Cystic fibrosis transdermal conduction modulator, drug compositions, treatment methods, and process for making the modulator

Abstract

Compounds of formula (I), pharmaceutically acceptable salts, deuterated derivatives of the foregoing, and metabolites of each of the foregoing are disclosed in this invention. Pharmaceutical compositions comprising the same, methods of treating cystic fibrosis using the same, and methods of producing the same are disclosed in this invention. Solid forms of compound 1 and salts and solvents thereof are also disclosed.

Description

Cystic fibrosis transdermal conduction modulator, drug compounds and modulator manufacturing process

[0001] Disclosed herein are modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), pharmaceutical compositions containing the modulators, methods of treating cystic fibrosis, and a process for making the modulators.

[0002] Cystic fibrosis (CF) is a genetic disease that affects approximately 70,000 children and adults worldwide. Despite advances in the treatment of CF, there is still no definitive cure.

[0003] In patients with CF, CFTR mutations that occur endogenously in the respiratory epithelium result in reduced apical anion secretion, which disrupts the balance of ion and fluid transport. This reduction in anion transport leads to increased sputum accumulation in the lungs and, with it, microbial infections, which ultimately lead to death in CF patients. In addition to respiratory disease, CF patients suffer from gastrointestinal problems and pancreatic insufficiency, which, if untreated, can lead to death. In addition, most men with cystic fibrosis are infertile, and fertility is also low among women with cystic fibrosis.

[0004] Analysis of the CFTR gene sequence reveals disease variants that result from mutations (Cutting, J. R. et al. (1990) Nature 346:366-369; Dean et al. (1990) Cell 61:863:870; and Kram B. S. et al. (1989) Science 245:1073:-1080; and Kram B. S. et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447, -8451). To date, over 2000 mutations in the CF gene have been identified; currently, the CFTR2 database contains information on only 322 of these identified mutations, with sufficient evidence to determine 281 mutations as the cause of disease. The most common pathogenic mutation is the deletion of phenylalanine at position 508 of the CFTR amino acid sequence, commonly referred to as the F508del mutation. This mutation occurs in approximately 70% of cystic fibrosis cases and is associated with severe disease.

[0005] Deletion of residue 508 in CFTR prevents the newly formed protein from folding properly. This results in the inability of the mutant protein to exit the endoplasmic reticulum (ER) and cross the plasma membrane. As a result, the number of CFTR channels for anion transport in the membrane is much lower than that seen in cells secreting wild-type CFTR, i.e., CFTR without the mutation. In addition to causing a defect in the translocation, the mutation results in incomplete channel disruption. The reduction in the number of channels in the membrane and the incomplete disruption, together, result in reduced anion and fluid transport across the epithelium. (Kinton, P. M. (1990), FASEB J. 4: 2709-2727). Channels that are defective due to the F508del mutation can still function, although their efficiency is less than that of wild-type CFTR. Dalmans et al. (1991) in Nature Lond 354: 526-528; Pasik and Foskett (1995), J. Cell. Biochem. 270: 12347-50).In addition to F508del, other pathogenic mutations in CFTR that can cause defective trafficking and synthesis and / or channel disruption can be up- or down-regulated to alter anion secretion and disease progression and / or severity.

[0006] CFTR is a cAMP / ATP-gated anion channel expressed in a variety of 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 ions in the channels and proteins. In epithelial cells, normal function of CFTR is essential for maintaining electrolyte flow throughout the body, including in respiratory and digestive tissues. CFTR is composed of approximately 1480 amino acids that encode a protein that consists of a paired repeat of transmembrane domains, each containing six helices and a nucleotide-binding domain. The two transmembrane domains are joined by a large, polar, regulatory (R) domain with multiple phosphorylation sites that control channel activity and cellular trafficking.

[0007] Chloride transport is mediated by the coordinated activity of ENaC and CFTR present on the apical membrane and the Na+-K+-ATPase pump and secreted Cl channels on the basolateral surface of the cell. A second active transport of chloride from the luminal compartment leads to an accumulation of intracellular chloride, which can then passively leave the cell through Cl- channels, causing vectorial transport. The arrangement of the Na+ / 2Cl- / K+ cotransporter, the Na+-K+-ATPase pump and the basolateral membrane K+ channels on the basolateral surface and CFTR on the luminal compartment facilitates chloride secretion via CFTR on the luminal surface. Since water is probably never actively transported on its own, its flow across the epithelia depends on the micro-transepithelial osmotic gradients generated by the major influx of sodium and chloride.

[0008] Accordingly, innovative treatments are needed for CFTR-related diseases.

[0009] The present invention provides novel compounds, including compounds of formula (I)-(VI) and pharmaceutically acceptable salts thereof. For example, a compound of formula (I) can be depicted as follows: (I), A pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, Where: - One of Y1 and Y2 is N and the other is CH; - X is selected from O, NH and N(C1-C4alkyl) groups; - R1 is –(C(R2)2)kO-(C(R2)2)mR7 - each R2 is independently selected from hydrogen; halogens; cyano; hydroxy; C1-C2 alkoxy groups, and the C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy, and C3-5 cycloalkyl groups, which are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - each R3 is independently selected from C1-C4 alkyl groups optionally substituted with one or more hydroxy groups or two R3 pairs; together with the carbon atom to which they are attached, are of a C3-4 cycloalkyl; - each R4 is independently selected from halogens; - R5 is selected from hydrogen and C1-C4 alkyl groups; - each R6 is independently selected from halogens, cyano, hydroxy, hydroxymethyl, C1-C2 alkoxy groups, C1-C2 alkyl groups and halogenated C1-C2 alkyl groups; - each R7 is selected from hydrogen; halogens; cyano; the C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy; and the C3-C10 cycloalkyl groups are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - k is equal to 0 or 1. - r is equal to 0 or 1. - m is 0, 1, 2, or 3. - p is 0, 1 or 2; and - q is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0010] Also described herein are pharmaceutical compositions comprising at least one of the inventive compounds described herein and / or at least one pharmaceutically acceptable salt thereof, which compositions may comprise at least one additional pharmaceutically active ingredient and / or at least one carrier. Methods for treating a CFTR-related disease, cystic fibrosis, are also described, comprising administering at least one of the inventive compounds described herein and / or at least one pharmaceutically acceptable salt thereof, optionally as part of a pharmaceutical composition comprising at least one additional ingredient.

[0011] Also described are methods for treating the CFTR-associated disease, cystic fibrosis, comprising administering to a patient in need thereof 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-3-carboxamide (Compound III), as part of a pharmaceutical composition containing at least one additional component.

[0012] Compound 1 is also described herein:

[0013] N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.

[0014] Also described are pharmaceutical compositions of Compound 1, and forms thereof, which may contain at least one additional pharmaceutically active ingredient and at least one carrier, and methods of treating CFTR-associated disease cystic fibrosis, comprising administering Compound 1 to a patient in need thereof. A process for obtaining Compound 1 is also described.

[0015] Brief description of the figures

[0016] Figure 1 shows the structure of unlimited examples of the innovative composition described herein.

[0017] Figure 2 is an XRPD of Form A of Compound 1.

[0018] Figure 3 is an experimental XRPD of Form A of Compound 1 (top) compared to the calculated XRD (bottom) calculated from single crystal data.

[0019] Figure 4 is an overlay of experimental and computational XRPD of Form A of Compound 1 of Figure 3.

[0020] Figure 5 is an XRPD of a spray drying (SSD) dispersion of 50 wt% of Compound 1 with HPMCAS-HG.

[0021] Figure 6 is an MDSC spectrum of an SSD of 50 wt% compound 1 with HPMCAS-HG.

[0022] Figure 7 shows a list of CFTR mutations.

[0023] Figure 8 is the solid-state Carbon-13 NMR spectrum of Form A of compound 1, with MAS rotating at 12.5 kHz, adamantane 29.5 ppm, at 275 K. The spectrum was taken on a Bruker 400MHz WB SSNMR; BH085908; asset V019431 (console), V015741 (magnet).

[0024] Figure 9 is the solid-state Fluorine-19 NMR spectrum of Form A of Compound 1, with MAS rotating at 12.5 kHz, adamantane 29.5 ppm, at 275 K. The spectrum was taken on a Bruker 400MHz WB SSNMR; BH085908; asset V019431 (console), V015741 (magnet).

[0025] Figure 10 shows the ball-and-stick diagram of crystalline form A of compound 1.

[0026] Figure 11 shows the TGA plot of crystalline Form A of Compound 1.

[0027] Figure 12 shows the dynamic vapor adsorption (DVS) scheme of crystalline Form A of Compound 1.

[0030] Figure 13 shows the X-ray diffractogram of crystalline form M of compound 1.

[0031] Figure 14 shows the X-ray diffractogram of crystalline form E of compound 1.

[0032] Figure 15 shows the X-ray diffractogram of crystalline form X of a potassium salt of compound 1.

[0033] Figure 16 shows the X-ray powder diffractogram of crystalline form Y of a sodium salt of compound 1.

[0034] Figure 17 shows the X-ray diffractogram of the P2 crystalline form of compound 1. Definitions

[0037] The term "alkyl" as used herein refers to an unbranched or branched aliphatic hydrocarbon containing carbon atoms (including, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms). Alkyl groups can be substituted or unsubstituted.

[0038] The term "alkoxy" as used herein refers to an alkyl or cycloalkyl covalently bonded to an oxygen atom. Alkoxy groups may be substituted or unsubstituted.

[0039] The term "cycloalkyl" as used herein refers to cyclic, bicyclic, tricyclic, or polycyclic non-aromatic hydrocarbon groups having 3 to 12 carbons (e.g., 3-10 carbons). "Cycloalkyl" groups include monocyclic, bicyclic, tricyclic, bridged, fused, and spiro rings, including monospiro and dispiro rings. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and dispiro[2.0.2.1]heptane. Cycloalkyl groups may be substituted or unsubstituted.

[0040] "Substituted," whether preceded by "optionally" or not, indicates that at least one hydrogen of the "substituted" group has been replaced by a substituent. An "optionally substituted" group may have a suitable substituent at any substitutable position of the group, and when more than one position in any structure is substituted by one or more substituents selected from a particular group, that substituent may be the same or different at each position, unless otherwise stated.

[0041] In this context, "deuterated derivative(s)" means the same chemical structure but with one or more additional hydrogen atoms replaced by a deuterium atom.

[0042] In this context, "CFTR" means cystic fibrosis transmembrane conductance regulator modulator.

[0043] In this context, "mutations" can refer to mutations in the CFTR gene or in the CFTR protein. "CFTR gene mutation" means a mutation in the CFTR gene and "CFTR protein mutation" means a mutation in the CFTR protein. A genetic defect or mutation, or a change in the nucleotides of a gene, generally results in a mutation in the CFTR protein of that gene or a change in the template.

[0044] The term "F508del" refers to a mutant CFTR protein that lacks the amino acid phenylalanine at position 508.

[0045] In this context, a patient "homozygous" for a particular gene mutation has the same mutation on each allele.

[0046] In this context, a patient who is "heterozygous" for a particular gene mutation has one mutation on one allele and a different mutation on the other allele.

[0047] As used herein, 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 the activity of CFTR. The increase in activity resulting from a CFTR modulator includes, but is not limited to, compounds that modify, enhance, stabilize, and / or enlarge CFTR.

[0048] As used herein, the term "CFTR modulator" refers to a compound that facilitates the processing and trafficking of CFTR to increase the amount of CFTR at the cell surface. The compounds of formula (I), (II), (III), (IV), (V) and (VI) and compound II and their pharmaceutically acceptable salts described herein are CFTR modulators.

[0049] As used herein, the term "CFTR potentiator" refers to a compound that increases the activity of the CFTR protein channel located on the cell surface, thereby inhibiting ion transport. Compound III described herein is a CFTR potentiator.

[0050] In this context, "active pharmaceutical ingredient" ("API") refers to a biologically active compound.

[0051] "Pharmaceutically acceptable salt" as used herein refers to a salt form of a compound described herein, the salt of which is non-toxic. Pharmaceutically acceptable salts of the compounds described herein are the salt forms prepared from suitable organic and inorganic acids and bases. Pharmaceutically acceptable salts are familiar to those skilled in the art. For example, S. M. Berg et al. have described pharmaceutically acceptable salts in detail in the Journal of Pharmaceutical Sciences, 1977, 66, 1-19.

[0052] In this context, the term "unstructured" refers to a solid that does not have a long-range order in its cell positions. Unstructured solids are generally supercooled liquids in which the molecules are randomly arranged so that there is no definite order, such as molecular packing. Unstructured solids are generally isotopic, i.e., exhibit similar characteristics in all directions and do not have a defined melting point. For example, an unstructured material is a solid that does not have any sharp crystalline peaks in its X-ray diffraction pattern (XRPD) (i.e., is not defined in the crystalline XRPD). Rather, one or more broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of an unstructured solid. For a comparison of XRPDs of an unstructured material and a crystalline material, see US 2004 / 0006237.

[0053] In this context, the term "substantially disordered" refers to a solid material that has no long-range order or limited order in the arrangement of its cells. For example, essentially disordered materials are less than 15% crystalline (e.g., less than 10% crystalline or less than 5% crystalline). It should also be noted that the term essentially disordered includes the adjective "unordered" which refers to materials with no (0%) crystalline properties.

[0054] In this context, the term "dispersion" refers to a dispersion system in which a substance, the dispersed phase, is dispersed in discrete units throughout a second substance (the continuous phase or vehicle). The size of the dispersed phase can vary greatly (e.g., from nanometer-sized colloidal particles to several microns). In general, the dispersed phases can be solid, liquid, or gaseous. In the case of a solid dispersion, both the dispersed and continuous phases are solid. In pharmaceutical applications, a solid dispersion can contain a crystalline drug (dispersed phase) in a non-dispersed polymer (continuous phase); or conversely, a non-dispersed drug (dispersed phase) in a non-dispersed polymer (continuous phase). In some embodiments, the solid dispersion comprises a polymer containing the dispersed phase, and the drug forms the continuous phase. Or, the solid dispersion comprises the drug that forms the dispersed phase, and the polymer forms the continuous phase.

[0055] The terms "patient" and "subject" are used interchangeably and refer to a living being, including a human.

[0056] The terms "effective dose" and "effective amount" are used interchangeably and refer to the amount of a compound that will produce the desired effect for which it is prescribed (e.g., ameliorating CF or CF symptoms or alleviating the severity of CF or CF symptoms). The precise amount of an effective dose will depend on the purpose of the treatment, and can be determined by one skilled in the art (e.g., Lloyd (1999) Art, Science and Technology of Pharmaceutical Medicine).

[0057] As used herein, the terms "treatment," "treating," and the like generally mean improving CF or its symptoms or reducing the severity of CF or its symptoms in a subject. "Treatment," as used herein, includes, but is not limited to, the following: increasing the subject's growth, increasing weight, reducing phlegm in the lungs, improving pancreatic and / or liver function, reducing chest infections, and / or reducing cough or shortness of breath. Improvement or reduction in the severity of these symptoms can be readily measured based on standard methods and techniques familiar to those skilled in the art.

[0058] The term "in combination with", as used herein, when referring to two or more additional active pharmaceutical ingredients, agents, or components, means administering two or more additional active pharmaceutical ingredients, agents, or components to a patient before, simultaneously with, or after each other.

[0059] The words "about" and "approximately", in connection with doses, amounts, or percentages by weight for a portion of a composition or dosage amount, mean the value of a specific dose, amount, or percentage by weight, or a range of doses, amounts, or weights determined by one of the methods conventional in the art to have the same pharmacological effect as that of the specific dose, amount, or percentage by weight.

[0060] Each of the compounds of Formulas (I), (II), (III), (IV), (V) and (VI) and Compounds II, III, IV and their pharmaceutically acceptable salts and deuterated derivatives described herein can be administered once, twice or three times daily. In some embodiments, at least one compound selected from the compounds of Formulas (I), (II), (III), (IV), (V) and (VI) and their pharmaceutically acceptable salts and deuterated derivatives is administered once daily. In some embodiments, at least one compound selected from the compounds of Formulas (I), (II), (III), (IV), (V) and (VI) and their pharmaceutically acceptable salts and deuterated derivatives is administered twice daily. In some embodiments, at least one compound selected from Compound II and their pharmaceutically acceptable salts is administered once daily. In some embodiments, at least one compound selected from Compound II and their pharmaceutically acceptable salts is administered twice daily. In some embodiments, at least one compound selected from Compound III and pharmaceutically acceptable salts thereof is administered once daily.In some embodiments, at least one compound selected from Compound III and pharmaceutically acceptable salts thereof are administered twice daily. In some embodiments, at least one compound selected from Compound IV and pharmaceutically acceptable salts thereof are administered once daily. In some embodiments, at least one compound selected from Compound IV and pharmaceutically acceptable salts thereof are administered twice daily. In some embodiments, a deuterated derivative of Compound II, III and / or IV or a pharmaceutically acceptable salt thereof is employed in each of these embodiments.

[0061] In some embodiments, 10 mg to 1,500 mg of a compound described herein, a pharmaceutically acceptable salt thereof, or a deuterated derivative of the compound or salt is administered daily.

[0062] Those skilled in the art will appreciate that when determining the amount of "a compound or a pharmaceutically acceptable salt thereof", the amount of the pharmaceutically acceptable salt of the compound is an amount equal to the concentration of the free base of that compound. It should be noted that the determined amounts of the compounds or their pharmaceutically acceptable salts described herein are based on their free base form. For example, "10 mg of at least one compound selected from the compounds of Formula (I) and pharmaceutically acceptable salts thereof" contains 10 mg of the compound of Formula (I) and the concentration of the pharmaceutically acceptable salt of the compound of Formula (I) is equal to 10 mg of the compounds of Formula (I).

[0063] As stated above, the compounds of formula (I) described herein are: (I), A pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, Where: - One of Y1 and Y2 is N and the other is CH; - X is selected from O, NH and N(C1-C4alkyl) groups; - R1 is –(C(R2)2)kO-(C(R2)2)mR7 - each R2 is independently selected from hydrogen; halogens; cyano; hydroxyl; C1-C2 alkoxy groups, and the C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxyl, and C3-5 cycloalkyl groups, which are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - each R3 is independently selected from C1-C4 alkyl groups optionally substituted with one or more hydroxyl groups or two R3 pairs; together with the carbon atom to which they are attached, are of a C3-4 cycloalkyl; - each R4 is independently selected from halogens; - R5 is selected from hydrogen and C1-C4 alkyl groups; - each R6 is independently selected from halogens, cyano, hydroxyl, hydroxymethyl, C1-C2 alkoxy groups, C1-C2 alkyl groups and halogenated C1-C2 alkyl groups; - R7 is selected from hydrogen; halogens; cyano; C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy; and C3-C10 cycloalkyl groups are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - k is equal to 0 or 1. - r is equal to 0 or 1. - m is 0, 1, 2, or 3. - p is 0, 1 or 2; and - q is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0064] Also, compounds of formula (II) described herein include: (II) A pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, Where: - X is selected from O, NH and N(C1-C4alkyl) groups; - R1 is –(C(R2)2)kO-(C(R2)2)mR7 - each R2 is independently selected from hydrogen; halogens; cyano; hydroxyl; C1-C2 alkoxyl groups, and the C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxyl, and C3-5 cycloalkyl groups, which are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - each R3 is independently selected from C1-C4 alkyl groups optionally substituted with one or more hydroxyl groups or two R3 pairs; together with the carbon atom to which they are attached, are of a C3-4 cycloalkyl; - each R4 is independently selected from halogens; - R5 is selected from hydrogen and C1-C4 alkyl groups; - each R6 is independently selected from halogens, cyano, hydroxyl, hydroxymethyl, C1-C2 alkoxy groups, C1-C2 alkyl groups and halogenated C1-C2 alkyl groups; - R7 is selected from hydrogen; halogens; cyano; C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy; and C3-C10 cycloalkyl groups are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - k is equal to 0 or 1. - r is equal to 0 or 1. - m is 0, 1, 2, or 3. - p is 0, 1 or 2; and - q is 0, 1, 2, 3, 4, 5, 6, 7, or 8. Within the scope of formula (I) and (II) are compounds containing a group or (wherein R' is H or C1-C4alkyl), i.e., in which X is selected from NH and N(C1-C4alkyl) and pharmaceutically acceptable salts thereof, or a deuterated derivative of any of the foregoing. In some embodiments, a compound of each of the structural formulas is shown in Figure 1, but one of the sulfonamide (S=O) groups in each formula is also present, either as an isomeric compound or as identically enriched isomers (e.g., >90% ee, >95% ee, or >98% ee).

[0065] Also, compounds of formula (III) described herein include: (III) A pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, Where: - R1 is –(C(R2)2)kO-(C(R2)2)mR7 - each R2 is independently selected from hydrogen; halogens; cyano; hydroxy; C1-C2 alkoxy groups, and the C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy, and C3-5 cycloalkyl groups, which are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - each R3 is independently selected from C1-C4 alkyl groups optionally substituted with one or more hydroxy groups or two R3 pairs; together with the carbon atom to which they are attached, are of a C3-4 cycloalkyl; - each R4 is independently selected from halogens; - R5 is selected from hydrogen and C1-C4 alkyl groups; - each R6 is independently selected from halogens, cyano, hydroxy, hydroxymethyl, C1-C2 alkoxy groups, C1-C2 alkyl groups and halogenated C1-C2 alkyl groups; - R7 is selected from hydrogen; halogens; cyano; C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy; and C3-C10 cycloalkyl groups are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - k is equal to 0 or 1. - r is equal to 0 or 1. - m is 0, 1, 2, or 3. - p is 0, 1 or 2; and - q is 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0066] In some embodiments, in compounds of formulas (I), (II), and (III), their pharmaceutically acceptable salts and / or deuterated derivatives of any of the foregoing: - each R2 is selected from hydrogen and C1-C2 alkyl groups; - R5 is selected from hydrogen and C1-C2 alkyl groups; and - each R6 is independently selected from C1-C2 alkyl groups;

[0067] In some embodiments, in compounds of Formulae (I), (II) and (III), their pharmaceutically acceptable salts and / or deuterated derivatives of any of the foregoing: - R1 is –O-(CH2)(C(R2)2)(m-1)R7, - R7 is independently selected from C1-C2 alkyl groups optionally substituted with one or more substituents independently selected from halogens, hydroxy; and C3-C10 cycloalkyl groups optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - each R2 is independently selected from C1-C2 alkyl groups, OH, C1-C2 alkoxyl groups and halogens; - R4 is H; and - q is 0, 1, 2, 3 or 4.

[0068] In some embodiments, in compounds of Formulas (I), (II), and (III), their pharmaceutically acceptable salts, and / or deuterated derivatives of any of the foregoing, r is equal to 0.

[0069] Also, compounds of formula (IV) described herein include: (IV), (V), or (IV), A pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, Where: - R1 is -O-(CH2)(C(R2)2)(m-1)R7, - each R2 is independently selected from C1-C2 alkyl groups, OH, C1-C2 alkoxy groups and halogens; - R7 is independently selected from C1-C2 alkyl groups optionally substituted with one or more substituents independently selected from halogens, hydroxy; and C3-C10 cycloalkyl groups optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - R5 is selected from hydrogen and C1-C2 alkyl groups; - each R6 is independently selected from C1-C2 alkyl groups; and - p is 0, 1 or 2.

[0070] In some cases, p is either 0 or 1. In some cases, p is equal to 0.

[0071] In some embodiments, in compounds of Formulae (I), (II), (III), (IV), (V) and (VI) and pharmaceutically acceptable salts thereof, each R2 is independently selected from CH3, OH, F and OCH3. In some instances, p is either 0 or 1. In some instances, p is 0.

[0072] In some embodiments, in compounds of Formulae (I), (II), (III), (IV), (V) and (VI) and pharmaceutically acceptable salts thereof, p is 1; R5 is methyl and R6 is methyl.

[0073] In some embodiments, in compounds of formulae (I), (II), (III), (IV), (V) and (VI) and pharmaceutically acceptable salts thereof, R7 is a cyclopropyl group. In some embodiments, R7 is a cyclopropyl group substituted with a hydrogenated C1 alkyl group. In some embodiments, R7 is a cyclopropyl group substituted with one or more halogens. In some embodiments, R7 is a cyclopropyl group substituted with one or more halogens and one or more C1 alkyl groups. In another embodiment, R7 is a CF3 group; In some embodiments, R7 is selected from C4 cycloalkyl groups that are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens. In some embodiments, R7 is selected from C5 cycloalkyl groups that are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens.In another mechanism, C5 cycloalkyl groups are bicyclic.

[0074] In some embodiments, R7 is selected from C7 cycloalkyl groups that are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens. In another embodiment, the C7 cycloalkyl groups are bicyclic. In another embodiment, the C7 cycloalkyl groups are tricyclic.

[0075] Also described herein are compounds having a formula selected from any of the formulas shown in Figure 1 and a pharmaceutically acceptable salt thereof.

[0076] Also described herein is a compound having the following formula: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing.

[0077] Also described herein is a compound having the following formula: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing.

[0078] Also described herein is a compound having the following formula: , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing.

[0079] Also described herein is a compound having the following formula: , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing.

[0080] Also described herein is a compound having the following formula: , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing.

[0081] Also described herein is a compound having the following formula: , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing.

[0082] Also described herein is a compound having the following formula: , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing.

[0083] Also described herein is a compound having the following formula: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing.

[0084] Also described herein is a compound having the following formula: Or, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing.

[0085] Also described herein is a composition comprising any of the following formulas: , or , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing.

[0086] Also described herein is a compound comprising any of the following formulas:, , , , , , , , or , , or , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing.

[0087] Suitable pharmaceutically acceptable salts are described, for example, in S. M. Berg et al. J. Pharmaceutical Sciences, 1977, 66, 1-19. For example, Table 1 of that article provides the following pharmaceutically acceptable salts: Table 1: Acetate Iodide Benzathine Benzene Sulfonate Isethionate Chloroprocaine Benzoate Lactate Choline Bicarbonate Lactobionate Diethanolamine Biartrate Ethylenediamine Bromide Maleate Meglumine Calcium Edetate Mandelate Procaine Camsylate Aluminum Mesylate Carbonate Calcium Chloride Methyl Nitrate Lithium Citrate Methyl Sulfate Magnesium Dihydrochloride Mucate Potassium Edetate Napsilate Sodium Idicylate Zinc Nitrate Acetate Pamoate (Ambonate) Pantothenate Acetate Fumarate Phosphate / Diphosphate Gluseptate Polygalacturonate Gluconate Salicylate Glutamate Stearate Glycolic Acid Substate Hexyl Resorcinate Succinate Hydrabamine Sulfate Hydrobromide Tannate Hydrochloride Tartrate Hydroxynaphthoate Theocyanate Triethiodide

[0088] Non-limiting examples of acceptable pharmaceutically acceptable salts derived from suitable acids include: salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid; salts formed with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, succinic acid, or malonic acid; and salts formed using other methods used in the art, such as ion exchange.Non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, Tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts. Pharmaceutically acceptable salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4alkyl)4 salts. This text also contemplates the tetravalent composition of each nitrogen-containing base group of these compounds.Suitable and non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium and magnesium. Other non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfate. Other suitable examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0089] In some embodiments, at least one selected compound of the inventive compounds described herein, its pharmaceutically acceptable salt and deuterated derivatives of the foregoing, is administered in combination with at least one selected compound of Compound II, its pharmaceutically acceptable salts and deuterated derivatives of the foregoing. In some embodiments, at least one selected compound of the inventive compounds described herein, its pharmaceutically acceptable salt and deuterated derivatives of the foregoing, is administered in combination with at least one selected compound of Compound III and its pharmaceutically acceptable salts. In some embodiments, at least one selected compound of the inventive compounds described herein, its pharmaceutically acceptable salt and deuterated derivatives of the foregoing, is administered in combination with at least one selected compound of Compound IV and its pharmaceutically acceptable salts.In some embodiments, at least one selected compound of the inventive compounds described herein, its pharmaceutically acceptable salt and deuterated derivatives thereof, is administered in combination with at least one selected compound of Compound II, or its pharmaceutically acceptable salts and deuterated derivatives thereof, and at least one selected compound of Compound III, its pharmaceutically acceptable salt, or a deuterated derivative of any of the foregoing. In some embodiments, at least one selected compound of the inventive compounds described herein, its pharmaceutically acceptable salt and deuterated derivatives thereof, is administered in combination with at least one selected compound of Compound III, its pharmaceutically acceptable salts and deuterated derivatives thereof, and at least one selected compound of Compound IV, its pharmaceutically acceptable salt, or a deuterated derivative of any of the foregoing.

[0090] In some cases, at least one novel compound (and / or at least one pharmaceutically acceptable salt thereof and / or at least one deuterated derivative of the compound or salt) can be administered together with at least one additional active pharmaceutical ingredient. In some examples, the additional active pharmaceutical ingredient is selected from: (a) Compound II: and its pharmaceutically acceptable salt. A chemical name for compound II is (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide; (b)Compound III: and its pharmaceutically acceptable salt. A chemical name for compound III is N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide; and (c)Compound IV: and its pharmaceutically acceptable salt.

[0091] A chemical name for Compound IV is 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid. In some embodiments, Compound I and / or a pharmaceutically acceptable salt thereof can be administered in combination with Compound II and / or a pharmaceutically acceptable salt thereof. In some embodiments, Compound I and / or a pharmaceutically acceptable salt thereof can be administered in combination with Compound III and / or a pharmaceutically acceptable salt thereof. In some embodiments, Compound I and / or a pharmaceutically acceptable salt thereof can be administered in combination with Compound IV and / or a pharmaceutically acceptable salt thereof. In some embodiments, Compound I and / or a pharmaceutically acceptable salt thereof can be administered in combination with Compound II and / or a pharmaceutically acceptable salt thereof and Compound III and / or a pharmaceutically acceptable salt thereof. In some cases, Compound I and / or a pharmaceutically acceptable salt thereof can be administered in combination with Compound II and / or a pharmaceutically acceptable salt thereof and Compound IV and / or a pharmaceutically acceptable salt thereof.

[0092] In one aspect, this disclosure describes a pharmaceutical composition comprising Compound 1 and / or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0093] In one aspect, this disclosure describes a pharmaceutical composition comprising Compound 1 and / or a pharmaceutically acceptable salt thereof, Compound II and / or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0094] In one aspect, this disclosure describes a pharmaceutical composition comprising Compound 1 and / or a pharmaceutically acceptable salt thereof, Compound III and / or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0095] In one aspect, this disclosure describes a pharmaceutical composition comprising Compound 1 and / or a pharmaceutically acceptable salt thereof, Compound II and / or a pharmaceutically acceptable salt thereof, Compound III and / or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0096] Any of the inventive compounds described herein, for example, compounds of formula (I), (II), (III), (IV), (V) or (VI) and their pharmaceutically acceptable salts and deuterated derivatives thereof, can be combined into a single pharmaceutical composition or multiple pharmaceutical compositions together with other additional active pharmaceutical ingredients (e.g., Compound II, III or IV or their pharmaceutically acceptable salts or a deuterated derivative thereof or salt). These pharmaceutical compositions can be administered once or more times per day, for example twice per day. In some embodiments, a pharmaceutical composition described comprises at least one compound selected from each of the compounds and their pharmaceutically acceptable salts and at least one pharmaceutically acceptable carrier.

[0097] In some embodiments, a pharmaceutical composition is described comprising at least one compound selected from each of Compounds and a pharmaceutically acceptable salt thereof, at least one compound selected from Compound II and a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0098] In some embodiments, a pharmaceutical composition is described comprising at least one compound selected from each of the compounds and a pharmaceutically acceptable salt thereof, at least one compound selected from compound III and a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0099] In some embodiments, a pharmaceutical composition is described comprising at least one compound selected from each of Compounds and a pharmaceutically acceptable salt thereof, at least one compound selected from Compound II and a pharmaceutically acceptable salt thereof, at least one compound selected from Compound III and a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[00100] In some embodiments, a pharmaceutical composition is described comprising at least one compound selected from each of Compounds and a pharmaceutically acceptable salt thereof, at least one compound selected from Compound III and a pharmaceutically acceptable salt thereof, at least one compound selected from Compound IV and a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[00101] In some embodiments, the pharmaceutical compositions described herein comprise at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR modulator. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR modifier. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR enhancer. In some embodiments, the pharmaceutical composition comprises (1) a compound of formulae (I), (II), (III), (IV), (V) or (VI) or a pharmaceutically acceptable salt thereof or a deuterated derivative of the compound or salt; and (2) at least two additional active pharmaceutical ingredients, one of which is a CFTR modifier and one of which is a CFTR enhancer.

[00102] In some cases, at least one additional active pharmaceutical ingredient is selected from mucolytic agents, bronchodilators, antibiotics, antiseptic agents, and anti-inflammatory agents.

[00103] The pharmaceutical compositions can also include at least one pharmaceutically acceptable carrier. In some cases, the at least one pharmaceutically acceptable carrier is selected from pharmaceutically acceptable excipients and pharmaceutically acceptable adjuvants. In some cases, the at least one pharmaceutically acceptable carrier is selected from pharmaceutically acceptable fillers, extenders, surfactants, binders, lubricants.

[00104] It is also contemplated that a pharmaceutical composition described herein, including a pharmaceutical composition comprising the compounds described herein, can be administered in conjunction with other therapies; that is, the compounds can be administered concurrently with, before or after, at least one additional active pharmaceutical ingredient or medical procedure.

[00105] Pharmaceutical compositions containing these compounds are useful for treating cystic fibrosis.

[00106] As mentioned above, the pharmaceutical compositions described herein can optionally also include at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier can be selected from the group consisting of vehicles and auxiliaries. The at least one pharmaceutically acceptable carrier, as used herein, includes one of solvents, diluents, other liquid vehicles, dispersing acids, suspending acids, surface active agents, isotonic agents, thickening agents, emulsifying agents, preservatives, gel binders, and lubricants, depending on the particular dosage required. Remington: The Science and Practice of Pharmacy, 21st Edition, 2005, eds., D. B. Troy, Lippincott Williams & Wilkins; Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, describe the various types of carriers used in formulating pharmaceutical compositions and the known techniques for their preparation. Except where a conventional carrier is incompatible with the compositions of this text, for example by producing an undesirable biological effect or any other interferenceIn a detrimental manner with any other combination of these medicinal compounds, their use is considered within the scope of this text. Non-limiting examples of acceptable pharmaceutical carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffering agents (e.g., phosphates, glycine, sorbic acid, and potassium sorbate), incomplete glyceride compounds of vegetable saturated fatty acids, water, salts, and electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene polyoxypropylene block polymers, wool fat, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate), powdered starch, malt, gelatin, Talc, extenders (such as cocoa butter, and suppository waxes), oils (such as peanut oil, linseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols(e.g. propylene glycol and polyethylene glycol), esters (e.g. ethyl oleate and ethyl laurate), agar, buffering agents (e.g. magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffered solutions, non-toxic lubricants (e.g. sodium lauryl sulfate and magnesium stearate), coloring agents, release agents, coating agents, sweetening agents, flavoring agents, perfume agents, preservatives, and antioxidants.

[00107] In some embodiments, the methods of this disclosure comprise administering at least one compound selected from each of the described compounds and a pharmaceutically acceptable salt thereof and at least one compound selected from Compound II, Compound III, Compound IV and pharmaceutically acceptable salts of any of the foregoing.

[00108] Any suitable pharmaceutical composition known in the art can be used for the inventive compounds of this disclosure, Compound II, Compound III, Compound IV and pharmaceutically acceptable salts thereof. Some exemplary pharmaceutical compositions for Compound I and pharmaceutically acceptable salts thereof are set forth in the Examples section. Some exemplary pharmaceutical compositions for Compound II and pharmaceutically acceptable salts thereof can be found in WO 2011 / 119984 and WO 2014 / 015841, all of which are incorporated herein by reference. Some exemplary pharmaceutical compositions for Compound III and pharmaceutically acceptable salts thereof can be found in WO 2007 / 134279, WO 2010 / 019239, WO 2011 / 019413, WO 2012 / 027731 and WO 2013 / 130669, all of which are incorporated herein by reference. Some exemplary pharmaceutical compositions for compound IV and its pharmaceutically acceptable salts can be found in WO 2010 / 037066, WO 2011 / 127241, WO 2013 / 112804 and WO 2014 / 071122, all of which are incorporated herein by reference.

