Heteroaryl aminopropanol derivatives as inhibitors of LTA4H

Abstract

The present application relates to a compound of formula (I) for use in the treatment of various disorders. [Formula 1] TIFF2024513988000117.tif67170 The present invention relates to leukotriene A4 hydrolase (LTA4H) inhibitors.

Description

[Technical Field]

[0001] The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof and their use in inhibiting LTA4H. Therefore, the compounds of the present invention may be useful in treating diseases and / or disorders associated with LTA4H. Such diseases and / or disorders include, for example, inflammatory and autoimmune diseases and inflammation of the lungs and airways. The present invention further relates to pharmaceutical compositions comprising the novel heteroarylaminopropanol derivatives of formula (I), methods of using the compounds in the treatment of various diseases and disorders, and processes for preparing the novel compounds. [Background technology]

[0002] Leukotriene A4 hydrolase (LTA4H) catalyzes the hydrolysis of LTA4 to produce LTB4. LTB4 stimulates many inflammatory responses that may involve, for example, leukocyte chemotaxis or cytokine release. Inhibition of LTA4H further increases the biosynthesis of the anti-inflammatory, pro-inflammatory lipoxin A4, which can promote the resolution of chronic inflammation. Thus, LTA4H inhibition may be useful in diseases in which chronic, non-resolving inflammation may be a significant component of the pathology and may appear to include a wide range of autoinflammatory and autoimmune diseases. Summary of the Invention

[0003] The present invention provides compounds that are LTA4H inhibitors, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof. The present invention further provides a method for treating diseases and / or disorders mediated by LTA4H, comprising administering to a subject in need thereof an effective amount of an LTA4H inhibitor.

[0004] Various embodiments of the present invention are described herein. Within certain aspects, compounds of formula (I): [ka] (In the formula, Ring B is a 5-membered heteroaryl; R 1 is H or C 1~4 is alkyl; X 1 is N or CH; X 2 is N or CR 2 and R 2 is H or C 1~4 is alkyl; R 3 teeth, [ka] and; X 3 is N or CH; X 4 is N or CH; Y, O, NR a or CH; and R a is H or C 1~4 is alkyl; R 4 Ha, Halo, Halo C 1~4 Alkoxy, C 1~4 Alkoxy, HaloC 1~4 Alkyl, C 1~4 Alkyl, 5-membered heteroaryl and C 1~5 cycloalkyl; and R 5 is H or halo) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

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

[0006] In another aspect, the present invention provides combinations, especially pharmaceutical combinations, comprising a compound of the invention and one or more therapeutically active agents. [Brief explanation of the drawings]

[0007] [Figure 1A] FIG. 1A provides an exemplary XRPD spectrum of the compound of Example 41, designated herein as Form C. [Figure 1B] FIG. 1B provides an exemplary DSC of the compound of Example 41, designated herein as Form C. [Figure 1C] FIG. 1C provides an exemplary TGA of the compound of Example 41, designated herein as Form C. [Figure 2A] FIG. 2A provides an exemplary XRPD spectrum of the compound of Example 42, designated herein as Form D. [Figure 2B] FIG. 2B provides an exemplary DSC of the compound of Example 42, designated herein as Form D. [Figure 2C] FIG. 2C provides an exemplary TGA of the compound of Example 42, designated herein as Form D. [Figure 3A] FIG. 3A provides an exemplary XRPD spectrum of the compound of Example 43, designated herein as Form E. [Figure 3B] FIG. 3B provides an exemplary DSC of the compound of Example 43, designated herein as Form E. [Figure 3C] FIG. 3C provides an exemplary TGA of the compound of Example 43, designated herein as Form E. [Figure 4A] FIG. 4A provides an exemplary XRPD spectrum of the compound of Example 44, designated herein as Form B. [Figure 4B] FIG. 4B provides an exemplary DSC of the compound of Example 44, designated herein as Form B. [Figure 4C] FIG. 4C provides an exemplary TGA of the compound of Example 44, designated herein as Form B. [Figure 5A] FIG. 5A provides an exemplary XRPD spectrum of the compound of Example 45, designated herein as Form A. [Figure 5B] FIG. 5B provides an exemplary DSC of the compound of Example 45, designated herein as Form A. [Figure 5C] FIG. 5C provides an exemplary TGA of the compound of Example 45, designated herein as Form A. [Figure 6A] FIG. 6A provides an exemplary XRPD spectrum of the compound of Example 46, designated herein as Form F. [Figure 6B] FIG. 6B provides an exemplary DSC of the compound of Example 46, designated herein as Form F. [Figure 6C] FIG. 6C provides an exemplary TGA of the compound of Example 46, designated herein as Form F. DETAILED DESCRIPTION OF THE INVENTION

[0008] A more detailed listing of the XRPD peaks for any one of Forms A-F is provided in the table below, where the % (I / I x 100) of relative intensity is also provided. It should be understood that in an X-ray powder diffraction spectrum or pattern, there is inherent variability in values ​​measured in degrees 2θ (°2θ), for example, as a result of instrumental variability (including instrument-to-instrument differences). Accordingly, it should be understood that there may be variability in XRPD peak measurements of up to ±0.2°2θ, and that such peak values ​​would still be considered to be representative of a particular solid-state form of the crystalline materials described herein. It should also be understood that other measurements from XRPD and DSC / TGA experiments, such as relative intensity and water content, may vary, for example, as a result of sample preparation and / or storage and / or environmental conditions, and that the measurements would still be considered to be representative of a particular solid-state form of the crystalline materials described herein.

[0009] Thus, the present invention provides a compound of formula (I): [ka] (In the formula, Ring B is a 5-membered heteroaryl; R 1 is H or C 1~4 is alkyl; X 1 is N or CH; X 2 is N or CR 2 and R 2 is H or C 1~4 is alkyl; R 3 teeth, [ka] and; X 3 is N or CH; X 4 is N or CH; Y, O, NR a or CH; and R a is H or C 1~4 is alkyl; R 4 Ha, Halo, Halo C 1~4 Alkoxy, C 1~4 Alkoxy, HaloC 1~4 Alkyl, C 1~4 Alkyl, 5-membered heteroaryl and C 1~5 cycloalkyl; and R 5 is H or halo) or a pharmaceutically acceptable salt thereof.

[0010] Unless otherwise specified, the term "compounds of the invention" or "compounds of the invention" refers to compounds of Formula (I) and subformulas thereof (i.e., Formulas (IA), (IB), (II)-(V)), as well as exemplified compounds and salts thereof, and all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers and isotopically labeled compounds (including deuterium substitution), and moieties formed inherently.

[0011] definition 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 specified, it refers to a hydrocarbon moiety having from 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, etc.

[0012] As used herein, the term "C1-C4 alkoxy" refers to alkyl-O-, where alkyl is defined herein above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, and the like. Typically, an alkoxy group has about 1 to 4 carbon atoms, or 1 to 2 carbon atoms.

[0013] As used herein, the term "haloC1-C4 alkyl" refers to a C1-C4 alkyl 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.

[0014] As used herein, the term "haloC1-C4 alkoxy" refers to a C1-4 alkoxy as defined above that is substituted with one or more halogens.

[0015] As used herein, the term "C3-C5 cycloalkyl" refers to a saturated monocyclic hydrocarbon group of 3 to 5 carbon atoms. Cycloalkyl may also be referred to as carbocycle, and vice versa, further indicating the number of carbon atoms present. Unless otherwise specified, cycloalkyl refers to a cyclic hydrocarbon group having 3 to 5 ring carbon atoms or 3 to 4 ring carbon atoms. Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, and cyclopentyl.

[0016] As used herein, the term "halogen" or "halo" refers to fluoro, chloro, bromo, and iodo.

[0017] 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-oxazolyl, or 3-, 4-, or 5-isoxazolyl.

[0018] As used herein, the term "tautomer" is used to refer to two molecules that have the same molecular formula but differ in connectivity and are capable of interconverting in rapid equilibrium. For example, certain heteroaryl groups exist in various tautomeric forms. Representative examples of tautomers are R 3 is a pyrazolyl group. [ka]

[0019] Other examples of tautomers are as follows: [ka]

[0020] As used herein, the terms "about" and "substantially" indicate that values ​​may vary with respect to features such as endotherms, endothermic peaks, exotherms, and baseline shifts. With respect to X-ray diffraction peak positions, "about" or "substantially" means that typical peak position and intensity variability is taken into account. For example, those skilled in the art will recognize that peak positions (2θ) typically exhibit some inter-instrument variability of as much as 0.2°. Occasionally, variability may be higher than 0.2° depending on differences in instrument calibration. Furthermore, those skilled in the art will recognize that relative peak intensities exhibit inter-instrument variability as well as variability due to crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be taken only as a qualitative measure. With respect to DSC, observed temperature variations depend on the rate of temperature change and sample preparation technique and the particular instrument utilized. Therefore, the endotherm / melting point values ​​reported herein associated with DSC / TGA thermograms may vary by ±5°C (and still be considered characteristic of the particular crystalline form described herein). When used in connection with other characteristics, such as weight percent (wt %), reaction temperature, etc., the term "about" indicates a variation of ±5%.

[0021] Various enumerated embodiments of the present invention are described herein, and it will be recognized that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention.

[0022] In embodiment 1, the present invention provides a compound of formula (I): [ka] (In the formula, Ring B is a 5-membered heteroaryl; R 1 is H or C 1~4 is alkyl; X 1 is N or CH; X 2 is N or CR 2 and R 2 is H or C1~4 is alkyl; R 3 teeth, [ka] and; X 3 is N or CH; X 4 is N or CH; Y, O, NR a or CH; and R a is H or C 1~4 is alkyl; R 4 Ha, Halo, Halo C 1~4 Alkoxy, C 1~4 Alkoxy, HaloC 1~4 Alkyl, C 1~4 Alkyl, 5-membered heteroaryl and C 1~5 cycloalkyl; and R 5 is H or halo) or a pharmaceutically acceptable salt thereof. In one aspect of this embodiment, R 3 is attached at the meta or para position relative to the point of attachment to ring B.

[0023] In embodiment 2, the present invention provides a compound of formula (IA): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , X 1 , X 2 , X 3 , Y, R 4 and R 5 is as defined above.

[0024] In embodiment 3, the present invention provides a compound of formula (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein ring B, R 1 and X 4 is as defined above. In one aspect of this embodiment, X 4 is N. In another aspect of this embodiment, X 4 is CH.

[0025] In embodiment 4, the present invention provides a compound of formula (IC): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 4 , R 5 , X 3 , Y is as defined above.

[0026] In embodiment 5, the present invention provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, according to embodiment 1, 2, 3, or 4, having the formula:

[0027] In embodiment 6, the present invention provides a compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof, according to embodiment 1, 2, 3, or 4, having the formula:

[0028] In embodiment 7, the present invention provides a compound of formula (IV): [ka] or a pharmaceutically acceptable salt thereof, according to embodiment 1, 2, 3, or 4, having the formula:

[0029] In embodiment 8, the present invention provides a compound of formula (V): [ka] or a pharmaceutically acceptable salt thereof, according to embodiment 1, 2, 3, or 4, having the formula:

[0030] In embodiment 9, the present invention provides a compound of formula (VI): [ka] or a pharmaceutically acceptable salt thereof, according to embodiment 1, 2, 3, or 4, having the formula:

[0031] In embodiment 10, the present invention provides a method for producing a compound comprising: 1 or a pharmaceutically acceptable salt thereof. In one aspect of this embodiment, X 2 is N. In another aspect of this embodiment, X 2 is CH or CC 1~4 Alkyl, preferably CH or C-CH3.

[0032] In embodiment 10a, the present invention provides a compound comprising X 1 is N, and X 2or a pharmaceutically acceptable salt thereof, according to any of embodiments 1, 2, and 5-9, wherein is CH.

[0033] In embodiment 11, the present invention provides a compound comprising R 1 is H; or a pharmaceutically acceptable salt thereof.

[0034] In embodiment 11a, the present invention provides a compound comprising R 1 is methyl; or a pharmaceutically acceptable salt thereof.

[0035] In embodiment 12, the present invention provides a method for producing a compound comprising: 3 is N; and Y is O; or a pharmaceutically acceptable salt thereof.

[0036] In embodiment 12a, the present invention provides a compound comprising X 3 and Y is O; or a pharmaceutically acceptable salt thereof.

[0037] In embodiment 13, the present invention provides a compound comprising R 5 is H or halo, and R 4 Halo, Halo C 1~4 Alkoxy, C 1~4 Alkoxy, HaloC 1~4 Alkyl, C 1~4 Alkyl, 5-membered heteroaryl and C 3~5 or a pharmaceutically acceptable salt thereof, according to any of embodiments 1, 2, 4 to 11, 11a, 12 and 12a, wherein R is selected from cycloalkyl.

[0038] In embodiment 14, the present invention provides a compound comprising R 4 is selected from cyclopropyl, Cl, Br, —OCH3, —OCHF2, CF3, pyrazolyl, oxazolyl, and R 5is H or F; or a pharmaceutically acceptable salt thereof.

[0039] In embodiment 15, the invention relates to a compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, selected from: (S)-2-amino-3-(3-(3-((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol; (S)-2-amino-3-(3-(3-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol; (S)-2-amino-3-(3-(3-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol; (S)-2-amino-3-(3-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol; (S)-2-amino-3-(3-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol; Ethyl (S)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-3-yl)propanoate; tert-butyl ((2S)-1-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate; (R)-2-amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol; tert-butyl (S)-(1-(3-(3-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate; (S)-2-amino-3-(3-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol; (S)-2-amino-3-(3-(3-((R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol; (S)-2-amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol; (S)-3-(3-(4-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-2-aminopropan-1-ol; (S)-2-amino-3-(5-(3-((R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl)-2H-tetrazol-2-yl)propan-1-ol; (S)-2-amino-3-(3-(3-((R)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol; (S)-2-amino-3-(3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol; (S)-2-amino-3-(3-(4-(((R)-1-phenylpropan-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol; (3S)-3-amino-4-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)butan-2-ol; (R)-3-(5-(4-((5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)-2-aminopropan-1-ol; (R)-3-(5-(4-((5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)-2-aminopropan-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)propan-1-ol; (S)-2-amino-3-(5-(5-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)pyridin-2-yl)-2H-tetrazol-2-yl)propan-1-ol; (S)-2-amino-3-(3-(5-((5-chloro-3-fluoropyridin-2-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)propan-1-ol; (S)-2-amino-3-(3-(3-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol; (S)-2-amino-3-(4-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol; (S)-2-amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol; (S)-2-amino-3-(5-(4-(4-chlorophenoxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol; (S)-2-amino-3-(5-(4-((5-cyclopropylpyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol; (S)-2-amino-3-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol; (R)-2-amino-3-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol; (R)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol; (S)-2-amino-3-(5-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol; (S)-2-amino-3-(5-(4-((5-bromopyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol; (S)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol; (S)-2-amino-3-(5-(6-(4-chlorophenoxy)pyridin-3-yl)-2H-tetrazol-2-yl)propan-1-ol; (S)-3-(3-(4-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)-2-aminopropan-1-ol; (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol; (2S)-2-amino-3-[5-(4-[[3-fluoro-5-(1,3-oxazol-2-yl)pyridin-2-yl]oxy]phenyl)-2H-1,2,3,4-tetrazol-2-yl]propan-1-ol; (S)-2-amino-3-(2-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)propan-1-ol; (R)-2-amino-3-(2-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)propan-1-ol; and (2S)-2-Amino-3-(2-(4-((3-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)propan-1-ol.

[0040] In embodiment 15a, the present invention relates to compounds of formula (I) according to embodiment 13 or a pharmaceutically acceptable salt thereof selected from 2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol; (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-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)propan-1-ol or a tautomer thereof and / or a pharmaceutically acceptable salt thereof.

[0041] In embodiment 15b, the present invention provides a method for producing a composition comprising: [ka] or a pharmaceutically acceptable salt thereof. As mentioned above, the compound of embodiment 15b relates to a compound of formula (I) according to embodiment 13, which is (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol, which is also represented as: [ka] It also exists as ((S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol).

[0042] In embodiment 15c, the present invention provides (R)-2-amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol, (S)-2-amino-3-(3-(3-((R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol, (S)-2-amino-3-(5 14. The compound of formula (I) according to embodiment 13, wherein the compound is selected from -(3-((R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl)-2H-tetrazol-2-yl)propan-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)propan-1-ol or a pharmaceutically acceptable salt thereof.

[0043] In another aspect of the invention, a compound of formula (I) or any subformula described herein according to any one of the preceding embodiments is not a substrate of the organic anion transporter OAT3.

[0044] Depending on the selection of starting materials and procedures, the compounds may exist in one of the possible stereoisomers or as mixtures thereof, e.g., pure optical isomers or mixtures of stereoisomers, such as racemates and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. The present invention is intended to encompass all such possible stereoisomers, including racemic mixtures, diastereomeric 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. When the compounds contain double bonds, the substituents may be in the E- or Z-configuration. When the compounds contain disubstituted cycloalkyls, the cycloalkyl substituents may have cis- or trans-configurations. All tautomeric forms are also intended to be included.

[0045] As used herein, the term "salt" or "salts" refers to an acid addition salt or base addition salt of a compound of the present invention. "Salts" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compound of the present invention and are not usually biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid salts and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto. When both basic and acid groups are present in the same molecule, the compounds of the present invention may also form internal salts, e.g., zwitterionic molecules.

[0046] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0047] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0048] Organic acids from which salts can be derived 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, and sulfosalicylic acid.

[0049] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0050] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, with particularly suitable salts including ammonium, potassium, sodium, calcium, and magnesium salts.

[0051] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, naturally occurring substituted amines, cyclic amines, and substituted amines including basic ion exchange resins, etc. Particular organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0052] In another aspect, the present invention provides an anti-inflammatory agent comprising an anti-inflammatory agent selected from the group consisting of acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl phosphate, lauric acid ... In some embodiments, the compounds of the present invention are provided in the form of a methylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate or xinafoate salt.

[0053] In one embodiment, the present invention provides a compound of formula (I) comprising acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malon ... 16. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 15, wherein the compound is in the form of a salt selected from methylsulfate, mandelate, mesylate, methylsulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate or xinafoate.

[0054] In another embodiment, the present invention provides the fumarate, maleate, adipate, tartrate, glutamate, and hippurate salt forms of the compounds of the present invention.

[0055] In one embodiment, the present invention provides a compound of formula I, II, III, IV ... Provided is (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol in the sulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate or xinafoate salt form.

[0056] 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)propan-1-ol in the fumarate, maleate, adipate, tartrate, glutamate, and hippurate forms.

[0057] 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)propan-1-ol in the hippurate salt form.

[0058] Any formula described herein is intended to represent the unlabeled form and isotopically labeled form of the compound.Isotopically labeled compounds have the structure described herein by the formula described herein, except that one or more atoms are replaced by atoms with selected atomic mass or mass number.The isotopes that can be incorporated into the compounds of the present invention include, for example, hydrogen isotopes.

[0059] At a minimum, the expert should provide a relatively narrow subgenus that approximates the identified development compound and indicate that at least one site (more preferably multiple sites) in the general structure can be a deuterium atom. Examples of what the expert recommends are as follows:

[0060] Additionally, certain isotopes, especially deuterium (i.e. 2Incorporation of H or D) may result in certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, or improved therapeutic index or tolerability. It will be appreciated that deuterium in this context is considered a substituent of the compounds of the present invention. The concentration of deuterium can be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a particular isotope. When a substituent in a compound of the invention is designated as deuterium, such compounds have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation for each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It will be appreciated that the term "isotopic enrichment factor" can be applied to any isotope, just as it is described for deuterium.

[0061] Other examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 3 H, 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 123 I, 124 I, 125 It will therefore be appreciated that the present invention encompasses, for example, 3 H and 14Compounds incorporating one or more of any of the above isotopes, including radioactive isotopes such as C, or 2 H and 13 These include compounds in which non-radioactive isotopes such as C are present. Such isotope-labeled compounds are useful for metabolic studies ( 14 C), reaction kinetics studies (e.g. 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including tissue distribution assays of drugs or substrates, or radiotherapy of patients. 18 F or labeled compounds may be particularly 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 processes similar to those described in the accompanying examples and preparations, using appropriate isotopically labeled reagents in place of previously used non-labeled reagents.

[0062] Further definitions As used herein, the term "pharmaceutical composition" refers to a compound of the present invention or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration.

[0063] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance useful in the preparation or use of a pharmaceutical composition, and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonicity agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof, as would be known to those skilled in the art (see, e.g., Remington The Science and Practice of Pharmacy, 22 nd Ed. Pharmaceutical Press, 2013, pp. 1049-1070).

[0064] The term "therapeutically effective amount" of a compound of the present invention refers to the amount of a compound of the present invention that elicits a biological or medical response in a subject (e.g., reducing or inhibiting the activity of an enzyme or protein or ameliorating symptoms, alleviating a pathological condition, slowing or delaying disease progression, or preventing a disease). In one embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviate, prevent, and / or ameliorate a condition, disorder, or disease that is (i) mediated by LTA4H, or (ii) associated with LTA4H activity, or (iii) characterized by LTA4H activity (normal or abnormal), or (2) reduce or inhibit the activity of LTA4H. In another embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a cell or tissue or non-cellular biological material or medium, is effective to at least partially reduce or inhibit the activity of LTA4H.

[0065] As used herein, the term "subject" refers to primates (e.g., humans, male or female), dogs, rabbits, guinea pigs, pigs, rats, and mice. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0066] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the alleviation or suppression of a given condition, symptom, or disorder or disease, or a significant reduction in the baseline activity of a biological activity or process.

[0067] As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or preventing the onset of the disease or at least one of its clinical symptoms) or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder (including those that may not be discernible to the patient).

[0068] As used herein, the terms "prevent," "preventing," or "prevention" of any disease or disorder refers to prophylactic treatment of the disease or disorder or delay in the onset or progression of the disease or disorder.

[0069] As used herein, a subject is "in need of" a treatment if the subject would benefit from such treatment biologically, medically, or in quality of life.

[0070] As used herein, the terms "a," "an," "the," and similar terms as used in the context of the present invention (particularly in relation to the claims) are to be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0071] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any example or exemplary language (e.g., "etc.") described herein is solely for the purpose of providing a better understanding of the invention and does not impose limitations on the scope of the invention as otherwise claimed.

[0072] Any asymmetric atom (e.g., carbon, etc.) of the compounds of the present invention can be present in racemic or enantiomerically enriched form, for example, in the (R), (S) or (R,S) configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) or (S) configuration. Substituents at atoms with unsaturated double bonds may be present in cis-(Z) or trans-(E) form, where possible.

[0073] Thus, as used herein, a compound of the present invention may be in the form of one of its possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as a substantially pure geometric (cis or trans) stereoisomer, diastereomer, optical isomer (enantiomer), racemate or mixture thereof.

[0074] Any resulting mixture of stereoisomers can be separated on the basis of the physical chemical differences of the components into pure or substantially pure geometric or optical isomers, diastereomers, or racemates, for example, by chromatography and / or fractional crystallization.

[0075] Any resulting racemic compounds of the compounds of the present invention or intermediates can be separated into their optical antipodes by known methods, for example, by separating their diastereomeric salts obtained with optically active acids or bases to liberate the optically active acidic or basic compounds. Thus, compounds of the present invention can be separated into their optical antipodes using basic moieties, particularly by fractional crystallization of salts formed with optically active acids, for example, tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. Racemic compounds or racemic intermediates of the present invention can also be resolved by chiral chromatography, for example, high-pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0076] The compounds of the present invention, including their salts, hydrates and solvates, may be isolated in one or more crystalline forms under appropriate conditions.

[0077] 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)propan-1-ol of its free base, as characterized in Figures 1A, 1B, and 1C and Example 41. Crystalline Form C is characterized by one or more of the following properties: (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, including representative peaks at 2θ points of 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 containing 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, 22.8±0.2°2θ, 24.6±0.2°2θ, and 28.6±0.2°2θ, measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5406 Å; (iii) an X-ray powder diffraction pattern 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, measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5406 Å; iv) an X-ray diffraction spectrum substantially identical to the X-ray powder diffraction spectrum shown in Figure 1A; v) a differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 1B, i.e., when heated from 30 to 300°C at a rate of 10 K / min, with a dehydration endotherm at about 45°C with an enthalpy of 19 J / g, followed by a small melting endotherm and a closely spaced exothermic recrystallization event at about 110°C; vi) Thermogravimetric analysis (TGA) diagram substantially the same as that shown in Figure 1C, i.e., with a loss on drying of about 1.4% when heated between 30 and 300 °C at a rate of 10 K / min.

[0078] 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)propan-1-ol of its free base, as characterized in Figures 2A, 2B, and 2C and Example 42. Crystalline Form D is characterized by one or more of the following properties: (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, including representative peaks at 2θ points of 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 containing 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, 21.6±0.2°2θ, 22.8±0.2°2θ, 24.2±0.2°2θ, and 28.6±0.2°2θ, measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5406 Å; (iii) an X-ray powder diffraction pattern containing five 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, 21.6±0.2°2θ, 22.8±0.2°2θ, 24.2±0.2°2θ, and 28.6±0.2°2θ, measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5406 Å; iv) an X-ray diffraction spectrum substantially identical to the X-ray powder diffraction spectrum shown in Figure 2A; v) a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in Figure 2B, i.e., when heated from 30 to 300°C at a rate of 10 K / min, having a melting endotherm at about 146°C with an enthalpy of about 121 J / g; vi) A thermogravimetric analysis (TGA) diagram substantially the same as that shown in Figure 2C, i.e., with a loss on drying of about 0.15% at about 140°C when heated from 30 to 300°C at a rate of 10 K / min.

[0079] 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)propan-1-ol hippurate, as characterized in Figures 5A, 5B, and 5C and Example 45. It has: (i) an X-ray powder diffraction pattern comprising 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, measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5406 Å; (ii) an X-ray powder diffraction pattern comprising 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, 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, measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5406 Å; (iii) an X-ray powder diffraction pattern containing 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, 21.0±0.2°2θ, 22.3±0.2°2θ, 22.6±0.2°2θ, and 23.1±0.2°2θ, measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5406 Å; iv) an X-ray diffraction spectrum substantially identical to the X-ray powder diffraction spectrum shown in Figure 5A; v) a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in Figure 5B, i.e., having a melting endotherm at about 172°C with an enthalpy of about 106 J / g when heated from 30 to 300°C at a rate of 10 K / min; vi) Thermogravimetric analysis (TGA) diagram substantially the same as that shown in Figure 5C, i.e., with a loss on drying of about 0.2% at about 170°C when heated from 30 to 300°C at a rate of 10 K / min.

[0080] 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)propan-1-ol hippurate, as characterized in Figures 4A, 4B, and 4C and in Example 44. Crystalline form B is characterized by one or more of the following properties: (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, including representative peaks at 2θ points of 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 containing 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, 18.8±0.2°2θ, 23.5±0.2°2θ, and 24.2±0.2°2θ, measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5406 Å; (iii) an X-ray powder diffraction pattern 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, measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5406 Å; iv) an X-ray diffraction spectrum substantially identical to the X-ray powder diffraction spectrum shown in Figure 4A; v) a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in Figure 4B, i.e., when heated from 30 to 300°C at a rate of 10 K / min, having a melting endotherm at about 180°C with an enthalpy of about 134 J / g; vi) Thermogravimetric analysis (TGA) diagram substantially the same as that shown in Figure 4C, i.e., with a loss on drying of about 0.3% at about 170°C when heated from 30 to 300°C at a rate of 10 K / min.

[0081] 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)propan-1-ol hydrochloride, as characterized in Figures 3A, 3B, and 3C and in Example 43. Crystalline Form E is characterized by one or more of the following properties: (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, including representative peaks at 2θ points of 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 containing 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, 21.0±0.2°2θ, 22.0±0.2°2θ, 22.4±0.2°2θ, 23.8±0.2°2θ, 26.2±0.2°2θ, and 27.6±0.2°2θ, measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5406 Å; (iii) an X-ray powder diffraction pattern containing 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, 26.2±0.2°2θ, and 27.6±0.2°2θ, measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5406 Å; iv) an X-ray diffraction spectrum substantially identical to the X-ray powder diffraction spectrum shown in Figure 3A; v) a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in Figure 3B, i.e., having a melting endotherm at about 236°C with an enthalpy of about 127 J / g when heated from 30 to 300°C at a rate of 10 K / min; vi) Thermogravimetric analysis (TGA) diagram substantially the same as that shown in Figure 3C, i.e., with a loss on drying of about 0.5% at about 230°C when heated from 30 to 300°C at a rate of 10 K / min.

[0082] 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)propan-1-ol hydrochloride, as characterized in Figures 6A, 6B, and 6C and in Example 46. Crystalline Form F is characterized by one or more of the following properties: (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, including representative peaks at 2θ points of 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 comprising four 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, measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5406 Å; (iii) an X-ray powder diffraction pattern containing 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, measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5406 Å; iv) an X-ray diffraction spectrum substantially identical to the X-ray powder diffraction spectrum shown in Figure 6A; v) a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in Figure 6B, i.e., with a melting at about 215°C with an enthalpy accompanied by decomposition when heated between 30 and 300°C at a rate of 10 K / min; vi) Thermogravimetric analysis (TGA) diagram substantially the same as that shown in Figure 6C, i.e., with a loss on drying of about 0.4% at about 195°C when heated from 30 to 300°C at a rate of 10 K / min.

[0083] Compounds of the present invention, i.e., compounds of Formula (I), containing groups capable of acting as hydrogen bond donors and / or acceptors, may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals can be prepared from compounds of Formula (I), (IA), (IB), or (IC) and any of Formulas (II)-(VI) by known co-crystal formation procedures. Such procedures include grinding, heating, co-sublimation, co-melting, or contacting a compound of Formula (I) in solution with a co-crystal former under crystallization conditions and isolating the co-crystal thus formed. Suitable co-crystal formers include those described in WO 2004 / 078163. Accordingly, the present invention further provides co-crystals comprising compounds of Formula (I), (IA), (IB), (IC), and any one of Formulas (II)-(VI).

[0084] Furthermore, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or can include other solvents used in their crystallization. The compounds of the present invention can inherently or intentionally form solvates with pharmaceutically acceptable solvents (including water). Therefore, it is intended that the present invention encompasses 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 commonly used in the pharmaceutical field and are known to be harmless to recipients, such as water, ethanol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0085] Synthesis scheme Compounds of formula (II) can be prepared according to general schemes A or B. [ka]

[0086] The cyano group of a suitable building block A.1 can be treated with an azide in the presence of an organotin oxide to give the tetrazole A.2, which can be reacted with a protected serine derivative A.3 to give the intermediate A.4. Sequential or simultaneous deprotection can give compounds of formula (II). [ka]

[0087] Alternatively, tetrazole A.2 can be reacted with protected 4-(hydroxymethyl)-1,2,3-oxathiazolidine 2,2-dioxide B.1 in the presence of base to give intermediate B.2, which can be deprotected to give compounds of formula (II).

[0088] Compounds of formula (III) can be prepared according to general Scheme C. [ka]

[0089] A suitable building block C.1 can be reacted with a protected or unprotected boron reagent C.2 in the presence of a catalyst to give intermediate C.3. Alternatively, the corresponding boronic ester can be used instead of the acid. Treatment with a protected building block B.1 and subsequent removal of the protecting group can give compounds of formula (III).

