Inhibitor compounds

Abstract

To provide compounds beneficial for inhibiting dihydroceramide desaturase 1 (Des1) in diseases, specifically for treating fibrosis, compositions containing the compounds as well as methods.SOLUTION: There are provided compounds having Des1 inhibitory activity and compositions containing the compounds as well as a method for treating a disease, specifically fibrosis, in which administration of the composition is beneficial for inhibiting Des1. The compounds having Des1 inhibitory activity is specifically represented for example by the formula shown below.SELECTED DRAWING: None

Description

[Technical Field]

[0001]

[0001] This disclosure relates generally, but not exclusively, to compounds and their uses in therapy, for example, as enzyme interacting agents that interact with one or more enzymes in the sphingolipid biosynthetic pathway, e.g., dihydroceramide desaturase. This disclosure further relates to the use of such compounds as research tools, their use in therapy, compositions and medicaments containing said compounds, their manufacture, and methods of treatment using said compounds. [Background technology]

[0002]

[0002] Reference in this specification to any prior publication (or information derived therefrom) or to any publicly known matter is not, and should not be, treated as an acknowledgement, admission, or any form of suggestion that the prior publication (or information derived therefrom) or publicly known matter forms part of the common general knowledge in the field to which this specification relates.

[0003]

[0003] Sphingolipids are a class of compounds defined by their common 18-carbon aminoalcohol backbone that mediate cell-cell and cell-substratum interactions, modulate the behavior of cellular proteins and receptors, and participate in signal transduction. Sphingolipids are synthesized de novo from palmitoyl-CoA and serine via a pathway in which the carbon backbone, alcohol, and amino groups are modified to form various bioactive compounds, such as dihydroceramide, ceramide, sphingosine, and sphingosine-1-phosphate (Scheme 1). Disruptions in the sphingolipid biosynthetic pathway are implicated in numerous physiological and pathophysiological processes, including cancer, diabetes, fibrosis, inflammation, viral infection, and Alzheimer's disease.

[0004] [ka]

[0005]

[0004] Dihydroceramide desaturase (Des) introduces a double bond at C4 of the C18 backbone, converting dihydroceramide (dhCer) to ceramide (Cer). Two isoforms of Des exist: Des1 and Des2. Des1 is considered the major component of Cer production in most tissues, while Des2 primarily acts as a C4-hydroxylase, converting Cer to phytoceramides. Des1 is found in most tissues, while Des2 expression is primarily restricted to the skin, intestine, and kidney. Because both dhCer and Cer can undergo reversible conversion to other sphingolipids, including sphingosine (Sph) and sphingosine-1-phosphate (S1P), Des1 effectively controls the C4 saturation state of all sphingolipids. The activation state of Des1 controls the ratio of dihydrosphingolipids to C4-unsaturated sphingolipids, which have different and sometimes opposing effects on cellular function. Increased expression and / or activity of Des1 increases the levels of bioactive C4-unsaturated sphingolipids and is associated with disease progression in numerous diseases, including cancer, inflammation, fibrosis, and metabolic disorders. Therefore, the use of Des1 inhibitors in drug therapy for the treatment of various diseases, including cancer, inflammatory bowel disease (IBD), diabetes, nonalcoholic steatohepatitis (NASH), cystic fibrosis, heart failure, chronic kidney disease, and viral and bacterial infections, has been proposed (Gagliostro V et al., Prog. Lipid Res. 2012, 51, 82-94; Siddique, MM et al., J. Biol. Chem. 2015, 290, 15371-15379; Magaye, R., R. et al., Cell. Mol. Life Sci. 2019, 76, 1107-1134; Vieira, CR et al., Chem. Biol. 2010, 17, 766-775). Summary of the Invention [Means for solving the problem]

[0006] In one or more embodiments, the present disclosure provides compounds having Des1 inhibitory activity. In one or more embodiments, the present disclosure provides compounds that may have beneficial therapeutic activity in the treatment of diseases or conditions mediated by excessive or otherwise undesirable Des1 and / or fibrotic activity.

[0007] In one aspect, the present disclosure provides a compound of formula (I'):

[0008] [ka]

[0009] (In the formula, A 1 ~A 5 is CR a and N are independently selected from A 1 ~A 5 any 0, 1, 2, 3 or 4 of may be N; Each R a are independently H or R aa and R aa is selected from halo, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, cycloamino, halocycloamino, alkoxylalkyl, and alkoxyalkoxy; Q is a 5-membered aromatic heterocycle having two, three, or four ring heteroatoms, at least one of which must be N, the remainder being independently selected from N, O, and S, and the ring carbon atom bearing a hydrogen atom or the ring nitrogen atom bearing a hydrogen atom, when present, is optionally selected from halo, haloalkyl, and alkyl. a may be substituted with W is

[0010] [ka]

[0011] is a 6-membered N-containing heterocycle selected from R b teeth, -OH (where R b is OH, with the proviso that W is (E) or (I). ( -K-NR c -Y, or its tautomer, -(CH2) p -NH-OH, and

[0012] [ka]

[0013] is selected from K is SO, SO2, C(=X') or NHC(=X'), where X' is O or NH; R c is H, C 1~6 Alkyl or hydroxy C 1~6 is alkyl, Y, OH, NHR e (R e is H, C 1~6 Alkyl, -(C=O)H or -(C=O)C 1~6 alkyl), hydroxy C 1~6 Alkyl or (SC 1~6 Alkyl)C 1~6 is alkyl, p is 0 or 1, R d H, OH, halo, C 1~6 Alkyl and C 1~6 alkoxy) provided that the compound has the formula

[0014] [ka]

[0015] provided that the A 1 ~A 5Any four of these are CH and the others are CR a and R a is H, halo, CH3, or OCH3, or a pharmaceutically acceptable salt or solvate thereof.

[0016] In another embodiment, the compound of formula (I") (wherein R b and R d is rearranged), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the 5-membered aromatic heterocycle has two or three ring heteroatoms.

[0017] [ka]

[0018] (wherein # represents a bond connecting to NH, * is aryl or A 1 ~A 5 represents a bond connecting to a heteroaryl ring defined by In some embodiments, Q a Ha, Halo, C 1~6 alkyl (i.e., C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl), and haloC 1~6 alkyl (i.e., haloC1 alkyl, haloC2 alkyl, haloC3 alkyl, haloC4 alkyl, haloC5 alkyl or haloC6 alkyl).

[0019] In some embodiments, A 1 ~A 5 Each of the a In some further embodiments thereof, CR a One or two of the following are CR aa and the remainder are CH. In some further embodiments, at least A 3 is CR aa is.

[0020] In some embodiments, A 1 , A 2 , A 4 and A 5 In some embodiments thereof, 0, 1, 2, 3 or 4 of A are N. 3 is CR aa is. In some embodiments, at least A 3 is CR aa In some further embodiments, A 3 is CR aa and A 1 , A 2 , A 4 and A 5 Each A is CH. 3 is CR aa and A 4 or A 2 One of the same or different CR aa In some embodiments, A 1 , A 2 , A 3 , A 4 or A 5 Any one or two of A may be N. In some embodiments, A 3 is CR aa and A 1 or A 5 is N. In a further embodiment thereof, A 3 is CR aa and A 1 or A 5 is N and the remaining A's are CH.

[0021] In some embodiments, A 5 Or A 1 is N or A 2 Or A 4 is N or A 1 and A 5 are both N or A 2 and A 4 are both N or A 1 and A4 , or A 2 and A 5 are both N or A 1 and A 2 Or A 4 and A 5 are both N. In some of these embodiments, A 3 is CR aa is.

[0022] In some embodiments, W contains one or two ring nitrogen atoms, i.e., (A), (B), (D), (E), (F), (H), and (I). b In some embodiments where R is not OH, W is not a group of formula (E). b In some embodiments where R is not OH, W is not a group of formula (I). b In some embodiments where R is not OH, W is not a group of formula (I) or (E). b In some embodiments where R is not OH, W is b is a group having at least one N ring atom adjacent to or ortho to a ring carbon atom having

[0023] In some embodiments, Rb is OH and W is (E) or (I). In some embodiments, R b is K-NR C -Y, or its tautomer, or -(CH2) p In a further embodiment, NHR e NH2, NHC 1~3 Alkyl, NHC(=O)H, NH(C(=O)C 1~3 It is alkyl.

[0024] In some embodiments, R b is K-NR C -Y, or its tautomer, or -(CH2) p In a further embodiment, NHR is —NH—OH, and W is one of (A), (B), (C), (D), (F), (G), (H), (J). e NH2, NHC1~3 Alkyl, NHC(=O)H, NH(C(=O)C 1~3 It is alkyl.

[0025] R d may be selected from H, OH, F, Cl, Br, I, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C1 alkoxy, C2 alkoxy, C3 alkoxy, C4 alkoxy, C5 alkoxy, C6 alkoxy. d is H, OH, F, Cl, Br, I, CH3 or OCH3.

[0026] In another aspect, the disclosure provides a composition comprising a compound of formula (I') and / or (I"), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0027] The present disclosure also provides a compound of formula (I') and / or (I"), or a pharmaceutically acceptable salt or solvate thereof, or a composition comprising said compound or a pharmaceutically acceptable salt or solvate thereof, for use as an agent for inhibiting or otherwise interacting with Des1.

[0028] The present disclosure also provides compounds of formula (I') and / or (I"), or a pharmaceutically acceptable salt or solvate thereof, or compositions comprising said compounds or pharmaceutically acceptable salts or solvates thereof, for use in therapy, e.g., in the treatment of diseases or conditions in which Des1 inhibition is beneficial, and / or for treating fibrosis or fibrotic diseases.

[0029] A further aspect disclosed herein provides a method of treating a disease or condition in a subject in need thereof in which Des1 inhibition is beneficial, comprising administering to the subject a compound of formula (I') and / or (I"), or a pharmaceutically acceptable salt or solvate thereof.

[0030] In some embodiments, the disease or condition is a proliferative, inflammatory, or fibrotic disease. Yet another embodiment disclosed herein provides the use of a compound of formula (I') and / or (I"), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating a disease in which Des1 inhibition is beneficial.

[0031] Yet another embodiment disclosed herein provides the use of a compound of Formula (I') and / or (I"), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating fibrosis or a fibrotic disease.

[0032] Yet another aspect disclosed herein provides a method of treating fibrosis or a fibrotic disease in a subject in need thereof, comprising administering to the subject a compound of Formula (I') and / or (I"), or a pharmaceutically acceptable salt or solvate thereof.

[0033] In some embodiments, the compounds disclosed herein may also be useful as research tools, e.g., in investigating the role and activity of Des1, and / or as candidate, comparator, or control molecules in assays or models for Des1 activity or its inhibition, and / or as candidate, comparator, or control molecules in assays or models for one or more potential therapeutic uses, e.g., anti-fibrotic activity for the prevention or treatment of fibrosis. [Brief explanation of the drawings]

[0034] [Figure 1]Figure 1A is a graph illustrating proline uptake in renal mesangial cells stimulated with TGF-β1 (5 ng / ml) in the presence or absence of compound 8 at 0.01, 0.1, 3, and 10 M. Figure 1B is a graph illustrating proline uptake in renal mesangial cells stimulated with TGF-β1 (5 ng / ml) in the presence or absence of compound 46 at 0.01, 0.1, 3, and 10 M. Data are presented as the mean + / - standard deviation of raw H-proline counts per minute normalized to micrograms of protein. Data are from three independent experiments. One-way ANOVA with Tukey's post hoc analysis to correct for multiple differences. ***, **** = p<0.001 & 0.0001 compared to the zero control. ##, ###, #### = p<0.01, 0.001 & 0.0001 compared to TGF-β1 alone. [Figure 2] 2A and 2B are graphs showing concentration-dependent inhibition of TGF-β1-mediated αSMA expression in IPF donors in the presence of compound 8 (FIG. 2A) and compound 46 (FIG. 2B). The graphs show normalized data for percentage inhibition (PIN) and remaining cells (%). DETAILED DESCRIPTION OF THE INVENTION

[0035] Throughout this specification and the claims that follow, unless the context requires otherwise, the word "comprise" or variations such as "comprises" and "comprising" will be understood to imply the inclusion of a stated integer or step or group of integers, but not the exclusion of any other integer or step or group of integers or steps.

[0036] Throughout this specification and the claims that follow, unless the context requires otherwise, the phrase "consisting essentially of" or variations such as "consists essentially of" will be understood to indicate that the recited element(s) are essential or required elements of the invention. The phrase permits the presence of other unrecited elements that do not materially affect the characteristics of the invention, but excludes additional unspecified elements that would affect the basic and novel characteristics of the method being defined.

[0037] All aspects, embodiments and examples described herein are intended to be illustrative and not restrictive. is encompassed and contemplated by the term. As used throughout, the singular forms "a", "an" and "the" are intended to include plural aspects where appropriate unless the context clearly dictates otherwise.

[0038] Unless the context dictates otherwise, the features described below may apply independently to any aspect or embodiment of the invention. As used herein, the term "halo" (or "halogen") refers to fluoro (fluorine), chloro (chlorine), bromo (bromine) or iodo (iodine).

[0039] As used herein, the term "alkyl" (or "alk"), when used alone or in compounds such as alkoxy, haloalkyl, etc., refers to saturated straight or branched chain alkyl, preferably C 1~20 Alkyl, e.g., C 1~10 or C 1~6Examples of straight-chain and branched-chain alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, and 1,2,2-trimethylpropyl. , 1,1,2-trimethylpropyl, heptyl, 5-methylhexyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl, 6-methylheptyl, 1-methylheptyl, and 1,1,3,3-tetramethylbutyl. When an alkyl group is referred to generically as "propyl," "butyl," etc., it will be understood that this can refer to either the straight-chain or branched-chain isomer, where appropriate. An alkyl group may be used alone or in combination with R a and may be unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, 5, etc., where permitted) of the same or different optional substituents, either as part of a group such as alkoxy, haloalkyl, or haloalkoxy as defined for

[0040] The term "cycloalkyl" refers to non-aromatic monocyclic, bicyclic and polycyclic (including fused or bridged) hydrocarbon residues, such as C 3~20 (For example, C 3~10 or C 3~8 or C 3~6) monocyclic 5- to 6-membered or bicyclic 9- to 10-membered ring systems. Suitable examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopentenyl, cyclohexenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl, cyclooctatetraenyl, and decalinyl. The cycloalkyl group may be optionally substituted with one or more optional substituents as defined herein. In some embodiments, a monocycloalkyl group may be substituted with a bridging group to form a bicyclic bridged group.

[0041] "Halocycloalkyl" refers to a cycloalkyl group, as defined herein, that is substituted one or more times independently with one or more of the same or different halogen atoms. One or more carbon atoms (e.g., one, two or more) are independently substituted with one or more halogen atoms. In some embodiments, two hydrogen atoms bonded to any one carbon ring atom are replaced with the same or different halogen atoms. In some embodiments, one hydrogen atom bonded to any one carbon ring atom is replaced with a halogen atom. Some non-limiting examples include chloro-, iodo-, fluoro- or bromo-cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. and dichloro-, diiodo-, difluoro- or dibromo-cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0042] "Cycloalkoxy," when used alone or in compound words, represents cycloalkyl as defined herein when linked to an oxygen atom. Some non-limiting examples include OC 3~6 Includes cycloalkyl (eg, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy).

[0043] The term "cycloamino" refers to a cycloalkyl group, as defined herein, in which a carbon atom is replaced by a nitrogen atom. The cycloamino group may be linked via a carbon ring atom or a nitrogen ring atom. In some embodiments, the carbon atom linked to the group is replaced by nitrogen, i.e., the cycloamino group is linked through a nitrogen atom. Some exemplary groups include 3-, 4-, 5-, and 6-membered rings, such as aziridinyl, azetidinyl, pyrrolidinyl, and piperidinyl. In embodiments in which the cycloamino group is linked via a carbon atom, the ring nitrogen may be unsubstituted or may be substituted with one or two of the same or different C 1~6 It may be substituted with an alkyl group, for example, a C1 alkyl, a C2 alkyl, a C3 alkyl, a C4 alkyl, a C5 alkyl, or a C6 alkyl.

[0044] The term "halocycloamino" refers to a cycloamino group that is substituted one or more times, independently, with one or more of the same or different halogen atoms. One or more carbon atoms (e.g., one, two or more) are independently substituted with one or more halogen atoms. In some embodiments, all hydrogen atoms bonded to any one carbon atom are replaced with the same or different halogen atoms. In some embodiments, two hydrogen atoms bonded to any one carbon atom are replaced with the same or different halogen atoms. In some embodiments, one hydrogen atom bonded to any one carbon atom is replaced with a halogen atom. Some non-limiting examples include chloro-, iodo-, fluoro- or bromo-aziridinyl, azetidinyl, pyrrolidinyl, and piperidinyl, as well as dichloro-, diiodo-, difluoro- or dibromo-aziridinyl, azetidinyl, pyrrolidinyl, and piperidinyl.

[0045] "Alkoxy," when used alone or in compound words, represents alkyl, as defined herein, when attached to an oxygen atom. Some non-limiting examples include OC 1~6Included are alkyls (e.g., OMe, OEt, On-Pr, Oi-Pr, On-Bu, Oi-Bu, Ot-Bu).

[0046] "Haloalkyl" refers to an alkyl group, as defined herein, that is substituted one or more times, independently with one or more of the same or different halogen atoms. When an "alkyl" contains multiple carbon atoms, some (e.g., one, two or more) or all of the carbon atoms are independently substituted with one or more halogen atoms. In some embodiments, all hydrogen atoms bonded to any one carbon atom are replaced with the same or different halogen atoms. In some embodiments, two hydrogen atoms bonded to any one carbon atom are replaced with the same or different halogen atoms. In some embodiments, one hydrogen atom bonded to any one carbon atom is replaced with a halogen atom. An alkyl group may be straight-chain or branched-chain. Some non-limiting examples of "haloalkyl" include haloC 1~6 Alkyl, e.g., -(CH2) q CF3, -(CH2) q CCl3, -(CH2) q CBr3, -(CH2) q CHF2, -(CH2) q CHCl2, -(CH2) q CHBr2, -(CH2) q CH2F, -(CH2) q CH2Cl and -(CH2) q CH2Br (wherein q is 0, 1, 2, 3, 4, or 5).

[0047] "Haloalkoxy" refers to a haloalkyl group as defined above when linked to an oxygen atom. Some non-limiting examples include O(haloC 1~6 alkyl), e.g., -O(CH2) q CF3, -O(CH2) q CCl3, -O(CH2) q CBr3, -O(CH2) q CHF2, -O(CH2) q CHCl2 and -O(CH2)q CHBr2, -O(CH2) q CH2F, -O(CH2) q CH2Cl and -O(CH2) q CH2Br (wherein q is 0, 1, 2, 3, 4, or 5).

[0048] "Alkoxyalkyl" refers to an alkyl group, as defined herein, that is independently substituted one or more times with an alkoxy group. If the "alkyl" contains multiple carbon atoms, some (e.g., one, two or more) or all of the carbon atoms may be independently substituted with one or more of the same or different alkoxy groups. The alkyl group may be straight or branched chain, and the alkoxy group may be straight or branched chain. Some non-limiting examples of "alkoxyalkyl" include C 1~3 Alkoxy C 1~6 Alkyl, C 1~6 Alkoxy C 1~3 Alkyl and C 1~3 Alkoxy C 1~3 C containing alkyl 1~6 Alkoxy C 1~6 Some further non-limiting examples include -(CH2) q O(CH2) t H, where q is 1, 2, 3, 4, 5, or 6, and for any value of q, t is 1, 2, 3, 4, 5, or 6.

[0049] "Alkoxyalkoxy" refers to an alkoxy group, as defined herein, that is independently substituted one or more times with an alkoxy group. Some non-limiting examples include one or more times with the same or different C 1~6 Alkoxy groups (e.g., C 1~3 alkoxy), C 1~6 Alkoxy (e.g., C 1~3Some non-limiting examples include -OCH2OCH3, -O(CH2)2OCH3, -O(CH2)3OCH3, -OCHOCH2CH3, -O(CH2)2OCH2CH3, -O(CH2)2OCH2CH3, -O(CH2)3OCH2CH3, -OCHO(CH2)2CH3, -O(CH2)2O(CH2)2CH3, -O(CH2)3O(CH2)2CH3.

[0050] "Hydroxyalkyl" refers to an alkyl group, as defined herein, that is independently substituted one or more times (e.g., 1, 2, or 3 times) with a hydroxy group. Some non-limiting examples include hydroxy C 1~6 alkyl, i.e., C substituted one or more times (e.g., one, two, or three times) with a hydroxyl group; 1~6 The alkyl group may be straight or branched. In a further example, hydroxyalkyl includes hydroxy C 1~3 alkyl, i.e., C substituted one or more times (e.g., one, two, or three times) with hydroxy groups; 1~3 It refers to alkyl. Some non-limiting examples include -(CH2)OH, -(CH2)2OH, -CH(OH)CH2OH, CH(OH)CH3, -(CH2)3OH, -CH(OH)(CH2)2OH, -CH2CH(OH)CH2OH, -(CH(OH))2CH3 and -(CH(OH))2CH2OH.

[0051] "(SC 1~6 Alkyl)C 1~6 "Alkyl" may be represented by one or more (e.g., one, two, or three) occurrences of -SC. 1~6 C, as defined herein, independently substituted with an alkyl group. 1~6 Some non-limiting examples include the group -SC, which occurs one or more times (e.g., once, twice, or three times) 1~6 C substituted with alkyl group 1~3and alkyl. Alkyl groups may be straight-chained or branched. In a further example, some non-limiting examples include -(CH2)SCH3, -(CH2)2SCH3, -CH(SCH3)CH2SCH3, CH(SCH3)CH3, -(CH2)3SCH3, -CH(SCH3)(CH2)2SCH3, -CH2CH(SCH3)CH2SCH3, -(CH(SCH3))2CH3 and -(CH(SCH3))2CH2SCH3.

[0052] As defined herein, groups may be optionally substituted, i.e., substituted The optional substituents for "alkyl" or "alk", whether used alone or in a compound word, or as referenced in the definition of a term such as cycloalkyl or cycloamino, which may be further substituted as set forth below, include: Alkyl, (e.g., C 1~6 alkyl (e.g., methyl, ethyl, propyl, butyl), Cycloalkyl (e.g., C 3~6 cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), Hydroxyalkyl (e.g., hydroxy C 1~6 alkyl, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl); Alkoxyalkyl (e.g., C 1~6 Alkoxy C 1~6 alkyl, for example, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl); Alkoxy (e.g., C 1~6 alkoxy, for example methoxy, ethoxy, propoxy, butoxy); Alkoxyalkoxy (e.g., C 1~6 Alkoxy C 1~6Alkoxy, for example methoxymethoxy, methoxyethoxy, methoxypropoxy, ethoxymethoxy, ethoxyethoxy, ethoxypropoxy, propoxymethoxy, propoxyethoxy, propoxypropoxy), cycloalkoxy (e.g. cyclopropoxy, cyclobutoxy, cyclopentoxyl, cyclohexyloxy), Hello, Haloalkyl (mono-, di- and trihalo, e.g., haloC 1~6 alkyl, including, for example, trifluoromethyl, trichloromethyl, tribromomethyl); Haloalkoxy (mono-, di- and trihalo, e.g., haloC 1~6 alkoxy, including, for example, trifluoromethoxy, trichloromethoxy, tribromomethoxy; Hydroxy, Thiol (-SH), Alkylthio (e.g., -SC 1~6 alkyl), Phenyl (itself, e.g., C 1~6 Alkyl, halo, hydroxy, hydroxy C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, nitro, -OC(O)C 1~6 Alkyl, -NH2, -NHC 1~6 Alkyl, -NHC(O)C 1~6 Alkyl and -N(C 1~6 Alkyl)(C 1~6 alkyl), Benzyl (benzyl itself is e.g. C 1~6 Alkyl, halo, hydroxy, hydroxy C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Alkoxy C 1~6Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, nitro, -OC(O)C 1~6 Alkyl, -NH2, -NHC 1~6 Alkyl, -NHC(O)C 1~6 Alkyl and -N(C 1~6 Alkyl)(C 1~6 alkyl), Phenoxy (phenyl itself is e.g. C 1~6 Alkyl, halo, hydroxy, hydroxy C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, nitro, -OC(O)C 1~6 Alkyl, -NH2, -NHC 1~6 Alkyl, -NHC(O)C 1~6 Alkyl and -N(C 1~6 Alkyl)(C 1~6 alkyl), Benzyloxy (benzyl itself is e.g. C 1~6 Alkyl, halo, hydroxy, hydroxy C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy , cyano, nitro, -OC(O)C 1~6 Alkyl, -NH2, -NHC 1~6 Alkyl, -NHC(O)C 1~6 Alkyl and -N(C 1~6 Alkyl)(C 1~6 alkyl), -NH2, Alkylamino (e.g., -NHC 1~6 alkyl, for example, methylamino, ethylamino, propylamino, etc.), dialkylamino (for example, -NH(C 1~6 alkyl) 2, for example, dimethylamino, diethylamino, dipropylamino), acylamino (for example, -NHC(O)C 1~6 alkyl, for example -NHC(O)CH3), Phenylamino (i.e., -NHphenyl, phenyl itself can be used, e.g., C 1~6 Alkyl, halo, hydroxy, hydroxy C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, nitro, -OC(O)C 1~6 Alkyl, -NH2, -NHC 1~6 Alkyl, -NHC(O)C 1~6 Alkyl and -N(C 1~6 Alkyl)C 1~6 may be further substituted with one or more alkyl Nitro, Cyano, Formyl, -C(O)-alkyl (e.g., -C(O)C 1~6 acyl, including alkyl (e.g., acetyl); -OC(O)-alkyl (e.g., -OC(O)C 1~6 alkyl, e.g., acetyloxy), Benzoyl (benzyl itself is e.g. C 1~6 Alkyl, halo, hydroxy, hydroxy C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6Alkoxy, cyano, nitro, -OC(O)C 1~6 Alkyl, -NH2, -NHC 1~6 Alkyl, -NHC(O)C 1~6 Alkyl and -N(C 1~6 Alkyl)(C 1~6 alkyl), Benzoyloxy (benzyl itself is e.g. C 1~6 Alkyl, halo, hydroxy, hydroxy C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, nitro, -OC(O)C 1~6 Alkyl, -NH2, -NHC 1~6 Alkyl, -NHC(O)C 1~6 Alkyl and -N(C 1~6 Alkyl)(C 1~6 alkyl), CO2H, CO2 alkyl (e.g. CO2C 1~6 alkyl, e.g., methyl ester, ethyl ester, propyl ester, butyl ester); CO2 phenyl (phenyl itself is, for example, C 1~6 Alkyl, halo, hydroxy, hydroxy C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, nitro, -OC(O)C 1~6 Alkyl, -NH2, -NHC 1~6 Alkyl, -NHC(O)C 1~6 Alkyl and -N(C 1~6 Alkyl)(C 1~6alkyl), CO2 benzyl (benzyl itself is, for example, C 1~6 Alkyl, halo, hydroxy, hydroxy C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, nitro, -OC(O)C 1~6 Alkyl, -NH2, -NHC 1~6 Alkyl, -NHC(O)C 1~6 Alkyl and -N(C 1~6 Alkyl)(C 1~6 alkyl), -CONH2, -C(O)NHphenyl (phenyl itself is, for example, C 1~6 Alkyl, halo, hydroxy , hydroxy C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Alkoxy C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, nitro, -OC(O)C 1~6 Alkyl, -NH2, -NHC 1~6 Alkyl, -NHC(O)C 1~6 Alkyl and -N(C 1~6 Alkyl)(C 1~6 alkyl), -C(O)NHbenzyl (benzyl itself is, for example, C 1~6 Alkyl, halo, hydroxy, hydroxy C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Alkoxy C1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, nitro, -OC(O)C 1~6 Alkyl, -NH2, -NHC 1~6 Alkyl, -NHC(O)C 1~6 Alkyl and -N(C 1~6 Alkyl)(C 1~6 alkyl), -C(O)NH alkyl (e.g., C(O)NHC 1~6 alkyl, e.g., methyl ester, ethyl ester, propyl ester, butyramide); -C(O)NHdialkyl (e.g., C(O)NH(C 1~6 alkyl)2), Aminoalkyl (e.g., HNC 1~6 Alkyl-, C 1~6 AlkylHN-C 1~6 Alkyl- and (C 1~6 Alkyl)2N-C 1~6 alkyl-), Thioalkyl (e.g., HSC 1~6 alkyl-), Carboxyalkyl (e.g., HO2CC 1~6 alkyl-), Carboxy ester alkyl (e.g., C 1~6 Alkyl O2CC 1~6 alkyl-), amidoalkyl (e.g., HN(O)CC 1~6 Alkyl-, H(C 1~6 alkyl)N(O)CC 1~6 alkyl-), Formyl alkyl (e.g., H(O)CC 1~6 alkyl-), Acylalkyl (e.g., C 1~6 Alkyl(O)CC 1~6 alkyl-), Nitroalkyl (e.g., O2NC 1~6 alkyl-), Replacement of CH2 with C=O, and Two carbon atoms (1,2 or 1,3) are bonded to -O-(CH2)n -O- or -NH-(CH2) n It includes the case where each end is substituted with an —NH— group (wherein n is 1 or 2).