[00109] In some embodiments, a pharmaceutical composition comprising at least one compound selected from the inventive compounds of this disclosure and their pharmaceutically acceptable salts is administered in conjunction with a composition comprising Compound II and Compound III. Pharmaceutical compositions comprising Compounds II and III are described in PCT Publication No. WO 2015 / 160787, which is incorporated herein by reference. An example is shown in Table 2:

[00110] Table 2. Sample table containing 100mg of Compound II and 150mg of Compound III. Ingredients Amount per tablet (mg) Intra-granular Compound II SSD (spray-dried dispersion) (80 wt % Compound II, and 20 wt % HPMC) 125 Compound III SSD (80 wt % Compound III, and 19.5 wt% HPMCAS-HG, and 0.5 wt% sodium lauryl sulfate) 187.5 Microcrystalline cellulose 131.4 Croscarmellose cellulose 29.6 Total 473.5 Extra-granular Microcrystalline cellulose 112.5 Magnesium stearate 5.9 Total 118.4 Total uncoated tablets 591.9 Opadry film coating 17.7 Total coated tablets 609.6

[00111] In some embodiments, a pharmaceutical composition comprising at least one compound selected from the inventive compounds of this disclosure and their pharmaceutically acceptable salts is administered in conjunction with a composition comprising Compound III. Pharmaceutical compositions comprising Compound III are described in PCT Publication No. WO 2010 / 019239, which is incorporated herein by reference. An example is shown in Table 3:

[00112] Table 3: Ingredients for example tablets of Compound III. Tablet formulation Dosage percentage Batch dosage %Wt. / Wt. (mg) (g) Compound III SSD (80 wt % Compound III, and 19.5 wt% HPMCAS-HG, and 0.5 wt% Sodium Lauryl Sulfate) 34.09% 187.5 23.86 Microcrystalline cellulose 30.51% 167.8 21.36 Lactose 30.40% 167.2 21.28 Croscarmellose sodium 3.000% 16.50 2.100 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

[00113] Pharmaceutical compositions containing Compound III are described in PCT Publication No. WO 2013 / 130669, which is incorporated herein by reference. Exemplary mini-tablets (~2 mm diameter, ~2 mm thickness, each mini-tablet weighing approximately 6.9 mg) were formulated to contain approximately 50 mg of Compound III per 26 mini-tablets and approximately 75 mg of Compound III per 39 mini-tablets using the ingredient amounts in Table 4 below.

[00114] Table 4: Ingredients of small tablets for 50 mg and 75 mg Tablet formulation Dosage percentage Dosage (mg) Dosage (mg) Batch %Wt. / Wt. 50 mg dose 75 mg dose (g) Compound III SSD (80 wt % Compound III, and 19.5 wt% HPMCAS-HG, and 0.5 wt% 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 silicon dioxide 1.0 1.8 2.7 50.0 Magnesium stearate 1.5 2.7 4.0 74.19 Total 100 178.6 268 5003.15

[00115] In some embodiments, the pharmaceutical compositions are a tablet. In some embodiments, the pharmaceutical compositions are suitable for oral administration.

[00116] The compounds, pharmaceutically acceptable salts thereof, and deuterated isomers of any of the foregoing, and the pharmaceutical compositions of this disclosure, whether in single therapy or in combination therapy, are useful for the treatment of cystic fibrosis.

[00117] In some embodiments, described herein, methods for treating, alleviating the severity of, or alleviating symptoms of cystic fibrosis in a patient are described, comprising administering an effective amount of a compound, pharmaceutically acceptable salts thereof, or deuterated isoforms of any of the foregoing; or a pharmaceutical composition, as described herein, to a patient, e.g., a human, suffering from cystic fibrosis. In some embodiments, the patient has the F508del / minimal function (MF) genotype, the F508del / F508del genotype, the F508del / truncated genotype, or the F508del / residual function (RF) genotype.

[00118] Patients with the F508del / Minimal Function (MF) genotype are heterozygous F508del-CFTR patients with a second CFTR allele that contains a mutation predicted to result in a minimally functional CFTR protein and are not expected to respond to Compound II, Compound III, or a mixture of Compound II and Compound III. CFTR mutations have been defined using 3 primary sources:  Biological probability of responding mutations (i.e. mutation class) Evidence for clinical severity by population (per registered CFTR patient, available on 15 February 2016) oMean sweat chloride >86 mmol / L, and oPrevalence of pancreatic insufficiency (PI) >50% Laboratory tests oMutations resulting in baseline chloride transport <10% of wild-type CFTR were considered to have minimal function. oMutants resulting in chloride transport <10% of wild-type CFTR after addition of compound II and / or compound III were considered non-responsive.

[00119] Patients with the F508del / residual function (RF) genotype were defined as patients who were heterozygous for F508del-CFTR with a second CFTR allele containing a mutation that reduces the amount or function of the protein at the cell surface, which could lead to defective CFTR activity. CFTR gene mutations that result in loss-of-function phenotypes include, in some cases, a loss-of-function mutation selected from 2789+5G A, 3849+10kbCT, 3272-26A G, 711+3A G, E56K, P67L, R74W, D110E, D110H, R117C, L206W, R347H, R352Q, A455E, D579G, E831X, S945L, S977F, F1052V, R1070W, F1074L, D1152H, D1270N, E193K, and K1060T. In some embodiments, the CFTR loss-of-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 loss-of-function mutation is selected from R117H, S1235R, I1027T, R668C, G576A, M470V, L997F, R75Q, R1070Q, R31C, D614G, G1069R, R1162L, E56K, A1067T, E193K, or K1067T.

[00120] Patients with the F508del / truncating mutation are defined as patients who are heterozygous for F508del-CFTR with a second CFTR allele, a mutation associated with a truncating defect, who have clinically responded to combination III. Examples of these mutations include: G178R, S549N, S549R, G551D, G551S, G1244E, S1251N, S1255P, and G1349D.

[00121] In some embodiments, the methods of treating, alleviating, or alleviating symptoms of cystic fibrosis described herein each independently increase chloride transport above baseline in the patient.

[00122] In some embodiments, in the methods of treating, alleviating, or ameliorating symptoms of cystic fibrosis, provided herein, the patient is heterozygous for F508del, and the other CFTR mutation is any mutation that causes CF. In some embodiments, the patient is heterozygous for F508del, and the other CFTR mutation is any mutation that causes CF and is expected to respond based on laboratory and / or clinical data to any of the novel compounds described herein, such as Compound I, Compound II, Compound III, and / or the genotypes of Compound IV. In some embodiments, the patient is heterozygous for F508del, and the other CFTR mutation is any mutation that causes CF and is expected to respond based on laboratory and / or clinical data to a combination of any of the novel compounds described herein, such as Compound I, and (2) Compound II, Compound III, and / or the genotypes of Compound IV. In some embodiments, in the methods of treating, alleviating, or eliminating symptoms of cystic fibrosis provided herein, the patient has a CFTR mutation selected from any of the mutations listed in Table 5. Table 5. CFTR mutations 078delT 444delA 297-1G  A 1078delT 11234V 1154insTC 1119delA 1161delC 1138insG 1213delT 1248+1G→A 1249-1G→A 124del23bp 1259insA 1288insTA 1341+1G->A 1342-2A->C 1461ins4 1471delA 1497delGG 1507del 1525-1G→A 1525-2A→G 1548delG 1577delTA 1609del CA 1677delTA 1716G / A 1717-1G→A 1717-8G→A 1782delA 1811+1G->C 1811+1.6kbA→G 1811+1G→C 1812-1G->A 1898+1G->A 1812-1G→A 1824delA 182delT 185+1G→T 1898+1G->T 1898+1G→A 1898+1G→C 1898+3A->G 1898+5G->T 1924del7 1949del84 2043delG 2055del9→A 2105-2117del13insAGAAA 2118del14 2143delT 2183AA→G a 2183delAA→G 2184delA 2184insA 2307insA 2347delG 2556insAT 2585delT 2594delGT 2622+1G->A 2659delC 2711delT 271delT 2721del11 2732insA 2789+2insA 2789+5G→A 2790-1G→C 2790-lG->C 2869insG 2896insAG 2942insT 2957delT 296+1G→A 2991del32 3007delG 3028delA 3040G→C 306insA 306insA 1138insG 3120G→A 3120 + 1G  A 3121-1G→A 3121-2A→G 3121-977_3499+248 del2515 3132delTG 3141del9 3171delC 3195del6 3199del6 3272-26A->G 3500-2A→G 3600+2insT 365-366insT 3659delC 3667ins4 3737delA3791delC 3821delT 3849+10kbC→T 3849+lOkbC->T 3850-1G→A 3850-3T->G 3850-lG->A 3876delA 3878delG 3905InsT 394delTT 4005+1G->A 4005+2T->C 4005+1G→A 4005+lG->A 4010del4 4015delA 4016insT 4021dupT 4040delA 405+1G→A 405+3A→C 405+lG->A 406-1G→A 406-lG->A 4209TGTT->A 4209TGTT→AA 4279insA 4326delTC 4374+1G→T 4374+lG->T 4382delA 4428insGA 442delA 457TAT→G 541delC 574delA 5T 621+1G→T 621+3A->G 663delT 663delT 675del4 711+1G->T 711+1G→T 711+3A→G 711+5G→A 712-1G->T 7T 852del22 935delA 991del5 A1006E A120T A234D A349V A455E A460 A613T A46D A46Db A559T A559Tb A561E C276X C524R C524X CFTRdel2,3 CFTRdele22-23 D110E D110H D1152H D1270N D192G D443Y D513G D579G D614G D836Y D924N D979V E1104X E116K E1371X E193K E193X E403D E474K E56K E585X E588V E60K E60X E822K E822X E831X E92K E92X F1016S F1052V F1074L F1099L F191V F311del F311L F508C F508del F575Y G1061R G1069R G1244E G1249R G126D G1349D G149R G178R G194R G194V G27R G27X G314E G330X G458V G463V G480C G542X G550X G551D G551S G576A G622D G628R G628R(G->A)G673X G85E G91R G970D G970R G970R H1054D H1085P H1085R H1375P H139R H199R H199Y H609R H939R I336K I1005R I1027T I1234V I1269N I1366N I148T I175V I3336K I502T I506S I506T I507del I507del I601F I618T I807M I980K IVS14b+5G->A K710X K710X K710X L102R L1065P L1077P L1077Pb L1254X L1324P L1335P L138ins L1480P L15P L165S L206W L218X L227R L320V L346P L453S L467P L467Pb L558S L571S L732X L927P L967S L997F M1101K M1101R M152V M1T M1V M265R M470V M952I M952T N1303K P205S P574H P5L P67L P750L P99L Q1100P Q1291H Q1291R Q1313X Q1382X Q1411X Q1412X Q220X Q237E Q237H Q290X Q359K / T360K Q39X Q414 Q414X Q452P Q493X Q525X Q552X Q685X Q890X Q890X Q98R Q98X R1066C R1066H R1066M R1070Q R1070W R1102X R1158X R1162L R1162X R117C R117G R117H R117L R117P R1283M R1283S R170H R258G R31C R31L R334L R334Q R334W R347H R347L R347P R352Q R352W R516G R553Q R553X R560K R560S R560T R668C R709X R74W R751L R75Q R75X R764X R785X R792G R792X R851X R933G S1118F S1159F S1159P S1196X S1235R S1251N S1255P S1255X S13F S341P S434XS466X S489X S492F S4X S549N S549R S549R(A->C) S549R(T->G) S589N S737F S912L S912X S945L S977F T1036N T1053I T1246I T338I T604I V1153E V1240G V1293G V201M V232D V456A V456F V520F V562I V754M W1089X W1098C W1098R W1098X W1204X W1282R W1282X W361R W401X W496X W57G W57R W57X W846X Y1014C Y1032C Y1092X Y109N Y122X Y161D Y161S Y563D Y563N Y569C Y569D Y569Db Y849X Y913C Y913X aAlso known as 2183delAA→G.

[00123] In some embodiments, in the methods of treating, alleviating, or alleviating symptoms of cystic fibrosis, provided herein, the patient has a CFTR mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, 621+3A->G, 1949del84, 3141del9, 3195del6, 3199del6, 3905InsT, 4209TGTT->A, A1006E, A120T, A234D, A349V, A613T, C524R, D192G, D443Y, D513G, D836Y, D924N, D979V, E116K, E403D, E474K, E588V, E60K, E822K, F1016S, F1099L, F191V, F311del, F311L,F508C, F575Y, G1061R, G1249R, G126D, G149R, G194R, G194V, G27R, G314E, G458V, G463V, G480C, G622D, G628R, G628R(G->A), G91R, G970D, H1054D, H1085P, H1085R, H1375P, H139R, H199R, H609R, H939R, I1005R, I1234V, I1269N, I1366N, I175V, I502T, I506S, I506T, I601F, I618T, I807M, I980K, L102R, L1324P, L1335P, L138ins, L1480P, L15P, L165S, L320V, L346P, L453S, L571S, L967S, M1101R, M152V, M1T, M1V, M265R, M952I, M952T, P574H, P5L, P750L, P99L, Q1100P, Q1291H, Q1291R, Q237E, Q237H, Q452P, Q98R, R1066C, R1066H, R117G, R117L, R117P, R1283M, R1283S, R170H, R258G, R31L, R334L, R334Q, R347L, R352W, R516G, R553Q, R751L, R792G, R933G, S1118F, S1159F, S1159P, S13F, S549R(A->C), S549R(T->G), S589N, S737F, S912L, T1036N, T1053I, T1246I, T604I, V1153E, V1240G, V1293G, V201M, V232D, V456A, V456F, V562I, W1098C, W1098R, W1282R, W361R, W57G, W57R, Y1014C, Y1032C, Y109N, Y161D, Y161S, Y563D, Y563N, Y569C and Y913C are selected.,

[00124] In some examples, the patient has at least one combination mutation from: G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C and 621+3A->G.

[00125] In some examples, the patient has at least one combination mutation from: 1949del84, 3141del9, 3195del6, 3199del6, 3905InsT, 4209TGTT->A, A1006E, A120T, A234D, A349V, A613T, C524R, D192G, D443Y, D513G, D836Y, D924N, D979V, E116K, E403D, E474K, E588V, E60K, E822K, F1016S, F1099L, F191V, F311del, F311L, F508C, F575Y, G1061R, G1249R, G126D, G149R, G194R, G194V, G27R, G314E, G458V, G463V, G480C, G622D, G628R, G628R(G->A), G91R, G970D, H1054D, H1085P, H1085R, H1375P, H139R, H199R, H609R, H939R, I1005R, I1234V, I1269N, I1366N, I175V, I502T, I506S, I506T, I601F, I618T, I807M, I980K, L102R, L1324P, L1335P, L138ins, L1480P, L15P, L165S, L320V, L346P, L453S, L571S, L967S, M1101R, M152V, M1T, M1V, M265R, M952I, M952T, P574H, P5L, P750L, P99L, Q1100P, Q1291H, Q1291R, Q237E, Q237H, Q452P, Q98R, R1066C, R1066H, R117G, R117L, R117P, R1283M, R1283S, R170H, R258G, R31L, R334L, R334Q, R347L, R352W, R516G, R553Q, R751L, R792G, R933G, S1118F, S1159F, S1159P, S13F, S549R(A->C), S549R(T->G), S589N, S737F, S912L,T1036N, T1053I, T1246I, T604I, V1153E, V1240G, V1293G, V201M, V232D, V456A, V456F, V562I, W1098C, W1098R, W1282R, W361R, W57G, W57R, Y1014C, Y1032C, Y109N, Y161D, Y161S, Y563D, Y563N, Y569C وY913C.,

[00126] In some embodiments, in the methods of treating, alleviating, or ameliorating symptoms of cystic fibrosis, provided herein, the patient has a CFTR G551D mutation. In some embodiments, the patient is homozygous for the G551D mutation. In some embodiments, the patient is heterozygous for the G551D mutation. In some embodiments, the patient is heterozygous for the G551D mutation, with the G551D mutation on one allele and a CF-causing mutation on the other allele. In some instances, the patient is heterozygous for the G551D mutation, with the G551D mutation on one allele and a CF-causing mutation on one of F508del, G542X, N1303K, W1282X, R117H, R553X, 1717-1G->A, 621+1G->T, 2789+5G->A, 3849+10kbC->T, R1162X, G85E, 3120+1G->A, ΔI507, 1898+1G->A, 3659delC, R347P, R560T, R334W, A455E, 2184delA, or 711+1G->T. In some examples, the patient is heterozygous for the G551D mutation and the other CFTR mutation is an F508del. In some examples, the patient is heterozygous for the G551D mutation and the other CFTR mutation is an R117H.

[00127] In some embodiments, in the methods of treating, alleviating, or ameliorating symptoms of cystic fibrosis, provided herein, the patient has a CFTR F508del mutation. In some embodiments, the patient is homozygous for the F508del mutation. In some embodiments, the patient is heterozygous for the F508del mutation, with the F508del mutation on one allele and a CF-causing mutation on the other allele. In some examples, the patient is heterozygous for the F508del mutation, and other CFTR mutations that cause CF include, but are not limited to, G551D, G542X, N1303K, W1282X, R117H, R553X, 1717-1G->A, 621+1G->T, 2789+5G->A, 3849+10kbC->T, R1162X, G85E, 3120+1G->A, ΔI507, 1898+1G->A, 3659delC, R347P, R560T, R334W, A455E, 2184delA, or 711+1G->T. In some examples, the patient is heterozygous for the F508del mutation and the other CFTR mutation is a G551D. In some examples, the patient is heterozygous for the F508del mutation and the other CFTR mutation is a R117H.

[00128] In some embodiments, the patient has at least one combination mutation from: (i)D443Y;G576A;R668C, (ii), F508C; S1251N (iii),G576A; R668C (iv),G970R; M470V (v),R74W; D1270N (vi)R74W;V201M, and (vii) R74W;V201M;D1270N.

[00129] In some embodiments, in the methods of treating, alleviating, or ameliorating symptoms of cystic fibrosis, provided herein, the patient has a CFTR mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, and G1069R. In some embodiments, the patient has a CFTR mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, and S1251N. In some embodiments, the patient's CFTR mutation is selected from E193K, F1052V, and G1069R. In some instances, the procedure causes an increase in chloride transport relative to the patient's baseline chloride transport.

[00130] In some embodiments, in the methods of treating, alleviating, or ameliorating symptoms of cystic fibrosis provided herein, the patient has a CFTR mutation selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, and D1152H.

[00131] In some examples, the patient's CFTR mutation is selected from 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C and 621+3A->G are selected. In some examples, the patient's CFTR mutation is selected from 1717-1G->A, 1811+1.6kbA->G, 2789+5G->A, 3272-26A->G and 3849+10kbC->T. In some examples, the patient's CFTR mutation is selected from 2789+5G->A and 3272-26A->G.

[00132] In some embodiments, in the methods of treating, alleviating, or alleviating symptoms of cystic fibrosis, provided herein, the patient has a CFTR mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C and 621+3A->G were selected and one CFTR mutation was selected from F508del, R117H and G551D.

[00133] In some embodiments, in the methods of treating, alleviating, or alleviating symptoms of cystic fibrosis, provided herein, the patient has a CFTR mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, 621+3A->G and one CFTR mutation among F508del, R117H and G551D and one CFTR mutation among F508del, R117H and G551D.

[00134] In some embodiments, the patient has a CFTR mutation selected from 178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, and G1069R, and a CFTR mutation selected from F508del, R117H, and G551D. In some embodiments, the patient's CFTR mutation is selected from COPY-PASTE, and a CFTR mutation selected from F508del, R117H, and G551D. In some embodiments, the patient's CFTR mutation is selected from E193K, F1052V, and G1069R, and a CFTR mutation selected from F508del, R117H, and G551D.

[00135] In some embodiments, the patient's CFTR mutation is selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, and D1152H, and a CFTR mutation is selected from F508del, R117H, and G551D.

[00136] In some examples, the patient's CFTR mutation is selected from 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G / A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C and 621+3A->G are selected and a CFTR mutation is selected from F508del, R117H and G551D. In some examples, the patient's CFTR mutation is selected from 1717-1G->A, 1811+1.6kbA->G, 2789+5G->A, 3272-26A->G and 3849+10kbC->T, and a CFTR mutation is selected from F508del, R117H and G551D. In some examples, the patient's CFTR mutation is selected from 2789+5G->A and 3272-26A->G, and a CFTR mutation is selected from F508del and R117H.

[00137] In some embodiments, the patient is heterozygous, with a CF-causing mutation on one allele and a CF-causing mutation on the other allele. In some embodiments, the patient is heterozygous for F508del, and the other CFTR-causing mutation is any mutation that causes CF, including, but not limited to, F508del on one CFTR allele and a CFTR mutation on the secondary CFTR allele that is associated with minimal CFTR function, residual CFTR function, or a defect in CFTR channel-blocking activity. In some embodiments, the CF-causing mutation is selected from Table 5. In some embodiments, the CF-causing mutation is selected from Table 6. In some embodiments, the CF-causing mutation is selected from Table 7. .

[00138] In some embodiments, the patient is heterozygous and has a CFTR mutation on one CFTR allele selected from the mutations listed in the table of FIG. 7 and a CFTR mutation on the other CFTR allele selected from the mutations listed in Table 6: Table 6: CFTR mutations Q39X W57X E60X R75X E92X Q98X Y122X L218X Q220X C276X Q290X G330X W401X Q414X S434X S466X S489X Q493X W496X Q525X G542X Q552X R553X E585X G673X R709X K710X L732X R764X R785X R792X E822X W846X R851X Q890X S912X W1089X Y1092X E1104X R1158X R1162X S1196X W1204X S1255X W1282X Q1313X 621+1G→T 711+1G→T 711+5G→A 712-1G→T 405+1G→A 405+3A→C 406-1G→A 621+1G → T 1248+1G→A 1341+1G→A 1717-1G→A 1811+1.6kbA → G 1811+1G → C 1812-1G→A 1898+1G→A 2622+1G→A 3120+1G→A 3120G → A 3850-1G→A 4005+1G→A 4374+1G→T 663delT 2183AA→G CFTRdel2,3 3659delC 394delTT 2184insA 3905insT 2184delA 1078delT 1154insTC 2183delAA→G 2143delT 1677delTA 3876delA 2307insA 4382delA 4016insT 2347delG 3007delG 574delA 2711delT 3791delC CFTRdele22-23 457TAT→G 2043delG 2869insG 3600+2insT 3737delA 4040delA 541delC A46D T338I R347P L927P G85E S341P L467P I507del V520F A559T R560T R560S A561E Y569D L1065P R1066C R1066M L1077P H1085R M1101K N1303K 3849+10kbC → T 3272-26A → G 711+3A → G E56K P67L R74W D110E D110H R117C L206W R347H R352Q A455E D579G E831X S945L S977F F1052V R1070W F1074L D1152H D1270N G178R S549N S549R G551D G551S G1244E S1251N S1255P G1349D. جدول 7: جهش‌های CFTR Mutation criteria Short mutations  %PI >50% and / or SwCl - >86 mmol / L  Full-length protein variant S4X C276X G542X R792X E1104X G27X Q290X G550X E822X R1158X Q39X G330X ​​Q552X W846X R1162X W57X W401X R553X Y849X S1196X E60X Q414X E585X R851X W1204X R75X S434X G673X Q890X L1254X E92X S466X Q685X S912X S1255X Q98X S489X R709X Y913X W1282X Y1220 Q493X K710X W1089X Q1313X E193X W496X L732X Y1092X E1371X L218X C524X R764X W1098X Q1382X Q220X Q525X R785X R1102X Q1411X Linkage mutations  %PI >50% and / or SwCl - >86 mmol / L  No or little mRNA 185+ 1G→T 711+5G→A 1717-8G→A 2622+1G→A 3121-1G→A 296+1G→A 712-1G→T 1717-1G→A 2790-1G →C 3500-2A→G 405+1G→A 1248+1G→A 1811+1G→C 3040G →C (G970R) 3600+2insT 405+3A→C 1249-1G→A 1811+1.6kbA→G 3850-1G→A 406-1G→A 1341+1G→A 1812-1G→A 3120G→A 4005+1G→A 621+1G→T 1525-2A→G 1898+1G→A 3120+1G→A 4374+1G→T 711+1G→T 1525-1G→A 1898+1G→C 3121-2A→G Small (≤3 nucleotides) deletion / insertion (ins / del) frameshift mutations  %PI >50% and / or SwCl - >86 mmol / L  Disorganized or truncated protein 182delT 1119delA1782delA 2732insA 3876delA 306insA 1138insG 1824delA 2869insG 3878delG 365-366insT 1154insTC 2043delG 2896insAG 3905insT 394delTT 1161delC 2143delT 2942insT 4016insT 442delA 1213delT 2183AA→G a 2957delT 4021dupT 444delA 1259insA 2184delA 3007delG 4040delA 457TAT→G 1288insTA 2184insA 3028delA 4279insA 541delC 1471delA 2307insA 3171delC 4326delTC 574delA 1497delGG 2347delG 3659delC 663delT 1548delG 2585delT 3737delA 935delA 1609del CA 2594delGT 3791delC 1078delT 1677delTA 2711delT 3821delT Non-small (>3 nucleotides) deletion / insertion (ins / del) frameshift mutations  %PI >50% and / or SwCl - >86 mmol / L  Scrambled or truncated protein CFTRdele2,3 1461ins4 2991del32 CFTRdele22,23 1924del7 3667ins4 124del23bp 2055del9→A 4010del4 852del22 2105-2117del13insAGAAA 4209TGTT→AA 991del5 2721del11 Mutations II, III, IV No response to compound III alone or in combination with compound II or compound IV  %PI>50% and / or SwCl >86 mmol / L and  No response to compound III alone or in combination with compound II or compound IV A46D b V520F Y569D b N1303K G85EA559T b L1065P R347P R560T R1066C L467P b R560S L1077P b I507del A561E M1101K Note: %PI: Percentage of F508del-CFTR CFTR2 patients with pancreatic insufficiency; SwCl -: Mean chloride of F508del-CFTR among CFTR2 patients a Also known as 2183delAA→G. b Unpublished data.

[00139] Table 7 contains specific examples of CFTR minimal loss of function mutations identified through FDA genotypic evaluation but this is not an exhaustive list.

[00140] In some embodiments, the patient is one of the following: with the F508del / MF (F / MF) genotype (heterozygous for F508del and an MF mutation that is not expected to respond to CFTR modulators, e.g., compound III); with the F508del / F508del (F / F) genotype (homozygous for F508del); and / or with the F508del / gating (F / G) genotype (heterozygous for F508del and an truncating mutation that is known to respond to a CFTR modulator (e.g., compound III). In some embodiments, the patient with the F508del / MF (F / MF) genotype has an MF mutation that is not expected to respond to compound II, compound III, or both compound II and compound III. In some cases, patients with the F508del / MF (F / MF) genotype have one of the MF mutations listed in Table 7.

[00141] In some embodiments, the patient is heterozygous for F508del and the other CFTR genetic mutation is any of a number of CF-causing mutations, including truncating mutations, splicing mutations, small (≤3 nucleotides) insertion or deletion mutations (ins / del); non-small (>3 nucleotides) insertion or deletion mutations (ins / del); and class II, III, IV mutations that do not respond to compound III alone or in combination with compound II or compound IV.

[00142] In some embodiments, the patient is heterozygous for the F508del mutation and the other CFTR mutation is a truncating mutation. In some embodiments, the truncating mutation is one of the truncating mutations listed in Table 7.

[00143] In some embodiments, the patient is heterozygous for the F508del mutation and the other CFTR mutation is a splicing mutation. In some embodiments, the splicing mutation is one of the splicing mutations listed in Table 7.

[00144] In some embodiments, the patient is heterozygous for the F508del mutation and the other CFTR mutation is a small (≤3 nucleotide) insertion or deletion (ins / del) mutation. In some embodiments, the small (≤3 nucleotide) insertion or deletion (ins / del) mutation is one of the small (≤3 nucleotide) insertion or deletion (ins / del) mutations listed in Table 7.

[00145] In some embodiments, the patient is heterozygous for F508del and the other CFTR genetic mutation is any mutation leading to CF that is expected, based on laboratory and clinical data, to respond to any combination of (1) a novel compound of the kind described herein (e.g., a compound of formula (I), (II), (III), (IV), (V) or (VI), and pharmaceutically acceptable salts thereof and deuterated derivatives thereof) and (2) Compound II and / or Compound III and / or Compound IV.

[00146] In some embodiments, the patient is heterozygous for F508del and the other CFTR genetic mutation is any mutation leading to CF that is expected, based on in vitro and clinical data, to respond to any combination of a novel compound of the invention described herein (e.g., a compound of formula (I), (II), (III), (IV), (V) or (VI), and pharmaceutically acceptable salts thereof and deuterated derivatives thereof) and Compound II and Compound III.

[00147] In some embodiments, the patient is heterozygous for the F508del mutation and the other CFTR mutation is a non-small (>3 nucleotide) insertion or deletion (ins / del) mutation. In some embodiments, the non-small (>3 nucleotide) insertion or deletion (ins / del) mutation is one of the non-small (>3 nucleotide) insertion or deletion (ins / del) mutations listed in Table 6.

[00148] In some embodiments, the patient is heterozygous for F508del, and the other CFTR genetic mutation is a class II, III, IV mutation that does not respond to compound III alone or in combination with compound II or compound IV. In some embodiments, the class II, III, IV mutation that does not respond to compound III alone or in combination with compound II or compound IV is one of the class II, III, IV mutations that do not respond to compound III alone or in combination with compound II or compound IV and is listed in Table 7.

[00149] In some examples, the patient is heterozygous for the F508del mutation and the other CFTR mutation is one of the mutations listed in Table 7.

[00150] In some examples, the patient is heterozygous for the F508del mutation and the other CFTR mutation, other than F508del, is one of the mutations listed in Tables 5, 6, 7 and Figure 7.

[00151] In some examples, the patient is heterozygous for the F508del mutation and the other CFTR genetic mutation is one of the mutations listed in Table 5. In some examples, the patient is heterozygous for the F508del mutation and the other CFTR genetic mutation is one of the mutations listed in Table 6. In some examples, the patient is heterozygous for the F508del mutation and the other CFTR genetic mutation is one of the mutations listed in Table 7. In some examples, the patient is heterozygous for the F508del mutation and the other CFTR genetic mutation is one of the mutations listed in Figure 7.

[00152] In some examples, the patient is homozygous for F508del.

[00153] In some embodiments, the patient is heterozygous and has a CF-causing mutation on one CFTR allele selected from the mutations listed in Table 7 and Figure 7 and a CF-causing mutation on the other CFTR allele selected from the mutations listed in Table 7.

[00154] In some embodiments, the compounds described herein are useful for treating, alleviating, or alleviating symptoms of cystic fibrosis in patients who exhibit residual CFTR activity in the apical membrane of respiratory and non-respiratory epithelia. The presence of residual CFTR activity at the epithelial surface can be detected using methods known in the art, such as standard electrophysiological, biochemical, or histochemical techniques. These methods detect CFTR activity using in vitro or in vivo electrophysiological techniques, measurement of sweat or salivary Cl- concentrations, or in vitro histochemical or biochemical techniques to monitor cell surface density. Using these methods, residual CFTR activity can be identified for patients who are heterozygous or homozygous for a variety of mutations, including patients heterozygous for the most common mutation, F508del, as well as mutations such as G551D or the R117H mutation. In some embodiments, the compounds described herein are useful for treating, alleviating the severity of, or alleviating symptoms of cystic fibrosis in patients who have very low or no residual CFTR activity.In some embodiments, the compounds described herein are useful for treating, alleviating the severity of, or eliminating the symptoms of cystic fibrosis in patients who have very low or zero residual CFTR activity in the apical membrane of respiratory epithelium.

[00155] In some embodiments, the compounds described herein are useful for treating, alleviating the severity of, or eliminating symptoms of cystic fibrosis in patients who have residual CFTR activity using pharmacological methods. These methods increase the amount of CFTR present on the cell surface, thereby inactivating CFTR in a patient or increasing the existing level of residual CFTR activity.

[00156] In some embodiments, the compounds described herein are useful for treating, alleviating the severity of, or alleviating symptoms of cystic fibrosis in patients who have residual CFTR activity.

[00157] In some embodiments, the compounds described herein are useful for treating, alleviating, or alleviating symptoms of cystic fibrosis in patients with a particular clinical phenotype, e.g., a mild to moderate clinical phenotype that is typically associated with the amount of residual CFTR activity in the apical membrane of the epithelium. These phenotypes include patients who exhibit pancreatic dysfunction.

[00158] In some embodiments, the compounds described herein are for treating, alleviating the severity or alleviating the symptoms of cystic fibrosis in patients diagnosed with pancreatic insufficiency, idiopathic pancreatitis, congenital bilateral absence of efferent arterioles, or mild lung disease in which the patient exhibits residual CFTR activity.

[00159] In some embodiments, this disclosure relates to a method for increasing or inducing anion channel activity in vitro or in vivo, comprising contacting the channel with one of the compounds described herein. In some embodiments, the anion channel is a chloride channel or a bicarbonate channel. In some embodiments, the anion channel is a chloride channel.

[00160] The exact amount required will vary from subject to subject and will depend on the type, age, and general condition of the subject, the severity of the disease, the particular subject, and the method of administration, and the like. The compositions of this disclosure may be formulated in dosage units for ease of administration and uniformity of dosage. The term "dosage units" as used herein refers to a discrete physical unit of an agent that is appropriate for the patient being treated. However, it is understood that the total daily dosage of the compositions and mixtures of this invention will be determined by the physician within the scope of his or her medical diagnosis. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including the disorder being treated, the severity of the disorder, the activity of the compound employed, the particular compound employed, the age, weight, general health, sex, and diet of the patient, the time of administration, the route of administration, and the rate of excretion of the particular compound employed, the duration of treatment, the drugs used in combination with or in conjunction with the particular compound employed, and similar factors known to those skilled in the art.The word "patient" as used in this text means a living being, such as a mammal or even a human.

[00161] In some embodiments, herein referred to methods of treatment using isotopically labeled compounds are compounds having the same structure except that one or more atoms have been replaced by one or more atoms having an atomic mass or atomic number different from that which occurs naturally (isotopic labeling). Examples of isotopes available and suitable for this application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F and 36Cl.

[00162] Isotopically labeled compounds and salts can be used in a number of useful ways. They can be useful for drugs and / or assays, such as tissue distribution assays. For example, tritium (3H)- and / or carbon 14 (14C)-labeled compounds are particularly useful for assays, such as tissue distribution assays, due to their ease of preparation and excellent detectability. For example, deuterium (2H)-labeled forms are therapeutically useful with potential therapeutic advantages over non-2H-labeled compounds. In general, deuterium (2H)-labeled forms and salts can have higher metabolic stability than non-isotopically labeled forms due to the kinetic effect of the isotope, as described below. Higher metabolic stability directly leads to increased in vivo half-life or lower doses, which can be desirable.Isotopically labeled compounds and salts can often be prepared by following the methods outlined in the synthetic schemes and associated descriptions in the Examples and Preparations sections of this text, by replacing a nonisotopic reaction with an isotopic reaction.

[00163] In some embodiments, the isotopically labeled compounds and salts are deuterium (2H)-labeled forms. In certain embodiments, the isotopically labeled compounds and salts are deuterium (2H)-labeled forms in which one or more hydrogen atoms have been replaced by deuterium. In chemical structures, deuterium is represented as “2H” or “D.”

[00164] Deuterium (2H)-labeled compounds and salts can alter the oxidative metabolism of a compound as a result of the primary isotopic kinetic effect. The primary isotopic kinetic effect is the change in the rate of a chemical reaction that occurs as a result of the exchange of isotopic nuclei, which can itself change the energy background required for covalent bonding after isotopic exchange. The exchange of a larger isotope often lowers the background energy for a chemical bond, thereby reducing the rate-limiting break. If the bond break occurs at or near the saddle point region during the coordination of a multiproduct reaction, the rate of product distribution can be greatly altered. To illustrate: If deuterium bonds to a carbon atom in a non-exchange position, the rate difference kM / kD = 2-7 ​​is normal. For further discussion, see S. L. Harbson and R. De Tag, Deuterium in Drug Discovery and Development, Ann. Rep. . Med. Chem. 2011, 46, 403-417; and T. J. Ghent "The use of deuterium in drug discovery: drug labeling" J. Med. Chem.2014, 57, 3595-3611, relevant sections independently referenced in this text.