[0090] Compounds of formula (IV) can be prepared according to general Scheme D. [ka]

[0091] Treatment of nitrile A.1 with hydroxylamine in the presence of base can provide intermediate D.2, which can be reacted with a protected active ester D.3 to give intermediate D.4. Reduction with a borohydride reagent can provide alcohol D.5. Deprotection can give compounds of formula (IV).

[0092] Compounds of formula (V) can be prepared according to Scheme E. [ka]

[0093] Ester E.4 can be saponified and converted to acid chloride E.2. Treatment with hydroxyacetimidamide E.3 in the presence of DMAP and base can result in the formation of intermediate E.4. Heating E.4 in an inert solvent can provide oxadiazole E.5. Treatment of E.6 with an organolithium reagent at low temperature, followed by addition of E.5, can provide intermediate E.7, which can be converted to intermediate E.8 in the presence of acid. Reduction of the acid can provide compounds of formula (V).

[0094] Compounds of formula (VI) can be prepared according to general scheme F. [ka]

[0095] Dioxaborolane F.1 can be treated with NaIO to provide boronic acid F.2. Reaction with tetrazole F.3 in the presence of Cu catalyst, O, and base can provide intermediate F.6. Tetrazole F.3 can be prepared from protected nitrile F.5 by reaction with azide. Reduction with a borohydride reagent can provide alcohol F.6. Deprotection can provide compounds of formula (VI).

[0096] Additional Scheme GI for the synthesis of intermediate A.1 in Schemes A and D. [ka]

[0097] Reaction of G.1 with an aromatic halide G.2 in the presence of a base can provide intermediate A.1(G). [ka]

[0098] Reaction of compound H.1 with bromide H.2 in the presence of base can provide compound H.3. Rh-catalyzed reduction can provide H.4. In the presence of a chiral ligand, enantiomerically pure H.4 can be obtained. Treatment with Cu at elevated temperature can provide compound A.1(H). [ka]

[0099] Reaction of halide I.1 with phenol I.2 in the presence of a base can provide intermediate A.1(I).

[0100] Additional Schemes J-L for the synthesis of intermediate C.1 in Scheme C: [ka]

[0101] Reaction of halide J.1 with phenol J.2 in the presence of base can provide intermediate C.1(J). [ka]

[0102] Reaction of compound K.1 with bromide K.2 in the presence of base can provide compound K.3. Rh-catalyzed reduction can give K.4. In the presence of a chiral ligand, enantiomerically pure K.4 can be obtained. Cu-catalyzed treatment at elevated temperature can provide compound C.1(K). [ka]

[0103] Reaction of halide L.1 with phenol L.2 in the presence of base can provide intermediate C.1(L).

[0104] Additional Schemes MO for the Synthesis of Intermediate E.1 for Scheme E [ka]

[0105] Reaction of halide M.1 with phenol M.2 in the presence of base can provide intermediate E.1(M). [ka]

[0106] Reaction of compound N.1 with bromide N.2 in the presence of base can provide compound N.3. Rh-catalyzed reduction can provide N.4. In the presence of a chiral ligand, enantiomerically pure N.4 can be obtained. Treatment with Cu at elevated temperature can provide compound E.1(N). [ka]

[0107] Reaction of halide O.1 with phenol O.2 in the presence of base can provide intermediate E.1(O).

[0108] Additional Schemes P-R for the Synthesis of Intermediate F.1 in Scheme F [ka]

[0109] Reaction of halide P.1 with phenol P.2 in the presence of base can lead to intermediate F.1(P). [ka]

[0110] Reaction of compound Q.1 with bromide Q.2 in the presence of a base can provide compound Q.3. Reduction with a Rh catalyst can give Q.4. In the presence of a chiral ligand, enantiomerically pure Q.4 can be obtained. Treatment with a Cu catalyst at elevated temperature can give compound F.1(Q). [ka]

[0111] Reaction of halide R.1 with phenol R.2 in the presence of base can provide intermediate F.1(R).

[0112] The present invention further includes any variant of the process of the present invention in which an intermediate obtainable at any stage of the process is used as a starting material and the remaining steps are carried out, or in which the starting material is formed in situ under the reaction conditions, or in which a reactant is used in the form of its salt or optically pure material. The compounds and intermediates of the present invention may also be converted into each other according to methods generally known to those skilled in the art.

[0113] 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 a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical composition can be formulated for a specific route 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 can be in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or liquid form (including, but not limited to, solutions, suspensions, or emulsions). Tablets can be either film-coated or enteric-coated by methods known in the art. Typically, pharmaceutical compositions comprise an active ingredient in a pharmaceutical composition comprising: a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, such as silica, talcum, stearic acid, its magnesium or calcium salts and / or polyethylene glycol (also for tablets); c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (if required); d) disintegrants, such as starch, agar, alginic acid or its sodium salt or effervescent mixtures, and e) Absorbents, colorants, flavorings and sweeteners and one or more of the following:

[0114] The compounds of the present invention, in free form or in pharmaceutically acceptable salt form, exhibit useful pharmacological properties, e.g., LTA4H modulatory properties, as demonstrated in the in vitro and in vivo tests provided in the next section, and are therefore suitable for use as therapeutic or research chemicals, e.g., tool compounds.

[0115] The compounds of the present invention may be useful in the treatment of an indication selected from the following: acute or chronic inflammation, anaphylactic reactions, allergic 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 post-surgical trauma), gastrointestinal ulcers, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), neutrophilic dermatoses (including but not limited to pyoderma gangrenosum, Sweet's syndrome, acne and neutrophilic urticaria), immune complex-mediated glomerulonephritis, hidradenitis suppurativa, autoimmune diseases (including insulin-dependent diabetes mellitus, multiple sclerosis, and the like). sclerosis, rheumatoid arthritis, osteoarthritis and systemic lupus erythematosus), vasculitis (including but not limited to cutaneous vasculitis, Behcet's disease and Henoch-Schönlein purpura), cardiovascular disorders (including but not limited to hypertension, atherosclerosis, aneurysms, critical limb ischemia, peripheral arterial occlusive disease, pulmonary arterial hypertension and Raynaud's syndrome), sepsis, inflammatory and neuropathic pain including arthralgia, periodontal disease including gingivitis, ear infections, migraine headaches, benign prostatic hyperplasia, Sjogren-Larsson syndrome and cancer (including but not limited to leukemia and lymphoma, prostate cancer, breast cancer, lung cancer, malignant melanoma, renal carcinoma, head and neck tumors and colorectal cancer).

[0116] Thus, in a further aspect, the present invention provides the use of a compound of any of formulae (I) to (V) or a pharmaceutically acceptable salt thereof, or the use of a compound of any of Examples 1 to 46, in therapy. In a further embodiment, the therapy is selected from diseases that can be treated by inhibition of LTA4H activity. In another embodiment, the disease is selected from the list above, preferably from ulcerative colitis, acne, hidradenitis suppurativa, asthma, e.g., neutrophilic asthma, psoriasis, and neutrophilic inflammatory conditions such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[0117] In a further aspect, the present invention provides a compound of 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)propan-1-ol; (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-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)propan-1-ol, or a pharmaceutically acceptable salt thereof, for use in therapy. In a further aspect of this embodiment, the therapy is selected from a disease that can be treated by inhibition of LTA4H. In another aspect of this embodiment, the disease is selected from the list above, preferably from ulcerative colitis, acne, hidradenitis suppurativa, asthma, e.g. neutrophilic asthma, psoriasis and neutrophilic inflammatory conditions such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[0118] Thus, in a further aspect, the present invention provides a compound of formula (I) which is (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol or a pharmaceutically acceptable salt thereof for use in therapy. In a further aspect of this embodiment, the therapy is selected from diseases which can be treated by inhibition of LTA4H. In another aspect of this embodiment, the disease is selected from the list above, preferably from ulcerative colitis, acne, hidradenitis suppurativa, asthma, e.g. neutrophilic asthma, psoriasis and neutrophilic inflammatory conditions such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[0119] In a further aspect, the present invention provides (R)-2-amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol, (S)-2-amino-3-(3-(3-((R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol, (S)-2 and (S)-2-amino-3-(5-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol, or a pharmaceutically acceptable salt thereof. In a further aspect of this embodiment, the therapy is selected from a disease that can be treated by inhibition of LTA4H. In another aspect of this embodiment, the disease is selected from the list above, preferably from ulcerative colitis, acne, hidradenitis suppurativa, asthma, e.g. neutrophilic asthma, psoriasis and neutrophilic inflammatory conditions such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[0120] In another aspect, the present invention provides a method for treating a disease treated by inhibition of LTA4H, comprising the administration of a therapeutically acceptable amount of a compound of the invention (e.g., a compound of any of Formulae (I)-(V) or any of the specific compounds of Examples 1-46, or a pharmaceutically acceptable salt thereof). In a further embodiment, the disease is selected from the list above, preferably from ulcerative colitis, acne, hidradenitis suppurativa, asthma, e.g., neutrophilic asthma, psoriasis, and neutrophilic inflammatory conditions such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[0121] Thus, in a further aspect, the present invention provides the use of a compound of the invention (e.g., any compound of Formulae (I) to (V) or any of the specific compounds of Examples 1 to 46, or a pharmaceutically acceptable salt thereof) for the manufacture of a medicament. In a further embodiment, the medicament is for the treatment of a disease that can be treated by inhibition of LTA4H. In another embodiment, the disease is selected from the list above, preferably from ulcerative colitis, acne, hidradenitis suppurativa, asthma, e.g. neutrophilic asthma, psoriasis, and neutrophilic inflammatory conditions such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[0122] The pharmaceutical composition or combination of the present invention may be administered in a unit dose of, for example, about 1 to 1000 mg of the active ingredient for a subject weighing about 50 to 70 kg.

[0123] combination: "Combination" refers to either a combination or combined administration in a single unit dosage form, where a compound of the present invention and a combination partner (e.g., another drug described below, also referred to as a "therapeutic agent" or "co-drug") can be administered independently simultaneously or separately within a time interval (particularly where this time interval allows the combination partners to exert a cooperative, e.g., synergistic, effect). Each single component may be packaged in a kit or separately. One or both of the components (e.g., powder or liquid) may be reconstituted or diluted to the desired dosage before administration. As used herein, terms such as "co-administration" or "combined administration" are intended to encompass the administration of selected combination partners to a single subject (e.g., patient) in need thereof, and include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term "pharmaceutical combination," as used herein, refers to a product obtained by mixing or combining two or more therapeutic agents, and includes both combined and uncombined therapeutic agents. The term "combined preparation" means that both therapeutic agents, e.g., a compound of the present invention and a combination partner, are administered to a patient simultaneously in the form of a single entity or single dosage. The term "non-combined preparation" means that both therapeutic agents, e.g., a compound of the present invention and a combination partner, are administered to a patient as separate entities either simultaneously, concurrently, or sequentially without any specific time limit, such administration providing therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more therapeutic agents.

[0124] "Combination" means either a fixed combination in one dosage unit form or a combined administration in which the compound of the present invention and the combination partner can be administered independently, simultaneously or separately, particularly within a time interval that allows the combination partners to exert a cooperative effect, e.g., a synergistic effect. The single components can be packaged together in a kit or separately. One or both of the components (e.g., powder or liquid) can be reconstituted or diluted to the desired dosage before administration.

[0125] The term "pharmaceutical combination," as used herein, refers to either combined agents in a single unit dosage form or uncombined agents or kit-of-parts for combined administration, where two or more therapeutic agents may be administered independently simultaneously or separately within a time interval, particularly one that allows the combination partners to exert a cooperative effect, e.g., a synergistic effect.

[0126] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a condition or disorder to be treated, as described in the present disclosure. Such administration includes co-administration of these therapeutic agents substantially simultaneously, such as in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration includes co-administration in multiple or separate containers (e.g., tablets, capsules, powders, and liquids) for each active ingredient. The powders and / or liquids may be reconstituted or diluted to the desired dosage before administration. In addition, such administration also includes sequential use of each type of therapeutic agent, either at about the same time or at different times. In either case, the treatment regimen will provide the beneficial effects of the drug combination in treating the condition or disorder described herein.

[0127] The compounds of the present invention can be administered together with one or more other therapeutic agents, either simultaneously or before or after the other therapeutic agents. The compounds of the present invention can be administered separately by the same or different routes of administration, or together in the same pharmaceutical composition with other agents. The therapeutic agents are, for example, compounds, peptides, antibodies, antibody fragments, or nucleic acids that are therapeutically active or enhance the therapeutic activity when administered to a patient in combination with the compounds of the present invention.

[0128] In one embodiment, the present invention provides an article of manufacture comprising a compound of the present invention and at least one other therapeutic agent as a combined formulation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is treatment of a disease or condition mediated by LTA4H. An article of manufacture provided as a combined formulation includes a composition comprising a compound of the present invention and another therapeutic agent together in the same pharmaceutical composition or a composition comprising a compound of the present invention and another therapeutic agent in separate forms, for example, in the form of a kit.

[0129] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable carrier as described above.

[0130] In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the present invention. In one embodiment, the kit includes means for keeping the compositions separate, such as containers, separate bottles, or separate foil packets. An example of such a kit is a blister pack, such as those commonly used for packaging tablets, capsules, and the like.

[0131] The kits of the invention can be used to administer different dosage forms, e.g., oral and parenteral dosage forms, to administer separate compositions at different dosage intervals, or to titrate separate compositions relative to one another. To aid compliance, the kits of the invention typically include instructions for administration.

[0132] In the combination therapy of the present invention, the compound of the present invention and the other therapeutic agent can be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compound of the present invention and the other therapeutic agent can be combined into a combination therapy (i) before the combination product reaches the physician (e.g., in the case of a kit containing the compound of the present invention and the other therapeutic agent), (ii) immediately prior to administration by the physician (or under the physician's supervision), or (iii) by the patient themselves, for example, during sequential administration of the compound of the present invention and the other therapeutic agent.

[0133] Thus, the present invention provides the use of a compound of the present invention to treat a disease or condition mediated by LTA4H when the medicament is prepared for administration with another therapeutic agent. The present invention also provides the use of another therapeutic agent to treat a disease or condition mediated by LTA4H when the medicament is administered together with a compound of the present invention.

[0134] The present invention also provides compounds of the present invention for use in a method of treating a disease or condition mediated by LTA4H, when the compounds of the present invention are prepared for administration 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, when the other therapeutic agent is prepared for administration with a compound of the present invention. The present invention also provides compounds of the present invention for use in a method of treating a disease or condition mediated by LT14H, when the compounds of the present invention are administered 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, when the other therapeutic agent is administered with a compound of the present invention.

[0135] The present invention also provides for the use of a compound of the present invention to treat a disease or condition mediated by LTA4H where the patient has previously (e.g., within 24 hours) been treated with another therapeutic agent. The present invention also provides for the use of another therapeutic agent to treat a disease or condition mediated by LTA4H where the patient has previously (e.g., within 24 hours) been treated with a compound of the present invention.

[0136] In one embodiment, the other therapeutic agent is selected from COX inhibitors, cysteinyl-leukotriene receptor antagonists (including montelukast, pranlukast, and zafirlukast), leukotriene C4 synthase (LTC4S) inhibitors, NLRP3 inhibitors, statins, sulfasalazine, mesalamine, calcineurin inhibitors such as cyclosporine A or FK 506; mTOR inhibitors such as rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, biolimus-7, or biolimus-9; immunosuppressive ascomycins such as ABT-281 and ASM981; corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribine; mycophenolic acid or a salt; mycophenolate mofetil; and IL-1β inhibitors.

[0137] Particular individual combinations that may offer particular therapeutic benefit include NLRP3 inhibitors or LTC4S inhibitors.

[0138] In one embodiment, the invention relates to a combination of a compound according to any one of Formulas (I) to (V) or a pharmaceutically acceptable salt thereof and an NLRP3 inhibitor.

[0139] Examples of NLRP3 inhibitors for use in the combination are described in 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 / 079119, WO 2020 / and those described in International Publication Nos. 010143, 2020 / 102096, 2020 / 010118, 2020 / 086732, 2020 / 086728, 2020 / 102576, 2020 / 102574, 2020 / 102100, 2020 / 102098, 2020 / 154321 and 2020 / 154499.

[0140] More particularly, the NLRP3 inhibitor for use in the combination is selected from the group consisting of:

[0141] [Table 1]

[0142] [Table 2]

[0143] The NLRP3 inhibitor for use in the combination is preferably [ka] or a pharmaceutically acceptable salt thereof.

[0144] More particularly, the NLRP3 inhibitor for use in the combination is [ka] or a pharmaceutically acceptable salt thereof.

[0145] In another embodiment, the NLRP3 inhibitor for use in the combination is selected from the 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)pyridazin-3-yl)-5-(trifluoromethyl)phenol, (S)-3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol and (R)-3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof, preferably (R)-3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-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)pyridazin-3-yl)-5-(trifluoromethyl)phenol, (S)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol and (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof, preferably (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof.In yet another aspect of this embodiment, the NLRP3 inhibitor disclosed in WO 2020 / 234715 is 2-(6-((3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, 2-(6-(((1S,3R)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, 2-(6-(((1R,3R)-3-hydroxycyclohexyl)amino) pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, 2-(6-(((1S,3S)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof, preferably the compound is 2-(6-(((1R,3S)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof.

[0146] 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 as described above, for use in the treatment of HS or NASH.

[0147] In one embodiment, the invention relates to the combination of any one of the compounds of Formulae (I) to (V), or a pharmaceutically acceptable salt thereof, with an LTC4S inhibitor.

[0148] An example of an LTC4S inhibitor for use in the combination is one of Examples 1-120 described in PCT Patent Application WO 2022 / 034529, which is incorporated herein by reference.

[0149] More particularly, the LTC4S inhibitor for use 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]undecan-2-one; 9-(2-amino-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; (R)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5] undecan-2-one; (S)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-amino-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one and 9-(2-amino-6-(1,1-difluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one or a pharmaceutically acceptable salt thereof.

[0150] In one embodiment, the present invention relates to a combination of any one of the compounds of formulae (I) to (V), or a pharmaceutically acceptable salt thereof, and an LTC4S inhibitor for use in the treatment of asthma or atopic dermatitis.

[0151] In one embodiment of the present invention, there is provided a product comprising (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol or a pharmaceutically acceptable salt thereof and an NLRP3 inhibitor as defined above as a combined formulation for simultaneous, separate or sequential use in therapy.

[0152] In another embodiment of the present invention there is provided a product comprising (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol or a pharmaceutically acceptable salt thereof and an LTC4S inhibitor as defined above as a combined formulation for simultaneous, separate or sequential use in therapy.

[0153] In one embodiment of the present invention, there is provided a pharmaceutical composition comprising (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol or a pharmaceutically acceptable salt thereof, an NLRP3 inhibitor as defined above, and a pharmaceutically acceptable carrier.

[0154] In a further embodiment of the present invention, there is provided a pharmaceutical composition comprising (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol or a pharmaceutically acceptable salt thereof, an LTC4S inhibitor and a pharmaceutically acceptable carrier.

[0155] Biological Assays and Data The compounds of formula (I) or pharmaceutically acceptable salts thereof exhibit beneficial pharmacological properties, for example, susceptibility to LTA4H, as shown in the tests provided in the next section, and are therefore indicated for therapy involving LTA4H.

[0156] a) Human LTA4H enzyme assay: Leukotriene A4 hydrolase (LTA4H) catalyzes the hydrolysis of the vinyl analog of epoxide, leukotriene A4 (LTA4), to the proinflammatory mediator LTB4. LTA4H can catalyze the hydrolysis of di- and tripeptide substrates and chromogenic 7-amino-4-methylcoumarin (AMC) derivatives of amino acids. The AMC derivative of arginine (Arg-AMC) can be used as a surrogate substrate for LTA4H, and enzyme activity and compound IC can be determined by monitoring the fluorescence intensity upon AMC release. 50 Allows values ​​to be measured.

[0157] For compound testing, compounds are delivered as 10 mM stock solutions in 90% DMSO (10% water) in matrix tubes. From this, a 1:5 dilution series is prepared down to 0.64 μM, starting at 10 mM. For enzyme assays, 0.5 μL of compound solution is transferred to each well, and 24.5 μL of assay buffer (50 mM Tris buffer, pH 7.5, 150 mM NaCl, 10 mM CaCl) is added to the well, followed by 25 μL of enzyme solution (36 nM human LTA4H in assay buffer). The enzyme-compound mixture is incubated at room temperature for 15 minutes before the addition of 50 μL substrate solution. A final substrate concentration of 600 μM is selected, which approximates the K value of Arg-AMC at a final enzyme concentration of 9 nM. Upon addition of the substrate, the plate is immediately placed in a fluorescence reader and fluorescence is measured every 10 minutes for 60 minutes using filter settings λ excitation = 380 nm and λ emission = 460 nm. Various concentrations (0.00128-100 μM) of AMC in assay buffer are used as a standard curve. Raw data are converted to rates (moles per second) using an AMC calibration curve calculated from the AMC standards. Data are analyzed using nonlinear regression in GraphPad Prism (GraphPad software Inc.) to determine the IC of LTA4H inhibitors. 50 The value is determined.

[0158] Depending on the assay setup, the maximum detectable potency of a compound is approximately 2-3 nM. Therefore, an IC lower than 2 nM is required. 50Compounds with a potency that could theoretically yield a value of 2 nM (=low cutoff of the assay) are given. The potencies of the tested compounds are shown in Table 1 (average values ​​of at least three determinations are given).

[0159] b) Human Whole Blood Assay: Compounds are tested in a human whole blood assay (hWB) to test their ability to inhibit LTB4 biosynthesis in human cell lines. For this purpose, fresh blood is collected from volunteers by venipuncture into heparinized vacutainers. The blood is diluted 1:3 with RPMI (Roswell Park Memorial Institute) medium, and 200 μL aliquots are transferred to 96-well round-bottom cell culture plates. For compound testing, compounds are delivered as 10 mM stock solutions in 90% DMSO in matrix tubes. From this, 4-fold serial dilutions are prepared down to 2.45 μM, starting at a concentration of 250 μM. 4 μL of compound dilution or vehicle is added to 200 μL of blood and incubated for 4 hours at 37 °C in a humidified incubator. Blood was then stimulated with 10 μg / ml calcium ionophore A23187 (Sigma) or an equal volume of DMSO (control) and incubated for an additional 15 minutes at 37°C in a humidified incubator. The incubation was stopped by centrifugation at 300g for 10 minutes at 22°C. Plasma supernatants were collected and, after a 1:20 dilution in assay buffer, transferred to a 96-well plate for eicosanoid measurement by ELISA (Assay Designs) according to the manufacturer's protocol. Data were analyzed in GraphPad Prism (GraphPad software Inc.) using nonlinear regression to determine the IC values ​​of LTA4H inhibitors. 50 The potencies of the tested compounds are shown in Table 1.

[0160] [Table 3]

[0161] [Table 4]

[0162] Preparation of compounds The compounds of the present invention can be prepared as described in the examples below. Abbreviation: Boc: tert-butyloxycarbonyl CAN: Ammonium cerium nitrate DCM: dichloromethane DIAD: (E)-Di-tert-butyldiazene-1,2-dicarboxylate DMAP: 4-(dimethylamino)-pyridine DMF: dimethylformamide DMSO: dimethyl sulfoxide Hal: Halogen HPLC: High-performance liquid chromatography MTBE: Methyl tert-butyl ether NMR: nuclear magnetic resonance PdCl2(dtbpf): 1,1'-bis(di-t-butylphosphino)ferrocene palladium dichloride rt: room temperature SFC: Supercritical Fluid Chromatography TBDMSCl: tert-butyldimethylsilyl chloride THF: tetrahydrofuran TMEDA: Tetramethylethylenediamine TMS: Trimethylsilyl UPLC: Ultra-high performance liquid chromatography

[0163] Analysis details NMR spectroscopy NMR spectra were obtained using a Bruker Ultrashield™ 400 (400 MHz) spectrometer. 1 H NMR spectra are reported in δ units (ppm) and were recorded in, for example, CDCl 3 , DMSO-d 6 or CD 3 OD and referenced to the solvent peak.

[0164] Analytical Liquid Chromatography A Waters Acquity UPLC / MS system (Waters, Milford, MA) was equipped with a binary solvent manager, sample manager, column manager, photodiode array detector (PDA), and a Waters ZQ2000 MS detector. UV absorption was monitored from λ = 210 to 450 nM. The MS detector was operated in continuous positive / negative ESI alternating mode with a full scan from 120 to 1200 Da in 0.3 seconds. Mass spectra were acquired and stored in centroid mode. MS-based confirmation of molecular mass was obtained by the pseudomolecular ion [M+H] in positive mode. + was based on the formation of

[0165] Method A: Column: Acquity UPLC HSS T3, 1.8 μm, 2.1 × 50 mm at 60 °C; Eluent A: HO + 0.05% HCOOH + 3.75 mM ammonium acetate; B: ACN + 0.04% HCOOH; Gradient: 5 → 98% B in 1.4 min, 98% B for 0.4 min, 98 → 5% B in 0.1 min, 5% B for 0.1 min; Flow rate: 1.0 mL / min.

[0166] Method B: Column: Acquity UPLC HSS T3, 1.8 μm, 2.1 × 50 mm at 60 °C; Eluent A: HO + 0.05% HCOOH + 3.75 mM ammonium acetate; B: ACN + 0.04% HCOOH; Gradient: 5 to 98% B in 9.4 min, 98% B for 0.4 min, 98 → 5% B in 0.1 min, 5% B for 0.1 min; Flow rate: 1.0 mL / min.

[0167] Method C: Column: Acquity CORTECS C18+, 2.7 μm, 2.1 × 50 mm at 80 °C; Eluent A: HO + 0.05% HCOOH + 4.76% iPrOH + 3.75 mM ammonium acetate; B: iPrOH + 0.05% HCOOH; Gradient: initial 1% B, 1 → 50% B in 1.4 min, 50 → 98% B in 0.3 min; 0.1 min 98% B; Flow rate: 1.0 mL / min.

[0168] Preparative method: Flash chromatography: Teledyne ISCO, CombiFlash Rf. Column: Pre-packed RediSep Rf cartridge. Samples were typically adsorbed onto ISOLUTE™.

[0169] 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.

[0170] Preparative HPLC: Waters Autopurification-MS System; detection: Waters 2998 photodiode array detector and Waters MS single quadrupole detector; column temperature: room temperature; eluent A: water; eluent B: acetonitrile, both containing 0.1% TFA or 0.1% NH4OH.

[0171] All reagents, starting materials and intermediates utilized in these examples were either available from commercial sources or readily prepared by methods known to those skilled in the art.

[0172] Synthesis of intermediates: Intermediate A [ka] Step a) Methyl N-(tert-butoxycarbonyl)-O-(tert-butyldimethylsilyl)-D-serinate (A.2). To a solution of A.1 (5.0 g, 22.8 mmol) and imidazole (2.33 g, 34.2 mmol) in CHCl (75 mL) was added a solution of TBDMSCl (4.70 g, 29.6 mmol) in CHCl (25 mL) within 20 min under argon and ice cooling. The resulting colorless suspension was stirred for an additional 40 min under ice cooling. The still cold reaction mixture was diluted with water and extracted with MTBE. The combined organic phases were washed with brine and dried over NaSO. Evaporation gave compound A.2 as a yellowish oil (8.44 g, quantitative), which was used in the next step without further purification. TLC: R f = 0.73 (cyclohexane / ethyl acetate 7:3, KMnO4-stained); 1 H 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).

[0173] Step b) tert-Butyl (S)-(1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)carbamate (A.3). To a solution of A.2 (7.16 g, 21.5 mmol) in THF (70 mL) was added LiBH (0.94 g, 42.9 mmol) with ice cooling under argon. During the addition, weak effervescence could be observed. Stirring was continued overnight at 25 °C. The reaction mixture was then poured into semi-saturated NH Cl solution (250 mL) and extracted with MTBE. The combined organic layers were washed with brine and dried over Na SO . Evaporation to dryness afforded compound A.3 as a colorless oil (6.30 g, 96%), which was used in the next step without further purification. TLC: R f = 0.17 (cyclohexane / ethyl acetate 8:2, KMnO4-stained); 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).

[0174] Step c) tert-Butyl (R)-4-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (A). Under argon, imidazole (8.42 g, 124 mmol) was suspended in CHCl (100 mL) and cooled to 0 °C. Within 10 min, a solution of SOCl (2.70 mL, 37.1 mmol) in CHCl (25 mL) was added while maintaining the internal temperature below 5 °C. The formed thick, colorless suspension was stirred for 1 h at 25 °C. The internal temperature was then lowered to −10 °C, and a solution of A.3 (6.30 g, 20.6 mmol) was added dropwise over 10 min. The cooling bath was removed, and stirring was continued for 1.5 h. Water (150 mL) was then added, and the mixture was extracted with CHCl. The combined organic extracts were washed with 10% aqueous citric acid and brine and dried over Na2SO4. The solvent was removed, and the yellowish oil (6.82 g, 94%, diastereoisomeric sulfoxide mixture) was taken up in acetonitrile (150 mL). RuCl3·H2O (93 mg, 0.4 mmol, 2 mol%) was then added, followed by the dropwise addition of a solution of NaIO4 (6.62 g, 30.1 mmol) in water (75 mL) with ice cooling to maintain the internal temperature below 5 °C. After stirring for an additional 45 min at 0 °C, ethyl acetate (150 mL) and Hyflow (25 g) were added to the tan suspension. All solids were removed by filtration, 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, 5% aqueous sodium thiosulfate, and brine again. Drying over Na2SO4 and evaporation of the solvent gave a yellowish oil contaminated with solids. The solid could be removed by trituration with cyclohexane. Flash chromatography on silica (gradient: cyclohexane / ethyl acetate) gave compound A as a colorless oil that solidified on standing (3.88 g, 51%). TLC:R f= 0.41 (cyclohexane / ethyl acetate 85:15, KMnO4-stained); [α]D 23 :-25°(c=1, CH2Cl2); 1 H 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).

[0175] Intermediate B [ka] Intermediate B was prepared by a procedure similar to that used for the synthesis of intermediate A, substituting A.1 for its S-enantiomer B.1. [α]D 23 :+20.2°(c=1, CH2Cl2); 1 H 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).

[0176] Example Synthesis: Example 1 (S)-2-amino-3-(3-(3-((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol [ka] Step a) 3-(2-(2-iodophenoxy)acetyl)benzonitrile (1.1). According to WO 2013 / 134226. A 250 mL single-neck flask equipped with a magnetic stirrer was charged with 2-iodophenol (10.51 g, 46.8 mmol), acetonitrile (16.5 ml), and potassium carbonate (7.12 g, 51.5 mmol). The pink suspension was stirred for 1.5 hours at room temperature. 3-(2-Bromoacetyl)benzonitrile (12.15 g, 51.5 mmol) dissolved in acetonitrile (33 ml) was added dropwise over 10 minutes. The reaction mixture was stirred overnight at room temperature. Additional potassium carbonate (380 mg) and 3-(2-bromoacetyl)benzonitrile (600 mg) were added. After 2 hours, the reaction mixture was cooled to 15°C and quenched 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 x 100 ml) and brine (100 ml), dried over sodium sulfate, filtered, and concentrated in vacuo to give 1.1 as a light brown resin (19.24 g, quantitative). UPLC retention time 1.15 min (Method A). 1 H NMR (DMSO-d6): δ=5.71(s,2H),6.77(t,J=7.52Hz,1H),7.00(d,J=8.19Hz,1H),7.31(t,J=7.64Hz,1H) ,7.76-7.86(m,2H),8.17(d,J=7.70Hz,1H),8.27(d,J=7.95Hz,1H),8.52(s,1H).MS / ESI+364.3[M+H] + .381.1[M+NH4 + ] + .

