Novel heteroaryl aminopropanol derivatives

Abstract

This invention provides a compound having formula (I) or a pharmaceutically acceptable salt thereof; a method for preparing the compound of this invention; and its therapeutic use. This invention further provides combinations of pharmacologically active agents and pharmaceutical components.

Description

[Technical Field]

[0001] This invention relates to compounds having formula (I) or pharmaceutically acceptable salts thereof, and their use in inhibiting LTA4H. Therefore, the compounds of this invention can be used to treat diseases and / or disorders involving LTA4H. Such diseases and / or disorders include, for example, inflammation and autoimmune disorders, as well as inflammation of the lungs and respiratory tract. This invention further relates to pharmaceutical compositions comprising novel heteroarylaminopropanol derivatives having formula (I), methods for treating various diseases and disorders using said compounds, and processes for preparing said novel compounds. [Previous Technology]

[0002] Leukotriene A4 hydrolase (LTA4H) catalyzes the hydrolysis of LTA4 to produce LTB4. LTB4 stimulation may involve a range of pro-inflammatory responses, such as leukocyte chemotaxis or intercytokine release. Furthermore, inhibition of LTA4H further increases the biosynthesis of anti-inflammatory, pro-inflammatory lipoxygenin A4, which can promote the resolution of chronic inflammation. Therefore, LTA4H inhibition may be beneficial for diseases in which chronic uncontrolled inflammation may be a key component of pathology, and appears to include a wide range of autoinflammatory and autoimmune diseases. [Summary of the Invention]

[0003] This invention provides compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof, wherein the compounds are LTA4H inhibitors. This invention also provides methods for treating LTA4H-mediated diseases and / or disorders, the methods comprising administering an effective amount of an LTA4H inhibitor to a subject in need.

[0004] Various embodiments of the present invention are described herein. In some aspects, this document provides a compound having formula (I) or a pharmaceutically acceptable salt thereof: (I), or a pharmaceutically acceptable salt thereof, wherein: cyclic B is a 5-membered heteroaryl ring; R1 is H or C1-4 alkyl; X1 is N or CH; X2 is N or CR2, wherein R2 is H or C1-4 alkyl; R3 is: or; X3 is N or CH; X4 is N or CH; Y is O, NRa or CH2; and Ra is H or C1-4 alkyl; R4 is selected from the group consisting of: halogenated, halogenated C1-4 alkoxy, C1-4 alkoxy, halogenated C1-4 alkyl, C1-4 alkyl, 5-membered heteroaryl and C1-5 cycloalkyl; and R5 is H or halogenated.

[0005] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention and one or more pharmaceutically acceptable carriers.

[0006] In another aspect, the present invention provides a combination, particularly a pharmaceutical combination, comprising the compounds of the present invention and one or more therapeutically active agents.

Implementation Method

[0026] Therefore, the present invention provides a compound having formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: cyclic B is a 5-membered heteroaryl ring; R1 is H or C1-4 alkyl; X1 is N or CH; X2 is N or CR2, wherein R2 is H or C1-4 alkyl; R3 is: or; X3 is N or CH; X4 is N or CH; Y is O, NRa or CH2; and Ra is H or C1-4 alkyl; R4 is selected from the group consisting of: halogenated, halogenated C1-4 alkoxy, C1-4 alkoxy, halogenated C1-4 alkyl, C1-4 alkyl, 5-membered heteroaryl and C1-5 cycloalkyl; and R5 is H or halogenated.

[0027] Unless otherwise specified, the term "compounds of the present invention (one or more)" refers to compounds having formula (I) and its sub-formulas (i.e., formulas (IA), (IB), (II) to (V)), example compounds and their salts, and all stereoisomers (including non-mirror image isomers and mirror image isomers), rotational isomers, tautomers and isotopically labeled compounds (including deuterated derivatives) and the inherently formed moieties. Definitions

[0028] As used herein, the term "C1-C4 alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety having up to four carbon atoms. Unless otherwise provided, it refers to a hydrocarbon moiety having one to four carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, isobutyl, tert-butyl, etc.

[0029] As used herein, the term "C1-C4 alkoxy" refers to an alkyl-O- group, wherein the alkyl group is as defined above. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, etc. Typically, an alkoxy group has about 1 to 4 carbon atoms or 1 to 2 carbon atoms.

[0030] As used herein, the term "halogenated C1-C4 alkyl" refers to a C1-C4 alkyl group as defined above that is substituted with one or more halogens. Examples include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, and 1-bromomethyl-2-bromoethyl.

[0031] As used herein, the term "halogenated C1-C4 alkoxy" refers to a C1-4 alkoxy group as defined above that is substituted with one or more halogens.

[0032] As used herein, the term "C3-C5 cycloalkyl" refers to a saturated monocyclic hydrocarbon group having 3 to 5 carbon atoms. Cycloalkyl can also be referred to as a carbocyclic and vice versa, and further refers to the number of carbon atoms present. Unless otherwise indicated, cycloalkyl refers to a cycloalkyl group having 3 to 5 or 3 to 4 cyclic carbon atoms. Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, and cyclopentyl.

[0033] As used herein, the terms “halogen” or “halogenated” refer to fluorine, chlorine, bromine and iodine.

[0034] As used herein, the term "5-membered heteroaryl" refers to a 5-membered monocyclic aromatic ring system having 1 to 4 heteroatoms selected from O, N, or S. Typical heteroaryl groups include, for example, 2-, 4-, or 5-imidazolyl; 3-, 4-, or 5-pyrazolyl; 2-, 4-, or 5-thiazolyl; 3-, 4-, or 5-isothiazolyl; 2-, 4-, or 5-isoazolyl; or 3-, 4-, or 5-isoisoazolyl.

[0035] As used herein, the term "tautomer" is used to refer to two molecules having the same molecular formula but different linkages, which can interconvert in a rapid equilibrium state. For example, certain heteroaryl groups exist in various tautomeric forms. A representative example of a tautomer is a compound having formula (I), wherein R3 is a pyrazolyl group:

[0036] Other specific examples of tautomers are: ; ; ; and

[0037] As used herein, the terms “about” and “substantially” indicate that their values ​​may vary for characteristics such as endothermic, endothermic peaks, exothermic, baseline shifts, etc. Regarding X-ray diffraction peak positions, “about” or “substantially” means taking into account typical peak position and intensity variability. For example, those skilled in the art will understand that peak position (2θ) will show some variability between devices, typically up to 0.2°. Occasionally, variability may be greater than 0.2°, depending on differences in device calibration. Furthermore, those skilled in the art will understand that relative peak intensities will show variability between devices as well as variability due to crystallinity, preferably orientation, the prepared sample surface, and other factors known to those skilled in the art, and should be considered only as qualitative measurements. For DSC, the observed temperature changes will depend on the rate of temperature change and the sample preparation technique and the specific instrument used. Therefore, the endothermic / melting point values ​​reported herein for DSC / TGA thermal analysis plots may vary by ±5°C (and are still considered characteristic of the specific crystalline form described herein). When used in the context of other characteristics such as weight percentage (by weight) and reaction temperature, the term "about" indicates a variation of ± 5%.

[0038] This document describes various enumerated embodiments of the present invention. It should be understood that the features specified in each embodiment can be combined with other specified features to provide further embodiments of the present invention.

[0039] In Embodiment 1, the present invention relates to a compound having formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: cyclic B is a 5-membered heteroaryl ring; R1 is H or C1-4 alkyl; X1 is N or CH; X2 is N or CR2, wherein R2 is H or C1-4 alkyl; R3 is: or; X3 is N or CH; X4 is N or CH; Y is O, NRa or CH2; and Ra is H or C1-4 alkyl; R4 is selected from the group consisting of: halogenated, halogenated C1-4 alkoxy, C1-4 alkoxy, halogenated C1-4 alkyl, C1-4 alkyl, 5-membered heteroaryl and C1-5 cycloalkyl; and R5 is H or halogenated.

[0040] In one aspect of this embodiment, R3 is attached to or aligned with the attachment point of ring B.

[0041] In Embodiment 2, the present invention relates to a compound having formula (I), the compound having formula (IA):; or a pharmaceutically acceptable salt thereof, wherein R1, X1, X2, X3, Y, R4 and R5 are as previously defined.

[0042] In Embodiment 3, the present invention relates to a compound having formula (I), the compound having formula (IB):, or a pharmaceutically acceptable salt thereof, wherein rings B, R1 and X4 are as previously defined.

[0043] In one aspect of this embodiment, X4 is N. In another aspect of this embodiment, X4 is CH.

[0044] In Embodiment 4, the present invention relates to a compound having formula (I), the compound having formula (IC):; or a pharmaceutically acceptable salt thereof, wherein R1, R4, R5, X3, Y are as previously defined.

[0045] In embodiment 5, the present invention relates to a compound having formula (I), (IA), (IB) or (IC) as in embodiment 1, 2, 3 or 4, the compound having formula (II): (II); or a pharmaceutically acceptable salt thereof, wherein all variables are as previously defined in embodiment 1, 2, 3 or 4.

[0046] In embodiment 6, the present invention relates to a compound having formula (I), IA), (IB) as in embodiment 1, 2, 3 or 4, the compound having formula (III): (III); or a pharmaceutically acceptable salt thereof, wherein all variables are as previously defined in embodiment 1, 2 or 3.

[0047] In embodiment 7, the present invention relates to a compound having formula (I), (IA), (IB) or (IC) as in embodiment 1, 2, 3 or 4, the compound having formula (IV): formula (IV); or a pharmaceutically acceptable salt thereof, wherein all variables are as previously defined in embodiment 1, 2, 3 or 4.

[0048] In embodiment 8, the present invention relates to a compound having formula (I), (IA), (IB) or (IC) as in embodiment 1, 2, 3 or 4, the compound having formula (V): (V); or a pharmaceutically acceptable salt thereof, wherein all variables are as previously defined in embodiment 1, 2, 3 or 4.

[0049] In embodiment 9, the present invention relates to a compound having formula (I), (IA), (IB) or (IC) as in embodiment 1, 2, 3 or 4, the compound having formula (VI): (VI); or a pharmaceutically acceptable salt thereof, wherein all variables are as previously defined in embodiment 1, 2, 3 or 4.

[0050] In Embodiment 10, the present invention relates to a compound as described in any one of Embodiments 1, 2, and 5-9, wherein X1 is CH; or a pharmaceutically acceptable salt thereof. In one aspect of this embodiment, X2 is N. In another aspect of this embodiment, X2 is CH or C-C1-4 alkyl, preferably CH or C-CH3.

[0051] In embodiment 10a, the present invention relates to a compound as described in any one of embodiments 1, 2 and 5-9, wherein X1 is N and X2 is CH; or a pharmaceutically acceptable salt thereof.

[0052] In Embodiment 11, the present invention relates to a compound as described in any one of Embodiments 1, 2 to 10 and 10a, wherein R1 is H; or a pharmaceutically acceptable salt thereof.

[0053] In embodiment 11a, the present invention relates to a compound as described in any one of embodiments 1 to 10 and 10a, wherein R1 is a methyl group; or a pharmaceutically acceptable salt thereof.

[0054] In Embodiment 12, the present invention relates to a compound as described in any one of Embodiments 1, 2, 4 to 11, 11a, wherein X3 is N and Y is O, or a pharmaceutically acceptable salt thereof.

[0055] In embodiment 12a, the present invention relates to a compound as described in any one of embodiments 1, 2, 4 to 11, 11a, wherein X3 is CH and Y is O; or a pharmaceutically acceptable salt thereof.

[0056] In Embodiment 13, the present invention relates to the compounds described in any one of Embodiments 1, 2, 4 to 11, 11a, 12 and 12a, wherein R5 is H or halogenated, and R4 is selected from halogenated, halogenated C1-4 alkoxy, C1-4 alkoxy, halogenated C1-4 alkyl, C1-4 alkyl, 5-membered heteroaryl and C3-5 cycloalkyl; or pharmaceutically acceptable salts thereof.

[0057] In Embodiment 14, the present invention relates to the compound as described in Embodiment 13, wherein R4 is selected from cyclopropyl, Cl, Br, -OCH3, -OCHF2, CF3, pyrazolyl, acezolyl, and R5 is H or F; or a pharmaceutically acceptable salt thereof.

[0058] In Embodiment 15, the present invention relates to a compound as described in Embodiment 1, wherein the compound is selected from: (S)-2-amino-3-(3-(3-((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-diazol-5-yl)prop-1-ol; (S)-2-amino-3-(3-(3-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol; (S)-2-amino-3-(3-(3-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol; (S)-2-amino-3-(3-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol; (S)-2-amino-3-(3-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol; (S)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-3-yl)propionate ethyl ester; ((2S)-1-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester; (R)-2-amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol; (S)-(1-(3-(3-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester; (S)-2-amino-3-(3-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol; (S)-2-amino-3-(3-(3-((R)-2,3-dihydro-[1,4]diacino[2,3-b]pyridin-3-yl)phenyl)-1,2,4-diazol-5-yl)prop-1-ol; (S)-2-amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol; (S)-3-(3-(4-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-2-aminoprop-1-ol; (S)-2-amino-3-(5-(3-((R)-2,3-dihydro-[1,4]diacino[2,3-b]pyridin-3-yl)phenyl)-2H-tetrazol-2-yl)prop-1-ol;(S)-2-amino-3-(3-(3-((R)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-diazol-5-yl)prop-1-ol; (S)-2-amino-3-(3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol; (S)-2-amino-3-(3-(4-((((R)-1-phenylprop-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol; (3S)-3-amino-4-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)but-2-ol; (R)-3-(5-(4-((5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)-2-aminoprop-1-ol; (R)-3-(5-(4-((5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)-2-aminoprop-1-ol; (S)-2-amino-3-(3-(5-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)prop-1-ol; (S)-2-amino-3-(5-(5-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)pyridin-2-yl)-2H-tetrazole-2-yl)prop-1-ol; (S)-2-amino-3-(3-(5-((5-chloro-3-fluoropyridin-2-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)prop-1-ol; (S)-2-amino-3-(3-(3-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol; (S)-2-amino-3-(4-(4-(((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol; (S)-2-amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol; (S)-2-amino-3-(5-(4-(4-chlorophenoxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol; (S)-2-amino-3-(5-(4-((5-cyclopropylpyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol; (S)-2-amino-3-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol; (R)-2-amino-3-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol;(R)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol; (S)-2-amino-3-(5-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol; (S)-2-amino-3-(5-(4-((5-bromopyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol; (S)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol; (S)-2-amino-3-(5-(6-(4-chlorophenoxy)pyridin-3-yl)-2H-tetrazol-2-yl)prop-1-ol; (S)-3-(3-(4-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)-2-aminoprop-1-ol; (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol; (2S)-2-amino-3-[5-(4-[[3-fluoro-5-(1,3-azo-2-yl)pyridin-2-yl]oxy]phenyl)-2H-1,2,3,4-tetrazol-2-yl]prop-1-ol; (S)-2-amino-3-(2-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)prop-1-ol; (R)-2-amino-3-(2-(4-(((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)prop-1-ol; and (2S)-2-amino-3-(2-(4-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)prop-1-ol; or a pharmaceutically acceptable salt thereof.

[0059] In embodiment 15a, the present invention has formula (I) with respect to embodiment 13. The compound or its pharmaceutically acceptable salt thereof, wherein the compound is selected from 2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol; (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol; and (R)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol; or its tautomers and / or its pharmaceutically acceptable salts.

[0060] In Embodiment 15b, the present invention relates to a compound having formula (I) as in Embodiment 13, or a pharmaceutically acceptable salt thereof, wherein the compound is (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol, also represented as:; or a pharmaceutically acceptable salt thereof. As previously stated, the compound of Embodiment 15b also exists in its tautomeric form: ((S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol).

[0061] In Embodiment 15c, the present invention relates to a compound having formula (I) as in Embodiment 13, wherein the compound is selected from (R)-2-amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol, (S)-2-amino-3-(3-(3-((R)-2,3-dihydro-[1,4]dioxin-[2,3-b]pyridin-3-yl)phenyl)-1,2,4-diazol-5-yl)prop-1-ol, (S)-2-amino-3-(5-(3-((R)-2,3-dihydro-[1,4]dioxin-[2,3-b]pyridin-3-yl)phenyl)-2H-tetrazol-2-yl)prop-1-ol and (S)-2-amino-3-(5-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol; or pharmaceutically acceptable salts thereof.

[0062] In another aspect of the invention, the compound having formula (I) or any subform of any of the foregoing embodiments described herein is not a substrate of the organic anion transport protein OAT3.

[0063] Depending on the choice of starting materials and procedures, these compounds may exist in possible stereoisomer forms or as mixtures thereof (e.g., as pure optical isomers or as mixtures of stereoisomers, such as racemic and non-mirror image isomer mixtures), depending on the number of asymmetric carbon atoms. This invention is intended to include all such possible stereoisomers, including racemic mixtures, non-mirror image isomer mixtures, and optically pure forms. Optically active (R)- and (S)- stereoisomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be E or Z configurations. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may have cis or trans configurations. All tautomeric forms are also included.

[0064] As used herein, the term "salt" refers to an acid addition salt or a base addition salt of the compounds of the present invention. "Salt" particularly includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy and properties of the compounds of the present invention and is generally not biologically or otherwise undesirable. In many cases, the compounds of the present invention can form acid salts and / or base salts due to the presence of amino and / or carboxyl groups or similar groups. When both basic and acidic groups are present in the same molecule, the compounds of the present invention can also form internal salts, such as zwitterionic molecules.

[0065] Pharmaceutically acceptable acid addition salts can be formed from inorganic acids and organic acids.

[0066] Inorganic acids that can produce salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.

[0067] Organic acids that can be used to derive salts include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, etc.

[0068] Pharmaceutically acceptable base addition salts can be formed from inorganic bases and organic bases.

[0069] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from Groups I to XII of the periodic table. In some embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0070] Organic bases that can derive salts include, for example, primary, secondary, and tertiary amines; substituted amines (including naturally occurring substituted amines); cyclic amines; basic ion exchange resins, etc. Some organic amines include isopropylamine, benzylethylenediamine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperidine, and trimethylamine.

[0071] In another aspect, the present invention provides compounds of the present invention in the form of: acetate, ascorbate, adipic acid salt, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, decanoate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluconate, gluconate, glucuronate, glutamate, glycolate, hippurate, and hydroiodide. Salts / iodides, hydroxyethyl sulfonates, lactates, lacturonates, dodecyl sulfates, malates, maleates, malonates, amygdalinates, methanesulfonates, methyl sulfates, mucilages, naphthates, naphthalenesulfonates, nicotinates, nitrates, octadecanoates, oleates, oxalates, palmitates, dihydroxynaphthalates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalacturonates, propionates, sebates, stearates, succinates, sulfosalisates, sulfates, tartrates, toluenesulfonates, triphenylacetates, trifluoroacetates, or sine naphthalates.

[0072] In one embodiment, the present invention provides a compound having formula (I) or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 15, in the form of a salt selected from the following: acetate, ascorbate, adipate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, decanoate, chloride / hydrochloride, chlorourea, citrate, ethanedisulfonate, fumarate, gluconate, gluconate, glucuronate, glutamate, glycolic acid, hippurate, hydroiodate / iodide, hydroxyethylsulfonate, Lactates, lacturonates, dodecyl sulfates, malates, maleates, malonates, amygdalinates, methanesulfonates, methyl sulfates, mucilages, naphthates, naphthalenesulfonates, nicotinates, nitrates, octadecanoates, oleates, oxalates, palmitates, dihydroxynaphthalates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalacturonates, propionates, sebates, stearates, succinates, sulfosalicylates, sulfates, tartrates, toluenesulfonates, triphenylacetates, trifluoroacetates, or sine naphthates.

[0073] In another aspect, the present invention provides compounds of the present invention in the form of transbutenedioic acid salt, maleic acid salt, adipate, tartrate, glutamate and hippurate.

[0074] In one embodiment, the present invention provides (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol in the following forms: acetate, ascorbate, adipate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, decanoate, chloride / hydrochloride, chlorourea, citrate, ethanedisulfonate, fumarate, gluconate, glucuronate, glucuronate, glutaraldehyde, etc. Amino acids, glutarates, glycolates, hippurates, hydroiodates / iodides, hydroxyethyl sulfonates, lactates, lacturonates, dodecyl sulfates, malates, maleates, malonates, amygdalinates, methanesulfonates, methyl sulfates, mucilages, naphthates, naphthalenesulfonates, nicotinates, nitrates, octadecanoates, oleates, oxalates, palmitates, dihydroxynaphthalates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalacturonates, propionates, sebates, stearates, succinates, sulfosalicylates, sulfates, tartrates, toluenesulfonates, triphenylacetates, trifluoroacetates, or sine naphthalates.

[0075] In another embodiment, the present invention provides (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol in the form of transbutenedioate, maleic acid, adipate, tartrate, glutamate and hippurate.

[0076] In yet another embodiment, the present invention provides (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol in the form of hippurate.

[0077] Any formula given herein is also intended to represent both unlabeled and isotopically labeled forms of the compound. The isotopically labeled compound has the structure described by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic weight or mass number. Isotopes that may be incorporated into the compounds of the present invention include, for example, isotopes of hydrogen.

[0078] The medical practitioner should at least provide a relatively narrow subgenus of the identified radiopaque compound and indicate that at least one site (more preferably multiple sites) in the general structure can be a deuterium atom. An example is recommended below:

[0079] Furthermore, the incorporation of certain isotopes, particularly deuterium (i.e., 2H or D), can provide certain therapeutic advantages due to increased metabolic stability, such as increased in vivo half-life or reduced dose requirements or therapeutic index or improved tolerability. It should be understood that deuterium is considered a substituent in the compounds of the present invention herein. The concentration of deuterium can be defined by an isotope enrichment factor. As used herein, the term "isotope enrichment factor" refers to the ratio between the isotopic abundance of a specified isotope and its native abundance. If the substituents in the compounds of this invention indicate deuterium, then such compounds have an isotopic enrichment factor for each specified deuterium atom of at least 3500 (52.5% deuterium doping on each specified deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping). It should be understood that the term "isotopic enrichment factor" can be applied to any isotope in the same manner as described for deuterium.

[0080] Other examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 3H, 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl, 123I, 124I, and 125I, respectively. Therefore, it should be understood that the present invention includes compounds incorporated with one or more of the above-mentioned isotopes, including, for example, radioactive isotopes such as 3H and 14C, or those incorporated with non-radioactive isotopes such as 2H and 13C. Such isotopically labeled compounds can be used in metabolic studies (with 14C), reaction kinetic studies (with, for example, 2H or 3H), detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays), or for use in the radiotherapy of patients. In particular, 18F or labeled compounds may be especially desirable for PET or SPECT studies. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples and preparations, using a suitable isotopically labeled reagent instead of an unlabeled previously used reagent. Further definitions

[0081] As used herein, the term "pharmaceutical composition" refers to the compound of the present invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration.

[0082] As used herein, the term “pharmaceutically acceptable carrier” means a substance that can be used in the preparation or use of a pharmaceutical composition, and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delay agents, salts, pharmaceutical stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof, as known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22nd edition, Pharmaceutical Press, 2013, pp. 1049-1070).

[0083] The term "therapeuticly effective amount" for the compounds of the present invention refers to an amount of the compound of the present invention that will elicit a biological or medical response in a subject (e.g., reduction or inhibition of enzyme or protein activity, or improvement of symptoms, relief of symptoms, slowing or delaying disease progression, or prevention of disease, etc.). In one embodiment, the term "therapeuticly effective amount" refers to an amount of the compound of the present invention that, when administered to a subject, is effective in: (1) at least partially relieving, preventing, and / or improving symptoms or disorders or diseases that are (i) mediated by LTA4H, or (ii) associated with LTA4H activity, or (iii) characterized by LTA4H activity (normal or abnormal); or (2) reducing or inhibiting LTA4H activity. In another embodiment, the term "therapeuticly effective amount" refers to an amount of the compound of the present invention that, when administered to cells, or tissues, or noncellular biological materials, or media, is effective in at least partially reducing or inhibiting LTA4H activity.

[0084] As used herein, the term "subject" refers to a primate (e.g., a human, male or female), dog, rabbit, guinea pig, pig, rat, and mouse. In some embodiments, the subject is a primate. In still other embodiments, the subject is a human.

[0085] As used herein, the term "inhibit (inhibition or inhibiting)" means a reduction or inhibition of a given condition, symptom or disorder, or disease, or a significant reduction in baseline activity of a biological activity or process.

[0086] As used herein, the term “treatment” for any disease or disorder means relief or improvement of the disease or disorder (i.e., slowing or halting the development of the disease or at least one of its clinical symptoms); or relief or improvement of at least one physical parameter or biomarker associated with the disease or disorder, including those physical parameters or biomarkers that the patient may not be able to identify.

[0087] As used herein, the term "prevent, preventing, or prevention" for any disease or disorder means preventive treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0088] As used herein, a subject is “need” the treatment if the subject will benefit biologically, medically, or in terms of quality of life from the treatment.

[0089] As used herein, the terms “a / an”, “the”, and similar terms used in the context of this invention (especially in the context of the claims) should be interpreted as encompassing both the singular and the plural, unless otherwise indicated or clearly contradicted by the context.

[0090] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise obviously contradicted by the context. Any and all instances or exemplary language (such as "such as") provided herein are intended only to better illustrate the invention and not to limit the scope of the invention as otherwise claimed.

[0091] Any asymmetric atom (e.g., carbon, etc.) in one or more compounds of the present invention may be present in racemic or mirror-isomer enriched forms, such as (R)-, (S)-, or (R,S)- configurations. In some embodiments, each asymmetric atom has a (R)- or (S)- configuration with at least 50% mirror-isomer excess, at least 60% mirror-isomer excess, at least 70% mirror-isomer excess, at least 80% mirror-isomer excess, at least 90% mirror-isomer excess, at least 95% mirror-isomer excess, or at least 99% mirror-isomer excess. If possible, substituents on atoms having unsaturated double bonds may be present in cis-(Z)- or trans-(E)- forms.

[0092] Therefore, as used herein, the compounds of the present invention may be in the form of one of the possible stereoisomers, rotational isomers, configurational isomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, non-mirror image isomers, optical isomers (mirror images), racemates or mixtures thereof.

[0093] Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric or optical isomers, non-mirror isomers, or racemates based on the physicochemical differences of the components, for example by chromatography and / or fractional crystallization.

[0094] Any racemic derivative of the compound or intermediate of the present invention obtained can be resolved into optical mirror images by known methods, for example, by separating its non-mirror image isomer salt obtained with an optically active acid or base, and releasing an optically active acidic or basic compound. In particular, the compound of the present invention can therefore be resolved into its optical mirror images using a basic fraction, for example, by fractional crystallization of a salt formed with an optically active acid, such as tartaric acid, dibenzoyltartaric acid, diacetylated tartaric acid, di-O,O'-p-tolyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. The racemic compound or racemic intermediate of the present invention can also be resolved by chiral chromatography (e.g., high-performance liquid chromatography (HPLC) using a chiral adsorbent).

[0095] The compounds of the present invention, including their salts, hydrates and solvates, can be separated in one or more crystalline forms under suitable conditions.

[0096] In one embodiment, the present invention provides crystalline form C of (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol in its free base form as characterized in FIG1A, 1B and 1C and in Example 41. Crystalline form C is characterized by one or more of the following features: (i) an X-ray powder diffraction pattern measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5406 Å, which contains representative peaks about 2θ at 11.4 ± 0.2 °2θ, 15.2 ± 0.2 °2θ, 22.8 ± 0.2 °2θ, and 28.6 ± 0.2 °2θ; (ii) an X-ray powder diffraction pattern measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5406 Å, which contains four or more 2θ values ​​selected from the group consisting of: 11.4 ± 0.2 °2θ, 15.2 ± 0.2 °2θ, 15.9 ± 0.2 °2θ, 16.9 ± 0.2 °2θ, 18.3 ± 0.2 °2θ, and 22.8 ± 0.2 °2θ. (iii) X-ray powder diffraction pattern measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5406 Å, containing five or more 2θ values ​​selected from the group consisting of: 11.4 ± 0.2 °2θ, 15.2 ± 0.2 °2θ, 15.9 ± 0.2 °2θ, 16.9 ± 0.2 °2θ, 18.3 ± 0.2 °2θ, 22.8 ± 0.2 °2θ, 24.6 ± 0.2 °2θ, and 28.6 ± 0.2 °2θ; (iv) X-ray diffraction pattern substantially identical to the X-ray powder diffraction pattern shown in Figure 1A; (v) Differential scanning calorimetry (DSC) thermal analysis pattern substantially identical to that shown in Figure 1B; i.e., when measured at 10... When heated from 30°C to 300°C at a rate of K / min, dehydration endothermic occurs at approximately 45°C with an enthalpy of 19 J / g, followed by small melting endothermic event and an immediate exothermic recrystallization event at approximately 110°C; vi) Thermogravimetric analysis (TGA) plot is essentially the same as shown in Figure 1C, i.e., when heated from 30°C to 300°C at a rate of 10 K / min, the drying loss is approximately 1.4%.

[0097] In one embodiment, the present invention provides crystalline form D of (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol in its free base form as characterized in FIG2A, 2B and 2C and Example 42. Crystalline form D is characterized by one or more of the following features: (i) an X-ray powder diffraction pattern measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5406 Å, which contains representative peaks about 2θ at 11.3 ± 0.2 °2θ, 18.3 ± 0.2 °2θ, 24.2 ± 0.2 °2θ, and 28.6 ± 0.2 °2θ; (ii) an X-ray powder diffraction pattern measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5406 Å, which contains four or more 2θ values ​​selected from the group consisting of: 11.3 ± 0.2 °2θ, 15.2 ± 0.2 °2θ, 18.3 ± 0.2 °2θ, 19.2 ± 0.2 °2θ, 20.3 ± 0.2 °2θ, and 21.6 ± 0.2 °2θ. (iii) X-ray powder diffraction patterns measured at approximately 25°C and an X-ray wavelength λ of 1.5406 Å, containing five or more 2θ values ​​selected from the following groups: 11.3 ± 0.2 °2θ, 15.2 ± 0.2 °2θ, 18.3 ± 0.2 °2θ, 19.2 ± 0.2 °2θ, 20.3 ± 0.2 °2θ, 21.6 ± 0.2 °2θ, 22.8 ± 0.2 °2θ, 24.2 ± 0.2 °2θ, and 28.6 ± 0.2 °2θ; (iv) X-ray diffraction patterns substantially identical to those shown in Figure 2A; (v) The differential scanning calorimetry (DSC) thermal analysis plot is essentially the same as that shown in Figure 2B; that is, when heated from 30°C to 300°C at a rate of 10 K / min, melting endothermic occurs at approximately 146°C with an enthalpy of approximately 121 J / g; vi) The thermogravimetric analysis (TGA) plot is essentially the same as that shown in Figure 2C; that is, when heated from 30°C to 300°C at a rate of 10 K / min, the drying loss at approximately 140°C is approximately 0.15%.

[0098] In another embodiment, the present invention provides crystalline form A of (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol hippurate as characterized in FIG5A, 5B and 5C and in Example 45. (i) An X-ray powder diffraction pattern measured at a temperature of approximately 25°C and an X-ray wavelength λ of 1.5406 Å, containing representative peaks at 8.1 ± 0.2 °2θ, 16.2 ± 0.2 °2θ, 16.3 ± 0.2 °2θ, 20.4 ± 0.2 °2θ, 21.0 ± 0.2 °2θ, and 23.1 ± 0.2 °2θ; (ii) An X-ray powder diffraction pattern measured at a temperature of approximately 25°C and an X-ray wavelength λ of 1.5406 Å, containing four or more 2θ values ​​selected from the group consisting of: 8.1 ± 0.2 °2θ, 11.2 ± 0.2 °2θ, 12.2 ± 0.2 °2θ, 16.2 ± 0.2 °2θ, 16.3 ± 0.2 °2θ. (iii) X-ray powder diffraction patterns measured at a temperature of approximately 25°C and an X-ray wavelength λ of 1.5406 Å, comprising five or more 2θ values ​​selected from the group consisting of: 8.1 ± 0.2 °2θ, 11.2 ± 0.2 °2θ, 12.2 ± 0.2 °2θ, 16.2 ± 0.2 °2θ, 16.3 ± 0.2 °2θ, 18.8 ± 0.2 °2θ, 19.7 ± 0.2 °2θ, 20.4 ± 0.2 °2θ, 18.8 ± 0.2 °2θ, 19.7 ± 0.2 °2θ, 20.4 ± 0.2 °2θ, 21.0 ± 0.2 °2θ, 22.3 ± 0.2 °2θ, 22.6 ± 0.2 °2θ, and 23.1 ± 0.2 °2θ; 0.2 °2θ, 21.0 ± 0.2 °2θ, 22.3 ± 0.2 °2θ, 22.6 ± 0.2 °2θ and 23.1 ± 0.2 °2θ; iv) X-ray diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in Figure 5A; v) Differential scanning calorimetry (DSC) thermal analysis plot substantially the same as shown in Figure 5B; that is, when heated from 30°C to 300°C at a rate of 10 K / min, melting endothermic occurs at approximately 172°C with an enthalpy of approximately 106 J / g; vi) Thermogravimetric analysis (TGA) plot substantially the same as shown in Figure 5C, that is, when heated from 30°C to 300°C at a rate of 10 K / min, the drying loss at approximately 170°C is approximately 0.2%.

[0099] In another embodiment, the present invention provides crystalline form B of (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol hippurate as characterized in FIG4A, 4B and 4C and in Example 44. Crystalline form B is characterized by one or more of the following features: (i) an X-ray powder diffraction pattern measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5406 Å, which contains representative peaks about 2θ at 13.0 ± 0.2 °2θ, 17.1 ± 0.2 °2θ, 18.0 ± 0.2 °2θ, 18.8 ± 0.2 °2θ, and 23.5 ± 0.2 °2θ; (ii) an X-ray powder diffraction pattern measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5406 Å, which contains four or more 2θ values ​​selected from the group consisting of: 9.3 ± 0.2 °2θ, 11.1 ± 0.2 °2θ, 13.0 ± 0.2 °2θ, 17.1 ± 0.2 °2θ, 18.0 ± 0.2 °2θ. (iii) X-ray powder diffraction pattern measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5406 Å, containing five or more 2θ values ​​selected from the group consisting of: 9.3 ± 0.2 °2θ, 11.1 ± 0.2 °2θ, 13.0 ± 0.2 °2θ, 17.1 ± 0.2 °2θ, 18.0 ± 0.2 °2θ, 18.8 ± 0.2 °2θ, 23.5 ± 0.2 °2θ, and 24.2 ± 0.2 °2θ; (iv) X-ray diffraction pattern substantially identical to the X-ray powder diffraction pattern shown in Figure 4A; (v) The differential scanning calorimetry (DSC) thermal analysis plot is essentially the same as that shown in Figure 4B; that is, when heated from 30°C to 300°C at a rate of 10 K / min, melting endothermic occurs at approximately 180°C with an enthalpy of approximately 134 J / g; vi) The thermogravimetric analysis (TGA) plot is essentially the same as that shown in Figure 4C; that is, when heated from 30°C to 300°C at a rate of 10 K / min, the drying loss at approximately 170°C is approximately 0.3%.

[0100] In another embodiment, the present invention provides crystalline form E of (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol hydrochloride as characterized in FIG3A, 3B and 3C and in Example 43. Crystalline form E is characterized by one or more of the following features: (i) an X-ray powder diffraction pattern measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5406 Å, which contains representative peaks about 2θ at 15.8 ± 0.2 °2θ, 16.4 ± 0.2 °2θ, 21.0 ± 0.2 °2θ, 22.0 ± 0.2 °2θ, 22.0 ± 0.2 °2θ, and 27.6 ± 0.2 °2θ; (ii) an X-ray powder diffraction pattern measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5406 Å, which contains four or more 2θ values ​​selected from the group consisting of: 15.8 ± 0.2 °2θ, 16.4 ± 0.2 °2θ, 18.3 ± 0.2 °2θ, 19.3 ± 0.2 °2θ. (iii) X-ray powder diffraction patterns measured at a temperature of approximately 25°C and an X-ray wavelength λ of 1.5406 Å, comprising five or more 2θ values ​​selected from the group consisting of: 15.8 ± 0.2 °2θ, 16.4 ± 0.2 °2θ, 18.3 ± 0.2 °2θ, 19.3 ± 0.2 °2θ, 21.0 ± 0.2 °2θ, 22.0 ± 0.2 °2θ, 22.4 ± 0.2 °2θ, 23.8 ± 0.2 °2θ, and 27.6 ± 0.2 °2θ; 21.0 ± 0.2 °2θ, 22.0 ± 0.2 °2θ, 22.4 ± 0.2 °2θ, 23.8 ± 0.2 °2θ, and 27.6 ± 0.2 °2θ; 21.0 ± 0.2 °2θ, 22.0 ± 0.2 °2θ, 22.4 ± 0.2 °2θ, 23.8 ± 0.2 °2θ, and 27.6 ± 0.2 °2θ; 22.4 ± 0.2 °2θ, 23.8 ± 0.2 °2θ, and 27.6 ± 0.2 °2θ. ± 0.2 °2θ and 27.6 ± 0.2 °2θ; iv) X-ray diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in Figure 3A; v) Differential scanning calorimetry (DSC) thermal analysis plot substantially the same as shown in Figure 3B; that is, melting endothermic occurs at about 236°C with an enthalpy of about 127 J / g when heated from 30°C to 300°C at a rate of 10 K / min; vi) Thermogravimetric analysis (TGA) plot substantially the same as shown in Figure 3C; that is, drying loss at about 230°C is about 0.5% when heated from 30°C to 300°C at a rate of 10 K / min.

[0101] In yet another embodiment, the present invention provides crystalline form F of (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol hydrochloride as characterized in FIG6A, 6B and 6C and in Example 46.The crystalline form F is characterized by one or more of the following features: (i) an X-ray powder diffraction pattern measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5406 Å, which contains representative peaks about 2θ at 5.3 ± 0.2 °2θ, 15.9 ± 0.2 °2θ, 16.8 ± 0.2 °2θ, 17.7 ± 0.2 °2θ, 21.0 ± 0.2 °2θ, 21.3 ± 0.2 °2θ, 22.3 ± 0.2 °2θ, and 23.7 ± 0.2 °2θ; (ii) an X-ray powder diffraction pattern measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5406 Å, which contains four or more 2θ values ​​selected from the group consisting of: 5.3 ± 0.2 °2θ, 11.4 ... (iii) An X-ray powder diffraction pattern measured at a temperature of approximately 25°C and an X-ray wavelength λ of 1.5406 Å, comprising five or more 2θ values ​​selected from the group consisting of: 5.3 ± 0.2 °2θ, 11.4 ± 0.2 °2θ, 15.9 ± 0.2 °2θ, 16.8 ± 0.2 °2θ, 17.2 ± 0.2 °2θ, 17.7 ± 0.2 °2θ, 18.0 ± 0.2 °2θ, 21.0 ± 0.2 °2θ, 21.3 ± 0.2 °2θ, 22.3 ± 0.2 °2θ, 23.7 ± 0.2 °2θ, and 26.8 ± 0.2 °2θ; (iii) an X-ray powder diffraction pattern measured at approximately 25°C and an X-ray wavelength λ of 1.5406 Å, comprising five or more 2θ values ​​selected from the group consisting of: 5.3 ± 0.2 °2θ, 11.4 ± 0.2 °2θ, 15.9 ± 0.2 °2θ, 16.8 ± 0.2 °2θ, 17.2 ± 0.2 °2θ, 17.7 ± 0.2 °2θ, 18.0 ± 0.2 °2θ, 21.0 ± 0.2 °2θ, 21.3 ± 0.2 °2θ, 22.3 ± 0.2 °2θ, 23.7 ± 0.2 °2θ, and 26.8 ± 0.2 °2θ; 0.2 °2θ, 17.7 ± 0.2 °2θ, 18.0 ± 0.2 °2θ, 21.0 ± 0.2 °2θ, 21.3 ± 0.2 °2θ, 22.3 ± 0.2 °2θ, 23.7 ± 0.2 °2θ, and 26.8 ± 0.2 °2θ; iv) X-ray diffraction spectra substantially the same as the X-ray powder diffraction spectra shown in Figure 6A; v) Differential scanning calorimetry (DSC) thermal analysis plot substantially the same as shown in Figure 6B; i.e., melting at approximately 215 °C with a decomposition enthalpy when heated from 30 °C to 300 °C at a rate of 10 K / min; vi) Thermogravimetric analysis (TGA) plot substantially the same as shown in Figure 6C; i.e., drying loss of approximately 0.4% at approximately 195 °C when heated from 30 °C to 300 °C at a rate of 10 K / min.

[0102] The compounds of the present invention, i.e., compounds of formula (I) containing groups capable of acting as hydrogen bond donors and / or acceptors, are capable of forming cocrystals with suitable cocrystal forgings. These cocrystals can be prepared by known cocrystal forming procedures from compounds having formulas (I), (IA), (IB), or (IC) and any one of formulas (II) to (VI). Such procedures include grinding, heating, co-sublimation, co-melting, or contacting a compound having formula (I) with a cocrystal forging in solution under crystallization conditions and separating the resulting cocrystal. Suitable cocrystal forgings include those described in WO 2004 / 078163. Therefore, the present invention further provides cocrystals comprising compounds having formulas (I), (IA), (IB), (IC), and any one of formulas (II) to (VI).

[0103] Furthermore, the compounds of the present invention (including their salts) can also be obtained in their hydrated form, or include other solvents for their crystallization. The compounds of the present invention can inherently or by design form solvates having pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to include both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of the compounds of the present invention (including their pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical field and are known to be harmless to the recipient, such as water, ethanol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water. Synthetic Regimen

[0104] Compounds having formula (II) can be prepared according to general scheme A or B: Scheme A

[0105] The cyano group of a suitable basic component A.1 can be treated with an azide in the presence of an organotin oxide to give a tetrazolium A.2, which can react with a protected serine derivative A.3 to give an intermediate A.4. Sequential or simultaneous deprotection yields a compound having formula (II). Scheme B

[0106] Alternatively, in the presence of a base, tetrazolium A.2 can be reacted with protected 4-(hydroxymethyl)-1,2,3-thiazolidinyl 2,2-dioxide B.1 to give intermediate B.2, which can be deprotected to give a compound having formula (II).

[0107] Compounds having formula (III) can be prepared according to general scheme C: Scheme C

[0108] In the presence of a catalyst, a suitable basic component C.1 can be reacted with a boron reagent C.2, which may be protected or unprotected, to give intermediate C.3. Alternatively, the corresponding borate ester can be used instead of the acid. Treatment with the protected basic component B.1, followed by removal of the protecting group, yields a compound having formula (III).

