EA040454B1 - MODULATOR OF CYSIC FIBROUS TRANSMEMBRANE CONDUCTIVITY REGULATOR, PHARMACEUTICAL COMPOSITIONS, METHODS OF TREATMENT AND METHODS OF OBTAINING THE MODULATOR - Google Patents

Description

This document discloses a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, pharmaceutical compositions containing the modulator, methods for treating cystic fibrosis, and a method for producing the modulator.

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

In CF patients, mutations in CFTR endogenously expressed in the respiratory epithelium lead to a decrease in apical anion secretion, causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to lung mucus accumulation and associated microbial infections that ultimately cause death in CF patients. In addition to respiratory problems, CF patients commonly suffer from gastrointestinal problems and pancreatic insufficiency, which, if left untreated, lead to death. In addition, most men with cystic fibrosis are infertile, and women with cystic fibrosis are less fertile.

Sequence analysis of the CFTR gene has revealed various 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 2,000 mutations in the CF gene have been identified; the CFTR2 database currently contains information on only 322 of these identified mutations, and there is enough data to identify 281 mutations as causing the disease. The most common disease-causing mutation is the deletion of phenylalanine at position 508 of the CFTR amino acid sequence and is commonly referred to as the F508del mutation. This mutation occurs in approximately 70% of CF cases and is associated with severe disease.

Removal of residue 508 in CFTR prevents the nascent protein from folding properly. This results in the inability of the mutant protein to leave the endoplasmic reticulum (ER) and move to the plasma membrane. As a result, the number of anion transport CFTR channels present in the membrane is much smaller than that observed in cells expressing wild-type CFTR, ie, CFTR that does not have mutations. In addition to impaired transport, the mutation results in defective ion channel gate mechanisms. Together, the reduced number of channels in the membrane and defective ion channel gate mechanisms result in decreased anion and fluid transport across the epithelium. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). Channels that are defective 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 ion channel transport, synthesis and/or gate mechanism can be decreased or increased to alter anion secretion and alter disease progression and/or severity.

CFTR is a cAMP/ATP-mediated anion channel that is expressed in various cell types, including absorptive and secretory epithelial cells, where it regulates the flow of anions across the membrane, as well as the activity of other ion channels and proteins. In epithelial cells, normal CFTR function is critical to maintaining electrolyte transport throughout the body, including respiratory and intestinal tissue. CFTR is composed of approximately 1480 amino acids that code for a protein that consists of tandem repeats of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by a large polar regulatory (R) domain with multiple phosphorylation sites that regulate channel activity and cellular transport.

Chloride transport is carried out by the coordinated activity of ENaC (epithelial sodium channel) and CFTR present on the apical membrane and Na ⁺ -K ⁺ -ATPase pump and Cl ^- channels expressed on the basolateral surface of the cell. The secondary active transport of chlorine from the inside leads to the accumulation of intracellular chlorine, which can then passively leave the cell through ^Cl channels, which leads to vector transport. The location of Na ⁺ /2Cl7K ⁺ cotransporter, Na ⁺ -K ⁺ -ATPase and K ⁺ channels of the basolateral membrane on the basolateral surface and CFTR on the inner side coordinate the secretion of chlorine through CFTR on the inner side. Because water probably never actively transports itself, its flow through the epithelium depends on small transepithelial osmotic gradients generated by the bulk flow of sodium and chloride.

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

This document describes new compounds, including compounds of formulas I-IV, their pharmaceutically acceptable salts or their deuterated derivative. For example, compounds of formula I can be represented as follows:

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or their pharmaceutically acceptable salts, or their deuterated derivative, where:

one of Y ¹ and Y ² is N and the other is CH;

X is selected from O, NH and N(C1-C ₄ alkyl) group;

R ¹ is -(CR ₂ ) _k -O-(CR ₂ ) _m (CR) _n (Ring A) _n+1 , where each Ring A is a C3-C ₁₀ cycloalkyl group optionally substituted with one or more substituents, each independently selected from C ₁ -C ₂ alkyl group, halogenated C 1 -C 2 alkyl group and halogen, and where each R is independently selected from H, OH and C ₁ -C ₂ alkyl group, optionally substituted with one or more halogen atoms;

each R ² is independently selected from C 1 -C 2 alkyl, OH, C ₁ -C ₂ alkoxy, halo, and cyano;

each R ³ is independently selected from a C ₁ -C ₂ alkyl group optionally substituted with one or more OH groups;

each R ⁴ is independently selected from a halogen atom;

k is 0 or 1;

r is 0 or 1;

m is 0, 1, 2 or 3;

n is 0 or 1;

p is 0, 1, 2, 3, 4 or 5; and q is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

This document also describes pharmaceutical compositions containing at least one of the novel compounds described herein and/or at least one pharmaceutically acceptable salt thereof, and said compositions may additionally contain at least one additional active pharmaceutical ingredient and/ or at least one carrier. Methods for the treatment of CFTR-mediated cystic fibrosis disease are also described, including the administration of at least one of the novel 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. , the subject in need of it.

Methods for treating CFTR-mediated cystic fibrosis disease are also described, 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(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol- 5-yl)cyclopropanecarboxamide (compound II) and N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3carboxamide (compound III), optionally in the composition at least one pharmaceutical composition containing at least one additional component, to a patient in need thereof.

Brief description of graphic materials

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

In FIG. 2 is an X-ray powder diffraction (XRD) plot of a spray dried dispersion (SDD) of 50% Compound 1 in HPMCAS-HG.

In FIG. 3 is a spectrum showing a modulated differential scanning calorimetry (MDSC) spectrum of a spray dried dispersion (SDD) of 50% Compound 1 in HPMCAS-HG.

In FIG. 4 is an illustrative list of CFTR genetic mutations.

In FIG. 5 is a diagram of the XRD of the sodium salt of Compound 1 prepared as described in the Preparation Example of the Sodium Salt of Compound 1.

Definitions

In this context, the term alkyl refers to a saturated, branched or straight chain aliphatic hydrocarbon containing carbon atoms (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,

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11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms). Alkyl groups may be substituted or unsubstituted.

The term alkoxy in this context refers to an alkyl or cycloalkyl covalently bonded to an oxygen atom. Alkoxy groups may be substituted or unsubstituted.

As used herein, cycloalkyl refers to cyclic, bicyclic, tricyclic, or polycyclic non-aromatic hydrocarbon groups containing 3 to 12 carbon atoms (eg, 3 to 10 carbon atoms).

Cycloalkyl groups include monocyclic, bicyclic, tricyclic, bridged, fused and spiro rings, including monospiro and dispiro rings. Non-limiting examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, and dispiro[2.0.2.1]heptane. Cycloalkyl groups may be substituted or unsubstituted.

Substituted, with or without the preceding term, means that at least one hydrogen atom in the substituted group has been replaced by a substituent. Unless otherwise indicated, an optionally substituted group may contain a suitable substituent at each substitutable position of that group, and if more than one position can be substituted in any given structure by more than one substituent selected from a particular group, then that substituent may be the same or different. in every position.

In this context, a deuterated derivative(s) means the same chemical structure in which one or more hydrogen atoms are replaced by a deuterium atom.

In this context, CFTR stands for transmembrane conductance regulator in cystic fibrosis.

In this context, mutations may refer to mutations in the CFTR gene or in the CFTR protein. A CFTR gene mutation refers to a mutation in the CFTR gene, and a CFTR protein mutation refers to a mutation in the CFTR protein. A genetic defect or mutation or nucleotide change in a gene typically results in a mutation in the CFTR protein translated from said gene or frameshift(s).

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

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

In this context, a patient who is heterozygous for a particular genetic mutation has said mutation in one allele and another mutation in the other allele.

In this context, the term modulator refers to a compound that increases the activity of a biological compound, such as a protein. For example, a CFTR modulator is a compound that increases CFTR activity. The increase in activity under the action of a CFTR modulator includes, but is not limited to, compounds that correct, enhance, stabilize and/or amplify CFTR.

As used herein, a CFTR corrector refers to a compound that promotes the processing and targeted migration of CFTR to increase the amount of CFTR on the cell surface. The compounds of formulas (I), (II), (III), (IV) and (V) and compound II, as well as their pharmaceutically acceptable salts described herein, are CFTR correctors.

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

In this context, the term active pharmaceutical ingredient (API) refers to a biologically active compound.

As used herein, the term pharmaceutically acceptable salt refers to the salt form of a compound as described herein, said salt being 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, the authors of S. M. Berge et al. Pharmaceutically acceptable salts are described in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19.

In this context, the term amorphous refers to a solid material that does not have a long range order of its molecules. Amorphous solids are usually supercooled liquids in which the molecules are arranged randomly so that there is no pronounced order, such as molecular packing, and no long-range order. Amorphous solids are usually isotropic, i.e. have the same properties in all directions and do not have a defined melting point. For example, an amorphous material is a solid material that does not have a sharp characteristic crystalline peak(s) in the X-ray powder diffraction (XRD) pattern (ie, is not crystalline, as measured by XRD). On the contrary, one or more broad peaks (for example, a halo) are present in its XRD diagram. Broad peaks are characteristic of an amorphous solid. See, for example, US 2004/0006237 for a comparison of the XRD of an amorphous material and a crystalline material.

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As used herein, the term substantially amorphous refers to a solid material having little or no long-range order of its molecules. For example, substantially amorphous materials have less than 15% crystallinity (eg, less than 10% crystallinity or less than 5% crystallinity). It should also be noted that the term substantially amorphous includes the keyword amorphous which refers to materials having no crystallinity (0%).

In this context, the term dispersion refers to a dispersed system in which one substance, the dispersed phase, is distributed as discrete particles in a second substance (continuous phase or carrier). The size of the dispersed phase can vary significantly (eg, from colloidal particles of nanometer size to many microns). In general, the dispersed phases may be solid, liquid or gaseous. In the case of a solid dispersion, both the dispersed and the continuous phase are solid. In pharmaceutical applications, a solid dispersion may include a crystalline drug substance (dispersed phase) in an amorphous polymer (continuous phase); or alternatively an amorphous drug substance (dispersed phase) in an amorphous polymer (continuous phase). In some embodiments, the solid dispersion includes a polymer forming a discontinuous phase and a drug substance forming a continuous phase. Or, the solid dispersion includes a drug substance forming a dispersed phase and a polymer forming a continuous phase.

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

The terms effective dose and effective amount are used interchangeably herein and refer to that amount of a compound that produces the desired effect for which it is administered (eg, improvement in CF or CF symptom, or amelioration of the severity of CF or CF symptom). The exact size of the effective dose depends on the goal of treatment and can be determined by a person skilled in the art using known technologies (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

In this context, the terms treat, treatment, etc. generally means an improvement in CF or its symptoms, or an amelioration of the severity of CF or its symptoms in a subject. Treatment in this context includes, but is not limited to, the following: increased growth of the subject, increased weight gain, decreased mucus in the lungs, improved pancreatic and/or liver function, decreased chest infections, and/or decreased cough or shortness of breath. Relief or amelioration of the severity of any of these symptoms can be easily determined in accordance with standard methods and techniques known in the art.

In this context, the term in combination, used in relation to two or more compounds, agents or additional active pharmaceutical ingredients, means the introduction to the patient of two or more compounds, agents or active pharmaceutical ingredients before, simultaneously or after each other.

The terms about and about as used in relation to doses, amounts, or weight percent of the ingredients of a composition or dosage form include the meaning of a particular dose, amount, or weight percent, or the range of dose, amount, or weight percent that, from the point of view of a person skilled in the art, provides a pharmacological effect equivalent to the effect obtained when using this specific dose, amount or mass percent.

Each of the compounds of formulas (I), (II), (III), (IV) and (V) and compounds II, III, IV and their pharmaceutically acceptable salts, as well as their deuterated derivatives described herein, can be independently administered once a day, twice a day or three times a day. In some embodiments, at least one compound selected from compounds of formulas (I), (II), (III), (IV) and (V), and their pharmaceutically acceptable salts, as well as their deuterated derivatives, is administered once per day. In some embodiments, at least one compound selected from compounds of formulas (I), (II), (III), (IV) and (V), and their pharmaceutically acceptable salts, as well as their deuterated derivatives, is administered twice in day. In some embodiments, at least one compound selected from compound II and pharmaceutically acceptable salts thereof is administered once a day. In some embodiments, at least one compound selected from compound II and pharmaceutically acceptable salts thereof is administered twice a day. In some embodiments, 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 pharmaceutically acceptable salts thereof is administered once a day. In some embodiments, at least one compound selected from compound IV and pharmaceutically acceptable salts thereof is administered twice daily. In some embodiments, a deuterated derivative of compound II, III, and/or IV, or a pharmaceutically acceptable salt thereof, is used in any of these embodiments.

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

Those skilled in the art will understand that when an amount of a compound or a pharmaceutically acceptable salt thereof is described, the amount of the pharmaceutically acceptable salt form of the compound is an amount equivalent to the concentration of the free base of that compound. It should be noted that the described amounts of compounds or their pharmaceutically acceptable salts in this context are expressed relative to their free base form. For example, 10 mg of at least one compound selected from compounds of formula (I) and their pharmaceutically acceptable salts comprises 10 mg of a compound of formula (I) and a pharmaceutically acceptable salt concentration of compounds of formula (I) equivalent to 10 mg of compounds of formula (I).

As stated above, this document describes compounds of formula (I):

their pharmaceutically acceptable salts, or their deuterated derivative, where one of Y ¹ and Y ² represents N and the other represents CH;

X is selected from O, NH and N(C ₁ -C4 alkyl) group;

R1 is -(CR ₂ ) _k -O- (CR ₂ )m (CR) _n (Ring A) _n+1 , where each Ring A is a C3-C ₁₀ cycloalkyl group optionally substituted with one or more substituents, each wherein each R is independently selected from a C ₁ -C ₂ alkyl group, a halogenated C 1 -C 2 alkyl group, and halogen, and wherein each R is independently selected from H, OH, and a C 1 -C 2 alkyl group optionally substituted with one or more halogen atoms;

each R ² is independently selected from C1-C2 alkyl, OH, C1-C2 alkoxy, halo, and cyano;

each R3 is independently selected from a C1-C2 alkyl group optionally substituted with one or more OH groups;

each R ⁴ is independently selected from a halogen atom;

k is 0 or 1;

r is 0 or 1;

m is 0, 1, 2 or 3;

n is 0 or 1;

p is 0, 1, 2, 3, 4 or 5; and q is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

This document also describes compounds of formula (II):

their pharmaceutically acceptable salts, or their deuterated derivative, where

X is selected from O, NH and N(C1-C4 alkyl) groups;

R ¹ is -(CR ₂ ) _k -O-(CR ₂ ) _m (CR) _n (Ring A) _n+1 where each Ring A is a C ₃ -C ₁₀ cycloalkyl group, optionally substituted

- 5 040454 with one or more substituents each independently selected from a C1-C2 alkyl group, a halogenated C1-C2 alkyl group and halogen, and where each R is independently selected from H, OH and a C1-C2 alkyl group optionally substituted with one or more halogen atoms;

each R2 is independently selected from C1-C2 alkyl, OH, C1-C2 alkoxy, halo, and cyano;

each R ³ is independently selected from a C1-C2 alkyl group optionally substituted with one or more OH groups;

each R ⁴ is independently selected from a halogen atom;

k is 0 or 1;

r is 0 or 1;

m is 0, 1, 2 or 3;

n is 0 or 1;

p is 0, 1, 2, 3, 4 or 5; and q is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

The scope of formulas (I) and (II) includes compounds containing the group

(where R' is H or C _r C ₄ alkyl), i.e. in which X is selected from NH and N(C1-C ₄ alkyl) groups. Non-limiting examples of such compounds include compounds having the following structure:

and their pharmaceutically acceptable salts, either as an isomeric mixture or enantiomerically enriched isomers (eg, >90% ee, >95% ee, or >98% ee).

This document also describes compounds of formula (III)

and their pharmaceutically acceptable salts or their deuterated derivative, where

R ¹ is selected from the groups - (CR ₂ ) _k -O-(CR ₂ ) _m (CR) _n (Ring A) _n+1 where each Ring A is independently selected from a C ₃ -C ₁₀ cycloalkyl group optionally substituted with one or more substituents each independently selected from a C1-C2 alkyl group, a halogenated C1-C2 alkyl group, and halogen atoms, and wherein each R is independently selected from H, OH, and a C1-C2 alkyl group optionally substituted with one or more halogen atoms;

each R ² is independently selected from C1-C2 alkyl, OH, C1-C2 alkoxy, halo, and cyano;

each R ³ is independently selected from a C1-C2 alkyl group optionally substituted with one or more OH groups;

each R ⁴ is independently selected from halogen atoms;

k is 0 or 1;

r is 0 or 1;

m is 0, 1, 2 or 3;

- 6 040454 n is 0 or 1;

p is 0, 1.2, 3, 4 or 5; and q is 0, 1.2, 3, 4, 5, 6, 7, or 8.

In some embodiments, in compounds of formula (I), (II), (III) and their pharmaceutically acceptable salts, if R ² is cyano, then R ² is meta or para relative to the sulfur atom.

In some embodiments, in compounds of formula (I), (II), (III) and their pharmaceutically acceptable salts or their deuterated derivatives, each Ring A is a C ₃ -C ₁₀ cycloalkyl group optionally substituted with one or more substituents, each of which independently selected from a C1-C2 alkyl group, a halogenated C1-C2 alkyl group, and halogen atoms, and each R is independently selected from H and OH;

each R ² is independently selected from a C1-C2 alkyl group, OH, a C1-C2 alkoxy group, and halo;

R ⁴ is F;

k is 0;

p is 0, 1 or 2;

q is 0, 1.2, 3 or 4;

r is 0 or 1; and moreover m. and n are not equal to 0 at the same time.

In some embodiments, in the compounds of formula (I), (II), (III) and their pharmaceutically acceptable salts or their deuterated derivatives

R ¹ is -O-(CR ₂ ) _m -Ring A, where Ring A is a C ₃ -C ₁₀ cycloalkyl group optionally substituted with one or more substituents each independently selected from a C1-C2 alkyl group halogenated with C1 -C2 alkyl group and halogen atoms, and m is 1 or 2.

In some embodiments, in compounds of formula (I), (II), (III) and their pharmaceutically acceptable salts and their deuterated derivatives, each R ³ is a methyl group and q is 3 or 4.

This document also describes compounds of formula (IV)

their pharmaceutically acceptable salts and their deuterated derivatives, where

Ring A is a C3-C10 cycloalkyl group optionally substituted with one or more substituents each independently selected from a C1-C2 alkyl group, a halogenated C1-C2 alkyl group, and halogen atoms; and each R ² is independently selected from C1-C2 alkyl, OH, F, Cl, and C1-C2 alkoxy;

m is 1 or 2; and p is 0, 1, or 2.

In some implementations, p is 0 or 1. In some implementations, p is 0.

This document also describes compounds of formula V

their pharmaceutically acceptable salts and their deuterated derivatives, where

Ring A is a C3-C10 cycloalkyl group optionally substituted with one or more substituents each independently selected from a C1-C2 alkyl group, halo

- 7 040454 of a fixed C1-C2 alkyl group and halogen atoms; and each R2 is independently selected from C1-C2 alkyl, OH, F, Cl, and C1-C2 alkoxy;

m is 1 or 2; and p is 0, 1, or 2.

In some embodiments, in compounds of formula (I), (II), (III), (IV), (V), their pharmaceutically acceptable salts, and their deuterated derivatives, each R ² is independently selected from CH ₃ , OH, F, and OCH ₃ . In some implementations, p is 0 or 1. In some implementations, p is 0.

In some embodiments, in compounds of formula (I), (II), (III), (IV), (V), their pharmaceutically acceptable salts, and their deuterated derivatives, Ring A is a cyclopropyl group substituted with a halogenated C1 alkyl group or a halogenated C ₂ alkyl group. In some embodiments, Ring A is a cyclopropyl group substituted with a CF ₃ group.

In some embodiments, in compounds of formula (I), (II), (III), (IV), (V), their pharmaceutically acceptable salts, and their deuterated derivatives, m is 1, Ring A is a cyclopropyl group substituted with a CF ₃ group , p is 0 or 1, and R ² , if present, is a methyl group, a hydroxy group, or a methoxy group. In some embodiments, m is 2, Ring A is a cyclopropyl group substituted with a CF3 group, and p is 0.

In some embodiments, in compounds of formula (I), (II), (III), (IV), (V), their pharmaceutically acceptable salts, and their deuterated derivatives, m is 2, Ring A is a C3 cycloalkyl group substituted with a CF3 group , p is 0 or 1, and R ² , if present, is a methyl group, a hydroxy group, or a methoxy group. In some embodiments, m is 2, Ring A is a cyclopropyl group substituted with a CF3 group, and p is 0.

In some embodiments, m is 2, Ring A is a cyclopropyl group substituted with a CF ₃ group, and p is 0.

In some embodiments, in compounds of formula (I), (II), (III), (IV), (V), their pharmaceutically acceptable salts, and their deuterated derivatives, Ring A is selected from a C ₅ bicycloalkyl group optionally substituted with one or more substituents , each independently selected from a C1-C2 alkyl group, a halogenated C1-C2 alkyl group, and halogen atoms.

In some embodiments, in compounds of formula (I), (II), (III), (IV), (V), their pharmaceutically acceptable salts, and their deuterated derivatives, Ring A is selected from a C ₇ bicycloalkyl group and a C ₇ tricycloalkyl group, each of which is optionally substituted with one or more substituents each independently selected from a C1-C2 alkyl group, a halogenated _C1 - _C2 alkyl group, and halogen atoms.

In some embodiments, Ring A is an unsubstituted C ₇ tricycloalkyl group.

This document also describes compounds having a formula selected from any of the formulas selected from

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IV Ii ^N Χπ 11 ^H LJ /^N'^N^N'X ψΝ ) 0 and \ V7 1 ¥ f-¥? ί¥Γι ¥Ί ^F '—\ ν ΑΛΑ LJ ί_ 5

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a pharmaceutically acceptable salt thereof or a deuterated derivative thereof.

This document also describes a compound having the following formula:

and its pharmaceutically acceptable salts.

This document also describes a compound having the following formula:

and its pharmaceutically acceptable salts.

This document also describes a compound having the following formula:

and its pharmaceutically acceptable salts.

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

a pharmaceutically acceptable salt thereof or a deuterated derivative thereof;

chemical name of compound II: (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-5-yl)cyclopropanecarboxamide; and compounds III

a pharmaceutically acceptable salt thereof or a deuterated derivative thereof;

chemical name of compound III: N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3

- 15 040454 carboxamide.

Suitable pharmaceutically acceptable salts are, for example, those described in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, 1-19. For example, in table. 1 of this article presents the following pharmaceutically acceptable salts.

Table 1

Acetate Iodide benzathine Benzenesulfonate Isethionate Chlorprocaine Benzoate lactate Choline Bicarbonate Lactobionate Diethanolamine bitartrate Malat Ethylenediamine Bromide Maleate Meglumine Edetate calcium Mandelat Procaine Kamzilat Mesylate Aluminum Carbonate Methyl bromide Calcium Chloride Methyl nitrate Lithium Citrate Methyl sulfate Magnesium dihydrochloride Mukat Potassium Edetat Napzilat Sodium Edisilat Nitrate Zinc Estolat Pamoat (embonat) Ezilat Pantothenate Fumarate Phosphate/diphosphate Gluceptate Polygalacturonate Gluconate salicylate Glutamate Stearate Glycollylarasanilate Subacetate Hexylresorcinate Succinate Hydrabamine Sulfate Hydrobromide Tannat Hydrochloride Tartrate Hydroxysinaphthoate Theoclatus triethiodide

Non-limiting examples of pharmaceutically acceptable salts derived from suitable acids include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid; salts derived from organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid; and salts obtained using other methods used in the art, such as ion exchange. Uncipital examples of pharmaceutically acceptable salts include adipat, alginate, ascorbate, aspartate, benzulosphone, benzoate, bisulfate, borage, butyrate, campformal, citrate, cyclopentant -pro, excessive, dodeculfate, thickeeping, format, famaratic, glucoPotonic, glucoPotonal, glucogeprofinic, gluco -glyardos. heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, pectinate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, ptoluenesulfonate, undecanoate and valerate salts. Pharmaceutically acceptable salts obtained

- 16 040454 some of the suitable bases include salts of alkali metals, alkaline earth metals, ammonium and K ⁺ (C ₁ . ₄ alkyl) ₄ . This description also provides for the quaternization of any basic nitrogen-containing groups of the compounds described in this document. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium and magnesium salts. Additional non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cation salts prepared using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

In some embodiments, at least one compound selected from the novel compounds described herein, their pharmaceutically acceptable salts, and their deuterated derivatives, is administered in combination with at least one compound selected from compound II, its pharmaceutically acceptable salts, and their deuterated derivatives. In some embodiments, at least one compound selected from the novel compounds described herein, their pharmaceutically acceptable salts, and their deuterated derivatives 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 described herein, their pharmaceutically acceptable salts, and their deuterated derivatives, is administered in combination with Compound II, or a pharmaceutically acceptable salt or deuterated derivative thereof, and at least one compound selected from compound III, its pharmaceutically acceptable salts and their deuterated derivatives.

Any of the new compounds described herein, such as, for example, compounds of formula (I), (II), (III), (IV), (V) and their pharmaceutically acceptable salts and deuterated derivatives of such compounds and salts, may be in the same pharmaceutical composition or in different pharmaceutical compositions in combination with another additional active pharmaceutical ingredient(s) (for example, a compound II or III, 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, this description refers to a pharmaceutical composition containing at least one compound selected from any of the compounds described herein, and their pharmaceutically acceptable salts, and at least one pharmaceutically acceptable carrier.

In some embodiments, this description refers to a pharmaceutical composition containing at least one compound selected from the novel compounds described herein and their pharmaceutically acceptable salts, at least one compound selected from compound II and its pharmaceutically acceptable salts, and at least one pharmaceutically acceptable carrier.

In some embodiments, this description relates to a pharmaceutical composition containing at least one compound selected from the novel compounds described herein and their pharmaceutically acceptable salts, at least one compound selected from compound III and its pharmaceutically acceptable salts, and at least one pharmaceutically acceptable carrier.

In some embodiments, this description refers to a pharmaceutical composition containing at least one compound selected from the novel compounds described herein and their pharmaceutically acceptable salts, at least one compound selected from compound II and its pharmaceutically acceptable salts, at least one compound selected from compound III and its pharmaceutically acceptable salts, and at least one pharmaceutically acceptable carrier.

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

It should also be understood that a pharmaceutical composition as described herein, including a pharmaceutical composition containing the combinations described above, can be used in combination therapy; that is, the proposed compositions can be administered simultaneously, before or after at least one additional active pharmaceutical ingredient or medical procedures.

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

As described above, the pharmaceutical compositions described herein may optionally additionally contain at least one pharmaceutically acceptable carrier. By

- 17 040454 at least one pharmaceutically acceptable carrier may be selected from adjuvants and media. At least one pharmaceutically acceptable carrier as used herein includes any and all solvents, diluents and other liquid media, dispersion aids, suspension aids, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders, and lubricants, as appropriate. for the specific dosage form required. In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and in Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, describes various carriers used in the formulation of pharmaceutical compositions, as well as known technologies for their preparation. Unless a conventional carrier is incompatible with the compounds of this specification, as in the case of obtaining an undesirable biological effect or other adverse interaction with any other component(s) of the pharmaceutical composition, its use is within the scope of this description. Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchange resins, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering agents (such as phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or 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 copolymers, animal fat, sugars (such as lactose, glucose and sucrose), starches (such as cornstarch and potato starch), cellulose and its derivatives (such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as e.g. peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffering agents (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, release agents, coating agents, sweeteners, flavoring agents, flavors, preservatives and antioxidants.

It should also be understood that a pharmaceutical composition as described herein, including a pharmaceutical composition containing any of the combinations described above, may be used in combination therapy; that is, the proposed compositions can be administered simultaneously, before or after at least one active pharmaceutical ingredient or medical procedures.

In some embodiments, the methods of this disclosure utilize administering to a patient in need thereof at least one compound selected from any of the compounds described herein and their pharmaceutically acceptable salts, and at least one compound selected from compound II , compounds III and their pharmaceutically acceptable salts.

Any suitable pharmaceutical compositions known in the art can be used for the novel compounds described herein, Compound II, Compound III, and their pharmaceutically acceptable salts. Some illustrative pharmaceutical compositions of Compound 1 and its pharmaceutically acceptable salts are described in the Examples section. Some illustrative pharmaceutical compositions of compound II and its pharmaceutically acceptable salts are presented in publications WO 2011/119984 and WO 2014/015841, incorporated herein by reference. Some exemplary pharmaceutical compositions of Compound III and its pharmaceutically acceptable salts are provided in WO 2007/134279, WO 2010/019239, WO 2011/019413, WO 2012/027731 and WO 2013/130669, incorporated herein by reference. Some illustrative pharmaceutical compositions of Compound IV and its pharmaceutically acceptable salts are provided in WO 2010/037066, WO 2011/127241, WO 2013/112804 and WO 2014/071122, incorporated herein by reference.

In some embodiments, a pharmaceutical composition containing at least one compound selected from the novel compounds described herein and their pharmaceutically acceptable salts is administered with a pharmaceutical composition containing Compound II and Compound III. pharmaceutical compositions containing Compound II and Compound III are described in PCT Publication No. WO 2015/160787, incorporated herein by reference. An exemplary implementation is presented in the following table.

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Table 2. Exemplary tablet containing 100 mg of Compound II and 150 mg of Compound III

Ingredient Amount per tablet (mg) 1. Intragranular 2. Compound II SDD (spray dried dispersion) 3. (80% wt. Compounds II, 20; wt. HPMC) 4 . 125 5. 6. III SDD connection 7. (80% wt. compound III, 19.5% wt. HPMCASHG; 0.5% wt. sodium lauryl sulfate) 8.187.5 9. 10. Microcrystalline cellulose 11.131.4 12 . 13. Croscarmellose sodium 14.29.6 15. 16. Total 17.473.5 18. Extragranular 19. Microcrystalline cellulose 20.112.5 21. 22. Magnesium Stearate 23.5.9 24. 2 5. Total 26.118.4 27. Total per uncoated tablet 28. 29.591.9 30. Film coating 31. Opadry 32.17.7 33. Total per coated tablet 34 . 35.609.6

In some embodiments, a pharmaceutical composition containing at least one compound selected from the novel compounds described herein and their pharmaceutical salts is administered with a pharmaceutical composition containing Compound III. Pharmaceutical compositions containing Compound III are described in PCT Publication No. WO 2010/0192 39, incorporated herein by reference. An exemplary implementation is presented in the following table.

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Table 3. Ingredients for an exemplary Compound III tablet

Tablet composition Percentage % May./May. Dose (mg) The consignment (G) 36. Compound III SDD (80% w/w Compound III, 19.5% w/w HPMCAS-HG; 0.5% w/w 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 Sodium lauryl sulfate (SLS) 0.500% 2,750 0.3500 colloidal silicon dioxide 0.500% 2,750 0.3500 magnesium stearate 1.000% 5,500 0.7000 Total 100% 550 70

Additional pharmaceutical compositions containing Compound III are described in PCT Publication No. WO 2013/130669, incorporated herein by reference. Exemplary mini-tablets (~2 mm diameter, ~2 mm thick, each mini-tablet weighing about 6.9 mg) were formulated such that the content of compound III per 26 mini-tablets was approximately 50 mg and the content of compound III per 39 mini-tablets was approximately 75 mg, and for this used the amount of ingredients listed below in table. 4.

Table 4. Ingredients for 50mg and 75mg minitablets

Composition of the tablet Percentage % May./May. Dose (mg) activity 50 mg Dose (mg) activity 75 mg The consignment (G) 37. Compound III SDD (80% May. compounds III, 19.5% May. HPMCAS-HG; 0.5% May. 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 silica 10 18 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 in the form of a tablet. In some embodiments, the tablets are suitable for oral administration.

- 20 040454

These combinations are useful for the treatment of cystic fibrosis.

In some embodiments, disclosed herein is a method of treating cystic fibrosis in a patient, comprising administering an effective amount of at least one pharmaceutical composition of this invention to a patient, such as a human, said patient having cystic fibrosis and selected from patients with F508del/minimal function (MF ), patients with F508del/F508del genotypes, patients with F508del/gateway genotypes, and patients with F508del/residual function (RF) genotypes.

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 respond to any combinations of (i) the novel compounds disclosed herein, such as compound 1 and (ii) compound II and/or compound III, genotypes based on in vitro and/or clinical data.

F508del/minimal function patients are defined as heterozygous F508del-CFTR patients with a second CFTR allele containing a mutation predicted to result in a minimal function CFTR protein that should not respond to Compound II, Compound III, or the combination of Compound II and compounds III. These CFTR mutations were identified using 3 main sources: the biological plausibility of the mutation response (i.e., class of mutation) evidence of clinical severity on a population basis (from the CFTR2 Patient Registry; accessed February 15, 2016) mean sodium chloride in sweat fluid >86 mmol/l and pancreatic insufficiency prevalence (PI) >50% in vitro testing Mutations resulting in baseline chloride transport <10% wild-type CFTR were considered minimal function Mutations resulting in chloride transport <10% wild-type CFTR type after the addition of compound II and/or compound III were considered non-responders.

In some embodiments, disclosed herein is a method for treating, ameliorating, or symptomatic treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition of the invention to a patient, such as a human, the patient having the CFTR G551D genetic mutation. 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, has the G551D mutation on one allele, and any other CF-causing mutation on the other allele. In some embodiments, the patient is heterozygous for the G551D genetic mutation on one allele and the other CF-causing genetic mutation on the other allele is any of F508del, G542X,

N1303K, W1282X, R117H, R553X, 1717-1G->A, 621+1G->T, 2789+5G->A,

3849+10kbC->T, R1162X, G85E, 312O+1G->A, ΔΙ507, 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, disclosed herein is a method of treating, ameliorating, or symptomatic treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition of the invention to a patient, such as a mammal, wherein the patient has a CFTR F508del genetic mutation. In some embodiments, the patient is homozygous for the F508del genetic mutation. In some embodiments, the patient is heterozygous for the F508del genetic mutation, wherein the patient has the F508del genetic mutation at one allele and any CF-causing genetic mutation at the other allele. In some embodiments, the patient is heterozygous for F508del and the other CFTR genetic mutation is any mutation that causes CF, 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, 312O+1G->A, ΔΙ507,

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.

- 21 040454

In some embodiments, disclosed herein is a method of treating, ameliorating, or symptomatic treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition of the invention to a patient, such as a mammal, wherein the patient has a CFTR genetic mutation selected from

G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R,

S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, ->T, 312O+1G->A, 1898+1G->A,

711+1G->T, 2622+lG->A, 4O5+1G->A, 4O6-1G->A, 4OO5+1G->A, 18121G->A, 1525-1G->A, 712-1G ->T, 1248+1G->A, 1341+1G->A, 3121-1G>A, 4374+lG->T, 385O-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 . 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 H10985R H1375P H139R H939R, I1005R, I1234V,

I1269N, I1366N, I175V, I502T, I506S, I506T, I601F, I618T, i807M, I980K, L102R, L1324P, L1335P, L138ins, L1480P, L15P, L165S, L346P, L453S, M1, M1 m1v,

M265R, M952I, M952T, P574H, P5L, P750L, P99L, Q1100P, Q1291H, Q1291R, Q237E, Q237H, Q452P, Q98R, R1066C, R1066H, R117G, R117L, R117P, R1283M, R1283S, R170H, R258G, R31L, R334L, R334Q, R347L, R352W, R516G, R553Q, R751L, R792G, R933G, S1118F, S1159F,

S1159P S13F S549R(A->C), S549R(T->G), S589N W1098C, W1098R, W1282R, W361R, W57G, W57R, Y1014C, Y1032C, Y109N, Y161D, Y161S, Y563D, Y563N, Y569C, and Y913C.

In some embodiments, the patient has at least one combination mutation selected from

- 22 040454

G178R,

G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N,

E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D11OE,

D1270N, D1152H, 1717-1G->A, 621+1G->T, 312O+1G->A, 1898+1G->A,

711+1G->T, 2622+lG->A, 4O5+1G->A, 4O6-1G->A, 4OO5+1G->A, 18121G->A, 1525-1G->A, 712-1G ->T, 1248+1G->A, 1341+1G->A, 3121-1G>A, 4374+lG->T, 385O-1G->A, 2789+5G->A, 3849+10kbC-> T, 3272-26A>G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342 -2A->C, 405+3A->C, 1716G/A, 1811+1G->C, 1898+5G>T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T , 4005+2T->C, and 621+3A>G.

In some embodiments, the patient has at least one combination mutation selected from

1949del84, 3141del9, 3195del6, 3199del6, 3905InsT, 4209TGTT->A, A1006E, A120T, A234D, A349V, A613T, C524R, D192G, D443Y, D513G, D836Y, D924N, D979V, E116K, E403D, E474K, E588V, E60K, E822K , F1016S, F1099L, F191V, F311del, F311L, F508C, F575Y, G1061R,

G1249R G126D G149R G194R G194V G27R G314E G458V G463V G480C G622D G628R G628R(G->A) G91R G970D H1054D H1085P H10985R H1375P H139R H939R, I1005R, I1234V,

I1269N, I1366N, I175V, I502T, I506S, I506T, I601F, I618T, I807M, I980K, L102R, L1324P, L1335P, L138ins, L1480P, L15P, L165S, L320V, L346P, L453S, M1, M1 m1v,

M265R, M952I, M952T, P574H, P5L, P750L, P99L, Q11OOP, Q1291H,

Q1291R, Q237E, Q237H, Q452P, Q98R, R1066C, R1066H, R117G, R117L, R117P, R1283M, R1283S, R170H, R258G, R31L, R334L, R334Q, R347L, R352W, R516G, R553Q, R751L, R792G, R933G, S1118F, S1159F,

S1159P, S13F, S549R(A->C), S549R(T->G), S589N, S737F, S912L,

T1036N, T1053I, T1246I, T604I, V1153E, V1240G, V1293G, V201M,

V232D, V456A, V456F, V562I, W1098C, W1098R, W1282R, W361R, W57G, W57R, Y1014C, Y1032C, Y109N, Y161D, Y161S, Y563D, Y563N, Y569C, and Y913C.

In some embodiments, the patient has at least one combination mutation selected from

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D443Y; G576A; R668C,

F508C; S1251N,

G576A; R668C,

G970R; M470V,

R74W; D1270N,

R74W; V201M, and

R74W; V201M; D1270N.

In some embodiments, this document discloses a method of treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition according to this invention to a patient, such as a mammal, and the patient has a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V and G1069R. In some embodiments, this disclosure provides a method of treating CFTR, comprising administering a compound of formula (I), (II), (III), (IV), (V), or a pharmaceutically acceptable salt thereof, to a patient having a human CFTR mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R and S1251N. In some embodiments, disclosed herein is a method of treating, ameliorating, or symptomatic treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition of this invention to a patient, such as a mammal, wherein the patient has a CFTR genetic mutation selected from E193K, F1052V, and G1069R . In some embodiments, the implementation of the method provides an increase in chloride transport compared with the original chloride transport in the patient.

In some embodiments, this document discloses a method of treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition according to this invention to a patient, such as a mammal, and 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 implementation of the method provides an increase in chloride transport above the initial level of chloride transport in the patient.

In some embodiments, disclosed herein is a method for treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition of the invention to a patient, such as a mammal, the patient having a CFTR genetic mutation selected from

1717-1G->A, 621+1G->T, 312O+1G->A, 1898+1G->A,

711+1G->T, 2622+lG->A, 4O5+1G->A, 4O6-1G->A, 4OO5+1G->A, 18121G->A, 1525-1G->A, 712-1G ->T, 1248+1G->A, 1341+1G->A, 3121-1G>A, 4374+lG->T, 385O-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, disclosed herein is a method of treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition of this invention to a patient, such as a mammal, wherein 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, disclosed herein is a method of cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition of the invention to a patient, such as a mammal, the patient having a CFTR genetic mutation selected from 2789+5G^A and 3272-26A^G.

In some embodiments, disclosed herein is a method of treating, ameliorating, or symptomatic treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition of the invention to a patient, such as a mammal, wherein the patient has a CFTR genetic mutation selected from

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G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R,

S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K,

P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E,

D1270N, D1152H, 1717-1G->A, 621+1G->T, 312O+1G->A, 1898+1G->A,

711+1G->T, 2622+1G-RA, 4O5+1G->A, 4O6-1G->A, 4005+1G-RA, 18121G->A, 1525-1G->A, 712-1G-> T, 1248+1G->A, 1341+1G->A, 3121-1G>A, 4374+lG->T, 385O-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A>G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A ->C, 405+3A->C, 1716G/A, 1811+1G->C, 1898+5G>T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005 +2T->C and 621+3A>G, and a human CFTR mutation selected from F508del, R117H and G551D.

In some embodiments, this document discloses a method of treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition according to this invention to a patient, such as a mammal, and the patient has a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V and G1069R, and a human CFTR mutation selected from F508del, R117H and G551D. In some embodiments, this document discloses a method of treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition according to this invention to a patient, such as a mammal, and the patient has a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R and S1251N, and a human CFTR mutation selected from F508del, R117H and G551D. In some embodiments, disclosed herein is a method of treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition of this invention to a patient, such as a mammal, wherein the patient has a CFTR genetic mutation selected from E193K, F1052V, and G1069R and a human CFTR mutation selected from F508del, R117H and G551D. In some embodiments, the implementation of the method provides an increase in chloride transport compared with the original chloride transport in the patient.

In some embodiments, this document discloses a method of treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition according to this invention to a patient, such as a mammal, and 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 a human CFTR mutation selected from F508del, R117H and G551D. In some embodiments, the implementation of the method provides an increase in chloride transport, which exceeds the initial chloride transport in the patient.

In some embodiments, disclosed herein is a method of treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition of this invention to a patient, such as a mammal, wherein the patient has a CFTR genetic mutation selected from 1717-1G->A, 621+1G-> T, 312O+1G->A, 1898+1G->A,

711+1G->T, 2622+1G-RA, 405+1G-RA, 4O6-1G->A, 4005+1G-RA, 18121G->A, 1525-1G->A, 712-1G->T , 1248+1G->A, 1341+1G->A, 3121-1G>A, 4374+lG->T, 385O-1G->A, 2789+5G->A, 3849+1OkbC->T, 3272 -26A>G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A- >C, 405+3A->C, 1716G/A, 1811+1G->C, 1898+5G>T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+ 2T->C and 621+3A>G, and a human CFTR mutation selected from F508del, R117H, and G551D. In some embodiments, this document discloses a method of treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition according to this invention to the patient, and

- 25 040454 coma as a mammal, wherein the patient has a CFTR genetic mutation selected from 17171G>A, 1811+1.6kbA>G, 2789+5G>A, 3272-26A>G and 3849+10kbC>T and a human CFTR mutation, selected from F508del, R117H and G551D. In some embodiments, this document discloses a method of treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition according to this invention to a patient, such as a mammal, and the patient has a CFTR genetic mutation selected from 2789+5G>A and 3272-26A>G, and a human CFTR mutation selected from F508del, R117H.

In some embodiments, disclosed herein is a method for treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition of the invention to a patient, such as a mammal, the patient having a CFTR genetic mutation selected from

G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N,

S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H,

R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G ->A, 711+1G->T, 2622+1G-AA, 405+1G-AA, 406-1G-AA,

4OO5+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374 +1G-AT, 3850-1G-AA, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA-> G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C,

1716G/A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A,

1898+1G->T, 4005+2T->C and 621+3A->G, and a human CFTR mutation selected from F508del, R117H and G551D.

In some embodiments, this document discloses a method of treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition according to this invention to a patient, such as a mammal, and the patient has a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V and G1069R. In some embodiments, disclosed herein is a method of cystic fibrosis in a patient comprising administering an effective amount of a pharmaceutical composition of this invention to a patient, such as a mammal, wherein the patient has a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N , S549R and S1251N. In some embodiments, disclosed herein is a method of treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition of the invention to a patient, such as a mammal, the patient having a CFTR genetic mutation selected from E193K, F1052V, and G1069R. In some embodiments, the implementation of the method provides an increase in chloride transport compared with the original chloride transport in the patient.

In some embodiments, this document discloses a method of treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition according to this invention to a patient, such as a mammal, and 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 implementation of the method provides an increase in chloride transport, which exceeds the initial chloride transport in the patient.

In some embodiments, disclosed herein is a method for treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition of the invention to a patient, such as a mammal, the patient having a CFTR genetic mutation selected from

- 26 040454

1717-1G->A, 621+1G->T, 312O+1G->A, 1898+1G->A,

711+1G->T, 2622+lG->A, 4O5+1G->A, 4O6-1G->A, 4OO5+1G->A, 18121G->A, 1525-1G->A, 712-1G ->T, 1248+1G->A, 1341+1G->A, 3121-1G>A, 4374+lG->T, 385O-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, disclosed herein is a method of treating, ameliorating, or symptomatic treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition of this invention to a patient, such as a mammal, wherein 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, disclosed herein is a method of treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition of this invention to a patient, such as a mammal, wherein the patient has a CFTR genetic mutation selected from 2789+5G>A and 3272-26A>G.

In some embodiments, disclosed herein is a method for treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition of the invention to a patient, such as a mammal, the patient having a CFTR genetic mutation selected from

G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N,

S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H,

R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G ->A, 711+1G->T, 2622+1G-AA, 405+1G-AA, 406-1G-AA,

4OO5+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374 +1G-AT, 3850-1G-AA, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA-> G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C,

1716G/A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A,

1898+1G->T, 4005+2T->C and 621+3A->G, and a human CFTR mutation selected from F508del, R117H and G551D, and one or more human CFTR mutations selected from F508del, R117H and G551D.

In some embodiments, this document discloses a method of treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition according to this invention to a patient, such as a mammal, and the patient has a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V and G1069R, and one or more human CFTR mutations selected from F508del, R117H and G551D. In some embodiments, this document discloses a method of treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition according to this invention to a patient, such as a mammal, and the patient has a CFTR genetic mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R and S1251N, and one or more human CFTR mutations selected from F508del, R117H and G551D. In some embodiments, disclosed herein is a method of treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition of this invention to a patient, such as a mammal, wherein the patient has a CFTR genetic mutation selected from E193K, F1052V, and G1069R, and one or more CFTR mutations. human selected from F508del, R117H and G551D. In some embodiments, the implementation of the method provides an increase in chloride transport compared with the original chloride transport in the patient.

- 27 040454

In some embodiments, this document discloses a method of treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition according to this invention to a patient, such as a mammal, and 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 one or more human CFTR mutations selected from F508del, R117H and G551D. In some embodiments, the implementation of the method provides an increase in chloride transport, which exceeds the initial chloride transport in the patient.

In some embodiments, disclosed herein is a method for treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition of the invention to a patient, such as a mammal, the patient having a CFTR genetic mutation selected from

1717-1G->A, 621+1G->T, 312O+1G->A, 1898+1G->A,

711+1G->T, 2622+lG->A, 4O5+1G->A, 4O6-1G->A, 4OO5+1G->A, 18121G->A, 1525-1G->A, 712-1G ->T, 1248+1G->A, 1341+1G->A, 3121-1G>A, 4374+lG->T, 385O-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 one or more human CFTR mutations selected from F508del, R117H and G551D. In some embodiments, this document discloses a method of treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition according to this invention to a patient, such as a mammal, and 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, and one or more human CFTR mutations selected from F508del, R117H and G551D. In some embodiments, this document discloses a method of treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition according to this invention to a patient, such as a mammal, and the patient has a CFTR genetic mutation selected from 2789+5G>A and 3272-26A>G, and one or more human CFTR mutations selected from F508del, R117H and G551D.

In some embodiments, the patient is heterozygous, has one CF-causing mutation on one allele and another CF-causing mutation on the other allele. In some embodiments, the patient is heterozygous for F508del and the other CFTR genetic mutation is any mutation that causes CF, 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 CFTR function or a defect in the activity of the CFTR ion channel gate mechanism.

In some embodiments, the implementation of the mutation that causes CF, selected from the table. 5A. In some embodiments, the patient is heterozygous, has one CF-causing mutation on one CFTR allele, selected from the mutations listed in the table in FIG. 4 and another CF-causing mutation on a different CFTR allele is selected from the CFTR mutations listed in Table 1. 5A.

- 28 040454

Table 5A

CFTR mutations

Q39X

W57X

E60X

R75X

E92X

Q98X

Y122X

L218X

Q220X

S276X

Q290X

G330X

W401X

Q414X

S434X

S466X

S489X

Q493X

W496X

Q52 5X

G542X

Q552X

R553X

E585X

G673X

R7 0 9X

K710X

L732X

R764X

- 29 040454

R7 8 5X

R792X

E822X

W846X

R851X

Q890X

S912X

W1089X

Y1092X

E1104X

R1158X

R1162X

S1196X

W1204X

S1255X

W1282X

Q1313X

621+1GAT

711+lG^T

711+5G^A

712-1GAT

405+lG^A

05+3A-^C

406-lG^A

621+1GAT

1248+lG^A

1341+lG^A

1717-lG^A

1811 + 1.6kbA-^G

- 30 040454

1811+lG^C

1812-lG^A

1898+lG^A

2622+lG^A

3120+lG^A

3120G^A

3850-lG^A

4005+lG^A

4374+1GAT

663delT

218 3AA-^G

CFTRdel2,3

3659delC

394delTT

2184insA

3905insT

2184delA

1078delT

1154insTC

2183delAA-^G

2143delT

1677delTA

3876delA

2307insA

4382delA

4016insT

2347delG

3007delG

574delA

- 31 040454

2711delT

3791delC

CFTRdele22-23

457TAT^G

2043delG

869insG

3600+2insT

3737delA

04

541delC

A46D

T338I

R347P

L927P

G85E

S341P

L467P

I507del

V520F

A559T

R560T

R560S

A561E

Y569D

L1065P

R1066C

R1066M

L1077P

H1085R

R117H

G178R

S549N

S549R

G551D

- 32 040454

M1101K

N1303K

2789+5G^A

3849+lOkbC^T

72-2 6A-+3

711 + ZA-SCZ

E56K

P67L

R74W

D110E

D110H

R117C

L2 0 6W

R347H

R352Q

A455E

D579G

E831X

S945L

S977F

F1052V

R1070W

F1074L

D1152H

D1270N

G551S

G1244E

S1251N

S1255P

G1349D

- 33 040454

Table 5B. CFTR mutations

Criteria Mutation S4X C276X G542X R792X E1104X G27X Q290X G550X E822X R1158X Q39X G330X Q552X W846X R1162X W57X W401X R553X Y849X S1196X Mutations from E60X Q414X E585X R851X W1204X truncation %PI >50% R75X S434X G673X Q890X L1254X and/or SwCl ^- >86 mmol/l E92X S466X S489X Q685X R7 0 9X S912X Y913X S1255X W1282X Q98X incomplete protein Y122X Q493X K710X W1089X Q1313X E193X W496X L732X Y1092X E1371X L218X C524X R764X W1098X Q1382X Q220X Q52 5X R7 8 5X R1102X Q1411X 711+5G 2622+lG^ 3121- 185+1GAT ^A 1717-8G^A A IG^A 712- 2790- 3500- 296+lG^A 1GAT 1717-lG^A IG^C 2A-^G Splicing 405+lG^A 1248+1 1811+lG^C 3600+2 mutations G^A 3040G^C insT %PI >50% 1249- 1811+1.6kbA (G970R) 3850- and/or SwCl ^- >86 mmol/l 4 05+ZA-^S IG^A ^G IG^A absence 1341+1 4005+1 mRNA or 406-lG^A G^A 1812-lG^A 3120G^A G^A immature mRNA 621+1GAT 1525- 1898+lG^A 312O+1G^ 4374+1 2A-DZ A G^T 1525- 3121- 711+1GAT IG^A 1898+lG^C 2A-+G Small (<3 182delT 1119de 1782delA 2732insA 3876de nucleotide) 1A 1A

- 34 040454

insertion/d selective 306insA 1138in sG 1824delA 2 8 69insG 3878de 1G (ins/del) mutations with 365- 366insT 1154in sTC 2043delG 2896insA G 3905in ST frame shift readings 394delTT 1161de IC 2143delT 2942insT 4016in ST % PI >50% and/or SwCl >86 mmol/L distorted and/or truncated protein 442delA 444delA 457TATAG 1213de IT 1259in SA 1288in sTA 2183AA-DZ ^a 2184delA 2184insA 2957delT 3007delG 3028delA 4021dupt 404 Ode 1A 4279in sA 541delC 1471de 1A 2307insA 3171delC 4326de 1TC 574delA 1497de 1GG 2347delG 3659delC 663delT 1548de 1G 2585delT 3737delA 935delA 1609de 1CA 2594delGT 3791delC

1677de

1078delT 2711delT 3821delT

1TA

Large (>3 CFTRdele2,3 1461ins4 2991del32 nucleotide) insertion/d CFTRdele22,23 1924del7 3667ins4 selective (ins/del) co mutations 124del23bp 2055del9^A 2105- 4010del4 frameshift % PI >50% and/or SwCl >86 mmol/l 852del22 2117dell3insAGA AA 4209TGTT^AA distorted 991del5 2721dell

and/or truncated protein

- 35 040454

Class mutations A4 6D ^b G85E V520F ^A559Tb Y569D ^to L1065P N1303K II, III, IV, not responding per connection R347P R560T R1066C III separately ^L467Pb R560S ^L1077Pb or in combinations with I507del A561E M1101K compound II or compound IV % PI >50% and/or SwCl >86 mmol/l and

not responding in vitro to Compound III alone or in combination with Compound II or Compound IV Notes:

% PI: Percentage of F508del-CFTR heterozygous patients in the CFTR2 Patient Registry with Pancreatic Insufficiency

SwCl ^- : mean sodium chloride in sweat fluid F508del-CFTR of heterozygous patients in the CFTR2 patient registry ^a Also known as 2183delAA^G ^b Unpublished data

In table. 5B above includes some illustrative CFTR minimal function mutations that are detected by FDA approved genotyping but does not include an exhaustive list.

In some embodiments, this document discloses a method of treating cystic fibrosis in a patient with F508del/MF (F/MF) genotypes (heterozygous for F508del and an MF mutation that is not expected to respond to CFTR modulators such as Compound III); with genotype F508del/F508del (F/F) (homozygous for F508del); and/or with F508del/Gateway (F/G) genotypes (heterozygous for F508del and a gated mutation known to respond to a CFTR modulator (e.g., respond to Compound III). In some embodiments, a patient with F508del genotypes /M.F (F/MF) has an MF mutation that is not expected to respond to Compound II, Compound III, and Compound II and Compound III simultaneously In some embodiments, a patient with F508del/MF (F/MF) genotypes has any of the MF mutations in Table 5B.

In some embodiments, the patient is heterozygous for F508del and the other CFTR genetic mutation is any mutation that causes CF, including truncation mutations, splicing mutations, small (<3 nucleotides) insertion or deletion (ins/del) frameshift mutations ; large (>3 nucleotides) insertion or deletion (ins/del) frameshift mutations; and class II, III, IV mutations not responding to Compound III alone or in combination with Compound II.

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 the truncation mutation shown in Table 1. 5V.

In some embodiments, the patient is heterozygous for F508del and the other CFTR genetic mutation is a splicing mutation. In some specific embodiments, the implementation of the splicing mutation is a splicing mutation listed in table. 5V.

In some embodiments, the patient is heterozygous for F508del and the other CFTR genetic mutation is a small (<3 nucleotides) insertion or deletion (ins/del) frameshift mutation. In some specific embodiments, the small (<3 nucleotides) insertion or deletion (ins/del) frameshift mutation is the small (<3 nucleotides) insertion or deletion (ins/del) frameshift mutation listed in Table 1. 5V.

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 respond, based on in vitro and/or clinical data, to any combination of (i )

- 36 040454 a new compound selected from those disclosed herein (for example, compounds of formula (I), (II), (III), (IV) or (V) and their pharmaceutically acceptable salts, and their deuterated derivatives ), and (ii) compounds II and/or compounds III.

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 respond, based on in vitro and/or clinical data, to a three-component combination of the novel compound , selected from those disclosed herein (for example, compounds of formula (I), (II), (III), (IV) or (V) and their pharmaceutically acceptable salts, and their deuterated derivatives), and compounds II , and compounds III.

In some embodiments, the patient is heterozygous for F508del and the other CFTR genetic mutation is a large (>3 nucleotides) insertion or deletion (ins/del) frameshift mutation. In some specific embodiments, the large (>3 nucleotides) insertion or deletion (ins/del) frameshift mutation is the large (>3 nucleotides) insertion or deletion (ins/del) frameshift mutation listed in Table 1. 5V.

In some embodiments, the patient is heterozygous for F508del and the other CFTR genetic mutation is a Class II, III, IV mutation not responding to Compound III alone or in combination with Compound II. In some specific embodiments, Class II, III, IV mutations not responding to Compound III, alone or in combination with Compound II, are Class II, III, IV mutations not responding to Compound III alone or in combination with Compound II, indicated in the table. 5V.

In some embodiments, the patient is heterozygous for F508del and the other CFTR genetic mutation is any of the mutations listed in Table 1. 5V.

In some embodiments, the patient is heterozygous for F508del and the other CFTR genetic mutation is any of the mutations listed in Table 1. 5A, 5B, and in FIG. 4.

In some embodiments, the patient is heterozygous for F508del and the other CFTR genetic mutation is any of the mutations listed in Table 5A. In some embodiments, the patient is heterozygous for F508del and the other CFTR genetic mutation is any of the mutations listed in Table 1. 5V. In some embodiments, the patient is heterozygous for F508del and the other CFTR genetic mutation is any of the mutations indicated in FIG. 4.

In some embodiments, the patient is homozygous for F508del.

In some embodiments, the patient is heterozygous, has one CF-causing mutation on one CFTR allele, selected from the mutations listed in Table 1. in fig. 4 and another CF-causing mutation on a different CFTR allele is selected from the CFTR mutations listed in Table 1. 5V.

Patients with the F508del/gateway mutant genotype are defined as heterozygous F508del-CFTR patients with a second CFTR allele that contain a gate defect-associated mutation clinically proven to respond to Compound III. Examples of such mutations include G178R, S549N, S549R, G551D, G551S, G1244E, S1251N, S1255P and G1349D.

Patients with the F508del genotype/residual function are defined as heterozygous F508del-CFTR patients with a second CFTR allele who contain a mutation that results in a reduction in the amount or function of a cell surface protein, which may result in partial CFTR activity. Mutations in the CFTR gene that result in a residual function phenotype are known to include, in some embodiments, a CFTR residual function mutation selected from 2789+5G>A, 3849+10kbC>T, 3272-26A>G, 711+3A>G, E56K A455E, D579G, E831X, S945L, S977F, F1052V, R1070W, F1074L, D1152H, D1270N, E193K, and K1060T In some embodiments, the CFTR residual function mutation is selected from R117H, S1235R, I1027T, R668C, G576A, M470V, L997F, R75Q, R1070Q, R31C, D614G, G1069R, R1162L, E56K, A1067T, E193K, or K1060T. In some embodiments, the CFTR residual function mutation is selected from R117H, S1235R, I1027T, R668C, G576A, M470V, L997F, R75Q, R1070Q, R31C, D614G, G1069R, R1162L, E56K, or A1067T.

In some embodiments, disclosed herein is a method of treating cystic fibrosis in a patient, comprising administering an effective amount of a pharmaceutical composition of the invention to a patient, such as a mammal, the patient having a CFTR genetic mutation selected from the mutations listed in FIG. 4.

In some embodiments, the composition disclosed herein is useful for the treatment of cystic fibrosis in patients who exhibit residual CFTR activity on the apical membrane of the respiratory and non-respiratory epithelium. The presence of residual CFTR activity on the surface of the epithelium can be readily detected using methods known in the art, such as standard electrophysiological, biochemical, or histochemical methods.