[0177] Step b) (S)-3-(1-hydroxy-2-(2-iodophenoxy)ethyl)benzonitrile (1.2). Based on WO 2013 / 134226, p. 79A-8. To a 500 mL three-neck flask equipped with a magnetic stirrer and a thermometer, 3-(2-(2-iodophenoxy)acetyl)benzonitrile (1.1) (19.2 g, 46.5 mmol) was added, followed by acetonitrile (86 mL). Argon was bubbled through the slightly cloudy mixture for 5 minutes. 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 at room temperature and stirred for 1.5 hours. The reaction mixture was cooled to 0 °C, and formic acid (6.25 mL, 163 mmol) was added dropwise over 10 minutes at less than 15 °C. After 30 minutes 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 in vacuo to give 1.2 (19.76 g crude). Chromatography on silica (gradient: heptane / ethyl acetate) afforded 1.2 as a colorless resin (13.86 g, 77%). UPLC retention time: 1.08 minutes (Method A). 1 H NMR (DMSO-d6): δ=4.09(dd,J=9.78,5.50Hz,1H),4.18(dd,J=9.66,5.75Hz,1H),5.03(t,J=5.20Hz,1H),5.89(s,1H)6.73(t,J=7.46Hz,1H),7. 00(d,J=8.31Hz,1H),7.32(t,J=7.76Hz,1H),7.52-7.62(m,1H),7.70-7.78(m,2H),7.87(d,J=7.70Hz,1H),7.96(s,1H).MS / ESI+383.1[M+NH4 + ] + .

[0178] Step c) (S)-3-(2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)benzonitrile (1.3). To a 500 mL two-neck flask equipped with a magnetic stirrer and a reflux condenser was added (S)-3-(1-hydroxy-2-(2-iodophenoxy)ethyl)benzonitrile (1.2) (8.76 g, 21.59 mmol), followed by DMF (72 mL). Cesium carbonate (14.07 g, 43.2 mmol), Cu(I) iodide (0.411 g, 2.159 mmol), and N,N-dimethylglycine hydrochloride were added, and the mixture was stirred at 135 °C for 4 h under argon. The cold reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed twice with saturated aqueous ammonium chloride solution. The aqueous phase was back-extracted with ethyl acetate, and the combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 1.3 (6.28 g crude). Chromatography on silica (gradient: heptane / ethyl acetate) gave 1.3 as an off-white resin (3.55 g, 66%). UPLC retention time 1.13 min (Method A). 1 H NMR (DMSO-d6): δ=4.15(dd,J=11.49,8.07Hz,1H),4.49(dd,J=11.49,2.20Hz,1H),5.31-5.40(m,1H),6.85-6.97(m,3H),6.97-7.05(m ,1H),7.62-7.71(m,1H),7.88(d,J=7.70Hz,1H),7.85(d,J=8.07Hz,1H),7.97(s,1H).MS / ESI+255.2[M+NH4+]+,MS / ESI-236.3[MH]-.

[0179] Step d) (S,E)-3-(2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)-N'-hydroxybenzimidamide (1.4). To a 100 mL two-neck flask equipped with a magnetic stirrer and a reflux condenser was added (S)-3-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)benzonitrile (1.3) (1.2 g, 5.06 mmol) and ethanol (17 mL). 50% aqueous hydroxylamine (1.19 mL, 20.23 mmol) was added dropwise, and the reaction mixture was refluxed for 1 h to give a clear solution. The mixture was concentrated in vacuo to give crude product (1.4) (1.39 g, 99%), which was used in the next step without further purification. A small amount of the probe (60 mg) was triturated in dichloromethane / pentane to give 38 mg of a white powder. UPLC retention time: 0.79 min (Method A). 1 H NMR (DMSO-d6): δ=4.11(dd,J=11.43,8.38Hz,1H),4.45(dd,J=11.49,2.45Hz,1H),5.27(dd,J=8.31,2.20Hz,1H),5.8 4(s,2H),6.85-7.02(m,3H),7.40-7.52(m,2H),7.69(d,J=7.70Hz,1H),7.80(s,1H),9.66(s,1H).MS / ESI+271.2[M+H] + .

[0180] Step e) Benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (1.5). A 100 mL two-neck flask equipped with a magnetic stirrer and reflux condenser was charged with (S,E)-3-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)-N'-hydroxybenzimidamide (1.4) (505 mg, 1.87 mmol) and 2-Me-THF (18.7 mL), followed by Boc-Asp(OSu)-OBzl [CAS 140171-25-1] (1179 mg, 2.81 mmol, Bachem). The reaction mixture was stirred at 87 °C for 4 days. The solvent was evaporated on a rotavap to give 2.05 g of crude product. Chromatography on silica (gradient: cyclohexane / ethyl acetate) gave 1.5 (1122 mg, 100%). UPLC retention time 1.38 min (Method A). H NMR (DMSO-d6): δ = ppm 1.27-1.37 (m, 9H), 3.43 (dd, J = 15.71, 8.74 Hz, 1H), 3.55 (dd, J = 15.65, 5.99 Hz, 1H), 4.12 (dd, J = 11.49, 8.31 Hz, 1H), 4.50 (dd, J = 11.55, 2.38 Hz, 1H), 4.67 (d, J = 6.11 Hz, 1H), 5.16 (s, 2H). ,5.40(dd,J=8.19,2.08Hz,1H),6.87-6.97(m,3H),6.99-7.04(m,1H),7.27-7.38(m,5H),7. 57-7.67(m,2H),7.69-7.74(m,1H),8.00(d,J=7.70Hz,1H),8.11(s,1H).MS / ESI+558.3[M+H] + .

[0181] Step f) tert-Butyl ((S)-1-(3-(3-((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (1.6). A 100 mL single-neck flask equipped with a magnetic stirrer was charged with benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (1.5) (723 mg, 1.206 mmol) and THF (16 mL). 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 by adding three scoops of Isolute HM-N (Biotage 9800-1000) after 30 min. The solvent was evaporated on a rotavap, 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 tert-butyl ((S)-1-(3-(3-((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (1.6) (303 mg, 54.3%). UPLC retention time: 1.17 min (Method A). 1 H NMR(DMSO-d6):δ=ppm 1.29(s,9H),2.99(dd,J=14.79,9.17Hz,1H),3.27(dd,J=14.79,4.52Hz,1H),3.33-3.53( m,2H),3.92(br.s.,1H),4.11(dd,J=11.49,8.31Hz,1H),4.50(dd,J=11.49,2.45Hz,1H), 4.92(t,J=5.62Hz,1H),5.40(dd,J=8.19,2.08Hz,1H),6.81-7.06(m,5H),7.63(t,J=7.64 Hz,1H),7.71(d,J=7.83Hz,1H),8.01(d,J=7.70Hz,1H),8.12(s,1H).MS / ESI+454.3[M+H] + .

[0182] Step g) (S)-2-Amino-3-(3-(3-((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol (Example 1). A 100 mL single-neck flask equipped with a magnetic stir bar was charged with tert-butyl ((S)-1-(3-(3-((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (1.6) (275 mg, 0.606 mmol) and dichloromethane (6 mL). TFA (0.934 mL, 12.13 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, and the remaining oil was dissolved in ethyl acetate and washed three times with saturated aqueous sodium bicarbonate, a small amount of 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 sticky solid was lyophilized and finally triturated with isopropyl ether to give (S)-2-amino-3-(3-(3-((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol (Example 1) as a white powder (56 mg, 26%). UPLC retention time: 0.77 min (Method A). 1 H NMR(DMSO-d6):δ=ppm 2.09(br.s.,3H),3.06-3.28(m,2H),3.57-3.68(m,2H),3.75-3.82(m,1H),4.07(dd,J=11.43,8.86Hz,1H),4.42(dd,J=11.43,2.38H z,1H),5.22(dd,J=8.86,2.14Hz,1H),6.89-7.06(m,4H),7.52-7.65(m,2H),8.10(d,J=7.46Hz,1H),8.16(s,1H).MS / ESI+354.2[M+H] + .

[0183] Example 2 (S)-2-amino-3-(3-(3-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol [ka] Step a) 3-((5-chloropyridin-2-yl)oxy)benzonitrile (2.3). To a 100 mL single-neck round-bottom flask equipped with a magnetic stir bar and reflux condenser was added 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). The suspension was stirred at 100 °C for 113 h. The reaction mixture was cooled to room temperature, and water / EtOAc was added. The aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over Na2SO4. Concentration in vacuo afforded a brown oil. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 0-10% EtOAc in cyclohexane) gave 3-((5-chloropyridin-2-yl)oxy)benzonitrile (2.3) as a white solid (1.55 g, 85%). UPLC retention time 1.07 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.11(d,J=2.5Hz,1H),7.71(dd,J=8.7,2.6Hz,1H),7.54-7.47(m,2H),7.45(s,1H),7.42-7.36(m,1H),6.96(d,J=8.7Hz,1H).MS / ESI+231.2[M+H] + .

[0184] Step b) (Z)-3-((5-chloropyridin-2-yl)oxy)-N'-hydroxybenzimidamide (2.4). To a 50 mL single-neck pear-shaped flask equipped with a magnetic stir bar was added 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) in water (10.0 mL). The white suspension was heated to 85 °C and stirred for 65 min. The reaction mixture was cooled to room temperature. EtOH was removed in vacuo. To the remaining white suspension was added water and EtOAc. The aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over Na2SO4. Analysis by LC-MS and 1H NMR revealed high purity of the work-up product (Z)-3-((5-chloropyridin-2-yl)oxy)-N'-hydroxybenzimidamide (2.4) (1.1 g, 95%).

[0185] UPLC retention time 0.71 min (Method A). 1 H NMR(400MHz,DMSO-d6)δ=ppm 9.68(s,1H),8.21(d,J=2.6Hz,1H),7.97(dd,J=8.8,2.7Hz,1H),7.55(d,J=8.0Hz,1H),7.44-7. 39(m,2H),7.15(dd,J=7.8,2.0Hz,1H),7.12(d,J=8.8Hz,1H),5.82(s,2H).MS / ESI+264.3[M+H] + .

[0186] Step c) Benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (2.6). A 20 mL microwave vial equipped with a magnetic stir bar was charged with the product (Z)-3-((5-chloropyridin-2-yl)oxy)-N'-hydroxybenzimidamide (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). The colorless solution was heated to 120 °C and stirred for 19 hours, resulting in a yellow solution. The THF was removed in vacuo. Purification by column chromatography (ISCO CombiFlash Rf, absorbed on silica, 0-18% EtOAc in cyclohexane) gave benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (2.6) (871 mg, 93%). UPLC retention time: 1.41 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.11(d,J=2.5Hz,1H),7.85(d,J=7.8Hz,1H),7.77(s,1H),7.66(dd,J=8.7,2.6Hz,1H),7.49(t,J=8.0Hz,1H),7.28-7.24(m,6H),6.93(d, J=8.7Hz,1H),5.54(d,J=7.3Hz,1H),5.23-5.11(m,2H),4.90-4.83(m,1H),3.49(qd,J=16.1,4.9Hz,2H),1.42(s,9H).MS / ESI+551.4[M+H] + .

[0187] Step d) tert-Butyl (S)-(1-(3-(3-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (2.7). To a 25 mL two-neck round-bottom flask equipped with a magnetic stir bar, a rubber septum, and a gas inlet was added benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (2.6) (506 mg, 0.918 mmol). The flask was evacuated and filled with Ar five times. Anhydrous THF (volume: 10.0 mL) was added, and the colorless solution was cooled to 0 °C. LiBH4 (100 mg, 4.59 mmol) was added in one portion and the reaction mixture was stirred for 70 min.

[0188] The reaction was quenched with MeOH (3 ml). Saturated aqueous NH4Cl and EtOAc were added. The aqueous phase was extracted twice with EtOAc, and the organic layers were washed with brine, combined, and dried over Na2SO4. Purification by column chromatography (ISCO CombiFlash Rf, 20-50% EtOAc in cyclohexane adsorbed onto silica gel) gave tert-butyl (S)-(1-(3-(3-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (2.7) (317 mg, 77%). UPLC retention time 1.13 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.08(d,J=2.6Hz,1H),7.88(d,J=7.8Hz,1H),7.81-7.77(m,1H),7.63(dd,J=8.7,2.7Hz,1H),7.47(t,J=8.0Hz,1H),7.28-7.21(m,1H),6.90( d,J=8.7Hz,1H),5.37(d,J=8.5Hz,1H),4.14(s,1H),3.78-3.64(m,2H),3.35(s,1H),3.22(d,J=5.8Hz,2H),1.37(s,9H).MS / ESI+447.3[M+H] + .

[0189] Step e) (S)-2-Amino-3-(3-(3-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol (Example 2). To a 25 mL single-neck round-bottom flask equipped with a magnetic stirrer was added tert-butyl (S)-(1-(3-(3-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (2.7) (316 mg, 0.707 mmol), dioxane (4.0 mL), and aqueous HCl (4.0 mL, 8.00 mmol). The cloudy solution was stirred at room temperature for 5 days. The solvent was removed in vacuo. Approximately 0.2 M aqueous NaOH (10 mL) was added, causing precipitation of a white solid. EtOAc was 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 onto silica gel, 0-8.5% MeOH in CHCl2) afforded light white crystals (S)-2-amino-3-(3-(3-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol (Example 2) (202 mg, 82%). UPLC retention time: 0.71 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.11(d,J=2.6Hz,1H),7.92(d,J=7.8Hz,1H),7.85-7.80(m,1H),7.66(dd,J =8.7,2.7Hz,1H),7.50(t,J=8.0Hz,1H),7.30-7.23(m,1H),6.92(d,J=8.7Hz ,1H),3.67(dd,J=10.6,4.4Hz,1H),3.53(dd,J=10.6,6.2Hz,1H),3.49-3.4 1(m,1H),3.11(dd,J=15.6,4.7Hz,1H),2.97(dd,J=15.6,8.2Hz,1H),2.07(s br,3H).MS / ESI+347.3[M+H] + .

[0190] Example 3 (S)-2-amino-3-(3-(3-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol [ka] Step a) 3-((5-(difluoromethoxy)pyridin-2-yl)oxy)benzonitrile (3.2). To a 100 mL one-neck pear-shaped flask equipped with a magnetic stir bar and a reflux condenser was added 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). The suspension was then stirred at 90 °C for 7 days. The reaction mixture was cooled to room temperature. 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 onto silica gel, 0-16% EtOAc in cyclohexane) afforded 3-((5-(difluoromethoxy)pyridin-2-yl)oxy)benzonitrile (3.2) as a colorless oil (1.02 g, 67.6%). UPLC retention time 1.04 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.03(d,J=2.7Hz,1H),7.58(dd,J=8.8,2.9Hz,1H),7.52-7.48(m,2H),7.47-7.44(m,1H ),7.43-7.37(m,1H),7.01(d,J=8.9Hz,1H),6.50(t,J=72.6Hz,1H).MS / ESI+263.2[M+H] + .

[0191] Step b) (Z)-3-((5-(difluoromethoxy)pyridin-2-yl)oxy)-N'-hydroxybenzimidamide (3.3). To a 50 mL one-neck round-bottom flask equipped with a magnetic stir bar and a condenser (air) was added 3-((5-(difluoromethoxy)pyridin-2-yl)oxy)benzonitrile (3.2) (545 mg, 2.078 mmol), hydroxylamine hydrochloride (722 mg, 10.39 mmol), NaHCO (873 mg, 10.39 mmol), and ethanol (6.0 ml) in water (3.0 ml). The suspension was stirred for 1 h at 85 °C. EtOH was removed in vacuo. EtOAc and water were added. The aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over NaSO. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 20-45% EtOAc in cyclohexane) gave (Z)-3-((5-(difluoromethoxy)pyridin-2-yl)oxy)-N'-hydroxybenzimidamide (3.3) (564 mg, 92%). UPLC retention time: 0.69 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.22(s br,1H),8.04(d,J=2.8Hz,1H),7.52(dd,J=8.9,2.9Hz,1H),7.48-7.45(m,1H),7.45-7.39(m,2H),7.19(dd d,J=7.7,2.3,1.4Hz,1H),6.94(d,J=8.9Hz,1H),6.47(t,J=72.9Hz,1H),4.87(s,2H).MS / ESI+296.5[M+H] + .

[0192] Step c) Benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (3.4). To a 20 mL microwave vial equipped with a magnetic stir bar was added (Z)-3-((5-(difluoromethoxy)pyridin-2-yl)oxy)-N'-hydroxybenzimidamide (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). The vial was sealed, and the colorless solution was stirred at 100 °C for 66 h. The solvent was removed in vacuo. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 0-20% EtOAc in cyclohexane) afforded a colorless, sticky oil, benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (3.4) (945 mg, 88%). UPLC retention time: 1.35 min (Method A). 1 H NMR (400 MHz, CDCl3) δ = ppm 8.03(d,J=2.7Hz,1H),7.85(d,J=7.8Hz,1H),7.78(d,J=1.8Hz,1H),7.53(dd, J=8.9,2.9Hz,1H),7.49(t,J=8.0Hz,1H),7.31-7.22(m,6H),6.98(d,J=8.9Hz, 1H),6.47(t,J=72.9Hz,1H),5.54(d,J=7.5Hz,1H),5.23-5.10(m,2H),4.86(d ,J=6.9Hz,1H),3.49(qd,J=16.1,4.9Hz,2H),1.41(s,9H).MS / ESI+583.5[M+H] + .

[0193] Step d) tert-Butyl (S)-(1-(3-(3-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (3.5). To a 25 mL two-neck round-bottom flask equipped with a magnetic stir bar, a gas inlet, and a rubber septum was added benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (3.4) (514 mg, 0.882 mmol). The flask was evacuated and backfilled with Ar four times. Anhydrous THF (9.0 mL) was added, and the colorless solution was cooled to 0 °C. LiBH4 (96 mg, 4.41 mmol) was then added, and the reaction mixture was stirred for 1 h. MeOH was added, and the volatiles were removed in vacuo. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 20-50% EtOAc in cyclohexane) afforded tert-butyl (S)-(1-(3-(3-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (3.5) (292 mg, 69.2%). UPLC retention time 1.09 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.05(d,J=2.7Hz,1H),7.92(d,J=7.8Hz,1H),7.84(s,1H),7.57-7.49(m,2H ),7.32-7.27(m,1H),6.98(d,J=8.9Hz,1H),6.48(t,J=72.9Hz,1H),5.19(s br,1H),4.22-4.14(m,1H),3.85-3.73(m,2H),3.28(d,J=5.8Hz,2H),1.42(s,9H).MS / ESI+479.4[M+H] + .

[0194] Step e) (S)-2-Amino-3-(3-(3-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol (Example 3). To a 25 mL one-neck pear-shaped flask equipped with a magnetic stir bar was added tert-butyl (S)-(1-(3-(3-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (3.5) (283 mg, 0.591 mmol), dioxane (6.0 mL), and aqueous HCl (6.0 mL, 12.00 mmol). The cloudy solution was stirred at room temperature for 2 days. 2 M aqueous NaOH (6.0 mL) was added, and the volatiles were removed in vacuo. To the resulting suspension was added EtOAc and approximately 0.1 M aqueous NaOH. 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 onto silica gel, 0-8% MeOH in CHCl2) afforded (S)-2-amino-3-(3-(3-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol (Example 3) as a pale yellow, clear, viscous oil (182 mg, 79%). UPLC retention time 0.69 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.01(d,J=2.8Hz,1H),7.89(d,J=7.8Hz,1H),7.83-7.79(m,1H),7.55-7. 44(m,2H),7.25(dd,J=7.8,1.6Hz,1H),6.94(d,J=8.9Hz,1H),6.47(t,J=7 2.9Hz,1H),3.63(dd,J=10.7,4.4Hz,1H),3.50(dd,J=10.7,6.1Hz,1H),3 .46-3.38(m,1H),3.09(dd,J=15.6,4.7Hz,1H),2.98-2.92(m,1H),2.34(s br,3H).MS / ESI+379.2[M+H] + .

[0195] Example 4 (S)-2-amino-3-(3-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol [ka] Step a) 4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzonitrile (4.3). To a 100 mL single-neck round-bottom flask equipped with a magnetic stir bar and a reflux condenser was added 2-fluoro-5-(trifluoromethyl)pyridine (4.1) (0.990 g, 6.00 mmol), 4-cyanophenol (4.2) (0.786 g, 6.60 mmol), KCO (2.486 g, 17.99 mmol), and DMF (30.0 ml). The reaction mixture was then stirred at 65 °C for 16 h. Water and EtOAc were added. The aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over NaSO. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 0-7% EtOAc in cyclohexane, several fractions) gave 4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzonitrile (4.3) (1.51 g, 95%). UPLC retention time 1.10 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.44(s,1H),7.98(dd,J=8.6,2.3Hz,1H),7.73(d,J=8.7Hz,2H),7.28(d,J=8.7Hz,2H),7.12(d,J=8.6Hz,1H).MS / ESI+265.3[M+H] + .

[0196] Step b) N-Hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzimidamide (4.4). To a 50 mL one-neck pear-shaped flask equipped with a magnetic stir bar and a condenser (air) was added 4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzonitrile (4.3) (0.794 g, 3.01 mmol), hydroxylamine hydrochloride (1.044 g, 15.03 mmol), NaHCO (1.262 g, 15.03 mmol), and ethanol (15.0 ml) in water (5.0 ml). The white suspension was stirred for 2 h at 85 °C. The reaction mixture was cooled to room temperature. EtOH was removed in vacuo. Water and EtOAc were added. The aqueous phase was extracted twice with EtOAc, and the organic layers were washed with brine, combined, and dried over NaSO. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 20-40% EtOAc in cyclohexane) afforded N-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzimidamide (4.4) as white crystals (828 mg, 93%). UPLC retention time: 0.75 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.47-8.43(m,1H),7.93(dd,J=8.7,2.5Hz,1H),7.73-7.68(m,2H),7.23-7.17(m,2H),7.05(d,J=8.7Hz,1H),4.89(s,2H).MS / ESI+298.2[M+H] + .Consistent with the desired product.

[0197] Step c) Benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (4.5). To a 20 mL microwave vial equipped with a magnetic stir bar was added N-hydroxy-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzimidamide (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). The colorless solution was stirred at 110° C. for 17 hours. The solvent was removed in vacuo. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 0-18% EtOAc in cyclohexane) gave benzyl (S)-2-((tert-butoxy-carbonyl)amino)-3-(3-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (4.5) (1.41 g, 99%). UPLC retention time 1.42 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.46(s,1H),8.07(d,J=8.7Hz,2H),7.95(dd,J=8.6,2.4Hz,1H),7.31-2.27(m,5H),7.26(d,J=8.6Hz,2H),7.09(d,J=8.6Hz,1H ),5.58(d,J=7.7Hz,1H),5.24-5.16(m,2H),4.94-4.86(m,1H),3.52(qd,J=16.2,4.9Hz,2H),1.44(s,9H).MS / ESI+585.4[M+H] + .

[0198] Step d) tert-Butyl (S)-(1-hydroxy-3-(3-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-2-yl)carbamate (4.6). To a 25 mL two-neck round-bottom flask equipped with a magnetic stir bar, a gas inlet, and a rubber septum was added benzyl (S)-2-((tert-butoxy-carbonyl)amino)-3-(3-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (4.5) (737 mg, 1.261 mmol). The flask was evacuated and filled with Ar five times. Anhydrous THF (10 mL) was then added, and the colorless solution was cooled to 0 °C. LiBH4 (51.9 mg, 2.383 mmol) was added in one portion. The reaction mixture was stirred for 75 min. After 50 min, additional LiBH4 (27.5 mg, 1.26 mmol, 1.00 equiv) was added. The yellow suspension was quenched with MeOH. The mixture was stored in the freezer over the weekend. The volatiles were removed in vacuo. Purification by column chromatography (ISCO CombiFlash Rf, 20-40% EtOAc in cyclohexane adsorbed onto silica gel) gave tert-butyl (S)-(1-hydroxy-3-(3-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-2-yl)carbamate (4.6) (399 mg, 65.9%) as a sticky, colorless oil. UPLC retention time 1.17 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.45(s,1H),8.14(d,J=8.6Hz,2H),7.94(dd,J=8.6,2.3Hz,1H),7.29-7.26(m,2H),7.08(d,J=8.6Hz,1 H),5.23(s,1H),4.20(s,1H),3.80(dq,J=11.3,5.9,4.7Hz,2H),3.30(d,J=5.9Hz,2H),1.44(s,9H).19F NMR(376MHz,CDCl3)δ-61.73.MS / ESI+481.4[M+H] + .

[0199] Step e) (S)-2-Amino-3-(3-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol (Example 4). To a 25 mL one-neck pear-shaped flask equipped with a magnetic stirrer was added tert-butyl (S)-(1-hydroxy-3-(3-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-2-yl)carbamate (4.6) (393 mg, 0.818 mmol), dioxane (8.0 ml), and aqueous HCl (8.0 ml, 16.00 mmol). The cloudy solution was stirred for 40 hours at room temperature. A white suspension was obtained. The solvent was removed in vacuo. 2 M aqueous NaOH (10 ml) was added. EtOAc and approximately 0.2 M aqueous NaOH were then added, and the aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over Na2SO4. A light yellow (almost white) solid was obtained. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 0-10% MeOH in CHCl2) afforded a white solid (S)-2-amino-3-(3-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol (Example 4) (212 mg, 68.1%). UPLC retention time: 0.75 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.45(s,1H),8.15(d,J=8.7Hz,2H),7.94(dd,J=8.6,2.3Hz,1H),7.28(d,J=8.7Hz,3H),7.08(d,J=8.6Hz,1H),3.71(dd,J=10.5, 4.3Hz,1H),3.56(dd,J=10.5,6.3Hz,1H),3.54-3.46(m,1H),3.15(dd,J=15.5,4.7Hz,1H),3.01(dd,J=15.5,8.1Hz,1H),1.72(s br,3H).19F NMR(376MHz,CDCl3)δ-61.73.MS / ESI+381.3[M+H] + .

[0200] Example 5 (S)-2-amino-3-(3-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol [ka] Step a) 4-((5-(Difluoromethoxy)pyridin-2-yl)oxy)benzonitrile (5.1). To a 10 mL microwave vial equipped with a magnetic stir bar was added 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). After sealing the vial, the white suspension was heated to 110 °C and stirred for 5 days. The reaction mixture was cooled to room temperature. 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 onto silica gel, 0-25% EtOAc in cyclohexane) gave a colorless oil, 4-((5-(difluoromethoxy)pyridin-2-yl)oxy)-benzonitrile (5.1) (0.25 g, 84%). UPLC retention time: 1.04 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.06(d,J=2.8Hz,1H),7.71-7.67(m,2H),7.59(dd,J=8.8,2.9Hz,1H),7.25-7. 21(m,2H),7.03(d,J=8.8Hz,1H),6.51(t,J=72.6Hz,1H).MS / ESI+263.2[M+H]+.

[0201] Step b) (Z)-4-((5-(difluoromethoxy)pyridin-2-yl)oxy)-N'-hydroxybenzimidamide (5.2). A 25 mL one-neck pear-shaped flask equipped with a magnetic stirrer and a condenser (air) was charged with NaHCO3 (400 mg, 4.77 mmol), hydroxylamine hydrochloride (331 mg, 4.77 mmol), and water (2.0 mL). The white suspension (Caution: Gas formation) was stirred for 5 min at room temperature. 4-((5-(Difluoromethoxy)pyridin-2-yl)oxy)-benzonitrile (5.1) (250 mg, 0.953 mmol) in EtOH (5.0 mL) was then added, and the reaction mixture was heated to 85 °C and stirred for 80 min. A colorless solution was obtained within approximately 15 min. LC-MS after 30 min revealed almost complete consumption of the starting material. EtOH was removed in vacuo. 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 onto silica gel, 0-65% EtOAc in cyclohexane) gave a cloudy oil (Z)-4-((5-(difluoromethoxy)pyridin-2-yl)oxy)-N'-hydroxybenzimidamide (0.248 g, 88%) (5.2), which slowly crystallized. UPLC retention time 0.65 min (Method A). 1 H 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) (NH2 and NOH peaks were not observed due to the use of CDCl3 (not DMSO-d6) as the solvent!). MS / ESI + 296.1 [M+H] + .

[0202] Step c) Benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (5.3). To a mL microwave vial equipped with a magnetic stir bar was added (Z)-4-((5-(difluoro-methoxy)pyridin-2-yl)oxy)-N'-hydroxybenzimidamide (5.2) (0.239 g, 0.810 mmol), Boc-Asp(OSu)-OBzl (2.5) (0.374 g, 0.890 mmol), and 3.0 mL of Benzyl (S)-4-((5-(difluoro-methoxy)pyridin-2-yl)oxy)-N'-hydroxybenzimidamide (5.2). The colorless solution was stirred for 100 min at room temperature. LC-MS revealed complete consumption within 90 min. The reaction mixture was then heated to 120 °C and stirred for 3 h. EtOAc was added to the colorless solution, and the mixture was stored in the freezer over the weekend. The solvent was removed in vacuo. CHCl and silica gel were added. Purification by column chromatography (ISCO CombiFlash Rf, 0-25% EtOAc in cyclohexane adsorbed onto silica gel) afforded benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (0.443 g, 94%) (5.3). UPLC retention time 1.34 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.08(d,J=2.7Hz,1H),8.04(d,J=8.7Hz,2H),7.57(dd,J=8.9,2.9Hz,1H),7.29(s,5H),7.22(d,J=8.7Hz,2H),7.00(d,J=8.9Hz,1H),6.50(t,J =72.8Hz,1H),5.58(d,J=7.6Hz,1H),5.20(d,J=2.7Hz,2H),4.93-4.85(m,1H),3.51(qd,J=16.2,5.0Hz,2H),1.44(s,9H).MS / ESI+583.2[M+H] + .

[0203] Step d) tert-Butyl (S)-(1-(3-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (5.4). To a 10 mL two-neck conical flask equipped with a magnetic stir bar, a rubber septum, and a gas inlet was added benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-((5-(difluoromethoxy)-pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (5.3) (0.220 g, 0.378 mmol). The vial was evacuated and backfilled with Ar three times. Dry THF (2.0 ml) was added, and the solution was cooled to 0 °C. LiBH4 (0.041 g, 1.888 mmol) was then added in one portion, and the suspension was stirred for 70 min. The reaction was quenched with MeOH. The solvent was removed in vacuo. CHCl2 and silica gel were added. Purification by column chromatography (ISCO CombiFlash Rf, 0-55% EtOAc in cyclohexane adsorbed onto silica gel) gave tert-butyl (S)-(1-(3-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (0.100 g, 55.3%) (5.4). UPLC retention time 1.07 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.13(d,J=8.7Hz,2H),8.10(d,J=2.7Hz,1H),7.59(dd,J=8.9,2.9Hz,1H),7.27(d,J=8.7Hz,2H),7.02(d,J=8.9Hz,1H),6.52 (t,J=72.8Hz,1H),5.24(s,1H),4.22(s,1H),3.84(p,J=6.7Hz,2H),3.32(d,J=5.9Hz,2H),1.46(s,9H).MS / ESI+479.3[M+H] + .