[00165] The concentration of isotope(s) (e.g., deuterium) in isotopically labeled compounds and salts herein can be defined in terms of the isotopic radioactivity factor. The term "isotopic radioactivity factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a given isotope. In some instances, if a substituent in one of the compounds of this text is deuterium, the isotopic radioactivity factor for each specific deuterium atom in that compound will be at least 3500 (52.5% deuterium), at least 4000 (60% deuterium), at least 4500 (67.5% deuterium), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium), at least 6000 (90% deuterium), at least 6333.3 (95% deuterium), at least 6466.7 (97% deuterium), at least 6600 (99% deuterium), or at least 6633.3 (99.5% deuterium).

[00166] When identifying and developing therapeutic agents, practitioners strive to improve pharmacokinetic parameters while maintaining desirable laboratory characteristics. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism.

[00167] Those skilled in the art will appreciate that deuteration of one or more metabolically variable sites on a compound or active metabolite can improve one or more of the key properties of a DMPK while maintaining biological activity compared to hydrogenated counterparts. The key property or properties of a DMPK can affect the location, half-life, clearance, metabolism, and / or even dietary requirements for maximum absorption of the drug product. Deuteration can also alter metabolism at other non-deuterated sites of the deuterated compound.

[00168] In some examples, this text provides deuterated derivatives of the novel compounds and their pharmaceutically acceptable salts. Non-limiting examples of deuterated compounds are provided in Figure 1.

[00169] In some embodiments, Compound III, as used herein, comprises the deuterated compounds described in US Patent No. 8,865,902 (incorporated herein by reference) and CTP-656.

[00170] In some embodiments, compound III is: .

[00171] Examples of this text include: The novel compounds described herein (e.g., compounds of Formulae (I)-(VI), a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, including the compounds of Figure 1 and those specifically mentioned herein) can be prepared by methods conveniently known in the art. For example, they can be prepared according to the methods described in WO 2016 / 057572 and the exemplary syntheses set forth in the Examples below. For example, deuterated derivatives of the novel compounds of Formulae (I)-(VI) and their pharmaceutically acceptable salts can be prepared in a manner analogous to the compounds of Formulae (I)-(VI) and their pharmaceutically acceptable salts using intermediates and / or reagents in which one or more hydrogen atoms are replaced by deuterium. See, for example, T. J. Gent "Use of Deuterium in Drug Discovery: Drug Labeling" J. Med. Chem. 2014, 57, 3595-3611, relevant sections independently referenced in this text.

[00172] In some embodiments, compounds of formulas (X), (III), (IV), (V), and (VI), and pharmaceutically acceptable salts thereof, and deuterated derivatives of each of the foregoing, are prepared as set forth in Schemes 1-2, wherein the variables are each as set forth in Formulas (I), (II), (III), (IV), (V), or (VI) above, and wherein Ra is independently selected from C1-C4 alkyl groups; and each Xa is independently selected from F or Cl. Suitable conditions for each of the steps shown in the Schemes can be provided as is known in the art. 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 examples, each Xa for formulas (D), (L), (O), and (P) in Scheme 6 is independently F. In some examples, r in formulas (X), (B), (C), (D), and (F) is independently 0.

[00173] In some embodiments, as set forth in Scheme 1, the methods comprise reacting a compound of formula (F) or a salt thereof with a compound of formula (G) or a salt thereof to produce a compound of formula (X), a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing. Plan 1

[00174] In some examples, in formula (F), (G) and (X): - One of Y1 and Y2 is N and the other is CH; - R1 is –(C(R2)2)kO-(C(R2)2)mR7 - each R2 is independently selected from hydrogen; halogens; cyano; hydroxy; C1-C2 alkoxy groups, and the C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy, and C3-5 cycloalkyl groups, which are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - each R3 is independently selected from C1-C4 alkyl groups optionally substituted with one or more hydroxy groups or two R3 pairs; together with the carbon atom to which they are attached, are of a C3-4 cycloalkyl; - each R4 is independently selected from halogens; - R5 is selected from hydrogen and C1-C4 alkyl groups; - each R6 is independently selected from halogens, cyano, hydroxy, hydroxymethyl, C1-C2 alkoxy groups, C1-C2 alkyl groups and halogenated C1-C2 alkyl groups; - R7 is selected from hydrogen; halogens; cyano; C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy; and C3-C10 cycloalkyl groups are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - Xa is F or Cl; - k is equal to 0 or 1. - r is equal to 0 or 1. - m is 0, 1, 2, or 3. - p is 0, 1 or 2; and - q is 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[00175] In some examples, r in formula (X) is equal to 0.

[00176] Any suitable conditions, including those known in the art for a nucleophilic amino reaction, can be used. In some embodiments, the reaction shown in Scheme 1 is carried out in the presence of a base such as a metal carbonate (e.g., Na2CO3 or K2CO3).

[00177] In some embodiments, compounds of formula (X), pharmaceutically acceptable salts thereof, or deuterated derivatives thereof, wherein Y2 is N and Y1 is CH in each of formula (F), (G), and (X), are prepared using the methods of Scheme 1. In some embodiments, a salt of a compound of formula (G) is used. In some embodiments, the HCl salt of a compound of formula (G) is used.

[00178] 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, those described in WO 2016 / 57572 and the synthetic examples given in the examples below.

[00179] In some embodiments, as set forth in Scheme 2, a compound of formula (F) or a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, is prepared using a method comprising reacting a compound of formula (D) or a salt thereof with a compound of formula (E) or a salt thereof. In some embodiments, compounds of formula (D), their salts, or deuterated derivatives of any of the foregoing are prepared using a method comprising reacting a compound of formula (A) or a salt thereof with a compound of formula (B) or a salt thereof to produce a compound of formula (C) or a salt thereof; and hydrolyzing the –C(O)ORa of a compound of formula (C) to produce a compound of formula (D) or a salt thereof. All the favorable conditions known in the art can be used for steps (A), (B) and (C) of Scheme 2 below, for example those for the coupling reaction between the carboxylic acid and the sulfonamide or those for the acylation of the sulfonamide for step (A), those for the ester hydrolysis for step (B), and those for the nucleophilic amino reaction for step (C).

[00180] In some embodiments, step (A) of Scheme 2 below is carried out in the presence of a base. In some embodiments, step (A) of Scheme 2 below is carried out in the presence of a non-nucleophilic base. In some embodiments, in step (A) the reaction of a compound of formula (D) or a salt thereof with a compound of formula (E) or a salt thereof comprises reacting the compound of formula (D) or a salt thereof with a coupling reagent such as carbonyldiimidazole (CDI) and then with the compound of formula (E) or a salt thereof in the presence of a base such as a non-nucleophilic base. In some embodiments, the compound of formula (D) or a salt thereof is reacted with CDI before reacting with the compound of formula (E) or a salt thereof and then with the 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).

[00181] In some examples, step (B) of Scheme 2 below is carried out in the presence of a base. In some examples, step (B) is carried out in the presence of an aqueous base such as aqueous hydroxide. In some examples, step (B) is carried out in the presence of an aqueous metal hydroxide such as aqueous NaOH. In some examples, step (B) of Scheme 2 below is carried out in the presence of an acid. In some examples, step (B) is carried out in the presence of an aqueous acid such as aqueous HCl.

[00182] In some examples, step (C) of Scheme 2 below is carried out in the presence of a base. In some examples, step (C) is carried out in the presence of a metal carbonate (e.g., Na2CO3 or K2CO3).

[00183] In some examples, a method for preparing a compound of the following formula (Compound 1) is described: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing. This method comprises reacting a compound of formula (F-1) a salt thereof with a compound of formula (G-1) a salt thereof, wherein Xa is F or Cl, as set forth in Scheme 3: Plan 3 .

[00184] Any suitable conditions, including those known in the art for a nucleophilic amino reaction, can be used. In some embodiments, the reaction shown in Scheme 3 is carried out in the presence of a base such as a metal carbonate (e.g., Na2CO3 or K2CO3).

[00185] In some examples, a salt of a compound of formula (G-1) is employed. In some examples, the HCl salt of a compound of formula (G-1) is employed.

[00186] 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, for example, those described in WO 2016 / 57572 and the synthetic examples given in the following examples.

[00187] In some embodiments, as set forth in Scheme 4, a compound of formula (F-1) or a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, is prepared using a method comprising reacting 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), their salts, or deuterated derivatives are prepared using a method comprising reacting a compound of formula (A-1) or a salt thereof with a compound of formula (B-1) or a salt thereof to produce a compound of formula (C-1) or a salt thereof; and hydrolyzing –C(O)ORa of a compound of formula (C-1) to produce a compound of formula (D-1) or a salt thereof. All favorable conditions known in the art can be used for steps (A-1), (B-1), and (C-1) of Scheme 4 below, for example, those for the coupling reaction between the carboxylic acid and the sulfonamide or those for the acylation of the sulfonamide for step (A-1), those for the ester hydrolysis for step (B-1), and those for the nucleophilic amino reaction for step (C-1).

[00188] In some embodiments, step (A-1) of Scheme 4 below is carried out in the presence of a base. In some embodiments, step (A-1) of Scheme 4 below is carried out in the presence of a non-nucleophilic base. In some embodiments, in step (A-1) the reaction of a compound of formula (D-1) or a salt thereof with a compound of formula (E-1) or a salt thereof comprises reacting the compound of formula (D-1) or a salt thereof with a coupling reagent such as carbonyldiimidazole (CDI) and then with the compound of formula (E-1) or a salt thereof in the presence of a base such as a non-nucleophilic base. In some embodiments, (1) 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 (2) the reaction product of step (1) is reacted with a compound of 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).

[00189] In some examples, step (B-1) of Scheme 4 below is carried out in the presence of a base. In some examples, step (B-1) is carried out in the presence of an aqueous base such as aqueous hydroxide. In some examples, step (B-1) is carried out in the presence of an aqueous metal hydroxide such as aqueous NaOH. In some examples, step (B-1) of Scheme 4 below is carried out in the presence of an acid. In some examples, step (B-1) is carried out in the presence of an aqueous acid such as aqueous HCl.

[00190] In some examples, step (C-1) of Scheme 4 below is carried out in the presence of a base. In some examples, step (C-1) is carried out in the presence of a metal carbonate (e.g., Na2CO3 or K2CO3).

[00191] In Scheme 4, Ra is selected from C1-C4 alkyl groups; and each Xa is independently F or Cl.

[00192] In some embodiments, methods for preparing a compound of Formulas (I) and (II) wherein X is NH or N(C1-C4alkyl) or a deuterated derivative of any of the foregoing, comprise reacting a compound of Formula (L) or a salt thereof with NR*3 wherein R* is H or C1-C4alkyl, as set forth in Schemes 5 and 6. Plan 5 . Plan 6

[00193] Any of the favorable conditions known in the art can be used for the sulfoxamination reaction, such as for electrophilic additions by amines. In some embodiments, the sulfoxamination reaction is carried out in the presence of a chlorinating or oxidizing agent, such as N-chlorosuccinimide (NCS).

[00194] In some embodiments, a compound of formula (L) or a salt thereof is prepared by a method comprising oxidizing a sulfur moiety of a compound of formula (M) or a salt thereof, as set forth in Scheme 7 below: Plan 7

[00195] Any of the favorable conditions known in the art can be used for the oxidation reaction. In some examples, the oxidation is carried out in the presence of a peroxycarboxylic acid, such as meta-chlorobenzoic acid (m-CPBA).

[00196] In some embodiments, a compound of formula (M) or a pharmaceutically acceptable 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 of the preferred conditions known in the art can be used.

[00197] In some embodiments, a compound of formula (O) or a pharmaceutically acceptable 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 pharmaceutically acceptable salt thereof is prepared by amidating the -C(O)OH group of a compound of formula (D) or a salt thereof. Any of the preferred conditions known in the art can be used.

[00198] Other examples include: #x200e1#x200e#x200f.#x200fA compound of formula I: (I), A pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, Where: - One of Y1 and Y2 is N and the other is CH; - X is selected from O, NH and N(C1-C4alkyl) groups; - R1 is –(C(R2)2)kO-(C(R2)2)mR7 - each R2 is independently selected from hydrogen; halogens; cyano; hydroxy; C1-C2 alkoxy groups, and the C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy, and C3-5 cycloalkyl groups, which are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - each R3 is independently selected from C1-C4 alkyl groups optionally substituted with one or more hydroxy groups or two R3 pairs; together with the carbon atom to which they are attached, are of a C3-4 cycloalkyl; - each R4 is independently selected from halogens; - R5 is selected from hydrogen and C1-C4 alkyl groups; - each R6 is independently selected from halogens, cyano, hydroxy, hydroxymethyl, C1-C2 alkoxy groups, C1-C2 alkyl groups and halogenated C1-C2 alkyl groups; - each R7 is selected from hydrogen; halogens; cyano; the C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy; and the C3-C10 cycloalkyl groups are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - k is equal to 0 or 1. - r is equal to 0 or 1. - m is 0, 1, 2, or 3. - p is 0, 1 or 2; and - q is 0, 1, 2, 3, 4, 5, 6, 7 or 8. #x200e2#x200e#x200f.#x200fA compound of formula II: (II) A pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, Where: - X is selected from O, NH and N(C1-C4alkyl) groups; - R1 is –(C(R2)2)kO-(C(R2)2)mR7 - each R2 is independently selected from hydrogen; halogens; cyano; hydroxy; C1-C2 alkoxy groups, and the C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy, and C3-5 cycloalkyl groups, which are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - each R3 is independently selected from C1-C4 alkyl groups optionally substituted with one or more hydroxy groups or two R3 pairs; together with the carbon atom to which they are attached, are of a C3-4 cycloalkyl; - each R4 is independently selected from halogens; - R5 is selected from hydrogen and C1-C4 alkyl groups; - each R6 is independently selected from halogens, cyano, hydroxy, hydroxymethyl, C1-C2 alkoxy groups, C1-C2 alkyl groups and halogenated C1-C2 alkyl groups; - each R7 is selected from hydrogen; halogens; cyano; the C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy; and the C3-C10 cycloalkyl groups are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - k is equal to 0 or 1. - r is equal to 0 or 1. - m is 0, 1, 2, or 3. - p is 0, 1 or 2; and - q is 0, 1, 2, 3, 4, 5, 6, 7 or 8. #x200f #x200f#x200e3#x200e#x200f.#x200fA compound of formula III: (III) A pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, Where: - R1 is –(C(R2)2)kO-(C(R2)2)mR7 - each R2 is independently selected from hydrogen; halogens; cyano; hydroxy; C1-C2 alkoxy groups, and the C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy, and C3-5 cycloalkyl groups, which are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - each R3 is independently selected from C1-C4 alkyl groups optionally substituted with one or more hydroxy groups or two R3 pairs; together with the carbon atom to which they are attached, are of a C3-4 cycloalkyl; - each R4 is independently selected from halogens; - R5 is selected from hydrogen and C1-C4 alkyl groups; - each R6 is independently selected from halogens, cyano, hydroxy, hydroxymethyl, C1-C2 alkoxy groups, C1-C2 alkyl groups and halogenated C1-C2 alkyl groups; - each R7 is selected from hydrogen; halogens; cyano; the C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy; and the C3-C10 cycloalkyl groups are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - k is equal to 0 or 1. - r is equal to 0 or 1. - m is 0, 1, 2, or 3. - p is 0, 1 or 2; and - q is 0, 1, 2, 3, 4, 5, 6, 7 or 8. #x200e4#x200e#x200f.#x200fA compound according to any one of Examples 1-3, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: - each R2 is selected from hydrogen and C1-C2 alkyl groups; - R5 is selected from hydrogen and C1-C2 alkyl groups; and - each R6 is independently selected from C1-C2 alkyl groups; #x200e5#x200e#x200f.#x200fA compound according to any one of Examples 1-3, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: - R1 is –O-(CH2)(C(R2)2)(m-1)R7 - each R7 is selected from hydrogen; halogens; cyano; the C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy; and the C3-C10 cycloalkyl groups are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; and - each R2 is independently selected from C1-C2 alkyl groups, OH, C1-C2 alkoxy groups and halogens; - r is equal to 0; and - q is 0, 1, 2, 3 or 4. 6. A compound based on Example 4 having formula IV or V: (IV) or (V), A pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, Where: - R1 is –O-(CH2)(C(R2)2)(m-1)R7, - each R2 is independently selected from C1-C2 alkyl groups, OH, C1-C2 alkoxy groups and halogens; - each R7 is selected from hydrogen; halogens; cyano; the C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy; and the C3-C10 cycloalkyl groups are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - R5 is selected from hydrogen and C1-C2 alkyl groups; - each R6 is independently selected from C1-C2 alkyl groups; and - p is 0, 1 or 2. #x200e7#x200e#x200f.#x200fA compound according to Example 6, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein p is 0 or 1. #x200e8#x200e#x200f.#x200fA compound according to Example 6, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein p is 1. #x200f #x200f#x200e9#x200e#x200f.#x200fA compound according to any one of Examples 1-8, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein R2 is independently selected from CH3, OH, F, and OCH3. #x200e10#x200e#x200f.#x200fA compound according to Example 9, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein p is 0 or 1. #x200e11#x200e#x200f.#x200fA compound according to Example 10, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: - p is equal to 1; - R5 is methyl; and - R6 is methyl. #x200e12#x200e#x200f.#x200fA compound according to Example 6, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein R7 is a cyclopropyl group. #x200e13#x200e#x200f.#x200fA compound according to Example 6, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein R7 is a cyclopropyl group substituted with a halogenated C1 alkyl group. #x200e14#x200e#x200f.#x200fA compound according to Example 13, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein R7 is a cyclopropyl group substituted with a CF3 group. #x200e15#x200e#x200f.#x200fA compound according to Example 6, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein R7 is a cyclopropyl group substituted with one or more halogens. 15. A compound according to Example 6, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein R7 is a cyclopropyl group substituted with one or more C1 alkyl groups. #x200e15#x200e#x200f.#x200fA compound according to Example 6, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein R7 is a cyclopropyl group substituted with one or more halogens and one or more C1 alkyl groups. #x200e16#x200e#x200f.#x200fA compound according to Example 6, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein R7 is a CF3 group. #x200e17#x200e#x200f.#x200fA compound according to Example 6, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein R7 is selected from C4 cycloalkyl groups optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens. #x200e18#x200e#x200f.#x200fA compound according to Example 6, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein R7 is selected from C5 cycloalkyl groups optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens. #x200e19#x200e#x200f.#x200fA compound according to Example 18, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein the C5 cycloalkyl groups are bicyclic. #x200e20#x200e#x200f.#x200fA compound according to Example 6, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein R7 is selected from C7 cycloalkyl groups optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens. #x200e21#x200e#x200f.#x200fA compound according to Example 20, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein the C7 cycloalkyl groups are bicyclic. #x200e22#x200e#x200f.#x200fA compound according to Example 20, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein the C7 cycloalkyl groups are tricyclic. #x200e23#x200e#x200f.#x200fA compound having a formula selected from any of the formulas shown in Figure 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing. #x200e24#x200e#x200f.#x200fA combination based on Example 1 has the following formula: A pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing #x200e25#x200e#x200f.#x200fA combination based on Example 1 has the following formula: , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing. #x200e26#x200e#x200f.#x200fA combination based on Example 1 has the following formula: , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing. #x200e27#x200e#x200f.#x200fA combination based on Example 1 has the following formula: , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing. #x200e28#x200e#x200f.#x200fA combination based on Example 1 has the following formula: , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing. #x200e29#x200e#x200f.#x200fA combination based on Example 1 has the following formula: , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing. #x200e30#x200e#x200f.#x200fA combination based on Example 1 has the following formula: , , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing. #x200e31#x200e#x200f.#x200fA combination based on Example 1 has the following formula: a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing. #x200e32#x200e#x200f.#x200fA combination based on Example 1 has any of the following formulas: , Or , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing. #x200e33#x200e#x200f.#x200fA combination based on Example 1 has any of the following formulas: , , , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing. #x200e34#x200e#x200f.#x200fA combination based on Example 1 has any of the following formulas: , , , , , , or , or , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing. #x200e35#x200e#x200f.#x200fA pharmaceutical composition comprising at least one compound selected from the compounds of Examples 1-34, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, and optionally, one or more of: (a) Compound II: , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing; (b) Compound III: , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing; and (c) a pharmaceutically acceptable carrier. #x200e36#x200e#x200f. #x200fA method for treating cystic fibrosis comprises administering to a patient in need thereof a combination of any of Examples 1-34, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing; or a pharmaceutical composition according to Example 35. #x200f #x200f#x200e37#x200e#x200f.#x200fMethod for preparing formula (X): , A pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, comprising a combination of formula (F) or a salt thereof with a compound of formula (G) or a salt thereof to produce said compound of formula (X) or a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing: Where in each of the aforementioned formulas: - One of Y1 and Y2 is N and the other is CH; - R1 is –(C(R2)2)kO-(C(R2)2)mR7 - each R2 is independently selected from hydrogen; halogens; cyano; hydroxy; C1-C2 alkoxy groups, and the C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy, and C3-5 cycloalkyl groups, which are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - each R3 is independently selected from C1-C4 alkyl groups optionally substituted with one or more hydroxy groups or two R3 pairs; together with the carbon atom to which they are attached, are of a C3-4 cycloalkyl; - each R4 is independently selected from halogens; - R5 is selected from hydrogen and C1-C4 alkyl groups; - each R6 is independently selected from halogens, cyano, hydroxy, hydroxymethyl, C1-C2 alkoxy groups, C1-C2 alkyl groups and halogenated C1-C2 alkyl groups; - each R7 is selected from hydrogen; halogens; cyano; the C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy; and the C3-C10 cycloalkyl groups are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - Xa is F or Cl; - k is equal to 0 or 1. - r is equal to 0 or 1. - m is 0, 1, 2, or 3. - p is 0, 1 or 2; and - q is 0, 1, 2, 3, 4, 5, 6, 7 or 8. #x200e38#x200e#x200f. #x200fMethod of Example 37, where Y2 is N; and each Y1 is CH. #x200e39#x200e#x200f.#x200fThe method of Example 37 or 38, wherein reacting 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. #x200e40#x200e#x200f.#x200fThe method of one of Examples 37-39 wherein a salt of the compound of formula (G) is used. #x200e41#x200e#x200f.#x200fThe method of Example 40, wherein said salt of the compound of formula (G) is an HCl salt of the compound of formula (G). #x200e42#x200e#x200f.#x200fA method for preparing formula (F) or a salt thereof: , or a deuterated derivative of any of the foregoing, comprising a combination of formula (D) or a salt thereof with a compound of formula (E) or a salt thereof to produce a compound of formula (F) or a salt thereof: , Where in each of the aforementioned formulas: - One of Y1 and Y2 is N and the other is CH; - R1 is –(C(R2)2)kO-(C(R2)2)mR7 - each R2 is independently selected from hydrogen; halogens; cyano; hydroxy; C1-C2 alkoxy groups, and the C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy, and C3-5 cycloalkyl groups, which are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - each R4 is independently selected from halogens; - each R5 is independently selected from hydrogen and C1-C4 alkyl groups; - each R6 is independently selected from halogens, cyano, hydroxy, hydroxymethyl, C1-C2 alkoxy groups, C1-C2 alkyl groups and halogenated C1-C2 alkyl groups; - each R7 is selected from hydrogen; halogens; cyano; the C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy; and the C3-C10 cycloalkyl groups are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - Xa is F or Cl; - k is equal to 0 or 1. - r is equal to 0 or 1. - m is 0, 1, 2, or 3; and - p is 0, 1 or 2. #x200e43#x200e#x200f.#x200fMethod of Example 42, where Y2 is N; and each Y1 is CH. #x200e44#x200e#x200f.#x200fThe method of Example 42 or 43, wherein reacting 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. #x200e45#x200e#x200f.#x200fThe method of Example 42 or 43, wherein 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) with a coupling reagent and then a compound of formula (E) or a salt thereof in the presence of a base. #x200e46#x200e#x200f.#x200fA method for preparing a mixture of the following formulas: Composition 1: A pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, comprising reacting a compound of formula (F-1) or a salt thereof wherein Xa is F or Cl with a compound of formula (G-1) or a salt thereof to produce said compound or a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing: Where Xa in formula (F-1) is F or Cl. #x200e47#x200e#x200f.#x200fThe method of Example 46, wherein reacting 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. #x200e48#x200e#x200f.#x200fThe method of Example 46 or 47 wherein a salt of the compound of formula (G-1) is used. #x200e49#x200e#x200f.#x200fThe method of Example 48, wherein said salt of the compound of formula (G-1) is an HCl salt of the compound of formula (G-1). #x200e50#x200e#x200f.#x200fA method for preparing formula (F-1) or a salt thereof: , or a deuterated derivative of any of the foregoing, comprising a compound of formula (D-1) and a compound of formula (E-1) to produce a compound of formula (F-1) or a salt thereof: , Wherein, in each of the aforementioned formulas, Xa represents F or Cl. #x200e51#x200e#x200f.#x200fThe method of Example 50, wherein reacting 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. #x200e52#x200e#x200f.#x200fThe method of Example 50 wherein 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 a coupling reagent and then a compound of formula (E-1) in the presence of a base. #x200e53#x200e#x200f.#x200fA method for preparing formula (D) or a salt thereof: , or a deuterated derivative of any of the foregoing, including: (i) reacting a compound of formula (A) or a salt thereof with a compound of formula (B) or a salt thereof to produce a compound of formula (C) or a salt thereof: ; and (ii) hydrolyzing the -C(O)ORa group of a compound of formula (C) to produce a compound of formula (D) or a salt thereof, Where in each of the aforementioned formulas: - One of Y1 and Y2 is N and the other is CH; - R1 is –(C(R2)2)kO-(C(R2)2)mR7 - each R2 is independently selected from hydrogen; halogens; cyano; hydroxy; C1-C2 alkoxy groups, and the C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy, and C3-5 cycloalkyl groups, which are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - each R4 is independently selected from halogens; - each R7 is selected from hydrogen; halogens; cyano; the C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy; and the C3-C10 cycloalkyl groups are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - Xa is F or Cl; - k is equal to 0 or 1. - r is equal to 0 or 1; and - m is 0, 1, 2, or 3. #x200e54#x200e#x200f.#x200fMethod of Example 53, where Y2 is N; and each Y1 is CH. #x200e55#x200e#x200f.#x200fThe method of Example 53 or 54, wherein the hydrolysis of the –C(O)ORa group is carried out in the presence of a base or acid. #x200e56#x200e#x200f.#x200fThe method of any one of Examples 53-55, wherein reacting 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. #x200e57#x200e#x200f.#x200fThe method of any of Examples 53 to 56, wherein Ra is ethyl or t-butyl. #x200e58#x200e#x200f.#x200fA method for preparing formula (D-1) or a salt thereof: , or a deuterated derivative of any of the foregoing, including: (i) reacting a compound of formula (A-1) or a salt thereof with a compound of formula (B-1) or a salt thereof to produce a compound of formula (C-1) or a salt thereof: ; and (ii) hydrolyzing the -C(O)ORa group of a compound of formula (C-1) or a salt thereof to produce a compound of formula (D-1) or a salt thereof, wherein in each of the aforementioned formulas, Ra is independently selected from C1-C4 alkyl groups; and each Xa is independently F or Cl. #x200e59#x200e#x200f.#x200fThe method of Example 58 in which the hydrolysis of the -C(O)ORa group is carried out in the presence of a base or acid. #x200e60#x200e#x200f.#x200fMethod 58 or 59, wherein reacting 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. #x200e61#x200e#x200f.#x200fThe method of any of Examples 58 to 60, wherein Ra is ethyl or t-boil. #x200e62#x200e#x200f.#x200fA compound of formula (F) or a salt thereof: , or a deuterated derivative of any of the foregoing, wherein in each of the aforementioned formulas: - R1 is –(C(R2)2)kO-(C(R2)2)mR7 - each R2 is independently selected from hydrogen; halogens; cyano; hydroxy; C1-C2 alkoxy groups, and the C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy, and C3-5 cycloalkyl groups, which are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - each R4 is independently selected from halogens; - R5 is selected from hydrogen and C1-C4 alkyl groups; - each R6 is independently selected from halogens, cyano, hydroxy, hydroxymethyl, C1-C2 alkoxy groups, C1-C2 alkyl groups and halogenated C1-C2 alkyl groups; - each R7 is selected from hydrogen; halogens; cyano; the C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy; and the C3-C10 cycloalkyl groups are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - Xa is F or Cl - k is equal to 0 or 1. - r is equal to 0 or 1. - m is 0, 1, 2, or 3; and - p is 0, 1 or 2. #x200e63#x200e#x200f.#x200fA compound according to Example 62, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Y2 is N; and each Y1 is CH. #x200e64#x200e#x200f.#x200fA compound of formula (F-1) or a salt thereof: , or a deuterated derivative of any of the foregoing, wherein each Xa is F or Cl. 65. A compound of formula (C) or (D) or a salt thereof: Or,, or a deuterated derivative of any of the foregoing, wherein in each of the aforementioned formulas: - One of Y1 and Y2 is independently N and the other is independently CH; - R1 is –(C(R2)2)kO-(C(R2)2)mR7 - each R2 is independently selected from hydrogen; halogens; cyano; hydroxy; C1-C2 alkoxy groups, and the C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy, and C3-5 cycloalkyl groups, which are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - each R4 is independently selected from halogens; - each R7 is selected from hydrogen; halogens; cyano; the C1-C2 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxy; and the C3-C10 cycloalkyl groups are optionally substituted with one or more substituents each independently selected from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogens; - Ra represents C1-C4 alkyl; - Xa is F or Cl; - k is equal to 0 or 1. - r is equal to 0 or 1; and - m is 0, 1, 2, or 3. #x200e66#x200e#x200f.#x200fA compound according to Example 65, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein, Y2 is independently N; and each Y1 is independently CH. #x200e67#x200e#x200f.#x200fA compound according to Example 65, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ra is ethyl or t-butyl. #x200e68#x200e#x200f.#x200fA compound of formula (C-1) or (D-1) or a salt thereof: Or, or a deuterated derivative of any of the foregoing, wherein Ra is C1-C4 alkyl; and each Xa is independently F or Cl. #x200e69#x200e#x200f.#x200fA compound according to Example 68, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ra is ethyl or t-butyl. #x200e70#x200e#x200f.#x200fA compound of formula (A-1), (C-1) or (D-1) or a salt thereof: , or, or a deuterated derivative of any of the foregoing, wherein Ra is C1-C4 alkyl; and each Xa is independently F or Cl. #x200e71#x200e#x200f. #x200fUse of at least one compound selected from the compounds of Examples 1-34, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, and optionally, one or more of: (a) Compound II: , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing; and (b) Compound III: , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing; for the treatment of cystic fibrosis. 72. Crystalline form A of compound 1: 1. 73. Crystalline form A based on sample 72 in a completely pure state. 74. Crystalline Form A based on Example 72, characterized by an X-ray diffractogram with a signal at at least three two-theta times selected from 6.6 ± 0.2, 7.6 ± 0.2, 9.6 ± 0.2, 12.4 ± 0.2, 13.1 ± 0.2, 15.2 ± 0.2, 16.4 ± 0.2, 18.2 ± 0.2 and 18.6 ± 0.2. 75. Crystalline Form A based on Sample 72, characterized by an X-ray diffractogram with a signal at at least three two-theta times selected from 6.6 ± 0.2, 9.6 ± 0.2, 13.1 ± 0.2, 15.2 ± 0.2, 18.2 ± 0.2 and 18.6 ± 0.2. 76. Crystalline Form A based on Sample 72, characterized by an X-ray diffractogram with a signal at at least three two-theta times selected from 6.6 ± 0.2, 13.1 ± 0.2, 18.2 ± 0.2. 77. Crystalline Form A based on Sample 72, characterized by an X-ray diffractogram with a signal at at least six two-theta times selected from 6.6 ± 0.2, 9.6 ± 0.2, 13.1 ± 0.2, 15.2 ± 0.2, 18.2 ± 0.2 and 18.6 ± 0.2. 78. Crystalline form A of sample 72, characterized by an X-ray diffractogram quite similar to that shown in Figure 2. 79. Crystalline Form A of Compound 1 is prepared by a process comprising removing the solvent from at least one crystalline form of Compound 1 selected from Crystalline Form M, Crystalline Form E, Crystalline Form P1, Crystalline Form P2, and Crystalline Form AA2. 80. Crystalline Form A of Compound 1 prepared by a process comprising separating at least one solvent selected from methanol solvents, ethanol solvents, acetic acid solvents, toluene solvents, sulfolane solvents, 1-propanol solvents, 2-propanol solvents, propionic acid solvents, methyl tert-butyl ether solvents, and isobutyric acid solvents of Compound 1 (e.g., methanol solvents, ethanol solvents, acetic acid solvents, toluene solvents, sulfolane solvents, propionic acid solvents, methyl tert-butyl ether solvents, and isobutyric acid solvents of Compound 1, as well as e.g., methanol solvents, ethanol solvents, acetic acid solvents, toluene solvents, sulfolane solvents of Compound 1, and also e.g., methanol solvents and ethanol solvents of Compound 1) and then drying the separated solvent under vacuum at room temperature for 12 to 100 hours. 81. At least one solvent of compound 1: 1 Selected from methanol solvents, ethanol solvents, acetic acid solvents, toluene solvents, sulfolane solvents, 1-propanol solvents, 2-propanol solvents, propionic acid solvents, methyl tert-butyl ether solvents, and isobutyric acid solvents, anisole solvents, methyl butyl ketone solvents, and xylene solvents of compound 1. 83. Crystalline form M of compound 1: 1. 84. Crystalline form M based on sample 83 in a completely pure state. 85. Crystalline form M based on sample 83, characterized by an X-ray diffractogram with a signal at at least three two-theta times selected from 7.0 ± 0.2, 11.6 ± 0.2, 13.1 ± 0.2, 13.7 ± 0.2, 15.2 ± 0.2, 15.9 ± 0.2, 16.4 ± 0.2, 17.8 ± 0.2, and 19.3 ± 0.2. 86. Crystalline form M based on sample 83, characterized by an X-ray diffractogram with a signal at at least three two-theta times selected from 11.6 ± 0.2, 13.1 ± 0.2, 13.7 ± 0.2, 15.2 ± 0.2, 17.8 ± 0.2 and 19.3 ± 0.2. 87. Crystalline form M based on sample 83, characterized by an X-ray diffractogram with a signal at at least three two-theta times selected from 11.6 ± 0.2, 17.8 ± 0.2 and 13.1 ± 0.2. 88. Crystalline form M based on sample 83, characterized by an X-ray diffractogram with a signal at at least six two-theta times selected from 11.6 ± 0.2, 13.1 ± 0.2, 13.7 ± 0.2, 15.2 ± 0.2, 17.8 ± 0.2 and 19.3 ± 0.2. 89. Crystalline form M of sample 83, characterized by an X-ray diffractogram quite similar to that shown in Figure 13. 90. Crystalline form E of compound 1: 1. 91. Crystalline form E based on sample 90 in a completely pure state. 92. Crystalline Form E based on Sample 90, characterized by an X-ray diffractogram with a signal at at least three two-theta times selected from 7.0 ± 0.2, 11.2 ± 0.2, 12.8 ± 0.2, 13.2 ± 0.2, 14.1 ± 0.2, 15.1 ± 0.2, 16.1 ± 0.2, 17.8 ± 0.2, and 18.9 ± 0.2. 93. Crystalline form E based on sample 90, characterized by an X-ray diffractogram with a signal at at least three two-theta times selected from 11.2 ± 0.2, 12.8 ± 0.2, 13.2 ± 0.2, 15.1 ± 0.2, 16.1 ± 0.2 and 17.8 ± 0.2. 94. Crystalline form E based on sample 90, characterized by an X-ray diffractogram with a signal at at least three two-theta times selected from 12.8 ± 0.2, 16.1 ± 0.2 and 17.8 ± 0.2. 95. Crystalline form E based on sample 90, characterized by an X-ray diffractogram with a signal at at least six two-theta times selected from 11.2 ± 0.2, 12.8 ± 0.2, 13.2 ± 0.2, 15.1 ± 0.2, 16.1 ± 0.2 and 17.8 ± 0.2. 96. Crystalline form E of sample 90, characterized by an X-ray diffractogram quite similar to that shown in Figure 14. 97. A method for preparing crystalline form A of compound 1: 1 involves stirring a solution or suspension of compound 1 in a solvent system at a temperature between 50oC and 85oC. 98. A method for preparing crystalline form A of compound 1: 1 comprising separating a solvent from compound 1 selected from methanol solvents, ethanol solvents, acetic acid solvents, toluene solvents, sulfolane solvents, 1-propanol solvents, 2-propanol solvents, propionic acid solvents, methyl tert-butyl ether solvents, and isobutyric acid solvents, anisole solvents, methyl butyl ketone solvents, and xylene solvents of compound 1. 99. Crystalline form X of a potassium salt of compound 1: 1. 100. Crystalline form X based on sample 99 in a completely pure state. 101. Crystalline form X based on sample 99, characterized by an X-ray diffractogram with a signal at at least three two-theta times selected from 4.9 ± 0.2, 5.9 ± 0.2, 8.1 ± 0.2, 8.5 ± 0.2, 10.3 ± 0.2, 13.0 ± 0.2, 13.9 ± 0.2, 14.6 ± 0.2 and 17.0 ± 0.2. 102. Crystalline form X based on sample 99, characterized by an X-ray diffractogram with a signal at at least three two-theta times selected from 4.9 ± 0.2, 5.9 ± 0.2, 8.1 ± 0.2, 13.0 ± 0.2, 13.9 ± 0.2 and 17.0 ± 0.2. 103. Crystalline form X based on sample 99, characterized by an X-ray diffractogram with a signal at at least three two-theta times selected from 4.9 ± 0.2, 5.9 ± 0.2 and 13.0 ± 0.2. 104. Crystalline form X based on sample 99, characterized by an X-ray diffractogram with a signal at at least six two-theta times selected from 4.9 ± 0.2, 5.9 ± 0.2, 8.1 ± 0.2, 13.0 ± 0.2, 13.9 ± 0.2 and 17.0 ± 0.2. 105. Crystalline form X of sample 99, characterized by an X-ray diffractogram quite similar to that shown in Figure 15. 106. Crystalline form Y of a sodium salt of compound 1: 1. 107. Crystalline form Y based on sample 106 in a completely pure state. 108. Crystalline form y based on sample 106, characterized by an X-ray diffractogram with a signal at at least three two-theta times selected from 3.5 ± 0.2, 7.0 ± 0.2, 11.7 ± 0.2, 12.8 ± 0.2, 13.2 ± 0.2, 14.2 ± 0.2, 15.4 ± 0.2, 16.6 ± 0.2 and 18.0 ± 0.2. 109. Crystalline form Y based on sample 106, characterized by an X-ray diffractogram with a signal at at least three two-theta times selected from 3.5 ± 0.2, 7.0 ± 0.2, 11.7 ± 0.2, 13.2 ± 0.2, 14.2 ± 0.2 and 18.0 ± 0.2. 110. Crystalline form Y based on sample 106, characterized by an X-ray diffractogram with a signal at at least three two-theta times selected from 7.0 ± 0.2, 11.7 ± 0.2 and 13.2 ± 0.2. 111. Crystalline form Y based on sample 106, characterized by an X-ray diffractogram with a signal at at least six two-theta times selected from 3.5 ± 0.2, 7.0 ± 0.2, 11.7 ± 0.2, 13.2 ± 0.2, 14.2 ± 0.2 and 18.0 ± 0.2. 112. Crystalline form Y of sample 106, characterized by an X-ray diffractogram quite similar to that shown in Figure 16. 113. Solid dispersion containing compound 1 and a polymer. 114. The solid dispersion of Example 113 contains 50 wt% of Compound 1 and 50 wt% of a polymer by weight of the total solid dispersion or 80 wt% of Compound 1 and 20 wt% of a polymer by weight of the total solid dispersion. 115. The solid disintegration of Example 113 or 114, wherein the polymer is a hypromellose acetate succinate, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, or polyvinyl pyrrolidone. 116. A pharmaceutical formulation comprising at least a crystalline form according to any of Examples 72-96 and 99-112 and an acceptable pharmaceutically acceptable carrier. 117. A method for treating cystic fibrosis comprising administering to a patient in need thereof at least one crystalline form according to any one of embodiments 72-96 and 112-199. 118. A method for treating cystic fibrosis comprising administering a solid dispersion to a patient in need thereof according to any of examples 113-115. 119. Crystalline form P2 of compound 1: 1. 120. Crystalline form P2 based on sample 119 in a completely pure state. 121. Crystalline form P2 based on sample 119, characterized by an X-ray diffractogram with a signal at at least three two-theta times selected from 10.2 ± 0.2, 10.9 ± 0.2, 12.6 ± 0.2, 12.9 ± 0.2, 15.0 ± 0.2, 15.9 ± 0.2, 16.2 ± 0.2, 16.5 ± 0.2, and 17.6 ± 0.2. 122. Crystalline form P2 based on sample 119, characterized by an X-ray diffractogram with a signal at at least three two-theta times selected from 10.9 ± 0.2, 12.6 ± 0.2, 12.9 ± 0.2, 15.0 ± 0.2, 16.5 ± 0.2 and 17.6 ± 0.2. 123. Crystalline form P2 based on sample 119, characterized by an X-ray diffractogram with a signal at at least three two-theta times selected from 10.9 ± 0.2, 12.6 ± 0.2 and 17.6 ± 0.2. 124. Crystalline form P2 based on sample 119, characterized by an X-ray diffractogram with a signal at at least six two-theta times selected from 10.9 ± 0.2, 12.6 ± 0.2, 12.9 ± 0.2, 15.0 ± 0.2, 16.5 ± 0.2 and 17.6 ± 0.2. 125. Crystalline form P2 of sample 119, characterized by an X-ray diffractogram quite similar to that shown in Figure 17. Other examples include: A.Compound 1 of the formula . B. A pharmaceutically acceptable salt of compound 1 of formula. C. A pharmaceutical composition containing: (i) Compound 1 of the formula and (2) A pharmaceutically acceptable carrier. D. Pharmaceutical composition of Example C also includes compound II: . E. Pharmaceutical composition of Example C also includes a pharmaceutically acceptable salt of compound II: . F. Pharmaceutical composition of Example C also includes compound III: . G. Pharmaceutical composition of Example C also includes a pharmaceutically acceptable salt of compound III: . H. Pharmaceutical composition of Example D also includes compound III: . I. Pharmaceutical composition of Example D also includes a pharmaceutically acceptable salt of compound III: . J. Pharmaceutical composition of Example E also includes compound III: . K. Pharmaceutical composition of Example E also includes a pharmaceutically acceptable salt of compound III: . L. A medicinal composition containing: (A) A pharmaceutically acceptable salt of compound 1 of the formula and (B) A pharmaceutically acceptable carrier. M. Pharmaceutical composition of Example L also includes compound II: . N. Pharmaceutical composition of Example L also includes a pharmaceutically acceptable salt of compound II: . O. Pharmaceutical composition of Example L also includes compound III: . P. Pharmaceutical composition of Example L also includes a pharmaceutically acceptable salt of compound III: . Q. Pharmaceutical composition of Example M also includes compound III: . R. Pharmaceutical composition of Example M also includes a pharmaceutically acceptable salt of compound III: . S. Pharmaceutical composition of Example M also includes compound III: . T. Pharmaceutical composition of Example M also includes a pharmaceutically acceptable salt of compound III: . U. A method for treating cystic fibrosis comprising administering compound 1 of the formula to a patient in need thereof. . V. A method for treating cystic fibrosis comprising administering a pharmaceutically acceptable salt of Compound 1 of Formula to a patient in need thereof. . W. A method for treating cystic fibrosis comprising administering to a patient in need thereof a pharmaceutical composition comprising: (A) Compound 1 of the formula and (B) A pharmaceutically acceptable carrier. X. A method for treating cystic fibrosis comprising administering to a patient in need thereof a pharmaceutical composition comprising: A pharmaceutically acceptable salt of compound 1 of the formula and A pharmaceutically acceptable carrier.