[0053] In some embodiments, each R a H, chloro, fluoro, bromo, iodo, haloC 1~6 Alkyl, (e.g., fluoroC 1~6 alkyl, e.g., -CHF2 and -CF3), C 1~6 Alkyl, C 1~6 Alkoxy C 3~6 Cycloalkyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, haloaziridinyl, haloazetidinyl, halopyrrolidinyl, halopiperidinyl and haloC 1~6 Alkoxy (e.g., fluoro C 1~6 In a further embodiment, each R a H, chloro, fluoro, bromo, iodo, haloC 1~3 Alkyl, C 1~3 Alkyl, C 1~3 Alkoxy, C 3~6 Cycloalkyl and HaloC 1~3 alkoxy.

[0054] In some embodiments, A 1 ~A 5 Each of the a In yet a further embodiment, A 3 In some further embodiments thereof, CR is not CH. a One or two of the following are CR aa and R aa is not H and the remainder are CH. In still further embodiments, R aa is selected from F, Cl, I, Me, cyclopropyl, difluoroazetidinyl, OMe, CHF2, CF3OCHF2, and OCF3.

[0055] In some embodiments, at least A 3 is CRaa and in a further embodiment thereof, A 3 is not CH. In some further embodiments, A 3 is CR aa and A 1 , A 2 , A 4 and A 5 Each A is CH. 3 is CR aa and A 4 or A 2 One of the same or different CR aa In still further embodiments, each R aa is F, Cl, I, Me, cyclopropyl, difluoroazetidinyl , OMe, CHF2, CF3OCHF2 and OCF3.

[0056] In some embodiments, A 1 , A 2 , A 3 , A 4 or A 5 Any one or two of A may be N. In some embodiments, A 5 Or A 1 is N or A 2 Or A 4 is N or A 1 and A 5 are both N, or A 2 and A 4 are both N, or A 1 and A 4 , or A 2 and A 5 are both N, or A 1 and A 2 Or A 4 and A 5 are both N. In some of these embodiments, A 3 is CR aa In still further embodiments, R aa are F, Cl, I, Me, cyclopropyl, difluoroazetidinyl, OMe, CHF2, CF3 It is selected from OCHF2 and OCF3.

[0057] In some embodiments, Q is a 5-membered aromatic heterocycle having 2, 3, or 4 ring heteroatoms, at least one of which must be N, the remainder being independently selected from N, O, and S, and optionally Q where permitted. a Heterocyclic groups (a) to (kk) optionally substituted with a group

[0058] [ka]

[0059] where the bond labeled # is attached to NH; * The bond labeled A 1 ~A 5 attached to an aryl ring defined by is selected from.

[0060] When Q contains a carbon or nitrogen ring atom bearing a hydrogen atom (e.g., (a), (b), (e), (f), (i), (j), (l), (m), (n), (o), (q), (r), (t), (u), (v), (w), (x), (y), (bb), (cc), (dd), (ee), (ff), (gg), (hh), and (ii)), that carbon or nitrogen atom is optionally substituted with a Q selected from halo, haloalkyl, and alkyl. a It may be substituted (i.e., a hydrogen atom is replaced) with a group, for example, Q a are Cl, F, Br, I, C 1~6 Alkyl (e.g., methyl, ethyl, n- and i-propyl, n-, sec- and t-butyl, pentyl, hexyl) and haloC 1~6 Alkyl (e.g. (CH2) q CF3, (CH2) q CCl3, (CH2) q CBr3, (CH2) q CHF2, (CH2) q CHCl2 and (CH2) q CHBr2, (CH2)q CH2F, (CH2) q CH2Cl and (CH2) q CHBr, where q is 0, 1, 2, 3, 4, or 5. In a further embodiment, Q a is selected from Cl, F, Br, I, CH3, CF3, CBr3, and CCl3. In some embodiments, the carbon or nitrogen ring atom is unsubstituted. In other embodiments, the carbon or nitrogen ring atom is selected from Q a is replaced by .

[0061] Q a Further non-limiting examples of some of Q having a carbon or nitrogen ring atom substituted with

[0062] [ka]

[0063] Includes: In further embodiments, Q a For example, Cl, F, Br, I, C 1~6 Included are alkyl (e.g., methyl, ethyl, n- and i-propyl). a is methyl.

[0064] In some embodiments, Q is a 5-membered aromatic heterocycle having two or three ring heteroatoms, at least one of which must be N, and the remainder being independently selected from N, O, and S, and the carbon or nitrogen ring atoms may be optionally substituted as described above.

[0065] In some embodiments, Q is Q1, Q2, Q3, Q4, or Q5

[0066] [ka]

[0067] (In the formula, X1 is O, S or NH, and X2 and X3 are independently CH or N, provided that they are not both CH (formulas (a), (b), (e), (f), (k), (p), (s), (t) and (u)); X5 is O, S or NH, and X4 and X6 are independently CH or N, provided that they are not both CH (formulas (c), (g), (j), (f), (m), (o), (r), (cc), (ee) and (gg)); X9 is O, S or NH, and X7 and X8 are independently CH or N, provided that they are not both CH (formulas (d), (h), (i), (l), (n), (q), (bb), (dd) and (ff)); X 10 ~X 13 are independently CH or N (formulas (v), (w), (x) and (y)). selected from one or more of Q is unsubstituted or a may be substituted with.

[0068] In some embodiments, Q has three ring heteroatoms (formulas (c), (d), (g), (h), (k)(p), (s), (v), w), (jj), and (kk)). In some examples thereof, Q has two ring nitrogen atoms and one ring oxygen atom. In other examples, Q has two ring nitrogen atoms and one ring sulfur atom. In other examples, Q has three ring nitrogen atoms.

[0069] In other embodiments, Q has two ring heteroatoms (formulas (a), (b), (e), (f), (i), (j), (l), (m), (n), (o), (q), (r), (t), (u), (x), (y), (hh), and (ii)). In some examples thereof, Q has one ring nitrogen atom and one ring oxygen atom. In other examples, Q has one ring nitrogen atom and one ring sulfur atom. In other examples, Q has two ring nitrogen atoms.

[0070] In other embodiments, Q has one or two nitrogen ring atoms and one ring oxygen atom (formulas (c), (d), (e), (f), (k)(l)(m), (n) and (o)). In other embodiments, Q has one or two nitrogen ring atoms and one ring sulfur atom (formulas (a), (b), (g), (h), (i)(j)(p), (q) and (r)).

[0071] In other embodiments, Q has two or three or four nitrogen ring atoms and no O or S ring atoms (formulas (s), (t), (u), (v), (w), (x), (y), (z), (aa), (bb), (cc), (dd), (ee), (ff), (gg) (hh), (ii), (jj), and (kk)).

[0072] In some embodiments, Q is selected from (c), (d), (f), (g), (h), (i), (j), (k), and (p). In some embodiments, Q is selected from (c), (d), (f), (h), (i), (j), (k), and (p).

[0073] In some embodiments, Q is selected from (c), (d), (f), (i), (j), (k), and (p). In some embodiments, Q is an oxadiazolyl group (formulas (c), (d), and (k)).

[0074] In some embodiments, Q is selected from (d), (f), (i), (k), (l), (n), (v), (y), (ee), (ff) (hh), and (kk). In some further embodiments, Q is selected from (f) and (k).

[0075] Any embodiment of Q as described above, including when Q is selected from (f), (i), (k), (n), and (v), wherein a ring carbon or nitrogen atom is optionally Q aIn some embodiments, W contains one or two nitrogen ring atoms, including when it is optionally substituted with CR. In some embodiments, W contains one or two nitrogen ring atoms, including when it is optionally substituted with CR. b and in the ortho position, i.e., having formula (A), (B), (C), (D), (F), (G), or (J). In a further example of any one such embodiment, R d is H, OH, C, Br, F, I, CH or OCH. In some further embodiments, W is

[0076] [ka]

[0077] is selected from R d is H, OH, F, I, Cl, Br, CH3 or OCH3. b is K-NR C It may be -Y or a tautomer thereof.

[0078] In some embodiments, including any of the embodiments of Q described above, such as when Q is selected from (f), (i), (k) (n), and (v), and where a ring carbon or nitrogen atom is optionally substituted with Qa, W is

[0079] [ka]

[0080] (In the formula, R d is H, OH, F, CL, I, Br, CH3 or OCH3, and R b Ha-K-NR C -Y, or its tautomer) is a 6-membered N-containing heterocycle (aromatic or non-aromatic) selected from:

[0081] In some embodiments, including any one of the above embodiments, R b -K-NRC -Y or a tautomer thereof, K is SO2, C(=O), C(=NH) or NHC(=O); R c is H, C 1~6 Alkyl (e.g., C 1~3 alkyl, such as CH3, CH2CH3 or (CH2)2CH3), or hydroxyC 1~6 Alkyl (e.g., hydroxy C 1~3 alkyl, for example, —(CH2)OH, —(CH2)2OH, —CH(OH)CH2OH, CH(OH)CH3, —(CH2)3OH, —CH(OH)(CH2)2OH, —CH2CH(OH)CH2OH, —(CH(OH))2CH3 and —(CH(OH))2CH2OH); Y is OH, NH2, NHC 1~6 Alkyl, NHC(=O)H, NH(C(=O)C 1~6 Alkyl, hydroxy C 1~6 Alkyl (e.g., hydroxy C 1~3 alkyl, such as -(CH2)OH, -(CH2)2OH, -CH(OH)CH2OH, CH(OH)CH3, -(CH2)3OH, -CH(OH)(CH2)2OH, -CH2CH(OH)CH2OH, -(CH(OH))2CH3 and -(CH(OH))2CH2OH), or (SC 1~6 Alkyl)C 1~6 Alkyl (e.g., (SC 1~3 Alkyl)C 1~3 Alkyl, for example, -(CH2)SCH3, -(CH2)2SCH3, -CH(SCH3)CH2SCH3, CH(SCH3)CH3, -(CH2)3SCH3, -CH(SCH3)(CH2)2SCH3, -CH2CH(SCH3)CH2SCH3, -(CH(SCH3))2CH3 and -(CH(SCH3))2CH2SCH3).

[0082] In some embodiments, R b teeth,

[0083] [ka]

[0084] (In the formula, X' is O or NH; R c is H or C 1~6 Alkyl or hydroxy C 1~6 is alkyl, Y is OH or NH2 or W is formula (H).

[0085] In still further embodiments, R b teeth,

[0086] [ka]

[0087] or a tautomer thereof. By way of example, in some further embodiments, R b teeth,

[0088] [ka]

[0089] It may be either of the following. The amidine group may be present as a substantially pure (e.g., >90%, or 95% or 99%) E- or Z-isomer, or may be a mixture of E- and Z-isomers.

[0090] In some further embodiments, Q is of formula (f) or (k), and R b is -C(=X' )-NR C -Y (wherein X' is O or NH, and R c is H or Me, and Y is OH or NH2).

[0091] In some embodiments, W comprises the moiety C(=O)-N-OH, e.g., W has the formula (H), or R bis C(=O)-NR'-OH or NHC(=O)-NR'-OH (wherein R' is H, C 1~6 Alkyl or hydroxy C 1~6 In yet a further embodiment, R d is H, OH, F, Cl, I, Br, CH3 or OCH3.

[0092] In some embodiments, R b is OH and W is (E) or (I). d may be selected from H, OH, F, Cl, Br, I, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C1 alkoxy, C2 alkoxy, C3 alkoxy, C4 alkoxy, C5 alkoxy, C6 alkoxy. d is H, OH, F, Cl, Br, I, CH3 or OCH3.

[0093] In some embodiments, R b is K-NR C -Y, or its tautomer, or -(CH2) p In a further embodiment, NHR e NH2, NHC 1~3 Alkyl, NHC(=O)H, NH(C(=O)C 1~3 It is alkyl. R d may be selected from H, OH, F, Cl, Br, I, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C1 alkoxy, C2 alkoxy, C3 alkoxy, C4 alkoxy, C5 alkoxy, C6 alkoxy. d is H, OH, F, Cl, Br, I, CH3 or OCH3.

[0094] In some embodiments, R b is K-NR C -Y, or its tautomer, or -(CH2) pIn a further embodiment, NHR is —NH—OH, and W is one of (A), (B), (C), (D), (F), (G), (H), (J). e NH2, NHC 1~3 Alkyl, NHC(=O)H, NH(C(=O)C 1~3 It is alkyl. R d may be selected from H, OH, F, Cl, Br, I, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C1 alkoxy, C2 alkoxy, C3 alkoxy, C4 alkoxy, C5 alkoxy, C6 alkoxy. d is H, OH, F, Cl, Br, I, CH3 or OCH3.

[0095] Any of the embodiments of Q as described above, including those in which a ring carbon or nitrogen atom is optionally Q a In some embodiments, W is (E) or (I) and R is OH, including when substituted with d is H, OH, F, Cl, I, Br, CH3 or OCH3.

[0096] In some embodiments, when W is of formula (I), R b is not -(C=O)-NH-OH. The present disclosure provides R b and R d Also provided are compounds of formula (I") in which is rearranged, as well as pharmaceutically acceptable salts and solvates thereof.

[0097] In another embodiment, compounds of formula (I') and pharmaceutically acceptable salts and solvates thereof, and R b and R d Compounds of formula (IA) are provided, including compounds of formula (I"), and pharmaceutically acceptable salts and solvates thereof, in which: Does not contain.

[0098] For compounds where tautomerism is possible under certain conditions, e.g., solvent, salt form, pH, etc., one tautomer may be preferred over another, but a change in conditions may result in the formation of the other tautomer. Where appropriate, tautomers of formula (I'), e.g., certain R b It will be understood that groups may be present and are encompassed by the present disclosure. Unless otherwise specified, a compound represented in one tautomeric form also discloses the other tautomeric forms. Some exemplary tautomeric R b The basis is,

[0099] [ka]

[0100] Includes: It will be understood that tautomers can exist in the E- and Z-form where appropriate, either as substantially pure (e.g., >90%, or 95% or 99%) E- or Z-isomers, or as mixtures of isomers.

[0101] In some embodiments, the compounds disclosed herein are those having a structure similar to that of A, as represented in the compounds disclosed or described in Examples 1-120. 1 ~A 5 , R a , R aa , Q., W., R. b , R c , R d and R e Thus, any combination as shown in any one of Examples 1 to 120, such as A 1 ~A 5 and Q,A. 1 ~A 5 and W,Q and W,R b and W are also expressly disclosed herein.

[0102] It will also be recognized that certain compounds of the present disclosure may have asymmetric centers and thus may exist in multiple stereoisomeric forms, such as enantiomers and diastereomers. Thus, the present invention relates to optically active compounds and substantially pure isomeric forms at one or more asymmetric centers, e.g., enantiomers with greater than about 90% ee, e.g., about 95% or 97% ee, or greater than 99% ee, as well as mixtures thereof, including racemic mixtures. Such isomers may be prepared by asymmetric synthesis, e.g., using chiral intermediates or reagents, enzymes, or mixtures may be resolved by conventional methods, e.g., chromatography, recrystallization, or the use of resolving agents.

[0103] In some embodiments, R a , R b , R c R d and R e In further such embodiments, at least one of R a , R b and R c One of them, R d and R e has a chiral center. In some embodiments, R a , R b , R c , R d or R e One of the groups may have one chiral center, and the compound may exist as a mixture of enantiomers, e.g., a racemic mixture, or the compound may be substantially enantiomerically pure, i.e., substantially in the R- or S-form. b =-CH2C * H(OH)CHOH, C * is a chiral center. R b =-CH2C * H(OH)CH2 Compounds having an OH group may be present as a mixture of enantiomers (eg, a racemic mixture), or may be in substantially enantiomerically pure R or S forms.

[0104] The compounds of the present disclosure may be prepared using any suitable method.The Examples section describes numerous methods that can be further estimated for the preparation of the compounds of the present disclosure by using conventional techniques and knowledge, for example, by using various starting materials and reagents, solvents, etc. known in the art and methods for preparing heterocycles (see, for example, Aurelio, L. et al., J. Med. Chem., 2016, vol. 59, pp. 965-984; Sharma, S., Sulfur Reports, 1989, vol. 8, pp. 327-469).In some non-limiting embodiments, the compounds are R a In another non-limiting embodiment, the compound can be prepared by coupling a precursor comprising a phenyl substituted with R and a Q moiety (or precursor thereof) with an appropriate W moiety or precursor thereof. a The compounds of formula (I') may be prepared by internal cyclization of a precursor compound containing a phenyl substituted with and a W moiety (or precursor thereof). As used herein, "precursor" includes chemical compounds or moieties that can be converted into the desired compound or moiety by one or more chemical transformations and / or couplings. Some exemplary generalized schemes for the preparation of various compounds of formula (I') and / or their precursors are set forth in Schemes A-V below.

[0105] [ka]

[0106] [ka]

[0107] [ka]

[0108] [ka]

[0109]

change

[0110]

change

[0111]

change

[0112]

change

[0113]

change

[0114]

change

[0115]

change

[0116]

change

[0117] It will be recognized that during the processes for preparing the compounds of the present disclosure, it may be necessary or desirable to protect certain functional groups that may be reactive or sensitive to the reaction or change conditions being performed. Examples of such groups include OH (including diols), NH, COH, SH, and C=O. Suitable protecting groups for such functional groups are known in the art and may be used in accordance with standard procedures. As used herein, the term "protecting group" refers to a derivatized functionality that renders a particular functional group temporarily inactive under certain conditions. Such protecting groups, as well as methods for their installation and subsequent removal at appropriate stages, are described in Protective Groups in Organic Chemistry, 3rd Edition, by T.W.G. Reene and P.G. Wutz, John Wiley and Sons, 1999. Representative forms of protecting groups include: For amino (NH2) - carbamates (e.g. Cbz, Boc, Fmoc), benzylamines, acetamides (e.g. acetamide, trifluoroacetamide); For carbonyls - acetals, ketals, dioxanes, dithianes and hydrazones; Regarding hydroxy - ethers (e.g. alkyl ethers, alkoxy alkyl ethers, allyl ethers, silyl ethers, benzyl ethers (e.g., p-methoxybenzyl, tetrahydropyranyl ether), carboxylic acid esters, acetals (e.g., acetonides and benzylidene acetals); For thio(SH) - ethers (e.g., alkyl ethers, benzyl ethers), esters, and For CO2H - esters (e.g. alkyl esters, benzyl esters).

[0118] Further general procedures for the preparation of compounds of the present disclosure and / or their precursors are set out below. General Procedure 1: General Procedure for Amidoximes (Scheme GP1)

[0119] [ka]

[0120] Method 1: NHOH (aq. 50%, 1.05 equiv.) was added dropwise to a solution of the nitrile (1.0 equiv.) in EtOH at room temperature, and the mixture was stirred at this temperature for 1 h or refluxed for 8 h. The solvent was removed in vacuo, thus affording the title amidoxime as a white solid in quantitative yield.

[0121] Method 2: NH2OH·HCl (3-8 equiv.) and Et3N (3-8 equiv.) were added to a suspension of the nitrile in dry MeOH or EtOH. The mixture was stirred at reflux for 1-16 h. LCMS showed the reaction was complete. The volatiles were removed, and the precipitated solid was suspended in water, collected by filtration, and then washed well with HO. The solid was washed with Et2O and DCM and dried to give the title compound. If required, the compound can be further purified by preparative HPLC.

[0122] Method 3: NH2OH·HCl (3-8 equiv.) and Et3N (3-8 equiv.) were added to a suspension of the nitrile in dry MeOH. The mixture was stirred at reflux for 1-3 h. LCMS or TLC indicated the reaction was complete. The reaction was cooled to room temperature, and the precipitated solid was collected by filtration and then washed thoroughly with HO. If no solid formed at room temperature, the reaction was diluted with water (at least 3 times the MeOH volume) and then filtered to induce precipitation. The solid was washed with Et2O and with CHCl2 as indicated, then dried to give the title compound. If needed, the compound can be further purified by preparative HPLC.

[0123] General Procedure 2: Nucleophilic Substitution (Scheme GP2)

[0124] [ka]

[0125] Method 1: A mixture of oxazole chloride or bromide (1.0 equiv.) and aromatic or heteroaromatic amine (1.5-2.0 equiv.) in anhydrous 2-propanol was stirred at reflux for 16 h. Upon cooling, the reaction mixture was concentrated in vacuo. The resulting crude was suspended in HO, filtered, and washed with EtO. If required, the filtered solid was purified by reverse-phase chromatography (HO, MeCN 10-100%) to afford the desired product.

[0126] Method 2: NaH (1.5–3.0 equiv., 60% dispersion in mineral oil) was added to a solution of an aromatic or heteroaromatic amine (1.5–2.0 equiv.) in DMF at 0°C under a nitrogen atmosphere. The mixture was stirred at this temperature for 0.5 h. A solution of chloride (1.0 equiv.) in DMF was added dropwise to the mixture. After an additional 16 h at room temperature, the solid was collected by filtration, washed with water, DCM, EtO, and dried under vacuum. If necessary, the filtered solid was purified by reverse-phase chromatography (HO, MeCN 10–100%) to give the desired product.

[0127] General Procedure 3: General Procedure for Amino-Oxadiazoles (Scheme GP3)

[0128] [ka]

[0129] Trichloroacetic anhydride (1.1 equiv.) was added dropwise to a suspension of amidoxime (1.0 equiv.) in toluene at room temperature, and the mixture was refluxed for 5-8 h. The volatiles were removed in vacuo to give the trichloromethyloxadiazole intermediate (used without further purification), which was then added dropwise to an aqueous solution of NH3 (28-30%). The mixture was stirred overnight at room temperature. The solid was filtered and washed with water (3 x 20 mL), then with PE / DCM (1:1, 3 x 20 mL), to give the title compound.

[0130] General Procedure 4: General Procedure for Buchwald-Hartwig Couplings (Scheme GP4)

[0131] [ka]

[0132] Method 1: A resealable Schlenk tube was charged with amine (1.0 equiv.), Pd(dba) (0.02–0.20 equiv., typically 5 mol%), Xantphos (0.04–0.40 equiv., typically 10 mol%), (hetero)aryl halide (typically 0.5–5.0 equiv., typically 1.0–1.5 equiv.), CsCO (1.5–3.0 equiv.), and 1,4-dioxane. After degassing the mixture, it was carefully subjected to three cycles of evacuation and filling with N. The reaction was stirred at 95–110 °C for 5–16 h. The volatiles were evaporated. The mixture was then suspended in HO, filtered, and washed with HO, aq. potassium ethylxanthate solution (10%), and DCM to afford the title compound. If required, compounds were purified by column chromatography using mixtures of petroleum distillate, DCM, EtOAc and / or MeOH as eluents or by reverse phase chromatography.

[0133] Method 2: Nitrogen nucleophile, (hetero)aryl halide, CsCO (1.5-3 equiv.), and tBuBrettphos Pd G (0.02-0.20 equiv., typically 5 mol%) precatalyst were placed in a sealable vessel under a N atmosphere, N-sparged tBuOH was added, the vessel was sealed, and heated to the specified temperature for the specified time. Unless otherwise noted, the reaction was then concentrated, diluted with water and EtOAc, brine was added to aid phase separation as needed, the phases were separated, and the organic layer was washed with brine, dried over MgSO, filtered, concentrated onto silica, and then purified by silica gel flash chromatography using the specified solvent, typically a mixture of petroleum distillate, DCM, EtOAc, and / or MeOH.

[0134] General Procedure 5: Oxazole Formation from Azidoketones (Scheme GP5)

[0135] [ka]

[0136] A solution of the appropriate 2-azido-ketone (1 equiv.) and isothiocyanate (1 equiv.) and PPh3 (1 equiv.) in dry 1,4-dioxane (0.15 M) was heated to 90 °C for a specified time, typically 1-8 h. Upon cooling, the mixture was concentrated to a solid and triturated with an organic solvent, such as DCM, EtOAc, or Et2O. The product was collected by filtration and further washed with the same organic solvent. If required, the product can be purified on silica gel or reverse phase (C18).

[0137] General Procedure 6: Isothiocyanate Formation (Scheme GP6)

[0138] [ka]

[0139] To a suspension of the appropriate aromatic amine (1 equiv.) in a 3:2 mixture of acetone:25% NaHCO3 (aq.) (0.25 M in substrate), a solution of thiophosgene (1.2 equiv.) in acetone (1.5 M) was added at 0 °C, and the mixture was stirred at room temperature for a specified time, typically 1-24 h. The progress of the reaction was monitored. 1 The reaction mixture was monitored by H NMR, LCMS, or TLC. Once the starting amine was completely consumed, the mixture was diluted with EtOAc and washed with H2O. The organic layer was dried over MgSO4 and concentrated to give the crude product, which in most cases can be used without purification. If required, the crude isothiocyanate can be further purified on silica gel using petroleum distillation and EtOAc or a mixture of DCM and EtOAc to give the pure product.

[0140] General Procedure 7: Oxadiazole Formation (Scheme GP7)

[0141] [ka]

[0142] A solution of the appropriate aromatic isothiocyanate (1 equivalent, 0.2–0.5 M concentration) and hydrazide (1 equivalent) in DMF or THF was stirred at room temperature for the specified time, typically 2–18 hours. EDCI·HCl (1.2 equivalents) was then added, and the mixture was heated at 60°C for 2 hours. Upon cooling, water (1–2 volumes of the organic solvent) was added, and the mixture was stirred at room temperature for 0.5 hours. The resulting precipitate was filtered and washed with water and, if solubility permitted, an organic solvent, such as DCM or EtO, to afford the desired oxadiazole.

[0143] General Procedure 8: Alkyl Deprotection with BBr3 (Scheme GP8)

[0144] [ka]

[0145] BBr3 (3–20 equivalents, as a commercial solution, in organic solvent or neat) was added dropwise to a solution of the protected substrate in dry DCM (0.2–0.5 M concentration) under N2 at 0 °C. The resulting reaction was stirred at room temperature for the specified time, typically 2–18 h. Saturated aqueous NaHCO3 solution was then poured into the flask to quench the BBr3, and the mixture was stirred for 2 h. In some cases, the bulk of the organic solvent was removed in vacuo before quenching with saturated NaHCO3 solution. After removal of the volatile solvent, the product was isolated by filtration and washing with water. In some cases, the product was purified using preparative HPLC.

[0146] General Procedure 9: Isoxazole Formation (Scheme GP9)

[0147] [ka]

[0148] NH2OH·HCl (3.0 equiv.) and NaOAc (3.0 equiv.) were stirred in CH3OH at room temperature for 1 hour, and then β-ketonitrile / -ester (1.0 equiv.) was added to the mixture. The reaction mixture was allowed to react until the starting material was completely consumed, as determined by TLC detection. Water was added to the reaction, which was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous Na2SO4. The crude reaction mixture was purified by silica gel column chromatography using a mixture of petroleum distillate, DCM, EtOAc, and / or MeOH.

[0149] General Procedure 10: Chloro-isoxazole formation (Scheme GP10)

[0150] [ka]

[0151] Triethylamine (0.6 equiv.) was added dropwise to a stirred suspension of isoxazol-5(4H)-one (1.0 equiv.) in POCl3 (10 equiv.) at 0 °C. The mixture was stirred at 60 °C for the specified time, typically 36–50 h, poured into ice, carefully basified to a pH of 6–7 by addition of 10% aq. KOH, and extracted with DCM. The organic layer was dried over Na2SO4 and filtered. The solvent was evaporated, and the product was purified by column chromatography (petrol: EtOAc, 10:1) to give the desired chloroisoxazole.