[0204] Step e) (S)-2-Amino-3-(3-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol (Example 5). To a 10 mL single-neck pear-shaped flask equipped with a magnetic stir bar was added tert-butyl (S)-(1-(3-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (5.4) (0.100 g, 0.209 mmol), dichloromethane (2.0 mL), and TFA (0.081 mL, 1.045 mmol). The solution was stirred at room temperature for 3 days. The solvent and acid were removed in vacuo. Purification by column chromatography (ISCO CombiFlash Rf, absorbed on silica gel, 0-10% MeOH in CHCl) afforded (S)-2-amino-3-(3-(4-((5-(difluoromethoxy)-pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol (82 mg, 99%) (Example 5) as a white (light yellow) foam. UPLC retention time 0.70 min (Method A). 1 H NMR(400MHz,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=72.8Hz,1H),4.01-3.72(m,3H),3.42-3.20(m,2H).MS / ESI+379.3[M+H] + .

[0205] Example 6 Ethyl (S)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-3-yl)propanoate [ka] Step a) Methyl 4-((5-chloropyridin-2-yl)oxy)benzoate (6.2). To a 250 mL one-neck pear-shaped flask equipped with a magnetic stir bar and reflux condenser was added 5-chloro-2-fluoropyridine (2.1) (2.31 g, 17.56 mmol), methyl 4-hydroxybenzoate (6.1) (2.94 g, 19.32 mmol), KCO (4.85 g, 35.1 mmol), and DMF (100 ml). The white suspension was heated to 100 °C and stirred for 19 h. The reaction mixture was cooled to room temperature. Water and EtOAc were added. The aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over NaSO. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 0-7% EtOAc in cyclohexane) afforded methyl 4-((5-chloropyridin-2-yl)oxy)benzoate (3.18 g, 68.7%) (6.2) as a white crystalline solid. UPLC retention time 1.14 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.14(d,J=2.5Hz,1H),8.11-8.05(m,2H),7.69(dd,J=8.7,2.7Hz,1H),7.2 0-7.14(m,2H),6.94(d,J=8.7Hz,1H),3.91(s,3H).MS / ESI+264.2,266.2.

[0206] Step b) 4-((5-chloropyridin-2-yl)oxy)benzoic acid (6.3). To a 250 mL one-neck pear-shaped flask equipped with a magnetic stir bar and a condenser (air) was added 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). The suspension was stirred for 2 h at 45 °C. The mixture was cooled to room temperature and stirred over the weekend (4 days). The volatiles were removed in vacuo. To the resulting white solid was added water, 2 M aqueous HCl (40 mL, 80 mmol), and EtOAc. The aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over Na₂SO₄. Concentration in vacuo gave 4-((5-chloropyridin-2-yl)oxy)benzoic acid (2.93 g, 100%) (6.3) as a white solid. UPLC retention time 0.92 min (Method A). 1 H NMR(400MHz,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.

[0207] Step c) 4-((5-chloropyridin-2-yl)oxy)benzoyl chloride (6.4). To a 50 mL two-necked round-bottom flask equipped with a magnetic stir bar, rubber septum, and gas inlet was added 4-((5-chloropyridin-2-yl)oxy)benzoic acid (6.3) (1.3 g, 5.21 mmol). The flask was evacuated and carefully filled with Ar three times. Anhydrous dichloromethane (7.0 mL) was added, and the white suspension was cooled to 0 °C. Oxalyl chloride (1.0 mL, 11.42 mmol) was added in one portion. After the addition of two drops of DMF, gas formation was observed, and the reaction mixture slowly turned pale yellow. It was stirred for 19.5 h at 0 °C. After 1 h 35 min: additional oxalyl chloride (0.50 mL, 5.71 mmol) was added. After 19 hours: Additional oxalyl chloride (0.20 mL, 2.29 mmol) and 4 drops of DMF were added. Dichloromethane was added to the reaction mixture. It was filtered, and the residue was washed with additional dichloromethane. A white solid was obtained, which was dried under high vacuum. 4-((5-chloropyridin-2-yl)oxy)benzoyl chloride (770 mg, 55.2%) (6.4). The intermediate acyl chloride was not characterized. However, LC-MS showed the formation of the methyl ester (Rt=1.15) in the presence of MeOH!

[0208] Step d) (E)-2-Chloro-N'-((4-((5-chloropyridin-2-yl)oxy)benzoyl)oxy)acetimidamide (6.6). To a 50 mL single-neck pear-shaped flask equipped with a magnetic stirrer was added 4-((5-chloropyridin-2-yl)oxy)benzoyl chloride (6.4) (1.25 g, 4.66 mmol), (Z)-2-chloro-N'-hydroxyacetimidamide (6.5) (WO 2004 / 14370 A2 (2004); Page / Page column 44) (0.557 g, 5.13 mmol), DMAP (0.057 g, 0.466 mmol), and DCM (30 mL). The suspension was stirred for 1 h at room temperature. After 30 min, DIPEA (0.814 mL, 4.66 mmol) was added. The volatiles were removed in vacuo. EtOAc and saturated aqueous 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 by column chromatography (ISCO CombiFlash Rf, 23-38% to 43% EtOAc in cyclohexane adsorbed onto silica gel) afforded (E)-2-chloro-N'-((4-((5-chloropyridin-2-yl)oxy)benzoyl)oxy)acetimidamide (1.05 g, 66.2%) (6.6) as a white solid. UPLC retention time 0.97 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.25(d,J=2.6Hz,1H),8.19(d,J=8.7Hz,2H),8.02(dd,J=8.7,2.7Hz,1H),7.26(d,J=8.7Hz,2H),7.20(d,J=8.8Hz,1H),6.91(s br,2H),4.17(s,2H).MS / ESI+342.1,340.1.

[0209] Step e) 3-(chloromethyl)-5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazole (6.7). To a 250 mL single-neck pear-shaped flask equipped with a magnetic stir bar and a reflux condenser was added (£)-2-chloro-N'-((4-((5-chloropyridin-2-yl)oxy)benzoyl)oxy)acetimidamide (6.6) (1.05 g, 3.09 mmol) and toluene (50.0 mL). The solution was then stirred at 130 °C for 17.5 h and concentrated in vacuo. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 0-12% EtOAc in cyclohexane) afforded 3-(chloro-methyl)-5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazole (463 mg, 46.6%) (6.7) as a white solid. UPLC retention time 1.23 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.22-8.17(m,2H),8.16(d,J=2.5Hz,1H),7.72(dd,J=8.7,2.7Hz,1H),7.3 1-7.27(m,2H),6.99(d,J=8.7Hz,1H),4.67(s,2H).MS / ESI+322.1,324.1.

[0210] Step f) 5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-3-(((2S,5R)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazin-2-yl)methyl)-1,2,4-oxadiazole (6.9). A 10 mL two-neck conical flask equipped with a magnetic stir bar, gas inlet, and rubber septum was heated under vacuum and backfilled with Ar three times. Schoellkopf Auxiliary [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). nBuLi (0.95 mL, 2.375 mmol) in hexane was added dropwise, and the brown solution was stirred for 30 min. A brown solution was obtained. Then, 3-(chloro-methyl)-5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazole (6.7) (441 mg, 1.369 mmol) in anhydrous THF (3.0 mL) was added dropwise. It was stirred for 16 h, during which time it was allowed to warm to room temperature. A light brown solution was obtained. The reaction was quenched with a few drops of saturated aqueous NH4Cl. More saturated aqueous NH4Cl and EtOAc were 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 onto silica gel, 0-9.1% EtOAc in cyclohexane) afforded 5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-3-(((2S,5R)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazin-2-yl)methyl)-1,2,4-oxadiazole (368 mg, 54%) (6.9%) as a yellow oil. UPLC retention time 1.60 min (Method A). 1H NMR(400MHz,CDCl3)δ=ppm 8.17-8.12(m,3H),7.70(dd,J=8.7,2.7Hz,1H),7.25(dd,J=9.0,2.4Hz,2H),6.97(d,J=8.7Hz,1H),4.48(ddd,J=7.4,5.0,3.7Hz,1H),4.24-3.93(m,4H),3.88(t,J=3.5Hz,1H),3.37-3.28(m,1H),3.12(dd,J=14.5,7.3Hz,1H),2.24(ddt,J=10.2,6.8,3.4Hz,1H),1.28-1.24(m,3H),1.23-1.18(m,3H),1.04(dd,J=13.7,6.9Hz,3H),0.70(dd,J=15.4,6.8Hz,3H).MS / ESI+498.3,500.3.

[0211] Step g) Ethyl (S)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-3-yl)propanoate (6.10). To a 25 mL single-neck round-bottom flask equipped with a magnetic stir bar was added 5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-3-(((2S,5R)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazin-2-yl)methyl)-1,2,4-oxadiazole (6.9) (368 mg, 0.739 mmol) and 8.0 mL). After addition of aqueous HCl (2.0 mL, 4.00 mmol) to the golden yellow solution, it immediately turned pale orange and then yellow again over time. The reaction mixture was stirred for 90 min at room temperature. The reaction was quenched with saturated aqueous NaHCO3. EtOAc was added, and the aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over Na2SO4. Concentration in vacuo afforded a yellow oil. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 0-2.3% MeOH in CHCl2) afforded ethyl (S)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-3-yl)propanoate (272 mg, 95%) (6.10) as a colorless oil, which slowly crystallized at room temperature. UPLC retention time 0.82 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.18-8.11(m,3H),7.71(dd,J=8.7,2.7Hz,1H),7.30-7.23(m,2H),6.97(d,J=8.7Hz,1H),4.22(qq,J=7.1,3.6Hz,2H),4.01(dd,J=8. 0,4.7Hz,1H),3.28(dd,J=15.1,4.7Hz,1H),3.13(dd,J=15.1,8.0Hz,1H),1.86(s,2H),1.28(t,J=7.1Hz,3H).MS / ESI+389.2,391.2.

[0212] Step h) Ethyl (S)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-3-yl)propanoate (Example 6). To a 25 mL two-neck pear-shaped flask equipped with a magnetic stir bar, a rubber septum, and a gas inlet was added ethyl (S)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-3-yl)propanoate (6.10) (272 mg, 0.700 mmol). The flask was evacuated and filled with Ar five times. Anhydrous THF (5.00 ml) was added, and the solution was cooled to 0° C. After the addition of LiAlH (2 M) in THF (0.350 mL, 0.700 mmol) (gas formation was observed), the reaction mixture was stirred for 65 min at 0° C. The reaction was quenched with MeOH (still cooled at 0 °C) and then with water. Saturated aqueous NH4Cl 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 onto silica gel, 0-10% MeOH in CHCl2) afforded ethyl (S)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-3-yl)propanoate (64.6 mg, 26.4%) (Example 6) as a light brown solid. UPLC retention time 0.70 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.13(dd,J=5.9,2.9Hz,3H),7.70(dd,J=8.7,2.7Hz,1H),7.29-7.21(m,2H),6.96(d,J=8.7Hz,1H),3.68(dd,J=10.8,4.2Hz,1H) ,3.52(dd,J=10.8,6.5Hz,1H),3.40(dq,J=11.2,4.7Hz,1H),2.97(dd,J=14.9,4.7Hz,1H),2.84(dd,J=14.9,8.2Hz,1H),2.57(s br,3H).MS / ESI+347.2,349.2.

[0213] Example 7 tert-Butyl ((2S)-1-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate [ka] Step a) 4-((5-Bromo-3-fluoropyridin-2-yl)oxy)benzonitrile (7.2). To a 100 mL single-neck round-bottom flask equipped with a magnetic stir bar and reflux condenser was added 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). The suspension was heated to 110 °C and stirred for 17 h. The reaction mixture was cooled to room temperature. Water / EtOAc was added, and the yellow aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over Na2SO4. Concentration in vacuo afforded a strong orange oil. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 0-10% then 20% EtOAc in cyclohexane) afforded 4-((5-bromo-3-fluoropyridin-2-yl)oxy)benzonitrile (2.97 g, 64.9%) (7.2) as a white solid. UPLC retention time 1.14 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.37(dd,J=9.6,2.0Hz,1H),8.18(d,J=2.0Hz,1H),7.93(d,J=8.7Hz,2H),7.43(d,J=8.7Hz,2H).19F NMR(376MHz, CDCl3)δ-132.46(d,J=8.4Hz).MS / ESI+293.0,295.0(weak).

[0214] Step b) 4-((3-Fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)benzonitrile (7.3). A 50 mL two-neck round-bottom flask equipped with a magnetic stir bar, gas inlet, and rubber septum was charged with 4-((5-bromo-3-fluoropyridin-2-yl)oxy)benzonitrile (7.2) (0.786 g, 2.68 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [CAS:903550-26-5] (1.000 g, 3.49 mmol), KPO (1.708 g, 8.05 mmol), [Pd(PPh)] (0.155 g, 0.134 mmol), and toluene (15.0 mL). The flask was carefully evacuated and backfilled with Ar three times. The reaction mixture was then flushed with Ar for 10 minutes. The rubber septum was removed, and a reflux condenser (pre-flushed with Ar) was installed (through a rubber septum and an Ar balloon on top). The pale yellow suspension was then stirred for 3 h at 110 °C. The reaction mixture was cooled to room temperature. Water / EtOAc was added, and the yellow aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over Na2SO4. Concentration in vacuo gave a dark orange oil. The crude mixture was purified twice by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 0-30% EtOAc in cyclohexane in both cases) to give 4-((3-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)benzonitrile (0.628 g, 64.3%) (7.3) as a white solid. UPLC retention time 1.06 min (Method A). 11H 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 + ionization not observed, R f (Cyclohexane / EtOAc, 3:1) = 0.26.

[0215] Step c) 4-((3-Fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)-N-hydroxybenzimidamide (7.4). To a 50 mL one-neck pear-shaped flask equipped with a magnetic stir bar was added hydroxylamine hydrochloride (0.599 g, 8.62 mmol), NaHCO (0.724 g, 8.62 mmol), and water (4.0 ml). The white suspension (Caution: gas formation) was stirred for 5 min at room temperature. Then, 4-((3-Fluoro-5-(1-(tetrahydro-2H-pyran-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 room temperature, the EtOH was removed in vacuo. 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 onto silica gel, 0-66% EtOAc in cyclohexane) afforded 4-((3-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)-N-hydroxybenzimidamide (0.570 g, 83%) (7.4) as a white foam. UPLC retention time 0.80 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.08(d,J=1.9Hz,1H),7.77-7.70(m,3H),7.62(d,J=1.6Hz,1H),7.29-7.25(m,2H),6.38(d,J=1.7Hz,1H),5.15(dd,J=10.0,2.4Hz,1H),4.87(s br,2H),4.17-4.05(m,1H),3.62(td,J=11.5,2.2Hz,1H),2.66-2.49(m,1H),2.15-2.06( m,1H),1.90(d,J=13.5Hz,1H),1.82-1.68(m,1H),1.67-1.53(m,2H).MS / ESI+398.3[M+H] + .R f (cyclohexane / EtOAc, 1:2) = 0.33.

[0216] Step d) Benzyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (7.5). In a 20 mL microwave vial equipped with a magnetic stir bar was added 4-((3-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)-N-hydroxybenzimidamide (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). The vial was sealed, and the colorless solution was stirred for 1 h at room temperature. The reaction mixture was then heated to 120 °C and stirred for 140 min. The solution was cooled to room temperature. The solvent was removed in vacuo. CHCl and silica gel were added. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 0-35% EtOAc in cyclohexane) afforded benzyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (270 mg, only 67% pure!) (7.5). UPLC retention time 1.40 min (Method A). MS / ESI + 685.4 [M+H] + .R f (cyclohexane / EtOAc, 1:2)=0.43.

[0217] Step e) tert-Butyl ((2S)-1-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (7.6). To a 10 mL two-neck conical flask equipped with a magnetic stir bar, rubber septum, and gas inlet was added benzyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (7.5) (0.134 g, 0.196 mmol). (Note: The starting material is not pure but approximately 67% pure.) The vial was evacuated and filled with Ar three times. THF (1 ml) was added, and the colorless solution was cooled to 0 °C. LiBH (0.021 g, 0.979 mmol) was added in one portion, and the suspension was stirred for 45 min. The reaction mixture was quenched with MeOH, and the solvent was removed in vacuo. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 0-65% EtOAc in cyclohexane). A second purification by column chromatography (gradient: 20-55% EtOAc in cyclohexane) only slightly improved the purity. tert-Butyl ((2S)-1-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (48.9 mg, 43%) (7.6%).

[0218] UPLC retention time 1.16 min (Method A). MS / ESI+581.4[M+H] + .R f (cyclohexane / EtOAc, 1:2)=0.48.

[0219] Step e) tert-butyl ((2S)-1-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (Example 7). To a 10 mL single-neck pear-shaped flask equipped with a magnetic stir bar was added tert-butyl ((2S)-1-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (7.6) (48.9 mg, 0.084 mmol), DCM (0.800 mL), and TFA (33 μL, 0.428 mmol). The colorless solution was stirred for 5 days. LC-MS analysis revealed rapid consumption of the starting material. Cleavage of the THP ether was fast. However, Boc-deprotection was slow, as expected. Equilibrium was reached after 4 days. The solvent and acid were removed in vacuo. Purification by column chromatography (ISCO CombiFlash Rf, adsorbed onto silica gel, 0-10-15% MeOH in CHCl) afforded tert-butyl ((2S)-1-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (10.9 mg, 24%) (Example 7) as a cloudy oil. UPLC retention time 0.65 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.28(d,J=1.8Hz,1H),8.05(d,J=8.7Hz,2H),7.90(dd,J=10.5,1.8Hz,1H),7.57(d,J=2.1Hz,1H),7.24(d,J=8.7Hz,2H),6.54(d,J=1.9 Hz,1H),3.90(dd,J=11.9,3.3Hz,1H),3.87-3.78(m,1H),3.73(dd,J=12.0,5.7Hz,1H),3.32(dd,J=6.7,4.5Hz,2H).MS / ESI+397.2[M+H]+ .

[0220] Example 8 (R)-2-amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol [ka] Step a) 4-((5-chloro-3-fluoropyridin-2-yl)oxy)-N-hydroxybenzimidamide (8.1). To a 100 mL one-neck pear-shaped flask equipped with a magnetic stirrer and a condenser (air) was added 4-((5-chloro-3-fluoropyridin-2-yl)oxy)benzonitrile (29.3) (2.82 g, 11.34 mmol), NaHCO (4.76 g, 56.7 mmol), hydroxylamine hydrochloride (3.94 g, 56.7 mmol), ethanol (40 ml), and water (15 ml) (Caution: gas formation). The white suspension was heated to 85 °C and stirred for 100 min. It was then cooled to room temperature. EtOH was removed in vacuo. Water / EtOAc was added, and the aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over Na SO . LC-MS and H NMR analysis revealed high purity of the resulting white solid 4-((5-chloro-3-fluoropyridin-2-yl)oxy)-N-hydroxybenzimidamide (3.18 g, 97%) (8.1). Therefore, no further purification was necessary. UPLC retention time 0.73 min (Method A). 1 H NMR(400MHz,DMSO-d6)δ=ppm 9.62(s,1H),8.23(dd,J=9.9,1.9Hz,1H),8.06(d,J=2.0Hz,1H),7.71(d,J=8.7Hz,2H),7.20(d,J=8.6Hz,2H),5.82(s,2H).MS / ESI+282.2,284.2.

[0221] Step b) Benzyl (R,Z)-4-(((amino(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)methylene)-amino)oxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate (8.3). To a 50 mL single-neck round-bottom flask equipped with a magnetic stir bar was added 4-((5-chloro-3-fluoropyridin-2-yl)oxy)-N-hydroxybenzimidamide (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). After adding 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 for 17.5 h at room temperature. THF was removed in vacuo. Saturated aqueous NaHCO3 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, brine, combined, and dried over Na2SO4. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 15–40% EtOAc in cyclohexane) afforded benzyl (R,Z)-4-(((amino(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-methylene)-amino)oxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate (1.35 g, 97%) (8.3) as a white solid. UPLC retention time 1.25 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 7.92(d,J=2.1Hz,1H),7.75(d,J=8.7Hz,2H),7.56(dd,J=9.0,2.1Hz,1H),7.36(s,5H),7.22(d,J=8.7Hz,2H) ,5.23(d,J=2.0Hz,2H),4.82-4.74(m,1H),3.16(qd,J=17.0,4.9Hz,2H),1.45(s,9H).MS / ESI+587.4,589.4.R f (cyclohexane / EtOAc, 2:1)=0.23.

[0222] Step c) Benzyl (R)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (8.4). To a 20 mL microwave vial equipped with a magnetic stir bar was added benzyl (R,Z)-4-(((amino(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-methylene)-amino)oxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate (8.3) (1.34 g, 2.055 mmol) and THF (13.0 ml). The vial was sealed and the reaction mixture was stirred at 100° C. for 2.5 days. The resulting orange solution was cooled to room temperature and the solvent was removed in vacuo. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 0-18% EtOAc in cyclohexane) afforded benzyl (R)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (0.806 g, 68.9%) (8.4) as a colorless viscous oil. UPLC retention time 1.40 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.05(d,J=8.7Hz,2H),7.93(d,J=2.2Hz,1H),7.55(dd,J=9.0,2.2Hz,1H),7.28(s,5H),7.25(d,J=8.4Hz,2H),5.58(d,J= 7.8Hz,1H),5.25-5.13(m,2H),4.90(d,J=7.3Hz,1H),3.51(qd,J=16.2,5.0Hz,2H),1.44(s,9H).MS / ESI+569.3,571.3.R f (cyclohexane / EtOAc, 5:1)=0.33.

[0223] Step d) tert-Butyl (R)-(1-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (8.5). To a 25 mL two-necked round-bottom flask equipped with a magnetic stir bar, a rubber septum, and a gas inlet was added benzyl (R)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (8.4) (489 mg, 0.859 mmol). The flask was evacuated and filled with Ar four times. THF (8.0 ml) was added, and the colorless solution was cooled to 0 °C. After addition of LiBH4 (94 mg, 4.30 mmol), the suspension was stirred for 90 min at 0 °C. Complete conversion of starting material occurred within 1 h. The reaction was quenched with MeOH. The solvent was then removed in vacuo. Purification by column chromatography (ISCO CombiFlash Rf, 20-46% EtOAc in cyclohexane adsorbed onto silica gel) afforded tert-butyl (R)-(1-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (0.240 g, 60.1%) (8.5) as a colorless, viscous oil. UPLC retention time 1.17 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.12(d,J=8.8Hz,2H),7.93(d,J=2.2Hz,1H),7.55(dd,J=9.0,2.2Hz,1H),7.27(d,J=8.7Hz,2H),5.21(s,1H), 4.24-4.16(s,1H),3.81(hept,J=5.7,5.1Hz,2H),3.30(d,J=5.9Hz,2H),1.44(s,9H).MS / ESI+465.3,467.3.R f (cyclohexane / EtOAc, 1:1)=0.43.

[0224] Step e) (R)-2-Amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol (Example 8). To a 50 mL single-neck round-bottom flask equipped with a magnetic stir bar was added tert-butyl (R)-(1-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (8.5) (227 mg, 0.488 mmol), dioxane (5.0 mL), and aqueous HCl (5.0 mL, 10.00 mmol). The cloudy solution was stirred for 18 hours at room temperature. 2 M aqueous NaOH (5.0 mL, 10.0 mmol, 20.48 equiv.) was added, and the dioxane was removed in vacuo. The resulting clear aqueous phase was basified (pH 7.5) with additional 2M aqueous NaOH. 最終 >10). A white solid precipitated. 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 onto silica gel, 0-10% MeOH in CHCl2) afforded (R)-2-amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol (131 mg, 72.1%) (Example 8) as a colorless oil, which crystallized overnight in the freezer. UPLC retention time 0.76 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.13(d,J=8.7Hz,2H),7.93(d,J=2.2Hz,1H),7.55(dd,J=9.0,2.2Hz,1H),7.27(d,J=8.6Hz,2H),3.71(dd,J=10.5,4.3Hz,1H),3. 56(dd,J=10.6,6.2Hz,1H),3.53-3.45(m,1H),3.14(dd,J=15.6,4.7Hz,1H),3.00(dd,J=15.6,8.1Hz,1H).MS / ESI+365.3,367.3.

[0225] Example 9 tert-Butyl (S)-(1-(3-(3-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate [ka] Step a) 3-((5-iodopyridin-2-yl)oxy)benzonitrile (9.2). To a 250 mL one-neck pear-shaped flask equipped with a magnetic stirrer and reflux condenser was added 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). The suspension was stirred for 15 h at 100 °C. A brown suspension was obtained. Water and EtOAc were added. The aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over Na2SO4. Concentration in vacuo gave a light brown oil, which slowly crystallized at room temperature. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 0-6% to 7.7% EtOAc in cyclohexane) afforded 3-((5-iodopyridin-2-yl)oxy)benzonitrile (1.95 g, 92%) (9.2) as a white solid. UPLC retention time 1.15 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.35(d,J=2.1Hz,1H),7.98(dd,J=8.6,2.3Hz,1H),7.50(d,J=5.0Hz,2H),7.47-7. 43(m,1H),7.38(td,J=4.7,2.4Hz,1H),6.84(d,J=8.6Hz,1H).MS / ESI+323.1[M+H] + .

[0226] Step b) (Z)-N'-Hydroxy-3-((5-iodopyridin-2-yl)oxy)benzimidamide (9.3). To a 50 mL single-neck pear-shaped flask equipped with a magnetic stir bar was added 3-((5-iodopyridin-2-yl)oxy)benzonitrile (9.2) (1.95 g, 6.05 mmol), hydroxylamine hydrochloride (2.103 g, 30.3 mmol), NaHCO (2.54 g, 30.3 mmol), and ethanol (20.0 mL) in water (10.0 mL). The white suspension was heated to 85 °C and stirred for 90 min. The reaction mixture was cooled to room temperature. EtOH was removed in vacuo. Water and EtOAc were added, and the aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over NaSO. Concentration in vacuo gave (Z)-N'-hydroxy-3-((5-iodopyridin-2-yl)oxy)benzimidamide (1.87 g, 86%) (9.3) as a white solid. UPLC retention time 0.77 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 9.67(s,1H),8.37(d,J=2.2Hz,1H),8.16(dd,J=8.6,2.4Hz,1H),7.54(d,J=7.9Hz,1H),7.43-7. 38(m,2H),7.14(dd,J=8.0,1.7Hz,1H),6.95(d,J=8.6Hz,1H),5.82(s,2H).MS / ESI+356.1[M+H] + .

[0227] Step c) Benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-((5-iodopyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (9.4). To a 20 mL microwave vial equipped with a magnetic stir bar was added (Z)-N'-hydroxy-3-((5-iodopyridin-2-yl)oxy)benzimidamide (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). The colorless solution was stirred at 100 °C for 3 days. The volatiles were removed in vacuo. Purification by column chromatography (ISCO CombiFlash Rf, adsorbed onto silica gel, 0-15.9% EtOAc in cyclohexane) afforded benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-((5-iodopyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (1.44 g, 93%) (9.4%). UPLC retention time 1.44 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.35(d,J=2.1Hz,1H),7.95(dd,J=8.6,2.3Hz,1H),7.86(d,J=7.8Hz,1H),7.78(s,1H),7.50(t,J=8.0Hz,1H),7.29-7.26(m,6H),6.82(d, J=8.6Hz,1H),5.55(d,J=7.5Hz,1H),5.24-5.12(m,2H),4.91-4.83(m,1H),3.50(qd,J=16.2,5.0Hz,2H),1.43(s,9H).MS / ESI+643.3[M+H] + .

[0228] Step d) Benzyl (S)-3-(3-(3-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-2-((tert-butoxycarbonyl)amino)propanoate (9.6). A 100 mL two-neck round-bottom flask equipped with a magnetic stir bar, a gas inlet, and a rubber septum was charged with benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-((5-iodopyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (9.4) (1.41 g, 2.195 mmol), dioxane (20.0 mL) in water (10.0 mL), KPO (1.398 g, 6.58 mmol), and 4-pyrazoleboronic acid pinacol ester (9.5) (0.459 g, 2.247 mmol, [CAS: 844501-71-9]). The suspension was purged with Ar for 10 min. Pd(dtbpf)Cl2 (0.143 g, 0.219 mmol) was then added, and the reaction mixture was stirred for 25 min at 70 °C. LC-MS analysis revealed complete conversion of the starting material within 25 min, but the product was mostly saponified. The reaction mixture was allowed to cool to room temperature. Volatiles were removed in vacuo. EtOAc, water, and 2 M aqueous HCl (10 mL) were added. The aqueous phase was extracted twice with EtOAc. The organic layers were then washed with approximately 0.1 M aqueous NaOH and brine, combined, and dried over sodium sulfate. Purification by column chromatography (ISCO CombiFlash Rf, adsorbed onto silica gel, 20-50% EtOAc in cyclohexane) afforded benzyl (S)-3-(3-(3-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-2-((tert-butoxycarbonyl)amino)propanoate (325.4 mg, 25.4%) (9.6%). UPLC retention time 1.22 min (Method A). 1H NMR(400MHz,CDCl3)δ=ppm 8.59(d,J=2.2Hz,1H),8.16(dd,J=8.5,2.3Hz,1H),7.89-7.81(m,2H),7.64(d,J=2.3Hz,1H),7.51(t,J=8.0Hz,1H),7.35-7.30(m,1H),7.27(s,5H),7.03(d,J=8.5Hz,1H),6.60(d,J=2.3Hz,1H),5.57(d,J=7.8Hz,1H),5.24-5.11(m,2H),4.91-4.83(m,1H),3.50(qd,J=16.2,4.7Hz,2H),1.42(s,9H).MS / ESI+583.4[M+H] + .

[0229] Step e) tert-Butyl (S)-(1-(3-(3-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (9.7). To a 25 mL two-neck pear-shaped flask equipped with a magnetic stir bar, a gas inlet, and a rubber septum was added benzyl (S)-3-(3-(3-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-2-((tert-butoxycarbonyl)amino)propanoate (9.6) (229 mg, 0.393 mmol). The flask was evacuated and backfilled with Ar five times. Anhydrous THF (4.0 mL) was added, and the colorless solution was cooled to 0 °C. LiBH4 (42.6 mg, 1.956 mmol) was then added in one portion and the reaction mixture was stirred for 90 min. The ice bath was removed and the suspension was stirred for an additional 30 min. The reaction was quenched with MeOH. The reaction mixture (rm) was stored in the freezer overnight. The volatiles were removed in vacuo. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 40-70-80-85% EtOAc in cyclohexane). Due to impurities, the product was again purified by column chromatography (ISCO CombiFlash Rf, 55-68-70% EtOAc in cyclohexane adsorbed onto silica gel) to give tert-butyl (S)-(1-(3-(3-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (86.3 mg, 44.5%) (9.7%) as a colorless oil. UPLC retention time 0.92 min (Method A). 1H NMR(400MHz,CDCl3)δ=ppm 8.58(d,J=2.4Hz,1H),8.15(dd,J=8.5,2.4Hz,1H),7.92(d,J=7.8Hz,1H),7.87(d,J=2.0Hz,1H),7.64(d,J=2.3Hz,1H),7.52(t,J=8.0Hz,1H),7.32(dd,J=7.8,2.0Hz,1H),7.03(d,J=8.5Hz,1H),6.60(d,J=2.2Hz,1H),5.22(d,J=6.8Hz,1H),4.22-4.15(m,1H),3.84-3.74(m,2H),3.28(d,J=5.9Hz,2H),1.42(s,9H).MS / ESI+479.4[M+H] + .