[0109] Compounds having formula (IV) can be prepared according to general scheme D: Scheme D

[0110] Treatment of nitrile A.1 with hydroxylamine in the presence of a base yields intermediate D.2, which reacts with the protected active ester D.3 to give intermediate D.4. Reduction with a borohydride reagent yields alcohol D.5. Deprotection yields a compound having formula (IV).

[0111] A compound having formula (V) can be prepared according to scheme E: Scheme E

[0112] Ester E.4 can be saponified and converted into acid chloride E.2. Treatment with hydroxyacetimidamide E.3 in the presence of DMAP and a base can form intermediate E.4. Heating E.4 in an inert solvent yields acediazole E.5. Treatment of E.6 with an organolithium reagent at low temperature, followed by the addition of E.5, yields intermediate E.7, which can be converted into intermediate E.8 in the presence of an acid. Reduction with an acid yields a compound having formula (V).

[0113] Compounds having formula (VI) can be prepared according to general scheme F: Scheme F

[0114] Dioxane F.1 can be treated with NaIO4 to give boric acid F.2. Reacting it with tetrazolium F.3 in the presence of a Cu catalyst, O2, and a base yields intermediate F.6. Tetrazolium F.3 can be prepared from a protected nitrile F.5 by reaction with an azide. Reduction with a borohydride reagent yields alcohol F.6. Deprotection yields a compound having formula (VI).

[0115] Other schemes GI used for intermediate A.1 in synthetic schemes A and D. Scheme G

[0116] Reacting G.1 with aromatic halide G.2 in the presence of a base yields intermediate A.1(G). Scheme H

[0117] Compound H.1 reacts with bromide H.2 in the presence of a base to give compound H.3. Reduction with an Rh catalyst yields H.4. In the presence of a chiral ligand, mirror-isomerically pure H.4 is obtained. Treatment with a Cu catalyst at high temperature yields compound A.1(H). Scheme I

[0118] The intermediate A.1(I) can be obtained by reacting halide I.1 with phenol I.2 in the presence of a base.

[0119] Other schemes JL used for intermediate C.1 in synthesis scheme C: Scheme J

[0120] The intermediate C.1(J) can be obtained by reacting halide J.1 with phenol J.2 in the presence of a base. (Scheme K)

[0121] Compound K.3 is obtained by reacting compound K.1 with bromide K.2 in the presence of a base. Reduction with an Rh catalyst yields K.4. In the presence of a chiral ligand, mirror-isomerically pure K.4 is obtained. Treatment with a Cu catalyst at high temperature yields compound C.1(K). Scheme L

[0122] The intermediate C.1(L) can be obtained by reacting halide L.1 with phenol L.2 in the presence of a base.

[0123] Other schemes MO for intermediate E.1 used in the synthesis of scheme E: Scheme M

[0124] The intermediate E.1(M) can be obtained by reacting halide M.1 with phenol M.2 in the presence of a base. Scheme N

[0125] Compound N.1 reacts with bromide N.2 in the presence of a base to give compound N.3. Reduction with an Rh catalyst yields N.4. In the presence of a chiral ligand, mirror-isomerically pure N.4 is obtained. Treatment with a Cu catalyst at high temperature yields compound E.1(N). Scheme O

[0126] The intermediate E.1(O) can be obtained by reacting halide O.1 with phenol O.2 in the presence of a base.

[0127] Other schemes PR scheme P used for intermediate F.1 in synthesis scheme F.

[0128] The intermediate F.1(P) can be obtained by reacting halide P.1 with phenol P.2 in the presence of a base. Scheme Q

[0129] Compound Q.1 reacts with bromide Q.2 in the presence of a base to give compound Q.3. Reduction with an Rh catalyst yields Q.4. In the presence of a chiral ligand, mirror-isomerically pure Q.4 is obtained. Treatment with a Cu catalyst at high temperature yields compound F.1(Q). Scheme R

[0130] The intermediate F.1(R) can be obtained by reacting halide R.1 with phenol R.2 in the presence of a base.

[0131] This invention further includes any variations of the method of the invention, wherein an intermediate available at any stage is used as a starting material and the remaining steps are carried out, or wherein the starting material is formed in situ under reaction conditions, or wherein the reaction component is used in the form of its salt or an optically pure material. The compounds and intermediates of the invention can also be converted into each other according to methods commonly known to those skilled in the art.

[0132] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In another embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical composition may be formulated for specific routes of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration may also involve inhalation or intranasal application. The pharmaceutical composition of the present invention may be formulated in solid form (including but not limited to capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (including but not limited to solutions, suspensions, or emulsions). Tablets may be film-coated or enteric-coated according to methods known in the art. Typically, a pharmaceutical composition system comprises an active ingredient and one or more of the following in tablets or gelatin capsules: a) a diluent, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine; b) a lubricant, such as silica, talc, stearic acid, its magnesium or calcium salt, and / or polyethylene glycol; for tablets, it also comprises c) a binder, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose, and / or polyvinylpyrrolidone; d) a disintegrant, such as starch, agar, alginic acid, or its sodium salt, or an effervescent mixture, if necessary; and e) an absorbent, colorant, flavoring agent, and sweetener.

[0133] The compounds of the present invention in free form or in pharmaceutically acceptable salt form exhibit valuable pharmacological properties, such as LTA4H modulatory properties, as shown by in vitro and in vivo tests provided in the following sections, and thus indicate their use in therapeutics or as research chemicals, such as as tool compounds.

[0134] The compounds of the present invention can be used to treat the following indications: acute or chronic inflammation, allergic reactions, hypersensitivity reactions, atopic dermatitis, psoriasis, acute respiratory distress syndrome, immune complex-mediated lung injury and chronic obstructive pulmonary disease, inflammatory bowel disease (including ulcerative colitis, Crohn's disease, and postoperative trauma), gastrointestinal ulcers, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), neutrophilic dermatoses (including but not limited to gangrenous varicose veins, Sweet's syndrome, acne, and neutrophilic urticaria), immune complex-mediated glomerulonephritis, hidradenitis suppurativa, autoimmune diseases (including insulin-dependent diabetes mellitus, multiple sclerosis, rheumatoid arthritis, osteoarthritis, and systemic lupus erythematosus), vasculitis (including but not limited to cutaneous vasculitis, Behcet's disease, and Henoch-Schönlein purpura). Purpura), cardiovascular diseases (including but not limited to hypertension, atherosclerosis, aneurysm, severe lower limb ischemia, peripheral arterial occlusive disease, pulmonary hypertension and Reynaud's syndrome), sepsis, inflammatory and neuropathic pain (including arthritis pain), periodontal disease (including gingivitis), ear infections, migraines, benign prostatic hyperplasia, Sjogren-Larsson syndrome, and cancers (including but not limited to leukemia and lymphoma, prostate cancer, breast cancer, lung cancer, malignant melanoma, kidney cancer, head and neck tumors, and colorectal cancer).

[0135] Therefore, as another aspect, the present invention provides the use of a compound having any one of formulas (I) to (V) or a pharmaceutically acceptable salt thereof in a therapeutic manner, or the use of a compound having any one of Examples 1 to 46 in a therapeutic manner. In another embodiment, the therapeutic is selected from diseases that can be treated by inhibiting LTA4H activity. In another embodiment, the disease is selected from the above list, suitably including ulcerative colitis, acne, hidradenitis suppurativa, asthma such as neutrophilic asthma, psoriasis, and neutrophilic inflammatory conditions such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[0136] In another aspect, the present invention provides a compound having formula (I) selected from 2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol, (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol, or (R)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol, or a pharmaceutically acceptable salt thereof, for use in a therapeutic manner. In another aspect of this embodiment, the therapy is selected from diseases that can be treated by inhibiting LTA4H. In another aspect of this implementation, the disease is selected from the above list and is suitably ulcerative colitis, acne, hidradenitis suppurativa, asthma such as neutrophilic asthma, psoriasis, and neutrophilic inflammatory diseases such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[0137] Therefore, as another aspect, the present invention provides a compound having formula (I) of (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol, or a pharmaceutically acceptable salt thereof, for use in a therapeutic manner. In another aspect of this embodiment, the therapeutic is selected from diseases that can be treated by inhibiting LTA4H. In another aspect of this embodiment, the diseases are selected from the above list, suitably including ulcerative colitis, acne, hidradenitis suppurativa, asthma such as neutrophilic asthma, psoriasis, and neutrophilic inflammatory conditions such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[0138] As another aspect, the present invention provides a product selected from (R)-2-amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol, (S)-2-amino-3-(3-(3-((R)-2,3-dihydro-[1,4]dioxano[2,3-b]pyridin-3-yl)phenyl)-1,2,4-diazol-5-yl)prop-1-ol, and (S)-2-amino-3-(3-(3-((R)-2,3-dihydro-[1,4]dioxano[2,3-b]pyridin-3-yl)phenyl)-1,2,4-diazol-5-yl)prop-1-ol. (S)-2-amino-3-(5-(3-((R)-2,3-dihydro-[1,4]dioxin-[2,3-b]pyridin-3-yl)phenyl)-2H-tetrazol-2-yl)prop-1-ol and (S)-2-amino-3-(5-(4-(((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol having formula (I), or pharmaceutically acceptable salts thereof, are used in a therapeutic manner. In another aspect of this embodiment, the therapy is selected from diseases that can be treated by inhibiting LTA4H. In another aspect of this implementation, the disease is selected from the above list and is suitably ulcerative colitis, acne, hidradenitis suppurativa, asthma such as neutrophilic asthma, psoriasis, and neutrophilic inflammatory diseases such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[0139] In another aspect, the present invention provides a method for treating a disease by inhibiting LTA4H, the method comprising administering a therapeutically acceptable amount of a compound of the present invention (e.g., a compound having any one of formulas (I) to (V) or any one of specific compounds of examples 1 to 46 or a pharmaceutically acceptable salt thereof). In another embodiment, the disease is selected from the above list and is suitably ulcerative colitis, acne, hidradenitis suppurativa, asthma such as neutrophilic asthma, psoriasis, and neutrophilic inflammatory conditions such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).

[0140] Therefore, as another aspect, the present invention provides the use of the compounds of the present invention (e.g., compounds having any one of formulas (I) to (V) or any one of the specific compounds of examples 1 to 46 or their pharmaceutically acceptable salts) in the preparation of a medicament. In another embodiment, the medicament is used to treat a disease that can be treated by inhibiting LTA4H. In another embodiment, the disease is selected from the above list and is suitably ulcerative colitis, acne, hidradenitis suppurativa, asthma such as neutrophilic asthma, psoriasis, and neutrophilic inflammatory conditions such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[0141] The pharmaceutical composition or combination of the present invention may, for example, be in a unit dose form having one or more active ingredients of about 1-1000 mg for a subject weighing about 50-70 kg. Combination:

[0142] "Combination" means a fixed combination or combination administration in the form of a single dose unit, wherein the compound of the invention and the combination partner (e.g., another drug explained below, also referred to as a "therapeutic agent" or "co-agent") can be administered independently at the same time or separately at time intervals, especially where such time intervals allow the combination partner to exhibit a synergistic (e.g., co-effect) effect. Individual components may be packaged in a kit or separately. One or two components (e.g., powder or liquid) may be reconstituted or diluted to the desired dose prior to administration. As used herein, the terms "co-administration" or "combination administration" are intended to cover administration of a selected combination partner to a single subject (e.g., a patient) in need, and are intended to include treatment regimens in which the agents are not necessarily administered via the same route of administration or administered simultaneously. As used herein, the term "drug combination" means a product resulting from a mixture or combination of more than one therapeutic agent, and includes both fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" refers to the simultaneous administration of therapeutic agents (e.g., the compounds of the present invention and the combined pair) to a patient as a single entity or dose. The term "non-fixed combination" refers to the simultaneous, parallel, or sequential administration of therapeutic agents (e.g., the compounds of the present invention and the combined pair) to a patient as separate entities (without a specific time limit), wherein such administration provides a therapeutically effective level of the two compounds in the patient's body. The latter also applies to cocktail therapies, such as the administration of three or more therapeutic agents.

[0143] "Combination" refers to a fixed combination or combination of doses in the form of a single dose unit, wherein the compound of the present invention and the combination pair can be administered independently at the same time or separately at time intervals, such time intervals particularly allowing the combination pair to exhibit synergistic (e.g., co-existing) effects. Multiple single components can be packaged together in a kit or separately. One or two components (e.g., powder or liquid) can be reconstituted or diluted to the desired dose prior to administration.

[0144] As used herein, the term “drug combination” means a fixed combination in the form of a single dose unit; or a non-fixed combination or set for combined administration, wherein two or more therapeutic agents may be administered independently at the same time or separately at time intervals, especially where such time intervals allow the combination couple to exhibit a synergistic (e.g., co-existing) effect.

[0145] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat the therapeutic condition or disorder described in this disclosure. Such administration encompasses the co-administration of these therapeutic agents in a substantially simultaneous manner, such as administration in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration encompasses co-administration in multiple containers or in separate containers (e.g., tablets, capsules, powders, and liquids) for each active ingredient. Powders and / or liquids may be reconstituted or diluted to the desired dose prior to administration. Furthermore, such administration also encompasses the use of each type of therapeutic agent at substantially the same time or in a different time sequence. In any case, the treatment regimen will provide the beneficial effect of the combination of drugs in treating the condition or disorder described herein.

[0146] The compounds of the present invention may be administered simultaneously with, before, or after one or more other therapeutic agents. The compounds of the present invention may be administered separately via the same or different routes of administration as other pharmaceutical agents, or together in the same pharmaceutical composition. The therapeutic agents are, for example, chemical compounds, peptides, antibodies, antibody fragments, or nucleic acids, which, when administered to a patient in combination with the compounds of the present invention, have therapeutic activity or enhance therapeutic activity.

[0147] In one embodiment, the present invention provides a product comprising the compound of the present invention and at least one other therapeutic agent as a combination formulation for simultaneous, separate, or sequential use in a therapy. In one embodiment, the therapy is for treating a disease or condition mediated by [LTA4H]. The product provided as a combination formulation comprises compositions that collectively comprise the compound of the present invention and one or more other therapeutic agents in the same pharmaceutical composition, or comprises the compound of the present invention and one or more other therapeutic agents in a separate form (e.g., in a kit).

[0148] In one embodiment, the present invention provides a pharmaceutical composition comprising the compound of the present invention and one or more therapeutic agents. Where desired, the pharmaceutical composition may comprise a pharmaceutically acceptable carrier as described above.

[0149] In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, wherein at least one pharmaceutical composition contains a compound of the present invention. In one embodiment, the kit includes means for individually retaining the compositions, such as containers, separate bottles, or separate foil bags. Examples of such kits are blister packs, typically used for packaging tablets, capsules, etc.

[0150] The kits of the present invention can be used to administer different dosage forms (e.g., oral and parenteral), to administer individual components at different dose intervals, or to titrate individual components relative to each other. To aid compliance, the kits of the present invention typically include dosing instructions.

[0151] In the combination therapy of the present invention, the compounds of the present invention and other therapeutic agents may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compounds of the present invention and other therapeutic agents may be combined to form a combination therapy: (i) before the combination product is given to a physician (e.g., in the case of a kit containing the compounds of the present invention and other therapeutic agents); (ii) shortly before administration, by the physician himself (or under the guidance of a physician); (iii) in the patient himself, for example during the sequential administration of the compounds of the present invention and other therapeutic agents.

[0152] Therefore, the present invention provides the use of the compounds of the present invention for treating diseases or conditions mediated by LTA4H, wherein the preparation of the medicament is for administration together with another therapeutic agent. The present invention also provides the use of another therapeutic agent for treating diseases or conditions mediated by LTA4H, wherein the medicament is administered together with the compounds of the present invention.

[0153] The present invention also provides the compound of the present invention for use in a method of treating a disease or condition mediated by LTA4H, wherein the compound of the present invention is prepared for administration together with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by LTA4H, wherein the other therapeutic agent is prepared for administration together with the compound of the present invention. The present invention also provides the compound of the present invention for use in a method of treating a disease or condition mediated by LTA4H, wherein the compound of the present invention is administered together with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by LTA4H, wherein the other therapeutic agent is administered together with the compound of the present invention.

[0154] The present invention also provides the use of the compounds of the present invention for treating diseases or conditions mediated by LTA4H, wherein the patient has previously (e.g., within 24 hours) been treated with another therapeutic agent. The present invention also provides the use of another therapeutic agent for treating diseases or conditions mediated by LTA4H, wherein the patient has previously (e.g., within 24 hours) been treated with the compounds of the present invention.

[0155] In one embodiment, the other therapeutic agents are selected from: COX inhibitors, cysteine-leukotriene receptor antagonists (including montelukast, pranlukast, and zafirlukast), leukotriene C4 synthase (LTC4S) inhibitors, NLRP3 inhibitors, statins, sulfasalazine, mesalamine, calcineurin inhibitors such as cyclosporin A, or FK. 506; mTOR inhibitors, such as rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, biolimus-7, or basiloxane-9; ascomycins with immunosuppressive properties, such as ABT-281 or ASM981; corticosteroids; cyclophosphamide; imidazothiopurine; methotrexate; leflunomide; mizoribine; mycophenolic acid or salt; mycophenolic esters; IL-1β inhibitors.

[0156] Specific individual combinations that can provide specific therapeutic benefits include NLRP3 inhibitors or LTC4S inhibitors.

[0157] In one embodiment, the present invention relates to a combination of a compound according to any one of formulas (I) to (V) or a pharmaceutically acceptable salt thereof with an NLRP3 inhibitor.

[0158] Examples of NLRP3 inhibitors used in the combination are those described in the following PCT patent applications: WO / 2020 / 234715, WO / 2020 / 021447, WO / 2017 / 184624, WO / 2017 / 184623, WO / 2017 / 184604, WO / 2019 / 023147, WO / 2019 / 023145, WO / 2020 / 010140, WO / 2019 / 0 79119、WO / 2020 / 010143、WO / 2020 / 102096、WO / 2020 / 010118、WO / 2020 / 086732、WO / 2020 / 086728、WO / 2 020 / 102576, WO / 2020 / 102574, WO / 2020 / 102100, WO / 2020 / 102098, WO / 2020 / 154321 and WO / 2020 / 154499.

[0159] More specifically, the NLRP3 inhibitor used in the combination is selected from the group consisting of: , , , , , , , , , ,

[0160] or a pharmaceutically acceptable salt thereof, preferably selected from the group consisting of: , , , , , , or a pharmaceutically acceptable salt thereof.

[0161] More particularly, the NLRP3 inhibitor used in the combination is: or a pharmaceutically acceptable salt thereof.

[0162] In another embodiment, the NLRP3 inhibitor used in the combination is selected from compounds specifically disclosed in WO 2020 / 234715. In one aspect of this embodiment, the NLRP3 inhibitor is selected from 3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)tardi-3-yl)-5-(trifluoromethyl)phenol, (S)-3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)tardi-3-yl)-5-(trifluoromethyl)phenol, and (R)-3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)tardi-3-yl)-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof, preferably (R)-3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)tardi-3-yl)-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof. In another aspect of this embodiment, the NLRP3 inhibitor disclosed in WO 2020 / 234715 is selected from 2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)tardi-3-yl)-5-(trifluoromethyl)phenol, (S)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)tardi-3-yl)-5-(trifluoromethyl)phenol, and (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)tardi-3-yl)-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof, preferably (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)tardi-3-yl)-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof. In yet another aspect of this embodiment, WO The NLRP3 inhibitor disclosed in 2020 / 234715 is selected from 2-(6-(((1S,3R)-3-hydroxycyclohexyl)amino)-3-methyl-5-(trifluoromethyl)phenol, 2-(6-(((1S,3R)-3-hydroxycyclohexyl)amino)-3-methyl-5-(trifluoromethyl)phenol, 2-(6-(((1R ... 2-(6-(((1S,3S)-3-hydroxycyclohexyl)amino) ...

[0163] In one embodiment, the present invention relates to a compound according to any one of formulas (I) to (V) or a pharmaceutically acceptable salt thereof or a combination of a pharmaceutically acceptable salt thereof with the above-described NLRP3 inhibitor for the treatment of HS or NASH.

[0164] In one embodiment, the present invention relates to a combination of any one of the compounds having formula (I) to (V) or a pharmaceutically acceptable salt thereof with an LTC4S inhibitor.

[0165] An example of an LTC4S inhibitor used in the combination is one of Examples 1 to 120 described in PCT patent application WO 2022 / 034529, which is hereby incorporated by reference.

[0166] More specifically, the LTC4S inhibitor used in the combination is selected from the group consisting of: 1-(3,4-difluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecane-2-one; 9-(2-amino-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one; (R)-9-(2-amino-6-((1,1,1-trifluoroprop-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1, 9-diazaspiro[5.5]undecane-2-one; (S)-9-(2-amino-6-((1,1,1-trifluoroprop-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecane-2-one; 9-(2-amino-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one and 9-(2-amino-6-(1,1-difluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one; or pharmaceutically acceptable salts thereof.

[0167] In one embodiment, the present invention relates to a combination of any one of the compounds of formula (I) to (V) or a pharmaceutically acceptable salt thereof with an LTC4S inhibitor for the treatment of asthma or atopic dermatitis.

[0168] In one embodiment of the present invention, a product is provided in the form of a combination formulation comprising (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol or a pharmaceutically acceptable salt thereof and an NLRP3 inhibitor as defined above for use in a therapy, simultaneously, separately or sequentially.

[0169] In another embodiment of the invention, a product is provided in the form of a combination formulation comprising (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol or a pharmaceutically acceptable salt thereof and an LTC4S inhibitor as defined above for use in a therapy, simultaneously, separately or sequentially.

[0170] In one embodiment of the present invention, a pharmaceutical composition is provided comprising (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol or a pharmaceutically acceptable salt thereof, an NLRP3 inhibitor as defined above, and a pharmaceutically acceptable carrier.

[0171] In another embodiment of the present invention, a pharmaceutical composition is provided comprising (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol or a pharmaceutically acceptable salt thereof, an LTC4S inhibitor as defined above, and a pharmaceutically acceptable carrier. Biological assays and data

[0172] Compounds having formula (I) or pharmaceutically acceptable salts thereof exhibit valuable pharmacological properties, such as sensitivity to LTA4H (as indicated in tests provided in the following sections), and thus indicate use in LTA4H-related therapies. a) Human LTA4H enzyme assay:

[0173] Leukotriene A4 hydrolase (LTA4H) catalyzes the hydrolysis of epoxide leukotriene A4 (LTA4) intercalation into the pro-inflammatory mediator LTB4. LTA4H can also catalyze the hydrolysis of dipeptide and tripeptide substrates, as well as the chromogenic 7-amino-4-methylcoumarin (AMC) derivative of amino acids. Arginine AMC derivatives (Arg-AMC) can be used as alternative substrates for LTA4H, allowing for the measurement of enzyme activity and compound IC50 values ​​by monitoring the fluorescence intensity after AMC release.

[0174] For compound assays, the compound was delivered in matrix tubes as a stock solution of 10 mM in 90% DMSO (10% water). Thus, a 1:5 dilution series was prepared from a starting concentration of 10 mM up to 0.64 µM. For enzymatic assays, 0.5 µL of the compound solution was transferred to each well, and 24.5 μL of assay buffer (50 mM Tris buffer (pH 7.5), 150 mM NaCl, 10 mM CaCl2) was added to the well, followed by 25 μL of enzyme solution (36 nM human LTA4H in assay buffer). The enzyme-compound mixture was incubated at room temperature for 15 min, followed by the addition of 50 µL of substrate solution. A final substrate concentration of 600 μM was selected at a final enzyme concentration of 9 nM, which is approximately the KM value of Arg-AMC. Immediately after adding the substrate, the plate was placed in a fluorescence reader, and fluorescence was measured every 10 minutes for 60 minutes using filters set to λ excitation = 380 nm and λ emission = 460 nm. Standard curves were obtained using AMC at different concentrations (0.00128–100 μM) in the assay buffer. The raw data were converted to rates (mol / min) using AMC calibration curves calculated from AMC standards. The data were analyzed using nonlinear regression analysis in GraphPad Prism (GraphPad software Inc.) to determine the IC50 values ​​of the LTA4H inhibitor.

[0175] Due to the assay setup, the maximum detectable potency of a compound is approximately 2-3 nM. Therefore, compounds with a potency that theoretically produces an IC50 value below 2 nM are given as 2 nM (= lower limit of detection). The potency of the tested compounds is shown in Table 1 (providing the average of at least 3 measurements). b) Human whole blood assay:

[0176] The compound was tested in human whole blood assay (hWB) to assess its ability to inhibit LTB4 biosynthesis in human cellular systems. For this purpose, fresh blood was collected from volunteers via venipuncture in heparinized vacuum blood collection tubes. Blood was diluted 1:3 with RPMI (Roswell Park Memorial Institute) medium, and 200 μL aliquots were transferred to 96-well round-bottom cell culture plates. For compound testing, the compound was delivered in matrix tubes as a stock solution of 10 mM in 90% DMSO. Thus, a four-fold serial dilution was prepared from a starting concentration of 250 µM up to 2.45 µM. 4 μL of the compound dilution or medium was added to 200 μL of blood and incubated in a humidified incubator at 37°C for 4 hours. Blood was then stimulated with 10 µg / ml calcium ionophore A23187 (Sigma) or an equal volume of DMSO (control) and incubated for 15 min at 37°C in a humidified incubator. Incubation was terminated by centrifugation at 300 g for 10 min at 22°C. The plasma supernatant was collected and transferred to 96-well plates for arachidonic acid determination using ELISA (Assay Designs) according to the manufacturer's protocol after dilution with assay buffer 1:20. The IC50 values ​​of the LTA4H inhibitors were determined using nonlinear regression analysis data in GraphPad Prism (GraphPad software Inc.). The potency of the tested compounds is shown in Table 1. [Table 1] ArgAMC IC 50 (nM) hWB IC 50 (nM) nM nM Example 01 0.6 91 Example 02 2.1 72 Example 03 1.5 100 Example 04 11.8 327 Example 05 28.3 1850 Example 06 9.4 510 Example 07 1.8 117 Example 08 1.4 54 Example 09 2.5 74 Example 10 6.3 141 Example 11 1.0 44 Example 12 3.6 115 Example 13 2.5 51 Example 14 2.3 39 Example 15 2.9 79 Example 16 2.4 229 Example 17 16.7 297 Example 18 6.1 343 Example 19 4.9 65 Example 20 3.2 75 Example 21 3.1 123 Example 22 2.7 89 Example 23 37.6 753 Example 24 2.0 379 Example 25 160.2 nt Example 26 2.6 89 Example 27 3.3 214 Example 28 6.2 504 Example 29 1.5 162 Example 30 1.3 69 Example 31 4.5 179 Example 32 2.9 45 Example 33 2.4 290 Example 34 4.0 800 Example 35 15.8 nt Example 36 2.9 60 Example 37 2.6 47 Example 38 7.4 515 Example 39 2.2 63 Example 40 2.6 62 Preparation of compounds

[0177] The compounds of the present invention can be prepared as described in the following examples. Abbreviations: Boc: tributyloxycarbonyl CAN: cerium ammonium nitrate DCM: dichloromethane DIAD: (E)-diazepine-1,2-dicarboxylic acid dibutyl ester DMAP: 4-(dimethylamino)-pyridine DMF: dimethylformamide DMSO: dimethyl sulfoxide Hal: halogen HPLC: high performance liquid chromatography MTBE: methyl tributyl ether NMR: nuclear magnetic resonance PdCl2(dtbpf): 1,1'-bis(dibutylphosphino)ferrocene palladium dichloride rt: room temperature SFC: supercritical fluid chromatography TBDMSCl: tributyldimethylsilyl chloride THF: tetrahydrofuran TMEDA: tetramethylethylenediamine TMS: trimethylsilyl UPLC: ultra-high performance liquid chromatography Analysis details NMR spectroscopy

[0178] NMR spectra were obtained using a Bruker Ultrashield™ 400 (400 MHz) spectrometer. All 1H NMR spectra are reported in δ units (ppm) and recorded with reference to solvent peaks, for example, CDCl3, DMSO-d6, or CD3OD. Analytical liquid chromatography.

[0179] A Waters Acquity UPLC / MS system (Waters, Milford, MA) was used, equipped with a binary solvent manager, sample manager, column manager, photodiode array detector (PDA), and a Waters ZQ2000 MS detector. UV absorption was monitored in the range of λ = 210–450 nM. The MS detector operated in a continuous positive / negative ESI alternating mode, performing a full scan of 120–1200 Da over 0.3 seconds. Mass spectra were obtained and stored in centroid mode. Molecular weight determination based on MS confirmed the formation of pseudomolecular ions [M+H]+ based on the positive mode.

[0180] Method A: Column: Acquity UPLC HSS T3, 1.8 μm, 2.1 × 50 mm, at 60°C, eluent A: H2O + 0.05% HCOOH + 3.75 mM ammonium acetate, B: ACN + 0.04% HCOOH, gradient: 5% → 98% B over 1.4 min, 98% B for 0.4 min, 98% → 5% B over 0.1 min, 5% B for 0.1 min; flow rate: 1.0 mL / min.

[0181] Method B: Column: Acquity UPLC HSS T3, 1.8 μm, 2.1 × 50 mm, at 60°C, eluent A: H2O + 0.05% HCOOH + 3.75 mM ammonium acetate, B: ACN + 0.04% HCOOH, gradient: 5% → 98% B over 9.4 min, 98% B for 0.4 min, 98% → 5% B over 0.1 min, 5% B for 0.1 min; flow rate: 1.0 mL / min.

[0182] Method C: Column: Acquity CORTECS C18+, 2.7 μm, 2.1 × 50 mm, at 80°C; eluent A: H2O + 0.05% HCOOH + 4.76% iPrOH + 3.75 mM ammonium acetate, B: iPrOH + 0.05% HCOOH; gradient: initial 1% B, 1%→50% B within 1.4 min, 50%→98% B within 0.3 min; 98% B within 0.1 min; flow rate: 1.0 mL / min. Preparative method:

[0183] Rapid chromatography: Teledyne ISCO, CombiFlash Rf. Column: Pre-packed RediSep Rf cartridge. Typically, the sample is adsorbed onto the ISOLUTE™.

[0184] SFC: Waters preparative SFC-100-MS; Detection: Waters 2998 photodiode array detector and Waters MS single quadrupole detector; Modifier: methanol; ABPR: 120 bar; Column temperature: 40°C; Flow rate: 100 g / min.

[0185] Prep HPLC: Waters automated purification-MS system; Detection: Waters 2998 photodiode array detector and Waters MS single quadrupole detector; Column temperature: RT; Eluent A: water; Eluent B: acetonitrile, both containing 0.1% TFA or 0.1% NH4OH.

[0186] All reagents, starting materials, and intermediates used in these examples are commercially available or readily prepared by methods known to those skilled in the art. Synthesis of intermediates: Intermediate A

[0187] Step a) Methyl N-(tributoxycarbonyl)-O-(tributyldimethylsilyl)-D-serine (A.2). Under ice-cooled conditions and argon atmosphere, a solution of TBDMSCl (4.70 g, 29.6 mmol) in CH2Cl2 (25 mL) was added over 20 min to a solution of A.1 (5.0 g, 22.8 mmol) and imidazole (2.33 g, 34.2 mmol) in CH2Cl2 (75 mL). The resulting colorless suspension was stirred for another 40 min under ice-cooled conditions. The still-cold reaction mixture was diluted with water and extracted with MTBE. The combined organic phases were washed with brine and dried over Na2SO4. Evaporation yielded compound A.2 (8.44 g, quantified) as a pale yellow oil, which was used in the next step without further purification. TLC: Rf = 0.73 (cyclohexane / ethyl acetate 7:3, KMnO4 staining); 1H NMR (CDCl3): δ = 5.31 (1H, br d), 4.33 (1H, ddd), 4.02 (1H, dd), 3.80 (1H, dd), 3.72 (3H, s), 1.44 (9H, s), 0.84 (9H, s), 0.01 (3H, s), 0.00 (3H, s).

[0188] Step b) (S)-(1-((tributyldimethylsilyl)oxy)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester (A.3). Under ice-cooled conditions and argon atmosphere, LiBH4 (0.94 g, 42.9 mmol) was added to a solution of A.2 (7.16 g, 21.5 mmol) in THF (70 mL). Weak boiling was observed during the addition. The mixture was stirred continuously overnight at 25°C. The reaction mixture was then poured onto a semi-saturated NH4Cl solution (250 mL) and extracted with MTBE. The combined organic layers were washed with brine and dried over Na2SO4. Evaporation to dryness gave compound A.3 (6.30 g, 96%) as a colorless oil, which was used in the next step without further purification. TLC: Rf = 0.17 (cyclohexane / ethyl acetate 8:2, KMnO4 staining); 1H NMR (CDCl3): δ = 5.06 (1H, br s), 3.70-3.89 (3H, m), 3.49-3.65 (2H, m), 1.38 (9H, s), 0.82 (9H, s), 0.02 (3H, s), 0.00 (3H, s).

[0189] Step c) (R)-4-(((tributyldimethylsilyl)oxy)methyl)-1,2,3-thiazolidin-3-carboxylic acid tributyl ester 2,2-dioxide (A). Under argon atmosphere, imidazole (8.42 g, 124 mmol) was suspended in CH2Cl2 (100 mL) and cooled to 0°C. A solution of SOCl2 (2.70 mL, 37.1 mmol) in CH2Cl2 (25 mL) was added over 10 min while maintaining the internal temperature below 5°C. The resulting thick, colorless suspension was stirred at 25°C for 1 hour. Then, the internal temperature was lowered to -10°C, and a solution of A.3 (6.30 g, 20.6 mmol) was added dropwise over 10 min. The ice bath was removed, and stirring continued for 1.5 h. Saturated water (150 mL) was then added, and the mixture was extracted with CH2Cl2. The combined organic extracts were washed with 10% aqueous citric acid and brine, and dried over Na₂SO₄. The solvent was removed, and a pale yellow oil (6.82 g, 94%, non-mirror image isomerate mixture) was dissolved in acetonitrile (150 mL). RuCl₃·H₂O (93 mg, 0.4 mmol, 2 mol%) was then added under ice-cooling, followed by dropwise addition of a solution of NaIO₄ (6.62 g, 30.1 mmol) in water (75 mL), while maintaining the internal temperature below 5°C. After stirring at 0°C for 45 min, ethyl acetate (150 mL) and Hyflow (25 g) were added to the yellow-brown suspension. All solids were filtered off, and the aqueous layer of the filtrate was extracted with ethyl acetate / MTBE 3:1 (100 mL). The combined organic layers were washed with brine and 5% aqueous sodium thiosulfate, and then washed again with brine. Drying with Na₂SO₄ and evaporating the solvent yielded a pale yellow oily substance contaminated with solids. The solids could be removed by grinding with cyclohexane. Silicone rapid chromatography (gradient: cyclohexane / ethyl acetate) yielded compound A as a colorless oil, which solidified upon standing (3.88 g, 51%). TLC: Rf = 0.41 (cyclohexane / ethyl acetate 85:15, KMnO₄ staining); [α]D₂₃: -25° (c = 1, CH₂Cl₂); ¹H NMR (CDCl₃): δ = 4.47–4.57 (2H, m), 4.18 (1H, m), 3.78 (1H, dd), 3.69 (1H, t), 1.47 (9H, s), 0.81 (9H, s), 0.01 (3H, s), 0.00 (3H, s). Intermediate B

[0190] Intermediate B was prepared by a similar procedure to that used for the synthesis of intermediate A, replacing A.1 with its mirror isomer B.1. [α]D23: +20.2° (c = 1, CH2Cl2); 1H NMR (CDCl3): δ = 4.48-4.58 (2H, m), 4.18 (1H, m), 3.78 (1H, dd), 3.69 (1H, t), 1.47 (9H, s), 0.81 (9H, s), 0.00 (6H, s). Synthesis of Examples: Example 1 (S)-2-amino-3-(3-(3-((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-diazol-5-yl)prop-1-ol

[0191] Step a) 3-(2-(2-iodophenoxy)acetyl)benzonitrile (1.1). According to WO 2013 / 134226: Add 2-iodophenol (10.51 g, 46.8 mmol), acetonitrile (16.5 ml), and potassium carbonate (7.12 g, 51.5 mmol) to a 250 mL single-necked flask equipped with a magnetic stir bar. Stir the pale pink suspension at rt for 1.5 hr. Add 3-(2-bromoacetyl)benzonitrile (12.15 g, 51.5 mmol) dissolved in acetonitrile (33 ml) dropwise over 10 min. Stir the reaction mixture at rt overnight. Add potassium carbonate (380 mg) and 3-(2-bromoacetyl)benzonitrile (600 mg). After 2 hr, cool the reaction mixture to 15°C and quench with 2 M hydrochloric acid (30 ml). Water (100 ml) was added, and the reaction mixture was extracted with ethyl acetate (200 ml). The organic layer was washed with water (2 × 100 ml) and brine (100 ml), dried over sodium sulfate, filtered, and concentrated under vacuum to give a beige raisin-like (1.1) (19.24 g, quantified). UPLC retention time was 1.15 min (Method A). 1H NMR (DMSO-d6): δ = 5.71 (s, 2 H), 6.77 (t, J = 7.52 Hz, 1 H), 7.00 (d, J = 8.19 Hz, 1 H), 7.31 (t, J = 7.64 Hz, 1 H), 7.76 - 7.86 (m, 2 H), 8.17 (d, J = 7.70 Hz, 1 H), 8.27 (d, J = 7.95 Hz, 1 H), 8.52 (s, 1 H). MS / ESI+ 364.3 [M + H]+.381.1 [M + NH4+]+.

[0192] Step b) (S)-3-(1-hydroxy-2-(2-iodophenoxy)ethyl)benzonitrile (1.2). According to WO 2013 / 134226 p 79 A-8: Add 3-(2-(2-iodophenoxy)acetyl)benzonitrile (1.1) (19.2 g, 46.5 mmol) to a 500 mL three-necked flask equipped with a magnetic stir bar and a thermometer, followed by the addition of acetonitrile (86 mL). Bubble argon gas through the slightly turbid mixture for 5 min. N-((1R,2R)-2-amino-1,2-diphenylethyl)-4-methylbenzenesulfonamide (0.239 g, 0.651 mmol), Cp*RhCl2 dimer (CAS: 12354-85-7) (0.173 g, 0.279 mmol), and triethylamine (15.48 ml, 112 mmol) were added under rt and stirred for 1.5 hr. The reaction mixture was cooled to 0°C and formic acid (6.25 ml, 163 mmol) was added dropwise over 10 min at below 15°C. After 30 min at 10°C, the reaction mixture was cooled to 0°C and quenched with water (200 ml) under vigorous stirring. The mixture was extracted twice with ethyl acetate, and the organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated under vacuum to give (1.2) (19.76 g crude substance). Silicone chromatography (gradient: heptane / ethyl acetate) yielded colorless raisin-like (1.2) (13.86 g, 77%). UPLC retention time was 1.08 min (Method A). 1H NMR (DMSO-d6): δ = 4.09 (dd, J = 9.78, 5.50 Hz, 1 H), 4.18 (dd, J = 9.66, 5.75 Hz, 1 H), 5.03 (t, J = 5.20 Hz, 1 H), 5.89 (s, 1 H) 6.73 (t, J = 7.46 Hz, 1 H), 7.00 (d, J = 8.31 Hz, 1 H), 7.32 (t, J = 7.76 Hz, 1 H), 7.52 - 7.62 (m, 1 H), 7.70 - 7.78 (m, 2 H), 7.87 (d, J = 7.70 Hz, 1 H), 7.96 (s, 1 H). MS / ESI+ 383.1 [M + NH4+]+.

[0193] Step c) (S)-3-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)benzonitrile (1.3). Add (S)-3-(1-hydroxy-2-(2-iodophenoxy)ethyl)benzonitrile (1.2) (8.76 g, 21.59 mmol) to a 500 mL two-necked flask equipped with a magnetic stir bar and a reflux condenser, followed by the addition of DMF (72 mL). Add cesium carbonate (14.07 g, 43.2 mmol), Cu(I) iodide (0.411 g, 2.159 mmol), and N,N-dimethylglycine salt, and stir the mixture at 135°C under argon for 4 hr. Dilute the cold reaction mixture with water and extract with ethyl acetate. Wash the organic phase twice with a saturated aqueous ammonium chloride solution. The aqueous phase was back-extracted twice with ethyl acetate, and the organic layer was washed with water and brine. The mixture was dried over sodium sulfate, filtered, and concentrated under vacuum to give (1.3) (6.28 g crude material). Silica gel chromatography (gradient: heptane / ethyl acetate) yielded (1.3) (3.55 g, 66%) in a milky white, raisin-like form. UPLC retention time was 1.13 min (Method A). 1H NMR (DMSO-d6): δ = 4.15 (dd, J = 11.49, 8.07 Hz, 1 H), 4.49 (dd, J = 11.49, 2.20 Hz, 1 H), 5.31 - 5.40 (m, 1 H), 6.85 - 6.97 (m, 3 H), 6.97 - 7.05 (m, 1 H), 7.62 - 7.71 (m, 1 H), 7.88 (d, J = 7.70 Hz, 1 H), 7.85 (d, J = 8.07 Hz, 1 H), 7.97 (s, 1 H). MS / ESI+ 255.2 [M + NH4+]+, MS / ESI- 236.3 [M - H]-.

[0194] Step d) (S,E)-3-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)-N'-hydroxybenzomidine (1.4). Add (S)-3-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)benzonitrile (1.3) (1.2 g, 5.06 mmol) and ethanol (17 ml) to a 100 mL two-necked flask equipped with a magnetic stir bar and a reflux condenser. Add dropwise 50% aqueous hydroxylamine (1.19 ml, 20.23 mmol) and reflux the reaction mixture for 1 hr to obtain a clear solution. Concentrate the mixture under vacuum to obtain crude (1.4) (1.39 g, 99%), which is used in the next step without further purification. Grind the small probe (60 mg) in dichloromethane / pentane to obtain 38 mg of white powder. UPLC residence time 0.79 min (Method A). ¹H NMR (DMSO-d⁶): δ = 4.11 (dd, J = 11.43, 8.38 Hz, ¹H), 4.45 (dd, J = 11.49, 2.45 Hz, ¹H), 5.27 (dd, J = 8.31, 2.20 Hz, ¹H), 5.84 (s, 2H), 6.85 - 7.02 (m, 3H), 7.40 - 7.52 (m, 2H), 7.69 (d, J = 7.70 Hz, ¹H), 7.80 (s, 1H), 9.66 (s, 1H). MS / ESI 271.2 [M⁺H]⁺.