- 37 040454 methods. Such methods identify CFTR activity using in vivo or ex vivo electrophysiological methods, by measuring the concentration of Cl- in sweat or saliva, or ex vivo biochemical or histochemical methods to measure cell surface density. Using such methods, one can easily detect residual CFTR activity in patients who are heterozygous or homozygous for a variety of different mutations, including patients heterozygous for the most common mutation, F508del, as well as other mutations such as the G551D mutation, or the R117H mutation. In some embodiments, 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 in the treatment of cystic fibrosis in patients who exhibit 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 patient's existing level of residual CFTR activity.

In some embodiments, the compositions disclosed herein are useful for treating cystic fibrosis in patients with certain genotypes that exhibit residual CFTR activity.

In some embodiments, the compositions disclosed herein are useful for the treatment of cystic fibrosis in patients with certain clinical phenotypes, such as a mild to moderate clinical phenotype that generally correlates with the amount of residual CFTR activity in the apical epithelial membrane. Such phenotypes include patients exhibiting pancreatic insufficiency.

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

The exact amount of pharmaceutical composition required will vary from subject to subject, depending on the type, age and general condition of the subject, the severity of the disease, the particular agent, its route of administration, and the like. The compounds of this invention may be formulated in unit dosage form for ease of administration and dose uniformity. As used herein, unit dosage form refers to a physically discrete unit of an agent suitable for the patient to be treated. It should be understood, however, that the total daily dosage of the compounds and compositions of this invention will be determined by the physician in charge upon careful medical evaluation. 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 disorder; the activity of the particular compound used; specific composition used; age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular compound used; duration of treatment; drugs used in combination or simultaneously with the specific compound used, and like factors well known in medicine. The term patient as used herein means an animal, such as a mammal, and additionally, such as a human.

In some embodiments, this disclosure also relates to methods of treatment using the aforementioned isotopically labeled compounds that have the same structure as described herein, except that one or more of their atoms are replaced by an atom or atoms having an atomic a mass or mass number other than the atomic mass or mass number of the atom normally found in nature (isotopically labelled). Examples of isotopes that are commercially available and suitable for this description include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ 0, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl, respectively.

Isotopically labeled compounds and their salts can be advantageously used for many purposes. They may be suitable for drugs and/or various types of assays such as tissue distribution of a substrate. For example, compounds labeled with tritium ( ³ H) and/or carbon-14 ( ¹⁴ C) are particularly suitable for various types of assays such as tissue substrate distribution assays due to their relative ease of preparation and excellent detectability. For example, deuterium ( ² H) labeled compounds are therapeutically useful and have a potential therapeutic advantage over unlabeled ² H compounds. In general, deuterium ( ² H) labeled compounds and their salts may have higher metabolic stability than compounds without an isotope label, due to the kinetic isotope effect described below. high

- 38 040454 metabolic stability leads directly to an increase in the half-life in vivo or dose reduction, which may be desirable. Isotopically labeled compounds and their salts can generally be prepared by following the procedures described in the synthesis schemes and in the corresponding description, in the Examples section and in the preparative section of this description, replacing the non-isotopically labeled reagent with a commonly available isotopically labeled reagent.

In some embodiments, the isotopically labeled compounds and salts are deuterium ( ² H) labeled compounds and salts. In some specific embodiments, isotopically labeled compounds and salts are deuterium ( ² H) labeled and have one or more hydrogen atoms replaced with deuterium. In chemical structures, deuterium is denoted as ² H or D.

Compounds and salts with a deuterium ( ² H) label can alter the oxidative metabolism of the compound due to a primary kinetic isotope effect. The primary kinetic isotope effect is a change in the rate of a chemical reaction due to 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 said isotopic exchange. An exchange for a heavier isotope usually results in a decrease in the ground state energy for a chemical bond and, therefore, causes a reduction in the limiting bond breaking. If the bond break occurs at the saddle point or near the saddle point along the reaction coordinate of the formation of several products, then the composition ratio of the products can be significantly changed. Explanation: if deuterium is bound to a carbon atom in a non-replaceable position, then the typical speed difference k _M /k _D =2-7. Additional description is provided in SL Harbeson and RD 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, the relevant parts of which are independently incorporated herein by reference.

The concentration of isotope(s) (eg, deuterium) embedded in isotopically labeled compounds and salts as described herein can be determined using the isotopic enrichment factor. The term isotopic enrichment factor in this context means the ratio between the abundance of an isotope and the natural abundance of a particular isotope. In some embodiments, if a substituent on a compound of this disclosure has a deuterium label, then said compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation per designated deuterium atom), at least 4000 (60% deuterium insertion), at least 4500 (67.5% deuterium insertion), at least 5000 (75% deuterium insertion), at least 5500 (82.5% deuterium insertion), at least 6000 (90 % deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99 .5% deuterium incorporation).

When discovering and developing therapeutic agents, those skilled in the art seek to optimize pharmacokinetic parameters while maintaining desired in vitro properties. It may be reasonable to assume that many compounds with unsatisfactory pharmacokinetic profiles are subject to oxidative metabolism.

Those skilled in the art will recognize that deuteration of one or more metabolically labile positions of a compound or active metabolite may provide an improvement in one or more of the superior pharmacokinetic properties of a drug compound (DMPK) while maintaining biological activity over the corresponding hydrogen counterparts. The best property or properties of DMPK can influence the exposure, half-life, clearance, metabolism and/or even dietary requirements for optimal absorption of the drug product. Deuteration can also alter the metabolism at other, non-deuterated positions of the deuterated compound.

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

In some embodiments, Compound III' as used herein includes the deuterated compound described in US Pat. No. 8,865,902 (incorporated herein by reference) and STR-656.

In some embodiments, Compound III' is

- 39 040454

Exemplary embodiments of this specification include the novel compounds described herein (e.g., compounds of formulas (I)-(V), their pharmaceutically acceptable salts, and their deuterated derivatives, including the compounds of Figure 1 and the compounds specifically depicted herein) , can be obtained by suitable methods known in the art. For example, they can be prepared according to the methods described in WO 2016/057572 and the illustrative synthetic methods described below in the Examples section. For example, deuterated derivatives of the new compounds of formulas (I)-(V) and their pharmaceutically acceptable salts can be obtained in the same manner as the compounds of formulas (I)-(V) and their pharmaceutically acceptable salts, using intermediates and/or reagents, in which one or more hydrogen atoms have been replaced by deuterium. See, for example, T.G. Gant Using deuterium in drug discovery: leaving the label in the drug J. Med. Chem. 2014, 57, 3595-3611, the relevant parts of which are incorporated herein by reference.

In some embodiments, the compounds of formulas (III), (IV), and (V) and their pharmaceutically acceptable salts, as well as their deuterated derivatives, are prepared as shown in Schemes 1-2, where all variables are independently those for formulas ( I), (II), (III), (IV) or (V) described above, and where each Ra is independently selected from C 1 -C ₄ alkyl groups; and each X ^a is independently selected from F or Cl. For each step depicted in the diagrams, suitable condition(s) known in the art may be used. In some embodiments, each Xa for Formulas B, C, D, F, B-1, C-1, D-1, and F-1 in Schemes 2-4 is independently Cl. In some embodiments, each Xa for Formulas D, L, O, and P in Scheme 6 is independently F.

In some embodiments, as shown in Scheme 1, the provided methods comprise reacting a compound of formula (F), or a salt thereof, with a compound of formula (G), or a salt thereof, to obtain a compound of formula (IIIa), a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof. .

Scheme 1

You can use any suitable conditions, such as conditions for the nucleophilic reaction of the amine, known in the art. In some embodiments, the reaction shown in Scheme 1 is carried out in the presence of a base such as a metal carbonate (eg, Na ₂ CO ₃ or K 2 CO 3 ).

In some embodiments of the compounds of formula (IIIa), their pharmaceutically acceptable salts or their deuterated derivatives, where Y ² represents N and Y ¹ represents CH in each of formulas (F), (G) and (IIIa), are obtained by methods, shown in diagram 1.

In some embodiments, a salt of a compound of formula (G) is used. In some embodiments, an HCl salt of a compound of formula (G) is used.

A compound of formula (F) or a salt thereof and a compound of formula (G) or a salt thereof can be prepared by any suitable method known in the art, for example as described in WO 2016/57572 and by the method described in the illustrative syntheses below in the section Examples.

In some embodiments, as shown in Scheme 2, a compound of formula (F), a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof is prepared by a process comprising reacting a compound of formula (D), or a salt thereof, with a compound of formula (E), or a salt thereof. In some embodiments, the compounds of formula (D), their salts, or their deuterated derivatives are prepared by a process which comprises reacting a compound of formula (A), or a salt thereof, with a compound of formula (B), or a salt thereof, to obtain a compound of formula (C); and hydrolysis of -C(O)OR ^a in a compound of formula (C) to give a compound of formula (D) or a salt thereof. In steps (a), (b) and (c) of Scheme 2 below, any suitable conditions known in the art may be used, such as conditions for a coupling reaction between a carboxylic acid and a sulfonamide, or conditions for acylation of a sulfonamide in the step (a), conditions for ester hydrolysis in step (b) and amine nucleophilic reaction conditions in step (c).

In some embodiments, step (a) of Scheme 2 below is carried out in the presence of a base. In some specific embodiments, step (a) is carried out in the presence of a non-nucleophilic base. In some embodiments, in step (a), reacting a compound of formula (D) or a salt thereof with a compound of formula (E) or a salt thereof comprises reacting a compound of formula (D) or a salt thereof with a coupling agent such as carbonyldiimidazole (CDI), and then with a compound of formula (E) or a salt thereof in the presence of a base such as not

- 40 040454 nucleophilic base. In some embodiments, a compound of formula (D) or a salt thereof is reacted with CDI prior to reaction with a compound of formula (E) or a salt thereof and then with a compound of formula (E) or a salt thereof in the presence of a base such as DBU (1,8 diazabicyclo (5.4.0)undec-7-ene).

In some embodiments, step (b) of Scheme 2 below is carried out in the presence of a base. In some embodiments, step (b) is carried out in the presence of an aqueous base, such as aqueous hydroxide. In some embodiments, step (b) is carried out in the presence of an aqueous metal hydroxide such as aqueous NaOH.

In some embodiments, step (c) of Scheme 2 below is performed in the presence of a base. In some embodiments, step (c) is carried out in the presence of a metal carbonate (eg Na ₂ CO3 or K ₂ CO3).

Scheme 2

ABOUT

(b)

_{SO2NH2 _}

In some embodiments, this document describes a method for preparing a compound having the formula:

or a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof. The proposed method involves reacting a compound of formula (F-1) or a salt thereof with a compound of formula (G-1) or a salt thereof, where X ^a is F or Cl, as shown in Scheme 3.

Scheme 3

Connection (1)

You can use any suitable conditions, such as conditions for the nucleophilic reaction of the amine, known in the art. In some embodiments, the reaction shown in Scheme 3 is carried out in the presence of a base such as a metal carbonate (eg, Na2CO3 or K2CO3).

In some embodiments, a salt of a compound of formula (G-1) is used. In some embodiments, an HCl salt of a compound of formula (G-1) is used.

A compound of formula (F-1) or a salt thereof and a compound of formula (G-1) or a salt thereof can be prepared by any suitable method known in the art, such as described in WO 2016/57572, and by the method described in the illustrative syntheses given below in the Examples section.

In some embodiments, as shown in Scheme 4, a compound of formula (F-1), or a salt or deuterated derivative thereof, is prepared by a process involving

- 41 040454 action of a compound of formula (D-1) or a salt thereof with a compound of formula (E-1) or a salt thereof. In some embodiments, compounds of formula (D-1), or salts or deuterated derivatives thereof, are prepared by a process which comprises reacting a compound of formula (A-1), or a salt thereof, with a compound of formula (B-1), or a salt thereof, with obtaining a compound of formula (C-1) or a salt thereof; and hydrolysis of -C(O)OR ^a in a compound of formula (C-1) or a salt thereof to obtain a compound of formula (D-1) or a salt thereof. In steps (a-1), (b-1) and (c-1) of Scheme 4 below, any suitable conditions known in the art may be used, such as conditions for a coupling reaction between a carboxylic acid and a sulfonamide, or conditions for the acylation of the sulfonamide in step (a-1), the conditions for hydrolysis of the ester in step (b-1), and the conditions for the nucleophilic reaction of the amine in step (c-1).

In some embodiments, step (a-1) of Scheme 4 below is performed in the presence of a base. In some embodiments, step (a-1) of Scheme 4 below is performed in the presence of a non-nucleophilic base. In some embodiments, in step (a-1), reacting a compound of formula (D-1) or a salt thereof with a compound of formula (E-1) or a salt thereof comprises reacting a compound of formula (D-1) or a salt thereof with a coupling agent such as carbonyldiimidazole (CDI) and then with a compound of formula (E-1) or a salt thereof in the presence of a base such as a non-nucleophilic base. In some embodiments, (i) a compound of formula (D-1) or a salt thereof is reacted with CDI prior to reaction with a compound of formula (E-1) or a salt thereof, and then (ii) the reaction product of step (i) is reacted with a compound formula (E-1) or a salt thereof in the presence of a base such as DBU (1,8-diazabicyclo(5.4.0)undec-7-ene).

In some embodiments, step (b-1) of Scheme 4 below is performed in the presence of a base. In some embodiments, step (b-1) is carried out in the presence of an aqueous base, such as aqueous hydroxide. In some embodiments, step (b-1) is carried out in the presence of an aqueous metal hydroxide such as aqueous NaOH.

In some embodiments, step (c-1) of Scheme 4 below is performed in the presence of a base. In some embodiments, step (c-1) is carried out in the presence of a metal carbonate (eg, Na2CO3 or K2CO3).

Scheme 4

Connection (1)

In Scheme 4, R ^a is selected from C1-C4 alkyl groups; and each Xa is independently selected from F or Cl.

In some embodiments, methods for preparing a compound of formulas (I) and (II) wherein X is NH or N(C1-C ₄ alkyl), or a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, comprises reacting a compound of formula (L) or its salts with NR*3 where R* is H or C1-C4 alkyl as shown in Schemes 5 and 6.

- 42 040454

Scheme 5

Scheme 6

Any suitable conditions known in the art can be used for the sulfoxamination reaction, such as conditions for electrophilic addition using amines. In some embodiments, the sulfoxamination reaction is carried out in the presence of a chlorinating or oxidizing agent such as N-chlorosuccinimide (NCS).

In some embodiments, a compound of formula (L), or a salt thereof, is prepared by the method |_| including the oxidation of the sulfur link in the group of the compound of formula (M) or its salt, as shown below in scheme 7.

Scheme 7

Any suitable conditions known in the art can be used for the oxidation reaction. In some embodiments, the oxidation is carried out in the presence of a peroxycarboxylic acid, such as meta-chloroperoxybenzoic acid (m-CPBA).

In some embodiments, a compound of formula (M) or a salt thereof is prepared by a process comprising reacting a compound of formula (O) with a compound of formula (G) or a salt thereof. Any suitable conditions known in the art may be used.

In some embodiments, a compound of formula (O), or a salt thereof, is prepared by a process comprising reacting a compound of formula (P), or a salt thereof, with a phenyl disulfide of formula (Q)

In some embodiments, a compound of formula (P), or a salt thereof, is prepared by amidation

- 43 040454 groups -C(O)OH in the compound of formula (D) or its salt. Any suitable conditions known in the art may be used.

Additional embodiments of the invention include the following.

1. The compound of formula I, its pharmaceutically acceptable salt or their deuterated derivative, where one of Y ¹ and Y ² is N and the other is CH;

X is selected from O, NH and N(C1-C4 alkyl) group;

R ¹ is -(CR ₂ ) _k -O-(CR2) _m (CR) _n (Ring A) _n+1 where each Ring A is a C3-C10 cycloalkyl group optionally substituted with one or more substituents, each of which is independently selected from a C1-C2 alkyl group, a halogenated C1-C2 alkyl group, and halogen, and wherein each R is independently selected from H, OH, and a C1-C2 alkyl group optionally substituted with one or more halogen atoms;

each R ² is independently selected from C1-C2 alkyl, OH, C1-C2 alkoxy, halo, and cyano;

each R3 is independently selected from a C1-C2 alkyl group optionally substituted with one or more OH groups;

each R ⁴ is independently selected from a halogen atom;

k is 0 or 1;

r is 0 or 1;

m is 0, 1, 2 or 3;

n is 0 or 1;

p is 0, 1, 2, 3, 4 or 5; and q is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

2. The compound of formula II, its pharmaceutically acceptable salt, or their deuterated derivative, where

X is selected from O, NH and N(C1-C ₄ alkyl) groups;

R ¹ is -(CR ₂ ) _k -O-(CR ₂ ) _m (CR) _n (Ring A) _n+1 , where each Ring A is a C3-C10 cycloalkyl group optionally substituted with one or more substituents, each wherein each R is independently selected from a C1-C2 alkyl group, a halogenated C1-C2 alkyl group, and halogen, and wherein each R is independently selected from H, OH, and a C1-C2 alkyl group optionally substituted with one or more halogen atoms;

each R ² is independently selected from C1-C2 alkyl, OH, C1-C2 alkoxy, halo, and cyano;

each R ³ is independently selected from a C1-C2 alkyl group optionally substituted with one or more OH groups;

each R ⁴ is independently selected from a halogen atom;

k is 0 or 1;

r is 0 or 1;

m is 0, 1, 2 or 3;

- 44 040454 n is 0 or 1;

p is 0, 1, 2, 3, 4 or 5; and q is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

3. Compound of formula III

its pharmaceutically acceptable salt, or their deuterated derivative, where

R ¹ is selected from the groups - (CR ₂ ) _k -O-(CR ₂ ) _m (CR) _n (Ring A) _n+1 where each Ring A is independently selected from a C ₃ -C ₁₀ cycloalkyl group optionally substituted with one or more substituents each independently selected from a C1-C2 alkyl group, a halogenated C1-C2 alkyl group, and halogen atoms, and wherein each R is independently selected from H, OH, and a C1-C2 alkyl group optionally substituted with one or more halogen atoms;

each R ² is independently selected from C1-C2 alkyl, OH, C1-C2 alkoxy, halo, and cyano;

each R ³ is independently selected from a C1-C2 alkyl group optionally substituted with one or more OH groups;

each R ⁴ is independently selected from halogen atoms;

k is 0 or 1;

r is 0 or 1;

m is 0, 1, 2 or 3;

n is 0 or 1;

p is 0, 1, 2, 3, 4 or 5; and q is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

4. A compound according to any one of embodiments 1-3, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein if R ² is cyano, then said R ² is meta or para relative to the sulfur atom.

5. A compound according to any one of embodiments 1-3, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein each Ring A is a C ₃ -C ₁₀ cycloalkyl group optionally substituted with one or more substituents each independently selected from a C1-C2 alkyl group, a halogenated C1-C2 alkyl group, and halogen atoms, and each R is independently selected from H and OH;

each R ² is independently selected from a C1-C2 alkyl group, OH, a C1-C2 alkoxy group, and halo;

R ⁴ is F;

k is 0;

p is 0, 1 or 2;

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

r is 0 or 1; and moreover, m and n are not equal to 0 at the same time.

6. The compound of embodiment 5, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, characterized in that

R ¹ is -O-(CR ₂ ) _m -Ring A, where Ring A is a C ₃ -C ₁₀ cycloalkyl group optionally substituted with one or more substituents each independently selected from a C1-C2 alkyl group halogenated with C1 -C2 alkyl group and halogen atoms, and m is 1 or 2.

7. The compound of Embodiment 6, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein each R ³ is a methyl group and q is 3 or 4.

8. Compound of Embodiment 7 having formula IV

- 45 040454

its pharmaceutically acceptable salt or their deuterated derivative, where

Ring A is a C3-C10 cycloalkyl group optionally substituted with one or more substituents each independently selected from a _C1 -C2 alkyl group, a halogenated C] _-C2 alkyl group, and halogen atoms; and each R ² is independently selected from C1-C2 alkyl, OH, F, Cl, and C1-C2 alkoxy;

m is 1 or 2; and p is 0, 1, or 2.

9. Connection according to implementation variant 8, characterized in that p is equal to 0 or 1.

10. Connection according to implementation variant 8, characterized in that p is equal to 0.

11. Compound of Embodiment 8 having formula V

its pharmaceutically acceptable salt or their deuterated derivative, where

Ring A is a C3- _C10 cycloalkyl group optionally substituted with one or more substituents each independently selected from a _C1 - _C2 alkyl group, a halogenated _C1 - _C2 alkyl group, and halogen atoms; and each R ² is independently selected from C1-C2 alkyl, OH, F, Cl, and C1-C2 alkoxy;

m is 1 or 2; and p is 0, 1, or 2.

12. A compound according to any one of embodiments 1-11, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein each R ² is independently selected from CH3, OH, F, and OCH3.

13. The compound of Embodiment 12, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, characterized in that p is 0 or 1.

14. The compound of embodiment 13, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, characterized in that p is 0.

15. The compound of Embodiment 11, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein Ring A is a cyclopropyl group substituted with a halogenated C ₁ alkyl group or a halogenated C ₂ alkyl group.

16. The compound of Embodiment 15, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein Ring A is a cyclopropyl group substituted with a CF ₃ group.

17. The compound of Embodiment 11, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, characterized in that m is 1, Ring A is a cyclopropyl group substituted with a CF ₃ group, p is 0 or 1, and R ² , if present , represents a methyl group, a hydroxy group or a methoxy group.

18. The compound of Embodiment 11, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, characterized in that m is 2, Ring A is a C ₃ cycloalkyl group substituted with a CF3 group, p is 0 or 1, and R ² , when it present, is a methyl group, a hydroxy group, or a methoxy group.

19. The compound of embodiment 17 or 18, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein m is 2, Ring A is a cyclopropyl group substituted with a CF3 group, and p is 0.

- 46 040454

20. The compound of Embodiment 11, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein Ring A is selected from a C ₅ bicycloalkyl group optionally substituted with one or more substituents each independently selected from a C ₁ C ₂ alkyl group, halogenated C ₁ -C ₂ alkyl group and halogen atoms.

21. The compound of Embodiment 20, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein Ring A is a C ₅ bicycloalkyl group optionally substituted with halogen.

22. The compound of Embodiment 11, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein Ring A is selected from a C ₇ bicycloalkyl group and a C ₇ tricycloalkyl group, each of which is optionally substituted with one or more substituents each independently selected of a C ₁ -C ₂ alkyl group, a halogenated C ₁ -C ₂ alkyl group, and halogen atoms.

23. The compound of Embodiment 22, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein Ring A is an unsubstituted C7 tricycloalkyl group.

24. Connection selected from

- 47 040454

- 48 040454

- 49 040454

- 50 040454

- 51 040454

a pharmaceutically acceptable salt thereof or a deuterated derivative thereof.

25. Compound according to embodiment 1 having the following formula:

a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof.

26. Compound according to embodiment 1 having the following formula:

- 52 040454 its pharmaceutically acceptable salt or their deuterated derivative.

27. Compound according to embodiment 1 having the following formula:

CF ₃ its pharmaceutically acceptable salt or their deuterated derivative.

28. Compound according to embodiment 1 having the following formula:

CF ₃ its pharmaceutically acceptable salt or their deuterated derivative.

29. Compound according to embodiment 1 having the following formula:

a pharmaceutically acceptable salt thereof or a deuterated derivative thereof. 30. A compound having the following formula:

or a pharmaceutically acceptable salt thereof. 31. A compound having the following formula:

or a pharmaceutically acceptable salt thereof.

32. A compound having the following formula:

or a pharmaceutically acceptable salt thereof.

33. A pharmaceutical composition containing at least one compound selected from compounds according to any one of embodiments 1-32, their pharmaceutically acceptable salts or their deuterated derivatives, and a pharmaceutically acceptable carrier, and optionally one or more of

- 53 040454 (a) compounds II

a pharmaceutically acceptable salt thereof or a deuterated derivative thereof; and (b) compounds III

a pharmaceutically acceptable salt thereof or a deuterated derivative thereof.

34. A method for treating cystic fibrosis, comprising administering to a patient in need thereof a pharmaceutical composition according to embodiment 33.

35. Process for the preparation of a compound of formula (IIIa)

a pharmaceutically acceptable salt thereof or a deuterated derivative thereof, comprising reacting a compound of formula (F), a salt thereof, or a deuterated derivative thereof, with a compound of formula (G), a salt thereof, or a deuterated derivative thereof

where in each of these formulas, one of Y ¹ and Y ² is N and the other is CH;

X is selected from O, NH and N(C1-C4 alkyl) group;

R ¹ is -(CR ₂ ) _k -O-(CR ₂ ) _m (CR) _n (Ring A) _n+1 where each Ring A is a C ₃ -C ₁₀ cycloalkyl group optionally substituted with one or more substituents each independently selected from a C1-C2 alkyl group, a halogenated C1-C2 alkyl group, and halogen, and wherein each R is independently selected from H, OH, and a C1-C2 alkyl group optionally substituted with one or more halogen atoms;

each R ² is independently selected from C1-C2 alkyl, OH, C1-C2 alkoxy, halo, and cyano;

each R ³ is independently selected from a C1-C2 alkyl group optionally substituted with one or more OH groups;

each R ⁴ is independently selected from a halogen atom;

k is 0 or 1;

r is 0 or 1;

m is 0, 1, 2 or 3;

n is 0 or 1;

p is 0, 1, 2, 3, 4 or 5; and q is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

36. The method of embodiment 35, wherein each Y ² is independently N; and each Y ¹ is independently CH.

- 54 040454

37. The method of embodiment 35 or 36 wherein said reaction of a compound of formula (F) or a salt thereof with a compound of formula (G) or a salt thereof is carried out in the presence of a base selected from metal carbonates.

38. The method of any one of embodiments 35-37, characterized in that a salt of a compound of formula (G) is used.

39. The method of Embodiment 38 wherein said salt of the compound of formula (G) is the HCl salt of the compound of formula (G).

40. Method for obtaining a compound of formula (F), or a salt thereof:

or a deuterated derivative thereof, comprising reacting a compound of formula (D), a salt thereof, or a deuterated derivative thereof, with a compound of formula (E), a salt thereof, or a deuterated derivative thereof

where in each of these formulas, one of Y ¹ and Y ² is N and the other is CH;

X is selected from O, NH and N(C ₁ -C4 alkyl) group;

R ¹ is -(CR ₂ ) _k -O-(CR ₂ ) _m (CR) _n (Ring A) _n+1 where each Ring A is a C ₃ -C ₁₀ cycloalkyl group optionally substituted with one or more substituents , each independently selected from C ₁ -C ₂ alkyl group, halogenated C ₁ -C ₂ alkyl group and halogen, and where each R is independently selected from H, OH and C ₁ -C ₂ alkyl group, optionally substituted with one or more a halogen atom;

each R ² is independently selected from C ₁ -C ₂ alkyl, OH, C ₁ -C ₂ alkoxy, halo, and cyano;

each R ³ is independently selected from a C ₁ -C ₂ alkyl group optionally substituted with one or more OH groups;

each R ⁴ is independently selected from a halogen atom;

k is 0 or 1;

r is 0 or 1;

m is 0, 1, 2 or 3;

n is 0 or 1;

p is 0, 1, 2, 3, 4 or 5; and q is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

41. The method of embodiment 40, wherein each Y ² is independently N; and each Y ¹ is independently CH.

42. The method of embodiment 40 or 41, wherein said reaction of a compound of formula (D) or a salt thereof with a compound of formula (E) or a salt thereof is carried out in the presence of a base selected from non-nucleophilic bases.

43. The method of embodiment 40 or 41, wherein said reacting a compound of formula (D), or a salt thereof, with a compound of formula (E), a salt thereof, or a deuterated derivative thereof, comprises reacting a compound of formula (D) with an amide coupling reagent , which is a carbonyldiimidazole (CDI), and then with a compound of formula (E), or a salt thereof, or a deuterated derivative thereof, in the presence of a base selected from non-nucleophilic bases.

44. A method for obtaining a compound of the following formula:

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a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, comprising reacting a compound of formula (F-1), a salt thereof, or a deuterated derivative thereof, where X ^{a is} selected from F or Cl, with a compound of formula (G-1) or a salt thereof, with obtaining the specified compound, or its pharmaceutically acceptable salt, or their deuterated derivative:

45. The method of embodiment 44, wherein said reaction of a compound of formula (F-1) or a salt thereof with a compound of formula (G-1) or a salt thereof is carried out in the presence of a base selected from metal carbonates.

46. The method of embodiment 44 or 45, wherein a salt of a compound of formula (G-1) is used.

47. The method of Embodiment 46 wherein said salt of the compound of formula (G-1) is the HCl salt of the compound of formula (G-1).

48. Method for obtaining the compound of formula (F-1), or its salt:

(F-1) or a deuterated derivative thereof, comprising reacting a compound of formula (D-1) or a deuterated derivative thereof with a compound of formula (E-1) or a deuterated derivative thereof to obtain a compound of formula (F-1) or a salt thereof

(D-1) (F-1) where each X ^a is independently selected from F or Cl.

49. The method of embodiment 48, wherein said reaction of a compound of formula (D-1) or a salt thereof with a compound of formula (E-1) or a salt thereof is carried out in the presence of a base selected from non-nucleophilic bases.

50. The method of embodiment 48 wherein said reacting a compound of formula (D-1) or a salt thereof with a compound of formula (E-1) or a salt thereof comprises reacting a compound of formula (D-1) with an amide coupling agent , representing carbonyldiimidazole (CDI), and then with the compound of formula (E-1) in the presence of a base selected from non-nucleophilic bases.

51. Method for obtaining a compound of formula (D), or its salt:

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or their deuterated derivative, which includes (!) the interaction of a compound of formula (A), or a salt thereof, or a deuterated derivative thereof, with a compound of formula (B), or its salt, or a deuterated derivative thereof, to obtain a compound of formula (C), its salt or their deuterated derivative

(i) hydrolysis of the -C(O)OR ^a group in a compound of formula (C), wherein in each of said formulas, one of Y and Y is N and the other is CH;

X is selected from O, NH and X(C1-Cd alkyl) group;

each R ^a is independently selected from C1-C4 alkyl;

each X ^{a is} independently selected from F or C1;

R ¹ is -(CR2)kO-(CR2) _m (CR) _n (Ko4b4O A) _n+b where each Ring A is a C3-C10 cycloalkyl group optionally substituted with one or more substituents each independently selected from a C1-C2 alkyl group, a halogenated C1-C2 alkyl group, and halogen, and wherein each R is independently selected from H, OH, and a C1-C2 alkyl group optionally substituted with one or more halogen atoms;

each R is independently selected from C1-C2 alkyl, OH, C1-C2 alkoxy, halo, and cyano;

each R ³ is independently selected from a C1-C2 alkyl group optionally substituted with one or more OH groups;

each R ⁴ is independently selected from a halogen atom;

k is 0 or 1;

r is 0 or 1;

m is 0, 1,2 or 3;

η is 0 or 1;

p is 0, 1.2, 3, 4 or 5; and q is 0, 1.2, 3, 4, 5, 6, 7, or 8.

52. The method of Embodiment 51, wherein each Y ² is independently N; and each Y ¹ is independently CH.

53. The method of embodiment 51 or 52, wherein the hydrolysis of the -C(O)OR ^a group is carried out in the presence of a base selected from aqueous bases.

54. The method of any one of embodiments 51-53, wherein said reaction of a compound of formula (A) or a salt thereof with a compound of formula (B) or a salt thereof is carried out in the presence of a base selected from metal carbonates.

55. The method of any one of embodiments 51-54, wherein R ^a is ethyl or t-butyl.

56. Method for obtaining the compound of formula (D-1), or its salt:

(D-1) or a deuterated derivative thereof, comprising

-57040454 (i) reacting a compound of formula (A-1) or a salt or a deuterated derivative thereof with a compound of formula (B-1) or a salt thereof to obtain a compound of formula (C-1) or a salt or a deuterated derivative thereof:

(ii) hydrolyzing the -C(O)OR ^a group in a compound of formula (C-1) or a salt thereof to give a compound of formula (D-1), a salt thereof, or a deuterated derivative thereof, where each R ^a is independently selected from C1-C4 alkyl; and each -Xa is independently selected from F or Cl.

57. The method of embodiment 56 wherein the hydrolysis of the -C(O)OR ^a group is carried out in the presence of a base selected from aqueous bases.

58. The method of embodiment 56 or 57, wherein said reaction of a compound of formula (A-1) or a salt thereof with a compound of formula (B-1) or a salt thereof is carried out in the presence of a base selected from metal carbonates.

59. The method of any one of embodiments 56-59, wherein R ^a is ethyl or t-butyl.

60. A method for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, comprising reacting a compound of formula (L), or a salt thereof, or a deuterated derivative thereof, with NR* ₃ :

where in each of the indicated formulas

X is NH or N(C _r C ₄ alkyl);

R* represents H or C ₁ -C ₄ alkyl;

Xa is selected from F or Cl;

one of Y ¹ and Y ² is N and the other is CH;

R ¹ is -(CR ₂ ) _k -O-(CR ₂ ) _m (CR) _n (Ring A) _n+1 where each Ring A is a C ₃ -C ₁₀ cycloalkyl group optionally substituted with one or more substituents each independently selected from a C1-C2 alkyl group, a halogenated _C1 - _C2 alkyl group, and halogen, and wherein each R is independently selected from H, OH, and a C1-C2 alkyl group optionally substituted with one or more halogen atoms;

each R ² is independently selected from C1-C2 alkyl, OH, C1-C2 alkoxy, halo, and cyano;

each R ³ is independently selected from a C1-C2 alkyl group optionally substituted with one or more OH groups;

each R ⁴ is independently selected from a halogen atom;

k is 0 or 1;

r is 0 or 1;

m is 0, 1, 2 or 3;

n is 0 or 1;

p is 0, 1, 2, 3, 4 or 5; and q is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

63. The use of at least one compound selected from the compounds of any one of embodiments 1-32, their pharmaceutically acceptable salts, or their deuterated derivatives, and optionally one or more of (a) Compound II

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a pharmaceutically acceptable salt thereof or a deuterated derivative thereof; and (b) compounds III

a pharmaceutically acceptable salt thereof or a deuterated derivative thereof; for the treatment of cystic fibrosis.

62. Compound formula

in the form of a pharmaceutically acceptable salt. 63. Compound formula

64. Pharmaceutical composition for the treatment of cystic fibrosis, comprising an effective amount of the compound according to embodiment 25.

65. Pharmaceutical composition for the treatment of cystic fibrosis, comprising an effective amount of the compound according to embodiment 64.

66. Pharmaceutical composition for the treatment of cystic fibrosis, comprising an effective amount of the compound according to embodiment 65.

67. Pharmaceutical composition comprising a compound of the following formula:

its pharmaceutically acceptable salt or their deuterated derivative; a pharmaceutically acceptable carrier; and one of (a) Compound II:

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its pharmaceutically acceptable salt or their deuterated derivative;

(b) Compound III:

its pharmaceutically acceptable salt or their deuterated derivative.

68. The pharmaceutical composition of embodiment 67, wherein the compound having the formula

is in the form of a pharmaceutically acceptable salt.

69. A method of treating cystic fibrosis, comprising administering to a patient in need thereof a compound of any one of embodiments 25, 62, or 63, or a pharmaceutical composition of any one of embodiments 64-68.

Methods for obtaining compounds

General experimental methods

Reagents and starting materials were purchased from commercial suppliers, unless otherwise indicated, and used without purification. Proton and carbon NMR spectra were recorded on a Bruker Biospin DRX 400 MHz Fourier 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 recorded using a broadband observation probe (BBFO) with the sample rotated at a frequency of 20 Hz, at a digital resolution of 0.1834 and 0.9083 Hz/Pt, respectively. All proton and carbon spectra were recorded at a controlled temperature of 30° C. using standard previously published pulse sequences and conventional process parameters. The final purity of the compounds was determined by reverse phase UPLC on a Waters Acquity UPLC BEN C ¹⁸ column (50 x 2.1 mm, particles 1.7 µm) (p/n 186002350) using dual chromatography with a gradient of 1-99% mobile phase B over 3 .0 min. Mobile phase A=H2O (0.05% CF ₃ CO2H). Mobile phase B=CH ₃ CN (0.035% CF3CO2H). Flow rate=1.2 ml/min, injected sample volume=1.5 μl, and column temperature=60°C. The final purity was calculated from the average area under the curve (AUC) of two UV lines (220 nm, 254 nm). Low-resolution mass spectra were recorded in [M+H]+ particle format, obtained using a single quadrupole mass spectrometer equipped with an electrospray ionization (ESI) source, providing the possibility of obtaining a mass determination accuracy of 0.1 Da and a minimum resolution of 1000 (for resolution no units) over 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 a Restek Rt-(3DEXcst column (30mx0.25mmx0.25 µm df), at a flow rate of 2.0 ml/min (carrier gas H ₂ ), at an injection temperature of 220°C and an oven temperature of 120°C, for 15 min.

Example 1 Preparation of a Spray-Dried Dispersion (SDD) of Compound 1

A spray-dried dispersion of Compound 1 was prepared using a Buchi B290 miniature spray dryer. HPMCAS-HG (6.0 g) was dissolved in 200 ml MeOH (methanol)/DCM (dichloromethane) (1/1), Compound 1 (6.0 g) was added and stirred for 30 min to obtain a clear solution. The resulting solution was spray dried under the following conditions to obtain a 50% spray-dried dispersion of 1/50% HPMCAS-HG compound (yield: 80%, solids content 6%).

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Conditions Inlet temperature (°C) 77 Outlet temperature (°C) 39 Nitrogen pressure (psi) (kPa) 95 Aspirator (%) 100 Pump (%) thirty Rotameter (mm) 60 Filter pressure (mbar) -50 Refrigerator temperature (°C) -10

Powder x-ray diffraction

Powder X-ray diffraction measurements were carried out on a PANalytical X-pert Pro diffractometer at room temperature using copper radiation (1.54060 A). The incident beam collimation system consisted of a variable divergence slit to ensure a constant exposure length of the sample and the side of the diffracted beam; used a fast linear solid state detector with an active length of 2.12° 2 theta, measured in scan mode. The powdered sample was compacted on a notched section of a zero background silicon sample holder and rotated to improve statistics. Symmetric scanning was measured at 4-40° degrees 2 theta with 0.017° steps and a scan step time of 15.5 s.

In FIG. 2 shows the SDD spectrum of 50% Compound 1 in HPMCAS-HG and shows that Compound 1 is amorphous in SDD.

Modulated differential scanning calorimetry (MDSC)

MDSC was used to determine the glass transition temperature of an amorphous substance. MDSC was performed on a TA Discovery DSC differential scanning calorimeter (TA Instruments, New Castle, Delaware). The instrument was calibrated using indium. Samples weighing approximately 1-3 mg were weighed into sealed crucibles, which were closed with single-hole lids. The MDSC sample was scanned from -20°C to 210°C at a heating rate of 2°C/min±1°C modulation per 1 min. Data were recorded and analyzed using TA Instruments Trios software (TA Instruments, New Castle, Delaware).

In FIG. 3 shows the MDSC spectrum of SDD of 50% Compound 1 in HPMCAS-HG and shows that SDD has an onset temperature at about 75.6°C, a midpoint at about 82.7°C, and an end temperature at about 89.7°C.

Example 2 Synthesis of compound II. (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-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-1,3dioxolan-4-yl )methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate.

Cesium carbonate (8.23 g, 25.3 mmol) was added to a mixture of benzyl 2-(6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate (3.0 g, 8.4 mmol) and (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl-4-methylbenzenesulfonate (7.23 g, 25.3 mmol) in DMF (N,N-dimethylformamide) (17 ml ). The reaction mixture was stirred at 80° C. for 46 hours under nitrogen. 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 oily substance which contained both of the above products, was directly used on

- 61 040454 the next stage 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 , EER-MS m/z calc. 470.2, found 471.5 (M+1)+. Retention time 2.20 min. ((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)methyl 2-(1-(((R)-2,2-dimethyl1,3-dioxolan-4-yl)methyl)- 6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate, ESI-MS m/z calc. 494.5, found 495.7 (M+1) ⁺ . Retention time 2.01 min.

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 (tetrahydrofuran) (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 completion of the addition, the mixture was stirred for another 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 solid was washed with THF and ethyl acetate. The filtrate was concentrated and purified by column chromatography (30-60% ethyl acetate/hexanes) to give (R)-2-(l-((2,2-dimethyl-1,3-duoxolαn-4yl)methyl)-6-fluoro- 5-nitro-1H-indol-2-yl)-2-methylpropan-1-ol as a brown oil (2.68 g, 87% over 2 steps). EER-MS m/z calc. 366.4, found 367.3 (M+1) ⁺ . Retention time 1.68 min. ¹ H NMR (400 MHz, DMSO^) 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 - 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 purged with N2. Then Pd-C (250 mg, 5 wt%) was added. The reaction mixture was again purged with nitrogen and then stirred under H ₂ (atm.). After 2.5 hours, according to LCMS, only partial conversion to the product was observed. The reaction mixture was filtered through celite and concentrated. The residue was re-subjected to the conditions described above. 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%). EER-MS m/z calc. 336.2, found 337.5 (M+1) ⁺ . Retention time 0.86 min. 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-dioxolane-4 -yl)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-5yl)cyclopropanecarboxylic acid (1.87 g, 7.7 mmol) and thionyl chloride (1.30 mL, 17.9 mmol). After 1 h, a clear solution was obtained. 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 a mixture of (R)-2-(5-amino-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6- fluoro-1 H-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 1N hydrochloric acid. HCl solution, saturated NaHCO ₃ solution and brine, dried over MgSO ₄ and concentrated to give the product (3 g, 100%). EER-MS m/z calc. 560.6, found 561.7 (M+1) ⁺ . Retention time 2.05 min. 1H NMR (400 MHz, DMSO^) δ 8.31 (s, 1H), 7.53 (s, 1H), 7.42-7.40 (m, 2H), 7.347.30 (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 34 min. The solution was concentrated and then partitioned between ethyl acetate and saturated NaHCO3 solution. The ethyl acetate layer was dried over MgSO4 and concentrated. The residue was purified by column chromatography (50-100% ethyl acetate/hexanes) to give the product. (1.3 g, 47%, ee >98% by GLC). EER-MS m/z calc. 520.5, found 521.7 (M+1) ⁺ . Retention time 1.69 min. 1H NMR (400 MHz, DMSO-d ₆ ) 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.

Example 3 Synthesis of Compound III: N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide.

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Part A. Synthesis of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid.

Oh Oh

Stage 1. Diethyl ester of 2-phenylaminomethylenmalonic acid.

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 give 2-phenylaminomethylenemalonic acid diethyl ester as a solid, which was used in the next step without further purification. SH NMR (DMSOd ₆ ) 5 11.00 (d, 1H), 8.54 (d, J=13.6 Hz, 1H), 7.36-7.39 (m, 2H), 7.13-7 .17 (m, 3H), 4.17-4.33 (m, 4H), 1.18-1.40 (m, 6H).

Stage 2. Ethyl ester of 4-hydroxyquinoline-3-carboxylic acid.

A 1 L three-necked flask equipped with a mechanical stirrer was charged with 2-phenylaminomethylenemalonic 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 mixture 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 in the next step without further purification.

Stage 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 i., 150 ml) and stirred for 2 h at reflux. After cooling, the mixture was filtered and the filtrate was acidified to pH 4 with 2N hydrochloric acid. BUT. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 4oxo-1,4-dihydroquinoline-3-carboxylic acid as a pale white solid (10.5 g, 92%). SH NMR (DMSO) 5 15.34 (s, 1H), 13.42 (s, 1H), 8.89 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 7 .88 (m, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.60 (m, 1H).

Part B. Synthesis of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide.

Stage 1. Methyl ester of 2,4-di-tert-butylphenyl ester of carbonic acid.

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) 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 (ca. 1 L) using 10% ethyl acetate/hexanes (~4 L) as eluent. The combined filtrates were concentrated to give 2,4-di-tert-butylphenyl carbonic acid methyl ester as a yellow oil (132 g, quant.). SH NMR (400 MHz, DMSO-4 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-nitrophenyl carbonic acid methyl ester and 2,4-di-tert-butyl-6-nitrophenyl carbonic acid methyl ester.

To a stirred mixture of 2,4-di-tert-butylphenyl carbonic acid methyl ester (4.76 g, 180 mmol) in conc. sulfuric acid (2 ml) cooled in an ice bath was added chilled

-63 040454 mixture of sulfuric acid (2 ml) and nitric acid (2 ml). The addition was carried out slowly so that the reaction temperature did not exceed 50°C. The reaction mixture was allowed to stir for 2 h while warming to room temperature. The reaction mixture was then added to ice water and extracted into diethyl ether. The ether layer was dried (MgSO ₄ ), concentrated and purified by column chromatography (0-10% mixture of ethyl acetate and hexanes) to obtain a mixture of methyl ester of 2,4-di-tert-butyl-5-nitrophenyl carbonic acid ester and methyl ester of 2,4-di -tert-butyl-6-nitrophenyl ester of carbonic acid as a pale yellow solid (4.28 g), which was used directly in the next step.

Step 3 2,4-di-tert-Butyl-5-nitrophenol and 2,4-di-tert-butyl-6-nitrophenol.

A mixture of 2,4-di-tert-butyl-5-nitrophenyl carbonic acid methyl ester and 2,4-di-tert-butyl-6-nitrophenyl carbonic acid methyl ester (4.2 g, 14.0 mmol) was dissolved in MeOH (65 ml), then KOH (2.0 g, 36 mmol) was added. 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 (MgSO ₄ ), concentrated and purified by column chromatography (0-5% ethyl acetate/hexanes) to give 2,4-di-t-butyl-5-nitrophenol (1.31 g, 29% over 2 steps) and 2 ,4-di-tert-butyl-6-nitrophenol. 2,4-di-tert-Butyl-5nitrophenol: ¹ H NMR (400 MHz, DMSO^) δ 10.14 (s, 1H, OH), 7.34 (s, 1H), 6.83 (s, 1H ), 1.36 (s, 9H), 1.30 (s, 9H). 2,4-Di-tert-butyl-6-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-butylphenol.

Pd-5 wt .% on activated carbon (900 mg). The reaction mixture was stirred at the boil under reflux for 2 h, cooled to room temperature and filtered through celite. The Celite was washed with methanol and the combined filtrates were concentrated to 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 ), 1.27 (m, 18H); HPLC, retention time 2.72 minutes, 10-99% CH3CN, chromatography 5 minutes; ESI-MS 222.4 m/z [M+H]+.

Step 5 N-(5-Hidroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide.

Et ₃ N (63.0 ml, 451 mmol) at room temperature. The mixture became homogeneous and was allowed to stir for 10 minutes, then 5-amino-2,4-di-tert-butylphenol (50.0 g, 226 mmol) was added in small portions. The mixture was allowed to stir overnight at room temperature. During the reaction, the mixture became homogeneous. After all the acid was consumed (LC-MS analysis, MH+ 190, 1.71 min), the solvent was removed in vacuo. EtOH (ethyl alcohol) was added to an 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 collected solid was washed with hexanes to give a white solid which was a crystalline precipitate with EtOH. Et ₂ O (diethyl ether) was added to the solid obtained above until a suspension was obtained. 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 collected. The described procedure was repeated five times in total. The solid obtained after the fifth precipitation was placed under vacuum overnight to give N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide (38 g, 52% ). HPLC, retention time 3.45 min, 10-99% CH3CN, chromatography 5 min; 1H NMR (400 MHz, DMSO-d ₆ ) δ 12.88 (s, 1H), 11.83 (s, 1H), 9.20 (s, 1H), 8.87 (s, 1H), 8, 33 (dd, J=8.2, 1.0 Hz, 1H), 7.83-7.79 (m, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.54 -7.50 (m, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 1.38 (s, 9H), 1.37 (s, 9H); EER-MS m/z calc. 392.21; found 393.3 [M+H] ⁺ .

Example 4 Synthesis of Compounds 1-65

Synthesis Example 1 Synthesis of N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidine -1-yl]pyridine-3-carboxamide (compound 1).

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Part A. Synthesis of (4S)-2,2,4-trimethylpyrrolidine hydrochloride.

o D O, O 9 ______NO ₂ * I Raney lipase palatase Ni, H _2g HN xG i) L1AIH4 ΗΝ'^\ί^ ⁰ THF, base T T -2 T ^- ™ ii) HCI - no ₂ ¹ no ₂ ¹ /

Stage 1. Synthesis of methyl 2,4-dimethyl-4-nitropentanoate.

Tetrahydrofuran (THF, 4.5 L) was added to a 20 L glass reactor and stirred under N2 at room temperature. Then 2-nitropropane (1.5 kg, 16.83 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.282 kg, 8.42 mol) were loaded into the reactor and the temperature of the jacket was increased up to 50°С. When the contents of the reactor were heated to about 50° C., methyl methacrylate (1.854 kg, 18.52 mol) was added slowly over 100 minutes. The reaction mixture was maintained at or near 50° C. for 21 hours. The reaction mixture was concentrated in vacuo, then transferred back to the reactor and diluted with methyl tert-butyl ether (MTBE) (14 L). 2 M HCl (7.5 L) was added and the resulting mixture was stirred for 5 minutes, then left to stand. Two transparent layers were observed - the lower yellow aqueous phase and the upper green organic phase. The aqueous layer was removed and the organic layer was stirred again with 2 M HCl (3 L). After separation, the HCl wash solutions were combined again and stirred with MTBE (3 L) for 5 minutes. The aqueous layer was removed and all organic layers in the reactor were combined and stirred with water (3 L) for 5 minutes. After separation, the organic layers were concentrated in vacuo to give a cloudy green oil. It was dried with MgSO ₄ and filtered to give methyl 2,4-dimethyl-4-nitropentanoate as a clear green oil (3.16 kg, 99% yield). 1H NMR (400 MHz, chloroformd) δ 3.68 (s, 3H), 2.56-2.35 (m, 2H), 2.11-2.00 (m, 1H), 1.57 (s, 3H), 1.55 (s, 3H), 1.19 (d, J=6.8 Hz, 3H).

Stage 2. Synthesis of methyl-(2S)-2,4-dimethyl-4-nitropentanoate.

Purified water (2090 L; 10 vol) was charged to the reactor followed by potassium phosphate monobasic (27 kg, 198.4 mol; 13 g/L for a given volume of water). The pH of the reactor contents was adjusted to pH 6.5 (±0.2) with a 20% (w/v) potassium carbonate solution. Racemic methyl 2,4-dimethyl4-nitropentanoate (209 kg; 1104.6 mol) and lipase palatase 20000L (13 L, 15.8 kg; 0.06 vol) were charged to the reactor.

The reaction mixture was brought to 32±2° C., stirred for 15-21 hours and maintained at pH 6.5 using a pH stat with automatic addition of 20% potassium carbonate solution. When the conversion of the starting racemic material was >98% e.i. S-enantiomer, according to the results of determination using chiral GC, turned off the external heating. The reactor was then charged with MTBE (35 L; 5 vol) and the aqueous MTBE layer was extracted (3 times, 400-1000 L). The combined organic extracts were washed with aqueous Na ₂ CO ₃ (4 times, 522 L, 18% w/w, 2.5 vol.), water (523 L; 2.5 vol.) and 10% aqueous NaCl solution ( 314 l, 1.5 vol.). The organic layer was concentrated in vacuo to give methyl (2S)-2,4dimethyl-4-nitropentanoate as a mobile yellow oil (e.i. >98%, 94.4 kg; 45% yield).

Stage 3. Synthesis of (3B)-3,5,5-trimethylpyrrolidin-2-one.

The 20 L reactor was purged with N ₂ . The reactor was charged successively with deionized water-washed wet Raney® Ni catalyst (grade 2800, 250 g), methyl-(2S)-2,4dimethyl-4-nitropentanoate (1741 g, 9.2 mol) and ethanol (13.9 l, 8 vol.). The reaction mixture was stirred at 900 rpm and the reactor was purged with H ₂ and maintained at ~2.5 bar pressure. The reaction mixture was then heated to 60° C. for 5 hours. The reaction mixture was cooled, filtered to remove Raney nickel and the filter cake was washed with ethanol (3.5 L, 2 vol). The ethanol solution of the product was combined with a second batch of the same size and concentrated in vacuo to the minimum volume of ethanol (~1.5 volume). Added heptane (2.5 l) and again concentrated the suspension to ~1.5 volumes. The described technique was repeated 3 times; the resulting suspension was cooled to 0-5°C, filtered with

- 65 040454 suction and washed with heptane (2.5 l). The product was dried under vacuum for 20 min, then transferred to drying trays and dried in a vacuum oven at 40°C overnight to give (3S)-3,5,5trimethylpyrrolidin-2-one as a white crystalline solid (2.042 kg, 16.1 mol, 87%). 1H NMR (400 MHz, chloroform-d) δ 6.39 (s, 1H), 2.62 (ddc, J=9, 9, 8.6, 7.1 Hz, 1H), 2.17 (dd, J=12.4, 8.6 Hz, 1H), 1.56 (dd, J=12.5, 9.9 Hz, 1H), 1.31 (s, 3H), 1.25 (s, 3H ), 1.20 (d, J=7.1 Hz, 3H).

Step 4 Synthesis of (4S)-2,2,4-trimethylpyrrolidine hydrochloride.

i) LiAlH ₄ ii) HC1

In a glass-lined reactor with a volume of 120 l was loaded with pellets of lithium aluminum hydride (2.5 kg, 66 mol) and dry THF (60 l) and heated to 30°C. The resulting suspension was charged with (S)-3,5,5trimethylpyrrolidin-2-one (7.0 kg, 54 mol) in THF (25 L) for 2 hours while maintaining the reaction temperature at 30 to 40°C. After completion of the addition, the reaction temperature was raised to 60-63° C. and maintained overnight. The reaction mixture was cooled to 22°C, then carefully quenched by adding ethyl acetate (EtOAc) (1.0 L, 10 mol), then a mixture of THF (3.4 L) and water (2.5 kg, 2.0 eq.) and then a mixture of water (1.75 kg) with 50% aqueous sodium hydroxide solution (750 g, 2 equivalents of water with 1.4 equivalents of sodium hydroxide relative to aluminum), then 7.5 liters of water. After the addition was complete, the reaction mixture was cooled to room temperature, the solid was removed by filtration and washed with THF (3x25 L). The filtrate and washing solutions were combined and treated with 5.0 l (58 mol) of an aqueous 37% HCl solution (1.05 eq.), maintaining the temperature below 30°C. The resulting solution was concentrated by vacuum distillation to a suspension.

Isopropanol (8 L) was added and the solution was concentrated by vacuum distillation almost to dryness. Added isopropanol (4 l) and suspended the product, heating to about 50°C. Added MTBE (6 l) and cooled the suspension to 2-5°C. The product was collected by filtration and washed with 12 L of MTBE and dried in a vacuum oven (55°C/300 torr/N2 flow) to give (4S)-2,2,4-trimethylpyrrolidine'ΉCl as a white crystalline solid (6, 21 kg, 75% yield. 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.34 (bd, 2H), 3.33 (dd, J=11.4, 8.4 Hz, 1H), 2.75 (dd, J=11 .4, 8.6 Hz, 1H), 2.50-2.39 (m, 1H), 1.97 (dd, J=12.7, 7.7 Hz, 1H), 1.42 (s, 3H), 1.38 (dd, J=12.8, 10.1 Hz, 1H), 1.31 (s, 3H), 1.05 (d, J=6.6 Hz, 3H).

Part B. Synthesis of N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]-2-[(4S)-2,2,4-trimethylpyrrolidine-1- yl]pyridine-3-carboxamide.

Cl

DABCO

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Synthesis of starting materials

Synthesis of tert-butyl-2,6-dichloropyridine-3-carboxylate.

A solution of 2,6-dichloropyridine-3-carboxylic acid (10 g, 52.08 mmol) in THF (210 mL) was treated successively with di-tert-butyl dicarbonate (17 g, 77.89 mmol) and 4-(dimethylamino)pyridine ( 3.2 g, 26.19 mmol) and stirred overnight at room temperature. At this time, 1 n. HCl (400 ml) and vigorously stirred the mixture for about 10 minutes. The product was extracted with ethyl acetate (2x300 ml), the combined organic layers were washed with water (300 ml) and brine (150 ml), dried over sodium sulfate and concentrated under reduced pressure to give 12.94 g (96% yield) t-butyl 2,6-dichloropyridine-3-carboxylate as a colorless oily substance. EER-MS m/z calc. 247.02, found 248.1 (M+1)+; retention time 2.27 min. ¹ H NMR (300 MHz, CDOj) ppm 1.60 (s, 9H), 7.30 (d, J=7.9 Hz, 1H), 8.05 (d, J=8.2 Hz, 1H).

Synthesis of tert-butyl-3-oxo-2,3-dihydro-1 H-pyrazole-1-carboxylate.

A 50 L reactor was used and the jacket was set to 20° C. with stirring at 150 rpm, reflux (10° C.) and nitrogen purge. MeOH (2.860 L) and methyl-(E)-3-methoxyprop-2-enoate (2.643 kg, 22.76 mol) were added and the reactor was closed. The reaction mixture was heated to an internal temperature of 40°C and the system jacket was maintained at 40°C. Hydrazine hydrate (1300 g, 55% w/w, 22.31 mol) was added in portions via addition funnel over 30 minutes. 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 while maintaining the reaction temperature <30°C. A solution of Boc anhydride (di-tert-butyl dicarbonate) (4.967 kg, 5.228 L, 22.76 mol) in MeOH (2.860 L) was added portionwise while maintaining the temperature <45°C. The reaction mixture was stirred at 20°C for 16 h.

The reaction solution was partially concentrated to remove MeOH to give a clear, light amber oil. The resulting oily substance was transferred to a 50 L reactor, stirred and water (7.150 L) and heptane (7.150 L) were added. As a result of the addition, a small amount of product precipitated out. The aqueous layer was poured into a clean container and the interface and the heptane layer were filtered to isolate 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. An addition funnel was attached to the reactor, into which acetic acid (1.474 kg, 1.396 L, 24.54 mol) was charged and added dropwise to the reactor. The jacket was set to 0° C. to absorb the quench exotherm. After the addition was complete (pH=5), the reaction mixture was stirred for 1 hour. The solid was collected by filtration, washed with water (7.150 L) and washed with water a second time (3.575 L). The crystalline material was transferred to a 20 L rotary evaporator flask and heptane (7.150 L) was added. The mixture was suspended at 45° C. for 30 min and 1-2 volumes of solvent were distilled off. The suspension in the rotary evaporator flask was filtered and the solid was washed with heptane (3.575 L). The solid was further dried in vacuo (50° C., 15 mbar) to give tert-butyl 5-oxo-1H-pyrazole-2-carboxylate (2921 g, 71%) as a coarse crystalline solid. 1H 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).

Synthesis of 2-[1-(trifluoromethyl)cyclopropyl]ethanol.

To a solution of lithium aluminum hydride (293 mg, 7.732 mmol) in THF (10.00 ml) in an ice bath was added 2-[1-(trifluoromethyl)cyclopropyl]acetic acid (1.002 g, 5.948 mmol) in THF (3.0 ml) for 30 min, keeping the reaction temperature below 20°C. The mixture was allowed to gradually warm to room 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), NaOH (297 μl of a 6 M solution, 1.784 mmol) and

- 67 040454 followed by water (884.0 µl, 49.07 mmol) to give a granular solid in the mixture. The solid was filtered through celite and the precipitate was washed with ether. The filtrate was further dried with MgSO ₄ and filtered and concentrated in vacuo to give the product with residual THF and ether. The mixture was directly used in the next step without further purification.

Step 1: 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) combined in THF (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. sodium hydroxide solution (30 ml). The organic layer was separated, washed with brine (30 ml), dried over sodium sulfate and concentrated. The crude material was purified by silica gel chromatography eluting with a gradient of ethyl acetate in hexanes (0-30%) to give t-butyl 3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-1-carboxylate (1.03 g , 57%). EER-MS m/z calc. 320.13, found 321.1 (M+1)+; retention time: 0.72 min.

Step 2 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 (2.47 8 ml, 32.16 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated and the resulting oily substance 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]-1Hpyrazole (612 mg, 86%). EER-MS m/z calc. 22 0.08, found 221.0 (M+1)+; retention time 0.5 min. ¹ H NMR (400 MHz, DMSO-de) 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).