[0230] Step f) (S)-3-(3-(3-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-2-aminopropan-1-ol (Example 9). To a 12 mL one-neck pear-shaped flask equipped with a magnetic stirrer was added tert-butyl (S)-(1-(3-(3-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (9.7) (86.3 mg, 0.180 mmol) and dioxane (2.0 mL) at room temperature. After the addition of HCl in dioxane (4 M solution) (0.451 mL, 1.804 mmol), the reaction mixture immediately became a white suspension. It was stirred at room temperature for 17.5 hours. The solvent was removed in vacuo. EtOAc and 2M aqueous NaOH 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 by RP C18 column chromatography (ISCO CombiFlash Rf, liquid injection, 10-35% MeCN in water, fractions 21-27). The fractions were combined, and MeCN was removed in vacuo. 2M aqueous NaOH (ca. 5 mL) was added, and the aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over Na2SO4. Concentration in vacuo afforded (S)-3-(3-(3-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-2-aminopropan-1-ol (50.1 mg, 72.7%) (Example 9) as a white foam. UPLC retention time 0.60 min (Method A). 1H NMR(400MHz,CDCl3)δ=ppm 8.59(d,J=2.3Hz,1H),8.14(dd,J=8.5,2.4Hz,1H),7.93(d,J=7.8Hz,1H),7.90-7.87(m,1H),7.6 2(d,J=2.4Hz,1H),7.52(t,J=8.0Hz,1H),7.32(dd,J=8.1,1.5Hz,1H),7.02(d,J=8.5Hz,1H),6.5 9(d,J=2.4Hz,1H),3.70(dd,J=10.6,4.3Hz,1H),3.55(dd,J=10.6,6.3Hz,1H),3.48(ddd,J=10.8 ,7.2,4.5Hz,1H),3.13(dd,J=15.6,4.7Hz,1H),2.99(dd,J=15.6,8.1Hz,1H).MS / ESI+379.3[M+H] + .

[0231] Example 10 (S)-2-amino-3-(3-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol [ka] Step a) 3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzonitrile (10.1). To a 250 mL one-neck pear-shaped flask equipped with a magnetic stir bar and a condenser (air) was added 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). The suspension was heated to 65 °C and stirred for 19 h. Water / EtOAc was 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, adsorbed onto silica gel, 0-10% EtOAc in cyclohexane) gave 3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzonitrile (1.97 g, 95%) (10.1). UPLC retention time 1.11 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.44-8.41(m,1H),7.97(dd,J=8.6,2.4Hz,1H),7.57-7.53(m,2H),7.51-7.48( m,1H),7.43(tq,J=5.4,2.7Hz,1H),7.10(d,J=8.6Hz,1H).MS / ESI+265.0[M+H] + .

[0232] Step b) (Z)-N'-Hydroxy-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzimidamide (10.2). To a 100 mL one-neck pear-shaped flask equipped with a magnetic stir bar and a condenser (air) was added 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) in water (10.0 ml). The white suspension was stirred for 80 min at 85 °C. The reaction mixture was stored in the freezer over the weekend. EtOH was removed in vacuo. 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. Concentration in vacuo and drying under high vacuum gave (Z)-N'-hydroxy-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzimidamide (2.25 g, 100%) (10.2) as a brown sticky foam. UPLC retention time 0.80 min (Method A). 1 H NMR(400MHz,DMSO-d6)δ=ppm 9.69(s,1H),8.57(s,1H),8.24(dd,J=8.7,2.5Hz,1H),7.60(d,J=7.9Hz,1H),7.50-7.41(m ,2H),7.26(d,J=8.7Hz,1H),7.21(dd,J=8.0,1.7Hz,1H),5.84(s,2H).MS / ESI+298.2[M+H] + .

[0233] Step c) Benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (10.3). To a 20 mL microwave vial equipped with a magnetic stir bar was added (Z)-N'-hydroxy-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzimidamide (10.2) (758 mg, 2.55 mmol), Boc-Asp(Su)-OBzl (2.5) (1179 mg, 2.81 mmol), and 13.0 mL). The light brown solution was stirred at room temperature for 10 minutes, then at 110° C. for 17.5 hours. The solvent was removed in vacuo. Dichloromethane and silica gel were added. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 0-18% EtOAc in cyclohexane) afforded benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (1.40 g, 94%) (10.3%) as a colorless, viscous oil. UPLC retention time 1.41 min (Method A). 1 H NMR(400MHz,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=8.2,2.4,0.9Hz,1H),7.29-7.26(m,5H),7.08(d,J= 8.7Hz,1H),5.55(d,J=7.8Hz,1H),5.25-5.11(m,2H),4.92-4.84(d,J=7. 3Hz,1H),3.51(qd,J=16.2,5.0Hz,2H),1.42(s,9H).MS / ESI+585.3[M+H] + .

[0234] Step d) tert-Butyl (S)-(1-hydroxy-3-(3-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-2-yl)carbamate (10.4). To a 25 mL two-necked round-bottom flask equipped with a magnetic stir bar, a rubber septum, and a gas inlet was added benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (10.3) (550 mg, 0.941 mmol). The flask was evacuated and filled with Ar five times. THF (6.0 ml) was added, and the colorless solution was cooled to 0 °C. LiBH4 (41.0 mg, 1.882 mmol) was then added, and the reaction mixture was stirred for 80 min. Additional LiBH4 (20.5 mg, 0.941 mmol) was added after 50 min. The yellow suspension was quenched with MeOH. The volatiles were then removed in vacuo. Purification by column chromatography (ISCO CombiFlash Rf, 25-50% EtOAc in cyclohexane adsorbed onto silica gel) afforded tert-butyl (S)-(1-hydroxy-3-(3-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-2-yl)carbamate (298 mg, 65.9%) (10.4%) as a viscous, colorless oil. UPLC retention time 1.17 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.44-8.41(m,1H),7.96(d,J=7.8Hz,1H),7.92(dd,J=8.7,2.4Hz,1H),7. 88-7.82(m,1H),7.54(t,J=8.0Hz,1H),7.30(ddd,J=8.1,2.3,0.8Hz,1H), 7.06(d,J=8.7Hz,1H),5.28(d,J=7.7Hz,1H),4.23-4.12(m,1H),3.76(q,J =6.5,5.2Hz,2H),3.27(d,J=5.9Hz,2H),1.40(s,9H).MS / ESI+481.2[M+H] + .

[0235] Step e) (S)-2-Amino-3-(3-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol (Example 10). To a 25 mL one-neck pear-shaped flask equipped with a magnetic stirrer was added tert-butyl (S)-(1-hydroxy-3-(3-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-2-yl)carbamate (10.4) (297 mg, 0.618 mmol), dioxane (6.0 mL), and aqueous HCl (6.0 mL, 12.00 mmol). The cloudy solution was stirred at room temperature for 4 days, during which time a colorless, clear solution was obtained. 2 M aqueous NaOH (6.0 mL, 12.00 mmol) was added. The dioxane was removed in vacuo. EtOAc and approximately 0.2 M aqueous NaOH 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 onto silica gel, 0-7.7% MeOH in CHCl2) afforded (S)-2-amino-3-(3-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol (184 mg, 78%) (Example 10) as a colorless oil that crystallized to a white solid at room temperature. UPLC retention time 0.78 min (Method A). 1 H NMR(400MHz,CDCl3)δ=ppm 8.37(s,1H),7.91(t,J=7.6Hz,2H),7.81(s,1H),7.51(t,J=7.9Hz,1H),7.27(d,J=7.4Hz,1H),7.03 (d,J=8.6Hz,1H),3.70(d,J=8.3Hz,1H),3.59-3.45(m,2H),3.16-3.09(m,2H).MS / ESI+381.2[M+H] + .

[0236] Example 11 (S)-2-amino-3-(3-(3-((R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol [ka] Step a) 1-(3-Bromophenyl)-2-((2-iodopyridin-3-yl)oxy)ethan-1-one (11.3). To a 1000 mL one-neck flask equipped with a magnetic stir bar was added 2-chloropyridin-3-ol (10.90 g, 82 mmol), 2-bromo-1-(3-bromophenyl)ethanone (23.38 g, 82 mmol), acetone (330 mL), and cesium carbonate (32.2 g, 99 mmol). The orange suspension was stirred for 16 hours at room temperature. The reaction mixture was filtered, and the filter cake was washed with cold acetone. The filtrate was concentrated in vacuo to give 33.31 g of crude material, which was taken up in ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 29.8 g of a brown, sticky mass. Chromatography on silica gel (cyclohexane / ethyl acetate) gave 1-(3-bromophenyl)-2-((2-iodopyridin-3-yl)oxy)ethan-1-one (9.1 g, 23%) (11.3%). UPLC retention time 1.07 min (Method A). 1 H NMR(400MHz,chloroform-d)δ=ppm ppm 5.34(s,2H)7.14-7.21(m,2H),7.41(t,J=7.85Hz,1H),7.78(d,J=7.73Hz,1H),7.95(dt,J=7. 82,1.28Hz,1H),8.07(dd,J=4.28,1.96Hz,1H),8.16(t,J=1.71Hz,1H).MS / ESI+326,328,330.

[0237] Step b) (R)-1-(3-Bromophenyl)-2-((2-iodopyridin-3-yl)oxy)ethan-1-ol (11.5). To a 1000 mL two-neck flask equipped with a magnetic stirrer and a thermometer was added 1-(3-bromophenyl)-2-((2-iodopyridin-3-yl)oxy)ethan-1-one (11.3) (5.22 g, 15.18 mmol), followed by 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) was added. The reaction mixture was degassed with argon for 20 minutes at 0 °C. Formic acid-triethylamine complex 5:2 (4.66 ml, 11.16 mmol, CAS: 115077-13-1) was added over 15 minutes at 0 °C. Stirring was continued at 0 °C for 50 minutes. The reaction mixture was then poured into water (230 ml), extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give (R)-1-(3-bromophenyl)-2-((2-iodopyridin-3-yl)oxy)ethan-1-ol (5.45 g, 100%) (11.5). This material was used in the next step without further purification. UPLC retention time 0.99 minutes (Method A). 1 H NMR(400MHz,chloroform-d)δ=ppm ppm 4.06(dd,J=9.29,8.31Hz,1H),4.19(dd,J=9.41,3.42Hz,1H),5.18(dd,J=8.25,3.36Hz,1H),7.17-7.26(m,2H),7.28 -7.31(m,1H),7.41(d,J=7.70Hz,1H),7.49(d,J=7.95Hz,1H),7.66(s,1H),7.99-8.11(m,1H).MS / ESI+328,330,332.

[0238] Step c) (R)-3-(3-Bromophenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (11.6). To a 500 mL two-neck flask equipped with a magnetic stirrer and a reflux condenser was added (R)-1-(3-bromophenyl)-2-((2-iodopyridin-3-yl)oxy)ethan-1-ol (11.5) (5.45 g, 15.76 mmol), followed by DME (197 mL). 1 M KHMDS in THF (15.95 mL, 15.95 mmol, [CAS: 40949-94-8]) was added dropwise at 60 °C under argon. The reaction mixture was stirred at this temperature for 1.5 h. Additional 1 M KHMDS in THF (3 mL) was added at 60 °C, and stirring was continued for an additional 60 min. The reaction mixture was quenched with water (100 mL) at room temperature, extracted with ethyl acetate, thoroughly washed with water, saturated aqueous NH4Cl, and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (gradient: cyclohexane / ethyl acetate) afforded (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). 1 H NMR(400MHz,DMSO-d6)δ=ppm 4.16(dd,J=11.62,8.19Hz,1H),4.49(dd,J=11.55,2.51Hz,1H),5.49(dd,J=8.01,2.26Hz,1H),7.00(dd,J=7.82,4.77Hz,1H),7.37(d,J=7.63 Hz,1H),7.42(t,J=7.95Hz,1H),7.52(d,J=7.70Hz,1H),7.61(d,J=8.07Hz,1H),7.72(s,1H),7.81(dd,J=4.77,1.34Hz,1H).MS / ESI+292,294.

[0239] Step d) (R)-3-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)benzonitrile (11.7). To a 100 mL two-neck flask equipped with a magnetic stirrer and a reflux condenser was added (R)-3-(3-bromophenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (11.6) (1.158 g, 3.96 mmol), followed by DMF (21 mL). Zinc cyanide (1.862 g, 15.86 mmol), 1,1'-bis(diphenylphosphino)ferrocene (1.758 g, 3.17 mmol, [CAS: 12150-46-8]), and Pd2(dba)3 (0.726 g, 0.793 mmol) were added, and the reaction mixture was degassed with argon. The mixture was stirred at 80° C. for 20 hours under argon. The cold reaction mixture was diluted with ethyl acetate (250 ml), washed twice with 5% sodium bicarbonate solution, water, and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (gradient: cyclohexane / ethyl acetate) afforded (R)-3-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)benzonitrile (750 mg, 79%) (11.7). UPLC retention time: 0.86 min (Method A). 1 H NMR(400MHz,DMSO-d6)δ=ppm 4.19(dd,J=11.55,8.13Hz,1H),4.52(dd,J=11.55,2.51Hz,1H),5.56(dd,J=8.07,2.20Hz,1H),7.01(dd,J=7.82,4. 77Hz,1H),7.38(dd,J=7.89,1.53Hz,1H),7.68(t,J=7.48Hz,1H),7.81-7.91(m,3H),7.98(s,1H).MS / ESI+239[M+H] + .

[0240] Step e) (R,Z)-3-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-N'-hydroxybenzimidamide (11.8). To a 50 mL two-neck flask equipped with a magnetic stirrer and a reflux condenser was added (R)-3-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)benzonitrile (11.7) (380 mg, 1.59 mmol) and ethanol (7 mL). 50% aqueous hydroxylamine (0.376 mL, 6.38 mmol) was added dropwise, and the reaction mixture was refluxed for 3.5 hours to give a clear solution. The mixture was extracted twice with dichloromethane and concentrated in vacuo to give crude (R,Z)-3-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-N'-hydroxybenzimidamide (477 mg, 85%) (11.8), which was used in the next step without further purification. A small amount of the probe (51 mg) was purified by SFC to give 38 mg of a light brown foam. UPLC retention time 0.54 min (Method A). 1 H NMR(400MHz,chloroform-d)δ=ppm 2.30(br s,4H),4.02(dd,J=11.68,8.86Hz,1H),4.41(dd,J=11.62,2.45Hz,1H),5.09(br s,2H),5.36(dd,J=8.80,2.20Hz,1H),6.94(dd,J=7.82,4.77Hz,1H),7.26(br s,1H),7.44-7.57(m,2H),7.68(d,J=7.70Hz,1H),7.78(s,1H),7.90(dd,J=4.71,1.53Hz,1H).MS / ESI+272[M+H] + .

[0241] Step f) Benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-((R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (11.9). A 50 mL two-neck flask equipped with a magnetic stirrer and reflux condenser was charged with (R,Z)-3-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-N'-hydroxybenzimidamide (11.8) (477 mg, 1.35 mmol) and 2-Me-THF (13.5 mL), followed by Boc-Asp(OSu)-OBzl (2.5) [CAS 140171-25-1] (655 mg, 1.55 mmol, Bachem). The reaction mixture was refluxed for 2 days. The solvent was evaporated on a rotavap to give 1.30 g of crude product. Chromatography on silica gel (gradient: cyclohexane / ethyl acetate) afforded benzyl (S)-2-((tert-butoxycarbonyl)-amino)-3-(3-(3-((R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (374 mg, 45.5%) (11.9%). UPLC retention time: 1.27 min (Method A). 1 H NMR(400MHz,chloroform-d)δ=ppm 1.27(s,2H),1.44(s,11H),1.60(br s,3H),3.51(br d,J=4.89Hz,2H),4.06(dd,J=11.68,8.86Hz,1H),4.43(dd,J=11.61,2.32Hz,1H),4.90(br s,1H),5.14-5.27(m,3H),5.36-5.44(m,1H,)5.47-5.63(m,1H),6.95(dd,J=7.89,4.83Hz,1H),7.29(br s,3H),7.35(s,2H),7.55(t,J=7.76Hz,1H),7.66(br d,J=7.70Hz,1H),7.91(dd,J=4.77,1.34Hz,1H),8.03(d,J=7.70Hz,1H),8.09(s,1H).MS / ESI+559[M+H] + .

[0242] Step g) tert-Butyl ((S)-1-(3-(3-((R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (11.10). A 100 mL single-neck flask equipped with a magnetic stir bar was charged with benzyl (S)-2-((tert-butoxycarbonyl)-amino)-3-(3-(3-((R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (11.9) (350 mg, 0.627 mmol) and THF (8.3 mL). At 0°C, lithium borohydride (54.6 mg, 2.506 mmol) was added, and the cooling bath was removed after 10 min. After stirring at room temperature for 7 h, 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 in vacuo. Chromatography on silica gel (gradient: cyclohexane / ethyl acetate) afforded tert-butyl ((S)-1-(3-(3-((R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (63 mg, 22%) (11.10). UPLC retention time: 0.96 min (Method A). 1 H NMR(400MHz,chloroform-d)δ=ppm 1.44(s,9H),3.31(br d,J=6.11Hz,2H),3.83(t,J=4.22Hz,2H),4.07(dd,J=11.68,8.86Hz,1H),4.21(br s,1H),4.45(dd,J=11.68,2.51Hz,1H),5.13-5.27(m,1H),5.42(dd,J=8.80,2.32Hz,1H),6.95(dd,J=7.89,4.83Hz,1H),7.28-7.30(m,1 H),7.56(t,J=7.76Hz,1H),7.66(d,J=7.82Hz,1H),7.91(dd,J=4.77,1.59Hz,1H),8.10(d,J=7.70Hz,1H),8.17(s,1H).MS / ESI+455[M+H] + .

[0243] Step h) (S)-2-Amino-3-(3-(3-((R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol (Example 11) A 25 mL single-neck flask equipped with a magnetic stirrer was charged with tert-butyl ((S)-1-(3-(3-((R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (11.10) (46 mg, 0.101 mmol) and dioxane (1 mL). 2 M HCl in dioxane (0.506 mL, 1.012 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, and the remaining white solid was triturated twice with dichloromethane and evaporated. The crude white powder was triturated twice with ethyl ether in an ultrasonic bath and decanted to give (S)-2-amino-3-(3-(3-((R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol hydrochloride salt (38 mg, 99%) (Example 11) as a white powder. UPLC retention time 0.59 min (Method A). 1 H NMR(400MHz,DMSO-d6)δ=ppm 3.29-3.47(m,2H),3.59-3.79(m,3H),4.17(dd,J=11.55,8.25Hz,1H),4.55(br dd,J=11.61,2.45Hz,2H),5.62(dd,J=8.13,2.14Hz,1H),7.02(dd,J=7.82,4.77Hz,1H),7.40(dd,J=7.82,1 .59Hz,1H),7.64-7.76(m,2H),7.83(dd,J=4.77,1.47Hz,1H),8.06(d,J=7.70Hz,1H),8.18(s,1H),8.29(br s,3H).MS / ESI+355[M+H] + .

[0244] Example 12 (S)-2-amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol [ka] Step a) (Z)-4-((5-chloro-3-fluoropyridin-2-yl)oxy)-N'-hydroxybenzimidamide (12.1). To a 100 mL one-neck flask equipped with a magnetic stir bar and a condenser (air) was added 26.3 (2.82 g, 11.34 mmol), NaHCO (4.76 g, 56.7 mmol), hydroxylamine hydrochloride (3.94 g, 56.7 mmol), ethanol (40 ml), and water (15 ml) (Caution: gas formation). The white suspension was heated to 85 °C and stirred for 100 min. It was then cooled to 25 °C. The ethanol was removed in vacuo. Water and ethyl acetate were added, and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over NaSO, and the solvent was removed to give 12.1 as a colorless solid (3.18 g, 97%). UPLC retention time: 0.73 min (Method A). 1 H 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] + .

[0245] Step b) (S)-Benzyl 2-((tert-butoxycarbonyl)amino)-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (12.3). A 20 mL microwave vial equipped with a magnetic stir bar was charged with 12.1 (0.60 g, 2.066 mmol), 12.2 (0.985 g, 2.343 mmol), and THF (13 ml). The colorless solution was stirred for 30 min at 25° C. It was then heated to 110° C. and stirred for 15 h. The solvent was removed in vacuo. Chromatography on silica (gradient: cyclohexane / ethyl acetate) afforded 12.3 as a colorless oil (829 mg, 71%). UPLC retention time 1.41 min (Method A). 1 H 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] + .

[0246] Step c) (S)-tert-Butyl (1-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (12.4). To a 25 mL two-neck round-bottom flask equipped with a magnetic stir bar, a gas inlet, and a rubber septum was added 12.3 (474 ​​mg, 0.833 mmol). The flask was evacuated and filled with argon three times. Dry THF (8.0 mL) was added, and the solution was cooled to 0 °C. LiBH (91 mg, 4.17 mmol) was added in one portion, and the suspension was stirred for 1.5 h. The reaction mixture was quenched with methanol. The solvent was removed, and the crude product was dissolved in dichloromethane and adsorbed onto silica. Chromatography on silica (gradient: cyclohexane / ethyl acetate) gave 12.4 as a viscous colorless oil (229 mg, 58%). UPLC retention time 1.17 min (Method A). 1H NMR(400MHz,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] + .

[0247] Step d) (S)-2-Amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol (Example 12). A 25 mL pear-shaped flask equipped with a magnetic stirrer was charged with 12.4 (225 mg, 0.484 mmol), CHCl (5.0 mL), and TFA (0.186 mL, 2.42 mmol). The colorless solution was stirred for 65 h at 25 °C. 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 NaSO, filtered, and concentrated. Purification on silica (gradient: CHCl / MeOH) gave the product Example 12 as a colorless oil, which slowly solidified at 25 °C (64 mg, 36%). UPLC retention time 0.74 min (Method A). 1 H 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). OH and NH2 were not observed. ES / ESI 365.2 [M+H] + .

[0248] Example 13 (S)-3-(3-(4-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-2-aminopropan-1-ol [ka] 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 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 (gradient: cyclohexane / ethyl acetate) to give compound 13.3 as a colorless solid (3.30 g, 84%). UPLC retention time 1.10 min (Method A). 1 H 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] + .

[0249] Step b) 4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)benzonitrile (13.5). To a 250 mL two-necked round-bottom flask equipped with a magnetic stir bar, a rubber septum, and a gas inlet was added 13.3 (3.23 g, 11.74 mmol), KPO (7.48 g, 35.2 mmol), 13.4 (3.92 g, 14.1 mmol), Pd(PPh) (0.678 g, 0.587 mmol), and toluene (70 mL). The suspension was purged with argon for 15 min. The gas inlet was replaced with a reflux condenser, and the reaction mixture was heated to 110 °C and stirred for 2 h. The suspension was cooled to 25 °C and then stored in a freezer for 16 h. 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 removed. Chromatography on silica (gradient: cyclohexane / ethyl acetate) and crystallization from ethyl acetate gave compound 13.5 as a colorless solid (1.54 g, 38%). 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] + .

[0250] Step c) (Z)-N'-Hydroxy-4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)benzimidamide (13.6). To a 100 mL one-neck flask equipped with a magnetic stir bar was added hydroxylamine hydrochloride (1.54 g, 22.1 mmol), NaHCO (1.86 g, 22.1 mmol), and water (10 ml). The colorless suspension (Caution: gas formation) was stirred for 5 min at 25 °C. Compound 13.5 (1.53 g, 4.42 mmol) and ethanol (25 ml) were added, and the reaction mixture was stirred for 90 min at 85 °C. 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 NaSO. The solvent was removed and the residue was purified on silica (gradient: cyclohexane / ethyl acetate) to give compound 13.6 as a colorless solid (1.62 g, 97%). UPLC retention time 0.71 min (Method A). 1 H 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] + .

[0251] Step d) (2S)-Benzyl 2-((tert-butoxycarbonyl)amino)-3-(3-(4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (13.8). To a 50 mL two-neck round-bottom flask equipped with a magnetic stir bar, reflux condenser, and rubber septum was added 13.6 (1.31 g, 3.45 mmol), 13.7 (1.60 g, 3.80 mmol), and THF (20 ml). The colorless solution was stirred for 30 min at 25 °C and then heated to 90 °C for 7 days. The solvent was removed and the residue was purified on silica (gradient: cyclohexane / ethyl acetate) to give 13.8 as a mixture of epimers (1.68 g, 73%), which was used in the next step. UPLC retention time 1.39 min (Method A). MS / ESI 667.4 [M+H] + .

[0252] Step e) tert-Butyl ((2S)-1-hydroxy-3-(3-(4-((5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-2-yl)carbamate (13.9). To a 25 mL two-neck round-bottom flask equipped with a magnetic stir bar, a gas inlet, and a rubber septum was added 13.8 (634 mg, 0.951 mmol). The flask was evacuated and filled with argon three times. Dry THF (5.0 mL) was added and the colorless solution was cooled to 0° C. Lithium borohydride (104 mg, 4.75 mmol) was added and the suspension was stirred for 1 h. The reaction mixture was quenched with methanol. The solvent was removed and the crude product was dissolved in dichloromethane and purified on silica (gradient: cyclohexane / ethyl acetate) to give 13.9 (white solid) as a mixture of epimers (276 mg, 52%), which was used in the next step. UPLC retention time 1.14 min (Method A). MS / ESI 563.4 [M+H] + .

[0253] Step f) (S)-3-(3-(4-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-2-aminopropan-1-ol (Example 13). To a 25 mL single-neck round-bottom flask equipped with a magnetic stir bar was added 13.9 (276 mg, 0.491 mmol), dioxane (5.0 mL), and aqueous HCl (5.0 mL, 10.00 mmol, 2 M solution). The cloudy solution was stirred for 18 h at 25 °C. Dioxane and water were removed, and the residue was purified by RP C18 column chromatography (ISCO CombiFlash Rf, liquid injection, 10-35% MeCN in water). Acetonitrile was removed, and the aqueous phase was basified 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 as a colorless solid (112 mg, 60%). UPLC retention time 0.59 min (Method A). 1 H 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] + .

[0254] Example 14 (S)-2-amino-3-(5-(3-((R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl)-2H-tetrazol-2-yl)propan-1-ol [ka] Step a) (R)-3-(3-(2H-tetrazol-5-yl)phenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (14.1). A suspension of (R)-3-(2,3-dihydro-[1,4]dioxino[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 for 21.5 h. The cold reaction mixture was diluted with methanol (50 ml) and concentrated in vacuo. The crude product was triturated with diethyl ether / dichloromethane (1:1) supplemented with a small amount of methanol and filtered. The solid was washed with diethyl ether / dichloromethane (1:1) and dried to give (R)-3-(3-(2H-tetrazol-5-yl)phenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (386 mg, 65.4%) (14.1) as a light brown powder. UPLC retention time: 0.70 min (Method A). 1 H NMR(400MHz,DMSO-d6)δ=ppm 2.99-3.66(m,4H),4.17(dd,J=11.62,8.31Hz,1H),4.55(dd,J=11.62,2.45Hz,1H),5.61(dd,J=8.19,2.20Hz,1H),7.02(dd,J=7.95,4. MS / ESI + 282[M+H] + .

[0255] Step b) Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(5-(3-((R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl)-2H-tetrazol-2-yl)propanoate (14.3). To a solution of (R)-3-(3-(2H-tetrazol-5-yl)phenyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (14.1) (336 mg, 0.729 mmol) in THF (14.6 mL) was added 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) under nitrogen at 0 °C. The resulting mixture was stirred at room temperature for 4.5 h. Isolute was added, the mixture was concentrated in vacuo, 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]dioxino[2,3-b]pyridin-3-yl)phenyl)-2H-tetrazol-2-yl)propanoate (490 mg, 98%) (14.3%). UPLC retention time 1.09 min (Method A). 1 H NMR(400MHz,chloroform-d)δ=ppm 1.44(s,9H),3.80(s,7H),3.95(dd,J=11.43,3.73Hz,4H),4.04-4.17(m,2H),4.34-4.49(m,1H),4.91(br s,1H),5.05-5.22(m,1H),5.27-5.50(m,4H),6.95(dd,J=7.89,4.83Hz,1H),7.28-7.32(m,1H) ,7.52-7.65(m,2H),7.91(dd,J=4.77,1.59Hz,1H),8.15(d,J=7.58Hz,1H),8.24(s,1H).MS / ESI + 483[M+H] + .

[0256] Step c) tert-Butyl ((S)-1-(5-(3-((R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl)-2H-tetrazol-2-yl)-3-hydroxypropan-2-yl)carbamate (14.4). At 0° C., LiBH (3.54 mL 2 molar THF solution, 7.09 mmol) was added dropwise to a solution of methyl (S)-2-((tert-butoxycarbonyl)-amino)-3-(5-(3-((R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl)-2H-tetrazol-2-yl)propanoate (14.3) (950 mg, 1.772 mmol) in THF (17.7 mL), and the mixture was stirred at 0° C. overnight. The mixture was cooled to 0° C. and quenched with water and 1 M hydrochloric acid to a pH of about 7. The mixture was diluted with dichloromethane, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified on silica gel (ethyl acetate / cyclohexane) to give tert-butyl ((S)-1-(5-(3-((R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl)-2H-tetrazol-2-yl)-3-hydroxypropan-2-yl)carbamate (264 mg, 32%) (14.4). UPLC retention time: 0.94 min (Method A). 1 H NMR(400MHz,chloroform-d)δ=ppm 1.42(s,10H),3.75(t,J=4.95Hz,2H),4.08(dd,J=11.61,8.80Hz,1H),4.27(br s,1H),4.46(dd,J=11.62,2.45Hz,1H),4.91(br d,J=5.87Hz,2H),5.08-5.20(m,1H),5.43(dd,J=8.86,2.26Hz,1H),6.95(dd,J=7.82,4.77Hz,1H),7.28-7 .30(m,1H),7.53-7.63(m,2H),7.90(dd,J=4.83,1.53Hz,1H),8.17(d,J=7.46Hz,1H),8.25(s,1H).MS / ESI + 455[M+H] + .

[0257] Step d) (S)-2-Amino-3-(5-(3-((R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl)-2H-tetrazol-2-yl)propan-1-ol (Example 14). To a solution of tert-butyl ((S)-1-(5-(3-((R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl)-2H-tetrazol-2-yl)-3-hydroxypropan-2-yl)carbamate (14.4) (230 mg, 0.506 mmol) in dioxane (5.06 mL) was added hydrochloric acid in dioxane (1.265 ml, 5.06 mmol, 4 M solution) at 0° C. under nitrogen. The reaction mixture was stirred at room temperature over the weekend and then concentrated in vacuo. The resulting solid was triturated three times with diethyl ether and lyophilized from water / acetonitrile to give (S)-2-amino-3-(5-(3-((R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl)-2H-tetrazol-2-yl)propan-1-ol (206 mg, 100%) (Example 14) as the HCl salt. UPLC retention time 0.58 min (Method A). 1 H NMR(400MHz,DMSO-d6)δ=ppm 3.60-3.68(m,1H),3.70-3.76(m,2H),4.12-4.23(m,2H),4.56(br d,J=11.74Hz,1H),4.91-5.14(m,2H),5.63(br d,J=7.95Hz,1H),6.96-7.07(m,1H),7.40(br d,J=7.70Hz,1H),7.64-7.74(m,2H),7.83(br d,J=3.55Hz,1H),8.12(br d,J=6.97Hz,1H),8.24(br s,1H),8.34(br s,3H).MS / ESI + 355[M+H] + .

[0258] Example 15 (S)-2-amino-3-(3-(3-((R)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol [ka] (S)-2-Amino-3-(3-(3-((R)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol (Example 15) was prepared by a procedure similar to that used in the synthesis of Example 1, substituting the chiral sulfonamide for its S,S-enantiomer [CAS: 167316-27-7]. Example 15 was isolated as the free base. UPLC retention time 0.76 min (Method A). 1 H NMR(400MHz,chloroform-d)δ=ppm ppm 1.82(br.s.,3H),3.02(dd,J=15.59,8.01Hz,1H),3.16(dd,J=15.53,4.65Hz,1H),3.47-3.61(m,2H),3.73(dd,J=10.45,4.22Hz,1H),4.07(dd,J=1 1.49,8.93Hz,1H),4.42(dd,J=11.49,2.45Hz,1H),5.22(dd,J=8.86,2.2 6Hz,1H),6.88-7.06(m,4H),7.53-7.64(m,2H),8.07-8.19(m,2H).MS / ESI + 354[M+H] + .