[00199] General Laboratory Practices

[00200] Definitions of specific abbreviations for the following examples are summarized below: Anhydrous Boc (Boc)2O): di-tert-butyl dicarbonate CDI: Carbonyl Diimidazole DABCO: 1,4-diazabicyclo[2.2.2]octane DBU: 1,8-diazabicyclo(5.4.0)undec-7-ene DCM: Dichloromethane DIAD: Diisopropyl azodicarboxylate DIEA (DIPEA; N,N-diisopropylethylamine) DMA: N,N-Dimethylacetamide DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide Et2O: Diethyl ether EtOH: Ethanol HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate IPA: Isopropanol MeOH: methanol NMP: N-methyl-2-pyrrolidone MTBE: Methyl tert-butyl ether TBS-Cl: tert-butyldimethylsilyl chloride TFA: Trifluoroacetic acid THF: Tetrahydrofuran p-TsOH: p-Toluenesulfonic acid TPPO-DIAD complex: a complex of triphenylphosphine oxide with diisopropyl azodicarboxylate

[00201] Reagents and starting materials were obtained from commercial sources, unless otherwise stated, and were used without purification. Proton and carbon NMR spectra were obtained on either a Bruker Biospin DRX 400 MHz FTNMR spectrometer operating at 1H and 13C resonance frequencies of 400 and 100 MHz, respectively, or on a 300 MHz NMR spectrometer. A proton and carbon dimensional spectrum was obtained using a 20 Hz sample rotation observation detector with a digital resolution of 0.1843 and 0.9083 Hz / Pt, respectively. All proton and carbon spectra were obtained with temperature control at 30 °C using standard parameters, previously published pulse sequences, and routine processing. The final purity of the compounds was determined by reversed-phase UPLC using an Acquity UPLC BEH C18 column (50 × 2.1 mm, 1.7 μm particle) manufactured by Waters (pn: 186002350), and a double gradient of 1–99% of mobile phase B in 0.3 min. Mobile phase A = H2O (0.05 % CF3CO2H). Mobile phase B = CH3CN (0.035 % CF3CO2H). Flow rate 1.2 mL / min, injection volume 1.5 μL, and column temperature 60 °C.The final purity was calculated by averaging the area under the curve (AUC) of the two UV traces (220 nm, 254 nm). The low-resolution mass spectrum, reported as [M+H]+, was obtained using a 4-pole mass spectrometer equipped with an ionization source (ESI) capable of achieving a mass accuracy of 0.1 DA and a minimum resolution of 1000 (without units in resolution) over the entire detection range. The optical purity of methyl (2S)-2,4-dimethyl-4-nitro-pentanoate was determined by chiral gas chromatography (GC) analysis on an Agilent 7890A / MSD 5975C instrument using a Restek Rt-βDEXcst column (30m x 0.25mm x 0.25um_df), at a flow rate of 2.0 mL / min (H2 carrier gas), at a spray temperature of 220°C and an oven temperature of 120°C for 15 min.

[00202] X-ray powder diffraction

[00203] X-ray powder diffraction measurements were performed using PANalytical's X-pert Pro diffractometer at room temperature with copper (1.54060 Å) radiation. The optical beam included a variable divergence slit to ensure a constant light path length on the sample and on the diffracted beam side; a linear solid-state detector with an active length of 2.12 degrees 2 theta was used, measured in a scanning mode. The powder sample was compressed onto the area of ​​interest with a zero-field silicon holder and rotated to achieve better statistics. A symmetric scan from 4 to 40 degrees 2 theta was measured with a step size of 0.017 degrees and a time of 15.5 seconds.

[00204] Figure 2 shows the XRPD spectrum of Form A of Compound 1. The single crystal structure of Form A is illustrated. The crystal structure confirms the absolute configuration of the molecule, and the calculated XRPD patterns show good agreement with the experimental patterns. Form A of Compound 1 is formed as a rhombic unit cell of P212121, a=15.74 b=22.86 c=26.59 (angstroms) and α=β=γ=90, Z=12 V= 9575 Flack =0.08. One of ordinary skill in the art will recognize that there may be variations in these crystal parameters depending on, for example, temperature, pressure, or instrument-to-instrument variations.

[00205] Figure 3 shows a laboratory XRPD of Form A of Compound 1 (top) compared to a calculated XRD (bottom) calculated from single crystal data. Figure 3 shows an overlay of the laboratory and calculated XRPD of Form A of Compound 1 from Figure 3.

[00206] Figure 5 shows the XRPD spectrum of amorphous compound 1 prepared by spray drying (SDD) of 50 wt% compound 1 in HPMCAS-HG.

[00207] Modulated Differential Scanning Calorimetry (MDSC)

[00208] Modulated differential scanning calorimetry is used to determine the glass transition temperature of amorphous solids. MDSC was performed using a TA Discovery calorimeter (TA Instruments, New Castle, DE). The instrument was calibrated with indium. Samples of approximately 1-3 mg were weighed into hermetic containers sealed with a perforated lid. The MDSC sample was scanned between -20°C and 200°C at a heating rate of 2°C / min with + / - 1°C modulation per minute. Data were collected and analyzed with TA Instruments Trios Software (TA Instruments, New Castle, DE).

[00209] Figure 6 shows an MDSC spectrum of a spray-dried dispersion (SDD) of 50 wt% of compound 1 in HPMCAS-HG, showing that the SDD has a midpoint temperature of about 106°C.

[00210] Single-crystal analysis

[00211] X-ray diffraction data were obtained at 100K or 298K on a Bruker diffractometer equipped with Mo Kα (λ = 0.71073 Å) or Cu Kα (λ = 1.5478) beam and a CCD detector. The structure was solved and refined using the SHELX program (Sheldrick, GM, Acta Cryst., (2008) A64, 112-122).

[00212] Thermal Gravimetric Analysis (TGA)

[00213] TGA was used to check for residual solvents in a given amount and to determine the decomposition temperature of the sample. TGA data were collected on a TA Discovery thermogravimetric analyzer or equivalent instrument. A sample weighing approximately 1 to 5 mg was scanned between 25 °C and 350 °C at a heating rate of 10 °C / min. Data were collected and analyzed using Trios software (TA Instruments, New Castle, DE) or collected using Thermal Advantage Q SeriesTM software and then analyzed using Universal Analysis software (TA Instruments, New Castle, DE).

[00214] Differential Scanning Calorimetry (DSC)

[00215] DSC data were obtained using a TA Instruments Q2000 or similar. A sample weighing between 1 and 10 mg was weighed into an aluminum pan. This pan was placed in the sample position in the calorimeter pan. An empty pan was placed in the reference position. The calorimeter pan was closed and a stream of nitrogen was passed through the pan. The heating program was set to heat the sample at a rate of 10° C. / min from 200-350° C. Once the run was complete, the data was analyzed using the DSC analysis program in the system software. Observed endotherms and exotherms were integrated between the baseline temperature points that were above and below the temperature range at which the endotherm was observed. Data reported were the onset of decomposition temperature, peak temperature, and heat content (enthalpy).

[00216] Synthetic Examples

[00217] Synthesis of Compound II: (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide

[00218] Step 1: (R)-Benzyl 2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate و ((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)methyl 2-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate

[00219] 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 h under nitrogen, then the mixture was 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 MgSO4, filtered, and concentrated. The crude product, a viscous brown oil (granular) containing both products shown above, was directly carried forward to the next step without further purification. (R)-Benzyl 2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate, ESI-MS m / z calc. 470.2, found 471.5 (M+1)+. Retention time 2.20 minutes. ((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)methyl 2-(1-((((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate, ESI-MS m / z calc.494.5, found 495.7 (M+1)+. Retention time 2.01 min.

[00220] Step 2: (R)-2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropan-1-ol

[00221] The crude reaction mixture obtained in step (a) was dissolved in tetrahydrofuran (THF) (42 mL) and cooled in an ice-water bath. LiAlH4 (16.8 mL of a 1 M solution, 16.8 mmol) was added dropwise. After the addition was complete, the mixture was stirred for another 5 minutes. The solution was quenched by the addition of water (1 mL, 15% NaOH solution (1 mL) and then water (3 mL). The mixture was filtered over Celite, and the solids were washed with tetrahydrofuran and ethyl acetate. The supernatant was concentrated and purified by column chromatography (30-60% ethyl acetate-hexane) to give (R)-2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropan-1-ol as a brown oil (2.68g, 87% over 2 steps) ESI-MS m / z calc. 366.4, found 367.3 (M+1)+. with a retention time of 1.68 min. 1H NMR (400 MHz, DMSO- d 6) δ 8.34 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 13.4 Hz, 1H), 6.57 (s, 1H), 4.94 (t, J = 5.4 Hz, 1H), 4.64 - 4.60 (m, 1H), 4.52 - 4.42 (m, 2H), 4.16 - 4.14 (m, 1H), 3.76 - 3.74 (m, 1H), 3.63 - 3.53 (m, 2H), 1.42 (s, 3H), 1.38 - 1.36 (m, 6H) and 1.19 (s, 3H) ppm. (DMSO is dimethyl sulfoxide).

[00222] Step 3: (R)-2-(5-amino-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-1H-indol-2-yl)-2-methylpropan-1-ol

[00223] (R)-2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropan-1-ol (2.5 g, 6.82 mmol) was dissolved in ethanol (70 mL) and the reaction was purged with N2. Pd-C (250 mg, 5% wt) was then added. The reaction was purged again with nitrogen and then stirred under H2(atm). After 2.5 h, only partial conversion to product was observed by LCMS. The reaction was filtered through celite and concentrated. The residue was subjected to the above conditions again. After 2 h, LCMS showed complete conversion to product. The reaction was filtered through celite. The filtrate was concentrated to yield the product (1.82 g, 79%). ESI-MS m / z calc. 336.2, found 337.5 (M+1)+. with a retention time of 0.86. 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.

[00224] Step 4: (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide

[00225] Three drops of DMF were added to a stirred mixture of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (1.87 g, 7.7 mmol) and thionyl chloride (1.30 mL, 17.9 mmol). After 1 h, a clear solution formed. The solution was concentrated under vacuum, then 3 mL of toluene 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 min. The acid chloride was then dissolved in dichloromethane (10 ml) and added to a mixture of (R)-2-(5-amino-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-1H-indol-2-yl)-2-methylpropan-1-ol (1.8 g, 5.4 mmol) and triethylamine (2.24 mL, 16.1 mmol) in dichloromethane (45 ml). The reaction was stirred at room temperature for 1 h. The reaction was washed with 1N HCl, saturated NaHCO3 solution and brine, dried over MgSO4 and concentrated to give the product (3 g, 100%). ESI-MS m / z calc. 560.6, found 561.7 (M+1)+. Retention time 2.05 min. 1H NMR (400 MHz, DMSO- d 6) δ 8.31 (s, 1H), 7.53 (s, 1H), 7.42 - 7.40 (m, 2H), 7.34 - 7.30 (m, 3H), 6.24 (s, 1H), 4.51 - 4.48 (m, 1H), 4.39 - 4.34 (m,2H), 4.08 (dd, J = 6.0, 8.3 Hz, 1H), 3.69 (t, J = 7.6 Hz, 1H), 3.58 - 3.51 (m, 2H), 1.48 - 1.45 (m, 2H), 1.39 (s, 3H), 1.34 - 1.33 (m, 6H), 1.18 (s, 3H) و 1.14 - 1.12 (m, 2H) ppm.

[00226] مرحله 5: (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide

[00227] (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (3.0 g, 5.4 mmol) was dissolved in 52 mL of methanol. 5.2 mL of water was added followed by p-TsOH.H2O (p-toluenesulfonic acid hydrate) (204 mg, 1.1 mmol). The reaction was heated at 80 °C for 45 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-hexane) to afford the product (1.3 g, 47 %, ee >98% by SFC). ESI-MS m / z calc. 520.5, found 521.7 (M+1)+. Retention time 1.69 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.

[00228] Synthesis of Compound 3: N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

[00229] Part A: Synthesis of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid

[00230] Step 1: 2-Phenylaminomethylene-malonic acid diethyl ester

[00231] 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 concentrated under reduced pressure to give 2-phenylaminomethylene-malonic acid diethyl ester as a solid, which was used in the next step without further purification. 1H NMR (DMSO-d6) δ 11.00 (d, 1H), 8.54 (d, J = 13.6 Hz, 1H), 7.36-7.39 (m, 2H), 7.13-7.17 (m, 3H), 4.17-4.33 (m, 4H), 1.18-1.40 (m, 6H).

[00232] Step 2: 4-Hydroxyquinoline-3-carboxylic acid ethyl ester

[00233] A 1 L three-necked flask equipped with a mechanical stirrer was charged with 2-phenylaminomethylene-malonic acid diethyl ester (26.3 g, 0.100 mol), polyphosphoric acid (270 g) and phosphoryl chloride (750 g). The mixture was heated to 70 °C and stirred for 4 h. The mixture was cooled to room temperature and filtered. The residue was triturated with aqueous Na2CO3, filtered and washed with water and finally dried. 4-Hydroxyquinoline-3-carboxylic acid ethyl ester was obtained as an opaque brown solid (15.2 g, 70%). The crude product was used in the next step without further purification.

[00234] Step 3: 4-Oxo-1,4-dihydroquinoline-3-carboxylic acid

[00235] 4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred at reflux for 2 h. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HCl. The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 4-oxo-1,4-dihydroquinoline-3-carboxylic acid as an off-white solid (10.5 g, 92%). 1H NMR (DMSO-d6) δ 15.34 (s, 1H), 13.42 (s, 1H), 8.89 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.60 (m, 1H).

[00236] Section (b): Synthesis of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

[00237] Step 1: Carbonic acid 2,4-di-tert-butyl-phenyl ester methyl ester

[00238] Methyl chloroformate (58 mL, 750 mmol) was added dropwise to a solution of 2,4-di-tert-butyl-phenol (103.2 g, 500 mmol), Et3N (139 mL, 1000 mmol) and DMAP (3.05 g, 25 mmol) in dichloromethane (400 mL) in an ice-water bath cooled to 0 °C. The mixture was allowed to warm to room temperature while stirring overnight, then filtered through silica gel (approximately 1 L) using 10% ethyl acetate-hexanes (approximately 4 L) as eluent. The combined filtrate was concentrated to afford carbonic acid 2,4-di-tert-butyl-phenyl ester methyl ester as a yellow oil (132 g, quantitative). 1H NMR (400 MHz, DMSO-d6) 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).

[00239] Step 2: Carbonic acid 2,4-di-tert-butyl-5-nitro-phenyl ester methyl ester and Carbonic acid 2,4-di-tert-butyl-6-nitro-phenyl ester methyl ester

[00240] To a stirred mixture of carbonic acid 2,4-di-tert-butyl-phenyl ester methyl ester (4.76 g, 180 mmol) in concentrated sulfuric acid (2 ml), cooled in an ice-water bath, was added a cooled mixture of sulfuric acid (2 ml) and nitric acid (2 ml). The addition was done slowly so that the reaction temperature did not exceed 50 °C. The reaction was allowed to stir for 2 hours while warming to room temperature. The reaction was then added to ice-water and extracted into diethyl ether. The ether layer was concentrated and purified by column chromatography (0-10% ethyl acetate-hexanes) dried (MgSO4) to give a mixture of carbonic acid 2,4-di-tert-butyl-5-nitro-phenyl ester methyl ester and carbonic acid 2,4-di-tert-butyl-6-nitro-phenyl ester methyl ester as a A yellow opaque solid (4.28g) was produced, which was used directly in the next step.

[00241] Step 3: 2,4-Di-tert-butyl-5-nitro-phenol and 2,4-Di-tert-butyl-6-nitro-phenol

[00242] A mixture of carbonic acid 2,4-di-tert-butyl-5-nitro-phenyl ester methyl ester and carbonic acid 2,4-di-tert-butyl-6-nitro-phenyl ester methyl ester (4.2 g, 14.0 mmol) was dissolved in MeOH (65 mL) before KOH (2.0 g, 36 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction mixture was acidified (pH 2-3) by adding concentrated HCl and partitioned between water and diethyl ether. The ether layer was concentrated and purified by column chromatography (0-5% ethyl acetate-hexanes) to provide 2,4-di-tert-butyl-5-nitro-phenol (in two steps) and 2,4-di-tert-butyl-6-nitro-phenol. 2,4-Di-tert-butyl-5-nitro-phenol. 1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H, OH), 7.34 (s, 1H), 6.83 (s, 1H), 1.36 (s, 9H), 1.30 (s, 9H). 2,4-Di-tert-butyl-6-nitro-phenol: 1H NMR (400 MHz, CDCl3) 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).

[00243] Step 4: 5-Amino-2,4-di-tert-butyl-phenol

[00244] To a refluxing solution of 2,4-di-tert-butyl-5-nitro-phenol (1.86 g, 7.40 mmol) and ammonium formate (1.86 g) in ethanol (75 ml) was added Pd-5% wt on activated carbon (900 mg). The reaction mixture was stirred at reflux for 2 h, cooled to room temperature and filtered through Celite. The Celite was washed with methanol and the combined filtrates were concentrated to afford 5-amino-2,4-di-tert-butyl-phenol as a grey solid (1.66 g, yield). 1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H, OH), 6.84 (s, 1H), 6.08 (s, 1H), 4.39 (s, 2H, NH2), 1.27 (m, 18H); HPLC retention time 2.72 min, 10-99 % CH3CN, 5 min run; ESI-MS 222.4 m / z [M+H]+.

[00245] Step 5: N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide

[00246] To a suspension of 4-oxo-1,4-dihydroquinolin-3-carboxylic acid (35.5 g, 188 mmol) and HBTU (85.7 g, 226 mmol) in DMF (280 mL), Et3N (63.0 mL, 451 mmol) was added at ambient temperature. The mixture was homogenized and allowed to stir for 10 min before 5-amino-2,4-di-tert-butyl-phenol (50.0 g, 226 mmol) was added in small portions. The mixture was allowed to stir overnight at ambient temperature. The mixture became heterogeneous during the reaction. After all the acid was consumed (LC-MS analysis, MH+ 190, 1.71 min), the solvent was removed in vacuo. Ethyl alcohol (EtOH) was added to the orange solid to produce a slurry. The mixture was stirred on a rotovap (bath temperature 65 °C) for 15 min without applying vacuum. The mixture was filtered and the solid obtained was washed with hexane to give a white solid, which was the EtOH crystalate. Diethyl ether (Et2O) was added to the solid obtained above until a slurry was formed. The mixture was stirred on a rotovap (bath temperature 25 °C) for 15 min without applying vacuum. The mixture was filtered and the solid was obtained.This process was performed a total of 5 times. The solid was obtained after the fifth precipitate was placed under vacuum overnight to give N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (38 g, 52%). HPLC ret. time 3.45 min, 10-99% CH3CN, ; 5 min run;. 1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 11.83 (s, 1H), 9.20 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J = 8.2, 1.0 Hz, 1H), 7.83-7.79 (m, 1H), 7.76 (d, J) = 7.7 Hz, 1H), 7.54-7.50 (m, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 1.38 (s, 9H), 1.37 (s, 9H); ESI-MS m / z calc'd 392.21; Found 393.3 [M+H]+.

[00247] Synthesis of compound 4: 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid

[00248] Compound 4 may be prepared by coupling half of the acid chloride and half of the amine according to Schemes 4-A through 4-D. Figure 4-a. Synthesis of half-acid chloride.

[00249] Figure 4-a shows the preparation of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride, which is used in Figure 4-c to construct the amide bond of compound 4.

[00250] The starting material, 2,2-difluorobenzo[d][1,3]dioxole-5-carboxylic acid, is commercially available from Saltigo (a subsidiary of Lanxess). Reduction of the carboxylic acid moiety of 2,2-difluorobenzo[d][1,3]dioxole-5-carboxylic acid to the primary alcohol, followed by conversion to the corresponding chloride using thionyl chloride (SOCl2), affords 5-(chloromethyl)-2,2-difluorobenzo[d][1,3]dioxole, which is subsequently converted to -(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetonitrile using sodium cyanide. Treatment of 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetonitrile with base (alkali) and 1-bromo-2-chloroethane gives 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile. The nitrile moiety in 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile is converted to the carboxylic acid using base to give 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid, which is converted to the desired acid chloride using thionyl chloride. Figure 4-b. Alternative synthesis of the acid chloride half.

[00251] Figure 4-B shows an alternative synthesis of the required acid chloride. 5-bromomethyl-2,2-difluoro-1,3-benzodioxole is coupled with ethyl cyanoacetate in the presence of a palladium catalyst to form the corresponding alpha cyanoethyl ester. Saponification of the ester moiety to the carboxylic acid cyanoethyl compound 4 gives the cyanoethyl compound 4. Alkylation of the cyanoethyl compound with -bromo-2-chloro ethane 1 in the presence of base gives the cyanocyclopropyl compound. Purification of the cyanocyclopropyl compound with base gives the carboxylate salt, which is converted to the carboxylic acid by purification with acid. Conversion of the carboxylic acid to the acid chloride is then accomplished using a chlorinating agent such as thionyl chloride or the like. Figure 4-c. Synthesis of the amino moiety.

[00252] Figure 4C shows the preparation of the required tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate, which is coupled with 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride in Figure 4C to give compound 4. Coupling of 2-bromo-3-methylpyridine with 3-(tert-butoxycarbonyl)phenylboronic acid in the presence of a palladium catalyst gives tert-butyl 3-(3-methylpyridin-2-yl)benzoate, which is subsequently converted to the desired compound. Figure 4-d. Formation of an acid salt of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid.

[00253] Figure 4-d shows the coupling of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride with tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate using triethylamine and 4-dimethylaminopyridine to initially afford the tert-butyl ester of compound 4.

[00254] Synthesis of Compounds

[00255] Synthesis of Compound 1

[00256] Part A: سنتز ( 4S )-2,2,4-trimethylpyrrolidine hydrochloride

[00257] مرحله 1: methyl-2,4-dimethyl-4-nitro-pentanoate

[00258] Tetrahydrofuran (THF, 4.5 L) was added to a 20 L gas reactor and stirred under N2 at room temperature. 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 then charged to the reactor and the jacket temperature was raised to 50 °C. Once the temperature of the reactor contents approached 50 °C, methyl methacrylate (1.854 kg, 18.52 mol) was added slowly over 100 min. The reaction temperature was maintained at or near 50 °C for 21 h. The reaction mixture was concentrated in vacuo then returned to the reactor and diluted with methyl tert-butyl ether (MTBE) (14 L). 2 M HCl (7.5 L) was added, and the mixture was stirred for 5 min then allowed to settle. Two clear layers were visible - a lower yellow-blue phase and an upper green organic phase. The aqueous layer was removed, and the organic layer was again stirred with 2 M HCl (3 L). After separation, the HCl washes were combined again and stirred with MTBE (3 L) for 5 min. The aqueous layer was discarded, and all organic layers in the reactor were combined and stirred with water (3 L) for 5 min.After separation, the organic layers were concentrated in vacuo to give a dark green oil. The crude product was purified with MgSO4 and filtered to yield methyl-2,4-dimethyl-4-nitro-pentanoate as a clear green oil (3.16 kg, 99% yield).

[00259] 1H NMR (400 MHz, chloroform - d ) 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).

[00260] Step 2: Synthesis of methyl (2S)-2,4-dimethyl-4-nitro-pentanoate

[00261] A reactor was charged with pure water (2090 L; 10 vol) and then potassium phosphate monobasic (27 kg, 198.4 moles; 13 g / L for the charge water). The pH of the reactor contents was adjusted to pH 6.5 (± 0.2) with 20% (w / v) potassium carbonate solution. The reactor was charged with racemic methyl-2,4-dimethyl-4-nitro-pentanoate (209 kg; 1104.6 moles), and Palatase 20000L lipase (13 L, 15.8 kg; 0.06 vol).

[00262] The reaction mixture was adjusted to 32 ± 2 °C and stirred for 15 to 21 hours, and pH 6.5 was maintained using a pH adjuster with the automatic addition of 20% potassium carbonate solution. When the racemic starting material was converted to >98% ee s-enantiomer, as determined by chiral GC, the external heat was turned off. The reactor was then charged with MTBE (35 L; 5 vol), and the aqueous layer was extracted with MTBE (3 times, 400-1000L). The combined organic extracts were washed with aqueous Na2CO3 (4 times, 522 L, 18 % w / w 2.5 vol), water (523 L; 2.5 vol), and 10 % aqueous NaCl (314 L, 1.5 vol). The organic layer was concentrated in vacuo to afford methyl (2S)-2,4-dimethyl-4-nitro-pentanoate as a mobile yellow oil (>98% ee, 94.4 kg; 45% yield).

[00263] Step 3: Synthesis of (3S)-3,5,5-trimethylpyrrolidin-2-one

[00264] A 20 L reactor was purged with N2. The vessel was charged with DI water rinsed, Raney® Ni dump (2800 grade, 250 g), methyl (2S)-2,4-dimethyl-4-nitro-pentanoate (1741 g, 9.2 mol), and ethanol (13.9 L, 8 vol). The reaction was stirred at 900 RPM, and the reactor was sparged with H2 and maintained at ~2.5 bar. The reaction mixture was then heated to 60 °C for 5 h. The reaction mixture was cooled and filtered to remove Raney nickel, and the solid cake was washed with ethanol (3.5 L, 2 vol). The product ethanol solution was combined with an equal second batch and concentrated in vacuo to a minimum volume of ethanol (1.5 vol). Heptane (2.5 L) was added, and the suspension was reconcentrated to 1.5 volumes. This was done 3 times; the resulting suspension was cooled to 0-5 °C, filtered under 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)-3,5,5-trimethylpyrrolidin-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 (ddq, 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).

[00265] Step 4: Synthesis of (4S)-2,2,4-trimethylpyrrolidine hydrochloride

[00266] A 120 L glass lined reactor was charged with lithium aluminum hydride pellets (2.5 kg, 66 mol) and THF (60 L) and heated to 30 °C. The resulting suspension was charged with (S)-3,5,5-trimethylpyrrolidin-2-one (7.0 kg, 54 mol) in THF (25 L) over 2 hours while maintaining the reactor temperature at 30-40 °C. After complete addition, the reactor temperature was increased to 60-63 °C and maintained overnight. The reaction mixture was cooled to 22 °C, then quenched by the careful addition of ethyl acetate (EtOAc) (1.0 L, 10 mol), followed by 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 (750 g, 2 equiv water with 1.4 equiv sodium hydroxide based on aluminum), then quenched with 7.5 L of water. After the addition was complete, the reaction mixture was cooled to room temperature, and the solid was removed by filtration and washed with THF (3 x 25 L). The filtered and washed materials were combined and purified with 5 L (58 moles) of 37% aqueous HCl (1.05 equiv) while maintaining the temperature below 30 °C. The resulting solution was concentrated to a slurry by vacuum distillation.8 L of isopropanol was added and the solution was concentrated by distillation to near dryness. 4 L of isopropanol was added, and the product was slurried by heating to about 50 °C. 6 L of MTBE was added, and the slurry was cooled to 2-5 °C. The product was collected by filtration, washed with 12 L of MTBE, and dried in a vacuum oven (55 °C / 300 torr / N2bleed) to give (4S)-2,2,4-trimethylpyrrolidine•HCl as a white crystalline solid (6.21 kg, 75% yield). 1H NMR (400 MHz, DMSO- d 6) δ 9.34 (br d, 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).