Step 3: tert-Butyl-2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine3-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 DMSO (13.75 ml). 1,4-diazabicyclo[2.2.2]octane (DABCO (1,4-diazabicyclo[2.2.2]octane), 62 mg, 0.5540 mmol) was added and the mixture was stirred at room temperature under nitrogen atmosphere for 16 h. 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 t-butyl 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylate (1.01 g, 84 %). EER-MS m/z calc. 431.12, found 432.1 (M+1) ⁺ ; retention time: 0.88 min.

Step 4 2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid.

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tert-Butyl 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylate (1.01 g, 2.339 mmol) and trifluoroacetic acid ( 1.8 ml, 23.39 mmol) were combined in dichloromethane (10 ml) and heated at 40° C. for 3 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]pyridine-3-carboxylic acid (873 mg, 99%) ESI -MS m/z calc. 375.06, found 37 6.1 (M+1)+; retention time 0.69 min.

Step 5 n-(Benzenesulfonyl)-2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridine-3-carboxamide.

A solution of 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (0.15 g, 0.3992 mmol) and carbonyldiimidazole (77 mg, 0.4790 mmol) in THF (2.0 ml) was stirred for 1 h and benzenesulfonamide (81 mg, 0.5190 mmol) and DBU (72 μl, 0.4790 mmol) were added. The reaction mixture was stirred for 16 hours, acidified with 1M aqueous citric acid and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography eluting with a gradient of methanol in dichloromethane (0-5%) to give N-(benzenesulfonyl)-2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole- 1yl]pyridine-3-carboxamide (160 mg, 78%). EER-MS m/z calc. 514.07, found 515.1 (M+1) ⁺ ; retention time 0.74 min.

Step 6. R-(Benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2[(4S)-2,2,4-trimethylpyrrolidin-1- yl]pyridine-3-carboxamide.

Mixture of N-(benzenesulfonyl)-2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridine-3-carboxamide (160 mg, 0.3107 mmol), hydrochloride salt (4S)-2,2,4-trimethylpyrrolidine (139 mg, 0.9321 mmol) and potassium carbonate (258 mg, 1.864 mmol) in DMSO (1.5 ml) was stirred at 130°C for 17 hours. The reaction mixture acidified with 1M aqueous citric acid and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and evaporated to give a crude product which was purified by reverse phase HPLC using a gradient of 10-99% acetonitrile in 5 mM aqueous HCl to give R-(benzenesulfonyl)-6-[3-[2- [1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3 carboxamide (87 mg, 47%). EER-MS m/z calc. 591.21, found 592.3 (M+1) ⁺ ; retention time 2.21 min. Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.48 (s, 1H), 8.19 (d, J=2.8 Hz, 1H), 8.04-7.96 (m, 2H), 7.81 (d, J=8.2 Hz, 1H), 7.77-7.70 (m, 1H), 7.70-7.62 (m, 2H), 6.92 (d, J= 8.2 Hz, 1H), 6.10 (d, J=2.8 Hz, 1H), 4.31 (t, J=7.0 Hz, 2H), 2.42 (t, J=10, 5 Hz, 1H), 2.28 (dd, J=10.2, 7.0 Hz, 1H), 2.17-2.01 (m, 3H), 1.82 (dd, J=11.9 , 5.5 Hz, 1H), 1.52 (d, J=9.4 Hz, 6H), 1.36 (t, J=12.1 Hz, 1H), 1.01-0.92 (m , 2H), 0.92-0.85 (m, 2H), 0.65 (d, J=6.3 Hz, 3H). pKa:

4.95±0.06.

Synthesis of sodium salt R-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol1-yl]-2-[(4S)-2,2,4-Ίrimethylpyrrolidin-1-yl ]pyridine-3-carboxamide (sodium salt of compound 1).

N-(benzenesulfonyl)-6-[3-[2-[1-(Ίrifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4trimethylpyrrolidin-1-yl]pyridin- 3-carboxamide (1000 mg, 1.679 mmol) was dissolved in ethanol (19.87 ml) with heating, filtered through a syringe filter (0.2 μm), washed with warm ethanol (10 ml) and

- 69 040454 was treated with a warm solution of 1 M NaOH solution (1.679 ml, 1.679 mmol). The solution was evaporated at 3035° C., co-evaporated 3 times with ethanol (~20 ml) to give a solid which was dried overnight under vacuum in an oven at 45° C. under nitrogen flow to give 951 mg of an off-white solid. The solid was further dried under vacuum in an oven at 45° C. under a stream of nitrogen over the weekend. 930 mg (89%) of the sodium salt of N(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2.2, 4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide as an off-white amorphous substance. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J=2.7 Hz, 1H), 7.81 (dd, J=6.7, 3.1 Hz, 2H), 7.61 (d, J=7.9 Hz, 1H), 7.39 (dd, J=4.9, 2.0 Hz, 3H), 6.74 (d, J=7.9 Hz, 1H), 6 .01 (d, J=2.6 Hz, 1H), 4.29 (t, J=7.0 Hz, 2H), 2.93-2.78 (m, 2H), 2.07 (t, J=7.1 Hz, 3H), 1.78 (dd, J=11.8, 5.6 Hz, 1H), 1.52 (d, J=13.6 Hz, 6H), 1.33 ( t, J=12.0 Hz, 1H), 1.00-0.92 (m, 2H), 0.89 (c, J=5.3, 4.6 Hz, 2H), 0.71 (d , J=6.3 Hz, 3H). EER-MS m/z calc. 591.2127, found 592.0 (M+1)+; retention time: 3.28 min. PRD (see Fig. 5).

Alternative synthesis of 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine3-carboxylic acid.

Stage 1. Ethyl 3-hydroxy-1H-pyrazole-4-carboxylate.

A mixture of EtOH (20.00 L, 10 vol.) and diethyl 2-(ethoxymethylene) propanedioate (2000 g, 9.249 mol, 1.0 eq.) was added under nitrogen flow to a 50 L reactor equipped with a reflux condenser (10° C) and jacket set to 40°C. The mixture was stirred and then hydrazine hydrate (538.9 g, 55% w/w, 523.7 ml, 55% w/w, 9.249 mol, 1.00 eq.) was added in portions via an addition funnel. After completion of the addition, the reaction mixture was heated to 75°C for 22 hours to obtain a solution of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate, which was directly used in the next step.

Step 2 1-(tert-Butyl)-4-ethyl-3-hydroxy-1H-pyrazole-1,4-dicarboxylate.

A solution of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate was cooled from 75°C to 40°C, then triethylamine (TEA) (46.80 g, 64.46 ml, 462.5 mmol, 0.05 eq. .). A solution of Vossanhydride (2.119 kg, 9.711 mol, 1.05 eq.) in EtOH (2.000 L, 1 eq.) was added to the reactor over 35 minutes. The mixture was stirred for 4 hours to complete the reaction; then water (10.00 L, 5.0 vol.) was added over 15 minutes. The reaction mixture was cooled to 20°C to complete the crystallization of the product. The crystals were left to mature for 1 hour, then the mixture was filtered. The solid was washed with a mixture of EtOH (4.000 L, 2.0 vol.) and water (2.000 L, 1.0 vol.). The solid was then dried in vacuo to give 1-(tert-butyl)-4-ethyl-3-hydroxy-1H-pyrazole-1,4-dicarboxylate (1530 g, 65%) as a colorless fine needle crystalline solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.61 (s, 1H), 8.40 (s, 1H), 4.20 (q, J=7.1 Hz, 2H), 1.56 (s, 9H), 1.25 (t, J=7.1 Hz, 3H).

Step 3 1-(tert-Butyl)-4-ethyl-3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)-1H-pyrazole-1,4-dicarboxylate.

EtO ₂ C

A 5 L reactor was used, jacketed at 40° C., with agitation at 450 rpm, reflux at room temperature and nitrogen purge. The reactor was charged with toluene (1.0 L, 10.0 vol.), 2-[1-(trifluoromethyl)cyclopropyl]ethanol (100.0 g, 648.8 mmol, 1.0 eq.) and 1-(tert -butyl)-4-ethyl-3-hydroxy-1H-pyrazole-1,4-dicarboxylate (166.3 g, 648.8 mmol) and the mixture was stirred. Triphenylphosphine (195.7 g, 746.1 mmol, 1.15 eq.) was charged to the reaction mixture, then the reactor was set to maintain an internal temperature of 40°C. IN

- 70 040454 an addition funnel was loaded with azodicarboxylate (150.9 g, 746.1 mmol, 1.15 eq.), which was added to the reaction mixture while maintaining the reaction temperature from 40 to 50 ° C (the addition was exothermic, the addition exotherm was controlled), and stirred for a total of 2.5 hours. After completion of the reaction, according to HPLC, heptane (400 ml, 4 vol.) was added, the solution was cooled to 20 ° C in 60 minutes, and crystals of the triphenylphosphine oxide-DIAD complex (TPPO-DIAD) precipitated ). The mixture was filtered at room temperature, the solid was washed with heptane (400 ml, 4.0 vol) and dried. The filtrate was used in the next step as a solution in a mixture of toluene and heptane without further purification.

Step 4 Ethyl 3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)-1H-pyrazole-4-carboxylate.

A 500 ml reactor was used, jacketed at 40° C., with agitation at 450 rpm, reflux at room temperature and nitrogen purge. The reactor was charged with a toluene solution consisting of about 160 mmol, 65.0 g of 1-(tert-butyl)-4-ethyl-3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)-1H-pyrazole-1,4- dicarboxylate in 3 volumes of toluene (obtained by concentrating on a rotary evaporator 25% of the filtrate from the previous reaction to 4 volumes). The reaction mixture was maintained at an internal temperature of 40° C. and KOH (33.1 g, 1.5 equiv. 45% KOH aqueous solution) was added in one portion, and this addition caused a mild exothermic reaction with the formation of CO 2 upon removal of the protecting group. The reaction was carried out for 1.5 hours, monitored by HPLC, and during the course of the reaction the product partially crystallized. Heptane (160 ml, 2.5 vol) was added to the reaction mixture and the reaction mixture was cooled to room temperature over 30 minutes. The resulting mixture was filtered and the solid was washed with heptane (80.00 ml, 1.25 vol), dried, then dried in vacuo (55°C, vacuum). 52.3 g of ethyl 3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)-1H-pyrazole-4-carboxylate was obtained as a crude colorless solid which was used without further purification.

Step 5 3-(2-(1-(Trifluoromethyl)cyclopropyl)ethoxy)-1H-pyrazole-4-carboxylic acid.

A 500 ml reactor was used, jacketed at 40° C., with agitation at 450 rpm, reflux at room temperature and nitrogen purge. The reactor was charged with methanol (150.0 ml, 3.0 vol.), a solution of ethyl 3-(2-(1(trifluoromethyl)cyclopropyl)ethoxy)-1H-pyrazole-4-carboxylate (50.0 g, 171, 1 mmol, 1.0 eq.) and stirred the reaction mixture to suspend the solid. The reactor was adjusted to maintain an internal temperature of 40°C. KOH (96 g of 45% aqueous KOH solution, 1.71 mol, 10.0 eq.) was added to the mixture in portions while maintaining the internal temperature <50°C. After completion of the addition, the reaction mixture was maintained at 50° C. and the reaction was continued for 23 h, monitored by HPLC. After completion of the reaction, the mixture was cooled to 10°C, then partially concentrated on a rotary evaporator to remove most of the MeOH. The resulting solution was diluted with water (250 ml, 5.0 vol.) and 2-Me-THF (150 ml, 3.0 vol.) and transferred to the reactor, stirred at room temperature, then stopped stirring and left the layers to separate. The layers were analyzed and found that the TPPO-DIAD complex remained in the organic layer and the product remained in the aqueous layer. The aqueous layer was washed again with 2-Me-THF (100 ml, 2.0 vol), the layers were separated and the aqueous layer was returned to the reaction vessel. The stirrer was turned on and set to 450 rpm and the reactor jacket was set to 0°C. The pH was adjusted to an acidic pH by portionwise addition of 6M aqueous HCl (427 mL, 15 eq.) while maintaining the internal temperature at 10 to 30°C. At a pH close to neutral, the product began to crystallize, accompanied by a vigorous evolution of gas, and therefore the acid was added slowly and then, after the evolution of gas ceased, the addition was continued until pH 1 was reached. To the resulting suspension was added 2-Me-THF (400 ml, 8.0 vol.) and left the product to dissolve in the organic layer. Stirring was stopped, the layers were separated and the aqueous layer was returned to the reactor, mixed and re-extracted with 2-Me-THF (100 ml, 2.0 vol.). The organic layers were combined in the reactor and

- 71 040454 stirred at room temperature, washed with brine (100 ml, 2 vol.), dried over Na ₂ SO ₄ , filtered through celite and washed with solid 2-Me-THF (50 ml, 1.0 vol.) . The filtrate was transferred to a clean rotary evaporator flask, stirred, heated to 50° C. and heptane (200 ml, 4.0 vol) was added and then partially concentrated with the addition of heptane (300 ml, 6.0 vol) and then added seeded with 50 mg of 3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)-1H-pyrazole-4-carboxylic acid, and the product crystallized upon removal of the solvent. The distillation was stopped after distillation of the main part of 2-Me-THF. The bath heater was turned off, the vacuum removed, and the mixture was allowed to stir and cool to room temperature. The mixture was filtered (low speed) and the solid was washed with heptane (100 ml, 2.0 vol) and the solid was collected and dried in vacuo (50°C, rotary evaporator). 22.47 g of 3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)1H-pyrazole-4-carboxylic acid was obtained as an off-white solid. 1H NMR (400 MHz, DMSO-de) δ 12.45 (s, 2H), 8.01 (s, 1H), 4.26 (t, J=7.0 Hz, 2H), 2.05 (t , J=7.0 Hz, 2H), 0.92 (m, 4H).

Step 6 3-(2-(1-(Trifluoromethyl)cyclopropyl)ethoxy)-1H-pyrazole

ZVCF ₃ ZVCF ₃ / DBU \ °\^Ν °\^Ν

Γ ΝΗ F ΝΗ

_HO2C

A mixture of toluene (490.0 ml), 3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)-1H-pyrazole-4-carboxylic acid (70.0 g, 264.9 mmol) and DMSO (70.00 ml) was loaded into the reactor and heated to 100°C with stirring. DBU (about 20.16 g, 19.80 ml, 132.4 mmol) was added to the reactor over 15 minutes. The mixture was stirred for 20 hours to complete the reaction and then cooled to 20°C. The mixture was washed with water (350.0 ml) then 0.5N. HCl aqueous solution (280.0 ml), then water (2x140.0 ml) and finally brine (210.0 ml). The organic layer was dried with Na2SO4 and then activated charcoal (5 g, Darco 100 mesh) was added to the stirred slurry. The dried mixture was filtered through celite, the solid was washed with toluene (140.0 ml) and then dried.

The filtrate was concentrated on a rotary evaporator (50°C, vacuum) to give 3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]-1H-pyrazole (30.89 g, 53%) as an amber oil. 1H NMR (400 MHz, DMSO-d ₆ ) δ 11.87 (s, 1H), 7.50 (d, J=2.4 Hz, 1H), 5.63 (d, J=2.4 Hz, 1H), 4.234.06 (m, 2H), 2.01 (t, J=7.1 Hz, 2H), 1.00-0.77 (m, 4H).

Step 7 Ethyl 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylate.

A mixture of DMF (180.0 ml), ethyl 2,6-dichloropyridine-3-carboxylate (about 29.97 g, 136.2 mmol), 3[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]-1H- pyrazole (30.0 g, 136.2 mmol) and K2CO3, (325 mesh, approximately 24.48 g, 177.1 mmol) were added with stirring to the reactor at 20°C. Then DABCO (about 2.292 g, 20.43 mmol) was added to the reactor and the mixture was stirred at 20°C for 1 hour, and then the temperature was raised to 30°C and the mixture was stirred for 24 hours to complete the reaction. The mixture was cooled to 20°C; then water (360 ml) was slowly added. The mixture was then decanted from the reactor and the solid was isolated by filtration. The solid was then washed with water (2x150 ml), then the solid was dried under vacuum at 55° C. to give ethyl 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl] pyridine-3-carboxylate (51.37 g, 93%) as a fine beige solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J=2.9 Hz, 1H), 8.41 (d, J=8.5 Hz, 1H), 7.75 (d, J=8.5Hz, 1H), 6.21(d, J=2.9Hz, 1H), 4.34(m, 4H), 2.09(t, J=7.1Hz, 2H) , 1.34 (t, J=7.1 Hz, 3H), 1.00-0.84 (m, 4H).

Step 8 2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid.

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A solution of ethyl 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylate (50.0 g, 123.8 mmol) in THF ( 300.0 ml) was obtained in a reactor at 20°C. EtOH (150.0 ml) was added followed by an aqueous solution of NaOH (about 59.44 g of a 10% w/w solution, 148.6 mmol). The mixture was stirred for 1 hour to complete the reaction; then slowly added 1 N. aqueous HCl solution (750.0 ml). The resulting suspension was stirred for 30 min at 10° C. and then the solid was isolated by filtration. The solid was washed with water (150 ml, then 2x100 ml) and then dried under vacuum. The solid was then further dried under vacuum with heating to give 2-chloro-6-[3[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (42.29 g, 91%). 1H NMR (400 MHz, DMSO-d6) δ 13.63 (s, 1H), 8.48-8.35 (m, 2H), 7.73 (d, J=8.4 Hz, 1H), 6 .20 (d, J=2.9 Hz, 1H), 4.35 (t, J=7.1 Hz, 2H), 2.09 (t, J=7.1 Hz, 2H), 1.01 -0.82 (m, 4H).

Synthetic example 2.

Synthesis of compound 2, (R)-N-(phenylsulfonyl)-6-(3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)-1Hpyrazol-1 -yl)-2-(2,2,4-trimethylpyrrolidine -1 -yl)nicotinamide.

(R)-N-(Phenylsulfonyl)-6-(3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)-1H-pyrazol-1-yl)-2-(2,2,4trimethylpyrrolidin-1-yl )nicotinamide was synthesized in the same manner as compound 1 using X(benzenesulfonyl)-2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3carboxamide (1 .5 g, 2.91 mmol), potassium carbonate (2.0 g, 14.56 mmol), (4R)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (1.0 g, 6.7 mmol) in NMP (N-methyl-2-pyrrolidone) (7.5 ml) and 1,2-diethoxyethane (1.5 ml) to give N-(benzenesulfonyl)-6-[3-[2-[1-( trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]-2-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (1.38 g, 79%). EER-MS m/z calc. 591.2127, found 592.0 (M+1)+; retention time 2.3 min. 1H NMR (400 MHz, DMSO-66) δ 12.51 (s, 1H), 8.19 (d, J=2.8 Hz, 1H), 8.03-7.96 (m, 2H), 7 .81 (d, J=8.2 Hz, 1H), 7.76-7.69 (m, 1H), 7.66 (dd, J=8.3, 6.7 Hz, 2H), 6, 91 (d, J=8.2 Hz, 1H), 6.11 (d, J=2.8 Hz, 1H), 4.31 (t, J=7.0 Hz, 2H), 2.41 ( t, J=10.5 Hz, 1H), 2.27 (t, J=8.7 Hz, 1H), 2.07 (t, J=7.1 Hz, 3H), 1.82 (dd, J=11.9, 5.5 Hz, 1H), 1.52 (d, J=9.4 Hz, 6H), 1.36 (t, J=12.1 Hz, 1H), 0.99- 0.92 (m, 2H), 0.88 (tg, J=3.9, 1.6 Hz, 2H), 0.64 (d, J=6.3 Hz, 3H).

Synthetic example 3.

Synthesis of compound 3, (S)-N-((4-hydroxy-3-methoxyphenyl)sulfonyl)-6-(3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)-1H-pyrazol-1-yl) -2-(2,2,4-trimethylpyrrolidin-1-yl)nicotinamide.

Step A. 2-Chloro-N-((4-hydroxy-3-methoxyphenyl)sulfonyl)-6-(3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)-1H-pyrazol-1-yl) nicotinamide.

NH ₂ O=S=O

A solution of 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (0.843 g, 2.24 mmol) and carbonyldimidazole (434 mg, 2.68 mmol) in THF (2.5 ml) was stirred for 2.5 h and 4-hydroxy-3-methoxybenzenesulfonamide (0.500 g, 2.46 mmol) and DBU (0.5 ml, 3.35 mmol) were added ). The reaction mixture was stirred for 21 h, diluted with ethyl acetate (5 ml), acidified with 1N. aqueous hydrochloric acid solution (10 ml) and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate in hexanes (50-100%) to give 2-chloro-N-((4-hydroxy-3-methoxyphenyl)sulfonyl)-6-(3-(2-(1- (trifluoromethyl)cyclopropyl)ethoxy)-1H-pyrazol-1-yl)nicotinamide (906 mg, 72%). EER-MS m/z calc. 560.07, found 515.1 (M+1) ⁺ ; retention time 0.74 min.

Step B. (S)-N-((4-P idroxy-3-methoxyphenyl)sulfonyl)-6-(3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)-1 H-pyrazol-1-yl )-2-(2,2,4-trimethylpyrrolidin-1-yl)nicotinamide.

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A mixture of 2-chloro-N-((4-hydroxy-3-methoxyphenyl)sulfonyl)-6-(3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)-1H-pyrazol-1-yl)nicotinamide (906 mg, 1.62 mmol), (4S)-2,2,4trimethylpyrrolidine hydrochloride (545 mg, 3.64 mmol) and potassium carbonate (1.29 g, 9.33 mmol) in DMSO (5.5 ml) was stirred at 120° C. for 24 hours. The reaction mixture was diluted with 15 ml of water and 5 ml of ethyl acetate. The reaction mixture was then acidified with 6N HCl. aqueous hydrochloric acid solution and separated the layers. The aqueous layer was extracted using 10 ml of ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and evaporated to give the crude product, which was purified by silica gel chromatography using an ethyl acetate gradient in hexanes to give (S)-N-((4-hydroxy-3-methoxyphenyl)sulfonyl) -6-(3-(2-(1(trifluoromethyl)cyclopropyl)ethoxy)-1H-pyrazol-1-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)nicotinamide (470 mg, 45% ). EER-MS m/z calc. 637.2, found 638.2 (M+1)+; retention time: 10.07 min.

Synthetic example 4.

Synthesis of compound 4 1-yl]pyridine-3-carboxamide.

Step A. 2-Chloro-N-(o-tolylsulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridine-3-carboxamide

To 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (196 mg, 0.5217 mmol) in THF (1.739 mL) 1,1'-carbonyldiimidazole (ca. 106.6 mg, 0.6573 mmol) was added and the reaction mixture was stirred for 1 h. 2-methylbenzenesulfonamide (ca. 89.32 mg, 0.5217 mmol) was added, then diazabicyclo(5.4.0)undec-7-ene (DBU) (about 262.2 mg, 257.6 μl, 1.722 mmol) and the reaction mixture was stirred for 3 h. The reaction mixture was diluted with ethyl acetate and 1 M aqueous citric acid and separated the layers. The organic layers were dried and concentrated, and the resulting solid 2-chloro-N-(o-tolylsulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (about 252 mg) was used in the next step without characterization.

Step B. N-(o-tolylsulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2[(4S)-2,2,4-trimethylpyrrolidin- 1-yl]pyridine-3-carboxamide.

To 2-chloro-N-(o-tolylsulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (about 252 mg) and potassium carbonate (392 mg, 2.84 mmol) in 0.4 ml of DMSO was added (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (212 mg, 1.42 mmol) and the reaction mixture was stirred at 130°C for 16 hours The reaction mixture was cooled, diluted with ethyl acetate and 1 M aqueous citric acid solution and the layers were separated. The organic layers were dried, concentrated and the resulting residue was purified on silica gel (24 g) eluting with a 0-14% gradient of methanol in dichloromethane to give N-(o-tolylsulfonyl)-6-[3-[2-[1-(trifluoromethyl) cyclopropyl]ethoxy]pyrazol-1-yl]-2[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (60.6 mg, 19%). 1H NMR (400 MHz,

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DMSO-d6) δ 12.63 (s, 1H), 8.19 (d, J=2.8 Hz, 1H), 8.04 (dd, J=7.9, 1.4 Hz, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.58 (td, J=7.5, 1.5 Hz, 1H), 7.50-7.40 (m, 2H), 6 .93 (d, J=8.3 Hz, 1H), 6.10 (d, J=2.7 Hz, 1H), 4.31 (t, J=7.1 Hz, 2H), 2.64 (s, 3H), 2.39 (d, J=8.8 Hz, 2H), 2.16 (ddt, J=11.8, 9.0, 4.5 Hz, 1H), 2.08 ( t, J=7.0 Hz, 2H), 1.82 (dd, J=11.9, 5.6 Hz, 1H), 1.52 (s, 6H), 1.35 (t, J=12 .1 Hz, 1H), 1.00-0.93 (m, 2H), 0.92-0.84 (m, 2H), 0.69 (d, J=6.2 Hz, 3H). EER-MS m/z calc. 605.23, found 606.4 (M+1)+; retention time 1.92 min.

Synthetic example 5.

Synthesis of compound 5, N-(3-fluorophenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4 -trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.

Step A 2-Chloro-N-(3-fluorophenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide.

NH ₂ O=S=O

To 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (0.200 g, 0.532 mmol) in THF (1.7 mL) 1,1'-carbonyldiimidazole (108.8 mg, 0.6707 mmol) was added and the reaction mixture was stirred for 1 h. 5.4.0)undec-7-ene (DBU) (267.5 mg, 262.8 μl, 1.757 mmol) and the reaction mixture was stirred for 2 hours. The reaction mixture was diluted with ethyl acetate and 1 M aqueous citric acid solution and the layers were separated. The organic layers were dried and concentrated, and the resulting solid 2-chloro-N-(3-fluorophenyl)sulfonyl-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (about 259 mg) was used in the next step without characterization.

Step C. N-(3-Fluorophenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]-2-[(4S)-2,2,4-trimethylpyrrolidine- 1-yl]pyridine-3-carboxamide.

To 2-chloro-N-(3-fluorophenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridine-3-carboxamide (about 259 mg, 0.486 mmol) and potassium carbonate (389.6 mg, 2.819 mmol) in 0.4 ml DMSO was added (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (211.0 mg, 1.41 mmol) and the reaction mixture was stirred at 130 °C for 16 hours. The reaction mixture was cooled, diluted with ethyl acetate and 1 M aqueous citric acid solution and the layers were separated. The organic layers were dried, concentrated and the resulting residue was purified on silica gel (24 g) eluting with a 0-14% gradient of methanol in dichloromethane to give N-(3-fluorophenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl )cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (50.0 mg, 15%). 1H NMR (400 MHz, methanol^) δ 8.23 (d, J=2.7 Hz, 1H), 7.96-7.89 (m, 1H), 7.87-7.77 (m, 2H ), 7.65 (td, J=8.1, 5.3 Hz, 1H), 7.46 (td, J=8.5, 2.5, 1.0 Hz, 1H), 7.02 ( d, J=8.3 Hz, 1H), 5.95 (d, J=2.8 Hz, 1H), 4.37 (t, J=7.0 Hz, 2H), 3.34 (s, 1H), 2.68 (t, J=10.3 Hz, 1H), 2.56-2.48 (m, 1H), 2.28-2.16 (m, 1H), 2.10 (t , J=7.0 Hz, 2H), 1.89 (dd, J=11.9, 5.7 Hz, 1H), 1.59 (d, J=9.7 Hz, 6H), 1.48 (t, J=12.1 Hz, 1H), 1.02-0.96 (m, 2H), 0.86-0.77 (m, 5H). EER-MS m/z calc. 609.2, found 610.3 (M+1)+; retention time 0.81 min.

Synthetic example 6.

Synthesis of compound 6 -[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3carboxamide.

Step A 2-Chloro-N-(4-hydroxyphenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide.

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2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (0.100 g, 0.266 mmol) and CDI (about 51.38 mg, 0.3169 mmol) was combined in THF (600.0 μl) and stirred at room temperature for 2 h. 4-Hydroxybenzenesulfonamide (ca. 53.45 µl, 0.3574 mmol) and stirred the reaction mixture for an additional 16 hours at room temperature. The reaction mixture was diluted with 10 ml of 1 M aqueous citric acid solution and extracted with three 10 ml portions of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give a white solid, 2-chloro-N-(4-hydroxyphenyl)sulfonyl-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy] pyrazol-1-yl]pyridine-3-carboxamide (128 mg, 91%), which was used in the next step without further purification. EER-MS m/z calc. 530.1, found 531.0 (M+1)+; Retention time 0.69 min.

Step B. 2-[(4S)-3,3-Dideuterio-2,2-dimethyl-4-(trideuteriomethyl)pyrrolidin-1-yl]-N-(4hydroxyphenyl)sulfonyl-6-[3-[2-[ 1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3carboxamide.

2-Chloro-K-(4-hydroxyphenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridine-3-carboxamide (1.0 g, 1.9 mmol ), hydrochloride salt (S)-2,2-dimethyl-4-(methyl-d ₃ ) pyrrolidine-3,3-d ₂ (0.892 g, 5.66 mmol) and potassium carbonate (1.55 g, 11, 2 mmol) was combined in DMSO (6 ml) and heated to 130° C. for 16 hours. The reaction mixture was cooled to room temperature and diluted with water (10 ml). After stirring for 15 minutes, ethyl acetate (50 ml) was added to the mixture. The mixture was acidified with 1 M aqueous citric acid (pH~3-4) (30 ml) and the layers were separated. The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated. The resulting crude material was purified by column chromatography (24 g silica gel) using a gradient of 0-30% ethyl acetate in heptane. Individual fractions were analyzed by HPLC and fractions that met the required purity parameters were combined, evaporated and triturated in a mixture of 9:1 ethyl acetate/MTBE. The organic layers were evaporated to 10%, the resulting solid was filtered off and dried overnight under high vacuum to give 2-[(4S)-3,3dideuterio-2,2-dimethyl-4-(trideuteriomethyl)pyrrolidin-1-yl]- N-(4-hydroxyphenyl)sulfonyl-6-[3[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (0.38 g, 32%). EER-MS m/z calc. 612.2, found 613.7 (M+1)+; retention time 1.40 min.

Synthetic example 7.

Synthesis of compound 7, N-(benzenesulfonyl)-2-[(4S)-3,3-dideuterio-2,2-dimethyl-4-(trideuteriomethyl)pyrrolidin-1-yl]-6-[3-[2-hydroxy -2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3carboxamide.

N-(benzenesulfonyl)-2-chloro-6-[3-[2-hydroxy-2-[1]

- 76 040454 (trifluoromethyl) cyclopropyl] ethoxy] pyrazol-1-yl] pyridine-3-carboxamide (0.500 g, 0.942 mmol), (4S) 3,3-dideutherio-2,2-dimethyl-4- (1rideutheriomethyl) pyrrolidine (hydrochloride salt) (320 mg, 2.07 mmol), NMP (3.000 ml) and 1,2-diethoxyethane (500.0 μl) under nitrogen atmosphere. Potassium carbonate (650.8 mg, 4.709 mmol) was added and the reaction mixture was heated to 130°C. The reaction mixture was stirred overnight. The reaction mixture was cooled, diluted with water (2.000 ml) and adjusted to pH <3 with aqueous HCl solution (1.3 ml of a 6 M solution, 7.800 mmol) which was added dropwise. The pH was then adjusted with hydrogen chloride (146.0 μl of a 6 M solution, 0.8760 mmol). The aqueous layer was extracted twice with ethyl acetate (4 ml) and the combined organic layers were washed twice with water, brine and dried over sodium sulfate. The organic layer was then concentrated to a residue which was purified on silica gel using a gradient of 0-60% ethyl acetate in hexanes. Then the resulting material was triturated in a mixture of heptanes and MTBE to obtain X-(benzenesulfonyl)-2-[(48)3,3-dideuterio-2,2-dimethyl-4-(trideuteriomethyl)pyrrolidin-1-yl]-6-[ 3-[2-hydroxy-2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (266 mg, 46%). EER-MS m/z calc. 612.2, found 613.1 (M+1) ⁺ ; retention time: 1.67 min. 'H NMR (400 MHz, DMSO-sc) δ 12.51 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 8.05-7.94 (m, 2H), 7.81 (d, J=8.3 Hz, 1H), 7.72 (d, J=7.3 Hz, 1H), 7.65 (t, J=7.6 Hz, 2H), 6, 90 (d, J=8.2 Hz, 1H), 6.12 (d, J=2.8 Hz, 1H), 5.57 (dd, J=5.5, 2.7 Hz, 1H), 4.42-4.28 (m, 1H), 4.23-4.09 (m, 1H), 3.89 (d, J=4.9 Hz, 1H), 2.39 (d, J= 10.5 Hz, 1H), 2.37-2.22 (m, 1H), 2.06 (dd, J=10.6, 7.0 Hz, 1H), 1.52 (d, J=9 .7 Hz, 6H), 1.04-0.83 (m, 4H).

Synthesis of (48)-3,3-dideuterio-2,2-dimethyl-4-(trideuteriomethyl)pyrrolidine hydrochloride.

palatase enzyme

Ni Raney

LiAIH ₄

HCI

Step A. Methyl 43-4-methyl-2-(methyl-43)-4-nitropentanoate-3,3-42.

A 500 ml three-necked round-bottom flask equipped with a magnetic stirrer, a nitrogen supply line, and a J-Kem thermocouple with mantle heater was charged with 2-nitropropane (34.3 g, 385 mmol), dg-methyl methacrylate (50.0 g, 460 mmol) and stirred at room temperature, after which 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.47 g, 9.62 mmol) was added in one portion. The reaction solution exhibited an exothermic reaction from 20 to ~40°C and was allowed to stir without heating or cooling for 16 hours. The reaction was only partially complete (HPLC), so the solution was heated at 80°C for 4 hours. The reaction mixture was diluted with MTBE (170 ml), washed with 1 M HCl solution (15 ml), dried over magnesium sulfate, filtered and concentrated (29 inches (736 mm) Hg at 60°C) to remove the solvent and residual starting materials to obtain the product in as a light yellow oily substance (75 g, 99%). It was used in the next step without further purification by distillation.

Step C. Methyl 43-(8)-4-methyl-2-(methyl-43)-4-nitropentanoate-3,3-42.

palatase enzyme

Methyl- _43-4 -methyl-2(methyl-43)-4-nitropentanoate-3,3-4 ₂ (75 g, 380 mmol) and 2000 ml Na-phosphate buffer at 0.8 M pH 7.5. Lipase from Rhizomucor miehei (Sigma L4277, palatase from Novozymes) (0.5 vol) was added to the resulting mixture and stirred at 30°C for 25 h. Chiral HPLC (ADH 4.6x250 mm, 5 µm, 1. 0 ml/min, 98% heptane/2% IP A) showed an enantiomeric ratio of 99.8/0.2. The reaction mixture was extracted twice with MTBE (1 L each time). The organic layers contained the emulsion formed during the extraction. The combined organic layers were washed twice with aqueous sodium bicarbonate (5 vol), brine (5 vol), dried over sodium sulfate and concentrated in vacuo to give the desired product, methyl-4 ₃ -(8)-4-methyl -2-(methyl-4 ₃ )-4-nitropentanoate-3D-yr as a yellow oily substance (32.5 g, 43% yield).

Step C. (8)-5,5-Dimethyl-3-(methyl-43)pyrrolidin-2-one-4,4-42.

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The high pressure reactor (Parr mixing flask, 500 ml) was purged and maintained under N ₂ atmosphere. Washed (3 times) with deionized water, wet Raney catalyst Raney® 2800 Ni (6.1 g), methyl-d ₃ -(S)-4-methyl-2-(methyl-d ₃ )-4-nitropentanoate was sequentially loaded into the reactor -3,3-d ₂ (32.5 g, 165 mmol) and ethanol (2 x 90 ml). The reactor was closed and evacuated/filled with N2 (3 times). The reactor was then evacuated without agitation and filled with H ₂ (30 psi (207 kPa)). The Parr flask was shaken while heating the contents to 60° C. and maintaining the H ₂ pressure at 30 psi (207 kPa) for 8 hours. The reactor was evacuated/filled with N 2 (3 times) and the contents were removed by vacuum filtration (through a pad of celite; in an N2 atmosphere). The flask/filter bed was washed with ethanol (3x50 ml).

After the last wash, the solvent-wet filter cake was transferred to another receiver and covered with water for disposal. Note: The catalyst must not be completely dried (must be kept moist during filtration). The filtrate and washings were combined and concentrated (40° C./40 torr (5.3 kPa)) to give (S)-5,5-dimethyl-3-(methyl-d ₃ )pyrrolidin-2one-4,4-d ₂ as a white solid (20 g, 92%).

Step D. (4S)-3,3-Dideuterio-2,2-dimethyl-4-(trideuteriomethyl)pyrrolidine hydrochloride.

A 1 L three-necked round-bottom flask equipped with an overhead mechanical stirrer, a nitrogen supply line, and a J-Kem thermocouple was charged with lithium aluminum hydride pellets (7.6 g, 202 mmol) in THF (80 mL, 4 vol.), heated from 20 to 36°C (heat of stirring). A solution of (S)5,5-dimethyl-3-(methyl-d ₃ )pyrrolidin-2-one-4,4-d ₂ (20 g, 150 mmol) in THF (120 ml, 6 vol) was added to the suspension. for 30 min, leaving the reaction mixture to warm up to ~60°C. The reaction temperature was raised to about boiling point (~68° C.) and maintained for 16 hours. The reaction mixture was cooled to below 40° C. and diluted with 200 ml (10 vol.) MTBE. The mixture was quenched by adding slowly, dropwise, saturated aqueous sodium sulfate solution (1 vol.) over 2 h. After completion of the addition, the reaction mixture was cooled to room temperature. The solid was removed by filtration (through a pad of celite) and washed with ethyl acetate (4 vol.). Under external cooling and under a protective N ₂ layer, the filtrate and washing solutions were combined and processed by adding dropwise anhydrous 4 M HCl solution in dioxane (38 ml, 152 mmol), maintaining the temperature below 20°C. After completion of the addition (20 min), the resulting suspension was concentrated under vacuum at 45°C.

The suspension was filled twice with heptanes (4 vol.) during the concentration. The suspension was cooled to a temperature below 30°C, then the solid was collected by filtration under a N ₂ protective pad. The solid was dried under N ₂ suction and further dried under high vacuum at 45° C. to give (4S)-3,3-dideuterio-2,2-dimethyl-4-(trideuteriomethyl)pyrrolidine hydrochloride (17.5 g, 75% ). The product was very hygroscopic, so the work with it was carried out in a nitrogen atmosphere.

Synthetic example 8.

Synthesis of compound 8, 6-[3-(dispiro [2.0.2 ⁴ .1 ³ ]heptan-7-ylmethoxy)pyrazol-1-yl]-N-(o-tolylsulfonyl)-2-[(4S)-2, 2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.

2-Chloro-6-[3-(dispiro[2.0.2 ^{4.1 3} ]heptan-7-ylmethoxy)pyrazol-1-yl]-N-(o-tolylsulfonyl)pyridine-3carboxamide (0.170 g, 0.341 mmol) and (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (0.116 g, 1.02 mmol) were combined and dissolved in DMSO (2 ml). Finely ground potassium carbonate (95 mg, 0.68 mmol) was added. The reaction mixture was closed and heated overnight to 130°C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 ml) and washed with aqueous citric acid (1 M, 2x50 ml) and brine (1x50 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure.

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The product was isolated by silica gel column chromatography eluting with a gradient of 0-20% methanol in dichloromethane on a 12 g silica gel column to give 6-[3-(dispiro[2.0.2 ^4.13 ]heptan-7ylmethoxy)pyrazol-1-yl] -N-(o-tolylsulfonyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3carboxamide (0.030 g, 15%). EER-MS m/z calc. 575.26, found 576.36 (M+1)+; retention time 2.46 min.

Synthetic example 9.

Synthesis of compound 9, N-(benzenesulfonyl)-2-[4-(hydroxymethyl)-2,2-dimethylpyrrolidin-1-yl]-6[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1 -yl]pyridine-3-carboxamide.

Step A. 2-Hydroxymethyl-4-methyl-4-nitropentanoic acid methyl ester.

1,8-Diazabicyclo[5.4.0]undec-7-ene (3.6 ml, 24 mmol) was added to 2-nitropropane (26.5 ml, 292 mmol). The resulting mixture was heated to 65°C and turned off the heat, and added dropwise methyl-2(hydroxymethyl)acrylate (25 ml, 243 mmol). Then again included heating at 80°C. After heating for 1 h, the heat was turned off and the reaction mixture was stirred at room temperature overnight, then heated at 80°C for another 2 h. bicarbonate (125 ml) and brine (125 ml). The reaction product mixture was chromatographed on a 330 g silica gel column using 0-60% hexanes:ether, the product was eluted at 55-60% to give 2-hydroxymethyl-4-methyl-4-nitropentanoic acid methyl ester (29.68 g, 60%) as a light green oily substance. EER-MS m/z calc. 205.21, found 206.1 (M+1) ⁺ . Retention time: 1.67 min. 1H NMR (250 MHz, CDCl ₃ ) ppm 1.50-1.59 (m, 6H) 1.85-1.98 (m, 1H) 2.10-2.23 (m, 1H) 2.36-2.50 (m, 1H) 2, 60 (d, J=5.71 Hz, 1H) 3.66-3.77 (s, 3H).

Step B. 3-Hydroxymethyl-5,5-dimethylpyrrolidin-2-one.

Hydroxymethyl-4-methyl-4-nitropentanoic acid methyl ester (4.45 g, 21.7 mmol) was added to absolute ethanol (60 mL) followed by Raney nickel (1.7 g, ~15 wt %). The reaction mixture was heated at 60° C. under H2 (2 bar) overnight. Added additional amount of Raney Nickel (1.0 g, ~50 wt.%) and heated the reaction mixture at 60°C in an atmosphere of H ₂ (5 bar) for 3.5 h. At this time, was added additional amount of methyl ester 2- hydroxymethyl-4-methyl-4-nitropentanoic acid (3.95 g, 19.3 mmol) and heated the reaction mixture for 72 h, adding H2 to maintain a pressure of 5 bar. The reaction mixture was filtered through celite and washed with methanol. The crude reaction mixture was chromatographed on silica gel using 0-10% dichloromethane:methanol, the product was eluted at 10% to give 3-hydroxymethyl-5,5dimethylpyrrolidin-2-one (3.69 g, 63%) as a white solid. 1H NMR (250 MHz, CDCl ₃ ) δ ppm 1.31 (d, J=9.01 Hz, 6H) 1.72 (dd, J=12.52, 10.33 Hz, 1H) 2.04 (dd, J=12.58, 8.84 Hz , 1H) 2.73-2.91 (m, 1H) 3.31 (d, J=4.72 Hz, 1H) 3.64-3.95 (m, 2H) 5.93 (brw, 1H ).

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Step C. (5,5-Dimethylpyrrolidin-3-yl)methanol.

Lithium aluminum hydride (3.90 g, 103.00 mmol) was suspended in tetrahydrofuran (60 ml). Then hydroxymethyl-5,5-dimethylpyrrolidin-2-one (3.69 g, 25.77 mmol) in tetrahydrofuran (30 ml) was added dropwise and the reaction mixture was heated at 65°C for 40 h. The reaction mixture was diluted with 2-methyltetrahydrofuran ( 125 ml) and then cooled in an ice bath, then a saturated aqueous solution of Rochelle's salt (200 ml) was added dropwise. The organic layer was extracted with 2-methyltetrahydrofuran (2x200ml) and dried over sodium sulfate to give crude (5,5dimethylpyrrolidin-3-yl)methanol (3.47g, 104%). ¹ H NMR (250 MHz, CDC13) δ ppm 1.06-1.24 (m, 6 H) 1.29 (dd, J=12.58, 7.20 Hz, 2 H) 1.43 (s, 1H) 1.68-1.89 (ws , 1H) 2.31-2.52 (m, 1H) 2.83 (dd, J=11.10, 5.49 Hz, 1H) 3.05-3.26 (m, 1H) 3.48- 3.71 (m, 1H).

Step D. 4-(tert-Butyl-dimethylsilanyloxymethyl)-2,2-dimethylpyrrolidine.

1.8- diazabicyclo[5.4.0]undec-7-ene (5.3 ml, 35.7 mmol). The reaction mixture was stirred for 3.5 hours. The reaction mixture was diluted with chloroform (250 ml) and washed with water (125 ml) and brine (125 ml), then dried over sodium sulfate. The crude product was chromatographed on silica gel and eluted with dichloromethane/methanol eluting with 15-35% methanol to give 4-(t-butyldimethylsilanyloxymethyl)-2,2dimethylpyrrolidine (3.88 g, 67%) as a yellow oil after passing through two columns. EER-MS m/z calc. 243.47, found 244.2 (M+1)+, retention time: 2.52 min. 1H NMR (250 MHz, CDCI3) δ ppm -0.05-0.11 (m, 6H) 0.89 (s, 9H) 1.19 (d, J=18.02 Hz, 6H) 1.25-1.32 (m, 1H) 1, 74 (dd, J=12.63, 8.79 Hz, 1H) 1.92 (shs, 1H) 2.32-2.50 (m, 1H) 2.81 (dd, J=11.54, 6 .37 Hz, 1H) 3.11 (dd, J=11.48, 7.97 Hz, 1H) 3.45-3.61 (m, 2H).

Step E. N-(Benzenesulfonyl)-2-[4-(hydroxymethyl)-2,2-dimethyl-pyrrolidin-1-yl]-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol- 1 -yl]pyridine-3-carboxamide.

N-(Benzenesulfonyl)-2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine3-carboxamide (25 mg, 0.04855 mmol), t-butyl -[(5,5-dimethylpyrrolidin-3-yl)methoxy]dimethylsilane (ca. 35.45 mg, 0.1456 mmol) and K2CO3 (ca. 33.56 mg, 0.2428 mmol) were combined in DMSO (0.5 mL ) and heated at 130° C. for 16 hours. The reaction mixture was partitioned between 1 M citric acid solution and ethyl acetate and the organic layers were separated. The organic layers were washed with brine, dried over sodium sulfate and evaporated. The crude material was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give N(benzenesulfonyl)-2-[4-[[tert-butyl (dimethyl)silyl]oxymethyl]-2,2-dimethylpyrrolidine-1- yl]-6-[3-[2[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (15 mg, 43%). EER-MS m/z calc. 721.2941, found 722.4 (M+1) ⁺ ; retention time 0.97 min.

Step F. N-(Benzenesulfonyl)-2-[4-(hydroxymethyl)-2,2-dimethyl-pyrrolidin-1-yl]-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazol- 1 -yl]pyridine-3-carboxamide.

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N-(Benzenesulfonyl)-2-[4-[[tert-butyl (dimethyl)silyl]oxymethyl]-2,2-dimethylpyrrolidin-1 -yl]6-[3-[2-[1-(trifluoromethyl)cyclopropyl] ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (15 mg, 43%) was dissolved in THF (1 ml) and cooled in an ice bath. Added tetra-n-butylammonium fluoride in THF (300 μl of 1 M solution, 0.3000 mmol) and left the reaction mixture to warm to room temperature. The reaction mixture was stirred for 1 hour and then partitioned between ethyl acetate and 1M citric acid. The organic layers were washed with brine, dried over sodium sulfate and evaporated. The crude material was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give N-(benzenesulfonyl)-2-[4(hydroxymethyl)-2,2-dimethyl-pyrrolidin-1-yl]-6-[3 -[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol1-yl]pyridine-3-carboxamide (8.5 mg, 29%). EER-MS m/z calc. 607.20764, found 608.4 (M+1)+; retention time 1.9 min.

Synthetic example 10.

Synthesis of compound 10, N-(benzenesulfonyl)-6-[3-[[1-(trifluoromethyl)cyclobutyl]methoxy]pyrazol1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl] pyridine-3-carboxamide.

(1-Trifluoromethylcyclobutyl)methanol.

1-Trifluoromethylcyclobutanecarboxylic acid (5.0 g, 30 mmol) was dissolved in diethyl ether (60 ml) and cooled to 0°C. Lithium aluminum hydride (38.66 ml, 1M in diethyl ether) was added dropwise and the solution was allowed to warm to room temperature overnight. The reaction solution was cooled to 0° C. with stirring, and sodium sulfate decahydrate was added, whereby gradual evolution of gas was observed. The addition was continued in portions until no visible gas evolution at room temperature. Then, the reaction solution was filtered through a pad of celite, washing with diethyl ether. The filtrate was concentrated under reduced pressure to give 5.44 g of a mixture containing the desired product and a small amount of residual diethyl ether (36%, by NMR integration). This gave 1-trifluoromethylcyclobutylmethanol (3.46 g, 78%) as a colorless oil. ¹ H NMR (250 MHz, CDCl ₃ ) δ (ppm): 3.82 (s, 2H), 2.392.14 (m, 2H), 2.10-1.85 (m, 4H).

3-(1-Trifluoromethylcyclobutylmethoxy)-pyrazole-1-carboxylic acid tert-butyl ester.

1-Trifluoromethylcyclobutylmethanol (1.50 g, 9.73 mmol) and 3-oxo-2,3-dihydropyrazole-1-carboxylic acid tert-butyl ester (1.63 g, 8.85 mmol) were dissolved in anhydrous tetrahydrofuran (32 ml) . The solution was degassed by sonication and purged with nitrogen gas. Triphenylphosphine (2.55 g, 9.73 mmol) and diisopropyl azodicarboxylate (1.92 ml, 9.73 mmol) were then added dropwise. After the addition was complete, the reaction mixture was heated to 50°C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 ml) and washed with 1 M sodium hydroxide solution (2x100 ml), then with brine (125 ml). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude yellow oil was purified by flash chromatography using a 0-10% ethyl acetate in hexanes gradient method to give 3-(1trifluoromethylcyclobutylmethoxy)pyrazole-1-carboxylic acid tert-butyl ester (2.48 g, 87%) as off-white solid. EER-MS m/z calc. 320.31, found 321.1 (M+1) ⁺ . Retention time 3.74 min.

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3-(1-Trifluoromethylcyclobutylmethoxy)-1H-pyrazole hydrochloride salt.

3-(1-Trifluoromethylcyclobutylmethoxy)pyrazole-1-carboxylic acid tert-butyl ester (2.48 g, 7.74 mmol) was dissolved in a 4 M solution of hydrogen chloride in dioxane (77 ml). The solution was stirred overnight at room temperature, then the volatiles were removed under reduced pressure to give 3-(1-trifluoromethyl-cyclobutylmethoxy)-1H-pyrazole hydrochloride salt (1.95 g, 98%) as a white powder. EER-MS m/z calc. 220.20, found 221.2 (M+1)+. Retention time 2.67 min.

tert-Butyl-2-chloro-6-(3-((1-(trifluoromethyl)cyclobutyl)methoxy)-1H-pyrazol-1-yl)nicotinate.

3-(1-Trifluoromethylclobutylmethoxy)-1H-pyrazole hydrochloride salt (1.95 g, 7.61 mmol) and 2,6-dichloronicotinic acid tert-butyl ester (1.89 g, 7.62 mmol) were dissolved in dimethylformamide ( 15 ml) and potassium carbonate (4.21 g, 30.5 mmol) was added followed by 1,4-diazabicyclo[2.2.2]octane (0.43 g, 3.8 mmol). The reaction mixture was stirred at room temperature overnight, then water (150 ml) was added and the aqueous layer was extracted 4:1 with ethyl acetate:hexanes (100 ml). The organic phase was washed with brine (70 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude oily substance was purified by silica gel chromatography using a gradient method with 0-10% ethyl acetate in hexanes to give 2-chloro-6-[3-(1-trifluoromethylcyclobutylmethoxy)pyrazol-1-yl]nicotinic acid tert-butyl ester (1, 94 g, 66%) as a white solid. EER-MS m/z calc. 431.85, found 432.2 (M+1) ⁺ . Retention time 4.61 min.

2-Chloro-6-[3-(1-trifluoromethylcyclobutylmethoxy)pyrazol-1-yl]nicotinic acid.

2-Chloro-6-[3-(1-trifluoromethylcyclobutylmethoxy)pyrazol-1-yl]nicotinic acid tert-butyl ester (1.9 g, 4.40 mmol) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (5 .0 ml). The reaction solution was stirred at room temperature overnight, after which the volatiles were removed under reduced pressure to obtain 2-chloro-6-[3-(1-trifluoromethylcyclobutylmethoxy)pyrazol-1-yl]nicotinic acid (1.61 g, 97% ) as a white solid. EER-MS m/z calc. 375.74, found 376.2 (M+1) ⁺ . Retention time 3.57 min.

Synthesis of N-(benzenesulfonyl)-2-chloro-6-[3-[[1-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide.

To a stirred solution of 2-chloro-6-[3-[[1-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-1yl]pyridine-3-carboxylic acid (0.150 g, 0.399 mmol) in anhydrous tetrahydrofuran (3.0 ml) was added CDI (78 mg, 0.4810 mmol) per serving. The solution was stirred at room temperature for 2 hours. Then solid benzenesulfonamide (76 mg, 0.48 mmol) was added in one portion, followed by DBU (183 mg, 1.20 mmol) and the tea color solution was stirred at room temperature for another 2 hours. the reaction mixture was slowly added citric acid (2.5 ml of a 1.0 M solution, 2.500 mmol), then

- 82 040454 saturated saline solution (5 ml). After stirring for 10 min, the homogeneous material was extracted with ethyl acetate (3x25 ml). The combined organic extracts were washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Drying in vacuo for 1 hour gave N-(benzenesulfonyl)-2chloro-6-[3-[[1-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (181 mg, 88% ) as a white solid. It contained a small amount of the starting acid impurity and was used in the next step without further purification. EER-MS m/z calc. 514.0689, found 515.1 (M+1)+; retention time 1.98 min.

Synthesis of N-(benzenesulfonyl)-6-[3-[[1-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-1-yl]-2-[(4S)2,2,4-trimethylpyrrolidin-1-yl]pyridin- 3-carboxamide.

A mixture of N-(benzenesulfonyl)-2-chloro-6-[3-[[1-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (0.160 g, 0.311 mmol), (4S)- 2,2,4-trimethylpyrrolidine (hydrochloride salt) (139 mg, 0.932 mmol) and potassium carbonate (215 mg, 1.554 mmol) were stirred in anhydrous dimethyl sulfoxide (2.7 ml) under nitrogen at 130°C for 18 hours. The reaction mixture was left to cool to room temperature and diluted with water (15 ml), and was extracted with ethyl acetate (3x25 ml). The combined organic layers were washed successively with 1 M aqueous citric acid (310 μl of a 1.0 M solution, 0.3107 mmol) and brine, dried over anhydrous sodium sulfate, filtered and evaporated to give a crude yellow material. It was purified on a CombiFlashRf system using a 40 g silica gel gold column eluting with 0-5% methanol in methylene chloride (over 45 min). The product was obtained after 25 min (at 2.6% methanol). The desired fractions were combined and concentrated under reduced pressure. After further drying overnight under high vacuum, N-(benzenesulfonyl)-6-[3-[[1-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-1-yl]-2-[(4S)-2.2, 4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (HCl salt, 40 mg, 20%). EER-MS m/z calc. 591.2127, found 592.3 (M+1)+; retention time 2.25 min. ¹ H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.22 (d, J=2.8 Hz, 1H), 8.00 (dd, J=8.2, 2 .1 Hz, 2H), 7.82 (d, J=8.2 Hz, 1H), 7.72 (tt, J=8.2, 2.0 Hz, 1H), 7.65 (dt, J =8.2, 2.0 Hz, 2H), 6.95 (d, J=8.2 Hz, 1H), 6.18 (d, J=2.8 Hz, 1H), 4.48 (s , 2H), 2.42 (t, J=10.5 Hz, 1H), 2.36-2.22 (m, 3H), 2.11 (td, J=12.1, 5.7 Hz, 4H), 1.95 (dc, J=9.7, 4.3 Hz, 1H), 1.83 (dd, J=12.0, 5.6 Hz, 1H), 1.54 (s, 3H ), 1.51 (s, 3H), 1.37 (t, J=12.2 Hz, 1H), 0.65 (d, J=6.3 Hz, 3H).

Synthesis Example 11 Synthesis of Compound 11 2,2,4-trimethylpyrrolidin-1-yl]pyridine-3carboxamide.

Step A 2-Chloro-N-(4-cyano-2-methylphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide.

A solution of 2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (186.4 mg, 0.5 mmol) and 1.1' -carbonyldiimidazole (97.29 mg, 0.60 mmol) in THF (2.5 ml) was stirred for 30 min and 4-cyano-2-methylbenzenesulfonamide (127.5 mg, 0.65 mmol) was added and 1.8 -diazabicyclo(5.4.0)undec-7-ene (DBU) (89.7 µl, 0.60 mmol). After 16 hours, the reaction mixture was diluted with 1M aqueous citric acid and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography using 0-5% methanol in dichloromethane to give 2-chloro-N-(4-cyano-2methylphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazole -1-yl]pyridine-3-carboxamide (270 mg, 100%). EER-MS m/z calc. 539.06, found 540.1 (M+1)+; retention time: 0.73 min.

Step B. N-(4-cyano-2-methylphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S)-2,2, 4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.

- 83 040454

A mixture of 2-chloro-Ni(4-cyano-2-methylphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (270 mg, 0. 50 mmol), (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (168.1 mg, 1.123 mmol) and potassium carbonate (310.4 mg, 2.246 mmol) in DMSO (1.87 ml) was stirred at 130°C for 15 hours the Reaction mixture was acidified with 1 M aqueous citric acid solution and was extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography using 0-5% methanol in dichloromethane to give the crude product. The crude product was repurified by reverse phase HPLC-MS using a column

Luna C18 (2) (75x30 mm, particle size 5 µm), commercially available from Phenomenex (part number: 00C-4252-U0-AX), and double chromatography with a gradient of 1-99% mobile phase B for 15.0 min. Mobile phase A=H2O (5 mM HCl). Mobile phase B=CH ₃ CN. Flow rate=50 ml/min and column temperature=25° C. to give N-(4-cyano-2-methylphenyl)sulfonyl-6-[3-[[1(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1 - yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3 carboxamide (150 mg, 48%). EER-MS m/z calc. 616.21, found 617.3 (M+1)+; retention time 2.06 min. ¹ H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 8.23-8.18 (m, 2H), 8.03 (d, J=1.6 Hz, 1H), 7.97 (dd, J=8.0, 1.8 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 6.95 (d, J=8.3 Hz, 1H ), 6.16 (d, J=2.7 Hz, 1H), 4.43-4.32 (m, 2H), 2.67 (s, 3H), 2.27 (d, J=3, 5 Hz, 1H), 2.25 (s, 1H), 2.17 (dd, J=11.3, 5.7 Hz, 1H), 1.83 (dd, J=11.9, 5.3 Hz, 1H), 1.52 (d, J=4.4

Hz, 6H), 1.36 (s, 1H), 1.09 (dt, J=5.5, 1.6 Hz, 4H), 0.70 (d, J=6.0 Hz, 3H).

Synthetic example 12.

Synthesis of compound 12, N-(2-methoxy-4-methylphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S)-2,2 ,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.

Step A 2-Chloro-N-(2-methoxy-4-methylphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide.

A solution of 2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (186.4 mg, 0.5 mmol) and 1.1' -carbonyldiimidazole (97.29 mg, 0.60 mmol) in THF (2.5 ml) was stirred for 30 min and 2-methoxy-4-methylbenzenesulfonamide (130.8 mg, 0.65 mmol) was added and 1.8 -diazabicyclo(5.4.0)undec-7-ene (DBU) (89.7 µl, 0.60 mmol). After 16 hours, the reaction mixture was diluted with 1M aqueous citric acid and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography using 0-5% methanol in dichloromethane to give 2-chloro-N-(2-methoxy-4-methylphenyl)sulfonyl-6[3-[[1-(trifluoromethyl)cyclopropyl]methoxy] pyrazol-1-yl]pyridine-3-carboxamide (210 mg, 77%). IERMS m/z calc. 544.1, found 545.1 (M+1) ⁺ ; retention time 0.73 min, as a colorless solid.

Step B. N-(2-Methoxy-4-methylphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S)-2,2, 4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.