[0195] Step e) (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-((S)-2,3-dihydrobenzo[b][1,4]-dioxin-2-yl)phenyl)-1,2,4-diazol-5-yl)benzyl propionate (1.5). Add (S,E)-3-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)-N'-hydroxybenzomidine (1.4) (505 mg, 1.87 mmol) and 2-Me-THF (18.7 ml) to a 100 mL two-necked flask equipped with a magnetic stir bar and reflux condenser, followed by Boc-Asp(OSu)-OBzl [CAS 140171-25-1] (1179 mg, 2.81 mmol, from Bachem). The reaction mixture was stirred at 87°C for 4 days. The solvent was evaporated on a rotary evaporator (rotavap) to give 2.05 g of crude product. Silica gel chromatography (gradient: cyclohexane / ethyl acetate) yielded (1.5) (1122 mg, 100%). UPLC retention time was 1.38 min (Method A). 1H NMR (DMSO-d6): δ = ppm 1.27 - 1.37 (m, 9 H), 3.43 (dd,J= 15.71, 8.74 Hz, 1 H), 3.55 (dd,J= 15.65, 5.99 Hz, 1 H), 4.12 (dd,J= 11.49, 8.31 Hz, 1H), 4.50 (dd,J= 11.55, 2.38 Hz, 1 H), 4.67 (d,J= 6.11 Hz, 1 H), 5.16 (s, 2 H), 5.40 (dd,J= 8.19, 2.08 Hz, 1 H), 6.87 - 6.97 (m, 3 H), 6.99 - 7.04 (m, 1 H), 7.27 -7.38 (m, 5 H), 7.57 - 7.67 (m, 2 H), 7.69 - 7.74 (m, 1 H), 8.00 (d,J= 7.70 Hz, 1 H), 8.11 (s, 1 H). MS / ESI+ 558.3 ​​[M + H]+.

[0196] Step f) ((S)-1-(3-(3-((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester (1.6). Add (S)-2-((tributoxycarbonyl)amino)-3-(3-(3-((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-diazol-5-yl)propionate benzyl ester (1.5) (723 mg, 1.206 mmol) and THF (16 ml) to a 100 mL single-necked flask equipped with a magnetic stir bar. Lithium borohydride (105 mg, 4.82 mmol) was added at 0°C, and the cooling bath was removed after 10 min. The reaction mixture was quenched after 30 min by adding 3 spoonfuls of Isolute HM-N (Biotage 9800-1000). The solvent was evaporated on a rotary evaporator, and the remaining product adsorbed on the Isolute was purified using a Redisep RP-C18 (86 g) column with a water / acetonitrile gradient to give tributyl ((S)-1-(3-(3-((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate (1.6) (303 mg, 54.3%). UPLC retention time was 1.17 min (Method A). 1H NMR (DMSO-d6): δ = ppm 1.29 (s, 9 H), 2.99 (dd,J= 14.79, 9.17 Hz, 1 H), 3.27 (dd,J= 14.79, 4.52 Hz, 1 H), 3.33 - 3.53 (m, 2 H), 3.92 (br. s., 1 H), 4.11 (dd,J= 11.49, 8.31 Hz, 1 H), 4.50 (dd,J= 11.49, 2.45 Hz, 1 H), 4.92 (t,J= 5.62 Hz, 1 H), 5.40 (dd,J= 8.19, 2.08 Hz, 1 H), 6.81 - 7.06 (m, 5 H), 7.63 (t,J= 7.64 Hz, 1 H), 7.71 (d,J= 7.83 Hz, 1 H), 8.01 (d,J= 7.70 Hz, 1 H), 8.12 (s, 1 H). MS / ESI+ 454.3 [M + H]+.

[0197] Step g) (S)-2-amino-3-(3-(3-((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-diazol-5-yl)prop-1-ol (Example 1): Tributyl ((S)-1-(3-(3-((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-diazol-5-yl)-3-hydroxyprop-2-yl)aminocarbamate (1.6) (275 mg, 0.606 mmol) and dichloromethane (6 ml) were added to a 100 mL single-necked flask equipped with a magnetic stir bar. TFA (0.934 ml, 12.13 mmol) was added, and the mixture was stirred at rt for 2 hr. The reaction mixture was concentrated under vacuum, and the remaining oil was dissolved in ethyl acetate and washed three times with saturated aqueous sodium bicarbonate solution, very little water, and brine. The crude product (245 mg) was purified using a Redisep RP-C18 (43 g) column with a water / acetonitrile gradient to give 70 mg. The viscous solid was lyophilized and finally ground with isopropyl ether to give isopropyl ether, which yielded (S)-2-amino-3-(3-(3-((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-diazol-5-yl)prop-1-ol (Example 1) (56 mg, 26%) as a white powder. UPLC retention time was 0.77 min (Method A). 1H NMR (DMSO-d6): δ = ppm 2.09 (br. s., 3 H), 3.06 - 3.28 (m, 2 H), 3.57 - 3.68 (m, 2 H), 3.75 - 3.82 (m, 1 H), 4.07 (dd,J= 11.43, 8.86 Hz, 1 H), 4.42 (dd,J= 11.43, 2.38 Hz, 1 H), 5.22 (dd,J= 8.86, 2.14 Hz, 1 H), 6.89 - 7.06 (m, 4 H), 7.52 - 7.65 (m, 2 H), 8.10 (d,J= 7.46 Hz, 1 H), 8.16 (s, 1 H). MS / ESI+ 354.2 [M + H]+. Example 2 (S)-2-amino-3-(3-(3-(((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol

[0198] Step a) 3-((5-chloropyridin-2-yl)oxy)benzonitrile (2.3). Add 3-cyanophenol (Sigma-Aldrich) (2.2) (1.036 g, 8.70 mmol), 5-chloro-2-fluoropyridine (Apollo Scientific Ltd.) (2.1) (1.04 g, 7.91 mmol), K₂CO₃ (3.28 g, 23.72 mmol), and DMF (40.0 ml) to a 100 mL single-necked round-bottom flask equipped with a magnetic stir bar and reflux condenser. Stir the suspension at 100°C for 113 hours. Cool the reaction mixture to rt and add water / EtOAc. Extract the aqueous phase twice with EtOAc. Wash the organic layers with brine, combine, and dry with Na₂SO₄. Concentrate under vacuum to give a brown oil. Purification by column chromatography (ISCO CombiFlash Rf, absorbed on silicone, EtOAc in cyclohexane, 0-10%) yielded 3-((5-chloropyridin-2-yl)oxy)benzonitrile (2.3) (1.55 g, 85%) as a white solid. UPLC retention time: 1.07 min (Method A). ¹H NMR (400 MHz, CDCl₃) δ = ppm 8.11 (d, J = 2.5 Hz, 1H), 7.71 (dd, J = 8.7, 2.6 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.45 (s, 1H), 7.42 - 7.36 (m, 1H), 6.96 (d, J = 8.7 Hz, 1H). MS / ESI+ 231.2 [M + H]+.

[0199] Step b) (Z)-3-((5-chloropyridin-2-yl)oxy)-N'-hydroxybenzoamide (2.4). Add 3-((5-chloropyridin-2-yl)oxy)benzonitrile (2.3) (1.00 g, 4.34 mmol), hydroxylamine hydrochloride (1.506 g, 21.68 mmol), NaHCO3 (1.821 g, 21.68 mmol), and ethanol (20.0 ml) / water (10.0 ml) to a 50 mL single-necked pear-shaped flask equipped with a magnetic stir bar. Heat the white suspension to 85°C and stir for 65 minutes. Cool the reaction mixture to rt. Remove EtOH under vacuum. Add water and EtOAc to the remaining white suspension. Extract the aqueous phase twice with EtOAc. Wash the organic layers with brine, combine, and dry with Na2SO4. LC-MS and 1H NMR analysis revealed the high purity of the treated product (Z)-3-((5-chloropyridin-2-yl)oxy)-N'-hydroxybenzomidine (2.4) (1.1 g, 95%).

[0200] UPLC residence time 0.71 min (Method A). 1H NMR (400 MHz, DMSO-d6) δ = ppm 9.68 (s, 1H), 8.21 (d,J= 2.6 Hz, 1H), 7.97 (dd,J= 8.8, 2.7 Hz, 1H), 7.55 (d,J= 8.0 Hz, 1H), 7.44 - 7.39 (m, 2H), 7.15 (dd,J= 7.8, 2.0 Hz, 1H), 7.12 (d,J= 8.8 Hz, 1H), 5.82 (s, 2H). MS / ESI+ 264.3 [M + H]+.

[0201] Step c) (S)-2-((tributoxycarbonyl)amino)-3-(3-(3-(((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propionate (2.6). Add product (Z)-3-((5-chloropyridin-2-yl)oxy)-N'-hydroxybenzomidine (2.4) (450 mg, 1.707 mmol), Boc-Asp(OSu)-OBzl [CAS 140171-25-1] (2.5) (789 mg, 1.877 mmol), and THF (10.0 ml) to a 20 mL microwave-safe vial equipped with a magnetic stir bar. Heat the colorless solution to 120°C and stir for 19 hours. A yellow solution is obtained. Remove THF under vacuum. Benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-(((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propionate (2.6) (871 mg, 93%) was purified by column chromatography (ISCO CombiFlash Rf, absorbed on silicone, EtOAc in cyclohexane, 0-18%). UPLC retention time was 1.41 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.11 (d,J= 2.5 Hz, 1H), 7.85 (d,J= 7.8 Hz, 1H), 7.77 (s, 1H), 7.66 (dd,J= 8.7, 2.6 Hz, 1H), 7.49 (t,J= 8.0 Hz, 1H), 7.28 - 7.24 (m, 6H), 6.93 (d,J= 8.7 Hz, 1H), 5.54 (d,J= 7.3 Hz, 1H), 5.23 - 5.11 (m, 2H), 4.90 - 4.83 (m, 1H), 3.49 (qd,J= 16.1, 4.9 Hz, 2H), 1.42 (s, 9H). MS / ESI+ 551.4 [M + H]+.

[0202] Step d) Tributyl (S)-(1-(3-(3-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate (2.7). Add benzyl (S)-2-((tributoxycarbonyl)amino)-3-(3-(3-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propionate (2.6) (506 mg, 0.918 mmol) to a 25 mL two-necked round-bottom flask equipped with a magnetic stir bar, rubber septum, and gas inlet. Vacuum the flask and backfill with Ar five times. Add anhydrous THF (volume: 10.0 mL) and cool the colorless solution to 0°C. LiBH4 (100 mg, 4.59 mmol) was added in one go, and the reaction mixture was stirred for 70 minutes.

[0203] The reaction was quenched with MeOH (3 ml). Saturated NH4Cl solution and EtOAc were added. The aqueous phase was extracted twice with EtOAc, and the organic layer was washed with brine. The extracts were combined and dried over Na2SO4. The solution was purified by column chromatography (ISCO CombiFlash Rf, EtOAc in cyclohexane, 20%-50%) to give (S)-(1-(3-(3-(((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester (2.7) (317 mg, 77%). UPLC retention time was 1.13 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.08 (d,J= 2.6 Hz, 1H), 7.88 (d,J= 7.8 Hz, 1H), 7.81 - 7.77 (m, 1H), 7.63 (dd,J= 8.7, 2.7 Hz, 1H), 7.47 (t,J= 8.0 Hz, 1H), 7.28 - 7.21 (m, 1H), 6.90 (d,J= 8.7 Hz, 1H), 5.37 (d,J= 8.5 Hz, 1H), 4.14 (s, 1H), 3.78 - 3.64 (m, 2H), 3.35 (s, 1H), 3.22 (d,J= 5.8 Hz, 2H), 1.37 (s, 9H). MS / ESI+ 447.3 [M + H]+.

[0204] Step e) (S)-2-amino-3-(3-(3-(((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-aminodiazol-5-yl)prop-1-ol (Example 2). Add (S)-(1-(3-(3-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-aminodiazol-5-yl)-3-hydroxyprop-2-yl)aminocarbamate tributyl ester (2.7) (316 mg, 0.707 mmol), diethylcarbamate (4.0 ml), and aqueous HCl (4.0 ml, 8.00 mmol) to a 25 mL single-necked round-bottom flask equipped with a magnetic stir bar. Stir the resulting turbid solution at rt for 5 days. Remove the solvent under vacuum. Add approximately 0.2 M NaOH aqueous solution (10 ml), and a white solid precipitates. Add EtOAc. The aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over Na2SO4. Purification was performed by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, MeOH in CH2Cl2, 0–8.5%) to give pale white crystals of (S)-2-amino-3-(3-(3-(((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol (Example 2) (202 mg, 82%). UPLC retention time was 0.71 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.11 (d,J= 2.6 Hz, 1H), 7.92 (d,J= 7.8 Hz, 1H), 7.85 - 7.80 (m, 1H), 7.66 (dd,J= 8.7, 2.7 Hz, 1H), 7.50 (t,J= 8.0 Hz, 1H), 7.30 - 7.23 (m, 1H), 6.92 (d,J= 8.7 Hz, 1H), 3.67 (dd,J= 10.6, 4.4 Hz, 1H), 3.53 (dd,J= 10.6, 6.2 Hz, 1H), 3.49 - 3.41 (m, 1H), 3.11 (dd, J = 15.6, 4.7 Hz, 1H), 2.97 (dd, J = 15.6, 8.2 Hz, 1H), 2.07 (s br, 3H). MS / ESI+ 347.3 [M + H]+. Example 3 (S)-2-amino-3-(3-(3-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol

[0205] Step a) 3-((5-(difluoromethoxy)pyridin-2-yl)oxy)benzonitrile (3.2). Add 5-(difluoromethoxy)-2-fluoropyridine (3.1) (0.938 g, 5.75 mmol), 3-cyanophenol (Sigma-Aldrich) (2.2) (0.754 g, 6.33 mmol), potassium carbonate (2.385 g, 17.25 mmol), and DMF (30.0 ml) to a 100 mL single-necked pear-shaped flask equipped with a magnetic stir bar and reflux condenser. Then stir the suspension at 90°C for 7 days. Cool the reaction mixture to rt. Add water / EtOAc and extract the aqueous phase twice with EtOAc. Wash the organic layers with brine, combine, and dry with Na2SO4. Purification by column chromatography (ISCO CombiFlash Rf, absorbed on silicone, EtOAc in cyclohexane, 0-16%) yielded a colorless oily 3-((5-(difluoromethoxy)pyridin-2-yl)oxy)benzonitrile (3.2) (1.02 g, 67.6%). UPLC retention time was 1.04 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.03 (d, J = 2.7 Hz, 1H), 7.58 (dd, J = 8.8, 2.9 Hz, 1H), 7.52 - 7.48 (m, 2H), 7.47 - 7.44 (m, 1H), 7.43 - 7.37 (m, 1H), 7.01 (d, J = 8.9 Hz, 1H), 6.50 (t,J = 72.6 Hz, 1H). MS / ESI+ 263.2 [M + H]+.

[0206] Step b) (Z)-3-((5-(difluoromethoxy)pyridin-2-yl)oxy)-N'-hydroxybenzoamide (3.3). Add 3-((5-(difluoromethoxy)pyridin-2-yl)oxy)benzonitrile (3.2) (545 mg, 2.078 mmol), hydroxylamine hydrochloride (722 mg, 10.39 mmol), NaHCO3 (873 mg, 10.39 mmol), and ethanol (6.0 ml) / water (3.0 ml) to a 50 mL single-necked round-bottom flask equipped with a magnetic stir bar and a condenser (air). Stir the suspension at 85°C for 1 hour. Remove EtOH under vacuum. Add EtOAc and water. Extract the aqueous phase twice with EtOAc. Wash the organic layer with brine, combine, and dry with Na2SO4. Purification by column chromatography (ISCO CombiFlash Rf, absorbed on silicone, EtOAc in cyclohexane, 20%–45%) yielded (Z)-3-((5-(difluoromethoxy)pyridin-2-yl)oxy)-N'-hydroxybenzomidine (3.3) (564 mg, 92%). UPLC retention time was 0.69 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.22 (s br, 1H), 8.04 (d,J= 2.8 Hz, 1H), 7.52 (dd,J= 8.9, 2.9 Hz, 1H), 7.48 - 7.45 (m, 1H), 7.45 - 7.39 (m, 2H), 7.19 (ddd,J= 7.7, 2.3, 1.4 Hz, 1H), 6.94 (d,J= 8.9 Hz, 1H), 6.47 (t,J= 72.9 Hz, 1H), 4.87 (s, 2H). MS / ESI+ 296.5 [M+H]+.

[0207] Step c) (S)-2-((tributoxycarbonyl)amino)-3-(3-(3-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)benzyl propionate (3.4). Add (Z)-3-((5-(difluoromethoxy)pyridin-2-yl)oxy)-N'-hydroxybenzomidine (3.3) (546 mg, 1.849 mmol) and Boc-Asp(OSu)-OBzl [CAS 140171-25-1] (2.5) (855 mg, 2.034 mmol) in THF (10 ml) to a 20 mL microwave-safe vial equipped with a magnetic stir bar. Seal the vial and stir the colorless solution at 100°C for 66 hours. Remove the solvent under vacuum. Purification by column chromatography (ISCO CombiFlash Rf, absorbed on silicone, EtOAc in cyclohexane, 0-20%) yielded a colorless, viscous oily (S)-2-((tributoxycarbonyl)amino)-3-(3-(3-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propionate (3,4) (945 mg, 88%). UPLC retention time was 1.35 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.03 (d,J= 2.7 Hz, 1H), 7.85 (d,J= 7.8 Hz, 1H), 7.78 (d,J= 1.8 Hz, 1H), 7.53 (dd,J= 8.9, 2.9 Hz, 1H), 7.49 (t,J= 8.0 Hz, 1H), 7.31 - 7.22 (m, 6H), 6.98 (d,J= 8.9 Hz, 1H), 6.47 (t,J= 72.9 Hz, 1H), 5.54 (d,J= 7.5 Hz, 1H), 5.23 - 5.10 (m, 2H), 4.86 (d,J= 6.9 Hz, 1H), 3.49 (qd,J= 16.1, 4.9 Hz, 2H), 1.41 (s, 9H). MS / ESI+ 583.5 [M+H]+.

[0208] Step d) Tributyl (S)-(1-(3-(3-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate (3.5). Add (S)-2-((tributylbutoxycarbonyl)amino)-3-(3-(3-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propionate (3.4) (514 mg, 0.882 mmol) to a 25 mL two-necked round-bottom flask equipped with a magnetic stir bar, gas inlet, and rubber septum. Vacuum the flask and backfill with Ar four times. Add anhydrous THF (9.0 mL) and cool the colorless solution to 0°C. LiBH4 (96 mg, 4.41 mmol) was then added, and the reaction mixture was stirred for 1 hour. MeOH was added, and volatiles were removed under vacuum. Purification by column chromatography (ISCO CombiFlash Rf, absorption on silica gel, EtOAc in cyclohexane, 20%–50%) yielded (S)-(1-(3-(3-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester (3.5) (292 mg, 69.2%). UPLC retention time was 1.09 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.05 (d,J= 2.7 Hz, 1H), 7.92 (d,J= 7.8 Hz, 1H), 7.84 (s, 1H), 7.57 - 7.49 (m, 2H), 7.32 - 7.27 (m, 1H), 6.98 (d,J= 8.9 Hz, 1H), 6.48 (t,J= 72.9 Hz, 1H), 5.19 (s br, 1H), 4.22 - 4.14 (m, 1H), 3.85 - 3.73 (m, 2H), 3.28 (d,J= 5.8 Hz, 2H), 1.42 (s, 9H). MS / ESI+ 479.4 [M + H]+.

[0209] Step e) (S)-2-amino-3-(3-(3-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol (Example 3). Add (S)-(1-(3-(3-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxyprop-2-yl)aminocarbamate tributyl ester (3.5) (283 mg, 0.591 mmol), dibutyl phthalate (6.0 ml), and aqueous HCl (6.0 ml, 12.00 mmol) to a 25 mL single-necked pear-shaped flask equipped with a magnetic stir bar. Stir the resulting turbid solution at rt for 2 days. Add 2 M NaOH aqueous solution (6.0 ml) and remove volatiles under vacuum. EtOAc and approximately 0.1 M aqueous NaOH were added to the resulting suspension. The aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over Na2SO4. Purification was performed by column chromatography (ISCO CombiFlash Rf, absorption on silica gel, MeOH in CH2Cl2, 0–8%) to give (S)-2-amino-3-(3-(3-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol (Example 3) (182 mg, 79%), which was a pale yellow, clear, viscous oil. UPLC retention time was 0.69 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.01 (d,J= 2.8 Hz, 1H), 7.89 (d,J= 7.8 Hz, 1H), 7.83 - 7.79 (m, 1H), 7.55 - 7.44 (m, 2H), 7.25 (dd,J= 7.8, 1.6 Hz, 1H), 6.94 (d,J= 8.9 Hz, 1H), 6.47 (t,J= 72.9 Hz, 1H), 3.63 (dd,J= 10.7, 4.4 Hz, 1H), 3.50 (dd,J= 10.7, 6.1 Hz, 1H), 3.46 - 3.38 (m, 1H), 3.09 (dd, J = 15.6, 4.7 Hz, 1H), 2.98 - 2.92 (m, 1H), 2.34 (s br, 3H). MS / ESI+ 379.2 [M + H]+. Example 4 (S)-2-amino-3-(3-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol

[0210] Step a) 4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzonitrile (4.3). Add 2-fluoro-5-(trifluoromethyl)pyridine (4.1) (0.990 g, 6.00 mmol), 4-cyanophenol (4.2) (0.786 g, 6.60 mmol), K₂CO₃ (2.486 g, 17.99 mmol), and DMF (30.0 ml) to a 100 mL single-necked round-bottom flask equipped with a magnetic stir bar and reflux condenser. Then stir the reaction mixture at 65°C for 16 hours. Add water and EtOAc. Extract the aqueous phase twice with EtOAc. Wash the organic layers with brine, combine, and dry with Na₂SO₄. Purification by column chromatography (ISCO CombiFlash Rf, absorption on silicone, EtOAc (0-7%) in cyclohexane, fractionation) yielded 4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzonitrile (4.3%) (1.51 g, 95%). UPLC retention time 1.10 min (Method A). ¹H NMR (400 MHz, CDCl₃) δ = ppm 8.44 (s, 1H), 7.98 (dd, J = 8.6, 2.3 Hz, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 8.6 Hz, 1H). MS / ESI⁺ 265.3 [M⁺H]⁺.

[0211] Step b) N-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzomidine (4.4). Add 4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzonitrile (4.3) (0.794 g, 3.01 mmol), hydroxylamine hydrochloride (1.044 g, 15.03 mmol), NaHCO3 (1.262 g, 15.03 mmol), and ethanol (15.0 ml) / water (5.0 ml) to a 50 mL single-necked pear-shaped flask equipped with a magnetic stir bar and a condenser (air). Stir the white suspension at 85°C for 2 hours. Cool the reaction mixture to rt. Remove EtOH under vacuum. Add water and EtOAc. Extract the aqueous phase twice with EtOAc, wash the organic layer with brine, combine the extracts, and dry with Na2SO4. Purification by column chromatography (ISCO CombiFlash Rf, absorbed on silica gel, EtOAc in cyclohexane, 20%–40%) yielded N-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzamidin (4,4) white crystals (828 mg, 93%). UPLC retention time was 0.75 min (Method A). ¹H NMR (400 MHz, CDCl₃) δ = ppm 8.47–8.43 (m, 1H), 7.93 (dd, J = 8.7, 2.5 Hz, 1H), 7.73–7.68 (m, 2H), 7.23–7.17 (m, 2H), 7.05 (d, J = 8.7 Hz, 1H), 4.89 (s, 2H). MS / ESI+ 298.2 [M + H]+. Consistent with the desired product.

[0212] Step c) (S)-2-((tributoxycarbonyl)amino)-3-(3-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)benzyl propionate (4.5). Add N-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzamidinium (4.4) (726 mg, 2.443 mmol), Boc-Asp(OSu)-OBzl [CAS 140171-25-1] (2.5) (1130 mg, 2.69 mmol), and THF (13.0 ml) to a 20 mL microwave-safe vial equipped with a magnetic stir bar. Stir the colorless solution at 110°C for 17 hours. Remove the solvent under vacuum. Benzyl (S)-2-((tributoxy-carbonyl)amino)-3-(3-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-adiazol-5-yl)propionate (4.5 g) (1.41 g, 99%) was purified by column chromatography (ISCO CombiFlash Rf, absorbed on silicone, EtOAc in cyclohexane, 0-18%). UPLC retention time was 1.42 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.46 (s, 1H), 8.07 (d,J= 8.7 Hz, 2H), 7.95 (dd,J= 8.6, 2.4 Hz, 1H), 7.31-2.27 (m, 5H), 7.26 (d,J= 8.6 Hz, 2H), 7.09 (d,J= 8.6 Hz, 1H), 5.58 (d,J= 7.7 Hz, 1H), 5.24 - 5.16 (m, 2H), 4.94 - 4.86 (m, 1H), 3.52 (qd,J= 16.2, 4.9 Hz, 2H), 1.44 (s, 9H). MS / ESI+ 585.4 [M + H]+.

[0213] Step d) Tributyl (S)-(1-hydroxy-3-(3-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-2-yl)aminocarbamate (4.6). Add (S)-2-((tributoxy-carbonyl)amino)-3-(3-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propionate (4.5) (737 mg, 1.261 mmol) to a 25 mL two-necked round-bottom flask equipped with a magnetic stir bar, gas inlet, and rubber septum. Vacuum the flask and backfill with Ar five times. Then add anhydrous THF (10 mL) and cool the colorless solution to 0°C. LiBH4 (51.9 mg, 2.383 mmol) was added in a single dose. The reaction mixture was stirred for 75 minutes. After 50 minutes, LiBH4 (27.5 mg, 1.26 mmol, 1.00 equivalent) was added again. The yellow suspension was quenched with MeOH. The mixture was stored in a refrigerator over the weekend. Volatiles were removed under vacuum. The mixture was purified by column chromatography (ISCO CombiFlash Rf, absorbed on silicone, EtOAc in cyclohexane, 20%–40%) to give a viscous, colorless, oily tributyl (S)-(1-hydroxy-3-(3-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propyl-2-yl)aminocarbamate (4.6%) (399 mg, 65.9%). UPLC retention time was 1.17 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.45 (s, 1H), 8.14 (d,J= 8.6 Hz, 2H), 7.94 (dd,J= 8.6, 2.3 Hz, 1H), 7.29 - 7.26 (m, 2H), 7.08 (d,J= 8.6 Hz, 1H), 5.23 (s, 1H), 4.20 (s, 1H), 3.80 (dq,J= 11.3, 5.9, 4.7 Hz, 2H), 3.30 (d,J= 5.9 Hz, 2H), 1.44 (s, 9H). 19F NMR (376 MHz, CDCl3) δ -61.73. MS / ESI+ 481.4 [M + H]+.

[0214] Step e) (S)-2-amino-3-(3-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol (Example 4): Add (S)-(1-hydroxy-3-(3-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-2-yl)aminocarbamate tributyl ester (4.6) (393 mg, 0.818 mmol), diethylcarbamate (8.0 ml), and aqueous HCl (8.0 ml, 16.00 mmol) to a 25 mL single-necked pear-shaped flask equipped with a magnetic stir bar. Stir the turbid solution at rt for 40 hours. A white suspension is obtained. Remove the solvent under vacuum. Add 2 M NaOH aqueous solution (10 ml). Then, EtOAc and approximately 0.2 M NaOH aqueous solution were added, and the aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over Na2SO4. A pale yellow (mostly white) solid was obtained. Purification was performed by column chromatography (ISCO CombiFlash Rf, absorption on silica gel, MeOH in CH2Cl2, 0-10%) to give a white solid (S)-2-amino-3-(3-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol (Example 4) (212 mg, 68.1%). UPLC retention time was 0.75 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.45 (s, 1H), 8.15 (d,J= 8.7 Hz, 2H), 7.94 (dd,J= 8.6, 2.3 Hz, 1H), 7.28 (d,J= 8.7 Hz, 3H), 7.08 (d,J= 8.6 Hz, 1H), 3.71 (dd,J= 10.5, 4.3 Hz, 1H), 3.56 (dd,J= 10.5, 6.3 Hz, 1H), 3.54 - 3.46 (m, 1H), 3.15 (dd,J= 15.5, 4.7 Hz, 1H), 3.01 (dd,J= 15.5, 8.1 Hz, 1H), 1.72 (s br, 3H). 19F NMR (376 MHz, CDCl3) δ -61.73. MS / ESI+ 381.3 [M + H]+. Example 5 (S)-2-amino-3-(3-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol

[0215] Step a) 4-((5-(difluoromethoxy)pyridin-2-yl)oxy)benzonitrile (5.1). Add 5-(difluoromethoxy)-2-fluoropyridine (0.186 g, 1.140 mmol, Enamine Ltd.) (3.1), 4-cyanophenol (0.177 g, 1.483 mmol, Sigma-Aldrich) (4.2), K2CO3 (0.473 g, 3.42 mmol), and DMF (volume: 4.0 ml) to a 10 mL microwave-safe vial equipped with a magnetic stir bar. After sealing the vial, heat the white suspension to 110°C and stir for 5 days. Cool the reaction mixture to rt. Add water / EtOAc and extract the aqueous phase twice with EtOAc. Wash the organic layers with brine, combine, and dry with Na2SO4. Purification by column chromatography (ISCO CombiFlash Rf, absorbed on silicone, EtOAc in cyclohexane, 0-25%) yielded colorless 4-((5-(difluoromethoxy)pyridin-2-yl)oxy)benzonitrile (5.1) (0.25 g, 84%). UPLC retention time was 1.04 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.06 (d, J = 2.8 Hz, 1H), 7.71 - 7.67 (m, 2H), 7.59 (dd, J = 8.8, 2.9 Hz, 1H), 7.25 - 7.21 (m, 2H), 7.03 (d, J = 8.8 Hz, 1H), 6.51 (t, J = 72.6 Hz, 1H). MS / ESI+ 263.2 [M + H]+.

[0216] Step b) (Z)-4-((5-(difluoromethoxy)pyridin-2-yl)oxy)-N'-hydroxybenzomidine (5.2).

[0217] Add NaHCO3 (400 mg, 4.77 mmol), hydroxylamine hydrochloride (331 mg, 4.77 mmol), and water (2.0 ml) to a 25 mL single-necked pear-shaped flask equipped with a magnetic stir bar and a condenser (air). Stir the white suspension at rt (caution: gas formation) for 5 min. Then add 4-((5-(difluoromethoxy)pyridin-2-yl)oxy)benzonitrile (5.1) (250 mg, 0.953 mmol) in EtOH (5.0 ml), heat the reaction mixture to 85°C, and stir for 80 min. A colorless solution is obtained within about 15 min. After 30 min, LC-MS reveals that the starting material has been almost completely consumed. Remove EtOH under vacuum. Add water / EtOAc and extract the aqueous phase twice with EtOAc. Wash the organic layer with brine, combine, and dry with Na2SO4. Purification by column chromatography (ISCO CombiFlash Rf, absorbed on silicone, EtOAc in cyclohexane, 0-65%) yielded a slowly crystallizing, turbid oily substance (Z)-4-((5-(difluoromethoxy)pyridin-2-yl)oxy)-N'-hydroxybenzomidine (0.248 g, 88%) (5.2). UPLC retention time: 0.65 min (Method A). ¹H NMR (400 MHz, CDCl₃) δ = ppm 8.02 (d, J = 2.8 Hz, 1H), 7.67 - 7.60 (m, 2H), 7.53 (dd, J = 8.9, 2.9 Hz, 1H), 7.17 - 7.11 (m, 2H), 6.94 (d, J = 8.9 Hz, 1H), 6.48 (t, J = 72.8 Hz, 1H) (No NH₂ and NOH peaks were observed due to the use of CDCl₃ (instead of DMSO-d₆) as the solvent!). MS / ESI⁺ 296.1 [M⁺H]⁺.

[0218] Step c) (S)-2-((tributoxycarbonyl)amino)-3-(3-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)benzyl propionate (5.3). Add (Z)-4-((5-(difluoro-methoxy)pyridin-2-yl)oxy)-N'-hydroxybenzomidine (5.2) (0.239 g, 0.810 mmol), Boc-Asp(OSu)-OBzl (2.5) (0.374 g, 0.890 mmol), and THF (3.0 ml) to a microwave-safe vial equipped with a magnetic stir bar. Stir the colorless solution at rt for 100 min. LC-MS showed complete consumption within 90 min. The reaction mixture was then heated to 120°C and stirred for 3 h. Add EtOAc to a colorless solution and store the mixture in a refrigerator over the weekend. Remove the solvent under vacuum. Add CH2Cl2 and silica gel. Purify by column chromatography (ISCO CombiFlash Rf, EtOAc in cyclohexane, absorbed on silica gel, 0-25%) to give (S)-2-((tributoxycarbonyl)amino)-3-(3-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propionate (0.443 g, 94%) (5.3). UPLC retention time 1.34 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.08 (d,J= 2.7 Hz, 1H), 8.04 (d,J= 8.7 Hz, 2H), 7.57 (dd,J= 8.9, 2.9 Hz, 1H), 7.29 (s, 5H), 7.22 (d,J= 8.7 Hz, 2H), 7.00 (d,J= 8.9 Hz, 1H), 6.50 (t,J= 72.8 Hz, 1H), 5.58 (d,J= 7.6 Hz, 1H), 5.20 (d,J= 2.7 Hz, 2H), 4.93 - 4.85 (m, 1H), 3.51 (qd,J= 16.2, 5.0 Hz, 2H), 1.44 (s, 9H). MS / ESI+ 583.2 [M + H]+.

[0219] Step d) Tributyl (S)-(1-(3-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate (5.4). Add (S)-2-((tributoxycarbonyl)amino)-3-(3-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propionate (5.3) (0.220 g, 0.378 mmol) to a 10 mL two-necked conical flask equipped with a magnetic stir bar, rubber septum, and gas inlet. Vacuum the vial and backfill with Ar three times. Add anhydrous THF (2.0 mL) and cool the solution to 0°C. Then, LiBH4 (0.041 g, 1.888 mmol) was added in a single batch, and the suspension was stirred for 70 min. The reaction was quenched with MeOH. The solvent was removed under vacuum. CH2Cl2 and silica gel were added. The solution was purified by column chromatography (ISCO CombiFlash Rf, absorbed on silica gel, EtOAc in cyclohexane, 0-55%) to give (S)-(1-(3-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester (0.100 g, 55.3%) (5.4). UPLC retention time was 1.07 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.13 (d,J= 8.7 Hz, 2H), 8.10 (d,J= 2.7 Hz, 1H), 7.59 (dd,J= 8.9, 2.9 Hz, 1H), 7.27 (d,J= 8.7 Hz, 2H), 7.02 (d,J= 8.9 Hz, 1H), 6.52 (t,J= 72.8 Hz, 1H), 5.24 (s, 1H), 4.22 (s, 1H), 3.84 (p,J= 6.7 Hz, 2H), 3.32 (d,J= 5.9 Hz, 2H), 1.46 (s, 9H). MS / ESI+ 479.3 [M + H]+.

[0220] Step e) (S)-2-amino-3-(3-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol (Example 5). Add (S)-(1-(3-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxyprop-2-yl)aminocarbamate tributyl ester (5.4) (0.100 g, 0.209 mmol), dichloromethane (2.0 ml), and TFA (0.081 ml, 1.045 mmol) to a 10 mL single-necked pear-shaped flask equipped with a magnetic stir bar. Stir the solution at rt for 3 days. Remove the solvent and acid under vacuum. Purification by column chromatography (ISCO CombiFlash Rf, absorbed on silicone, MeOH in CH2Cl2, 0-10%) yielded (S)-2-amino-3-(3-(4-((5-(difluoromethoxy)-pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol (82 mg, 99%), a white (pale yellow) foamy substance (Example 5). UPLC retention time was 0.70 min (Method A). ¹H NMR (400 MHz, CDCl₃) δ = ppm 8.02 - 7.89 (m, 3H), 7.54 - 7.44 (m, 1H), 7.15 - 7.07 (m, 2H), 6.92 - 6.86 (m, 1H), 6.47 (t, J = 72.8 Hz, 1H), 4.01 - 3.72 (m, 3H), 3.42 - 3.20 (m, 2H). MS / ESI+ 379.3 [M + H]+. Example 6: Ethyl (S)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-aminodiazol-3-yl)propionate

[0221] Step a) Methyl 4-((5-chloropyridin-2-yl)oxy)benzoate (6.2). Add 5-chloro-2-fluoropyridine (2.1) (2.31 g, 17.56 mmol), methyl 4-hydroxybenzoate (6.1) (2.94 g, 19.32 mmol), K₂CO₃ (4.85 g, 35.1 mmol), and DMF (100 ml) to a 250 mL single-necked pear-shaped flask equipped with a magnetic stir bar and reflux condenser. Heat the white suspension to 100°C and stir for 19 hours. Cool the reaction mixture to rt. Add water and EtOAc. Extract the aqueous phase twice with EtOAc. Wash the organic layers with brine, combine, and dry with Na₂SO₄. Methyl 4-((5-chloropyridin-2-yl)oxy)benzoate (3.18 g, 68.7%) was purified by column chromatography (ISCO CombiFlash Rf, absorbed on silica gel, EtOAc in cyclohexane, 0-7%) to obtain a white solid crystalline solid (6.2). UPLC retention time was 1.14 min (Method A). ¹H NMR (400 MHz, CDCl₃) δ = ppm 8.14 (d, J = 2.5 Hz, 1H), 8.11 - 8.05 (m, 2H), 7.69 (dd, J = 8.7, 2.7 Hz, 1H), 7.20 - 7.14 (m, 2H), 6.94 (d, J = 8.7 Hz, 1H), 3.91 (s, 3H). MS / ESI+ 264.2, 266.2.

[0222] Step b) 4-((5-chloropyridin-2-yl)oxy)benzoic acid (6.3). Methyl 4-((5-chloropyridin-2-yl)oxy)benzoate (6.2) (3.09 g, 11.72 mmol), MeOH (50.0 ml) / THF (50.0 ml), and LiOH × 1H2O (2.459 g, 58.6 mmol) were added to a 250 mL single-necked pear-shaped flask equipped with a magnetic stir bar and a condenser (air). The suspension was stirred at 45°C for 2 hours. The mixture was cooled to rt and stirred over the weekend (4 days). Volatile substances were removed under vacuum. Water, 2 M aqueous HCl (40 mL, 80 mmol), and EtOAc were added to the resulting white solid. The aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over Na2SO4. Concentrated under vacuum, 4-((5-chloropyridin-2-yl)oxy)benzoic acid (2.93 g, 100%) was obtained as a white solid (6.3). UPLC retention time was 0.92 min (Method A). ¹H NMR (400 MHz, CDCl₃) δ = ppm 8.10 - 7.88 (m, 3H), 7.64 - 7.53 (m, 1H), 7.09 - 6.97 (m, 2H), 6.89 - 6.78 (m, 1H). MS / ESI+ 250.1, 252.1.

[0223] Step c) 4-((5-chloropyridin-2-yl)oxy)benzoic acid (6.4). Add 4-((5-chloropyridin-2-yl)oxy)benzoic acid (6.3) (1.3 g, 5.21 mmol) to a 50 mL two-necked round-bottom flask equipped with a magnetic stir bar, rubber septum, and gas inlet. Vacuum the flask and carefully backfill with Ar three times. Add anhydrous dichloromethane (7.0 mL) and cool the white suspension to 0°C. Add oxalichlor (1.0 mL, 11.42 mmol) all at once. After adding 2 drops of DMF, gas formation was observed, and the reaction mixture slowly turned pale yellow. Stir at 0°C for 19.5 h. After 1 h 35 min: add oxalichlor (0.50 mL, 5.71 mmol). After 19 h: Add oxalichlorophenoxy ...

[0224] Step d) (E)-2-chloro-N'-((4-(((5-chloropyridin-2-yl)oxy)benzyl)oxy)acetamidine (6.6). Add 4-((5-chloropyridin-2-yl)oxy)benzylchloro (6.4) (1.25 g, 4.66 mmol), (Z)-2-chloro-N'-hydroxyacetamidine (6.5) (WO 2004 / 14370 A2 (2004); page / column 44) (0.557 g, 5.13 mmol), DMAP (0.057 g, 0.466 mmol), and DCM (30 ml) to a 50 mL single-necked pear-shaped flask equipped with a magnetic stir bar. Stir the suspension at rt for 1 hour. After 30 minutes, add DIPEA (0.814 mL, 4.66 mmol). Remove volatiles under vacuum. EtOAc and a saturated aqueous solution of NH4Cl were added to the residue. The aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over Na2SO4. Purification was performed by column chromatography (ISCO CombiFlash Rf, EtOAc in cyclohexane absorbed on silica gel, 23%–38%–43%) to give (E)-2-chloro-N'-((4-(((5-chloropyridin-2-yl)oxy)benzoyl)oxy)acetamidine (1.05 g, 66.2%) as a white solid (6.6). UPLC retention time was 0.97 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.25 (d,J= 2.6 Hz, 1H), 8.19 (d,J= 8.7 Hz, 2H), 8.02 (dd,J= 8.7, 2.7 Hz, 1H), 7.26 (d,J= 8.7 Hz, 2H), 7.20 (d,J= 8.8 Hz, 1H), 6.91 (sbr, 2H), 4.17 (s, 2H). MS / ESI+ 342.1, 340.1.

[0225] Step e) 3-(chloromethyl)-5-(4-(((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazole (6.7). Add (E)-2-chloro-N'-((4-(((5-chloropyridin-2-yl)oxy)benzoyl)oxy)acetamidine (6.6) (1.05 g, 3.09 mmol) and toluene (50.0 ml) to a 250 mL single-necked pear-shaped flask equipped with a magnetic stir bar and a reflux condenser. Then stir the solution at 130°C for 17.5 hours and concentrate under vacuum. Purification by column chromatography (ISCO CombiFlash Rf, absorbed on silica gel, EtOAc in cyclohexane, 0-12%) yielded a white solid 3-(chloro-methyl)-5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazole (463 mg, 46.6%) (6.7). UPLC retention time was 1.23 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.22 - 8.17 (m, 2H), 8.16 (d,J= 2.5 Hz, 1H), 7.72 (dd,J= 8.7, 2.7 Hz, 1H), 7.31 - 7.27 (m, 2H), 6.99 (d,J= 8.7 Hz, 1H), 4.67 (s, 2H). MS / ESI+ 322.1, 324.1.