[0152] General Procedure 11: PMB Deprotection with TFA (Scheme GP11)

[0153] [ka]

[0154] The protected substrate was stirred in a mixture of TFA (0.2-0.5 M concentration) and EtSiH (5% by volume) at a specified temperature, typically room temperature, but occasionally at reflux. In some cases, anisole was used instead of EtSiH. The reaction progress was monitored by LCMS. Upon complete consumption of the starting material, typically after 1-18 h, the volatile solvent was evaporated to dryness in vacuo, and the residue was purified by preparative HPLC to afford the desired deprotected product. Alternatively, if the reaction resulted in a suspension, the product could be isolated by filtration followed by washing with water and, if solubility permits, an organic solvent.

[0155] General Procedure 12: Suzuki Coupling (Scheme GP12)

[0156] [ka]

[0157] Method 1: To a degassed biphasic solution of THF (3.5 mL) and 1 M aq. Na2CO3 (1.5 mL) was added a (hetero)aryl halide (1.0 equiv.), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (1.0 M in THF, 1.1 equiv.), and PdCl2(PPh3)2 (0.1 equiv.), and the mixture was heated to 100 °C and stirred for 16 h. Upon completion, the reaction mixture was diluted with EtOAc, and the organic layer was filtered through cotton wool and washed with saturated NaHCO3. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo to give the crude product. The crude product was subjected to purification by flash column chromatography (PhMe, 0–20% EtOAc) to give the desired product.

[0158] Method 2: To a solution of (hetero)aryl halide (1.0 equiv.), boronic acid (1.3 equiv.), potassium phosphate (3.0 equiv.), and tricyclohexylphosphine (0.01 equiv.) in toluene / water (10:1, 0.1-0.2 M) under a nitrogen atmosphere, Pd(OAc) (0.005 equiv.) was added. The mixture was heated to 100 °C overnight and then cooled to room temperature. Water was added, the mixture was extracted with EtOAc, and the combined organics were washed with brine, dried over MgSO, and concentrated in vacuo. Purification by column chromatography afforded the desired compound.

[0159] General Procedure 13: Synthesis of Aldehydes (Scheme GP13)

[0160] [ka]

[0161] Method 1: n-BuLi (1.6 M in hexanes, 1.1 equiv.) was added to a solution of bromide (1.0 equiv.) in dry THF (0.5 M) over 10 min at −78 °C under a nitrogen atmosphere. After an additional 0.5 h, DMF (3.0–6.0 equiv.) was added, and the mixture was stirred at −78 °C for 1 h, then brought to 0 °C for 2 h. Saturated aq. NH4Cl solution was added, and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over MgSO4, filtered, concentrated, and subjected to silica gel flash chromatography (2%–10%, EtOAc / distilled petroleum).

[0162] Method 2: i-PrMgCl (2 M in EtO, 1.15 equiv.) was added to the bromide (1.0 equiv.) in DCM (0.3-0.5 M) over 3 min at -2 °C. After stirring for 40 min at 0-6 °C, the mixture was cooled to -20 °C and DMF (2.0 equiv.) was added in one portion. The mixture was warmed to 0 °C for 20 min and then quenched by the addition of saturated aqueous NaHCO in one portion, followed by filtration through a Celite pad, extraction with EtOAc, drying over NaSO, and concentration under reduced pressure to give the desired product. If required, the compound was purified by column chromatography using a mixture of petroleum distillate, DCM, EtOAc, and / or MeOH.

[0163] General Procedure 14: Synthesis of Oxazoles (Scheme GP14)

[0164] [ka]

[0165] A suspension of arylaldehyde (1.0 equiv.), K2CO3 (1.2 equiv.), and TosMIC (1.1 equiv.) in MeOH was heated to reflux for the specified time. The volatiles were removed in vacuo, followed by the addition of H2O, followed by extraction with Et2O. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The resulting crude residue was subjected to silica gel flash chromatography (3%-20%, EtOAc / distilled petroleum) to afford the specified oxazole.

[0166] General Procedure 15: Halogenation of Oxazoles (Scheme GP15)

[0167] [ka]

[0168] Method 1: LiHMDS (1.0 M in THF, 1.05–1.2 equiv.) was added to a solution of oxazole (1.0 equiv.) in dry THF (0.1–0.2 M) at −78°C under a N2 atmosphere. After an additional 0.5 h, a solution of C2Cl6 (1.5 equiv.) in THF (2 M) was added. The resulting reaction mixture was stirred at −78°C for an additional 2 h and allowed to warm to room temperature over 14 h. The reaction was quenched with saturated aqueous NaHCO3 solution. The aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, concentrated, and subjected to silica gel flash chromatography (2%–10%, EtOAc / distilled petroleum).

[0169] Method 2: BrCFCFBr (2.0 equiv.) and t-BuOLi (2.0 equiv.) were added to a solution of oxazole (1.0 equiv.) in DMF / m-xylene (1:1 ratio, 0.3-0.5 M). The resulting mixture was stirred at 60 °C for 3 h and quenched with saturated aqueous NaHCO solution. The aqueous phase was extracted with EtOAc. The combined organic phases were dried over NaSO, filtered, concentrated, and subjected to silica gel flash chromatography (3%-10%, EtOAc / distilled petroleum).

[0170] 1 1 H NMR spectra were recorded at 400 MHz. 13C NMR spectra were recorded at 101 MHz. All chemical shifts were calibrated using residual non-deuterated solvent (e.g., chloroform) as an internal standard and reported in parts per million (δ) relative to trimethylsilane (δ = 0). Thin-layer chromatography (TLC) was performed using 0.25 mm thick plates precoated with Merck Kieselgel 60 F254 silica gel and visualized using UV light (254 nm and 365 nm). Liquid chromatography mass spectrometry (LCMS) was performed using either APCI or ESI LCMS. Each method used 254 nm and 214 nm detectors and a reversed-phase C8(2) 5μ 50 × 4.6 mm 100 A column. The column temperature was 30 °C. The elution systems used were solvent A (HO with 0.1% formic acid) and solvent B (MeCN with 0.1% formic acid). LCMS (ESI) method: The gradient started at 95% solvent A / 5% solvent B for 1 min, reached 100% solvent B over 1.5 min, held for 1.3 min, and then changed to 95% solvent A / 5% solvent B over 1.2 min. High-resolution mass spectra (HRMS) were recorded on both a time-of-flight mass spectrometer fitted with either an electrospray (ESI) or atmospheric pressure chemical ionization (APCI) source, or an accurate mass spectrometer fitted with an ASAP ion source, with a capillary voltage of 4000 V.

[0171] Without limiting the present disclosure by theory, in some embodiments, the compounds described herein may interact with Des1 and be useful in treating diseases or conditions mediated by Des1 activity. As used herein, the term "interaction," at least in the context of the compounds of the present disclosure, includes the association of a compound with an enzyme in a manner that partially or completely inhibits, interferes with, or prevents the enzyme's biochemical activity (e.g., the induction of a Δ4 double bond in dihydroceramide to produce ceramide). This can occur by any method, such as chemical or associative binding at one or more sites on the enzyme, that associates in a way that facilitates reaction with other endogenous molecules or causes degradation or a conformational change in the enzyme. Determining the interaction of a compound with one or more enzymes can be determined according to any suitable method in the art, including methods for measuring enzyme activity inhibition, such as the procedures described in the Examples. In some embodiments, a compound may be considered to interact with an enzyme if it exhibits at least a measurable or otherwise determinable level of enzyme activity inhibition according to the procedure used. Selective interaction, eg, selective inhibition, refers to the interaction of a compound with an enzyme and / or its binding site in a wholly or partially preferential manner over another enzyme and / or binding site.

[0172] In some embodiments, the compounds may selectively inhibit one Des isoform over another. For example, one or more compounds may be selective Des1 inhibitors. In other embodiments, one or more compounds may be selective Des2 inhibitors.

[0173] In further embodiments, one or more compounds have an IC of less than about 100 μM for Des (e.g., Des1 and / or Des2) activity. 50 In further embodiments, one or more compounds may exhibit an IC of less than about 50 μM for Des (e.g., Des1 and / or Des2) activity. 50In further embodiments, one or more compounds may exhibit an IC for Des (e.g., Des1 and / or Des2) activity in the range of less than about 10-5 μM. 50 In further embodiments, one or more compounds may exhibit an IC of less than about 1 μM for Des (e.g., Des1 and / or Des2) activity. 50 In further embodiments, one or more compounds may exhibit an IC of less than about 1 μM for Des (e.g., Des1 and / or Des2) activity. 50 In still further embodiments, one or more compounds may exhibit an IC of less than about 0.1 μM for Des (e.g., Des1 and / or Des2) activity. 50 In still further embodiments, one or more compounds may exhibit an IC of less than about 0.01 μM for Des (e.g., Des1 and / or Des2) activity. 50 In still further embodiments, one or more compounds may exhibit an IC of less than about 0.001 μM for Des (e.g., Des1 and / or Des2) activity. 50 In still further embodiments, one or more compounds may exhibit an IC of less than about 0.0001 μM for Des (e.g., Des1 and / or Des2) activity. 50 In still further embodiments, the one or more compounds may exhibit an IC for Des (e.g., Des1 and / or Des2) activity in the range of about 1.0-10 μM, or 0.1-1.0 μM, or 0.01-0.1 μM, or 0.001-0.01 μM, or 0.0001-0.001 μM. 50 may be shown.

[0174] In some embodiments, one or more compounds of formula (I') and / or (II") exhibit inhibitory activity of Des (e.g., Des1 and / or Des2) and are therefore useful in the treatment and / or prevention of diseases mediated by undesired or excessive Des activity and / or in which inhibition of Des enzymatic activity is therapeutically beneficial. In some embodiments, compounds of formula (I') and / or (II") exhibit inhibitory activity of Des1. In some embodiments, Des activity, e.g., Des1 activity, may be associated with fibrotic or proliferative diseases. Thus, without limiting the present disclosure by theory, in some embodiments, In embodiments, Des inhibition, such as Des1 inhibition, can be useful in treating fibrotic or proliferative diseases. In some embodiments, compounds of the present disclosure exhibit antiproliferative and / or antifibrotic activity.

[0175] Some compounds with Des1 inhibition have also been shown to have antiproliferative activity (see Aurelio, L. et al., supra). In some embodiments, one or more compounds of Formula (I') and / or (II") exhibit antiproliferative activity. In still further examples, antiproliferative activity may be observed against a single cell line or type, or may be observed in two or more different cell lines or cancer types. Thus, one or more compounds of the present disclosure may be useful in the treatment of a single cancer type or two or more cancer types.

[0176] In some embodiments, compounds of the present disclosure may be useful for treating Des1-mediated diseases or conditions, including, for example, treating or inhibiting cancer and / or metastasis, or treating fibrotic diseases, where excessive or unwanted Des1 activity is implicated, e.g., where unwanted cell proliferation is involved, and may be administered to a subject in a therapeutically or inhibiting-effective amount. A therapeutically or inhibiting-effective amount is intended to include an amount that, when administered according to a desired dosing regimen, at least partially achieves the desired therapeutic treatment or inhibitory effect, which may include one or more of alleviating, eliminating, or reducing the frequency of occurrence of one or more symptoms, preventing or delaying the onset, inhibiting the progression, or halting or reversing (partially or completely) the onset or progression of the particular disorder or condition being treated or its pathology. As used herein, "inhibiting unwanted cell proliferation" includes preventing, stopping, impeding the rate or extent of, or otherwise slowing or reversing excessive, uncontrolled, harmful, or otherwise unwanted cell proliferation, such as may occur in cancer growth or metastasis.

[0177] In some embodiments, the compounds of the present disclosure and / or their salts or solvates can therefore be useful as antiproliferative agents, for example, in treating unwanted cell proliferation, such as that observed in cancer conditions, including hormone-related cancers, such as breast cancer and prostate cancer, and their metastasis.Other cancer conditions that may be suitable for treatment with the compounds described herein include lung, colon, pancreas, and brain cancer, and lymphoma.The compounds described herein can be useful in treating primary cancer and / or treating or inhibiting metastasis (i.e., secondary cancer).

[0178] In some embodiments, the compounds of the present disclosure, including their pharmaceutically acceptable salts and solvates, can be useful in treating fibrosis and / or fibrotic diseases.As used herein, fibrosis and fibrotic diseases include the formation of excess fibrous connective tissue in organs or tissues, which can interfere with normal organ or tissue function, for example, the reactive or repair reaction to injury, for example, organ transplantation, or pathological conditions, for example, inflammation.Fibrosis can be found in blood vessels, heart, lung, liver, skin or kidney tissue, and can include pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease and cardiac fibrosis associated with various cardiovascular diseases.

[0179] Some examples of fibrotic diseases or conditions that may be treated by one or more embodiments of the present disclosure include pulmonary (lung) fibrosis, including idiopathic pulmonary fibrosis and cystic fibrosis; liver fibrosis (cirrhosis), such as that resulting from chronic liver disease or hepatitis B, C, or D virus infection; cardiac (heart) fibrosis, including myocardial fibrosis, atrial fibrosis, and fibrosis resulting from myocardial infarction (heart attack); renal fibrosis, such as that resulting from diabetic nephropathy; primary biliary cirrhosis, gallbladder fibrosis, skin or dermal fibrosis, such as scleroderma, hypertrophic scars, and keloids; bone marrow fibrosis, and intestinal fibrosis, such as Crohn's disease.

[0180] In some embodiments, for example, one or more compounds of the present disclosure that inhibit or otherwise interact with Des1, including pharmaceutically acceptable salts and solvates thereof, may be useful in treating metabolic diseases, particularly non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH) (NAFLD / NASH) (see, e.g., B. Chaurasia et al., Science, 2019, 365(6451), 386-392). Further examples of diseases that may be treated with one or more compounds of the present disclosure may include cardiovascular disease, hypertension, type 2 diabetes, cystic fibrosis, chromic kidney disease, diabetic nephropathy, scleroderma, cancer (including but not limited to prostate cancer, breast cancer, brain cancer, hepatocellular carcinoma, multiple myeloma, acute lymphoid myeloma, and colon cancer), neurodegenerative diseases, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and viral diseases (Magaye, R., R. et al., Cell. Mol. Life Sci. 2019, 76, 1107-1134; Vieira, C. R. et al., Chem. Biol. 2010, Vol. 17, pp. 766-775).

[0181] The subjects to be treated include mammalian subjects: humans, primates, livestock animals (including cattle, horses, sheep, pigs and goats), companion animals (including dogs, cats, rabbits, guinea pigs) and captive wild animals.Experimental animals, such as rabbits, mice, rats, guinea pigs and hamsters, are also contemplated because they can provide a convenient test system.Non-mammals, such as birds, amphibians and fish, can also be contemplated in certain embodiments of the present invention.

[0182] Suitable dosages and dosing regimens can be determined by the attending physician and may depend on the particular condition being treated, the severity of the condition, and the subject's overall age, health, and weight. Suitable dosages may range from 1 μg to 1 g of compound, salt, or solvate, for example, 1 μg to 1 mg (e.g., 100 μg, 250 μg, 500 μg, 750 μg), 1 mg to 10 mg (e.g., 2, 5, or 7 mg), 10 mg to 50 mg (e.g., 15, 20, 25, 30, or 40 mg), 50 mg to 100 mg (e.g., 60, 70, 80, 90 mg), or 100 mg to 500 mg (e.g., 200, 250, 300, 400 mg). Dosages may be administered one or more times daily (e.g., 2, 3, or 4 times), or one or more times weekly, biweekly, or monthly. Administration may be for a limited period of time, for example 1, 2, 3 or 4 weeks, or 2 or 3 months, to treat an acute disorder or condition, or may be for a longer period of time, for example more than 3 months, for example 6 or 12 months, 1 to 2 years or longer, to treat a chronic disorder or condition.

[0183] The active ingredient may be administered in a single dose or in a series of doses. While it is possible for the active ingredient to be administered alone, it is preferable to provide it as a composition, preferably as a pharmaceutical composition, together with one or more pharmaceutically acceptable additives. The compound may also be packaged or provided in combination with one or more other therapeutic agents and / or antiproliferative or anticancer agents. The components of the combination may be administered together with each other, either simultaneously or at different times, as a single composition or as separate compositions, if desired. Thus, the compositions contemplated herein may contain a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, as the sole therapeutic or antiproliferative / anticancer or antifibrotic agent, or may further contain one or more additional therapeutic or antiproliferative / anticancer or antifibrotic agents. Thus, the present disclosure also relates to the use of a compound of formula (I') or (I") or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of a disease or condition in which excessive or unwanted sphingosine kinase activity is implicated, or for the inhibition of unwanted cell proliferation, for example in the treatment of cancer or the inhibition or prevention of metastasis, or the treatment of a fibrotic disease.

[0184] The formulation of such compositions is well known to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, 21st Edition, Mack Publishing, 2005. The compositions may contain any suitable additive, carrier, diluent or excipient, including all conventional solvents, dispersion media, fillers, solid carriers, coatings, antifungal and antibacterial agents, dermal penetration agents, These include surfactants, isotonicity and absorption agents, etc. It will be appreciated that the compositions of the present invention may also contain other supplementary physiologically active agents.

[0185] Excipients must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the composition and not injurious to the subject. Compositions include those suitable for oral, rectal, nasal, topical (including transdermal, buccal, and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing the active ingredient into association with the excipient, which constitutes one or more accessory ingredients. Generally, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid excipients or finely divided solid excipients, or both, and then, if necessary, shaping the product.

[0186] Compositions containing compounds of the present disclosure may be administered to a subject by any suitable method, including orally, parenterally, topically, rectally, vaginally, or by inhalation. Compositions of the invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.

[0187] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, mixed in a suitable machine with binders (e.g., inert diluents), preservatives, disintegrants (e.g., sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose), surfactants, or dispersants, as needed. Molded tablets may be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets may be coated or scored as needed, and may be formulated to provide sustained or controlled release of the active ingredient therein, for example, using hydroxypropyl methylcellulose in various proportions to provide a desired release profile. Tablets may optionally be provided with an enteric coating to provide release in parts of the intestine other than the stomach.

[0188] Compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth gum; pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia gum; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0189] Compositions suitable for topical administration to the skin may contain the compound dissolved or suspended in any suitable carrier or base and may be in the form of lotions, gels, creams, pastes, ointments, etc. Suitable carriers include mineral oil, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. Transdermal delivery devices, such as patches, may also be used to administer the compounds of the present invention.

[0190] Compositions for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter, glycerin, gelatin or polyethylene glycol. Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.

[0191] Compositions suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions, which may contain antioxidants, buffers, bactericides, and solutes that render the composition isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and may be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the type described above.

[0192] Preferred unit dosage compositions are those containing a daily dose or unit, daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. In addition to the active ingredients specifically mentioned above, the compositions of the present disclosure may contain other additives or agents conventional in the art, taking into account the type of composition. For example, those suitable for oral administration may contain additional agents such as binders, sweeteners, thickeners, flavorings, disintegrants, coating agents, preservatives, lubricants, and / or time delay agents. Suitable sweeteners include sucrose, lactose, glucose, aspartame, or saccharin. Suitable disintegrants include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid, or agar. Suitable flavoring agents include peppermint oil, oil of wintergreen, cherry, orange, or raspberry flavoring. Suitable coating agents include polymers or copolymers of acrylic acid and / or methacrylic acid and / or their esters, waxes, fatty alcohols, zein, shellac, or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methylparaben, propylparaben, or sodium bisulfite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride, or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate.

[0193] The present disclosure also relates to prodrugs of formula (I') and (I") Any compound that is a prodrug of a compound of formula (I') or (I") is within the scope and spirit of the present invention. The term "prodrug" is used in the broadest sense and encompasses derivatives that are converted in vivo to the compounds of the invention, either enzymatically or hydrolytically. Such derivatives will readily occur to those skilled in the art and include, for example, compounds in which a free thiol or hydroxy group is converted to an ester, such as a phosphonate, sulfonate, and carboxy ester, such as an acetate ester or thioester, or a free amino group is converted to an amide, such as a carboxy, phosphonate, or sulfonate amide. Procedures for acylation of the compounds of the present invention, for example to prepare ester and amide prodrugs, are well known in the art and may include treatment of the compound with the appropriate carboxylic acid anhydride or chloride in the presence of a suitable catalyst or base. Esters of carboxylic acid (carboxy) groups are also contemplated. Suitable esters C 1~6 Alkyl ester; C 1~6 Alkoxymethyl esters, such as methoxymethyl or ethoxymethyl; C 1~6 Alkanoyloxymethyl esters, for example, pivaloyloxymethyl; phthalidyl esters; C 3~8 Cycloalkoxycarbonyl C 1~6 Alkyl esters, for example, 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, for example, 5-methyl-1,3-dioxolen-2-onylmethyl; and C 1~6Alkoxycarbonyloxyethyl esters, for example, 1-methoxycarbonyloxyethyl. Prodrugs of amino functional groups include amides (see, e.g., Kyncl, J. et al., Adv. BioSci., 1979, Vol. 20, p. 369), enamines (see, e.g., Caldwell, H. et al., J. Pharm. Sci., 1971, Vol. 60, p. 1810), Schiff bases (see, e.g., U.S. Pat. No. 2,923,661 and Smyth, R. et al., Antimicrob. Agents Chemother., 1981, Vol. 19, p. 1004), oxazolidines (see, e.g., Johansen, M. et al., J. Pharm. Sci., 1983, Vol. 72, p. 1294), Mannich bases (see, e.g., Bundgaard, H. et al. and J. Am. Sci., 1980, Vol. 69, p. 44), and the like. Chem. Soc., 1959, Vol. 81, p. 1198, Gottstein, W. et al.), hydroxymethyl derivatives (see, e.g., J. Pharm. Sci., 1981, Vol. 70, p. 855, Bansal, P. et al.), and N-(acyloxy)alkyl derivatives and carbamates (see, e.g., J. Med. Chem., 1980, Vol. 23, p. 469, Bodor, N. et al.; J. Med. Chem., 1984, Vol. 27, p. 1037, Firestone, R. et al.; J. Med. Chem., 1967, Vol. 10, p. 960, Kreiger, M. et al.; U.S. Pat. No. 5,684,018; and J. Med. Chem., 1988, Vol. 31, pp. 318-322, Alexander, J. et al.). Other conventional procedures for the selection and preparation of suitable prodrugs are known in the art and are described, for example, in WO00 / 23419; Design of Prodrugs, H. Bundgaard, ed., Elsevier Science Publishers, 1985; Methods in Enzymology, Vol. 42:309-396, K. Widder, ed., Academic Press, 1985; A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Edited by Bundgaard, Chapter 5, pp. 113-191 (1991); Advanced Drug Delivery Reviews, Vol. 8, pp. 1-38 (1992); Journal of Pharmaceutical Sciences, Vol. 77, pp. 285 (1988), H. Bundgaard et al.; Chem Pharm Bull, 32692 (1984), N. Kakeya et al., and The Organic Chemistry of Drug Design and Drug Action, Chapter 8, pp. 352-401, Academic Press, Inc., 1992.

[0194] Suitable pharmaceutically acceptable salts of the compounds of the present disclosure include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid, and hydrobromic acid, or salts of pharmaceutically acceptable organic acids such as acetic acid, propionic acid, butyric acid, tartaric acid, maleic acid, hydroxymaleic acid, fumaric acid, maleic acid, citric acid, lactic acid, mucic acid, gluconic acid, benzoic acid, succinic acid, oxalic acid, phenylacetic acid, methanesulfonic acid, toluenesulfonic acid, benzonesulfonic acid, salicylic acid, sulfanilic acid, aspartic acid, glutamic acid, edetic acid, stearic acid, palmitic acid, oleic acid, lauric acid, pantothenic acid, tannic acid, ascorbic acid , fendizoic acid, 4-4'-methylenebis-3-hydroxy-2-naphthoic acid, o-(p-hydroxybenzoyl)benzoic acid, 4'-4"-dihydroxytriphenylmethane-2-carboxylic acid, and valeric acid. Basic salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium, and alkylammonium. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides, e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides, or dialkyl sulfates, e.g., dimethyl sulfate and diethyl sulfate.

[0195] An example of a pharmaceutically acceptable salt of any of the compounds described herein in any of the aspects, embodiments or examples is the hydrochloride salt. The compounds of the present disclosure may be in crystalline form as free compounds or salts, or as solvates, and both forms are intended to be within the scope of the present disclosure.The term "solvate" refers to a complex or aggregate formed by one or more molecules of a solute, i.e., one or more molecules of a compound of the present disclosure, and one or more molecules of a solvent.Suitable solvents are well understood in the art and include, for example, water, i.e., to form hydrates, and common organic solvents, such as alcohols (MeOH, ethanol, isopropanol) and acetic acid.Solvation methods, such as recrystallization from a suitable solvent, are generally known in the art.

[0196] It is also recognized that certain compounds of formula (I') may possess asymmetric centers and therefore may exist as more than one stereoisomer, for example, enantiomers and diastereoisomers. The present invention therefore relates to optically active compounds and compounds in substantially pure isomeric form at one or more asymmetric centers, for example, enantiomers having greater than about 90% ee, for example, greater than about 95% or 97% ee or 99% ee, as well as mixtures of these isomers, including racemic mixtures. Such isomers can be prepared, for example, by asymmetric synthesis using chiral intermediates, and the mixtures can be resolved by conventional methods, for example, chromatography, recrystallization, or the use of resolving agents.

[0197] The compounds of the present disclosure may also be presented for use in veterinary compositions. These may be prepared by any suitable means known in the art. Examples of such compositions include those compatible with: Oral administration, topical application (e.g., drenches including aqueous and non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pellets for mixing with livestock feed, pastes for application to the tongue; Parenteral administration, for example, subcutaneous, intramuscular, or intravenous injection as a sterile solution or suspension; Topical applications, such as creams, ointments, gels, lotions, etc.

[0198] The following examples are presented for the purpose of illustrating some embodiments of the present disclosure, but should not be construed as limiting the general principles set forth above. [Example]

[0199] Example 1 1,5-((5-(4-chlorophenyl)oxazol-2-yl)amino)-N-hydroxypicolinamide (Scheme 1)

[0200] [ka]

[0201] To a suspension of methyl 5-aminopicolinate (0.380 g, 2.50 mmol) in acetone (6 mL) and 25% NaHCO (aq.) (4 mL) was added a solution of thiophosgene (0.230 mL, 3.00 mmol) in acetone (2 mL) at 0 °C, and the mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc (30 mL) and washed with HO (2 × 15 mL). The organic layer was dried over MgSO and concentrated to give methyl 5-isothiocyanatopicolinate as a cream-colored semisolid (0.387 g, 80% yield). 1 H NMR (401 MHz, CDCl3) δ 8.66 - 8.55 (m, 1H), 8.15 (dd, J = 8.4, 0.6 Hz, 1H), 7.64 (dd, J = 8.4, 2.4 Hz, 1H), 4.02 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 164.7 (C=O), 147.0 (CH), 145.3 (C), 141.5 (C), 133.2 (CH), 132.8 (C), 126.0 (CH), 53.3 (CH3). LCMS R f (min)=5.52, MS m / z=195.1[M+H]+ .