[0259] Example 16 (S)-2-amino-3-(3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol [ka] Step a) 4-((5-chloropyridin-2-yl)oxy)-N-hydroxybenzimidamide (16.1). To a 100 mL single-neck round-bottom flask equipped with a magnetic stir bar and a condenser (open air) were added hydroxylamine hydrochloride (3.89 g, 55.9 mmol), NaHCO3 (4.70 g, 55.9 mmol), and water (8 mL). The white suspension (Caution: Gas Formation) was stirred 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 room temperature and stored in the freezer for 2 days. EtOH was removed in vacuo, 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. Concentration in vacuo afforded 4-((5-chloropyridin-2-yl)oxy)-N-hydroxybenzimidamide (2.91 g, 99%) (16.1) as a white solid. UPLC retention time 0.65 min (Method A). 1 H NMR(400MHz,DMSO-d6)δ=9.60(s,1H),8.21(d,J=2.3Hz,1H),7.97(dd,J=8.8,2.7Hz,1H) ,7.70(d,J=8.8Hz,2H),7.14(d,J=8.7Hz,2H),7.12(d,J=8.7Hz,1H),5.81(s,2H).MS / ESI + 264.1, 266.1[M+H] + .

[0260] Step b) Benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (16.2). To a 20 mL microwave vial equipped with a magnetic stir bar was added 4-((5-chloropyridin-2-yl)oxy)-N-hydroxybenzimidamide (16.1) (1.45 g, 5.50 mmol), Boc-Asp(OSu)-OBzl (2.5) (2.54 g, 6.05 mmol), and THF (15 ml). The vial was sealed, and the colorless solution was stirred for 7 h at room temperature. Complete conversion to the ester occurred within 6 h. The reaction mixture was stored in the freezer overnight. It was then heated to 120 °C and stirred for 5 h. The resulting yellow solution was cooled to room temperature and the THF was removed in vacuo to give a yellow oil. Column chromatography (absorbed onto silica gel, 0-25% EtOAc in cyclohexane) afforded benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (2.94 g, 97%) (16.2%) as a pale yellow sticky foam. UPLC retention time 1.39 min (Method A). 1 H NMR(400MHz,CDCl3)δ=8.15(d,J=2.4Hz,1H),8.04(d,J=8.8Hz,2H),7.69(dd,J=8.7,2.7Hz,1H),7.30-7.28(m,5H),7.22(d,J=8.8Hz,2H) ,6.95(d,J=8.7Hz,1H),5.58(d,J=8.0Hz,1H),5.20(d,J=2.7Hz,2H),4.93-4.86(m,1H),3.51(qd,J=16.2,5.0Hz,2H),1.44(s,9H).MS / ESI + 551.2, 553.2[M+H] + .

[0261] Step c) tert-Butyl (S)-(1-(3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (16.3). To a 25 mL two-neck round-bottom flask equipped with a magnetic stir bar was added benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (16.2) (0.681 g, 1.236 mmol). The flask was evacuated and filled with Ar three times. Dry THF (5.0 ml) was added and the solution was cooled to 0 °C. LiBH (0.081 g, 3.71 mmol) was added to the reaction mixture, which was stirred for 45 min. The suspension was filtered and CHCl was added. It was stored in the freezer overnight. Silica gel was added (Caution: gas formation). Column chromatography (ISCO CombiFlash Rf, 0-50% EtOAc in cyclohexane) afforded tert-butyl (S)-(1-(3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (0.272 g, 49.2%) (16.3) as a white foam. UPLC retention time 1.11 min (Method A). 1 H NMR(400MHz,CDCl3)δ=8.15(d,J=2.6Hz,1H),8.10(d,J=8.7Hz,2H),7.69(dd,J=8.7,2.6Hz,1H),7.23(d,J=8.7Hz,2H),6.95(d,J=8.7Hz,1H),5.23(s MS / ESI + 447.3, 449.3 [M+H] + .

[0262] Step d) (S)-2-Amino-3-(3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol (Example 16). To a 50 mL one-neck round-bottom flask equipped with a magnetic stirrer was added tert-butyl (S)-(1-(3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (16.3) (0.270 g, 0.604 mmol), dichloromethane (8 ml), and TFA (0.233 ml, 3.02 mmol). The colorless solution was stirred at room temperature for 6 days. Slow reaction: no complete conversion within 2 days. Also, formation of a by-product. Silica gel and additional dichloromethane were added. The solvent was then removed in vacuo. Purification by column chromatography (ISCO CombiFlash Rf, adsorbed onto silica gel, 0-10% MeOH in CH2Cl2) afforded (S)-2-amino-3-(3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol (0.147 g, 70.2%) (Example 16) as a white solid. UPLC retention time 0.73 min (Method A). 1 H NMR(400MHz,DMSO-d6)δ=8.25(d,J=2.5Hz,1H),8.07(d,J=8.7Hz,2H),8.03(dd,J=8.8,2.7Hz,1H),7.35(d,J=8.7H MS / ESI + 347.1, 349.1[M+H] + .

[0263] Example 17 (S)-2-amino-3-(3-(4-(((R)-1-phenylpropan-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol [ka] Step a) (R)-4-((1-phenylpropan-2-yl)oxy)benzonitrile (17.2). To a 50 mL single-neck round-bottom flask equipped with a magnetic stir bar was added (S)-1-phenylpropan-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). After complete dissolution of all solids, DIAD (1.836 ml, 9.44 mmol) was added. The yellow solution (Caution: Becomes very warm) was stirred for 3.5 hours at room temperature. It was then stored in the freezer over the weekend. The solvent was removed in vacuo. Diisopropyl ether and cyclohexane were added, and the yellow solution was filtered through a silica pad (to remove some Ph3PO). The solution was concentrated in vacuo to give a strong yellow oil. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 0-5% EtOAc in cyclohexane, several fractions) gave (R)-4-((1-phenylpropan-2-yl)oxy)benzonitrile (0.954 g, 55.4%) (17.2). UPLC retention time 1.24 min (Method A). 1 H 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). No MS / ESI ionization was observed [M+H]. + TLC R f = 0.32 (cyclohexane / ethyl acetate 10:1, silica gel).

[0264] Step b) (R,Z)-N'-Hydroxy-4-((1-phenylpropan-2-yl)oxy)benzimidamide (17.3). To a 50 mL one-neck round-bottom flask equipped with a magnetic stirrer and a condenser (air) were added hydroxylamine hydrochloride (1.397 g, 20.10 mmol), NaHCO3 (1.689 g, 20.10 mmol), and water (5.0 ml). The suspension (Caution: Gas Formation) was stirred for 10 min at room temperature. Afterwards, (R)-4-((1-phenylpropan-2-yl)oxy)benzonitrile (17.2) (0.954 g, 4.02 mmol) in EtOH (15 ml) was added, and the reaction mixture was heated to 85 °C. It was stirred for 100 min. The white suspension was then stored in the freezer overnight. EtOH was removed in vacuo, and water / EtOAc was added. The aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over Na2SO4. Concentration in vacuo gave a pale yellow oil. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 0–50% EtOAc in cyclohexane, several fractions) gave (R,Z)-N'-hydroxy-4-((1-phenylpropan-2-yl)oxy)benzimidamide (0.976 g, 90%) (17.3) as a cloudy oil. UPLC retention time 0.81 min (Method A). 1 H NMR(400MHz,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 =6.1Hz,1H),3.11(dd,J=13.7,5.9Hz,1H),2.85(dd,J=13.7,6.6Hz,1H),1.33(d,J=6.1Hz,3H).MS / ESI + 271.2[M+H] + .

[0265] Step c) Benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-(((R)-1-phenylpropan-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (17.4). To a 20 mL microwave vial equipped with a magnetic stir bar was added (R,Z)-N'-hydroxy-4-((1-phenylpropan-2-yl)oxy)benzimidamide (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). The colorless solution was stirred for 2 h at room temperature. Complete consumption within 105 min by LC-MS analysis. The reaction mixture was then heated to 120 °C and stirred for 3 h. EtOAc was then added to the pale yellow solution, and the mixture was stored in the freezer over the weekend. The solvent was removed in vacuo. Dichloromethane and silica gel were added. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 0-15% EtOAc in cyclohexane) afforded benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-(((R)-1-phenylpropan-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (0.814 g, 81%) (17.4%) as a "gray" oil. UPLC retention time 1.48 min (Method A). 1 H NMR(400MHz,CDCl3)δ=7.94-7.88(m,2H),7.34-7.22(m,10H),6.97-6.92 (m,2H),5.60(d,J=8.1Hz,1H),5.25-5.12(m,2H),4.95-4.83(m,1H),4.68 (dt,J=12.3,6.1Hz,1H),3.59-3.39(m,2H),3.12(dd,J=13.7,5.9Hz,1H),2.87(dd,J=13.7,6.5Hz,1H),1.44(s,9H),1.35(d,J=6.1Hz,3H).MS / ESI + 558.4[M+H] + .

[0266] Step d) Benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-(((R)-1-phenylpropan-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (17.5). To a 10 mL two-neck conical flask equipped with a magnetic stir bar, a rubber septum, and a gas inlet was added benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-(((R)-1-phenylpropan-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (17.4) (0.443 g, 0.794 mmol). The vial was evacuated and backfilled with Ar three times. Dry THF (3.0 ml) was added, and the solution was cooled to 0 °C. LiBH4 (0.087 g, 3.97 mmol) was then added in one portion, and the suspension was stirred for 45 min. The reaction was quenched with MeOH. The solvent was removed in vacuo. Dichloromethane and silica gel were added. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 0-50% and 0-50% EtOAc in cyclohexane) twice gave benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-(((R)-1-phenylpropan-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (0.168 g, 46.6%) (17.5%). UPLC retention time 1.24 min (Method A). 1 H NMR(400MHz,CDCl3)δ=7.96(d,J=8.8Hz,2H),7.34-7.20(m,5H),6.96(d,J= 8.8Hz,2H),5.29-5.19(m,1H),4.67(h,J=6.2Hz,1H),4.23-4.14(m,1H),3. 86-3.74(m,2H),3.34-3.19(m,2H),3.11(dd,J=13.7,5.9Hz,1H),2.87(dd, J=13.7,6.5Hz,1H),2.73(s,1H),1.43(s,9H),1.34(d,J=6.1Hz,3H).MS / ESI + 454.3[M+H] + .

[0267] Step e) (S)-2-Amino-3-(3-(4-(((R)-1-phenylpropan-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol (Example 17). To a 10 mL single-neck pear-shaped flask equipped with a magnetic stir bar was added benzyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4-(((R)-1-phenylpropan-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propanoate (17.5) (0.168 g, 0.370 mmol), DCM (4.0 mL), and TFA (0.143 mL, 1.852 mmol). The colorless solution was stirred at room temperature for 3 days, during which time the solution turned orange. The solvent and acid were removed in vacuo. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 0-10% MeOH in CHCl). The product was purified again under the same conditions to give (S)-2-amino-3-(3-(4-(((R)-1-phenylpropan-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol (0.108 g, 78%) (Example 17) as a colorless oil. UPLC retention time 0.84 min (Method A). 1 H NMR(400MHz,CDCl3)δ=7.86(d,J=8.8Hz,2H),7.30-7.19(m,5H),6.89(d,J=8.9Hz,2H),4.61(h,J=6.1Hz,1H),3.97(d,J=9.1Hz,1H),3.90-3.83( MS / ESI + 354.3[M+H] + .

[0268] Example 18 (3S)-3-amino-4-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)butan-2-ol [ka] Step a) 4-((5-Bromo-3-fluoropyridin-2-yl)oxy)-N-hydroxybenzimidamide (18.1). To a 50 mL one-neck pear-shaped flask equipped with a magnetic stirrer and a condenser (air) was added 4-((5-Bromo-3-fluoropyridin-2-yl)oxy)benzonitrile (7.2) (763 mg, 2.60 mmol), hydroxylamine hydrochloride (905 mg, 13.02 mmol), NaHCO (1093 mg, 13.02 mmol), and EtOH (15.0) in water (5.0 mL). The white suspension was stirred for 80 min at 85 °C. EtOH was removed in vacuo. Water and EtOAc were added. The aqueous phase was extracted twice with EtOAc. The organic layers were washed with brine, combined, and dried over NaSO. Concentration in vacuo gave 4-((5-bromo-3-fluoropyridin-2-yl)oxy)-N-hydroxybenzimidamide (0.849 g, 98%) (18.1) as a white solid. UPLC retention time 0.75 min (Method A). MS / ESI + 326.2, 328.2[M+H] + .

[0269] Step b) Benzyl (S)-3-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-2-((tert-butoxycarbonyl)amino)propanoate (18.2). To a 20 mL microwave vial equipped with a magnetic stir bar was added 4-((5-bromo-3-fluoropyridin-2-yl)oxy)-N-hydroxybenzimidamide (18.1) (470 mg, 1.441 mmol), Boc-Asp(OSu)-OBzl (2.5) (666 mg, 1.585 mmol), and THF (13.0 ml). The solution was stirred for 16 hours at 110° C. A suspension was obtained. The volatiles were removed in vacuo. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 0-16% EtOAc in cyclohexane) afforded benzyl (S)-3-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-2-((tert-butoxycarbonyl)amino)propanoate (433 mg, 49%) (18.2%). UPLC retention time 1.44 min (Method A). 1 H NMR(400MHz,CDCl3)δ=8.05-8.01(m,2H),7.99(d,J=2.1Hz,1H),7.66(dd,J=8.8,2.1Hz,1H),7.28-7.21(m,7H) ),5.56(d,J=7.7Hz,1H),5.23-5.12(m,2H),4.91-4.83(m,1H),3.49(qd,J=16.3,5.1Hz,2H),1.42(s,9H).19F NMR(376MHz,CDCl3)δ=-132.98.MS / ESI + 613.3,615.3[M+H] + .

[0270] Step c) tert-Butyl (S)-(1-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (18.3). To a 25 mL two-neck round-bottom flask equipped with a magnetic stir bar, a rubber septum, and a gas inlet was added benzyl (S)-3-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-2-((tert-butoxycarbonyl)amino)propanoate (18.2) (433 mg, 0.706 mmol). The flask was evacuated and filled with Ar five times. Anhydrous THF (8.0 ml) was added, and the clear solution was cooled to 0 °C. After addition of LiBH4 (61.5 mg, 2.82 mmol), the reaction mixture was stirred for 2.5 h. The volatiles were removed in vacuo. Purification by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 20-45% EtOAc in cyclohexane) afforded tert-butyl (S)-(1-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (217 mg, 60.4%) (18.3%) as a colorless, viscous oil. UPLC retention time 1.18 min (Method A). 1 H NMR(400MHz,CDCl3)δ=8.12(dd,J=9.1,2.2Hz,2H),8.01(d,J=2.1Hz,1H),7.67(dd,J=8.8,2.1Hz,1H),7.28(d,J=1.9Hz,2H),5.22(s br,1H),4.24-4.15(m,1H),3.86-3.76(m,2H),3.29(d,J=6.0Hz,2H),1.44(s,9H).19F NMR(376MHz,CDCl3)δ=-132.96.MS / ESI + 509.2,511.2[M+H] + .

[0271] Step d) tert-Butyl (S)-(1-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-oxopropan-2-yl)carbamate (18.4). To a 12 mL one-neck pear-shaped flask equipped with a magnetic stir bar was added tert-butyl (S)-(1-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate (18.3) (217 mg, 0.426 mmol), DCM (5.0 ml), and DMP (208 mg, 0.490 mmol). The white suspension was stirred for 28 min at room temperature. A few drops of saturated aqueous NaHCO3 and saturated aqueous Na2S2O3 were added, and the biphasic system was stirred for 2 h at room temperature, during which time both phases became clear. Water and dichloromethane were added. The aqueous phase was extracted once with CHCl2 and once with EtOAc. The organic layers were washed with brine, combined, and dried over Na2SO4. Purification by column chromatography (ISCO CombiFlash Rf, 20–26.5% to 34.3% EtOAc in cyclohexane adsorbed onto silica gel) afforded tert-butyl (S)-(1-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-oxopropan-2-yl)carbamate (177 mg, 82%) (18.4%) as a stiff white foam. UPLC retention time 1.22 min (Method A). 1 H NMR(400MHz,CDCl3)δ=9.75(s,1H),8.12-8.07(m,2H),8.01(d,J=2.1Hz,1H),7.67(dd,J=8.8,2.1Hz,1H), 7.28(d,J=2.0Hz,2H),5.67(d,J=6.9Hz,1H),4.69-4.56(m,1H),3.50(d,J=5.3Hz,2H),1.46(s,9H).MS / ESI + 507.1, 509.1[M+H] + .

[0272] Step e) tert-Butyl ((2S)-1-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxybutan-2-yl)carbamate (18.5). To a 10 mL two-neck conical flask equipped with a magnetic stir bar, a rubber septum, and a gas inlet was added tert-butyl (S)-(1-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-oxopropan-2-yl)carbamate (18.4) (91.3 mg, 0.180 mmol). The flask was evacuated and backfilled with Ar five times. Anhydrous THF (1.00 mL) was added, and the colorless solution was cooled to 0 °C. Then, MeMgBr (0.25 mL, 0.750 mmol) in THF was carefully added (gas formation during the addition), and the reaction mixture was stirred for 2.5 h (the ice bath was removed after 2 h). The reaction was quenched with a few drops of MeOH and then with saturated aqueous NH₄Cl. It was stored in the freezer 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. Purification by column chromatography (ISCO CombiFlash Rf, 15–27.5% to 40% EtOAc in cyclohexane adsorbed onto silica gel) gave tert-butyl ((2S)-1-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxybutan-2-yl)carbamate (60.2 mg, 63.9%) (18.5%). UPLC retention time 1.22 minutes (Method A). 1 H NMR(400MHz,CDCl3)δ=8.12(dd,J=8.9,2.2Hz,2H),8.01(d,J=2.0Hz,1H),7.67(dd,J=8.8,2.0Hz,1H),7.28(d,J =1.9Hz,3H),5.14(d,J=6.7Hz,1H),4.07-3.93(m,2H),3.38-3.18(m,2H),1.43(s,9H),1.26(d,J=2.3Hz,3H).19F NMR(376MHz,CDCl3)δ=-132.99.MS / ESI +523.3, 525.3[M+H] + .

[0273] Step f) (3S)-3-Amino-4-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)butan-2-ol (Example 18). To a 12 mL one-neck pear-shaped flask equipped with a magnetic stirrer was added tert-butyl ((2S)-1-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxybutan-2-yl)carbamate (18.5) (60.2 mg, 0.115 mmol), dioxane (1.00 mL), and aqueous HCl (1.00 mL, 2.000 mmol). The cloudy solution was stirred at room temperature 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 by column chromatography (ISCO CombiFlash Rf, absorbed onto silica gel, 0-5% MeOH in CHCl2) afforded (3S)-3-amino-4-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)butan-2-ol (33.9 mg, 67.5%) (Example 18) as a colorless oil and as a 78:22 diastereomeric mixture. UPLC retention time 0.79 min (Method A). 1 H NMR(400MHz,CDCl3)δ=8.16-8.09(m,2H),8.00(d,J=2.1Hz,1H),7.67(dd,J=8.8,2.1Hz,1H),7.27(d, MS / ESI + 423.2, 425.2 [M+H] + .

[0274] Example 19 (R)-3-(5-(4-((5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)-2-aminopropan-1-ol [ka] Step a) 2-(4-(2H-tetrazol-5-yl)phenoxy)-5-bromopyridine (19.1). At room temperature, BuSnO (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 for 16 hours at 100 °C. The mixture was concentrated, the crude product was triturated with diethyl ether, and 19.1 (1.28 g, 70%) was filtered off as a white solid. UPLC retention time: 0.86 min (Method A). 1 H NMR(DMSO-d6):δ=16.82(s,br,1H),8.33(d,J=2.5Hz,1H),8.24-8.00(m,3H),7.51-7.29(m,2H),7.17(d,J=8.7Hz,1H).MS / ESI 318.1[M+H] + .

[0275] 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 dioxane (15 ml) and water (15 ml). KPO (2.402 g, 11.32 mmol) and PdCl(dtbpf) (0.246 g, 0.377 mmol) were then added under argon, and the reaction mixture was stirred for 16 hours at 120 °C. The reaction mixture was absorbed into Isolute and dried on a rotavap. The reaction mixture was purified on silica (gradient: ethyl acetate / MeOH) to give compound 19.3 (1.41 g, 81% purity). UPLC retention 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). No tetrazole H was observed. MS / ESI 306.2 [M+H] + .

[0276] Step c) tert-Butyl (R)-(1-(5-(4-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)carbamate (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 CsCO (368 mg, 1.13 mmol) in DMA (4 mL). The reaction mixture was stirred for 16 hours at 70 °C. Brine and CHCl were added, and the mixture was extracted with CHCl (3x). The combined organic layers were dried over NaSO and concentrated, and the residue was purified on silica (gradient: ethyl acetate / MeOH) to give 19.4 as a white solid (30 mg, 83% purity). UPLC retention time 0.89 min (Method A). MS / ESI 479.4[M+H] + .

[0277] Step d) (R)-3-(5-(4-((5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)-2-aminopropan-1-ol (Example 19). A 4 M solution of HCl in dioxane (0.157 mL, 0.627 mmol) was added to a solution of 19.4 (30 mg, 0.063 mmol) in dioxane (0.5 ml). The resulting suspension was stirred at room temperature for 1 hour and diluted with diethyl ether. The colorless solid was filtered off and purified by SFC to give Example 19 as a colorless powder (10 mg, 39%). 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). No pyrazole NH was observed. MS / ESI 379.3 [M+H] + .

[0278] Example 20 (S)-3-(5-(4-((5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)-2-aminopropan-1-ol [ka] Example 20 was prepared by a procedure similar to that used in the synthesis of Example 19, substituting Intermediate B for its R-enantiomer, Intermediate A. Example 20 was isolated as the hydrochloride salt. UPLC retention time 0.58 min (Method A). 1 H 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). OH and pyrazole NH were not observed. MS / ESI 379.2 [M+H] + .

[0279] 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)propan-1-ol [ka] 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 for 5 hours at 80 °C. 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 (gradient: cyclohexane / ethyl acetate) to give 21.3 (271 mg, 73%). UPLC retention time 1.10 min (Method A). 1 H 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] + .

[0280] Step b) 5-chloro-3-fluoro-2-((6-(1-(tetrahydro-2H-pyran-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), KPO (1888 mg, 8.90 mmol), and PdCl(dtbpf) (145 mg, 0.222 mmol) in a mixture of dioxane (15 mL) and water (5 mL) was stirred under argon for 15 minutes at 25 °C. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified on silica (gradient: cyclohexane / ethyl acetate) to give 21.5 (1390 mg, 73%). UPLC retention time 1.16 min (Method A). 1 H 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),6.2 5(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] + .

[0281] Step c) 2-((6-(1H-pyrazol-3-yl)pyridin-3-yl)oxy)-5-chloro-3-fluoropyridine (21.6). To a solution of 21.5 (1380 mg, 3.68 mmol) in methanol (12 mL) was added 2N HCl (11.05 mL, 22.1 mmol) and the mixture was stirred for 1 hour at 25 °C. A suspension formed. Filtration gave a colorless solid which was dissolved in CHCl (20 mL). Water was added and the pH was adjusted to 10 by the addition of 2N KCO. The layers were separated and the aqueous layer was extracted with CHCl. ​​The combined organic layers were dried over NaCO, filtered and concentrated to give 21.6 (960 mg, 89%). UPLC retention time 0.89 min (Method A). 1 H 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] + .

[0282] Step d) (S)-tert-Butyl (1-((tert-butyldimethylsilyl)oxy)-3-(3-(5-((5-chloro-3-fluoropyridin-2-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)propan-2-yl)carbamate (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 for 70 h under argon. 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 and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified on silica (gradient: cyclohexane / ethyl acetate) to give 21.7 (518 mg, 28%). UPLC retention 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 MS / ESI 578.3[M+H] + .

[0283] Step e) tert-Butyl ((2S)-1-((tert-butyldimethylsilyl)oxy)-3-(3-(5-((3-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)propan-2-yl)carbamate (21.8). A suspension of 21.7 (250 mg, 0.432 mmol), 21.4 (241 mg, 0.865 mmol), KPO (275 mg, 1.297 mmol) and PdCl(dtbpf) (145 mg, 0.222 mmol) in a mixture of dioxane (2.5 mL) and water (1 mL) was stirred at 90 °C for 15 min under argon. 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 (gradient: cyclohexane / ethyl acetate) to give 21.8 (180 mg, 60%). UPLC retention time 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(1H,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] + .

[0284] 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)propan-1-ol (Example 21). A 4 M solution of HCl in dioxane (0.612 mL, 2.45 mmol) was added to a solution of 21.8 (170 mg, 0.245 mmol) in acetone (2.5 mL). The resulting suspension was stirred for 16 hours at room temperature. The colorless solid was filtered off, washed with acetone, and purified by SFC and silica chromatography (gradient: CHCl / MeOH) to give Example 21 as a colorless powder (12 mg, 12%). UPLC retention time: 0.55 min (Method A). 1 H 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] + .

[0285] Example 22 (S)-2-Amino-3-(5-(5-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)pyridin-2-yl)-2H-tetrazol-2-yl)propan-1-ol [ka] Step a) 5-((5-chloro-3-fluoropyridin-2-yl)oxy)picolinonitrile (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 for 16 h under argon. 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 (gradient: CH2Cl2 / MeOH) to give 22.3 (1181 mg, 54%). UPLC retention time 1.01 min (Method A). 1 H 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] + .

[0286] Step b) 2-((6-(2H-Tetrazol-5-yl)pyridin-3-yl)oxy)-5-chloro-3-fluoropyridine (22.4). Under argon, a solution of 22.3 (1120 mg, 4.49 mmol), BuSnO (112 mg, 0.449 mmol), and TMSN (1034 mg, 8.97 mmol) in dry toluene (8 mL) was heated in a sealed tube on a heating block at 90 °C for 18 h. Additional BuSnO and TMSN were added, and heating was 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 (gradient: cyclohexane / ethyl acetate, then CHCl / MeOH) to give 29.4 as a colorless powder (960 mg, 73%). UPLC retention time: 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 tetrazole NH was observed. MS / ESI 293.1 [M+H] + .

[0287] Step c) (S)-tert-Butyl (1-((tert-butyldimethylsilyl)oxy)-3-(5-(5-((5-chloro-3-fluoropyridin-2-yl)oxy)pyridin-2-yl)-2H-tetrazol-2-yl)propan-2-yl)carbamate (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 for 1.5 hours under argon. 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 (gradient: cyclohexane / ethyl acetate) to give 22.5 (773 mg, 51%). UPLC retention time 1.50 min (Method A). 1 H 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] + .

[0288] Step d) tert-Butyl ((2S)-1-((tert-butyldimethylsilyl)oxy)-3-(5-(5-((3-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)pyridin-2-yl)-2H-tetrazol-2-yl)propan-2-yl)carbamate (22.7). A suspension of 22.5 (330 mg, 0.569 mmol), 22.6 (264 mg, 0.948 mmol), KPO (302 mg, 1.423 mmol) and PdCl(dtbpf) (30.9 mg, 0.047 mmol) in a mixture of dioxane (3.5 mL) and water (1.17 mL) was stirred at 90 °C for 1.25 h under argon. 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 (gradient: cyclohexane / ethyl acetate) to give 22.7 (118 mg, 30%). UPLC retention time 1.52 min (Method A). 1 H 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] + .

[0289] 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)propan-1-ol (Example 22). A 4 M solution of HCl in dioxane (0.284 mL, 1.15 mmol) was added to a solution of 22.7 (80 mg, 0.115 mmol) in acetone (1 ml). The resulting suspension was stirred for 4 hours at room temperature. The mixture was concentrated, the residue was dissolved in water, and CHCl was added. The pH was adjusted to 9 with saturated NaHCO solution, and the aqueous layer was extracted with CHCl / isopropanol (3:1). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified on silica (gradient: CHCl / MeOH) to give Example 22 (15 mg, 31%) as a colorless solid. UPLC retention time 0.52 min (Method A). 1 H 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] + .

[0290] Example 23 (S)-2-Amino-3-(3-(5-((5-chloro-3-fluoropyridin-2-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)propan-1-ol [ka] Step a) 2-((6-Bromopyridin-3-yl)oxy)-5-chloro-3-fluoropyridine (23.3). Under argon, 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 for 18 h at 80 °C. 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 HO and dried over NaSO. Evaporation afforded the crude product as a yellow oil. Crystallization from cyclohexane (4 mL) afforded compound 23.3 as an off-white solid (1.57 g, 81%). UPLC retention time: 1.15 min (Method A). 1 H 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] + .

[0291] Step b) 2-((6-(1H-pyrazol-3-yl)pyridin-3-yl)oxy)-5-chloro-3-fluoropyridine (23.5). To a suspension of 23.3 (686 mg, 2.26 mmol) and 23.4 (582 mg, 5.20 mmol) in dioxane (22.6 mL) was added 2 M aqueous NaCO (2.26 mL, 4.52 mmol) and tetrakis(triphenylphosphine)-palladium(0) (313 mg, 0.271 mmol). After purging with argon, the reaction mixture was stirred in a sealed tube at 85 °C for 20 h. After cooling, the suspension was partitioned 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 NaCO and half-saturated brine. Drying over NaSO and evaporation gave a yellow oil. Flash chromatography (gradient: cyclohexane / ethyl acetate) gave a pale yellow oil. The residue was crystallized from EtOH / Et2O to give pure compound 23.5 as a white solid (353 mg, 48%). 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] + .

[0292] Step c) (S)-2-Amino-3-(3-(5-((5-chloro-3-fluoropyridin-2-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)propan-1-ol (23.6, Example 23). To a solution of 23.5 (117 mg, 0.40 mmol) and Intermediate A (177 mg, 0.482 mmol) in DMA (4.5 mL) was added CsCO (392 mg, 1.204 mmol). The suspension was stirred for 1.5 h at 0 °C under argon, then for an additional 2 h at room temperature, and then at 45 °C overnight. 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 phase was washed four times with brine and dried over NaSO. Evaporation of the solvent gave a yellow oil. Separation by flash chromatography (gradient: CH2Cl2 / MeOH / NH3) gave pure compound Example 23 as a colorless oil (89 mg, 55%). UPLC retention time 0.71 min (Method A). 1 H 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] + .

[0293] The material was converted to its hydrochloride salt by treating a solution in acetone (5 mL) with 1.25 M HCl in MeOH (0.6 mL), followed by evaporation and trituration with EtO. The precipitate that formed was filtered off and dried in vacuo at 80 °C to give the product as a colorless crystalline solid (81.2 mg). Additionally, the regioisomeric product (S)-2-amino-3-(5-(5-((5-chloro-3-fluoropyridin-2-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)propan-1-ol 23' could be isolated. Recrystallization from EtO gave a colorless crystalline solid (17.2 mg, 12%). UPLC retention time 0.67 min (Method A). 1 H 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] + .