[0226] Step f) 5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-3-(((2S,5R)-3,6-diethoxy-5-isopropyl-2,5-dihydropyridine-2-yl)methyl)-1,2,4-diazole (6.9). A 10 mL two-necked conical flask equipped with a magnetic stir bar, gas inlet, and rubber septum was heated under vacuum and backfilled three times with Ar. Schöllkopf adjuvant [CAS: 110117-71-0] (6.8) (0.50 mL, 1.369 mmol) and anhydrous THF (volume: 5.0 mL, ratio: 1.667) were added, and the brown, clear solution was cooled to -69°C (isopropyl ether / dry ice). A hexane solution of nBuLi (0.95 mL, 2.375 mmol) was added dropwise, and the dark brown solution was stirred for 30 minutes. A dark brown solution was obtained. Then, 3-(chloro-methyl)-5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazole (6.7 mg, 441 mg, 1.369 mmol) was added dropwise to anhydrous THF (3.0 mL). The mixture was stirred for 16 hours while being warmed to rt. A light brown solution was obtained. The reaction was quenched with a few drops of saturated NH4Cl aqueous solution. Saturated NH4Cl aqueous solution and EtOAc were then added. The aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, dried over Na2SO4, and concentrated to give a yellow oil. Purification by column chromatography (ISCO CombiFlash Rf, absorbed on silicone, EtOAc in cyclohexane, 0-9.1%) yielded a yellow oily 5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-3-(((2S,5R)-3,6-diethoxy-5-isopropyl-2,5-dihydropyridine-2-yl)methyl)-1,2,4-diazole (368 mg, 54%) (6.9). UPLC retention time was 1.60 min (Method A).1H NMR (400 MHz, CDCl3) δ = ppm 8.17 - 8.12 (m, 3H), 7.70 (dd,J= 8.7, 2.7 Hz, 1H), 7.25 (dd,J= 9.0, 2.4 Hz, 2H), 6.97 (d,J= 8.7 Hz, 1H), 4.48 (ddd,J= 7.4, 5.0, 3.7 Hz, 1H), 4.24 - 3.93 (m, 4H), 3.88 (t,J= 3.5 Hz, 1H), 3.37 - 3.28 (m, 1H), 3.12 (dd,J= 14.5, 7.3 Hz, 1H), 2.24 (ddt,J= 10.2, 6.8, 3.4 Hz, 1H), 1.28 - 1.24 (m, 3H), 1.23 - 1.18 (m, 3H), 1.04 (dd,J= 13.7, 6.9 Hz, 3H), 0.70 (dd,J= 15.4, 6.8 Hz, 3H)。MS / ESI+ 498.3, 500.3。

[0227] Step g) Ethyl (S)-2-amino-3-(5-(4-(((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-acediazole-3-yl)propionate (6.10). Add 5-(4-(((5-chloropyridin-2-yl)oxy)phenyl)-3-(((2S,5R)-3,6-diethoxy-5-isopropyl-2,5-dihydropyridine-2-yl)methyl)-1,2,4-acediazole (6.9) (368 mg, 0.739 mmol) and THF (8.0 ml) to a 25 mL single-necked round-bottom flask equipped with a magnetic stir bar. Upon addition of aqueous HCl (2.0 mL, 4.00 mmol) to the bright yellow solution, it immediately turns pale orange and then yellow again over time. Stir the reaction mixture at rt for 90 minutes. The reaction was quenched with a saturated NaHCO3 aqueous solution. EtOAc was added, and the aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over Na2SO4. The solution was concentrated under vacuum to give a yellow oil. Purification was performed by column chromatography (ISCO CombiFlash Rf, absorbed on silica gel, MeOH in CH2Cl2, 0–2.3%) to give a colorless oily ethyl (S)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-3-yl)propionate (272 mg, 95%) (6.10), which crystallized slowly at rt. UPLC retention time was 0.82 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.18 - 8.11 (m, 3H), 7.71 (dd,J= 8.7, 2.7 Hz, 1H), 7.30 - 7.23 (m, 2H), 6.97 (d,J= 8.7 Hz, 1H), 4.22 (qq,J= 7.1, 3.6 Hz, 2H), 4.01 (dd,J= 8.0, 4.7 Hz, 1H), 3.28 (dd,J= 15.1, 4.7 Hz, 1H), 3.13 (dd,J= 15.1, 8.0 Hz, 1H), 1.86 (s, 2H), 1.28 (t,J= 7.1 Hz, 3H). MS / ESI+ 389.2, 391.2.

[0228] Step h) Ethyl (S)-2-amino-3-(5-(4-(((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-3-yl)propionate (Example 6). Ethyl (S)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-3-yl)propionate (6.10) (272 mg, 0.700 mmol) was added to a 25 mL two-necked pear-shaped flask equipped with a magnetic stir bar, rubber septum, and gas inlet. The flask was evacuated and backfilled with Ar five times. Anhydrous THF (5.00 mL) was added, and the solution was cooled to 0°C. LiAlH4 (2 M) (0.350 mL, 0.700 mmol) was added to THF (gas formation was observed), and the reaction mixture was stirred at 0°C for 65 minutes. The reaction was quenched with MeOH (while still cooled at 0°C) and then with water. A saturated NH4Cl solution and EtOAc were added. The aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over Na2SO4. Purification by column chromatography (ISCO CombiFlash Rf, absorbed on silica gel, MeOH in CH2Cl2, 0–10%) yielded ethyl (S)-2-amino-3-(5-(4-(((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-3-yl)propionate (64.6 mg, 26.4%) as a light brown solid (Example 6). UPLC retention time: 0.70 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.13 (dd,J= 5.9, 2.9 Hz, 3H), 7.70 (dd,J= 8.7, 2.7 Hz, 1H), 7.29 - 7.21 (m, 2H), 6.96 (d,J= 8.7 Hz, 1H), 2.84 (dd,J= 14.9, 8.2 Hz, 1H), 2.57 (s br, 3H). MS / ESI+ 347.2, 349.2. Example 7 ((2S)-1-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)tributylaminocarbamate

[0229] Step a) 4-((5-bromo-3-fluoropyridin-2-yl)oxy)benzonitrile (7.2). Add 5-bromo-2,3-difluoropyridine (7.1) (3.0 g, 15.47 mmol), 4-cyanophenol (4.2) (2.395 g, 20.11 mmol), K₂CO₃ (6.41 g, 46.4 mmol), and DMF (50.0 ml) to a 100 mL single-necked round-bottom flask equipped with a magnetic stir bar and a reflux condenser. Heat the suspension to 110°C and stir for 17 hours. Cool the reaction mixture to rt. Add water / EtOAc and extract the yellow aqueous phase twice with EtOAc. Wash the organic layers with brine, combine, and dry with Na₂SO₄. Concentrate under vacuum to give a strong orange oil. Purification by column chromatography (ISCO CombiFlash Rf, absorption on silica gel, EtOAc in cyclohexane, 0-10% then to 20%) yielded 4-((5-bromo-3-fluoropyridin-2-yl)oxy)benzonitrile (2.97 g, 64.9%) as a white solid (7.2). UPLC retention time 1.14 min (Method A). ¹H NMR (400 MHz, CDCl₃) δ = ppm 8.37 (dd, J = 9.6, 2.0 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.93 (d, J = 8.7 Hz, 2H), 7.43 (d, J = 8.7 Hz, 2H). 19F NMR (376 MHz, CDCl3) δ -132.46 (d,J= 8.4 Hz). MS / ESI+ 293.0, 295.0 (weak).

[0230] Step b) 4-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)benzonitrile (7.3). Add 4-((5-bromo-3-fluoropyridin-2-yl)oxy)benzonitrile (7.2) (0.786 g, 2.68 mmol), 1-(tetrahydro-2H-piperan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrazole [CAS: 903550-26-5] (1.000 g, 3.49 mmol), K3PO4 (1.708 g, 8.05 mmol), [Pd(PPh3)4] (0.155 g, 0.134 mmol), and toluene (15.0 ml) to a 50 ml two-necked round-bottom flask equipped with a magnetic stir bar, gas inlet, and rubber septum. Carefully evacuate the flask and backfill with Ar three times. Then purge the reaction mixture with Ar for 10 minutes. Remove the rubber septum and install a reflux condenser (previously rinsed with Ar) (with a rubber septum and Ar balloon at the top). Then stir the pale yellow suspension at 110°C for 3 hours. Cool the reaction mixture to rt. Add water / EtOAc and extract the yellow aqueous phase twice with EtOAc. Wash the organic layers with brine, combine, and dry with Na2SO4. Concentrate under vacuum to give a deep orange oil. Purify the crude mixture twice by column chromatography (in both cases, ISCO CombiFlash Rf, absorbed on silica gel, EtOAc in cyclohexane, 0-30%) to give 4-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)benzonitrile (0.628 g, 64.3%) as a white solid (7.3). UPLC retention time 1.06 min (Method A).1H NMR (400 MHz, CDCl3) δ = ppm 8.10 (d,J= 1.9 Hz, 1H), 7.79 (dd,J= 10.3, 2.0 Hz, 1H), 7.76 - 7.72 (m, 2H), 7.62 (d,J= 1.7 Hz, 1H), 7.37 - 7.32 (m, 2H), 6.39 (d,J= 1.8 Hz, 1H), 5.15 (dd,J= 9.9, 2.5 Hz, 1H), 4.18 - 4.06 (m, 1H), 3.62 (td,J= 11.5, 2.3 Hz, 1H), 2.64 - 2.52 (m, 1H), 2.17 - 2.07 (m, 1H), 1.95 - 1.87 (m, 1H), 1.79 - 1.69 (m, 1H), 1.63 - 1.56 (m, 2H). MS / ESI+ is non-ionized, Rf(cyclohexane / EtOAc, 3 : 1) = 0.26.

[0231] Step c) 4-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)-N-hydroxybenzomidine (7.4). Add hydroxylamine hydrochloride (0.599 g, 8.62 mmol), NaHCO3 (0.724 g, 8.62 mmol), and water (4.0 ml) to a 50 mL single-necked pear-shaped flask equipped with a magnetic stir bar. Stir the white suspension at rt (caution: gas formation) for 5 minutes. Then, 4-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)benzonitrile (7.3) (0.628 g, 1.724 mmol) and EtOH (10 ml) were added, and the reaction mixture was heated to 85°C and stirred for 110 min. After cooling to rt, the EtOH was removed under vacuum. Water / EtOAc was added, and the aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over Na2SO4. Purification by column chromatography (ISCO CombiFlash Rf, absorbed on silicone, EtOAc in cyclohexane, 0-66%) yielded a white, foamy 4-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)-N-hydroxybenzomidine (0.570 g, 83%) (7.4). UPLC retention time was 0.80 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.08 (d,J= 1.9 Hz, 1H), 7.77 - 7.70 (m, 3H), 7.62 (d,J= 1.6 Hz, 1H), 7.29 - 7.25 (m, 2H), 6.38 (d,J= 1.7 Hz, 1H), 5.15 (dd,J= 10.0, 2.4 Hz, 1H), 4.87 (s br, 2H), 4.17 - 4.05 (m, 1H), 3.62 (td, J = 11.5, 2.2 Hz, 1H), 2.66 - 2.49 (m, 1H), 2.15 - 2.06 (m, 1H), 1.90 (d, J = 13.5 Hz, 1H), 1.82 - 1.68 (m, 1H), 1.67 - 1.53 (m, 2H). MS (ESI) m / z 398.3 [M + H]+. Rf(cyclohexane / EtOAc, 1 : 2) = 0.33.

[0232] Step d) (2S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazole-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)benzyl propionate (7.5). Add 4-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazole-5-yl)pyridin-2-yl)oxy)-N-hydroxybenzomidine (7.4) (0.563 g, 1.417 mmol), Boc-Asp(OSu)-Obzl (2.5) (0.655 g, 1.558 mmol) and THF (7.0 ml) to a 20 mL microwave-safe vial equipped with a magnetic stir bar. The vial was sealed and the colorless solution was stirred at rt for 1 hour. The reaction mixture was then heated to 120°C and stirred for 140 minutes. The solution was cooled to rt. The solvent was removed under vacuum. CH2Cl2 and silica gel were added. The solution was purified by column chromatography (ISCO CombiFlash Rf, absorbed on silica gel, EtOAc in cyclohexane, 0-35%) to give (2S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)benzyl propionate (270 mg, purity only 67%) (7.5). UPLC retention time 1.40 min (Method A). MS / ESI+ 685.4 [M + H]+. Rf(cyclohexane / EtOAc, 1 : 2) = 0.43.

[0233] Step e) ((2S)-1-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester (7.6). Add (2S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)benzyl propionate (7.5) (0.134 g, 0.196 mmol) (Note: the starting material is not pure, with a purity of approximately 67%) to a 10 mL two-necked conical flask equipped with a magnetic stir bar, rubber septum, and gas inlet. Vacuum the vial and backfill three times with Ar. Add THF (1 mL) and cool the colorless solution to 0°C. Add LiBH4 (0.021 g, 0.979 mmol) in a single addition and stir the suspension for 45 minutes. Quench the reaction mixture with MeOH and remove the solvent under vacuum. Purification was performed by column chromatography (ISCO CombiFlash Rf, absorption on silicone, EtOAc in cyclohexane, 0-65%). A second purification by column chromatography (gradient: EtOAc in cyclohexane, 20%-55%) only slightly improved the purity. ((2S)-1-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester (48.9 mg, 43%) (7.6).

[0234] UPLC residence time 1.16 min (Method A). MS / ESI+ 581.4 [M+H]+. Rf(cyclohexane / EtOAc, 1 : 2) = 0.48.

[0235] Step e) ((2S)-1-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester (Example 7). Tributyl ((2S)-1-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate (7.6 mg, 0.084 mmol), DCM (0.800 mL), and TFA (33 µl, 0.428 mmol) were added to a 10 mL single-necked pear-shaped flask equipped with a magnetic stir bar. The solution was stirred until colorless for 5 days. LC-MS analysis revealed rapid consumption of the starting material: rapid cleavage of the THP ether. However, Boc deprotection was as slow as expected. Equilibrium was reached after 4 days. The solvent and acid were removed under vacuum. The turbid, oily tributyl ((2S)-1-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate (10.9 mg, 24%) was purified by column chromatography (ISCO CombiFlash Rf, absorbed on silicone, MeOH in CH2Cl2, 0-10%-15%) (Example 7). The UPLC retention time was 0.65 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.28 (d,J= 1.8 Hz, 1H), 8.05 (d,J= 8.7 Hz, 2H), 7.90 (dd,J= 10.5, 1.8 Hz, 1H), 7.57 (d,J= 2.1 Hz, 1H), 7.24 (d,J= 8.7 Hz, 2H), 6.54 (d,J= 1.9 Hz, 1H), 3.90 (dd,J= 11.9, 3.3 Hz, 1H), 3.87 - 3.78 (m, 1H), 3.73 (dd,J= 12.0, 5.7 Hz, 1H), 3.32 (dd,J= 6.7, 4.5 Hz, 2H). MS / ESI+ 397.2 [M + H]+. Example 8 (R)-2-amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol

[0236] Step a) 4-((5-chloro-3-fluoropyridin-2-yl)oxy)-N-hydroxybenzoamide (8.1). Add 4-((5-chloro-3-fluoropyridin-2-yl)oxy)benzonitrile (29.3) (2.82 g, 11.34 mmol), NaHCO3 (4.76 g, 56.7 mmol), hydroxylamine hydrochloride (3.94 g, 56.7 mmol), ethanol (40 ml), and water (15 ml) (Caution: gas formation) to a 100 mL single-necked pear-shaped flask equipped with a magnetic stir bar and a condenser (air). Heat the white suspension to 85°C and stir for 100 min. Then cool it to rt. Remove EtOH under vacuum. Add water / EtOAc and extract the aqueous phase twice with EtOAc. Wash the organic layer with brine, combine, and dry with Na2SO4. LC-MS and 1H NMR analyses revealed that the obtained white solid 4-((5-chloro-3-fluoropyridin-2-yl)oxy)-N-hydroxybenzamide (3.18 g, 97%) (8.1) had high purity. Therefore, no further purification was required. UPLC retention time was 0.73 min (Method A). 1H NMR (400 MHz, DMSO-d6) δ = ppm 9.62 (s, 1H), 8.23 ​​(dd, J = 9.9, 1.9 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 5.82 (s, 2H). MS / ESI+ 282.2, 284.2.

[0237] Step b) (R,Z)-4-(((amino(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)methylene)-amino)oxy)-2-((tert-butoxycarbonyl)amino)-4-sideoxybenzyl butyrate (8.3). Add 4-((5-chloro-3-fluoropyridin-2-yl)oxy)-N-hydroxybenzomidine (8.1) (0.600 g, 2.130 mmol), Boc-D-Asp-OBzl (8.2) (1.033 g, 3.20 mmol, [CAS: 92828-64-3]), HATU (1.215 g, 3.20 mmol), THF (10.0 ml) and DMF (5.0 ml) to a 50 mL single-necked round-bottom flask equipped with a magnetic stir bar. Upon addition of DIPEA (0.558 ml, 3.20 mmol) to the white suspension, it immediately turned yellow, and the particles slowly dissolved. The yellow solution was stirred at rt for 17.5 hours. THF was removed under vacuum. Saturated NaHCO3 aqueous solution and EtOAc were added, and the aqueous phase was extracted twice with EtOAc. The organic layers were washed with approximately 0.1 M aqueous HCl and brine, combined, and dried over Na2SO4. Purification by column chromatography (ISCO CombiFlash Rf, EtOAc in cyclohexane, 15%–40%) yielded (R,Z)-4-(((amino(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-methylene)-amino)oxy)-2-((tert-butoxycarbonyl)amino)-4-sideoxybenzyl butyrate (1.35 g, 97%) as a white solid (8.3). UPLC residence time 1.25 min (Method A). ¹H NMR (400 MHz, CDCl₃) δ = ppm 7.92 (d, J = 2.1 Hz, 1H), 7.75 (d, J = 8.7 Hz, 2H), 7.56 (dd, J = 9.0, 2.1 Hz, 1H), 7.36 (s, 5H), 7.22 (d, J = 8.7 Hz, 2H), 5.23 (d, J = 2.0 Hz, 2H), 4.82 - 4.74 (m, 1H), 3.16 (qd, J = 17.0, 4.9 Hz, 2H), 1.45 (s, 9H). MS / ESI+ 587.4, 589.4. Rf(cyclohexane / EtOAc, 2 : 1) = 0.23.

[0238] Step c) (R)-2-((tributoxycarbonyl)amino)-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)benzyl propionate (8.4). Add (R,Z)-4-(((amino(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-methylene)-amino)oxy)-2-((tributoxycarbonyl)amino)-4-butoxybenzyl butyrate (8.3) (1.34 g, 2.055 mmol) and THF (13.0 ml) to a 20 mL microwave-safe vial equipped with a magnetic stir bar. Seal the vial and stir the reaction mixture at 100°C for 2.5 days. Cool the resulting orange solution to rt and remove the solvent under vacuum. The product was purified by column chromatography (ISCO CombiFlash Rf, absorbed on silicone, EtOAc in cyclohexane, 0-18%) to obtain a colorless, viscous oily (R)-2-((tributoxycarbonyl)amino)-3-(3-(4-(((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-adiazol-5-yl)propionate (0.806 g, 68.9%) (8.4). UPLC retention time was 1.40 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.05 (d,J= 8.7 Hz, 2H), 7.93 (d,J= 2.2 Hz, 1H), 7.55 (dd,J= 9.0, 2.2 Hz, 1H), 7.28 (s, 5H), 7.25 (d,J= 8.4 Hz, 2H), 5.58 (d,J= 7.8 Hz, 1H), 5.25 - 5.13 (m, 2H), 4.90 (d,J= 7.3 Hz, 1H), 3.51 (qd,J= 16.2, 5.0 Hz, 2H), 1.44 (s, 9H). MS / ESI+ 569.3, 571.3. Rf(cyclohexane / EtOAc, 5 : 1) = 0.33.

[0239] Step d) Tributyl (R)-(1-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate (8.5). Add (R)-2-((tributoxycarbonyl)amino)-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propionate (8.4) (489 mg, 0.859 mmol) to a 25 mL two-necked round-bottom flask equipped with a magnetic stir bar, rubber septum, and gas inlet. Vacuum the flask and backfill with Ar four times. Add THF (8.0 mL) and cool the colorless solution to 0°C. After adding LiBH4 (94 mg, 4.30 mmol), the suspension was stirred at 0°C for 90 min. The starting material was completely converted within 1 hour. The reaction was quenched with MeOH. The solvent was then removed under vacuum. Purification by column chromatography (ISCO CombiFlash Rf, absorbed on silicone, EtOAc in cyclohexane, 20%–46%) yielded a colorless, viscous oily tributyl (R)-(1-(3-(4-(((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate (0.240 g, 60.1%) (8.5). UPLC retention time 1.17 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.12 (d,J= 8.8 Hz, 2H), 7.93 (d,J= 2.2 Hz, 1H), 7.55 (dd,J= 9.0, 2.2 Hz, 1H), 7.27 (d,J= 8.7 Hz, 2H), 5.21 (s, 1H), 4.24 - 4.16 (s, 1H), 3.81 (hept,J= 5.7, 5.1 Hz, 2H), 3.30 (d,J= 5.9 Hz, 2H), 1.44 (s, 9H). MS / ESI+ 465.3, 467.3. Rf(cyclohexane / EtOAc, 1 : 1) = 0.43.

[0240] Step e) (R)-2-amino-3-(3-(4-(((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol (Example 8). Add (R)-(1-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxyprop-2-yl)aminocarbamate tributyl ester (8.5) (227 mg, 0.488 mmol), diethylcarbamate (5.0 mL), and aqueous HCl (5.0 mL, 10.00 mmol) to a 50 mL single-necked round-bottom flask equipped with a magnetic stir bar. Stir the turbid solution at rt for 18 hours. Add 2 M NaOH aqueous solution (5.0 ml, 10.0 mmol, 20.48 equivalents) and remove dioxane under vacuum. Then, alkalize the resulting clear aqueous phase with 2 M aqueous NaOH (final pH > 10); a white solid precipitates. Add EtOAc and extract the aqueous phase twice with EtOAc. Wash the organic layers with brine, combine, and dry with Na2SO4. Purify by column chromatography (ISCO CombiFlash Rf, absorbed on silica gel, MeOH in CH2Cl2, 0-10%) to obtain a colorless oily (R)-2-amino-3-(3-(4-(((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol (131 mg, 72.1%) (Example 8), which crystallizes overnight in a refrigerator. UPLC residence time: 0.76 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.13 (d,J= 8.7 Hz, 2H), 7.93 (d,J= 2.2 Hz, 1H), 7.55 (dd,J= 9.0, 2.2 Hz, 1H), 7.27 (d,J= 8.6 Hz, 2H), 3.71 (dd,J= 10.5, 4.3 Hz, 1H), 3.56 (dd,J= 10.6, 6.2 Hz, 1H), 3.53 - 3.45 (m, 1H), 3.14 (dd,J= 15.6, 4.7 Hz, 1H), 3.00 (dd,J= 15.6, 8.1 Hz, 1H). MS / ESI+ 365.3, 367.3. Example 9: (S)-(1-(3-(3-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester

[0241] Step a) 3-((5-iodopyridin-2-yl)oxy)benzonitrile (9.2). Add 2-fluoro-5-iodopyridine (9.1) (1.47 g, 6.59 mmol), 3-cyanophenol (2.2) (0.864 g, 7.25 mmol), K2CO3 (1.822 g, 13.18 mmol), and DMF (50.0 ml) to a 250 mL single-necked pear-shaped flask equipped with a magnetic stir bar and a reflux condenser. Stir the suspension at 100°C for 15 hours. A brown suspension is obtained. Add water and EtOAc. Extract the aqueous phase twice with EtOAc. Wash the organic layers with brine, combine, and dry with Na2SO4. Concentrate under vacuum to give a light brown oily substance that slowly crystallizes under reflux. Purification by column chromatography (ISCO CombiFlash Rf, absorbed on silicone, EtOAc in cyclohexane, 0-6% to 7.7%) yielded 1.95 g (92%) of 3-((5-iodopyridin-2-yl)oxy)benzonitrile as a white solid (9.2). UPLC retention time was 1.15 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.35 (d,J= 2.1 Hz, 1H), 7.98 (dd,J= 8.6, 2.3 Hz, 1H), 7.50 (d,J= 5.0 Hz, 2H), 7.47 - 7.43 (m, 1H), 7.38 (td,J= 4.7, 2.4 Hz, 1H), 6.84 (d,J= 8.6 Hz, 1H). MS / ESI+ 323.1 [M + H]+.

[0242] Step b) (Z)-N'-hydroxy-3-((5-iodopyridin-2-yl)oxy)benzomidine (9.3). Add 3-((5-iodopyridin-2-yl)oxy)benzonitrile (9.2) (1.95 g, 6.05 mmol), hydroxylamine hydrochloride (2.103 g, 30.3 mmol), NaHCO3 (2.54 g, 30.3 mmol), and ethanol (20.0 ml) / water (10.0 ml) to a 50 mL single-necked pear-shaped flask equipped with a magnetic stir bar. Heat the white suspension to 85°C and stir for 90 minutes. Cool the reaction mixture to rt. Remove EtOH under vacuum. Add water and EtOAc, and extract the aqueous phase twice with EtOAc. Wash the organic layers with brine, combine, and dry with Na2SO4. Concentrated under vacuum, (Z)-N'-hydroxy-3-((5-iodopyridin-2-yl)oxy)benzamidin (1.87 g, 86%) was obtained as a white solid (9.3). UPLC retention time was 0.77 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 9.67 (s, 1H), 8.37 (d,J= 2.2 Hz, 1H), 8.16 (dd,J= 8.6, 2.4 Hz, 1H), 7.54 (d,J= 7.9 Hz, 1H), 7.43 - 7.38 (m, 2H), 7.14 (dd,J= 8.0, 1.7 Hz, 1H), 6.95 (d,J= 8.6 Hz, 1H), 5.82 (s, 2H). MS / ESI+ 356.1 [M + H]+.

[0243] Step c) Benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-(((5-iodopyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propionate (9.4). Add (Z)-N'-hydroxy-3-((5-iodopyridin-2-yl)oxy)benzamidinium (9.3) (0.852 g, 2.375 mmol), Boc-Asp(Su)-OBzl (2.5) (1.048 g, 2.494 mmol), and THF (13.0 ml) to a 20 mL microwave-safe vial equipped with a magnetic stir bar. Stir the colorless solution at 100°C for 3 days. Remove volatiles under vacuum. Benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-(((5-iodopyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propionate (1.44 g, 93%) was purified by column chromatography (ISCO CombiFlash Rf, absorbed on silicone, EtOAc in cyclohexane, 0-15.9%) (9.4). UPLC retention time was 1.44 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.35 (d,J= 2.1 Hz, 1H), 7.95 (dd,J= 8.6, 2.3 Hz, 1H), 7.86 (d,J= 7.8 Hz, 1H), 7.78 (s, 1H), 7.50 (t,J= 8.0 Hz, 1H), 7.29 - 7.26 (m, 6H), 6.82 (d,J= 8.6 Hz, 1H), 5.55 (d,J= 7.5 Hz, 1H), 5.24 - 5.12 (m, 2H), 4.91 - 4.83 (m, 1H), 3.50 (qd,J= 16.2, 5.0 Hz, 2H), 1.43 (s, 9H). MS / ESI+ 643.3 [M + H]+.

[0244] Step d) (S)-3-(3-(3-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-2-((tert-butoxycarbonyl)amino)benzyl propionate (9.6). Add (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-(((5-iodopyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propionate (9.4) (1.41 g, 2.195 mmol), diisocyanate (20.0 ml) / water (10.0 ml), K3PO4 (1.398 g, 6.58 mmol), and 4-pyrazolboronic acid methyl ester (9.5) (0.459 g, 2.247 mmol, [CAS: 844501-71-9]) to a 100 mL two-necked round-bottom flask equipped with a magnetic stir bar, gas inlet, and rubber septum. Purge the suspension with Ar for 10 min. Then, Pd(dtbpf)Cl2 (0.143 g, 0.219 mmol) was added, and the reaction mixture was stirred at 70°C for 25 minutes. LC-MS analysis revealed complete conversion of the starting material within 25 minutes, but most of the product was saponified. The reaction mixture was cooled to rt. Volatiles were removed under vacuum. EtOAc, water, and 2 M aqueous HCl (10 mL) were added. The aqueous phase was extracted twice with EtOAc. The organic layer was then washed with approximately 0.1 M NaOH aqueous solution and brine, combined, and dried over sodium sulfate. Purification by column chromatography (ISCO CombiFlash Rf, absorbed on silicone, EtOAc in cyclohexane, 20%–50%) yielded (S)-3-(3-(3-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-2-((tert-butoxycarbonyl)amino)benzyl propionate (325.4 mg, 25.4%) (9.6). UPLC retention time was 1.22 min (Method A).1H NMR (400 MHz, CDCl3) δ = ppm 8.59 (d,J= 2.2 Hz, 1H), 8.16 (dd,J= 8.5, 2.3 Hz, 1H), 7.89 - 7.81 (m, 2H), 7.64 (d,J= 2.3 Hz, 1H), 7.51 (t,J= 8.0 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.27 (s, 5H), 7.03 (d,J= 8.5 Hz, 1H), 6.60 (d,J= 2.3 Hz, 1H), 5.57 (d,J= 7.8 Hz, 1H), 5.24 - 5.11 (m, 2H), 4.91 - 4.83 (m, 1H), 3.50 (qd,J= 16.2, 4.7 Hz, 2H), 1.42 (s, 9H)。MS / ESI+ 583.4 [M + H]+。

[0245] Step e) Tributyl (S)-(1-(3-(3-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate (9.7). Add benzyl (S)-3-(3-(3-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-2-((tributoxycarbonyl)amino)propionate (9.6) (229 mg, 0.393 mmol) to a 25 mL two-necked pear-shaped flask equipped with a magnetic stir bar, gas inlet, and rubber septum. Vacuum the flask and backfill with Ar five times. Add anhydrous THF (4.0 mL) and cool the colorless solution to 0°C. Then, LiBH4 (42.6 mg, 1.956 mmol) was added in a single batch, and the reaction mixture was stirred for 90 minutes. The ice bath was removed, and the suspension was stirred for another 30 minutes. The reaction was quenched with MeOH. The rm was stored in a refrigerator overnight. Volatile substances were removed under vacuum. Purification was performed by column chromatography (ISCO CombiFlash Rf, absorbed on silicone, EtOAc in cyclohexane, 40%-70%-80%-85%). Due to impurities, the product was purified by column chromatography (ISCO CombiFlash Rf, absorbed on silicone, EtOAc in cyclohexane, 55%-68%-70%) to give a colorless oily tributyl (S)-(1-(3-(3-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate (86.3 mg, 44.5%) (9.7). UPLC retention time was 0.92 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.58 (d,J= 2.4 Hz, 1H), 8.15 (dd,J= 8.5, 2.4 Hz, 1H), 7.92 (d,J= 7.8 Hz, 1H), 7.87 (d,J= 2.0 Hz, 1H), 7.64 (d,J= 2.3 Hz, 1H), 7.52 (t,J= 8.0 Hz, 1H), 7.32 (dd,J= 7.8, 2.0 Hz, 1H), 7.03 (d,J= 8.5 Hz, 1H), 6.60 (d,J= 2.2 Hz, 1H), 5.22 (d,J= 6.8 Hz, 1H), 4.22 - 4.15 (m, 1H), 3.84 - 3.74 (m, 2H), 3.28 (d,J= 5.9 Hz, 2H), 1.42 (s, 9H).MS / ESI+ 479.4 [M + H]+.

[0246] Step f) (S)-3-(3-(3-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-2-aminoprop-1-ol (Example 9). Add (S)-(1-(3-(3-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxyprop-2-yl)aminocarbamate tributyl ester (9.7) (86.3 mg, 0.180 mmol) and diethylcarbamate (2.0 ml) to a 12 mL single-necked pear-shaped flask equipped with a magnetic stir bar at rt. Upon addition of HCl (4 M solution) (0.451 mL, 1.804 mmol) to the dimethyl methacrylate (DMSO) solution, the reaction mixture immediately became a white suspension. It was stirred at rt for 17.5 h. The solvent was removed under vacuum. EtOAc and 2 M NaOH aqueous solution were added (until pH > 10). The aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over Na2SO4. Purification was performed by RP C18 column chromatography (ISCO CombiFlash Rf, liquid injection, MeCN (10%–35%) in water, fractions 21–27). The fractions were combined, and MeCN was removed under vacuum. Approximately 5 mL of 2 M NaOH aqueous solution was added, and the aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over Na2SO4. Concentrated under vacuum, (S)-3-(3-(3-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-2-aminoprop-1-ol (50.1 mg, 72.7%) was obtained as a white foam (Example 9). UPLC retention time was 0.60 min (Method A).1H NMR (400 MHz, CDCl3) δ = ppm 8.59 (d,J= 2.3 Hz, 1H), 8.14 (dd,J= 8.5, 2.4 Hz, 1H), 7.93 (d,J= 7.8 Hz, 1H), 7.90 - 7.87 (m, 1H), 7.62 (d,J= 2.4 Hz, 1H), 7.52 (t,J= 8.0 Hz, 1H), 7.32 (dd,J= 8.1, 1.5 Hz, 1H), 7.02 (d,J= 8.5 Hz, 1H), 6.59 (d,J= 2.4 Hz, 1H), 3.70 (dd,J= 10.6, 4.3 Hz, 1H), 3.55 (dd, J = 10.6, 6.3 Hz, 1H), 3.48 (ddd, J = 10.8, 7.2, 4.5 Hz, 1H), 3.13 (dd, J = 15.6, 4.7 Hz, 1H), 2.99 (dd, J = 15.6, 8.1 Hz, 1H). MS / ESI+ 379.3 [M + H]+. Example 10 (S)-2-amino-3-(3-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-acediazol-5-yl)prop-1-ol.

[0247] Step a) 3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzonitrile (10.1). Add 2-fluoro-5-(trifluoromethyl)pyridine (4.1) (1.30 g, 7.87 mmol), 3-cyanophenol (2.2) (1.032 g, 8.66 mmol), K₂CO₃ (2.177 g, 15.75 mmol), and DMF (30.0 ml) to a 250 mL single-necked pear-shaped flask equipped with a magnetic stir bar and a condenser (air). Heat the suspension to 65°C and stir for 19 hours. Add water / EtOAc. Extract the aqueous phase twice with EtOAc. Wash the organic layers with brine, combine, and dry with Na₂SO₄. Purification by column chromatography (ISCO CombiFlash Rf, absorbed on silicone, EtOAc in cyclohexane, 0-10%) yielded 3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzonitrile (1.97 g, 95%) (10.1). UPLC retention time was 1.11 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.44 - 8.41 (m, 1H), 7.97 (dd,J= 8.6, 2.4 Hz, 1H), 7.57 - 7.53 (m, 2H), 7.51 - 7.48 (m, 1H), 7.43 (tq,J= 5.4, ​​2.7 Hz, 1H), 7.10 (d,J= 8.6 Hz, 1H). MS / ESI+ 265.0 [M+H]+.

[0248] Step b) (Z)-N'-hydroxy-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzomidine (10.2). Add 3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzonitrile (10.1) (1.93 g, 7.30 mmol), hydroxylamine hydrochloride (2.54 g, 36.5 mmol), NaHCO3 (3.07 g, 36.5 mmol), and ethanol (30.0 ml) / water (10.0 ml) to a 100 mL single-necked pear-shaped flask equipped with a magnetic stir bar and a condenser (air). Stir the white suspension at 85°C for 80 minutes. Store the reaction mixture in a refrigerator over the weekend. Remove EtOH under vacuum. Add EtOAc and water. Extract the aqueous phase twice with EtOAc. Wash the organic layers with brine, combine, and dry with Na2SO4. The product was concentrated under vacuum and dried under high vacuum to obtain (Z)-N'-hydroxy-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzamidin (2.25 g, 100%) as a brown, viscous foam (10.2). UPLC retention time was 0.80 min (Method A). 1H NMR (400 MHz, DMSO-d6) δ = ppm 9.69 (s, 1H), 8.57 (s, 1H), 8.24 (dd,J= 8.7, 2.5 Hz, 1H), 7.60 (d,J= 7.9 Hz, 1H), 7.50 - 7.41 (m, 2H), 7.26 (d,J= 8.7 Hz, 1H), 7.21 (dd,J= 8.0, 1.7 Hz, 1H), 5.84 (s, 2H). MS / ESI+ 298.2 [M + H]+.

[0249] Step c) (S)-2-((tributoxycarbonyl)amino)-3-(3-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)benzyl propionate (10.3). Add (Z)-N'-hydroxy-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzamide (10.2) (758 mg, 2.55 mmol), Boc-Asp(Su)-OBzl (2.5) (1179 mg, 2.81 mmol), and THF (13.0 ml) to a 20 mL microwave-safe vial equipped with a magnetic stir bar. Stir the light brown solution at rt for 10 min, then at 110°C for 17.5 h. Remove the solvent under vacuum. Add dichloromethane and silicone. Purification by column chromatography (ISCO CombiFlash Rf, absorbed on silicone, EtOAc in cyclohexane, 0-18%) yielded a colorless, highly viscous oil, (S)-2-((tributoxycarbonyl)amino)-3-(3-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propionate (1.40 g, 94%) (10.3). UPLC retention time was 1.41 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.45 - 8.42 (m, 1H), 7.96 - 7.89 (m, 2H), 7.83 - 7.80 (m, 1H), 7.54 (t,J= 8.0 Hz, 1H), 7.31 (ddd,J= 8.2, 2.4, 0.9 Hz, 1H), 7.29 - 7.26 (m, 5H), 7.08 (d,J= 8.7 Hz, 1H), 5.55 (d,J= 7.8 Hz, 1H), 5.25 - 5.11 (m, 2H), 4.92 - 4.84 (d,J= 7.3 Hz, 1H), 3.51 (qd,J= 16.2, 5.0 Hz, 2H), 1.42 (s, 9H). MS / ESI+ 585.3 [M + H]+.

[0250] Step d) Tributyl (S)-(1-hydroxy-3-(3-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-2-yl)aminocarbamate (10.4). Add (S)-2-((tributoxycarbonyl)amino)-3-(3-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propionate (10.3) (550 mg, 0.941 mmol) to a 25 mL two-necked round-bottom flask equipped with a magnetic stir bar, rubber septum, and gas inlet. Vacuum the flask and backfill with Ar five times. Add THF (6.0 mL) and cool the colorless solution to 0°C. LiBH4 (41.0 mg, 1.882 mmol) was then added, and the reaction mixture was stirred for 80 minutes. LiBH4 (20.5 mg, 0.941 mmol) was added again after 50 minutes. The yellow suspension was quenched with MeOH. Volatile substances were then removed under vacuum. Purification by column chromatography (ISCO CombiFlash Rf, absorbed on silica gel, EtOAc in cyclohexane, 25%–50%) yielded a viscous, colorless, oily tributyl (S)-(1-hydroxy-3-(3-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propyl-2-yl)aminocarbamate (298 mg, 65.9%) (10.4). UPLC retention time: 1.17 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.44 - 8.41 (m, 1H), 7.96 (d,J= 7.8 Hz, 1H), 7.92 (dd,J= 8.7, 2.4 Hz, 1H), 7.88 - 7.82 (m, 1H), 7.54 (t,J= 8.0 Hz, 1H), 7.30 (ddd,J= 8.1, 2.3, 0.8 Hz, 1H), 7.06 (d,J= 8.7 Hz, 1H), 5.28 (d,J= 7.7 Hz, 1H), 4.23 - 4.12 (m, 1H), 3.76 (q,J= 6.5, 5.2 Hz, 2H), 3.27 (d,J= 5.9 Hz, 2H), 1.40 (s, 9H). MS / ESI+ 481.2 [M + H]+.

[0251] Step e) (S)-2-amino-3-(3-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol (Example 10). Add (S)-(1-hydroxy-3-(3-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-2-yl)aminocarbamate tributyl ester (10.4) (297 mg, 0.618 mmol), diethylcarbamate (6.0 ml), and aqueous HCl (6.0 ml, 12.00 mmol) to a 25 mL single-necked pear-shaped flask equipped with a magnetic stir bar. Stir the resulting turbid solution at rt for 4 days. Simultaneously, a colorless, clear solution is obtained. Add 2 M NaOH aqueous solution (6.0 ml, 12.00 mmol). Remove diethyl sulfoxide under vacuum. Add EtOAc and about 0.2 M aqueous NaOH. Extract the aqueous phase twice with EtOAc. Wash the organic layer with brine, combine and dry with Na2SO4. Purify by column chromatography (ISCO CombiFlash Rf, absorbed on silica gel, MeOH in CH2Cl2, 0-7.7%) to give (S)-2-amino-3-(3-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol (184 mg, 78%) (Example 10), which is a colorless oil and crystallizes at rt to give a white solid. UPLC retention time 0.78 min (Method A). 1H NMR (400 MHz, CDCl3) δ = ppm 8.37 (s, 1H), 7.91 (t,J= 7.6 Hz, 2H), 7.81 (s, 1H), 7.51 (t,J= 7.9 Hz, 1H), 7.27 (d,J= 7.4 Hz, 1H), 7.03 (d,J= 8.6 Hz, 1H), 3.70 (d,J= 8.3 Hz, 1H), 3.59 - 3.45 (m, 2H), 3.16 - 3.09 (m, 2H). MS / ESI+ 381.2 [M+H]+. Example 11 (S)-2-amino-3-(3-(3-((R)-2,3-dihydro-[1,4]dioxano[2,3-b]pyridin-3-yl)phenyl)-1,2,4-diazol-5-yl)prop-1-ol

[0252] Step a) 1-(3-bromophenyl)-2-((2-iodopyridin-3-yl)oxy)ethyl-1-one (11.3). Add 2-chloropyridin-3-ol (10.90 g, 82 mmol), 2-bromo-1-(3-bromophenyl)ethyl one (23.38 g, 82 mmol), acetone (330 ml), and cesium carbonate (32.2 g, 99 mmol) to a 1000 mL single-necked flask equipped with a magnetic stir bar. Stir the orange suspension at rt for 16 hr. Filter the reaction mixture and wash the filter cake with cold acetone. Concentrate the filtrate under vacuum to give 33.31 g of crude material. Dissolve it in ethyl acetate, wash with water and brine, dry over sodium sulfate, filter, and concentrate under vacuum to give 29.8 g of brown viscous substance. 1-(3-bromophenyl)-2-((2-iodopyridin-3-yl)oxy)ethyl-1-one (9.1 g, 23%) (11.3) was obtained by silica gel chromatography (cyclohexane / ethyl acetate). The UPLC retention time was 1.07 min (Method A). 1H NMR (400 MHz, chloroform-d) δ = ppm ppm 5.34 (s, 2 H) 7.14 - 7.21 (m, 2 H), 7.41 (t, J = 7.85 Hz, 1 H), 7.78 (d, J = 7.73 Hz, 1 H), 7.95 (dt, J = 7.82, 1.28 Hz, 1 H), 8.07 (dd, J = 4.28, 1.96 Hz, 1 H), 8.16 (t, J = 1.71 Hz, 1 H). MS / ESI+ 326, 328, 330.