[00267] Part B: Preparation of N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (compound 1)

[00268] Preparation of raw materials

[00269] 3,3,3-Trifluoro-2,2-dimethyl-propan-1-ol

[00270] A 1 L three-necked round-bottomed flask was equipped with a mechanical stirrer, cooling bath, an addition funnel, and a J-Kem temperature detector. The flask was charged with lithium aluminum hydride (LAH) pellets (6.3 g, 0.1665 mol) under a nitrogen atmosphere. The flask was then charged with 200 ml of tetrahydrofuran under a nitrogen atmosphere. The mixture was allowed to stir at room temperature for 0.5 h to allow the pellets to dissolve. The cooling bath was then charged with crushed ice and the temperature of the reaction mixture was lowered to 0°C. The addition funnel was charged with a solution of 3,3,3-trifluoro-2,2-dimethyl-propanoic acid (20 g, 0.1281 mol) in 60 ml of tetrahydrofuran, and the opaque yellow solution was added dropwise over 1 h. After the addition was complete, the mixture was allowed to warm slowly to room temperature and stirring was continued for 24 h. The suspension was cooled to 0°C in a water-ice cooling bath and then quenched by very slow dropwise addition of 6.3 mL of water, followed by sodium hydroxide solution (15% w / v; 6.3 mL) and finally by 18.9 mL of water. The reaction temperature of the resulting white suspension was recorded at 5°C.The suspension was stirred at 5°C for 30 min and then filtered through a 20 mm pad of Celite. The filter cake was washed with tetrahydrofuran (2 x 100 mL). The filtrate was dried over 150 g of sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to give a clear colorless oil (15 g) containing a mixture of the product 3,3,3-trifluoro-2,2-dimethyl-propan-1-ol in THF (73 wt. % solution ~10.95 g, and 27 wt. % THF determined by 1H-NMR). The rotary evaporation product was distilled at atmospheric pressure using a 30 cm Vigreux column to give 8.75 g of residue consisting of 60 wt. % tetrahydrofuran and 40 wt. % product (~3.5 g). The estimated total product amount is 14.45g (79% yield). 1H NMR (400 MHz, DMSO-d6) δ 4.99 (t, J = 5.7 Hz, 1H), 3.38 (dd, J = 5.8, 0.9 Hz, 2H), 1.04 (d, J = 0.9 Hz, 6H).

[00271] tert-Butyl 3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate

[00272] A 50L Syrris controlled reactor was started and set to jacket at 20 °C, stirred at 150 rpm, reflux condenser (10 °C) and nitrogen purged. MeOH (2.860 L) and methyl (E)-3-methoxyprop-2-enoate (2.643 kg, 22.76 mol) were added and the reactor was capped. The reaction mixture was heated to an internal temperature of 40 °C and the system was set to maintain the jacket temperature at 40 °C. Hydrazine hydrate (1300 g 55 %w / w, 22.31 mol) was added portionwise via a funnel over 30 min. The reaction mixture was heated to 60 °C for 1 h. The reaction mixture was cooled to 20 °C and triethylamine (2.483 kg, 3.420 L, 24.54 mol) was added portionwise (exothermic) while maintaining the reaction temperature <30 °C. A solution of anhydrous Boc (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 for 16 h at 20 °C. The reaction solution was concentrated to remove the MeOH, yielding a clear, light amber oil. The resulting oil was transferred to a 50 L reactor, stirred, and mixed with water (7.150 L) and heptane (7.150L) was added. The additions precipitated a small amount of product. The aqueous layer was drained into a clean container and the intermediate layer and heptane layer were filtered to separate the solid (product). The aqueous layer was returned to the reactor, and the collected solid was put back into the reactor and mixed with the aqueous layer. A dropping funnel was added to the reactor and charged with acetic acid (1.474 kg, 1.396 L, 24.54 mol), then the acid was added dropwise. The jacket was set at 0 °C to absorb the exothermicity of the reaction. After the addition (pH=5), the reaction mixture was stirred for 1 h. The solid was collected by filtration and washed with water (7.150L), and washed a second time with water (3.575L) and dried. The crystalline solid was scooped from the filter into a 20 L bubble rotavapor and heptane (7.150 L) was added. The mixture was stirred at 45 °C for 30 min, and then distilled with 1-2 volumes of solvent. The slurry in the rotavapor was filtered and the solids were washed with heptane (3.575 L) and dried.The solid was then dried in vacuo (50 °C, 15 mbar) to afford tert-butyl 5-oxo-1H-pyrazole-2-carboxylate (2921 g, 71%) as a thick crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.98 (d, J = 2.9 Hz, 1H), 5.90 (d, J = 2.9 Hz, 1H), 1.54 (s, 9H).

[00273] Step (a): tert -Butyl 3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazole-1-carboxylate

[00274] A mixture of 3,3,3-trifluoro-2,2-dimethyl-propan-1-ol (10 g, 70.36 mmol) and tert-butyl 3-hydroxypyrazole-1-carboxylate (12.96 g, 70.36 mmol) in toluene (130 mL) was treated with triphenylphosphine (20.30 g, 77.40 mmol) followed by isopropyl N-isopropoxycarbonyliminocarbamate (14.99 mL, 77.40 mmol) and the mixture was stirred at 110 °C for 16 h. The yellow solution was concentrated under reduced pressure, diluted with heptane (100 mL), and the precipitated triphenylphosphine oxide was removed by filtration and washed with heptane / toluene 4:1 (100 mL). The filtered yellow material was evaporated and the residue was purified by silica gel chromatography with a linear gradient of ethyl acetate in hexane (0-40%) to give tert-butyl 3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazole-1-carboxylate (12.3 g, 57%) as a cream solid. ESI-MS m / z calc. 308.13477, found 309.0 (M+1)+; retention time: 1.84 min. 1H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J = 3.0 Hz, 1H), 6.15 (d, J = 3.0 Hz, 1H), 4.18 (s, 2H), 1.55 (s, 9H), 1.21 (s, 6H).

[00275] Step (b): 3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)-1H-pyrazole

[00276] tert-Butyl 3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazole-1-carboxylate (13.5 g, 43.79 mmol) was treated with 4M hydrogen chloride in dioxane (54.75 mL, 219.0 mmol) and the mixture was stirred at 45 °C for 1 h. The reaction mixture was evaporated to dryness and the residue was extracted with 1 M aqueous NaOH (100 mL) and methyl tert-butyl ether (100 mL), washed with brine (50 mL) and extracted with methyl tert-butyl ether (50 mL). The combined organic phases were dried, filtered and evaporated to give 3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)-1H-pyrazole (9.0 g, 96%) as a cream-colored waxy solid. ESI-MS m / z calc. 208.08235, found 209.0 (M+1)+; retention time: 1.22 min. 1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 7.52 (d, J = 2.2 Hz, 1H), 5.69 (t, J = 2.3 Hz, 1H), 4.06 (s, 2H), 1.19 (s, 6H).

[00277] Step (c): tert -Butyl 2,6-dichloropyridine-3-carboxylate

[00278] A solution of 2,6-dichloropyridine-3-carboxylic acid (10 g, 52.08 mmol) in tetrahydrofuran (210 mL) was successively treated with di-tert-butyl dicarbonate (17 g, 77.89 mmol) and 4-(dimethylamino)pyridine (3.2 g, 26.19 mmol) and stirred overnight at room temperature. At this point, 1N HCl (400 mL) was added and the mixture was stirred vigorously for 10 min. The product was extracted with ethyl acetate (2x300mL) and the combined organic layers were washed with 300mL water and 150mL brine, dried over sodium sulfate, and concentrated under reduced pressure to give 12.94g (96% yield) of tert-butyl 2,6-dichloropyridine-3-carboxylate as a colorless oil ESI-MS m / z calc. 247.01668, found 248.1 (M+1)+; retention time: 2.27 min. 1H NMR (300 MHz, CDCl3) ppm 1.60 (s, 9H), 7.30 (d, J =7.9 Hz, 1H), 8.05 (d, J =8.2 Hz, 1H).

[00279] Step (d): tert -Butyl 2-chloro-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridine-3-carboxylate

[00280] To a solution of tert-butyl 2,6-dichloropyridine-3-carboxylate (10.4 g, 41.9 mmol) and 3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)-1H-pyrazole (9.0 g, 41.93 mmol) in DMF (110 mL) were added potassium carbonate (7.53 g, 54.5 mmol) and 1,4-diazabicyclo[2.2.2]octane (706 mg, 6.29 mmol) and the mixture was stirred at room temperature for 16 h. The creamy suspension was cooled in a cold water bath and 130 mL of cold water was added slowly. This thick suspension was stirred at room temperature for 1 h, filtered, and washed with copious amounts of water to afford tert-butyl 2-chloro-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridine-3-carboxylate (17.6 g, 99%) as a cream solid. ESI-MS m / z calc. 419.12234, found 420.0 (M+1)+; retention time: 2.36 min. 1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 2.9 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 6.26 (d, J = 2.9 Hz, 1H), 4.27 (s, 2H), 1.57 (s, 9H), 1.24 (s, 6H).

[00281] Step (e): 2-chloro-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridine-3-carboxylic acid

[00282] tert-butyl 2-chloro-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridine-3-carboxylate (17.6 g, 40.25 mmol) was suspended in 85 mL isopropanol, treated with hydrochloric acid (34 mL 6 M, 201 mmol) and heated to reflux for 3 h (almost completely dissolved and began to precipitate again). The suspension was diluted with 51 mL of water at reflux and stirred at room temperature for 2.5 h. The solid was collected by filtration, washed with 1:1 isopropanol / water (50 mL), copious amounts of water, and dried in a vacuum drying cabinet at 45-50 °C with a nitrogen bleed overnight to give 2-chloro-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (13.7 g, 91%) as a cream solid. ESI-MS m / z calc. 363.05975, found 364.0 (M+1)+; retention time: 1.79 min. 1H NMR (400 MHz, DMSO-d6) δ 13.61 (s, 1H), 8.44 (d, J = 2.9 Hz, 1H), 8.39 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 6.25 (d, J = 2.9 Hz, 1H), 4.28 (s, 2H), 1.24 (s, 6H).

[00283] مرحله (و): 2-Chloro- N -(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridine-3-carboxamide

[00284] 2-Chloro-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (100 mg, 0.2667 mmol) and CDI (512 mg, 3.158 mmol) were combined in tetrahydrofuran (582.0 µL) and the mixture was stirred at room temperature. During this, 1,3-dimethylpyrazole-4-sulfonyl chloride (62 mg, 0.3185 mmol) was immediately combined with ammonia (in methanol) in a sample vial to form a white solid. After an additional 20 min of stirring, the volatiles were removed by evaporation, and 1 mL of dichloromethane was added to the residue, which was also evaporated. DBU (100 µL, 0.6687 mmol) was then added and the mixture was stirred for 5 min at 60 °C, followed by the addition of tetrahydrofuran (1 mL) which was subsequently evaporated. The contents of the sample vial containing the activated CDI carboxylic acid in tetrahydrofuran were then added to the sample vial containing the sulfonamide and the freshly formed DBU, and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with 10 mL of ethyl acetate and washed with 10 mL of citric acid solution (1 M).The aqueous layer was extracted with ethyl acetate (2x 10 mL) and the combined organics were washed with brine, dried over sodium sulfate, and concentrated to give the product as a white solid (137 mg, 99%) which was used in the next step without further purification. ESI-MS m / z calc. 520.09076, found 521.1 (M+1)+; retention time: 0.68 min.

[00285] Step (y): N -(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[( 4S )-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide

[00286] 2-Chloro-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridine-3-carboxamide (137 mg, 0.2630 mmol), (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (118 mg, 0.7884 mmol) and potassium carbonate (219 mg, 1.585 mmol) were combined in DMSO (685.0 µL) and the mixture was heated at 130 °C for 16 h. The reaction was cooled to room temperature, and 1 mL of water was added. After stirring for 15 minutes, the contents of the sample vial were allowed to settle, and the liquid portion was removed via pipette, and the remaining solids were dissolved in 20 mL of ethyl acetate and washed with 1 M citric acid (15 mL). The layers were separated, and the aqueous layer was extracted twice more with 15 mL of ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated.The resulting solid was then purified by silica gel chromatography eluting with a gradient of methanol in dichloromethane (0-10%) to afford N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (72 mg, 41%) as a white solid. ESI-MS m / z calc. 597.2345, found 598.3 (M+1)+; retention time: 2.1 min. 1H NMR (400 MHz, DMSO) δ 12.36 (s, 1H), 8.37 (s, 1H), 8.22 (d, J = 2.8 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.17 (d, J = 2.8 Hz, 1H), 4.23 (s, 2H), 3.81 (s, 3H), 2.56 (d, J = 10.4 Hz, 1H), 2.41 (t, J = 8.7 Hz, 1H), 2.32 (s, 3H), 2.18 (dd, J = 12.4, 6.1 Hz, 1H), 1.87 (dd, J = 11.7, 5.5 Hz, 1H), 1.55 (d, J = 11.2 Hz, 6H), 1.42 (t, J = 12.0 Hz, 1H), 1.23 (s, 6H), 0.81 (d, J = 6.2 Hz, 3H).

[00287] Alternative steps (f) and (i):

[00288] Alternative step (f): 2-chloro- N -((1,3-dimethyl-1 H -pyrazol-4-yl)sulfonyl)-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1 H -pyrazol-1-yl)nicotinamide

[00289]

[00290]

[00291] To a suspension of 2-chloro-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (20.0 g, 53.89 mmol) in tetrahydrofuran (78.40 mL) was added solid carbonyl diimidazole (approximately 10.49 g, 64.67 mmol) portionwise and the resulting solution was stirred at room temperature (a slight exotherm was observed at 18-21 °C). After 1 h, solid 1,3-dimethylpyrazole-4-sulfonamide (ca. 11.33 g, 64.67 mmol) was added followed by DBU (ca. 9.845 g, 9.671 mL, 64.67 mmol) in two equal portions over 1 min (exotherm from 19 to 35 °C). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with 118 mL of ethyl acetate and then HCl (ca. 107.8 mL of 2 M, 215.6 mmol). The phases were separated and the aqueous phase was extracted with 78 mL of ethyl acetate. The organic layers were washed with 39.2 mL of water and then 40 mL of brine, dried over sodium sulfate.The resulting sponge was crystallized from a 1:1 isopropanol:heptane mixture (80 mL) to give 2-chloro-N-((1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl)-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl)nicotinamide (26.1 g, 93%) as a white solid. ESI-MS m / z calc. 520.0, found 520.9 (M+1)+; retention time: 1.83 min.

[00292] Alternative step (y): N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide

[00293]

[00294] 2-chloro-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridine-3-carboxamide (20.0 g, 38.39 mmol), (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (approximately 14.36 g, 95.98 mmol), and K2CO3 (approximately 26.54g, 192.0 mmol) were combined in 80.00 mL of DMSO and 1,2-diethoxyethane (20.00 mL) in a 500 L flask with a reflux condenser. The reaction mixture was heated at 120 °C for 16 h and then cooled to room temperature. The reaction mixture was diluted with 200.0 mL of DCM and HCl (approximately 172.8 mL of 2 M, 345.5 mmol); aqueous pH ~1. The phases were separated, and the aqueous phase was extracted with 100.0 mL of DCM. The organic phases were combined, washed with water (100.0 mL) (3 x), and dried (Na2SO4) to give an amber solution. The solution was filtered through a DCM-coated pad of silica gel (80 g; 4 g / g) and washed with 20% EtOAc / DCM (5 x 200 mL). The filtrate and washes were concentrated to give 22.2 g of a cream-colored powder. The powder was slurried in 140 mL of MTBE for 30 min.The solid was collected by filtration (sintered glass or paper) to give 24 g after air drying. The solid was transferred to a drying pan and dried overnight under vacuum (40 °C / 200 torr / N2 bleed) to give 20.70 g (90%) of a white powder. ESI-MS m / z calc. 597.2345, found 598.0 (M+1)+; retention time: 2.18 min.

[00295] 1H NMR (400 MHz, chloroform -d) δ 13.85 (s, 1H), 8.30 (d, J = 8.6 Hz, 1H), 8.23 ​​(d, J = 2.8 Hz, 1H), 8.08 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 5.98 (d, J = 2.8 Hz, 1H), 4.24 (s, 2H), 3.86 (s, 3H), 3.44 (dd, J = 10.3, 8.4 Hz, 1H), 3.09 (dd, J = 10.3, 7.8 Hz, 1H), 2.67 – 2.52 (m, 1H), 2.47 (s, 3H), 2.12 (dd, J = 12.3, 7.8 Hz, 1H), 1.70 (dd, J = 12.4, 9.6 Hz, 1H), 1.37 (s, 3H), 1.33 (s, 3H), 1.27 (s, 6H), 1.20 (d, 3H).

[00296] Alternative synthesis of 3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)-1H-pyrazole Step 1: Preparation of 3,3,3-trifluoro-2,2-dimethylpropan-1-ol A reactor was charged with toluene (300 mL) and 3,3,3-trifluoro-2,2-dimethylpropanoic acid (30 g, 192.2 mmol), capped, purged under nitrogen. The reaction was adjusted to control the internal temperature to 40 °C. A solution of vitride (65% in toluene. Approximately (119.6 g 65 %w / w, 115.4 mL 65 %w / w, 384.4 mmol) was arranged for addition via syringe, and the addition was initiated at 40 °C, with the target addition temperature between 40 and 50 °C. The reaction was stirred at 40 °C for 90 min. The reaction was cooled to 10 °C, then the remaining vitride was quenched by the slow addition of 6 mL of water. A 15 % aq NaOH solution (30 mL) was added in portions, and solids precipitated halfway through the addition. Water (60.00 mL) was added. The mixture was warmed to 30 °C and held for at least 15 min. The mixture was then cooled to 20 °C. The aqueous layer was removed. The organic layer was washed with water (60 mL x 3), and then Washed with brine (60 mL). The washed organic layer was dried over Na2SO4 followed by MgSO4. The mixture was filtered through celite, and the cake was washed with toluene (60.00 mL) and then dried.The product 3,3,3-trifluoro-2,2-dimethyl-propan-1-ol (22.5 g, 82%) was obtained as a clear colorless solution. Step 2: Preparation of 1-(tert-butyl) 4-ethyl 3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazole-1,4-dicarboxylate A reactor was charged with a solution of 3,3,3-trifluoro-2,2-dimethylpropan-1-ol (17.48 g, 123.0 mmol) in toluene (250 g), 1-(tert-butyl) 4-ethyl 3-hydroxy-1H-pyrazole-1,4-dicarboxylate (30.0 g, 117.1 mmol) and PPh3 (35.33 g, 134.7 mmol). The reaction was heated to 40 °C. DIAD (26.09 mL, 134.7 mmol) was weighed and placed in a syringe and added over 10 min while maintaining the internal temperature between 40 and 50 °C. The reaction was then heated to 100 °C over 30 min. After holding at 100 °C for 30 min, the reaction was complete, and the mixture was cooled to 70 °C for 15 min. Heptane (180.0 mL) was added, the jacket was cooled to 15 °C for 1 h. (TPPO began to crystallize at ~35 °C). The stirred mixture at 15 °C was filtered (rapidly), the cake was washed with a premixed solution of toluene (60 mL) and heptane (60 mL) and then dried. The clear solution was concentrated to a waxy solid (45 °C, vacuum, rotovap). 1-(tert-butyl) 4-ethyl 3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazole-1,4-dicarboxylate (53.49g) of crude was obtained as a waxy solid (120% of the assumed mass was recovered). Step 3: Preparation of 3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazole-4-carboxylic acid A solution of 1-(tert-butyl) 4-ethyl 3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazole-1,4-dicarboxylate (50.0 g, 131 mmol) in 2-methyltetrahydrofuran (500 mL) was prepared in a reactor and stirred at 40 °C. KOt-Bu (80.85 g, 720.5 mmol) was added in portions over 30 min. The addition was exothermic. After 20 min, UPLC-MS showed complete removal of the Boc group, so water (3.53 g, 3.53 mL, 196 mmol) was added dropwise via syringe over 20 min to maintain the reaction temperature between 40–50 °C. The mixture was then stirred for 17 h to complete the reaction. The mixture was then cooled to 20 °C and 400 mL of water was added. Stirring was stopped and the layers were separated. The desired product in the aqueous layer was washed with 200 mL of 2-Me-THF. Isopropanol (50 mL) was added followed by HCl solution (131 mL of 6.0 M, 786.0 mmol) to adjust the pH to <3 while maintaining the temperature below 30 °C. The resulting solid was then isolated by filtration and the filter cake was washed with water (100 mL) and dried until a sticky cake was obtained.The solids were then dried under vacuum at 55 °C to afford 3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazole-4-carboxylic acid (23.25 g) as a thin cream-colored solid.

[00297] Step 4: Preparation of 3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)-1H-pyrazole 3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazole-4-carboxylic acid (1.0 equiv) was added to the reactor followed by DMF (6.0 vol, 2.6 wt equiv). The mixture was stirred at 18–22 °C. DBU (0.2 equiv) was charged to the mixture at a rate of approximately 45 mL / min. The reaction temperature was raised to 98–102 °C over 45 min. The reaction mixture was stirred at 98–102 °C for 10 h or more. The reaction mixture was then cooled to -2°C to 2 °C over approximately 1 h and used without isolation to give ethyl 2-chloro-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl)nicotinate.

[00298] Alternative procedure for the preparation of 2-chloro-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridine-3-carboxylic acid

[00299] مرحله 1. Ethyl 2-chloro-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl)nicotinate

[00300] A solution of ethyl 2,6-dichloronicotinate (256 g, 1.16 mol) and 3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)-1H-pyrazole (242 g, 1.16 mol) in DMF (1.53 L) was treated with potassium carbonate (209 g, 1.51 mol) and DABCO (19.6 g, 174 mmol). The resulting suspension was allowed to stir at 14 to 25 °C to exotherm and then maintained at 20–25 °C for 3 days with external cooling. The suspension was cooled to below 10 °C when 2.0 L of water was added in a thin stream while maintaining the temperature below 25 °C. After the addition was complete, the suspension was stirred for an additional 1 h. The solid was collected by filtration (glass polypad or sintered) and the filter cake was washed with water (2 x 500-mL) and dried with suction for 2 h to afford ethyl 2-chloro-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl)nicotinate (512 g, 113% yield) as a white powder, which was used in the next reaction without further steps.

[00301] Step 2: 2-chloro-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1h-pyrazol-1-yl)nicotinic acid

[00302] Ethyl 2-chloro-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl)nicotinate (455g, 1.16mol; assuming 100% yield from the previous step) was wetted in EtOH (1.14 L) and tetrahydrofuran (455mL) while 1 M NaOH (1.16 L, 1.16 mol) was added and stirred at ambient temperature (17 °C). The reaction mixture was heated to 30 °C from the outside (exothermic) and then heated at 40 °C for 2 h. The solution was quenched with 1M HCl (1.39 L, 1.39 mol) which resulted in immediate precipitation which thickened upon addition of acid. The creamy suspension was allowed to cool to room temperature and stirred overnight. The solid was collected by filtration (glass polypad or sintered). The filter cake was washed with water (2 x 500-mL). The filter cake was dried with suction for 1 h but remained wet. The wet solid was transferred to a 10 L Buchi flask for further drying (50 °C / 20 torr), but was ineffective. Further attempts at drying followed by elution with i-PrOH were also ineffective.Successful drying was achieved after the wet solid was charged with i-PrOAc (3 L), the suspension was heated at 60 °C (homogenization), and reconcentrated to dryness (50 °C / 20 torr) to afford 2-chloro-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1h-pyrazol-1-yl)nicotinic acid (408 g; 97% yield for 2 steps) as a fine white powder. The product was further dried in a vacuum oven (50 °C / 10 torr / N2 bleed) for 2 h but a marginal weight loss was observed. 1H NMR (400 MHz, DMSO-d6) δ 13.64 (s, 1H), 8.49 – 8.36 (m, 2H), 7.77 (d, J = 8.4 Hz, 1H), 6.26 (d, J = 2.8 Hz, 1H), 4.28 (s, 2H), 1.24 (s, 6H). 19F NMR (376 MHz, DMSO-d6) δ -75.2. KF analysis: 0.04% water. 2. Preparation of Form A from Compound 1

[00303] Crystalline form (A) of compound 1 was obtained by the following synthesis. 2-chloro-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridine-3-carboxamide (108 g, 207.3 mmol) and (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (77.55 g, 518.2 mmol) were mixed, combined with K2CO3 (143.2 g, 1.036 mol) in 432.0 mL DMSO and 1,2-diethoxyethane (108.0 mL) in a 1-L RB flask with a reflux condenser. The resulting suspension was heated to 120°C and stirred at room temperature overnight. The reaction mixture was then diluted with DCM (1.080L) and HCl (933.0 mL 2 M, 1.866 mol) was added slowly. The liquid phases were separated, and the aqueous phase was extracted with DCM (540.0mL). The organic phases were combined, washed with water (540.0mL) (3 x ), then dried (Na2SO4) to give an amber solution. 25 g of silica gel was added and the drying agent / silica gel was filtered. The filter cake was washed with DCM (3 x 50-mL).The organic phases were combined and concentrated (40 °C / 40 torr) to give crude N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (198.6 g, 160% theory) as a cream-colored solid. The solid was diluted with MTBE (750 mL), heated to 60 °C (external temperature), and combined to a homogeneous suspension. The suspension was cooled to 30 °C with stirring, and the solid was collected by filtration, air-dried, and dried in vacuo to give compound 1 (111.1 g; 90%) as a fine white powder.

[00304] Crystalline Form (A) of Compound 1 was also obtained by the following procedure. A suspension of Compound 1 (150.0 g, 228.1 mmol) in iPrOH (480 mL) and water (120 mL) was heated at 82 °C to give a solution. The solution was cooled at a rate of 10 °C / h with a J-Kem controller. Once the temperature reached 74 °C, the solution was sprayed with a sample of Compound 1 in crystalline Form (A). Rapid crystallization occurred. The suspension was cooled to 20 °C. The solid was collected by filtration, washed with i-PrOH (2 x 75 mL), air dried, and dried in vacuo (55 °C / 300 torr / N2bleed) to give Compound 1, Form (A) (103.3 g) as a white powder. The sample was cooled to ~5 °C, stirred for 1 h, and then the solid was collected by filtration (sintered paper or glass). The filter cake was washed with i-PrOH (75 mL) (2 x), air-dried by suction, air-dried on a drying tray (mainly 120.6 g dried), dried in vacuum for 4 h (55 °C / 300 torr / N2 bleed), and then left overnight at room temperature. Drying overnight yielded 118.3 g (87% yield) of a white powder.

[00305] Preparation of crystalline Form M of Compound 1 (methanol solvation of Compound 1)

[00306] Compound 1 (neutral form of free acid) (800mg) was added to 9.2g of methanol and a clear solution formed. An additional 701.2g of compound 1 was added, and a suspension formed. The temperature was raised to 45ºC, at which point a clear solution formed. The solution was slowly cooled, and the solids precipitated.

[00307] The XRPD data of crystalline form M of compound 1 are summarized below. The X-ray powder diffractogram of crystalline form M of compound 1 is shown in Figure 13. Table. XRPD data for crystalline ferrocene M of compound 1 Position [°2Th.] D Spacing 6.99 12.64 11.61 7.60 13.08 6.76 13.66 6.48 15.24 5.81 15.91 5.56 16.44 5.39 17.82 4.97 19.25 4.61

[00308] Preparation of crystalline form (E) of compound 1 (methanol solvent extraction of compound 1)

[00309] Compound 1 (neutral form of free acid) (800mg) was added to 9.2g of ethanol and heated to 80ºC. A clear solution formed. The solution was slowly cooled, and the solids precipitated.

[00310] The XRPD data of crystalline form E of compound 1 are summarized below. The X-ray powder diffractogram of crystalline form E of compound 1 is shown in Figure 14. Table. XRPD data for crystalline ferrocene E of compound 1 Position [°2Th.] D Spacing 7.03 12.56 11.16 7.92 12.79 6.91 13.21 6.70 15.08 5.87 16.12 5.49 14.08 6.28 17.79 4.98 18.92 4.69

[00311] Preparation of crystalline form (P2) of compound 1 (isopropanol solvent extraction of compound 1)

[00312] A 200mg / mL solution of compound 1 in 2-propanol was heated to 75ºC, and all solids dissolved. The solution was cooled to 50ºC, and precipitation occurred. The mixture was kept at 50ºC for several hours, then cooled to room temperature and allowed to settle for several hours.

[00313] The XRPD data of the P2 crystalline form of compound 1 are summarized below. The X-ray powder diffractogram of the P2 crystalline form of compound 1 is shown in Figure 17. Table. XRPD data for crystalline P2 of compound 1 Position [°2Th.] D Spacing 10.15 8.71 10.86 8.14 12.55 7.05 12.88 6.87 15.01 5.90 15.87 5.58 16.22 5.46 16.52 5.36 17.63 5.03

[00314] Preparation of various solvents from compound 1

[00315] Various solvents of Compound 1 were prepared by stirring the amorphous Compound 1 in a relatively dry solvent as shown in Table 8 for 3 weeks at room temperature for sulfolane, propionic acid, MTBE, isobutyric acid, anisole, methyl butyl ketone, acetic acid and xylene solvents, or at 40°C for toluene solvents. The solid forms observed after drying in vacuo. The solvents obtained in vacuo at room temperature are also summarized in the table. As used herein, "PA crystalline form" refers to the crystalline form of Compound 1 prepared from propionic acid as described herein, "AN crystalline form" refers to the crystalline form of Compound 1 prepared from anisole as described herein. "Crystalline form MK" refers to a crystalline form of compound 1 prepared from methyl butyl ketone as described herein, and "Crystalline form AA1" refers to a crystalline form of compound 1 prepared from acetic acid as described herein. Table 8. Solvent Concentration (mg / mL) Form after dissolution Toluene 74 Form A Sulphalan 249 Form A Propionic acid 420 Form A MTBE 123 Form A Isobutyric acid 213 Form A Anisole 194 Not determined Methyl butyl ketone 465 Not determined Acetic acid 267 Form A Xylene 126 Largely amorphous

[00316] Synthesis of N -(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4 S )-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (compound 15)

[00317] Synthesis of starting materials:

[00318] Synthesis of tert -butyl 2,6-dichloropyridine-3-carboxylate A solution of 2,6-dichloropyridine-3-carboxylic acid (10 g, 52.08 mmol) in tetrahydrofuran (210 mL) was successively treated with di-tert-butyl dicarbonate (17 g, 77.89 mmol) and 4-(dimethylamino)pyridine (3.2 g, 26.19 mmol) and stirred overnight at room temperature. At this point, 1N HCl (400 mL) was added, and the mixture was stirred vigorously for 10 min. The product was extracted with ethyl acetate (2x300 mL), and the combined organic layers were washed with 300 mL of water and 150 mL of brine, dried over sodium sulfate, and concentrated under reduced pressure to give 12.94 g (96% yield) of tert-butyl 2,6-dichloropyridine-3-carboxylate as a colorless oil. ESI-MS m / z calc. 247.02, found 248.1 (M+1)+; retention time: 2.27 min. 1H NMR (300 MHz, CDCl3) ppm 1.60 (s, 9H), 7.30 (d, J =7.9 Hz, 1H), 8.05 (d, J =8.2 Hz, 1H).