[0202] A solution of 2-bromo-4'-chloroacetophenone (0.20 g, 0.75 mmol) and NaN3 (0.097 g, 1.5 mmol) in acetone (10 mL) was stirred at room temperature for 16 h. The reaction mixture was then concentrated in vacuo, and the residue was redissolved in DCM (30 mL) and washed with HO (2 × 15 mL). The organic layer was dried over MgSO4 and concentrated to an orange semi-solid (0.14 g). 2-Azido-1-(4-chlorophenyl)ethan-1-one (0.094 g, 0.41 mmol) was then dissolved in dry 1,4-dioxane (4 mL), and methyl 5-isothiocyanatopicolinate (0.080 g, 0.41 mmol) and PPh3 (0.11 g, 0.41 mmol) were added, and the mixture was heated to 90 °C for 1.5 h. The mixture was then concentrated to a solid and triturated with DCM to give methyl 5-((5-(4-chlorophenyl)oxazol-2-yl)amino)picolinate as a cream solid (0.089 g, 73% yield). 1 H NMR (401 MHz, DMSO-d6) δ 11.14 (s, 1H, NH), 8.82 (d, J = 2.2 Hz, 1H), 8.30 (dd, J = 8.7, 2.7 Hz, 1H), 8.11 - 8.05 (m, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.62 (s, 1H), 7.52 (d, J = 8.7 Hz, 2H), 3.85 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 164.9 (C=O), 155.5 (C), 143.8 (C), 139.5 (C), 138.9 (C), 138.5 (CH), 131.7 (C), 129.2 (CH), 126.6 (C), 126.0 (CH), 124.5 (CH), 123.4 (CH), 122.5 (CH), 52.0 (CH3). LiOH.HO (0.031 g, 0.74 mmol) in HO (0.75 mL) was dissolved in methyl 5-((5-(4-chlorophenyl)oxazol-2-yl)amino)picolinate (0.0 mL) in 1,4-dioxane (1.5 mL) and EtOH (1.5 mL). To a solution of 5-((5-(4-chlorophenyl)oxazol-2-yl)amino)picolinic acid was added HCl (81 g, 0.25 mmol), and the mixture was heated at reflux for 3.5 h. The volatiles were removed in vacuo, and NaCl (0.5 g) was added to the suspension, followed by the dropwise addition of 1.0 M HCl (aq.) at 0 °C. The resulting precipitate was filtered and washed with HO (3 mL) to give 5-((5-(4-chlorophenyl)oxazol-2-yl)amino)picolinic acid as a yellow solid, which was recrystallized from HO (0.67 g, 86% yield). 1 H NMR (401 MHz, DMSO-d6) δ 10.87 (s, 1H, NH), 8.73 (d, J = 2.4 Hz, 1H), 8.15 (dd, J = 8.6, 2.5 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.59 (s, 1H), 7.51 (d, J = 8.7 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 166.7 (C=O), 155.9 (C), 143.5 * (C), 137.4 (CH), 131.6 (C), 129.1 (CH), 126.7 * (C), 124.8 (CH), 124.4 (CH), 123.4 (CH), 123.0 (CH). * Quaternary carbon resonance overlap A solution of 5-((5-(4-chlorophenyl)oxazol-2-yl)amino)picolinic acid (0.040 g, 0.13 mmol), HOBt.HO (0.021 g, 0.15 mmol), and EDCI.HCl (0.032 g, 0.17 mmol) in dry DMF (1.5 mL) was stirred at room temperature for 2 h. After this time, O-benzylhydroxylamine hydrochloride (0.10 g, 0.64 mmol) and EtN (0.090 mL, 0.64 mmol) were added, and the mixture was stirred at room temperature for an additional 16 h. DMF was removed in vacuo and washed with toluene (2 mL × 3) to aid in this process. HO (2 mL) was then added, and the mixture was left stirring at room temperature for 10 min. The resulting precipitate was filtered and washed with HO (1 mL) to give a grey solid (0.035 g), which was chromatographed on silica gel eluting with 25% EtOAc in DCM to give N-(benzyloxy)-5-((5-(4-chlorophenyl)oxazol-2-yl)amino)picolinamide as a white solid (0.017 g, 32% yield). 1 H NMR (401 MHz, DMSO-d6) δ 11.83 (s, 1H, NH), 11.02 (s, 1H, NH), 8.76 (d, J = 2.6 Hz, 1H), 8.28 (dd, J = 8.7, 2.6 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 8.7 Hz, 2H), 7.61 (s, 1H), 7.52 (d, J = 8.7 Hz, 2H), 7.46 (s, 2H), 7.42 - 7.32 (m, 3H), 4.93 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 161.6 (C=O), 155.7 (C), 143.7 (C), 142.1 (C), 138.5 (C), 137.2 (CH), 136.0 (C), 131.8 (C), 129.2 (CH), 128.8 (CH), 128.3 (CH), 128.3 (CH), 126.6 (C), 124.5 (CH), 123.4 (CH), 123.4 (CH), 123.0 (CH), 77.1 (CH2).LCMS Rf ( min) = 3.58, MS m / z = 420.8 [M+H] + .

[0203] [ka]

[0204] 1.0 M BBr3 in heptane (0.22 mL, 0.22 mmol) was added dropwise to a solution of N-(benzyloxy)-5-((5-(4-chlorophenyl)oxazol-2-yl)amino)picolinamide (0.047 g, 0.11 mmol) in dry DCM (1 mL) at 0 °C, and the mixture was stirred at room temperature for 2 h. The volatiles were removed in vacuo, and the residue was suspended in saturated NaHCO3 (aq.) (3 mL) and stirred at room temperature for 20 min. The precipitate was filtered and washed with HO (10 mL) and Et2O (2 mL) to give the title compound as a brown solid (0.030 g, 81% yield). Mp 264-269 °C dec. 1 H NMR (401 MHz, DMSO-d6) δ 11.20 (s, 1H, NH), 10.97 (s, 1H, OH), 8.96 (s, 1H, NH), 8.75 (d, J = 2.4 Hz, 1H), 8.26 (dd, J = 8.6, 2.6 Hz, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.61 (s, 1H), 7.52 (d, J = 8.7 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 161.4 (C=O), 155.7 (C), 143.6 (C), 142.7 (C), 138.0 (C), 137.1 (CH), 131.6 (C), 129.1 (CH), 126.6 (C), 124.4 (CH), 123.4 (CH), 123.3 (CH), 122.6 (CH).LCMS R f (min) = 5.73, MS m / z = 329.0 [MH ]- . HRMS(ESI)C 15 H 12 ClN4O3 + [M+H] + The calculated value was 331.0592 and the measured value was 331.0593. 2. N-Hydroxy-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide (Scheme 1) (Intermediate A - 2-Azido-1-(4-(trifluoromethyl)phenyl)ethan-1-one) Sodium azide (2 equiv.) was added to a solution of 2-bromo-1-(4-(trifluoromethyl)phenyl)ethan-1-one (0.400 g, 1.498 mmol) in acetone (10 mL), and the mixture was stirred at room temperature for 1 h. Upon formation of the azide intermediate, the mixture was concentrated to a residue and then partitioned between DCM (30 mL) and HO (10 mL). The organic layer was collected, and the aq. layer was back-extracted with DCM (3 × 20 mL). The combined organic layers were dried over MgSO and concentrated to afford 2-azido-1-(4-(trifluoromethyl)phenyl)ethan-1-one as an orange semi-solid (0.327 g, 95.3% yield).

[0205] A solution of 2-azido-1-(4-(trifluoromethyl)phenyl)ethan-1-one (0.279 g, 1.22 mmol), methyl 5-isothiocyanatopicolinate (0.250 g, 1.22 mmol), and PPh (0.320 g, 1.22 mmol) in dry 1,4-dioxane (8 mL) was heated to 90 °C for 1.5 h. Upon cooling, the mixture was concentrated to a solid and triturated with DCM (5 mL) to give methyl 5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinate as an off-white solid (0.256 g, 58% yield). 1H NMR (401 MHz, DMSO-d6) δ 11.25 (s, 1H, NH), 8.83 (d, J = 2.3 Hz, 1H), 8.31 (dd, J = 8.7, 2.7 Hz, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.82 (s, 4H), 7.80 (s, 1H), 3.85 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 164.9 (C=O), 156.1 (C), 143.5 (C), 139.7 (C), 138.9 (C), 138.6 (CH), 131.4 (C), 127.1 (C), 126.2 (q, J = 3.9 Hz, CF3), 126.1 (CH), 125.3 (CH), 123.2 * (CH), 122.8 (CH), 52.1 (CH3).LCMS R f (min)=5.98, MS m / z=364.1[M+H] + . * CH resonance overlap (CH from pyridine ring and CH from oxazole) (Intermediate B - 5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinic acid) LiOH.HO (0.052 g, 1.2 mmol) in HO (1 mL) was added to a solution of methyl 5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinate (0.15 g, 0.41 mmol) in 1,4-dioxane (2 mL) and EtOH (2 mL), and the mixture was heated at reflux for 3 h. The volatiles were removed in vacuo, and NaCl (0.5 g) was added to the suspension, followed by the dropwise addition of 1.0 M HCl (aq.) at 0 °C. The resulting precipitate was filtered and washed with HO (3 mL) to give 5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinic acid as a yellow solid, which was recrystallized from HO (0.12 g, 84% yield). 1H NMR (401 MHz, DMSO-d6) δ 11.07 (s, 2H, OH, NH), 8.78 (s, 1H), 8.21 (d, J = 8.2 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.81 (s, 4H), 7.77 (s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 166.3 (C=O), 156.4 (C), 143.6 (C), 138.5 (C), 138.3 (CH), 131.6 (C), 127.6 (C), 127.3 (C), 126.3 (q, J = 3.7 Hz, CF3), 125.8 (CH), 125.4 (CH), 123.4 * (CH), 123.2 (CH). * CH resonance overlap (CH from pyridine ring and CH from oxazole) A solution of 5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinic acid (0.050 g, 0.14 mmol), HOBt.HO (0.022 g, 0.17 mmol), and EDCI.HCl (0.034 g, 0.18 mmol) in dry DMF (2 mL) was stirred at room temperature for 2 h. After this time, O-benzyl hydroxyl Amine hydrochloride (0.11 g, 0.69 mmol) and EtN (0.10 mL, 0.69 mmol) were added, and the mixture was stirred at room temperature for an additional 16 h. The mixture was then diluted with EtOAc (20 mL) and washed with HO (3 × 10 mL). The combined organic layers were dried over MgSO and concentrated to a gray solid (0.092 g), which was triturated with refined petroleum (4 mL) to give N-(benzyloxy)-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide as a white solid (0.024 g, 39% yield). 1H NMR (401 MHz, DMSO-d6) δ 11.84 (s, 1H, NH), 11.12 (s, 1H, NH), 8.77 (s, 1H), 8.34 - 8.25 (m, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.82 (s, 4H), 7.79 (s, 1H), 7.47 (d, J = 6.7 Hz, 2H), 7.43 - 7.31 (m, 3H), 4.93 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 161.5 (C=O), 156.2 (C), 143.3 (C), 142.2 (C), 138.4 (C), 137.2 (CH), 136.0 (C), 131.5 (C), 128.7 (CH), 128.3 (CH), 128.2 (CH), 127.0 (C), 126.1 (q, J = 3.8 Hz, CF3), 125.3 (CH), 123.5 (CH), 123.1 * (CH), 123.0 (CH), 77.1 (CH2).LCMS R f (min)=3.58, MS m / z=454.8[M+H] + . * CH resonance overlap (CH from pyridine ring and CH from oxazole)

[0206] [ka]

[0207] 1.0 M BBr in heptane (0.33 mL, 0.33 mmol) was added to a solution of N-(benzyloxy)-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide (0.050 g, 0.11 mmol) in dry DCM (1.5 mL) at 0 °C, and the mixture was stirred at room temperature for 3 h. The volatiles were removed in vacuo, and the residue was suspended in saturated NaHCO (aq.) (3 mL) and stirred at room temperature for 20 min. The precipitate was filtered and washed with HO (10 mL) and EtO (2 mL) to give the title compound as a yellow solid (0.021 g, 53% yield). Mp 184-188 °C. 1 H NMR (401 MHz, DMSO-d6) δ 11.22 (d, J = 1.9 Hz, 1H, NH), 11.07 (s, 1H, OH), 8.97 (d, J = 2.0 Hz, 1H, NH), 8.76 (d, J = 2.3 Hz, 1H), 8.31 - 8.24 (m, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.81 (s, 4H), 7.78 (s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 161.4 (C=O), 156.3 (C), 143.2 (C), 142.8 (C), 137.9 (C), 137.2 (CH), 131.5 (C), 127.3 (C), 126.1 (q, J = 3.9 Hz, CF3), 125.3 (CH), 123.5 (CH), 123.1 * (CH), 122.6 (CH).LCMS R f (min) = 3.66, MS m / z = 364.8 [M+H ] + . HRMS(ESI)C 16 H 11 F3N4O3 + [M+H] + Calculated value: 365.0856, measured value: 365.0856. * CH resonance overlap (CH from pyridine ring and CH from oxazole) 3. N'-Hydroxy-6-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)nicotinimidamide hydrochloride (Scheme 2)

[0208] [ka]

[0209] To a suspension of 6-amino-3-pyridinecarbonitrile (0.300 g, 2.52 mmol) in THF (4 mL) and 25% NaHCO (aq.) (5 mL) was added a solution of thiophosgene (0.210 mL, 2.77 mmol) in THF (1 mL) at 0 °C, and the mixture was stirred at room temperature for 0.5 h. The mixture was then diluted with DCM (20 mL) and washed with HO (2 × 10 mL). The combined organic layers were dried over MgSO and concentrated to a dark brown oil, which was chromatographed on silica gel eluting with 100% DCM to give 6-isothiocyanatonicotinonitrile as a light brown semi-solid (0.117 g, 29% yield). 1 H NMR (401 MHz, CDCl3) δ 8.71 (s, 1H), 7.97 (dd, J = 8.3, 2.3 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ153.3 (CH), 149.9 (C), 145.9 (C), 142.0 (CH), 119.5 (CH), 116.0 (C), 107.9 (C).LCMS R f (min)=3 .11, MS m / z=161.9[M+H] + .

[0210] A solution of 2-azido-1-(4-(trifluoromethyl)phenyl)ethan-1-one (Intermediate A) (0.074 g, 0.33 mmol), 6-isothiocyanatopicolinonitrile (0.052 g, 0.32 mmol), and PPh (0.085 g, 0.32 mmol) in dry 1,4-dioxane (3 mL) was heated to 90 °C for 1.5 h. Upon cooling, the mixture was concentrated to a brown solid, which was triturated with DCM (4 mL) to give 6-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)nicotinonitrile as a white solid (0.11 g, 100% yield). 1 H NMR (401 MHz, DMSO-d6) δ 11.77 (s, 1H, NH), 8.74 (d, J = 1.6 Hz, 1H), 8.24 (dd, J = 8.9, 2.2 Hz, 1H), 8.16 (d, J = 9.1 Hz, 1H), 7.83 (s, 4H), 7.82 (s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 155.2 (C), 154.3 (C), 152.3 (CH), 143.9 (C), 141.9 (CH), 131.3 (C), 126.1 (q, J = 3.9 Hz, CF3), 125.1 (CH), 123.3 * (CH), 122.8 (C), 117.7 (C), 110.3 (CH), 101.2 (C).LCMS R f (min) = 3.24, MS m / z = 129.0 [M−H] - . * Resonance overlap of two CHs (CH from the pyridine ring and CH from the oxazole ring)

[0211] [ka]

[0212] 6-((5-(4-(trifluoromethyl)phenyl)oxa A solution of (2-(2-yl)amino)nicotinonitrile (0.050 g, 0.15 mmol), HONH2.HCl (0.042 g, 0.60 mmol), and Et3N (0.085 mL, 0.60 mmol) was heated at reflux for 16 h. Upon cooling, the mixture was diluted with HO (5 mL), and the resulting precipitate was filtered and washed with HO (3 mL) to give a cream-colored solid (0.045 g). This material was then salted by diluting in EtOAc (1 mL), adding 4.0 M HCl in 1,4-dioxane (0.030 mL, 0.12 mmol), and stirring at room temperature for 16 h. The resulting precipitate was filtered and washed with EtOAc (3 mL) to give a yellow solid (0.027 g), which was further purified using RP-HPLC with AA 30-100B solvent system to give the title compound as a pale yellow solid (0.012 g, 22% yield). Mp 257-261°C. 1 H NMR (401 MHz, DMSO-d6) δ 11.24 (s, 1H, NH), 9.77 (s, 1H, OH), 8.58 (s, 1H), 8.05 (s, 2H), 7.81 (s, 4H), 7.77 (s, 1H), 6.04 (s, 2H, NH2). 13 C NMR (101 MHz, DMSO-d6) δ 155.7 (C), 154.3 (C), 146.0 * (CH), 143.7 (C), 137.4 (CH), 131.4 † (C), 126.1 (q, J = 3.7 Hz, CF3), 125.6 (C), 125.1 (CH), 123.3 ‡ (CH), 122.9 (C).LCMS R f (min)=4.91, M S m / z=362.0[MH] - . HRMS(ESI)C 16 H 13 F3N5O2 + [M+H] + The calculated value was 364.1016, and the measured value was 364.1012. * Missing resonance: CH signal was found using HSQC13 C NMR shows signal-to-noise ratio below † Quaternary carbon resonance overlap ‡CH resonance overlap (-CF3 substituted ring) 4. N-(6-(hydroxyamino)pyridin-3-yl)-5-(4-(trifluoromethyl)phenyl)oxazol-2-amine (Scheme 3)

[0213] [ka]

[0214] To a suspension of 6-nitropyridin-3-amine (0.050 g, 0.36 mmol) in DCM (1.5 mL) and 25% NaHCO (aq.) (1.5 mL) was added neat thiophosgene (0.030 mL, 0.40 mmol) at 0 °C, and the mixture was stirred at room temperature for 16 h. After this time, the mixture was diluted with DCM (30 mL) and washed with HO (2 × 15 mL). The organic layer was dried over MgSO and concentrated to give 5-isothiocyanato-2-nitropyridine as a cream-colored solid (0.051 g, 79% yield). 1 H NMR (401 MHz, CDCl3) δ 3.73 (d, J = 2.4 Hz, 1H), 3.54 (dd, J = 8.6, 0.5 Hz, 1H), 3.03 (dd, J = 8.6, 2.5 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 153.4 (C), 145.8 (CH), 143.4 (C), 135.6 (CH), 135.5 (C), 119.3 (CH).LCMS R f (min)=5.43, MS m / z=180.1[M+H] + .

[0215] 2-Azido-1-(4-(trifluoromethyl)phenyl)ethan-1-one (Intermediate A) (0.425 g, 1.86 mmol), 5-isothiocyanato-2-nitropyridine (0.336 g, 1.86 mmol) and PPh3 (0.4 A solution of N-(6-nitropyridin-3-yl)-5-(4-(trifluoromethyl)phenyl)oxazol-2-amine (86 g, 1.86 mmol) was heated to 90 °C for 1.5 h. Upon cooling, the mixture was concentrated to a dark brown solid, which was triturated with DCM (5 mL) to give N-(6-nitropyridin-3-yl)-5-(4-(trifluoromethyl)phenyl)oxazol-2-amine as a brown solid (0.432 g, 67% yield). Mp 319-324 °C. 1 H NMR (401 MHz, DMSO-d6) δ 11.62 (s, 1H, NH), 8.74 (d, J = 2.5 Hz, 1H), 8.47 (dd, J = 9.0, 2.7 Hz, 1H), 8.39 (d, J = 8.9 Hz, 1H), 7.84 (s, 1H), 7.83 (s, 4H). 13 C NMR (101 MHz, DMSO-d6) δ 155.7 (C), 149.9 (C), 143.9 (C), 141.1 (C), 136.7 (CH), 131.3 (C), 127.7 (C), 126.2 (q, J = 3.8 Hz, CF3), 125.2 (CH), 124.9 (CH), 123.4 * (CH), 120.0 (CH).LCMS R f (min)=3.96, MS m / z=350.8[M+H] + . HRMS(ESI)C 15 H 10 F3N4O3 + [M+H] + The calculated value was 351.0700 and the measured value was 351.0703. * Resonance overlap (-CF3 substituted ring)

[0216] [ka]

[0217] Pd / C 10% (0.025 g) was added to a solution of N-(6-nitropyridin-3-yl)-5-(4-(trifluoromethyl)phenyl)oxazol-2-amine (0.040 g, 0.11 mmol) in MeOH (1.5 mL), and the mixture was placed under vacuum and flushed with H × 3 to remove any oxygen. The reaction mixture was then stirred under H gas at room temperature for 16 h. After this time, the solution was filtered through celite to remove Pd / C and concentrated to a light brown solid (0.028 g), which was triturated with EtOAc (4 mL) to give the title compound as a cream-colored solid (0.011 g, 29% yield). Mp 212-215 °C. 1 H NMR (401 MHz, DMSO-d6) δ 10.26 (s, 1H, NH), 8.51 (d, J = 2.0 Hz, 1H, NH), 8.42 (d, J = 1.8 Hz, 1H, OH), 8.34 (d, J = 2.3 Hz, 1H), 7.92 (dd, J = 8.9, 2.7 Hz, 1H), 7.76 (ABq, J = 8.7 Hz, 4H), 7.66 (s, 1H), 6.90 (d, J = 8.9 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 158.9 (C), 157.7 (C), 142.4 (C), 136.8 (CH), 131.8 (C), 128.9 (C), 127.6 (CH), 126.0 (q, J = 3.9 Hz, CF3), 125.6 (CH), 122.9 (C), 122.6 * (CH), 107.4 (CH).LCMS R f (min)=4.89, MS m / z=336.8[M+H] + . HRMS(ESI)C 15 H 12 F3N4O2 + [M+H] + The calculated value was 337.0907, and the measured value was 337.0905. * Resonance overlap (-CF3 substituted ring) 5. 5-((5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl)amino)-N-hydroxy-pyridine-2-carboximidamide (Scheme 4, X=H)

[0218] [ka]

[0219] H2SO4 (3 mL) was added dropwise to 4-(trifluoromethyl)benzoic acid (10.000 g, 52.598 mmol) in MeOH (250 mL) at 0 °C, and the mixture was refluxed for 16 h. Upon cooling, hydrazine monohydrate (73.700 mL) was added, and the mixture was stirred at room temperature for 1 h. The solution was then concentrated under reduced pressure. Ice water was added, and the resulting precipitate was filtered and washed with HO (10 mL) and Et2O (3 mL) to give 4-(trifluoromethyl)benzohydrazide as a white crystalline solid (0.847 g, 78.9% yield). 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 7.94 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 4.68 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 164.6, 150.1, 132.4, 129.2, 121.2, 120.6.LCMS R f (min)=5.29, MS m / z=220.1[M+H] + .

[0220] Thiophosgene (1.1 equiv.) was added to a suspension of 5-aminopicolinonitrile (1.000 g, 8.394 mmol) in toluene (40 mL), and the mixture was heated at reflux for 2 h. The volatiles were then removed in vacuo, and the residue was redissolved in dry DMF (6 mL). 4-(trifluoromethyl)benzohydrazide (1 equiv.) was then added to the solution, and the mixture was stirred at room temperature for 16 h. EDCI·HCl (1.2 equiv.) was then added, and the mixture was heated at 60 °C for 2 h. Upon cooling, HO (5 mL) was added, and the mixture was stirred at room temperature for 0.5 h. The resulting precipitate was filtered and washed with HO (5 mL) and DCM (2 mL) to give 5-((5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)amino)picolinonitrile as a yellow solid (1.165 g, 86.1% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 8.85 (d, J = 2.2 Hz, 1H), 8.29 (dd, J = 8.6, 2.4 Hz, 1H), 8.12 (d, J = 8.1 Hz, 2H), 8.06 (d, J = 8.6 Hz, 1H), 7.97 (d, J = 8.2 Hz, 2H). 13 LCMS R f (min)=3.381, MS m / z=331.8[M+H] + .

[0221] [ka]

[0222] A solution of 5-((5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)amino)picolinonitrile (0.076 g, 0.229 mmol), NHOH (2.5 equiv.), and EtN (2.5 equiv.) in EtOH (2 mL) was heated to reflux for 4 h. Upon completion of the reaction, the crude material was purified using preparative HPLC with a 95% A:5% B to 100% B solvent system. TFA and ACN were removed via rotary evaporation, and HO was removed via use of a freeze-dryer, affording the title compound as a white solid (0.036 g, 43.1% yield). 1 H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 10.20 (s, 1H), 8.62 (s, 2H), 8.16 (d, J = 9.1 Hz, 1H), 8.12 (d, J = 8.1 Hz, 2H), 7.99 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 7.5 Hz, 2H. 13 C NMR (101 MHz, DMSO-d6) δ165.77, 164.00, 159.82, 159.69, 157.60, 143.84, 138.49, 137.54, 137.44, 127.29, 126.67, 126.52, 126.45, 125.17, 125.17, 124.22, 122.80, 122.46.LCMS R f (min)=4.926, MS m / z=364.8[M+H] + . HRMS(ESI)C 15 H 12 F3N6O2 + [M+H] + The calculated value was 365.097 and the measured value was 365.0968. 6. 5-((5-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl)amino)-N-hydroxypyridine-2-carboximidamide (Scheme 4, X=F) H2SO4 (0.270 mL) was added dropwise to 3-fluoro-4-(trifluoromethyl)benzoic acid (1.000 g, 4.805 mmol) in MeOH (25 mL) at 0 °C, and the mixture was refluxed for 16 h. Upon cooling, hydrazine monohydrate (6.730 mL) was added, and the mixture was stirred at room temperature for 1 h. The solution was then concentrated under reduced pressure. Ice water was added, and the resulting precipitate was filtered and washed with HO (10 mL) and Et2O (3 mL) to give 3-fluoro-4-(trifluoromethyl)benzohydrazide as a white crystalline solid (0.869 g, 81.4% yield). 1 H NMR (400 MHz, CDCl3) δ 7.74 (t, J = 7.4 Hz, 1H), 7.63 (t, J = 10.1 Hz, 2H), 7.40 (s, 1H), 4.15 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 164.6, 150.1, 132.4, 129.2, 121.2, 120.6.LCMS R f (min)=3.0 03, MS m / z=222.9[M+H] + .

[0223] Thiophosgene (1.1 equiv.) was added to a suspension of 5-amino-2-pyridinecarbonitrile (0.134 g, 1.125 mmol) in toluene (8 mL), and the mixture was heated to reflux for 2 h. The volatiles were then removed in vacuo, and the residue was redissolved in dry DMF (6 mL). To the solution, 3-fluoro-4-(trifluoromethyl)benzohydrazide (1 equiv.) was then added, and the mixture was stirred at room temperature for 16 h. EDCI·HCl (1.2 equiv.) was then added, and the mixture was heated at 60 °C for 2 h. Upon cooling, HO (5 mL) was added, and the mixture was stirred at room temperature for 0.5 h. The resulting precipitate was filtered and washed with HO (5 mL) and DCM (1 mL) to give 5-((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)amino)picolinonitrile as a yellow solid (0.277 g, 70.5% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.05 (dd, J = 15.0, 8.0 Hz, 2H), 7.96 ( dd, J = 15.6, 9.9 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 174.82, 160.05, 140.90, 138.76, 130.27, 130.06, 129.35, 125.17, 124.06, 122.69, 118.22, 114.62, 114.40.LCMS R f (min)=3.523, MS m / z=349.8[M+H] + .

[0224] [ka]

[0225] A solution of 5-((5-(3-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)amino)picolinonitrile (0.100 g, 0.286 mmol), NHOH HCl (2.5 equiv.), and EtN (2.5 equiv.) in EtOH (2 mL) was heated to reflux for 4 h. Upon completion of the reaction, HO (50 mL) was added and the solution was extracted with EtOAc (3 × 15 mL). The combined organic layers were dried over MgSO and concentrated to give the title compound as a white solid (0.028 g, 26.9% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 9.80 (s, 1H), 8.80 (d, J = 2.5 Hz, 1H), 8.10 (dd, J = 8.8, 2.6 Hz, 1H), 8.04 (t, J = 7.7 Hz, 1H), 7.93 (m, 3H), 5.80 (s, 2H). 13C NMR (101 MHz, DMSO-d6) δ 160.19, 157.77, 156.38, 149.26, 143.85, 137.19, 135.44, 129.84, 128.86, 124.62, 123.62, 122.11, 120.92, 119.84, 114.10, 113.87.LCMS R f (min)=5.319. HRMS(ESI)C 15 H 11 F4N6O2 + [M+H] + The calculated value was 383.0874 and the measured value was 383.0875. 7. 1-Hydroxy-4-((5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl)amino)-1,2-dihydropyridin-2-one (Scheme 5)

[0226] [ka]

[0227] H2O2. Urea (2 equiv.) in dry DCM (60 mL) To a solution of TFAA (2.000 g, 13.514 mmol) was added. Upon cooling to 0 °C, a solution of TFAA (2 equiv.) in dry DCM was added dropwise, and the mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with sat. NaSO (15 mL), stirred at room temperature for 0.5 h, then poured into HO (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with 1 M NaOH (15 mL), dried over MgSO, and concentrated to a cream-colored semi-solid. The solid was then chromatographed on silica gel eluting with 5% EtOH in DCM to give a yellow crystalline solid (2.068 g, 93.3% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.29-8.23 (m, 1H), 7.51 (d, J = 2.9 Hz, 1H), 7.20 (dd, J = 7.1, 2.9 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 142.9, 140.9, 131.4, 127.0, 124.5.LCMS R f (min)=1.88. MS m / z 164.0[M+H] + .