[0253] Step b) (R)-1-(3-bromophenyl)-2-((2-iodopyridin-3-yl)oxy)ethyl-1-ol (11.5). Add 1-(3-bromophenyl)-2-((2-iodopyridin-3-yl)oxy)ethyl-1-one (11.3) (5.22 g, 15.18 mmol) to a 1000 mL two-necked flask equipped with a magnetic stir bar and a thermometer, followed by the addition of DMF (67.3 mL). N-((1S,2S)-2-amino-1,2-diphenylethyl)-4-methylbenzenesulfonamide (11.4) (0.170 g, 0.456 mmol, [CAS: 167316-27-0], Strem Chemicals) and Cp*RhCl2 dimer (CAS: 12354-85-7) (0.094 g, 0.152 mmol) were added. The reaction mixture was degassed with argon at 0°C for 20 min. Formic acid-triethylamine complex 5:2 (4.66 ml, 11.16 mmol, CAS: 115077-13-1) was added after 15 min at 0°C. The mixture was stirred continuously at 0°C for 50 min. The reaction mixture was then poured into water (230 ml) and extracted with ethyl acetate. The mixture was washed with water and brine, dried over sodium sulfate, filtered, and concentrated under vacuum to give (R)-1-(3-bromophenyl)-2-((2-iodopyridin-3-yl)oxy)ethanol-1-ol (5.45 g, 100%) (11.5). This material was used in the next step without further purification. UPLC retention time was 0.99 min (Method A). 1H NMR (400 MHz, chloroform-d) δ = ppm ppm 4.06 (dd, J = 9.29, 8.31 Hz, 1 H), 4.19 (dd, J = 9.41, 3.42 Hz, 1 H), 5.18 (dd, J = 8.25, 3.36 Hz, 1 H), 7.17 - 7.26 (m, 2 H), 7.28 - 7.31 (m, 1 H), 7.41 (d, J = 7.70 Hz, 1 H), 7.49 (d, J = 7.95 Hz, 1 H), 7.66 (s, 1 H), 7.99 - 8.11 (m, 1 H). MS / ESI+ 328, 330, 332.

[0254] Step c) (R)-3-(3-bromophenyl)-2,3-dihydro-[1,4]dioxinco[2,3-b]pyridine (11.6). (R)-1-(3-bromophenyl)-2-((2-iodopyridin-3-yl)oxy)ethyl-1-ol (11.5) (5.45 g, 15.76 mmol) was added sequentially to a 500 mL two-necked flask equipped with a magnetic stir bar and a reflux condenser, followed by DME (197 mL). 1 M KHMDS (15.95 mL, 15.95 mmol, [CAS: 40949-94-8]) in THF was added dropwise at 60°C under argon atmosphere. The reaction mixture was stirred at this temperature for 1.5 hr. Then, 1 M KHMDS (3 mL) in THF was added again at 60°C, and stirring was continued for 60 min. The reaction mixture was quenched with water (100 ml) at rt and extracted with ethyl acetate. The mixture was thoroughly washed with water, saturated NH4Cl aqueous solution, and brine, dried over sodium sulfate, filtered, and concentrated under vacuum. Silica gel chromatography (gradient: cyclohexane / ethyl acetate) yielded (R)-3-(3-bromophenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (2.95 g, 42.2%) (11.6). UPLC retention time 1.06 min (Method A). 1H NMR (400 MHz, DMSO-d6) δ = ppm 4.16 (dd, J = 11.62, 8.19 Hz, 1 H), 4.49 (dd, J = 11.55, 2.51 Hz, 1 H), 5.49 (dd, J = 8.01, 2.26 Hz, 1 H), 7.00 (dd, J = 7.82, 4.77 Hz, 1 H), 7.37 (d, J = 7.63 Hz, 1 H), 7.42 (t, J = 7.95 Hz, 1 H), 7.52 (d, J = 7.70 Hz, 1 H), 7.61 (d, J = 8.07 Hz, 1 H), 7.72 (s, 1 H), 7.81 (dd, J = 4.77, 1.34 Hz, 1 H). MS / ESI+ 292, 294.

[0255] Step d) (R)-3-(2,3-dihydro-[1,4]dioxindo[2,3-b]pyridin-3-yl)benzonitrile (11.7). Add (R)-3-(3-bromophenyl)-2,3-dihydro-[1,4]dioxindo[2,3-b]pyridine (11.6) (1.158 g, 3.96 mmol) to a 100 mL two-necked flask equipped with a magnetic stir bar and a reflux condenser, followed by the addition of DMF (21 mL). Add zinc cyanide (1.862 g, 15.86 mmol), 1,1'-bis(diphenyl-phospho)ferrocene (1.758 g, 3.17 mmol, [CAS: 12150-46-8]), and Pd2(dba)3 (0.726 g, 0.793 mmol), and degas the reaction mixture with argon. The mixture was stirred at 80°C for 20 hr under argon atmosphere. The cold reaction mixture was diluted with ethyl acetate (250 ml) and washed twice with 5% sodium bicarbonate solution, water, and brine. It was dried over sodium sulfate, filtered, and concentrated under vacuum. Silica gel chromatography (gradient: cyclohexane / ethyl acetate) yielded (R)-3-(2,3-dihydro-[1,4]dioxano[2,3-b]pyridin-3-yl)benzonitrile (750 mg, 79%) (11.7). UPLC retention time was 0.86 min (Method A). 1H NMR (400 MHz, DMSO-d6) δ = ppm 4.19 (dd, J = 11.55, 8.13 Hz, 1 H), 4.52 (dd, J = 11.55, 2.51 Hz, 1 H), 5.56 (dd, J = 8.07, 2.20 Hz, 1 H), 7.01 (dd, J = 7.82, 4.77 Hz, 1 H), 7.38 (dd, J = 7.89, 1.53 Hz, 1 H), 7.68 (t, J = 7.48 Hz, 1 H), 7.81 - 7.91 (m, 3 H), 7.98 (s, 1 H). MS / ESI+ 239[M+H]+.

[0256] Step e) (R,Z)-3-(2,3-dihydro-[1,4]dioxano[2,3-b]pyridin-3-yl)-N'-hydroxybenzoamide (11.8). Add (R)-3-(2,3-dihydro-[1,4]dioxano[2,3-b]pyridin-3-yl)benzonitrile (11.7) (380 mg, 1.59 mmol) and ethanol (7 ml) to a 50 mL two-necked flask equipped with a magnetic stir bar and a reflux condenser. Add dropwise 50% aqueous hydroxylamine (0.376 ml, 6.38 mmol) and reflux the reaction mixture for 3.5 hr to obtain a clear solution. The mixture was extracted twice with dichloromethane and concentrated under vacuum to give crude (R,Z)-3-(2,3-dihydro-[1,4]dioxano[2,3-b]pyridin-3-yl)-N'-hydroxybenzomidine (477 mg, 85%) (11.8), which was used in the next step without further purification. The small probe (51 mg) was purified by SFC to give 38 mg of beige foam. UPLC retention time was 0.54 min (Method A). 1H NMR (400 MHz, chloroform-d) δ = ppm 2.30 (br s, 4 H), 4.02 (dd, J = 11.68, 8.86 Hz, 1 H), 4.41 (dd, J = 11.62, 2.45 Hz, 1 H), 5.09 (br s, 2 H), 5.36 (dd, J = 8.80, 2.20 Hz, 1 H), 6.94 (dd, J = 7.82, 4.77 Hz, 1 H), 7.26 (br s, 1 H), 7.44 - 7.57 (m, 2 H), 7.68 (d, J = 7.70 Hz, 1 H), 7.78 (s, 1 H), 7.90 (dd, J = 4.71, 1.53 Hz, 1H). MS / ESI+ 272[M+H]+.

[0257] Step f) (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-((R)-2,3-dihydro-[1,4]diacino[2,3-b]pyridin-3-yl)phenyl)-1,2,4-diazol-5-yl)benzyl propionate (11.9). (R,Z)-3-(2,3-dihydro-[1,4]dioxano[2,3-b]pyridin-3-yl)-N'-hydroxybenzomidine (11.8) (477 mg, 1.35 mmol) and 2-Me-THF (13.5 ml) were added to a 50 mL two-necked flask equipped with a magnetic stir bar and a reflux condenser, followed by Boc-Asp(OSu)-OBzl (2.5) [CAS 140171-25-1] (655 mg, 1.55 mmol, from Bachem). The reaction mixture was refluxed for 2 days. The solvent was evaporated on a rotary evaporator to give 1.30 g of crude product. Benzyl (S)-2-((tert-butoxycarbonyl)-amino)-3-(3-(3-((R)-2,3-dihydro-[1,4]dioxin-[2,3-b]pyridin-3-yl)phenyl)-1,2,4-diazol-5-yl)propionate (374 mg, 45.5.%) (11.9%) was obtained by silica gel chromatography (gradient: cyclohexane / ethyl acetate). UPLC retention time was 1.27 min (Method A). 1H NMR (400 MHz, chloroform-d) δ = ppm 1.27 (s, 2 H), 1.44 (s, 11 H), 1.60 (br s, 3 H), 3.51 (br d, J = 4.89 Hz, 2 H), 4.06 (dd, J = 11.68, 8.86 Hz, 1 H), 4.43 (dd, J = 11.61, 2.32 Hz, 1 H), 4.90 (br s, 1 H), 5.14 - 5.27 (m, 3 H), 5.36 - 5.44 (m, 1 H,) 5.47 - 5.63 (m, 1 H), 6.95 (dd, J = 7.89, 4.83 Hz, 1H), 7.29 (br s, 3 H), 7.35 (s, 2 H), 7.55 (t, J = 7.76 Hz, 1 H), 7.66 (br d, J = 7.70 Hz, 1 H), 7.91 (dd, J = 4.77, 1.34 Hz, 1 H), 8.03 (d, J = 7.70 Hz, 1 H), 8.09 (s, 1 H). MS / ESI+ 559[M+H]+.

[0258] Step g) ((S)-1-(3-(3-((R)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-3-yl)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester (11.10). Add (S)-2-((tributoxycarbonyl)-amino)-3-(3-(3-((R)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-3-yl)phenyl)-1,2,4-diazol-5-yl)propionate benzyl ester (11.9) (350 mg, 0.627 mmol) and THF (8.3 ml) to a 100 mL single-necked flask equipped with a magnetic stir bar. Lithium borohydride (54.6 mg, 2.506 mmol) was added at 0°C, and the cooling bath was removed after 10 min. After stirring at rt for 7 hr, the reaction mixture was poured into ice water and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. Silica gel chromatography (gradient: cyclohexane / ethyl acetate) yielded tributyl ((S)-1-(3-(3-((R)-2,3-dihydro-[1,4]dioxindo[2,3-b]pyridin-3-yl)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate (63 mg, 22%) (11.10). UPLC retention time was 0.96 min (Method A). 1H NMR (400 MHz, chloroform-d) δ = ppm 1.44 (s, 9 H), 3.31 (br d, J = 6.11 Hz, 2 H), 3.83 (t, J = 4.22 Hz, 2 H), 4.07 (dd, J = 11.68, 8.86 Hz, 1 H), 4.21 (br s, 1 H), 4.45 (dd, J = 11.68, 2.51 Hz, 1 H), 5.13 - 5.27 (m, 1 H), 5.42 (dd, J = 8.80, 2.32 Hz, 1 H), 6.95 (dd, J = 7.89, 4.83 Hz, 1 H), 7.28 - 7.30 (m, 1 H), 7.56 (t, J = 7.76 Hz, 1 H), 7.66 (d, J = 7.82 Hz, 1 H), 7.91 (dd, J = 4.77, 1.59 Hz, 1 H), 8.10 (d, J = 7.70 Hz, 1 H), 8.17 (s, 1 H). MS / ESI+ 455[M+H]+.

[0259] Step h) (S)-2-amino-3-(3-(3-((R)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-3-yl)phenyl)-1,2,4-diazol-5-yl)prop-1-ol (Example 11): Add ((S)-1-(3-(3-((R)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-3-yl)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester (11.10) (46 mg, 0.101 mmol) and diethylcarbamate (1 ml) to a 25 mL single-necked flask equipped with a magnetic stir bar. 2 M HCl (0.506 ml, 1.012 mmol) was added to dichloromethane, and the mixture was stirred overnight at rt. The reaction mixture was concentrated under vacuum, and the remaining white solid was milled twice with dichloromethane and evaporated. The coarse white powder was milled twice with diethyl ether in an ultrasonic bath and decanted to give (S)-2-amino-3-(3-(3-((R)-2,3-dihydro-[1,4]dioxindo[2,3-b]pyridin-3-yl)phenyl)-1,2,4-diazol-5-yl)prop-1-ol (38 mg, 99%) as a white powder (Example 11). UPLC retention time: 0.59 min (Method A). 1H NMR (400 MHz, DMSO-d6) δ = ppm 3.29 - 3.47 (m, 2 H), 3.59 - 3.79 (m, 3 H), 4.17 (dd, J = 11.55, 8.25 Hz, 1 H), 4.55 (br dd, J = 11.61, 2.45 Hz, 2 H), 5.62 (dd, J = 8.13, 2.14 Hz, 1 H), 7.02 (dd, J = 7.82, 4.77 Hz, 1 H), 7.40 (dd, J = 7.82, 1.59 Hz, 1 H), 7.64 - 7.76 (m, 2 H), 7.83 (dd, J = 4.77, 1.47 Hz, 1 H), 8.06 (d, J = 7.70 Hz, 1 H), 8.18 (s, 1 H), 8.29 (br s, 3 H). MS / ESI+ 355 [M + H]+. Example 12 (S)-2-amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol

[0260] Step a) (Z)-4-((5-chloro-3-fluoropyridin-2-yl)oxy)-N'-hydroxybenzamide (12.1). Add 26.3 (2.82 g, 11.34 mmol), NaHCO3 (4.76 g, 56.7 mmol), hydroxylamine hydrochloride (3.94 g, 56.7 mmol), ethanol (40 ml), and water (15 ml) to a 100 mL single-necked flask equipped with a magnetic stir bar and a condenser (air) (Caution: gas formation). Heat the white suspension to 85°C and stir for 100 min. Then cool it to 25°C. Remove the ethanol under vacuum. Add water and ethyl acetate, and extract the aqueous phase with ethyl acetate. Wash the organic layer with brine, dry with Na2SO4 to remove the solvent, and give 12.1 (3.18 g, 97%) as a colorless solid. UPLC retention time: 0.73 min (Method A). 1H NMR (DMSO-d6): δ = ppm 9.62 (1H, s), 8.23 ​​(1H, dd), 8.06 (1H, d), 7.71 (2H, d), 7.20 (2H, d), 5.82 (2H, s). MS / ESI 282.2 [M + H]+.

[0261] Step b) (S)-2-((tributoxycarbonyl)amino)-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propionate (12.3). 12.1 (0.60 g, 2.066 mmol), 12.2 (0.985 g, 2.343 mmol), and THF (13 mL) were added to a 20 mL microwave-safe vial equipped with a magnetic stir bar. The colorless solution was stirred at 25°C for 30 min. It was then heated to 110°C and stirred for 15 h. The solvent was removed under vacuum. Silica gel chromatography (gradient: cyclohexane / ethyl acetate) yielded 12.3 (829 mg, 71%) as a colorless oil. UPLC retention time was 1.41 min (Method A). 1H NMR (CDCl3): δ = ppm 8.05 (2H, d), 7.93 (1H, d), 7.55 (1H, dd), 7.28 (5H, s), 7.25 (2H, s), 5.58 (1H, d), 5.25 - 5.13 (2H, m), 4.90 (1H, d), 3.51 (2H, dq), 1.44 (9H, s). MS / ESI 569.4 [M + H]+.

[0262] Step c) (S)-(1-(3-(4-(((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester (12.4). Add 12.3 (474 ​​mg, 0.833 mmol) to a 25 mL two-necked round-bottom flask equipped with a magnetic stir bar, gas inlet, and rubber septum. Vacuum the flask and backfill with argon three times. Add anhydrous THF (8.0 mL) and cool the solution to 0°C. Add LiBH4 (91 mg, 4.17 mmol) in a single addition and stir the suspension for 1.5 h. Quench the reaction mixture with methanol. Remove the solvent, dissolve the crude product in dichloromethane, and adsorb it onto silica gel. Silica gel chromatography (gradient: cyclohexane / ethyl acetate) yielded 12.4 (229 mg, 58%) as a viscous, colorless oil. UPLC retention time was 1.17 min (Method A). ¹H NMR (400 MHz, CDCl₃): δ = ppm 8.12 (2H, d), 7.93 (1H, d), 7.55 (1H, dd), 7.27 (2H, d), 5.21 (1H, s), 4.24 - 4.16 (1H, s, br), 3.81 (2H, m), 3.30 (2H, d), 1.44 (9H, s). MS / ESI 465.3 [M + H]⁺.

[0263] Step d) (S)-2-amino-3-(3-(4-(((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol (Example 12). 12.4 (225 mg, 0.484 mmol), CH2Cl2 (5.0 mL), and TFA (0.186 mL, 2.42 mmol) were added to a 25 mL pear-shaped flask equipped with a magnetic stir bar. The colorless solution was stirred at 25°C for 65 h. The solvent and acid were removed, and the residue was dissolved in ethyl acetate. Aqueous NaOH (0.1 M) and ethyl acetate were added, and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Silicone purification (gradient: CH2Cl2 / MeOH) yielded a colorless oily product, Example 12, which slowly solidified at 25°C (64 mg, 36%). UPLC retention time: 0.74 min (Method A). ¹H NMR (CDCl3): δ = ppm 8.13 (2H, d), 7.93 (1H, d), 7.55 (1H, dd), 7.27 (2H, d), 3.71 (1H, dd), 3.56 (1H, dd), 3.53 - 3.45 (1H, d), 3.14 (1H, dd), 3.00 (1H, dd). No OH or NH2 observed. ES / ESI 365.2 [M + H]+. Example 13 (S)-3-(3-(4-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-2-aminoprop-1-ol

[0264] Step a) 4-((5-bromopyridin-2-yl)oxy)benzonitrile (13.3). A suspension of 13.1 (2.5 g, 14.2 mmol), 13.2 (1.86 g, 15.6 mmol), and K2CO3 (5.9 g, 42.6 mmol) in DMF (70 mL) was heated to 110°C and maintained for 18 h. The reaction mixture was cooled to 25°C. Water and ethyl acetate were added, and the aqueous phase was extracted twice with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and the solvent was removed. The residue was purified on silica gel (gradient: cyclohexane / ethyl acetate) to give compound 13.3 (3.30 g, 84%) as a colorless solid. UPLC retention time 1.10 min (Method A). 1H NMR (CDCl3): δ = ppm 8.23 ​​(1H, d), 7.85 (1H, dd), 7.72-7.67 (2H, m), 7.25-7.20 (2H, m), 6.94 (1H, d). MS / ESI 275.1 [M + H]+.

[0265] Step b) 4-((5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)benzonitrile (13.5). Add 13.3 (3.23 g, 11.74 mmol), K3PO4 (7.48 g, 35.2 mmol), 13.4 (3.92 g, 14.1 mmol), Pd(PPh3)4 (0.678 g, 0.587 mmol), and toluene (70 mL) to a 250 mL two-necked round-bottom flask equipped with a magnetic stir bar, rubber septum, and gas inlet. Purge the suspension with argon for 15 min. Replace the gas inlet with a reflux condenser, heat the reaction mixture to 110°C, and stir for 2 h. Cool the suspension to 25°C and store in a refrigerator for 16 h. Add water and ethyl acetate, and extract the aqueous phase twice with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and the solvent removed. Silica gel chromatography (gradient: cyclohexane / ethyl acetate) and crystallization from ethyl acetate yielded compound 13.5 (1.54 g, 38%) as a colorless solid. UPLC retention time: 1.09 min (Method A). 1H NMR (CDCl3): δ = ppm 8.33 (1H, d), 7.94 (1H, dd), 7.75-7.69 (2H, m), 7.62 (1H, d), 7.34 - 7.28 (2H, m), 7.11 (1H, d), 6.36 (1H, d), 5.14 (1H, dd), 4.16-4.05 (1H, m), 3.59 (1H, dt), 2.58 (1H, ddt), 2.14-2.05 (1H, m), 1.95-1.85 (1H, m), 1.82-1.68 (1H, m), 1.62 - 1.51 (2H, m). MS / ESI 347.2 [M + H]+.

[0266] Step c) (Z)-N'-hydroxy-4-((5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)benzamidinium (13.6). Hydroxylamine hydrochloride (1.54 g, 22.1 mmol), NaHCO3 (1.86 g, 22.1 mmol), and water (10 ml) were added to a 100 mL single-necked flask equipped with a magnetic stir bar. The colorless suspension was stirred at 25°C (caution: gas formation) for 5 minutes. Compound 13.5 (1.53 g, 4.42 mmol) and ethanol (25 ml) were added, and the reaction mixture was stirred at 85°C for 90 minutes. The ethanol was removed, and water and ethyl acetate were added. The aqueous phase was extracted twice with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4. The solvent was removed, and the residue was purified on silica gel (gradient: cyclohexane / ethyl acetate) to give compound 13.6 (1.62 g, 97%) as a colorless solid. UPLC retention time: 0.71 min (Method A). 1H NMR (CDCl3): δ = ppm 8.33 (1H, d), 7.89 (1H, dd), 7.74-7.68 (m, 2H), 7.62 (1H, d), 7.25-7.20 (2H, m), 7.04 (1H, d), 6.35 (1H, d), 5.14 (1H, dd), 4.87 (s, 2H), 4.09 (1H, dd), 3.59 (1H, td), 2.65-2.51 (1H, m), 1.88 (1H, d), 1.82-1.68 (1H, m), 1.65-1.52 (2H, m). MS / ESI 380.4 [M+H]+.

[0267] Step d) (2S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-((5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)benzyl propionate (13.8). Add 13.6 (1.31 g, 3.45 mmol), 13.7 (1.60 g, 3.80 mmol), and THF (20 ml) to a 50 mL two-necked round-bottom flask equipped with a magnetic stir bar, reflux condenser, and rubber septum. Stir the colorless solution at 25°C for 30 minutes, then heat to 90°C and maintain for 7 days. The solvent was removed, and the residue was purified on silica gel (gradient: cyclohexane / ethyl acetate) to give 13.8 g (1.68 g, 73%) as a mixture of epimers, which was used in the next step. UPLC retention time 1.39 min (Method A). MS / ESI 667.4 [M + H]+.

[0268] Step e) ((2S)-1-hydroxy-3-(3-(4-((5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propyl-2-yl)aminocarbamate tributyl ester (13.9). Add 13.8 (634 mg, 0.951 mmol) to a 25 mL two-necked round-bottom flask equipped with a magnetic stir bar, gas inlet, and rubber septum. Evacuate the flask and backfill with argon three times. Add anhydrous THF (5.0 mL) and cool the colorless solution to 0°C. Add lithium borohydride (104 mg, 4.75 mmol) and stir the suspension for 1 h. Quench the reaction mixture with methanol. The solvent was removed, the crude product was dissolved in dichloromethane and purified on silica gel (gradient: cyclohexane / ethyl acetate) to give 13.9 g (white solid) (276 mg, 52%) as a mixture of epimers, which was used in the next step. UPLC retention time 1.14 min (Method A). MS / ESI 563.4 [M + H]+.

[0269] Step f) (S)-3-(3-(4-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-2-aminoprop-1-ol (Example 13). Add 13.9 g (276 mg, 0.491 mmol), diazonium (5.0 mL), and aqueous HCl (5.0 mL, 10.00 mmol, 2 M solution) to a 25 mL single-necked round-bottom flask equipped with a magnetic stir bar. Stir the turbid solution at 25°C for 18 h. Remove diazonium and water, and purify the residue by RP C18 column chromatography (ISCO CombiFlash Rf, liquid injection, MeCN in water, 10%–35%). Remove acetonitrile, and alkalize the aqueous phase with 2 M aqueous NaOH. Ethyl acetate was added, and the aqueous phase was extracted twice with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give Example 13 (112 mg, 60%) as a colorless solid. UPLC retention time was 0.59 min (Method A). 1H NMR (DMSO-d6): δ = ppm 13.00 (1H, s), 8.65 (1H, s), 8.30 (1H, d), 8.07 (2H, d), 7.83 (1H, s, br), 7.35 (2H, d), 7.20 (1H, d), 6.79 (1H, s), 4.80 (1H, m), 3.38 (2H, m), 3.22 (1H, m), 3.15 (1H, dd), 2.88 (1H, dd), 1.75 (2H, m). MS / ESI 379.4 [M + H]+. Example 14 (S)-2-amino-3-(5-(3-((R)-2,3-dihydro-[1,4]diaoxino[2,3-b]pyridin-3-yl)phenyl)-2H-tetrazole-2-yl)prop-1-ol

[0270] Step a) (R)-3-(3-(2H-tetrazol-5-yl)phenyl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine (14.1). A suspension of (R)-3-(2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-3-yl)benzonitrile (11.7) (500 mg, 2.099 mmol), dibutyltin oxide (104 mg, 0.42 mmol, [CAS: 818-08-6]) and TMS-azide (509 mg, 4.2 mmol, [CAS: 4648-54-8]) in toluene (11.70 ml) was heated to 100°C and maintained for 21.5 h. The cold reaction mixture was diluted with methanol (50 ml) and concentrated under vacuum. The crude product was ground with a small amount of methanol in a 1:1 mixture of diethyl ether and dichloromethane and filtered. The solid was washed with a 1:1 mixture of diethyl ether and dichloromethane and dried to give (R)-3-(3-(2H-tetrazol-5-yl)phenyl)-2,3-dihydro-[1,4]dioxano[2,3-b]pyridine (386 mg, 65.4%) (14.1) as a beige powder. UPLC retention time was 0.70 min (Method A). 1H NMR (400 MHz, DMSO-d6) δ = ppm 2.99 - 3.66 (m, 4 H), 4.17 (dd, J = 11.62, 8.31 Hz, 1 H), 4.55 (dd, J = 11.62, 2.45 Hz, 1 H), 5.61 (dd, J = 8.19, 2.20 Hz, 1 H), 7.02 (dd, J = 7.95, 4.77 Hz, 1 H), 7.39 (dd, J = 7.82, 1.47 Hz, 1 H), 7.64 - 7.76 (m, 2 H), 7.84 (dd, J = 4.65, 1.47 Hz, 1 H), 8.06 (d, J = 7.21 Hz, 1 H), 8.21 (s, 1 H). MS / ESI+282[M+H]+.

[0271] Step b) Methyl propionate (S)-2-((tert-butoxycarbonyl)amino)-3-(5-(3-((R)-2,3-dihydro-[1,4]diaoxin[2,3-b]pyridin-3-yl)phenyl)-2H-tetrazole-2-yl)propionate (14.3). DIAD (419 g, 1.822 mmol), PPh3 (478 mg, 1.822 mmol, 2.50 mmol), and Boc-L-Ser-OMe (14.2) (420 mg, 1.822 mmol) were added to a solution of (R)-3-(3-(2H-tetrazol-5-yl)phenyl)-2,3-dihydro-[1,4]diacino[2,3-b]pyridine (14.1) (336 mg, 0.729 mmol) in THF (14.6 mL) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4.5 h. Isolute was added, the mixture was concentrated under vacuum, and the residue was purified on silica gel (ethyl acetate / cyclohexane) to give methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(5-(3-((R)-2,3-dihydro-[1,4]dioxindo[2,3-b]pyridin-3-yl)phenyl)-2H-tetrazol-2-yl)propionate (490 mg, 98%) (14.3). UPLC retention time 1.09 min (Method A). 1H NMR (400 MHz, chloroform-d) δ = ppm 1.44 (s, 9 H), 3.80 (s, 7 H), 3.95 (dd, J = 11.43, 3.73 Hz, 4 H), 4.04 - 4.17 (m, 2 H), 4.34 - 4.49 (m, 1 H), 4.91 (br s, 1 H), 5.05 - 5.22 (m, 1 H), 5.27 - 5.50 (m, 4 H), 6.95 (dd, J = 7.89, 4.83 Hz, 1 H), 7.28 - 7.32 (m, 1 H), 7.52 - 7.65 (m, 2 H), 7.91 (dd, J = 4.77, 1.59 Hz, 1 H), 8.15 (d, J = 7.58 Hz, 1 H), 8.24 (s, 1 H). MS / ESI+483[M+H]+.

[0272] Step c) ((S)-1-(5-(3-((R)-2,3-dihydro-[1,4]diaoxin-[2,3-b]pyridin-3-yl)phenyl)-2H-tetrazole-2-yl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester (14.4). LiBH4 (3.54 mL, 2 mmol in THF, 7.09 mmol) was added dropwise to a solution of (S)-2-((tributoxycarbonyl)-amino)-3-(5-(3-((R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl)-2H-tetrazol-2-yl)propionate (14.3) (950 mg, 1.772 mmol) in THF (17.7 mL), and the mixture was stirred overnight at 0°C. The mixture was cooled to 0°C and quenched with water and 1 M hydrochloric acid to obtain a pH of approximately 7. The mixture was diluted with dichloromethane, washed with water and brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified on silica gel (ethyl acetate / cyclohexane) to give tributyl ((S)-1-(5-(3-((R)-2,3-dihydro-[1,4]dioxano[2,3-b]pyridin-3-yl)phenyl)-2H-tetrazol-2-yl)-3-hydroxypropyl-2-yl)aminocarbamate (264 mg, 32%) (14.4). UPLC retention time was 0.94 min (Method A). 1H NMR (400 MHz, chloroform-d) δ = ppm 1.42 (s, 10 H), 3.75 (t, J = 4.95 Hz, 2 H), 4.08 (dd, J = 11.61, 8.80 Hz, 1 H), 4.27 (br s, 1 H), 4.46 (dd, J = 11.62, 2.45 Hz, 1 H), 4.91 (br d, J = 5.87 Hz, 2 H), 5.08 - 5.20 (m, 1 H), 5.43 (dd, J = 8.86, 2.26 Hz, 1 H), 6.95 (dd, J = 7.82, 4.77 Hz, 1 H), 7.28 - 7.30 (m, 1 H), 7.53 - 7.63 (m, 2 H), 7.90 (dd, J = 4.83, 1.53 Hz, 1 H), 8.17 (d, J = 7.46 Hz, 1 H), 8.25 (s, 1 H). MS / ESI+455[M+H]+.

[0273] Step d) (S)-2-amino-3-(5-(3-((R)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-3-yl)phenyl)-2H-tetrazol-2-yl)prop-1-ol (Example 14). At 0°C under nitrogen, add hydrochloric acid (1.265 ml, 5.06 mmol, 4 M solution) in dimethyl methacrylate (14.4) (230 mg, 0.506 mmol) in a solution of ((S)-1-(5-(3-((R)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-3-yl)phenyl)-2H-tetrazol-2-yl)-3-hydroxyprop-2-yl)aminocarboxylic acid in dimethyl methacrylate (5.06 mL) to the solution. The reaction mixture was stirred at rt over the weekend and then concentrated under vacuum. The resulting solid was milled three times with diethyl ether and lyophilized from water / acetonitrile to give (S)-2-amino-3-(5-(3-((R)-2,3-dihydro-[1,4]dioxindo[2,3-b]pyridin-3-yl)phenyl)-2H-tetrazol-2-yl)prop-1-ol in HCl salt form (206 mg, 100%) (Example 14). UPLC retention time 0.58 min (Method A). 1H NMR (400 MHz, DMSO-d6) δ = ppm 3.60 - 3.68 (m, 1 H), 3.70 - 3.76 (m, 2 H), 4.12 - 4.23 (m, 2 H), 4.56 (br d, J = 11.74 Hz, 1 H), 4.91 - 5.14 (m, 2 H), 5.63 (br d, J = 7.95 Hz, 1 H), 6.96 - 7.07 (m, 1 H), 7.40 (br d, J = 7.70 Hz, 1 H), 7.64 - 7.74 (m, 2 H), 7.83 (br d, J = 3.55 Hz, 1 H), 8.12 (br d, J = 6.97 Hz, 1 H), 8.24 (br s, 1 H), 8.34 (br s, 3 H). MS / ESI+355 [M + H]+. Example 15 (S)-2-amino-3-(3-(3-((R)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-diazol-5-yl)prop-1-ol

[0274] Using a similar procedure to that used in the synthesis of Example 1, (S)-2-amino-3-(3-(3-((R)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-diazol-5-yl)prop-1-ol was prepared by replacing the chiral sulfonamide with its S,S-mirror isomer [CAS: 167316-27-7] (Example 15). Example 15 was isolated to the form of a free base. UPLC retention time was 0.76 min (Method A). 1H NMR (400 MHz, chloroform-d) δ = ppm ppm 1.82 (br. s., 3 H), 3.02 (dd,J= 15.59, 8.01 Hz, 1 H), 3.16 (dd,J= 15.53, 4.65 Hz, 1 H), 3.47 - 3.61 (m, 2 H), 3.73 (dd,J= 10.45, 4.22 Hz, 1 H), 4.07 (dd,J= 11.49, 8.93 Hz, 1 H), 4.42 (dd,J= 11.49, 2.45 Hz, 1 H), 5.22 (dd,J= 8.86, 2.26 Hz, 1 H), 6.88 - 7.06 (m, 4 H), 7.53 - 7.64 (m, 2 H), 8.07 - 8.19 (m, 2 H). MS / ESI+354 [M + H]+. Example 16 (S)-2-amino-3-(3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol

[0275] Step a) 4-((5-chloropyridin-2-yl)oxy)-N-hydroxybenzoamide (16.1). Hydroxylamine hydrochloride (3.89 g, 55.9 mmol), NaHCO3 (4.70 g, 55.9 mmol), and water (8 ml) were added to a 100 mL single-necked round-bottom flask equipped with a magnetic stir bar and a condenser (pure air). The white suspension was stirred (caution: gas formation) for approximately 10 minutes. 4-((5-chloropyridin-2-yl)oxy)benzonitrile (31.3) (2.58 g, 11.19 mmol) and EtOH (30 ml) were added, and the reaction mixture was heated to 85°C and stirred for 90 minutes. LC-MS analysis revealed complete conversion within 70 minutes. The reaction mixture was cooled to rt and stored in a refrigerator for 2 days. The EtOH was removed under vacuum, and water / EtOAc was added to the white solid. The aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over Na2SO4. The solution was concentrated under vacuum to give 2.91 g (99%) of 4-((5-chloropyridin-2-yl)oxy)-N-hydroxybenzamide as a white solid (16.1). UPLC retention time: 0.65 min (Method A). 1H NMR (400 MHz, DMSO-d6) δ = 9.60 (s, 1H), 8.21 (d,J= 2.3 Hz, 1H), 7.97 (dd,J= 8.8, 2.7 Hz, 1H), 7.70 (d,J= 8.8 Hz, 2H), 7.14 (d,J= 8.7 Hz, 2H), 7.12 (d,J= 8.7 Hz, 1H), 5.81 (s, 2H). MS / ESI+264.1, 266.1 [M + H]+.

[0276] Step b) Benzyl (S)-2-((tributoxycarbonyl)amino)-3-(3-(4-(((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propionate (16.2). Add 4-((5-chloropyridin-2-yl)oxy)-N-hydroxybenzomidine (16.1) (1.45 g, 5.50 mmol), Boc-Asp(OSu)-OBzl (2.5) (2.54 g, 6.05 mmol), and THF (15 ml) to a 20 mL microwave-safe vial equipped with a magnetic stir bar. Seal the vial and stir the colorless solution at rt for 7 hours. Complete conversion to ester occurs within 6 hours. Store the reaction mixture in a refrigerator overnight. Then heat to 120°C and stir for 5 hours. Cool the resulting yellow solution to room temperature and remove THF under vacuum to obtain a yellow oil. Column chromatography (absorbed on silicone, EtOAc in cyclohexane, 0-25%) yielded a pale yellow, viscous, foamy (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-(((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propionate (2.94 g, 97%) (16.2). UPLC retention time was 1.39 min (Method A). 1H NMR (400 MHz, CDCl3) δ = 8.15 (d,J= 2.4 Hz, 1H), 8.04 (d,J= 8.8 Hz, 2H), 7.69 (dd,J= 8.7, 2.7 Hz, 1H), 7.30 - 7.28 (m, 5H), 7.22 (d,J= 8.8 Hz, 2H), 6.95 (d,J= 8.7 Hz, 1H), 5.58 (d,J= 8.0 Hz, 1H), 5.20 (d,J= 2.7 Hz, 2H), 4.93 - 4.86 (m, 1H), 3.51 (qd,J= 16.2, 5.0 Hz, 2H), 1.44 (s, 9H). MS / ESI+551.2, 553.2 [M + H]+.

[0277] Step c) Tributyl (S)-(1-(3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-acediazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate (16.3). Add (S)-2-((tributoxycarbonyl)amino)-3-(3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-acediazol-5-yl)propionate (16.2) (0.681 g, 1.236 mmol) to a 25 mL two-necked round-bottom flask equipped with a magnetic stir bar. Vacuum the flask and refill it three times with Ar. Add anhydrous THF (5.0 mL) and cool the solution to 0°C. Add LiBH4 (0.081 g, 3.71 mmol) to the reaction mixture and stir for 45 minutes. Filter the suspension and add CH2Cl2. Store it in the refrigerator overnight. Add silicone (caution: gas formation). Column chromatography (ISCO CombiFlash Rf, EtOAc in cyclohexane, 0-50%) yields tributyl (S)-(1-(3-(4-(((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate (0.272 g, 49.2%) (16.3), appearing as a white foam. UPLC retention time 1.11 min (Method A). 1H NMR (400 MHz, CDCl3) δ = 8.15 (d,J= 2.6 Hz, 1H), 8.10 (d,J= 8.7 Hz, 2H), 7.69 (dd,J= 8.7, 2.6 Hz, 1H), 7.23 (d,J= 8.7 Hz, 2H), 6.95 (d,J= 8.7 Hz, 1H), 5.23 (s br, 1H), 4.23 - 4.15 (m, 1H), 3.80 (dq,J= 11.2, 5.8, 4.7 Hz, 2H), 3.29 (d,J= 5.9 Hz, 2H), 2.01 (s br, 1H), 1.43 (s, 9H). MS / ESI+447.3, 449.3 [M + H]+.

[0278] Step d) (S)-2-amino-3-(3-(4-(((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol (Example 16). --Add (S)-(1-(3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxyprop-2-yl)aminocarbamate tributyl ester (16.3) (0.270 g, 0.604 mmol), dichloromethane (8 ml), and TFA (0.233 ml, 3.02 mmol) to a 50 mL single-necked round-bottom flask equipped with a magnetic stir bar. Stir the colorless solution at rt for 6 days. The reaction is slow: incomplete conversion still occurs within 2 days. In addition, byproducts are formed. Add silicone and more dichloromethane. The solvent was then removed under vacuum. Purification was performed by column chromatography (ISCO CombiFlash Rf, absorbed onto silicone, MeOH in CH2Cl2, 0-10%) to obtain (S)-2-amino-3-(3-(4-(((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol (0.147 g, 70.2%) as a white solid (Example 16). UPLC retention time was 0.73 min (Method A). 1H NMR (400 MHz, DMSO-d6) δ = 8.25 (d,J= 2.5 Hz, 1H), 8.07 (d,J= 8.7 Hz, 2H), 8.03 (dd,J= 8.8, 2.7 Hz, 1H), 7.35 (d,J= 8.7 Hz, 2H), 7.21 (d,J= 8.8 Hz, 1H), 5.51 (t,J= 4.7 Hz, 1H), 3.76 - 3.59 (dq,J= 31.2, 6.0 Hz, 3H), 3.44 - 3.25 (m, 2H). MS / ESI+347.1, 349.1 [M + H]+. Example 17 (S)-2-amino-3-(3-(4-(((R)-1-phenylprop-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol

[0279] Step a) (R)-4-((1-phenylprop-2-yl)oxy)benzonitrile (17.2). Add (S)-1-phenylprop-2-ol (17.1) (0.999 ml, 7.26 mmol, ABCR GmbH), 4-cyanophenol (4.2) (0.865 g, 7.26 mmol), PPh3 (2.476 g, 9.44 mmol), and THF (25.0 ml) to a 50 mL single-necked round-bottom flask equipped with a magnetic stir bar. After all solids have completely dissolved, add DIAD (1.836 ml, 9.44 mmol). Stir the yellow solution at rt (caution: it will become very warm) for 3.5 hours. Then store it in the refrigerator over the weekend. Remove the solvent under vacuum. Add diisopropyl ether and cyclohexane and filter the yellow solution on a silicone mat (to remove some Ph3PO). The solution was concentrated under vacuum to give a strong yellow oil. Purification was performed by column chromatography (ISCO CombiFlash Rf, absorbed onto silicone, EtOAc (0-5%) in cyclohexane, fractionation) to give (R)-4-((1-phenylprop-2-yl)oxy)benzonitrile (0.954 g, 55.4%) (17.2). UPLC retention time was 1.24 min (Method A). ¹H NMR (400 MHz, CDCl₃) δ = 7.57 - 7.52 (m, 2H), 7.32 - 7.27 (m, 2H), 7.25 - 7.20 (m, 3H), 6.93 - 6.88 (m, 2H), 4.65 (h, J = 6.1 Hz, 1H), 3.08 (dd, J = 13.8, 6.2 Hz, 1H), 2.87 (dd, J = 13.8, 6.3 Hz, 1H), 1.34 (d, J = 6.1 Hz, 3H). Ionization of [M⁺H⁺]⁺ was not observed by MS / ESI. TLC Rf = 0.32 (cyclohexane / ethyl acetate 10:1, silicone).

[0280] Step b) (R,Z)-N'-hydroxy-4-((1-phenylprop-2-yl)oxy)benzomid (17.3). Add hydroxylamine hydrochloride (1.397 g, 20.10 mmol), NaHCO3 (1.689 g, 20.10 mmol), and water (5.0 ml) to a 50 mL single-necked round-bottom flask equipped with a magnetic stir bar and a condenser (air). Stir the suspension at rt (caution: gas formation) for 10 min. Then add (R)-4-((1-phenylprop-2-yl)oxy)benzonitrile (17.2) (0.954 g, 4.02 mmol) to EtOH (15 ml) and heat the reaction mixture to 85°C. Stir for 100 min. Then store the white suspension in a refrigerator overnight. Remove EtOH under vacuum and add water / EtOAc. Extract the aqueous phase twice with EtOAc. The organic layers were washed with brine, combined, and dried over Na2SO4. Concentration under vacuum yielded a pale yellow oil. Purification was achieved by column chromatography (ISCO CombiFlash Rf, absorption on silica gel, EtOAc (0-50%) in cyclohexane, fractionation) to obtain a turbid oily (R,Z)-N'-hydroxy-4-((1-phenylprop-2-yl)oxy)benzamidinium (0.976 g, 90%) (17.3). UPLC retention time: 0.81 min (Method A). 1H NMR (400 MHz, CDCl3) δ = 7.59 - 7.52 (m, 2H), 7.34 - 7.21 (m, 5H), 6.93 - 6.88 (m, 2H), 4.87 (s, 2H), 4.63 (h,J= 6.1 Hz, 1H), 3.11 (dd,J= 13.7, 5.9 Hz, 1H), 2.85 (dd,J= 13.7, 6.6 Hz, 1H), 1.33 (d,J= 6.1 Hz, 3H). MS / ESI+271.2 [M + H]+.