A mixture of 2-chloro-N-(2-methoxy-4-methylphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (210 mg, 0 .3854 mmol), (4S)-2,2,4-trimethylpyrrolidine

- 84 040454 (hydrochloride salt) (168.1 mg, 1.123 mmol) and potassium carbonate (310.4 mg, 2.246 mmol) in DMSO (1.87 ml) was stirred at 130°C for 15 hours. The reaction mixture was acidified 1 M aqueous citric acid solution and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography using 0-5% methanol in dichloromethane to give the crude product. The crude product was repurified by reverse phase HPLC-MS using a Luna C18 (2) column (75x30 mm, particle size 5 µm) commercially available from Phenomenex (part number: 00C-4252-U0-AX) and a double chromatography with a gradient of 1-99% of mobile phase B in 15.0 minutes. Mobile phase A=H2O (5 mM HCl). Mobile phase B=CH ₃ CN. Flow rate=50 ml/min and column temperature=25° C. to give N-(2-methoxy-4-methylphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclonpropyl]methoxy]pyrazole-1 -yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (95 mg, 39.25%). EER-MS m/z calc. 621.2, found 622.3 (M+1)+; retention time: 2.19 min. 1H

NMR (400 MHz, DMSOCH) δ 12.39 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.78 (t, J=8.5 Hz, 2H), 7 .10 (d, J=1.4 Hz, 1H), 6.94 (dd, J=10.1, 8.1 Hz, 2H), 6.15 (d, J=2.7 Hz, 1H) , 4.43-4.30 (m, 2H), 3.89 (s, 3H), 2.49-2.38 (m, 2H), 2.37 (s, 3H), 2.21 (dd , J=11.2, 6.1 Hz, 1H), 1.85 (dd, J=11.9, 5.5 Hz, 1H), 1.53 (d, J=11.0 Hz, 6H) , 1.37 (s, 1H), 1.12-1.04 (m, 4H), 0.78 (d, J=6.2 Hz, 3H).

Synthetic example 13.

Synthesis of compound 13 -trimethylpyrrolidin-1 -yl]pyridine-3-carboxamide.

Step A 2-Chloro-N-(2,4-dimethoxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide.

A solution of 2-chloro-6-[3-[[ 1 - (trifluoromethyl) cyclopropyl] methoxy] pyrazol-1 -yl] pyridine-3-carboxylic acid (186.4 mg, 0.5 mmol) and 1.1' -carbonyldiimidazole (97.29 mg, 0.60 mmol) in THF (2.5 ml) was stirred for 30 min and 2,4-dimethoxybenzenesulfonamide (141.2 mg, 0.65 mmol) and 1,8 diazabicyclo(5.4 .0) undec-7-ene (DBU) (89.7 µl, 0.60 mmol). After 16 hours, the reaction mixture was diluted with 1M aqueous citric acid and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography using 0-5% methanol in dichloromethane to give 2-chloro-N-(2,4-dimethoxyphenyl)sulfonyl-6-[3-[[1(trifluoromethyl)cyclopropyl]methoxy]pyrazole- 1-yl]pyridine-3-carboxamide (210 mg, 75%). EER-MS m/z calc. 560.1, found 561.1 (M+1) ⁺ ; retention time: 0.71 min, as a colorless solid.

Step B. N-(2,4-Dimethoxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4- trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.

2-Chloro-N-(2,4-dimethoxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide mixture (210 mg, 0.3744 mmol), (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (168.1 mg, 1.123 mmol) and potassium carbonate (310.4 mg, 2.246 mmol) in DMSO (1.87 ml) was stirred at 130 °C for 15 hours. The reaction mixture was acidified with 1 M aqueous citric acid solution and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography using 0-5% methanol in dichloromethane to give the crude product. The crude product was repurified by reverse phase HPLC-MS using a Luna C18 (2) column (75x30 mm, particle size 5 µm) commercially available from Phenomenex (part number: 00C4252-U0-AX) and double chromatography with 1-99% gradient of mobile phase B over 15.0 min. Mobile phase A=H ₂ O (5 mM HCl). Mobile phase B=CH ₃ CN. Flow rate=50 ml/min and column temperature=25°C to give N-(2,4-dimethoxyphenyl)sulfonyl-6-[3-[[1(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl ]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridin-3

- 85 040454 carboxamide (110 mg, 46%). EER-MS m/z calc. 637.2, found 638.3 (M+1)+; retention time 2.14 min. 1H NMR (400 MHz, DMSO-d ₆ ) δ 12.34 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.77 (d, J=8.3 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.74 (d, J=2.3 Hz, 1H) , 6.70 (dd, J=8.8, 2.3 Hz, 1H), 6.15 (d, J=2.7 Hz, 1H), 4.43-4.31 (m, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 2.54 (s, 1H), 2.42 (dd, J=10.5, 7.0 Hz, 1H), 2.21 (dd, J=11.6, 5.9 Hz, 1H), 1.85 (dd, J=11.9, 5.5 Hz, 1H), 1.55 (s, 3H), 1.52 ( s, 3H), 1.38 (s, 1H), 1.09 (dt, J=5.9, 1.6 Hz, 4H), 0.80 (d, J=6.3 Hz, 3H).

Synthetic example 14.

Synthesis of compound 14 yl]pyridine-3-carboxamide.

F F F

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

F F

A 5000 ml three neck round bottom flask was equipped with a mechanical stirrer, heating mantle, J-Kem temperature sensor/regulator and addition funnel, water-cooled reflux condenser and nitrogen inlet/removal. The flask was charged under nitrogen atmosphere with tert-butyl-5-oxo-1Hpyrazole-2-carboxylate (70 g, 0.3800 mol) and tetrahydrofuran (840 ml, 12 ml/g) to give a clear pale yellow solution. Started stirring and recorded the temperature in the reactor, 19°C. The reactor was then charged with [1-(trifluoromethyl)cyclopropyl]methanol (58.56 g, 0.4180 mol) which was added neat in one portion followed by triphenylphosphine (109.6 g, 0.4180 mol) as a solid substances, one portion. The resulting clear pale yellow solution was then treated with diisopropyl azodicarboxylate (clear reddish-orange liquid) (82.3 mL, 0.4180 mol) which was added dropwise undiluted over 1 hour to give a smooth exotherm to 40°C and a clear light amber solution. The reaction mixture was then heated to a reactor temperature of 50° C. and maintained under these conditions 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 oily substance was suspended in toluene (560 ml) and stirred at room temperature for 1 hour, during which time a solid (triphenylphosphine oxide, MW = 278.28) precipitated. ). The thick suspension was filtered through a Buchner funnel with a glass filter and the filter cake was washed by displacement using toluene (150 ml) and then dried for 30 min. The clear amber filtrate was concentrated under reduced pressure to give a clear amber oil. The material was purified by flash column chromatography on silica gel (solid pack on a 1.5 kg Celite column) eluting with a gradient of 100% hexane to 20% EtOAc in hexane and collecting 450 ml fractions. The product was eluted with about 5% EtOAc in hexane. The desired fractions were combined and concentrated under reduced pressure to give a clear, pale yellow oil which was the desired product, t-butyl-3[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1-carboxylate (81 g, 0.264 mol , 70%). 1H NMR (400 MHz, DMSO-d6) 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). EER-MS m/z calc. 306.11914, found 259.0 (M-48)+; retention time 1.76 min.

- 86 040454

Step B. 3-[[1-(Trifluoromethyl)cyclopropyl]methoxy]-1H-pyrazole.

A 5000 ml three neck round bottom flask was equipped with a mechanical stirrer, heating mantle, J-Kem temperature probe, water-cooled reflux condenser, addition funnel and nitrogen inlet/removal. The reactor was charged under nitrogen atmosphere with tert-butyl 3-[[1(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1-carboxylate (80 g, 0.2612 mol), dichloromethane (320 ml, 4 ml/g) and methyl alcohol (320 ml, 4 ml/g) to give a clear pale yellow solution. Started stirring and recorded the temperature in the reactor, 19°C. An addition funnel was loaded with a 4 M solution of HCl in 1,4-dioxane (195.9 ml, 0.7836 mol), which was then added dropwise over 1 hour to obtain a smooth exotherm to 30°C. The resulting clear pale yellow solution was heated to a reactor temperature of 45° C. and maintained under these conditions for 1 hour when LC/MS analysis indicated completion of the reaction. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The remaining residue was dissolved in methyl tert-butyl ether (640 ml) and then transferred to a separatory funnel and separated 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 methyl tert-butyl ether (2x200 ml). The combined organic layers were washed with saturated sodium chloride solution (500 ml), dried over sodium sulfate (300 g) and then filtered through a Buchner funnel with a glass filter. 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%) which was the desired product, 3-[ [1-(trifluoromethyl)cyclopropyl]methoxy]-1H-pyrazole. 1H 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). EER-MS m/z calc. 206.0667, found 207.0 (M+1)+; retention time 1.07 min.

Step C. tert-Butyl-2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine3-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-cooled reflux condenser, an addition funnel, and nitrogen inlet/removal. 3-[[1-(Trifluoromethyl)cyclopropyl]methoxy]-1H-pyrazole (45g, 0.2183mol) and N,Ndimethylformamide (540mL, 12mL/g) were charged to a reactor under nitrogen to give a clear, pale yellow solution. Started stirring and recorded the temperature in the reactor, 17°C. The reactor was then charged with tert-butyl-2,6-dichloropyridine-3-carboxylate (54.16 g, 0.2183 mol) as a solid, in one portion. The resulting clear pale yellow solution was then treated with potassium carbonate (39.22 g, 0.2838 mol) which was added in one portion as a solid, then 1,4-diazabicyclo[2.2.2]octane (3.67 g, 0 .03274 mol), which was added in one portion as a solid. The resulting pale yellow suspension was allowed to stir at room temperature for 24 hours. The reaction mixture was cooled to 10° C. in a crushed ice/water cooling bath. The addition funnel was charged with water (540 ml), which was added dropwise over 45 min to obtain a thick suspension and an exotherm to 15°C. The resulting suspension was stirred at 15° C. for 30 minutes and then filtered through a Buchner funnel with a glass filter. The filter cake was washed by displacement using water (2 x 500 ml) and then dried on a Buchner funnel with suction for 2 h. a solid, which is tert-butyl-2-chloro-6-[3-[[1(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylate. EER-MS m/z calc. 361.0441, found 361.9 (M+1) ⁺ ; retention time 2.27 min.

Step D 2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid.

- 87 040454

A 1000 ml three neck round bottom flask was equipped with a mechanical stirrer, heating mantle, J-Kem temperature sensor/controller, addition funnel, water-cooled reflux condenser and nitrogen inlet/outlet. tert-Butyl-2-chloro-6[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylate (70 g, 0.1675 mol) and 2-propanol (350 ml) to give an off-white suspension. Started stirring and recorded the temperature in the reactor, 19°C. An addition funnel was charged with 6M aqueous HCl (139.6 mL, 0.8375 mol) which was then added dropwise over 10 minutes to give an exotherm to 30°C. Then the resulting suspension was heated to boiling (temperature in the reactor ~82°C). Upon heating, the suspension became a clear, pale yellow solution (at this point in time, the temperature in the reactor was ~75°C). After stirring at reflux for ~30 min, a solid began to precipitate. The suspension was stirred at the boil for another 30 minutes, at which time water (210 ml) was added dropwise over 15 minutes. Then the heating was stopped and the suspension was stirred and allowed to cool slowly to room temperature. The material was collected by vacuum filtration on a Buchner funnel with glass filter and the filter cake was washed by displacement using 1:1 water/2-propanol (100 ml) followed by water (2x100 ml) and then dried on a Buchner funnel with suction for 30 min. The material was further dried in a vacuum oven at 45°C for 24 h to give 2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (56 g, 0.155 mol, 92%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) 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). EER-MS m/z calc. 361.0441, found 361.9 (M+1)+; retention time 3.23 min.

Step E. Na(Benzenesulfonyl)-2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1yl]pyridine-3-carboxamide.

F f F f

2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (150 mg, 0.4144 mmol) was dissolved in THF (2.000 ml). CDI (about 80.64 mg, 0.4973 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 hours. Benzenesulfonamide (ca. 84.68 mg, 0.5387 mmol) was added followed by DBU (ca. 126.2 mg, 124.0 μl, 0.8288 mmol). The reaction mixture was allowed to stir at room temperature for an additional 1.5 hours. The reaction mixture was concentrated to half volume, diluted with dichloromethane and loaded directly onto a 12 g silica gel column and eluted with a gradient of 0-10% methanol in dichloromethane; the product was eluted at 10%. Fractions containing the desired product were combined and concentrated. N (benzenesulfonyl)-2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (168 mg, 81%) was obtained as a colorless oily substance . EER-MS m/z calc. 500.05328, found 501.0 (M+1) ⁺ ; retention time 1.92 min (chromatographic time 3 min).

Step F. N-(Benzenesulfonyl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2[(4S)-2,2,4-trimethylpyrrolidin-1-yl] pyridine-3-carboxamide.

F f F _F

N-(Benzenesulfonyl)-2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine3-carboxamide (168 mg, 0.3354 mmol) and (4S)-2 ,2,4-trimethylpyrrolidine (hydrochloride salt) (about 150.6 mg, 1.006 mmol) was combined and dissolved in DMSO (0.5 ml). Finely ground potassium carbonate (ca. 278.1 mg, 2.012 mmol) was added and the reaction mixture was allowed to stir at 130° C. overnight. The reaction mixture was diluted with EtOAc (50 ml) and washed with 1 M aqueous citric acid solution (2x50 ml) and brine (1x50 ml). The organic layer was dried over

- 88 040454 sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography: 24 g silica gel column, 0-5% MeOH/DCM gradient; the product was eluted at 2.5%. Pure fractions were combined and concentrated under reduced pressure and azeotropically distilled with MeOH to give R-(benzenesulfonyl)-6[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S) -2,2,4-trimethylpyrrolidin-1 yl]pyridine-3-carboxamide (74.9 mg, 39%). Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.51 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 8.05-7.95 (m, 2H), 7.82 (d, J=8.2 Hz, 1H), 7.78-7.70 (m, 1H), 7.66 (dd, J=8.3, 6.7 Hz, 2H), 6 .92 (d, J=8.3 Hz, 1H), 6.15 (d, J=2.7 Hz, 1H), 4.43-4.30 (m, 2H), 2.40 (t, J=10.5 Hz, 1H), 2.26 (t, J=8.6 Hz, 1H), 2.09 (dt, J=12.3, 6.4 Hz, 1H), 1.82 ( dd, J=12.0, 5.6 Hz, 1H), 1.53 (s, 3H), 1.51 (s, 3H), 1.36 (t, J=12.1 Hz, 1H), 1.151.04 (m, 4H), 0.64 (d, J=6.2 Hz, 3H). EER-MS m/z calc. 577.1971, found 578.3 (M+1)+; retention time: 2.16 min (chromatographic time 3 min).

Synthetic example 15.

Synthesis of compound 15. R-(o-tolylsulfonyl)-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidine -1-yl]pyridine-3-carboxamide.

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

To a degassed solution of Ph ₃ P (ca. 51.28 g, 195.5 mmol) in toluene (360.0 ml) under nitrogen gas at 0°C was added DIAD (diisopropyl azodicarboxylate) (ca. 39.53 g, 37. 86 ml, 195.5 mmol). The mixture was stirred at 0° C. for 30 minutes to give a white suspension. To this mixture was added dropwise a solution of (2,2,3,3-tetramethylcyclopropyl) methanol (about 29.84 g of a 70% w/w solution, 162.9 mmol) and tert-butyl-3-hydroxypyrazole-1- carboxylate (30 g, 162.9 mmol) in toluene (600.0 ml) at ~5°C for 2 hours. The mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was heated to 75°C in total 6 h and then allowed to cool to room temperature. The suspension was diluted with heptane (900.0 ml) and stirred at room temperature for 3 hours. The suspension was filtered through celite and the precipitate was washed 3X using 100 ml heptane. The filtrate was concentrated in vacuo to give a thick yellow oil. The crude product was chromatographed on a 750 g silica gel column saturated with dichloromethane eluting with a gradient of 0-20% EtOAc/hexanes. The collected product containing fractions were concentrated in vacuo to give an off-white solid. Received tert-butyl-3-[(2,2,3,3tetramethylcyclopropyl)methoxy]pyrazole-1-carboxylate (30.1 g, 63%). 1H 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 ). EER-MS m/z calc. 294.19434, found 295.0 (M+1) ⁺ ; retention time 2.19 min.

Step B 3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]-1 H-pyrazole.

To a solution of tert-butyl 3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazole-1-carboxylate (127 g, 431.4 mmol) in THF (317.5 ml) and ethyl alcohol (635, 0 ml) sodium hydroxide (about 431.4 ml of a 2 M solution, 862.8 mmol) was slowly added and 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 again one

- 89 040454 times the aqueous phases were extracted with methyl tert-butyl ether (250 ml). The combined organic phases were dried, filtered and evaporated to give 3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]-1Hpyrazole (75 g, 89%) as a viscous oil. 1H NMR (400 MHz, DMSO-d ₆ ) δ 11.78 (s, 1H), 7.48 (t, J=2.1 Hz, 1H), 5.65 (s, 1H), 4.05 ( e, J=7.7 Hz, 2H), 1.08 (s, 6H), 1.00 (s, 6H), 0.67 (t, J=7.7 Hz, 1H). EER-MS m/z calc. 194.1419, found 195.0 (M+1)+; retention time 1.43 min.

Step C Ethyl 2-chloro-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine-3carboxylate.

ABOUT

To ethyl 2,6-dichloropyridine-3-carboxylate (16.8 g, 76.35 mmol) and 3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]-1H-pyrazole (about 14.83 g , 76.35 mmol) in DMF (201.6 ml) was added potassium carbonate (about 13.72 g, 99.26 mmol) followed by DABCO (about 1.284 g, 11.45 mmol). The suspension was stirred at room temperature for 16 hours. The cream-colored thin suspension was slowly diluted with water (201.6 ml) and the resulting thick suspension was stirred at room temperature for 30 minutes using an overhead stirrer. The precipitate was collected using a medium sintered filter and washed 3 times with 25 ml of water. The solid was air dried for 30 minutes and then dried in vacuo using an EtOAc azeotrope. Ethyl 2-chloro-6-[3-[(2,2,3,3tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine-3-carboxylate (28.8 g, 100%) was obtained as an off-white solid. EER-MS m/z calc. 377.1506, found 378.37 (M+1) ⁺ ; retention time 2.47 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (dd, J=2.9, 0.9 Hz, 1H), 8.39 (dd, J=8.5, 0.9 Hz, 1H) , 7.76 (dd, J=8.5, 0.9 Hz, 1H), 6.24 (dd, J=2.9, 0.9 Hz, 1H), 4.34 (td, J=7 .5, 6.6 Hz, 2H), 4.28 (d, J=7.8 Hz, 2H), 1.34 (td, J=7.1, 0.9 Hz, 3H), 1.11 (s, 6H), 1.05 (s, 6H), 0.75 (t, J=7.8 Hz, 1H).

Step D 2-Chloro-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid.

Ethyl 2-chloro-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine-3-carboxylate (146 g, 386.4 mmol) in THF (730, 0 ml) and EtOH (292.0 ml) was treated with NaOH (about 772.8 ml of a 1 M solution, 772.8 mmol) and the solution was stirred at room temperature for 5 hours. Most of the solvent was removed under reduced pressure and the solution was acidified, adding citric acid (about 148.5 g, 89.19 ml, 772.8 mmol) while cooling on ice. The resulting thick suspension (pH 2-3) was stirred in an ice bath for 1 h, filtered, washed with plenty of water and dried in a vacuum oven at 45° C. under nitrogen flow for two days to give 2-chloro-6- [3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (128.2 g, 90%) as an off-white solid. EER-MS m/z calc. 349.11932, found 350.0 (M+1) ⁺ ; retention time: 2.11 min. 1H NMR (400 MHz, DMSO-d ₆ ) δ 13.64 (s, 1H), 8.69-8.22 (m, 2H), 7.73 (d, J=8.4 Hz, 1H), 6.22 (d, J=2.9 Hz, 1H), 4.28 (d, J=7.8 Hz, 2H), 1.08 (d, J=24.9 Hz, 12H), 0, 75 (t, J=7.8 Hz, 1H).

Step E. 2-Chloro-N-(o-tolylsulfonyl)-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazole-1-

yl]pyridine-3-carboxamide.

O

CDI, DBU

2-Chloro-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (150 mg, 0.429 mmol) was dissolved/suspended in THF (2 ml ) and carbonyldiimidazole (64.2 mg, 0.396 mmol) was added. The suspension was allowed to stir at room temperature for 1.5 hours. Then 2-methylbenzenesulfonamide (73.4 mg, 0.429 mmol) was added followed by DBU (59.2 μl, 0.396 mmol). Then the resulting solution was stirred for another 1.5 hours. The volatiles were evaporated. The remaining residue was dissolved in dichloromethane (2 ml) and washed with 1 M aqueous citric acid solution (1x2 ml).

The organic layer was injected into a silica gel column for chromatography: silica gel

- 90 040454 12 g column, 0-10% MeOH/DCM gradient. 2-Chloro-N-(o-tolylsulfonyl)-6-[3-[(2,2,3,3tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine-3-carboxamide (115 mg, 53%) was obtained. EER-MS m/z calc. 502.14417, found 503.0 (M+1)+; retention time 2.25 min.

Step F. R-(o-tolylsulfonyl)-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]-2[(4S)-2,2,4-trimethylpyrrolidine -1-yl]pyridine-3-carboxamide.

2-Chloro-X-methylsulfonyl-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine3-carboxamide (115 mg, 0.229 mmol) and (4S)-2, 2,4-trimethyl-pyrrolidine (hydrochloride salt) (106 mg, 0.935 mmol) was combined and dissolved in DMSO (1 ml). Finely ground potassium carbonate (258 mg, 1.87 mmol) was added. The reaction mixture was closed and heated overnight at 130°C. After cooling to room temperature, the reaction mixture was diluted with EtOAc (50 ml) and washed with aqueous citric acid solution (1 M, 2x50 ml) and brine (1x50 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was isolated by silica gel column chromatography eluting with a gradient of 0-5% MeOH/DCM on a 12 g silica gel column. -1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (57.2 mg, 42%). EER-MS m/z calc. 579.2879, found 580.3 (M+1) ⁺ ; retention time 2.52 min. Ή NMR (400 MHz, DMSO-Q) δ 12.62 (s, 1H), 8.18 (d, J=2.8 Hz, 1H), 8.04 (dd, J=8.0, 1, 4 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.59 (td, J=7.5, 1.5 Hz, 1H), 7.50-7.40 ( m, 2H), 6.93 (d, J=8.2 Hz, 1H), 6.13 (d, J=2.7 Hz, 1H), 4.24 (d, J=7.8 Hz, 2H), 2.63 (s, 3H), 2.38 (d, J=8.8 Hz, 2H), 2.16 (d, J=10.3 Hz, 1H), 1.82 (dd, J=11.9, 5.5 Hz, 1H), 1.52 (d, J=1.6 Hz, 6H), 1.35 (t, J=12.1 Hz, 1H), 1.10 ( s, 6H), 1.04 (d, J=1.1 Hz, 6H), 0.77-0.67 (m, 4H).

Synthetic example 16.

Synthesis of Compound 16 4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.

Step A. 2-Chloro-N-(3-fluorophenyl)sulfonyl-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine-3-carboxamide.

2-Chloro-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (150 mg, 0.429 mmol) was dissolved/suspended in THF (2 ml ) and carbonyldiimidazole (64.2 mg, 0.396 mmol) was added. The suspension was allowed to stir at room temperature for 1.5 hours. Then 3-fluorobenzenesulfonamide (75.1 mg, 0.429 mmol) was added followed by DBU (59.2 μl, 0.396 mmol). Then the resulting solution was stirred for another 1.5 hours. The volatiles were evaporated. The remaining residue was dissolved in dichloromethane (2 ml) and washed with 1 M aqueous citric acid solution (1x2 ml). The organic layer was loaded onto a silica gel column for purification by chromatography: 12 g silica gel column, 0-10% MeOH/DCM gradient. 2-Chloro-N-(3-fluorophenyl)sulfonyl-6-[3-[(2,2,3,3tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine-3-carboxamide (150 mg, 70%) was obtained. EER-MS m/z calc. 506.11908, found 507.0 (M+1) ⁺ ; retention time 2.24 min.

Step B. R-(3-fluorophenyl)sulfonyl-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1yl]-2-[(4S)-2,2,4-trimethylpyrrolidine -1-yl]pyridine-3-carboxamide.

2-Chloro-N-(3-fluorophenyl)sulfonyl-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1yl]pyridine-3-carboxamide (158 mg, 0.312 mmol) and ( 4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (105.9 mg, 0.935 mmol) was combined and dissolved in DMSO (1 ml). Finely ground potassium carbonate (258 mg, 1.87 mmol) was added. The reaction mixture was closed and heated overnight at 130°C. After cooling to room temperature, the reaction mixture was diluted with EtOAc (50 ml) and washed with aqueous citric acid (1 M, 2x50 ml) and brine (1x50 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was isolated by column chromatography, eluting with a gradient of 0-5%

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MeOH/DCM on a 12 g silica gel column. N-(3-fluorophenyl)sulfonyl-6-[3-[(2,2,3,3tetramethylcyclopropyl)methoxy]pyrazol-1-yl]-2-[(4S) -2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (28.4 mg, 16%). EER-MS m/z calc. 583.2629, found 584.6 (M+1)+; retention time 2.46 min. 1H NMR (400 MHz, DMSO^) δ 12.61 (s, 1H), 8.19 (d, J=2.8 Hz, 1H), 7.87-7.81 (m, 2H), 7, 79-7.71 (m, 2H), 7.63 (tdd, J=8.6, 2.6, 1.1 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H) , 6.13 (d, J=2.8 Hz, 1H), 4.24 (d, J=7.7 Hz, 2H), 2.44 (t, J=10.4 Hz, 1H), 2 .36-2.26 (m, 1H), 2.13 (td, J=11.8, 6.0 Hz, 1H), 1.84 (dd, J=11.8, 5.5 Hz, 1H ), 1.54 (s, 3H), 1.52 (s, 3H), 1.39 (t, J=12.1 Hz, 1H), 1.10 (s, 6H), 1.04 (s , 6H), 0.74 (d, J=7.7 Hz, 1H), 0.70 (t, J=6.6 Hz, 3H).

Synthetic example 17.

Synthesis of compound 17 -(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide.

N-(Benzenesulfonyl)-2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine3-carboxamide (2 g, 3.884 mmol) was dissolved in NMP (10, 00 ml) and 1,2-diethoxyethane (2.000 ml) was added. Potassium carbonate (about 2.684 g, 19.42 mmol) and (4S)-3,3-dideuterio-2,2-dimethyl-4(trideuteriomethyl)pyrrolidine (hydrochloride salt) (about 1.502 g, 9.710 mmol) were added and the resulting suspension to 130°C, and stirred overnight. The reaction mixture was cooled and poured into rapidly stirred ice (60.00 ml) with acetic acid (about 3.499 g, 3.313 ml, 58.26 mmol). After stirring for 20 minutes to give a fairly uniformly flowing solid, the solid was filtered off and washed with water. The filter cake was dissolved in dichloromethane and the aqueous pomace was separated. The dichloromethane layer was washed twice with water and brine, dried over sodium sulfate and concentrated. Ethanol (20 ml) was added and the solution was concentrated to a few milliliters. Water was added very slowly, drop by drop. The resulting suspension was heated until a fine suspension formed and allowed to cool for 30 min. The crystalline solid was filtered off and washed with a little ethanol to give N-(benzenesulfonyl)-2-[(4S)-3,3-dideuterio-2,2-dimethyl-4-(trideuteriomethyl)pyrrolidin-1-yl]-6- [3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3carboxamide (600 mg, 26%). EER-MS m/z calc. 596.24, found 597.0 (M+1) ⁺ ; retention time 2.29 min.

Synthetic example 18.

Synthesis of compound 18 ]pyridine-3-carboxamide.

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Step A: tert-Butyl-3-(2-bromoethoxy)-1H-pyrazole-1-carboxylate.

To a solution of 2-bromoethanol (1.69 g, 13.53 mmol), tert-butyl-2,3-dihydro-3-oxopyrazole-1-carboxylate (2.08 g, 11.28 mmol) and triphenylphosphine (3.55 g , 13.53 mmol) in anhydrous tetrahydrofuran (45 ml) at 0° C. diisopropyl azodicarboxylate (2.74 g, 13.53 mmol) was added dropwise. After the addition was completed, the reaction solution was stirred at 0° C. for 1 h, then warmed to room temperature and stirred for another 2 h. Ether (400 ml) was added. The organic solution was washed with saturated aqueous sodium carbonate (80 ml), brine (50 ml), then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a hexanes-ethyl acetate (0 to 15% ethyl acetate) gradient method to give t-butyl-3-(2-bromoethoxy)-1H-pyrazole-1-carboxylate (2.56 g, 78 %) as a white solid. 1H NMR (250 MHz, CDCl ₃ ) δ (ppm): 7.85 (d, J=3.0 Hz, 1H), 5.92 (d, J=3.0 Hz, 1H), 4 .63 (t, J=6.0 Hz, 2H), 3.68 (t, J=6.0 Hz, 2H), 1.64 (s, 9H). EER-MS m/z calc. 292.0, found 292.9 (M+1)+; retention time 4.91 min.

Step B. tert-Butyl-3-(vinyloxy)-1H-pyrazole-1-carboxylate.

Vg

1)tBuOK, THF I ----------* °'^ ^N

2) VoSzO G ^Νβ 0θ

I NBoc

To a solution of tert-butyl-3-(2-bromoethoxy)-1H-pyrazole-1-carboxylate (2.52 g, 8.66 mmol) in anhydrous tetrahydrofuran (90 ml) was added potassium tert-butoxide (1.46 g, 13.0 mmol). The resulting solution was stirred for 2 h, then di-tert-butyl dicarbonate (5.67 g, 26.0 mmol) was added and stirred for another 1 h. Diethyl ether (400 ml) was added. The organic layers were washed with water (50 ml), brine (2x50 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography,

- 93 040454 using a gradient method with a mixture of hexanes and ethyl acetate (from 0 to 10% ethyl acetate) to obtain tert-butyl-3-(vinyloxy)-1H-pyrazole-1-carboxylate (1.10 g, 60%) as a colorless oily substance. ¹ H NMR (250 MHz, CDCF) δ (ppm): 7.89 (d, J=3.0 Hz, 1H), 7.24 (dd, J=6, 13.5 Hz, 1H) , 5.95 (d, J=3.0 Hz, 1H), 4.88 (dd, J=1.8, 13.5 Hz, 1H), 4.50 (dd, J=1.8, 6 .0 Hz, 1n), 1.62 (s, 9H). EER-MS m/z calc. 210.1, found 211.0 (M+1)+. Retention time 4.74 min.

Step C: tert-Butyl-3-(2-(trifluoromethyl)cyclopropoxy)-1H-pyrazole-1-carboxylate.

Water (20 ml) was added to tert-butyl 3-(vinyloxy)-1H-pyrazole-1-carboxylate (1.10 g, 5.23 mmol) in a pear-shaped flask (100 ml) and argon was bubbled through for 5 minutes, then sodium acetate (85.8 mg, 1.05 mmol) was added, followed by 2,2,2-trifluoroethylamine hydrochloride (3.57 g, 26.17 mmol) and concentrated sulfuric acid (51.3 mg, 0.523 mmol) . Argon was bubbled through the solution for another 5 minutes, then bis[rhodium (a,a,a',a'-tetramethyl-1,3-benzenedipropionic acid)] (397 mg, 0.523 mmol) was added. The reaction solution was kept under argon from a balloon, adding an aqueous solution of sodium nitrite (2.17 g, 31.4 mmol) in water (12.8 ml) through a syringe filter over 10 h. After completion of the addition, the resulting solution was stirred for another 6 h Diethyl ether (300 ml) was added and the organic layer separated. The organic layer was then washed with brine (30 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a gradient method with hexanes and dichloromethane (from 0 to 100% dichloromethane). The resulting residue was again chromatographed on silica gel (hexanes and ethyl acetate, gradient 0 to 10% ethyl acetate) to give t-butyl 3-(1,2-trans-2(trifluoromethyl)cyclopropoxy)-1H-pyrazole-1-carboxylate and tert-butyl-3-(1,2-cis-2-(trifluoromethyl)cyclopropoxy)-1H-pyrazole-1-carboxylate. tert-Butyl-3-(1,2-trans-2-(trifluoromethyl)cyclopropoxy)-1H-pyrazole-1-carboxylate: (366 mg, 24%); white solid. 1H NMR (250 MHz, CDCl ₃ ) δ (ppm): 7.84 (d, J=2.8 Hz, 1H), 5.91 (d, J=2.8 Hz, 1H), 4 .49 (m, 1H), 1.75 (m, 1H), 1.62 (s, 9H), 1.56-1.25 (m, 2H). EER-MS m/z calc. 292.1, found 293.1 (M+1) ⁺ . Retention time: 5.22 min. tert-Butyl 3-(1,2cis-2-(trifluoromethyl)cyclopropoxy)-1H-pyrazole-1-carboxylate: (314 mg, 21%); white solid. Ή NMR (250 MHz, CDCl3) δ (ppm): 7.90 (d, J=2.8 Hz, 1H), 5.92 (d, J=2.8 Hz, 1H), 4, 49 (m, 1H), 1.94 (m, 1H), 1.62 (s, 9H), 1.30 (m, 2H). EER-MS m/z calc. 292.1, found 293.1 (M+1) ⁺ . Retention time 5.48 min.

Step D. 3-(1,2-cis-2-(Trifluoromethyl)cyclopropoxy)-1H-pyrazole.

Trifluoroacetic acid (2.76 g, 24.3 mmol) was added to a solution of tert-butyl 3-(1,2-cis-2(trifluoromethyl)cyclopropoxy)-1H-pyrazole-1-carboxylate (708 mg, 2.43 mmol) in anhydrous dichloromethane (24 ml). The resulting solution was stirred at room temperature for 16 hours. 1,2-Dichloroethane (10 ml) was added to the reaction solution. All solvents were removed under reduced pressure. The resulting residue was dissolved in ethyl ether (150 ml), washed with saturated aqueous sodium bicarbonate (30 ml). The organic solution was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give crude 3-(1,2-cis-2(trifluoromethyl)cyclopropoxy)-1H-pyrazole (461 mg, 99%) as a tan oil. The crude product was directly used in the next step without further purification. EER-MS m/z calc. 192.1, found 193.0 (M+1) ⁺ . Retention time 3.26 min.

Step E. tert-Butyl-6-(3-(1,2-cis-2-(trifluoromethyl)cyclopropoxy)-1H-pyrazol-1-yl)-2chloropyridine-3-carboxylate.

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To a solution of crude 3-(1,2-cis-2-(trifluoromethyl)cyclopropoxy)-1H-pyrazole (461 mg, 2.43 mmol) in dimethylformamide (8 ml) -carboxylate (659 mg, 2.67 mmol), potassium carbonate (669 mg, 4.85 mmol) and 1,4-diazabicyclo[2.2.2]octane (55 mg, 0.49 mmol). The reaction mixture was stirred at room temperature for 48 hours. The reaction solution was diluted with ether (200 ml), washed with water (4x20 ml) and brine (20 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a gradient method with hexanes and dichloromethane (0 to 100% dichloromethane) to give tert-butyl-6-(3-(1,2-cis-2(trifluoromethyl)cyclopropoxu)-1H- pyrazol-1-yl)-2-chloropyridine-3-carboxylate (731 mg, 68%) as a white solid. Ή NMR (250 MHz, CDCl ₃ ) δ (ppm): 8.39 (d, J=2.8 Hz, 1H), 8.22 (d, J=8.5 Hz, 1H), 7 .74 (d, J=8.5 Hz, 1H), 6.01 (d, J=2.8 Hz, 1H), 4.33 (m, 1H), 1.93 (m, 1H), 1 .62 (s, 9H), 1.45-1.26 (m, 2H). EER-MS m/z calc. 403.1, found 404.1 (M+1)+. Retention time 7.29 min.

Step F. 6-(3-(1,2-cis-2-(Trifluoromethyl)cyclopropoxy)-1H-pyrazol-1-yl)-2-chloropyridine-3-carboxylic acid.

Trifluoroacetic acid (2.03 g, 17.8 mmol) was added to a solution of tert-butyl-6-(3-(1,2-cis-2(trifluoromethyl)cyclopropoxy)-III-pyrazol-1-yl)-2- chloropyridine-3-carboxylate (718 mg, 1.78 mmol) in anhydrous dichloromethane (18 mL). The resulting solution was stirred at room temperature for 16 hours. 1,2-Dichloroethane (10 ml) was added to the reaction solution. All solvents were removed under reduced pressure. To the resulting crude solid was added 10% ethyl ether in hexanes (25 ml) and sonicated for 30 min, filtered, washed with 105 ethyl ether in hexanes (10 ml), and dried under high vacuum to give 6-(3-( 1,2-cis-2(trifluoromethyl)cyclopropoxy)-1H-pyrazol-1-yl)-2-chloropyridine-3-carboxylic acid (517 mg, 84%) as a white solid. 1H NMR (500 MHz, DMSO) δ (ppm): 13.6 (br s, 1H), 8.47 (d, J=3.0 Hz, 1H), 8.42 (d, J=8 .8 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 6.27 (d, J=3.0 Hz, 1H), 4.46 (m, 1H), 2, 40 (m, 1H), 1.47 (m, 1H), 1.32 (m, 1H). EER-MS m/z calc. 347.0, found 34 7.9 (M+1) ⁺ . Retention time 5.20 min.

Step G N-(Benzenesulfonyl)-2-chloro-6-[3-[(cis)-2-(trifluoromethyl)cyclopropoxy]pyrazol-1yl]pyridine-3-carboxamide.

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CDI, DBU

6-(3-(1,2-Cis-2-(trifluoromethyl)cyclopropoxy)-1H-pyrazol-1-yl)-2-chloropyridine-3-carboxylic acid (125 mg, 0.360 mmol) was dissolved in THF (1 ml ). 1,1'-carbonyldiimidazole (75.6 mg, 0.431 mmol) was added. The reaction mixture was allowed to stir at room temperature for 1 hour. Benzenesulfonamide (67.8 mg, 0.431 mmol) was added followed by DBU (64.5 μl, 0.431 mmol). The final reaction mixture was allowed to stir overnight at room temperature. Volatiles were removed by evaporation. The residue was dissolved in EtOAc (50 ml) and washed with 1 M aqueous citric acid solution (2x50 ml) and brine (1x50 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. N(benzenesulfonyl)-2-chloro-6-[3-[(cis)-2-(trifluoromethyl)cyclopropoxy]pyrazol-1-yl]pyridine-3carboxamide (201 mg) was obtained. EER-MS m/z calc. 486.03763, found 486.9 (M+1)+; retention time 0.67 min (chromatographic time 1 min).

Step H. N-(Benzenesulfonyl)-6-[3-[(cis)-2-(trifluoromethyl)cyclopropoxy]pyrazol-1-yl]-2-[(4S)2,2,4-trimethylpyrrolidin-1-yl ]pyridine-3-carboxamide.

N-(benzenesulfonyl)-2-chloro-6-[3-[(cis)-2-(trifluoromethyl)cyclopropoxy]pyrazol-1-yl]pyridine-3carboxamide (175 mg, 0.3595 mmol) was dissolved in DMSO (1 ml). (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (161 mg, 1.08 mmol) was added followed by potassium carbonate (298 mg, 2.16 mmol). The reaction mixture was allowed to stir at 130° C. overnight. After cooling to room temperature, the reaction mixture was diluted with EtOAc (50 ml) and washed with aqueous citric acid solution (1 M, 2x50 ml) and brine (1x50 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was isolated by silica gel column chromatography using a 12 g silica gel column eluting with a 0-10% EtOAc/hexane gradient. N-(benzenesulfonyl)-6-[3-[(cis)-2-(trifluoromethyl)cyclopropoxy]pyrazol-1 yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine was obtained -3-carboxamide (114.3 mg, 56%). EER-MS m/z calc. 563.1814, found 564.5 (M+1) ⁺ ; retention time 2.08 min.

Synthetic example 19.

Synthesis of compound 19 -yl]pyridine-3-carboxamide.

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Step A. 3-(1,2-trans-2-(Trifluoromethyl)cyclopropoxy)-1H-pyrazole.

TFK

Trifluoroacetic acid (3.15 g, 27.64 mmol) was added to a suspension of tert-butyl 3-(1,2-trans-2(trifluoromethyl)cyclopropoxy)-1H-pyrazole-1-carboxylate (807 mg, 2.76 mmol) in anhydrous dichloromethane (28 ml). The resulting solution was stirred at room temperature for 16 hours. 1,2-Dichloroethane (15 ml) was added to the reaction solution. All solvents were removed under reduced pressure. The resulting residue was dissolved in ethyl ether (200 ml), washed with saturated aqueous sodium bicarbonate (30 ml). The organic solution was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give crude 3-(1,2-trans-2(trifluoromethyl)cyclopropoxy)-1H-pyrazole (525 mg, 99%) as a tan oil. The crude product was directly used in the next step without further purification. EER-MS m/z calc. 192.1, found 193.0 (M+1)+. Retention time 2.97 min.

Step B. tert-Butyl-6-(3-(1,2-trans-2-(trifluoromethyl)cyclopropoxy)-1H-pyrazol-1-yl)-2chloropyridine-3-carboxylate.

To a solution of crude 3-(1,2-trans-2-(trifluoromethyl)cyclopropoxy)-1H-pyrazole (525 mg,

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2.76 mmol) in dimethylformamide (9.2 ml) was added tert-butyl-2,6-dichloropyridine-3-carboxylate (751 mg, 3.04 mmol), potassium carbonate (763 mg, 5.53 mmol) and 1 ,4-diazabicyclo[2.2.2]octane (62 mg, 0.55 mmol). The reaction mixture was stirred at room temperature for 48 hours. The reaction solution was diluted with ether (250 ml), washed with water (4x20 ml) and brine (20 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a gradient method with hexanes and dichloromethane (0 to 100% dichloromethane) to give t-butyl-6-(3-(1,2-trans-2(trifluoromethyl)cyclopropoxy)-1H- pyrazol-1-yl)-2-chloropyridine-3-carboxylate (314 mg, 21%) as a colorless oily substance. EER-MS m/z calc. 403.1, found 404.1 (M+1)+. Retention time: 6.92 min. Ή NMR (250 MHz, CDCh) δ (ppm): 8.38 (d, J=3.0 Hz, 1H), 8.20 (d, J=8.5 Hz, 1H), 7, 73 (d, J=8.5 Hz, 1H), 6.03 (d, J=3.0 Hz, 1H), 4.39 (m, 1H), 1.77 (m, 1H), 1, 62 (s, 9H), 1.44 (m, 1H), 1.31 (m, 1H).

Step C. 6-(3-(1,2-Trans-2-(trifluoromethyl)cyclopropoxy)-1H-pyrazol-1-yl)-2-chloropyridine-3carboxylic acid.

Trifluoroacetic acid (2.39 g, 21.0 mmol) was added to a solution of tert-butyl-6-(3-(1,2-trans-2(trifluoromethyl)cyclopropoxy)-1H-pyrazol-1-yl)-2- chloropyridine-3-carboxylate (847 mg, 2.10 mmol) in anhydrous dichloromethane (21 ml). The resulting solution was stirred at room temperature for 20 hours. 1,2-Dichloroethane (15 ml) was added to the reaction mixture. All solvents were removed under reduced pressure. To the obtained crude solid was added 10% ethyl ether in hexanes (30 ml) and sonicated for 30 min, filtered, washed with 10% ethyl ether in hexanes (10 ml), hexanes (10 ml) and dried under high vacuum to obtain 6-(3(1,2-trans-2-(trifluoromethyl)cyclopropoxy)-1H-pyrazol-1-yl)-2-chloropyridine-3-carboxylic acid (600 mg, 82%) as a white solid. EER-MS m/z calc. 347.0, found 347.9 (M+1) ⁺ . Retention time 4.91 min. 1H NMR (500 MHz, DMSO) δ (ppm): 8.46 (d, J=2.8 Hz, 1H), 8.41 (d, J=8.3 Hz, 1H), 7, 74 (d, J=8.3 Hz, 1H), 6.30 (d, J=2.8 Hz, 1H), 4.46 (m, 1H), 2.15 (m, 1H), 1, 40 (m, 1H), 1.34 (m, 1H).

Step D N-(Benzenesulfonyl)-2-chloro-6-[3-[(trans)-2-(trifluoromethyl)cyclopropoxy]pyrazol-1yl]pyridine-3-carboxamide.

F

6-(3-(1,2-Trans-2-(trifluoromethyl)cyclopropoxy)-1H-pyrazol-1-yl)-2-chloropyridine-3-carboxylic acid (125 mg, 0.360 mmol) was dissolved in THF (1 ml ). 1,1'-carbonyldiimidazole (75.6 mg, 0.431 mmol) was added. The reaction mixture was allowed to stir at room temperature for 1 hour. Benzenesulfonamide (67.8 mg, 0.431 mmol) was added followed by DBU (64.5 μl, 0.431 mmol). The final reaction mixture was allowed to stir at room temperature overnight. Volatiles were removed by evaporation. The residue was dissolved in EtOAc (50 ml) and washed with 1 M aqueous citric acid solution (2x50 ml) and brine (1x50 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. N(benzenesulfonyl)-2-chloro-6-[3-[(trans)-2-(trifluoromethyl)cyclopropoxy]pyrazol-1-yl]pyridine-3carboxamide (199 mg) was obtained. EER-MS m/z calc. 486.0, found 486.9 (M+1) ⁺ ; retention time 0.65 min (chromatographic time 1 min).

- 98 040454

Step E. N-(Benzenesulfonyl)-6-[3-[(trans)-2-(trifluoromethyl)cyclopropoxy]pyrazol-1-yl]-2[(4S)-2,2,4-trimethylpyrrolidin-1-yl ]pyridine-3-carboxamide.

N-(Benzenesulfonyl)-2-chloro-6-[3-[(trans)-2-(trifluoromethyl)cyclopropoxy]pyrazol-1-yl]pyridine-3carboxamide (175 mg, 0.3595 mmol) was dissolved in DMSO (1 ml). (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (161 mg, 1.08 mmol) was added followed by potassium carbonate (298 mg, 2.16 mmol). The reaction mixture was allowed to stir at 130° C. overnight. After cooling to room temperature, the reaction mixture was diluted with EtOAc (50 ml) and washed with aqueous citric acid (1 M, 2x50 ml) and brine (1x50 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was isolated by silica gel column chromatography using a 12 g silica gel column eluting with a 0-10% EtOAc/hexane gradient. N-(benzenesulfonyl)-6-[3-[(trans)-2-(trifluoromethyl)cyclopropoxy]pyrazol-1yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridin- 3-carboxamide (115.7 mg, 57%). EER-MS m/z calc. 563.1814, found 564.5 (M+1)+; retention time 2.01 min.

Synthetic example 20.

Synthesis of compound 20 -1-yl]pyridine-3-carboxamide

Step A 2-Chloro-N-(2-hydroxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide.

A solution of 2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (181 mg, 0.5 mmol) and carbonyldiimidazole (about 97.3 mg , 0.60 mmol) in DMF (2.5 ml) was stirred for 30 min. A solution of 2-hydroxybenzenesulfonamide (about 113 mg, 0.65 mmol) and sodium hexamethyldisilazide (about 600 µl of a 1 M solution, 0.60 mmol) in DMF (2.5 ml) was stirred for 30 minutes. The two solutions were combined and stirred for 15 hours at room temperature. The reaction mixture was acidified using 10 ml of 1M aqueous citric acid solution and extracted using 10 ml of ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-5% methanol in dichloromethane to give 2-chloro-N-(2-hydroxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazole- 1-yl]pyridine-3-carboxamide (82 mg, 32%). EER-MS m/z calc. 516.0, found 517.2 (M+1) ⁺ ; retention time 0.67 min.

Step B. N-(2-Hydroxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1- yl]pyridine-3-carboxamide.

2-Chloro-N-(2-hydroxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1yl]pyridine-3-carboxamide (82 mg, 0.16 mmol), (4S )-2,2,4-trimethylpyrrolidine (hydrochloride salt)

- 99 040454 (about 71 mg, 0.48 mmol) and potassium carbonate (about 132 mg, 0.95 mmol) were combined in DMSO (793 μl) and heated at 130°C for 15 hours. The reaction mixture was filtered and purified by the method reverse phase HPLC-MS using a Luna C18 (2) column (75x30 mm, particle size 5 µm) commercially available from Phenomenex (part number: 00C-4252-U0-AX) and double chromatography with a gradient of 30-99% mobile phase B in 15.0 min (mobile phase A=H ₂ O (5 mM HCl); mobile phase B=acetonitrile; flow rate=50 ml/min and column temperature=25°C) to give N-(2hydroxyphenyl )sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (44 mg, 46%). EER-MS m/z calc. 593.2, found 594.3 (M+1)+; retention time 2.07 min.

Synthetic example 21.

Synthesis of compound 21 -1-yl]pyridine-3-carboxamide.

Step A 2-Chloro-N-(3-hydroxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide.

2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (181 mg, 0.50 mmol) and carbonyldiimidazole (about 97 mg, 0.50 mmol) 60 mmol) in DMF (2.5 ml) was stirred for 30 min. 3-Hydroxybenzenesulfonamide (ca. 113 mg, 0.65 mmol) and NaH (ca. 24.0 mg, 60% w/w, 0.60 mmol) in DMF (2.5 ml) were stirred for 30 min. The two solutions were combined and stirred for 4 hours at room temperature. The reaction mixture was acidified using 10 ml of 1 M aqueous citric acid solution and extracted using 10 ml of ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-8% methanol in dichloromethane to give 2-chloro-N(3-hydroxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1 -yl]pyridine-3-carboxamide (250 mg, 97%). EER-MS m/z calc. 516.0482, found 517.2 (M+1) ⁺ ; retention time 0.67 min.

Step B. Ν-(3-Γhydroxyphenyl)sulfonyl-6-[3-[[1 -(trifluoromethyl)cyclopropyl]methoxy]pyrazol1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1- yl]pyridine-3-carboxamide.

2-Chloro-N-(3-hydroxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1yl]pyridine-3-carboxamide (290 mg, 0.56 mmol), (4S )-2,2,4-trimethylpyrrolidine (hydrochloride salt) (about 252 mg, 1.68 mmol) and potassium carbonate (about 465 mg, 3.37 mmol) in DMSO (2.80 ml) were heated at 130°C in for 15 hours. The reaction mixture was filtered and purified by reverse phase HPLCMS using a Luna C18 (2) column (75x30 mm, particle size 5 µm) commercially available from Phenomenex (product number: 00C-4252-U0-AX) , and double chromatography with a 30-99% gradient of mobile phase B over 15.0 min [mobile phase A=H ₂ O (5 mM HCl); mobile phase B=acetonitrile; flow rate=50 ml/min and column temperature=25°C] to give N-(3hydroxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2- [(4S)-2,2,4trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (37 mg, 11%). EER-MS m/z calc. 593.2, found 594.3 (M+1) ⁺ ; retention time 1.98 min.

Synthetic example 22.

Synthesis of compound 22 -1-yl]pyridine-3-carboxamide.

Step A 2-Chloro-N-(4-hydroxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide.

- 100 040454

2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (181 mg, 0.50 mmol) and carbonyldiimidazole (about 97 mg, 0.50 mmol) 60 mmol) in DMF (2.5 ml) was stirred for 30 min. 4-Hydroxybenzenesulfonamide (ca. 113 mg, 0.65 mmol) and NaH (ca. 24.0 mg, 60% w/w, 0.60 mmol) in DMF (2.5 ml) were stirred for 30 minutes. The two solutions were combined and stirred for 4 hours at room temperature. The reaction mixture was acidified using 10 ml of 1M aqueous citric acid and extracted using 10 ml of ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-8% methanol in dichloromethane to give 2-chloro-N-(4-hydroxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazole- 1yl]pyridine-3-carboxamide (210 mg, 81%). EER-MS m/z calc. 516.0, found 517.2 (M+1)+; retention time 0.64 min.

Step B. N-(4-Hydroxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1- yl]pyridine-3-carboxamide.

2-Chloro-N-(4-hydroxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1yl]pyridine-3-carboxamide (220 mg, 0.42 mmol), (4S )-2,2,4-trimethylpyrrolidine (hydrochloride salt) (about 191 mg, 1.28 mmol) and potassium carbonate (about 353 mg, 2.56 mmol) in DMSO (2.13 ml) were heated at 130°C in for 15 hours. The reaction mixture was filtered and purified by reverse phase HPLCMS using a Luna C18 (2) column (75x30 mm, particle size 5 µm) commercially available from Phenomenex (product number: 00C-4252-U0-AX) , and double chromatography with a 30-99% gradient of mobile phase B over 15.0 min [mobile phase A=H ₂ O (5 mM HCl); mobile phase B=acetonitrile; flow rate=50 ml/min and column temperature=25°C] to give N-(4-hydroxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]- 2-[(4S)-2,2,4-trimethylpyrrolidin-1yl]pyridine-3-carboxamide (48 mg, 19%). EER-MS m/z calc. 593.2, found 594.3 (M+1) ⁺ ; retention time 1.98 min.

Synthetic example 23.

Synthesis of compound 23 1-yl]pyridine-3-carboxamide.

Step A 2-Chloro-N-(o-tolylsulfonyl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1yl]pyridine-3-carboxamide.

2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (200 mg, 0.5529 mmol) and CDI (about 107.6 mg, 0.6635 mmol) was combined in THF (960 μl) and stirred at room temperature for 2 h. 21 µl, 0.6635 mmol) and stirred the reaction mixture for another 16 h at room temperature.

A 1 M citric acid solution (1 ml) was added and the reaction mixture was stirred for 20 minutes. The resulting solid was collected by vacuum filtration (washing with water) and dried.

- 101 040454 under vacuum to obtain a white powder, which was used in the next step without further purification. 2-Chloro-N-(o-tolylsulfonyl)-6-[3-[[1 -(trifluoromethyl)cyclopropyl]methoxy]pyrazol1-yl]pyridine-3-carboxamide (280 mg, 98%), ESI-MS m/ z calc. 514.1, found 515.1 (M+1)+; retention time 0.73 min. Ή NMR (400 MHz, DMSO) δ d 13.56-12.55 (s, 1H), 8.42 (d, J=2.8 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.47 (t, J=7.6 Hz, 2H), 6.23 (d, J=2.9 Hz, 1H), 4.39 (s, 2H), 2.64 (s, 3H), 1.12-1.06 (m, 4H).

Step B. N-(o-tolylsulfonyl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2[(4S)-2,2,4-trimethylpyrrolidin-1- yl]pyridine-3-carboxamide.

2-Chloro-N-(o-tolylsulfonyl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (114.7 mg, 0.2227 mmol) , (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (100 mg, 0.6682) and K ₂ CO ₃ (184.6 mg, 1.336 mmol) were combined in DMSO (0.5 ml) in a flask with screw cap and heated to 130°C for 16 hours After cooling to room temperature, the reaction mixture was diluted with 20 ml of ethyl acetate and 10 ml of water, and transferred to a separating funnel. 15 ml of 1M citric acid aqueous solution was added and the organic layer was separated. The aqueous layer was extracted two more times with 15 ml of ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The resulting crude material was purified by silica gel flash chromatography eluting with a gradient of 0-10% methanol in dichloromethane to give N-(o-tolylsulfonyl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1- yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (101 mg, 77%). EER-MS m/z calc. 591.21, found 592.3 (M+1) ⁺ ; retention time: 2.22 min. 1H NMR (400 MHz, DMSO) δ 12.74 (s, 1H), 8.38 (t, J=1.7 Hz, 1H), 8.33-8.22 (m, 2H), 8.21 (d, J=2.8 Hz, 1H), 7.90 (d, J=7.9 Hz, 1H), 7.89-7.85 (m, 1H), 6.93 (d, J= 8.3 Hz, 1H), 6.15 (d, J=2.7 Hz, 1H), 4.41-4.31 (m, 2H), 3.36-3.29 (m, 3H), 2.40 (t, J=10.4 Hz, 1H), 2.27 (t, J=8.6 Hz, 1H), 2.11 (t, J=12.1, 6.3 Hz, 1H ), 1.88-1.81 (m, 1H), 1.53 (d, J=9.8 Hz, 6H), 1.39 (t, J=12.1 Hz, 1H), 1.09 (dt, J=6.7, 2.2 Hz, 4H), 0.68 (d, J=6.2 Hz, 3H).

Synthetic example 24.

Synthesis of compound 24 1-yl]pyridine-3-carboxamide

Step A 2-Chloro-N-(p-tolylsulfonyl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1yl]pyridine-3-carboxamide.

2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (200 mg, 0.5529 mmol) and CDI (about 107.6 mg, 0.6635 mmol) was combined in THF (1.200 mL) and stirred at room temperature for 2 h. 4-methylbenzenesulfonamide (ca. 123.1 mg, 0.7188 mmol) was added followed by DBU (ca. 21 µl, 0.6635 mmol) and stirred the reaction mixture for another 16 h at room temperature. The reaction mixture was diluted with 1 M aqueous citric acid and water, then extracted with 3x20 ml of ethyl acetate. The combined organic layers were washed using 10 ml of 1M citric acid solution, then brine, dried over sodium sulfate and concentrated, then purified by silica gel chromatography eluting with 0-10% methanol/dichloromethane to give 2-chloro-N- (p-tolylsulfonyl)-6-[3-[[1(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (262 mg, 92%). EER-MS m/z calc. 514.0689, found 515.1 (M+1) ⁺ ; retention time 0.74 min.

Step B. N-(p-tolylsulfonyl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2[(4S)-2,2,4-trimethylpyrrolidin-1- yl]pyridine-3-carboxamide.

- 102 040454

2-ΧΛορ-Ν-(p-tolylsulfonyl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine3-carboxamide (114.7 mg, 0.2227), (4S )-2,2,4-trimethylpyrrolidine (hydrochloride salt) (100 mg, 0.6682) and K ₂ CO ₃ (184.6 mg, 1.336 mmol) were combined in DMSO (0.5 ml) in a screw cap flask and heated to 130°C for 16 hours After cooling to room temperature, the reaction mixture was diluted with 20 ml of ethyl acetate and 10 ml of water and transferred to a separating funnel.

15 ml of 1 M citric acid solution was added and the organic layer was separated. The aqueous layer was extracted two more times with 15 ml of ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The resulting crude material was purified by silica gel flash chromatography eluting with a gradient of 0-10% methanol in dichloromethane to give N-(p-tolylsulfonyl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1- yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (65 mg, 49%). EER-MS m/z calc. 591.21, found 592.3 (M+1)+; retention time: 2.25 min. 1H NMR (400 MHz,

DMSO) δ 12.74 (s, 1H), 8.38 (t, J=1.7 Hz, 1H), 8.33-8.22 (m, 2H), 8.21 (d, J=2 .8 Hz, 1H), 7.90 (d, J=7.9 Hz, 1H), 7.89-7.85 (m, 1H), 6.93 (d, J=8.3 Hz, 1H ), 6.15 (d, J=2.7 Hz, 1H), 4.41-4.31 (m, 2H), 3.36-3.29 (m, 3H), 2.40 (t, J=10.4 Hz, 1H), 2.27 (t, J=8.6 Hz, 1H), 2.11 (tt, J=12.1, 6.3 Hz, 1H), 1.88- 1.81 (m, 1H), 1.53 (d, J=9.8 Hz, 6H), 1.39 (t, J=12.1 Hz, 1H), 1.09 (dt, J=6 .7, 2.2 Hz, 4H), 0.68 (d, J=6.2 Hz, 3H).

Synthetic example 25.

Synthesis of compound 25 -1-yl]pyridine-3-carboxamide.

Step A. 2-Chloro-N-(3-cyanophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl) and δ-clopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide.

2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (200 mg, 0.5529 mmol) and CDI (about 107.6 mg, 0.6635 mmol) was combined in THF (1.200 ml) and stirred at room temperature for 2 h. 21 µl, 0.6635 mmol) and stirred the reaction mixture for another 16 h at room temperature. The reaction mixture was diluted with 1 M aqueous citric acid and water and extracted with 3x20 ml of ethyl acetate. The combined organic layers were washed using 10 ml of 1 M citric acid solution, then brine, then dried over sodium sulfate, concentrated and used in the next step without further purification. 2-Chloro-N-(3-cyanophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (228 mg, 78%), ESI-MS m /z calc. 525.0485, found 526.0 (M+1) ⁺ ; retention time 0.7 min.