[00319] Synthesis of tert -butyl 3-oxo-2,3-dihydro-1 H -pyrazole-1-carboxylate A 50 L reactor was set up, and the jacket was set to 20 °C, with stirring at 150 rpm, reflux condenser (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 capped. The reactor was heated to an internal temperature of 40 °C, and the system was adjusted to maintain the jacket temperature at 40 °C. Hydrazine hydrate (1300 g 55 %w / w, 22.31 mol) was added portionwise via an addition funnel over 30 min. The reaction mixture was heated to 60 °C for 1 h. The reaction mixture was cooled to 20 °C and triethylamine (2.483 kg, 3.420 L, 24.54 mol) was added portionwise, maintaining the reaction temperature at <30 °C. A solution of anhydrous Boc (di-tert-butyl dicarbonate) (4.967 kg, 5.228 L, 22.76 mol) in MeOH (2.860 L) was added portionwise, maintaining the temperature at <45 °C. The reaction mixture was stirred at 20 °C for 16 h. The reaction solution was concentrated to remove the MeOH, yielding a clear, amber oil. The resulting oil was transferred to a 50 L reactor, stirred, and water (7.150 L) and heptane (7.150 L) were added.The additions caused a small amount of product to precipitate. The aqueous layer was drained into a clean container, and the intermediate layer and heptane layer were filtered to separate the solid (product). The aqueous layer was returned to the reactor, and the collected solid was placed back into the reactor and mixed with the aqueous layer. A dropping funnel was added to the reactor and charged with acetic acid (1.474 kg, 1.396 L, 24.54 mol), which was added dropwise. The jacket was set at 0 °C to absorb the induced exotherm. After the addition was complete (pH=5), the reaction mixture was stirred for 1 h. The solid was collected by filtration and washed with water (7.150 L), and washed a second time with water (3.575 L). The crystalline solid was transferred to a 20 L rotavapor, and heptane (7.150 L) was added. The mixture was stirred at 45 °C for 30 min, and evaporated to 1–2 volumes relative to the solvent. The slurry in the rotary evaporator was filtered, and the solids were washed with heptane (3.575 L). The solid was then dried in vacuo (50 °C, 15 mbar)) to afford tert-butyl 5-oxo-1H-pyrazole-2-carboxylate (2921 g, 71%) as a thick crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.98 (d, J = 2.9 Hz, 1H), 5.90 (d, J = 2.9 Hz, 1H), 1.54 (s, 9H). سنتز 1,3-dimethyl-1 H -pyrazole-4-sulfonamide Ammonium hydroxide (approximately 186.5 mL 28 %w / v, 1.490 mol) was cooled to 0–5 °C in a jacketed reaction vessel. A solution of 1,3-dimethylpyrazole-4-sulfonyl chloride (29.0 g, 149.0 mmol) in DCM (116.0 mL) was added while maintaining the reaction temperature between 0 and 5 °C. The two phases were separated and the organic phase was washed with water (100 mL). The aqueous phases were combined and concentrated to remove most of the remaining ammonia. The aqueous phase was extracted twice with ethyl acetate (200 mL and 100 mL). The combined organic phases were dried over sodium sulfate and concentrated to give 14.1 g of a white solid. The aqueous phase was acidified with citric acid (approximately 28.63 g, 17.20 mL, 149.0 mmol) (pH ~ 2). The acidic water was extracted twice with ethyl acetate (200 mL and 100 mL). The combined organic phases were dried over sodium sulfate and concentrated to give 7.8 g of a white solid. The solids were combined and recrystallized from hot (78 °C) ethyl acetate (50 mL) to give 16.1 g of 1,3-dimethyl-1H-pyrazole-4-sulfonamide as a white crystalline solid. 1H NMR (400 MHz, DMSO) δ 8.01 (s, 1H), 7.16 (s, 2H), 3.77 (s, 3H), 2.77 (s, 3H). 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, 2-[1-(trifluoromethyl)cyclopropyl]acetic acid (1.002 g, 5.948 mmol) in THF (3.0 mL) was added dropwise over 30 min while maintaining the reaction temperature below 20 ºC. The mixture was allowed to gradually warm to ambient temperature and stirred for 18 h. The mixture was cooled in an ice bath and quenched stepwise with water (294 mg, 295 µL, 16.36 mmol), NaOH (297 µL 6 M, 1.784 mmol) and then 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 again dried over MgSO4, filtered and concentrated in vacuo to give residual THF and ether. The mixture was taken directly to 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 triphenyl phosphine (1.637 g, 6.243 mmol) were combined in THF (10.48 mL) and the reaction was cooled in an ice bath. Diisopropyl azodicarboxylate (1.288 g, 1.254 mL, 6.368 mmol) was added dropwise to the reaction mixture and the reaction was allowed to warm to room temperature for 16 h. The mixture was evaporated and the resulting material was partitioned between ethyl acetate (30 mL) and 1 N sodium hydroxide (30 mL). The organic layer was separated, washed with brine (30 mL), dried over sodium sulfate and concentrated. The crude material was purified using silica gel chromatography and eluted with a gradient of ethyl acetate in hexane (0-30%) to afford tert-butyl 3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-1-carboxylate (1.03 g, 57%). ESI-MS m / z calc. 320.13, found 321.1 (M+1)+; retention time: 0.72 min 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 trisulfuric acid (2.478 mL, 32.16 mmol), and the reaction was stirred at room temperature for 2 h. The reaction was evaporated, and the resulting oil was partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated to give 3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]-1H-pyrazole (612 mg, 86%). ESI-MS m / z calc. 220.08, found 221.0 (M+1)+; retention time: 0.5 min. 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 7.50 (t, J = 2.1 Hz, 1H), 5.63 (t, J = 2.3 Hz, 1H), 4.14 (t, J = 7.1 Hz, 2H), 2.01 (t, J = 7.1 Hz, 2H), 0.96 - 0.88 (m, 2H), 0.88 - 0.81 (m, 2H). Step 3: tert -Butyl 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylate tert-Butyl 2,6-dichloropyridine-3-carboxylate (687 mg, 2.770 mmol), 3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]-1H-pyrazole (610 mg, 2.770 mmol), and freshly ground potassium carbonate (459 mg, 3.324 mmol) were combined in anhydrous 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 for 16 h under nitrogen. The reaction mixture was diluted with water (20 mL) and stirred for 15 min. The resulting solid was collected and washed with water. The solid was dissolved in dichloromethane and dried over magnesium sulfate. The mixture was filtered and concentrated to give tert-butyl 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylate (1.01 g, 84%). ESI-MS m / z calc. 431.12, found 432.1 (M+1)+; retention time: 0.88 min Step 4: 2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid tert-Butyl 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylate (1.01 g, 2.339 mmol) and trifluoroacetic acid (1.8 mL, 23.39 mmol) were combined in dichloromethane (10 mL) and heated at 40 °C for 3 h. Hexanes were added and the mixture was reconcentrated to give 2-chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (873 mg, 99%). ESI-MS m / z calc. 375.06, found 376.1 (M+1)+; retention time: 0.69 min. Step 5: 2-Chloro-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide 2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (6 g, 15.97 mmol) in THF (60.00 mL) was treated with CDI (ca. 3.107 g, 19.16 mmol) and the cloudy solution was stirred at room temperature for 1 h. Then, 1,3-dimethylpyrazole-4-sulfonamide (ca. 3.110 g, 17.57 mmol) followed by DBU (ca. 2.917 g, 2.865 mL, 19.16 mmol) were added and the reaction was stirred at room temperature for 12 h. The mixture was treated with cold citric acid (ca. 83.84 mL of 1 M, 83.84 mmol) to give an emulsion. The majority of the THF was removed under reduced pressure and extracted with ethyl acetate (100 ml), washed with 0.5 M citric acid (80 ml) and brine (80 ml) and the aqueous phases were reverse extracted once with ethyl acetate (80 ml). The organic phases were combined, dried, filtered and evaporated. The crude material was purified by chromatography on silica gel with a linear gradient from dichloromethane to 2% methanol.Fractions of the product were evaporated to give 2-chloro-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (4.64 g, 53%). ESI-MS m / z calc. 532.09076, found 533.0 (M+1)+; retention time: 1.83 min. 1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 8.41 (d, J = 2.5 Hz, 2H), 8.10 (d, J = 8.3 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 6.19 (d, J = 2.9 Hz, 1H), 4.34 (t, J = 7.1 Hz, 2H), 3.84 (s, 3H), 2.35 (s, 3H), 2.09 (t, J = 7.1 Hz, 2H), 1.01 - 0.82 (m, 4H). Step 6: N -(1,3-Dimethylpyrazol-4-yl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4 S )-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide 2-Chloro-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (5.9 g, 10.74 mmol) was dissolved in NMP (28.62 mL) and 1,2-diethoxyethane (5.723 mL) and treated with potassium carbonate (ca. 7.422 g, 53.70 mmol) and (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (ca. 3.537 g, 23.63 mmol), vacuum / nitrogen rotated 3 times, and heated to 130 °C for 20 h (oil bath at 135 °C) while stirring under nitrogen. The reaction suspension was cooled, diluted with water (34.34 mL), and carefully added to a vigorously stirred solution of acetic acid (approximately 9.674 g, 9.161 mL, 161.1 mmol) in water (137.4 mL). The suspension was stirred at room temperature for 1 h, filtered, and washed with copious amounts of water. The crude material, which still contained water moisture, was dissolved in hot ethanol (~100 mL, brownish cloudy solution), clarified using charcoal over diatomaceous earth (only slightly lighter), and the hot, clear solution was exposed to water (~25 mL) until it became cloudy.The hot cloudy solution was cooled to room temperature with stirring for 2 h, forming a thick suspension. The solid was collected by filtration, washed with cold ethanol / water 1:1 and copious amounts of water. Over the weekend, the solid was dried using a nitrogen blanket under vacuum in a drying chamber at 45 °C to give N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (4.27 g, 65%). ESI-MS m / z calc. 609.2345, found 610.0 (M+1)+; retention time: 3.07 min 1H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 8.38 (s, 1H), 8.20 (d, J = 2.8 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.11 (d, J = 2.7 Hz, 1H), 4.31 (t, J = 7.0 Hz, 2H), 3.81 (s, 3H), 2.55 (t, J = 10.5 Hz, 1H), 2.41 (dd, J = 10.1, 7.1 Hz, 1H), 2.33 (s, 3H), 2.18 (dp, J = 17.8, 6.2 Hz, 1H), 2.07 (t, J = 7.1 Hz, 2H), 1.87 (dd, J = 11.9, 5.6 Hz, 1H), 1.55 (d, J = 11.1 Hz, 6H), 1.42 (t, J = 12.2 Hz, 1H), 0.99 - 0.86 (m, 4H), 0.82 (d, J = 6.3 Hz, 3H). سنتز N -(1,5-dimethylpyrazol-4-yl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4 S )-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide مرحله 1: 1,5-dimethylpyrazole-4-sulfonamide ( ترکیب 14 ) 1,5-Dimethylpyrazole-4-sulfonyl chloride (9 g, 46.24 mmol) was suspended in ammonium hydroxide (54 mL of 30 %w / w) and THF (27.00 mL) was added as a cosolvent, and the cloudy emulsion was stirred for 2 h at room temperature. The mixture was concentrated under reduced pressure (THF and ammonia were removed) to obtain a fine suspension. The solid was collected by filtration, washed with ice water, and dried to give 1,5-dimethylpyrazole-4-sulfonamide (7.35 g, 90%) as an off-white solid. ESI-MS m / z calc. 175.04155, found 176.0 (M+1)+; retention time: 2.8 min 1H NMR (400 MHz, DMSO-d6) δ 7.58 (s, 1H), 7.18 (s, 2H), 3.75 (s, 3H), 2.41 (s, 3H). Step 2: 2-Chloro-N-(1,5-dimethylpyrazol-4-yl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide 2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (6 g, 15.97 mmol) in THF (60.00 mL) was treated with CDI (approximately 3.107 g, 19.16 mmol), and the cloudy solution was stirred at room temperature for 1 h. Then, 1,5-dimethylpyrazole-4-sulfonamide (ca. 2.917 g, 2.865 mL, 19.16 mmol) was added, 1,5-dimethylpyrazole-4-sulfonamide (ca. 3.110 g, 17.57 mmol) was added, and then DBU (ca. 2.917 g, 2.865 mL, 19.16 mmol) was added, and the resulting thick suspension was stirred at room temperature for 4 h. The suspension was treated with cold citric acid (ca. 83.84 mL of 1 M, 83.84 mmol), and most of the THF was removed under reduced pressure, and the collected solid was washed by filtration with copious amounts of water and dried with suction. The crude material (8 g) was crystallized from ethanol (150 ml for refluxing solution) to give 2-chloro-N-(1,5-dimethylpyrazol-4-yl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (6.9 g, 80%) as an off-white solid. ESI-MS m / z calc. 532.09076, found 533.0 (M+1)+; retention time: 0.53 min. 1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 8.41 (d, J = 2.8 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.84 (s, 1H), 7.69 (d, J = 8.3 Hz, 1H), 6.19 (d, J = 2.9 Hz, 1H), 4.34 (t, J = 7.1 Hz, 2H), 3.82 (s, 3H), 2.52 (s, 3H), 2.08 (t, J = 7.1 Hz, 2H), 1.02 - 0.84 (m, 4H). Step 3: N -(1,5-Dimethylpyrazol-4-yl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4 S )-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide 2-Chloro-N-(1,5-dimethylpyrazol-4-yl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (137 mg, 0.2571 mmol) and (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (115 mg, 0.7684 mmol) and potassium carbonate (214 mg, 1.548 mmol) were combined in DMSO (685.0 µL) and heated to 130 °C for 16 h. The reaction was cooled to room temperature and then 1 mL of water was added. After stirring for 15 min, the contents of the vial were left as is, and the liquid portion was separated using a pipette and the remaining solid was dissolved in 20 mL of ethyl acetate and then washed with 15 mL of 1M citric acid. The aqueous and organic layers were separated and the aqueous layer was extracted twice more with 15 mL of ethyl acetate. The organics were combined, washed with brine, dried over sodium sulfate, and concentrated. The crude material was purified by silica gel chromatography using 0-10% methanol in dichloromethane to give N-(1,5-dimethylpyrazol-4-yl)sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (93 mg, 59%). ESI-MS m / z calc. 609.2345, یافت شد 610.3 (M+1)+; زمان نگهداری: دقیقه 2.09 1H NMR (400 MHz, DMSO) δ 12.31 (s, 1H), 8.20 (d, J = 2.8 Hz, 1H), 7.78 (s, 1H), 7.73 (d, J = 8.2 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.11 (d, J = 2.7 Hz, 1H), 4.31 (t, J = 7.0 Hz, 2H), 3.78 (s, 3H), 2.58 (d, J = 10.4 Hz, 1H), 2.53 (s, 3H), 2.41 (dd, J = 10.3, 7.0 Hz, 1H), 2.17 (dq, J = 11.9, 6.0 Hz, 1H), 2.07 (t, J = 7.1 Hz, 2H), 1.91 - 1.82 (m, 1H), 1.57 (s, 3H), 1.53 (s, 3H), 1.43 (t, J = 12.1 Hz, 1H), 0.96 (td, J = 5.0, 4.5, 3.2 Hz, 2H), 0.93 - 0.85 (m, 2H), 0.80 (d, J = 6.2 Hz, 3H). سنتز 6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]- N -(1,3,5-trimethylpyrazol-4-yl)sulfonyl-2-[(4 S )-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (18 ترکیب ) مرحله 1: 2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]- N -(1,3,5-trimethylpyrazol-4-yl)sulfonyl-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 (ca. 51.38 mg, 0.3169 mmol) were combined in THF (600.0 µL) and stirred at room temperature for 2 h. Meanwhile, 1,3,5-trimethylpyrazole-4-sulfonyl chloride (ca. 55.53 mg, 0.2661 mmol) was combined with ammonia (ca. 250.0 µL of 7 M, 1.750 mmol) (in methanol) in a separate vial and immediately gave a white solid. After stirring for another 20 min, the volatile gases were removed by evaporation, and 1 mL of dichloromethane was added to the remaining solid, and also evaporated. DBU (ca. 54.41 mg, 53.45 µL, 0.3574 mmol) was added and stirred at 60 °C for 5 min (to facilitate removal of ammonia from any residual ammonium chloride), followed by the addition of 1 mL of THF, which was then evaporated. The contents of the vial containing the CDI-activated carboxylic acid in THF were then added to the vial containing the freshly formed sulfonamide and DBU, and the reaction mixture was stirred at room temperature for 4 h.The reaction mixture was diluted with ethyl acetate (10 mL) and washed with citric acid (10 mL of 1 M). The aqueous layer was extracted with ethyl acetate (2 x 10 mL), and the combined organics were washed with brine, dried over sodium sulfate, and concentrated to give a white solid. This material was used in the next step without further purification. 2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]- N -(1,3,5-trimethylpyrazol-4-yl)sulfonyl-pyridine-3-carboxamide (139 mg, 96%). ESI-MS m / z calc. 546.1064, found 547.1 (M+1)+; retention time: 0.7 min. Step 2: 6-[3-[2-[1-(Trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]- N -(1,3,5-trimethylpyrazol-4-yl)sulfonyl-2-[(4 S )-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide 2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-N-(1,3,5-trimethylpyrazol-4-yl)sulfonyl-pyridine-3-carboxamide (139 mg, 0.2541 mmol), (4S)-2,2,4-trimethylpyrrolidine (Hydrochloride salt) (114 mg, 0.7617 mmol), and potassium carbonate (211 mg, 1.527 mmol) were combined in DMSO (508.2 µL) and heated at 130 °C for 16 h. The reaction was cooled to room temperature, and 1 mL of water was added. After stirring for 15 min, the contents of the vial were allowed to settle, the liquid portion was removed by pipette, and the remaining solids were dissolved in 20 mL of ethyl acetate and then washed with 15 mL of 1 M citric acid. The aqueous and organic layers were separated, and the aqueous layer was extracted twice more with 15 mL of ethyl acetate. The organics were combined, washed with brine, dried over sodium sulfate, and concentrated.The resulting solid was further purified using silica gel chromatography and eluted with 0-10% methanol in dichloromethane to give a white solid with the formula 6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-N-(1,3,5-trimethylpyrazol-4-yl)sulfonyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (80 mg, 50%). ESI-MS m / z calc. 623.2502, found 624.3 (M+1)+; retention time: 2.16 min Synthesis of N-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4 S )-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (compound 55) Step 1: 1-Methyl-3-(trifluoromethyl)pyrazole-4-sulfonamide 1-Methyl-3-(trifluoromethyl)pyrazole-4-sulfonyl chloride (250 mg, 1.006 mmol) was dissolved in THF (2 mL), and ammonia in methanol (750 µL of 7 M, 5.2 mmol) was added. The reaction was stirred at room temperature for 3 h. The reaction mixture was evaporated to dryness, and the residue was suspended in ethyl acetate and heated at 65 °C for 20 min. The mixture was filtered hot (to remove the ammonium chloride formed in the reaction), and the solids were discarded. The mother liquor was evaporated to give 1-methyl-3-(trifluoromethyl)pyrazole-4-sulfonamide (186 mg, 81%). ESI-MS m / z calc. 229.01328, found 230.0 (M+1)+; retention time: 0.28 min. Step 2: 2-Chloro-N-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide 2-Chloro-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (51 mg, 0.14 mmol) and CDI (37 mg, 0.23 mmol) were combined in THF (1 mL) and stirred for 1 h at room temperature. 1-Methyl-3-(trifluoromethyl)pyrazole-4-sulfonamide (34 mg, 0.15 mmol) and DBU (64 µL, 0.4280 mmol) were added, and the reaction was stirred for another 16 h. The reaction mixture was partitioned between ethyl acetate and 1 M citric acid solution. The organics were separated, washed with brine, dried over sodium sulfate, and evaporated. The crude material was used directly in the next step. 2-Chloro-N-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (82 mg, 100%) ESI-MS m / z calc. 586.0625, found 587.2 (M+1)+; retention time: 0.73 min Step 3: N -[1-Methyl-3-(trifluoromethyl)pyrazol-4-yl]sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4 S )-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide 2-Chloro-N-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]pyridine-3-carboxamide (82 mg, 0.14 mmol) and (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (64 mg, 0.43 mmol), and potassium carbonate (100 mg, 0.724 mmol) were combined in DMSO (1 mL) and heated at 130 °C for 16 h. The reaction mixture was diluted with water (3 mL), resulting in the formation of a gum. The water was slowly drained and discarded. The remaining solution was partitioned between ethyl acetate and 1 M citric acid solution. The organics were separated, washed with brine, dried over sodium sulfate, and evaporated. The crude material was purified by silica gel chromatography and eluted with 0-10% ethanol in dichloromethane to give N-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]sulfonyl-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (29.6 mg, 32%). ESI-MS m / z calc. 663.20624, found 664.4 (M+1)+; retention time: 2.16 min. 1H NMR (400 MHz, DMSO- d6) δ 12.87 (s, 1H), 8.79 (s, 1H), 8.20 (d, J = 2.8 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.11 (d, J = 2.8 Hz, 1H), 4.31 (t, J = 7.1 Hz, 2H), 3.99 (s, 3H), 2.56 (d, J = 10.5 Hz, 1H), 2.45 (dd, J = 3.9, 2.0 Hz, 1H), 2.29 – 2.12 (m, 1H), 2.07 (t, J = 7.1 Hz, 2H), 1.88 (dd, J = 12.0, 5.7 Hz, 1H), 1.56 (s, 3H), 1.54 (s, 3H), 1.42 (t, J = 12.1 Hz, 1H), 0.99 – 0.92 (m, 2H), 0.90 (d, J = 10.7 Hz, 2H), 0.80 (d, J = 6.2 Hz, 3H). سنتز N -(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-1-yl]-2-[(4 S )-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (19 ترکیب ) سنتز (1-trifluoromethyl-cyclobutyl)-methanol 1-Trifluoromethyl-cyclobutanecarboxylic acid (5.0 g, 30. mmol) was dissolved in diethyl ether (60 mL) and cooled to 0 ºC. Lithium aluminum hydride (38.66 mL, 1 M in diethyl ether) was added dropwise and the solution was allowed to warm to room temperature overnight. The reaction solution was cooled to 0 ºC with stirring and sodium sulfate decahydrate was added, resulting in gradual gas evolution. The addition was continued portionwise until no bubbles were observed at room temperature. The reaction solution was then filtered through a pad of diatomaceous earth and washed with diethyl ether. The filtrate was concentrated under reduced pressure to give 5.44 g of the mixture containing the desired product and some diethyl ether precipitate (36% by NMR integration). This gave 1-trifluoromethyl-cyclobutyl-methanol (3.46 g, 78%) as a colorless oil. 1H NMR (250 MHz, CDCl3) δ (ppm): 3.82 (s, 2H), 2.39-2.14 (m, 2H), 2.10-1.85 (m, 4H). Step 1: 3-(1-Trifluoromethyl-cyclobutylmethoxy)-pyrazole-1-carboxylic acid tert-butyl ester 1-Trifluoromethyl-cyclobutyl-methanol (1.50 g, 9.73 mmol) and 3-oxo-2,3-dihydro-pyrazole-1-carboxylic acid tert-butyl ester (1.63 g, 8.85 mmol) were dissolved in anhydrous tetrahydrofuran (32 mL). The solution was degassed by centrifugation (ultrasound) and purged with nitrogen gas. Triphenylphosphine (2.55 g, 9.73 mmol) was added, followed by diisopropyl azodicarboxylate (1.92 mL, 9.73 mmol) dropwise. After additions were complete, the reaction was heated to 50 ºC for 16 h. After cooling to room temperature, the reaction was diluted with ethyl acetate (100 mL) and washed with 1 M sodium hydroxide solution (2 x 100 mL) and then brine (125 mL). The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The yellow crude oil was purified by flash chromatography using a 0-10% ethyl acetate in hexane gradient to afford 3-(1-trifluoromethyl-cyclobutylmethoxy)-pyrazole-1-carboxylic acid tert-butyl ester (2.48 g, 87%) as an off-white solid. ESI-MS m / z calc. 320.31, found 321.1 (M+1)+. Retention time: 3.74 min Step 2: 3-(1-Trifluoromethyl-cyclobutylmethoxy)-1H-pyrazole hydrochloride salt 3-(1-Trifluoromethyl-cyclobutylmethoxy)-pyrazole-1-carboxylic acid tert-butyl ester (2.48 g, 7.74 mmol) was dissolved in 4 M hydrogen chloride in dioxane (77 mL). The solution was stirred overnight at room temperature, after which the volatile gases were removed under reduced pressure to give the hydrochloride salt of 3-(1-trifluoromethyl-cyclobutylmethoxy)-1H-pyrazole (1.95 g, 98%) as a white powder. ESI-MS m / z calc. 220.20, found 221.2 (M+1)+. Retention time: 2.67 min. Step 3: 2-Chloro-6-[3-(1-trifluoromethyl-cyclobutylmethoxy)-pyrazole-1-yl]-nicotinic acid tert-butyl ester 3-(1-Trifluoromethyl-cyclobutylmethoxy)-1H-pyrazole hydrochloride salt (1.95 g, 7.61 mmol) and 2,6-dichloro-nicotinic acid tert-butyl ester (1.89 g, 7.62 mmol) were dissolved in dimethylformamide (15 mL) and after addition of 1,4-diazabicyclo[2.2.2]octane (0.43 g, 3.8 mmol) potassium carbonate (4.21 g, 30.5 mmol) was added. The reaction was stirred overnight at room temperature, then water (150 mL) was added and the aqueous layer was extracted using 4:1 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 oil was purified by silica gel chromatography using a 0-10% ethyl acetate in hexane gradient method to afford 2-chloro-6-[3-(1-trifluoromethyl-cyclobutylmethoxy)-pyrazole-1-yl]-nicotinic acid tert-butyl ester (1.94 g, 66%) as a white solid. ESI-MS m / z calc. 431.85, found 432.2 (M+1)+. Retention time: 4.61 min. Step 4: 2-Chloro-6-[3-(1-trifluoromethyl-cyclobutylmethoxy)-pyrazole-1-yl]-nicotinic acid 2-Chloro-6-[3-(1-trifluoromethyl-cyclobutylmethoxy)-pyrazole-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) was added. The reaction solution was stirred overnight at room temperature, after which the volatile gases were removed under reduced pressure to give 2-chloro-6-[3-(1-trifluoromethyl-cyclobutylmethoxy)-pyrazole-1-yl]-nicotinic acid (1.61 g, 97%) as a white solid. ESI-MS m / z calc. 375.74, found 376.2 (M+1)+. Retention time: 3.57 min. Step 5: 2-Chloro-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide 2-Chloro-6-[3-[[1-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (100 mg, 0.2661 mmol) and CDI (51 mg, 0.3145 mmol) in THF (600.0 µL) were combined and stirred for 2 h in a vial at room temperature (vial 1). Meanwhile, 1,3-dimethylpyrazole-4-sulfonyl chloride (62 mg, 0.3185 mmol) was combined with ammonia (approximately 250.0 µL of 7 M, 1.750 mmol) (in methanol) in a separate vial (vial 2). After stirring for another 20 min, volatile gases were removed by evaporation from vial 2 and 1 mL of dichloromethane was added to the solid residue and stirred for 5 min at 60 °C (to facilitate the removal of ammonia from any remaining ammonium chloride). After cooling to room temperature, 1 mL of THF was added and then evaporated under reduced pressure. The contents of vial 1 were then added to vial 2 via syringe and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with 10 mL of ethyl acetate and washed with 10 mL of 1 M citric acid.The aqueous layer was extracted with 2 x 10 mL ethyl acetate, and the combined organics were washed with brine, dried over sodium sulfate, and concentrated to give a white solid. This material was used in the next step without further purification. 2-chloro-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (132 mg, 93%) ESI-MS m / z calc. 532.09076, found 533.1 (M+1)+; retention time: 0.7 min Step 6: N-(1,3-Dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-1-yl]-2-[(4 S )-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide 2-Chloro-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (132 mg, 0.2477 mmol), (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (111 mg, 0.7417 mmol), and potassium carbonate (206 mg, 1.491 mmol) were combined in DMSO (500 µL) and heated at 130 °C for 16 h. The reaction was cooled to room temperature and 1 mL of water was added. After stirring for 15 min, the liquid portion was removed by pipette, and the remaining solids were dissolved in 20 mL of ethyl acetate and then washed with 15 mL of 1 M citric acid. The aqueous and organic layers were separated and the aqueous layer was extracted twice more with 15 mL of ethyl acetate. The organics 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-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (93 mg, 62%) as a white solid. ESI-MS m / z calc. 609.2345, found 610.3 (M+1)+; retention time: 2.14 min. 1H NMR (400 MHz, DMSO) δ 12.36 (s, 1H), 8.37 (s, 1H), 8.22 (d, J = 2.8 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.18 (d, J = 2.7 Hz, 1H), 4.48 (s, 2H), 3.81 (s, 3H), 2.56 (d, J = 10.4 Hz, 1H), 2.41 (dd, J = 10.2, 7.0 Hz, 1H), 2.32 (s, 3H), 2.31 - 2.26 (m, 2H), 2.20 - 2.07 (m, 4H), 2.01 - 1.92 (m, 1H), 1.88 (dt, J = 11.8, 6.5 Hz, 1H), 1.55 (d, J = 11.3 Hz, 6H), 1.42 (t, J = 12.2 Hz, 1H), 0.81 (d, J = 6.2 Hz, 3H). سنتز N -(1,3-Dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4 S )-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (10 ترکیب ) مرحله الف: (1-(Trifluoromethyl)cyclopropyl)methanol Lithium aluminum hydride (ca. 78.45 g, 2.067 mol) (in tablet form) was added to the flask, THF (2.450 L) was added to the addition funnel, and the system was cycled 3 times with vacuum / nitrogen. The solvent was immediately added to the LAH tablets, stirred at room temperature for 0.5 h (the tablets began to disintegrate to give a gray suspension), and cooled in an ice bath. A solution of 1-(trifluoromethyl)cyclopropanecarboxylic acid (245 g, 1.590 mol) in THF (735.0 mL) was added slowly via the addition funnel over 0.5–1 h, while maintaining the internal temperature below 30 °C. The gray suspension was stirred for 14 h and cooled under ice-cooling with gradual addition of water (ca. 75.92 g, 75.92 mL, 4.214 mol), and then NaOH (ca. 76.32 mL of 6 M, 457.9 mmol) and water (ca. 75.92 g, 75.92 mL, 4.214 mol) were added. The gray suspension was stirred at ~50 °C until the solid became colorless (~0.5 h), treated with magnesium sulfate (20 g), filtered over diatomaceous earth, and the aluminum salts were washed with three portions of hot THF.The filtrate was again dried over magnesium sulfate, filtered, and concentrated by evaporation at 55 °C and 450 mbar to give [1-(trifluoromethyl)cyclopropyl]methanol as a 62 wt% (NMR) solution in THF (327 g, 91%). 1H NMR (400 MHz, DMSO-d6) δ 4.94 (t, J = 6.0 Hz, 1H), 3.56 (d, J = 6.0 Hz, 2H), 0.91 - 0.74 (m, 4H) Step 1: tert-Butyl 3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1-carboxylate A 5000 mL 3-neck round-bottom flask was equipped with a mechanical stirrer, a heat-generating jacket, a J-Kem temperature measuring / control device, an addition funnel, a water-cooled reflux condenser, and a nitrogen inlet / outlet. The vessel was charged with tert-butyl 5-oxo-1H-pyrazole-2-carboxylate (70 g, 0.3800 mol) and tetrahydrofuran (840 mL, 12 mL / g) under a nitrogen atmosphere, which gave a clear, pale yellow solution. Stirring was initiated, and the vessel temperature was recorded at 19 °C. The vessel was then charged with [1-(trifluoromethyl)cyclopropyl]methanol (58.56 g, 0.4180 mol), which was added in one portion, followed by triphenylphosphine (109.6 g, 0.4180 mol) as a solid in one portion. The pale yellow solution was then exposed to diisopropyl azodicarboxylate (as a clear reddish-orange liquid) (82.3 mL, 0.4180 mol) and added dropwise over 1 h, resulting in a gradual exotherm to 40 °C, yielding a pale amber, clear solution.The reaction mixture was then heated to 50 °C, and these conditions were maintained for 2 h, when analysis by LC / MS indicated complete consumption of the starting material. The clear amber reaction mixture was concentrated under reduced pressure and the resulting dark oil was suspended in toluene (560 mL) and stirred at room temperature for 1 h, during which time a solid (triphenylphosphine oxide MW = 278.28) precipitated. The thick slurry was filtered through a Buchner funnel with a glass frit, and the filter cake was washed by agitation through toluene (150 mL) and then drawn for 30 min. The clear amber filtrate was concentrated under reduced pressure to give a clear amber oil. This material was purified by silica gel flash column chromatography (solid load on 1.5 kg RediSep diatomaceous earth column) and eluted with a gradient of 100% hexane to 20% EtOAc in hexane, collecting 450 mL fractions. The product eluted in approximately 5% EtOAc in hexane.The desired components were combined and concentrated under reduced pressure to give a clear, pale yellow oil as the desired product tert-butyl 3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1-carboxylate, which was then dried over diatomaceous earth to give a white solid (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). ESI-MS m / z calc. 306.11914, found 259.0 (M-48)+; retention time: 1.76 min Step 2: 3-[[1-(Trifluoromethyl)cyclopropyl]methoxy]-1H-pyrazole A 5000 mL 3-neck round-bottom flask was connected to a mechanical stirrer, a heat mantle, a J-Kem temperature sensor, a water-cooled reflux condenser, an addition funnel, and a nitrogen inlet / outlet. The vessel was charged under a nitrogen atmosphere with tert-butyl 3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazole-1-carboxylate (80 g, 0.2612 mol), dichloromethane (320 mL, 4 mL / g), and methyl alcohol (320 mL, 4 mL / g) to give a clear, pale yellow solution. Stirring was initiated, and the temperature of the flask was recorded at 19 °C. The addition funnel was charged with 4 M HCl in 1,4-dioxane (195.9 mL, 0.7836 mol), which was then added dropwise over 1 h, resulting in a gradual exotherm to 30 °C. The resulting clear pale yellow solution was heated to 45 °C at room temperature, and these conditions were maintained for 1 h, when analysis by LC / MS indicated the reaction was complete. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The remaining precipitate was dissolved in tert-butyl methyl ether (640 mL) and then transferred to a separatory funnel and washed with 2 M sodium hydroxide solution (391.8 mL, 0.7836 mol) was partitioned. The organic layer was removed, and the precipitate was extracted with tert-butyl methyl ether (2 x 200 mL). The combined organic material was washed with saturated sodium chloride solution (500 mL), dried over sodium sulfate (300 g), and then filtered through a Buchner funnel with a glass frit. The clear pale yellow filtrate was concentrated under reduced pressure to give a clear pale yellow oil which solidified with a short wait to give a white solid (49.5 g, 0.240 mol, 92%) as the desired product with the formula 3-[[1-(trifluoromethyl)cyclopropyl]methoxy]-1H-pyrazole. 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 7.51 (d, J = 2.4 Hz, 1H), 5.67 (d, J = 2.4 Hz, 1H), 4.19 (s, 2H), 1.09 – 0.97 (m, 4H). ESI-MS m / z calc. 206.0667, found 207.0 (M+1)+; retention time: 1.07 min Step 3: tert -Butyl 2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]meth-oxy]pyrazol-1-yl]pyridine-3-carboxylate A 5000 mL 3-neck round-bottom flask was connected to a mechanical stirrer, a cooling bath that served as a secondary restraint, a J-Kem temperature sensor, a water-cooled reflux condenser, an addition funnel, and a nitrogen inlet / outlet. The flask was charged under a nitrogen atmosphere with 3-[[1-(trifluoromethyl)cyclopropyl]methoxy]-1H-pyrazole (45 g, 0.2183 mol) and N,N-dimethylformamide (540 mL, 12 mL / g), resulting in a clear, pale yellow solution. Stirring was initiated, and the flask temperature was recorded at 17 °C. The flask was then charged with tert-butyl 2,6-dichloropyridine-3-carboxylate (54.16 g, 0.2183 mol), which had been added as a solid in one portion. The resulting pale yellow clear solution was then treated with potassium carbonate (39.22 g, 0.2838 mol) added as a solid in one portion, followed by 1,4-diazabicyclo[2.2.2]octane (3.67 g, 0.03274 mol) added as a solid in one portion. The resulting yellow suspension was allowed to stir at room temperature for 24 h. The reaction mixture was cooled to 10 °C using a crushed ice / water cooling bath.The addition funnel was filled with water (540 mL) which was added dropwise over 45 min to form a thick suspension which exothermed to 15 °C. The resulting suspension was stirred for 30 min at 15 °C and then filtered through a Büchner funnel with a glass frit. The filtered cake was washed with water (2 x 500 mL) and stirred, then drawn into the Büchner for 2 h. The material was then allowed to air dry overnight to provide (73 g, 0.175 mol, 80%) of a white, granular solid as tert-butyl 2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylate. ESI-MS m / z calc. 361.0441, found 361.9 (M+1)+; retention time: 2.27 min. Step 4: 2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid A 1000 mL 3-neck round-bottom flask was connected to a mechanical stirrer, a heating mantle, a J-Kem temperature sensor / controller, an addition funnel, a water-cooled condenser, and a nitrogen inlet / outlet. The vessel was charged under a nitrogen atmosphere with tert-butyl 2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylate (70 g, 0.1675 mol) and 2-propanol (350 mL), which gave a pale white solution. Stirring was started, and the temperature of the flask was recorded at 19 ºC. The addition funnel was charged with 6 M aqueous HCl (139.6 mL, 0.8375 mol), which was added dropwise over 10 min, resulting in an exoderm at 30 ºC. The suspension was then heated to the boiler temperature (~82 ºC at this point). The suspension turned into a clear pale yellow solution upon heating (boiler temperature ~75 ºC at this point). After stirring at reflux for about 30 min, a solid began to precipitate. Stirring of the suspension at reflux was continued for another 30 min, at which point water (210 mL) was added dropwise over 15 min.The heat was then removed, and the suspension was stirred and allowed to cool gradually to room temperature. The product was collected by vacuum filtration on a glass-fritted Buchner funnel, and the filter cake was washed with 1:1 water / 2-propanol (100 mL) followed by water (2 x 100 mL) with agitation, and then drawn into the Buchner for 30 min. The product 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. 1H 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). ESI-MS m / z calc. 361.0441, found 361.9 (M+1)+; retention time: 3.23 min Step 5: 2-Chloro-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide To a solution of 2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (1.05 g, 2.903 mmol) in THF (20.0 mL), carbonyl diimidazole (670.8 mg, 4.137 mmol) was added. The solution was stirred at room temperature for 1 h. Then, 1,3-dimethylpyrazole-4-sulfonamide (580.5 mg, 3.313 mmol) and DBU (670.0 µL, 4.480 mmol) were added. The mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted using ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and evaporated to give 2-chloro-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (1.4 g, 93%) as a white, sticky solid, which was used as is in the next reaction. ESI-MS m / z calc. 518.0751, found 519.4 (M+1)+; retention time: 0.66 min Step 6: N -(1,3-Dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4 S )-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide 2-Chloro-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (190 mg, 0.3662 mmol) in DMSO (1 mL), and (4S)-2,2,4-trimethylpyrrolidine (ca. 124.4 mg, 1.099 mmol) were added, followed by finely ground potassium carbonate (ca. 303.6 mg, 2.197 mmol). The reaction mixture was stirred overnight at 130 °C. The reaction mixture was diluted with EtOAc (50 mL) and washed with 1 M aqueous citric acid (1×50 mL) and brine (1×50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting material was separated by silica gel column chromatography: 12 g silica gel column, gradient 0-5% MeOH / DCM. N-(1,3-Dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide was obtained (49.5 mg, 0.08310 mmol, 22.70%). ESI-MS m / z calc. 595.2189, found 596.5 (M+1)+; retention time: 2.06 min. 1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 8.35 (s, 1H), 8.21 (d, J = 2.8 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.14 (d, J = 2.8 Hz, 1H), 4.42 - 4.30 (m, 2H), 3.80 (s, 3H), 2.56 (t, J = 10.4 Hz, 1H), 2.44 (t, J = 8.6 Hz, 1H), 2.32 (s, 3H), 2.18 (dq, J = 12.0, 5.9 Hz, 1H), 1.87 (dd, J = 11.9, 5.6 Hz, 1H), 1.56 (s, 3H), 1.53 (s, 3H), 1.42 (t, J = 12.2 Hz, 1H), 1.12 - 1.05 (m, 4H), 0.82 (d, J = 6.3 Hz, 3H). سنتز دو انانتیومتر 2-(4- tert -butyl-2,2-dimethyl-pyrrolidin-1-yl)- N -(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide مرحله 1: 3,3-Dimethylbutanenitrile Sodium cyanide (9.20 g, 187.7 mmol) was added to a solution of 1-bromo-2,2-dimethylpropane (15.74 g, 104.2 mmol) in DMSO (100 mL), and the reaction mixture was stirred overnight at 90 °C. When the reaction mixture had cooled to room temperature, it was poured into water (900 mL) and extracted with diethyl ether (3 x 300 mL). The organic layers were combined, washed with 3 N HCl (300 mL), water (300 mL), and brine (300 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 3,3-dimethylbutanenitrile (11.78 g containing 50% of diethyl ether, 58% yield) as a clear liquid. 