[0281] Step c) Benzyl propionate (17.4) of (S)-2-((tributoxycarbonyl)amino)-3-(3-(4-(((R)-1-phenylprop-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propionate. Add (R,Z)-N'-hydroxy-4-((1-phenylprop-2-yl)oxy)benzamidinium (17.3) (0.487 g, 1.802 mmol), Boc-Asp(OSu)-Obzl (2.5) (0.833 g, 1.982 mmol), and THF (6.0 ml) to a 20 mL microwave-safe vial equipped with a magnetic stir bar. Stir the colorless solution at rt for 2 hours. The solution was completely consumed within 105 minutes according to LC-MS analysis. The reaction mixture was then heated to 120°C and stirred for 3 hours. EtOAc was then added to the pale yellow solution, and the mixture was stored in the refrigerator over the weekend. The solvent was removed under vacuum. Dichloromethane and silica gel were added. The mixture was purified by column chromatography (ISCO CombiFlash Rf, EtOAc in cyclohexane absorbed on silica gel, 0-15%) to give (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-((((R)-1-phenylprop-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propionate (0.814 g, 81%) (17.4), which appeared as a "gray" oil. The UPLC retention time was 1.48 min (Method A). 1H NMR (400 MHz, CDCl3) δ = 7.94 - 7.88 (m, 2H), 7.34 - 7.22 (m, 10H), 6.97 - 6.92 (m, 2H), 5.60 (d,J= 8.1 Hz, 1H), 5.25 - 5.12 (m, 2H), 4.95 - 4.83 (m, 1H), 4.68 (dt,J= 12.3, 6.1 Hz, 1H), 3.59 - 3.39 (m, 2H), 3.12 (dd,J= 13.7, 5.9 Hz, 1H), 2.87 (dd,J= 13.7, 6.5 Hz, 1H), 1.44 (s, 9H), 1.35 (d,J= 6.1 Hz, 3H). MS / ESI+558.4[M+H]+.

[0282] Step d) Benzyl (S)-2-((tributoxycarbonyl)amino)-3-(3-(4-((((R)-1-phenylprop-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propionate (17.5). Add (S)-2-((tributoxycarbonyl)amino)-3-(3-(4-(((((R)-1-phenylprop-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propionate (17.4) (0.443 g, 0.794 mmol) to a 10 mL two-necked conical flask equipped with a magnetic stir bar, rubber septum, and gas inlet. Vacuum the flask and backfill with Ar three times. Add anhydrous THF (3.0 mL) and cool the solution to 0°C. Then, LiBH4 (0.087 g, 3.97 mmol) was added in a single batch, and the suspension was stirred for 45 min. The reaction was quenched with MeOH. The solvent was removed under vacuum. Dichloromethane and silica gel were added. The solution was purified twice by column chromatography (ISCO CombiFlash Rf, absorbed on silica gel, EtOAc in cyclohexane, 0-50% and 0-50%) to give (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-(((R)-1-phenylprop-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propionate (0.168 g, 46.6%) (17.5). UPLC retention time was 1.24 min (Method A). 1H NMR (400 MHz, CDCl3) δ = 7.96 (d,J= 8.8 Hz, 2H), 7.34 - 7.20 (m, 5H), 6.96 (d,J= 8.8 Hz, 2H), 5.29 - 5.19 (m, 1H), 4.67 (h,J= 6.2 Hz, 1H), 4.23 - 4.14 (m, 1H), 3.86 - 3.74 (m, 2H), 3.34 - 3.19 (m, 2H), 3.11 (dd,J= 13.7, 5.9 Hz, 1H), 2.87 (dd,J= 13.7, 6.5 Hz, 1H), 2.73 (s, 1H), 1.43 (s, 9H), 1.34 (d,J= 6.1 Hz, 3H). MS / ESI+454.3[M+H]+.

[0283] Step e) (S)-2-amino-3-(3-(4-((((R)-1-phenylprop-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol (Example 17). Add (S)-2-((tributoxycarbonyl)amino)-3-(3-(4-((((R)-1-phenylprop-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)propionate (17.5) (0.168 g, 0.370 mmol), DCM (4.0 ml), and TFA (0.143 ml, 1.852 mmol) to a 10 mL single-necked pear-shaped flask equipped with a magnetic stir bar. Stir the colorless solution at rt for 3 days. Simultaneously, it turns orange. Remove the solvent and acid under vacuum. The product was purified by column chromatography (ISCO CombiFlash Rf, absorbed on silicone, with MeOH in CH2Cl2, 0-10%). The product was purified again under the same conditions to give (S)-2-amino-3-(3-(4-((((R)-1-phenylprop-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol (0.108 g, 78%) as a colorless oil (Example 17). UPLC retention time was 0.84 min (Method A). 1H NMR (400 MHz, CDCl3) δ = 7.86 (d,J= 8.8 Hz, 2H), 7.30 - 7.19 (m, 5H), 6.89 (d,J= 8.9 Hz, 2H), 4.61 (h,J= 6.1 Hz, 1H), 3.97 (d,J= 9.1 Hz, 1H), 3.90 - 3.83 (m, 1H), 3.79 (dd,J= 11.7, 6.5 Hz, 1H), 3.37 - 3.14 (m, 2H), 3.06 (dd,J= 13.7, 5.9 Hz, 1H), 2.82 (dd,J= 13.7, 6.5 Hz, 1H), 1.28 (d, J = 6.0 Hz, 3H). MS / ESI +354.3 [M + H]+. Example 18 (3S)-3-amino-4-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)but-2-ol

[0284] Step a) 4-((5-bromo-3-fluoropyridin-2-yl)oxy)-N-hydroxybenzoamide (18.1). Add 4-((5-bromo-3-fluoropyridin-2-yl)oxy)benzonitrile (7.2) (763 mg, 2.60 mmol), hydroxylamine hydrochloride (905 mg, 13.02 mmol), NaHCO3 (1093 mg, 13.02 mmol), and EtOH (15.0) / water (5.0 mL) to a 50 mL single-necked pear-shaped flask equipped with a magnetic stir bar and a condenser (air). Stir the white suspension at 85°C for 80 minutes. Remove EtOH under vacuum. Add water and EtOAc. Extract the aqueous phase twice with EtOAc. Wash the organic layer with brine, combine, and dry with Na2SO4. Concentrated under vacuum, 4-((5-bromo-3-fluoropyridin-2-yl)oxy)-N-hydroxybenzomidine (0.849 g, 98%) (18.1) was obtained as a white solid. UPLC retention time was 0.75 min (Method A). MS / ESI: 326.2, 328.2 [M + H]+.

[0285] Step b) (S)-3-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-2-((tert-butoxycarbonyl)amino)benzyl propionate (18.2). Add 4-((5-bromo-3-fluoropyridin-2-yl)oxy)-N-hydroxybenzomidazine (18.1) (470 mg, 1.441 mmol), Boc-Asp(OSu)-OBzl (2.5) (666 mg, 1.585 mmol), and THF (13.0 ml) to a 20 mL microwave-safe vial equipped with a magnetic stir bar. Stir the solution at 110°C for 16 hours. Obtain the suspension. Remove volatiles under vacuum. Purified by column chromatography (ISCO CombiFlash Rf, absorbed on silicone, EtOAc in cyclohexane, 0-16%), (S)-3-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-2-((tert-butoxycarbonyl)amino)benzyl propionate (433 mg, 49%) (18.2). UPLC retention time 1.44 min (Method A). 1H NMR (400 MHz, CDCl3) δ = 8.05 - 8.01 (m, 2H), 7.99 (d,J= 2.1 Hz, 1H), 7.66 (dd,J= 8.8, 2.1 Hz, 1H), 7.28 - 7.21 (m, 7H), 5.56 (d,J= 7.7 Hz, 1H), 5.23 - 5.12 (m, 2H), 4.91 - 4.83 (m, 1H), 3.49 (qd,J= 16.3, 5.1 Hz, 2H), 1.42 (s, 9H). 19F NMR (376 MHz, CDCl3) δ = -132.98. MS / ESI+613.3, 615.3 [M + H]+.

[0286] Step c) Tributyl (S)-(1-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate (18.3). Add benzyl (S)-3-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-2-((tributyloxycarbonyl)amino)propionate (18.2) (433 mg, 0.706 mmol) to a 25 mL two-necked round-bottom flask equipped with a magnetic stir bar, rubber septum, and gas inlet. Vacuum the flask and backfill with Ar five times. Add anhydrous THF (8.0 mL) and cool the clear solution to 0°C. After adding LiBH4 (61.5 mg, 2.82 mmol), the reaction mixture was stirred for 2.5 hr. Volatiles were removed under vacuum. Purification by column chromatography (ISCO CombiFlash Rf, absorbed on silicone, EtOAc in cyclohexane, 20%–45%) yielded a colorless, viscous oil of tributyl (S)-(1-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate (217 mg, 60.4%) (18.3). UPLC retention time was 1.18 min (Method A). 1H NMR (400 MHz, CDCl3) δ = 8.12 (dd,J= 9.1, 2.2 Hz, 2H), 8.01 (d,J= 2.1 Hz, 1H), 7.67 (dd,J= 8.8, 2.1 Hz, 1H), 7.28 (d,J= 1.9 Hz, 2H), 5.22 (s br, 1H), 4.24 - 4.15 (m, 1H), 3.86 - 3.76 (m, 2H), 3.29 (d, J = 6.0 Hz, 2H), 1.44 (s, 9H). 19F NMR (376 MHz, CDCl3) δ = -132.96. MS / ESI+509.2, 511.2 [M + H]+.

[0287] Step d) (S)-(1-(3-(4-(((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester (18.3) (217 mg, 0.426 mmol), DCM (5.0 ml), and DMP (208 mg, 0.490 mmol) were added to a 12 mL single-necked pear-shaped flask equipped with a magnetic stir bar. The white suspension was stirred at rt for 28 minutes. A few drops of saturated NaHCO3 aqueous solution and saturated Na2S2O3 aqueous solution were added, and the two-phase system was stirred at rt for 2 hours. Simultaneously, both phases became clear. Water and dichloromethane were added. The aqueous phase was extracted once with CH2Cl2 and once with EtOAc. The organic layer was washed with brine, combined, and dried over Na2SO4. Purification was performed by column chromatography (ISCO CombiFlash Rf, absorbed on silica gel, EtOAc in cyclohexane, 20%–26.5%–34.3%) to give tributyl (S)-(1-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-t-oxypropyl-2-yl)aminocarbamate (177 mg, 82%) (18.4), appearing as a white, hard foam. UPLC retention time was 1.22 min (Method A). 1H NMR (400 MHz, CDCl3) δ = 9.75 (s, 1H), 8.12 - 8.07 (m, 2H), 8.01 (d,J= 2.1 Hz, 1H), 7.67 (dd,J= 8.8, 2.1 Hz, 1H), 7.28 (d,J= 2.0 Hz, 2H), 5.67 (d,J= 6.9 Hz, 1H), 4.69 - 4.56 (m, 1H), 3.50 (d,J= 5.3 Hz, 2H), 1.46 (s, 9H). MS / ESI+507.1, 509.1 [M + H]+.

[0288] Step e) ((2S)-1-(3-(4-(((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxybut-2-yl)aminocarbamate tributyl ester (18.5). Add (S)-(1-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-dioxypropyl-2-yl)aminocarbamate tributyl ester (18.4) (91.3 mg, 0.180 mmol) to a 10 mL two-necked conical flask equipped with a magnetic stir bar, rubber septum, and gas inlet. Vacuum the flask and backfill with Ar five times. Add anhydrous THF (1.00 mL) and cool the colorless solution to 0°C. Then, MeMgBr (0.25 mL, 0.750 mmol) was carefully added to THF (gas was formed during the addition), and the reaction mixture was stirred for 2.5 hours (the ice bath was removed after 2 hours). The reaction was quenched with a few drops of MeOH, followed by saturated NH4Cl aqueous solution. It was stored in a refrigerator overnight. EtOAc and water were added. The aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over Na2SO4. The solution was purified by column chromatography (ISCO CombiFlash Rf, absorbed on silica gel, EtOAc in cyclohexane, 15%–27.5% to 40%) to give ((2S)-1-(3-(4-(((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxybut-2-yl)aminocarbamate tributyl ester (60.2 mg, 63.9%) (18.5). UPLC residence time 1.22 min (Method A). ¹H NMR (400 MHz, CDCl₃) δ = 8.12 (dd, J = 8.9, 2.2 Hz, 2H), 8.01 (d, J = 2.0 Hz, 1H), 7.67 (dd, J = 8.8, 2.0 Hz, 1H), 7.28 (d, J = 1.9 Hz, 3H), 5.14 (d, J = 6.7 Hz, 1H), 4.07 - 3.93 (m, 2H), 3.38 - 3.18 (m, 2H), 1.43 (s, 9H), 1.26 (d, J = 2.3 Hz, 3H). ¹⁹F NMR (376 MHz, CDCl₃) δ = -132.99. MS / ESI+523.3, 525.3 [M + H]+.

[0289] Step f) (3S)-3-amino-4-(3-(4-(((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)but-2-ol (Example 18). Add ((2S)-1-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxybut-2-yl)aminocarbamate tributyl ester (18.5) (60.2 mg, 0.115 mmol), dibutyl phthalate (1.00 ml), and aqueous HCl (1.00 mL, 2.000 mmol) to a 12 mL single-necked pear-shaped flask equipped with a magnetic stir bar. Stir the resulting turbid solution at rt for 4 days. Water, 2 M aqueous NaOH (5.0 mL), and EtOAc were added. The aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over Na2SO4. Purification was performed by column chromatography (ISCO CombiFlash Rf, absorption on silica gel, MeOH in CH2Cl2, 0–5%) to give (3S)-3-amino-4-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)but-2-ol (33.9 mg, 67.5%) as a colorless oil and a mixture of 78:22 non-mirror image isomers (Example 18). UPLC retention time was 0.79 min (Method A). 1H NMR (400 MHz, CDCl3) δ = 8.16 - 8.09 (m, 2H), 8.00 (d,J= 2.1 Hz, 1H), 7.67 (dd,J= 8.8, 2.1 Hz, 1H), 7.27 (d,J= 8.8 Hz, 3H), 3.71 - 3.61 (m, 1H), 3.22 - 3.12 (m, 2H), 3.02 - 2.92 (m, 1H), 1.28 (d,J= 6.2 Hz, 3H). MS / ESI+423.2, 425.2 [M + H]+. Example 19 (R)-3-(5-(4-((5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)-2-aminoprop-1-ol

[0290] Step a) 2-(4-(2H-tetrazol-5-yl)phenoxy)-5-bromopyridine (19.1). At room temperature, Bu2SnO (0.204 g, 0.818 mmol) was added to a solution of 13.3 (1.5 g, 5.45 mmol) and trimethylsilyl azide (1.447 mL, 10.91 mmol) in toluene (20 mL). The reaction mixture (yellow solution) was stirred at 100°C for 16 h. The mixture was concentrated, the crude product was ground with diethyl ether, and 19.1 (1.28 g, 70%) was filtered off as a white solid. UPLC retention time was 0.86 min (Method A). 1H NMR (DMSO-d6): δ = 16.82 (s, br, 1H), 8.33 (d, J = 2.5 Hz, 1H), 8.24 - 8.00 (m, 3H), 7.51 - 7.29 (m, 2H), 7.17 (d, J = 8.7 Hz, 1H). MS / ESI 318.1 [M + H]+.

[0291] Step b) 2-(4-(2H-tetrazol-5-yl)phenoxy)-5-(1H-pyrazol-3-yl)pyridine (19.3). Compounds 19.1 (1.2 g, 3.77 mmol) and 19.2 (0.732 g, 3.77 mmol) were dissolved in dimethyl ether (15 ml) and water (15 ml). K3PO4 (2.402 g, 11.32 mmol) and PdCl2 (dtbpf) (0.246 g, 0.377 mmol) were then added under argon, and the reaction mixture was stirred at 120°C for 16 h. The reaction mixture was absorbed onto an Isolute and dried to dryness using a rotary evaporator (RotaVap). The reaction mixture was purified on silicone (gradient: ethyl acetate / MeOH) to give compound 19.3 (1.41 g, 81% purity). UPLC residence time 0.67 min (Method A). ¹H NMR (DMSO-d6): δ = 12.97 (s, br, 1H), 8.62 (s, 1H), 8.25 (m, 1H), 8.05 (m, 2H), 7.78 (s, br, 1H), 7.25 (m, 2H), 7.10 (m, 1H), 6.76 (s, 1H). Tetrazolium H was not observed. MS / ESI 306.2 [M + H]+.

[0292] Step c) (R)-(1-(5-(4-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazole-2-yl)-3-((tributyldimethylsilyl)oxy)propyl-2-yl)aminocarbamate tributyl ester (19.4). At room temperature, intermediate B (166 mg, 0.452 mmol) was added to a mixture of 19.3 (115 mg, 0.377 mmol) and Cs2CO3 (368 mg, 1.13 mmol) in DMA (4 mL). The reaction mixture was stirred at 70°C for 16 h. Brine and CH2Cl2 were added, and the mixture was extracted with CH2Cl2 (3×). The combined organic layers were dried over Na2SO4, concentrated, and the residue was purified on silica gel (gradient: ethyl acetate / MeOH) to give 19.4 (30 mg, 83% purity) as a white solid. UPLC retention time: 0.89 min (Method A). MS / ESI: 479.4 [M + H]+.

[0293] Step d) (R)-3-(5-(4-((5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)-2-aminoprop-1-ol (Example 19). 4 M HCl (0.157 mL, 0.627 mmol) in dimethyl ether was added to a solution of 19.4 g (30 mg, 0.063 mmol) in dimethyl ether (0.5 mL). The resulting suspension was stirred at room temperature for 1 hr and diluted with ether. The colorless solid was filtered off and purified by SFC to give Example 19 (10 mg, 39%) as a colorless powder. UPLC retention time: 0.56 min (Method A). ¹H NMR (DMSO-d6): δ = 8.64 (¹H, d), 8.31 (¹H, dd), 8.13 (³H, m), 7.86 (²H, d), 7.43 (²H, d), 7.23 (¹H, d), 6.78 (¹H, d), 5.50 (¹H, m), 4.78 (¹H, dd), 4.63 (¹H, dd), 3.85 (¹H, m), 3.65 (¹H, dd), 3.55 (¹H, dd). Pyrazole NH was not observed. MS / ESI 379.3 [M + H]+. Example 20 (S)-3-(5-(4-((5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)-2-aminoprop-1-ol

[0294] Example 20 was prepared by a similar procedure used for the synthesis of Example 19, except that intermediate B was replaced with its R-mirror isomer intermediate A. Example 20 was isolated to the hydrochloride form. UPLC retention time: 0.58 min (Method A). ¹H NMR (DMSO-d6): δ = 8.64 (¹H, d), 8.38 (³H, m), 8.30 (¹H, dd), 8.14 (²H, d), 7.80 (¹H, m), 7.37 (²H, d), 7.20 (¹H, d), 6.78 (¹H, d), 5.05 (¹H, dd), 5.00 (¹H, dd), 3.84 (¹H, m), 3.75 (¹H, dd), 3.67 (¹H, dd). No OH or pyrazole NH was observed. MS / ESI 379.2 [M + H]+. Example 21 (S)-2-amino-3-(3-(5-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)prop-1-ol

[0295] Step a) 2-((6-bromopyridin-3-yl)oxy)-5-chloro-3-fluoropyridine (21.3). A mixture of 21.1 (189 mg, 1.264 mmol), 21.2 (200 mg, 1.149 mmol), and K2CO3 (318 mg, 2.299 mmol) in DMF (1.5 mL) was stirred at 80°C for 5 h. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel (gradient: cyclohexane / ethyl acetate) to give 21.3 (271 mg, 73%). UPLC retention time 1.10 min (Method A). 1H NMR (DMSO-d6): δ = 8.41 (1H, s), 8.27 (1H, dd), 8.07 (1H, d), 7.75 (2H, s). MS / ESI 303.0 [M+H]+.

[0296] Step b) 5-Chloro-3-fluoro-2-((6-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)oxy)pyridine (21.5). A suspension of 21.3 (1350 mg, 4.45 mmol), 21.4 (1299 mg, 4.67 mmol), K3PO4 (1888 mg, 8.90 mmol), and PdCl2(dtbpf) (145 mg, 0.222 mmol) in a mixture of dimethyl ether (15 mL) and water (5 mL) was stirred at 25°C under argon for 15 min. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel (gradient: cyclohexane / ethyl acetate) to give 21.5 (1390 mg, 73%). UPLC residence time 1.16 min (Method A). ¹H NMR (DMSO-d6): δ = 8.65 (¹H, d), 8.29 (¹H, dd), 8.10 (¹H, d), 7.83–7.89 (2H, m), 7.60 (¹H, d), 6.81 (¹H, d), 6.25 (¹H, dd), 3.86 (¹H, d), 3.46–3.56 (¹H, m), 2.33–2.46 (¹H, m), 1.88–2.06 (2H, m), 1.48–1.71 (3H, m). MS / ESI 375.1 [M+H]+.

[0297] Step c) 2-((6-(1H-pyrazol-3-yl)pyridin-3-yl)oxy)-5-chloro-3-fluoropyridine (21.6). 2 N HCl (11.05 mL, 22.1 mmol) was added to a solution of 21.5 (1380 mg, 3.68 mmol) in methanol (12 mL), and the mixture was stirred at 25°C for 1 h. A suspension was formed. The colorless solid was filtered and dissolved in CH2Cl2 (20 mL). Water was added, and the pH was adjusted to 10 by adding 2 N K2CO3. The layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2CO3, filtered, and concentrated to give 21.6 (960 mg, 89%). UPLC retention time was 0.89 min (Method A). ¹H NMR (DMSO-d6): δ = 13.50 and 13.05 (¹H, 2s), 8.52 (¹H, s br), 8.27 (¹H, dd), 7.95–8.10 (2H, m), 7.83 (¹H, s br), 7.71–7.80 (¹H, m), 6.83 (¹H, s br), a mixture of tautomers. MS / ESI 291.1 [M + H]+.

[0298] Step d) (S)-(1-((tributyldimethylsilyl)oxy)-3-(3-(5-(((5-chloro-3-fluoropyridin-2-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)propyl-2-yl)aminocarbamate (21.7). A mixture of 21.6 (900 mg, 3.10 mmol), intermediate A (1366 mg, 3.72 mmol), and K2CO3 (1284 mg, 9.29 mmol) in DMF (11 mL) was stirred at 25°C under argon for 70 h. The mixture was diluted with water and extracted with ethyl acetate. Brine was added and the layers were separated. The aqueous layer was extracted with ethyl acetate, the combined organic layers were dried with Na2SO4, filtered, and concentrated. The residue was purified on silica gel (gradient: cyclohexane / ethyl acetate) to give 21.7 (518 mg, 28%). UPLC residence time 1.54 min (Method A). ¹H NMR (DMSO-d6): δ = 8.50 (¹H, d), 8.26 (¹H, dd), 8.06 (¹H, d), 7.97 (¹H, d), 7.74 (¹H, dd), 7.71 (¹H, d), 6.83 (¹H, d br), 6.77 (¹H, d), 4.30 (¹H, dd), 4.13 (¹H, dd br), 3.93 (¹H, d br), 3.46–3.62 (2H, m), 1.32 (9H, s), 0.85–0.89 (9H, m), 0.02–0.06 (6H, m). MS / ESI 578.3 [M + H]+.

[0299] Step e) ((2S)-1-((tributyldimethylsilyl)oxy)-3-(3-(5-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)propyl-2-yl)aminocarbamate (21.8). The suspensions of 21.7 (250 mg, 0.432 mmol), 21.4 (241 mg, 0.865 mmol), K3PO4 (275 mg, 1.297 mmol), and PdCl2 (dtbpf) (145 mg, 0.222 mmol) in a mixture of dimethyl ether (2.5 mL) and water (1 mL) were stirred at 90°C under argon for 15 min. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel (gradient: cyclohexane / ethyl acetate) to give 21.8 g (180 mg, 60%). UPLC retention time was 1.55 min (Method A). 1H NMR (DMSO-d6): δ = 8.55 (1H, d), 8.10 (1H, s), 8.02-8.08 (1H, m), 8.00 (1H, d), 7.79 (1H, dd), 7.73 (1H, d), 7.61 (1H, s), 6.84 (1H, d br), 6.79 (1H, d), 6.59 (1H, d), 5.29 (1H, dd), 4.31 (1 H, dd), 4.14 (1H, dd br), 3.94 (2H, d br), 3.53-3.59 (3H, m), 2.28-2.44 (1H, m), 1.90-2.02 (1H, m), 1.77-1.88 (1H, m), 1.50-1.55 (3H, m), 1.33 (9H, s), 0.89 (9H, s), 0.05 (6H, s). MS / ESI 694.5 [M+H]+.

[0300] Step f) (S)-2-amino-3-(3-(5-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)prop-1-ol (Example 21). 4 M HCl (0.612 mL, 2.45 mmol) in dimethyl methacrylate was added to a solution of 21.8 (170 mg, 0.245 mmol) in acetone (2.5 mL). The resulting suspension was stirred at room temperature for 16 hr. The colorless solid was filtered off, washed with acetone, and purified by SFC and silica gel chromatography (gradient: CH2Cl2 / MeOH) to give Example 21 (12 mg, 12%) as a colorless powder. UPLC retention time: 0.55 min (Method A). 1H NMR (DMSO-d6): δ = 13.07 (1H, s br), 8.52 (1H, d), 8.41 (1H, s), 8.25 (1H, d br), 7.98 (1H, d), 7.76-7.85 (2H, m), 7.74 (1H, dd), 6.81 (2H, dd), 4.71 (1H, t), 4.22 (1H, dd), 3.99 (1H, dd), 3.25-3.30 (2H, m), 3.08-3.16 (1H, m), 1.58 (2H, s br). MS / ESI 396.2 [M + H]+. Example 22 (S)-2-amino-3-(5-(5-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)pyridin-2-yl)-2H-tetrazole-2-yl)prop-1-ol

[0301] Step a) 5-((5-chloro-3-fluoropyridin-2-yl)oxy)pyridinecarboxylonitrile (22.3). A mixture of 22.1 (1245 mg, 8.33 mmol), 22.2 (1000 mg, 8.33 mmol), and K2CO3 (2301 mg, 16.65 mmol) in DMF (10 mL) was stirred at 80°C under argon for 16 h. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel (gradient: CH2Cl2 / MeOH) to give 22.3 (1181 mg, 54%). UPLC retention time 1.01 min (Method A). 1H NMR (DMSO-d6): δ = 8.77 (1H, d), 8.34 (1H, dd), 8.18 (1H, d), 8.13 (1H, s), 8.03 (1H, dd). MS / ESI 250.1 [M + H]+.

[0302] Step b) 2-((6-(2H-tetrazol-5-yl)pyridin-3-yl)oxy)-5-chloro-3-fluoropyridine (22.4). 22.3 (1120 mg, 4.49 mmol), Bu2SnO (112 mg, 0.449 mmol), and TMSN3 (1034 mg, 8.97 mmol) in anhydrous toluene (8 mL) solution were heated in a sealed tube at 90°C under argon atmosphere on a heating block for 18 h. Bu2SnO and TMSN3 were then added, and heating continued for 3 h. After cooling to room temperature, MeOH (2 mL) was added, and the mixture was concentrated. The residue was purified on silica gel (gradient: cyclohexane / ethyl acetate, then CH2Cl2 / MeOH) to give 29.4 (960 mg, 73%) as a colorless powder. UPLC retention time was 0.85 min (Method A). 1H NMR (DMSO-d6): δ = 8.79 (1H, d), 8.28–8.35 (2H, m), 8.11 (1H, d), 8.02 (1H, dd), no tetrazolium NH was observed. MS / ESI 293.1 [M + H]+.

[0303] Step c) (S)-(1-((tributyldimethylsilyl)oxy)-3-(5-(5-(((5-chloro-3-fluoropyridin-2-yl)oxy)pyridin-2-yl)-2H-tetrazol-2-yl)propyl-2-yl)aminocarbamate (22.5). A mixture of 22.4 (950 mg, 2.60 mmol), intermediate A (1145 mg, 3.12 mmol), and K2CO3 (1077 mg, 7.79 mmol) in DMF (17 mL) was stirred at 25°C under argon for 1.5 h. The mixture was diluted with water and extracted with cyclohexane / ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel (gradient: cyclohexane / ethyl acetate) to give 22.5 (773 mg, 51%). UPLC residence time 1.50 min (Method A). ¹H NMR (DMSO-d6): δ = 8.69 (¹H, d), 8.32–8.36 (2H, m), 8.11 (¹H, d), 8.04 (¹H, dd), 6.83 (¹H, d), 5.08–5.23 (¹H, m), 4.61–4.75 (¹H, m), 3.90–4.01 (¹H, m), 3.62–3.68 (2H, m), 1.21 (9H, s), 0.84 (9H, s), 0.02–0.06 (6H, m). MS / ESI 580.2 [M+H]+.

[0304] Step d) ((2S)-1-((tri-butyldimethylsilyl)oxy)-3-(5-(5-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)pyridin-2-yl)-2H-tetrazole-2-yl)prop-2-yl)aminocarbamate tributyl ester (22.7). Suspensions of 22.5 (330 mg, 0.569 mmol), 22.6 (264 mg, 0.948 mmol), K3PO4 (302 mg, 1.423 mmol), and PdCl2(dtbpf) (30.9 mg, 0.047 mmol) in a mixture of dimethyl ether (3.5 mL) and water (1.17 mL) were stirred at 90°C under argon for 1.25 h. The mixture was diluted with water and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel (gradient: cyclohexane / ethyl acetate) to give 22.7 (118 mg, 30%). UPLC retention time was 1.52 min (Method A). 1H NMR (DMSO-d6): δ = 8.76 (1H, d), 8.23 ​​(1H, d), 8.13 (1H, s), 8.09 (1H, d), 7.99 (1H, dd), 7.60-7.68 (m, 1H, m), 6.96 (1H, d br), 6.61 (1H, d), 5.30 (1H, dd), 4.91 (1H, dd), 4.70 (1H, dd br), 3.91-4.12 (2H, m), 3.53-3.70 (3H, m), 2.26-2.48 (1H, m), 1.92-2.01 (1H, m), 1.77-1.89 (1H, m), 1.50-1.68 (3H, m), 1.02-1.28 (9H, m), 0.88 (9H, s), 0.07 (6H, s). MS / ESI 696.3 [M + H]+.

[0305] Step e) (S)-2-amino-3-(5-(5-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)pyridin-2-yl)-2H-tetrazol-2-yl)prop-1-ol (Example 22). 4 M HCl (0.284 mL, 1.15 mmol) in dimethyl methacrylate was added to a solution of 22.7 (80 mg, 0.115 mmol) in acetone (1 mL). The resulting suspension was stirred at room temperature for 4 hr. The mixture was concentrated, the residue was dissolved in water, and CH2Cl2 was added. The pH was adjusted to 9 with a saturated NaHCO3 solution, and the aqueous layer was extracted with CH2Cl2 / isopropanol (3:1). The combined organic layers were dried with Na2SO4, filtered, and concentrated. The residue was purified on silica gel (gradient: CH2Cl2 / MeOH) to give Example 22 (15 mg, 31%) as a colorless solid. UPLC retention time: 0.52 min (Method A). 1H NMR (DMSO-d6): δ = 13.09 (1H, s br), 8.72 (1H, s br), 8.45 (1H, s br), 8.28 (1H, d br), 8.23 ​​(1H, d br), 7.94 (1H, d br) 7.85 (1H, s br), 6.84 (1H, s br), 4.86 (1H, s br), 4.71-4.83 (1H, m), 4.50-4.71 (1H, m), 3.39 (2H, m), 3.35 (1H, m), 1.70 (2H, s br). MS / ESI 398.1 [M + H]+. Example 23 (S)-2-amino-3-(3-(5-(((5-chloro-3-fluoropyridin-2-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)prop-1-ol

[0306] Step a) 2-((6-bromopyridin-3-yl)oxy)-5-chloro-3-fluoropyridine (23.3). Under argon atmosphere, potassium carbonate (1.33 g, 9.63 mmol) was added to a solution of 23.1 (1.00 g, 6.42 mmol) and 23.2 (1.11 g, 6.42 mmol) in DMA (5 mL). The resulting suspension was stirred at 80°C for 18 h. After cooling, the reaction mixture was poured into water (40 mL) and MTBE (20 mL) and stirred vigorously for 10 min. The aqueous layer was then extracted twice with MTBE. The combined organic phases were washed with H2O and dried over Na2SO4. Evaporation yielded a crude product as a yellow oil. Crystallization from cyclohexane (4 mL) gave compound 23.3 (1.57 g, 81%) as a grayish-white solid. UPLC retention time was 1.15 min (Method A). 1H NMR (DMSO-d6): δ = 8.42 (1H, s), 8.29 (1H, dd), 8.08 (1H, d), 7.76 (2H, s). MS / ESI: m / z = 303.0 [M + H]+.

[0307] Step b) 2-((6-(1H-pyrazol-3-yl)pyridin-3-yl)oxy)-5-chloro-3-fluoropyridine (23.5). 2 M aqueous Na₂CO₃ (2.26 mL, 4.52 mmol) and tetrakis(triphenylphosphine)-palladium(O) (313 mg, 0.271 mmol) were added to the suspensions of 23.3 (686 mg, 2.26 mmol) and 23.4 (582 mg, 5.20 mmol) in dimethyl methacrylate (22.6 mL). After purging with argon, the reaction mixture was stirred in a sealed tube at 85°C for 20 h. After cooling, the suspension was distributed between ethyl acetate (50 mL) and water (75 mL). The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with 1 M aqueous Na₂CO₃ and semi-saturated brine. The residue was dried over Na₂SO₄ and evaporated to give a yellow oil. Rapid chromatography (gradient: cyclohexane / ethyl acetate) yielded a pale yellow oil. Crystallization of the residue from EtOH / Et₂O gave 23.5 (353 mg, 48%) of the pure compound as a white solid. UPLC retention time: 0.95 min (Method A). ¹H NMR (DMSO-d₆): δ 10.61 (br s), 8.57 (d, 1H), 8.29 (d, 1H), 8.08 (s), 8.07 (d), 7.86 (dd, 1H), 7.80 (s, 1H), 6.89 (s, 1H). MS / ESI: m / z = 291.1 [M + H]⁺.

[0308] Step c) (S)-2-amino-3-(3-(5-(((5-chloro-3-fluoropyridin-2-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)prop-1-ol (23.6, Example 23). Cs₂CO₃ (392 g, 1.204 mmol) was added to a solution of 23.5 (117 mg, 0.40 mmol) and intermediate A (177 mg, 0.482 mmol) in DMA (4.5 mL). The suspension was stirred at 0°C under argon for 1.5 h, followed by stirring at rt for another 2 h, and then stirred overnight at 45°C. The reaction mixture was poured into a mixture of ethyl acetate (50 mL) and water (25 mL). The aqueous layer was extracted twice with ethyl acetate. The combined organic phases were washed four times with brine and dried over Na₂SO₄. The solvent was evaporated to give a yellow oil. Example 23 (89 mg, 55%), a pure compound in a colorless oil, was obtained by rapid chromatography (gradient: CH2Cl2 / MeOH / NH3). UPLC retention time was 0.71 min (Method A). ¹H NMR (DMSO-d6): δ = 8.55 (¹H, d), 8.29 (¹H, d), 8.21 (3H, br s), 8.08 (¹H, d), 8.05 (¹H, dm), 7.90 (¹H, d), 7.80 (¹H, d), 6.87 (¹H, d), 4.52–4.37 (2H, m), 3.68–3.55 (2H, m), 3.54–3.45 (¹H, m). MS / ESI: m / z = 364.1 [M + H]+.

[0309] The material was converted to its hydrochloride by treating a solution in acetone (5 mL) with 0.6 mL of 1.25 M HCl MeOH solution, followed by evaporation and grinding with Et2O. The precipitate was filtered off and dried under vacuum at 80°C to give a product (81.2 mg) as a colorless crystalline solid. Additionally, the regioisomer (S)-2-amino-3-(5-(5-(((5-chloro-3-fluoropyridin-2-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)prop-1-ol 23' was isolated. Recrystallization from Et2O gave a colorless crystalline solid (17.2 mg, 12%). UPLC retention time was 0.67 min (Method A). ¹H NMR (DMSO-d6): δ = 8.63 (¹H, d), 8.29 (¹H, dd), 8.11 (¹H, d), 7.92–7.82 (2H, m), 7.54 (¹H, d), 6.78 (¹H, d), 4.62–4.51 (2H, m), 4.43 (¹H, dd), 3.29–3.07 (3H, m), 1.50 (2H, br s). MS / ESI: m / z = 364.2 [M + H]+. Example 24 (S)-2-amino-3-(3-(3-(((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol

[0310] Step a) 2-(3-bromophenoxy)-5-chloro-3-fluoropyridine (24.3). Under argon atmosphere, potassium carbonate (3.99 g, 28.9 mmol) was added to solutions of 24.1 (3.00 g, 19.26 mmol) and 24.2 (3.33 g, 19.26 mmol) in DMA (10 mL). The resulting suspension was stirred at 80°C for 18 h. After cooling, the reaction mixture was poured into water (120 mL) and MTBE (60 mL). The aqueous layer was extracted twice with MTBE. The combined organic phases were washed with 10% K2CO3, H2O, and brine. The organic phases were dried over Na2SO4. Evaporation yielded a crude product as a yellow oil. The residue was purified by rapid chromatography (cyclohexane / DCM) to give compound 24.3 (5.06 g, 87%) as a colorless oil. UPLC residence time 1.31 min (Method A). ¹H NMR (DMSO-d⁶): δ = 8.25 (¹H, dd), 8.09 (¹H, d), 7.52 (¹H, s), 7.47 (¹H, d), 7.41 (¹H, t), 7.25 (¹H, dd). MS / ESI: m / z = 302.0 [M⁺H]⁺.

[0311] Step b) 2-(3-(1H-pyrazol-3-yl)phenoxy)-5-chloro-3-fluoropyridine (24.5). KHCO3 (0.993 g, 9.91 mmol) and tetrakis(triphenylphosphine)-palladium(0) (286 mg, 0.248 mmol) were added to the suspensions of 24.3 (1.5 g, 4.96 mmol) and 24.4 (1.11 g, 9.92 mmol) in DMA (15 mL). After purging with argon, the reaction mixture was stirred in a sealed tube at 93°C for 24 h. After cooling, the suspension was divided between ethyl acetate (60 mL) and water (60 mL). The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with 1 M aqueous Na2CO3 and semi-saturated brine. The mixture was dried over Na2SO4 and evaporated to give a yellow oil. Rapid chromatography (gradient: cyclohexane / ethyl acetate) yielded 24.5 (547 mg, 38%) of pure compound as a colorless oil. UPLC retention time was 1.04 min (Method A). ¹H NMR (DMSO-d6): δ 12.96 (¹H, br s), 8.24 (¹H, s), 8.23 ​​(¹H, dd), 8.07 (¹H, d), 7.95 (¹H, br s), 7.51 (¹H, d), 7.47 (¹H, s), 7.40 (¹H, t), 7.00 (dd, ¹H). MS / ESI: m / z = 290.1 ​​[M + H]+.

[0312] Step c) (S)-(1-((tributyldimethylsilyl)oxy)-3-(3-(3-(((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propyl-2-yl)aminocarbamate tributyl ester (24.6). Cs₂CO₃ (1.765 g, 5.42 mmol) was added to a solution of 24.5 (523 mg, 1.805 mmol) and intermediate A (796 mg, 2.166 mmol) in DMA (12 mL). The suspension was stirred at rt for 4 h. RM was poured into a mixture of ethyl acetate (60 mL) and water (30 mL). The aqueous layer was extracted twice with ethyl acetate. The combined organic phases were washed four times with brine and dried over Na₂SO₄. The solvent was evaporated to give a yellow oil. The compound 24.6 (917 mg, 88%) was obtained as a pure, colorless oil by rapid chromatography (gradient: CH2CL2 / EtOAc). The UPLC retention time was 1.63 min (Method A). 1H NMR (DMSO-d6): δ 8.23 ​​(1H, dd), 8.07 (1H, d), 7.68 (1H, s), 7.67 (1H, d), 7.58 (1H, br s), 7.46 (1H, “t”), 7.12 (1H, dd), 6.78 (1H, d), 6.72 (1H, d), 4.26 (1H, dd), 4.16-4.05 (1H, m), 3.94-3.82 (1H, m), 3.61-3.45 (2H, m), 1.32 (9H, s), 0.87 (s, 9H), 0.04 (s, 6H). MS / ESI: m / z = 577.3 [M + H]+.

[0313] Step d) (S)-2-amino-3-(3-(3-(((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol (Example 24). Compound 24.6 (917 mg, 1.589 mmol) was dissolved in acetone (10 mL) and 4 M HCl (3.97 mL, 15.89 mmol) in dimethyl methacrylate was added. Gas release was immediately observed, and a thick suspension formed within 15 min. The mixture was stirred at 25°C for 16 h. The reaction was evaporated, leaving a viscous residue. The compound was purified by rapid chromatography (gradient: CH2Cl2 / MeOH-32% aqueous NH3) to give Example 24 as a colorless oil, which crystallized upon standing (531 mg, 92%). UPLC retention time: 0.76 min (Method A). 1H NMR (DMSO-d6): δ 8.23 ​​(1H, dd), 8.06 (1H, d), 7.76 (1H, d), 7.68 (1H, d), 7.59 (1H, “t”), 7.45 (1H, “t”), 7.11 (1H, dd), 6.73 (1H, d), 4.67 (1H, t), 4.17 (1H, dd), 3.94 (1H, dd), 3.31-3.21 (2H, m), 3.14-3.02 (1H, m), 1.48 (2H, br s). MS / ESI: m / z = 363.1 [M + H]+. Example 25 S)-2-amino-3-(4-(4-(((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol

[0314] Step a) 2-(4-bromophenoxy)-5-chloro-3-fluoropyridine (25.3). Under argon atmosphere, potassium carbonate (3.99 g, 28.9 mmol) was added to solutions of 25.1 (3.00 g, 19.26 mmol) and 25.2 (3.33 g, 19.26 mmol) in DMA (10 mL). The resulting suspension was stirred at 80°C for 18 h. After cooling, the reaction mixture was poured into water (120 mL) and MTBE (60 mL). The aqueous layer was extracted twice with MTBE. The combined organic phases were washed with 10% K2CO3, H2O, and brine. The organic phases were dried over Na2SO4. Evaporation yielded a crude product as a yellow oil. The residue was purified by rapid chromatography (cyclohexane / DCM) to give compound 25.3 (5.16 g, 89%) as a colorless oil. UPLC residence time 1.31 min (Method A). 1H NMR (DMSO-d6): δ = 8.24 (1H, dd), 8.07 (1H, d), 7.62 (2H, d), 7.21 (2H, d). MS / ESI: m / z = 301.9 [M + H]+.