Step B. N-(3-cyanophenyl)sulfonyl-6-[3-[[1 -(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1 yl]-2-[(4S)-2,2,4-trimethylpyrrolidine-1 -yl]pyridine-3-carboxamide.

2-Chloro-N-(3-cyanophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1yl]pyridine-3-carboxamide (117.1 mg, 0.2227), ( 4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (100 mg, 0.6682) and K2CO3 (184.6 mg, 1.336 mmol) were combined in DMSO (0.5 mL) in a screw cap flask and heated to 130°C for 16 hours After cooling to room temperature, the reaction mixture was diluted with 20 ml of ethyl acetate and 10 ml of water, and transferred to a separating funnel. 15 ml of 1M citric acid aqueous solution was added and the organic layer was separated. The aqueous layer was extracted two more times with 15 ml of ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated. received not

- 103 040454 the purified material was purified by flash chromatography on silica gel eluting with a gradient of 0-10% methanol in dichloromethane to give N-(3-cyanophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazole -1-yl]-2-[(4S)-2,2,4-Ίrimethylpyrrolidin-1-yl]pyridine-3-carboxamide (73 mg, 54%). EER-MS m/z calc. 602.19, found 603.3 (M+1)+; retention time: 2.04 min. 1H NMR (400 MHz, DMSO) δ 12.74 (s, 1H), 8.38 (t, J=1.7 Hz, 1H), 8.30 (ddd, J=8.1, 1.9, 1.1 Hz, 1H), 8.24 (dt, J=7.8, 1.3 Hz, 1H), 8.21 (d, J=2.8 Hz, 1H), 7.92-7, 84 (m, 2H), 6.93 (d, J=8.3 Hz, 1H), 6.15 (d, J=2.7 Hz, 1H), 4.42-4.31 (m, 2H ), 2.40 (t, J=10.4 Hz, 1H), 2.27 (t, J=8.6 Hz, 1H), 2.11 (t, J=12.1, 6.3 Hz , 1H), 1.89-1.78 (m, 1H), 1.53 (d, J=9.8 Hz, 6H), 1.39 (t, J=12.1 Hz, 1H), 1 .09 (dt, J=6.7, 2.2 Hz, 4H), 0.68 (d, J=6.2 Hz, 3H).

Synthetic example 26.

Synthesis of compound 26 -1-yl]pyridine-3-carboxamide.

Step A 2-Chloro-N-(2-cyanophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide.

CN

2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (200 mg, 0.5529 mmol) and CDI (about 107.6 mg, 0.6635 mmol) was combined in THF (1.200 ml) and stirred at room temperature for 2 h. 21 µl, 0.6635 mmol) and stirred the reaction mixture for another 16 h at room temperature. A 1 M citric acid solution (1 ml) was added and the reaction mixture was stirred for 20 minutes. The resulting solid was collected by vacuum filtration (washing with water) to give a white solid which was dried under high vacuum and used in the next step without further purification, 2-χλορ-Ν-(2cyanophenyl)sulfonyl-6-[3-[[1- (trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (279 mg, 96%), ESI-MS m/z calc. 525.0485, found 526.1 (M+1) ⁺ ; retention time: 0.69 min. ¹ H NMR (400 MHz, DMSO) δ 12.23 (s, 1H), 8.49 (d, J=2.9 Hz, 1H), 8.46-8.39 (m, 1H), 8, 35 (d, J=8.3 Hz, 1H), 8.21-8.13 (m, 1H), 7.96-7.90 (m, 2H), 7.82 (d, J=8, 3 Hz, 1H), 6.27 (d, J=2.9 Hz, 1H), 4.42 (s, 2H), 1.11 (dt, J=7.6, 2.2 Hz, 4H) .

Step B. N-(2-cyanophenyl)sulfonyl-6-[3-[[ 1 -(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1 yl]-2-[(4S)-2,2,4-trimethylpyrrolidine-1 -yl]pyridine-3-carboxamide.

2-Chloro-N-(2-cyanophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1yl]pyridine-3-carboxamide (117.1 mg, 0.2227), (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (100 mg, 0.6682) and K ₂ CO ₃ (184.6 mg, 1.336 mmol) were combined in DMSO (0.5 ml) in a flask with screw cap and heated to 130°C for 16 hours After cooling to room temperature, the reaction mixture was diluted with 20 ml of ethyl acetate and 10 ml of water, and transferred to a separating funnel. 15 ml of 1M citric acid aqueous solution was added and the organic layer was separated. The aqueous layer was extracted two more times with 15 ml of ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The resulting crude material was purified by silica gel flash chromatography eluting with a gradient of 0-10% methanol in dichloromethane to give N-(2-cyanophenyl)sulfonyl-6-[3-[[1(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1- yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (41 mg, 31%). EER-MS m/z calc. 602.19, found 603.2 (M+1) ⁺ ; retention time 2.12 min. 1H NMR (400 MHz, DMSO) δ 11.77 (s, 1H), 8.47 (s, 1H), 8.29 (d, J=2.8 Hz, 1H), 8.17-8.11 (m, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.94-7.87 (m, 2H), 6.97 (d, J=8.3 Hz, 1H) , 6.20 (d, J=2.8 Hz, 1H), 4.44-4.32 (m, 2H), 3.07-2.91 (m, 2H), 2.32 (d, J =19.0 Hz, 1H), 1.98 (k, J=5, 9, 5.5 Hz, 1H), 1.67 (s, 3H), 1.63 (s, 3H), 1.57 (t, J=10.4 Hz, 1H), 1.13-1.06 (m, 4H), 1.02 (d, J=6.3 Hz, 3H).

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Synthesis Example 27 Synthesis of Compound 27 4-trimethylpyrrolidin-1-yl]pyridine-3carboxamide.

Step A 2-Chloro-N-(4-cyanophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide.

2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (150 mg, 0.4147 mmol) and CDI (81 mg, 0.4995 mmol) was combined in THF (900.0 µl) and stirred at room temperature for 2 h. at room temperature for 2 hours. Additional DBU (80 μl, 0.5350 mmol) was added and the reaction mixture was stirred for another hour at room temperature. The reaction mixture was diluted with 20 ml of 1M citric acid solution and water and extracted with 3x20 ml of ethyl acetate. The combined organic layers were washed with 10 ml of 1M citric acid, then brine, then dried over sodium sulfate and concentrated. The resulting material was further purified by silica gel chromatography eluting with a gradient of 0-10% methanol in dichloromethane to give a white solid; 2-chloro-N-(4-cyanophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (192 mg, 88%), ESI- MS m/z calc. 525.0485, found 52 6.0 (M+1)+; retention time 0.71 min.

Step C. R-(4-cyanophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1 yl]-2-[(4S)-2,2,4-trimethylpyrrolidine-1 -yl]pyridine-3-carboxamide.

2-Chloro-N-(4-cyanophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1yl]pyridine-3-carboxamide (117.1 mg, 0.2227), ( 4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (100 mg, 0.6682) and K ₂ CO ₃ (184.6 mg, 1.336 mmol) were combined in DMSO (0.5 ml) in a flask with a screw cover and heated to 130°C for 16 hours After cooling to room temperature, the reaction mixture was diluted with 20 ml of ethyl acetate and 10 ml of water, and transferred to a separating funnel. 15 ml of 1M citric acid aqueous solution was added and the organic layer was separated. The aqueous layer was extracted two more times with 15 ml of ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The resulting crude material was purified by silica gel flash chromatography eluting with a gradient of 0-10% methanol in dichloromethane to give N-(4-cyanophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1 -yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3carboxamide (62 mg, 46%). EER-MS m/z calc. 602.19, found 603.3 (M+1) ⁺ ; retention time: 2.04 min. Ή NMR (400 MHz, DMSO) δ 12.77 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 8.16 (s, 4H), 7.87 (d, J = 8.3 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 6.15 (d, J=2.7 Hz, 1H), 4.50-4.17 (m , 2H), 2.33 (t, J=10.3 Hz, 1H), 2.20 (dd, J=10.2, 6.9 Hz, 1H), 2.11 (tt, J=11, 9, 6.4 Hz, 1H), 1.83 (dd, J=11.8, 5.4 Hz, 1H), 1.52 (d, J=5.6 Hz, 6H), 1.37 ( t, J=12.1 Hz, 1H), 1.13-1.05 (m, 4H), 0.66 (d, J=6.2 Hz, 3H).

Synthetic example 28.

Synthesis of compound 28 1-yl]pyridine-3-carboxamide.

Step A. 2-Chloro-R-(m-tolylsulfonyl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1yl]pyridine-3-carboxamide.

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2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (200 mg, 0.5529 mmol) and CDI (about 107.6 mg, 0.6635 mmol) was combined in THF (964.9 μl) and stirred at room temperature for 2 h. 99.21 μl, 0.6635 mmol) and stirred the reaction mixture for an additional 16 hours at room temperature. The reaction mixture was diluted with 1 M aqueous citric acid and water and extracted with 3x20 ml of ethyl acetate. The combined organic layers were washed with 10 ml of 1M citric acid, then brine, dried over sodium sulfate, concentrated and finally purified by silica gel chromatography eluting with 0-10% methanol/dichloromethane to give a white solid, 2-chloro -N-(m-tolylsulfonyl)-6[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (178 mg, 63%). IERMS m/z calc. 514.0689, found 515.1 (M+1) ⁺ ; retention time 0.74 min.

Step B. N-(m-tolylsulfonyl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2[(4S)-2,2,4-trimethylpyrrolidin-1- yl]pyridine-3-carboxamide.

2-Chloro-N-(m-tolylsulfonyl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine3-carboxamide (114.7 mg, 0.2227 mmol), ( 4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (100 mg, 0.6682) and K2CO3 (184.6 mg, 1.336 mmol) were combined in DMSO (0.5 mL) in a screw cap flask and heated to 130°C for 16 hours After cooling to room temperature, the reaction mixture was diluted with 20 ml of ethyl acetate and 10 ml of water, and transferred to a separating funnel. 15 ml of 1M citric acid aqueous solution was added and the organic layer was separated. The aqueous layer was extracted two more times with 15 ml of ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The resulting crude material was purified by silica gel flash chromatography eluting with a gradient of 0-10% methanol in dichloromethane to give N-(m-tolylsulfonyl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1- yl]-2-[(48)2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (45 mg, 34%). EER-MS m/z calc. 591.2, found 592.2 (M+1)+; retention time 2.24 min. 1H NMR (400 MHz, DMSO) δ 12.41 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.79 (tt, J=6.0, 2.5 Hz , 3H), 7.57-7.50 (m, 2H), 6.91 (d, J=8.2 Hz, 1H), 6.15 (d, J=2.7 Hz, 1H), 4.484 .24 (m, 2H), 2.46 (s, 1H), 2.42 (s, 3H), 2.29 (t, J=8.8 Hz, 1H), 2.11 (dt, J= 13.2, 6.5 Hz, 1H), 1.83 (dd, J=11.8, 5.5 Hz, 1H), 1.53 (d, J=12.0 Hz, 6H), 1, 38 (t, J=12.1 Hz, 1H), 1.09 (dd, J=4.5, 3.2 Hz, 4H), 0.66 (d, J=6.2 Hz, 3H).

Synthetic example 29.

Synthesis of compound 29: synthesis of N-(benzenesulfonyl)-6-[3-[(1-methylcyclopropoxy)methyl]pyrazol-1ul]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridin- 3-carboxamide.

Step A. (1-Methyl-1-(prop-2-yn-1-yloxy)cyclopropane.

___ NaH g-7

OH + Bl

1-Methylcyclopropan-1-ol (1.0 g, 13.9 mmol) was dissolved in Et2O (50 ml) and cooled to 0°C. NaH (50% in oil, 0.67 g, 13.9 mmol) was added in portions. The mixture was stirred for 10 min at 0° C., then propargyl bromide (80% in toluene, 3.1 g, 20.9 mmol) was added dropwise. The mixture was stirred for 1 h at 0°C. As no reaction proceeded, DMF (20 ml) was added. the mixture was stirred for another hour at 0° C. and quenched with saturated aqueous NH4Cl. The mixture was extracted with Et ₂ O (2x50 ml). The combined organic layers were washed twice with water and brine, dried over Na ₂ SO ₄ and concentrated (at 40°C, 500 mbar) to give crude (1-methyl-1-(prop-2in-1-yloxy)cyclopropane, which used as such in the next step 1H NMR (CDCl3, 300 MHz): δ 0.39 (m, 2H), 0.85 (m, 2H), 1.40 (s, 3H), 2.37 (s , 1H); 4.10 (s, 2H).

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Step B. 3-((1-Methylcyclopropoxy)methyl)-1H-pyrazole.

Crude (1-methyl-1-(prop-2-yn-1-yloxy)cyclopropane from several batches (not more than 27.8 mmol, 3.0 g) was mixed with trimethylsilyldiazomethane (2.0 M in hexane, 10 ml, 20 mmol) and stirred in a closed flask at 115° C. for 18 h. The mixture was cooled to 40° C. and quenched with MeOH (20 ml) and concentrated. After column chromatography (silica; heptanes/EtOAc 2:1) gave 3 ((1-methylcyclopropoxy)methyl)-1H-pyrazole as a colorless oil (1.2 g, 28% over two steps) 1 H NMR (CDCU 300 MHz): δ 0.44 (m, 2H); 85 (m, 2H), 1.44 (s, 3H), 4.60 (s, 2H), 6.23 (s, 1H), 7.51 (s, 1H), 13C-NMR (75 MHz, CDCl ₃ ): δ 13.4, 20.3, 58.4, 61.9, 103.9, 132.9 (one quaternary carbon not shown).

Step C. N-(Benzenesulfonyl)-6-[3-[(1-methylcyclopropoxy)methyl]pyrazol-1-yl]-2-[(4S)-2,2,4trimethylpyrrolidin-1-yl]pyridine-3 - carboxamide.

N-(Benzenesulfonyl)-6-chloro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (83 mg, 0.2035 mmol), 3-[(1- methylcyclopropoxy)methyl]-1H-pyrazole (62 mg, 0.4074 mmol) and scandium triflate (10 mg, 0.02032 mmol) were combined in DMSO (1.660 ml). NaH (41 mg, 60% w/w, 1.025 mmol) was added and the reaction mixture was stirred for 15 min, then closed and heated to 160°C for 16 h. The reaction mixture was cooled and partitioned between ethyl acetate and 1 M solution citric acid. The organic layer was separated, washed with brine and dried over sodium sulfate. The organic matter was then evaporated under reduced pressure and the crude material was purified by preparative HPLC (1-99 CH3CN in water with 5 mM HCl) over 30 minutes. Fractions containing product were diluted with water and extracted with ethyl acetate to give, after concentration, N(benzenesulfonyl)-6-[3-[(1-methylcyclopropoxy)methyl]pyrazol-1-yl]-2-[(4S)-2.2, 4-trimethylpyrrolidin1-yl]pyridine-3-carboxamide (10 mg, 9%) ESI-MS m/z calc. 523.22534, found 524.2 (M+1)+; retention time 2.04 min.

Synthetic example 30.

Synthesis of compound 30 -yl]pyridine-3-carboxamide.

Step A N-(Benzenesulfonyl)-2-chloro-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1yl]pyridine-3-carboxamide.

2-Chloro-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (200 mg, 0.5717 mmol) and CDI (111 mg, 0.6846 mmol) was combined in THF (1.2 ml) and stirred at room temperature for 2 h. mixture for another 6 h at room temperature. The reaction mixture was diluted with 1M citric acid and water and extracted with 3x20 ml ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated, then purified by silica gel chromatography using a gradient of 0-10% methanol in dichloromethane to give a white powder. N-(Benzenesulfonyl)-2-chloro-6-[3[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine-3-carboxamide (250 mg, 89%), ESI-MS m/z calc. 488.1285, found 489.2 (M+1) ⁺ ; retention time 0.81 min.

Step B. N-(Benzenesulfonyl)-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]-2[(4S)-2,2,4-trimethylpyrrolidin-1 -yl]pyridine-3-carboxamide.

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N-(Benzenesulfonyl)-2-chloro-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine-3carboxamide (115 mg, 0.2352 mmol), (4S )-2,2,4-trimethylpyrrolidine (hydrochloride salt) (ca. 105.9 mg, 0.7077 mmol) and potassium carbonate (ca. 195.6 mg, 1.415 mmol) were combined in DMSO (575.0 μl) and heated at 130°C for 16 hours the Reaction mixture was cooled to room temperature, diluted with 15 ml of water, 15 ml of 1 M citric acid solution and 30 ml of ethyl acetate. The aqueous and organic layers were separated and the aqueous layer was extracted two more times using 30 ml of ethyl acetate, the organic layers were combined, washed with brine, dried over sodium sulfate and concentrated. The resulting solid was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane, and then further purified by silica chromatography using 0-100% ethyl acetate in dichloromethane to give N-(benzenesulfonyl)-6-[3-[ (2,2,3,3tetramethylcyclopropyl)methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3carboxamide (43 mg, 32%). EER-MS m/z calc. 565.2723, found 566.3 (M+1)+; retention time: 2.43 min. 1H NMR (400 MHz, DMSO) δ 12.47 (s, 1H), 8.18 (d, J=2.8 Hz, 1H), 8.02-7.95 (m, 2H), 7.79 (d, J=8.3 Hz, 1H), 7.76-7.69 (m, 1H), 7.68-7.62 (m, 2H), 6.92 (d, J=8.3 Hz, 1H), 6.13 (d, J=2.7 Hz, 1H), 4.24 (d, J=7.7 Hz, 2H), 2.42 (t, J=10.5 Hz, 1H), 2.28 (dd, J=10.2, 7.1 Hz, 1H), 2.17-2.03 (m, 1H), 1.82 (dd, J=11.8, 5, 5 Hz, 1H), 1.52 (d, J=9.4 Hz, 6H), 1.36 (t, J=12.1 Hz, 1H), 1.10 (s, 6H), 1.04 (s, 6H), 0.73 (t, J=7.7 Hz, 1H), 0.65 (d, J=6.2 Hz, 3H).

Synthetic example 31.

Synthesis of compound 31 ,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.

Step A 2-Chloro-N-(4-hydroxyphenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide.

2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (100 mg, 0.2661 mmol) and CDI (about 51.38 mg, 0.3169 mmol) were combined in THF (600.0 μl) and stirred at room temperature for 2 h. 4-Hydroxybenzenesulfonamide (ca. µl, 0.3574 mmol) and the reaction mixture was stirred for another 16 h at room temperature. The reaction mixture was diluted with 10 ml of 1 M citric acid solution and extracted 3 times with 10 ml of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give a white solid which was used in the next step without further purification. 2-Chloro-N-(4-hydroxyphenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (128 mg, 91%), EER-MS m/z calc. 530.06384, found 531.0 (M+1) ⁺ ; retention time 0.69 min.

Step B. N-(4-Hydroxyphenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin- 1-yl]pyridine-3-carboxamide.

2-Chloro-N-(4-hydroxyphenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridine-3-carboxamide (134 mg, 0.2524 mmol), (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (113 mg, 0.7550 mmol) and potassium carbonate (210 mg, 1.519 mmol) were combined in dimethyl sulfoxide (670.0 μl) and heated at 130°C in for 16 hours the Reaction mixture was cooled to room temperature and was added 1 ml of water. After 15 minutes of stirring, the contents of the flask were left to settle, liquid

- 108 040454 some was removed with a pipette and the remaining solid was dissolved in 20 ml of ethyl acetate. The organic matter was washed with 15 ml of 1 M citric acid solution. The aqueous and organic layers were separated and the aqueous layer was extracted two more times using 15 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated. The resulting crude solid was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give N-(4-hydroxyphenyl)sulfonyl-6-[3-[2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-1 -yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (43 mg, 28%). EER-MS m/z calc. 607.20764, found 608.2 (M+1)+; retention time 2.07 min. 1H NMR (400 MHz, DMSO) δ 12.25 (s, 1H), 10.58 (s, 1H), 8.19 (d, J=2.8 Hz, 1H), 7.87-7.79 (m, 2H), 7.75 (d, J=8.2 Hz, 1H), 6.97-6.91 (m, 2H), 6.89 (d, J=8.2 Hz, 1H) , 6.10 (d, J=2.7 Hz, 1H), 4.31 (t, J=7.1 Hz, 2H), 2.44 (t, J=10.4 Hz, 1H), 2 .16-2.09 (m, 1H), 2.26 (t, J=8.8 Hz, 1H), 2.07 (t, J=7.0 Hz, 2H), 1.82 (dd, J=11.9, 5.5 Hz, 1H), 1.54 (s, 3H), 1.51 (s, 3H), 1.38 (t, J=12.1 Hz, 1H), 1, 00-0.93 (m, 2H), 0.91-0.86 (m, 2H), 0.69 (d, J=6.2 Hz, 3H).

Synthetic example 32.

Synthesis of compound 32 4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.

Step A N-(benzenesulfonyl)-2,6-dichloropyridine-3-carboxamide.

A 5000 ml three-necked round bottom flask was equipped with a mechanical stirrer, cooling bath, J-Kem temperature sensor/controller, water-cooled reflux condenser, addition funnel and nitrogen inlet/removal line. 60 wt% sodium hydride in mineral oil (26.04 g, 0.6510 mol) was charged to the vessel under nitrogen atmosphere. Then N,N-dimethylformamide (200 ml) was slowly loaded into the vessel. Started stirring and recorded the temperature in the reactor, 19°C. A solution of benzenesulfonamide (102.3 g, 0.6510 mol) in N,N-dimethylformamide (868 ml, ~8.5 ml/g, 0.75 M) was then charged to the addition funnel and slight gentle heating was required to obtain a homogeneous solution. The resulting pale yellow benzenesulfonamide solution was then added dropwise over 1 hour to a round bottom flask, whereby slight foaming and gas evolution were observed. After completion of the addition, the recorded temperature of the reactor was 28°C. The reactor was then equipped with a heating mantle and the greyish mixture was heated to 60°C. Stirring of the mixture was continued at 60° C. for 1 hour, at which time gas evolution ceased. Stirring of the mixture was continued while cooling the mixture to room temperature. At the same time, a 1000 ml 3-necked round-bottom flask was equipped with a mechanical stirrer, mantle heater, J-Kem temperature probe/controller, water-cooled reflux condenser, and nitrogen inlet/removal line. 2,6-Dichloropyridine-3-carboxylic acid (100 g, 0.5208 mol) and N,N-dimethylformamide (500 ml, 5 ml/g) were charged into a vessel under nitrogen atmosphere, resulting in a clear light yellow solution . Started stirring and recorded the temperature in the reactor, 17°C. Carbonyldiimidazole (84.45 g, 0.5208 mol) was then charged to the reactor piecemeal over 10 minutes as a solid, resulting in slight foaming and gas formation, with no exotherm. Stirring of the resulting clear solution of a light amber color was continued at room temperature for 1 h. A transparent amber solution of intermediate (2,6- dichloropyridin-3-yl)(1H-imidazol-1-yl)methanone. After completion of the addition, the vessel was equipped with a heating mantle and the mixture was heated to 60°C and maintained at such conditions.

- 109 040454 ions for 1 hour when LC/MS analysis indicated complete consumption of the intermediate. The reaction mixture was allowed to cool to room temperature and then poured into ice-cold 6 M HCl solution (500 ml). The resulting mixture was further diluted with water (500 ml) and then transferred to a separating funnel and separated with ethyl acetate (1000 ml). The organic layer was removed and the remaining aqueous layer was extracted with ethyl acetate (2x500 ml). The combined organic layers were washed with saturated sodium chloride solution (3x500 ml), dried over sodium sulfate (300 g) and then filtered through a Buchner funnel with a glass filter. The clear pale yellow solution was concentrated under reduced pressure to a volume of about 200 ml. The clear residual oily substance was diluted with methyl tert-butyl ether (1000 mL) and then concentrated again under reduced pressure at which time a solid precipitate began to form. The volume was reduced to about 200 ml. The resulting suspension was allowed to stand at room temperature for 30 minutes and then filtered through a Buchner funnel with a glass filter. The filter cake was filtered by displacement using methyl tert-butyl ether (2x150 ml) and then left on a Buchner funnel with suction for 30 minutes. The resulting material was further dried in a vacuum oven at 45° C. for 2 h to give a white solid (101 g, 0.305 mol, 58% yield) as the desired product, N-(benzenesulfonyl)-2,6-dichloropyridine-3- carboxamide. EER-MS m/z calc. 329.96326, found 330.9 (M+1)+; retention time 1.22 min.

Step B. N-(Benzenesulfonyl)-6-chloro-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.

A 5000 ml three neck round bottom flask was equipped with a mechanical stirrer, heating mantle, J-Kem temperature sensor/controller, water-cooled reflux condenser, and nitrogen inlet/outlet line. N-(benzenesulfonyl)-2,6dichloropyridine-3-carboxamide (100 g, 0.3020 mol), (4S)-2,2,4-trimethylpyrrolidine hydrochloride (54.24 g, 0.3624 mol) and dimethyl sulfoxide (500 ml, 5 ml/g) to give a clear, pale yellow solution. Started stirring and recorded the reaction temperature, 19°C. Potassium carbonate powder (167 g, 1.208 mol, 325 mesh) was then charged to the reactor piecemeal over 10 minutes as a solid, resulting in slight gas evolution and foaming. The resulting off-white suspension was stirred at room temperature for 10 min, then heated to a reaction temperature of 115° C. and kept under these conditions for 24 h. LC/MS analysis indicated the reaction was complete and the amber suspension was allowed to cool to room temperature. A 5000 ml three neck round bottom flask was equipped with a mechanical stirrer, cooling bath and J-Kem temperature probe. A 2M HCl solution (1057 mL, 2.114 mol) was charged to the reactor and stirring was started at high speed. The cooling bath was charged with crushed ice/water and the reaction temperature was lowered to 0°C. Then slowly, in parts, over 30 min was added to the reaction mixture in the form of a suspension of amber color, which led to the formation of a solid precipitate and exotherm up to 8°C. Note: Moderate foaming during addition. After completion of the addition, the resulting suspension was continued to stir at ~5°C for 1 h and then subjected to vacuum filtration on a Buchner funnel with a glass filter. The filter cake was washed by displacement using water (4x500 ml) and then left on a Buchner funnel with suction for 2 hours to give a white solid (150 g). A 5000 ml three-neck round bottom flask was equipped with a mechanical stirrer, mantle heater, J-Kem temperature sensor/controller, water-cooled reflux condenser, and nitrogen inlet/removal line. The isolated product (150 g) and 2-propanol (1050 ml, 7 ml/g) were charged to a container under nitrogen to give a pale yellow suspension. Started stirring and recorded the reaction temperature, 19°C. The reaction temperature was raised to boiling (~82°C) and maintained under these conditions for 10 min to obtain a clear solution of pale amber color. Stirring of the solution was continued and the solution was allowed to cool slowly to room temperature, during which time a solid began to form. Stirring of the slurry was continued and the reactor was equipped with a cooling bath into which crushed ice/water was charged. The reaction temperature was lowered to 0°C and stirring of the thick slurry was continued at 0°C for 1 h. then left on a Buchner funnel with suction for 30 min. The material was further dried in a vacuum oven at 45° C. for 15 h to give a white solid (100 g, 0.245 mol, 81% yield) as product, N-(benzenesulfonyl)-6-chloro-2-[(4S) -2,2,4-trimethylpyrrolidin-1-yl]pyridine-3carboxamide in the form of a solvate with 2-propanol containing 11 wt.% 2-propanol ESI-MS m/z calc.

- 110 040454

407.10703, found 4 0 8.1 (M+1)+; retention time 1.9 min.

Step C 5-Fluoro-3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]-1H-pyrazole.

Solution of 3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]-1H-pyrazole (0.68 g, 3.088 mmol) and 1(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (1.3 g, 3.7 mmol) in acetonitrile (15 ml) was stirred at 50° C. for 17 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate and evaporated. The residue was purified by silica gel column chromatography eluting with a gradient of 0-30% ethyl acetate in hexanes to give the still impure product as a brown oil which was further purified by reverse phase HPLC-MS using a Luna C18 column (2) ( 75x30 mm, particle size 5 µm) commercially available from Phenomenex (part number: 00C-4252-U0-AX) and double chromatography with a gradient of 1-99% mobile phase B in 15.0 min (mobile phase A= H ₂ O (5 mM HCl), mobile phase B=CH ₃ CN Flow rate=50 ml/min and column temperature=25° C.) to give 5-fluoro-3-[2-[1-(trifluoromethyl) cyclopropyl]ethoxy]-1Hpyrazole (90 mg) as a light brown oil. EER-MS m/z calc. 238.07292, found 239.1 (M+1) ⁺ ; retention time 0.56 min. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.70 (d, J=4.5 Hz, 1H), 4.30-4.16 (m, 2H), 2.04 (t, J=7 .1 Hz, 2H), 0.97-0.91 (m, 2H), 0.88-0.81 (m, 2H).

Step D. N-(benzenesulfonyl)-6-[5-fluoro-3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-1ul]-2-[(4S)-2,2,4-trimethylpyrrolidine -1-yl]pyridine-3-carboxamide.

A mixture of 5-fluoro-3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]-1H-pyrazole (87 mg, 0.3653 mmol), N(benzenesulfonyl)-6-chloro-2-[(4S)- 2,2,4-Ίrimethylpyrrolidin-1-yl]pyridine-3-carboxamide (79 mg, 0.19 mmol), scandium triflate (10 mg, 0.020 mmol) and sodium hydride (38 mg, 60% w/w). , 0.95 mmol) in DMSO (0.92 ml) was stirred at 160° C. for 15 h. The reaction mixture was filtered and purified by reverse phase HPLC-MS using a Luna C18 (2) column (75x30 mm, particle size 5 µm), commercially available from Phenomenex (part number: 00C-4252-U0-AX), and double chromatography with a gradient of 50-99% mobile phase B in 15.0 min (mobile phase A=H ₂ O (5 mM HCl), mobile phase B=CH ₃ CN Flow rate=50 ml/min and column temperature=25°C) to give N-(benzenesulfonyl)-6-[5-fluoro-3-[2-[1 -(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (11 mg, 10%). EER-MS m/z calc. 60 9.2033, found 610.3 (M+1) ⁺ ; retention time 2.3 min. 1H NMR (400 MHz, DMSO-d ₆ ) δ 12.53 (s, 1H), 8.26 (d, J=4.5 Hz, 1H), 8.00 (t, J=1.3 Hz, 1H), 7.98 (d, J=1.5 Hz, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.73 (d, J=7.4 Hz, 1H) , 7.66 (dd, J=8.2, 6.7 Hz, 2H), 6.90 (d, J=8.3 Hz, 1H), 4.41 (s, 2H), 2.38 ( d, J=10.5 Hz, 1H), 2.29-2.21 (m, 1H), 2.10 (c, J=7.0 Hz, 3H), 1.82 (dd, J=12 .0, 5.5 Hz, 1H), 1.52 (s, 3H), 1.50 (s, 3H), 1.36 (s, 1H), 0.96 (dd, J=3.7, 2.4 Hz, 2H), 0.89 (dt, J=3.7, 1.9 Hz, 2H), 0.64 (d, J=6.3 Hz, 3H).

Synthetic example 33.

Synthesis of compound 33 4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.

Step A 2-Chloro-N-(4-hydroxyphenyl)sulfonyl-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine-3-carboxamide.

2-Chloro-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (150 mg, 0.4288 mmol) and CDI (83 mg, 0.5119 mmol) was combined in THF (750 µl) and stirred at room temperature for 2 h. the reaction mixture for another 16 h at room temperature. The reaction mixture was diluted with 10 ml of 1 M citric acid solution and extracted with 3x10 ml of ethyl acetate. The combined organic layers were washed with water, washed with brine

- 111 040454 solution, dried over sodium sulfate and concentrated to obtain a white solid, which was used in the next step without further purification. 2-Chloro-N-(4-hydroxyphenyl)sulfonyl6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine-3-carboxamide (235 mg, 94%), IERMS m/z calc. 504.1234, found 505.2 (M+1)+; retention time 0.75 min.

Step 2. N-(4-r-hydroxyphenyl)sulfonyl-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol1-yl]-2-[(4S)-2,2,4- trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.

2-Chloro-N-(4-hydroxyphenyl)sulfonyl-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1yl]pyridine-3-carboxamide (235 mg, 0.4654 mmol) , (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (about 209.2 mg, 1.398 mmol) and potassium carbonate (about 387.4 mg, 2.803 mmol) were combined in DMSO (775.7 µl) and heated at 130° C. for 16 hours. The reaction mixture was cooled to room temperature and 1 ml of water was added. After 15 minutes of stirring, the contents of the flask were allowed to settle, the liquid part was removed with a pipette, and the remaining solid was dissolved in 20 ml of ethyl acetate, then washed with 15 ml of 1 M citric acid solution. The aqueous and organic layers were separated and the aqueous layer was extracted two more times using 15 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated. The resulting solid was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give N-(4-hydroxyphenyl)sulfonyl-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazole- 1yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (30 mg, 11%). EER-MS m/z calc. 581.2672, found 582.3 (M+1) ⁺ ; retention time 2.26 min. 1H NMR (400 MHz, DMSO) δ 12.24 (s, 1H), 10.58 (s, 1H), 8.18 (d, J=2.7 Hz, 1H), 7.86-7.78 (m, 2H), 7.74 (d, J=8.2 Hz, 1H), 6.97-6.92 (m, 2H), 6.90 (d, J=8.3 Hz, 1H) , 6.13 (d, J=2.6 Hz, 1H), 4.23 (d, J=7.7 Hz, 2H), 2.43 (t, J=10.4 Hz, 1H), 2 .26 (t, J=9.0 Hz, 1H), 2.10 (dt, J=13.1, 6.8 Hz, 1H), 1.82 (dd, J=11.9, 5.4 Hz, 1H), 1.54 (s, 3H), 1.51 (s, 3H), 1.37 (t, J=12.1 Hz, 1H), 1.10 (s, 6H), 1, 04 (s, 6H), 0.73 (t, J=7.7 Hz, 1H), 0.69 (d, J=6.2 Hz, 3H).

Synthetic example 34.

Synthesis of compound 34 -trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.

Step A 2-Chloro-N-(2-hydroxyphenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide.

HE

2-Chloro-6-[3-[2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (100 mg, 0.2661 mmol) and CDI (51 mg, 0 .3145 mmol) was combined in THF (600.0 µl) and stirred at room temperature for 2 h. the reaction mixture for another 16 h at room temperature. The reaction mixture was diluted with 10 ml of 1 M citric acid solution and extracted with 3x10 ml of ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated to give a white solid which was used in the next step without further purification. 2-Chloro-N-(2-hydroxyphenyl)sulfonyl6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (132 mg, 93%), IERMS m /z calc. 530.06384, found 531.1 (M+1) ⁺ ; retention time 0.7 min.

Step B. N-(2-hydroxyphenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin- 1 -yl]pyridine-3-carboxamide.

- 112 040454

2-Chloro-N-(2-hydroxyphenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridine-3-carboxamide (132 mg, 0.2486 mmol), (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (190 mg, 1.270 mmol) and potassium carbonate (345 mg, 2.496 mmol) were combined in DMSO (660.0 μl) and heated at 130°C for 16 h. The reaction mixture was cooled to room temperature and 1 ml of water was added. After 15 minutes of stirring, the contents of the flask were allowed to settle, the liquid part was removed with a pipette, and the remaining solid was dissolved in 20 ml of ethyl acetate, then washed with 15 ml of 1 M citric acid solution. The aqueous and organic layers were separated and the aqueous layer was extracted two more times using 15 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated. The resulting solid was further purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give N-(2-hydroxyphenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole- 1yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (51 mg, 31%). EER-MS m/z calc. 607.20764, found 608.3 (M+1)+; retention time: 2.14 min. 1H NMR (400 MHz, DMSO) δ 12.41 (s, 1H), 10.89 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.79 (dd, J = 8.1, 2.1 Hz, 2H), 7.56-7.43 (m, 1H), 7.07-6.95 (m, 2H), 6.88 (d, J=8.2 Hz, 1H), 6.11 (d, J=2.7 Hz, 1H), 4.31 (t, J=7.1 Hz, 2H), 2.64 (d, J=8.1 Hz, 1H), 2.58 (d, J=10.6 Hz, 1H), 2.19 (d, J=11.0 Hz, 1H), 2.08 (t, J=7.0 Hz, 2H) , 1.85 (dd, J=11.9, 5.6 Hz, 1H), 1.54 (d, J=8.1 Hz, 6H), 1.39 (t, J=12.1 Hz, 1H), 1.00-0.92 (m, 2H), 0.90 (d, J=10.8 Hz, 2H), 0.82 (d, J=6.3 Hz, 3H).

Synthetic example 35.

Synthesis of compound 35 -trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.

Step A 2-Chloro-N-(3-hydroxyphenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide.

2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (100 mg, 0.2661 mmol) and CDI (51 mg, 0 .3145 mmol) was combined in THF (600.0 µl) and stirred at room temperature for 2 h. another 16 hours at room temperature. The reaction mixture was diluted with 10 ml of 1 M citric acid solution and extracted

3x10 ml ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated to give a white solid which was used in the next step without further purification. 2-Chloro-N-(3-hydroxyphenyl)sulfonyl6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (135 mg, 96%), IERMS m /z calc. 530.06384, found 531.2 (M+1) ⁺ ; retention time 0.69 min.

Step B. N-(3-Hydroxyphenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin- 1-yl]pyridine-3-carboxamide.

2-Chloro-N-(3-hydroxyphenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridine-3-carboxamide (135 mg, 0.2543 mmol), (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (193 mg, 1.290 mmol) and potassium carbonate (352 mg, 2.547 mmol) were combined in DMSO (508.6 µl) and heated at 130°C for 16 h. The reaction mixture was cooled to room temperature and 1 ml of water was added. After 15 minutes of stirring, the contents of the flask were left to settle and the liquid was removed.

- 113 040454 part with a pipette, and discarded. The remaining solid was dissolved in 20 ml of ethyl acetate, then washed with 15 ml of 1 M citric acid solution. The aqueous and organic layers were separated and the aqueous layer was extracted two more times using 15 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated. The resulting solid was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give N-(3-hydroxyphenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-1 -yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (40 mg, 26%). EER-MS m/z calc. 607.20764, found 608.3 (M+1)+; retention time: 2.05 min. 1H NMR (400 MHz, DMSO) δ 12.44 (s, 1H), 10.19 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.40-7.37 (m, 2H), 7.06 (d, J=7.9 Hz , 1H), 6.91 (d, J=8.2 Hz, 1H), 6.11 (d, J=2.7 Hz, 1H), 4.31 (t, J=7.1 Hz, 2H ), 2.47 (d, J=10.0 Hz, 1H), 2.33 (s, 2H), 2.08 (m, J=8.1, 7.0 Hz, 2H), 1.84 (dd, J=11.8, 5.5 Hz, 1H), 1.54 (s, 3H), 1.52 (s, 3H), 1.38 (t, J=12.1 Hz, 1H) , 0.96 (td, J=5.0, 3.3 Hz, 2H), 0.90 (d, J=11.1 Hz, 2H), 0.70 (d, J=6.2 Hz, 3H).

Synthetic example 36.

Synthesis of compound 36 -trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.

Step A: Dideuterio-(2,2,3,3-tetramethylcyclopropyl)methanol.

2,2,3,3-Tetramethylcyclopropanecarboxylic acid (1.077 g, 7.574 mmol) was dissolved in anhydrous diethyl ether in a 100 ml round bottom flask purged with nitrogen. The reaction mixture was cooled to 0°C. Solid tetradeuterioaluminide (lithium salt) (420 mg, 10.01 mmol) was added in 3 portions. The reaction mixture was allowed to gradually reach room temperature and was stirred for a total of 16 hours. Then the reaction mixture was again cooled to 0°C. HCl (aq., 0.2N, 5 ml) was added dropwise followed by 20 ml of water. The aqueous phase was extracted with diethyl ether (2x30 ml). The combined organic phases were washed with aqueous NaHCO ₃ , then brine, then dried over sodium sulfate, filtered and evaporated to give deuterio-(2,2,3,3tetramethylcyclopropyl)methanol (920 mg, 93%). 1H NMR (400 MHz, DMSO) δ 4.11 (s, 1H), 1.04 (s, 6H), 0.93 (s, 6H), 0.37 (s, 1H).

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

DIAD (1.4 ml, 7.111 mmol) was added dropwise to a solution of triphenylphosphine (1.815 g, 6.920 mmol) in 40 ml anhydrous toluene at 0°C. After 30 min at 0°C, a solution of tert-butyl-3-hydroxypyrazole-1-carboxylate (1.155 g, 6.271 mmol) and dideutherio-(2,2,3,3tetramethylcyclopropyl)methanol (980 mg, 7.525 mmol) was added slowly via syringe. ) in 30 ml of toluene. The reaction mixture was heated to room temperature over 45 min and then heated to 55°C for 18 h. The mixture was evaporated and the resulting material was partitioned between ethyl acetate (30 ml) and 1N. sodium hydroxide solution (30 ml). The organic layer was separated, washed with brine (30 ml), dried over sodium sulfate and evaporated.

The crude material was purified by silica gel chromatography eluting with 0-30% ethyl acetate in hexanes to give an oil which eventually solidified to a light yellow solid: t-butyl-3-[dideuterio-(2,2,3 ,3-Tetramethylcyclopropyl)methoxy]pyrazole-1-carboxylate (820 mg, 44%), ESI-MS m/z calc. 296.2069, found 297.2 (M+1) ⁺ ; retention time 0.79 min.

Step C. 3-[Dideutherio-(2,2,3,3-tetramethylcyclopropyl)methoxy]-1H-pyrazole.

Sodium carbonate (460 mg, 4.340 mmol) in water (3 ml) and heated the reaction mixture to 90° C. for 16 hours in a screw cap flask. reaction mixture

- 114 040454 was cooled to room temperature and diluted with water (50 ml) and ethyl acetate (50 ml). The organic layer was separated and the aqueous layer was extracted with 2x25 ml of ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate, then concentrated to give a colorless oil. 3-[Dideuterio-(2,2,3,3-tetramethylcyclopropyl)methoxy]-1H-pyrazole (492 mg, 93%), ESI-MS m/z calc. 196.15446, found 197.1 (M+1)+; retention time 0.57 min, Ή NMR (400 MHz, DMSO) δ 11.78 (s, 1H), 7.48 (t, J=2.1 Hz, 1H), 5.65 (t, J=2 .3 Hz, 1H), 1.08 (s, 6H), 1.00 (s, 6H), 0.66 (s, 1H).

Step D Ethyl 2-chloro-6-[3-[dideuterio-(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1yl]pyridine-3-carboxylate.

O

A round bottom flask under nitrogen was charged with 3-[dideutherio-(2,2,3,3-tetramethylcyclopropyl)methoxy]-1H-pyrazole (485 mg, 2.471 mmol), ethyl 2,6-dichloropyridine-3-carboxylate (545 mg, 2.477 mmol), K ₂ CO ₃ (513 mg, 3.712 mmol) (freshly ground in a mortar) and anhydrous DMF (4.128 ml). DABCO (50 mg, 0.4457 mmol) was added and the mixture was stirred at room temperature under nitrogen atmosphere for 16 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and water (50 ml) and the two phases were separated. The aqueous phase was further extracted with ethyl acetate (2x30 ml) and the combined extracts washed with brine and dried over sodium sulfate, after which the solvent was removed under reduced pressure. The resulting material was subjected to flash chromatography on silica gel using a gradient of 0-20% ethyl acetate in hexanes. Pure fractions were combined and solvents removed under reduced pressure to give a white solid; ethyl 2-chloro-6-[3[dideuterio-(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine-3-carboxylate (505 mg, 54%), ESI-MS m/ z calc. 379.16318, found 380.1 (M+1) ⁺ ; retention time: 0.9 min. 1H NMR (400

MHz, DMSO) 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), 6.24 (d, J=2.9 Hz, 1H), 4.34 (k, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H) , 1.11 (s, 6H), 1.04 (s, 6H), 0.74 (s, 1H).

Step E 2-Chloro-6-[3-[dideuterio-(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine3-carboxylic acid.

A solution of sodium hydroxide (275 mg, 6.875 mmol) in water (2.500 ml) was added to a solution of ethyl 2chloro-6-[3-[dideuterio-(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl] pyridine-3-carboxylate (500 mg, 1.316 mmol) in isopropanol (2.500 ml) and stirred at 90° C. for 45 minutes. The reaction mixture was cooled to room temperature, then diluted with 50 ml of ethyl acetate, 20 ml of 1 M citric acid solution and 10 ml of water. The organic layer was separated and the aqueous part was extracted

2x25 ml ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The resulting solid was triturated in 40 ml of water, rapidly sonicated and collected by filtration, then dried to give a white solid, 2-chloro-6-[3-[dideutherio-(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazole -1yl]pyridine-3-carboxylic acid (404 mg, 87%). EER-MS m/z calc. 351.13187, found 352.1 (M+1) ⁺ ; retention time: 0.77 min. 1H NMR (400 MHz, DMSO) δ 8.41 (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=2.8 Hz, 1H), 1.11 (s, 6H), 1.04 (s, 6H), 0.74 (s, 1H).

Step F. R-(Benzenesulfonyl)-2-chloro-6-[3-[dideutherio-(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine-3-carboxamide.

2-Chloro-6-[3-[dideutherio-(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (100 mg, 0.2842 mmol) and CDI (55 mg, 0.3392 mmol) were combined in THF (600.0 μl) and stirred at room temperature for 2 h. Benzenesulfonamide (49 mg, 0.3117 mmol) was added followed by DBU (57 μl, 0. 3812 mmol) and the reaction mixture was stirred for another 16 h at room temperature. The reaction mixture was diluted with 10 ml of 1 M citric acid solution and extracted with 3x10 ml of ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated to give about 135 mg of a white solid which was used in the next step without further purification. X-(benzenesulfonyl)-2-chloro6-[3-[dideutherio-(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine-3-carboxamide, ESI-MS m/z calc. 490.14105, found 491.2 (M+1)+; retention time 0.81 min.

Step G. X-(Benzenesulfonyl)-6-[3-[dideutherio-(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4- trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.

X-(Benzenesulfonyl)-2-chloro-6-[3-[dideuterio-(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1yl]pyridine-3-carboxamide (135 mg, 0.2749 mmol), (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (128 mg, 0.8553 mmol) and potassium carbonate (237 mg, 1.715 mmol) were combined in DMSO (458.2 μl) and heated at 130°C in for 16 hours the Reaction mixture was cooled to room temperature and was added 1 ml of water. After 15 minutes of stirring, the contents of the flask were allowed to settle and the liquid part was removed with a pipette, and the remaining solid was dissolved in 20 ml of ethyl acetate, then washed with 15 ml of 1 M citric acid solution. The aqueous and organic layers were separated and the aqueous layer was extracted two more times using 15 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated. The resulting solid was further purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give X-(benzenesulfonyl)-6-[3-[dideutherio-(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazole- 1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (112 mg, 72%). IERMS m/z calc. 567.28485, found 568.3 (M+1)+; retention time: 2.42 min. ¹ H NMR (400 MHz, DMSO) δ 12.51 (s, 1H), 8.18 (d, J=2.8 Hz, 1H), 7.99 (dt, J=7.1, 1.4 Hz, 2H), 7.80 (d, J=8.3 Hz, 1H), 7.76-7.70 (m, 1H), 7.70-7.62 (m, 2H), 6.92 (d, J=8.3 Hz, 1H), 6.13 (d, J=2.7 Hz, 1H), 2.40 (t, J=10.4 Hz, 1H), 2.26 (t , J=8.7 Hz, 1H), 2.09 (dc, J=11.7, 6.0 Hz, 1H), 1.82 (dd, J=11.8, 5.4 Hz, 1H) , 1.52 (d, J=9.5 Hz, 6H), 1.36 (t, J=12.2 Hz, 1H), 1.10 (s, 6H), 1.04 (s, 6H) , 0.72 (s, 1H), 0.64 (d, J=6.2 Hz, 3H).

Synthetic example 37.

Synthesis of compound 37 yl]pyridine-3-carboxamide.

Step A. 3-(tert-Butoxymethyl)-1H-pyrazole.

tert-Butylpropargyl alcohol (2.5 g, 22.2 mmol) was mixed with trimethylsilyldiazomethane (2.0 M in hexane, 11.1 ml, 22.2 mmol) and stirred in a closed flask at 115°C for 18 hours. The mixture was cooled to 40° C. and quenched with methanol (5 ml) and concentrated. Column chromatography (silica; heptanes/EtOAc 2:1 to 1:1) gave 3-(tert-butoxymethyl)-1H-pyrazole as a colorless oil (1.5 g, 44%). 1 H NMR (CDCl ₃ , 300 MHz): δ 1.26 (s, 9H); 4.53 (s, 2H); 6.22 (s, 1H); 7.48 (s, 1H), ¹³ C-NMR (75 MHz, CDQ3): δ 27.3, 57.2, 73.9,103.5, 134.0 (one quaternary carbon not shown).

Step B. tert-Butyl-6-[3-(tert-butoxymethyl)pyrazol-1-yl]-2-chloropyridine-3-carboxylate.

A 100 ml round bottom flask under nitrogen was charged with 3-(tert-butoxymethyl)-1Hpyrazole (1.241 g, 8.047 mmol), tert-butyl-2,6-dichloropyridine-3-carboxylate (2.0 g, 8.061 mmol), K2CO3 (1.448 g, 10.48 mmol) (freshly ground in a mortar) and anhydrous DMF (12.41 ml). DABCO (163 mg, 1.453 mmol) was added and the mixture was stirred at room temperature under nitrogen for 16 h.

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The reaction mixture was diluted with ethyl acetate (50 ml) and water and brine (50 ml) and the two phases were separated. The aqueous phase was further extracted with ethyl acetate (2x30 ml). The combined extracts were washed with brine, dried over sodium sulfate and the solvent was removed under reduced pressure. The resulting material was subjected to flash chromatography on silica gel using a gradient of ethyl acetate (from 0 to 10%) in hexanes. Pure fractions were combined and solvents removed under reduced pressure to give tert-butyl 6-[3-(tert-butoxymethyl)pyrazol-1-yl]-2-chloropyridine-3-carboxylate (1.956 g, 66%) as a colorless oily substance, which solidified overnight to a white solid under high vacuum. EER-MS m/z calc. 365.1506, found 366.2 (M+1)+; retention time 0.82 min.

Step C. 2-Chloro-6-[3-(hydroxymethyl)pyrazol-1-yl]pyridine-3-carboxylic acid.

tert-Butyl-6-[3-(tert-butoxymethyl)pyrazol-1-yl]-2-chloropyridine-3-carboxylate (538 mg, 1.471 mmol) was dissolved in HCl in dioxane (8.0 ml of a 4 M solution, 32 .00 mmol) and heated at 60° C. for 2 hours. The reaction mixture was then cooled to room temperature and concentrated to dryness to give a white powder. 2-Chloro-6-[3-(hydroxymethyl)pyrazol-1-yl]pyridine-3-carboxylic acid (370 mg, 99%), ESI-MS m/z calc. 253.02542, found 254.1 (M+1) ⁺ ; retention time 0.33 min.

Step D. 2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxymethyl]pyrazol-1-yl]pyridine-3-carboxylic acid.

[1-(Trifluoromethyl)cyclopropyl]methyl-4-methylbenzenesulfonate (1.3 g, 4.417 mmol) and 2-chloro-6-[3(hydroxymethyl)pyrazol-1-yl]pyridine-3-carboxylic acid (370 mg, 1.459 mmol) were combined in anhydrous DMSO (9.250 ml). Potassium tert-butoxide (660 mg, 5.882 mmol) was added and the reaction mixture was stirred at room temperature. After 30 min the reaction mixture was poured into 1 M citric acid solution (15 ml) and extracted with 3x15 ml ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The resulting material was purified by silica gel chromatography using a 0-10% gradient of methanol in dichloromethane. Fractions containing product were collected and concentrated to give a white solid. 2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxymethyl]pyrazol-1-yl]pyridine-3-carboxylic acid (292 mg, 53%), ESI-MS m/z calc. 375.05975, found 37 6.1 (M+1) ⁺ ; retention time: 0.62 min.

Step E. N-(Benzenesulfonyl)-2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxymethyl]pyrazol-1-yl]pyridine-3-carboxamide.

2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxymethyl]pyrazol-1-yl]pyridine-3-carboxylic acid (60 mg, 0.1597 mmol) and CDI (31 mg, 0.1912 mmol) was combined in THF (360.0 µl) and stirred at room temperature for 2 h. h at room temperature. The reaction mixture was diluted with 10 ml of 1 M citric acid solution and extracted with 3x10 ml of ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated to give a white solid which was used in the next step without further purification. N-(benzenesulfonyl)-2-chloro-6-[3[[1-(trifluoromethyl)cyclopropyl]methoxymethyl]pyrazol-1-yl]pyridine-3-carboxamide (ca. 78 mg), ESI-MS m/z calc. 514.0689, found 515.1 (M+1) ⁺ ; retention time 0.69 min.

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Step G. K-(Benzenesulfonyl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxymethyl]pyrazol-1-yl]2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl] pyridine-3-carboxamide.

N-(Benzenesulfonyl)-2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxymethyl]pyrazol-1yl]pyridine-3-carboxamide (78 mg, 0.1515 mmol), (4S)-2 ,2,4-trimethylpyrrolidine (hydrochloride salt) (115 mg, 0.7684 mmol) and potassium carbonate (210 mg, 1.519 mmol) were combined in DMSO (390.0 µl) and heated at 130°C for 16 h. the mixture was cooled to room temperature and 1 ml of water was added. After 15 minutes of stirring, the contents of the flask were allowed to settle and the liquid part was removed with a pipette, and the remaining solid was dissolved in 20 ml of ethyl acetate, then washed with 15 ml of 1 M citric acid solution. The aqueous and organic layers were separated and the aqueous layer was extracted two more times using 15 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated. The resulting solid was further purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give N-(benzenesulfonyl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxymethyl]pyrazol-1yl]-2- [(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (46 mg, 51%). EER-MS m/z calc. 591.2127, found 592.3 (M+1)+; retention time: 2.11 min. 1H NMR (400 MHz, DMSO) δ 12.56 (s, 1H), 8.33 (d, J=2.6 Hz, 1H), 8.04-7.97 (m, 2H), 7.89 -7.79 (m, 1H), 7.73 (t, J=7.1 Hz, 1H), 7.70-7.60 (m, 2H), 7.07 (d, J=8.2 Hz, 1H), 6.56 (d, J=2.6 Hz, 1H), 4.55 (s, 2H), 3.59 (s, 2H), 2.42 (t, J=10.4 Hz, 1H), 2.29 (d, J=9.6 Hz, 1H), 2.18-2.04 (m, 1H), 1.83 (dd, J=11.7, 5.5 Hz , 1H), 1.54 (d, J=9.4 Hz, 6H), 1.37 (t, J=12.1 Hz, 1H), 1.03-0.94 (m, 2H), 0 .91-0.80 (m, 2H), 0.65 (d, J=6.2 Hz, 3H).

Synthetic example 38.

Synthesis of compound 38 4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.

Steps A, B. 1-[1-(Trifluoromethyl)cyclopropyl]prop-2-en-1-ol.

.) RSS he

Λ

ΌΗ V/

.) vinylmagnesium bromide

[1-(Trifluoromethyl)cyclopropyl]methanol (1 g, 7.138 mmol) was stirred in dry dichloromethane (30 ml) and cooled to 0° C. in an ice bath. Chromium hydroxychloride dioxide pyridine complex (2.77 g, 12.85 mmol) was added in one portion, the ice bath was removed and the reaction mixture was stirred for 24 hours at room temperature. The reaction mixture was poured into 100 ml of diethyl ether and filtered through a layer of silica covered with a layer of celite, eluting with diethyl ether. The resulting filtrate was dried over sodium sulfate, then filtered through cotton cloth and used in the next step without concentration due to the volatility of the aldehyde. The crude filtrate was cooled to 0°C and bromine(vinyl)magnesium (14.5 ml of a 1 M solution, 14.50 mmol) (in THF) was added slowly. The reaction mixture was allowed to warm slowly to almost room temperature over 2 hours. The reaction mixture was then cooled to 0° C., quenched with 1M HCl and diluted with water. The layers were separated and the aqueous layer was extracted with diethyl ether 4 more times. The combined organic layers were washed with brine, dried over sodium sulfate and partially concentrated. The resulting crude material was used in the next step without further purification. 1-[1-(trifluoromethyl)cyclopropyl]prop-2-en-1-ol (ca. 1.25 g crude, with significant residual THF). Crude product: 1H NMR (400 MHz, DMSO) δ 5.95-5.84 (m, 1H), 5.36 (d, J=5.2 Hz, 1H), 5.32 (ddd, J=17 .1, 2.1, 1.4 Hz, 1H), 5.18 (ddd, J=10.4, 2.0, 1.3 Hz, 1H), 4.17 (tt, J=6.4 , 1.4 Hz, 1H), 0.95-0.87 (m, 4H).

Step C: t-Butyldimethyl-[1-[1-(trifluoromethyl)cyclopropyl]allyloxy]silane.

1-[1-(Trifluoromethyl)cyclopropyl]prop-2-en-1-ol (270 mg, 1.625 mmol) and imidazole (220 mg, 3.232 mmol) were dissolved in DMF (2 ml) and cooled to 0°C on ice bath. TBS-Cl (tert-butyldimethylsilyl chloride) (370 mg, 2.455 mmol) was then added in one portion and after 15 min the ice bath was removed and the reaction mixture was allowed to stir for 16 h at room temperature. Then a saturated aqueous ammonium chloride solution (1 ml) was added and the reaction mixture was stirred for 20 minutes. Then the reaction mixture was diluted with 30 ml of diethyl ether and 20 ml of water. The organic layer was separated and the aqueous layer was extracted with 2x15 ml diethyl ether. The combined organic layers were washed with water then brine and dried over sodium sulfate and concentrated in vacuo. The crude material was then passed through a plug of silica gel, eluting with hexanes, and concentrated to an oily substance containing a significant amount of overlapping silyl-containing impurities, but used in the next step without further purification: t-butyl-dimethyl-[1-[1-(trifluoromethyl)cyclopropyl] allyloxy]silane (about 317 mg, crude).

Stages D-F. tert-Butyl-3-[2-[tert-butyl(dimethyl)silyl]oxy-2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-1-carboxylate.

tert-Butyl-dimethyl-[1-[1-(trifluoromethyl)cyclopropyl]allyloxy]silane (220 mg, 0.7846 mmol) (crude) was combined in dioxane (6 ml) and water (2 ml) with 2,6- dimethylpyridine (185 µl, 1.597 mmol) and sodium periodate (675 mg, 3.156 mmol). Osmium tetroxide (420 μl, 0.3139 mmol) was then added and the reaction mixture was stirred for 20 hours at room temperature. Then the reaction mixture was diluted with 30 ml of dichloromethane and 30 ml of water. The organic layer was separated and the aqueous layer was extracted with 2x25 ml dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to about 8 ml and used in the next step without isolation.

The crude mixture from the previous step was diluted with methanol (10 ml) and cooled to 0°C. Sodium borohydride (90 mg, 2.379 mmol) was added and the reaction mixture was stirred for 1 h. The reaction mixture was then quenched with acetic acid and concentrated. The resulting material was partitioned between ethyl acetate and an aqueous sodium bicarbonate solution, and the layers were separated. The aqueous portion was extracted 2x with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The resulting crude alcohol was used in the next step without purification. The crude product was combined with triphenylphosphine (300 mg, 1.144 mmol) and tert-butyl 3-hydroxypyrazole-1-carboxylate (145 mg, 0.7872 mmol) dissolved in THF (15 mL). The reaction mixture was cooled to 0°C and DIAD (230 μl, 1.187 mmol) was added slowly. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h, then heated to 55°C for another 16 h. NaOH solution, brine, dried over sodium sulfate and concentrated. The resulting material was purified by silica gel chromatography eluting with 0-50% ethyl acetate in hexanes to give, together with an overlapping UV active impurity, tert-butyl-3-[2-[tert-butyl(dimethyl)silyl]oxy-2-[1-( trifluoromethyl)cyclopropyl]ethoxy]pyrazole-1 carboxylate (63 mg, 18%). EER-MS m/z calc. 450.21616, found 451.3 (M+1)+; retention time 0.95 min.