1H NMR (300 MHz, CDCl3) ppm 1.09 (s, 9 H), 2.22 (s, 2 H). Step 2: 2- tert -Butyl-4-methyl-pent-4-enenitrile n-Butyllithium (27.2 mL of 2.5 M, 68.00 mmol) was added to a solution of diisopropylamine (8.7 mL, 62.07 mmol) in dry THF (100 mL) at −78 °C, and the mixture was stirred at this temperature for 15 min, warmed to 0 °C for 15 min, then cooled again to −78 °C. After that, 3,3-dimethylbutanenitrile (6.0 g, 61.75 mmol) was added, and the reaction mixture was stirred at −78 °C for 1 h. 3-Chloro-2-methyl-prop-1-ene (12.1 mL, 123.6 mmol) was added, and the reaction mixture was slowly warmed to room temperature and then stirred at room temperature overnight. The reaction mixture was diluted with DCM (200 mL) and washed with water (3x100 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 2-tert-butyl-4-methyl-pent-4-enenitrile (10.69 g, 87% purity (13% from THF), 99% yield) as a yellow oil. 1H NMR (300 MHz, CDCl3) ppm 1.08 (s, 9H), 1.78 (s, 3H), 2.17-2.28 (m, 2H), 2.46 (dd, J=11.3, 4.8 Hz, 1H), 4.91 (d, J=9.4 Hz, 2H). Step 3: 2- tert -Butyl-4-methyl-pent-4-en-1-amine Lithium aluminum hydride (9.33 g, 245.8 mmol) was suspended in dry diethyl ether (250 mL) at 0 °C. 2-tert-Butyl-4-methyl-pent-4-enenitrile (9.30 g, 61.49 mmol) was added, and the reaction mixture was stirred overnight under nitrogen at room temperature. The reaction mixture was cooled to 0 °C and quenched with water (10 mL), 2 N NaOH (10 mL), and water (30 mL). The resulting mixture was stirred at room temperature for 30 min, then magnesium sulfate was added, and stirring was continued for another 30 min. The reaction was filtered over diatomaceous earth, washed with ethyl ether, and concentrated under reduced pressure to afford 2-tert-butyl-4-methyl-pent-4-en-1-amine (10.70 g, containing 29 mol% of solvent, in 79% yield) as a yellowish liquid. 1H NMR (300 MHz, CDCl3) ppm 0.91 (s, 9H), 1.22-1.45 (m, 3H), 1.76 (s, 3H), 1.87-1.98 (m, 1H), 2.20 (d, J=14.1 Hz, 1H), 2.56 (dd, J=13.1, 6.0 Hz, 1H), 2.83 (dd, J=13.1, 3.7 Hz, 1H), 4.73-4.82 (m, 2H). Step 4: 4- tert -Butyl-2,2-dimethyl-pyrrolidine Bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (262 mg, 0.64 mmol) and DavePhos (305 mg, 0.77 mmol) were added to a solution of 2-tert-butyl-4-methyl-pent-4-en-1-amine (2.00 g, 12.88 mmol) in dioxane (12 mL) in a sealed tube, and the reaction mixture was refluxed under nitrogen for 5 min. The tube was sealed and heated at 120 °C for 48 h. When the mixture had cooled to room temperature, 4 M HCl in dioxane (6.0 mL) was added, and the reaction mixture was concentrated under reduced pressure. The residue was diluted with 1 N HCl (20 mL) and washed with diethyl ether (3x20 mL). The aqueous layer was adjusted to pH 8-9 with 2 N NaOH, and the resulting solution was extracted with diethyl ether (3x20 mL). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give 4-tert-butyl-2,2-dimethyl-pyrrolidine (1.18 g, 59% yield) as a brown liquid. 1H NMR (300 MHz, CDCl3) ppm 0.85 (s, 9H), 1.14 (s, 3H), 1.19 (s, 3H), 1.24-1.32 (m, 1H), 1.50-1.63 (m, 2H), 2.00-2.12 (m, 1H), 2.73 (dd, J=11.3, 8.7 Hz, 1H), 2.97 (dd, J=11.4, 8.2 Hz, 1H). مرحله 5: 2-(4- tert -Butyl-2,2-dimethyl-pyrrolidin-1-yl)- N -(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (40 ترکیب ) To a solution of 2-chloro-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (300.6 mg, 0.5793 mmol) and 4-tert-butyl-2,2-dimethyl-pyrrolidine (272.8 mg, 1.757 mmol) in anhydrous DMSO (6.012 mL) was added cesium fluoride (441.2 mg, 2.904 mmol). The reaction mixture was stirred for 16 h at 130 °C in an oil bath. The reaction mixture was filtered and purified by reverse-phase HPLC-MS using a gradient of 50-99% acetonitrile in 5 mM HCl to afford racemic 2-(4-tert-butyl-2,2-dimethyl-pyrrolidin-1-yl)-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (78 mg, 20%) as a white solid. ESI-MS m / z calc. 637.2658, found 638.6 (M+1)+; retention time: 2.32 min. 1H NMR (400 MHz, Chloroform-d) δ 8.37 - 8.31 (m, 1H), 8.24 (d, J = 2.8 Hz, 1H), 8.07 (s, 1H), 7.54 (d, J = 8.2 Hz, 1H), 5.99 (d, J = 2.8 Hz, 1H), 4.39 (s, 2H), 3.86 (s, 3H), 3.35 (dt, J = 19.1, 9.8 Hz, 2H), 2.46 (s, 3H), 2.44 - 2.37 (m, 1H), 1.94 - 1.86 (m, 2H), 1.36 (s, 3H), 1.32 (s, 3H), 1.20 - 1.12 (m, 2H), 0.99 - 0.94 (m, 2H), 0.97 (s, 9H). Step 6: Two enantiomers of 2-(4- tert -butyl-2,2-dimethyl-pyrrolidin-1-yl)- N -(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide Racemic 2-(4-tert-butyl-2,2-dimethyl-pyrrolidin-1-yl)-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (78 mg, 0.122 mmol) was purified by chiral SFC using a ChiralPak AD-3 column (250x10 mm, 5 µm), eluted with 15% methanol, 85% CO2, at 100 bar pressure, and a flow rate of 10 mL / min. Peak 1: Pure enantiomer 1 of 2-(4-tert-butyl-2,2-dimethyl-pyrrolidin-1-yl)-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (24.9 mg, 7%) with 100% purity and 98% ee (compound 53). ESI-MS m / z calc. 637.2658, found 638.6 (M+1)+; retention time: 1.19 min 1H NMR (400 MHz, Chloroform-d) δ 13.68 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.23 ​​(d, J = 2.8 Hz, 1H), 8.06 (s, 1H), 7.53 (d, J = 7.9 Hz, 1H), 5.98 (d, J = 2.7 Hz, 1H), 4.39 (s, 2H), 3.86 (s, 3H), 3.35 (t, J = 11.1 Hz, 2H), 2.46 (s, 3H), 2.39 (t, J = 9.1 Hz, 1H), 1.96 - 1.84 (m, 2H), 1.36 (s, 3H), 1.33 (s, 3H), 1.17 - 1.12 (m, 2H), 0.98 - 0.90 (m, 2H), 0.96 (s, 9H). Peak 2: Pure enantiomer 2 of 2-(4-tert-butyl-2,2-dimethyl-pyrrolidin-1-yl)-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (25.0 mg) with 100% purity and 98% ee (compound 54). ESI-MS m / z calc. 637.2658, found 638.6 (M+1)+; retention time: 1.18 min 1H NMR (400 MHz, Chloroform-d) δ 13.69 (s, 1H), 8.32 (d, J = 8.6 Hz, 1H), 8.24 (d, J = 2.8 Hz, 1H), 8.07 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H), 5.99 (d, J = 2.8 Hz, 1H), 4.40 (s, 2H), 3.86 (s, 3H), 3.43 - 3.27 (m, 2H), 2.46 (s, 3H), 2.44 - 2.32 (m, 1H), 1.94 - 1.87 (m, 2H), 1.36 (s, 3H), 1.33 (s, 3H), 1.18 - 1.13 (m, 2H), 0.99 - 0.94 (m, 2H), 0.97 (s, 9H). Synthesis of two enantiomers of N-(1,3-dimethylpyrazol-4-yl)sulfonyl-2-(4-isopropyl-2,2-dimethyl-pyrrolidin-1-yl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide Step 1: 2-Isopropyl-3-oxo-butyric acid ethyl ester To potassium tert-butoxide (61.7 g, 550 mmol) in tetrahydrofuran (1 L) in an ice bath, ethyl acetoacetate (64 mL, 500 mmol) was added dropwise. To this solution was added 2-isopropane (55 mL, 750 mmol). After heating overnight at 70 °C, the reaction was cooled, and 2-isopropane (18 mL, 250 mmol) was added, and the reaction was heated at 70 °C for an additional 24 h. Water (250 mL) and saturated aqueous sodium bicarbonate (250 mL) were added to the reaction, and extraction was performed with diethyl ether (3 x 250 mL). The crude material was concentrated in vacuo and purified using 0-7% hexane-ethyl acetate and silica gel column chromatography to afford 2-isopropyl-3-oxo-butyric acid ethyl ester (55.11 g, 64%) as a yellow oil. ESI-MS m / z calc. 172.2, found 173.0 (M1). Retention time: 2.99 min. 1H NMR (250 MHz, CDCl3) (ppm): 0.87 - 1.07 (m, 6 H) 1.27 (t, J=7.14 Hz, 3 H) 2.23 (s, 3 H) 2.32 - 2.52 (m, 1 H) 3.18 (d, J=9.45 Hz, 1 H) 4.19 (q, J=7.07 Hz, 2 H). Step 2: 3-Methyl-2-methylene-butyric acid ethyl ester A solution of 2-isopropyl-3-oxo-butyric acid ethyl ester (53.77 g, 312.2 mmol) in tetrahydrofuran (1.07 L) was cooled to −78 °C. A 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (343.0 mL, 343.0 mmol) was added dropwise, and the dry ice bath was removed for 30 min. The reaction was cooled again to −78 °C, and paraformaldehyde (43 g, 1.4 mol) was added in one portion. After 30 min, the dry ice bath was removed and allowed to warm to room temperature overnight. The reaction was then filtered through diatomaceous earth. The filtrate was concentrated in vacuo, and the crude material was purified by distillation, with partial boiling at 72-75 °C collected at 67 Torr to give 3-methyl-2-methylene-butyric acid ethyl ester (19.63 g, 40%) as a clear oil. 1H NMR (250MHz, CDCl3) (ppm): 1.09 (d, J=6.92 Hz, 6 H) 1.31 (t, J=7.14 Hz, 3 H) 2.75-2.90 (m, 1H) 4.22 (d, J=7.14 Hz, 2 H) 5.51 (d, J=1.21 Hz, 1 H) 6.12 (s, 1 H). Step 3: 2-Isopropyl-4-methyl-4-nitro-pentanoic acid ethyl ester 3-Methyl-2-methylene-butyric acid ethyl ester (15.6 g, 109.7 mmol) and 2-nitropropane (2.2 mL, 24.2 mmol) were added to acetonitrile (250 mL). 1,8-Diazabicyclo[5.4.0]undec-7-ene (3.6 mL, 24.2 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 16 h. The acetonitrile was removed under vacuum, and 1 M hydrochloric acid (200 mL) was added to the residue. The product was extracted with diethyl ether (3 x 150 mL) and concentrated. The crude residue was purified by silica gel column chromatography using 0-15% hexane-diethyl ether to afford 2-isopropyl-4-methyl-4-nitro-pentanoic acid ethyl ester (13.4 g, 53%) as a colorless oil. 1H NMR (250 MHz, CDCl3) (ppm): 0.83 - 0.97 (m, 6 H) 1.18 - 1.35 (m, 3 H) 1.54 (d, J=17.03 Hz, 6 H) 1.86 (d, J=13.21, 1 H) 2.06 - 2.22 (m, 2 H) 2.25 - 2.45 (m, 1H) 4.07 - 4.21 (m, 2H). Step 4: 3-Isopropyl-5,5-dimethyl-pyrrolidin-2-one To a solution of 2-isopropyl-4-methyl-4-nitro-pentanoic acid ethyl ester (14.6 g, 63.2 mmol) in ethanol (100 mL) was added Raney nickel (~ 2 g, 34.0 mmol), and the reaction was heated at 60 °C and 120 PSI for 24 h under a hydrogen atmosphere. Then, additional Raney nickel (~ 1 g, 17.0 mmol) was added, and the reaction was heated at 60 °C and 120 PSI overnight for 24 h. The reaction was filtered through diatomaceous earth and the mother liquor was concentrated to give a mixture of 4-amino-2-isopropyl-4-methyl-pentanoic acid and 3-isopropyl-5,5-dimethyl-pyrrolidin-2-one. The mixture was dissolved in toluene (125 mL) and heated at 110 °C for 16 h. The solvent was removed, and the residue was purified by silica gel column chromatography using 0–10% dichloromethane-methanol to afford 3-isopropyl-5,5-dimethyl-pyrrolidin-2-one (6.18 g, 63%) as a yellowish-brown solid. ESI-MS m / z calc. 155.0, found 155.3 [M+1]. Retention time: 2.14 min. 1H NMR (250 MHz, CDCl3) (ppm): 0.87 (d, J=6.81 Hz, 3 H) 0.97 (d, J=6.92 Hz, 3 H) 1.27 (d, J=10.66 Hz, 6 H) 1.64 - 1.76 (m, 1 H) 1.84 - 1.96 (m, 1 H) 2.13 - 2.30 (m, 1 H) 2.57 (ddd, J=10.57, 8.98, 4.61 Hz, 1 H) 5.59 (br. s., 1 H). مرحله 5: 4-Isopropyl-2,2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester To a solution of lithium aluminum hydride (1.00 g, 26.28 mmol) in tetrahydrofuran (15 mL) was added dropwise at room temperature a solution of (3-isopropyl-5,5-dimethyl-pyrrolidin-2-one (1.02 g, 6.57 mmol) in tetrahydrofuran (7 mL), and the reaction was heated at 60 °C for 3 days. The reaction was then cooled in an ice bath and 2-methyltetrahydrofuran (20 mL) was added, followed by the addition of Rochelle aqueous salt (50 mL). The reaction was then extracted with 2-methyltetrahydrofuran (4 x 50 mL), dried over sodium sulfate, and concentrated to give the crude 4-isopropyl-2,2-dimethyl-pyrrolidine. The crude was dissolved in dichloromethane (26 mL) and treated with di-tert-butyl dicarbonate (1.72 g, 7.88 mmol) and N,N-diisopropylethylamine (1.4 mL, 7.88 mmol) was placed at 0 °C and allowed to warm over 48 h. The reaction was then poured into 5% aqueous sodium bicarbonate (40 mL) and extracted with dichloromethane (2 x 50 mL).The organic layer was dried over sodium sulfate and purified by silica gel column chromatography using 0-30% hexane-diethyl ether to give 4-isopropyl-2,2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.23 g, 76%) as a yellow gel. ESI-MS m / z calc. 241.0, found 242.0 [M+1]. Retention time: 4.01 min. Step 6: 4-Isopropyl-2,2-dimethyl-pyrrolidine hydrochloride To 4-isopropyl-2,2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.23 g, 5.1 mmol) was added dichloromethane (15 mL) followed by 4 M hydrochloric acid in 1,4-dioxane (5 mL, 20.0 mmol). The reaction was stirred overnight at room temperature and concentrated. The residue was sonicated with hexane (30 mL) and filtered to give 4-isopropyl-2,2-dimethyl-pyrrolidine hydrochloride (669 mg, 74%) as a white crystalline solid. ESI-MS m / z calc. 141.0, found 140.6 [M+1]. Retention time: 1.53 min. 1H NMR (250 MHz, CDCl3) (ppm): 0.87 (dd, J=6.43, 3.46 Hz, 6 H) 1.30 (s, 3 H) 1.40 (s, 3 H) 1.42 - 1.59 (m, 2 H) 1.91 (dd, J=12.69, 7.53 Hz, 1 H) 1.99 - 2.21 (m, 1 H) 2.88 (t, J=9.72 Hz, 1 H). مرحله 7: N-(1,3-dimethylpyrazol-4-yl)sulfonyl-2-(4-isopropyl-2,2-dimethyl-pyrrolidin-1-yl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (41 ترکیب ) To a solution of 2-chloro-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (300 mg, 0.5781 mmol) and 4-isopropyl-2,2-dimethyl-pyrrolidine (250.0 mg, 1.770 mmol) in anhydrous DMSO (5.0 mL) was added cesium fluoride (450.0 mg, 2.962 mmol) and the reaction mixture was stirred at 130°C. The reaction mixture was poured onto crushed ice. The resulting brown solid was collected by filtration and dried. The crude material was purified by silica gel chromatography using 10-100% EtOAc-hexane to afford racemic N-(1,3-dimethylpyrazol-4-yl)sulfonyl-2-(4-isopropyl-2,2-dimethyl-pyrrolidin-1-yl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (90 mg, 25%) as a white amorphous solid. ESI-MS m / z calc. 623.2502, found 624.5 (M+1)+; retention time: 2.25 min 1H NMR (400 MHz, Chloroform-d) δ 8.32 (d, J = 8.5 Hz, 1H), 8.22 (d, J = 2.8 Hz, 1H), 8.06 (s, 1H), 7.54 (d, J = 8.5 Hz, 1H), 5.99 (d, J = 2.8 Hz, 1H), 4.39 (s, 2H), 3.86 (s, 3H), 3.46 (dd, J = 10.3, 8.5 Hz, 1H), 3.25 (dd, J = 10.4, 7.9 Hz, 1H), 2.46 (s, 3H), 2.16 (d, J = 9.6 Hz, 1H), 2.11 – 2.03 (m, 1H), 1.78 (dd, J = 12.0, 10.1 Hz, 1H), 1.67 (dt, J = 9.5, 6.6 Hz, 1H), 1.39 (s, 3H), 1.31 (s, 3H), 1.20 – 1.11 (m, 2H), 0.98 (d, J = 6.6 Hz, 3H), 0.96 - 0.94 (m, 2H), 0.92 (d, J = 6.6 Hz, 3H). مرحله 8: دو انانتیومر N-(1,3-dimethylpyrazol-4-yl)sulfonyl-2-(4-isopropyl-2,2-dimethyl-pyrrolidin-1-yl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide Racemic N-(1,3-dimethylpyrazol-4-yl)sulfonyl-2-(4-isopropyl-2,2-dimethyl-pyrrolidin-1-yl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (90 mg, 0.144 mmol) was purified by chiral SFC using a ChiralPak AD-3 column (250x10 mm, 5µm), eluted with 15% methanol and 85% CO2 at 100 bar and a flow rate of 10 mL / min. Peak 1: Pure enantiomer 1 of N-(1,3-dimethylpyrazol-4-yl)sulfonyl-2-(4-isopropyl-2,2-dimethyl-pyrrolidin-1-yl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (33.8 mg, 19%); (>98% ee) The pure enol tritiomer was obtained immediately. The residue was eluted on silica gel using hexane-diethyl ether. The residue was obtained with. ) (Compound 46) ESI-MS m / z calc. 623.2502, found 624.5 (M+1)+; retention time: 2.25 min 1H NMR (400 MHz, Chloroform-d) δ 13.91 (s, 1H), 8.30 (d, J = 8.5 Hz, 1H), 8.22 (d, J = 2.8 Hz, 1H), 8.07 (s, 1H), 7.52 (d, J = 8.5 Hz, 1H), 5.98 (d, J = 2.8 Hz, 1H), 4.39 (d, J = 1.7 Hz, 2H), 3.85 (s, 3H), 3.49 - 3.40 (m, 1H), 3.25 (dd, J = 10.4, 7.9 Hz, 1H), 2.46 (s, 3H), 2.16 (dt, J = 17.4, 8.7 Hz, 1H), 2.06 (dd, J = 12.0, 7.6 Hz, 1H), 1.77 (dd, J = 12.0, 10.1 Hz, 1H), 1.71 - 1.57 (m, 1H), 1.39 (s, 3H), 1.31 (s, 3H), 1.19 - 1.12 (m, 2H), 0.98 (d, J = 6.6 Hz, 3H), 0.96 - 0.94 (m, 2H), 0.92 (d, J = 6.5 Hz, 3H). PIK 2: Pure enantiomer 2 N-(1,3-dimethylpyrazol-4-yl)sulfonyl-2-(4-isopropyl-2,2-dimethyl-pyrrolidin-1-yl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (34.2) mg, 19%); (>98% ee) (Composition 47). ESI-MS m / z calc. 623.2502, Yafat pulled 624.5 (M+1) +; 1H NMR (400 MHz, Chloroform-d) δ 13.75 (s, 1H), 8.23 (d, J = 8.5 Hz, 1H), 8.20 (d, J = 2.8 Hz, 1H), 8.07 (s, 1H), 7.45 (d, J = 8.5 Hz, 1H), 5.96 (d, J = 2.8 Hz, 1H), 4.39 (m, 2H), 3.84 (s, 3H), 3.40 (dd, J = 10.3, 8.3 Hz, 1H), 3.24 (dd, J = 10.4, 8.0 Hz, 1H), 2.45 (s, 3H), 2.18 - 2.01 (m, 2H), 1.75 (dd, J = 11.9, 10.2 Hz, 1H), 1.64 (dp, J = 9.1, 6.6 Hz, 1H), 1.38 (s, 3H), 1.32 (s, 3H), 1.18 - 1.12 (m, 2H), 0.97 (d, J = 6.6 Hz, 3H), 0.96 - 0.92 (m, 2H), 0.90 (d, J = 6.5 Hz, 3H). سنتز N-(1,3-dimethylpyrazol-4-yl)sulfonyl-2-(7-methyl-5-azaspiro[3.4]octan-5-yl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (43 ترکیب ) To a solution of 2-chloro-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (50.0 mg, 0.09636 mmol) and 7-methyl-5-azaspiro[3.4] octane (hydrochloride salt) (50.0 mg, 0.3093 mmol) in anhydrous DMSO (1.000 mL) was added cesium fluoride (75.0 mg, 0.4937 mmol). The reaction mixture was stirred at 130 °C in an oil bath for 16 h. The reaction mixture was filtered and purified using reverse phase HPLC-MS by running a double gradient of 50-99% acetonitrile in 5 mM HCl to afford N-(1,3-dimethylpyrazol-4-yl)sulfonyl-2-(7-methyl-5-azaspiro[3.4]octan-5-yl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (8.6 mg, 15%). ESI-MS m / z calc. 607.2189, found 608.5 (M+1)+; retention time: 2.18 min 1H NMR (400 MHz, Chloroform-d) δ 8.45 (d, J = 8.5 Hz, 1H), 8.27 (d, J = 2.8 Hz, 1H), 8.06 (s, 1H), 7.63 (d, J = 8.5 Hz, 1H), 5.99 (d, J = 2.8 Hz, 1H), 4.40 (s, 2H), 3.86 (s, 3H), 3.63 - 3.54 (m, 1H), 2.97 (dd, J = 10.0, 6.7 Hz, 1H), 2.54 (q, J = 6.5, 5.2 Hz, 2H), 2.46 (s, 3H), 2.25 - 2.15 (m, 2H), 2.10 (t, J = 10.3 Hz, 1H), 2.03 - 1.95 (m, 1H), 1.91 (dd, J = 10.1, 5.5 Hz, 2H), 1.74 - 1.60 (m, 1H), 1.55 - 1.41 (m, 1H), 1.22 (d, J = 6.3 Hz, 3H), 1.19 - 1.12 (m, 2H), 1.02 - 0.90 (m, 2H). سنتز N-(1,3-dimethylpyrazol-4-yl)sulfonyl-2-(6-methyl-4-azaspiro[2.4]heptan-4-yl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide ( ترکیب 44 ) To a solution of 2-chloro-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (50.0 mg, 0.09636 mmol) and 6-methyl-4-azaspiro[2.4] heptane (hydrochloride salt) (45.0 mg, 0.3048 mmol) in DMSO (1 mL) was added cesium fluoride (75.0 mg, 0.4937 mmol). The reaction mixture was stirred overnight at 130°C. The reaction mixture was filtered and purified overnight by reverse phase HPLC-MS using a double gradient of 50-99% acetonitrile in 5 mM HCl to N-(1,3-dimethylpyrazol-4-yl)sulfonyl-2-(6-methyl-4-azaspiro[2.4]heptan-4-yl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (42.8 mg, 75%) was obtained. ESI-MS m / z calc. 593.2032, found 594.6 (M+1)+; retention time: 2.17 min 1H NMR (400 MHz, Chloroform-d) δ 8.40 (d, J = 8.6 Hz, 1H), 8.29 (d, J = 2.8 Hz, 1H), 8.06 (s, 1H), 7.59 (d, J = 8.5 Hz, 1H), 6.00 (d, J = 2.8 Hz, 1H), 4.39 (s, 2H), 3.86 (s, 3H), 3.64 (dd, J = 10.5, 7.9 Hz, 1H), 3.14 (dd, J = 10.5, 7.1 Hz, 1H), 2.75 - 2.59 (m, 1H), 2.46 (s, 3H), 2.33 (dd, J = 12.2, 8.8 Hz, 1H), 1.77 (dd, J = 12.3, 6.4 Hz, 1H), 1.22 (d, J = 6.8 Hz, 3H), 1.18 - 1.12 (m, 2H), 0.95 (tt, J = 5.6, 2.8 Hz, 2H), 0.72 - 0.54 (m, 4H). سنتز N-(1,3-dimethylpyrazol-4-yl)sulfonyl-2-(4-ethyl-2,2-dimethyl-pyrrolidin-1-yl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (49 ترکیب ) مرحله 1: Methyl 2-ethyl-4-methyl-4-nitro-pentanoate 2-Nitropropane (1.20 mL, 13.36 mmol) was dissolved in dioxane (10.0 mL). An aqueous solution of benzyl (trimethyl) ammonium hydroxide (110.0 µL 40 %w / v, 0.2631 mmol) was added. The reaction mixture was stirred at 70 °C for over 20 min while methyl 2-methylene butanoate (2.5 g, 21.90 mmol) was added dropwise. The reaction mixture was then allowed to stir at 100 °C for 4.5 h. The reaction was quenched by addition of aqueous HCl (50.0 mL 1 M, 50.00 mmol). The mixture was diluted with diethyl ether (75 mL) and washed with water (3× 75 mL) and brine (1× 75 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow liquid. The crude product was purified by silica gel column chromatography using a gradient of 5% to 25% EtOAc-hexane to give methyl 2-ethyl-4-methyl-4-nitro-pentanoate (1.6 g, 34%) as a colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 3.68 (s, 3H), 2.44 - 2.36 (m, 1H), 2.30 (tdd, J = 9.8, 6.9, 1.9 Hz, 1H), 2.10 (dd, J = 14.6, 2.0 Hz, 1H), 1.69 - 1.45 (m, 2H), 1.58 (s, 3H), 1.53 (s, 3H), 0.89 (t, J = 7.5 Hz, 3H). مرحله 2: 3-Ethyl-5,5-dimethyl-pyrrolidin-2-one A solution of methyl 2-ethyl-4-methyl-4-nitro-pentanoate (1.56 g, 7.676 mmol) and dichloronickel hexahydrate (366.4 mg, 1.541 mmol) in 1:4 water (5 mL) and MeOH (20.0 mL) was cooled to 0 °C. To this solution, sodium borohydride (730.8 mg, 19.32 mmol) was added gradually and portionwise. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 h. The reaction mixture was cooled again and a solution of aqueous potassium carbonate (1 M, 25 mL) was added. The color changed from black to gray and then to green. The mixture was left to settle for 3 h, and then diatomaceous earth was added. The solid was removed by filtration through a filter pad packed with diatomaceous earth and washed with MeOH (3 x 100 mL). The combined filtrate and washings were concentrated to remove most of the MeOH. Solid sodium chloride was added to the aqueous concentrate and extracted with diethyl ether. The combined organic extracts were washed with brine, dried over magnesium sulfate, and concentrated.The resulting residue was purified by silica gel column chromatography using 10% EtOAc-hexane to 100% EtOAc to afford 3-ethyl-5,5-dimethyl-pyrrolidin-2-one (608 mg, 14%) as a colorless oil with a purity of about 59%. ESI-MS m / z calc. 141.11537, found 142.2 (M+1)+; retention time: 0.38 min Step 3: 4-Ethyl-2,2-dimethyl-pyrrolidine To a solution of 3-ethyl-5,5-dimethyl-pyrrolidin-2-one (302.6 mg, 2.143 mmol) in dry THF (3 mL) was added dropwise a solution of lithium aluminum hydride (3.5 mL 2 M, 7.000 mmol) at 0 °C slowly under nitrogen. The mixture was allowed to warm to room temperature and stirred for 1 h, and then heated at 60 °C for 14 h. The mixture was cooled in an ice bath and quenched successively with water (150.0 µL, 8.326 mmol) (slowly) followed by NaOH (150.0 µL 6 M, 0.9000 mmol) and then water (500 µL, 27.75 mmol) to give a granular solid. The solid was filtered through diatomaceous earth, and the precipitate was washed with ether. The filtrate was again dried over magnesium sulfate, filtered, and concentrated in vacuo on a rotavap to give 4-ethyl-2,2-dimethyl-pyrrolidine (130.9 mg, 24%). The mixture was carried directly to the next step (E33068-152). Step 4: N-(1,3-Dimethylpyrazol-4-yl)sulfonyl-2-(4-ethyl-2,2-dimethyl-pyrrolidin-1-yl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide To a solution of 2-chloro-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (175.4 mg, 0.3380 mmol) and 4-ethyl-2,2-dimethyl-pyrrolidine (130.9 mg, 1.029 mmol) in DMSO (2 mL) was added cesium fluoride (267.2 mg, 1.759 mmol). The reaction mixture was stirred for 16 h at 130 °C in an oil bath. The reaction mixture was filtered and purified using reverse phase HPLC-MS by running a double gradient of 50-99% acetonitrile in 5 mM HCl to afford N-(1,3-dimethylpyrazol-4-yl)sulfonyl-2-(4-ethyl-2,2-dimethyl-pyrrolidin-1-yl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (4.5 mg, 2%). ESI-MS m / z calc. 609.2345, found 610.59 (M+1)+; retention time: 2.17 min 1H NMR (400 MHz, Chloroform-d) δ 8.35 (d, J = 8.5 Hz, 1H), 8.23 (d, J = 2.8 Hz, 1H), 8.06 (s, 1H), 7.56 (d, J = 8.5 Hz, 1H), 5.99 (d, J = 2.8 Hz, 1H), 4.39 (s, 2H), 3.86 (s, 3H), 3.56 - 3.48 (m, 1H), 3.15 (dd, J = 10.4, 7.5 Hz, 1H), 2.47 (s, 3H), 2.39 (dt, J = 16.9, 8.3 Hz, 1H), 2.13 (dd, J = 12.3, 7.9 Hz, 1H), 1.72 (dd, J = 12.4, 9.5 Hz, 1H), 1.59 (p, J = 7.3 Hz, 2H), 1.36 (s,3H), 1.30 (s,3H), 1.18 - 1.13 (m, 2H), 0.99 - 0.94 (m, 5H). سنتز N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide (42 ترکیب ) To a solution of 2-chloro-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (50.0 mg, 0.09636 mmol) and 2,2,5-trimethylpyrrolidine (35.0 mg, 0.3092 mmol) in anhydrous DMSO (1.000 mL) was added cesium fluoride (75.0 mg, 0.4937 mmol). The reaction mixture was stirred at 130 °C for 16 h in an oil bath. The reaction mixture was filtered and purified using reverse phase HPLC-MS by running a double gradient of 50-99% acetonitrile in 5 mM HCl to afford N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-(2,2,4-trimethylpyrrolidin-1-yl)pyridine-3-carboxamide (5.8 mg, 10%). ESI-MS m / z calc. 595.2189, found 596.6 (M+1)+; retention time: 1.91 min 1H NMR (400 MHz, Chloroform-d) δ 8.57 (d, J = 8.2 Hz, 1H), 8.24 (d, J = 2.7 Hz, 1H), 8.07 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 6.00 (d, J = 2.4 Hz, 1H), 4.40 (s, 2H), 4.26 - 4.18 (m, 1H), 3.87 (s, 3H), 2.48 (s, 3H), 2.39 - 2.36 (m, 1H), 2.23 - 2.12 (m, 1H), 1.99 -1.94 (m, 1H), 1.89 - 1.80 (m, 1H), 1.30 (s, 3H), 1.20 (d, J = 5.9 Hz, 3H), 1.18 - 1.14 (m, 2H), 1.10 (s, 3H), 0.99 - 0.93 (m, 2H). سنتز N -(1,5-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4 S )-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (9 ترکیب ) مرحله 1: 2-Chloro- N -(1,5-dimethylpyrazol-4-yl)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, 0.5529 mmol) was dissolved in THF (2 mL), and CDI (ca. 107.6 mg, 0.6635 mmol) was added. After stirring at room temperature for 1.5 h, 1,5-dimethylpyrazole-4-sulfonamide (ca. 125.9 mg, 0.7188 mmol) was added, followed by DBU (ca. 101.0 mg, 99.21 µL, 0.6635 mmol). The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was diluted with EtOAc (50 mL) and washed with 1 M aqueous citric acid (1×50 mL) and brine (1×50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 2-chloro-N-(1,5-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (332 mg). ESI-MS m / z calc. 518.08, found 519.0 (M+1)+; retention time: 0.65 min Step 2: N -(1,5-Dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4 S )-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide 2-Chloro-N-(1,5-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (286.8 mg, 0.5528 mmol) was dissolved in DMSO (2 mL). (4S)-2,2,4-Trimethylpyrrolidine (hydrochloride salt) (ca. 248.1 mg, 1.658 mmol) was added followed by finely ground potassium carbonate (ca. 458.4 mg, 3.317 mmol). The reaction mixture was allowed to stir at 130 °C overnight. After cooling to room temperature, EtOAc (50 mL) was added. The mixture was washed with 1 N HCl (1×50 mL) and brine (1×50 mL). The aqueous layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give N-(1,5-dimethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (72.7 mg). ESI-MS m / z calc. 595.22, یافت شد 596.4 (M+1)+;زمان نگهداری: دقیقه2.07 1H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 8.21 (d, J = 2.7 Hz, 1H), 7.78 (s, 1H), 7.73 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.14 (d, J = 2.7 Hz, 1H), 4.43 – 4.31 (m, 2H), 3.78 (s, 3H), 2.57 (t, J = 10.4 Hz, 1H), 2.53 (s, 3H), 2.43 (dd, J = 10.2, 7.1 Hz, 1H), 2.25 – 2.10 (m, 1H), 1.87 (dd, J = 11.9, 5.6 Hz, 1H), 1.57 (s, 3H), 1.53 (s, 3H), 1.44 (t, J = 12.1 Hz, 1H), 1.09 (dt, J = 6.7, 2.0 Hz, 4H), 0.81 (d, J = 6.2 Hz, 3H). سنتز N-(1H-pyrazol-4-ylsulfonyl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide ( ترکیب 5 ) مرحله 1: 2-Chloro-N-(1H-pyrazol-4-ylsulfonyl)-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, 0.5529 mmol) and CDI (ca. 107.6 mg, 0.6635 mmol) in THF (1.200 mL) were combined and stirred at room temperature for 2 h. 1H-Pyrazole-4-sulfonamide (ca. 105.8 mg, 0.7188 mmol) was added followed by DBU (ca. 101.0 mg, 99.21 µL, 0.6635 mmol) and the reaction mixture was stirred at room temperature for another 16 h. The reaction mixture was washed again with 1 M citric acid and water and extracted with 3x 20 mL ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, concentrated, and then purified by silica gel chromatography using a gradient of 0-10% methanol in dichloromethane to give a white solid. 2-chloro-N-(1H-pyrazol-4-ylsulfonyl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (190 mg, 70%) ESI-MS m / z calc. 490.0438, found, 491.1 (M+1)+; retention time: 0.61 min. Step 2: N-(1H-Pyrazol-4-ylsulfonyl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide 2-Chloro-N-(1H-pyrazol-4-ylsulfonyl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (115 mg, 0.2343 mmol), (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (105 mg, 0.7016 mmol), and potassium carbonate (194 mg, 1.404 mmol) were combined in DMSO (575.0 µL) and heated to 130 °C for 16 h. The reaction was cooled to room temperature and diluted with 15 mL of water, 15 mL of 1 M citric acid, and 30 mL of ethyl acetate. The aqueous and organic layers were separated, and the aqueous layer was extracted twice more with 30 mL of ethyl acetate. The organics were combined, washed with brine, dried over sodium sulfate, and concentrated. The resulting solid was purified by silica gel chromatography, eluting with a gradient of 0-10% methanol in dichloromethane to give a white solid: N-(1H-pyrazol-4-ylsulfonyl)-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (100 mg, 75%) ESI-MS m / z calc. 567.18756, found, 568.2 (M+1)+; retention time: 1.84 min. 1H NMR (400 MHz, DMSO) δ 13.71 (s, 1H), 12.30 (s, 1H), 8.49 (s, 1H), 8.21 (d, J = 2.8 Hz, 1H), 7.94 (s, 1H), 7.73 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.14 (d, J = 2.8 Hz, 1H), 4.47 - 4.26 (m, 2H), 2.60 (t, J = 10.4 Hz, 1H), 2.43 (t, J = 8.4 Hz, 1H), 2.15 (dd, J = 12.5, 6.6 Hz, 1H), 1.88 (dt, J = 11.6, 6.3 Hz, 1H), 1.55 (d, J = 17.6 Hz, 6H), 1.42 (t, J = 12.4 Hz, 1H), 1.14 - 1.05 (m, 4H), 0.79 (d, J = 6.3 Hz, 3H). سنتز N-(1-methylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (ترکیب 6) مرحله 1: 2-Chloro-N-(1-methylpyrazol-4-yl)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, 0.5529 mmol) and CDI (ca. 107.6 mg, 0.6635 mmol) in THF (1.200 mL) were combined and stirred at room temperature for 2 h. 1-Methylpyrazole-4-sulfonamide (ca. 115.9 mg, 0.7188 mmol) was added followed by DBU (ca. 101.0 mg, 99.21 µL, 0.6635 mmol) and the reaction mixture was stirred at room temperature for another 16 h. The reaction mixture was washed again with 1 M citric acid and water and extracted with 3x 20 mL ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, concentrated, and then purified by silica gel chromatography using a gradient of 0-10% methanol / dichloromethane to give a white solid. 2-chloro-N-(1-methylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (227 mg, 81%) ESI-MS m / z calc. 504.05945, found, 505.1 (M+1)+; retention time: 0.64 min. Step 2: N-(1-Methylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide 2-Chloro-N-(1-methylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (115 mg, 0.2278 mmol), (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (102 mg, 0.6815 mmol), and potassium carbonate (189 mg, 1.368 mmol) were combined in DMSO (575.0 µL) and heated to 130 °C for 16 h. The reaction was cooled to room temperature and diluted with 15 mL of water, 15 mL of 1 M citric acid, and 30 mL of ethyl acetate. The aqueous and organic layers were separated, and the aqueous layer was extracted twice more with 30 mL of ethyl acetate. The organics were combined, washed with brine, dried over sodium sulfate, and concentrated. The resulting solid was further purified using silica gel chromatography, eluting with a gradient of 0-10% methanol in dichloromethane to give N-(1-methylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (88 mg, 66%) ESI-MS m / z calc. 581.2032, found, 582.3 (M+1)+; retention time: 1.95 min. 1H NMR (400 MHz, DMSO) δ 12.35 (s, 1H), 8.51 (s, 1H), 8.21 (d, J = 2.8 Hz, 1H), 7.88 (s, 1H), 7.73 (d, J = 8.2 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.15 (d, J = 2.8 Hz, 1H), 4.43 - 4.31 (m, 2H), 3.90 (s, 3H), 2.64 (t, J = 10.4 Hz, 1H), 2.48 - 2.40 (m, 1H), 2.17 (dp, J = 18.4, 6.3 Hz, 1H), 1.88 (dd, J = 11.8, 5.6 Hz, 1H), 1.55 (d, J = 17.0 Hz, 6H), 1.44 (t, J = 12.1 Hz, 1H), 1.14 - 1.04 (m, 4H), 0.80 (d, J = 6.2 Hz, 3H). سنتز N-(1-ethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (ترکیب 7) مرحله 1: 2-Chloro-N-(1-ethylpyrazol-4-yl)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, 0.5529 mmol) and CDI (ca. 107.6 mg, 0.6635 mmol) in THF (1.200 mL) were combined and stirred at room temperature for 2 h. 1-Ethylpyrazole-4-sulfonamide (ca. 125.9 mg, 0.7188 mmol) was added followed by DBU (ca. 101.0 mg, 99.21 µL, 0.6635 mmol) and the reaction mixture was stirred at room temperature for another 6 h. A 1M citric acid solution (1 mL) was added and the reaction was stirred for 20 min. The reaction mixture was washed again with 1 M citric acid and water and extracted with 3x 20 mL ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, concentrated, and then purified by silica gel chromatography using a gradient of 0-10% methanol in dichloromethane to give a white solid. 2-chloro-N-(1-ethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (250 mg, 87%) ESI-MS m / z calc. 518.0751, found, 519.0 (M+1)+; retention time: 0.67 min. مرحله 2: N-(1-Ethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide 2-Chloro-N-(1-ethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (115 mg, 0.2216 mmol), (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (100 mg, 0.6682 mmol), and potassium carbonate (184 mg, 1.331 mmol) were combined in DMSO (570 µL) and heated to 130 °C for 16 h. The reaction was cooled to room temperature and diluted with 15 mL of water, 15 mL of 1 M citric acid, and 30 mL of ethyl acetate. The aqueous and organic layers were separated, and the aqueous layer was extracted twice more with 30 mL of ethyl acetate. The organics were combined, washed with brine, dried over sodium sulfate, and concentrated. The resulting material was purified by silica gel chromatography, eluting with a gradient of 0-10% methanol in dichloromethane to give a white solid. N-(1-ethylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (110 mg, 83%) ESI-MS m / z calc. 595.2189, found, 596.2 (M+1)+; retention time: 2.03 min. 1H NMR (400 MHz, DMSO) δ 12.34 (s, 1H), 8.53 (d, J = 0.8 Hz, 1H), 8.21 (d, J = 2.8 Hz, 1H), 7.91 (d, J = 0.7 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.15 (d, J = 2.7 Hz, 1H), 4.48 - 4.31 (m, 2H), 4.20 (qd, J = 7.3, 5.0 Hz, 2H), 2.66 (t, J = 10.4 Hz, 1H), 2.47 (s, 1H), 2.17 (dp, J = 18.3, 6.4 Hz, 1H), 1.92 - 1.83 (m, 1H), 1.55 (d, J = 17.5 Hz, 6H), 1.45 (d, J = 12.0 Hz, 1H), 1.39 (t, J = 7.2 Hz, 3H), 1.09 (dt, J = 5.2, 1.6 Hz, 4H), 0.80 (d, J = 6.3 Hz, 3H). سنتز N-(1-tert-butylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (ترکیب 8) مرحله 1: N-(1-tert-Butylpyrazol-4-yl)sulfonyl-2-chloro-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, 0.5529 mmol) and CDI (ca. 107.6 mg, 0.6635 mmol) in THF (1.200 mL) were combined and stirred at room temperature for 2 h. 1-tert-Butylpyrazole-4-sulfonamide (ca. 146.1 mg, 0.7188 mmol) was added followed by DBU (ca. 101.0 mg, 99.21 µL, 0.6635 mmol) and the reaction mixture was stirred at room temperature for another 6 h. A 1M citric acid solution (1 mL) was added and the reaction was stirred for 20 min. The reaction mixture was washed again with 1 M citric acid and water and extracted with 3x 20 mL ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, concentrated, and then purified by silica gel chromatography using a gradient of 0-10% methanol in dichloromethane to give a white solid. N-(1-tert-butylpyrazol-4-yl)sulfonyl-2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (190 mg, 63%) ESI-MS m / z calc. 546.1064, found, 547.1 (M+1)+; retention time: 0.73 min. مرحله 2: N-(1-tert-Butylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide N-(1-tert-Butylpyrazol-4-yl)sulfonyl-2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxamide (125 mg, 0.2285 mmol), (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (103 mg, 0.6882 mmol), and potassium carbonate (190 mg, 1.375 mmol) were combined in DMSO (600 µL) and heated to 130 °C for 16 h. The reaction was cooled to room temperature and diluted with 15 mL of water, 15 mL of 1 M citric acid, and 30 mL of ethyl acetate. The aqueous and organic layers were separated, and the aqueous layer was extracted twice more with 30 mL of ethyl acetate. The organics were combined, washed with brine, dried over sodium sulfate, and concentrated. The resulting solid was purified by silica gel chromatography, eluting with a gradient of 0-10% methanol in dichloromethane to give a white solid. N-(1-tert-butylpyrazol-4-yl)sulfonyl-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (122 mg, 86%) ESI-MS m / z calc. 623.2502, found, 624.3 (M+1)+; retention time: 2.19 min. 1H NMR (400 MHz, DMSO) δ 12.33 (s, 1H), 8.46 (s, 1H), 8.21 (d, J = 2.7 Hz, 1H), 7.95 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.15 (d, J = 2.7 Hz, 1H), 4.45 - 4.27 (m, 2H), 2.73 (t, J = 10.3 Hz, 1H), 2.58 (dd, J = 9.9, 7.1 Hz, 1H), 2.21 (dt, J = 11.3, 5.9 Hz, 1H), 1.89 (dd, J = 11.9, 5.5 Hz, 1H), 1.62 - 1.52 (m, 15H), 1.45 (t, J = 12.0 Hz, 1H), 1.13 - 1.06 (m, 4H), 0.83 (d, J = 6.5 Hz, 3H). سنتز 6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-N-(1,3,5-trimethylpyrazol-4-yl)sulfonyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (ترکیب 16) مرحله 1: 2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-N-(1,3,5-trimethylpyrazol-4-yl)sulfonyl-pyridine-3-carboxamide 2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid (100 mg, 0.2682 mmol) and CDI (ca. 52 mg, 0.3207 mmol) were combined in THF (582.0 mL) and stirred at room temperature for 2 h (vial 1). Meanwhile, 1,3,5-trimethylpyrazole-4-sulfonyl chloride (56 mg, 0.2684 mmol) was combined with ammonia (250 µL of 7 M, 1.750 mmol) (in methanol) in a separate vial (vial 2). After stirring for another 20 min, the volatiles were removed by evaporation from vial 2, and 1 mL of dichloromethane was added to the solid residue and evaporated. DBU (54 µL, 0.3611 mmol) was then added to vial 2 and stirred for 5 min at 60 °C (to facilitate the separation of ammonia from any residual ammonium chloride). Once cooled to room temperature, 1 mL of THF was added and then evaporated under reduced pressure. The contents of vial 1 were then added to vial 2, and the reaction mixture was stirred for 4 h at room temperature. The reaction mixture was diluted with 10 mL of ethyl acetate and washed with 10 mL of 1 M citric acid.The aqueous layer was extracted with 2 x 10 mL ethyl acetate and the combined organics were washed with brine, dried over sodium sulfate, and concentrated to a white solid. This material was used in the next step without further purification. 2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-N-(1,3,5-trimethylpyrazol-4-yl)sulfonyl-pyridine-3-carboxamide (140 mg, 98%) ESI-MS m / z calc. 532.09076, found, 533.1 (M+1)+; retention time: 0.67 min. Step 2: 6-[3-[[1-(Ttrifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-N-(1,3,5-trimethylpyrazol-4-yl)sulfonyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide 2-Chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-N-(1,3,5-trimethylpyrazol-4-yl)sulfonyl-pyridine-3-carboxamide (140 mg, 0.2627 mmol), (4S)-2,2,4-trimethylpyrrolidine (hydrochloride salt) (118 mg, 0.7884 mmol), and potassium carbonate (219 mg, 1.585 mmol) were combined in DMSO (700.0 µL) and heated to 130 °C for 16 h. The reaction was cooled to room temperature and then 1 mL of water was added. After stirring for 15 min, the contents of the vial were allowed to settle, the liquid portion was removed by pipette, and the remaining solids were dissolved in 20 mL of ethyl acetate and then washed with 15 mL of 1 M citric acid. The aqueous and organic layers were separated and the aqueous layer was extracted twice more with 15 mL of ethyl acetate. The organics were combined, washed with brine, dried over sodium sulfate, and concentrated. The resulting solid was purified by silica gel chromatography, eluting with a gradient of 0-10% methanol in dichloromethane to give a white solid.6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-N-(1,3,5-trimethylpyrazol-4-yl)sulfonyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (77 mg, 48%) ESI-MS m / z calc. 609.2345، یافته شده ، 610.3 (M+1)+؛ زمان نگهداری: 2.07 دقیقه. سنتز N-(1,5-dimethylpyrazol-4-yl)sulfonyl-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (ترکیب 21) مرحله 1: tert-Butyl 3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazole-1-carboxylate To a gas-free solution of triphenylphosphine (approximately 51.28 g, 195.5 mmol) in toluene (360.0 mL) at 0 ºC under nitrogen gas was added dropwise DIAD (diisopropylazodicarboxylate) (approximately 39.53 g, 37.86 mL, 195.5 mmol). The mixture was stirred for 30 min at 0 ºC to obtain a white liquid. A solution of (2,2,3,3-tetramethylcyclopropyl)methanol (approximately 29.84 g of 70 %w / ...