[0315] Step b) 2-(4-(1H-pyrazol-4-yl)phenoxy)-5-chloro-3-fluoropyridine (25.5). KHCO3 (0.993 g, 9.91 mmol) and tetrakis(triphenylphosphine)-palladium(0) (286 mg, 0.248 mmol) were added to the suspensions of 25.3 (1.5 g, 4.96 mmol) and 25.4 (1.11 g, 9.92 mmol) in DMA (15 mL). After purging with argon, the reaction mixture was stirred in a sealed tube at 90°C for 48 h. After cooling, the suspension was divided between ethyl acetate (100 mL) and water (100 mL). The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with 1 M aqueous Na2CO3 and semi-saturated brine. The mixture was dried over Na2SO4 and evaporated to give a yellow oil. Rapid chromatography (gradient: cyclohexane / ethyl acetate) yielded a viscous oil. The residue was crystallized from cyclohexane / Et₂O₂: 1 to give 25.5 (472 mg, 27%) of pure compound as a white solid. UPLC retention time: 0.99 min (Method A). ¹H NMR (DMSO-d₆): δ 12.93 (¹H, br s), 8.21 (¹H, dd), 8.18 (¹H, br s), 8.06 (¹H, d), 7.92 (¹H, br s), 7.65 (2H, d), 7.19 (2H, d). MS / ESI: m / z = 290.1 ​​[M + H]⁺.

[0316] Step c) (S)-(1-((tributyldimethylsilyl)oxy)-3-(4-(4-(((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propyl-2-yl)aminocarbamate tributyl ester (25.6). Cs₂CO₃ (660 mg, 2.027 mmol) was added to a solution of 25.5 (196 mg, 0.676 mmol) and intermediate A (323 mg, 0.878 mmol) in DMA (5.5 mL). The suspension was stirred at rt for 28 h. RM was poured into a mixture of ethyl acetate (60 mL) and water (30 mL). The aqueous layer was extracted twice with ethyl acetate. The combined organic phases were washed four times with brine and dried over Na₂SO₄. The solvent was evaporated to give a yellow oil. Compound 25.6, a colorless oil, was isolated by rapid chromatography (gradient: CH2CL2 / EtOAc) and crystallized upon standing (399 mg, 86%). The UPLC retention time was 1.60 min (Method A). 1H NMR (DMSO-d6): δ 8.22 (1H, dd), 8.09-8.01 (2H, m), 7.89 (1H, s), 7.59 (2H, “d”), 7.20 (2H, “d”), 6.78 (1H, br d), 4.25 (1H, dd), 4.15-4.06 (1H, m), 3.98-3.86 (1H, m)), 3.60-3.46 (2H, m), 1.33 (9H, s), 0.89 (9H, s), 0.05 (6H, s). MS / ESI: m / z = 577.4 [M + H]+.

[0317] Step d) (S)-2-amino-3-(4-(4-(((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol (Example 25). Compound 25.6 (388 mg, 0.672 mmol) was dissolved in acetone (5 ml) and 4 M HCl (1.68 mL, 6.72 mmol) in dimethyl methacrylate was added. Gas release was immediately observed, and a thick suspension was formed within 15 min. The mixture was stirred at 40°C for 2.5 h. Then 4 M HCl (0.84 mL, 3.36 mmol) in dimethyl methacrylate was added, and stirring was continued at 40°C for 4 h. The solution was evaporated to clarify, leaving a viscous residue. The compound was purified by rapid chromatography (gradient: CH2Cl2 / MeOH-32% aqueous NH3) to give a solid. Example 25 (157 mg, 64%) was obtained as a white solid after grinding with isopropanol and vacuum drying at 60°C. UPLC retention time was 0.76 min (Method A). ¹H NMR (DMSO-d6): δ 8.21 (¹H, dd), 8.14 (¹H, s), 8.06 (¹H, d), 7.88 (¹H, s), 7.62 (2H, d), 7.19 (2H, d), 4.68 (¹H, t), 4.17 (¹H, dd), 3.94 (¹H, dd), 3.33–3.21 (2H, m), 3.15–3.03 (¹H, m), 1.49 (2H, br s). MS / ESI: m / z = 363.1 [M + H]+. Example 26 (S)-2-amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol

[0318] Step a) 2-(4-bromophenoxy)-5-chloro-3-fluoropyridine (26.3). Under argon atmosphere, potassium carbonate (1.33 g, 9.63 mmol) was added to a solution of 26.1 (1.00 g, 6.42 mmol) and 26.2 (1.11 g, 6.42 mmol) in DMA (5 mL). The resulting suspension was stirred at 80°C for 18 h. After cooling, the reaction mixture was poured into water (40 mL) and MTBE (20 mL) and stirred vigorously for 10 min. The aqueous layer was then extracted twice with MTBE. The combined organic phases were washed with 10% aqueous K2CO3 and semi-saturated brine and dried over Na2SO4. Evaporation yielded a crude product as a colorless oil. Rapid silica gel chromatography (gradient: cyclohexane / CH2Cl2) yielded compound 26.3 (1.75 g, 90%) as a colorless solid. UPLC residence time 1.31 min (Method A). TLC: Rf = 0.25 (CH2Cl2 / cyclohexane 1:4), 1H NMR (DMSO-d6): δ = 8.24 (1H, dd), 8.06 (1H, s), 7.62 (2H, d), 7.21 (2H, d). MS / ESI: m / z = 302.0 [M + H]+.

[0319] Step b) 2-(4-(1H-pyrazol-3-yl)phenoxy)-5-chloro-3-fluoropyridine (26.5). 2 M aqueous Na₂CO₃ (1.65 mL, 3.30 mmol) and tetrakis(triphenylphosphine)-palladium(O) (0.31 g, 0.2 mmol) were added to the suspension of 26.3 (1.00 g, 3.31 mmol) in dimethyl methacrylate (14 mL). After purging with argon, the reaction mixture was stirred in a sealed tube at 75°C for 40 h. After cooling, the suspension was divided between ethyl acetate (50 mL) and water (75 mL). The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with 1 M aqueous Na₂CO₃ and semi-saturated brine. The mixture was dried over Na₂SO₄ and evaporated to give a yellow oil. Rapid chromatography (gradient: cyclohexane / ethyl acetate) yielded pure compound 26.5 (0.27 g, 28%) as a colorless oil. UPLC retention time: 1.01 min (Method A). TLC: Rf = 0.35 (ethyl acetate / cyclohexane 1:1), 1H NMR (DMSO-d6): δ = 8.24 (1H, dd), 8.08 (1H, d), 7.86 (2H, d), 7.79 (1H, d), 7.22 (2H, d), 6.72 (1H, d). MS / ESI: m / z = 290.1 ​​[M + H]+.

[0320] Step c) (S)-(1-((tributyldimethylsilyl)oxy)-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propyl-2-yl)aminocarbamate tributyl ester (26.6). Cs₂CO₃ (880 mg, 2.70 mmol) was added to a solution of 26.5 (261 mg, 0.90 mmol) and intermediate A (398 mg, 1.08 mmol) in DMA (10 mL). The colorless suspension was stirred at 25°C under argon for 2.5 h, then poured into a mixture of ethyl acetate (75 mL) and water (30 mL). The aqueous layer was extracted twice with ethyl acetate. The combined organic phases were washed four times with brine and dried over Na₂SO₄. Evaporation of the solvent yielded a colorless oil containing two possible regio-alkylated products in a ratio of 14:1 (UPLC, UV 215 nm). Separation by rapid chromatography (gradient: CH₂Cl₂ / ethyl acetate) yielded 26.6 mg (370 mg, 71%) of the desired regio-isomer, also present as a colorless oil. UPLC retention time was 7.63 min (Method B). TLC: Rf = 0.64 (ethyl acetate / CH2Cl2 1:1), 1H NMR (DMSO-d6): δ = 8.23 ​​(1H, dd), 8.08 (1H, d), 7.82 (2H, d), 7.68 (1H, d), 7.22 (2H, d), 6.80 (1H, br d), 6.69 (1H, d), 4.39 (1H, dd), 4.11 (1H, dd), 3.94 (1H, m), 3.55 (2H, m), 1.38 (9H, s), 0.89 (9H, s), 0.02 (3H, s), 0.02 (3H, s). MS / ESI: m / z = 577.4 [M + H]+. Also obtained was 26.6' (42 mg, 8%) of the undesired pyrazole reticulomer, which was a colorless oil. UPLC residence time was 7.53 min (Method B).TLC: Rf = 0.27 (ethyl acetate / CH₂CL₂ : 1), 1H NMR (DMSO-d₆): δ = 8.26 (1H, dd), 8.09 (1H, d), 7.54 (2H, d), 7.53 (1H, d), 7.30 (2H, d), 6.57 (1H, br d), 6.49 (1H, d), 4.29 (1H, dd), 4.10 (1H, dd), 3.94 (1H, m), 3.40 (2H, m), 1.33 (9H, s), 0.79 (9H, s), -0.04 (3H, s), -0.05 (3H, s). MS / ESI: m / z = 577.4 [M + H]⁺.

[0321] Step d) (S)-2-amino-3-(3-(4-(((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol (Example 26). Compound 26.6 (362 mg, 0.627 mmol) was dissolved in 4 M HCl (1.5 mL) in diethyl ether. Boiling was immediately observed, and a thick suspension was formed within 15 min. Acetone (4.5 mL) was added, and stirring was continued at 25°C for 1.5 h. The reaction was evaporated, leaving a viscous residue. Rapid chromatography (gradient: CH2Cl2 / MeOH-32% aqueous NH3) and recrystallization from diethyl ether / n-pentane gave Example 26 (166 mg, 73%) as a colorless powder. UPLC retention time was 0.76 min (Method A). TLC: Rf= 0.19 (CH2CL2 / MeOH / 25% aqueous NH390: 9: 1), 1H NMR (DMSO-d6): δ = 8.23 ​​(1H, dd), 8.07 (1H, d), 7.84 (2H, d), 7.76 (1H, d), 7.22 (2H, d), 6.69 (1H, d), 4.68 (1H, t, OH), 4.19 (1H, dd), 3.96 (1H, dd), 3.32-3.25 (3H, m), 3.11 (1H, m), 1.51 (2H, br s, NH2). MS / ESI: m / z = 363.2 [M + H]+. Example 27 (S)-2-amino-3-(5-(4-(4-chlorophenoxy)phenyl)-2H-tetrazole-2-yl)prop-1-ol

[0322] Step a) 5-(4-(4-chlorophenoxy)phenyl)-2H-tetrazole (26.3). Dibutyltin ketone (155 mg, 0.623 mmol) and azidotrimethylsilane (1.7 mL, 12.4 mmol) were added to a solution of nitrile 27.1 (1.43 g, 6.23 mmol) in anhydrous toluene (9 mL). The reaction mixture was heated to 100°C in a sealed vial and maintained for 17 h. After cooling to room temperature, all volatiles were removed under vacuum, the coarse material was ground with MeOH (6 mL) and concentrated again. The material was suspended in MeCN (6 mL) and filtered. The solid was washed with MeCN (2 × 3 mL) and dried under vacuum to give tetrazolium 27.2 (1.49 g, 86%) as a colorless powder. UPLC retention time was 0.99 min (Method A). 1H NMR (400 MHz, DMSO-d6): δ= 16.82 (s, br, 1H), 8.09-8.02 (m, 2H), 7.55-7.46 (m, 2H), 7.27-7.12 (m, 4H). MS / ESI: m / z = 273.0 [M + H]+.

[0323] Step b) Methyl (S)-2-((tributoxycarbonyl)amino)-3-(5-(4-(4-chlorophenoxy)phenyl)-2H-tetrazol-2-yl)propionate (27.3). Add a solution of di-tributyl azodicarbonate (2.53 g, 11.00 mmol) and Boc-Ser-OMe (2.41 g, 11.0 mmol) in THF (60 mL) to a solution of 27.2 (1.2 g, 4.40 mmol) and PPh3 (2.89 g, 11.0 mmol) in THF (20 mL). After stirring at room temperature for 19 h, all volatiles were removed under vacuum, and the crude material was adsorbed onto isolute™. Purified by rapid column chromatography (80 g SiO2, heptane, and EtOAc), a colorless solid (4.1 g) containing the title compound 27.3 and a large amount of BocNH-NHBoc was obtained. This material was used for further processing without additional purification. UPLC retention time was 1.34 min (Method A). ¹H NMR (400 MHz, DMSO-d6): δ = 8.15–8.07 (m, 2H), 7.40–7.31 (m, 2H), 7.31 (s, 1H), 7.14–7.06 (m, 2H), 7.06–6.98 (m, 2H), 5.14 (qd, 2H), 4.90 (dt, 1H), 3.85 (s, 3H), 1.45 (s, 9H). MS / ESI: m / z = 474.0 [M + H]+.

[0324] Step c) (S)-(1-(5-(4-(4-chlorophenoxy)phenyl)-2H-tetrazol-2-yl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester (27.4). A solution of 27.3 (414 mg, 0.874 mmol) in THF (10 mL) was treated with 2 N LiBH4 in THF (1.75 mL, 3.5 mmol) at 0°C. After 30 min, the reaction mixture was adsorbed onto isolute™ and dried under vacuum. Rapid column chromatography (43 g RP18 silica gel, 0.1% TFA in water:MeCN at a ratio of 19:1 to 0:1) yielded alcohol 27.4 (173 mg, 44%) as a colorless solid. UPLC retention time: 1.22 min (Method A). 1H NMR (400 MHz, DMSO-d6): δ= 8.09-8.02 (m, 2H), 7.54-7.45 (m, 2H), 7.23-7.11 (m, 4H), 6.88 (d, 1H, -NH), 5.03 (t, 1H, -OH), 4.89 (dd, 1H), 4.61 (dd, 1H), 3.99 (s, br, 1H), 3.48 (d, br, 2H), 1.25 (s, 9H). MS (ESI+): m / z = 446.1 [M + H]+.

[0325] Step d) (S)-2-amino-3-(5-(4-(4-chlorophenoxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol (Example 27). A solution of 27.4 (88 mg, 0.197 mmol) in DCM (4 mL) was treated with TFA (2 mL) and kept at room temperature for 1 h. The reaction mixture was concentrated under vacuum and adsorbed onto isolute™. Rapid column chromatography (43 g RP18 silica gel, 0.1% TFA in 19:1 to 0:1 water:MeCN) followed by lyophilization from an aqueous solution containing HCl yielded the hydrochloride of Example 27 as a colorless powder (71 mg, 92%). UPLC retention time: 0.81 min (Method A). 1H NMR (400 MHz, DMSO-d6): δ= 8.24 (s, br, 3H, -NH3), 8.12-8.06 (m, 2H), 7.55-7.47 (m, 2H), 7.25-7.12 (m, 4H), 5.56 (t, 1H, -OH), 5.04 (dd, 1H), 4.96 (dd, 1H), 3.81 (dq, 1H), 3.72 (dt, 1H), 3.63 (dt, 1H). MS (ESI+): m / z = 346.0 [M + H]+. Example 28 (S)-2-amino-3-(5-(4-((5-cyclopropylpyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol

[0326] Step a) 2-(4-(2H-tetrazol-5-yl)phenoxy)-5-bromopyridine (28.1). Two vials, each containing a solution of 13.3 (2.95 g, 10.72 mmol), Bu₂SnO (0.267 g, 1.073 mmol), and TMSN₃ (2.47 g, 21.45 mmol) in anhydrous toluene (10.5 mL), were sealed under argon atmosphere and stirred at 100°C for 8 h on a heating block. The resulting heterogeneous mixture was treated with MeOH and concentrated under reduced pressure. The solid residue was crystallized from MeOH to give 28.1 (2.60 g, 42%) as a colorless solid. UPLC retention time: 0.86 min (Method A). 1H NMR (DMSO-d6): δ = 16.5 (1H, s, br), 8.32 (1H, d), 8.11 (1H, dd), 8.04-8.09 (2H, m), 7.35-7.40 (2H, m), 7.14 (1H, d). MS / ESI 318.1 [M + H]+.

[0327] Step b) Methyl propionate (S)-3-(5-(4-((5-bromopyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)-2-((tributoxycarbonyl)amino)propionate (28.3). A solution of 28.1 (2.60 g, 8.17 mmol), triphenylphosphine (3.22 g, 12.26 mmol), DIAD (2.82 g, 12.26 mmol), and 28.2 (2.69 g, 12.26 mmol) in THF (60 ml) was stirred at 25°C for 1.5 h. Isolate was added and the mixture was dried under vacuum. Silica gel chromatography (gradient: cyclohexane / ethyl acetate) yielded 28.3 (5.65 g) as a colorless solid containing approximately 10% triphenylphosphine oxide, which was used in the next step. A small fraction was further purified by SFC to obtain the analytical sample. UPLC residence time 1.25 min (Method A). ¹H NMR (DMSO-d6): δ = 8.33 (¹H, d), 8.12 (¹H, dd), 8.08 (2H, d), 7.49 (¹H, d), 7.34 (2H, d), 5.11 (¹H, dd), 5.01 (¹H, dd), 4.71 (¹H, m), 3.70 (3H, s), 1.32 (9H, s). MS / ESI 519.1 [M + H]+.

[0328] Step c) (S)-(1-hydroxy-3-(5-(4-hydroxyphenyl)-2H-tetrazol-2-yl)propyl-2-yl)aminocarbamate tributyl ester (28.4). LiBH4 (2 N solution in THF, 10.28 mL, 20.56 mmol) was added dropwise to a solution of 28.3 (2.67 g, 5.14 mmol) in THF (50 mL) at 0°C, and the mixture was stirred at 0°C for 45 min. The mixture was neutralized with HCl (1 N aqueous solution), CH2Cl2 was added, the organic layer was separated, dried over Na2SO4, and the solvent was removed. Silica gel chromatography (gradient: cyclohexane / ethyl acetate) yielded compound 28.4 (553 mg, 21%) as a colorless solid. UPLC retention time: 1.11 min (Method A). 1H NMR (DMSO-d6): δ = 8.33 (1H, d), 8.12 (1H, dd), 8.08 (2H, d), 7.34 (2H, d), 7.24 (1H, d), 6.88 (1H, d), 5.03 (1H, t, br), 4.91 (1H, dd), 4.63 (1H, dd), 4.02 (1H, m), 3.48 (2H, m), 1.27 (9H, s). MS / ESI 491.2 [M + H]+.

[0329] Step d) (S)-(1-(5-(4-(((5-cyclopropylpyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester (28.6). A suspension of 28.4 (400 mg, 0.814 mmol), 28.5 (164 mg, 0.977 mmol), K3PO4 (518 mg, 2.442 mmol), and PdCl2 (dtbpf) (53.1 mg, 0.081 mmol) in a mixture of dimethyl ether (7.5 mL) and water (3.75 mL) was stirred at 85°C under argon for 2 h. The mixture was concentrated, and the residue was purified on silica gel (gradient: cyclohexane / ethyl acetate) to give 28.6 (80 mg, 21%). UPLC residence time 1.11 min (Method A). ¹H NMR (DMSO-d6): δ = 8.05 (3H, m), 7.57 (1H, dd), 7.25 (2H, d), 7.02 (1H, d), 6.88 (1H, d), 5.02 (1H, t, br), 4.90 (1H, dd), 4.62 (1H, dd), 4.02 (1H, m), 3.47 (2H, m), 1.95 (1H, m), 1.25 (9H, s), 0.96 (2H, m), 0.71 (2H, m). MS / ESI 453.4 [M + H]+.

[0330] Step e) (S)-2-amino-3-(5-(4-((5-cyclopropylpyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol (Example 28). HCl (0.638 mL, 2.55 mmol, 4 N solution in dichloroisocyanuric acid) was added to a solution of 28.6 (77 mg, 0.170 mmol) in CH2Cl2 (1.7 mL), and the mixture was stirred at 25°C for 1.5 h. Filtering yielded the hydrochloride of Example 28 (60 mg, 89%) as a colorless solid. UPLC retention time was 0.72 min (Method A). 1H NMR (DMSO-d6): δ = 8.42 (3H, s br), 8.12 (2H, d), 8.04 (1H, d), 7.57 (1H, dd), 7.28 (2H, d), 7.02 (1H, d), 5.56 (1H, s, br), 5.08-4.94 (2H, m), 3.81 (1H, m), 3.72 (1H, dd), 3.65 (1H, dd), 1.95 (1H, m), 0.96 (2H, m), 0.71 (2H, m). MS / ESI 353.3 [M + H]+. Example 29 (S)-2-amino-3-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol

[0331] Step a) 4-((5-chloro-3-fluoropyridin-2-yl)oxy)benzonitrile (29.3). A suspension of 29.1 (23.6 g, 158 mmol), 29.2 (17.9 g, 150 mmol), and K2CO3 (24.9 g, 180 mmol) in DMF (40 mL) was heated to 100°C and maintained for 3 h. The reaction mixture was partitioned between heptane-ethyl acetate (2:1, 500 mL) and water (250 mL). The organic layer was washed with Na2CO3 and brine, dried over Na2SO4, filtered, and concentrated to give a crude product, which was recrystallized from hexane / ethyl acetate. Pure product 29.3 (20.5 g, 53%) was given as a colorless solid. UPLC retention time 1.10 min (Method A). 1H NMR (DMSO-d6): δ = 8.30 (1H, dd), 8.13 (1H, dd), 7.93 (2H, d), 7.43 (2H, d). MS / ESI 249.0 [M+H]+.

[0332] Step b) 2-(4-(2H-tetrazol-5-yl)phenoxy)-5-chloro-3-fluoropyridine (29.4). Nine vials, each containing a solution of 29.3 (2.24 g, 9.00 mmol), Bu2SnO (0.224 g, 0.900 mmol), and TMSN3 (2.39 mL, 18.0 mmol) in anhydrous toluene (9 mL), were sealed under argon atmosphere and stirred at 90°C for 18 h on a heating block. The heterogeneous mixture was concentrated by treating the combined crude material with MeOH (100 mL) and concentrating again under reduced pressure to give a light brownish-orange solid. The solid residue was suspended in MeOH (100 mL), stirred for 20 min, and filtered. The solid was washed with heptane and dried to give compound 29.4 (18.5 g, 77%) as a colorless powder. UPLC retention time: 0.89 min (Method A). 1H NMR (DMSO-d6): δ = 16.8 (1H, s, br), 8.28 (1H, dd), 8.08-8.13 (3H, m), 7.43 (2H, d). MS / ESI 292.1 [M + H]+.

[0333] Step c) Methyl (S)-2-((tributoxycarbonyl)amino)-3-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propionate (29.6). At 0°C, PPh3 (29.5 g, 112.5 mmol), DIAD (25.9 g, 112.5 mmol), and 29.5 (24.6 g, 112.5 mmol) were added to a solution of 29.4 (13.1 g, 45.0 mmol) in THF (150 ml). The resulting mixture was stirred at 25°C for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and evaporated. Compound 29.6 (13.7 g, 62%) was obtained as a colorless solid by silica gel chromatography (15% ethyl acetate in petroleum ether solution). UPLC retention time was 1.26 min (Method A). ¹H NMR (DMSO-d6): δ = 8.28 (¹H, dd), 8.10 (³H, m), 7.49 (¹H, d), 7.41 (²H, d), 5.13 (¹H, dd), 5.01 (¹H, dd), 4.72 (¹H, m), 3.70 (³H, s), 1.31 (⁹H, s). MS / ESI 493.3 [M + H]⁺.

[0334] Step d) (S)-(1-(5-(4-(((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester (29.7). LiBH4 (2.94 mL, 5.88 mmol) in THF was added dropwise to a solution of 29.6 (724 mg, 1.47 mmol) in THF (15 mL) at 0°C, and the mixture was stirred at 0°C for 1 h. The mixture was neutralized with HCl (1 N aqueous solution), CH2Cl2 was added, the organic layer was separated, and the solvent was removed by drying with Na2SO4. Silica gel chromatography (gradient: cyclohexane / ethyl acetate) yielded compound 29.7 (555 mg, 72%) as a colorless oil. UPLC retention time was 1.13 min (Method A). 1H NMR (DMSO-d6): δ = 8.28 (1H, dd), 8.10 (3H, m), 7.40 (2H, d), 6.88 (1H, d), 5.03 (1H, t, br), 4.91 (1H, dd), 4.63 (1H, dd), 4.01 (1H, m), 3.48 (2H, m), 1.25 (9H, s). MS / ESI 465.3 [M + H]+.

[0335] Step e) (S)-2-amino-3-(5-(4-(((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol (Example 29). HCl (1.4 mL, 5.6 mmol, 4 N solution in dichloroisocyanuric acid) was added to a solution of 29.7 g (172 mg, 0.37 mmol) in CH2Cl2 (3 mL), and the mixture was stirred at 25°C for 1 h. Filtering yielded the hydrochloride of Example 29 (93 mg, 62%) as a colorless solid. UPLC retention time was 0.74 min (Method A). ¹H NMR (DMSO-d6): δ = 8.42 (3H, s, br), 8.29 (1H, dd), 8.15 (2H, d), 8.11 (1H, d), 7.42 (2H, d), 5.56 (1H, s, br), 5.08–4.94 (2H, m), 3.81 (1H, m), 3.77–3.60 (2H, m). MS / ESI 365.2 [M + H]+. Example 30 (R)-2-amino-3-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol

[0336] (R)-2-amino-3-(5-(4-(((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol (Example 30) hydrochloride was prepared by a similar procedure to that used in the synthesis of Example 29, except that 29.5 was replaced with its R-mirror isomer 30.5. UPLC retention time: 0.74 min (Method A). 1H NMR (DMSO-d6): δ = 8.37 (3H, s, br), 8.29 (1H, dd), 8.15 (2H, m), 8.11 (1H, d), 7.42 (2H, m), 5.57 (1H, t), 5.08–4.94 (2H, m), 3.82 (1H, m), 3.77–3.62 (2H, m). MS / ESI 365.2 [M + H]+. Example 31 (R)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol

[0337] Step a) 4-((5-chloropyridin-2-yl)oxy)benzonitrile (31.3). At room temperature, compound 31.1 (19.7 g, 150 mmol) was added dropwise to a suspension of 31.2 (16.99 g, 143 mmol) and powdered K2CO3 (23.66 g, 171 mmol) in DMF (volume: 30 mL). The reaction mixture remained a suspension, and no temperature change was observed. The mixture was heated to 140°C and maintained for 24 h. The RM was cooled to approximately 80°C to give a very thick yellow suspension. Ethyl acetate (100 mL) and water (100 mL) were added to give two clear layers. Cooling to room temperature initiated crystallization of the product in the upper organic layer. Colorless fine needles were collected by filtration, washed with MeOH (3 × 30 mL), and dried in an air stream to give 31.3 (17.5 g, yield 52%). The filtrate was diluted with water (200 ml) and ethyl acetate / heptane (1:2) (300 ml). The phases were separated, and the organic layer was washed with water (2 × 100 ml), NaHCO3 (100 mL), and brine (100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under vacuum to give a colorless solid, which was then suspended in MeOH (approximately 50 mL). A second batch of 31.3 was collected by filtration, washed with MeOH (2 × 30 mL), and dried over an air stream to give 11.4 g (34% yield). UPLC retention time was 1.06 min (Method A). ¹H NMR (DMSO-d6): δ = 8.27 (¹H, d), 8.04 (¹H, dd), 7.91 (2H, m), 7.36 (2H, m), 7.24 (¹H, d). MS / ESI 230.9 [M + H]+.

[0338] Step b) 2-(4-(2H-tetrazol-5-yl)phenoxy)-5-chloropyridine (31.4). Five solutions of 31.3 (1.442 g, 6.25 mmol), Bu2SnO (0.156 g, 0.625 mmol), and TMS-azide (1.659 mL, 12.50 mmol) in anhydrous toluene (9 mL) were prepared under argon atmosphere. The vials were sealed and the mixture was stirred on a heating block at 100°C for 65 h. The mixtures were combined and treated with MeOH (50 mL) to suspend the RM. All solvents were removed under reduced pressure. The solid residue was suspended in MeCN (70 mL) and filtered. The colorless powder was washed with MeCN (2 × 25 mL) and pentane and dried to give 31.4 (7.66 g, 88% yield) as a colorless powder. UPLC residence time 2.81 min (Method B). ¹H NMR (DMSO-d6): δ = 16.7 (¹H, s br), 8.27 (¹H, d), 8.04 (¹H, dd), 7.91 (2H, m), 7.36 (2H, m), 7.24 (¹H, d). MS / ESI 274.0 [M + H]+.

[0339] Step c) Methyl (R)-2-((tributoxycarbonyl)amino)-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-2H-tetrazole-2-yl)propionate (31.6). A mixture of triphenylphosphine (2.396 g, 9.13 mmol), DIAD (2.103 g, 9.13 mmol), and 31.4 (1.00 g, 3.65 mmol) and 31.5 (2.003 g, 9.13 mmol) in THF (65 ml) was stirred at 25°C for 1 h. Isolute was added and the mixture was dried under vacuum. Silica gel chromatography (gradient: cyclohexane / ethyl acetate) gave 31.6 (1.57 g, 89%) as a colorless solid. UPLC retention time was 1.33 min (Method A). 1H NMR (DMSO-d6): δ = 8.25 (1H, d), 8.09 (2H, d), 8.01 (1H, d), 7.49 (1H, d), 7.34 (2H, d), 7.20 (1H, d), 5.11 (1H, dd), 5.01 (1H, dd), 4.72 (1H, m), 3.71 (3H, s), 1.25-1.40 (9H, m). MS / ESI 475.3 [M + H]+.

[0340] Step d) (R)-(1-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester (31.7). LiBH4 (2.106 mL, 4.21 mmol in THF, 2 N solution) was added dropwise to a solution of 31.6 (500 mg, 1.053 mmol) in 10 mL of THF at 0°C, and the mixture was stirred at 0°C for 1 h. The mixture was neutralized with HCl (1 N aqueous solution), CH2Cl2 was added, the organic layer was separated, and the solvent was removed by drying with Na2SO4. Silica gel chromatography (gradient: cyclohexane / ethyl acetate) yielded compound 31.7 (555 mg, 72%) as a colorless oil. UPLC retention time: 1.10 min (Method A). 1H NMR (DMSO-d6): δ = 8.27 (1H, dd), 8.09 (2H, d), 8.03, (1H, d), 7.34 (2H, d), 7.20 (1H, d), 6.88 (1H, d), 5.03 (1H, t, br), 4.91 (1H, dd), 4.63 (2H, dd), 4.00 (1H, m), 3.40-3.51 (2H, m), 1.25 (9H, s). MS / ESI 447.2 [M + H]+.

[0341] Step d) (R)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol (Example 31). HCl (2.308 mL, 9.23 mmol, 4 N solution in dimethyl methacrylate, 31.7 g (275 mg, 0.615 mmol) in CH2Cl2 (6 mL) was added, and the mixture was stirred at 25°C for 2 h. Filtering yielded the first batch of Example 31 hydrochloride (40 mg, 18%) as a colorless solid. The filtrate was concentrated and the residue was purified by preparative HPLC. The TFA salt was converted to a free base and further purified on silica gel (gradient: CH2Cl2 / MeOH) to give Example 31 (37 mg, 15%). UPLC retention time: 0.70 min (Method A). ¹H NMR (DMSO-d6): δ = 8.26 (¹H, d), 8.10 (2H, d), 8.02 (¹H, dd), 7.34 (2H, d), 7.00 (1H, d), 4.85 (1H, t, br), 4.77 (1H, dd), 4.55 (1H, dd), 3.33–3.45 (2H, m), 3.25–3.30 (1H, m), 1.60 (2H, s br). MS / ESI 347.1 [M + H]+. Example 32 (S)-2-amino-3-(5-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol

[0342] Step a) (2S)-2-amino-3-(5-(4-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol (32.2). The suspensions of Example 29 (2000 mg, 5.48 mmol), 32.1 (2050 mg, 10.97 mmol), K3PO4 (2328 mg, 10.97 mmol), and PdCl2(dtbpf) (357 mg, 0.548 mmol) in a mixture of dimethyl ether (20 mL) and water (6.3 mL) were stirred at 120°C under argon for 1.5 min. Add a solution of 32.1 and PdCl2 (dtbpf) in 2 μL (5 mL), and continue heating at 120°C for 1 h. Dilute the mixture with water and extract with ethyl acetate. Dry the organic layer with Na2SO4, filter, and concentrate. Purify the residue on silica gel (gradient: CH2Cl2 / MeOH) to give 32.2 (1127 mg, 42%). Dissolve the material in THF (70 mL), add SiliaMetS DMT, and stir the mixture at 50°C for 16 h. Filter off the scavenging agent, wash the residue with THF, and concentrate to give a solid, which is used in the next step. UPLC retention time: 0.78 min (Method A). 1H NMR (DMSO-d6): δ = 8.12-8.17 (3H, m), 8.06 (1H, d), 7.62 (1H, d), 7.45 (2H, d), 6.61 (1H, d), 5.31 (1H, dd), 4.83-4.91 (1H, m), 4.77 (1H, dd), 4.56 (1H, dd), 3.95 (1H, d br), 3.53-3.62 (1H, m), 3.25-3.45 (3H, m), 2.33-2.44 (1H, m), 1.92-2.01 (1H, m), 1.85 (1H, d br), 1.49-1.72 (m, 5H). MS / ESI 481.2 [M + H]+

[0343] Step b) (S)-2-amino-3-(5-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol (Example 32). 2 N HCl (2.0 mL) was added to a solution of 32.2 (1125 mg, 2.341 mmol) in THF (15 mL), and the mixture was stirred at 25°C for 1.5 h. The mixture was concentrated, and the residue was purified on silica gel (gradient: CH2Cl2 / MeOH) to give Example 32 (421 mg, 41%). UPLC retention time: 0.63 min (Method A). ¹H NMR (DMSO-d6): δ = 8.54 (3H, s br), 8.48 (1H, d), 8.28 (1H, dd), 8.15 (2H, d), 7.83 (1H, d), 7.41 (2H, d), 6.85 (1H, d), 5.00–5.10 (2H, m), 3.75–3.85 (2H, m), 3.67–3.76 (2H, m). OH and pyrazole NH were not observed. MS / ESI 397.2 [M + H]+ Example 33 (S)-2-amino-3-(5-(4-((5-bromopyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol

[0344] Step a) (S)-2-amino-3-(5-(4-(((5-bromopyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol (Example 33). HCl (1.061 mL, 4.24 mmol in 4 N solution in dichloroisocyanuric acid) was added to a solution of 28.4 (139 mg, 0.283 mmol) in CH2Cl2 (2.8 mL), and the mixture was stirred at 25°C for 2 h. The mixture was filtered to obtain the hydrochloride of Example 33 (100 mg, 83%) as a colorless solid. UPLC retention time was 0.73 min (Method A). ¹H NMR (DMSO-d6): δ = 8.41 (2H, s br), 8.33 (1H, d), 8.10–8.17 (3H, m), 7.37 (2H, d), 7.17 (1H, d), 4.95–5.10 (2H, m), 3.82 (1H, m), 3.72 (1H, dd), 3.65 (1H, dd). MS / ESI 391.1 [M + H]+. Example 34 (S)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol

[0345] (S)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol (Example 34) was prepared as a hydrochloride salt by replacing 31.5 with its S-mirror isomer 34.5 using a similar procedure to that used in the synthesis of Example 31. UPLC retention time: 0.68 min (Method A). ¹H NMR (DMSO-d6): δ = 8.43 (3H, s br), 8.27 (1H, d), 8.14 (2H, m), 8.03 (1H, dd), 7.36 (2H, m), 7.21 (1H, d), 5.57 (1H, t), 4.95–5.10 (2H, m), 3.82 (1H, m), 3.73 (1H, dd), 3.65 (1H, dd), OH not observed. MS / ESI 347.2 [M + H]+. Example 35 (S)-2-amino-3-(5-(6-(4-chlorophenoxy)pyridin-3-yl)-2H-tetrazole-2-yl)prop-1-ol

[0346] Step a) 6-(4-chlorophenoxy)nicotinamide (35.3). A mixture of 35.1 (1.948 g, 15.16 mmol), 35.2 6-chloronicotinamide (2 g, 14.43 mmol), and K2CO3 (2.394 g, 17.32 mmol) in DMF (6 mL) was stirred at 120°C for 3 hr. The reaction was quenched by pouring the mixture into water (100 mL) and diluting with ethyl acetate / heptane (1:1) (150 mL). The phases were separated, and the organic phase was washed with water (100 mL) and brine (50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under vacuum to about 40 mL to initiate crystallization. The solid was collected by filtration, washed with heptane (3 × 10 mL), and dried under an air stream. Compound 35.3 was obtained as a colorless powder (2.15 g, 9.14 mmol, 63.3% yield). UPLC retention time was 1.10 min (Method A). ¹H NMR (DMSO-d6): δ = 8.65 (¹H, d), 8.34 (¹H, dd), 7.49–7.53 (²H, m), 7.26–7.29 (³H, m). MS / ESI 231.0 [M + H]+.

[0347] Step b) 2-(4-chlorophenoxy)-5-(2H-tetrazol-5-yl)pyridine (35.4). TMSN3 (1.726 mL, 13.01 mmol) was added to a mixture of 35.3 (1.50 g, 6.50 mmol) and Bu2SnO (0.162 g, 0.650 mmol) in toluene (8 mL) under Ar conditions. The mixture was heated to 100°C and maintained for 16 h. After cooling back to RT, the resulting suspension was dissolved in MeOH (50 mL) and concentrated under vacuum. The residue was suspended in MeCN (30 mL), filtered, and washed with several portions of MeCN (3 × 10 mL) and heptane (3 × 20 mL). The product was dried in an air stream to give 35.4 (990 mg, 3.29 mmol, 50.5% yield) as a colorless solid. UPLC residence time 0.86 min (Method A). ¹H NMR (DMSO-d6): δ = 17.1 (¹H, s br), 8.77 (¹H, d), 8.43 (¹H, dd), 7.49–7.53 (²H, m), 7.29 (¹H, d), 7.24–7.28 (²H, m). MS / ESI 274.2 [M + H]+.

[0348] Step c) Methyl propionate (S)-2-((tributoxycarbonyl)amino)-3-(5-(6-(4-chlorophenoxy)pyridin-3-yl)-2H-tetrazole-2-yl)propionate (35.6). A mixture of triphenylphosphine (575 mg, 2.192 mmol), DIAD (505 mg, 2.192 mmol), and 35.4 (400 mg, 1.462 mmol) and 35.5 (481 mg, 2.192 mmol) in THF (25 ml) was stirred at 25°C for 1.5 h. Isolute was added and the mixture was dried under vacuum. Silica gel chromatography (gradient: cyclohexane / ethyl acetate) gave 35.6 (1.57 g, 89%) as a colorless solid. UPLC retention time was 1.25 min (Method A). 1H NMR (DMSO-d6): δ = 8.79 (1H, d), 8.43 (1H, dd), 7.47-7.54 (3H, m), 7.44-7.30 (3H, m), 5.12 (1H, dd), 5.02 (1H, dd), 4.72 (1H, m), 3.71 (3H, s), 1.30 (9H, s). MS / ESI 475.1 [M + H]+.

[0349] Step d) (S)-(1-(5-(6-(4-chlorophenoxy)pyridin-3-yl)-2H-tetrazol-2-yl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester (35.7). LiBH4 (1.722 mL, 3.44 mmol) in 2 N THF was added dropwise to a solution of 35.6 (409 mg, 0.861 mmol) in 5 mL THF at 0°C, and the mixture was stirred at 0°C for 1 h. The mixture was neutralized with HCl (1 N aqueous solution), CH2Cl2 was added, the organic layer was separated, and the solvent was removed by drying with Na2SO4. Silica gel chromatography (gradient: cyclohexane / ethyl acetate) yielded compound 35.7 (197 mg, 51%) as a colorless solid. UPLC retention time was 1.13 min (Method A). 1H NMR (DMSO-d6): δ = 8.79 (1H, d), 8.43 (1H, dd), 7.48-7.54 (2H, m), 7.25-7.29 (3H, m), 6.88 (1H, d), 5.03 (1H, t), 4.93 (1H, dd), 4.53 (1H, dd), 4.00 (1H, m), 3.43-3.54 (2H, m), 1.25 (9H, s). MS / ESI 447.1 [M + H]+.

[0350] Step d) (S)-2-amino-3-(5-(6-(4-chlorophenoxy)pyridin-3-yl)-2H-tetrazol-2-yl)prop-1-ol (Example 35). HCl (1.527 mL, 6.11 mmol in 4 N solution in dichloroisocyanuric acid) was added to a solution of 35.7 (182 mg, 0.407 mmol) in CH2Cl2 (4 mL), and the mixture was stirred at 25°C for 2 h. Filtering yielded the hydrochloride of Example 35 as a colorless solid (151 mg, 97%). UPLC retention time was 0.72 min (Method A). ¹H NMR (DMSO-d6): δ = 8.83 (¹H, d), 8.48 (¹H, dd), 8.42 (³H, s br), 7.50–7.54 (²H, m), 7.25–7.30 (³H, m), 4.97–5.11 (²H, m), 3.80 (¹H, m), 3.72 (¹H, dd), 3.65 (¹H, dd), OH not observed. MS / ESI 347.1 [M + H]+. Example 36 (S)-3-(3-(4-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)-2-aminoprop-1-ol

[0351] Step a) 2-(4-bromophenoxy)-5-chloro-3-fluoropyridine (36.3). A mixture of compounds 36.1 (5.00 g, 33.4 mmol), 36.2 (6.36 g, 36.8 mmol), and K2CO3 (6.93 g, 50.2 mmol) in DMF (50 mL) was degassed and purged three times with N2, and then stirred at 80°C under N2 atmosphere for 4 h. The mixture was diluted with ethyl acetate (100 mL) and then washed with brine (3 × 100 mL) and H2O (100 mL). The organic layer was dried and concentrated to give the residue. The residue was purified on silica gel (gradient: petroleum ether / ethyl acetate) to give compound 36.3 (8.20 g, 80%) as a white solid. 1H NMR (CDCl3): δ = 7.81 (1H, d), 7.45 (3H, m), 6.92-7.06 (2H, m). MS / ESI 301.9 [M+H]+.