[0228] 2.37 M n-BuLi in cyclohexane (1.1 equiv.) was added dropwise to a solution of benzyl alcohol (1.5 equiv.) in dry THF (10 mL) under N at 0 °C, and the mixture was stirred at this temperature for 10 min. The mixture was transferred dropwise to a solution of 2,4-dichloropyridine-1-oxide (0.448 g, 2.732 mmol) in dry THF (10 mL), and the mixture was stirred at 0 °C for 15 min. The reaction mixture was quenched with HO (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with HO (2 × 10 mL), dried over MgSO, and concentrated to an orange-cream semi-solid. The solid was chromatographed on silica gel eluting with 20% EtOAc in DCM to give a white crystalline solid (1.282 g, 88.4% yield), which should be stored at -20 °C. 1 H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 6.9 Hz, 1H), 7.43 (dd, J = 7.9, 1.5 Hz, 2H), 7.40-7.30 (m, 3H), 6.88 (dd, J = 6.9, 2.7 Hz, 1H), 6.85 (d, J = 2.7 Hz, 1H), 5.39 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ157.87, 140.34, 134.09, 132.80, 128.99, 128.96, 127.75, 118.71, 112.02, 72.82.LCMS R f (min)=2.975, M S m / z=235.9[M+H] + .

[0229] A solution of 2-(benzyloxy)-4-chloropyridine-1-oxide (1.282 g, 5.440 mmol) in toluene (10 mL) was heated at 100° C. for 3 h. The solvent was then removed via rotary evaporation. The residual solid was chromatographed on silica gel eluting with 10% EtOAc in DCM to give 1-(benzyloxy)-4-chloropyridin-2(1H)-one as a yellow crystalline solid (0.620 g, 48.3% yield). 1 H NMR (400 MHz, CDCl3) δ 7.38 (m, 5H), 7.01 (d, J = 7.5 Hz, 1H), 6.70 (d, J = 2.6 Hz, 1H), 5.92 (dd, J = 7.6, 2.7 Hz, 1H), 5.25 (s, 2H). 13 C NMR (101 MHz, DMSO) δ 157.66, 145.80, 136.66, 133.36, 130.16, 129.61, 128.90, 121.10, 106.10, 78.65.LCMS R f (min)=3.222, MS m / z=257.8[M+Na] + .

[0230] NaN3 (3 equiv.) was added to a solution of 1-(benzyloxy)-4-chloropyridin-2-one (0.500 g, 2.122 mmol) in DMSO (10 mL). The solution was then heated at 80 °C for 28 h. The reaction mixture was cooled to room temperature and diluted with 1 N HCl (2 mL). The resulting mixture was poured into distilled water (20 mL), and the aq. layer was washed with EtOAc (2 × 20 mL). The aq. layer was slowly neutralized with saturated aq. NaHCO3 solution and extracted with EtOAc (2 × 20 mL). The combined organic layers were collected, dried over MgSO4, and concentrated to a cream-colored semi-solid. The solid was chromatographed on silica gel eluting with 1% Et3N in EtOAc to give 4-amino-1-(benzyloxy)pyridin-2(1H)-one as a yellow crystalline solid (0.220 g, 42.8% yield). 1H NMR (400 MHz, CDCl3) δ 7.42-7.30 (m, 5H), 6.83 (d, J = 7.6 Hz, 1H), 5.69 (d, J = 2.3 Hz, 1H), 5.41 (dd, J = 7.6, 2.5 Hz, 1H), 5.17 (s, 2H), 4.52 (s, 2H). 13 C NMR (101 MHz, CDCl3) δ 159.97, 155.23, 136.24, 134.18, 130.09, 129.16, 128.69, 97.51, 97.00, 78.58, 40.96.LCMS R f (min)=2.920, MS m / z=216.9[M+H ] + .

[0231] Thiophosgene (1.2 equiv.) was added dropwise to a solution of 1-benzyloxy-4-amino-2-pyridin-2-one (0.200 mg, 0.925 mmol) in dry toluene (5 mL) at room temperature. The solution was then heated at reflux for 2 h. The progress of the reaction was monitored. 1 After 2 h, the starting material had completely disappeared and a new product was formed. 1 The formation was confirmed by H NMR. The toluene and thiophosgene were removed in vacuo, and the residue was redissolved in dry DMF (5 mL). To the solution was then added 4-(trifluoromethyl)benzohydrazide (1 equiv.), and the mixture was stirred at room temperature for 16 h. EDCI·HCl (1.2 equiv.) was then added, and the mixture was heated to 60 °C for 2 h. Upon cooling, HO (5 mL) was added, and the mixture was stirred at room temperature for 0.5 h. The resulting precipitate was filtered and washed with HO (5 mL) to give 1-(benzyloxy)-4-((5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)amino)pyridin-2(1H)-one as a brown solid (0.176 g, 42.9% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.11 (d, J = 8.1 Hz, 2H), 7.97 (d, J = 8.3 Hz, 2H), 7.72 (d, J = 7.8 Hz, 1H), 7.49 (dd, J = 6.6, 3.1 Hz, 2H), 7.44 -7.40 (m, 3H), 6.91 (d, J = 2.9Hz, 1H), 6.23 (dd, J = 7.8, 2.9Hz, 1H), 5.19 (s, 2H). f ( min)=3.359, MS m / z=428.8[M+H] + .

[0232] [ka]

[0233] BBr3 (10 equiv.) was added dropwise to a solution of 1-(benzyloxy)-4-((5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)amino)pyridin-2(1H)-one (0.080 mg, 0.411 mmol) in dry DCM (4 mL) at 0 °C under N2. The reaction was stirred at room temperature for 30 h. Saturated NaHCO3 solution was then poured into the flask to quench the BBr3, and the mixture was stirred for 2 h. The crude material was purified using preparative HPLC with a 95% A:5% B to 100% B solvent system. TFA and ACN were removed via rotary evaporation, and HO was removed via freeze-drying, affording the title compound as a white solid (0.015 g, 29.0% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.11 (d, J = 8.1 Hz, 2H), 7.97 (d, J = 8.3 Hz, 2H), 7.85 (d, J = 7.7 Hz, 1H), 6.87 (d, J = 2.8 Hz, 1H), 6.33 (dd, J = 7.7, 2.9 Hz, 1H).LCMS R f(min)=6.009. HRMS(ESI)C 14 H 10 F3N 4O3 + [M+H] + The calculated value was 339.0700 and the measured value was 339.0697. 8. 5-((5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl)amino)-N-hydroxy-pyridine-2-carboximidamide (Scheme 6)

[0234] [ka]

[0235] (Intermediate C - 5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinonitrile) To a solution of 2-azido-1-(4-(trifluoromethyl)phenyl)ethan-1-one in dry 1,4-dioxane (Intermediate A) (10 mL) was added 5-isothiocyanatopicolinonitrile (1.15 equiv.) and PPh3 (1.15 equiv.), and the mixture was heated at 95 °C for 20 min. Upon completion, the reaction mixture was concentrated under reduced pressure. The crude residue was chromatographed on silica gel eluting with 30% EtOAc in toluene to afford 5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinonitrile as a yellow crystalline solid (0.380 g, 66.9% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.86 (d, J = 2.2 Hz, 1H), 8.34 (dd, J = 8.7, 2.7 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.83 (br s, 4H), 7.82 (s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 164.6, 150.1, 132.4, 129.2, 121.2, 120.6.LCMS R f(min)=6.079, MS m / z=329.1[MH] - .

[0236] [ka]

[0237] EtN (2.5 equiv.) was added to a solution of 5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinonitrile (0.080 g, 0.242 mmol) and NHOH HCl (2.5 equiv.) in EtOH (10 mL), and the mixture was heated at reflux for 4 h. Upon completion of the reaction, the solution was diluted with EtOAc (30 mL) and washed with HO (3 × 15 mL). The aqueous layer was then collected and back-extracted with EtOAc (3 × 15 mL). The combined organic layers were dried over MgSO and concentrated to a yellow solid. The crude product was then redissolved and recrystallized in EtOH to give the title compound as a yellow crystalline solid (0.036 g, 40.9% yield). 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.74 (s, 1H), 8.78 (d, J = 2.2 Hz, 1H), 8.13 (dd, J = 8.8, 2.6 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.80 (s, 4H), 7.76 (s, 1H), 5.76 (s, 2H).LCMS R f ( min) = 5.935. HRMS (ESI) C 16 H 13 F3N5O2 + [M+H] + The calculated value was 364.1025, and the measured value was 364.1016. 9. 5-([4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino)-N-hydroxypyrimidine-2-carboxamide (Scheme 7)

[0238] [ka]

[0239] Thiourea (6.841 g, 89.871 mmol) was added to a solution of 2-bromo-1-(4-chlorophenyl)ethan-1-one (2.000 g, 7.489 mmol) in acetonitrile (50 mL), and the mixture was heated to reflux for 16 h. Upon cooling, the mixture was concentrated in vacuo. The mixture was then washed with HO (10 mL) and DCM (5 mL) to give 4-(4-chlorophenyl)thiazol-2-amine as a pale yellow solid. 1 H NMR (401 MHz, DMSO-d6) δ 7.83 - 7.77 (m, 2H), 7.45 - 7.36 (m, 2H), 7.08 (s, 2H), 7.03 (s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ168.44, 148.65, 133.78, 131.62, 128.53, 127.28, 102.38.LCMS R f (min)=3.112, MS m / z=210 .9[M+H] + .

[0240] A resealable Schlenk tube was charged with Pd(dba) (0.02 equiv.), Xantphos (0.06 equiv.), 5-(4-chlorophenyl)thiazol-2-amine (1.2 equiv.), KPO (fine powder, 1.4 equiv.), methyl 5-bromopyrimidine-2-carboxylate (0.150 g, 0.691 mmol), and 1,4-dioxane (4 mL). The mixture was degassed and carefully evacuated and refilled with N (3 cycles) before the dropwise addition of HO (1.0 mmol). It was then sealed and immersed in an oil bath at 140 °C. After 15 h, the mixture was cooled and filtered. The precitipate was washed with H2O (5 mL) and DCM (2 mL) to give methyl 5-((4-(4-chlorophenyl)thiazol-2-yl)amino)pyrimidine-2-carboxylate as a grey solid (0.13 g, 54.2% yield). 1H NMR (401 MHz, DMSO) δ 9.32 (s, 2H), 8.18 - 7.91 (m, 2H), 7.61 (s, 1H), 7.53 - 7.43 (m, 2H), 3.88 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.19, 155.43, 148.43, 144.37, 144.35, 137.93, 135.93, 134.84, 128.11, 127.79, 125.72, 125.57, 122.90, 52.49.LCMS R f (min)=3.646, MS m / z=344.8[MH] - .

[0241] LiOH·HO (3 equiv.) in HO (1.5 mL) was added to a solution of methyl 5-((4-(4-chlorophenyl)thiazol-2-yl)amino)pyrimidine-2-carboxylate (0.200 g, 0.577 mmol) in 1,4-dioxane (2 mL) and EtOH (2 mL), and the mixture was refluxed for 3 h. The volatiles were removed in vacuo, and brine (3 mL) was added to the suspension, followed by the dropwise addition of 6 M HCl (2 mL) at 0 °C. The resulting precipitate was filtered and washed with HO (3 mL) to give 5-((4-(4-chlorophenyl)thiazol-2-yl)amino)pyrimidine-2-carboxylic acid as a yellow solid (0.180 g, 93% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.32 (s, 2H), 7.99 (d, J = 8.4 Hz, 2H), 7.63 (s, 1H), 7.52 (d, J = 8.4 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 164.70, 162.20, 149.48, 144.77, 137.53, 133.34, 132.79, 129.29, 127.95, 106.81. Oxalyl chloride (2.5 equiv.) was added dropwise to a solution of 5-((4-(4-chlorophenyl)thiazol-2-yl)amino)pyrimidine-2-carboxylic acid (0.100 g, 0.301 mmol) in dry DCM (2 mL) and dry DMF (1 drop) at 0 °C, and the mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo, and the residue was redissolved in dry DCM. O-benzylhydroxylamine hydrochloride (5 equiv.) and DIPEA (5 equiv.) were added, and the mixture was stirred at room temperature for an additional 16 h. Upon completion, all volatiles were removed under reduced pressure. HO (2 mL) was then added. The resulting precipitate was filtered and washed with DCM (2 mL), HO (1 mL) and EtO (1 mL) to give N-(benzyloxy)-5-((4-(4-chlorophenyl)thiazol-2-yl)amino)pyrimidine-2-carboxamide as a pale yellow solid (0.062 g, 90.4% yield). 1 H NMR (401 MHz, DMSO) δ 12.06 (s, 1H), 11.11 (s, 1H), 9.31 (s, 2H), 7.98 (d, J = 8.6 Hz, 2H), 7.64 (s, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 6.9 Hz, 2H), 7.43 - 7.36 (m, 3H), 4.95 (s, 2H).LCMS R f (min)=3.646, MS m / z=435.8[MH] - The crude material was used in the next step without further purification.

[0242] [ka]

[0243] 1.0 M BBr in heptane (3 equiv.) was added dropwise to a solution of N-(benzyloxy)-5-([4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino)pyrimidine-2-carboxamide (0.060 g, 0.132 mmol) in dry DCM (1 mL) at 0 °C, and the mixture was stirred at room temperature for 2 h. The volatiles were removed in vacuo, and the residue was suspended in sat. NaHCO (aq.) (3 mL) and stirred at room temperature for 20 min. The crude material was purified using preparative HPLC with a 95% A:5% B to 100% B solvent system. TFA and ACN were removed via rotary evaporation, and HO was removed via freeze-drying, affording the title compound as a white solid (0.015 g, 31.2% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.28 (s, 2H), 9.12 (s, 1H), 7.97 (d, J = 8.6 Hz, 2H), 7.61 (s, 1H), 7.52 (d, J = 8.6 Hz, 2H).LCMS R f (min)=3.2 36. HRMS(ESI)C 14 H 11 ClN5O2S + [M+H] + The calculated value was 348.0311 and the measured value was 348.0366. 10. N-Hydroxy-6-((5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl)amino)pyrimidine-3-carboxamide (Scheme 8)

[0244] [ka]

[0245] n-BuLi (2.17 M in cyclohexane) (1.2 equiv.) was added dropwise to a solution of (methoxymethyl)triphenylphosphonium chloride (1.2 equiv.) in dry THF (15 mL) at 0 °C, and the mixture was stirred at this temperature for 1 h. 4-(Trifluoromethyl)benzaldehyde (3.930 mL, 28.716 mmol) was then added, and the mixture was stirred at room temperature for 16 h. The mixture was quenched with HO (3 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were then dried over MgSO and concentrated to a yellow liquid. The crude material was chromatographed on silica gel eluting with 100% hexane to give (£)-1-(2-methoxyvinyl)-4-(trifluoromethyl)benzene as a colorless liquid (5.430 g, 77.9% yield). 1 H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H), 6.24 (d, J = 7.0 Hz, 1H), 5.25 (d, J = 7.0 Hz, 1H), 3.82 (s, 3H). (Synthesis of Intermediate D—5-(4-(trifluoromethyl)phenyl)oxazol-2-amine)NBS (1.1 equiv.) was added to a solution of (£)-1-trifluoromethyl-4-(2-methoxyvinyl)benzene (5.000 g, 24.730 mmol) in HO (25 mL) and 1,4-dioxane (25 mL) at 0° C., and the mixture was stirred at room temperature for 1 h. Urea (1 equiv.) was then added, and the mixture was heated at 70° C. for 16 h. Upon cooling, the volatiles were removed under reduced pressure, and the mixture was quenched with saturated NaHCO (aq.). The precipitate was then filtered and washed with HO (20 mL) and DCM (10 mL) to give 5-(4-(trifluoromethyl)phenyl)oxazol-2-amine as a white solid (3.200 g, 56.7% yield). 1 H NMR (401 MHz, CDCl3) δ 7.71 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.42 (s, 1H), 7.06 (s, 2H).LCMS R f(min)=3.331, MS m / z=228.9[M+H] + .

[0246] A resealable Schlenk tube was charged with Pd(dba) (0.02 equiv.), Xantphos (0.06 equiv.), 5-(4-(trifluoromethyl)phenyl)oxazol-2-amine (Intermediate D) (1.2 equiv.), KPO (fine powder, 1.4 equiv.), methyl 5-bromopyrimidine-2-carboxylate (0.250 g, 1.152 mmol), and 1,4-dioxane (4 mL). The mixture was degassed and carefully evacuated and refilled with N for three cycles before the dropwise addition of HO (0.021 g, 1.0 mmol). It was then sealed and immersed in an oil bath at 140 °C. After 15 h, the mixture was cooled, diluted with EtOAc (20 mL), and washed with HO (15 mL). The aqueous layer was then back-extracted with EtOAc (2 × 15 mL). The crude product was concentrated under reduced pressure and chromatographed on a SiO2 column (EtOAc:toluene=1:1) to give methyl 5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyrimidine-2-carboxylate as a white solid (0.21 g, 50.0% yield). 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 2H), 7.77 (s, 4H), 7.75 (s, 1H), 3.85 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.29, 147.65, 144.76, 143.29, 131.51, 126.06, 126.03, 125.43, 123.02, 52.37.LCMS R f (min)=3.523, MS m / z=364.8[M+H ] + .

[0247] LiOH·HO (3 equiv.) in HO (1 mL) was added to a solution of methyl 5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyrimidine-2-carboxylate (0.125 g, 0.343 mmol) in 1,4-dioxane (1.5 mL) and EtOH (1.5 mL), and the mixture was refluxed for 3 h. The volatiles were removed in vacuo, and brine (2 mL) was added to the suspension, followed by the dropwise addition of 6 M HCl (2 mL) at 0 °C. The resulting precipitate was filtered and washed with HO (2 mL) to give 5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyrimidine-2-carboxylic acid as a yellow solid (0.120 g, 99.8% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 9.16 (s, 2H), 7.83 (s, 5H). LCMS R f (minutes) = 3.660. 13 C NMR (101 MHz, DMSO-d6) δ 164.21, 155.68, 149.71, 144.45, 143.78, 135.52, 131.30, 127.48, 127.16, 126.11, 126.07, 125.52, 125.21, 123.21, 122.82.M S m / z=350.8[M+H] + .

[0248] A solution of 5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyrimidine-2-carboxylic acid (0.100 g, 0.286 mmol), anhydrous HOBt (1.2 equiv.), and EDCI HCl (1.3 equiv.) in dry DMF (2 mL) was stirred at room temperature for 2 h. O-benzylhydroxylamine hydrochloride (5 equiv.) and EtN (5 equiv.) were then added, and the mixture was stirred at room temperature for a further 16 h. DMF was removed in vacuo and washed with toluene (3 × 2 mL) to aid in the process. HO (2 mL) was then added, and the mixture was left stirring at room temperature for 10 min. The resulting precipitate was filtered and washed with HO (1 mL) and hexanes (2 mL) to give N-(benzyloxy)-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyrimidine-2-carboxamide as a brown solid (0.080 g, 61.7% yield). 1 H NMR (401 MHz, DMSO-d6) δ 12.05 (s, 1H), 9.15 (s, 2H), 7.83 (s, 5H), 7.62 - 7.20 (m, 5H), 4.94 (s, 2H).LCMS R f (min)=3.551, MS m / z=455.8[M+H] + .

[0249] [ka]

[0250] 1.0 M BBr in heptane (3 equiv.) was added dropwise to a solution of N-(benzyloxy)-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyrimidine-2-carboxamide (0.060 g, 0.132 mmol) in dry DCM (1 mL) at 0 °C, and the mixture was stirred at room temperature for 2 h. The volatiles were removed in vacuo, and the residue was suspended in sat. NaHCO (aq.) (3 mL) and stirred at room temperature for 20 min. The crude material was purified using preparative HPLC with a 95% A:5% B to 100% B solvent system. TFA and ACN were removed via rotary evaporation, and HO was removed via freeze-drying, affording the title compound as a white solid (0.023 g, 47.9% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 9.13 (s, 1H), 9.13 (s, 2H), 7.83 (s, 4H), 7.82 (s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ160.40, 156.27, 151.38, 144.86, 144.15, 135.68, 131.80, 127.60, 126.61, 126.01, 125.76, 123.65, 123.31, 40.63, 40.42.LCMS R f (min)=5.513 HRMS(ESI)C 15 H 11 F3N5O3 + [M+H] + The calculated value was 366.0809, and the measured value was 366.0807. 11. N-Hydroxy-6-((5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl)amino)pyridazine-3-carboxamide (Scheme 9)

[0251] [ka]

[0252] Oxalyl chloride (1 equiv.) was added dropwise to a solution of 6-chloro-3-pyridazinecarboxylic acid (1.000 g, 6.308 mmol) in dry DCM (30 mL) and dry DMF (1 drop) at 0 °C, and the mixture was stirred at this temperature for 1 h. The solvent was removed in vacuo, and the residue was redissolved in dry DCM. MeOH (1 equiv.) was added, and the mixture was stirred at room temperature for an additional 1 h. The mixture was quenched with HO (20 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were then dried over MgSO and concentrated to give methyl 6-chloropyridazine-3-carboxylate as a white solid (0.960 g, 88.2% yield). 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 4.09 (s, 3H). A resealable Schlenk tube was charged with Pd(dba) (0.1 equiv.), Xantphos (0.3 equiv.), 5-(4-(trifluoromethyl)phenyl)oxazol-2-amine (Intermediate D) (1.2 equiv.), KPO (fine powder, 1.4 equiv.), methyl 6-chloropyridazine-3-carboxylate (0.200 g, 1.159 mmol), and 1,4-dioxane (4 mL). The mixture was degassed and carefully evacuated and refilled with N for three cycles before the dropwise addition of HO (1.0 mmol). It was then sealed and immersed in an oil bath at 140 °C. After 15 h, the mixture was cooled, diluted with EtOAc (20 mL), and washed with HO (15 mL). The aqueous layer was then back-extracted with EtOAc (2 × 15 mL). The crude product was concentrated under reduced pressure and chromatographed on a SiO2 column (EtOAc:toluene=1:1) to give methyl 6-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridazine-3-carboxylate as a white solid (0.28 g, 66.3% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 9.5 Hz, 1H), 8.05 (d, J = 9.4 Hz, 1H), 7.79 (s, 4H), 7.75 (s, 1H), 3.90 (s, 3H).LCMS Rf (min)=3.907, MS m / z=364.8[M+H] + .

[0253] LiOH·HO (3 equiv.) in HO (1.5 mL) was added to a solution of methyl 6-((5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl)amino)pyridazine-3-carboxylate (0.140 g, 0.384 mmol) in 1,4-dioxane (2 mL) and EtOH (2 mL), and the mixture was refluxed for 3 h. The volatiles were removed in vacuo, and brine (2 mL) was added to the suspension, followed by the dropwise addition of 6 M HCl (2 mL) at 0 °C. The resulting precipitate was filtered and washed with HO (2 mL) to give 6-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridazine-3-carboxylic acid as a yellow solid (0.130 g, 96.6% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.20 (s, 1H), 7.84 (s, 5H).LCMS R f (min)=3.797, MS m / z=350.8[MH] - .

[0254] A solution of 6-((5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl)amino)pyridazine-3-carboxylic acid (0.080 g, 0.228 mmol), anhydrous HOBt (1.1 equiv.), and EDCI HCl (1.3 equiv.) in dry DMF (2 mL) was stirred at room temperature for 2 h. After this, O-benzylhydroxylamine hydrochloride (5 equiv.) and EtN (5 equiv.) were added, and the mixture was stirred at room temperature for an additional 16 h. DMF was removed in vacuo and washed with toluene (2 mL × 3) to aid in the process. HO (2 mL) was then added, and the mixture was left stirring at room temperature for 10 min. The resulting precipitate was filtered and washed with HO (1 mL) and hexanes (2 mL) to give N-(benzyloxy)-6-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridazine-3-carboxamide as a brown solid (0.090 g, 86.5% yield).1 H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 8.49 (s, 1H), 8.18 (s, 2H), 7.85 (s, 4H), 7.60-7.14 (m, 5H), 4.98 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 160.71, 144.42, 136.27, 131.78, 129.27, 128.75, 128.29, 128.03, 126.58, 125.99, 125.40, 123.76, 123.29, 77.61.LCMS R f (min)=3.879, MS m / z=455.8[M+H] + .

[0255] [ka]

[0256] 1.0 M BBr in heptane (3 equiv.) was added dropwise to a solution of N-(benzyloxy)-6-((5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl)amino)pyridazine-3-carboxamide (0.090 g, 0.198 mmol) in dry DCM (1 mL) at 0 °C, and the mixture was stirred at room temperature for 2 h. The volatiles were removed in vacuo, and the residue was suspended in sat. NaHCO (aq.) (3 mL) and stirred at room temperature for 20 min. The crude material was purified using preparative HPLC with a 95% A:5% B to 100% B solvent system. TFA and ACN were removed via rotary evaporation, and HO was removed via freeze-drying, affording the title compound as a white solid (0.031 g, 42.9% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 11.69 (s, 1H), 8.48 (s, 1H), 8.14 (d, J = 9.0 Hz, 1H), 7.84 (m, 4H), 7.84 (s, 1H). 13C NMR (101 MHz, DMSO-d6) δ 160.59, 156.64, 144.35, 131.79, 128.16, 128.01, 127.69, 126.55, 126.00, 125.34, 123.76, 123.30.LCMS R f (min)=5.501. HRMS(ESI)C 15 H 11 F3N5O3 + [M+H] + The calculated value was 366.0811 and the measured value was 366.0809. 12. N-Hydroxy-5-((4-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl)amino)pyrimidine-2-carboxamide (Scheme 10)

[0257] [ka]

[0258] (Synthesis of Intermediate E - 4-(4-(trifluoromethyl)phenyl)oxazol-2-amine)urea (12 equiv.) was added to a solution of 2-bromo-1-(4-(trifluoromethyl)phenyl)ethan-1-one (3.000 g, 11.234 mmol) in ACN (30 mL) and the mixture was heated to reflux for 16 h. Upon cooling, the mixture was concentrated under vacuum. The mixture was then filtered with HO (10 mL) and washed with DCM (5 mL) to afford 4-(4-(trifluoromethyl)phenyl)oxazol-2-amine as a pale yellow solid (2.200 g, 85.8% yield). 1 H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H), 7.53 (s, 1H), 5.09 (s, 2H).LCMS R f (min)=3.359, MS m / z=228.9[M+H] + .

[0259] A resealable Schlenk tube was charged with Pd(dba) (0.02 equiv.), Xantphos (0.06 equiv.), (4-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl)amine (1.2 equiv.), KPO (fine powder, 1.4 equiv.), methyl 5-bromopyrimidine-2-carboxylate (0.150 g, 0.691 mmol), and 1,4-dioxane (4 mL). The mixture was degassed and carefully evacuated and refilled with N for three cycles before the dropwise addition of HO (1.0 mmol). It was then sealed and immersed in an oil bath at 140 °C. After 15 h, the mixture was cooled, diluted with EtOAc (20 mL), and washed with HO (15 mL). The aqueous layer was then back-extracted with EtOAc (2 × 15 mL). The crude product was concentrated under reduced pressure and chromatographed on a SiO2 column (EtOAc:toluene=1:1) to give methyl 5-((4-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyrimidine-2-carboxylate as a white solid (0.18 g, 71.5% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 9.26 (s, 2H), 8.49 (s, 1H), 8.04 (d, J = 8.1 Hz, 2H), 7.81 (d, J = 8 .2 Hz, 2H), 3.89 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.19, 155.43, 148.43, 144.37, 144.35, 137.93, 135.93, 134.84, 128.11, 127.79, 125.72, 125.57, 122.90, 52.49.LCMS R f (min)=3.517, MS m / z=364.8[M+H] + .

[0260] LiOH·HO (3 equiv.) in HO (1 mL) was added to a solution of methyl 5-((4-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyrimidine-2-carboxylate (0.160 g, 0.439 mmol) in 1,4-dioxane (1.5 mL) and EtOH (1.5 mL), and the mixture was refluxed for 3 h. The volatiles were removed in vacuo, and brine (2 mL) was added to the suspension, followed by the dropwise addition of 6 M HCl (2 mL) at 0 °C. The resulting precipitate was filtered and washed with HO (2 mL) to give 5-((4-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyrimidine-2-carboxylic acid as a yellow solid (0.150 g, 97.0% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 9.27 (s, 2H), 8.50 (s, 2H), 8.04 (d, J = 8.1 Hz, 2H), 7.81 (d, J = 8.2 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 164.87, 155.92, 139.61, 138.92, 138.45, 137.90, 135.03, 125.93, 125.67, 125.53, 122.50, 64.11, 52.06, 52.04.LCMS R f (min)=3.811, MS m / z=348.9[MH] - .