Claims

CLAIMS 1. A compound having the following formula: (Compound 1), a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing.

2. A compound according to claim 1 having the following formula: , or a pharmaceutically acceptable salt thereof.

3. A compound having the following formula: (Compound 1).

4. A pharmaceutical composition comprising: (a) a compound having the following formula: (Compound 1); and (b) a pharmaceutically acceptable carrier.

5. The pharmaceutical composition according to claim 4, further comprising Compound II: .

6. The pharmaceutical composition according to claim 4, further comprising Compound III: .

7. The pharmaceutical composition according to claim 5, further comprising Compound III: .

8. A pharmaceutically acceptable salt of Compound 1: (Compound 1).

9. A pharmaceutical composition comprising: (a) a pharmaceutically acceptable salt of Compound 1: (Compound 1); and (b) a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9, further comprising Compound II: .

11. The pharmaceutical composition according to claim 9, further comprising Compound III: .

12. The pharmaceutical composition according to claim 10, further comprising Compound III: .

13. A compound of any one of claims 1-3, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing; or a pharmaceutical composition according to any one of claims 4-12 for use in treating cystic fibrosis in a patient.

14. A method of preparing a compound of Formula (X): , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, comprising reacting a compound of Formula (F) or a salt thereof with a compound of Formula (G) or a salt thereof to generate said compound of Formula (X) or a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing: wherein in each of said formulae: - one of Y1 and Y2 is N, and the other is CH; - R1 is –(C(R2)2)k-O-(C(R2)2)mR7, - each R2 is independently chosen from hydrogen; halogen; cyano; hydroxy; C1-C2 alkoxy groups; and C1-C2 alkyl groups optionally substituted with one or more substituents each independently chosen from halogen, hydroxy, and C3-5 cycloalkyl groups optionally substituted with one or more substituents each independently chosen from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogen; - each R3 is independently chosen from C1-C4 alkyl groups optionally substituted with one or more hydroxy groups, or optionally two geminal R3, together with the carbon atom to which they are attached, form a C3-4 cycloalkyl; - each R4 is independently chosen from halogen; - R5 is chosen from hydrogen and C1-C4 alkyl groups; - each R6 is chosen from halogen, cyano, hydroxy, hydroxymethyl, C1-C2 alkoxy groups, C1-C2 alkyl groups, and halogenated C1-C2 alkyl groups; - R7 is chosen from hydrogen, halogen, cyano, C1-C2 alkyl groups optionally substituted with one or more substituents each independently chosen from halogen and hydroxy, and C3-C10 cycloalkyl groups optionally substituted with one or more substituents each independently chosen from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogen; - Xa is F or Cl; - k is 0 or 1; - r is 0 or 1; - m is 0, 1, 2, or 3; - p is 0, 1, or 2; and - q is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

15. The method of claim 14, wherein Y2 is N, and Y1 is CH.

16. The method of claim 14 or 15, wherein said reacting a compound of Formula (F) or a salt thereof with a compound of Formula (G) or a salt thereof is performed in the presence of a base.

17. The method of any one of claims 14 to 16, wherein a salt of the compound of Formula (G) is employed.

18. The method of claim 17, wherein said salt of the compound of the Formula (G), is a HCl salt of the compound of Formula (G).

19. A method of preparing a compound of Formula (F) or a salt thereof: , or a deuterated derivative of any of the foregoing, comprising reacting a compound of Formula (D) or salt thereof with a compound of Formula (E) or a salt thereof to generate a compound of Formula (F) or a salt thereof: , wherein in each of said formulae: - one of Y1 and Y2 is N, and the other is CH; - R1 is –(C(R2)2)k-O-(C(R2)2)mR7, - each R2 is independently chosen from hydrogen; halogen; cyano; hydroxy; C1-C2 alkoxy groups; and C1-C2 alkyl groups optionally substituted with one or more substituents each independently chosen from halogen, hydroxy, and C3-5 cycloalkyl groups optionally substituted with one or more substituents each independently chosen from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogen; - each R4 is independently chosen from halogen; - each R5 is independently chosen from hydrogen and C1-C4 alkyl groups; - each R6 is chosen from halogen, cyano, hydroxy, hydroxymethyl, C1-C2 alkoxy groups, C1-C2 alkyl groups, and halogenated C1-C2 alkyl groups; - R7 is chosen from hydrogen, halogen, cyano, C1-C2 alkyl groups optionally substituted with one or more substituents each independently chosen from halogen and hydroxy, and C3-C10 cycloalkyl groups optionally substituted with one or more substituents each independently chosen from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogen; - Xa is F or Cl; - k is 0 or 1; - r is 0 or 1; - m is 0, 1, 2, or 3; and - p is 0, 1, or 2.

20. The method of claim 19, wherein Y2 is N, and Y1 is CH.

21. The method of claim 19 or 20, wherein said reacting a compound of Formula (D) or a salt thereof with a compound of Formula (E) or a salt thereof is performed in the presence of a base.

22. The method of claim 19 or 20, wherein said reacting a compound of Formula (D) or salt thereof with a compound of Formula (E) or a salt thereof comprises reacting a compound of Formula (D) with a coupling reagent and subsequently with a compound of Formula (E) in the presence of a base.

23. A method of preparing a compound of the following formula: (Compound 1) or a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, comprising reacting a compound of Formula (F-1) or a salt thereof, wherein Xa is F or Cl, with a compound of Formula (G-1) or a salt thereof to generate said compound or a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing: wherein Xa in Formula (F-1) is F or Cl.

24. The method of claim 23, wherein said reacting a compound of Formula (F-1) or a salt thereof with a compound of Formula (G-1) or a salt thereof is performed in the presence of a base.

25. The method of claim 23 or 24, wherein a salt of the compound of Formula (G-1) is employed.

26. The method of claim 25, wherein said salt of the compound of Formula (G-1), is a HCl salt of the compound of Formula (G-1).

27. A method of preparing a compound of Formula (F-1) or a salt thereof: , or a deuterated derivative of any of the foregoing, comprising reacting a compound of Formula (D-1) and a compound of Formula (E-1) to generate a compound of Formula (F-1) or a salt thereof: , wherein in each said formula, Xa is F or Cl.

28. The method of claim 27, wherein said reacting a compound of Formula (D-1) or a salt thereof with a compound of Formula (E-1) or a salt thereof is performed in the presence of a base.

29. The method of claim 27, 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 a coupling reagent and subsequently with a compound of Formula (E-1) in the presence of a base.

30. A method of preparing a compound of Formula (D) or a salt thereof: , or a deuterated derivative of any of the foregoing, comprising: reacting a compound of Formula (A) or a salt thereof with a compound of Formula (B) or a salt thereof to generate a compound of Formula (C) or a salt thereof: ; and hydrolyzing the –C(O)ORa group of the compound of Formula (C) to generate a compound of Formula (D) or a salt thereof, wherein in each said formulae: - one of Y1 and Y2 is N, and the other is CH; - R1 is –(C(R2)2)k-O-(C(R2)2)mR7, - each R2 is independently chosen from hydrogen; halogen; cyano; hydroxy; C1-C2 alkoxy groups; and C1-C2 alkyl groups optionally substituted with one or more substituents each independently chosen from halogen, hydroxy, and C3-5 cycloalkyl groups optionally substituted with one or more substituents each independently chosen from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogen; - each R4 is independently chosen from halogen; - R7 is chosen from hydrogen, halogen, cyano, C1-C2 alkyl groups optionally substituted with one or more substituents each independently chosen from halogen and hydroxy, and C3-C10 cycloalkyl groups optionally substituted with one or more substituents each independently chosen from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogen; - Xa is F or Cl; - k is 0 or 1; - r is 0 or 1; and - m is 0, 1, 2, or 3; with a proviso that the compound of Formula (A) is not: or .

31. The method of claim 30, wherein Y2 is N, and Y1 is CH.

32. The method of claim 30 or 31, wherein the hydrolysis of the –C(O)ORa group is performed in the presence of a base or acid.

33. The method of any one of claims 30 to 32, wherein said reacting a compound of Formula (A) or a salt thereof with a compound of Formula (B) or salt thereof is performed in the presence of a base.

34. The method of any one of claims 30 to 33, wherein Ra is ethyl or t-butyl.

35. A method of preparing a compound of Formula (D-1) or a salt thereof: , or a deuterated derivative of any of the foregoing, comprising: reacting a compound of Formula (A-1) or a salt thereof and a compound of Formula (B-1) or a salt thereof to generate a compound of Formula (C-1) or a salt thereof: ; and hydrolyzing the –C(O)ORa group of the compound of Formula (C-1) or a salt thereof to generate a compound of Formula (D-1) or a salt thereof, wherein in each said formulae, each Ra is independently chosen from C1-C4 alkyl; and each Xa is independently F or Cl.

36. The method of claim 35, wherein the hydrolysis of the –C(O)ORa group is performed in the presence of a base or acid.

37. The method of 35 or 36, wherein said reacting a compound of Formula (A-1) or a salt thereof and a compound of Formula (B-1) or a salt thereof is performed in the presence of a base.

38. The method of any one of claims 35 to 37, wherein Ra is ethyl or t-butyl.

39. A compound of Formula (F) or a salt thereof: , or a deuterated derivative of any of the foregoing, wherein in each of said formulae: - R1 is –(C(R2)2)k-O-(C(R2)2)mR7, - each R2 is independently chosen from hydrogen; halogen; cyano; hydroxy; C1-C2 alkoxy groups; and C1-C2 alkyl groups optionally substituted with one or more substituents each independently chosen from halogen, hydroxy, and C3-5 cycloalkyl groups optionally substituted with one or more substituents each independently chosen from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogen; - each R4 is independently chosen from halogen; - R5 is chosen from hydrogen and C1-C4 alkyl groups; - each R6 is chosen from halogen, cyano, hydroxy, hydroxymethyl, C1-C2 alkoxy groups, C1-C2 alkyl groups, and halogenated C1-C2 alkyl groups; - R7 is chosen from hydrogen, halogen, cyano, C1-C2 alkyl groups optionally substituted with one or more substituents each independently chosen from halogen and hydroxy, and C3-C10 cycloalkyl groups optionally substituted with one or more substituents each independently chosen from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogen; - Xa is F or Cl - k is 0 or 1; - r is 0 or 1; - m is 0, 1, 2, or 3; and - p is 0, 1, or 2.

40. A compound according to claim 39, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Y2 is N, and Y1 is CH.

41. A compound of Formula (F-1) or a salt thereof: , or a deuterated derivative of any of the foregoing, wherein Xa is F or Cl.

42. A compound of Formula (C) or (D), or a salt thereof: or , or a deuterated derivative of any of the foregoing, wherein in each said formulae: - one of Y1 and Y2 is independently N, and the other is independently CH; - R1 is –(C(R2)2)k-O-(C(R2)2)mR7, - each R2 is independently chosen from hydrogen; halogen; cyano; hydroxy; C1-C2 alkoxy groups; and C1-C2 alkyl groups optionally substituted with one or more substituents each independently chosen from halogen, hydroxy, and C3-5 cycloalkyl groups optionally substituted with one or more substituents each independently chosen from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogen; - each R4 is independently chosen from halogen; - R7 is chosen from hydrogen, halogen, cyano, C1-C2 alkyl groups optionally substituted with one or more substituents each independently chosen from halogen and hydroxy, and C3-C10 cycloalkyl groups optionally substituted with one or more substituents each independently chosen from C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, and halogen; - Ra is C1-C4 alkyl; - Xa is F or Cl; - k is 0 or 1; - r is 0 or 1; and - m is 0, 1, 2, or 3; with a proviso that the compound of Formula (C) is not: or ; and with a proviso that the compound of Formula (D) is not: or .

43. A compound according to claim 42, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each Y2 is independently N, and each Y1 is independently CH.

44. A compound according to claim 42, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ra is ethyl or t-butyl.

45. A compound of Formula (C-1) or (D-1), or a salt thereof: or , or a deuterated derivative of any of the foregoing, wherein Ra is C1-C4 alkyl, and each Xa is independently F or Cl.

46. A compound according to claim 45, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ra is ethyl or t-butyl.

47. A compound of Formula (A-1), (C-1) or (D-1), or a salt thereof: , , or , or a deuterated derivative of any of the foregoing, wherein Ra is C1-C4 alkyl, and each Xa is independently F or Cl.

48. At least one compound chosen from compounds of any one of claims 1-3, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, and optionally one or more of: (a) Compound II: , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing; and (b) Compound III: , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, for use in treating cystic fibrosis.

49. Crystalline Form A of Compound 1:

1.

50. Crystalline Form A according to claim 49 in substantially pure form.

51. Crystalline Form A according to claim 49, characterized by an X-ray powder diffractograph having a signal at at least three two-theta values chosen from 6.6 ± 0.2, 7.6 ± 0.2, 9.6 ± 0.2, 12.4 ± 0.2, 13.1 ± 0.2, 15.2 ± 0.2, 16.4 ± 0.2, 18.2 ± 0.2, and 18.6 ± 0.2.

52. Crystalline Form A according to claim 49, characterized by an X-ray powder diffractograph having a signal at at least three two-theta values chosen from 6.6 ± 0.2, 9.6 ± 0.2, 13.1 ± 0.2, 15.2 ± 0.2, 18.2 ± 0.2, and 18.6 ± 0.2.

53. Crystalline Form A according to claim 49, characterized by an X-ray powder diffractograph having a signal at three two-theta values of 6.6 ± 0.2, 13.1 ± 0.2, 18.2 ± 0.2.

54. Crystalline Form A according to claim 49, characterized by an X-ray powder diffractograph having a signal at six two-theta values of 6.6 ± 0.2, 9.6 ± 0.2, 13.1 ± 0.2, 15.2 ± 0.2, 18.2 ± 0.2, and 18.6 ± 0.2.

55. Crystalline Form A according to claim 49, characterized by an X-ray powder diffractograph substantially similar to that in FIG. 2.

56. Crystalline Form A of Compound 1 prepared by a process comprising desolvating at least one crystalline form of Compound 1 chosen from Crystalline Form M, Crystalline Form E, Crystalline Form P1, Crystalline Form P2, and Crystalline Form AA2.

57. Crystalline Form A of Compound 1 prepared by a process comprising desolvating at least one solvate chosen from methanol solvates, ethanol solvates, acetic acid solvates, toluene solvates, sulfolane solvates, 1-propanol solvates, 2-propanol solvates, propionic acid solvates, methyl tert-butyl ether solvates, and isobutyric acid solvates of Compound 1 followed by subjecting the resulting desolvate to vacuum drying at room temperature for 12 to 100 hours.

58. At least one solvate of Compound 1: (Compound 1), chosen from methanol solvates, ethanol solvates, 1-propanol solvates, 2-propanol solvates, acetic acid solvates, toluene solvates, sulfolane solvates, propionic acid solvates, methyl tert-butyl ether solvates, isobutyric acid solvates, anisole solvates, methylbutyl ketone solvates, and xylene solvates of Compound 1.

59. The at least one solvate of Compound 1 according to claim 58, chosen from methanol solvates, ethanol solvates, 1-propanol solvates, and 2-propanol solvates of Compound 1.

60. Crystalline Form M of Compound 1: (Compound 1).

61. Crystalline Form M according to claim 60 in substantially pure form.

62. Crystalline Form M according to claim 60, characterized by an X-ray powder diffractograph having a signal at at least three two-theta values chosen from 7.0 ± 0.2, 11.6 ± 0.2, 13.1 ± 0.2, 13.7 ± 0.2, 15.2 ± 0.2, 15.9 ± 0.2, 16.4 ± 0.2, 17.8 ± 0.2, and 19.3 ± 0.2.

63. Crystalline Form M according to claim 60, characterized by an X-ray powder diffractograph having a signal at at least three two-theta values chosen from 11.6 ± 0.2, 13.1 ± 0.2, 13.7 ± 0.2, 15.2 ± 0.2, 17.8 ± 0.2, and 19.3 ± 0.2.

64. Crystalline Form M according to claim 60, characterized by an X-ray powder diffractograph having a signal at three two-theta values of 11.6 ± 0.2, 17.8 ± 0.2, and 13.1 ± 0.2.

65. Crystalline Form M according to claim 60, characterized by an X-ray powder diffractograph having a signal at six two-theta values of 11.6 ± 0.2, 13.1 ± 0.2, 13.7 ± 0.2, 15.2 ± 0.2, 17.8 ± 0.2, and 19.3 ± 0.2.

66. Crystalline Form M according to claim 60, characterized by an X-ray powder diffractograph substantially similar to that in FIG.

13.

67. Crystalline Form E of Compound 1: (Compound 1) .

68. Crystalline Form E according to claim 67 in substantially pure form.

69. Crystalline Form E according to claim 67, characterized by an X-ray powder diffractograph having a signal at at least three two-theta values chosen from 7.0 ± 0.2, 11.2 ± 0.2, 12.8 ± 0.2, 13.2 ± 0.2, 14.1 ± 0.2, 15.1 ± 0.2, 16.1 ± 0.2, 17.8 ± 0.2, and 18.9 ± 0.2.

70. Crystalline Form E according to claim 67, characterized by an X-ray powder diffractograph having a signal at at least three two-theta values chosen from 11.2 ± 0.2, 12.8 ± 0.2, 13.2 ± 0.2, 15.1 ± 0.2, 16.1 ± 0.2, and 17.8 ± 0.2.

71. Crystalline Form E according to claim 67, characterized by an X-ray powder diffractograph having a signal at three two-theta values of 12.8 ± 0.2, 16.1 ± 0.2, and 17.8 ± 0.2.

72. Crystalline Form E according to claim 67, characterized by an X-ray powder diffractograph having a signal at six two-theta values of 11.2 ± 0.2, 12.8 ± 0.2, 13.2 ± 0.2, 15.1 ± 0.2, 16.1 ± 0.2, and 17.8 ± 0.2.

73. Crystalline Form E according to claim 67, characterized by an X-ray powder diffractograph substantially similar to that in FIG.

14.

74. A method of preparing crystalline Form A of Compound 1: (Compound 1), comprising stirring a solution or suspension of Compound 1 in a solvent system at a temperature in a range from 50 oC to 85 oC.

75. A method of preparing crystalline Form A of Compound 1: (Compound 1), comprising desolvating a solvate of Compound 1 chosen from methanol solvates, ethanol solvates, 1-propanol solvates, 2-propanol solvates, acetic acid solvates, toluene solvates, sulfolane solvates, propionic acid solvates, methyl tert-butyl ether solvates, isobutyric acid solvates, anisole solvates, methylbutyl ketone solvates, and xylene solvates of Compound 1.

76. A crystalline Form X of a potassium salt of Compound 1: (Compound 1).

77. Crystalline Form X according to claim 76 in substantially pure form.

78. Crystalline Form X according to claim 76, characterized by an X-ray powder diffractograph having a signal at at least three two-theta values chosen from 4.9 ± 0.2, 5.9 ± 0.2, 8.1 ± 0.2, 8.5 ± 0.2, 10.3 ± 0.2, 13.0 ± 0.2, 13.9 ± 0.2, 14.6 ± 0.2, and 17.0 ± 0.2.

79. Crystalline Form X according to claim 76, characterized by an X-ray powder diffractograph having a signal at at least three two-theta values chosen from 4.9 ± 0.2, 5.9 ± 0.2, 8.1 ± 0.2, 13.0 ± 0.2, 13.9 ± 0.2, and 17.0 ± 0.2.

80. Crystalline Form X according to claim 76, characterized by an X-ray powder diffractograph having a signal at three two-theta values of 4.9 ± 0.2, 5.9 ± 0.2, and 13.0 ± 0.2.

81. Crystalline Form X according to claim 76, characterized by an X-ray powder diffractograph having a signal at six two-theta values of 4.9 ± 0.2, 5.9 ± 0.2, 8.1 ± 0.2, 13.0 ± 0.2, 13.9 ± 0.2, and 17.0 ± 0.2.

82. Crystalline Form X according to claim 76, characterized by an X-ray powder diffractograph substantially similar to that in FIG.

15.

83. A crystalline Form Y of a sodium salt of Compound 1: (Compound 1).

84. Crystalline Form Y according to claim 83 in substantially pure form.

85. Crystalline Form Y according to claim 83, characterized by an X-ray powder diffractograph having a signal at at least three two-theta values chosen from 3.5 ± 0.2, 7.0 ± 0.2, 11.7 ± 0.2, 12.8 ± 0.2, 13.2 ± 0.2, 14.2 ± 0.2, 15.4 ± 0.2, 16.6 ± 0.2, and 18.0 ± 0.2.

86. Crystalline Form Y according to claim 83, characterized by an X-ray powder diffractograph having a signal at at least three two-theta values chosen from 3.5 ± 0.2, 7.0 ± 0.2, 11.7 ± 0.2, 13.2 ± 0.2, 14.2 ± 0.2, and 18.0 ± 0.2.

87. Crystalline Form Y according to claim 83, characterized by an X-ray powder diffractograph having a signal at three two-theta values of 7.0 ± 0.2, 11.7 ± 0.2, and 13.2 ± 0.2.

88. Crystalline Form Y according to claim 83, characterized by an X-ray powder diffractograph having a signal at six two-theta values of 3.5 ± 0.2, 7.0 ± 0.2, 11.7 ± 0.2, 13.2 ± 0.2, 14.2 ± 0.2, and 18.0 ± 0.2.

89. Crystalline Form Y according to claim 83, characterized by an X-ray powder diffractograph substantially similar to that in FIG.

16.

90. A solid dispersion comprising Compound 1 and a polymer.

91. The solid dispersion according to claim 90, comprising 50 wt% of Compound 1 and 50 wt% of a polymer by the total weight of the solid dispersion or 80 wt% of Compound 1 and 20 wt% of a polymer by the total weight of the solid dispersion.

92. The solid dispersion according to claim 90 or 91, wherein the polymer is a hypromellose acetate succinate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or Polyvinylpyrrolidone.

93. A pharmaceutical formulation comprising at least one crystalline form according to any one of claims 49 to 73 and 76 to 89, and a pharmaceutically acceptable carrier.

94. At least one crystalline form according to any one of claims 49 to 73 and 76 to 89 for use in treating cystic fibrosis in a patient.

95. A solid dispersion according to any one of claims 90 to 92 for use in treating cystic fibrosis in a patient.

96. Crystalline Form P2 of Compound 1: (Compound 1).

97. Crystalline Form P2 according to claim 96 in substantially pure form.

98. Crystalline Form P2 according to claim 96, characterized by an X-ray powder diffractograph having a signal at at least three two-theta values chosen from 10.2 ± 0.2, 10.9 ± 0.2, 12.6 ± 0.2, 12.9 ± 0.2, 15.0 ± 0.2, 15.9 ± 0.2, 16.2 ± 0.2, 16.5 ± 0.2, and 17.6 ± 0.2.

99. Crystalline Form P2 according to claim 96, characterized by an X-ray powder diffractograph having a signal at at least three two-theta values chosen from 10.9 ± 0.2, 12.6 ± 0.2, 12.9 ± 0.2, 15.0 ± 0.2,16.5 ± 0.2, and 17.6 ± 0.2.

100. Crystalline Form P2 according to claim 96, characterized by an X-ray powder diffractograph having a signal at three two-theta values of 10.9 ± 0.2, 12.6 ± 0.2, and 17.6 ± 0.2.

101. Crystalline Form P2 according to claim 96, characterized by an X-ray powder diffractograph having a signal at six two-theta values of 10.9 ± 0.2, 12.6 ± 0.2, 12.9 ± 0.2, 15.0 ± 0.2, 16.5 ± 0.2, and 17.6 ± 0.2.

102. Crystalline Form P2 according to claim 96, characterized by an X-ray powder diffractograph substantially similar to that in FIG. 17.

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