[0352] Step b) 2-(4-(1H-pyrazol-3-yl)phenoxy)-5-chloro-3-fluoropyridine (36.5). A mixture of 36.3 (7.0 g, 23.1 mmol), compound 36.4 (13.5 g, 69.4 mmol), Pd(PPh3)4 (1.34 g, 1.16 mmol), and Na2CO3 (3.84 g, 36.2 mmol) in H2O (20 mL) and dimethyl sulfoxide (100 mL) was degassed and purged three times with N2, and then stirred at 75°C under N2 atmosphere for 24 h. The mixture was diluted with H2O (100 mL) and then extracted with ethyl acetate (3 × 100 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated to obtain a residue, which was then purified on silica gel (gradient: petroleum ether / ethyl acetate) to give 36.5 g (3.0 g, 10.2 mmol, 44%) as a white solid. ¹H NMR (DMSO-d₆): δ = 12.90 (¹H, s br), 8.24 (br d, J = 9.8 Hz, ¹H), 8.08 (s, ¹H), 7.69–7.95 (m, 3H), 7.17–7.34 (m, 2H), 6.75–6.85 (m, 1H), a mixture of tautomers. MS / ESI 289.9 [M + H]⁺.

[0353] Step c) (S)-(1-((tributyldimethylsilyl)oxy)-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propyl-2-yl)aminocarbamate tributyl ester (36.6). A mixture of 36.5 (2.5 g, 8.53 mmol), intermediate A (3.76 g, 10.2 mmol), and Cs2CO3 (8.34 g, 25.6 mmol) in DMF (40 mL) was degassed and purged three times with N2, and then stirred at 20°C under N2 atmosphere for 2 h. The mixture was poured into ethyl acetate (100 mL) and water (50 mL). The aqueous layer was extracted twice with ethyl acetate. The combined organic phases were washed four times with brine and dried over Na2SO4. The solvent was evaporated to obtain the residue, which was then purified on silica gel (gradient: petroleum ether / ethyl acetate) to give 36.6 (2.3 g, 38%) as a colorless gel. 1H NMR (DMSO-d6): δ = 8.23 ​​(1H, dd), 8.06 (1H, d), 7.82 (2H, d), 7.68 (1H, d), 7.16-7.28 (2H, m), 6.84 (1H, d), 6.68 (1H, d), 4.26 (1H, dd), 4.01-4.13 (m, 1H), 3.88-3.95 (1H, m), 3.50-3.63 (2H, m), 1.20-1.35 (m, 9H), 0.88 (9H, s), 0.04 (s, 6H). MS / ESI 577.2 [M + H]+.

[0354] Step d) ((2S)-1-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester (36.8). A mixture of compound 36.6 (1.01 g, 1.65 mmol), compound 36.7 (682 mg, 2.47 mmol), PdCl2 (29.2 mg, 0.165 mmol), P(c-C6H11)3 (138 mg, 0.494 mmol), and CsF (500 mg, 3.29 mmol) in NMP (10 mL) and H2O (1 mL) was degassed and purged with N2, then stirred at 100°C under N2 atmosphere for 12 h. The mixture was diluted with ethyl acetate (50 mL) and washed with H2O (3 × 30 mL) and brine (30 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to give 36.8 (1.1 g, crude material), a pale yellow gel, which was used in step e) without further purification. MS / ESI 579.1 [M + H]+.

[0355] Step e) (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol (Example 36). A mixture of 1.1 g crude material from step d and HCl / ethyl acetate (20 mL, 4 M) was stirred for 36.8 h at 20°C under N2 atmosphere for 0.5 h. The mixture was concentrated and the residue was purified by preparative HPLC (column: Phenomenex luna C18 250 × 50 mm, 10 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 5ACN%-35ACN%, 35 min, 80% min) to give the hydrochloride of Example 36 as a pale yellow solid (317 mg, 44%). UPLC retention time: 0.52 min (Method C). 1H NMR (CD3OD): δ = 8.75 (1H, s br), 8.47-8.54 (1H, m), 7.03-7.08 (1H, m), 7.99 (2H, d), 7.78 (1H, m), 7.32 (2H, d), 7.23 (1H, d), 6.98-7.02 (1H, m), 6.78 (1H, d), 4.42-4.60 (2H, m), 3.63-3.70 (2H, m), 3.55-3.61 (1H, m). ¹H NMR (DMSO-d6): δ = 8.60 (¹H, d), 8.28 (³H, s br), 8.25 (¹H, dd), 7.84–7.89 (³H, m), 7.77 (¹H, d), 7.16–7.21 (²H, m), 7.10 (¹H, d), 6.76 (¹H, m), 4.35–4.46 (²H, m), 3.56–3.68 (²H, m), 3.45–3.52 (¹H, m). Pyrazole-NH and OH groups were not observed. MS / ESI 377.3 [M + H]+. Example 37 (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol

[0356] Step a) Tributyl ((2S)-1-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)-3-hydroxypropyl-2-yl)aminocarbamate (37.2). A mixture of 26.6 (1.01 g, 1.65 mmol), compound 37.1 (682 mg, 2.47 mmol), PdCl2 (29.2 mg, 0.165 mmol), P(c-C6H11)3 (138 mg, 0.494 mmol) and CsF (500 mg, 3.29 mmol) in NMP (10 mL) and H2O (1 mL) was degassed and stirred at 100°C under a nitrogen atmosphere for 12 h. The mixture was diluted with ethyl acetate (50 mL) and washed with brine (3 × 30 mL) and H₂O (30 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated to give a pale yellow gel, 37.2 g (1.1 g, crude material), which was used in step b) without further purification. MS / ESI 579.1 [M + H]⁺.

[0357] Step b) (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol (Example 37). The mixture of compound 37.2 (1.1 g) in HCl / ethyl acetate (20 mL, 4 M) was degassed and stirred at 20°C under a nitrogen atmosphere for 0.5 h. The mixture was concentrated and the residue was purified by preparative HPLC (column: Phenomenex luna C18 250 × 50 mm × 10 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 5ACN%-35ACN%, 35 min, 80% min) to give the hydrochloride of Example 37 as a pale yellow solid (317 mg, 44%, after 2 steps). UPLC residence time 0.60 min (Method C). 1H NMR (CD3OD): δ = 8.38 (1H, d), 8.13 (1H, dd), 7.90-7.95 (2H, m), 7.84-7.87 (1H, m), 7.74 (1H, d), 7.22-7.26 (2H, m), 6.83-6.86 (1H, m), 6.75 (1H, d), 4.43-4.56 (2H, m), 3.78-3.85 (2H, m), 3.65-3.71 (1H, m). ¹H NMR (DMSO-d6): δ = 8.42 (¹H, d), 8.16–8.28 (4H, m), 7.84–7.89 (3H, m), 7.80 (¹H, d), 7.22–7.26 (2H, m), 6.82 (¹H, d), 6.77 (¹H, d), 4.35–4.48 (2H, m), 3.56–3.68 (2H, m), 3.45–3.52 (¹H, m). Pyrazole-NH and OH groups were not observed. MS / ESI 395.4 [M + H]+. Example 38 (2S)-2-amino-3-[5-(4-[[3-fluoro-5-(1,3-azol-2-yl)pyridin-2-yl]oxy]phenyl)-2H-1,2,3,4-tetrazol-2-yl]prop-1-ol

[0358] Step a) 4-[(5-bromo-3-fluoropyridin-2-yl)oxy]benzonitrile (38.3). A mixture of 38.1 (8 g, 41.24 mmol), 4-hydroxybenzonitrile (5.43 g, 45.58 mmol), and K2CO3 (6.3 g, 45.25 mmol) in DMF (80 mL) was stirred at 120°C under argon for 16 h. The mixture was cooled to room temperature, diluted with H2O (300 mL), and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel (ethyl acetate / petroleum ether; 12: 88) to give 38.3 (7.00 g, 58%) as a colorless solid.

[0359] Step b) 4-[[3-fluoro-5-(1,3-azol-2-yl)pyridin-2-yl]oxy]benzonitrile (38.5). Under nitrogen atmosphere and reflux, a mixture of 38.3 (5.00 g, 17.06 mmol), 38.4 (18.33 g, 51.19 mmol), and Pd(PPh3)4 (2.00 g, 1.73 mmol) in CH3CN (150 mL) was heated for 16 h. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified on silica gel (ethyl acetate / petroleum ether; 25:75) to give 38.5 (4.00 g, 83%) as a colorless solid. MS / ESI 282.0 [M + H]+.

[0360] Step c) 3-Fluoro-5-(1,3-Azol-2-yl)-2-[4-(2H-1,2,3,4-tetraazol-5-yl)phenoxy]pyridine (38.6). Under nitrogen atmosphere and reflux, a mixture of 38.5 (4.00 g, 14.22 mmol), Bu2SnO (350 mg, 1.41 mmol), and TMSN3 (5.00 g, 43.40 mmol) in toluene (40 mL) was heated for 3 h. The mixture was concentrated under vacuum, and the residue was purified on silica gel (ethyl acetate / petroleum ether; 70:30) to give 38.6 (3.5 g, 76%) as a colorless solid.

[0361] Step d) Methyl propionate (38.8) (S)-2-((tributoxycarbonyl)amino)-3-(5-(4-((3-fluoro-5-(azolyl-2-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propionate. At 0°C under nitrogen, DIAD (6.20 g, 26.96 mmol), PPh3 (7.10 g, 27.07 mmol, 2.50) and 38.7 (6.00 g, 27.37 mmol) were added to a solution of 38.6 (3.50 g, 10.79 mmol) in THF (100 mL). The resulting mixture was stirred at room temperature for 16 h, concentrated, and the residue was purified on silica gel (ethyl acetate / petroleum ether; 45:55) to give 38.8 (3.20 g, 56%) as a colorless solid. MS / ESI 526.1 [M + H]+.

[0362] Step e) N-[(2S)-1-[5-(4-[[3-fluoro-5-(1,3-azol-2-yl)pyridin-2-yl]oxy]phenyl)-2H-1,2,3,4-tetraazol-2-yl]-3-hydroxypropyl-2-yl]aminocarbamate tributyl ester (38.9). LiBH4 (7.6 mL, 2 mmol solution in THF) was added dropwise to a solution of 38.8 in THF (40 mL) at 0°C, and the mixture was stirred at 0°C–10°C for 2 h. The mixture was cooled to 0°C, and AcOH (920 mg, 15.6 mmol) was added. The mixture was diluted with H2O (150 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified on silicon dioxide (ethyl acetate / petroleum ether: 60 / 40) to give 38.9 g (800 mg, 42%) as a colorless solid. MS / ESI 498.1 [M + H]+.

[0363] Step f) (2S)-2-amino-3-[5-(4-[[3-fluoro-5-(1,3-azol-2-yl)pyridin-2-yl]oxy]phenyl)-2H-1,2,3,4-tetraazol-2-yl]prop-1-ol (Example 38). HCl (8 mL of 4 M solution in dimethyl methacrylate) was added to a solution of 38.9 g (800 mg, 1.61 mmol) in CH2Cl2 (50 mL) and MeOH (10 mL) at 0°C under nitrogen atmosphere, and the mixture was stirred at room temperature for 16 h. The solution was diluted with diethyl ether (50 mL), and the solid was collected by filtration. The crude product was purified by preparative HPLC to give Example 38 (280 mg, 44 g) as a colorless solid. ¹H NMR (DMSO-d6): δ = 8.57 (¹H, d), 8.38 (¹H, dd), 8.30 (¹H, s), 8.14 (2H, d), 7.41–7.50 (3H, m), 4.85 (¹H, s br), 4.78 (¹H, dd), 4.56 (¹H, dd), 3.35–3.50 (3H, m), 1.75 (2H, s br). MS / ESI 398.1 [M + H]+. Example 39 2-amino-3-(2-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)prop-1-ol

[0364] Step a) 5-Chloro-3-fluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenoxy)pyridine (39.3). A solution of 39.1 (6.73 g, 45.0 mmol), 39.2 (9.00 g, 40.9 mmol), and K2CO3 (11.30 g, 82.0 mmol) in DMF (45 mL) was stirred at 80°C for 5 h. The mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, and the remaining aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered, and evaporated. The residue was purified on silica gel to give 39.3 (11.23 g, 76%). UPLC retention time 1.47 min (Method A). 1H NMR (DMSO-d6): δ = 8.24 (1H, dd), 8.08 (1H, s), 7.73 (2H, d), 7.19 (2H, d), 1.31 (12H, s). MS / ESI 350.2 [M + H]+.

[0365] Step b) (4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)boronic acid (39.4). NaIO4 (20.56 g, 96 mmol) was added to a solution of 39.3 (11.20 g, 32.0 mmol) in THF (90 mL) and water (90 mL), and the mixture was stirred at 25°C for 72 h. HCl (1N, 22.43 mL) was added, and stirring was continued for 1 h. The mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, the combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was ground with cyclohexane, the resulting solid was filtered off, washed with cyclohexane, and dried under vacuum to give 39.4 (7.02 g, 78%) as a solid. UPLC retention time was 0.91 min (Method A). 1H NMR (DMSO-d6): δ = 8.22 (1H, dd), 8.04-8.09 (3H, m), 7.84 (2H, d), 7.14 (2H, d). MS / ESI 268.2 [M + H]+.

[0366] Step c) Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(2H-tetrazole-5-yl)propionate (39.6). NaN3 (769 mg, 11.83 mmol) and NEt3× HCl (1628 mg, 11.83 mmol) were added to a solution of 39.5 (900 mg, 3.94 mmol) in DMF (9 mL), and the mixture was heated in a microwave oven at 130°C for 2 h. The mixture was filtered and the residue was washed with ethyl acetate. The organic layer was washed with aqueous HCl (pH 1), dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel (gradient: cyclohexane / ethyl acetate) to give 39.6 (480 mg, 44%). 1H NMR (DMSO-d6): δ = 16.13 (1H, s br), 7.39 (1H, d br), 4.46-4.54 (1H, m), 3.62 (3H, s), 3.39-3.18 (2H, m), 1.35 (9H, s). MS / ESI 272.1 [M + H]+.

[0367] Step d) Methyl 2-((tributoxycarbonyl)amino)-3-(2-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazole-5-yl)propionate (39.7). At 25°C under argon, 39.4 (631 mg, 2.359 mmol), K2CO3 (224 mg, 1.622 mmol), and [Cu(OH)(TMEDA)]2Cl2 (82 mg, 0.177 mmol) were added to a solution of 35.6 (400 mg, 1.475 mmol) in CH2Cl2 (8 mL). The blue mixture was stirred at 25°C under an oxygen atmosphere (balloon) for 72 h. The mixture was filtered through a hyflo filter, the residue was washed with CH2Cl2, and the combined solutions were concentrated. The residue was purified on silica gel (gradient: cyclohexane / ethyl acetate) to give 39.7 (375 mg, 48%). The material was further purified by SFC. UPLC retention time was 1.28 min (Method A). ¹H NMR (DMSO-d6): δ = 8.29 (¹H, dd), 8.08–8.14 (³H, m), 7.52 (²H, d), 7.27–7.49 (¹H, m), 4.58 (¹H, m), 3.67 (³H, s), 3.33–3.55 (²H, m), 1.34 (⁹H, s). MS / ESI 493.3 [M + H]⁺.

[0368] Step e) (1-(2-(4-(((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester (39.8). LiBH4 (2 N solution in THF, 0.651 mL, 1.302 mmol) was added dropwise to a solution of 39.7 (107 mg, 0.217 mmol) in THF (2 mL) at 0°C, and the mixture was stirred at 0°C for 2 h. The mixture was neutralized with HCl (1 N aqueous solution), CH2Cl2 was added, the organic layer was separated, dried over Na2SO4, and the solvent was removed. Silicone chromatography (gradient: cyclohexane / ethyl acetate) gave compound 39.8 (63 mg, 63%). UPLC retention time was 1.13 min (Method A). 1H NMR (DMSO-d6): δ = 8.29 (1H, dd), 8.00-8.21 (3H, m), 7.37-7.61 (2H, m), 6.71 (1H, d br), 4.84 (1H, t br), 3.79-3.96 (1H, m), 3.33-3.51 (2H, m), 3.28 (1H, dd), 2.95 (1H, dd), 1.12 - 1.31 (m, 9H). MS / ESI 465.3 [M + H]+.

[0369] Step f) 2-amino-3-(2-(4-(((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)prop-1-ol (Example 39). HCl (4 N solution in dichlorodiphenyl ether, 0.515 mL, 2.059 mmol) was added to a solution of 39.8 g (63 mg, 0.137 mmol) in CH2Cl2 (1.5 mL), and the mixture was stirred at 25°C for 2 h. The suspension was partially concentrated under an argon stream. Filtration yielded the hydrochloride of Example 39 (50 mg, 92%) as a colorless solid. UPLC retention time: 0.76 min (Method A). 1H NMR (DMSO-d6): δ = 8.30 (1H, dd), 8.12-8.23 (6H, m), 7.54 (2H, d), 5.47 (1H, t br), 3.65-3.78 (1H, m), 3.50-3.64 (2H, m), 3.25-3.33 (2H, m). MS / ESI 365.1 [M + H]+.

[0370] Example 39 was found to be a racemic mixture other than Example 39R (retention time: 9.98 min) and Example 39S (retention time: 11.48 min) (Chiralpak IA KL034, 5 μm, 250 × 4.6 mm; heptane / ethyl acetate / MeOH / diethylamine 40:30:30:0.05, 1 ml / min, 254 nm). (S) 2-amino-3-(2-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)prop-1-ol (Example 39S) was obtained from the racemate by chiral SFC (AD, 5 μm, 250 × 50 mm; mobile phase: 0.1% NH3× H2O in EtOH solution, 40%). Example 40 (2S)-2-amino-3-(2-(4-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)prop-1-ol (hydrochloride)

[0371] Step a) (2S)-2-amino-3-(2-(4-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)prop-1-ol (Example 40). The suspension of Example 39S (950 mg, 2.60 mmol), 40.1 (1449 mg, 5.21 mmol), K3PO4 (1106 mg, 5.21 mmol), and PdCl2(dtbpf) (136 mg, 0.208 mmol) in a mixture of dimethyl ether (9.5 mL) and water (3.166 mL) was stirred at 90°C under argon for 1.5 h. Then 40.1 and PdCl2(dtbpf) were added, and heating was continued for 1 h. The mixture was diluted with water and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel (gradient: cyclohexane / ethyl acetate) to give 40.2 (518 mg, 49%). This material was dissolved in DMF (20 mL), SiliaMetS DMT was added, and the mixture was stirred at 50°C for 16 h. The scavenging agent was filtered off, the residue was washed with CH2Cl2 / MeOH, and concentrated to give a solid, which was used in the next step. UPLC retention time was 0.78 min (Method A). 1H NMR (DMSO-d6): δ = 8.10-8.20 (3H, m), 8.07 (1H, dd), 7.62 (1H, d), 7.56 (2H, d), 6.61 (1H, d), 5.31 (1H, dd), 4.73 (1H, s br), 3.95 (1H, d br), 3.50-3.66 (1H, m), 3.37 (2H, m), 3.08-3.35 (2H) 2.83 (1H, dd), 2.25-2.45 (1H, m), 1.95-2.05 (1H, m), 1.83-1.93 (1H, m), 1.50-1.72 (5H, m). MS / ESI 481.3 [M + H]+.

[0372] Step b) (S)-2-amino-3-(2-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)prop-1-ol (Example 40). HCl (2 mL 2 N) was added to a solution of 40.2 (510 mg, 1.061 mmol) in THF (7 mL), and the mixture was stirred at 25°C for 1.5 h. The mixture was concentrated, and the residue was purified on silica gel (gradient: CH2Cl2 / MeOH) to give the hydrochloride of Example 40 (289 mg, 61%). UPLC retention time was 0.65 min (Method A). 1H NMR (DMSO-d6): δ = 8.47 (1H, d), 8.23-8.33 (4H, m), 8.07-8.23 (2H, m), 7.82 (1H, d), 7.47-7.59 (2H, m), 6.85 (1H, d), 5.82 (1H, m), 3.59-3.76 (3H, m), 3.26-3.43 (2H, m). MS / ESI 397.2 [M + H]+. Example 41: Free base of (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol in type I form C. Step-1: Synthesis of 2-(4-bromophenoxy)-5-chloro-3-fluoropyridine: Reaction scheme, synthetic procedure:

[0373] Potassium carbonate (69.32 g, 0.5016 mol, 1.50 equivalent), 2,3-difluoro-5-chloropyridine (50 g, 0.3344 mol, 1.0 equivalent), and 4-bromophenol (57.85 g, 0.3344 mol, 1.0 equivalent) were charged into a clean round-bottom (RB) flask containing DMF, and the mixture was stirred at 40°C ± 5°C. The reaction mixture was cooled and purified water was slowly added. The product was filtered and washed with purified water, and then dried to give 2-(4-bromophenoxy)-5-chloro-3-fluoropyridine.

[0374] ¹H NMR (DMSO-d6, 400 MHz): δ = 7.20 (dd, J = 5.2, 3.2 Hz, 2 H), 7.62 (dd, J = 5.6, 3.2 Hz, 2 H), 8.06 (d, J = 2.4 Hz 1 H), 8.25 (dd, J = 10, 2.4 Hz 1 H), HPLC purity: > 98% area, RT: 21.73 min. Steps 2 and 3: Experimental procedure for the synthesis of 2-(4-(1H-pyrazol-3-yl)phenoxy)-5-chloro-3-fluoropyridine using Scheme A1:

[0375] 2-Methyltetrahydrofuran-com, purified water, 1-(tetrahydro-2H-piperan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-1H-pyrazole (119.52 g, 0.4 mol, 1.30 equivalent), tripotassium phosphate (210.50 g, 1 mol, 3 equivalent), and Al-2 (100 g, 0.3 mol, 1.0 equivalent) were added to a round-bottom flask. The reactants were purged under nitrogen. Triphenylphosphine palladium(O) (19.09 g, 0.016 mol, 5 mol%) was added under purging. The mixture was heated to 70°C ± 5°C and maintained for 3 h. The mixture was cooled and purified water was added. The product was extracted with ethyl acetate. The aqueous layer was back-extracted with ethyl acetate. The combined organic layers were washed with purified water, followed by a brine solution. The organic layers were dried with sodium sulfate-Com and concentrated under vacuum at below 45°C until approximately 5.0 w / v. 4 M hydrochloric acid was added to the ethyl acetate reactants and stirred at 25°C ± 5°C for 3 h. The product was filtered and washed with ethyl acetate. Purified water and wet material were transferred to an RB flask containing ethyl acetate. The pH was adjusted to 7–8 using a saturated sodium bicarbonate solution. The organic layers were separated and washed with a brine solution, followed by drying with sodium sulfate. The organic layers were concentrated and crystallized from n-heptane to give 2-(4-(1H-pyrazol-3-yl)phenoxy)-5-chloro-3-fluoropyridine.

[0376] ¹H NMR (DMSO-d6, 400 MHz): δ = 6.72 (dd, J = 5.2, 3.2 Hz, 1 H), 7.22 (m, 2 H), 7.79 (m, 1 H), 7.86 (m, 2 H), 8.07 (d, J = 2 Hz, 1 H), 8.23 ​​(dd, J = 4.8 Hz, 2.4 Hz, 1 H), 13.08 (bs, 1 H), HPLC purity: >97% , HPLC RT: 17.27 min, MS / ESI+ 290.20. HPLC RT: 17.27 min Step-4: (S)-(1-((tributyldimethylsilyl)oxy)-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propyl-2-yl)aminocarbamate tributyl ester (A3) Reaction Protocol:

[0377] A1 (50 g, 0.1725 mol, 1.0 equivalent) and cesium carbonate (112.4 g, 0.345 mol, 2.0 equivalent) were charged into a clean RB flask containing DMF. A2 (69.80 g, 0.1898 mol, 1.10 equivalent) was prepared in a separate container in DMF. The A2 solution was slowly added to the reactants containing A1, and the reactants were maintained for 4 hours. The reactants were cooled and purified water was slowly added. The organic layer was separated and the aqueous layer was re-extracted with ethyl acetate. The combined organic layer was charged with purified water, and the pH was adjusted with 1% citric acid solution, followed by washing with saturated sodium bicarbonate solution, purified water, and brine solution. The organic layer was dried with sodium sulfate and concentrated under vacuum at below 50°C. The crude product was purified by column chromatography using 0-40% ethyl acetate in n-heptane. The pure fraction was collected and concentrated under vacuum to obtain (S)-(1-((tributyldimethylsilyl)oxy)-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propyl-2-yl)aminocarbamate tributyl ester, which is a viscous syrup.

[0378] 1H NMR (DMSO-d6, 400 MHz): δ = 0.046 (S, 6 H), 0.0850 (s, 9 H), 1.1372 (s, 9 H), 3.54 (m, 2 H), 3.943-3.909 (m, 1H), 4.38 (m, 1H), 4.28 (m, 1H), 6.68 (d, J = 2.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8 Hz, 2H), 7.68 (d, J = 2 Hz, 1H), 7.82 (d, J = 8.8, 2H), 8.06 (d, J = 2 Hz, 1H), 8.22 (dd, J = 10 Hz, 2.4 Hz, 1H) and other reagent and solvent information were observed. HPLC purity: > 95%. Chromatographic conditions: Step-5: Synthesis of tributyl ((2S)-1-((tributyldimethylsilyl)oxy)-3-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propyl-2-yl)aminocarbamate (A5) experimental procedure:

[0379] A3 (90 g, 0.1559 mol, 1.0 equivalent), K3PO4 (99.26 g, 0.4676 mol, 3.0 equivalent), and XPHOS (4.45 g, 0.009 mol, 0.06 equivalent) were added to a THF flask containing RB, followed by purified water. The reaction mixture was purged with nitrogen. Simultaneously, a THF solution of A4 was prepared. Pd(OAc)2 (2.09 g, 0.009 mol, 0.06 equivalent) was added, and the reaction mixture was heated to 50°C ± 5°C. The A4 solution was slowly added at 50°C ± 5°C. After the addition was complete, the reaction mixture was maintained at 50°C ± 5°C for 2–3 hours. The reaction mixture was cooled, and purified water was slowly added, followed by ethyl acetate. The reaction mixture was filtered through a diatomaceous earth bed, and the diatomaceous earth bed was washed with ethyl acetate. The layers were separated and the aqueous layer was back-extracted with ethyl acetate. The combined organic layers were washed with a 10% brine solution, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by column chromatography using silica gel and eluents of EtOAc (10%) and n-heptane (90%).

[0380] 1H NMR (DMSO-d6, 400 MHz): δ = 0.04 (s, 6 H), 0.09 (s, 9 H), 1.134 (s, 9 H), 1.53 (m, 4 H), 1.87 (m, 4H), 2.51 (m, 1H), 3.56 (m, 4H), 3.94 (m, 3H), 4.07 (m, 2H), 4.25 (m, 1H), 5.29 (m, 1H), 6.59 (d, J = 2 Hz, 1H), 6.70 (d, J = 2 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 7.27 (m, 2H), 7.61 (d, J = 1.6 7.69 (d, J = 2.4 Hz, 1H), 7.85 (m, 2H), 8.02 (dd, J = 11.2 Hz, 2.0 Hz, 1H), 8.10 (d, J = 2 Hz, 1H), HPLC purity: > 97%

[0381] Note: NMR signals with information about other reagents and solvents were observed. Experimental procedure for the synthesis of (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol (A6):

[0382] A5 and anhydrous alcohol were added to a clean RB flask. The mixture was cooled to 0°C–5°C, and 4 M HCl was slowly added to EtOAc. The temperature of the reactants was increased to 25°C ± 5°C and maintained for 12 hours. The reactants were concentrated to 1–2 vol under vacuum at below 50°C. Anhydrous alcohol was added, and the temperature of the reactants was increased to 50°C ± 5°C and maintained for 1 hour. The reactants were cooled and filtered. The mixture was washed with anhydrous alcohol; the material was alkalized with saturated NaHCO3, the product was filtered, and the mixture was washed. The product was slurried in purified water at 60°C ± 5°C for 1 hour. The material was cooled and filtered. The material was dried to VTD under vacuum at 55°C ± 5°C for 8 hours. The material was dissolved in THF and treated with silia bond thiol to remove residual metals. THF was concentrated, the product was dissolved in methanol and filtered to obtain (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol (A6).

[0383] 1H NMR (DMSO-d6, 400 MHz): δ = 1.55 (bs, 2 H), 3.10 (m, 1 H), 3.28 (m, 2 H), 3.96 (m, 1 H), 4.18 (m, 1H), 4.71 (t, 1H), 6.69 (d, J = 2 Hz, 1H), 6.82 (d, J = 2.4 Hz, 2H), 7.22 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 2 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 8.22 (dd, J = 11.2 Hz, 1.6 Hz, 1H), 8.42 (d, J = 1.6 Hz, 1H) HPLC purity: >99% area, HPLC RT: 10.03 min, MS / ESI+ 395.10

[0384] The separated material was characterized by various methods to determine its physicochemical properties. The separated material was a highly crystalline powder composed of needle-like and flaky particles. The separated material was analyzed by XRPD, DSC, and TGA (Figures 1A, 1B, and 1C, respectively). The material had high purity and showed endothermic dehydration at about 45°C with an enthalpy of 19 J / g, followed by endothermic melting and an immediate exothermic recrystallization event at about 110°C. Finally, a melting point of about 146°C with an enthalpy of 121 J / g was observed. The drying loss was determined to be 1.4% by TGA, which was confirmed by Karl Fischer titration. [Table 1]: XRPD peaks of Example 41 (free base type 1 form C) angle d value Net strength relative strength 11.4 7.787 12564 100% 15.2 5.824 11252 90% 15.9 5.567 1379 11% 16.2 5.483 786 6% 16.9 5.257 916 7% 17.4 5.079 441 4% 18.3 4.846 1135 9% 21.1 4.210 744 6% 21.6 4.103 779 6% 22.8 3.897 3981 32% 24.6 3.616 808 6% 27.8 3.211 355 3% 28.6 3.118 3532 28% 37.0 2.425 476 4% 40.7 2.215 325 3% Example 42: Free base type 2 form D of (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol

[0385] In a vial, 300 mg of Example 41 was added to 5 mL of ethanol. The sample was stirred at 500 rpm at 50°C. The suspension was vortexed periodically to break up any clumps that formed over time. After 4 h, the suspension was stirred overnight at 500 rpm at room temperature. The solids were recovered by centrifugation and filtration, and then vacuum dried at 50°C. The separated material was analyzed by XRPD, DSC, and TGA (Figures 2A, 2B, and 2C, respectively).

[0386] Crystalline form of free base type 2 (form D) melts at approximately 146°C and exhibits a glass transition at 52°C after reheating the melted sample.

[0387] According to TGA, the drying loss of crystalline free alkali type 2 (form D) is approximately 0.15%.

[0388] DVS shows that the crystalline form of free base type 2 (form D) is hygroscopic, and it reversibly absorbs 3% water at RH above 70%, thus transforming into the hydrated form. [Table 2]: XRPD peak - Example 42 angle d value Net strength relative strength 11.3 7.809 5736 55% 15.2 5.836 10359 100% 17.8 4.977 634 6% 18.3 4.857 2919 28% 19.2 4.627 1106 11% 20.3 4.373 1194 12% 21.6 4.109 1329 13% 22.8 3.902 3875 37% 23.6 3.764 555 5% 24.2 3.668 1351 13% 26.3 3.391 568 5% 28.6 3.122 1512 15% 29.3 3.042 789 8% [Table 3] Characterization of Example 42 parameter method result Melt initiation (°C) DSC, 10 K / min 146.7 Crystallinity XRPD, 2-40° (2θ) Highly crystalline Drying loss (% @°C) TGA, 10 K / min 0.15 @ 140 Water content (%) Karl Fischer titration method Not conducted Hygroscopicity (% @%RH) DVS 2.97 @ 95 form SEM flake particles Example 43: Hydrochloride of (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol / (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol (Form E)

[0389] In a vial, 300 mg of Example 41 was added to a mixture of 70 μL of 12 N hydrochloric acid and 3 mL of ethanol. The sample was stirred at 500 rpm at 50°C. Another 2 mL of ethanol was added to dilute the suspension, and the mixture was stirred for 3 h. The suspension was then stirred overnight at 300 rpm at room temperature. The solid was separated by centrifugation and filtration, and then vacuum dried overnight at 50°C. The separated material was analyzed by XRPD, DSC, and TGA (Figures 3A, 3B, and 3C, respectively).

[0390] The hydrochloride (form E) melts at about 236°C, and its corresponding glass transition occurs at 91°C.

[0391] According to TGA, the hydrochloride (form E) shows a drying loss of about 0.5%.

[0392] The hydrochloride (form E) is slightly hygroscopic, absorbing only 0.6% water vapor at 95% RH. [Table 4]: XRPD peaks: Example 43 angle d value Net strength relative strength 15.8 5.601 1711 43% 16.4 5.385 2495 63% 17.5 5.056 455 12% 18.3 4.836 884 twenty two% 19.3 4.592 817 twenty one% 21.0 4.236 1911 48% 22.0 4.039 3955 100% 22.4 3.959 3001 76% 23.8 3.740 712 18% 24.9 3.576 489 12% 25.2 3.532 437 11% 26.2 3.395 756 19% 27.6 3.231 1364 34% 29.6 3.019 400 10% 33.6 2.668 338 9% Example 44: (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol hippurate (form B)

[0393] 300 mg of Example 41, 150 mg of hippuric acid, and 3 mL of ethanol were added to a vial. The sample was stirred at 500 rpm at 50°C. 2 mL of ethanol was added to dilute the suspension, and the mixture was briefly ultrasonicated. After 3 h, the suspension was stirred overnight at 300 rpm at room temperature. The solids were separated by centrifugation and filtration for characterization. The separated materials were characterized by XRPD, DSC, and TGA (Figures 4A, 4B, and 4C, respectively). Hippurate (Form B) is a highly crystalline form with a melting point of approximately 180°C and an enthalpy of fusion of 134 J / g. TGA showed a weight loss of approximately 0.3% at 170°C. Variant B is only slightly hygroscopic, absorbing approximately 0.3% water at 95% RH.

[0394] Experimental procedure for the alternative synthesis of (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol.hippurate) (A7-form B):

[0395] Methanol and A6 (Example 41) (80 g, 0.202 mol, 1.0 equivalent) were added to a clean RB flask. The reactants were heated to 55°C ± 5°C to obtain a clear solution. Hippuric acid (40 g, 0.2244 mol, 1.1 equivalent) pre-dissolved in methanol was slowly added. 0.08 wt% A7 seed material was added at 55°C ± 5°C and maintained...

Claims

1. A compound having formula (I), (I), or a pharmaceutically acceptable salt thereof, wherein: Cyclic B series 5-membered heteroaryl; R1 series H or C1-4 alkyl; X1 series N or CH; X2 series N or CR2, wherein R2 series H or C1-4 alkyl; R3 series: or; X3 series N or CH; X4 series N or CH; Y series O, NRa or CH2; and Ra series H or C1-4 alkyl; R4 is selected from the group consisting of: halogenated, halogenated C1-4 alkoxy, C1-4 alkoxy, halogenated C1-4 alkyl, C1-4 alkyl, 5-membered heteroaryl and C1-5 cycloalkyl; and R5 series H or halogenated.

2. The compound as claimed in claim 1, having the formula (IA):; or a pharmaceutically acceptable salt thereof.

3. The compound as claimed in claim 1, having the formula (IB):; or a pharmaceutically acceptable salt thereof.

4. The compound as claimed in claim 1, having the formula (IC):; or a pharmaceutically acceptable salt thereof.

5. The compound as claimed in claims 1, 2, 3 or 4, having formula (II): (II), or a pharmaceutically acceptable salt thereof.

6. The compound as claimed in claims 1, 2, 3 or 4, having formula (III): (III), or a pharmaceutically acceptable salt thereof.

7. A compound as claimed in claims 1, 2, 3 or 4, having formula (IV): (IV); or a pharmaceutically acceptable salt thereof.

8. A compound as claimed in claims 1, 2, 3 or 4, having the formula (V): (V), or a pharmaceutically acceptable salt thereof.

9. A compound as claimed in claims 1, 2, 3 or 4, having formula (VI): (VI); or a pharmaceutically acceptable salt thereof.

10. A compound as claimed in any one of claims 1, 2 and 5 to 9, wherein X1 is CH; or a pharmaceutically acceptable salt thereof.

11. A compound as claimed in any one of claims 1 to 9, wherein R1 is H; or a pharmaceutically acceptable salt thereof.

12. A compound as claimed in any one of claims 1, 2 and 4 to 11, wherein X3 is N and Y is O; or a pharmaceutically acceptable salt thereof.

13. The compound as claimed in any one of claims 1, 2 and 4 to 12, wherein R5 is H or halogenated, and R4 is selected from halogenated, halogenated C1-4 alkoxy, C1-4 alkoxy, halogenated C1-4 alkyl, C1-4 alkyl, 5-membered heteroaryl and C3-5 cycloalkyl; or pharmaceutically acceptable salts thereof.

14. The compound as claimed in claim 13, wherein R4 is selected from cyclopropyl, Cl, Br, -OCH3, -OCHF2, CF3, pyrazolyl, acezolyl, and R5 is H or F; or a pharmaceutically acceptable salt thereof.

15. The compound as claimed in claim 1, wherein the compound is selected from: (S)-2-amino-3-(3-(3-((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-diazol-5-yl)prop-1-ol; (S)-2-amino-3-(3-(3-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol; (S)-2-amino-3-(3-(3-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol; (S)-2-amino-3-(3-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol; (S)-2-amino-3-(3-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol; (S)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-3-yl)propionate ethyl ester; ((2S)-1-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester; (R)-2-amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol; (S)-(1-(3-(3-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-3-hydroxypropyl-2-yl)aminocarbamate tributyl ester; (S)-2-amino-3-(3-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol; (S)-2-amino-3-(3-(3-((R)-2,3-dihydro-[1,4]diacino[2,3-b]pyridin-3-yl)phenyl)-1,2,4-diazol-5-yl)prop-1-ol; (S)-2-amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol; (S)-3-(3-(4-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)-2-aminoprop-1-ol; (S)-2-amino-3-(5-(3-((R)-2,3-dihydro-[1,4]diacino[2,3-b]pyridin-3-yl)phenyl)-2H-tetrazol-2-yl)prop-1-ol;(S)-2-amino-3-(3-(3-((R)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-diazol-5-yl)prop-1-ol; (S)-2-amino-3-(3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol; (S)-2-amino-3-(3-(4-((((R)-1-phenylprop-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)prop-1-ol; (3S)-3-amino-4-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-diazol-5-yl)but-2-ol; (R)-3-(5-(4-((5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)-2-aminoprop-1-ol; (R)-3-(5-(4-((5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)-2-aminoprop-1-ol; (S)-2-amino-3-(3-(5-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)prop-1-ol; (S)-2-amino-3-(5-(5-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)pyridin-2-yl)-2H-tetrazole-2-yl)prop-1-ol; (S)-2-amino-3-(3-(5-((5-chloro-3-fluoropyridin-2-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)prop-1-ol; (S)-2-amino-3-(3-(3-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol; (S)-2-amino-3-(4-(4-(((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol; (S)-2-amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol; (S)-2-amino-3-(5-(4-(4-chlorophenoxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol; (S)-2-amino-3-(5-(4-((5-cyclopropylpyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol; (S)-2-amino-3-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol; (R)-2-amino-3-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol;(R)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol; (S)-2-amino-3-(5-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol; (S)-2-amino-3-(5-(4-((5-bromopyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol; (S)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)prop-1-ol; (S)-2-amino-3-(5-(6-(4-chlorophenoxy)pyridin-3-yl)-2H-tetrazol-2-yl)prop-1-ol; (S)-3-(3-(4-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)-2-aminoprop-1-ol; (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)prop-1-ol; (2S)-2-amino-3-[5-(4-[[3-fluoro-5-(1,3-azo-2-yl)pyridin-2-yl]oxy]phenyl)-2H-1,2,3,4-tetrazol-2-yl]prop-1-ol; (S)-2-amino-3-(2-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)prop-1-ol; (R)-2-amino-3-(2-(4-(((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)prop-1-ol; and (2S)-2-amino-3-(2-(4-((3-fluoro-5-(1-(tetrahydro-2H-piperan-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)prop-1-ol; or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a therapeutically effective amount of any one of claims 1 to 15 of the compound and one or more pharmaceutically acceptable carriers.

17. A combination comprising a therapeutically effective amount of a compound as described in any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, and one or more therapeutically active co-pharmaceuticals.

18. The compound described in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, used as a medicine.

19. A compound as claimed in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for the treatment of diseases and / or disorders mediated by LTA4H inhibition.

20. A method of treating a subject for a disease and / or disorder mediated by LTA4H activity, wherein the method comprises administering to the subject a therapeutically effective amount of a compound as described in any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

21. A compound used as described in claim 19 or a treatment method as described in claim 20, wherein the disease and / or disorder is selected from: acute or chronic inflammation, allergic reactions, hypersensitivity reactions, atopic dermatitis, psoriasis, acute respiratory distress syndrome, immune complex-mediated lung injury and chronic obstructive pulmonary disease, inflammatory bowel disease (including ulcerative colitis, Crohn's disease, and postoperative trauma), gastrointestinal ulcers, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), neutrophilic dermatitis (including but not limited to gangrenous varicose veins, Sweet's syndrome, acne, and neutrophilic urticaria), immune complex-mediated glomerulonephritis, hidradenitis suppurativa, and other conditions. Somatic immune diseases (including insulin-dependent diabetes mellitus, multiple sclerosis, rheumatoid arthritis, osteoarthritis, and systemic lupus erythematosus), vasculitis (including but not limited to cutaneous vasculitis, Behcet's disease, and allergic purpura), cardiovascular diseases (including but not limited to hypertension, atherosclerosis, aneurysm, severe lower limb ischemia, peripheral arterial occlusive disease, pulmonary hypertension, and Raynaud's syndrome), sepsis, inflammatory and neuropathic pain including arthritis pain, periodontal diseases including gingivitis, ear infections, migraines, benign prostatic hyperplasia, Jurassic syndrome, and cancers (including but not limited to leukemia and lymphoma, prostate cancer, breast cancer, lung cancer, malignant melanoma, kidney cancer, head and neck tumors, and colorectal cancer).