[0261] A solution of 5-((4-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyrimidine-2-carboxylic acid (0.100 g, 0.286 mmol), anhydrous HOBt (1.2 equiv.), and EDCI HCl (1.3 equiv.) in dry DMF (2 mL) was stirred at room temperature for 2 h. After this, O-benzylhydroxylamine hydrochloride (5 equiv.) and EtN (5 equiv.) were added, and the mixture was stirred at room temperature for an additional 16 h. DMF was removed in vacuo and washed with toluene (2 mL × 3) to aid in the process. HO (2 mL) was then added, and the mixture was left stirring at room temperature for 10 min. The resulting precipitate was filtered and washed with HO (1 mL) and hexanes (2 mL) to give N-(benzyloxy)-5-((4-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyrimidine-2-carboxamide as a brown solid (0.11 g, 84.6% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 11.19 (s, 1H), 9.25 (s, 2H), 8.50 (s, 1H), 8.02 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 8.3 Hz, 2H), 7.57-7.30 (m, 5H), 4.95-4.86 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ159.82, 155.60, 150.06, 144.24, 137.88, 135.84, 135.64, 134.87, 131.15, 128.73, 128.27, 128.24, 128.08, 127.76, 125.71, 125.48, 122.90, 77.02, 45.64, 8.61.LCMS R f (min)=3.879 , MS m / z=455.8[M+H] + .

[0262] [ka]

[0263] 1.0 M BBr in heptane (3 equiv.) was added dropwise to a solution of N-(benzyloxy)-5-((4-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyrimidine-2-carboxamide (0.110 g, 0.242 mmol) in dry DCM (1 mL) at 0 °C, and the mixture was stirred at room temperature for 2 h. The volatiles were removed in vacuo, and the residue was suspended in sat. NaHCO (aq.) (3 mL) and stirred at room temperature for 20 min. The crude material was purified using preparative HPLC with a solvent system of 95% A:5% B to 100% B. TFA and ACN were removed via rotary evaporation, and HO was removed via freeze-drying to give the title compound as a white solid (0.035 g, 39.7% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 11.13 (s, 1H), 9.23 (s, 2H), 9.15 (s, 1H), 8.50 (s, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.2 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 160.44, 156.18, 151.31, 145.71, 144.76, 138.39, 135.81, 135.41, 131.59, 128.58, 128.26, 126.26, 126.22, 125.99, 123.39.LCMS R f (min)=5.571. HRMS(ESI)C 15 H 11 F3N5O3 + [M+H] + The calculated value was 366.0809, and the measured value was 366.0803. 13. N-Hydroxy-6-((4-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridazine-3-carboxamide (Scheme 11)

[0264] [ka]

[0265] Oxalyl chloride (1 equiv.) was added dropwise to a solution of 6-chloro-3-pyridazinecarboxylic acid (1.000 g, 6.308 mmol) in dry DCM (30 mL) and dry DMF (1 drop) at 0 °C, and the mixture was stirred at this temperature for 1 h. The solvent was removed in vacuo, and the residue was redissolved in dry DCM. MeOH (1 equiv.) was added, and the mixture was stirred at room temperature for an additional 1 h. The mixture was quenched with HO (20 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were then dried over MgSO and concentrated to give methyl 6-chloropyridazine-3-carboxylate as a white solid (0.960 g, 88.2% yield). 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 4.09 (s, 3H). In a resealable Schlenk tube, Pd2(dba)3 (0.02 equiv.), Xantphos (0.06 equiv.), 4-(4-(trifluoromethyl)phenyl)oxazol-2-amine (Intermediate E) (1.2 equiv.), K3PO4 (fine powder, 1.4 equiv.), methyl 6-chloropyridazine-3-carboxylate (0.250 g, 1.152 mmol), and 1 4-Dioxane (4 mL) was charged. The mixture was degassed and carefully evacuated and refilled with N2 three times before adding HO (1.0 mmol) dropwise. It was then sealed and immersed in an oil bath at 140 °C. After 15 h, the mixture was cooled, diluted with EtOAc (20 mL), and washed with HO (15 mL). The aq. layer was then back-extracted with EtOAc (2 × 15 mL). The crude product was concentrated under reduced pressure and chromatographed on a SiO2 column (EtOAc:toluene = 1:1) to give methyl 6-((4-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridazine-3-carboxylate as a white solid (0.27 g, 51.2% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 8.8 Hz, 1H), 8.53 (s, 1H), 8.25 (d, J = 9.1 Hz, 1H), 8.03 (d, J = 7.9 Hz, 2H), 7.81 (d, J = 8.3 Hz, 3H), 3.94 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 137.86, 134.86, 131.60, 130.00, 128.14, 127.82, 125.69, 125.58, 122.90, 52.57, 39.52.LCMS R f (min)=3.496, MS m / z=364.8[M+H] + .

[0266] LiOH·HO (3 equiv.) in HO (2 mL) was added to a solution of methyl 6-((4-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridazine-3-carboxylate (0.250 g, 0.686 mmol) in 1,4-dioxane (2 mL) and EtOH (2 mL), and the mixture was refluxed for 3 h. The volatiles were removed in vacuo, and brine (2 mL) was added to the suspension, followed by the dropwise addition of 6 M HCl (2 mL) at 0 °C. The resulting precipitate was filtered and washed with HO (2 mL) to give 6-((4-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridazine-3-carboxylic acid as a yellow solid (0.240 g, 99.8% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.52 (s, 1H), 8.21 (s, 1H), 8.03 (d, J = 8.1 Hz, 2H), 7.81 (d, J = 8.3 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 138.33, 135.38, 131.97, 130.56, 130.40, 128.77, 128.60, 128.28, 127.97, 126.15, 126.12, 126.05, 123.36.LCMS R f(min)=3.742, MS m / z=350.8[M+H] + .

[0267] A solution of 6-((4-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridazine-3-carboxylic acid (0.220 g, 0.628 mmol), anhydrous HOBt (1.2 equiv.), and EDCI HCl (1.3 equiv.) in dry DMF (3 mL) was stirred at room temperature for 2 h. After this, O-benzylhydroxylamine hydrochloride (5 equiv.) and EtN (5 equiv.) were added, and the mixture was stirred at room temperature for an additional 16 h. DMF was removed in vacuo and washed with toluene (2 mL × 3) to aid in this process. HO (2 mL) was then added, and the mixture was left stirring at room temperature for 10 min. The resulting precipitate was filtered and washed with HO (1 mL) and hexanes (2 mL) to give N-(benzyloxy)-6-((4-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridazine-3-carboxamide as a brown solid (0.20 g, 69.9% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.65 (d, J = 8.8 Hz, 1H), 8.54 (s, 1H), 8.19 (d, J = 9.4 Hz, 1H), 8.04 (d, J = 8.1 Hz, 2H), 7.82 (d, J = 8.3 Hz, 2H), 7.54 - 7.46 (m, 2H), 7.45 - 7.33 (m, 3H), 4.98 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 160.71, 144.42, 136.27, 131.78, 129.27, 128.75, 128.29, 128.03, 126.58, 125.99, 125.40, 123.76, 123.29, 77.61.LCMS R f (min)=3.852, MS m / z=455.8[M+H] + .

[0268] [ka]

[0269] 1.0 M BBr in heptane (3 equiv.) was added dropwise to a solution of N-(benzyloxy)-6-((4-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridazine-3-carboxamide (0.180 g, 0.395 mmol) in dry DCM (1 mL) at 0 °C, and the mixture was stirred at room temperature for 2 h. The volatiles were removed in vacuo, and the residue was suspended in sat. NaHCO (aq.) (3 mL) and stirred at room temperature for 20 min. The crude material was purified using preparative HPLC with a 95% A:5% B to 100% B solvent system. TFA and ACN were removed via rotary evaporation, and HO was removed via freeze-drying, affording the title compound as a white solid (0.050 g, 34.6% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 11.13 (s, 1H), 9.23 (s, 2H), 9.15 (s, 1H), 8.50 (s, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.2 Hz, 2H).LCMS R f (min)=3.386. HRMS(ESI)C 15 H 11 F3N5O3 + [M+H] + The calculated value was 366.0809, and the measured value was 366.0826. 14. N-Hydroxy-5-((4-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl)amino)picolinamide (Scheme 12)

[0270] [ka]

[0271] In a resealable Schlenk tube, add Pd2(dba)3 (0.02 equiv.), Xantphos (0.06 equiv.), 4-(4-(trifluoromethyl)phenyl)oxazole-2- The amine (Intermediate E) (1.2 equiv.), KPO (fine powder, 1.4 equiv.), methyl 5-bromopicolinate (0.250 g, 1.152 mmol), and 1,4-dioxane (4 mL) were charged. The mixture was degassed and carefully evacuated and refilled with N for three cycles before the dropwise addition of HO (1.0 mmol). It was then sealed and immersed in an oil bath at 140 °C. After 15 h, the mixture was cooled, diluted with EtOAc (20 mL), and washed with HO (15 mL). The aqueous layer was then back-extracted with EtOAc (2 × 15 mL). The crude product was concentrated under reduced pressure and chromatographed on a SiO column (EtOAc:toluene=1:1) to give methyl 5-((4-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinate as a white solid (0.21 g, 49.8% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.90 (d, J = 2.5 Hz, 1H), 8.44 (s, 1H), 8.36 (dd, J = 8.7, 2.6 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 8.00 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 3.85 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 164.22, 155.55, 149.46, 144.33, 137.96, 135.69, 135.68, 134.91, 131.18, 125.74, 125.57, 125.55.LCMS R f (min) = 3.907, MS m / z = 363.8[ M+H] + .

[0272] LiOH·HO (3 equiv.) in HO (2 mL) was added to a solution of methyl 5-((4-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinate (0.180 g, 0.495 mmol) in 1,4-dioxane (2 mL) and EtOH (2 mL), and the mixture was refluxed for 3 h. The volatiles were removed in vacuo, and brine (2 mL) was added to the suspension, followed by the dropwise addition of 6 M HCl (2 mL) at 0 °C. The resulting precipitate was filtered and washed with HO (2 mL) to give 5-((4-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinic acid as a yellow solid (0.240 g, 99.8% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.90 (d, J = 2.4 Hz, 1H), 8.46 (s, 1H), 8.34 (dd, J = 8.6, 2.6 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.81 (d, J = 8.2 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 166.27, 156.47, 146.55, 140.97, 139.20, 138.93, 138.75, 138.55, 138.36, 135.52, 131.28, 130.57, 128.94, 128.51, 128.19, 127.61, 127.05, 126.17, 125.99, 123.77, 123.39, 123.16.LCMS R f (min)=3.578, MS m / z =349.8[M+H] + .

[0273] A solution of 5-((4-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinic acid (0.110 g, 0.315 mmol), anhydrous HOBt (1.2 equiv.), and EDCI HCl (1.3 equiv.) in dry DMF (3 mL) was stirred at room temperature for 2 h. After this, O-benzylhydroxylamine hydrochloride (5 equiv.) and EtN (5 equiv.) were added, and the mixture was stirred at room temperature for an additional 16 h. DMF was removed in vacuo and washed with toluene (2 mL × 3) to aid in the process. HO (2 mL) was then added, and the mixture was left stirring at room temperature for 10 min. The resulting precipitate was filtered and washed with HO (1 mL) and hexanes (2 mL) to give N-(benzyloxy)-5-((4-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide as a brown solid (0.14 g, 97.8% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 10.97 (s, 1H), 8.91 (d, J = 2.4 Hz, 1H), 8.45 (s, 1H), 8.32 (dd, J = 8.7, 2.5 Hz, 1H), 8.01 (dd, J = 8.4, 3.3 Hz, 2H), 7.82 (d, J = 8.5 Hz, 2H), 7.51-7.24 (m, 5H), 4.94 (d, J = 3.0 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 162.01, 156.54, 142.58, 138.98, 138.35, 137.52, 136.46, 129.20, 128.75, 126.20, 125.97, 123.85, 123.39, 77.56, 77.51.LCMS R f (min)=4.043, MS m / z=454.8[M+H] + .

[0274] [ka]

[0275] 1.0 M BBr in heptane (3 equiv.) was added dropwise to a solution of N-(benzyloxy)-5-((4-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide (0.120 g, 0.264 mmol) in dry DCM (1 mL) at 0 °C, and the mixture was stirred at room temperature for 2 h. The volatiles were removed in vacuo, and the residue was suspended in sat. NaHCO (aq.) (3 mL) and stirred at room temperature for 20 min. The crude material was purified using preparative HPLC with a 95% A:5% B to 100% B solvent system. TFA and ACN were removed via rotary evaporation, and HO was removed via freeze-drying, affording the title compound as a white solid (0.029 g, 30.1% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 10.91 (s, 1H), 8.89 (d, J = 2.2 Hz, 1H), 8.45 (s, 1H), 8.29 (dd, J = 8.6, 2.6 Hz, 1H), 8.02 - 7.97 (m, 3H), 7.82 (d, J = 8.2 Hz, 2H), 5.76 (s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 161.41, 156.15, 142.74, 140.13, 138.08, 137.86, 137.02, 135.10, 130.66, 130.09, 129.27, 128.02, 127.70, 125.73, 125.69, 125.47, 123.37, 122.92, 122.50, 39.52.LCMS R f (min)=5.908. HRMS(ESI)C 16 H 12 F3N4O3 + [M+H] + The calculated value was 365.0856 and the measured value was 365.0861. 15. N-Hydroxy-N-methyl-5-((5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl)amino)pyridine-2-sulfonamide (Scheme 13)

[0276] [ka]

[0277] A solution of CsCO (29.227 g, 89.704 mmol) and benzyl mercaptan (10.511 mL, 89.704 mmol) in DMF (70 mL) was stirred for 15 min. 2,5-Dibromopyridine (5.000 g, 25.107 mmol) in DMF (30 mL) was added, and the resulting solution was stirred at room temperature for 30 min. The reaction mixture was diluted with water and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give crude 2-(benzylthio)-5-bromopyridine, which was used without further purification. 1 H NMR (400 MHz, CDCl3) δ 8.50 (dd, J = 2.5, 0.7 Hz, 1H), 7.57 (dd, J = 8.5, 2.4 Hz, 1H), 7.45 - 7.21 (m, 5H), 7.05 (dd, J = 8.5, 0.7 Hz, 1H), 4.40 (s, 2H).LCMS R f (min)=3 .956. MS m / z 323.9[M+H] + .

[0278] A resealable Schlenk tube was charged with Pd(dba) (0.327 g, 0.357 mmol), Xantphos (0.620 g, 1.071 mmol), 5-(4-(trifluoromethyl)phenyl)oxazol-2-amine (Intermediate D) (0.977 g, 4.283 mmol), KPO (fine powder, 1.061 g, 4.997 mmol), 2-(benzylthio)-5-bromopyridine (1.000 g, 3.569 mmol), and 1,4-dioxane (20 mL). The mixture was degassed and carefully evacuated and refilled with N for three cycles before the dropwise addition of HO (0.018 mL, 1.0 mmol). It was then sealed and immersed in a sand bath at 140 °C. After 15 h, the volatiles were evaporated. The mixture was then filtered and washed with HO (10 mL), 10% potassium ethylxanthate solution (10 mL) and ether (10 mL) to give N-(6-(benzylthio)pyridin-3-yl)-5-(4-(trifluoromethyl)phenyl)oxazol-2-amine as a gray solid (0.56 g, 43.1% yield). 1 H NMR (400 MHz, DMSO-d6) δ 1 0.68 (s, 1H), 8.73 (d, J = 2.3 Hz, 1H), 7.99 (dd, J = 8.7, 2.6 Hz, 1H), 7.78 (s, 4H), 7.71 (s, 1H), 7.42 - 7.20 (m, 5H), 4.38 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 156.79, 149.31, 142.84, 138.50, 138.23, 133.20, 131.60, 128.81, 128.36, 128.27, 127.04, 126.94, 126.72, 126.04, 126.01, 125.57, 125.38, 125.06, 122.10, 33.97.LCMS R f (min)=3.907, MS m / z=427.9[M+H] + .

[0279] Sulfuryl chloride (0.185 g, 2.293 mmol) was added to a solution of N-(6-(benzylthio)pyridin-3-yl)-5-(4-(trifluoromethyl)phenyl)oxazol-2-amine (0.140 g, 0.328 mmol) in DCM (2 mL) and HO (0.5 mL) at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred under N for 30 min. The gray suspension turned yellow as SOCl was slowly added before returning to a gray suspension again. After the sulfonyl chloride was formed, the solvent was completely evaporated. The mixture was then redissolved in DCM (2 mL). DIPEA (0.285 mL, 0.742 mmol) and O-(4-methoxybenzyl)-N-methylhydroxylamine (0.066 mg, 0.393 mmol) were added to the suspension, and the mixture was stirred at room temperature for 2 d. Upon completion, the mixture was extracted with EtOAc (3×20 mL). The organic layer was collected and washed with brine. The crude material (N-((4-methoxybenzyl)oxy)-N-methyl-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridine-2-sulfonamide) was used in the next step without further purification (0.062 g, 35.4% yield). 1 H NMR (401 MHz, DMSO-d6) δ 8.86 (d, J = 2.5 Hz, 1H), 8.43 (dd, J = 8.8, 2.6 Hz, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.82 (s, 4H), 7.80 (s, 1H), 7.37 - 7.19 (m, 2H), 7.01 - 6.83 (m, 2H), 4.85 (s, 2H), 3.74 (s, 3H), 2.90 (s, 3H).LCMS R f (min)=3.660, MS m / z=534.9[M+H] + .

[0280] [ka]

[0281] N-[(4-Methoxybenzyl)oxy]-N-methyl-5-((5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl)amino)pyridine-2-sulfonamide was dissolved in 10% triethylsilane in trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 4 h. Upon completion, the mixture was filtered and washed with EtO (2 mL) to give a pale yellow solid. The crude material was purified using preparative HPLC. TFA and ACN were removed via rotary evaporation, and HO was removed via use of a freeze-dryer to give the title compound as a white solid (0.040 g, 83.2% yield). 1 H NMR (401 MHz, DMSO-d6) 11.39 (s, 1H), 10.27 (s, 1H), 8.90 (d, J = 2.5 Hz, 1H), 8.43 (dd, J = 8.7, 2.5 Hz, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.83 (s, 4H), 7.82 (s, 1H), 2.95 (s, 3H).LCMS R f (min)=6.114. HRMS(ESI)C 16 H 14 F3N 4O4S + [M+H] + The calculated value was 415.0682 and the measured value was 415.0687. 16. rac-N-(2,3-dihydroxypropyl)-5-((5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl)amino)pyridine-2-sulfonamide (Scheme 14)

[0282] [ka]

[0283] A solution of CsCO (29.227 g, 89.704 mmol) and benzyl mercaptan (10.511 mL, 89.704 mmol) in DMF (70 mL) was stirred for 15 min. 2,5-Dibromopyridine (5.000 g, 25.107 mmol) in DMF (30 mL) was added, and the resulting solution was stirred at room temperature for 30 min. The reaction mixture was diluted with water and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give crude 2-(benzylthio)-5-bromopyridine, which was used without further purification. 1 H NMR (400 MHz, CHCl3) δ 8.50 (dd, J = 2.5, 0.7 Hz, 1H), 7.57 (dd, J = 8.5, 2.4 Hz, 1H), 7.45 - 7.21 (m, 5H), 7.05 (dd, J = 8.5, 0.7 Hz, 1H), 4.40 (s, 2H).LCMS R f (min)=3 .956, MS m / z=323.9[M+H] + .

[0284] Sulfuryl chloride (1.010 mL, 12.492 mmol) was added to a solution of 2-(benzylthio)-5-bromopyridine (0.500 g, 1.785 mmol) in DCM (10 mL) and HO (2 mL) at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 30 min. The mixture was then extracted with DCM (10 mL × 3). The organic layers were combined and completely evaporated to give a gray solid. The solid was then redissolved in DCM (10 mL). A solution of rac-2,2-dimethyl-1,3-dioxolan-4-yl)methanamine and EtN in DCM (2 mL) was added dropwise at 0 °C. The mixture was then stirred at room temperature for 2 h. Upon completion, the suspension was extracted with EtOAc (3 × 20 mL). The organic layer was collected and washed with brine. The crude product was further purified by silica column eluting with 30% DCM in petroleum distillate to give rac-5-bromo-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)pyridine-2-sulfonamide as a yellow solid (0.482 g, 69.98% yield). 1 H NMR (401 MHz, CHCl3) δ 8.75 (dd, J = 2.2, 0.6 Hz, 1H), 8.04 (dd, J = 8.3, 2.3 Hz, 1H), 7.88 (dd, J = 8.3, 0.7 Hz, 1H), 7.43 - 7.36 (m, 1H), 4.24 (qd, J = 6.3, 4.0 Hz, 1H), 4.03 (dd, J = 8.5, 6.4 Hz, 1H), 3.74 (dd, J = 8.5, 5.9 Hz, 1H), 3.32 (dd, J = 13.1, 4.0 Hz, 1H), 3.14 (dd, J = 13.1, 6.4 Hz, 1H), 1.39 (s, 3H), 1.32 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ156.06, 151.32, 140.71, 130.78, 128.93, 124.43, 123.47, 109.82, 74.76, 74.36, 66.58, 59.19, 46.04, 26.88, 25.27.LCMS R f (min)=3.770, MS m / z=292. 8[M+H] + .

[0285] A resealable Schlenk tube was charged with Pd(dba) (0.033 g, 0.057 mmol), Xantphos (0.099 g, 0.171 mmol), 5-(4-(trifluoromethyl)phenyl)oxazol-2-amine (Intermediate D) (0.156 g, 0.683 mmol), KPO (fine powder, 0.169 g, 0.797 mmol), rac-5-bromo-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)pyridine-2-sulfonamide (0.200 g, 0.569 mmol), and 1,4-dioxane (5 mL). The mixture was degassed and carefully evacuated and refilled with N for three cycles before HO (0.010 mL, 1.0 mmol) was added dropwise. It was then sealed and immersed in a sand bath at 140 °C. After 15 h, the volatiles were evaporated. The mixture was then filtered and washed with HO (10 mL), 10% potassium ethylxanthate solution (10 mL), and ether (10 mL) to give rac-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridine-2-sulfonamide as a yellow solid (0.164 g, 57.7% yield). 1 H NMR (401 MHz, DMSO-d6) δ 11.26 (s, 1H), 8.85 (d, J = 2.5 Hz, 1H), 8.35 (dd, J = 8.7, 2.6 Hz, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.89 (t, J = 6.2 Hz, 1H), 7.81 (s, 4H), 7.79 (s, 1H), 4.12 - 4.00 (m, 1H), 3.93 (dd, J = 8.4, 6.2 Hz, 1H), 3.66 (dd, J = 8.4, 5.5 Hz, 1H), 3.14 - 2.89 (m, 2H), 1.27 (s, 3H), 1.21 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 154.23, 147.95, 141.66, 136.65, 136.50, 129.58, 125.94, 125.62, 125.30, 124.99, 124.28, 124.25, 123.73, 123.39, 121.79, 121.35, 120.95, 106.78, 72.51, 64.72, 43.79, 27.73, 24.97, 23.43.

[0286] [ka]

[0287] rac-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-5-((5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl)amino)pyridine-2-sulfonamide was dissolved in 10% triethylsilane in trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 4 h. Upon completion, the mixture was filtered and washed with EtO (2 mL) to afford the title compound as a pale yellow solid (0.102 g, 67.6% yield). 1 H NMR (401 MHz, DMSO-d6) δ 11.27 (s, 1H), 8.85 (d, J = 2.4 Hz, 1H), 8.35 (dd, J = 8.7, 2.6 Hz, 1H), 7.93 (d, J = 8.7 Hz, 1H), 7.81 (s, 3H), 7.79 (s, 1H), 7.50 (t, J = 6.1 Hz, 1H), 3.62 - 3.38 (m, 10H), 3.32 - 3.20 (m, 3H), 3.10 - 2.95 (m, 1H), 2.85 - 2.74 (m, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 156.53, 150.22, 143.91, 138.87, 138.68, 131.85, 127.86, 127.54, 126.54, 126.01, 125.68, 124.06, 123.63, 123.29, 70.99, 63.96, 46.84.LCMS R f (min)=3.57 2, MS m / z=458.9[M+H] + . HRMS(ESI)C 18 H 18 F3N4O5S[M+H] + The calculated value was 459.0945 and the measured value was 459.0951. 17. rac-N-(2,3-dihydroxypropyl)-5-((5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl)amino)picolinamide (Scheme 15)

[0288] [ka]

[0289] HBTU (0.261 g, 0.687 mmol) and DIPEA (0.499 mL, 2.863 mmol) were added to a stirred solution of 5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinic acid (Intermediate B) (0.200 g, 0.573 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 10 min. Excess rac-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (0.090 g, 0.687 mmol) was added, and the resulting suspension was stirred at 60 °C for 3 h. The reaction mixture was partitioned with HO and EtOAc. The organic phase was separated and washed with aq. NaHCO, 10% w / v aq. citric acid, and brine. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure to give a crude residue which was subjected to column chromatography to give rac-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide (0.260 g, 98.3% yield). 1 H NMR (401 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.80 (d, J = 2.2 Hz, 1H), 8.59 (t, J = 6.2 Hz, 1H), 8.30 (dd, J = 8.6, 2.6 Hz, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.81 (s, 4H), 7.78 (s, 1H), 4.24 (p, J = 5.8 Hz, 1H), 3.98 (dd, J = 8.3, 6.3 Hz, 1H), 3.72 (dd, J = 8.3, 5.6 Hz, 1H), 3.42 (t, J = 6.1 Hz, 2H), 1.36 (s, 3H), 1.26 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 164.33, 156.70, 143.73, 143.04, 138.70, 137.61, 131.90, 127.74, 127.42, 126.53, 126.49, 126.02, 125.74, 123.99, 123.53, 123.15, 108.90, 74.64, 67.15, 42.06, 27.27, 25.73.LCMS R f (min)=3.633, MS m / z=462.8[M+H] + .

[0290] [ka]

[0291] HCl in EtO (0.054 mL, 0.216 mmol) was added dropwise to a solution of rac-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-((5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl)amino)picolinamide (0.050 g, 0.108 mmol) in MeOH (2 mL) and HO (0.5 mL). The mixture was stirred at room temperature for 4 h. Upon completion, the mixture was filtered and washed with EtO (2 mL) to afford the title compound as a light yellow solid (0.040 g, 87.6% yield). 1 H NMR (401 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.81 (s, 1H), 8.47 (s, 1H), 8.31 (d, J = 8.6 Hz, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.81 (s, 4H), 7.78 (s, 1H), 3.62 (dq, J = 10.8, 5.5 Hz, 1H), 3.56 - 3.45 (m, 1H), 3.35 (ddd, J = 26.5, 11.0, 5.6 Hz, 2H), 3.27 - 3.18 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 163.68, 156.26, 143.31, 142.65, 138.23, 137.12, 131.46, 128.28, 127.64, 127.32, 127.00, 126.68, 126.10, 126.06, 125.58, 125.27, 123.67, 123.10, 122.88, 122.62, 120.18, 70.26, 63.98, 42.40.LCMS Rf(min)=3.235, MS m / z=4 22.8[M+H] + . HRMS(ESI)C 19 H 18 F3N4O4[M+H] + The calculated value was 423.1275 and the measured value was 423.1285. 18. 6-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridin-3-ol (Scheme 16)

[0292] [ka]

[0293] To a suspension of 5-(4-(trifluoromethyl)phenyl)oxazol-2-amine (Intermediate D) (0.51 g, 2.235 mmol) in ACN (4 mL) was added CuBr (0.603 g, 2.839 mmol) at 0 °C. The solution turned dark green, and tert-butyl nitrite (0.705 mL, 5.879 mmol) was added dropwise at 0 °C, after which the mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water (5 mL) and DCM (5 mL), and the phases were separated. The aq. phase was extracted with DCM (3 × 5 mL), dried over NaSO, and evaporated to give the crude product. Purification by column chromatography gave 2-bromo-5-(4-(trifluoromethyl)phenyl)oxazole (0.153 g, 23.4% yield). 1 H NMR (401 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.81 (d, J = 8.3 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 153.25, 134.45, 130.11, 129.38, 129.06, 128.74, 128.42, 128.04, 126.98, 126.20, 126.16, 126.12, 126.09, 125.34, 124.48, 122.63.LCMS R f (min)=3.633, MS m / z=291.7[M+H] + .