Step G. 3 -(2-((tert-Butyldimethylsilyl)oxy)-2-( 1 -(trifluoromethyl)cyclopropyl)ethoxy)-1Hpyrazole.

tert-Butyl 3-[2-[tert-butyl(dimethyl)silyl]oxy-2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole 1-carboxylate (63 mg, 0.1398 mmol) (with main impurity) was dissolved in dichloromethane (1.312 ml) with TFA (trifluoroacetic acid) (about 194.3 mg, 131.3 μl, 1.704 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. Hexanes (1 ml) were added, the reaction mixture was evaporated and the resulting oily substance 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 a colorless oil, 3(2-((tert-butyldimethylsilyl)oxy)-2-(1-(trifluoromethyl)cyclopropyl)ethoxy)-1H-pyrazole (37 mg, 76%). EER-MS m/z calc. 350.16373, found 351.2 (M+1) ⁺ ; retention time 0.81 min.

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Step H. tert-Butyl-6-[3-[2-[tert-butyl(dimethyl)silyl]oxy-2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-chloropyridin-3 -carboxylate.

A round-bottom flask under nitrogen was charged with tert-butyl-dimethyl-[2-(1H-pyrazol-3-yloxy)1-[1-(trifluoromethyl)cyclopropyl]ethoxy]silane (37 mg, 0.1056 mmol), tert- butyl 2,6-dichloropyridine-3-carboxylate (26 mg, 0.1048 mmol), K ₂ CO ₃ (25 mg, 0.1809 mmol) (freshly ground in a mortar) and anhydrous DMF (250 µl). DABCO (2 mg, 0.01783 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (15 ml) and water (15 ml) and the two phases were separated. The aqueous phase was further extracted with ethyl acetate (2x15 ml). The combined extracts were washed with brine and dried over sodium sulfate, and the solvent was removed under reduced pressure. The material was subjected to flash chromatography on silica gel using a gradient of ethyl acetate (from 0 to 20%) in hexanes. Pure fractions were combined and solvents removed under reduced pressure to give a colorless oily substance, tert-butyl-6-[3-[2-[tert-butyl(dimethyl)silyl]oxy-2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole- 1-yl]-2-chloropyridine-3-carboxylate (20 mg, 34%). EER-MS m/z calc. 561.20374, found 562.4 (M+1)+; retention time: 0.84 min. 1H NMR (400 MHz, DMSO) δ 8.44 (d, J=2.9 Hz, 1H), 8.34 (d, J=8.4 Hz, 1H), 7.71 (d, J=8 .4 Hz, 1H), 6.17 (d, J=2.9 Hz, 1H), 4.44 (dd, J=10.7, 2.9 Hz, 1H), 0.13-0.03 (m, 6H), 4.32-4.25 (m, 1H), 3.89 (s, 1H), 1.56 (s, 9H), 0.98 (d, J=35.8 Hz, 4H), 0.86 (s, 9H).

Step I 6-[3-[2-[tert-Butyl(dimethyl)silyl]oxy-2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-chloropyridine-3-carboxylic acid.

tert-Butyl-6-[3-[2-[tert-butyl(dimethyl)silyl]oxy-2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-chloropyridine-3-carboxylate ( 20 mg, 0.03558 mmol) and TFA (50 μl, 0.6490 mmol) were combined in dichloromethane (0.75 ml) and heated at 45° C. for 3 h. The reaction mixture was evaporated. Hexanes were added and the mixture was evaporated again to give a white solid, 6-[3-[2-[tert-butyl(dimethyl)silyl]oxy-2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2- chloropyridine-3-carboxylic acid (18 mg, 100%). EER-MS m/z calc. 505.14114, found 50 6.3 (M+1)+; retention time 0.59 min.

Step J. K-(Benzenesulfonyl)-6-[3-[2-[tert-butyl(dimethyl)silyl]oxy-2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-chloropyridine -3-carboxamide.

6-[3-[2-[tert-Butyl(dimethyl)silyl]oxy-2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-chloropyridine-3-carboxylic acid (19 mg, 0 .03755 mmol) and CDI (8 mg, 0.04934 mmol) were combined in THF (200 µl) and stirred at room temperature for 2 h. Benzenesulfonamide (7 mg, 0.04453 mmol) was added followed by DBU (10 µl , 0.06687 mmol) and the reaction mixture was stirred for another 2 h at room temperature. Then the reaction mixture was diluted with 10 ml of 1 M citric acid solution and was extracted with 3x10 ml of ethyl acetate.

The combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated to give a white solid which was used in the next step without further purification. N-(Benzenesulfonyl)-6-[3-[2-[tert-butyl(dimethyl)silyl]oxy-2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-chloropyridin-3- carboxamide (about 22 mg), ESI-MS m/z calc. 644.1503, found 64 5.3 (M+1)+; retention time 0.8 min.

Step O. N-(Benzenesulfonyl)-6-[3-[2-[tert-butyl(dimethyl)silyl]oxy-2-[1-(trifluoromethyl)cyclo-120 040454 lopropyl]ethoxy]pyrazol-1-yl] -2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.

N-(Benzenesulfonyl)-6-[3-[2-[tert-butyl(dimethyl)silyl]oxy-2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-chloropyridin-3- carboxamide (22 mg, 0.03410 mmol), (4S)-2,2,4trimethylpyrrolidine (hydrochloride salt) (about 40.83 mg, 0.2728 mmol) and potassium carbonate (about 75.40 mg, 0.5456 mmol ) was combined in DMSO (180 μl) and heated at 130° C. for 24 hours. The reaction mixture was cooled to room temperature and diluted with 15 ml of 1 M citric acid solution and 20 ml of ethyl acetate. The aqueous and organic layers were separated and the aqueous layer was extracted two more times using 15 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated. The resulting solid was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give the TBS-protected compound as a white solid: N-(benzenesulfonyl)-6-[3-[2-[t-butyl(dimethyl)silyl ]oxy-2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (8 mg, 32% ). EER-MS m/z calc. 721.2941, found 722.4 (M+1) ⁺ ; retention time 0.88 min.

Step P. N-(Benzenesulfonyl)-6-[3-[2-hydroxy-2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidine -1 -yl]pyridine-3-carboxamide.

Then N-(benzenesulfonyl)-6-[3-[2-[tert-butyl(dimethyl)silyl]oxy-2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S )-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (8 mg, 0.0341 mmol) was dissolved in THF (0.4 ml), cooled to 0°C, and tetrabutylammonium fluoride ( 1M in THF, about 0.17 ml, 0.1705 mmol). After 5 minutes the reaction mixture was allowed to warm to room temperature. After 20 min at room temperature, the reaction mixture was poured into 10 ml of 1 M citric acid and extracted with 3x10 ml of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The resulting crude material was then purified twice by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give N-(benzenesulfonyl)-6-[3-[2-hydroxy-2-[1(trifluoromethyl)cyclopropyl]ethoxy]pyrazole -1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (3 mg, 14%). EER-MS m/z calc. 607.20764, found 608.3 (M+1) ⁺ ; retention time: 1.99 min. 1H NMR (400 MHz, DMSO) δ 12.51 (s, 1H), 8.19 (d, J=2.8 Hz, 1H), 7.97 (d, J=7.5 Hz, 2H), 7.79 (d, J=8.2 Hz, 1H), 7.70 (d, J=9.6 Hz, 1H), 7.64 (d, J=7.9 Hz, 2H), 6, 89 (d, J=8.2 Hz, 1H), 6.11 (d, J=2.8 Hz, 1H), 5.57 (dd, J=5.5, 2.6 Hz, 1H), 4.40-4.32(m, 1H), 2.46-2.39(m, 1H), 4.20-4.12(m, 1H), 3.89(s, 1H), 2, 28 (s, 1H), 2.09 (s, 1H), 1.82 (dd, J=12.1, 5.5 Hz, 1H), 1.52 (d, J=9.7 Hz, 6H ), 1.43-1.36 (m, 1H), 1.03-0.89 (m, 4H), 0.65 (d, J=6.2 Hz, 3H).

Synthetic example 39.

Synthesis of compound 39 -1-yl]pyridine-3-carboxamide.

Step A. tert-Butyl-3-(((1R,2S,4S)-bicyclo[2.2.1]heptan-2-yl)oxy)-1H-pyrazole-1-carboxylate.

tert-Butyl-3-hydroxypyrazole-1-carboxylate (1.632 g, 8.860 mmol), (+)-endo-2-norborneol (1 g,

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8.915 mmol) and triphenylphosphine (2.57 g, 9.798 mmol) were combined in THF (21.98 ml) and the reaction mixture was cooled in an ice bath. DIAD (2 ml, 10.16 mmol) was added dropwise to the mixture and the reaction mixture was allowed to warm to room temperature and stirred for 16 h. sodium hydroxide solution (30 ml). The organic layer was separated, washed with brine (30 ml), dried over sodium sulfate and evaporated. The crude material was purified by silica gel chromatography eluting with 0-30% ethyl acetate in hexanes to give m-tert-butyl-3-(((1R,2S,4S)bicyclo[2.2.1]heptan-2-yl)oxy)-1H -pyrazole-1-carboxylate (2.08 g, 84%). EER-MS m/z calc. 278.16306, found 2 7 9.3 (M+1)+; retention time: 0.72 min. ¹ H NMR (400 MHz, DMSO) δ 8.05 (d, J=3.0 Hz, 1H), 6.07 (d, J=3.0 Hz, 1H), 4.47 (d, J= 6.8 Hz, 1H), 2.43-2.36 (m, 1H), 2.32-2.22 (m, 1H), 1.75 (td, J=6.7, 2.4 Hz , 1H), 1.54 (s, 9H), 1.53-1.49 (m, 2H), 1.42 (ddt, J=14.8, 7.8, 4.4 Hz, 2H), 1.18-1.07 (m, 3H).

Step B. 3-[(1R,2S,4S)-norbornan-2-yl]oxy-1H-pyrazole.

H m-tert-Butyl-3-[(1R,2S,4S)-norbornan-2-yl]oxypyrazole-1-carboxylate (2.08 g, 7.473 mmol) was dissolved in CH ₂ Cl ₂ (20.80 ml) with trifluoroacetic acid (5.8 ml, 75.28 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure and the remaining oily substance was partitioned between ethyl acetate (50 ml) and saturated sodium bicarbonate solution (30 ml) . The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo to give an oil, 3-[(1R,2S,4S)-norbornan-2-yl]oxy-1H-pyrazole (1.29 g, 97%). EER-MS m/z calc. 178.11061, found 17 9.2 (M+1) ⁺ ; retention time 0.45 min.

Step C. tert-Butyl-2-chloro-6-[3-[(1R,2S,4S)-norbornan-2-yl]oxypyrazol-1-yl]pyridine-3carboxylate.

A 100 ml round bottom flask under nitrogen was charged with tert-butyl-2,6dichloropyridine-3-carboxylate (1.796 g, 7.239 mmol), 3-[(1R,2S,4S)-norbornan-2-yl]oxy-1H- pyrazole (1.29 g, 7.238 mmol) and K2CO3 (1.310 g, 9.479 mmol) (freshly ground in a mortar), and anhydrous DMF (12 mL). DABCO (146 mg, 1.302 mmol) was added and the reaction mixture was stirred at room temperature under nitrogen atmosphere for 8 hours. The reaction mixture was diluted with ethyl acetate (50 ml), water and brine (50 ml) and the two phases were separated. The aqueous phase was further extracted with ethyl acetate (2x50 ml). The combined extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. The material was subjected to flash chromatography on silica gel using a gradient of ethyl acetate (from 0 to 20%) in hexanes. Pure fractions were combined and solvents removed under reduced pressure to give m-tert-butyl-2-chloro-6-[3-[(1R,2S,4S)-norbornan-2yl]oxypyrazol-1-yl]pyridine-3-carboxylate (1.814 d, 64%). EER-MS m/z calc. 389.1506, found 390.3 (M+1) ⁺ ; retention time: 0.92 min. 1H NMR (400 MHz, DMSO) δ 8.40 (d, J=2.9 Hz, 1H), 8.32 (d, J=8.4 Hz, 1H), 7.72 (d, J=8 .4 Hz, 1H), 6.18 (d, J=2.9 Hz, 1H), 4.53 (d, J=6.6 Hz, 1H), 1.88-1.78 (m, 1H ), 2.45 (d, J=4.6 Hz, 1H), 2.29 (t, J=4.3 Hz, 1H), 1.56 (s, 9H), 1.55-1.39 (m, 4H), 1.22-1.08 (m, 3H).

Step D. 2-Chloro-6-[3-[(1R,2S,4S)-norbornan-2-yl]oxypyrazol-1-yl]pyridine-3-carboxylic acid.

H H m-tert-Butyl-2-chloro-6-[3-[(1R,2S,4S)-norbornan-2-yl]oxypyrazol-1-yl]pyridine-3-carboxylate (1.814 g, 4.653 mmol) and TFA (5 ml, 64.90 mmol) was combined in dichloromethane (18.14 ml) and heated at 40° C. for 2 hours. The reaction mixture was evaporated. Hexanes were added and the mixture was evaporated again with

- 122 040454 by irradiating a white solid which was used in the next step without further purification. 2-Chloro-6-[3-[(1R,2S,4S)-norbornan-2-yl]oxypyrazol-1-yl]pyridine-3-carboxylic acid (1.47 g, 79%), ESI-MS m /z calc. 333.088, found 334.2 (M+1)+; retention time 0.71 min.

Step E. N-(Benzenesulfonyl)-2-chloro-6-[3-[(1R,2S,4S)-norbornan-2-yl]oxypyrazol-1-yl]pyridine3-carboxamide.

2-Chloro-6-[3-[(1R,2S,4S)-norbornan-2-yl]oxypyrazol-1-yl]pyridine-3-carboxylic acid (100 mg)) and CDI (52 mg, 0.323 mmol) combined in THF and stirred for 2 h at room temperature. Then benzenesulfonamide (52 mg, 0.331 mmol) and DBU (0.048 ml, 0.323 mmol) were added and the reaction mixture was stirred for another 2 hours at room temperature. The reaction mixture was then poured into 20 ml

M citric acid solution and extracted with 3x20 ml of ethyl acetate. The combined organic layers were washed with water then brine, dried over sodium sulfate and concentrated to give about 122 mg of N-(benzenesulfonyl)-2-chloro-6-[3-[(1R,2S,4S)-norbornan-2yl] hydroxypyrazol-1-yl]pyridine-3-carboxamide, which was used in the next step without further purification. EER-MS m/z calc. 490.12, found 491.3 (M+1) ⁺ ; retention time 0.75 min.

Step F. N-(Benzenesulfonyl)-6-[3-[(1R,2S,4S)-norbornan-2-yl]oxypyrazol-1-yl]-2-[(4S)-2,2,4trimethylpyrrolidin-1 -yl]pyridine-3-carboxamide.

N-(Benzenesulfonyl)-2-chloro-6-[3-[(1R,2S,4S)-norbornan-2-yl]oxypyrazol-1-yl]pyridine-3carboxamide (120 mg, 0.2537 mmol), ( 4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (113.9 mg, 0.7611 mmol) and potassium carbonate (210.3 mg, 1.522 mmol) were combined in 0.423 ml DMSO in a screw cap flask and heated to 130°C for 16 hours Then the reaction mixture was cooled to room temperature and added 3 ml of water, which led to the formation of a precipitate. After 30 minutes, the liquid portion was removed with a syringe and discarded, and the remaining solid was dissolved in 15 ml of ethyl acetate. The organic layer was washed with 15 ml of 1 M citric acid solution and the aqueous layer was extracted again with 15 ml of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography using a gradient of 0-10% methanol in dichloromethane. Pure fractions were combined and concentrated to give N-(benzenesulfonyl)-6-[3-[(1R,2S,4S)-norbornan-2ul]oxypyrazol-1-yl]-2-[(4S)-2,2,4 -trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (59 mg, 40%). EER-MS m/z calc. 549.24, found 550.4 (M+1) ⁺ ; retention time: 2.37 min. ¹ H NMR (400 MHz,

DMSO) δ 12.50 (s, 1H), 8.17 (d, J=2.8 Hz, 1H), 8.02-7.97 (m, 2H), 7.80 (d, J=8 .2 Hz, 1H), 7.77-7.70 (m, 1H), 7.70-7.63 (m, 2H), 6.90 (d, J=8.2 Hz, 1H), 6 .08 (d, J=2.7 Hz, 1H), 4.49 (d, J=6.7 Hz, 1H), 2.46-2.37 (m, 2H), 2.27 (c, J=10.0, 7.6 Hz, 2H), 2.09 (dc, J=11.6, 5.9, 5.4 Hz, 1H), 1.86-1.77 (m, 1H) , 1.56 (d, J=6.9 Hz, 1H), 1.53 (s, 3H), 1.51 (s, 3H), 1.46 (dd, J=13.8, 6.6 Hz, 3H), 1.36 (t, J=12.1 Hz, 1H), 1.25-1.06 (m, 4H), 0.64 (d, J=6.3 Hz, 3H).

Synthetic example 40.

Synthesis of compound 40 trimethylpyrrolidin-1 -yl]pyridine-3-carboxamide.

Step A. tert-Butyl-3-[[(1S,4R)-norbornan-2-yl]methoxy]pyrazole-1-carboxylate.

- 123 040454 tert-Butyl-3-hydroxypyrazole-1-carboxylate (1.327 g, 7.204 mmol), [(1S,4R)-norbornan-2yl]methanol (1 g, 7.924 mmol) (mixture of endo- and exo-) and triphenylphosphine (2.09 g, 7.968 mmol) was combined in THF (17.87 ml) and the reaction mixture was cooled in an ice bath. DIAD (1.627 ml, 8.263 mmol) was added dropwise to the mixture and the reaction mixture was allowed to warm to room temperature and stirred for 72 h. sodium hydroxide solution (50 ml). The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated. The crude material was purified by silica gel chromatography eluting with 0-30% ethyl acetate in hexanes to give t-butyl 3[[(1S,4R)-norbornan-2-yl]methoxy]pyrazol-1-carboxylate (1.698 g, 81 %). EER-MS m/z calc. 292.17868, found 293.3 (M+1)+; retention time 0.77 min. (2 diastereomers - a mixture of endo- and exo-substituted norbornane). ¹ H NMR (400 MHz, DMSO) δ 8.06 (d, J=2.9 Hz, 1H), 6.10 (dd, J=2.9, 1.0 Hz, 1H), 4.23- 3.81 (m, 2H), 2.29-2.15 (m, 2H), 1.69 (dc, J=12.1, 4.2 Hz, 1H), 1.54 (d, J= 1.4 Hz, 9H), 1.51-1.03 (m, 7H), 0.75 (dd, J=5.0, 2.4 Hz, 1H).

Step B. 3-[[(1S,4R)-Norbornan-2-yl]methoxy]-1H-pyrazole.

tert-Butyl-3-[[(1S,4R)-norbornan-2-yl]methoxy]pyrazol-1-carboxylate (1.698 g, 5.808 mmol) was dissolved in CH ₂ Cl ₂ (16.98 ml) with trifluoroacetic acid ( about 6.622 g, 4.474 ml, 58.08 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated and the resulting oily substance was partitioned between ethyl acetate (50 ml) and saturated sodium bicarbonate solution (30 ml). The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo to give an oil, 3-[[(1S,4R)-norbornan-2-yl]methoxy]-1H-pyrazole (1.11 g, 99%). EER-MS m/z calc. 192.12627, found 193.2 (M+1) ⁺ ; retention time 0.52 min.

Step C. tert-Butyl-2-chloro-6-[3-[[(1S,4R)-norbornan-2-yl]methoxy]pypazol-1-yl]pyridine-3carboxylate.

A round bottom flask under nitrogen was charged with 3-[[(1S,4R)-norbornan-2-yl]methoxy]-1Hpyrazole (1.11 g, 5.774 mmol) (mixture of two diastereomers), tert-butyl-2,6- dichloropyridine-3-carboxylate (1.433 g, 5.776 mmol), K ₂ CO ₃ (1.05 g, 7.597 mmol) (freshly ground in a mortar) and anhydrous DMF (10 ml). DABCO (117 mg, 1.043 mmol) was added and the mixture was stirred at room temperature under nitrogen atmosphere for 16 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and water (50 ml) and the two phases were separated. The aqueous phase was further extracted with ethyl acetate (2x30 ml). The combined extracts were washed with brine, dried over sodium sulfate and the solvent was removed under reduced pressure. The material was subjected to flash chromatography on silica gel using a gradient of ethyl acetate (from 0 to 20%) in hexanes. Pure fractions were combined and solvents removed under reduced pressure to give tert-butyl-2-chloro-6-[3-[[(1S,4R)-norbornan-2yl]methoxy]pyrazol-1-yl]pyridine-3-carboxylate ( 1.88 g, 81%). EER-MS m/z calc. 403.16626, found 404.3 (M+1) ⁺ ; retention time 0.94 min.

Step D. 2-Chloro-6-[3-[[(1S,4R)-norbornan-2-yl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid.

tert-Butyl-2-chloro-6-[3-[[(1S,4R)-norbornan-2-yl]methoxy]pyrazol-1-yl]pyridine-3-carboxylate (1.88 g, 4.655 mmol) and TFA (5 ml, 64.90 mmol) was combined in dichloromethane (18.80 ml) and heated at 40° C. for 2 hours. The reaction mixture was evaporated. Hexanes were added and the mixture was evaporated again to give a white solid, 2-chloro-6-[3-[[(1S,4R)-norbornan-2-yl]methoxy]pyrazol-1

- 124 040454 yl]pyridine-3-carboxylic acid (1.58 g, 98%). EER-MS m/z calc. 347.10367, found 348.2 (M+1) ⁺ ; retention time 0.75 min.

Step E. N-(Benzenesulfonyl)-2-chloro-6-[3-[[(1R,4R)-norbornan-2-yl]methoxy]pyrazol-1yl]pyridine-3-carboxamide.

2-Chloro-6-[3-[[(1S,4R)-norbornan-2-yl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (100 mg, 0.2875 mmol) and CDI ( 60.59 mg, 0.3737 mmol) was stirred in THF (0.5 ml) at room temperature for 2 h. 3737) and stirred the reaction mixture for another 4 h at room temperature. Then the reaction mixture was diluted with 25 ml of ethyl acetate and poured with 25 ml of citric acid. The aqueous layer was extracted with another 25 ml of ethyl acetate and the combined organic layers were washed with water then brine, dried over sodium sulfate and concentrated to give N(benzenesulfonyl)-2-chloro-6-[3-[[(1 R, 4R)-norbornan-2-yl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (about 135 mg), which was used in the next step without further purification. EER-MS m/z calc. 486.11, found 487.2 (M+1) ⁺ ; retention time 0.84 min.

Step F. N-(benzenesulfonyl)-6-[3-[[(1R,4R)-norbornan-2-yl]methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4trimethylpyrrolidin- 1-yl]pyridine-3-carboxamide.

N-(Benzenesulfonyl)-2-chloro-6-[3-[[(1 R,4R)-norbornan-2-yl]methoxy]pyrazol-1-yl]pyridine-3 carboxamide, (135 mg, 0.2772 mmol), (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (124.5 mg, 0.8316 mmol) and potassium carbonate (229.8 mg, 1.663 mmol) were combined in DMSO in a screw cap flask and heated to 130°C for 16 hours Then the reaction mixture was cooled to room temperature and added 3 ml of water, which led to the formation of a precipitate. After 30 minutes, the liquid portion was removed with a syringe and discarded, and the remaining solid was dissolved in 15 ml of ethyl acetate. The organic layer was washed with 15 ml of 1M citric acid solution and the aqueous layer was extracted again with 15 ml of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography using a gradient of 0-10% methanol in dichloromethane. Pure fractions were combined and concentrated to give N-(benzenesulfonyl)-6-[3-[[(1R,4R)-norbornan-2ul]methoxy]pyrazol-1-yl]-2-[(4S)-2,2, 4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (a mixture of endo and exo-norbornane). EER-MS m/z calc. 563.26, found 564.4 (M+1)+; retention time 2.45 min. ¹ H NMR (400 MHz, DMSO) δ 12.50 (s, 1H), 8.18 (dd, J=2.8, 1.0 Hz, 1H), 7.99 (dd, J=7.2 , 1.7 Hz, 2H), 7.80 (dd, J=8.3, 1.1 Hz, 1H), 7.79-7.70 (m, 1H), 7.66 (dd, J= 8.3, 6.7 Hz, 2H), 6.92 (dd, J=8.3, 5.8 Hz, 1H), 6.12 (t, J=2.9 Hz, 1H), 4, 23-3.90 (m, 2H), 2.40 (t, J=10.5 Hz, 1H), 2.35-2.16 (m, 4H), 2.09 (tt, J=12, 3, 6.2 Hz, 1H), 1.82 (dd, J=11.9, 5.5 Hz, 1H), 1.73 (s, 1H), 1.52 (d, J=9.7 Hz, 7H), 1.50-1.45 (m, 1H), 1.42-1.27 (m, 4H), 1.21-1.08 (m, 2H), 0.75 (ddd, J=12.5, 5.0, 2.2 Hz, 1H), 0.64 (d, J=6.2 Hz, 3H).

Synthetic example 41.

Synthesis of compound 41 -carboxamide.

- 125 040454

Step A: tert-Butyl-3-(2,2-dicyclopropylethoxy)pyrazole-1-carboxylate.

Solution of 2,2-dicyclopropylethanol (500 mg, 3.962 mmol), tert-butyl-3-hydroxypyrazole-1-carboxylate (730 mg, 3.963 mmol) and triphenylphosphine (1.1 g, 4.194 mmol) in dry THF (20.0 ml ) was cooled in an ice bath and DIAD (800.0 μl, 4.063 mmol) was added slowly under N ₂ . The reaction mixture was allowed to slowly warm to room temperature and stirred for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography using 100% hexanes to 50% ethyl acetate in hexanes to give t-butyl 3-(2,2-dicyclopropylethoxy)pyrazole-1-carboxylate (783 mg, 68%) as a colorless oil substances. EER-MS m/z calc. 292.17868, found 293.3 (M+1)+; retention time: 1.98 min. 1H NMR (400 MHz, chloroform-d) δ 7.62 (d, J=3.0 Hz, 1H), 5.67 (s, 1H), 4.13 (d, J=5.3 Hz, 2H ), 1.44 (s, 9H), 0.58 (kt, J=8.2, 5.0 Hz, 2H), 0.36 (tt, J=8.9, 5.6 Hz, 1H) , 0.32-0.12 (m, 4H) 0.10-0.08 (m, 4H).

Step B. 3-(2,2-Dicyclopropylethoxy)-1H-pyrazole.

A solution of tert-butyl 3-(2,2-dicyclopropylethoxy)pyrazole-1-carboxylate (750 mg, 2.565 mmol) and trifluoroacetic acid (1.0 ml, 12.98 mmol) in dichloromethane (4 ml) was stirred for 2 .5 h. The volatiles were removed under reduced pressure, and the residue was made basic with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and evaporated to give 3-(2,2-dicyclopropylethoxy)-1H-pyrazole as a colorless oil which was used as such without further purification for the next reaction. EER-MS m/z calc. 192.12627, found 193.3 (M+1) ⁺ ; retention time 1.32 min.

Step C: tert-Butyl-2-chloro-6-[3-(2,2-dicyclopropylethoxy)pyrazol-1-yl]pyridine-3-carboxylate.

A mixture of 3-(2,2-dicyclopropylethoxy)-1H-pyrazole (493.0 mg, 2.564 mmol), tert-butyl-2,6-dichloropyridine-3-carboxylate (682.0 mg, 2.749 mmol), potassium carbonate (430, 0 mg, 3.111 mmol) and 1,4 diazabicyclo[2.2.2]octane (60 mg, 0.5349 mmol) in DMSO (20.0 ml) were stirred at room temperature for 15 h. The reaction mixture was diluted with water and extracted with ethyl acetate. unite

- 126 040454 The extracts were washed with brine and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel column chromatography using 100% hexanes to 20% ethyl acetate in hexanes to give t-butyl-2-chloro-6-[3-(2,2-dicyclopropylethoxy)pyrazol-1-yl]pyridin- 3-carboxylate (680 mg, 66%) as a colorless oil. EER-MS m/z calc. 403.16626, found 404.4 (M+1)+; retention time 2.49 min. 1H NMR (400 MHz, chloroform-d) δ 8.35 (d, J=2.8 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 5.98 (d, J=2.9 Hz, 1H), 4.32 (d, J=5.6 Hz, 2H), 1.61 (s, 9H), 0.92-0.75 (m, 2H), 0.70-0.56 (m, 1H), 0.54-0.36 (m, 4H), 0.32-0.13 (m, 4H ).

Step D 2-Chloro-6-[3-(2,2-dicyclopropylethoxy)pyrazol-1-yl]pyridine-3-carboxylic acid.

A solution of tert-butyl 2-chloro-6-[3-(2,2-dicyclopropylethoxy)pyrazol-1-yl]pyridine-3-carboxylate (675 mg, 1.671 mmol) in trifluoroacetic acid (1.5 ml, 19 47 mmol) and dichloromethane (4.5 ml) was stirred for 4 h at room temperature. The solvent was evaporated and the residue was dissolved twice in THF and concentrated in vacuo to give 2-chloro-6-[3-(2,2-dicyclopropylethoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (580 mg, 100%). EER-MS m/z calc. 347.10367, found 348.3 (M+1) ⁺ ; retention time 1.95 min.

Step E. Na(Benzenesulfonyl)-2-chloro-6-[3-(2,2-dicyclopropylethoxy)pyrazol-1-yl]pyridine-3carboxamide.

Solution of 2-chloro-6-[3-(2,2-dicyclopropylethoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (100 mg, 0.2875 mmol) and carbonyldiimidazole (60.0 mg, 0.3700 mmol ) in THF (2.0 ml) was stirred for 45 min. Then benzenesulfonamide (50 mg, 0.3181 mmol) and DBU (60 μl, 0.4012 mmol) were added and the reaction mixture was stirred for another 2 h at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give N-(benzenesulfonyl)-2-chloro-6-[3-(2,2-dicyclopropylethoxy)pyrazol-1-yl]pyridine-3-carboxamide, which was used in this form for the next reaction. EER-MS m/z calc. 486.11285, found 4 8 7.4 (M+1) ⁺ ; retention time 0.79 min.

Step F. N-(Benzenesulfonyl)-6-[3-(2,2-dicyclopropylethoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3 -carboxamide.

Mixture of N(benzenesulfonyl)-2-chloro-6-[3-(2,2-dicyclopropylethoxy)pyrazol-1-yl]pyridine-3-carboxamide (140.0 mg, 0.2875 mmol), (4S)-2 ,2,4-trimethylpyrrolidine (hydrochloride salt) (145.0 mg, 0.9689 mmol) and potassium carbonate (240.0 mg, 1.737 mmol) in DMSO (2 ml) was stirred at 130°C for 15 h. the mixture was filtered through a Whatman filter disc (Puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS using a double chromatography with a gradient of 50-99% mobile phase B over 15.0 min (mobile phase A=H ₂ O (5 mM HCl) and mobile phase B=CH ₃ CN), to give Na(benzenesulfonyl)-6-[3-(2,2-dicyclopropylethoxy)pyrazol-1-yl]-2[(4S)-2,2,4- trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (75.9 mg, 45%) as an off-white solid. EER-MS m/z calc. 563.25665, found 564.5 (M+1) ⁺ ; retention time 2.3 min. Ή NMR (400 MHz, chloroform-d) δ 8.35 (d, J=8.6 Hz, 1H), 8.21 (d, J=2.8 Hz, 1H), 8.18-8.08 (m, 2H), 7.667.47 (m, 5H), 5.96 (d, J=2.8 Hz, 1H), 4.32 (d, J=5.6 Hz, 2H), 3.48 (dd, J=10.4, 8.4 Hz, 1H), 3.08 (dd, J=10.4, 7.6

- 127 040454

Hz, 1H), 2.61 (dt, J=15.3, 7.8 Hz, 1H), 2.14 (dd, J=12.4, 7.9 Hz, 1H), 1.73 (dd , J=12.4, 9.5 Hz, 1H), 1.36 (s, 3H), 1.28 (s, 3H), 1.20 (d, J=6.6 Hz, 3H), 0 .81 (ct, J=8.3, 5.0 Hz, 2H), 0.61 (tt, J=8.8, 5.6 Hz, 1H), 0.55-0.38 (m, 4H ), 0.23 (n, J=4.8 Hz, 4H).

Synthetic example 42.

Synthesis of compound 42 carboxamide.

3,3-Dicyclopropylpropan-1-ol.

To a solution of 3,3-dicyclopropylpropanoic acid (200 mg, 1.297 mmol) in dry THF (2.000 mL) was added lithium aluminum hydride (845.0 μL of a 2 M solution, 1.690 mmol) slowly dropwise in an ice/water bath under N2 atmosphere. . The mixture was allowed to gradually warm to room temperature and stirred for 16 hours. The flask was again cooled in an ice bath and quenched successively with water (70.0 μl, 3.886 mmol) (slowly), then NaOH (70.0 μl of a 6 M solution, 0. 4200 mmol) then water (200 μl, 11.10 mmol) to give a white granular solid in mixture. Anhydrous MgSO ₄ was added to the resulting mixture and stirred for 10 minutes. The resulting white heterogeneous mixture was filtered through celite and the precipitate was washed with ether. The filtrate was concentrated to give 3,3-dicyclopropylpropan-1-ol (140 mg, 77%). EER-MS m/z calc. 140.12012, found 141.2 (M+1)+; retention time 0.5 min.

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

DIAD, RRp ₃

A solution of 3,3-dicyclopropylpropan-1-ol (140.0 mg, 0.9984 mmol), tert-butyl-3-hydroxypyrazole-1-carboxylate (185.0 mg, 1.004 mmol) and triphenylphosphine (278 mg, 1.060 mmol) in dry THF (7.0 ml) was cooled in an ice bath and DIAD (200.0 μl, 1.016 mmol) was slowly added under N 2 atmosphere. The reaction mixture was allowed to slowly warm to room temperature and stirred for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate and evaporated under vacuum. The residue was purified by silica gel chromatography using 100% hexanes to 50% ethyl acetate in hexanes to give t-butyl 3-(3,3-dicyclopropylpropoxy)pyrazole-1-carboxylate (255 mg, 83%) as a colorless oil. EER-MS m/z calc. 306.19434,

- 128 040454 found 307.4 (M+1)+; retention time 0.81 min.

Step B. 3-(3,3-dicyclopropylpropoxy)-1H-pyrazole.

A solution of tert-butyl 3-(3,3-dicyclopropylpropoxy)pyrazole-1-carboxylate (255 mg, 0.8322 mmol) and trifluoroacetic acid (325.0 μl, 4.218 mmol) in dichloromethane (1 ml) was stirred for 2 .5 h. The volatiles were removed in vacuo to give 3-(3,3-dicyclopropylpropoxy)-1H-pyrazole (trifluoroacetate salt) as a colorless oil which was used as such without further purification for the next reaction. EER-MS m/z calc. 206.1419, found 207.2 (M+1) ⁺ ; retention time 0.59 min.

Step C: 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-(3,3-dicyclopropylpropoxy)-1H-pyrazole (266.0 mg, 0.8305 mmol) , potassium carbonate (230 mg, 1.664 mmol) and 1,4diazabicyclo[2.2.2]octane (20 mg, 0.1783 mmol) in DMSO (10 mL) were stirred at room temperature for 15 h. The reaction mixture was diluted with water and extracted ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel column chromatography using 100% hexanes to 20% ethyl acetate in hexanes to give t-butyl-2-chloro-6-[3-(3,3dicyclopropylpropoxy)pyrazol-1-yl]pyridin-3- carboxylate (245 mg, 71%) as a colorless oily substance. EER-MS m/z calc. 417.18192, found 418.4 (M+1) ⁺ ; retention time 1.28 min.

Step D 2-Chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridine-3-carboxylic acid.

A solution of tert-butyl 2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridine-3-carboxylate (245.0 mg, 0.5862 mmol) in trifluoroacetic acid (500.0 μl, 6.490 mmol) and dichloromethane (1.5 ml) were stirred for 4 hours at room temperature. The solvent was evaporated and the residue was dissolved twice in THF and concentrated in vacuo to give 2-chloro-6-[3-(3,3-dicyclopropoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (204 mg, 96%) as a white solid which was used as such for the next reaction. EER-MS m/z calc. 361.11932, found 362.3 (M+1) ⁺ ; retention time 0.8 min. ¹ H NMR (400 MHz, methanol-b 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).

Step E. N-(Benzenesulfonyl)-2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridine-3carboxamide.

A solution of 2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (50.0 mg, 0.1382 mmol) and carbonyldiimidazole (30.0 mg, 0. 1850 mmol) in THF (2.0 ml) was stirred for 45 min. Benzenesulfonamide (25.0 mg, 0.1590 mmol) and DBU (30 μl, 0.2006 mmol) were then added.

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The reaction mixture was stirred for another 2 h at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give N-(benzenesulfonyl)-2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridine-3carboxamide (84 mg , 121%) as a light brown viscous oily substance, which was used (taking the conversion rate as 100%) as such for the next reaction. EER-MS m/z calc. 500.12 85, found 501.4 (M+1)+; retention time 0.83 min.

Step F. N-(Benzenesulfonyl)-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4trimethylpyrrolidin-1-yl]pyridine-3-carboxamide .

K ₂ CO ₃ , DMSO

N-(benzenesulfonyl)-2-chloro-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]pyridine-3carboxamide mixture (68.0 mg, 0.1357 mmol), (4S)-2, 2,4-trimethylpyrrolidine (hydrochloride salt) (70.0 mg, 0.4677 mmol) and potassium carbonate (115.0 mg, 0.8321 mmol) in DMSO (1 ml) was stirred at 130°C for 15 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 50-99% mobile phase B gradient double chromatography over 15.0 min (mobile phase A=H ₂ O (5 mM HCl, and mobile phase B=CH ₃ CN), to give N-(benzenesulfonyl)-6-[3-(3,3-dicyclopropylpropoxy)pyrazol-1-yl]-2[(4S)-2.2, 4-m-rimethylpyrrolidin-1-yl]pyridine-3-carboxamide (23.1 mg, 29%) ESI-MS m/z calc 577.2723, found 578.5 (M+1) ⁺ , retention time 1, 0 min ¹ H NMR (400 MHz, chloroform-d) δ 8.36 (d,

J=8.6 Hz, 1H), 8.21 (d, J=2.8 Hz, 1H), 8.17 (d, J=1.2 Hz, 1H), 8.15 (d, J= 1.6 Hz, 1H), 7.64-7.57 (m, 2H), 7.577.51 (m, 2H), 5.94 (d, J=2.8 Hz, 1H), 4.43 ( t, J=6.8 Hz, 2H), 3.49 (dd, J=10.3, 8.5 Hz, 1H), 3.09 (dd, J=10.4, 7.6 Hz, 1H ), 2.70-2.56 (m, 1H), 2.14 (dd, J=12.4, 7.9 Hz, 1H), 1.97 (k, J=6, 8 Hz, 2H) , 1.73 (dd, J=12.4, 9.4 Hz, 1H), 1.36 (s, 3H), 1.28 (s, 3H), 1.21 (d, J=6.7 Hz, 3H), 0.73-0.59 (m, 2H), 0.50-0.37 (m, 4H), 0.37-0.29 (m, 1H), 0.240.15 (m, 2H), 0.12-0.07 (m, 2H).

Synthetic example 43.

Synthesis of compound 43 -trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.

Step A 2-Chloro-N-(2-chlorophenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide.

CDI, DBU

Step 1 2-Chlorobenzenesulfonyl chloride (50 µl, 0.3667 mmol) was dissolved in a solution of ammonia in methanol (150 µl of a 7 M solution, 1.050 mmol) and stirred at room temperature for 30 minutes. The mixture was evaporated to dryness and re-evaporated from dichloromethane. The solid was dissolved in THF (1 ml) and DBU (60 μl, 0.4012 mmol) was added. The mixture was stirred at 70°C for 30 min to remove residual ammonia from the reaction mixture.

Step 2. 2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (100 mg, 0.2661 mmol) and carbonyldiimidazole (53 mg, 0.3269 mmol) was combined in THF (1.000 ml) and stirred for 2 hours. At this time, the resulting mixture was added to the sulfonamide mixture (from step 1) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with 1 M citric acid solution, then with brine. The organic layer was separated, dried over magnesium sulfate and evaporated to give 2-chloro-M-(2-chlorophenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine -3-carboxamide together with the starting material and the primary amide. The mixture was used as such for the next reaction. EER-MS m/z calc. 548.02997, found 549.28 (M+1) ⁺ ; retention time 0.76 min.

Step B. N-(2-Chlorophenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]-2-[(4S)-2,2,4-trimethylpyrrolidine -1-yl]pyridine-3-carboxamide.

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2-Chloro-Ni(2-chlorophenyl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1yl]pyridine-3-carboxamide mixture (50.0 mg, 0.09102 mmol ) (mixture as obtained in step A), (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (50.0 mg, 0.3341 mmol) and potassium carbonate (80.0 mg , 0.5788 mmol) in DMSO (2.0 ml) was stirred at 130° C. for 15 h. The reaction mixture was filtered through a Whatman filter disc (Puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS using double chromatography with a 50-99% gradient of mobile phase B over 15.0 min (mobile phase A=H2O (5 mM HCl), and mobile phase B=CH ₃ CN) to give N(2-chlorophenyl)sulfonyl-6-[3 -[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (18.7 mg, 31 %). EER-MS m/z calc. 625.17377, found 626.5 (M+1)+; retention time 2.35 min. ¹ H NMR (400 MHz, chloroform-d) δ 8.43-8.36 (m, 1H), 8.32 (d, J=8.5 Hz, 1H), 8.21 (d, J=2 .8 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.53-7.44 (m, 3H), 5.94 (d, J=2.7 Hz, 1H ), 4.40 (t, J=7.1 Hz, 2H), 3.51 (t, J=9.5 Hz, 1H), 3.13 (dd, J=10.6, 8.1 Hz , 1H), 2.73-2.55 (m, 1H), 2.16 (dd, J=12.4, 7.7 Hz, 1H), 2.09 (t, J=7.1 Hz, 2H), 1.77 (dd, J=12.5, 9.6 Hz, 1H), 1.47 (s, 3H), 1.41 (s, 3H), 1.20 (d, J=6 , 6 Hz, 3H), 1.09-0.97 (m, 2H), 0.81-0.64 (m, 2H).

Synthetic example 44.

Synthesis of compound 44 4-trimethylpyrrolidin-1-yl)nicotinamide.

Step A. Methyl 6-(3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)-1H-pyrazol-1-yl)-4-chloropyridine3-carboxylate.

ABOUT

To a solution of 3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)-1H-pyrazole (720 mg, 3.27 mmol) and methyl 4,6-dichloropyridine-3-carboxylate (742 mg, 3.60 mmol) in N,N-dimethylformamide (11 ml) was added potassium carbonate (9.36 g, 9.82 mmol) and 1,4-diazabicyclo[2.2.2]octane (110 mg, 0.98 mmol). The resulting solution was heated at 80° C. for 16 hours. The reaction solution was cooled to room temperature and diluted with diethyl ether (400 ml). Then water (50 ml) was added and the organic layers were separated. The organic layers were washed with 1 N. aqueous hydrogen chloride solution (15 ml), brine (3x15 ml), dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography using 0-20% hexanes and ethyl acetate to give methyl 6-(3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)-1H-pyrazol-1-yl)-4 -chloropyridine-3-carboxylate (631 mg, 49%) as a white solid. 1 H NMR (250 MHz, CDCl ₃ ) δ (ppm): 8.84 (s, 1H), 8.36 (d, J=2.8 Hz, 1H), 7.85 (s, 1H) , 5.96 (d, J=2.8 Hz, 1H), 4.42 (t, J=7.0 Hz, 2H), 3.96 (s, 3H), 2.11 (t, J= 7.0 Hz, 2H), 1.05 (m, 2H), 0.76 (m, 2H). EER-MS m/z calc. 389.1, found 390.0 (M1). Retention time 7.08 min.

Step B. 6-(3-(2-(1-(Trifluoromethyl)cyclopropyl)ethoxy)-1H-pyrazol-1-yl)-4-chloropyridine-3 carboxylic acid.

Methyl 6-(3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)-1H-pyrazol-1-yl)-4-chloropyridine-3carboxylate (553 mg, 1.42 mmol) was dissolved in a mixture of tetrahydrofuran (3 .5 ml) and methanol (3.5 ml), then 2N was added. aqueous sodium hydroxide solution (1.4 ml, 2.84 mmol). The resulting solution was stirred at room temperature for 3 h. All solvents were removed under reduced pressure.

- 131 040454 Research Institute. The residue was acidified with 1N. aqueous hydrogen chloride solution until pH 2 was reached, and then extracted with ethyl acetate (3x80 ml). The organic layer was washed with brine (2x20 ml), dried over magnesium sulfate, filtered and concentrated to give 6-(3-(2-(1(trifluoromethyl)cyclopropyl)ethoxy)-1H-pyrazol-1-yl)-4- chloropyridine-3-carboxylic acid (534 mg, 97%) as a white solid. ¹ H NMR (250 MHz, DMSO) δ (ppm): 8.85 (s, 1H), 8.51 (d, J=3.0 Hz, 1H), 7.76 (s, 1H) , 6.21 (d, J=3.0 Hz, 1H), 4.36 (t, J=7.0 Hz, 2H), 2.11 (t, J=7.0 Hz, 2H), 0 .95 (m, 2H), 0.90 (m, 2H). EER-MS m/z calc. 375.1, found 376.0 (M+1)+. Retention time 5.80 min.

Step C. 4-Chloro-Phenylsulfonyl)-6-(3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)-1H-pyrazol1-yl)nicotinamide.

CDI DBU

6-(3-(2-(1-(Trifluoromethyl)cyclopropyl)ethoxy)-1 H-pyrazol-1-yl)-4-chloropyridine-3-carboxylic acid (528 mg, 1.40 mmol) and 1.1 '-carbonyldiimidazole (341 mg, 2.11 mmol) in tetrahydrofuran (9 ml) was stirred for 2 h at room temperature, then benzenesulfonamide (220 mg, 1.40 mmol) and 1,8-diazabicyclo[5.4.0] were added undec-7-ene (641 mg, 4.21 mmol). The reaction solution was stirred for another 16 hours and diluted with ethyl acetate (200 ml). The solution was washed with saturated aqueous tartaric acid (25 ml), water (40 ml), brine (40 ml), then dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using ethyl acetate to give 4-chloro-phenylsulfonyl)-6-(3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)-1H-pyrazol-1-yl)nicotinamide (411 mg, 57%) as a white solid. 1H NMR (250 MHz, DMSO) δ (ppm): 8.56 (s, 1H), 8.47 (d, J=2.5 Hz, 1H), 7.94 (d, J=6 .8 Hz, 2H), 7.67 (s, 1H), 7.59 (m, 3H), 6.16 (d, J=2.5 Hz, 1H), 4.34 (t, J=7 .0 Hz, 2H), 2.09 (t, J=7.0 Hz, 2H), 0.94 (m, 2H), 0.89 (m, 2H). EER-MS m/z calc. 514.1, found 515.0 (M1). Retention time 6.31 min.

Step D. (S)-N-(Phenylsulfonyl)-6-(3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)-1H-pyrazol-1yl)-4-(2,2,4-trimethylpyrrolidin- 1-yl)nicotinamide.

To a solution of 4-chloro-M-(phenylsulfonyl)-6-(3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)-1Hpyrazol-1-yl)nicotinamide (54.6 mg, 0.11 mmol) in dimethyl sulfoxide (0.5 ml) (S)-2,2,4-trimethylpyrrolidine hydrochloride (96 mg, 0.64 mmol) and cesium fluoride (97 mg, 0.64 mmol) were added. The resulting solution was heated at 120° C. for 48 hours. The mixture was purified by reverse phase HPLC using 5-100% water/acetonitrile (containing 0.1% trifluoroacetic acid). Pure fractions were combined and lyophilized to give the product as a salt with trifluoroacetic acid, which was redissolved in 50% water/acetonitrile (with 0.1% hydrogen chloride) and lyophilized again to give the hydrochloride salt of (S)-N-(phenylsulfonyl)- 6-(3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)1H-pyrazol-1-yl)-4-(2,2,4-trimethylpyrrolidin-1-yl)nicotinamide (27.8 mg, 42 %). ¹ H NMR (250 MHz, DMSO) δ (ppm): 12.65 (s, 1H), 8.40 (s, 1H), 8.08 (d, J=1.3 Hz, 1H) , 8.02 (d, J=8.0 Hz, 2H), 7.70 (m, 3H), 7.24 (s, 1H), 6.05 (dd, J=1.3, 2.5 Hz, 1H), 4.34 (d, J=7.0 Hz, 2H), 2.50 (m, 3H), 2.09 (t, J=7.0 Hz, 2H), 2.10 ( m, 1H), 1.91 (m, 1H), 1.53 (s, 6H), 0.87 (m, 2H), 0.84 (m, 2H), 0.64 (d, J=6 .0 Hz, 3H). EER-MS m/z calc. 591.2, found 592.6 (Ml). Retention time 2.88 min.

Synthetic example 45.

Synthesis of ^compounds 45, 46 and 47 )-2-((S)-2,2,4-trimethylpyrrolidin-1 -yl)nicotinamide, isomer 1 and isomer 2.

Step A. tert-Butyl-2,6-difluoropyridine-3-carboxylate.

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2,6-Difluoropyridine-3-carboxylic acid (1.0 g, 6.3 mmol) was dissolved in anhydrous 2-methyltetrahydrofuran (12 ml). Di-tert-butyl dicarbonate (1.5 g, 6.9 mmol) was added in one portion followed by 4-(dimethylamino)pyridine (462 mg, 3.78 mmol). The mixture turned into a suspension when a large amount of gas was released. The heterogeneous mixture was stirred at room temperature over the weekend and then diluted with methyl tert-butyl ether (30 ml). The organic layer was washed successively with 1M aqueous HCl (10 ml), 5% w/v. saturated aqueous sodium bicarbonate solution (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-30% ethyl acetate in heptanes to give tert-butyl 2,6-difluoropyridine-3-carboxylate (360 mg, 26% yield) as a light yellow oil. 1H NMR (300 MHz, CDCl ₃ ) ppm 1.60 (s, 9 H), 6.88 (ddd, J=8.4, 3.0, 0.5 Hz, 1 H), 8.40-8.47 (m, 1 H). ¹⁹ F NMR (282 MHz, CDCL) ppm -61.5 - -61.4 (m, 1F), -60.3 (t, J=8.6 Hz, 1F).

Step B: tert-Butyl-2-fluoro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine3-carboxylate.

tert-Butyl 2,6-difluoropyridine-3-carboxylate (1.8 g, 8.4 mmol), 3-[[1-(trifluoromethyl)cyclopropyl]methoxy]-1H-pyrazole (1.8 g, 8.4 mmol) 7 mmol) and freshly ground potassium carbonate (1.7 g, 12 mmol) were added to anhydrous dimethyl sulfoxide (20 ml). The mixture was stirred at 20° C. under nitrogen for 16 h and then diluted with ethyl acetate (100 ml). The organic layer was washed with water (3x30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-15% ethyl acetate in heptanes to give t-butyl-2-fluoro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridin- 3-carboxylate (1.9 g, 57% yield) as a white solid. 1H NMR (300 MHz, CDCl ₃ ) ppm 0.92-0.99 (m, 2H), 1.13-1.18 (m, 2H), 1.60 (s, 9H), 4.40 (s, 2H), 6.00 (d , J=2.8 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 8.30 (d, J=2.8 Hz, 1H), 8.37 (t, J = 8.4 Hz, 1H). ¹⁹ F NMR (282 MHz, CDCb) ppm -69.7 (s, 3F), -62.2 (d, J=9.2 Hz, 1F). LCMS: [M+H]+ = 402.1.

Step C. 2-Fluoro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid.

Trifluoroacetic acid (4 ml) was added to a solution of tert-butyl-2-fluoro-6-[3-[[1(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylate (1.9 g, 4 .7 mmol) in dichloromethane (16 ml). The mixture was stirred at 40°C for 4 h, after which TLC showed complete conversion. The mixture was concentrated under reduced pressure and the residue was triturated with heptanes, filtered and dried under high vacuum to give 2-fluoro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (1.6 g, 98% yield) as a white solid. 1H NMR (300 MHz, DMSO-d ₆ ) ppm 1.06-1.11 (m, 4H), 4.39 (s, 2H), 6.24 (d, J=2.8 Hz, 1H), 7.66 (dd, J=8.3, 1.0 Hz, 1H), 8.43 (d, J=8.3 Hz, 1H), 8.47 (dd, J=9.6, 8.4 Hz, 1H). ¹⁹ F NMR (282 MHz, DMSOCH) ppm -67.9 (s, 3F), -63.2 (d, J=7.9 Hz, 1 F). LCMS: [M+H] ⁺ =346.1.

Step D. 2-Fluoro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboc

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To a suspension of 2-fluoro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (1.6 g, 4.6 mmol) in dichloromethane (20 ml) was added one drop of N,Ndimethylformamide, then oxalyl chloride (0.52 mL, 6.0 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 h until the evolution of gas bubbles ceased. 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% ammonium hydroxide (10 ml) and tetrahydrofuran (5 ml) cooled in an ice bath. The reaction mixture was stirred at room temperature for 1 h 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 2fluoro-6-[3-[[1 -(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (1.55 g, 98% yield) as a white solid. 1H NMR (300 MHz, CDCl ₃ ) ppm 1.06-1.11 (m, 4H), 4.38 (s, 2H), 6.21 (d, J=2.7 Hz, 1H), 7.61 (dd, J=8.2, 1.5 Hz, 1H), 7.76 (d, J=8.2 Hz, 2H), 8.33 (dd, J=9.4, 8.4 Hz, 1H), 8.4 (d, J=2.7 Hz, 1H). ¹⁹ F NMR (282 MHz, CDCl ₃ ) ppm -67.9 (s, 3F), -66.3 (d, J=8.9 Hz, 1 F). LCMS: [M+H]+ = 345.1.

Step E 2-Fluoro-N-phenylsulfanyl-6-[3-[[ 1 -(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1yl]pyridine-3-carboxamide.

Bromine (0.14 ml, 2.7 mmol) was slowly added to a suspension of diphenyl disulfide (596 mg, 2.73 mmol) in anhydrous acetonitrile (4 ml) at 0°C. The reaction mixture was stirred at room temperature for 2 minutes to give a solution. The resulting solution was added to a solution of 2-fluoro-6-[3-[[1(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (940 mg, 2.73 mmol) in anhydrous acetonitrile (4 ml ) and pyridine (4 ml) at 0°C. The resulting dark mixture was stirred at room temperature overnight, then concentrated under reduced pressure and co-evaporated with toluene (10 ml). The residual brown solid was purified by silica gel chromatography eluting with 0-30% ethyl acetate in heptanes to give 2-fluoro-N-phenylsulfanyl-6-[3-[[1(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl] pyridine-3-carboxamide (380 mg, 31% yield) as a white solid. 1H NMR (300 MHz, CDCl ₃ ) ppm 0.93-1.00 (m, 2H), 1.14-1.19 (m, 2H), 4.41 (s, 2H), 6.03 (d, J=3.0 Hz, 1H) , 7.20-7.26 (m, 1H), 7.30-7.42 (m, 4H), 7.73 (dd, J=8.4, 1.8 Hz, 1H), 7, 84 (d, J=15 Hz, 1H), 8.28 (d, J=3.0 Hz, 1H), 8.63 (t, J=9.0 Hz, 1H). LCMS: [M+H]+ = 453.0.

Step F. rac-N-(Benzenesulfinyl)-2-fluoro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol1-yl]pyridine-3-carboxamide.

meta-Chloroperoxybenzoic acid (469 mg, 77%, 2.1 mmol) was added to a solution of 2-fluoro-Chphenylsulfanyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridin-3 -carboxamide (860 mg, 1.90 mmol) in dichloromethane (30 ml) at 0°C and the reaction mixture was stirred at the same temperature for 1 h. The reaction mixture was diluted with dichloromethane (70 ml), washed successively with 10% wt./ about. sodium thiosulfate solution, 5% wt./about. sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-40% ethyl acetate in heptanes to give racemic N-(benzenesulfinyl)-2-fluoro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl ]pyridine-3-carboxamide (700 mg, 78% yield) as a white solid. 1H NMR (300 MHz, CDCl ₃ ) ppm 0.92-1.00 (m, 2H), 1.13-1.20 (m, 2H), 4.38 (d, J=12.1, 1H), 4.43 (d, J=12 ,1, 1H), 6.03 (d, J=3.0 Hz, 1H), 7.56-7.65 (m, 3H), 7.70-7.78 (m, 1H), 7, 80-7.88 (m, 2H), 8.24 (d, J=3.0 Hz, 1H), 8.40 (d, J=12 Hz, 1H), 9.61 (t, J=8 .5 Hz, 1H). ¹⁹ F NMR (282 MHz, CDCl ₃ ) ppm -69.7 (s, 3F), -63.2 (t, J=10.5 Hz, 1 F). HCMS:

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[M+H]+ = 469.0.

Step G. N-(Benzenesulfinyl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2[(4S)-2,2,4-trimethylpyrrolidin-1-yl] pyridine-3-carboxamide.

(4S)-2,2,4-Trimethylpyrrolidine hydrochloride (400 mg, 2.67 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 ml), the mixture was cooled in an ice bath and sodium hydride (287 mg of a 60% dispersion in mineral oil) was added , 7.2 mmol). The reaction mixture was stirred at room temperature for 10 min and cooled again to 0°C. A solution of racemic N(benzenesulfinyl)-2-fluoro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3carboxamide (960 mg, 2.05 mmol) in N,N was added -dimethylformamide (10 ml). After stirring at room temperature for 10 minutes, the reaction mixture was stirred at 50°C for 3 hours (LCMS showed 60% conversion; there was a lot of unspent sodium hydride present). Anhydrous tetrahydrofuran (0.5 ml) was added and the reaction mixture was stirred at room temperature overnight. The mixture was quenched with water (10 ml) at 0° C., then extracted with ethyl acetate (80 ml). The organic layer was washed with water (3x20 ml), brine (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-50% ethyl acetate in heptanes. Fractions containing product and starting material were combined and concentrated under reduced pressure. The residue was stirred in a mixture of heptanes (10 ml) and dichloromethane (10 ml) for 30 min and then filtered. The filtrate was concentrated under reduced pressure to give N-(benzenesulfinyl)-6-[3-[[1(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin- 1-yl]pyridine-3-carboxamide (500 mg, 88% purity by LCMS, 38% yield) as a yellow solid, which was used in the next step without further purification. LCMS: [M+H]+ = 562.2.

Step H. Synthesis of N-(phenylsulfonimidoyl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1- yl]pyridine-3-carboxamide.