[0294] Example 24 (S)-2-amino-3-(3-(3-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol [ka] Step a) 2-(3-Bromophenoxy)-5-chloro-3-fluoropyridine (24.3). Under argon, potassium carbonate (3.99 g, 28.9 mmol) was added to a solution 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 for 18 h at 80 °C. 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% KCO, HO, and brine. The organic phase was dried over NaSO. Evaporation afforded the crude product as a yellow oil. The residue was purified by flash chromatography (cyclohexane / DCM) to afford compound 24.3 as a colorless oil (5.06 g, 87%). UPLC retention time 1.31 min (Method A). 1 H 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] + .

[0295] Step b) 2-(3-(1H-pyrazol-3-yl)phenoxy)-5-chloro-3-fluoropyridinidine (24.5). To a suspension of 24.3 (1.5 g, 4.96 mmol) and 24.4 (1.11 g, 9.92 mmol) in DMA (15 mL) was added KHCO (0.993 g, 9.91 mmol) and tetrakis(triphenylphosphine)-palladium(0) (286 mg, 0.248 mmol). After purging with argon, the reaction mixture was stirred in a sealed tube at 93 °C for 24 h. After cooling, the suspension was partitioned 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 NaCO and half-saturated brine. Drying over NaSO and evaporation gave a yellow oil. Flash chromatography (gradient: cyclohexane / ethyl acetate) afforded pure compound 24.5 as a colorless oil (547 mg, 38%). UPLC retention time 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] + .

[0296] Step c) tert-Butyl (S)-(1-((tert-butyldimethylsilyl)oxy)-3-(3-(3-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-2-yl)carbamate (24.6). To a solution of 24.5 (523 mg, 1.805 mmol) and Intermediate A (796 mg, 2.166 mmol) in DMA (12 mL) was added Cs2CO3 (1.765 g, 5.42 mmol). The suspension was stirred for 4 h at room temperature. The reaction mixture 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. Evaporation of the solvent gave a yellow oil. Separation by flash chromatography (gradient: CH2CL2 / EtOAc) gave pure compound 24.6 as a colorless oil (917 mg, 88%). UPLC retention time 1.63 min (Method A). 1 H 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] + .

[0297] Step d) (S)-2-Amino-3-(3-(3-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol (Example 24). Compound 24.6 (917 mg, 1.589 mmol) was dissolved in acetone (10 mL) and 4 M HCl in dioxane (3.97 mL, 15.89 mmol) was added. Gas evolution was observed immediately, and a thick suspension formed within 15 minutes. The mixture was stirred at 25 °C for 16 hours. The reaction was evaporated to leave a sticky residue. The compound was purified by flash chromatography (gradient: CHCl / MeOH-32% NH in water) to give Example 24 as a colorless oil that crystallized on standing (531 mg, 92%). UPLC retention time: 0.76 min (Method A). 1 H 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] + .

[0298] Example 25 S)-2-Amino-3-(4-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol [ka] Step a) 2-(4-Bromophenoxy)-5-chloro-3-fluoropyridine (25.3). Under argon, potassium carbonate (3.99 g, 28.9 mmol) was added to a solution 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 for 18 hours at 80 °C. 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% KCO, HO, and brine. The organic phase was dried over NaSO. Evaporation afforded the crude product as a yellow oil. The residue was purified by flash chromatography (cyclohexane / DCM) to afford compound 25.3 as a colorless oil (5.16 g, 89%). UPLC retention time 1.31 min (Method A). 1 H 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] + .

[0299] Step b) 2-(4-(1H-pyrazol-4-yl)phenoxy)-5-chloro-3-fluoropyridine (25.5). To a suspension of 25.3 (1.5 g, 4.96 mmol) and 25.4 (1.11 g, 9.92 mmol) in DMA (15 mL) was added KHCO (0.993 g, 9.91 mmol) and tetrakis(triphenylphosphine)-palladium(0) (286 mg, 0.248 mmol). After purging with argon, the reaction mixture was stirred in a sealed tube at 90 °C for 48 h. After cooling, the suspension was partitioned 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 NaCO and half-saturated brine. Drying over NaSO and evaporation gave a yellow oil. Flash chromatography (gradient: cyclohexane / ethyl acetate) gave a viscous oil. The residue was crystallized from cyclohexane / Et2O (2:1) to give pure compound 25.5 as a white solid (472 mg, 27%). 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] + .

[0300] Step c) tert-Butyl (S)-(1-((tert-butyldimethylsilyl)oxy)-3-(4-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-2-yl)carbamate (25.6). To a solution of 25.5 (196 mg, 0.676 mmol) and Intermediate A (323 mg, 0.878 mmol) in DMA (5.5 mL) was added CsCO (660 mg, 2.027 mmol). The suspension was stirred for 28 h at room temperature. The reaction mixture 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 NaSO. Evaporation of the solvent yielded a yellow oil. Separation by flash chromatography (gradient: CH2CL2 / EtOAc) gave pure compound 25.6 as a colorless oil that crystallized upon standing (399 mg, 86%). UPLC retention time 1.60 min (Method A). 1 H 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] + .

[0301] Step d) (S)-2-Amino-3-(4-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol (Example 25). Compound 25.6 (388 mg, 0.672 mmol) was dissolved in acetone (5 ml) and 4 M HCl in dioxane (1.68 mL, 6.72 mmol) was added. Gas evolution was observed immediately and a thick suspension formed within 15 minutes. The mixture was stirred at 40° C. for 2.5 hours. Additional 4 M HCl in dioxane (0.84 mL, 3.36 mmol) was then added and stirring was continued for 4 hours at 40° C. The clear solution was evaporated to leave a sticky residue. The compound was purified by flash chromatography (gradient: CHCl / MeOH-32% NH in water) to give a solid. Trituration with isopropanol gave Example 25 as a white solid (157 mg, 64%) after drying under vacuum at 60° C. UPLC retention time 0.76 min (Method A). 1 H 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] + .

[0302] Example 26 (S)-2-amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol [ka] Step a) 2-(4-Bromophenoxy)-5-chloro-3-fluoropyridine (26.3). Under argon, 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 KCO solution, half-saturated brine, and dried over NaSO. Evaporation afforded the crude product as a colorless oil. Flash chromatography on silica (gradient: cyclohexane / CHCl) afforded compound 26.3 as a colorless solid (1.75 g, 90%). UPLC retention time 1.31 min (Method A). TLC:R f =0.25 (CH2Cl2 / cyclohexane 1:4), 1 H 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] + .

[0303] Step b) 2-(4-(1H-pyrazol-3-yl)phenoxy)-5-chloro-3-fluoropyridine (26.5). To a suspension of 26.3 (1.00 g, 3.31 mmol) and 26.4 (1.11 g, 9.92 mmol) in dioxane (14 mL) was added 2 M aqueous NaCO (1.65 mL, 3.30 mmol) and tetrakis(triphenylphosphine)-palladium(0) (0.31 g, 0.2 mmol). After purging with argon, the reaction mixture was stirred in a sealed tube at 75 °C for 40 h. After cooling, the suspension was partitioned 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 NaCO and half-saturated brine. Drying over NaSO and evaporation gave a yellow oil. Flash chromatography (gradient: cyclohexane / ethyl acetate) gave pure compound 26.5 as a colorless oil (0.27 g, 28%). UPLC retention time 1.01 min (Method A). TLC:R f =0.35 (ethyl acetate / cyclohexane 1:1), 1 H 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] + .

[0304] Step c) tert-Butyl (S)-(1-((tert-butyldimethylsilyl)oxy)-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-2-yl)carbamate (26.6). To a solution of 26.5 (261 mg, 0.90 mmol) and Intermediate A (398 mg, 1.08 mmol) in DMA (10 mL) was added CsCO (880 mg, 2.70 mmol). The colorless suspension was stirred for 2.5 h at 25 °C under argon and 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 phase was washed four times with brine and dried over NaSO. Evaporation of the solvent gave a colorless oil containing two possible regioisomeric alkylation products in a 14:1 ratio (UPLC, UV 215 nm). Separation by flash chromatography (gradient: CH2Cl2 / ethyl acetate) gave the desired regioisomer 26.6 as a colorless oil (370 mg, 71%). UPLC retention time 7.63 min (Method B). TLC:R f = 0.64 (ethyl acetate / CH2Cl2 1:1), 1 H 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] + The undesired pyrazole regioisomer 26.6' was also obtained as a colorless oil (42 mg, 8%). UPLC retention time 7.53 min (Method B). TLC: R f =0.27 (ethyl acetate / CH2CL2 1:1), 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),1.3 3(9H,s),0.79(9H,s),-0.04(3H,s),-0.05(3H,s).MS / ESI:m / z=577.4[M+H] + .

[0305] Step d) (S)-2-Amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol (Example 26). Compound 26.6 (362 mg, 0.627 mmol) was dissolved in 4 M HCl in dioxane (1.5 mL). Immediate effervescence was observed and a thick suspension formed within 15 min. Acetone (4.5 mL) was added and stirring at 25 °C was continued for an additional 1.5 h. The reaction was evaporated to leave a sticky residue. Flash chromatography (gradient: CHCl / MeOH-32% NH in water) and recrystallization from ethyl ether / n-pentane gave Example 26 as a colorless powder (166 mg, 73%). UPLC retention time 0.76 min (Method A). TLC: R f =0.19(CH2CL2 / MeOH / 25%NH3 aqueous solution 90:9:1), 1 H 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] + .

[0306] Example 27 (S)-2-Amino-3-(5-(4-(4-chlorophenoxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol [ka] Step a) 5-(4-(4-chlorophenoxy)phenyl)-2H-tetrazole (26.3). To a solution of nitrile 27.1 (1.43 g, 6.23 mmol) in dry toluene (9 mL) was added dibutylstannanone (155 mg, 0.623 mmol) and azidotrimethylsilane (1.7 mL, 12.4 mmol). The reaction mixture was heated to 100 °C in a sealed vial for 17 h. After cooling to room temperature, all volatiles were removed in vacuo, and the crude material was triturated 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 in vacuo to give tetrazole 27.2 as a colorless powder (1.49 g, 86%). UPLC retention time 0.99 min (Method A). 1 H NMR(400MHz,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] + .

[0307] Step b) Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(5-(4-(4-chlorophenoxy)phenyl)-2H-tetrazol-2-yl)propanoate (27.3). To a solution of 27.2 (1.2 g, 4.40 mmol) and PPh3 (2.89 g, 11.0 mmol) in 60 mL was added di-tert-butyl azodicarboxylate (2.53 g, 11.00 mmol) and Boc-Ser-OMe (2.41 g, 11.0 mmol) in THF (20 mL). After stirring at room temperature for 19 h, all volatiles were removed in vacuo and the crude material was adsorbed onto isolute™. Purification by flash column chromatography (80 g SiO, heptane to EtOAc) afforded a colorless solid (4.1 g) containing the title compound 27.3 and a significant amount of BocNH-NHBoc. The material was carried forward without further purification. UPLC retention time 1.34 min (Method A). 1H NMR(400MHz,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] + .

[0308] Step c) tert-Butyl (S)-(1-(5-(4-(4-chlorophenoxy)phenyl)-2H-tetrazol-2-yl)-3-hydroxypropan-2-yl)carbamate (27.4). A solution of 27.3 (414 mg, 0.874 mmol) in 10 mL was treated with 2N LiBH4 in THF (1.75 mL, 3.5 mmol) at 0 °C. After 30 min, the reaction mixture was adsorbed onto isolute™ and dried in vacuo. Flash column chromatography (43 g RP18 silica, 0.1% TFA:MeCN in water 19:1 to 0:1) afforded the alcohol 27.4 (173 mg, 44%) as a colorless solid. UPLC retention time 1.22 min (Method A). 1 H NMR(400MHz,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,1 H,-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] + .

[0309] Step d) (S)-2-Amino-3-(5-(4-(4-chlorophenoxy)phenyl)-2H-tetrazol-2-yl)propan-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 in vacuo and adsorbed onto isolute™. Flash column chromatography (43 g RP18 silica, 0.1% TFA:MeCN in water 19:1 to 0:1) followed by lyophilization from aqueous HCl gave the hydrochloride salt of Example 27 (71 mg, 92%) as a colorless powder. UPLC retention time 0.81 min (Method A). 1 H NMR(400MHz,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] + .

[0310] Example 28 (S)-2-Amino-3-(5-(4-((5-cyclopropylpyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol [ka] Step a) 2-(4-(2H-tetrazol-5-yl)phenoxy)-5-bromopyridine (28.1). Two vials containing solutions of 13.3 (2.95 g, 10.72 mmol), BuSnO (0.267 g, 1.073 mmol), and TMSN3 (2.47 g, 21.45 mmol) in dry toluene (10.5 mL) were sealed under argon and stirred at 100 °C on a heating block for 8 h. The heterogeneous mixtures were combined, treated with MeOH, and concentrated under reduced pressure. The solid residue was crystallized from MeOH to give 28.1 as a colorless solid (2.60 g, 42%). 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] + .

[0311] Step b) (S)-Methyl 3-(5-(4-((5-bromopyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate (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 for 1.5 h at 25 °C. Isolute was added, and the mixture was dried in vacuo. Chromatography on silica (gradient: cyclohexane / ethyl acetate) afforded 28.3 (5.65 g) containing approximately 10% triphenylphosphine oxide as a colorless solid, which was used in the next step. A small portion was further purified by SFC to give the analytical sample: UPLC retention time 1.25 min (Method A). 1 H 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] + .

[0312] Step c) (S)-tert-Butyl (1-hydroxy-3-(5-(4-hydroxyphenyl)-2H-tetrazol-2-yl)propan-2-yl)carbamate (28.4). At 0 °C, LiBH (2N THF solution, 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), and the mixture was stirred for 45 min at 0 °C. The mixture was neutralized with HCl (1N aqueous solution), CHCl was added, the organic layer was separated, dried over NaSO, and the solvent was removed. Chromatography on silica (gradient: cyclohexane / ethyl acetate) afforded compound 28.4 as a colorless solid (553 mg, 21%). UPLC retention time: 1.11 min (Method A). 1 H 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] + .

[0313] Step d) (S)-tert-Butyl (1-(5-(4-((5-cyclopropylpyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)-3-hydroxypropan-2-yl)carbamate (28.6). A suspension of 28.4 (400 mg, 0.814 mmol), 28.5 (164 mg, 0.977 mmol), KPO (518 mg, 2.442 mmol), and PdCl(dtbpf) (53.1 mg, 0.081 mmol) in a mixture of dioxane (7.5 mL) and water (3.75 mL) was stirred at 85 °C for 2 h under argon. The mixture was concentrated, and the residue was purified on silica (gradient: cyclohexane / ethyl acetate) to give 28.6 (80 mg, 21%). UPLC retention 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( MS / ESI 453.4[M+H] + .

[0314] Step e) (S)-2-Amino-3-(5-(4-((5-cyclopropylpyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol (Example 28). To a solution of 28.6 (77 mg, 0.170 mmol) in CHCl (1.7 mL) was added HCl (4 N in dioxane, 0.638 mL, 2.55 mmol) and the mixture was stirred for 1.5 h at 25° C. Filtration afforded the hydrochloride salt of Example 28 as a colorless solid (60 mg, 89%). UPLC retention time 0.72 min (Method A). 1 H 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),5.08-4.9 4(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] + .

[0315] Example 29 (S)-2-amino-3-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol [ka] 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 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 the crude product, which was recrystallized from hexane / ethyl acetate. The pure product 29.3 was obtained as a colorless solid (20.5 g, 53%). UPLC retention time 1.10 min (Method A). 1 H 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] + .

[0316] 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), BuSnO (0.224 g, 0.900 mmol), and TMSN3 (2.39 mL, 18.0 mmol) in dry toluene (9 mL) were sealed under argon and stirred on a heating block at 90 °C for 18 h. The heterogeneous mixture was concentrated, and the combined crude was treated with MeOH (100 mL) and concentrated once more under reduced pressure to give a light brown-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). 1 H 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] + .

[0317] Step c) (S)-Methyl 2-((tert-butoxycarbonyl)amino)-3-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propanoate (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 for 4 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over Na2SO4, filtered, and evaporated. Chromatography on silica (15% ethyl acetate in petroleum ether) gave compound 29.6 as a colorless solid (13.7 g, 62%). UPLC retention time 1.26 min (Method A). 1 H 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] + .

[0318] Step d) (S)-tert-Butyl (1-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)-3-hydroxypropan-2-yl)carbamate (29.7). At 0 °C, LiBH (2N THF solution, 2.94 mL, 5.88 mmol) was added dropwise to a solution of 29.6 (724 mg, 1.47 mmol) in THF (15 mL), and the mixture was stirred for 1 h at 0 °C. The mixture was neutralized with HCl (1N aqueous solution), CHCl was added, the organic layer was separated, dried over NaSO, and the solvent was removed. Chromatography on silica (gradient: cyclohexane / ethyl acetate) gave compound 29.7 as a colorless oil (555 mg, 72%). UPLC retention time: 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] + .

[0319] Step e) (S)-2-Amino-3-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol (Example 29). To a solution of 29.7 (172 mg, 0.37 mmol) in CHCl (3 mL) was added HCl (4N in dioxane, 1.4 mL, 5.6 mmol) and the mixture was stirred for 1 h at 25° C. Filtration afforded the hydrochloride salt of Example 29 as a colorless solid (93 mg, 62%). UPLC retention time 0.74 min (Method A). 1 H 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] + .

[0320] Example 30 (R)-2-amino-3-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol [ka] The hydrochloride salt of (R)-2-amino-3-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol (Example 30) was prepared by a procedure similar to that used for the synthesis of Example 29, substituting its R-enantiomer 30.5 for 29.5. 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] + .

[0321] Example 31 (R)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol [ka] Step a) 4-((5-chloropyridin-2-yl)oxy)benzonitrile (31.3). Compound 31.1 (19.7 g, 150 mmol) was added dropwise to a suspension of 31.2 (16.99 g, 143 mmol) and powdered KCO (23.66 g, 171 mmol) in DMF (volume: 30 mL) at room temperature. The reaction mixture remained a suspension, and no temperature change was observed. The mixture was heated to 140 °C for 24 h. The reaction mixture was cooled to approximately 80 °C, resulting in a very viscous yellow suspension. Ethyl acetate (100 mL) and water (100 mL) were added, resulting in two clear layers. Upon cooling to room temperature, the product began to crystallize in the upper organic layer. Fine colorless needles were collected by filtration, washed with MeOH (3 × 30 mL), and dried in a stream of air to give 31.3 (17.5 g, 52% yield). The filtrate was diluted with additional 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), NaHCO (100 mL), and brine (100 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated in vacuo to give a colorless solid, which was suspended in MeOH (ca. 50 mL). A second batch of 31.3 was collected by filtration, washed with MeOH (2 × 30 mL), and dried in a stream of air to give (11.4 g, 34% yield). UPLC retention time 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] + .

[0322] Step b) 2-(4-(2H-tetrazol-5-yl)phenoxy)-5-chloropyridine (31.4). A solution of 31.3 (1.442 g, 6.25 mmol), BuSnO (0.156 g, 0.625 mmol), and TMS-azide (1.659 mL, 12.50 mmol) in dry toluene (9 mL) was prepared under argon. The vial was sealed, and the mixture was stirred on a heating block at 100 °C for 65 h. The mixture was combined and treated with MeOH (50 mL), resulting in a suspension of the reaction mixture. 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 retention time 2.81 min (Method B). 1 H 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] + .

[0323] Step c) (R)-Methyl 2-((tert-butoxycarbonyl)amino)-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propanoate (31.6). A mixture of triphenylphosphine (2.396 g, 9.13 mmol), DIAD (2.103 g, 9.13 mmol), 31.4 (1.00 g, 3.65 mmol), and 31.5 (2.003 g, 9.13 mmol) in THF (65 ml) was stirred for 1 h at 25 °C. Isolute was added and the mixture was dried in vacuo. Chromatography on silica (gradient: cyclohexane / ethyl acetate) afforded 31.6 (1.57 g, 89%) as a colorless solid. UPLC retention time 1.33 min (Method A).1 H 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] + .

[0324] Step d) (R)-tert-Butyl (1-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)-3-hydroxypropan-2-yl)carbamate (31.7). At 0 °C, LiBH (2N THF solution, 2.106 mL, 4.21 mmol) was added dropwise to a solution of 31.6 (500 mg, 1.053 mmol) in THF (10 mL), and the mixture was stirred for 1 h at 0 °C. The mixture was neutralized with HCl (1N aqueous solution), CHCl was added, the organic layer was separated, dried over NaSO, and the solvent was removed. Chromatography on silica (gradient: cyclohexane / ethyl acetate) afforded compound 31.7 as a colorless oil (555 mg, 72%). UPLC retention time 1.10 min (Method A). 1 H 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] + .

[0325] Step d) (R)-2-Amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol (Example 31). To a solution of 31.7 (275 mg, 0.615 mmol) in CHCl (6 mL) was added HCl (4N in dioxane, 2.308 mL, 9.23 mmol), and the mixture was stirred for 2 hours at 25° C. Filtration afforded the first batch of Example 31 hydrochloride salt as a colorless solid (40 mg, 18%). The filtrate was concentrated, and the residue was purified by preparative HPLC. The TFA salt was converted to the free base, which was further purified on silica (gradient: CHCl / MeOH) to give Example 31 (37 mg, 15%). UPLC retention time 0.70 min (Method A). 1 H NMR(DMSO-d6):δ=8.26(1H,d),8.10(2H,d),8.02(1H,dd),7.34(2H,d),7.00,(1H,d),4.8 5(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] + .

[0326] Example 32 (S)-2-Amino-3-(5-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol [ka] Step a) (2S)-2-Amino-3-(5-(4-((3-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol (32.2). A suspension of Example 29 (2000 mg, 5.48 mmol), 32.1 (2050 mg, 10.97 mmol), KPO (2328 mg, 10.97 mmol) and PdCl(dtbpf) (357 mg, 0.548 mmol) in a mixture of dioxane (20 mL) and water (6.3 mL) was stirred at 120 °C for 1.5 min under argon. Additional 32.1 and PdCl(dtbpf) in dioxane (5 mL) were added, and heating at 120° C. was continued for 1 h. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified on silica (gradient: CHCl / MeOH) to give 32.2 (1127 mg, 42%). The material was dissolved in THF (70 mL), SiliaMetS DMT was added, and the mixture was stirred for 16 h at 50° C. The scavenger was removed by filtration, and the residue was washed with THF and concentrated to give a solid that was used in the next step. UPLC retention time 0.78 min (Method A). 1 H 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] +

[0327] Step b) (S)-2-Amino-3-(5-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol (Example 32). To a solution of 32.2 (1125 mg, 2.341 mmol) in THF (15 mL) was added 2 N HCl (2.0 mL) and the mixture was stirred for 1.5 hours at 25 °C. The mixture was concentrated and the residue was purified on silica (gradient: CHCl / MeOH) to give Example 32 (421 mg, 41%). UPLC retention time 0.63 min (Method A). 1 H NMR (DMSO-d6): δ = 8.54 (3H, sbr), 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] +

[0328] Example 33 (S)-2-Amino-3-(5-(4-((5-bromopyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol [ka] Step a) (S)-2-Amino-3-(5-(4-((5-bromopyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol (Example 33). To a solution of 28.4 (139 mg, 0.283 mmol) in CHCl (2.8 mL) was added HCl (4N in dioxane, 1.061 mL, 4.24 mmol) and the mixture was stirred for 2 h at 25° C. Filtration afforded the hydrochloride salt of Example 33 as a colorless solid (100 mg, 83%). UPLC retention time 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] + .

[0329] Example 34 (S)-2-Amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol [ka] (S)-2-Amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol (Example 34) was prepared as the hydrochloride salt by a procedure similar to that used for the synthesis of Example 31, substituting 31.5 for its S-enantiomer 34.5. UPLC retention time 0.68 min (Method A). 1 H 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). No OH was observed. MS / ESI 347.2 [M+H] + .

[0330] Example 35 S)-2-Amino-3-(5-(6-(4-chlorophenoxy)pyridin-3-yl)-2H-tetrazol-2-yl)propan-1-ol [ka] Step a) 6-(4-chlorophenoxy)nicotinonitrile (35.3). A mixture of 35.1 (1.948 g, 15.16 mmol), 35.2 6-chloronicotinonitrile (2 g, 14.43 mmol), and K2CO3 (2.394 g, 17.32 mmol) in DMF (6 mL) was stirred at 120 °C for 3 h. 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 in vacuo to approximately 40 mL, at which point crystallization began. The solid was collected by filtration, washed with heptane (3 × 10 mL), and dried in a stream of air. Compound 35.3 (2.15 g, 9.14 mmol, 63.3% yield) was obtained as a colorless powder. UPLC retention time 1.10 min (Method A). 1 H 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] + .

[0331] Step b) 2-(4-chlorophenoxy)-5-(2H-tetrazol-5-yl)pyridine (35.4). To a mixture of 35.3 (1.50 g, 6.50 mmol) and BuSnO (0.162 g, 0.650 mmol) in toluene (8 mL) was added TMSN3 (1.726 mL, 13.01 mmol) under Ar. The reaction mixture was heated to 100 °C for 16 h. After cooling to room temperature, the resulting suspension was dissolved in MeOH (50 mL) and concentrated in vacuo. 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 a stream of air to give 35.4 (990 mg, 3.29 mmol, 50.5% yield) as a colorless solid. UPLC retention 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] + .

[0332] Step c) (S)-Methyl 2-((tert-butoxycarbonyl)amino)-3-(5-(6-(4-chlorophenoxy)pyridin-3-yl)-2H-tetrazol-2-yl)propanoate (35.6). A mixture of triphenylphosphine (575 mg, 2.192 mmol), DIAD (505 mg, 2.192 mmol), 35.4 (400 mg, 1.462 mmol), and 35.5 (481 mg, 2.192 mmol) in THF (25 ml) was stirred for 1.5 hours at 25 °C. Isolute was added, and the mixture was dried in vacuo. Chromatography on silica (gradient: cyclohexane / ethyl acetate) afforded 35.6 (1.57 g, 89%) as a colorless solid. UPLC retention time 1.25 min (Method A). 1 H 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] + .

[0333] Step d) (S)-tert-Butyl (1-(5-(6-(4-chlorophenoxy)pyridin-3-yl)-2H-tetrazol-2-yl)-3-hydroxypropan-2-yl)carbamate (35.7). At 0 °C, LiBH (2N THF solution, 1.722 mL, 3.44 mmol) was added dropwise to a solution of 35.6 (409 mg, 0.861 mmol) in THF (5 mL), and the mixture was stirred for 1 h at 0 °C. The mixture was neutralized with HCl (1N aqueous solution), CHCl was added, the organic layer was separated, dried over NaSO, and the solvent was removed. Chromatography on silica (gradient: cyclohexane / ethyl acetate) afforded compound 35.7 as a colorless solid (197 mg, 51%). UPLC retention time: 1.13 min (Method A). 1 H 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] + .

[0334] Step d) (S)-2-Amino-3-(5-(6-(4-chlorophenoxy)pyridin-3-yl)-2H-tetrazol-2-yl)propan-1-ol (Example 35). To a solution of 35.7 (182 mg, 0.407 mmol) in CHCl (4 mL) was added HCl (4N in dioxane, 1.527 mL, 6.11 mmol) and the mixture was stirred for 2 hours at 25° C. Filtration afforded the hydrochloride salt of Example 35 as a colorless solid (151 mg, 97%). UPLC retention time: 0.72 min (Method A). 1 H NMR (DMSO-d6): δ = 8.83 (1H, d), 8.48 (1H, dd), 8.42 (3H, sbr), 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). No OH was observed. MS / ESI 347.1 [M+H] + .

[0335] Example 36 (S)-3-(3-(4-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)-2-aminopropan-1-ol [ka] Step a) 2-(4-Bromophenoxy)-5-chloro-3-fluoropyridine (36.3). A mixture of compound 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 replaced with N2 three times, and then the mixture was stirred at 80 °C for 4 h under a N2 atmosphere. The mixture was diluted with ethyl acetate (100 mL) and then washed with brine (3 x 100 mL) and HO (100 mL). The organic layer was dried and concentrated to give a residue. The residue was purified on silica (gradient petroleum ether / ethyl acetate) to give compound 36.3 (8.20 g, 80%) as a white solid. 1 H NMR(CDCl3):δ=7.81(1H,d),7.45(3H,m),6.92-7.06(2H,m).MS / ESI 301.9[M+H] + .

[0336] 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(PPh) (1.34 g, 1.16 mmol), NaCO (3.84 g, 36.2 mmol) in HO (20 mL) and dioxane (100 mL) was degassed and replaced with N three times, and then the mixture was stirred at 75 °C for 24 h under a N atmosphere. The mixture was diluted with HO (100 mL) and then extracted with ethyl acetate (3 × 100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give a residue which was purified on silica (gradient petroleum ether / ethyl acetate) to give 36.5 (3.0 g, 10.2 mmol, 44%) as a white solid.1 H NMR (DMSO-d6): δ=12.90(1H,sbr),8.24(brd,J=9.8Hz,1H),8.08(s,1H),7.69-7.95(m,3H),7.17-7.34(m,2H),6.75-6.85(m,1H), mixture of tautomers. MS / ESI 289.9[M+H] + .

[0337] Step c) tert-Butyl (S)-(1-((tert-butyldimethylsilyl)oxy)-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-2-yl)carbamate (36.6). A mixture of 36.5 (2.5 g, 8.53 mmol), Intermediate A (3.76 g, 10.2 mmol), and CsCO (8.34 g, 25.6 mmol) in DMF (40 mL) was degassed and replaced with N three times, and then the mixture was stirred at 20 °C for 2 hours under a N atmosphere. 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 phase was washed four times with brine and dried over NaSO. Evaporation of the solvent gave a residue which was purified on silica (gradient petroleum ether / ethyl acetate) to give 36.6 (2.3 g, 38%) as a colorless gum. 1 H 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),4.2 6(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] + .

[0338] Step d) tert-Butyl ((2S)-1-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)-3-hydroxypropan-2-yl)carbamate (36.8). A mixture of 36.6 (1.01 g, 1.65 mmol), 36.7 (682 mg, 2.47 mmol), PdCl (29.2 mg, 0.165 mmol), P(c-CH) in NMP (10 mL) and HO (1 mL) 11 A mixture of 36.8 (138 mg, 0.494 mmol) and CsF (500 mg, 3.29 mmol) was degassed and replaced with N, and then the mixture was stirred at 100 °C for 12 h under a N atmosphere. The mixture was diluted with ethyl acetate (50 mL) and washed with HO (3 × 30 mL) and brine (30 mL). The organic solution was dried over NaSO, filtered, and concentrated to give 36.8 (1.1 g, crude) as a pale yellow gum, which was used in step e) without further purification. MS / ESI 579.1 [M+H] + .

[0339] Step e) (S)-2-Amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol (Example 36). A mixture of 36.8 (1.1 g crude from Step d) in HCl / ethyl acetate (20 mL, 4 M) was stirred at 20 °C for 0.5 h under a N atmosphere. 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%: 5 ACN% to 35 ACN%, 35 min, 80% min) to give the hydrochloride salt of Example 36 (317 mg, 44%) as a pale yellow solid. 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). 1 H NMR (DMSO-d6): δ = 8.60 (1H, d), 8.28 (3H, sbr), 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 were not observed. MS / ESI 377.3 [M+H] + .