[0294] A resealable Schlenk tube was charged with Pd(dba) (0.047 g, 0.051 mmol), Xantphos (0.089 g, 0.154 mmol), 2-bromo-5-[4-(trifluoromethyl)phenyl]oxazole (0.150 g, 0.514 mmol), KPO (fine powder, 0.153 g, 0.719 mmol), 5-methoxypyridin-2-amine (0.077 g, 0.616 mmol), and 1,4-dioxane (5 mL). The mixture was degassed and carefully evacuated and refilled with N for three cycles before the dropwise addition of HO (0.009 mL, 1.0 mmol). The reaction was then sealed and immersed in a sand bath at 140 °C. After 15 h, the volatiles were evaporated. The mixture was then filtered and washed with HO (10 mL), 10% potassium ethylxanthate solution (10 mL), and ether (10 mL) to give a light yellow solid (0.092 g). The crude product (N-(5-methoxypyridin-2-yl)-5-(4-(trifluoromethyl)phenyl)oxazole) was obtained. -2-amine) was used in the next step without further purification. 1 H NMR (401 MHz, DMSO) δ 10.84 (s, 1H), 8.03 (d, J = 2.8 Hz, 1H), 8.00 (d, J = 9.1 Hz, 1H), 7.83 - 7.76 (m, 4H), 7.71 (s, 1H), 7.48 (dd, J = 9.1, 3.1 Hz, 1H), 3.82 (s, 3H). 13C NMR (101 MHz, DMSO) δ 157.28, 151.57, 146.12, 143.16, 134.83, 132.17, 127.43, 127.12, 126.54, 126.51, 126.47, 126.47, 126.43, 126.07, 125.72, 124.36, 123.31, 111.87, 56.32.LCMS R f (min) = 3.907, MS m / z = 336.0 [M+ H] + .

[0295] [ka]

[0296] 1.0 M BBr in heptane (0.079 mL, 0.823 mmol) was added dropwise to crude N-(5-methoxypyridin-2-yl)-5-(4-(trifluoromethyl)phenyl)oxazol-2-amine (0.092 g) in dry DCM (1 mL) at 0 °C, and the mixture was stirred at room temperature for 2 h. The volatiles were removed in vacuo, and the residue was suspended in saturated NaHCO (aq.) (3 mL) and stirred at room temperature for 20 min. The crude material was purified using preparative HPLC with a 95% A:5% B to 100% B solvent system. TFA and ACN were removed via rotary evaporation, and HO was removed via freeze-drying to give the title compound as a white solid (0.017 g, 19.3% yield). 1 H NMR (401 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.87 (d, J = 2.2 Hz, 1H), 8.35 (dd, J = 8.7, 2.7 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.83 (s, 4H), 7.83 (s, 1H).LCMS R f (min)=5.27 5. HRMS(ESI)C 15 H 11 F3N3O2 + [M+H] +The calculated value was 322.0798 and the measured value was 322.0802. 19. N-(2-hydroxyethyl)-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide (Scheme 17)

[0297] [ka]

[0298] 5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinic acid (Intermediate B) (105 mg, 0.30 mmol) was suspended in dry THF, CDI (1.5 eq) was added, and the resulting mixture was stirred at 55° C. for 24 h. Additional CDI (1 eq) was added, and stirring was continued for another 24 h. Ethanolamine (10 eq) was added, and stirring was continued at room temperature overnight. LCMS indicated the reaction was complete. The volatiles were removed, the residue was triturated with 1N HCl, and the solid was collected via filtration and washed with HO (3×). The solid product was freeze-dried from DMSO / dioxane to give the title product (containing approximately 20 mol % DMSO); 103 mg, 87.32%; 1 H NMR (401 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.80 (d, J = 2.4 Hz, 1H), 8.50 (t, J = 5.8 Hz, 1H), 8.29 (dd, J = 8.6, 2.5 Hz, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.81 (s, 4H), 7.78 (s, 1H), 4.80 (t, J = 5.4 Hz, 1H), 3.52 (m, 2H), 3.37 (m, 2H).LC MS R f (min)=4.081, MS m / z=393.0[M+H] + . HRMS(ESI)C 18 H 16 F3N4O3 + [M+H] + Calculated value: 393.1169, measured value: 393.1177 20. N-Hydroxy-N-methyl-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide (Scheme 18)

[0299] [ka]

[0300] 5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinic acid (Intermediate B) (92 mg, 0.263 mmol) was suspended in dry THF, CDI (1.5 equiv.) was added, and the resulting mixture was stirred at 55 °C for 24 h. Additional CDI (1 equiv.) was added, and stirring was continued for another 24 h. MeNHOH.HCl and EtN (10 equiv. each) were added, and stirring was continued at room temperature overnight. The volatiles were removed, and the solid was collected via filtration and washing with HO (3x). The residual solid product was purified on a basic ion exchange resin (Dowex@66) eluted with MeOH, followed by MeOH containing 0.1% EtN. The product-containing fractions were pooled, evaporated to dryness, and then purified by preparative HPLC to give the title compound (69 mg, 69.24% yield). 1 H NMR (401 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.80 (s, 1H), 8.24 (d, J = 8.5 Hz, 1H), 7.81 (s, 4H), 7.77 (s, 1H), 7.72 (br, 1H), 5.85 (br, 1H), 3.33 (s, 3H).LCMS R f (m in) = 4.130, MS m / z = 378.9 [M + H] + . HRMS(ESI)C 17 H 14 F3N4O3 + [M+H] + The calculated value was 379.1013, and the measured value was 379.1018. 21. N-Hydroxy-N,3-dimethyl-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide (Scheme 19)

[0301] [ka]

[0302] Intermediate D (5-(4-(trifluoromethyl)phenyl)oxazol-2-amine) (0.8 g, 3.506 mmol) was reacted with methyl 5-bromo-3-methylpicolinate (1.0 g, 4.382 mmol) as in General Procedure 4, Method 1. Upon completion, the volatile solvents were removed in vacuo, and the residue was treated with water and 1 N HCl to adjust the pH to 4-5. The solid precipitate was collected via filtration and washed with 5% potassium xanthate (2×), water (5×), and diethyl ether (5×) to afford methyl 3-methyl-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinate in 83.75% yield (1.108 g). 1 H NMR (401 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.64 (s, 1H), 8.07 (s, 1H), 7.78 (s, 4H), 7.76 - 7.74 (m, 1H), 3.81 (s, 3H), 2.50 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 166.42, 156.59, 143.74, 139.76, 138.24, 136.28, 136.19, 131.88, 127.74, 127.42, 126.53, 126.50, 126.01, 125.73, 125.53, 123.52, 123.31, 52.20, 20.40.LCMS Rf(min)=3.807. HRMS(ESI)C 18 H 15 F3N3O3 + [M+H] + The calculated value was 378.1060, and the measured value was 378.1065.

[0303] Methyl 3-methyl-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinate (0.297 g, 0.787 mmol) was hydrolyzed as per Scheme 12, step b to give 3-methyl-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinic in 93.71% yield (0.268 g). 1 H NMR (401 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.67 (s, 1H), 8.07 (s, 1H), 7.79 (s, 5H), 2.54 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ167.08, 156.62, 143.74, 140.05, 138.29, 136.25, 135.69, 131.88, 127.74, 127.43, 126.53, 126.50, 126.01, 125.91, 125.74, 123.52, 123.31, 20.52.H RMS(ESI)C 17 H 13 F3N3O3 + [M+H] + Calculated value 364.0904, Found value 364.0912. LCMS Rf(min)=3.695, MS m / z=363.9[M+H] + .

[0304] 3-Methyl-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinic acid (0.248 g, 0.682 mmol) was coupled with O-(4-methoxybenzyl)-N-methylhydroxylamine hydrochloride as per Scheme 12, step c to give N-((4-methoxybenzyl)oxy)-N,3-dimethyl -5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide was obtained in 60.88% yield (0.213 g). 1H NMR (401 MHz, CDCl3) δ 9.10 (brs, 1H), 8.55 (s, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.60 (s, 4H), 7.29 (s, 1H), 6.89 (s, 2H), 6.76 (s, 2H), 4.73 (s, 2H), 3.72 (s, 3H), 3.38 (s, 3H), 2.32 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.05, 156.50, 144.45, 135.87, 131.08, 129.28, 128.95, 125.95, 125.92, 125.77, 125.35, 123.43, 122.99, 122.65, 113.93, 55.23, 18.05.LCMS Rf(min)=3.479. HRMS(ESI)C 26 H 24 F3N4O4 + [M+H] + The calculated value was 513.1744, and the measured value was 513.1726.

[0305] [ka]

[0306] N-((4-Methoxybenzyl)oxy)-N,3-dimethyl-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide (0.193 g, 0.376 mmol) was deprotected in TFA and EtSiH as in general procedure 11 to give N-hydroxy-N,3-dimethyl-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide in 79.18% yield (0.117 g). 1H NMR (401 MHz, DMSO) δ 10.78 (s, 1H: two peaks due to isomers), 9.98 (brs, 1H), 8.60 (s, 2H), 7.98 (s, 1H: two peaks due to isomers), 7.78 (s, 4H), 7.73 (s, 1H), 3.28 (s, 2H: major isomer), 3.05 (m, 1H: minor isomer), 2.25 (s, 3H: two peaks due to isomers). 13 C NMR (101 MHz, DMSO) δ167.88, 157.10, 147.75, 143.41, 136.04, 135.72, 135.19, 131.98, 130.52, 128.71, 127.60, 127.28, 126.96, 126.50, 126.46, 126.02, 125.75, 125.22, 123.39, 123.32, 120.62, 36.07, 17.82.LCMS Rf(min)=3.234, MS m / z=392.9[M +H] + . HRMS(ESI)C 18 H 16 F3N4O3 + [M+H] + The calculated value was 393.1169, and the measured value was 393.1178. 22. N-Hydroxy-N-(2-hydroxyethyl)-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide (Scheme 20)

[0307] [ka]

[0308] 2-((tert-Butyldimethylsilyl)oxy)acetaldehyde (0.8 g, 4.59 mmol) was stirred with O-benzylhydroxylamine hydrochloride (1.1 g, 6.88 mmol) in pyridine (9 mL) at room temperature overnight. The reaction was judged complete by LCMS. The volatile pyridine was removed by rotavap, and the residue was dissolved in DCM and saturated NaHCO3 solution. The phases were separated, and the aq. phase was extracted with additional DCM (3x). The combined organic phases were dried over MgSO4 and evaporated to dryness. The residue was purified on silica gel using neat DCM to give the product, 2-((tert-butyldimethylsilyl)oxy)acetaldehyde O-benzyloxime, as a ca. 1:1 mixture of E and Z isomers (1.20 g, 93.5% yield). 1 H NMR (401 MHz, CDCl3; both chemical shifts are assigned) δ 7.48 (t, J = 5.6 Hz, 1H), 7.38 - 7.28 (m, 10H), 6.83 (t, J = 3.4 Hz, 1H), 5.09 (s, 2H), 5.07 (s, 2H), 4.48 (d, J = 3.4 Hz, 2H), 4.25 (d, J = 5.6 Hz, 2H), 0.91 - 0.90 (m, 9H), 0.88 (d, J = 2.9 Hz, 9H), 0.07 (s, 6H), 0.06 (s, 6H). CMS R f (min)=3.95, MS m / z=280.0[M+H] + .

[0309] 2-((tert-butyldimethylsilyl)oxy)acetaldehyde O-benzyloxime (1.14 g, 4.08 mmol) was dissolved in a mixture of EtOH (20 mL) and acetic acid (4 mL); NaBHCN (5 equiv.) was added portionwise, and the resulting reaction mixture was stirred at room temperature overnight. The reaction was judged complete by LCMS. The reaction mixture was cooled to 0 °C, neutralized with 2 N NaOH, and then further diluted with sat. NaHCO solution. The product was extracted with DCM (3 ×), which was dried over MgSO and evaporated to dryness. The residue was purified on silica gel using petroleum distillate / DCM to give O-benzyl-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)hydroxylamine (1.01 g, 87.96% yield). 1 H NMR (401 MHz, CDCl3) δ 7.38 - 7.27 (m, 5H), 6.5-5.5 (brs, 1H), 4.72 (s, 2H), 3.74 (t, J = 5.3 Hz, 2H), 3.02 (t, J = 5.3 Hz, 2H), 0.88 (s , 9H), 0.05 (s, 6H). LCMS R f (min)=4.426, MS m / z=282.1[M+H] + .

[0310] 5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinic acid (Intermediate B) (200 mg, 0.572 mmol) was suspended in DMF (11 mL), EDCI.HCl (1.3 equiv.) and HOBt (1.4 equiv.) were added, and the resulting mixture was stirred at room temperature for 3 h. O-Benzyl-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)hydroxylamine (2 equiv.) was added, and stirring was continued overnight. The reaction mixture was diluted with saturated NaHCO3 solution and EtOAc. After separation, the aq. phase was extracted with additional EtOAc (3x). The combined organic phases were dried over MgSO4 and evaporated to dryness. The residue was purified on silica gel using toluene and EtOAc mixture as eluent to give the product N-(benzyloxy)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide (263 mg, 74.95% yield). 1 H NMR (401 MHz, CDCl3) δ 8.69 (d, J = 2.3 Hz, 1H), 8.14 (dd, J = 8.6, 2.6 Hz, 1H), 7.80 (s, 1H), 7.60 (m, 4H), 7.28 (m, 5H), 5.02 (s, 2H), 3.99 (t, J = 5.7 Hz, 2H), 3.85 (m, 2H), 0.82 (s, 9H), -0.00 (s, 6H).LCMS R f (min ) = 4.001, MS m / z = 613.0 [M + H] + .

[0311] [ka]

[0312] N-(benzyloxy)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide (320 mg, 0.522 mmol) was suspended in DCM (2.6 mL) and BBr3 (2.5 equivalents of a 0.5 M DCM solution) was added at 0 °C. The reaction mixture was stirred at room temperature. After 1 h, additional BBr3 (1.2 equivalents) was added and stirring continued. LCMS indicated that after 1 h, some benzyl-protected intermediate was still present (ca. 15%). Additional BBr3 (1.2 equivalents, total = 4.8 equivalents) was added. After stirring for another 1 h, the volatiles were removed in vacuo and the residue was treated with MeOH containing 1% DIPEA to pH ∼9. The MeOH was removed, and the residue was stirred in HO / DMSO (1 / 1) for 0.5 h and then passed through a C18 silica gel plug. The crude product was purified by preparative HPLC. The fractions containing the desired product were combined, diluted with dioxane, and freeze-dried to give the title compound (83 mg, 31.88% yield), although the product still contained traces of dioxane. 1 H NMR (401 MHz, DMSO-d6) δ 11.32 (s, 1H), 8.86 (d, J = 2.5 Hz, 1H), 8.31 (dd, J = 8.7, 2.6 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.80 (s, 4H), 7.79 (s, 1H), 4.58 - 4.54 (m, 2H), 3.61 - 3.57 (m, 2H).L CMS R f (min)=3.060, MS m / z=408.9[M+H] + . HRMS(ESI)C 18 H 16 F3N4O4 + [M+H] + The calculated value was 409.1118, and the measured value was 409.1129. 23. 1-(Hydroxy)-4-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridin-2(1H)-one (Scheme 21)

[0313] [ka]

[0314] 4-Amino-1-(benzyloxy)pyridin-2(1H)-one (240 mg, 1.11 mmol) was suspended in a mixture of acetone (11 mL) and saturated NaHCO3 solution (11 mL) and cooled to 0 °C. Thiophosgene (1.2 equiv.) was added dropwise, and the resulting mixture was stirred at room temperature for 1 h. The reaction was judged complete by TLC (neat EtOAc). The reaction mixture was poured into saturated NaHCO3 solution, and the product was extracted with DCM (5x). The combined organic phases were dried over MgSO4 and evaporated to dryness. The residue was dissolved in dioxane (5.5 mL), and 2-azido-1-(4-(trifluoromethyl)phenyl)ethan-1-one (Intermediate A) and Ph3P (1.25 equiv. each) were added. The resulting mixture was stirred at reflux for 2 h. All volatile solvents were removed, and the residue was triturated with DCM. The solid was filtered with DCM and washed with Et2O to give the product 1-(benzyloxy)-4-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridin-2(1H)-one as a cream solid (206 mg, 43.53% yield). 1 H NMR (401 MHz, DMSO-d6) δ 10.90 (s, 1H), 7.81 (m, 4H), 7.78 (s, 1H), 7.66 (d, J LCMS R f (min)=3. 406, MS m / z=428.0[M+H] + .

[0315] [ka]

[0316] 1-(Benzyloxy)-4-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridin-2(1H)-one (100 mg, 0.233 mmol) was suspended in DCM and then cooled to 0 °C. BBr (0.089 mL; 0.935 mmol) was added dropwise. After 4 h of stirring at room temperature, LCMS indicated that all starting material had been consumed. The volatile solvents were removed and the residue was dissolved in saturated NaHCO solution. and quenched with MeOH for 1 h. The volatiles were removed and the residue was purified by preparative HPLC to give the title compound (32 mg, 40.5% yield). 1 H NMR (401 MHz, DMSO-d6) δ 10.84 (s, 1H), 7.80 (s, 5H), 7.76 (s, 1H), 6.94 (s, 1H), 6.32 (d, J = 5.6 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 158.49, 155.85, 146.34, 143.30, 135.71, 131.39, 127.40, 127.09, 126.11, 126.07, 125.54, 125.21, 123.18, 122.84, 100.42, 96.73.LCMS R f (min)=3.199. HRMS(ESI)C 15 H 11 F3N3O3 + [M+H] + Calculated value 338.0747, measured value 338.0743 24. N'-Hydroxy-5-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3yl)amino)picolinimidamide (Scheme 22)

[0317] [ka]

[0318] 4-(Trifluoromethyl)phenylboronic acid (6.661 g, 35.05 mmol), Cu(OAc)2.HO (5.251 g, 26.32 mmol), and pyridine (2.825 mL, 35.06 mmol) were added to a solution of 3-nitro-1H-1,2,4-triazole (2.0 g, 17.54 mmol) in DCM (100 mL). The resulting solution was stirred at 25 °C for 5 d. The solvent was removed under reduced pressure to give the crude product. The crude product was purified on a SiO2 column using a Revelis X2 flash chromatography system (EtOAc: petroleum distillate = 2-2.5:10) to give 3-nitro-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole as a white solid (2.55 g, 56.3% yield). 1 H NMR (401 MHz, CDCl3) δ 8.71 (s, 1H), 7.93 (d, J = 8.6 Hz, 2H), 7.88 (d, J = 8.6 Hz, 2H). Synthesis of Intermediate F—1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-amine)zinc dust (3.039 g) was added slowly to a stirred suspension of 3-nitro-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole (2.4 g) in aq. sat. NHCl (25 mL) and acetone (100 mL) at 0° C. After the addition was complete, the ice bath was removed and the mixture was allowed to warm to room temperature with stirring for 1 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure and then diluted with EtOAc (200 mL). The EtOAc layer was separated, washed with aq. sat. NaHCO3 (30 mL) and brine (2 x 50 mL), separated again, dried over MgSO4, filtered, and concentrated in vacuo to give 1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-amine (2.0 g, 94.3% yield), which was used without any purification. 1 H NMR (401 MHz, DMSO-d6) δ 8.98 (s, 1H), 7.93 (d, J = 8.6 Hz, 2H), 7.85 (d, J = 8.7 Hz, 2H), 5.85 (s, 2H). An oven-dried RBF was charged with Pd2(dba)3 (0.05 equiv.), xanthophos (0.1 equiv.), 1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-amine (Intermediate F) (0.680 g, 2.98 mmol), CsCO (1.5 equiv.), 5-bromopicolinonitrile (0.818 g, 1.5 mmol), and 1,4-dioxane (15 mL) were charged. Vacuum was applied to the reaction flask briefly, followed by refilling with N, and this procedure was repeated five times. The mixture was then heated to 100 °C and stirred for 5 h. LCMS indicated that no amine remained. The volatiles were removed in vacuo, and the residue was treated with HO and 1 N HCl to adjust the pH to 4-5. The solid precipitate was collected via filtration and washed with 5% potassium xanthate (2x), HO (5x), diethyl ether (5x) to give 5-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)amino)picolinonitrile (0.655 g, 66.54% yield). 1 H NMR (401 MHz, DMSO-d6) δ 10.56 (s, 1H), 9.34 (s, 1H), 8.84 (d, J = 2.2 Hz, 1H), 8.26 (dd, J = 8.6, 2.4 Hz, 1H), 8.09 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.4 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 160.18, 142.89, 141.32, 140.36, 139.88, 130.22, 127.69, 127.53, 127.49, 127.37, 125.80, 123.10, 122.68, 122.12, 119.20, 118.80.LCMS R f (min)=3.337 . HRMS(ESI)C 15 H 10 F3N6 + [M+H] + Calculated value 331.093, measured value 331.0914

[0319] [ka]

[0320] 5-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)amino)picolinonitrile (0.18 g, 0.545 mmol) was suspended in EtOH (25 mL) and NHOH·HCl (0.303 g, 4.36 mmol) was added. Approximately half of the EtOH was then removed in vacuo. EtN (0.595 mL, 4.36 mol) was then added and the resulting reaction mixture was stirred at reflux overnight. LCMS indicated that the reaction was complete. The volatiles were removed and the resulting solid was suspended in water and collected by filtration followed by thorough washing with HO. The solid was washed with EtO and dried to give the title compound (0.143 g, 72.2% yield). 1 H NMR (401 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.68 (s, 1H), 9.29 (s, 1H), 8.86 (s, 1H), 8.09-7.82 (m, 6H), 5.75 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 160.94, 150.03, 142.65, 142.07, 140.06, 138.68, 136.73, 127.52, 127.48, 127.38, 127.06, 125.85, 123.62, 123.16, 120.06, 118.98.LCMS R f (min)=2.924. HRMS(ESI)C 15 H 13 F3N7O + [M+H] + The calculated value was 364.1128, and the measured value was 364.1140.

[0321] 25. N-Hydroxy-N-methyl-5-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)amino)picolinamide (Scheme 23)

[0322] [ka]

[0323] An oven-dried RBF was charged with Pd(dba) (0.130 g, 0.05 equiv.), Xantphos (0.165 g, 0.1 equiv.), 1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-amine (Intermediate F) (0.650 g, 2.848 mmol), CsCO (1.392 g, 1.5 equiv.), methyl 5-bromopicolinate (0.823 g, 1.5 mmol), and 1,4-dioxane (15 mL). The reaction flask was briefly vacuumed and then backfilled with N, and the procedure was repeated five times. The mixture was then heated to 110 °C and stirred for 5 h. LCMS indicated no amine remained. The reaction was poured into HO, acidified (pH 4-5) with 1N HCl, and then extracted with chloroform (5x). The combined organic phases were dried over MgSO and evaporated to dryness. The residue was chromatographed on silica gel using a mixture of DCM / EtOAc as eluent to give methyl 5-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)amino)picolinate (0.42 g, 40.6% yield). 1 H NMR (401 MHz, DMSO-d6) δ 10.39 (s, 1H), 9.34 (s, 1H), 8.88 (d, J = 2.3 Hz, 1H), 8.23 ​​(dd, J = 8.7, 2.7 Hz, 1H), 8.10 (d, J = 9.0 Hz, 2H), 8.04 (d, J = 8.7 Hz, 1H), 7.93 (d, J = 8.6 Hz, 2H), 3.84 (s, 3H).LCMS R f (minutes)=3. 352. HRMS(ESI) calculated value C 16 H 13 F3N5O2 + [M+H] + 364.1016, actual value 364.1028 Methyl 5-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)amino)picolinate (0.4 g, 1.10 mmol) was mixed with LiOH.HO (0.138 g, 3.30 mmol), dioxane (1.8 mL), HO (1.1 mL), and EtOH (2.8 mL). The resulting mixture was heated to 100 °C and stirred for 3 h. All volatiles were removed in vacuo, and the residue was diluted with 1N Acidified with HCl (pH ∼ 4). The solid was filtered, washed with HO (3x), and dried under high vacuum to give 5-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)amino)picolinic acid (0.355 g, 92.3% yield). 1 H NMR (401 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.30 (s, 1H), 8.68 (s, 1H), 8.17 (d, J = 8.2 Hz, 1H), 8.07 (d, J = 8.0 Hz, 2H), 7.94 (m, 3H).LCMS R f ( min)=3.379, MS m / z=349.9[M+H] + .

[0324] 5-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)amino)picolinic acid (0.3 g, 0.858 mmol) was suspended in DMF (17 mL), and EDCI.HCl (0.214 g, 1.116 mmol) and HOBt (0.141 g, 1.1202 mmol) were added. The resulting mixture was stirred at room temperature for 3 hours. O-(4-Methoxybenzyl)-N-methylhydroxylamine (0.287 g, 1.717 mmol) was added, and stirring was continued overnight. The reaction mixture was diluted with saturated NaHCO3 solution and EtOAc. After separation, the aq. phase was extracted with additional EtOAc (3x). The combined organic phases were dried over MgSO4 and evaporated to dryness. The residue was purified on silica gel using a mixture of petroleum distillate and EtOAc as eluent. Fractions containing the desired product were combined and evaporated to dryness. The solid residue was filtered and washed thoroughly with EtO to give the product N-((4-methoxybenzyl)oxy)-N-methyl-5-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)amino)picolinamide (224 mg, 52.31% yield). 1 H NMR (401 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.33 (s, 1H), 8.85 (d, J = 2.5 Hz, 1H), 8.19 (d6, J = 8.6, 2.6 Hz, 1H), 8.12 (d, J = 8.5 Hz, 2H), 7.94 (d, J = 8.7 Hz, 2H), 7.64 (d, J = 8.6 Hz, 1H), 7.22 (d, J = 7.7 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 4.95 (s, 2H), 3.71 (s, 3H), 3.33 (s, 3H).LCMS R f (minutes)=3.517. HRMS(E SI) Calculated value C 25 H 22 F3N4O4 + [M+H] + 499.1588, actual value 499.1578.

[0325] [ka]

[0326] N-((4-Methoxybenzyl)oxy)-N-methyl-5-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)amino)picolinamide (0.105 g, 0.21 mmol) was stirred in a mixture of TFA (2 mL) and EtSiH (0.105 mL) at room temperature for 4 h. All volatiles were removed on a rotary evaporator, and the residue was filtered with toluene, followed by washing with DCM and EtO. The solid was freeze-dried from dioxane, followed by filtering with MeOH, and washing with a small amount of MeOH and EtO to give the title compound (0.051 g, 64.1% yield). 1 H NMR (401 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.32 (s, 1H), 8.83 (s, 1H), 8.16 (m, 1H), 8.10 (m, 2H), 7.94 (m, 2H), 7.71 (s, 1H) (N- Me (The resonance overlaps with H2O, so it cannot be assigned.) 13 LCMS R f (minutes)=3.337. HRMS(ESI) calculated value C 16 H 14 F3N6O2 + [M+H] + 379.1125, actual value 379.1138.

[0327] 26. N',3-Dihydroxy-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinimidamide (Scheme 24)

[0328] [ka]

[0329] (Intermediate G-5-Bromo-3-((4-methoxybenzyl)oxy)picolinonitrile) p-Methoxybenzyl alcohol (1.57 g, 11.4 mmol, 1.3 equiv) was dissolved in anhydrous THF (30 mL), cooled to 0 °C, and NaH (60%, 0.273 g, 11.4 mmol, 1.3 equiv) was added. The mixture was stirred at 0 °C for 30 min, and then 5-bromo-3-nitropicolinonitrile (2 g, 8.77 mmol) was added. The resulting reaction mixture turned black and was stirred at room temperature for 24 h. LCMS indicated that some starting material was still present, so more NaH (60%, 0.5 equiv) was added and stirring was continued for another 24 h. The reaction mixture was poured into saturated NaHCO3 solution (300 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over MgSO4 and concentrated to dryness. The solid residue was purified on silica gel eluting with neat toluene to give 5-bromo-3-((4-methoxybenzyl)oxy)picolinonitrile (Intermediate G) (1.02 g, 36.43% yield). 1 H NMR (401 MHz, CDCl3) δ 8.32 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.35 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 5.16 (s, 2H), 3.82 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.09, 157.63, 144.06, 144.04, 129.16, 128.24, 125.99, 125.09, 123.92, 122.59, 114.58, 114.41, 71.43, 55.37.LCMS R f (minutes)=3.337. HRMS(ESI) calculated value C 14 H 12 BrN2O2+[M+H] + 319.0077, actual value 319.0068.