Ammonia (7.8 ml of a 0.5 M solution in dioxane, 3.9 mmol) was added to a solution of N-(benzenesulfinyl)6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]- 2-[(4S)-2,2,4-trimethylpyrrolidin-1yl]pyridine-3-carboxamide (500 mg, 88% purity, 0.78 mmol) in anhydrous acetonitrile (20 ml) at 0°C. N-chlorosuccinimide (120 mg, 0.90 mmol) was added in one portion (the mixture turned orange) and the reaction mixture was stirred at 0°C for 1 h. Additional N-chlorosuccinimide (12 mg, 0.090 mmol) was added, the reaction mixture was stirred at the same temperature for 30 min and then extinguished 10% wt./about. aqueous sodium thiosulfate solution and extracted with ethyl acetate (50 ml). The organic layer was washed successively with 5% w/v. aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 5-45% ethyl acetate in heptanes to give a white solid (300 mg) which was triturated with acetonitrile (3 ml) to give the diastereomeric mixture of N-(amino(oxo)(phenyl)-λ ⁶ sulfaneylidene)-6-(3 -((1 -(trifluoromethyl)cyclopropyl)methoxy)-1 H-pyrazol-1 -yl)-2-((S)-2,2,4trimethylpyrrolidin-1-yl)nicotinamide ( compound 45) (180 mg, 97% pure by LC, 38% yield) as a white solid. 1H NMR (300 MHz, CDCl ₃ ) ppm 0.89-1.06 (m, 5H), 1.08-1.18 (m, 2H), 1.591.72 (m, 7H), 1.81-1.95 (m, 1H), 2 .07-2.40 (m, 1H), 2.59-2.71 (m, 0.4H), 2.82-2.96 (m, 0.6H), 3.18 (t, J= 10.6 Hz, 0.4H), 3.29 (t, J=10.7 Hz, 0.6H), 4.32-4.43 (m, 2H), 5.90 (d, J=2 .6 Hz, 1H), 6.25 (brw, 2H), 6.90-6.97 (m, 1H), 7.48-7.57 (m, 2H), 7.58-7.66 ( m, 1H), 7.97-8.09 (m, 2.6H), 8.16 (d, J=8.2 Hz, 0.4H), 8.20-8.23 (m, 1H) . ¹⁹ F NMR (282 MHz, CDCl3) ppm -69.7 (s, 3F). LCMS: [M+H]+ = 577.2.

The isomers were separated by chiral supercritical liquid chromatography using a Phenomenex Lux-1 column (250x21.2 mm), particle size 5 µm, and eluting with 20% MeOH, 80% CO2 at a flow rate of 70 ml/min.

Diastereomer 1 (compound 46): d.i. >98%. EER-MS m/z calc. 576.2131, found 577.4 (M+1) ⁺ ;

- 135 040454 retention time 1.82 min; 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.19 (d, J=2.7 Hz, 1H), 7.95 (dd, J=8.1, 1.6 Hz, 3H), 7, 75 (s, 2H), 7.68-7.49 (m, 3H), 6.85 (d, J=8.1 Hz, 1H), 6.12 (d, J=2.7 Hz, 1H ), 4.35 (s, 2H), 3.08 (t, J=10.6 Hz, 1H), 2.76 (dd, J=10.6, 7.1 Hz, 1H), 2.21 (dc, J=12.1, 6.2 Hz, 1H), 1.97-1.79 (m, 1H), 1.55 (d, J=1.7 Hz, 6H), 1.44 ( t, J=12.0 Hz, 1H), 1.09 (dd, J=4.5, 3.1 Hz, 4H), 0.92 (d, J=6.2 Hz, 3H).

Diastereomer 2 (compound 47): d.i. >98%. EER-MS m/z calc. 576.2131, found 577.3 (M+1)+; retention time: 1.81 min; 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.19 (d, J=2.7 Hz, 1H), 7.99-7.88 (m, 3H), 7.79 (s, 2H), 7.69-7.55 (m, 3H), 6.87 (d, J=8.1 Hz, 1H), 6.11 (d, J=2.7 Hz, 1H), 4.44-4 .28 (m, 2H), 2.63 (t, J=10.8 Hz, 1H), 2.21-2.03 (m, 1H), 1.80 (dd, J=11.8, 5 .4 Hz, 1H), 1.52 (d, J=1.7 Hz, 6H), 1.33 (t, J=12.2 Hz, 2H), 1.09 (dt, J=5.6 , 2.1 Hz, 4H), 0.71 (d, J=6.2 Hz, 3H).

Synthetic example 46.

Synthesis of compound 48

Step A. tert-Butyl-3-cyclopropoxy-1H-pyrazole-1-carboxylate.

O-° ⁿ

N DEAD, toluene [X? ^In °° „0=0 '

To a solution of cyclopropanol (30.8 mg, 0.531 mmol), tert-butyl-2,3-dihydro-3-oxopyrazole-1-carboxylate (97.7 mg, 0.531 mmol) and triphenylphosphine (139.3 mg, 0.531 mmol) in anhydrous toluene (2 ml) was added di-tert-butylazodicarboxylate (122.2 mg, 0.531 mmol). The solution was purged with argon for 1 min and stirred at room temperature for 30 min. Then, the reaction solution was heated at 110° C. for another 5 hours, after which it was cooled to room temperature. The solution was diluted with ether (50 ml), washed with aqueous NaOH, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane and ethyl acetate, 0 to 10% ethyl acetate gradient) to give tert-butyl-3-cyclopropoxy-1H-pyrazole-1-carboxylate (52 mg, 46%) as a white solid. EER-MS m/z calc. 224.116, found 225.0 (M+1)+; retention time: 4.38 min. 1H NMR (250 MHz, CDCl3) δ (ppm) 7.86 (d, J=2.8 Hz, 1H), 5.93 (d, J=2.8 Hz, 1H), 4.20 -4.15 (m, 1H), 1.61 (s, 9H), 0.85-0.72 (m, 4H).

Step B. 3-Cyclopropoxy-1H-pyrazole.

To a solution of tert-butyl-3-cyclopropoxy-1H-pyrazole-1-carboxylate (131 mg, 0.584 mmol) in dichloromethane (6 ml) was added TFA (667 mg, 0.38 ml, 5.84 mmol). The resulting solution was stirred at room temperature for 3 hours. All solvents were removed under reduced pressure. The resulting residue was dissolved in ether (100 ml), washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 3-cyclopropoxy-1H-pyrazole as a pale yellow oil. The resulting crude product was directly used in the next step.

Step 3: tert-Butyl-2-chloro-6-(3-cyclopropoxy-1H-pyrazol-1-yl)pyridine-3-carboxylate.

Crude 3-cyclopropoxy-1H-pyrazole (73 mg, 0.584 mmol), tert-butyl 2,6-dichloropyridine-3-carboxylate (159 mg, 0.643 mmol), K2CO3 (162 mg, 1.17 mmol) and DABCO (13 mg , 0.117 mmol) was dissolved in anhydrous DMF (1.5 ml). The reaction solution was stirred at room temperature for 16 hours. The reaction solution was diluted with ether (100 ml), washed with water (3x25 ml) and brine (25 ml). The organic layers were separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane and dichloromethane, gradient from 0 to 100% dichloromethane) to give tert-butyl-2-chloro-6-(3

- 136 040454 cyclopropoxy-1H-pyrazol-1-yl)pyridine-3-carboxylate (153 mg, 78%) as a sticky oily substance. EER-MS m/z calc. 335.104, found 33 6.1 (M+1)+; retention time 6.84 min.

Step D. 2-Chloro-6-(3-cyclopropoxy-1H-pyrazol-1-yl)pyridine-3-carboxylic acid.

TFA (519 mg , 0.35 ml, 4.56 mmol). The resulting solution was stirred at room temperature for 48 hours. Then 1,2-dichloroethane (2 ml) was added and all solvents were removed under reduced pressure. The resulting white solid was suspended in a mixture of hexane and ether (10 ml, hexane/ether, 19/1), sonicated, filtered, washed with hexane (10 ml) and dried to give 2-chloro-6-(3-cyclopropoxy-1H -pyrazol-1-yl)pyridine3-carboxylic acid (122 mg, 97%) as a white solid. EER-MS m/z calc. 279.041, found 279.9 (M+1) ⁺ ; retention time: 4.43 min. 1H NMR (500 MHz, DMSO-d ₆ ) δ (ppm) 13.6 (s, 1H), 8.43 (d, J=3.0 Hz, 1H), 8.39 (d, J = 8.5 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 6.28 (d, J=3.0 Hz, 1H), 4.16-4.13 (m , 1H), 0.79-0.71 (m, 4H).

Step E. N-(Benzenesulfonyl)-2-chloro-6-[3-(cyclopropoxy)pyrazol-1-yl]pyridine-3-carboxamide.

2-Chloro-6-[3-(cyclopropoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (30 mg, 0.1073 mmol) in DMF (600.0 µl), HATU (1-[bis(dimethylamino )methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate) (85 mg, 0.2235 mmol) and DIEA (diisopropylethylamine) (38 µl, 0.2182 mmol) combined and stirred at room temperature for 16 hours. The reaction mixture was filtered and purified by reverse phase HPLC using a gradient of 25-75% acetonitrile in water containing 5 mM HCl to give N-(benzenesulfonyl)-2-chloro-6- [3-(cyclonpropoxy)pyrazol-1-yl]pyridine-3-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ 12.97 (s, 1H), 8.43 (d, J=2.8 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H ), 8.01 (d, J=9.4 Hz, 2H), 7.77 (s, 1H), 7.69 (d, J=6.0 Hz, 3H), 6.31-6.26 (m, 1H), 4.16 (s, 1H), 0.76 (s, 4H). EER-MS m/z calc. 418.05026, found 419.0 (M+1) ⁺ ; retention time 1.63 min (chromatogram recording time 3 min).

Step F. N-(Benzenesulfonyl)-6-[3-(cyclopropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.

A mixture of N-(benzenesulfonyl)-2-chloro-6-[3-(cyclopropoxy)pyrazol-1-yl]pyridine-3-carboxamide, (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (about 24, 01 mg, 0.1604 mmol), CsF (about 36.00 mg, 0.2370 mmol), K ₂ CO ₃ (about 72.01 mg, 0.5210 mmol) in DMSO (0.5 ml) was stirred at 140 °C for 16 h. The reaction mixture was filtered and purified by reverse phase HPLC using a gradient of 25-75% acetonitrile in water containing 5 mM HCl to give N(benzenesulfonyl)-6-[3-(cyclopropoxy)pyrazole -1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine3-carboxamide (5.6 mg, 11% over 2 steps). EER-MS m/z calc. 495.19403, found 496.0 (M+1) ⁺ ; retention time 1.98 min (chromatogram recording time 3 min).

Synthetic example 47.

Synthesis of compound 49 -1-yl]pyridine-3-carboxamide.

Step A. (1-(Trifluoromethyl)cyclopropyl)methanol.

1-(Trifluoromethyl)cyclopropane-1-carboxylic acid (858 mg, 5.57 mmol, 1.00 eq) was dissolved in

- 137 040454 diethyl ether (15 ml). The reaction mixture was cooled to 0°C. Lithium aluminum hydride (274 mg, 7.24 mmol, 1.30 eq.) was added in portions.

The reaction mixture was stirred overnight and left to reach room temperature. The reaction mixture was cooled to 0°C. HCl (aq., 1N, 25 ml) was added dropwise. The aqueous phase was extracted with diethyl ether (2x25 ml). The combined organic phases were washed with brine (25 ml), dried over sodium sulfate, filtered and evaporated in vacuo (T bath <30°C) to give (1-(trifluoromethyl)cyclopropyl)methanol (547 mg, 3.90 mmol, yield 70%) as a colorless oily substance. ¹ H NMR (CDC13): δ 3.73 (s, 2H), 1.58 (br, 1H), 1.07-1.01 (m, 2H), 0.820.75 (m, 2H).

Step B. 1-(3-Hydroxypyrazol-1-yl)ethanone.

A 100 ml round bottom flask equipped with a stirrer and condenser was charged with 1Hpyrazol-5-ol (4.97 g, 59.11 mmol) and pyridine (25 ml, 309.1 mmol). The mixture was stirred at 95°C. A solution of acetic anhydride (5.6 ml, 59.35 mmol) in pyridine (10 ml, 123.6 mmol) was added dropwise over 3 minutes. The mixture was then stirred at 95° C. for another 3 hours. The solvents were removed under reduced pressure. The solid residue was triturated in 40 ml diethyl ether, filtered, washed with diethyl ether and dried to give 1-(3-hydroxypyrazol-1-yl)ethanone (6.96 g, 93%). ¹ H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.13 (d, J=3.0 Hz, 1H), 6.01 (d, J=3.0 Hz, 1H), 2.48 (s, 3H).

Step C. 1-(3-((1-(Trifluoromethyl)cyclopropyl)methoxy)-1H-pyrazol-1-yl)ethan-1-one.

1-(3-Hydroxy-1H-pyrazol-1-yl)ethan-1-one (443 mg, 3.51 mmol, 1.00 eq) was dissolved in THF (8 ml). (1-(trifluoromethyl)cyclopropyl)methanol (547 mg, 3.90 mmol, 1.11 eq) and triphenylphosphine (1.10 g, 4.21 mmol, 1.20 eq) were added. The reaction mixture was cooled to 0°C. Diisopropyl azodicarboxylate (829 ml, 851 mg, 4.21 mmol, 1.20 eq.) was added dropwise (keeping the temperature <5°C). The reaction mixture was stirred at room temperature over the weekend. Evaporation of the volatiles in vacuo gave a light yellow oil (2.88 g). The crude material was purified by silica gel chromatography eluting with 0-2 5% ethyl acetate in heptanes to give 1-(3-((1-(trifluoromethyl)cyclopropyl)methoxy)-1H-pyrazol-1-yl)ethan-1-one (701 mg, 2.82 mmol, 80% yield) as a white solid. ¹ H NMR (CDC13): δ 8.06 (d, 1H), 5.99 (d, 1H), 4.36 (d, 2H), 2.57 (s, 3H), 1.18-1, 12 (m, 2H), 0.98-0.90 (m, 2H). ¹⁹ F NMR (CDCI3): δ -69.77.

Step D. 3-((1-(Trifluoromethyl)cyclopropyl)methoxy)-1H-pyrazole.

1-(3-((1-(Trifluoromethyl)cyclopropyl)methoxy)-1H-pyrazol-1-yl)ethan-1-one (695 mg, 2.80 mmol, 1.00 eq) was dissolved in MeOH (30 ml). NaOH (aq., 30%, 421 ml, 560 mg, 4.20 mmol, 1.50 eq.) was added. The reaction mixture was stirred at room temperature overnight. Evaporation of the volatiles in vacuo gave a white solid (940 mg). The residue was partitioned between ethyl acetate (25 ml) and water (25 ml). The aqueous phase was extracted with ethyl acetate (2x25 ml). The combined organic phases were washed with brine (25 ml), dried over sodium sulfate, filtered and evaporated in vacuo to give 3-((1-(trifluoromethyl)cyclopropyl)methoxy)-1Hpyrazole (548 mg, 2.66 mmol, 95% yield). %) as a light yellow oily substance. ¹ H NMR (CDCI3): δ 9.10 (br, 1H), 7.36 (d, 1H), 5.77 (d, 1H), 4.29 (s, 2H), 1.14-1, 08 (m, 2H), 0.96-0.89 (m, 2H). ¹⁹ F NMR (CDCl3): δ -69.75.

Step E. tert-Butyl-2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine3-carboxylate.

tert-Butyl 2,6-dichloropyridine-3-carboxylate (about 451.3 mg, 1.819 mmol), 3-[[1-(trifluoromethyl- 138 040454 tyl)cyclopropyl]methoxy]-1H-pyrazole (375 mg, 1.819 mmol) and potassium carbonate (about 301.7 mg, 2.183 mmol) (freshly ground) were combined in anhydrous DMSO (9.026 ml). 1,4 Diazabicyclo[2.2.2]octane (ca. 40.81 mg, 0.3638 mmol) was added and the mixture was stirred at room temperature under nitrogen for 16 h. The reaction mixture was diluted with ethyl acetate (10 ml) and water (2x5 ml) and separate two phases. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The crude material was purified by silica gel chromatography eluting with 0-30% ethyl acetate in hexanes to give t-butyl-2-chloro-6-[3-[[1(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridin- 3-carboxylate (620 mg, 82%). EER-MS m/z calc. 417.1067, found 418.1 (M+1)+; retention time 0.85 min.

Step F 2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid.

tert-Butyl 2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylate (620 mg, 1.484 mmol) and TFA (about 1.692 g, 1.143 ml, 14.84 mmol) was combined in DCM (5 ml) and heated at 40° C. for 16 hours. The reaction mixture was evaporated to a white solid. Hexanes were added and the mixture was evaporated again to give 2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (500 mg, 93%). EER-MS m/z calc. 361.0441, found 362.1 (M+1) ⁺ ; retention time 0.66 min.

Step G 2-Chloro-N-(3-methoxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide.

2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (200 mg, 0.55 mmol) and carbonyldiimidazole (110 mg, 0.66 mmol) was combined in THF (2 ml) and stirred at room temperature for 2 h. for 2 h at room temperature. The reaction mixture was diluted with 10 ml of ethyl acetate and washed with 10 ml of 1M citric acid aqueous solution. The aqueous layer was extracted with ethyl acetate (2x10 ml) and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-10% methanol in dichloromethane to give 2-chloro-N-(3methoxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1- yl]pyridine-3-carboxamide (217 mg, 74%). EER-MS m/z calc. 530.06384, found 531.1 (M+1) ⁺ ; retention time: 0.72 min.

Step H. K-(3-methoxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1ul]-2-[(4S)-2,2,4-trimethylpyrrolidine-1- yl]pyridine-3-carboxamide.

2-Chloro-N-(3-methoxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1yl]pyridine-3-carboxamide (120 mg, 0.23 mmol), (4S )-2, 2,4-trimethylpyrrolidine (hydrochloride salt) (107 mg, 0.71 mmol) and potassium carbonate (173 mg, 1.25 mmol) were combined in DMSO (600 μl) and heated at 130°C for 16 h. The reaction mixture was divided between ethyl acetate and water. The organic layer was separated, washed with 1 M citric acid solution, dried over sodium sulfate and evaporated. The crude material was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give N-(3-methoxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclonpropyl]methoxy]purazol-1-yl] -2-[(4S)-2,2,4-trimethylpyrrolidin-1-ul]pyridine-3-carboxamide (92 mg, 67%). EER-MS m/z calc. 607.20764, found 608.3 (M+1) ⁺ ; retention time 2.17 min. 1H NMR (400 MHz, DMSO-de) δ 12.43 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H ), 7.61-7.53 (m, 2H), 7.48-7.45 (m, 1H), 7.32-7.27 (m, 1H), 6.92 (d, J=8 .2 Hz, 1H), 6.15 (d, J=2.8 Hz, 1H), 4.42-4.31 (m, 2H), 3.84 (s, 3H), 2.45 (d ,

- 139 040454

J=10.5 Hz, 1H), 2.35-2.28 (m, 1H), 2.20-2.03 (m, 1H), 1.84 (dd, J=11.9, 5, 6 Hz, 1H), 1.53 (d, J=10.9 Hz, 6H), 1.38 (t, J=12.1 Hz, 1H), 1.12-1.05 (m, 4H) , 0.67 (d, J=6.2 Hz, 3H).

Synthetic example 48.

Compound 50 synthesis -1 -yl]pyridine-3-carboxamide

Step A 2-Chloro-X-(2-fluorophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide.

_{F3CF3C _}

2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (181 mg, 0.5 mmol) and carbonyldiimidazole (97 mg, 0.6 mmol) was combined in THF (2.5 ml) and stirred at room temperature for 30 min. 2-fluorobenzenesulfonamide (114 mg, 0.65 mmol) was added followed by DBU (0.09 ml, 0.6 mmol) and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was diluted with 10 ml of ethyl acetate and washed with 10 ml of 1 M aqueous citric acid solution. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-8% methanol in dichloromethane to give 2-chloro-X-(2-fluorophenyl)sulfonyl-6-[3-[[1(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1 -yl]pyridine-3-carboxamide (180 mg, 69%). EER-MS m/z calc. 518.0439, found 519.1 (M+1)+; retention time 0.70 min.

Step C. X-(2-fluorophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]2-[(4S)-2,2,4-trimethylpyrrolidin-1 -yl]pyridine-3-carboxamide.

2-Chloro-X-(2-fluorophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1yl]pyridine-3-carboxamide (78 mg, 0.15 mmol), (4S )-2,2,4-trimethylpyrrolidine (hydrochloride salt) (67 mg, 0.45 mmol) and potassium carbonate (124 mg, 0.9 mmol) were combined in DMSO (600 µl) and heated at 130°C for 16 h. The reaction mixture was filtered and purified by LC/MS using a gradient of 30-99% acetonitrile in 5 mM aqueous HCl to give X-(2-fluorophenyl)sulfonyl-6-[3-[[1(trifluoromethyl) cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (28 mg, 31%). EER-MS m/z calc. 595.1876, found 596.3 (M+1) ⁺ ; retention time 2.08 min.

Synthetic example 49.

Synthesis of compound 51 X-(3-fluorophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1 -yl]-2-[(4S)-2,2,4-trimethylpyrrolidine -1 -yl]pyridine-3-carboxamide.

Step A 2-Chloro-X-(3-fluorophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide.

2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (181 mg, 0.5 mmol) and carbonyldiimidazole (97 mg, 0.6 mmol) was combined in THF (2.5 ml) and stirred at room temperature for 30 min. 3-fluorobenzenesulfonamide (114 mg, 0.65 mmol) was added followed by DBU (0.09 ml, 0.6 mmol) and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was diluted with 10 ml of ethyl acetate and washed with 10 ml of 1 M aqueous citric acid solution. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-8% methanol in dichloromethane to give 2-chloro-X-(3-fluorophenyl)sulfonyl-6-[3-[[1(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1 -yl]pyridine-3-carboxamide (190 mg, 73%). EER-MS m/z calc. 518.0439, found 519.1 (M+1) ⁺ ; retention time 0.72 min.

Step C. X-(3-Fluorophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1

- 140 040454 ul]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.

2-Chloro-Ni(3-fluorophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1yl]pyridine-3-carboxamide (78 mg, 0.15 mmol), (4S) -2,2,4-trimethylpyrrolidine (hydrochloride salt) (67 mg, 0.45 mmol) and potassium carbonate (124 mg, 0.9 mmol) were combined in DMSO (600 μl) and heated at 130°C for 16 h The reaction mixture was filtered and purified by LC-MS to give N(3-fluorophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S) -2,2,4trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (47 mg, 52%). EER-MS m/z calc. 595.1876, found 596.3 (M+1)+; retention time 2.14 min. ¹ H NMR (400 MHz, DMSO^) δ 8.21 (d, J=2.8 Hz, 1H), 7.907.82 (m, 2H), 7.80-7.69 (m, 2H), 7 .68-7.59 (m, 1H), 6.93 (d, J=8.2 Hz, 1H), 6.15 (d, J=2.8 Hz, 1H), 4.43-4, 27 (m, 2H), 2.44 (t, J=10.4 Hz, 1H), 2.30 (dd, J=10.2, 7.0 Hz, 1H), 2.23-2.08 (m, 1H), 1.84 (dd, J=11.9, 5.5 Hz, 1H), 1.53 (d, J=9.7 Hz, 6H), 1.39 (t, J= 12.2 Hz, 1H), 1.17-1.02 (m, 4H), 0.69 (d, J=6.3 Hz, 3H).

Synthetic example 50.

Synthesis of compound 52 -1-yl]pyridine-3-carboxamide.

Step A. 2-Χλορ-Ν-(4-fluorophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide.

2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (181 mg, 0.5 mmol) and carbonyldiimidazole (97 mg, 0.6 mmol) was combined in THF (2.5 ml) and stirred at room temperature for 30 min. 4-Fluorobenzenesulfonamide (114 mg, 0.65 mmol) was added followed by DBU (0.09 ml, 0.6 mmol) and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was diluted with 10 ml of ethyl acetate and washed with 10 ml of 1M citric acid aqueous solution. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-8% methanol in dichloromethane to give 2-chloro-N-(4-fluorophenyl)sulfonyl-6-[3-[[1(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1 -yl]pyridine-3-carboxamide (160 mg, 62%). EER-MS m/z calc. 518.0439, found 519.1 (M+1) ⁺ ; retention time 0.72 min.

Step C. N-(4-Fluorophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1 yl]-2-[(4S)-2,2,4-trimethylpyrrolidine-1 -yl]pyridine-3-carboxamide.

2-Chloro-N-(4-fluorophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1yl]pyridine-3-carboxamide (78 mg, 0.15 mmol), (4S )-2,2,4-trimethylpyrrolidine (hydrochloride salt) (67 mg, 0.45 mmol) and potassium carbonate (124 mg, 0.9 mmol) were combined in DMSO (600 μl) and heated at 130°C for 16 h. The reaction mixture was filtered and purified by LC/MS using a gradient of 30-99% acetonitrile in 5 mM aqueous HCl to give N-(4-fluorophenyl)sulfonyl-6-[3[[1-(trifluoromethyl)cyclopropyl ]methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (34 mg, 38%). EER-MS m/z calc. 595.1876, found 596.3 (M+1) ⁺ ; retention time 2.16 min. 1H NMR (400 MHz, DMSO^) δ 8.20 (d, J=2.8 Hz, 1H), 8.12-8.02 (m, 2H), 7.82 (d, J=8.3 Hz, 1H), 7.59-7.45 (m, 2H), 6.92 (d, J=8.2 Hz, 1H), 6.15 (d, J=2.7 Hz, 1H), 4.43-4.30 (m, 2H), 2.37 (t, J=10.4 Hz, 1H), 2.22 (dd, J=10.1, 7.0 Hz, 1H), 2 .18-2.05 (m, 1H), 1.83 (dd, J=11.9, 5.5 Hz, 1H), 1.52 (d, J=8.8 Hz, 6H), 1, 37 (t, J=12.1 Hz, 1H), 1.15-1.00 (m, 4H), 0.67 (d, J=6.3 Hz, 3H).

Synthetic example 51.

Synthesis of compound 53 -1-yl]pyridine-3-carboxamide.

Step A. 2-chloro-N-(2-methoxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pi- 141 040454 razol-1-yl]pyridine-3-carboxamide.

2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (200 mg, 0.55 mmol) and carbonyldiimidazole (110 mg, 0.66 mmol) was combined in THF (2 ml) and stirred at room temperature for 2 h. for 2 h at room temperature. The reaction mixture was diluted with 10 ml of ethyl acetate and washed with 10 ml of 1 M aqueous citric acid solution. The aqueous layer was extracted with ethyl acetate (2x10 ml) and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude material was used without further purification. 2Chloro-N-(2-methoxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1-yl]pyridine3-carboxamide (286 mg, 97%), ESI-MS m/z calc. 530.06384, found 531.1 (M+1)+; retention time 0.70 min.

Step B. N-(2-methoxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1yl]-2-[(4S)-2,2,4-trimethylpyrrolidine-1- yl]pyridine-3-carboxamide.

2-Chloro-N-(2-methoxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1yl]pyridine-3-carboxamide (120 mg, 0.23 mmol), (4S )-2,2,4-trimethylpyrrolidine (hydrochloride salt) (107 mg, 0.71 mmol) and potassium carbonate (173 mg, 1.25 mmol) were combined in DMSO (600 μl) and heated at 130°C for 16 h. The reaction mixture was divided between ethyl acetate and water. The organic layer was separated, washed with 1M citric acid, brine, dried over sodium sulfate and evaporated. The crude material was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give N-(2-methoxyphenyl)sulfonyl-6-[3-[[1(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2 -[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine3-carboxamide (82 mg, 60%). EER-MS m/z calc. 607.20764, found 608.3 (M+1)+; retention time 2.15 min.

Synthetic example 52.

Synthesis of compound 54 -1-yl]pyridine-3-carboxamide.

Step A. 2-Chloro-N-(4-methoxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide.

_{F3CF3C _}

2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (300 mg, 0.83 mmol) and carbonyldiimidazole (162 mg, 1.0 mmol) was combined in THF (4 ml) and stirred at room temperature for 30 min. 4-Methoxybenzenesulfonamide (203 mg, 1.08 mmol) was added followed by DBU (0.15 ml, 1.0 mmol) and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with 10 ml of ethyl acetate and washed with 10 ml of 1 M aqueous citric acid solution. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0-8% methanol in dichloromethane to give 2-chloro-N-(4-methoxyphenyl)sulfonyl-6[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1 -yl]pyridine-3-carboxamide (430 mg, 97%). IERMS m/z calc. 530.06384, found 531.1 (M+1) ⁺ ; retention time 0.71 min.

Step B. N-(4-Methoxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1yl]-2-[(4S)-2,2,4-trimethylpyrrolidine-1- yl]pyridine-3-carboxamide.

- 142 040454

2-Chloro-N-(4-methoxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1yl]pyridine-3-carboxamide (210 mg, 0.39 mmol), (4S )-2,2,4-trimethylpyrrolidine (hydrochloride salt) (180 mg, 1.2 mmol) and potassium carbonate (330 mg, 2.39 mmol) were combined in DMSO (2 ml) and heated at 130°C for 15 h. The reaction mixture was divided between ethyl acetate and water. The organic layer was separated, washed with 1 M citric acid solution, dried over sodium sulfate and evaporated. The crude material was purified by silica gel chromatography eluting with 0-5% methanol in dichloromethane. The material was further purified by LC/MS using a gradient of 30-99% acetonitrile in 5 mM aq. HCl, to give N-(4-methoxyphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidine -1-yl]pyridine-3-carboxamide (25 mg, 10%). EER-MS m/z calc. 607.20764, found 608.3 (M+1)+; retention time: 2.16 min. ¹ H NMR (400 MHz, DMSOCH) δ 8.19 (d, J=2.8 Hz, 1H), 7.99-7.87 (m, 2H), 7.77 (d, J=8.2 Hz, 1H), 7.26-7.10 (m, 2H), 6.91 (d, J=8.2 Hz, 1H), 6.14 (d, J=2.8 Hz, 1H), 4.44-4.28 (m, 2H), 3.84 (s, 3H), 2.40 (t, J=10.5 Hz, 1H), 2.29-2.21 (m, 1H) , 2.16-2.00 (m, 1H), 1.82 (dd, J=11.9, 5.6 Hz, 1H), 1.52 (d, J=10.7 Hz, 6H), 1.37 (t, J=12.1 Hz, 1H), 1.16-1.02 (m, 4H), 0.64 (d, J=6.3 Hz, 3H).

Synthetic example 53.

Synthesis of compound 55 pyridine-3-carboxamide.

Step A. tert-Butyl-3-((1-(difluoromethyl)cyclopropyl)methoxy)-1H-pyrazole-1-carboxylate.

_CF2H

H DIAD, RMzRDHF ^NBoc from 0 °C to room. θ'^'^'ΝΒοο t-ry, then 50 °C \__/

To a solution of (1-(difluoromethyl)cyclopropyl)methanol (867 mg, 7.11 mmol), tert-butyl-2,3-dihydro-3oxopyrazole-1-carboxylate (1.19 g, 6.46 mmol) and triphenylphosphine ( 1.86 g, 7.11 mmol) in tetrahydrofuran (22 ml) diisopropyl azodicarboxylate (1.44 g, 7.11 mmol) was added dropwise at 0°C. After completion of the addition, the reaction mixture was allowed to warm to room temperature, then heated at 50° C. for 1 h. The reaction solution was cooled to room temperature, and ethyl acetate (300 ml) was added. The solution was then washed with aqueous sodium hydroxide solution (20 ml, 1 M), water, brine and dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified by silica gel chromatography (hexane and dichloromethane, gradient 0 to 100% dichloromethane) to give t-butyl-3-((1-(difluoromethyl)cyclopropyl)methoxy)-1Hpyrazole-1-carboxylate as a white solid ( 1.50 g, 80% yield. EER-MS m/z calc. 288.1, found 289.2 (M+1) ⁺ . Retention time 3.08 min. 1H NMR (250 MHz, CDCl ₃ ) δ (ppm): 7.84 (d, J=3.0 Hz, 1H), 5.97 (t, J=57.8 Hz, 1H), 5 .89 (d, J=3.0 Hz, 1H), 4.32 (s, 2H), 1.61 (s, 9H), 0.97 (m, 2H), 0.75 (m, 2H) .

Step B. 3-((1-(Difluoromethyl)cyclopropyl)methoxy)-1H-pyrazole.

A cold solution of hydrogen chloride (30 ml, 4.0 M in 1,4-dioxane) was added to tert-butyl 3-((1(difluoromethyl)cyclopropyl)methoxy)-1H-pyrazole-1-carboxylate (1.69 g, 5.88 mmol) in a round bottom flask and warm the reaction solution to room temperature and stir for 3 hours. After removal of all solvents under reduced pressure, the residue thus obtained was partitioned between water (50 ml) and diethyl ether (80 ml). The organic layer was separated and the aqueous layer was extracted with diethyl ether (2x80 ml). The combined organic layers were washed with brine (2x30 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexanes and ethyl acetate, 0 to 40% ethyl acetate gradient) to give 3-((1-(difluoromethyl)cyclopropyl)methoxy)-1Hpyrazole as a white solid (997 mg, 90% yield). EER-MS m/z calc. 188.1, found 189.1 (M+1) ⁺ . Retention time 1.94 min. ¹ H NMR (250 MHz, DMSO) δ (ppm): 11.87 (s, 1H), 7.51 (m, 1H), 5.98 (t, J=57.0 Hz, 1H) , 5.66 (m, 1H), 4.10 (s, 2H), 0.80 (m, 4H).

Step C. tert-Butyl-2-chloro-6-[3-[[1-(difluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine3-carboxylate.

- 143 040454

tert-Butyl 2,6-dichloropyridine-3-carboxylate (about 659.2 mg, 2.657 mmol), 3-[[1-(difluoromethyl)cyclopropyl]methoxy]-1H-pyrazole (500 mg, 2.657 mmol) and carbonate potassium (about 440.6 mg, 3.188 mmol) (freshly ground) was combined in anhydrous DMSO (13.18 ml). 1,4diazabicyclo[2.2.2]octane (ca. 59.61 mg, 0.5314 mmol) was added and the mixture was stirred at room temperature under nitrogen for 16 h. The reaction mixture was diluted with water (20 ml) and stirred for 15 min . The resulting solid was collected and washed with water. The solid was dissolved in dichloromethane and a small amount of the aqueous layer was removed. The organic layer was dried over sodium sulfate and evaporated to give tert-butyl-2-chloro-6-[3-[[1(difluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylate (842 mg, 79% ). EER-MS m/z calc. 399.11612, found 400.1 (M+1)+; retention time 0.82 min.

Step D 2-Chloro-6-[3-[[1-(difluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid.

tert-Butyl 2-chloro-6-[3-[[1-(difluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylate (842 mg, 2.106 mmol) and TFA (about 2.401 g, 1.622 ml, 21.06 mmol) was dissolved in dichloromethane (8.420 ml) and heated at 40° C. for 3 h. The reaction mixture was evaporated and the resulting solid was triturated with hexanes and re-evaporated to give 2-chloro-6-[3-[[ 1(difluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (710 mg, 98%). IERMS m/z calc. 343.05353, found 344.1 (m+1) ⁺ ; retention time 0.62 min. ¹ H NMR (400 MHz, DMSO d6) δ 13.59 (s, 1H), 8.43 (d, J=2.9 Hz, 1H), 8.39 (d, J=8.4 Hz, 1H ), 7.73 (d, J=8.4 Hz, 1H), 6.22 (d, J=2.9 Hz, 1H), 5.98 (t, J=56.4 Hz, 1H), 4.32 (s, 2H), 0.93-0.84 (m, 4H).

Step E X-(Benzenesulfonyl)-2-chloro-6-[3-[[ 1 -(difluoromethyl)cyclopropyl]methoxy]pyrazol-1yl]pyridine-3-carboxamide.

2-Chloro-6-[3-[[1-(difluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (200 mg, 0.5819 mmol) and carbonyldiimidazole (about 113.2 mg, 0.6983 mmol) was combined in THF (2.5 mL) and stirred for 2 h. At this time, benzenesulfonamide (ca. 91.47 mg, 0.5819 mmol) was added, followed by DBU (ca. 1 µl, 1.746 mmol) and the reaction mixture was stirred for another 2 h at room temperature. A 1 M citric acid solution (5 ml) was added and the reaction mixture was stirred for 20 minutes. The solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The crude material was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give N(benzenesulfonyl)-2-chloro-6-[3-[[1-(difluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl] pyridine-3carboxamide (153.6 mg, 55%). EER-MS m/z calc. 482.0627, found 4 8 3.1 (M+1) ⁺ ; retention time 0.68 min.

Step F. N-(benzenesulfonyl)-6-[3-[[1-(difluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S)2,2,4-trimethylpyrrolidin-1-yl] pyridine-3-carboxamide.

- 144 040454

N-(Benzenesulfonyl)-2-chloro-6-[3-[[1-(difluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3carboxamide (116 mg, 0.24 mmol), (4S)-2 ,2,4-trimethylpyrrolidine (hydrochloride salt) (71 mg, 0.63 mmol) and potassium carbonate (145 mg, 1.05 mmol) were combined in DMSO (600 µl) and heated at 130°C for 16 h.

The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with 1M citric acid, brine, dried over sodium sulfate and evaporated. The crude material was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give N-(benzenesulfonyl)-6-[3-[[1-(difluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2- [(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (87 mg, 65%). EER-MS m/z calc. 559.2065, found 560.3 (M+1)+; retention time 2.06 min. ¹ H NMR (400 MHz,

DMSO) δ 12.47 (s, 1H), 8.19 (d, J=2.8 Hz, 1H), 8.00 (t, J=1.3 Hz, 1H), 7.98 (d, J=1.6Hz, 1H), 7.80(d, J=8.2Hz, 1H), 7.76-7.70(m, 1H), 7.65(tt, J=6.8 , 1.6 Hz, 2H), 6.91 (d, J=8.3 Hz, 1H), 6.13 (d, J=2.8 Hz, 2H), 4.324.23 (m, 2H), 2.47-2.37 (m, 1H), 2.28 (dd, J=10.3, 7.0 Hz, 1H), 2.09 (dc, J=11.9, 6.2 Hz, 1H), 1.82 (dd, J=11.9, 5.6 Hz, 1H), 1.52 (d, J=9.5 Hz, 6H), 1.36 (t, J=12.1 Hz, 1H), 0.87 (dt, J=5.1, 2.0 Hz, 4H), 0.65 (d, J=6.2 Hz, 3H).

Synthetic example 54.

Synthesis of compound 56 -3-carboxamide.

Step A N-(2,4,4-Trimethylpentan-2-yl)picolinamide.

To picolinic acid (20.5 g, 167 mmol) in DMF (200 ml) at 5°C was added HATU (65 g, 171 mmol, ~1.0 eq.), then 2,4,4-trimethylpentan-2- amine (27.0 ml, ~1.0 eq.) and then DIEA (65 ml, ~2.5 eq.). The reaction mixture was stirred at room temperature for 1.0 h. The reaction mixture was poured into ice water (350 ml) and extracted with EtOAc (2x600 ml). The combined extract was washed with water (2x300 ml) and brine (150 ml), dried over Na ₂ SO ₄ and concentrated to give the crude product, which was purified by filtration through a plug of silica gel, eluting with 25% 25% EtOAc in hexanes to give a light -yellow oily substance. N-(2,4,4 Trimethylpentan-2-yl) picolinamide (36 g, 92%); MS [M+1]: 235.

Step B: Pyridin-2-yl-(2,2,4,4-tetramethylpyrrolidin-1-yl)methanone.

N-(2,4,4-Trimethylpentan-2-yl)picolinamide (36.0 g, 153 mmol), Pd(OAc) ₂ (1.72 g, 5%), RS(OAc) ₂ (99.2 g, 308 mmol) was mixed in toluene (600 ml) and heated at 80° C. overnight (~18 h). The reaction mixture was concentrated to remove most of the toluene and loaded the residue on a silica gel column, eluted with 50% EtOAc in hexanes to give a light yellow solid. Pyridin-2-yl(2,2,4,4-tetramethylpyrrolidin-1-yl) methanone (32 g, 90%); MS [M+1]: 233. 1H NMR (250 MHz, CDCl ₃ ) δ.56 (d, J=4.8 Hz, 1H), 7.76 (td, J=7.7, 1.7 Hz , 1H), 7.61 (d, J=7.8 Hz, 1H), 7.35-7.25 (m, 1H), 3.36 (s, 2H), 1.79 (s, 2H) , 1.67 (s, 6H), 1.08 (s, 6H)

Step C. 2,2,4,4-tetramethylpyrrolidine (HCl salt).

Pyridin-2-yl(2,2,4,4-tetramethylpyrrolidin-1-yl)methanone (6 g, 25.9 mmol) was dissolved in NaOH (9.0 g, 225 mmol) in water (6 ml) and EtOH (18 ml) in a small pressure reactor (~45 ml) and heated at 140° C. for 48 hours. The reaction was complete. The mixture was dissolved in 80 ml of water and was extracted with Et ₂ O (3x200 ml). The extract was washed with water (2x100 ml) and dried over Mg ₂ SO ₄ . After filter

- 145 040454 gaseous HCl was bubbled through the filtrate for 5 minutes. An oily substance formed at the bottom of the flask. The top ether layer was carefully decanted, the remaining oily substance was washed with ether (2x30 ml) and the wash solutions were decanted. The resulting oil was evaporated to give a white semi-solid which was dried in a vacuum oven at 50° C. for 1 day to give an off-white solid. 2,2,4,4-Tetramethylpyrrolidine (HCl salt) (4.0 g, 95%). MS [M+1]: 128. 1H NMR (250 MHz, DMSO^) 9.39 (s, 2H), 3.01 (t, J=5.5 Hz, 2H), 1.69 (s, 2H ), 1.40 (s, 6H), 1.16 (s, 6H).

Step D. N-(benzenesulfonyl)-2-(2,2,4,4-tetramethylpyrrolidin-1-yl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine -3-carboxamide.

N-(Benzenesulfonyl)-2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1-yl]pyridine-3carboxamide (100 mg, 0.2 mmol), 2,2,4 ,4-tetramethylpyrrolidine (hydrochloride salt) (98 mg, 0.6 mmol) and potassium carbonate (138 mg, 1.0 mmol) were combined in DMSO (500 μl) and heated at 130°C for 16 h. The reaction mixture was diluted water (3 ml) and stirred for 20 min. A solid formed and the aqueous liquid was decanted. The solid was dissolved in ethyl acetate and washed with 1 M citric acid solution, then with brine. The organic layer was dried over sodium sulfate and evaporated. The crude material was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give N-(benzenesulfonyl)-2-(2,2,4,4tetramethylpyrrolidin-1-yl)-6-[3-[[1- (trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3 carboxamide (57 mg, 48%). EER-MS m/z calc. 591.2127, found 592.2 (M+1) ⁺ ; retention time 2.20 min. 1H NMR (400 MHz, DMSO-de) δ 12.52 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 8.04-7.97 (m, 2H), 7 .82-7.72 (m, 2H), 7.72-7.63 (m, 2H), 6.94 (d, J=8.0 Hz, 1H), 6.14 (d, J=2 .8 Hz, 1H), 4.36 (s, 2H), 2.38 (s, 2H), 1.72 (s, 2H), 1.58 (s, 6H), 1.14-1.04 (m, 4H), 0.81 (s, 6H).

Synthetic example 55.

Synthesis of compound 57 ,4-trimethylpyrrolidin-1 -yl]pyridine-3-carboxamide.

Step A 2-Chloro-M-(4-methoxy-2-methylphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide.

_{F3CF3C _}

2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (150 mg, 0.4023 mmol) and carbonyldiimidazole (82 mg, 0.5057 mmol) was combined in THF (1.299 mL) and stirred for 2 h. At this time, 4-methoxy-2-methyl-benzenesulfonamide (85 mg, 0.4224 mmol) was added followed by DBU (200 μL, 1.337 mmol) and stirred the reaction mixture for another 2 h at room temperature. The reaction mixture was diluted with ethyl acetate and washed with 1 M citric acid solution, then with brine. The organic layer was separated, dried over sodium sulfate and evaporated to give 2-chloro-N-(4-methoxy-2-methylphenyl)sulfonyl-6-[3-[[1(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl] pyridine-3-carboxamide (205 mg, 94%). EER-MS m/z calc. 544.0795, found 545.0 (M+1) ⁺ ; retention time 0.73 min.

Step B. N-(4-Methoxy-2-methylphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S)-2.2, 4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.

2-Chloro-N-(4-methoxy-2-methylphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (100 mg, 0. 18 mmol), (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (90 mg, 0.6 mmol) and potassium carbonate (138 mg, 1.0 mmol) were combined in DMSO (500 μl) and heated at 130° C. for 16 hours. The reaction mixture was diluted with water (3 ml) and stirred for 20 minutes. A solid formed and the aqueous liquid was decanted. Solid

- 146 040454 was dissolved in ethyl acetate and washed with 1 M citric acid solution, then with brine. The organic layer was dried over sodium sulfate and evaporated. The crude material was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give N-(4-methoxy-2-methylphenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazole- 1-yl]-2[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (75 mg, 67%). EER-MS m/z calc. 621.22327, found 622.3 (M+1)+; retention time 2.23 min. 1H NMR (400 MHz, DMSO-d ₆ ) δ 12.46 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 7.01-6.94 (m, 2H), 6.92 (d, J=8.2 Hz, 1H), 6, 14 (d, J=2.7 Hz, 1H), 4.41-4.32 (m, 2H), 3.82 (s, 3H), 2.59 (s, 3H), 2.41-2 .29 (m, 2H), 2.22-2.10 (m, 1H), 1.82 (dd, J=11.9, 5.6 Hz, 1H), 1.52 (s, 6H), 1.36 (t, J=12.1 Hz, 1H), 1.12-1.06 (m, 4H), 0.70 (d, J=6.2 Hz, 3H).

Synthetic example 56.

Synthesis of compound 58 1-yl]pyridine-3-carboxamide.

Step A. 2-Chloro-N-(o-tolylsulfonyl)-6-[3-[[1-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-1yl]pyridine-3-carboxamide.

2-Chloro-6-[3-[[1-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (150 mg, 0.3992 mmol) and carbonyldiimidazole (about 81.69 mg, 0.5038 mmol) was combined in THF (1.339 mL) and stirred for 2 h. At this time, 2-methylbenzenesulfonamide (ca. 71.77 mg, 0.4192 mmol) was added, followed by DBU (ca. 0 µl, 1.331 mmol) and the reaction mixture was stirred for another 2 h at room temperature. The reaction mixture was diluted with ethyl acetate and washed with 1 M citric acid solution, then with brine. The organic layer was separated, dried over sodium sulfate and evaporated to give 2-chloro-N-(o-tolylsulfonyl)-6-[3-[[1(trifluoromethyl)cyclobutyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (208 mg, 99%). EER-MS m/z calc. 528.0846, found 529.0 (M+1)+; retention time 0.77 min.

Step C. N-(o-tolylsulfonyl)-6-[3-[[1-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-1-yl]-2[(4S)-2,2,4-trimethylpyrrolidin-1- yl]pyridine-3-carboxamide.

2-Chloro-K-(o-tolylsulfonyl)-6-[3-[[1-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-1-yl]pyridine-3carboxamide (100 mg, 0.19 mmol), (4S) -2,2,4-trimethylpyrrolidine (hydrochloride salt) (90 mg, 0.6 mmol) and potassium carbonate (138 mg, 1.0 mmol) were combined in DMSO (500 μl) and heated at 130°C for 16 h The reaction mixture was diluted with water (3 ml) and stirred for 20 minutes. A solid formed and the aqueous liquid was decanted. The solid was dissolved in ethyl acetate and washed with 1 M citric acid solution, then with brine. The organic layer was dried over sodium sulfate and evaporated. The crude material was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give N-(o-tolylsulfonyl)-6-[3-[[1(trifluoromethyl)cyclobutyl]methoxy]pyrazol-1-yl]-2 -[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3carboxamide (69mg, 60%). EER-MS m/z calc. 605.22833, found 60 6.5 (M+1)+; retention time 2.33 min. 1H NMR (400 MHz, DMSO^) δ 12.63 (s, 1H), 8.22 (d, J=2.8 Hz, 1H), 8.04 (d, J=7.9 Hz, 1H) , 7.82 (d, J=8.2 Hz, 1H), 7.59 (td, J=7.5, 1.5 Hz, 1H), 7.49-7.40 (m, 2H), 6.96 (d, J=8.3 Hz, 1H), 6.18 (d, J=2.7 Hz, 1H), 4.48 (s, 2H), 2.63 (s, 3H), 2.39 (d, J=8.8 Hz, 2H), 2.35-2.23 (m, 2H), 2.21-2.04 (m, 4H), 2.02-1.91 ( m, 1H), 1.83 (dd, J=11.9, 5.6 Hz, 1H), 1.53 (s, 6H), 1.35 (t, J=12.1 Hz, 1H), 0.69 (d, J=6.2 Hz, 3H).

Synthetic example 57.

Synthesis of compound 59 -1-yl]pyridine-3-carboxamide.

Step A 2-Chloro-N-(3-fluorophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide.

- 147 040454

_{F3CF3C _}

2-Chloro-6-[3-[[1 -(trifluoromethyl)cyclobutyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (150 mg, 0.3992 mmol) and carbonyldiimidazole (about 81.69 mg, 0.5038 mmol) was combined in THF (1.339 mL) and stirred for 2 h. At this time, 3-fluorobenzenesulfonamide (ca. 69.93 mg, 0.3992 mmol) was added followed by DBU (ca. 202.6 mg, 199. 0 µl, 1.331 mmol) and the reaction mixture was stirred for another 2 h at room temperature.

The reaction mixture was diluted with ethyl acetate and washed with 1 M citric acid solution, then with brine. The organic layer was separated, dried over sodium sulfate and evaporated to give 2-chloro-N-(3-fluorophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-1-yl]pyridin-3 -carboxamide (210 mg, 99%). EER-MS m/z calc. 532.0595, found 533.0 (M+1)+; retention time 0.77 min.

Step B. N-(3-Fluorophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-1-yl]2-[(4S)-2,2,4-trimethylpyrrolidin-1 -yl]pyridine-3-carboxamide.

2-Chloro-N-(3-fluorophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-1yl]pyridine-3-carboxamide (100 mg, 0.19 mmol), (4S )-2,2,4-trimethylpyrrolidine (hydrochloride salt) (90 mg, 0.6 mmol) and potassium carbonate (138 mg, 1.0 mmol) were combined in DMSO (500 μl) and heated at 130°C for 16 h. The reaction mixture was diluted with water (3 ml) and stirred for 20 min. A solid formed and the aqueous liquid was decanted. The solid was dissolved in ethyl acetate and washed with 1 M citric acid solution, then with brine. The organic layer was dried over sodium sulfate and evaporated. The crude material was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give N-(3fluorophenyl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-1-yl]-2 -[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (73 mg, 63%). EER-MS m/z calc. 609.2033, found 610.2 (M+1) ⁺ ; retention time 2.27 min. 1H NMR (400 MHz, DMSO-d ₆ ) δ 12.63 (s, 1H), 8.22 (d, J=2.8 Hz, 1H), 7.86 (d, J=2.3 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.78-7.70 (m, 2H), 7.66-7.59 (m, 1H), 6.96 (d , J=8.2 Hz, 1H), 6.18 (d, J=2.7 Hz, 1H), 4.48 (s, 2H), 2.43 (d, J=10.4 Hz, 1H ), 2.35-2.25 (m, 3H), 2.19-2.05 (m, 4H), 1.96 (td, J=10.0, 5.3 Hz, 1H), 1, 84 (dd, J=11.8, 5.6 Hz, 1H), 1.55 (s, 3H), 1.52 (s, 3H), 1.40 (t, J=12.2 Hz, 1H ), 0.69 (d, J=6.2 Hz, 3H).

Synthetic example 58.

Synthesis of compound 60 ]pyridine-3-carboxamide.

Step A. Spiro[2.2]Pent-1-ylmethanol.

O

To a suspension of lithium aluminum hydride (888 mg, 23.4 mmol) in tetrahydrofuran (30 ml) was added dropwise spiro[2.2]pentane-1-carboxylic acid (1.75 g, 15.6 mmol) in tetrahydrofuran (5 ml) in within 5 min. The reaction mixture was heated to 50° C. for 16 hours. The reaction mixture was diluted with diethyl ether (20 ml) and quenched with sodium sulfate decahydrate. The mixture was diluted with diethyl ether (100 ml), filtered through a pad of celite and concentrated to give spiro[2.2]pent-1-ylmethanol (793 mg, 52%) as an oil. EER-MS m/z calc. 98.15, found 98.8 (M+1) ⁺ . Retention time: 2.54 min. ¹ H NMR (250 MHz, CDC^) ppm 0.58-0.89 (m, 4H) 0.91-1.09 (m, 1H) 1.20-1.37 (m, 1H) 1.43 (m, 1H) 3.60 (dd, J=11.98, 6.37 Hz, 2H).

Step B. 3-(spiro[2.2]Pent-1-ylmethoxy)pyrazole-1-carboxylic acid tert-butyl ester.

To a solution of crude spiro[2.2]pent-1-ylmethanol (966 mg, 9.8 mmol) in tetrahydrofuran

- 148 040454 (40 ml) was added triphenylphosphine (2.58 g, 9.8 mmol), 3-hydroxypyrazole-1 carboxylic acid tert-butyl ester (1.64 g, 8.9 mmol). The reaction mixture was cooled in an ice bath, then diisopropyl azodicarboxylate (1.9 ml, 9.8 mmol) was added. The ice bath was removed and the reaction mixture was stirred for 2 h. The solvent was removed in vacuo and the crude mixture was purified by column chromatography on silica gel using 10-20% hexanes in diethyl ether to give tert-butyl ester 3-(spiro[2.2]pent -1-ylmethoxy)pyrazole-1-carboxylic acid (1.20 g, 44%) as a clear oil. EER-MS m/z calc. 264.33, found 265.1 (M+1)+. Retention time 3.36 min.

Step C. 3-(spiro[2.2]Pent-1-ylmethoxy)-1H-pyrazole.

Dichloromethane (30 ml) and trifluoroacetic acid (3.4 ml, 45 mmol). The reaction mixture was stirred for 2 hours at room temperature and concentrated to dryness in vacuo. The residue was azeotropically distilled twice with 1,2-dichloroethane (15 ml) to give crude 3-(spiro[2.2]pent-1-ylmethoxy)-1H-pyrazole (1.87 g, 51%) as a yellow oil. EER-MS m/z calc. 164.09, found 164.6 (M+1) ⁺ . Retention time 2.11 min.

Step D. 2-Chloro-6-[3-(spiro[2.2]pent-1-ylmethoxy)pyrazol-1-yl]nicotinic acid methyl ester.

ABOUT

To crude 3-(spiro[2.2]pent-1-ylmethoxy)-1H-pyrazole (1.87 g, taken as 4.54 mmol) was added methyl 2,6-dichloronicotinate (935 mg, 4.54 mmol), 1,4-diazabicyclo[2.2.2]octane (102 mg, 0.91 mmol), dimethylformamide (8 ml) and potassium carbonate (1.9 g, 13.6 mmol). The reaction mixture was stirred for 48 h at room temperature, diluted with diethyl ether (75 ml) and washed with water containing a small amount of brine (3x50 ml) and brine (50 ml). The resulting organic layer was dried over sodium sulfate and concentrated in vacuo. The crude reaction mixture was purified by silica gel column chromatography using 0-15% hexanes:diethyl ether to give 2-chloro-6-[3(spiro[2.2]pent-1-ylmethoxy)pyrazol-1-yl]nicotinic acid methyl ester. acid (1.02 g, 67%) as an off-white solid. EER-MS m/z calc. 333.09, found 333.9 (M+1) ⁺ . Retention time 3.85 min.

Step E. 2-Chloro-6-[3-(spiro[2.2]pent-1-ylmethoxy)pyrazol-1-yl]nicotinic acid.

Water (6 ml), methanol (6 ml) and tetrahydrofuran (6 ml), then lithium hydroxide (285 mg, 11.88 mmol). The reaction mixture was stirred for 1 h and was added 1 M hydrochloric acid (12 ml). The resulting white solid was filtered off, washed with water and hexanes to give 2-chloro-6-[3-(spiro[2.2]pent-1-ylmethoxy)pyrazol-1-yl]nicotinic acid (927 mg, 98%) as white solid. EER-MS m/z calc. 319.07, found 320.0 (M+1) ⁺ . Retention time 3.25 min. 1 H NMR (250 MHz, CDCl ₃ ) ppm: 0.76-0.88 (m, 5H), 1.11-1.13 (m, 1H), 1.601.75 (m, 1H), 4 .22 (dd, J=7.0, 3.3, Hz, 2H) 6.00 (d, J=2.5 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H) , 8.38 (d, J=2.5 Hz, 1H), 8.43 (d, J=8.5 Hz, 1H).

Step F. N-(Benzenesulfonyl)-2-chloro-6-[3-(spiro[2.2]pentan-2-ylmethoxy)pyrazol-1-yl]pyridine3-carboxamide.

2-Chloro-6-[3-(spiro[2.2]pentan-2-ylmethoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (50 mg, 0.16 mmol) and carbonyldiimidazole (38 mg, 0.23 mmol) was combined in THF (1.5 ml) and stirred for 2 hours. At this time, benzenesulfonamide (25 mg, 0.16 mmol) was added, then DBU (70 μl, 0.47 mmol) and

- 149 040454 stirred the reaction mixture for another 2 hours at room temperature. The reaction mixture was diluted with ethyl acetate and washed with 1 M citric acid solution, then with brine. The organic layer was separated, dried over sodium sulfate and evaporated to give N(benzenesulfonyl)-2-chloro-6-[3-(spiro[2.2]pentan-2-ylmethoxy)pyrazol-1-yl]pyridine-3-carboxamide (72 mg, 98%). EER-MS m/z calc. 458.08154, found 459.2 (M+1)+; retention time 0.75 min.

Step G. N-(Benzenesulfonyl)-6-[3-(spiro[2.2]pentan-2-ylmethoxy)pyrazol-1-yl]-2-[(4S)-2,2,4trimethylpyrrolidin-1-yl]pyridine -3-carboxamide.

N-(benzenesulfonyl)-2-chloro-6-[3-(spiro[2.2]pentan-2-ylmethoxy)pyrazol-1-yl]pyridine-3carboxamide (72 mg, 0.16 mmol), (4S)-2 ,2,4-trimethylpyrrolidine (hydrochloride salt) (63 mg, 0.42 mmol) and potassium carbonate (97 mg, 0.7 mmol) were combined in DMSO (1 ml) and heated at 130°C for 16 h. the mixture was diluted with water (3 ml) and stirred for 20 minutes. A solid formed and the aqueous liquid was decanted. The solid was dissolved in ethyl acetate and washed with 1 M citric acid solution, then with brine. The organic layer was dried over sodium sulfate and evaporated. The crude material was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give N-(benzenesulfonyl)6-[3-(spiro[2.2]pentan-2-ylmethoxy)pyrazol-1-yl]-2-[ (4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3carboxamide (38 mg, 45%). EER-MS m/z calc. 535.22534, found 536.1 (M+1) ⁺ ; retention time 2.22 min.

Synthetic example 59.

Synthesis of compound 61 -2,7,13-triazatricyclo[7.4.0.02.6]trideca-1(9),10,12-trien-8-one.

N-(Benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4trimethylpyrrolidin-1-yl]pyridine- 3-carboxamide (52 mg, 0.08789 mmol), NaOAc (14 mg, 0.1707 mmol), water (16 µl, 0.89 mmol) and [Ir{dF(CF3)ppy}2(dtbpy)]PF6 (5 mg, 0.004 mmol) was combined in DMA (dimethylacetamide) (0.9 μl) and then the reaction mixture was placed under the light source, a 23 W compact fluorescent lamp (CFL) for 1.5 hours. The reaction mixture was directly injected into a silica gel column without any product isolation. The crude mixture was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexanes to give (5S)-7-(benzenesulfonyl)3,3,5-trimethyl-12-(3-{2-[1-(trifluoromethyl) cyclopropyl]ethoxy} -1 H-pyrazol-1 -yl)-2,7,13-triazatricyclo[7.4.0.02.6]trideca-1(9),10,12-trien-8-one (10 mg, 19 %). EER-MS m/z calc. 589.1971, found 590.3 (M+1) ⁺ ; retention time: 2.51 min. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.26 (d, J=2.8 Hz, 1H), 8.06 (d, J=7.7 Hz, 2H), 7.81 (d, J=8.2 Hz, 1H), 7.73 (t, J=7.4 Hz, 1H), 7.66 (t, J=7.6 Hz, 2H), 6.97 (d, J= 8.2 Hz, 1H), 6.07 (d, J=2.7 Hz, 1H), 6.02 (d, J=3.9 Hz, 1H), 4.36 (t, J=7, 0 Hz, 2H), 3.04 (dt, J=12.2, 5.7 Hz, 1H), 2.17 (dd, J=13.4, 7.3 Hz, 1H), 2.11 ( m, 2H), 1.86 (d, J=13.2 Hz, 1H), 1.71 (s, 3H), 1.61 (s, 3H), 1.21 (d, J=6.3 Hz, 3H), 0.97 (m, 2H), 0.88 (m, 2H).

