any one of claims 38-43 and a pharmaceutically acceptable carrier. 47. The pharmaceutical composition according to claim 46, where the composition further contains one or more of: (a) compounds II: - 605 044967 a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above; and (b) compound III or compound III-d: a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above. 48. Use of a compound, pharmaceutically acceptable salt or deuterated derivative according to any one of claims 1-35 and 38-43 or a pharmaceutical composition according to any one of claims 36, 37 and 44-47 for the treatment of cystic fibrosis. 49. Use according to claim 48, wherein the compound, pharmaceutically acceptable salt, deuterated derivative or pharmaceutical composition is administered in combination with compound III or compound III-d. 50. Use according to claim 48, wherein the compound, pharmaceutically acceptable salt, deuterated derivative or pharmaceutical composition is administered in combination with (a) compound II and (b) compound III or compound III-d. 51. Method for preparing a compound of formula (I): a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, comprising a combination of the NH group of the C ring and the Q ^b group of the B ring of a compound of formula (YI): a salt thereof or a deuterated derivative of any of the above, where Q ^b represents halogen; ring A is 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 represents O, NH or N(C ₁ -C ₄ -alkyl); each R ¹ is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group; m is 0, 1, 2, 3 or 4; each R ² is independently selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ alkoxy groups, C 1 -C 2 haloalkyl groups, C ₁ -C ₂ haloalkoxy groups, halogens, a cyano group and a hydroxyl group; n is 0, 1 or 2; - 606 044967 each R ³ represents methyl; each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and independently substituted with one or more groups selected from halogens, C1- _C2 alkyl groups, _C1 - _C2 haloalkyl groups, hydroxyl group, _C1 - _C2 alkoxy groups and _C1 - _C2 haloalkoxy groups; where k is 0, 1, 2, 3, 4, 5 or 6; each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y)kR ⁷ is not bonded to another heteroatom in -(Y)kR ⁷ , where each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3-5 cycloalkyl group or oxo; each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C ₁ -C ₂ alkyl groups, C ₁ -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ -haloalkoxy groups; and each R ^a is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; And R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected 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 bivalent linker of formula (L) _r , where r is 1, 2, 3, 4, 5 or 6; each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C ₁ -C ₂ haloalkyl groups, C1 -C2 alkyl groups, hydroxyl group, C ₁ -C ₂ alkoxy groups and C ₁ -C ₂ haloalkoxy groups; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; to form a compound of formula (I), a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the above; where each 5-membered heteroaryl or heterocyclyl ring contains 1-4 heteroatoms independently selected from O, N and S; where each 6-membered heteroaryl or heterocyclyl ring contains 1-5 heteroatoms independently selected from O, N and S; and wherein each heterocyclyl ring is a non-aromatic ring. 52. Method for preparing a compound of formula (I) a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the above, wherein ring D is (R ⁴ )?^ involving the interaction of a compound of formula (X), a salt thereof, or a deuterated derivative of any of the above with a compound of formula (Z-1), a salt thereof, or a deuterated derivative of any of the above: where Q ^a represents halogen; - 607 044967 ring A is 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 represents O, NH or N(C ₁ -C ₄ -alkyl); each R ¹ is independently selected from C1-C2 alkyl groups, C1- _C2 alkoxy groups, Ci- _C2 haloalkyl groups, C1- _C2 haloalkoxy groups, halogens, a cyano group and a hydroxyl group; m is 0, 1, 2, 3 or 4; each R ² is independently selected from C1- _C2 alkyl groups, C1- _C2 alkoxy groups, C1-C2 haloalkyl groups, C1- _C2 haloalkoxy groups, halogens, a cyano group and a hydroxyl group; n is 0, 1 or 2; each R ³ represents methyl; each R ⁴ is independently selected from halogens, oxo group, hydroxyl group, cyano group and -(Y)kR ⁷ groups, or optionally two R ⁴ together with the atoms to which they are attached form a 5-6 membered cycloalkyl or heterocyclyl ring, which is optional and is independently substituted with one or more groups selected from halogens, C1-C2 alkyl groups, C1- _C2 haloalkyl groups, hydroxyl group, C1- _C2 alkoxy groups and C1- _C2 haloalkoxy groups; where k is 0, 1, 2, 3, 4, 5 or 6; each Y is independently selected from the C(R ⁵ )(R ⁶ ) groups, -O- and -NR ^a groups, where the heteroatom in -(Y) _k - ^R7 is not bonded to another heteroatom in -(Y) ^kR7 , wherein each R ⁵ and R ⁶ are independently selected from hydrogen, halogens, hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R ⁵ and R ⁶ on the same carbon atom together form a C3_ ₅ cycloalkyl group or oxo; each of R ⁵ and R ⁶ is optionally independently substituted with one or more groups selected from C 1 -C ₂ alkyl groups, C 1 -C ₂ haloalkyl groups, halogens, hydroxyl group, C 1 -C 2 alkoxy groups and C ₁ -C ₂ haloalkoxy groups groups; and each R ^a is independently selected from hydrogen and C1- _C2 alkyl groups; And R ⁷ is selected from hydrogen, halogens, cyano groups and C ₃ -C ₁₀ cycloalkyl groups, optionally substituted by one or more groups selected 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 bivalent linker of formula (L) _r , where r is 1, 2, 3, 4, 5 or 6; each L is independently selected from the C(R ⁸ )(R ⁹ ) groups, -O- and -NR ^b groups, where the heteroatom in Z is not bonded to another heteroatom in Z, wherein each R ⁸ and R ⁹ are independently selected from hydrogen, halogens, C1-C ₂ haloalkyl groups, C1-C2 alkyl groups, hydroxyl group, C1-C ₂ alkoxy groups and C1-C ₂ haloalkoxy groups; and each R ^b is independently selected from hydrogen and C ₁ -C ₂ alkyl groups; where each 5-membered heteroaryl or heterocyclyl ring contains 1-4 heteroatoms independently selected from O, N and S; where each 6-membered heteroaryl or heterocyclyl ring contains 1-5 heteroatoms independently selected from O, N and S; and wherein each heterocyclyl ring is a non-aromatic ring.