[0340] Example 37 (S)-2-Amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol [ka] Step a) tert-Butyl ((2S)-1-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)-3-hydroxypropan-2-yl)carbamate (37.2). A mixture of 26.6 (1.01 g, 1.65 mmol), 37.1 (682 mg, 2.47 mmol), PdCl (29.2 mg, 0.165 mmol), P(c-CH) in NMP (10 mL) and HO (1 mL) 11A mixture of 37.2 (138 mg, 0.494 mmol) and CsF (500 mg, 3.29 mmol) was degassed and stirred under nitrogen at 100 °C for 12 h. The mixture was diluted with ethyl acetate (50 mL) and washed with brine (3 × 30 mL) and HO (30 mL). The organic layer was dried over NaSO, filtered, and concentrated to give 37.2 (1.1 g, crude) as a pale yellow gum, which was used in step b) without further purification. MS / ESI 579.1 [M+H] + .

[0341] Step b) (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol (Example 37). A mixture of compound 37.2 (1.1 g) in HCl / ethyl acetate (20 mL, 4 M) was degassed and stirred at 20 ° C. for 0.5 hours under nitrogen. 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 salt of Example 37 (317 mg, 44% over two steps) as a pale yellow solid. UPLC retention time: 0.60 min (Method C). 1 H 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). 1 H 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 were not observed. MS / ESI 395.4 [M+H] +.

[0342] Example 38 (2S)-2-Amino-3-[5-(4-[[3-fluoro-5-(1,3-oxazol-2-yl)pyridin-2-yl]oxy]phenyl)-2H-1,2,3,4-tetrazol-2-yl]propan-1-ol [ka] 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 for 16 h under argon. The mixture was cooled to room temperature, diluted with HO (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 (ethyl acetate / petroleum ether; 12:88) to give 38.3 (7.00 g, 58%) as a colorless solid.

[0343] Step b) 4-[[3-Fluoro-5-(1,3-oxazol-2-yl)pyridin-2-yl]oxy]benzonitrile (38.5). Under nitrogen, 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 at reflux for 16 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified on silica (ethyl acetate / petroleum ether; 25:75) to give 38.5 (4.00 g, 83%) as a colorless solid. MS / ESI 282.0 [M+H] + .

[0344] Step c) 3-Fluoro-5-(1,3-oxazol-2-yl)-2-[4-(2H-1,2,3,4-tetrazol-5-yl)phenoxy]pyridine (38.6). Under nitrogen, a mixture of 38.5 (4.00 g, 14.22 mmol), BuSnO (350 mg, 1.41 mg), and TMSN (5.00 g, 43.40 mmol) in toluene (40 mL) was heated at reflux for 3 hours. The mixture was concentrated in vacuo, 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.

[0345] Step d) Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(5-(4-((3-fluoro-5-(oxazol-2-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propanoate (38.8). To a solution of 38.6 (3.50 g, 10.79 mmol) in THF (100 mL) was added DIAD (6.20 g, 26.96 mmol), PPh3 (7.10 g, 27.07 mmol, 2.50 mmol), and 38.7 (6.00 g, 27.37 mmol) under nitrogen at 0 °C. The resulting mixture was stirred at room temperature for 16 h, concentrated, and the residue was purified on silica (ethyl acetate / petroleum ether; 45:55) to give 38.8 (3.20 g, 56%) as a colorless solid. MS / ESI 526.1[M+H] + .

[0346] Step e) tert-Butyl N-[(2S)-1-[5-(4-[[3-fluoro-5-(1,3-oxazol-2-yl)pyridin-2-yl]oxy]phenyl)-2H-1,2,3,4-tetrazol-2-yl]-3-hydroxypropan-2-yl]carbamate (38.9). At 0 °C, LiBH (7.6 mL 2 molar THF solution) was added dropwise to a solution of 38.8 in THF (40 mL), and the mixture was stirred for 2 h at 0–10 °C. The mixture was cooled to 0 °C, and AcOH (920 mg, 15.6 mmol) was added. The mixture was diluted with HO (150 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layer was washed with brine (50 mL), dried over NaSO, filtered, and concentrated. The residue was purified on silica (ethyl acetate / petroleum ether: 60 / 40) to give 38.9 (800 mg, 42%) as a colorless solid. MS / ESI 498.1 [M+H] + .

[0347] Step f) (2S)-2-Amino-3-[5-(4-[[3-fluoro-5-(1,3-oxazol-2-yl)pyridin-2-yl]oxy]phenyl)-2H-1,2,3,4-tetrazol-2-yl]propan-1-ol (Example 38). To a solution of 38.9 (800 mg, 1.61 mmol) in CHCl (50 mL) and MeOH (10 mL) was added HCl (8 mL 4 M in dioxane) at 0 °C under nitrogen, and the mixture was stirred at room temperature for 16 h. The solution was diluted with 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) as a colorless solid. 1 H 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] + .

[0348] Example 39 2-amino-3-(2-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)propan-1-ol [ka] Step a) 5-chloro-3-fluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 hours. 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 to give 39.3 (11.23 g, 76%). UPLC retention time 1.47 min (Method A). 1 H 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] + .

[0349] Step b) (4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)boronic acid (39.4). To a solution of 39.3 (11.20 g, 32.0 mmol) in THF (90 mL) and water (90 mL) was added NaIO (20.56 g, 96 mmol), and the mixture was stirred at 25 °C for 72 h. HCl (1 N, 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, and the combined organic layers were dried over NaSO, filtered, and concentrated. The residue was triturated with cyclohexane, and the resulting solid was filtered off, washed with cyclohexane, and dried in vacuo to give 39.4 (7.02 g, 78%) as a solid. UPLC retention time 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] + .

[0350] Step c) (S)-Methyl 2-((tert-butoxycarbonyl)amino)-3-(2H-tetrazol-5-yl)propanoate (39.6). To a solution of 39.5 (900 mg, 3.94 mmol) in DMF (9 mL) was added NaN (769 mg, 11.83 mmol) and NEt·HCl (1628 mg, 11.83 mmol), 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 NaSO, filtered, and concentrated. The residue was purified on silica (gradient: cyclohexane / ethyl acetate) to give 39.6 (480 mg, 44%). 1 H 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] + .

[0351] Step d) Methyl 2-((tert-butoxycarbonyl)amino)-3-(2-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)propanoate (39.7). To a solution of 35.6 (400 mg, 1.475 mmol) in CHCl (8 mL) at 25 °C under argon was added 39.4 (631 mg, 2.359 mmol) KCO (224 mg, 1.622 mmol) and [Cu(OH)(TMEDA)]Cl (82 mg, 0.177 mmol). The blue mixture was stirred at 25 °C for 72 h under an oxygen atmosphere (balloon). The mixture was filtered through hyflo, the residue was washed with CHCl, and the combined solution was concentrated. The residue was purified on silica (gradient: cyclohexane / ethyl acetate) to give 39.7 (375 mg, 48%). The material was further purified by SFC. UPLC retention time 1.28 min (Method A). 1 H NMR(DMSO-d6):δ=8.29(1H,dd),8.08-8.14(3H,m),7.52(2H,d),7.27-7-4 9(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] + .

[0352] Step e) tert-Butyl (1-(2-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)-3-hydroxypropan-2-yl)carbamate (39.8). At 0 °C, LiBH (2N THF solution, 0.651 mL, 1.302 mmol) was added dropwise to a solution of 39.7 (107 mg, 0.217 mmol) in THF (2 mL), and the mixture was stirred for 2 h at 0 °C. The mixture was neutralized with HCl (1N aqueous solution), CHCl was added, the organic layer was separated, dried over NaSO, and the solvent was removed. Chromatography on silica (gradient: cyclohexane / ethyl acetate) gave compound 39.8 (63 mg, 63%). UPLC retention time 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] + .

[0353] Step f) 2-Amino-3-(2-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)propan-1-ol (Example 39). To a solution of 39.8 (63 mg, 0.137 mmol) in CHCl (1.5 mL) was added HCl (4N in dioxane, 0.515 mL, 2.059 mmol) and the mixture was stirred for 2 h at 25° C. The suspension was partially concentrated under a stream of argon. Filtration afforded the hydrochloride salt of Example 39 as a colorless solid (50 mg, 92%). UPLC retention time 0.76 min (Method A). 1 H 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] + .

[0354] Example 39 was found to be a racemic mixture of 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)propan-1-ol (Example 39S) was obtained from the racemate by chiral SFC (AD, 5 μm, 250 × 50 mm; mobile phase: 0.1% NH₃ in EtOH x HO, 40%).

[0355] Example 40 (2S)-2-amino-3-(2-(4-((3-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)propan-1-ol (hydrochloride) [ka] Step a) (2S)-2-Amino-3-(2-(4-((3-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)propan-1-ol (Example 40). A suspension of Example 39S (950 mg, 2.60 mmol), 40.1 (1449 mg, 5.21 mmol), KPO (1106 mg, 5.21 mmol), and PdCl(dtbpf) (136 mg, 0.208 mmol) in a mixture of dioxane (9.5 mL) and water (3.166 mL) was stirred at 90° C. for 1.5 hours under argon. Additional 40.1 and PdCl(dtbpf) were added, and heating was continued for 1 hour. 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 (gradient: cyclohexane / ethyl acetate) to give 40.2 (518 mg, 49%). The material was dissolved in DMF (20 mL), SiliaMetS DMT was added, and the mixture was stirred for 16 hours at 50 °C. The scavengers were filtered off, and the residue was washed with CH2Cl2 / MeOH and concentrated to give a solid that was used in the next step. UPLC retention time 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] + .

[0356] Step b) (S)-2-Amino-3-(2-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)propan-1-ol (Example 40). To a solution of 40.2 (510 mg, 1.061 mmol) in THF (7 mL) was added HCl (2 mL 2N) and the mixture was stirred at 25° C. for 1.5 hours. The mixture was concentrated and the residue was purified on silica (gradient: CHCl / MeOH) to give the hydrochloride salt of Example 40 (289 mg, 61%). UPLC retention time 0.65 min (Method A). 1 H NMR(DMSO-d6):δ=8.47(1H,d),8.23-8.33(4H,m),8.07-8.23(2H,m),7.82(1H,d),7.4 7-7.59(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] + .

[0357] Example 41: Free Base Type 1 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)propan-1-ol / (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol Step 1: Synthesis of 2-(4-bromophenoxy)-5-chloro-3-fluoropyridine: Reaction scheme [ka] Synthesis Procedure: A cleaned round-bottom (RB) flask was charged with DMF, potassium carbonate (69.32 g, 0.5016 mol, 1.50 eq), 2,3-difluoro-5-chloropyridine (50 g, 0.3344 mol, 1.0 eq), and 4-bromophenol (57.85 g, 0.3344 mol, 1.0 eq), and the mixture was stirred at a temperature of 40±5°C. The reaction mass was cooled and slowly charged with purified water. The product was filtered and washed with purified water, followed by drying the material to give 2-(4-bromophenoxy)-5-chloro-3-fluoropyridine. 1 H NMR (DMSO-d6,400MHz): δ=7.20(dd,J=5.2,3.2Hz,2H),7.62(dd,J=5.6,3.2Hz,2H),8.06(d,J=2.4Hz 1H),8.25(dd,J=10,2.4Hz 1H), HPLC purity: >98% area, RT: 21.73 min

[0358] [Table 5]

[0359] Step 2 and Step 3: Synthesis of 2-(4-(1H-pyrazol-3-yl)phenoxy)-5-chloro-3-fluoropyridine Reaction scheme [ka]

[0360] A1 Experimental Procedure: A round-bottom flask was charged with 2-methyltetrahydrofuran-com, purified water, 1H-pyrazole, 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- (119.52 g, 0.4 mol, 1.30 eq), potassium phosphate tribasic (210.50 g, 1 mol, 3 eq), and A1-2 (100 g, 0.3 mol, 1.0 eq). The reaction mass was purged under nitrogen. Triphenylphosphine palladium(0) (19.09 g, 0.016 mol, 5 mol%) was purged and charged. The mass temperature was heated to 70 ± 5 °C for 3 hours. The mass temperature was cooled and purified water was charged. The product was extracted into ethyl acetate. The aqueous layer was back-extracted with ethyl acetate. The combined organic layers were washed with purified water followed by brine solution. The organic layer was dried over sodium sulfate-Com, and the organic layer was concentrated under vacuum at less than 45°C to approximately 5.0 w / v. 4M hydrochloric acid in ethyl acetate was added to the reaction mass and stirred at 25±5°C for 3 hours. The product was filtered and washed with ethyl acetate. Purified water and the wet material were placed in an RB flask and ethyl acetate was added. The pH was adjusted to 7-8 using saturated sodium bicarbonate solution. The organic layer was separated and washed with brine solution, followed by drying over sodium sulfate. The organic layer was concentrated and crystallized from n-heptane to give 2-(4-(1H-pyrazol-3-yl)phenoxy)-5-chloro-3-fluoropyridine. 1 H NMR (DMSO-d6,400MHz): δ=6.72(dd,J=5.2,3.2Hz,1H),7.22(m,2H),7.79(m,1H),7.86(m,2) H),8.07(d,J=2Hz,1H),8.23(dd,J=4.8Hz,2.4Hz,1H),13.08(bs,1H),HPLC purity:>97&area,HPLC RT: 17.27 minutes, MS / ESI+290.20. HPLC RT: 17.27 minutes

[0361] [Table 6]

[0362] Step 4: Synthesis of tert-butyl (S)-(1-((tert-butyldimethylsilyl)oxy)-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-2-yl)carbamate (A3) Reaction scheme [ka] Testing Procedure: A washed RB flask was charged with DMF, A1 (50 g, 0.1725 mol, 1.0 eq.), and cesium carbonate (112.4 g, 0.345 mol, and 2.0 eq.). In a separate vessel, A2 (69.80 g, 0.1898 mol, and 1.10 eq.) was prepared in DMF. The A2 solution was slowly added to the reaction mass containing A1, and the reaction mass was maintained for 4 hours. The reaction mass was 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 layers were charged with purified water, and the pH was adjusted using 1% citric acid solution. Subsequently, the organic layer was washed with saturated sodium bicarbonate solution, purified water, and brine solution. The organic layer was dried over sodium sulfate, and the organic layer was 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 fractions were collected and concentrated under vacuum to give tert-butyl (S)-(1-((tert-butyldimethylsilyl)oxy)-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-2-yl)carbamate as a viscous syrup. 1H NMR (DMSO-d6, 400 MHz): δ = 0.046 (s, 6H), 0.0850 (s, 9H), 1.1372 (s, 9H), 3.54 (m, 2H), 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 Hz, 2H), 8.06 (d, J = 2 Hz, 1H), 8.22 (dd, J = 10 Hz, 2.4 Hz, 1H) and additional reagent and solvent signals were observed. HPLC purity: >95% area.

[0363] Chromatography conditions:

[0364] [Table 7]

[0365] Step 5: Synthesis of tert-butyl ((2S)-1-((tert-butyldimethylsilyl)oxy)-3-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-2-yl)carbamate (A5) Reaction scheme [ka] Testing Procedure: An RB flask was charged with THF, A3 (90 g, 0.1559 mol, 1.0 eq.), K3PO4 (99.26 g, 0.4676 mol, 3.0 eq.), and XPHOS (4.45 g, 0.009 mol, 0.06 eq.), followed by purified water. The reaction mass was flushed with nitrogen. In parallel, solution A4 in THF was prepared. Pd(OAc)2 (2.09 g, 0.009 mol, 0.06 eq.) was charged, and the reaction mass was heated to 50 ± 5 °C. The A4 solution was added slowly at 50 ± 5 °C. After the addition was complete, the reaction mass was maintained at 50 ± 5 °C for 2-3 hours. The reaction mass was cooled, and purified water was added slowly, followed by ethyl acetate. The reaction mass was filtered through a celite bed, and the celite 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 10% brine solution, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using EtOAc (10%) and n-heptane (90%) as eluents. 1 H NMR(DMSO-d6,400MHz):δ=0.04(s,6H),0.09(s,9H),1.134(s,9H),1.53(m,4H),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=2Hz, 1H),6.70(d,J=2Hz,1H),6.83(d,J=8.8Hz,1H),7.27(m,2H),7.61(d,J=1.6Hz,1H),7.69(d,J =2.4Hz,1H),7.85(m,2H),8.02(dd,J=11.2Hz,2.0Hz,1H),8.10(d,J=2Hz,1H),HPLC purity:>97% area Note: Additional reagent and solvent signals were observed in the NMR signals.

[0366] [Table 8]

[0367] Step 6 Synthesis of (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol (A6) Reaction scheme [ka] Testing Procedure: A washed RB flask was charged with A5 and absolute alcohol. Cooled to 0-5°C and 4M HCl in EtOAc was slowly added. The reaction mass temperature was raised to 25±5°C for 12 hours. The reaction mass was concentrated under vacuum to 1-2 volumes below 50°C. Absolute alcohol was charged and the reaction mass temperature was raised to 50±5°C and maintained for 1 hour. The reaction mass was cooled and the mass was filtered. After washing with absolute alcohol, the material was basified with saturated NaHCO3, and the product was filtered and washed. The product was suspended in purified water at 60±5°C for 1 hour. The mass was cooled and the product was filtered. The material was dried under vacuum in a VTD at 55±5°C for 8 hours. The material was dissolved in THF and treated with silyl-bound thiol to remove residual metal. The THF was concentrated and the product was dissolved in methanol and filtered to give (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol (A6). 1 H NMR (DMSO-d6,400MHz):δ=1.55(bs,2H),3.10(m,1H),3.28(m,2H),3.96(m,1H),4.18(m,1H),4.71(t,1H),6.69(d,J=2Hz,1H),6.82(d,J=2.4Hz, 2H),7.22(d,J=8.8Hz,1H),7.76(d,J=2Hz,2H),7.83(d,J=8.4Hz,2H),8.22(dd,J=11.2Hz,1.6Hz,1H),8.42(d,J=1.6Hz,1H)HPLC purity:>99% area, HPLC RT: 10.03 minutes, MS / ESI+395.10

[0368] [Table 9]

[0369] The isolated material was characterized by various methods to determine its physicochemical properties. The isolated material was a highly crystalline powder consisting of needle-like and plate-like particles. The isolated material was analyzed by XRPD, DSC, and TGA (Figures 1A, 1B, and 1C, respectively). The material was highly pure and exhibited a dehydration endotherm at approximately 45°C with an enthalpy of 19 J / g, followed by a small melting endotherm and a closely spaced exothermic recrystallization event at approximately 110°C. Finally, a melting point at approximately 146°C with an enthalpy of 121 J / g can be seen. The loss on drying was determined to be 1.4% by TGA, which was confirmed by Karl Fischer titration.

[0370] [Table 10]

[0371] Example 42: (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol / (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol free base type 2 form D 300 mg of Example 41 was added to 5 mL of ethanol in a vial. The sample was stirred at 500 rpm at 50° C. The suspension was periodically vortexed to break up clumps that formed over time. After 4 hours, the suspension was stirred at 500 rpm at room temperature overnight. The solid was collected by centrifugal filtration and dried under vacuum at 50° C. The isolated material was analyzed by XRPD, DSC, and TGA (FIGS. 2A, 2B, and 2C, respectively).

[0372] The crystalline form of free base Type 2 (Form D) melted at about 146°C and exhibited a glass transition at 52°C after reheating the molten sample.

[0373] The crystalline form free base Type 2 (Form D) had a loss on drying of about 0.15% by TGA.

[0374] The crystalline form free base type 2 (form D) was shown by DVS to be hygroscopic, reversibly absorbing 3% water above 70% RH and converting to the hydrated form.

[0375] [Table 11]

[0376] [Table 12]

[0377] Example 43: (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol / (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol hydrochloride salt (Form E) 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. An additional 2 mL of ethanol was added to dilute the suspension, and the mixture was stirred for 3 hours. The suspension was then stirred at 300 rpm at room temperature overnight. The solid was isolated by centrifugal filtration and dried under vacuum at 50° C. overnight. The isolated material was analyzed by XRPD, DSC, and TGA (Figures 3A, 3B, and 3C, respectively).

[0378] The hydrochloride salt (Form E) melted at approximately 236°C with a corresponding glass transition at 91°C.

[0379] The hydrochloride salt (Form E) exhibited a loss on drying of approximately 0.5% by TGA.

[0380] The hydrochloride salt (Form E) was slightly hygroscopic, absorbing only 0.6% water vapor at 95% RH.

[0381] [Table 13]

[0382] Example 44: (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol hippurate (Form B) 300 mg of Example 41, 150 mg hippuric acid, and 3 mL ethanol were added to a vial. The sample was stirred at 500 rpm at 50°C. An additional 2 mL of ethanol was added to dilute the suspension, and the mixture was briefly sonicated. After 3 hours, the suspension was stirred at 300 rpm at room temperature overnight. The solid was isolated by centrifugal filtration for characterization. The isolated material was characterized by XRPD, DSC, and TGA (Figures 4A, 4B, and 4C, respectively). The hippuric acid salt (Form B) is a highly crystalline form with a melting point of approximately 180°C and a melting enthalpy of 134 J / g. It showed a weight loss of approximately 0.3% at 170°C by TGA. Modification B is very slightly hygroscopic, absorbing approximately 0.3% water at 95% RH.

[0383] 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)propan-1-ol hippurate) (A7-Form B) Reaction scheme [ka] Testing Procedure: A washed RB flask was charged with methanol and A6 (Example 41) (80 g, 0.202 moles, 1.0 equiv.). The reaction mass was heated to 55±5°C to obtain a clear solution. Hippuric acid (40 g, 0.2244 moles, 1.1 equiv.) predissolved in methanol was slowly added. 0.08 wt. % A7 seed material was added at 55±5°C and maintained for 6 hours. The mass was concentrated to a stirrable volume and filtered. The product was filtered and washed with methanol to obtain (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol hippurate) (A7). 1 H NMR (DMSO-d6,400MHz):δ=3.31(m,4H),3.84(d,J=6Hz,2H),4.06(m,1H),4.25(m,1H),6.72(d,J=2.4Hz,1H),6.83(d,J=2.4Hz,1H),7. 24(m,2H),7.51(m,3H),7.83(m,6H),8.23(dd,J=11.2Hz,1.6Hz,1H),8.43(d,J=2Hz,1H),8.61(t,1H), HPLC chemical purity: >99%, chiral purity: >99% area.

[0384] [Table 14]

[0385] [Table 15]

[0386] [Table 16]

[0387] Example 45: Hippuric Acid Salt 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)propan-1-ol / (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol The hippuric acid salt (Form A) was obtained by reverse antisolvent precipitation from tetrahydrofuran / water (95:5) into ethyl acetate. The isolated material was characterized by XRPD, DSC, and TGA (Figures 5A, 5B, and 5C, respectively). It exhibited a melting point of approximately 172°C with a melting enthalpy of approximately 106 J / g. Modification Form A was also very slightly hygroscopic, absorbing approximately 0.5% water at 95% RH. The hippuric acid salt (Form A) melted at approximately 172°C with a corresponding glass transition of 77°C, respectively. The hippuric acid salt (Form A) exhibited a loss on drying of 0.2% by TGA. The hippuric acid salt (Form A) was slightly hygroscopic, absorbing only 0.5% water vapor at 95% RH.

[0388] [Table 17]

[0389] Example 46: (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol / (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol L-Tartrate Salt (Form F) (2:1 ratio tartaric acid:compound) 300 mg of Example 41, 57 mg of L-tartaric acid, and 5 mL of ethanol were added to a vial. The mixture was stirred at 500 rpm at 50°C for 4 hours, periodically vortexing to break up clumps that formed over time. The suspension was then stirred at 500 rpm overnight at room temperature. The solid was isolated by centrifugal filtration and dried under vacuum at 50°C. The isolated material was characterized by XRPD, DSC, and TGA (Figures 6A, 6B, and 6C, respectively). The (2:1) L-tartrate salt melted with decomposition at 215°C.

[0390] [Table 18]

[0391] Summary of methods used for crystal morphology characterization: Powder X-ray diffraction X-ray powder diffraction (XRPD) patterns were obtained using a Bruker D8 Advance in reflection geometry. Powders were analyzed using a zero-background Si-wafer sample holder. Radiation was Cu Kα (1=1.5406 Å). Patterns were measured from 3° to 45° 2θ.

[0392] DSC: Differential scanning calorimetry was performed on each crystalline form using a TA Instrument (Q2000). For each analysis, 0.5-2 mg of sample was placed in an aluminum pan (TI20608). The heating rate was 10°C per second over the temperature range of 30-300°C. Temperatures are reported in degrees Celsius (°C), and enthalpies are reported in joules per second (J / g). The plot shows the endothermic peak downward. The endothermic melting peak (melting point) was estimated by the extrapolated onset temperature. The accuracy of the measured sample temperature by this method is within approximately ±1°C, and the heat of fusion can be measured within approximately ±5% relative error.

[0393] Thermogravimetric analysis (TGA): TGA curves were obtained using a TA-Instrument Q5000. Samples of 0.5 to 2 mg were placed in open aluminum pans. TGA curves were measured from 30 to 300°C at 10°C / min. LoD (loss on drying) was calculated from 30°C to 100°C or 150°C. Weight loss is plotted against the measured sample temperature. Temperature is reported in degrees Celsius (°C) and weight loss in %.

[0394] [Table 19]

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, Ring B is a 5-membered heteroaryl; R １ is H or C １～４ is alkyl; X １ is N or CH; X ２ is N or CR ２ and R ２ is H or C １～４ is alkyl; R ３ teeth, 【Chemistry 2】 and X ３ is N or CH; X ４ is N or CH; Y is O, NR ａ or CH ２ and R ａ is H or C １～４ is alkyl; R ４ Ha, Halo, Halo C １～４ Alkoxy, C １～４ Alkoxy, HaloC １～４ Alkyl, C １～４ Alkyl, 5-membered heteroaryl and C １～５ cycloalkyl; and R ５ is H or halo) or a pharma- ceutically acceptable salt thereof.

2. Formula (IA): 【Chemistry 3】 2. The compound of claim 1 having the formula:

3. Formula (IB): 【Chemistry 4】 2. The compound of claim 1 having the formula:

4. Formula (IC): 【Chemistry 5】 2. The compound of claim 1 having the formula:

5. A) Formula (II): 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof; B) Formula (III): 【Chemistry 7】 or a pharma- ceutically acceptable salt thereof; C) Formula (IV): 【Chemistry 8】 or a pharma- ceutically acceptable salt thereof; D) Formula (V): 【Chemistry 9】 or a pharma- ceutically acceptable salt thereof; and E) Formula (VI): 【Chemistry 10】 or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, selected from:

6. X １ or a pharma- ceutically acceptable salt thereof.

7. R １ is H; or a pharma- ceutically acceptable salt thereof.

8. X ３ 2. The compound of claim 1, wherein: R is N and Y is O; or a pharma- ceutically acceptable salt thereof.

9. R ５ is H or halo, and R ４ Ha, Halo, Halo C １～４ Alkoxy, C １～４ Alkoxy, HaloC １～４ Alkyl, C １～４ Alkyl, 5-membered heteroaryl and C ３～５ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, selected from: cycloalkyl.

10. R ４ is cyclopropyl, Cl, Br, -OCH ３ , -OCHF ２ , C.F. ３ , pyrazolyl, oxazolyl, and R ５ is H or F, or a pharma- ceutically acceptable salt thereof.

11. (S)-2-amino-3-(3-(3-((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol; (S)-2-amino-3-(3-(3-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol; (S)-2-amino-3-(3-(3-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol; (S)-2-amino-3-(3-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol; (S)-2-amino-3-(3-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol; Ethyl (S)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-3-yl)propanoate; tert-butyl ((2S)-1-(3-(4-((3-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate; (R)-2-amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol; tert-butyl (S)-(1-(3-(3-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypropan-2-yl)carbamate; (S)-2-amino-3-(3-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol; (S)-2-amino-3-(3-(3-((R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol; (S)-2-amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol; (S)-3-(3-(4-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)-2-aminopropan-1-ol; (S)-2-amino-3-(5-(3-((R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl)-2H-tetrazol-2-yl)propan-1-ol; (S)-2-amino-3-(3-(3-((R)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol; (S)-2-amino-3-(3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol; (S)-2-amino-3-(3-(4-(((R)-1-phenylpropan-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol; (3S)-3-amino-4-(3-(4-((5-bromo-3-fluoropyridin-2-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)butan-2-ol; (R)-3-(5-(4-((5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)-2-aminopropan-1-ol; (R)-3-(5-(4-((5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)-2-aminopropan-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)propan-1-ol; (S)-2-amino-3-(5-(5-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)pyridin-2-yl)-2H-tetrazol-2-yl)propan-1-ol; (S)-2-amino-3-(3-(5-((5-chloro-3-fluoropyridin-2-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)propan-1-ol; (S)-2-amino-3-(3-(3-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol; (S)-2-amino-3-(4-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol; (S)-2-amino-3-(3-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol; (S)-2-amino-3-(5-(4-(4-chlorophenoxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol; (S)-2-amino-3-(5-(4-((5-cyclopropylpyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol; (S)-2-amino-3-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol; (R)-2-amino-3-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol; (R)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol; (S)-2-amino-3-(5-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol; (S)-2-amino-3-(5-(4-((5-bromopyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol; (S)-2-amino-3-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)propan-1-ol; (S)-2-amino-3-(5-(6-(4-chlorophenoxy)pyridin-3-yl)-2H-tetrazol-2-yl)propan-1-ol; (S)-3-(3-(4-((5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)-2-aminopropan-1-ol; (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol; (2S)-2-amino-3-[5-(4-[[3-fluoro-5-(1,3-oxazol-2-yl)pyridin-2-yl]oxy]phenyl)-2H-1,2,3,4-tetrazol-2-yl]propan-1-ol; (S)-2-amino-3-(2-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)propan-1-ol; (R)-2-amino-3-(2-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)propan-1-ol; and (2S)-2-amino-3-(2-(4-((3-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-5-yl)propan-1-ol 2. The compound of claim 1, selected from:

12. The compound according to claim 1, which is (S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-5-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol, or its tautomer, ((S)-2-amino-3-(3-(4-((3-fluoro-5-(1H-pyrazol-3-yl)pyridin-2-yl)oxy)phenyl)-1H-pyrazol-1-yl)propan-1-ol), or a pharma-ceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 12 and one or more pharma- ceutically acceptable carriers.

14. A combination comprising a therapeutically effective amount of a compound according to any one of claims 1 to 12 or a pharma- ceutically acceptable salt thereof and one or more therapeutically active co-agents.

15. A compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, for use as a medicament.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 or a pharma- ceutical acceptable salt thereof for use in the treatment of diseases and / or disorders mediated by LTA4H inhibition, said diseases and / or disorders being acute or chronic inflammation, anaphylactic reactions, allergic reactions, atopic dermatitis, psoriasis, acute respiratory distress syndrome, immune complex-mediated pulmonary wounds and chronic obstructive pulmonary disease, inflammatory bowel disease (including ulcerative colitis, Crohn's disease and post-operative trauma), gastrointestinal ulcers, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), neutrophilic dermatoses (including but not limited to pyoderma gangrenosum, Sweet's syndrome, acne and neutrophilic urticaria), immune complex-mediated glomerulonephritis, suppuration. a pharmaceutical composition selected from hidradenitis purpura, autoimmune diseases (including but not limited to 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-Schonlein purpura), cardiovascular disorders (including but not limited to hypertension, atherosclerosis, aneurysm, critical limb ischemia, peripheral arterial occlusive disease, pulmonary arterial hypertension and Raynaud's syndrome), sepsis, inflammatory and neuropathic pain including arthralgia, periodontal disease including gingivitis, ear infections, migraine headaches, benign prostatic hyperplasia, Sjogren-Larsson syndrome and cancer (including but not limited to leukemia and lymphoma, prostate cancer, breast cancer, lung cancer, malignant melanoma, renal carcinoma, head and neck tumors and colorectal cancer).

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