Synthetic example 60.

Synthesis of compound 62 diazatricyclo[7.4.0.02.6]trideca-1(13),9,11-trien-8-one.

Step A. 6-[3-[2-[1-(Trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridin-3 -carboxylic acid.

Oh Oh

To a mixture of 2-chloro-6-[3-[2-[ 1 -(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (1 g, 2.661 mmol) and (4S)-2, 2,4-trimethylpyrrolidine (hydrochloride salt) (620 mg, 4.143 mmol) in N-methylpyrrolidinone (5 ml) and 1,2-diethoxyethane (1 ml) was added potassium carbonate (1.8 g, 13.02 mmol).

- 150 040454

The suspension was heated at 125°C for 68 hours LC/MS showed 40% conversion. Added additional amount of (4S)-2,2,4-trimethylpyrrolidine (400 mg) and continued the reaction for 18 h at 135°C. The reaction suspension was cooled to room temperature and slowly added to a rapidly stirred solution of HCl (2 ml of a 6 M solution, 12.00 mmol) in ice (foaming!) to obtain a brown suspension. The suspension was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. The crude material was purified by silica chromatography using a gradient of hexane in ethyl acetate. The product was eluted with ~30% ethyl acetate. 6-[3-[2-[1-(Trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxylic acid (667.8 mg, 55%), ESI-MS m/z calc. 452.20352, found 453.0 (M+1)+; retention time: 1.87 min. 1H NMR (400 MHz, DMSO-d ₆ ) δ 12.68 (s, 1H), 8.24 (s, 1H), 7.92 (d, J=8.2 Hz, 1H), 6.86 ( dd, J=32.9, 7.9 Hz, 1H), 6.29-6.01 (m, 1H), 4.31 (s, 2H), 3.54 (s, 1H), 2.89 (s, 1H), 2.33 (s, 1H), 2.08 (s, 2H), 1.95 (s, 1H), 1.74-1.46 (m, 7H), 1.121.01 ( m, 3H), 0.92 (d, J=29.3 Hz, 4H).

Step B. (5S)-3,3,5-Trimethyl-12-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy}-1H-pyrazol-1-yl)7-oxa-2,13- diazatricyclo[7.4.0.02.6]trideca-1(13),9,11-trien-8-one.

6-[3-[2-[1-(Trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1yl]pyridine-3-carboxylic acid (50 mg, 0.1105 mmol), water (20 µl, 1.110 mmol), NaOAc (18 mg, 0.22 mmol) and [Ir{dF(CF3)ppy}2(dtbpy)]PF6 (4 mg, 0.003565 mmol) was dissolved in DMA (0.9 ml) and then the reaction mixture was placed under an illumination source, a 23 W compact fluorescent lamp (CFL) for 1.5 h. The reaction mixture was directly injected into a silica gel column without any purification. The crude mixture was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexanes to give (5S)-3,3,5-trimethyl-12-(3-{2-[1-(trifluoromethyl)cyclopropyl]ethoxy} 1H-pyrazol-1-yl)-7-oxa-2,13-diazatricyclo[7.4.0.02.6]trideca-1(13),9,11-trien-8-one (30.8 mg, 62%) , EER-MS m/z calc. 450.18787, found 451.3 (M+1) ⁺ ; retention time 2.35 min.

Synthetic example 61.

Synthesis of compound 63 ,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.

Step A. tert-Butyl-3-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methoxy]pyrazole-1-carboxylate.

A solution of (3-fluoro-1-bicyclo[1.1.1]pentanyl)methanol (0.27 g, 2.3 mmol), tert-butyl-3-hydroxypyrazole-1-carboxylate (0.46 g, 2.5 mmol) and triphenylphosphine (0.67 g, 2.6 mmol) in THF (12 ml) was cooled in an ice bath and isopropyl-N-isopropoxycarbonyliminocarbamate (0.50 ml, 2.6 mmol) was added slowly. The reaction mixture was allowed to slowly warm to room temperature and stirred for three days. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and evaporated under vacuum. The residue was purified by silica gel chromatography using 0-40% ethyl acetate in hexanes to give tert-butyl 3-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methoxy]pyrazole-1-carboxylate (0. 43 g, 66%). EER-MS m/z calc. 282.13797, found 283.3 (M+1) ⁺ ; retention time 0.65 min.

Step B. 3-[(3-Fluoro-1-bicyclo[1.1.1]pentanyl)methoxy]-1H-pyrazole.

A solution of tert-butyl 3-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methoxy]pyrazole-1-carboxylate (0.43 g, 1.523 mmol) and trifluoroacetic acid (587 µl, 7.62 mmol ) in dichloromethane (4 mL) was stirred for 5 h. 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 and evaporated to give 3-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methoxy]-1H-pyrazole (0.28 g, 100%). EER-MS m/z calc. 182.08554, found 183.1 (M+1) ⁺ ; retention time 0.39 min.

Step C. tert-Butyl-2-chloro-6-[3-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methoxy]pyrazole-1 - 151 040454 yl]pyridine-3-carboxylate

A mixture of 3-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methoxy]-1H-pyrazole (0.28 g, 1.5 mmol), tert-butyl 2,6-dichloropyridine-3-carboxylate (0 .38 g, 1.5 mmol), potassium carbonate (0.26 g, 1.9 mmol) and 1,4 diazabicyclo[2.2.2]octane (34 mg, 0.30 mmol) in DMSO (7.5 ml) stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine and water, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography using 0-5% methanol in dichloromethane to give tert-butyl-2-chloro-6-[3-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methoxy]pyrazole -1yl]pyridine-3-carboxylate (0.50 g, 85%). EER-MS m/z calc. 393.12555, found 394.2 (M+1) ⁺ ; retention time 0.86 min.

Step D. 2-Chloro-6-[3-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methoxy]pyrazol-1-yl]pyridine-3carboxylic acid.

tert-Butyl 2-chloro-6-[3-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methoxy]pyrazol-1-yl]pyridine3-carboxylate solution (0.50 g, 1.270 mmol) and trifluoroacetic acid (978 μl, 12.7 mmol) in dichloromethane (6 ml) was stirred for 15 h. The solvent was evaporated and the residue was dissolved in acetonitrile. The solvent was evaporated to give 2-chloro-6-[3-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (0.43 g, 100 %). EER-MS m/z calc. 337.06296, found 338.1 (M+1) ⁺ ; retention time 0.63 min. 1H NMR (400 MHz, chloroform-d) δ 8.43 (d, J=8.5 Hz, 1H), 8.39 (d, J=2.9 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 6.00 (d, J=2.8 Hz, 1H), 4.51 (s, 2H), 2.13 (d, J=2.6 Hz, 6H).

Step E. N-(Benzenesulfonyl)-2-chloro-6-[3-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methoxy]pyrazol-1yl]pyridine-3-carboxamide.

2-Chloro-6-[3-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (100mg, 0.3mmol) and carbonyldiimidazole (58 mg, 0.36 mmol) was combined in THF (1.5 ml) and stirred for 2 h. ) and the reaction mixture was stirred for another 16 h at room temperature. The reaction mixture was diluted with ethyl acetate and washed with 1 M citric acid solution, then with brine. The organic layer was separated, dried over sodium sulfate and evaporated to give N-(benzenesulfonyl)-2-chloro-6-[3-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methoxy]pyrazol-1-yl ]pyridine-3 carboxamide (190 mg, 135%). EER-MS m/z calc. 476.07214, found 4 7 7.2 (M+1) ⁺ ; retention time 0.69 min.

Step F. N-(Benzenesulfonyl)-6-[3-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methoxy]pyrazol-1-yl]-2[(4S)-2,2,4 -trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.

N-(Benzenesulfonyl)-2-chloro-6-[3-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methoxy]pyrazol-1yl]pyridine-3-carboxamide (140 mg, 0. 29 mmol), (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (131 mg, 0.88 mmol) and potassium carbonate (243 mg, 1.76 mmol) were combined in DMSO (1.5 ml) and heated at 130° C. for 16 hours. The reaction mixture was filtered and purified by LC/MS using a gradient of 30-99% acetonitrile and 5 mm aq. HCl, to give N-(benzenesulfonyl)-6-[3-[(3-fluoro-1bicyclo[1.1.1]pentanyl)methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4 -trimethylpyrrolidin-1-yl]pyridine-3carboxamide (89 mg, 54%). EER-MS m/z calc. 553.2159, found 554.4 (M+1)+; retention time 2.16 min. ¹ H NMR (400 MHz, DMSO^) δ 8.19 (d, J=2.8 Hz, 1H), 8.05-7.95 (m, 2H), 7.81 (d, J=8, 3 Hz, 1H),

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7.77-7.70 (m, 1H), 7.70-7.61 (m, 2H), 6.91 (d, J=8.2 Hz, 1H), 6.14 (d, J= 2.8 Hz, 1H), 4.47 (s, 2H), 2.45-2.36 (m, 1H), 2.31-2.22 (m, 1H), 2.15-2.08 (m, 7H), 1.82 (dd, J=11.9, 5.5 Hz, 1H), 1.52 (d, J=9.2 Hz, 6H), 1.36 (t, J= 12.1 Hz, 1H), 0.64 (d, J=6.2 Hz, 3H)

Synthetic example 62.

Synthesis of compound 64 yl]pyridine-3-carboxamide.

Step A. tert-Butyl-3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)-1H-pyrazole-1-carboxylate.

Dispiro[2.0.2.1]heptan-7-ylmethanol solution (1.36 g, 11.0 mmol) (Meijere, et al., Eur. J. Org. Chem. 2002, 485-492), t-butyl-3 -hydroxypyrazole-1-carboxylate (2.3 g, 12 mmol) and triphenylphosphine (3.2 g, 12 mmol) in THF (28 ml) were cooled in an ice bath and diisopropyl azodicarboxylate (DIAD) (2.4 ml, 12 mmol). 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 and evaporated under vacuum. The residue was purified by silica gel chromatography eluting with 0-20% ethyl acetate in hexanes to give t-butyl-3(dispiro[2.0.2.1]heptan-7-ylmethoxy)-1H-pyrazole-1-carboxylate (1.57 g , yield 49%) as a colorless oily substance. EER-MS m/z calc. 290.16306, found 291.3 (M+1)+; retention time 0.76 min.

Step B. 3-(Dispiro[2.0.2.1]heptan-7-ylmethoxy)-1H-pyrazole.

Solution of tert-butyl-3-(dispuro[2.0.2.1]heptan-7-ylmethoxy)-1H-pyrazol-1-carboxylate (1.57 g, 5.41 mmol) and trifluoroacetic acid (2.2 ml, 29 mmol ) in dichloromethane (20 mL) was stirred for 3 h. 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 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. EER-MS m/z calc. 190.11061, found 191.1 (M+1) ⁺ ; retention time 0.52 min.

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

ABOUT

A mixture of 3-(dispyro[2.0.2.1]heptan-7-ylmethoxy)-1H-pyrazol (0.94 g, 4.9 mmol), ethyl 2,6-dichloropyridine-3-carboxylate (1.15 g, 5.23 mmol), potassium carbonate (0.83 g, 6.0 mmol) and 1,4diazabicyclo[2.2.2]octane (0.12 g, 1.1 mmol) in DMSO (16 mL) were stirred for 24 h. the mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine and water, dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-20% ethyl acetate in hexanes to give ethyl 2-chloro-6-(3-(dispuro[2.0.2.1]heptan-7-ylmethoxy)-1H-pyrazol-1- yl) nicotinate (1.39 g, 75% yield) as a colorless solid. EER-MS m/z calc. 373.11932, found 374.2 (M+1)+; retention time 0.87 min. ¹ H NMR (400 MHz, chloroform-d) δ 8.36 (d, J=2.8 Hz, 1H), 8.27 (d, J=8.5 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 5.96 (d, J=2.9 Hz, 1H), 4.41 (c, 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)

Step D. 2-Chloro-6-[3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)pyrazol-1-yl]pyridine-3-carboxylic acid.

Ethyl 2-chloro-6-(3-(dispyro[2.0.2.1]heptan-7-ylmethoxy)-1H-pyrazol-1-yl)nicotinate solution (1.39 g,

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3.72 mmol) and sodium hydroxide (7.5 ml of a 1 M solution, 7.5 mmol) in THF (6 ml) and ethanol (3 ml) were stirred for 90 min. The 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 a 1 M solution, 7.5 mmol) was added slowly. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate 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. EER-MS m/z calc. 345.088, found 346.1 (M+1)+; retention time 0.73 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.41 (d, J=2.9 Hz, 1H), 8.38 (d, J=8.4 Hz, 1H), 7.73 (d , J=8.4 Hz, 1H), 6.19 (d, J=2.8 Hz, 1H), 4.27 (d, J=7.0 Hz, 2H), 1.93 (t, J \u003d 7.0 Hz, 1H), 0.97-0.79 (m, 4H), 0.76-0.66 (m, 2H), 0.65-0.56 (m, 2H)

Step E. N-(Benzenesulfonyl)-2-chloro-6-[3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)pyrazol-1yl]pyridine-3-carboxamide.

A solution of 2-chloro-6-[3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (0.10 g, 0.29 mmol) and carbonyldiimidazole (0 06 g, 0.4 mmol) in THF (1.4 ml) was stirred for 45 min and benzenesulfonamide (55 mg, 0.35 mmol) and 1,8-diazabicyclo(5.4.0)undec-7-ene were added (DBU) (130 µl, 0.87 mmol). After 15 hours, the reaction mixture was diluted with 1M aqueous citric acid and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and evaporated to give crude N-(benzenesulfonyl)-2chloro-6-[3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)pyrazol-1-yl]pyridin- 3-carboxamide (0.16 g), which was used as such in the next step. EER-MS m/z calc. 484.0972, found 485.2 (M+1) ⁺ ; retention time 0.81 min.

Step F. N-(Benzenesulfonyl)-6-[3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)pyrazol-1-yl]-2-[(4S)2,2,4-trimethylpyrrolidin-1- yl]pyridine-3-carboxamide.

A mixture of N-(benzenesulfonyl)-2-chloro-6-[3-(dispuro[2.0.2.1]heptan-7-ylmethoxy)pyrazol-1-yl]pyridine3-carboxamide (0.14 g, 0.29 mmol), (4S)-2,2,4-trimethylpyrrolidine hydrochloride (0.14 g, 0.94 mmol) and potassium carbonate (0.24 g, 1.7 mmol) in NMP (1.3 ml) was stirred at 130°C for 15 hours. The reaction mixture was filtered and purified by reverse phase HPLC-MS using a double chromatography gradient of 30-99% acetonitrile in 5 mM aqueous HCl. N-(benzenesulfonyl)6-[3-(dispiro[2.0.2.1]heptan-7-ylmethoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl] was obtained pyridine3-carboxamide (65 mg, 40% yield). EER-MS m/z calc. 561.24097, found 562.3 (M+1)+; retention time 2.35 min.

Synthetic example 63.

Synthesis of compound 65

Step A: tert-Butyl-3-((1-ethylcyclopropyl)methoxy)-1H-pyrazole-1-carboxylate.

SK th DIAD, Ph ₃ P. THF / x G NBoc from O ° C to room O ^. ^ N t-ry, then 50 ° C T_ NBoo

To a solution of (1-ethylcyclopropyl)methanol (1.68 g, 16.73 mmol), tert-butyl-2,3-dihydro-3oxopyrazole-1-carboxylate (2.80 g, 15.21 mmol) and triphenylphosphine (4 .39 g, 16.73 mmol) in tetrahydrofuran (40 ml) at 0° C. diisopropyl azodicarboxylate (3.38 g, 16.73 mmol) was added dropwise. The reaction mixture was warmed to room temperature, then heated at 50° C. for 21 hours. The reaction solution was cooled to room temperature and ethyl acetate (500 ml) was added. The organic layer was washed with 0.3 M aqueous sodium hydroxide solution (100 ml), brine (2x50 ml) and dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient method from 0 to 80% hexanes in dichloromethane to give

- 154 040454 I eat tert-butyl 3-((1-ethylcyclopropyl)methoxy)-1H-pyrazole-1-carboxylate (1.73 g, 43%) as a yellow oily substance. EER-MS m/z calc. 266.2, found 267.3 (M+1)+. Retention time 3.47 min. 1H NMR (250 MHz, CDCl ₃ ) δ (ppm): 7.82 (d, J=2.5 Hz, 1H), 5.88 (d, J=2.5 Hz, 1H), 4 .09 (s, 2H), 1.60 (s, 9H), 1.48 (k, J=7.5 Hz, 2H), 0.94 (t, J=7.5 Hz, 3H), 0 .49 (m, 2H), 0.42 (m, 2H).

Step B. 3-((1-Ethylcyclopropyl)methoxy)-1H-pyrazole.

A solution of 4 M hydrogen chloride in 1,4-dioxane (65 mL) was added to tert-butyl 3-((1ethylcyclopropyl)methoxy)-1H-pyrazole-1-carboxylate (1.73 g, 6.49 mmol) and the reaction mixture was stirred. solution at room temperature for 16 hours and concentrated to dryness to give crude 3-((1-ethylcyclopropyl)methoxy)-1H-pyrazole as an oil, which was used directly in the next step. EER-MS m/z calc. 16 6.1, found 167.3 (M+1) ⁺ . Retention time 0.60 min.

Step C. Methyl 2-chloro-6-(3-((1-ethylcyclopropyl)methoxy)-1H-pyrazol-1-yl)nicotinate.

3-((1-Ethylcyclopropyl)methoxy)-1H-pyrazole (6.49 mmol) and methyl-2,6-dichloronicotinate (1.81 g, 8 mmol) were added to dimethylformamide (20 ml). Potassium carbonate (2.8 g, 20 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.167 g, 1.5 mmol) were added to the reaction mixture and allowed to stir at room temperature for 16 h. The reaction mixture was diluted water (60 ml) and extracted with diethyl ether (3x60 ml). The combined organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was flash chromatographed on silica gel using a gradient method of 0 to 100% hexanes in dichloromethane to give methyl 2-chloro-6-(3-((1ethylcyclopropyl)methoxy)-1H-pyrazol-1-yl)nicotinate ( 1.7 g, 77%) as a white solid. EER-MS m/z calc. 335.10, found 336.5 (M+1) ⁺ . Retention time 4.29 min. 1H NMR (250 MHz,

DMSO) δ (ppm): 8.43 (d, J=2.8 Hz, 1H), 8.41 (d, J=8.4 Hz, 1H), 7.74 (d, J= 8.4 Hz, 1H), 6.23 (d, J=2.8 Hz, 1H),

4.08 (s, 2H), 3.88 (s, 3H), 1.44 (k, J=7.4 Hz, 2H), 0.93 (t, J=7.4 Hz, 3H), 0.53 (m, 2H), 0.42 (m, 2H).

Step D. 2-Chloro-6-(3-((1-ethylcyclopropyl)methoxy)-1H-pyrazol-1-yl)nicotinic acid.

Methyl 2-chloro-6-(3-((1-ethylcyclopropyl)methoxy)-1H-pyrazol-1-yl)nicotinate (1.7 g, 50 mmol) was added to an ice-cold round bottom flask with tetrahydrofuran (5 ml ) and methanol (5 ml). Sodium hydroxide (0.4 g, 10 mmol) in water (5 ml) was added slowly, and the reaction solution was stirred at room temperature for 5 hours. The resulting reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran and acidified with 1N HCl. aqueous solution of hydrogen chloride to pH=1 in an ice bath. The resulting white solid was filtered off to give 2-chloro-6-(3-((1-ethylcyclopropyl)methoxy)-1H-pyrazol-1-yl)nicotinic acid (1.54 g, 95.0%). IERMS m/z calc. 321.09, found 322.2 (M+1) ⁺ , retention time: 3.59 min. 1H NMR (250 MHz, DMSO) δ (ppm): 8.43 (d, J=2.8 Hz, 1H), 8.42 (d, J=8.4 Hz, 1 H), 7 .72 (d, J=8.4 Hz, 1H), 6.24 (d, J=2.8 Hz, 1H), 4.09 (s, 2H), 1.45 (c, J=7, 4 Hz, 2H), 0.92 (t, J=7.4 Hz, 3H), 0.54 (m, 2H), 0.44 (m, 2H).

Step E. N-(Benzenesulfonyl)-2-chloro-6-[3-[(1-ethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine3-carboxamide.

2-Chloro-6-[3-[(1-ethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (157 mg, 0.4879 mmol) and carbonyldiimidazole (100 mg, 0.6167 mmol) were combined in THF (2 ml) and stirred for 2 hours. At this time, benzenesulfonamide (77 mg, 0.4899 mmol) was added, then DBU (243 μl,

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1.625 mmol) and the reaction mixture was stirred for another 30 min at room temperature. The reaction mixture was diluted with ethyl acetate and washed with 1 M citric acid solution, then with brine. The organic layer was separated, dried over sodium sulfate and evaporated to give crude N-(benzenesulfonyl)-2-chloro-6-[3-[(1-ethylcyclopropyl)methoxy]pyrazol-1yl]pyridine-3-carboxamide (224 mg, 100%). EER-MS m/z calc. 460.0972, found 461.1 (M+1)+; retention time 0.75 min.

Step F N-(Benzenesulfonyl)-2-chloro-6-(3-hydroxypyrazol-1-yl)pyridine-3-carboxamide.

N-(Benzenesulfonyl)-2-chloro-6-[3-[(1-ethylcyclopropyl)methoxy]pyridine-3carboxamide (224 mg, 100%) was dissolved in dichloromethane (2 ml) with TFA (1 ml, 12.98 mmol) and the reaction mixture was stirred for 4 h. , 74%). EER-MS m/z calc. 378.01895, found 379.1 (M+1) ⁺ ; retention time 0.54 min.

Step G N-(benzenesulfonyl)-6-(3-hydroxypyrazol-1-yl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1yl]pyridine-3-carboxamide.

N-(Benzenesulfonyl)-2-chloro-6-(3-hydroxypyrazol-1-yl)pyridine-3-carboxamide (100 mg, 0.26 mmol), (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt ) (110 mg, 0.76 mmol) and potassium carbonate (180 mg, 1.3 mmol) were combined in DMSO (0.5 ml) and heated at 130°C for 16 h. The reaction mixture was diluted with water (3 ml) and stirred for 20 min. A solid formed and the aqueous liquid was decanted. The solid was dissolved in ethyl acetate and washed with 1 M citric acid solution, then with brine. The organic layer was dried over sodium sulfate and evaporated. The crude material was purified by silica gel chromatography eluting with 010% methanol in dichloromethane to give N-(benzenesulfonyl)-6-(3-hydroxypyrazol-1-yl)2-[(4S)-2,2,4-trimethylpyrrolidin-1 -yl]pyridine-3-carboxamide (4.6 mg, 4%). EER-MS m/z calc. 455.16272, found 456.3 (M+1) ⁺ ; retention time 1.50 min.

Example 5 Analyzes and Data 5A.

An assay to detect and measure the properties of F508del-CFTR modulator compounds.

Optical methods for analyzing the properties of F508del-CFTR modulators using membrane potential.

This assay uses fluorescent voltage sensitive dyes to measure changes in membrane potential with a fluorescent plate reader (eg, FLIPR III, Molecular Devices, Inc.) as a read parameter for the increase in functional F508del in NIH 3T3 cells. The driving force for the response is the formation of a chloride ion gradient coupled with channel activation and concurrently with compound treatment through a single liquid addition step after cell prestaining with voltage sensitive dye.

5A-A1. Identification of F508del-CFTR modulators.

To identify F508del modulators, a fluorescence assay was developed in the High Throughput Screening (HTS) format. In this HTS assay, fluorescent voltage sensitive dyes were used to measure changes in membrane potential on FLIPR III as a measure of the increase in transmission (conductivity) of NIH 3T3 cells with F508del. The driving force for the response is the formation of a chloride ion gradient in combination with channel activation and concurrently with compound treatment through a single liquid addition step after cell prestaining with voltage sensitive dye. Data for compounds 1-65 obtained using the method described in this document are summarized below in table. 6. For example, in the method described, Compound 1 exhibited an EC ₅₀ of less than 3 μM and a % efficiency >100% compared to Compound II.

Solutions.

Bath solution #1: (in mM) NaCl 160, KCl 4.5, CaCl ₂ 2, MgCl ₂ 1, HEPES 10, pH 7.4 with NaOH, glucose 10.

Chloride Free Bath Solution: The chloride salts in Bath Solution #1 (described above) were replaced with gluconate salts.

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Cell culture.

For optical measurements of membrane potential, NIH3T3 mouse fibroblasts stably expressing F508del were used. Cells were maintained at 37° C. in 5% CO2 at 90% humidity in Dulbecco's Modified Eagle's Medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 X NEAA, β-ME, 1 X penicillin/streptavidin and 25 mM HEPES in 175 cm ² culture flasks. For all optical assays, cells were seeded at a density of 12,000 cells/well in 384-well Matrigel coated plates and grown for 18-24 hours at 37° C. for potentiator assay. For correction assays, cells were grown at 37°C with and without addition of compounds for 18-24 h.

Electrophysiological assays to evaluate the properties of F508del modulator compounds.

Analysis in the Ussing chamber.

Ussing chamber experiments were performed on polarized airway epithelial cells expressing F508del to further characterize the F508del modulators identified in optical analyses. Airway epithelium not affected by cystic fibrosis (Non-CF) and affected by cystic fibrosis (CF) was isolated from bronchial tissue, grown as described previously (Galietta, L.J.V., Lantero, S., Gazzolo, A., Sacco, 0., Romano, L., Rossi, G.A., & ZegarraMoran, 0. (1998) In Vitro Cell Dev Biol 34, 478-481) and placed on Costar® Snapwell™ filters pre-coated with NIH3T3 conditioned media. After four days, the apical medium was removed and the cells were grown at the air/liquid interface for >14 days before further use. As a result, a monolayer of fully differentiated cylindrical cells was obtained, which were provided with cilia characteristic of the epithelium of the respiratory tract. Non-CF HBE cells were taken from non-smokers with no known lung disease. CFHBE cells were taken from patients homozygous for F508del or compound heterozygous for F508del with a different disease causing mutation in a different allele.

HBE were grown on Costar® Snapwell™ cell culture inserts inserted into a Ussing chamber (Physiologic Instruments, Inc., San Diego, CA) and trans-epithelial resistance and short circuit current were measured in the presence of a basolateral-apical Cl ⁻ (I _sc ) using a potential clamp system (Department of Bioengineering, University of Iowa, Iowa). Briefly, HBE was studied under potential clamp recording conditions (V _ho i _d =0 mV) at 37°C. The basolateral solution contained (in mM) 145 NaCl, 0.83 K2HPO4, 3.3 KH ₂ PO ₄ , 1.2 MgCl ₂ , 1.2 CaCl ₂ , 10 glucose, 10 HEPES (pH adjusted to 7.35 with NaOH ), and the apical solution contained (in mM) 145 Na gluconate, 1.2 MgCl ₂ , 1.2 CaCl ₂ , 10 glucose, 10 HEPES (pH adjusted to 7.35 with NaOH).

5A-A2. Identification of F508del-CFTR modulators.

The standard technique uses a concentration gradient of Cl ^- from the basolateral membrane to the apical membrane. To adjust this gradient, normal Ringer's solution was used on the basolateral membrane, and NaCl was replaced on the apical membrane with an equimolar amount of sodium gluconate (titrated to pH 7.4 with NaOH) to obtain a large concentration gradient of Cl ^- through the epithelium. Modulators were added either from the basolateral side 18-24 hours before the analysis, or from the apical side during the analysis. During analysis, forskolin (10 mM) was added from the apical side to stimulate CFTR-mediated Cl ^- transport.

Registration of values by the patch-clamp method.

Total ^Cl current in F508del-NIH3T3 cells was monitored using the perforated membrane recording system described previously (Rae, J., Cooper, K., Gates, P., & Watsky, M. (1991) J. Neurosci. Methods 37 , 15-26). Clamped data recording was performed at 22° C. using an Axopatch 200B patch clamp amplifier (Axon Instruments Inc., Foster City, CA). The pipette solution contained (in mM) 150 N-methyl-D-glucamine (NMDG)-Cl, 2 MgCl ₂ , 2 CaCl ₂ , 10 EGTA, 10 HEPES and 240 μg/ml amphotericin-B (pH adjusted to 7.35 with HCl). The extracellular medium contained (in mM) 150 NMDG-C1, 2 MgCl ₂ , 2 CaCl ₂ , 10 HEPES (pH adjusted to 7.35 with HCl). Pulse generation, data acquisition, and analysis were performed using a PC equipped with a Digidata 1320 A/D interface in combination with Clampex 8 (Axon Instruments Inc.). To activate F508del, 10 μM forskolin and 20 μM genistein were added to the bath, and the relationship between current and voltage was read every 30 s.

5A-A3. Identification of F508del-CFTR modulators.

The ability of F508del-CFTR modulators to increase the macroscopic current of Cl ^- F508del (I _F508del ) in NIH3T3 cells stably expressing F508del was also studied using perforated membrane reading technology. Modulators identified based on optical assays caused a dose-dependent increase in IA _F505 with the same potency and efficacy as observed in optical assays.

Cell culture.

Whole cell readings were performed using NIH3T3 mouse fibroblasts stably expressing F508del. Cells were maintained at 37°C in an atmosphere of 5% CO2 and 90% humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine

- 157 040454 serum, 1 X NEAA, β-ME, 1 X penicillin/streptavidin and 25 mm HEPES in culture flasks with a volume of 175 cm ² . To read whole cells, 2500-5000 cells were seeded on glass coverslips coated with poly-L-lysine and grown for 18-24 hours in the presence or absence of modulators at 37°C.

Data recording for one channel.

Gating activity of F508del-CFTR expressed in NIH3T3 cells after treatment with the modulator was monitored by recording data on an excised and everted membrane flap as previously described (Dalemans, W., Barbry, P., Champigny, G., Jallat, S. , Dott, K., Dreyer, D., Crystal, RG, Pavirani, A., Lecocq, JP., Lazdunski, M. (1991) Nature 354, 526-528) using an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc.). The pipette contained (in mM): 150 NMDG, 150 aspartic acid, 5 CaCl ₂ , 2 MgCl ₂ and 10 HEPES (pH ADJUSTED TO 7.35 with Tris base). The bath contained (in mM): 150 NMDG-C1, 2 MgCl ₂ , 5 EGTA, 10 TES and 14 Tris bases (pH ADJUSTED TO 7.35 with HCl). After excision, wild-type and F508del samples were activated by the addition of 1 mM MdATP, 75 nM cAMP-dependent protein kinase catalytic subunit (PKA; Promega Corp., Madison, Wisconsin), and 10 mM NaF to inhibit protein phosphatases that interfere with current cycling. The pipette potential was maintained at 80 mV.

Channel activity was analyzed based on membrane flaps containing <2 active channels. The maximum number of simultaneously opening channels determines the number of active channels during the experiment. To determine the amplitude of the current in one channel, the data recorded during the 120 s measurement of F508del activity was filtered offline at 100 Hz and then used to plot amplitude histograms at all points, which were approximated to multi-Gaussian functions using the Bio-Patch Analysis software ( Bio-Logic Comp. France). The total microscopic current and the probability of opening (P _o ) were determined from the channel activity for 120 s. P _about was determined using software Bio-Patch or by the ratio P ₀ =I/i (N), where 1=average current, i=current amplitude in one channel, and N=number of active channels in the flap.

Cell culture.

Mouse fibroblasts NIH3T3 stably expressing F508del were used to read the patch clamps of the excised membrane. The cells were kept at 37°C in an atmosphere with 5% CO ₂ and a humidity of 90% in Eagle's medium, modified according to the method of Dulbecco, with the addition of 2 mm glutamine, 10% fetal bovine serum, 1 X NEAA, β-ME, 1 X penicillin / streptavidin and 25 mm HEPES in culture flasks with a volume of 175 cm ² . To read data from one channel, 2500-5000 cells were seeded on glass cover slips coated with poly-L-lysine and grown for 18-24 h in the presence or absence of modulators at 37°C.

5V. Chromatographic determination of human serum albumin (HSA).

Analysis.

Chromatographic determination of human serum albumin (HSA) was performed on an UPLC-MS system using a ChiralPak® HSA column (article number: 58469AST) manufactured by Sigma Aldrich. Mobile phase A consisted of 50 mM ammonium acetate buffer in water adjusted to pH=7.4 and mobile phase B was 2-propanol. The column compartment was maintained at a constant temperature of 30°C. Determination of the retention time on the HAS column was performed by injecting 3 ml of a 0.5 mM solution of the compound (in DMSO) using a linear gradient from 0 to 30% B over 2.5 min, then holding at 30% B for 2 min, and finally the equilibrate step from 30 to 0% B in 1.5 min, and the total chromatogram recording time was 6 min. The flow rate throughout the gradient was kept constant and set to 1.8 ml/min. Compound retention time on the HSA column was converted to %HSA values according to a previously published methodology (Valko, et. al., 2003) that correlates column retention time with standard plasma protein binding (PPB) values obtained from dialysis experiments. HSA data for some compounds are summarized in Table 1 below. 8.

Valko, K., Nunhuck, S., Bevan, C, Abraham, M. H., Reynolds, D. P. Fast Gradient HPLC Method to Determine Compounds Binding to Human Serum Albumin. Relationships with Octanol/Water and Immobilized Artificial Membrane Lipophilicity. J. of Pharm. sci. 2003, 92, 2236-2248.

5C. Experimental Protocol for IV and RO PK Tests in Rats.

The experimental compound was administered to male Sprague-Dawley rats as a single nominal intravenous dose of 3.0 mg/kg as a solution in 10% NMP, 10% Solutol, 15% EtOH, 35% PEG400 and 30% D5W. The experimental compound was also administered to male Sprague-Dawley rats as a single nominal oral dose of 3 mg/kg as a solution in 5% NMP, 30% PEG400, 10% TPGS, 5% PVP-K30 in a dose volume of 5 ml/kg. Plasma and dose preparation analyzes were performed by LC/MS/MS.

Time-dependence profiles of plasma concentrations of experimental compounds in Sprague-Dawley rats at the scheduled (nominal) time of sample collection were analyzed using non-compartmental pharmacokinetic methods using the PK function in the software.

- 158 040454 Watson LIMS version 7.4.2 (Thermo Scientific Inc, Waltham, MA). AUC values were calculated using the linear trapezoidal rule.

5D. Experimental protocol for PXR analysis.

The propensity for PXR-mediated CYP3A4 induction was assessed using the DPX-2 cell line in vitro. This cell line, used under license from Puracyp Inc., was derived from HepG2 cells and stably transfected with genes encoding human PXR, as well as a modified luciferase reporter associated with the CYP3A4 promoter region and appropriate distal and proximal enhancers.

The assay was run in a 384-well format and each test compound was administered at 11 doses from 0.1 to 60 μM. On day 1, DPX-2 cells, which had previously been expanded and cryopreserved in their laboratory, were thawed and plated on tissue culture plates. The next day, medium was changed and cells were grown in medium containing test compound, vehicle control, or a positive control compound, the clinically proven CYP3A4 inducer rifampicin. Cells were grown in the presence of test compound for 48 hours and then cell viability was assessed by fluorescent assay (Cell Titer-Fluor, Promega) using an EnVision plate reader (PerkinElmer). CYP3A4 transactivation, which is proportional to luciferase activity, was then measured by reading luminescence on a Promega OneGlo reagent system using the same plate reader.

Data processing using the Genedata software package provides the ability to determine the maximum fold induction compared to the control vehicle, the EC ₅₀ value for CYP3A4 inducers and the construction of an 11-point dose-response curve. Wells with cell viability less than 70% were not used for the assay, and no plates were recorded in which the response of the positive control rifampicin was outside the expected range, either in potency or maximum fold induction.

5E. CFTR data for compounds 1-65.

Compounds of formula (I) are useful as modulators of CFTR activity. In the table below. 6 shows the values of the EU ₅₀ for the compounds listed in the table. 6 obtained using the methods described above (assay described above in Example 5A-A1). In the table below. 6, the following designations are used:

EC ₅₀ : +++ means < 0.1 μM; + + means from 0.1 μM to 1 μM; + means more than 1 µM.

- 159 040454

Table 6. CFTR activity

connection no. EC50 CFTRdF508 (µM) 1 + + + 2 ++ 3 + + + 4 + + + 5 + + + 6 neither ^a 7 neither ^a 8 +++ 9 ++ 10 +++ eleven ++ 12 +++ 13 ++ 14 +++ 15 +++ 16 +++ 17 +++ 18 ++ 19 ++ 20 ++ 21 +++ 22 ++ 23 +++ 24 +++ 25 +++ 26 + 27 ++

- 160 040454

- 161 040454

62 + 63 ++ 64 + + + 65 +

^a : not measured. 5F

Metabolites.

Compound 1 has been found to be metabolized in vitro and in vivo, mainly through oxidative metabolism. Received and investigated the connection 1 and its metabolites presented in the following table.

Table 7. Data for metabolites

Metabolite EC50 CFTRdF5 08 (µM) Deuterated metabolite analogue Compound 1 (parent compound) _F OOO 0.03 Compound 17 ⁰ 0. .0 \| \=/_ Compound 38 U °' ⁰ , ΌΛ'Ό BUT Ο-//Ν Ν N F-)-/ F Δ 0.24 Connection 7 ° ° XX A X CT / 2 _H Compound 62 >30

- 162040454

5G. Acylsulfoxamides.

Compounds containing an acylsulfoxamide moiety (i.e., a sulfonimidoylamide moiety where X in formulas I or II is selected from substituted or unsubstituted amines) have been found to provide reduced binding to human serum albumin and increased free fraction compared to compounds containing an acylsulfonamide moiety. a group (i.e. where X in formulas I or II is selected from O). Human serum albumin (HAS) was measured as described in Example 5B above. A decrease in the binding of human serum albumin can lead to an increase in the content of free (unbound) drug compound, which can affect biological activity.

- 163 040454

Table 8. HSA data

In the table below. 8 summarizes CFTR activity (CFTR dF508 EC ₅ o ), maximum PXR induction, IV rat clearance, rat PO AUC, and data for rat PO administration of some of the compounds described above.

Table 9. Comparative data

Maxi Clear AUC maln NS at %F at CFTR and I at ro No. dF508 induction iv enter ro connect Connections EU50 tion enter research institute introduced eniya (µM) PXR research institute rat AI rats (% of rat m reefs m (mcg.

- 164 040454

picin a) (ml/m in. / To G) hours / ml at dose 3 mg/kg a Connect A 0 0 o nh ₂ ^z \=/ 0.06 2 17.8 1.2 ^a 28% Connection B X LX O 0.12 9 29.2 Connection C ⁰ 0 0 0 0.26 3 Connection D 0 ^s S-ζ >o O ¹⁼ T ° F _/ / 'o 0.4 20 Compound E 0 0 .0 NR <χΑ _Ν - ^δ γ^ι ν 1 ¥ ⁿ 11 a ⁰ \d 0.21 10

- 165 040454

Connect enenie 49 ^x o 7 o xt ° FF ' XL ° ^F /\ 0.02 19 Connect 4 °o.Y) 0.02 4 Connection 15 ο 0 0 I . .yv y 0.02 0 Connection 16 ⁰ 0..0 , Ν \j Dd 0.02 2 24.8 0.25 12% Connect 1 _F LLC DDR 0.03 3 1.6 21 63%

- 166 040454

Connection 50 OOO 0.03 32 Connection 23 0.03 22 2.7 12.5 69% Connection 28 A ⁰ 0.0 0.03 17 Connection 31 rd ⁰ °. 9 0.03 7 Connection 14 G OOO 0.04 19 2.0 14.7 58% Connection 53 4 HA? ίΝ D/ 0.04 39 2.3 13.7 98%

- 167 040454

Connection 10 ⁰ 0. 0 mF ^F F 0.04 6 11.2 2.2 41% Connection 32 o o jq 0.04 4 Connection 51 OOO ⁰ VJ .ί/s) 0.05 17 5.2 10.5 100% Connection 55 ^{0 0} λ 9 Φ'ν'έ ^α 'νΑ _-- 0.05 22 Connect 5 ° ° jOl IX/ /~s fS= 0.05 0 9, 6 2.7 50% Connection 58 ⁰ 0 0 wXO&i ^f < _f 4Л F / 0.05 4

- 168 040454

Connection 64 ⁰ 9..° l N 0.05 4 3.4 9b 79% Connection 43 0 0 0 ci V N 14¾ 0.05 12 Connection 42 ⁰ 9° 0.05 3 5.4 4, 4b 51% Connection 41 ⁰⁹⁹ 0.07 6 19 6.4 41% Connection 24 ⁰ about. .0 0.07 9 2, 6 20 98% Connection 37 ⁰ 0 0 ,Jo 0.07 8

- 169 040454

Connection 39 ⁰ 0. .0 0.07 13 Connection 30 ⁰ 0. .0 0.09 0 6.1 2.3 26% Connection 57 ⁰ 0. .0 F / 0.08 2 Connection 13 - O Oh D. _ o^=z r* A. 2—/ V 0.11 2 Connection 33 ⁰ 0 0 V A 0.08 0 Connection 40 θ 0..0 to > Χύ’Ό 6 b 0.08 2

- 170040454

Connection 27 °0, .0 0.27 8 3.6 20.3 100% Connection 44 _Ν rf* ° F °^ ^Ν O YES· 0.62 18 5.0 8.5 81% Connection 22 Ooo %N 0.12 4 6.7 3.6 31%

^a : 10 mg/kg for compound A and 3 mg/kg for other compounds

Example 6 Chloride Transfer Experiments

In one experiment in a Ussing chamber with F508del/F508del-HBE cells, Compound 1 enhanced chloride transport. The effect of compound 1 on chloride transport was additive with that of compound II. In addition, F508delCFTR delivered to the cell surface with pure compound 1 or in combination with compound II was potentiated with compound III. The ternary combination of compound 1/compound II/compound III provided an excellent (about 3-fold) increase in chloride transfer compared to 3 double schemes in most conditions tested.

Example 7 F508delCFTR processing and directed migration experiments in vitro.

In vitro, compound 1 improved the processing and targeted migration of F508delCFTR by increasing the amount of functional F508delCFTR protein on the cell surface. The CFTR protein delivered to the cell surface with Compound 1 alone or in combination with Compound II (Compound 1/Compound II) was potentiated with Compound III. In human bronchial epithelial cells (HBE) tested in vitro, the triple combination of Compound 1, Compound II, and Compound III (Compound 1/Compound 11/Compound III) increased CFTR chloride transport more effectively than either of the dual combinations (Compound 1/Compound III). II, Compound 1/Compound III and Compound II/Compound III) or individual components (Compound 1, Compound II and Compound III) under most conditions tested.

The processing and directed migration of F508delCFTR was directly controlled by the appearance of the 170-180 kDa band. As a result of this observation, compound 1 was found to be a CFTR corrector as it promotes the processing and directed migration of F508delCFTR to increase the amount of functional F508delCFTR on the cell surface.

Incubation of F508del/F508del-HBE cells for 16-24 h with 1 μM of pure compound 1 or in combination with 3 μM of compound II led to an increase in steady-state concentrations reaching 6.5-fold and 18.7-fold values compared with samples without treatment respectively.

Other Implementations

The foregoing description presents and describes only illustrative embodiments of the present invention. Based on the foregoing description, the accompanying drawings, and the claims, those skilled in the art will appreciate that various changes, modifications, and variations may be made thereto without departing from the spirit and scope of this description as defined in the appended claims.

Claims (66)

CLAIM 1. The compound of formula I, its pharmaceutically acceptable salt or their deuterated derivative, where one of Y ¹ and Y ² is N and the other is CH; X is selected from O, NH and N(C1-C ₄ alkyl) group; R ¹ is -(CR ₂ ) _k -O-(CR ₂ ) _m (CR) _n (Ring A) _n+1 , where each Ring A is a C3-C10 cycloalkyl group optionally substituted with one or more substituents, each wherein each R is independently selected from a C1-C2 alkyl group, a halogenated C1-C2 alkyl group, and halogen, and wherein each R is independently selected from H, OH, and a C1-C2 alkyl group optionally substituted with one or more halogen atoms; each R ² is independently selected from C1-C2 alkyl, OH, C1-C2 alkoxy, halo, and cyano; each R3 is independently selected from a C1-C2 alkyl group optionally substituted with one or more OH groups; each R ⁴ is independently selected from a halogen atom; k is 0 or 1; r is 0 or 1; m is 0, 1, 2 or 3; n is 0 or 1; p is 0, 1, 2, 3, 4 or 5; and q is 0, 1, 2, 3, 4, 5, 6, 7, or 8. 2. The compound of formula II, its pharmaceutically acceptable salt or their deuterated derivative, where X is selected from O, NH and N(C ₁ -C ₄ alkyl) groups; R ¹ is -(CR ₂ ) _k -O-(CR ₂ ) _m (CR) _n (Ring A) _n+1 , where each Ring A is a C3-C10 cycloalkyl group optionally substituted with one or more substituents, each wherein each R is independently selected from a C1-C2 alkyl group, a halogenated C1-C2 alkyl group, and halogen, and wherein each R is independently selected from H, OH, and a C1-C2 alkyl group optionally substituted with one or more halogen atoms; each R ² is independently selected from C1-C2 alkyl, OH, C1-C2 alkoxy, halo, and cyano; each R ³ is independently selected from a C1-C2 alkyl group optionally substituted with one or more OH groups; each R ⁴ is independently selected from a halogen atom; k is 0 or 1; r is 0 or 1; m is 0, 1, 2 or 3; n is 0 or 1; p is 0, 1, 2, 3, 4 or 5; and q is 0, 1, 2, 3, 4, 5, 6, 7, or 8. - 172 040454 3. The compound of formula III, its pharmaceutically acceptable salt, or their deuterated derivative, where R ¹ is selected from the groups - (CR ₂ ) _k -O-(CR ₂ ) _m (CR) _n (Ring A) _n+1 where each Ring A is independently selected from a C ₃ -C ₁₀ cycloalkyl group optionally substituted with one or more substituents each independently selected from a C1-C2 alkyl group, a halogenated C1- _C2 alkyl group and halogen atoms, and where each R is independently selected from H, OH and a C1-C2 alkyl group optionally substituted with one or more halogen atoms ; each R ² is independently selected from C1-C2 alkyl, OH, C1-C2 alkoxy, halo, and cyano; each R ³ is independently selected from a C1-C2 alkyl group optionally substituted with one or more OH groups; each R ⁴ is independently selected from halogen atoms; k is 0 or 1; r is 0 or 1; m is 0, 1, 2 or 3; n is 0 or 1; p is 0, 1, 2, 3, 4 or 5; and q is 0, 1, 2, 3, 4, 5, 6, 7, or 8. 4. A compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein if R ² is cyano, said R ² is meta or para relative to the sulfur atom. 5. The compound according to any one of claims 1-3, its pharmaceutically acceptable salt or their deuterated derivative, where: each Ring A is a C ₃ -C ₁₀ cycloalkyl group optionally substituted with one or more substituents each independently selected from a C 1 -C 2 alkyl group, a halogenated C 1 -C 2 alkyl group, and halogen atoms, and each R is independently selected from H and HE; each R ² is independently selected from a C1-C2 alkyl group, OH, a C1-C2 alkoxy group, and halo; R ⁴ is F; k is 0; p is 0, 1 or 2; q is 0, 1, 2, 3 or 4; r is 0 or 1; and moreover, m and n are not equal to 0 at the same time. 6. The compound according to claim 5, its pharmaceutically acceptable salt or their deuterated derivative, where R ¹ is -O-(CR ₂ ) m-Ring A, where Ring A is a C ₃ -C ₁₀ cycloalkyl group optionally substituted with one or more substituents each independently selected from a C ₁ -C ₂ alkyl group, a halogenated C1-C2 alkyl group and halogen atoms, and m is 1 or 2. 7. A compound according to claim 6, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein each R ³ is a methyl group and q is 3 or 4. 8. Compound according to claim 7 having the formula IV Ring A' - 173 040454 its pharmaceutically acceptable salt, or their deuterated derivative, where Ring A is a C3-C10 cycloalkyl group optionally substituted with one or more substituents each independently selected from a C1-C2 alkyl group, a halogenated C1-C2 alkyl group, and halogen atoms; and each R2 is independently selected from C1-C2 alkyl, OH, F, Cl, and C1-C2 alkoxy; m is 1 or 2; and p is 0, 1, or 2. 9. The compound or salt thereof according to claim 8, where p is 0 or 1. 10. The compound or salt thereof according to claim 8, where p is equal to 0. 11. The compound according to claim 8, having the formula V its pharmaceutically acceptable salt, or their deuterated derivative, where Ring A is a C3-C10 cycloalkyl group optionally substituted with one or more substituents each independently selected from a C ₁ -C ₂ alkyl group, a halogenated C ₁ -C ₂ alkyl group, and halogen atoms; and each R ² is independently selected from C1-C2 alkyl, OH, F, Cl, and C1-C2 alkoxy; m is 1 or 2; and p is 0, 1, or 2. 12. A compound according to any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein each R ² is independently selected from CH3, OH, F, and OCH3. 13. A compound according to claim 12, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein p is 0 or 1. 14. A compound according to claim 13, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein p is 0. 15. A compound according to claim 11, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein Ring A is a cyclopropyl group substituted with a halogenated C1 alkyl group or a halogenated _C2 alkyl group. 16. A compound according to claim 15, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein Ring A is a cyclopropyl group substituted with a CF3 group. 17. The compound of claim 11, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein m is 1 or 2, Ring A is a cyclopropyl group substituted with a CF ₃ group, p is 0 or 1, and R ² , if present, is is a methyl group, a hydroxy group or a methoxy group. 18. The compound of claim 11, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein m is 2, Ring A is a C ₃ cycloalkyl group substituted with a CF ₃ group, p is 0 or 1 and R ² , if present, is is a methyl group, a hydroxy group or a methoxy group. 19. A compound according to claim 17 or 18, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein m is 2, Ring A is a cyclopropyl group substituted with a CF ₃ group, and p is 0. 20. The compound of claim 11, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein Ring A is selected from a C ₅ bicycloalkyl group optionally substituted with one or more substituents each independently selected from a C 1 -C 2 alkyl group halogenated with C 1 -C 2 alkyl group and halogen atoms. 21. The compound of claim 20, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein Ring A is a C ₅ bicycloalkyl group optionally substituted with halogen. 22. The compound of claim 11, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein Ring A is selected from a C ₇ bicycloalkyl group and a C ₇ tricycloalkyl group, each of which is optionally substituted with one or more substituents each independently selected from C 1 - C2 alkyl group, halogenated C1-C2 alkyl group and halogen atoms. 23. The compound of claim 22, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein Ring A is an unsubstituted C ₇ tricycloalkyl group. 24. Connection selected from - 174 040454 - 175 040454 - 176 040454 - 177 040454 - 178 040454 - 179 040454 .,-J. k,-,, l „ f Τ Υ Ί X \ J 1Χ I °' ,-0 ΟΧι^ ^Ν ^%> 1 II ^H ° yJ % □ 0 O . k h' , 1. i n IJ JJ VN / / \ J γ · ', i'J ^v I °v° _F yzy.,akix 'r'F '->— |z Z\/!S) Ϊ V , . -.I, ? J \__/ 1 \ _ V ^F 'y^/is'T I v OOn-v ⁴ » Ο οΧΧχ U ^F OF ^= ⁷ —ΟΧ» FF / IV JI 1 ^H LJ ψΝ __L/(S) O and \ v 1 ¥ ^f ¥V OJi Г T¥ ^{F 4} -\ lx Jk A kJ \_J /(5} 5 - 180 040454 a pharmaceutically acceptable salt thereof or a deuterated derivative thereof. 28. The compound according to claim 1, having the following formula: a pharmaceutically acceptable salt thereof or a deuterated derivative thereof. 29. The compound according to claim 1, having the following formula: a pharmaceutically acceptable salt thereof or a deuterated derivative thereof. 30. The compound according to claim 1, having the following formula: or a pharmaceutically acceptable salt thereof. 31. A compound having the following formula: or a pharmaceutically acceptable salt thereof. 32. The compound according to claim 1, having the following formula: or a pharmaceutically acceptable salt thereof. 33. A pharmaceutical composition containing at least one compound selected from the compounds according to any one of claims 1 to 32, a pharmaceutically acceptable salt or deuterated derivative thereof, and a pharmaceutically acceptable carrier, and one or more of: (a) compounds II - 181 040454 its pharmaceutically acceptable salt or their deuterated derivative; and (b) compounds III a pharmaceutically acceptable salt thereof or a deuterated derivative thereof. 34. A method for treating cystic fibrosis, comprising administering to a patient in need thereof a pharmaceutical composition according to claim 33. 35. Process for the preparation of a compound of formula (IIIa) a pharmaceutically acceptable salt thereof or a deuterated derivative thereof, comprising reacting a compound of formula (F) a salt thereof or a deuterated derivative thereof with a compound of formula (G) its salt or their deuterated derivative, where X ^a is selected from F or Cl; And Y ¹ , Y ² , R ¹ , R ² , R ³ , R ⁴ , p, q and r are as defined in claim 1. 36. The method according to item 35, where each Y ² independently represents N; each Y ¹ is independently CH. 37. The method according to claim 35 or 36, wherein said reaction of a compound of formula (F) or a salt thereof with a compound of formula (G) or a salt thereof is carried out in the presence of a base selected from metal carbonates. 38. The method according to any one of claims 35-37, wherein a salt of a compound of formula (G) is used. 39. The method of claim 38, wherein said salt of the compound of formula (G) is the HCl salt of the compound of formula (G). 40. Process for the preparation of a compound of formula (F) or a salt thereof or a deuterated derivative thereof, comprising reacting a compound of formula (D) a salt thereof or a deuterated derivative thereof with a compound of formula (E) - 182 040454 or its salt, or their deuterated derivative, where X ^a is selected from F or Cl; And Y ¹ , Y ² , R ¹ , R ² , R ⁴ , p and r are as defined in claim 1. 41. The method according to item 40, where each Y ² independently represents N; each Y ¹ is independently CH. 42. The method according to claim 40 or 41, wherein said reaction of a compound of formula (D) or a salt thereof with a compound of formula (E) or a salt thereof is carried out in the presence of a base selected from non-nucleophilic bases. 43. The method of claim 40 or 41, wherein said reacting a compound of formula (D), or a salt thereof, with a compound of formula (E), or a salt thereof, or a deuterated derivative thereof, comprises reacting a compound of formula (D) with an amide coupling reagent , which is a carbonyldiimidazole (CDI) and then with a compound of formula (E), or a salt thereof, or a deuterated derivative thereof, in the presence of a base selected from non-nucleophilic bases. 44. A method for obtaining a compound of the following formula: a pharmaceutically acceptable salt thereof or a deuterated derivative thereof, comprising reacting a compound of formula (F-1) its salt or deuterated derivative thereof with a compound of formula (G-1) or its salt, or their deuterated derivative, where X ^a is selected from F and Cl. 45. The method of claim 44, wherein said reaction of a compound of formula (F-1) or a salt thereof with a compound of formula (G-1) or a salt thereof is carried out in the presence of a base selected from metal carbonates. 46. The method of claim 44 or 45 wherein a salt of a compound of formula (G-1) is used. 47. The method of claim 46, wherein said salt of the compound of formula (G-1) is the HCl salt of the compound of formula (G-1). 48. Process for preparing a compound of formula (F-1) or a salt thereof, or a deuterated derivative thereof, comprising reacting a compound of formula (D-1) - 183 040454 or its deuterated derivative with a compound of formula (E-1) PhSO ₂ NH ₂ (E-1) or its deuterated derivative, where each X ^{a is} independently selected from F or Cl. 49. The method of claim 48, wherein said reaction of a compound of formula (D-1) or a salt thereof with a compound of formula (E-1) or a salt thereof is carried out in the presence of a base selected from non-nucleophilic bases. 50. The method of claim 48 wherein said reacting a compound of formula (D-1) or a salt thereof with a compound of formula (E-1) or a salt thereof comprises reacting a compound of formula (D-1) with an amide coupling agent which is carbonyldiimidazole (CDI) and then with a compound of formula (E-1) in the presence of a base selected from non-nucleophilic bases. 51. Process for the preparation of a compound of formula (D) or a salt thereof, or a deuterated derivative thereof, comprising: (i) reacting a compound of formula (A) its salt or deuterated derivative thereof with a compound of formula (B) its salt or their deuterated derivative to obtain a compound of formula (C) its salts or their deuterated derivative; and (ii) hydrolysis of the -C(O)OR ^a group in the compound of formula (C), where each R ⁴ is independently selected from halogen atoms; each R ^a is independently selected from C1-C4 alkyl; each X ^a is independently selected from F or Cl; Y ¹ , Y ² , R ¹ , R ⁴ and r as defined in paragraph 1 52. The method according to item 51, where each Y ² independently represents N; and each Y ¹ is independently CH. 53. The method according to claim 51 or 52, wherein the hydrolysis of the -C(O)OR ^a group is carried out in the presence of a base selected from aqueous bases. 54. The method according to any one of claims 51-53, wherein said reaction of a compound of formula (A) or a salt thereof with a compound of formula (B) or a salt thereof is carried out in the presence of a base selected from metal carbonates. 55. The method according to any one of claims 51-54, wherein R ^a is ethyl or t-butyl. - 184 040454 56. Process for preparing a compound of formula (D-1) or a salt thereof or a deuterated derivative thereof, comprising: (i) reacting a compound of formula (A-1): its salt or deuterated derivative thereof with a compound of formula (B-1) its salt or their deuterated derivative to obtain a compound of formula (C-1) its salt or its deuterated derivative; and (ii) hydrolysis of the -C(O)OR ^a group in the compound of formula (C-1), a salt thereof, or a deuterated derivative thereof, where each R ^a is independently selected from C ₁ -C ₄ alkyl; and each X ^a is independently selected from F or Cl. 57. The method of claim 56, wherein the hydrolysis of the -C(O)OR ^a group is carried out in the presence of a base selected from aqueous bases. 58. The method according to claim 56 or 57, wherein said reaction of a compound of formula (A-1) or a salt thereof with a compound of formula (B-1) or a salt thereof is carried out in the presence of a base selected from metal carbonates. 59. The method according to any one of claims 56-58, wherein R ^a is ethyl or t-butyl. 60. Process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, comprising reacting a compound of formula (L) its salt or their deuterated derivative with NR*3, where X represents NH or N(C ₁ -C ₄ alkyl); R* represents H or C ₁ -C ₄ alkyl; Xa is selected from F or C1; Y ¹ , Y ² , R ¹ , R ² , R ³ , R ⁴ , p, q and r are as defined in claim 1. - 185 040454 61. The use of at least one compound selected from the compounds of any one of claims 1 to 32, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, and one or more of: (a) compounds II a pharmaceutically acceptable salt thereof or a deuterated derivative thereof; and (b) compounds III a pharmaceutically acceptable salt thereof or a deuterated derivative thereof; for the treatment of cystic fibrosis. 62. Compound formula in the form of a pharmaceutically acceptable salt. 63. Compound formula 64. A pharmaceutical composition for the treatment of cystic fibrosis, comprising an effective compound of claim 25 and a pharmaceutically acceptable carrier. 65. A pharmaceutical composition for the treatment of cystic fibrosis, comprising an effective compound of claim 62 and a pharmaceutically acceptable carrier. 66. A pharmaceutical composition for the treatment of cystic fibrosis, comprising an effective compound of claim 63 and a pharmaceutically acceptable carrier. 67. Pharmaceutical composition comprising a compound of the following formula: QOO number of number of their pharmaceutically acceptable salt or acceptable carrier; and one of: (a) compound II deuterated derivative; pharmaceutically its pharmaceutically acceptable salt or their deuterated derivative; and (b) Compound III - 186 040454 its pharmaceutically acceptable salt or their deuterated derivative. 68. The pharmaceutical composition according to claim 67, where the compound having the formula is in the form of a pharmaceutically acceptable salt. 69. A method of treating cystic fibrosis, comprising administering to a patient in need thereof a compound according to any one of claims 25, 62 or 63 or a pharmaceutical composition according to any one of claims 64-68.