[0330] An oven-dried RBF was charged with Pd2(dba)3 (0.064 g, 0.05 equiv.), Xantphos (0.081 g, 0.1 equiv.), 5-bromo-3-((4-methoxybenzyl)oxy)picolinonitrile (Intermediate G) (0.447 g, 1.402 mmol), Cs2CO3 (0.685 g, 1.5 equiv.), 5-(4-(trifluoromethyl)phenyl)oxazol-2-amine (Intermediate D) (0.32 g, 1.402 mmol), and 1,4-dioxane (7 mL). The reaction flask was briefly vacuumed and subsequently backfilled with N2, and the procedure was repeated five times. The mixture was then heated to 110 °C and stirred for 5 h. LCMS indicated that the starting material had been consumed. The volatiles were removed in vacuo, and the residue was purified with HO and The solution was treated with 1N HCl to adjust the pH to 4-5. The solid precipitate was collected by filtration and washed with 5% aqueous potassium ethylxanthate (2x), HO (5x), and EtO (5x) to give 3-((4-methoxybenzyl)oxy)-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinonitrile (0.502 g, 76.74% yield). 1 H NMR (401 MHz, DMSO-d6) δ 11.43 (br, 1H), 8.36 (s, 1H), 8.28 (s, 1H), 7.84 (s, 1H), 7.82 (s, 4H), 7.48 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 5.25 (s, 2H), 3.78 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ159.90, 159.02, 156.25, 144.08, 140.98, 133.28, 131.75, 130.44, 127.95, 127.60, 126.58, 126.00, 125.70, 123.71, 123.30, 116.55, 114.47, 113.84, 107.50, 70.65, 55.61. LCMS R f (min)=3.642, MS m / z=466.9[M+H] + .

[0331] 3-((4-Methoxybenzyl)oxy)-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinonitrile (0.208 g, 0.445 mmol) was suspended in EtOH (25 mL), NHOH.HCl (0.248 g, 3.567 mmol) was added, and approximately half of the EtOH was removed in vacuo. EtN (0.487 mL, 3.567 mol) was added, and the resulting reaction mixture was stirred at reflux overnight. LCMS indicated the reaction was complete. The volatiles were removed, and the resulting solid was suspended in water, collected by filtration, and then washed well with HO. The solid was washed with Et2O and dried under high vacuum to give N'-hydroxy-3-((4-methoxybenzyl)oxy)-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinimidamide (0.176 g, 79% yield). 1 H NMR (401 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.66 (s, 1H), 8.36 (s, 1H), 8.02 (s, 1H), 7.80 (s, 4H), 7.78 (s, 1H), 7.47 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 8.6 Hz, 2H), 5.73 (s, 2H), 5.12 (s, 2H), 3.75 (s, 4H).LCMS R f (minutes)=3.202. HRM S(ESI) calculated value C 24 H 21 F3N5O4 + (M) + 499.1574, actual value 499.1549.

[0332] [ka]

[0333] N'-hydroxy-3-((4-methoxybenzyl)oxy)-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinimidamide (0.163 g, 0.326 mmol) was stirred in a mixture of TFA (3.26 mL) and EtSiH (0.163 mL) at room temperature. LCMS showed the reaction was complete after 1 h. The reaction mixture was filtered to remove a black precipitate and washed with more TFA (3x). The combined TFA phases were evaporated to dryness, filtered with EtO, and then washed with toluene, DCM, and EtO. The residue was purified by preparative HPLC to give the title compound (0.072 g, 58.16% yield). 1 H NMR (401 MHz, DMSO-d6) δ 11.15 (s, 1H), 10.62 - 10.55 (brs, 1H), 8.30 (d, J = 2.1 Hz, 2H), 7.97 (s, 1H), 7.81 (s, 4H), 7.79 (s, 1H), 3.56 (s, 1H).LCMS R f (min)=3.243, MS m / z=379.9[M+H] + . HRMS(ESI) calculated value C 16 H 13 F3N5O3 + [M+H] + 380.0965, actual value 380.0977.

[0334] 27. 1-Hydroxy-6-methyl-4-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridin-2(1H)-one (Scheme 25)

[0335] [ka]

[0336] To a solution of 2,4-dichloro-6-methylpyridine (2.50 g, 15.43 mmol) in dry DCM (60 mL) was added HO and urea (2 equiv.). Upon cooling to 0 °C, a solution of TFAA (2 equiv.) in dry DCM was added dropwise, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated NaSO (15 mL), stirred at room temperature for 0.5 h, then poured into HO (20 mL) and extracted with DCM (7 × 20 mL). The combined organic layers were washed with 1 M NaOH (15 mL), dried over MgSO, and concentrated to a creamy semi-solid. The solid was chromatographed on silica gel eluting with 5% EtOH in DCM to give 2,4-dichloro-6-methylpyridine 1-oxide (2.4 g, 87.4% yield) as a yellow crystalline solid. 1 H NMR (401 MHz, CDCl3) δ 7.42 (dd, J = 2.9, 0.5 Hz, 1H), 7.22 (dd, J = 2.9, 0.5 Hz, 1H), 2.55 (s, 3H).LCMS R f (min)=1.734, MS m / z=177.9 / 179.9[M+H] + .

[0337] Benzyl alcohol (4.186 g, 38.76 mmol) was dissolved in anhydrous THF (40 mL) and cooled to 0°C, followed by addition of LiBu t0 (1.55 g, 19.38 mmol) was added. The mixture was stirred at 0 °C for 30 min, and 2,4-dichloro-6-methylpyridine 1-oxide (2.3 g, 12.92 mmol) was added. The resulting reaction mixture was stirred at room temperature for 3 h. The reaction was deemed complete by TLC (DCM / EtOAc 9 / 1). The reaction mixture was poured into saturated NaHCO3 and extracted with EtOAc (7x) until no product was detected in the extracted EtOAc phase. The combined organic phases were dried over MgSO4 and evaporated to dryness. The residue was dissolved in toluene (800 mL), BnOH (4 mL) was added, and the solution was heated at reflux for 28 h. A small amount of N-oxide remained unreacted. The toluene was removed, and the residue was freeze-dried from HO / dioxane to remove excess BnOH and BnCl. The remainder was purified by filtration using a mixture of DCM and EtOAc. Purification on silica gel gave the product 1-(benzyloxy)-4-chloro-6-methylpyridin-2(1H)-one (1.37 g, 42.46% yield). 1 H NMR (401 MHz, CDCl3) δ 7.49 - 7.42 (m, 2H), 7.42 - 7.34 (m, 3H), 6.61 - 6.55 (m, 1H), 5.96 - 5.85 (m, 1H), 5.25 (s, 2H), 2.15 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 158.54, 146.84, 145.31, 133.56, 130.03, 129.51, 128.78, 117.91, 106.37, 17.56.LCMS R f (minutes)=3.528. HRMS(ESI) calculated value C 13 H 13 ClNO2 + [M+H] + 250.0629, actual value 250.0636.

[0338] 1-(Benzyloxy)-4-chloro-6-methylpyridin-2(1H)-one (1.25 g, 5.0 mmol) was stirred with NaN3 (1.50 g, 25.0 mmol, 5 equiv.) in DMSO at 80 °C for 28 h. Some starting material still remained. Both the azide and amine were formed, along with other impurities. The solvent was removed by freeze-drying, and the solid was filtered and washed with DCM. The combined filtrates were evaporated to dryness. The residue was dissolved in MeOH, and dithiothreitol (DTT, 3.09 g, 20 mmol, 4 equiv.) and LiOH.HO (0.84 g, 20 mmol, 4 equiv.) were added. The reaction mixture was stirred at room temperature for 2 h and then poured into saturated NaHCO3 solution and DCM. The aqueous phase was extracted with more DCM, and the combined organic solutions were dried over MgSO4 and evaporated to dryness. The residue was purified on silica gel using a mixture of DCM and EtOAc, then DCM and MeOH to give 4-amino-1-(benzyloxy)-6-methylpyridin-2(1H)-one (0.176 g, 15.2% yield). 1 H NMR (401 MHz, MeOH-d4) δ 7.50 - 7.41 (m, 2H), 7.40 - 7.33 (m, 3H), 5.64 (s, 1H), 5.56 (d, J = 2.6 Hz, 1H), 5.13 (s, 2H), 2.10 (s, 3H). 13 C NMR (101 MHz, MeOH-d4) δ 161.73, 157.20, 145.65, 134.11, 129.69, 128.88, 128.27, 98.67, 92.21, 77.67, 16.23.HRMS(ESI) calculated value C 13 H 15 N2O2 + [M+H] + 231.1128, actual value 231.1132.

[0339] 4-Amino-1-(benzyloxy)-6-methylpyridin-2(1H)-one (0.157 g, 0.681 mmol) was dissolved in acetone (7 mL) and saturated NaHCO solution (7 mL) and cooled to 0 °C. Thiophosgene (1.2 equiv.) was added dropwise, and the resulting mixture was stirred at room temperature for 1 h. The reaction was deemed complete by TLC (neat EtOAc). The reaction mixture was poured into saturated NaHCO solution, and the product was extracted with DCM (5x). The combined organic phases were dried over MgSO and evaporated to dryness. The residue was dissolved in dioxane (4 mL), and 2-azido-1-(4-(trifluoromethyl)phenyl)ethan-1-one (Intermediate A) and PhP (1.25 equiv. each) were added. The resulting mixture was stirred at reflux for 2 h. All volatiles were removed, and the residue was triturated with DCM. The solid was filtered with DCM and washed with Et2O to give 1-(benzyloxy)-6-methyl-4-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridin-2(1H)-one (182 mg 60.47%) as a cream solid. 1 H NMR (401 MHz, DMSO-d6) δ 10.81 - 10.65 (br, 1H), 7.81 (s, 4H), 7.77 (s, 1H), 7.52 (m, J = 3.5 Hz, 2H), 7.43 (m, J = 3.2 Hz, 3H), 6.88 (d, J = 2.5 Hz, 1H), 6.15 (s, 1H), 5.19 (s, 2H), 2.26 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 159.41, 156.22, 147.02, 146.50, 143.84, 134.75, 131.81, 130.18, 129.51, 129.00, 127.90, 127.58, 126.56, 126.00, 125.69, 123.69, 99.75, 97.51, 77.15, 17.74.LCMS R f (min)=3.499, MS m / z=441.9[M+H] + .

[0340] [ka]

[0341] 1-(Benzyloxy)-6-methyl-4-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridin-2(1H)-one (165 mg, 0.373 mmol) was suspended in DCM and then cooled to 0 °C. BBr (0.142 mL; 1.495 mmol, 4 equiv) was added dropwise. After stirring at room temperature for 4 h, LCMS showed that all SM was consumed. Ice (5 g) was added, followed by slow addition of NaHCO until no more gas was evolved. The reaction mixture was stirred at room temperature for 3 h and the DCM was removed in vacuo. The residue was acidified with TFA and chromatographed on preparative HPLC to give the title compound (52 mg, 39.60%). 1 H NMR (401 MHz, DMSO-d6) δ 10.74 (s, 1H), 7.82 - 7.75 (m, 4H), 7.74 (s, 1H), 6.82 (d, J = 2.7 Hz, 1H), 6.24 (d, J = 2.2 Hz, 1H), 2.29 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 159.13, 156.40, 146.05, 144.64, 143.68, 131.87, 127.81, 127.49, 126.56, 126.52, 126.01, 125.68, 123.60, 123.31, 98.03, 96.69, 66.82, 17.87.LCMS R f (min)=3.325, MS m / z=351.9[M+H] + . HRMS(ESI) calculated value C 16 H 13 F3N3O3 + [M+H] + 352.0904, actual value 352.0910.

[0342] 28. N,3-Dihydroxy-N-methyl-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide (Scheme 26)

[0343] [ka]

[0344] 5-(4-(trifluoromethyl)phenyl)oxazol-2-amine (Intermediate D) (0.88 g, 3.576 mmol) was reacted with methyl 5-bromo-3-methoxypicolinate as per Scheme 23 (step a) to give methyl 3-methoxy-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinate in 82.46% yield (1.15 g). 1 H NMR (401 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.31 (s, 1H), 8.08 (s, 1H), 7.78 (s, J = 5.4 Hz, 4H), 3.87 (s, 3H), 3.78 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 165.14, 156.60, 156.29, 143.79, 139.83, 131.86, 130.98, 130.14, 127.81, 127.50, 126.58, 126.01, 125.73, 123.58, 123.32, 107.23, 66.82, 56.14, 52.20.HRMS(ESI) calculated value C 18 H 15 F3N3O4 + [M+H] + 394.1009, actual value 394.1016. LCMS R f (min)=3.555, MS m / z=393.9[M+H] + .

[0345] Methyl 3-methoxy-5-((5-(4(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinate (1.13 g, 2.872 mmol) was hydrolyzed as per Scheme 23 (step b) to give 3-methoxy-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinic acid in 94.5% yield (1.03 g). 1 H NMR (401 MHz, DMSO-d6) δ 12.44 (br, 1H), 11.12 (s, 1H), 8.32 (s, 1H), 8.06 (s, 1H), 7.80 (s, 5H), 3.87 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 165.87, 156.66, 156.10, 143.75, 139.62, 131.99, 131.87, 129.74, 127.79, 127.48, 126.57, 126.53, 126.01, 125.72, 123.56, 123.31, 107.39, 56.08.LCMS R f (min)=4.057, MS m / z=379.9[M+H] + .

[0346] 3-Methoxy-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinic acid (0.5 g, 1.318 mmol) was coupled with O-(4-methoxybenzyl)-N-methylhydroxylamine hydrochloride as per Scheme 23 (step c) to give the product (3-methoxy-N-((4-methoxybenzyl)oxy)-N-methyl-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide) in 85.1% yield (0.593 g). 1 H NMR (401 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.34 (t, J = 7.2 Hz, 1H), 8.00 (s, 1H), 7.81 (s, 4H), 7.77 (d, J = 8.5 Hz, 1H), 6.93 - 6.83 (m, 2H), 6.79 (br, 2H), 4.71 (s, 2H), 3.81 (s, 3H), 3.67 (s, 3H), 3.32 (d, J = 9.8 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 159.92, 157.02, 152.95, 143.55, 137.83, 131.97, 131.07, 127.69, 127.37, 126.58, 126.54, 126.03, 125.80, 123.48, 123.34, 114.16, 107.28, 56.04, 55.51.LCMS R f (min) = 3.650. HRMS (ESI) calculated value C 26 H 24 F3 N4O5 + [M+H] + 529.1693, measured value 529.1699.

[0347]

change

[0348] 3-Methoxy-N-((4-methoxybenzyl)oxy)-N-methyl-5-((5-(4-(trifluoromethyl)phenyl)-oxazol-2-yl)amino)picolinamide (193 mg, 0.365 mmol) was suspended in DCM and then cooled to 0 °C. BBr (0.173 mL; 1.825 mmol, 5 equiv) was added and the resulting mixture was stirred at room temperature for 4 h. The reaction was deemed complete by LCMS. The reaction was quenched with 1.5 mL of saturated NaHCO solution and solid NaHCO was added until gas evolution ceased. The mixture was stirred at room temperature for 2 h, then the DCM was removed in vacuo. The remaining suspension was acidified with TFA and purified by preparative HPLC. After evaporation to dryness, the title compound was collected by filtration with HO and washed with HO and EtO (73 mg, 50.69% yield). 1 H NMR (401 MHz, DMSO-d6) δ 11.56 (s, 1H), 11.02 (s, 1H), 8.20 (d, J = 1.9 Hz, 1H), 7.87 (d, J = 1.8 Hz, 1H), 7.79 (s, 4H), 7.75 (d, J = 7.8 Hz, 1H), 3.34 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.95, 156.71, 155.16, 143.67, 138.78, 131.91, 127.72, 127.41, 126.55, 126.51, 126.02, 125.76, 123.51, 123.32, 110.94.LCMS R f (minutes)=3.904. HRMS(ESI) calculated value C 17 H 14 F3N4O4 + [M+H] + 395.0962, actual value 395.0969.

[0349] 29. 6-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridine-3,4-diol (Scheme 27)

[0350] [ka]

[0351] 2-Bromo-5-methoxypyridin-4-ol (0.35 g, 1.715 mmol) and K2CO3 (0.711 g, 5.15 mmol) were suspended in DMF, and then PMB-Cl (0.403 g, 2.57 mmol) was added. The resulting mixture was stirred at room temperature overnight. The reaction was deemed complete by TLC (DCM / EtOAc 9:1). The reaction mixture was poured into saturated NaHCO3 solution, and the product was extracted with EtOAc (5x). The combined organic phases were dried over MgSO4 and evaporated to dryness. The residue was purified on silica gel using a mixture of DCM and EtOAc as the eluent to give 2-bromo-5-methoxy-4-((4-methoxybenzyl)oxy)pyridine (0.356 g, 64.01% yield). 1 H NMR (401 MHz, CDCl3) δ 7.85 (s, 1H), 7.34 (d, J = 8.7 Hz, 2H), 6.97 (s, 1H), 6.92 (d, J = 8.7 Hz, 2H), 5.06 (s, 2H), 3.88 (s, 3H), 3.81 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 159.92, 155.84, 146.23, 133.58, 133.07, 129.39, 126.89, 114.25, 111.79, 70.80, 56.76, 55.34.LCMS R f (minutes)=3.775, MS m / z=345.9 / 347.9[M+Na] + .

[0352] An oven-dried RBF was charged with Pd(dba) (0.090 g, 0.10 equiv.), Xantphos (0.114 g, 0.2 equiv.), 5-(4-(trifluoromethyl)phenyl)oxazol-2-amine (Intermediate D) (0.281 g, 1.233 mmol, 1.25 equiv.), CsCO (0.482 g, 1.5 equiv.), 2-bromo-5-methoxy-4-((4-methoxybenzyl)oxy)pyridine (0.32 g, 0.987 mmol), and 1,4-dioxane (5 mL). The reaction flask was briefly vacuumed and subsequently backfilled with N, and the procedure was repeated five times. The mixture was then heated to 110 °C and stirred for 18 h. The reaction mixture was poured into HO, acidified with 1 N HCl (pH 4–5), and extracted with EtOAc (5x). The combined organic phase was dried over MgSO and evaporated to dryness. The residue was chromatographed on silica gel using a mixture of DCM / EtOAc as the eluent to give N-(5-methoxy-4-((4-methoxybenzyl)oxy)pyridin-2-yl)-5-(4-(trifluoromethyl)phenyl)oxazol-2-amine (0.083 g, 17.83% yield). 1 H NMR (401 MHz, DMSO-d6) δ 10.83 (s, 1H), 7.95-7.85 (br, 2H), 7.82 - 7.76 (m, 4H), 7.75 (s, 1H), 7.45 (d, J = 8.7 Hz, 2H), 6.97 (d, J = 8.7 Hz, 2H), 5.11 (s, 2H), 3.78 (s, 3H), 3.76 (s, 3H).LCMS R f (minutes)=3.619. HRMS(ESI) calculated value C 24 H 21 F3N3O4 + [M+H] + 472.1479, actual value 472.1473.

[0353] [ka]

[0354] N-(5-Methoxy-4-((4-methoxybenzyl)oxy)pyridin-2-yl)-5-(4-(trifluoromethyl)phenyl)oxazol-2-amine (0.077 g, 0.163 mmol) was suspended in DCM and cooled to 0 °C. BBr (4 equiv.) was added dropwise. After stirring for 4 h at room temperature, LCMS showed that all starting material had been consumed. The volatiles were removed and the residue was quenched with saturated NaHCO solution and MeOH for 1 h. The volatiles were removed and the residue was chromatographed on preparative HPLC to give the title compound (0.042 g, 76.24% yield). 1 H NMR (401 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.82 (s, 5H), 7.73 (s, 1H), 7.15 (s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 155.76, 143.66, 140.34, 131.60, 128.06, 127.74, 126.56, 126.52, 125.98, 123.71, 123.28, 99.42.LCMS R f (min) = 3.333. HRMS(ESI ) Calculated value C 15 H 11 F3N3O3 + [M+H] + 338.0747, actual value 338.0751.

[0355] 30. 3-Hydroxy-4-((5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridin-2-yl)amino)cyclobut-3-ene-1,2-dione (Scheme 28)

[0356] [ka]

[0357] A resealable Schlenk tube was charged with Pd(dba) (0.05 equiv.), Xantphos (0.1 equiv.), 5-(4-(trifluoromethyl)phenyl)oxazol-2-amine (Intermediate D) (1.2 equiv.), KPO (1.4 equiv.), 5-bromo-2-nitropyridine (0.102 g), and 1,4-dioxane (3.0 mL). After degassing the mixture, it was carefully subjected to three cycles of evacuation and filling with N, and the reaction mixture was heated at 100 °C overnight under a N atmosphere. The mixture was cooled, diluted with EtOAc (50 mL), and washed with brine (20 mL). The organic layer was separated, dried (MgSO), filtered, and concentrated under reduced pressure to give the crude product, which was purified on a SiO column using a Revelis X2 flash chromatography system (1:1 EtOAc: petroleum distillate) to give N-(6-nitropyridin-3-yl)-5-(4-(trifluoromethyl)phenyl)oxazol-2-amine (130 mg, 74% yield) as a brown solid. 1 H NMR (401 MHz, DMSO-d6) δ 11.63 (s, 1H), 8.75 (d, J = 2.5 Hz, 1H), 8.48 (dd, J = 9.0, 2.6 Hz, 1H), 8.40 (d, J = 9.0 Hz, 1H), 7.97 - 7.74 (m, 5H). (Intermediate H-N5-(5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)pyridine-2,5-diamine) To a solution of N-(6-nitropyridin-3-yl)-5-(4-(trifluoromethyl)phenyl)oxazol-2-amine (0.11 g) in MeOH (5.0 mL) was added 10% Pd / C (0.15 g). The mixture was stirred under a hydrogen atmosphere (balloon) overnight. Upon completion, the reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified on a SiO column (MeOH:DCM = 0.05 to 1:10) to give N5-(5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)pyridine-2,5-diamine (70 mg, 70% yield) as a light brown solid. 1H NMR (401 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.15 (d, J = 2.4 Hz, 1H), 7.78-7.72 (m, 4H), 7.66 (dd, J = 8.8, 2.8 Hz, 1H), 7.63 (s, 1H), 6.48 (d, J = 8.8 Hz, 1H), 5.67 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ158.2, 155.7, 142.2, 137.8, 131.9, 128.6, 126.6, 126.3, 126.03, 126.0, 125.7, 125.6, 122.9, 122.5, 107.9.LCMS R f (minutes)=3.04. HRMS(ESI) calculated value C 15 H 12 F3N4O + [M+H] + 321.0958, actual value 321.0966.

[0358] [ka]

[0359] N 5 -(5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)pyridine-2,5-diamine (0.080 g, 0.249 mmol) was stirred with 3,4-diethoxycyclobut-3-ene-1,2-dione (0.064 g, 0.374 mmol) and EtN (0.041 mL, 0.299 mmol) in EtOH (3 mL) at reflux overnight. The solvent was removed in vacuo, and the remaining mixture was purified using preparative HPLC to give the title compound (0.073 g, 70.2% yield). 1 H NMR (401 MHz, DMSO-d6) δ 11.50 (s, 1H), 10.94 (s, 1H), 8.72 (s, 1H), 8.17 (d, J = 7.3 Hz, 1H), 7.78 (s, 4H), 7.74 (s, 1H), 7.39 (d, J = 7.3 Hz, 1H).LCMS R f (minutes)=3.672. HRMS(ESI) calculated value C 19 H 12 F3N4O4 + [M+H] + 417.0805, actual value 417.0805.

[0360] 31. N',3-Dihydroxy-5-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)amino)picolinimidamide (Scheme 29)

[0361] [ka]

[0362] 1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-amine (Intermediate F) (0.3 g, 1.314 mmol) was reacted with 5-bromo-3-((4-methoxybenzyl)oxy)picolinonitrile (Intermediate G) (0.419 g, 1.314 mmol) as per Scheme 24 (step b) to give the product, 3-((4-methoxybenzyl)oxy)-5-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)amino)picolinonitrile in 80.4% yield (0.493 g). 1 H NMR (401 MHz, DMSO-d6) δ 10.60 (s, 1H), 9.35 (s, 1H), 8.37 (s, 1H), 8.11 (s, 1H), 8.06 (d, J = 7.5 Hz, 2H), 7.93 (d, J = 7.7 Hz, 2H), 7.44 (d, J = 7.6 Hz, 2H), 6.95 (d, J = 7.7 Hz, 2H), 5.27 (s, 2H), 3.74 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 160.20, 159.77, 159.11, 142.79, 139.85, 133.15, 130.05, 127.83, 127.73, 127.54, 127.50, 125.79, 123.09, 119.24, 116.87, 114.44, 112.35, 106.44, 70.39, 66.82, 55.55.LCMS R f (min)=3.484, MS m / z=467.0[M+H] + .

[0363] 3-((4-Methoxybenzyl)oxy)-5-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)amino)picolinonitrile (0.471 g, 1.01 mmol) was reacted as per Scheme 24 (step c) to give N'-hydroxy-3-((4-methoxybenzyl)oxy)-5-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)amino)picolinimide amide in 93% yield (0.469 g). 1 H NMR (401 MHz, DMSO-d6) δ 10.00 (s, 1H), 9.59 (s, 1H), 9.29 (s, 1H), 8.42 (s, 1H), 8.04 (s, 2H), 7.92 (s, 3H), 7.45 (s, 2H), 6.92 (s, 2H), 5.59 (s, 2H), 5.17 (s, 2H), 3.72 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 160.90, 159.27, 153.65, 150.45, 142.67, 140.02, 139.28, 132.66, 129.58, 129.29, 129.08, 127.53, 127.50, 127.41, 127.09, 125. 85, 123.15, 118.97, 114.23, 108.94, 69.87, 55.48.LCMS R f (minutes)=3.06 7. HRMS(ESI) calculated value C 23 H 21 F3N7O3 + [M+H] + , 500.1652 Actual value 500.163.

[0364] [ka]

[0365] N'-hydroxy-3-((4-methoxybenzyl)oxy)-5-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)amino)picolinimidamide (0.45 g, 0.90 mmol) was deprotected as per Scheme 24 (step d) to give the title compound in 38.33% yield (0.131 g). 1 H NMR (401 MHz, DMSO-d6) δ 10.43 (brs, 1H), 10.22 (s, 1H), 9.33 (s, 1H), 8.34 (s, 1H), 8.10 (d, J = 7.8 Hz, 2H), 7.94 (d, J = 7.5 Hz, 2H), 7.88 (s, 1H), 7.19 (brs, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 160.65, 155.36, 154.95, 142.72, 141.06, 140.01, 130.26, 127.55, 127.18, 125.83, 123.13, 118.99, 109.80.LCMS R f (minutes)=3.072. HRMS(ESI) calculated value C 15 H 13 F3N7O2 + [M+H] + , 380.1077 Actual value 380.1085.

[0366] 32. N-Ethyl-N-hydroxy-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide (Scheme 30)

[0367] [ka]

[0368] 5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinic acid (Intermediate B) (0.31 g, 0.89 mmol) was added to a solution of HOBt (0.12 g, 1.07 mmol) and EDCI.HCl (0.19 g, 0.98 mmol) in anhydrous DMF (15 mL). The resulting mixture was stirred at room temperature for 3 h under N2. N-Ethyl-O-(4-methoxybenzyl)hydroxylamine (0.19 g, 1.07 mmol) was then added to the mixture and stirred for an additional 16 h. The reaction mixture was quenched with aq. NaHCO3 solution (20 mL) and extracted with EtOAc (20 mL). The mixture was diluted with 100 ml of ethyl acetate and the organic layer was extracted with EtOAc (3 × 25 mL). The combined organic fractions were dried over MgSO, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 50% EtOAc in DCM to give N-ethyl-N-((4-methoxybenzyl)oxy)-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide (0.243 g, 53% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.81 (d, J = 2.4 Hz, 1H), 8.24 (dd, J = 8.6, 2.6 Hz, 1H), 7.80 (s, 4H), 7.77 (s, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 8.3 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 4.92 (s, 2H), 3.77 (q, J = 7.0 Hz, 2H), 3.72 (s, 3H), 1.18 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 159.90, 156.87, 146.18, 143.66, 137.55, 137.39, 131.96, 131.28, 127.70, 127.39, 126.03, 125.79, 123.77, 123.50, 123.33, 114.16, 75.62, 67.86, 55.58, 55.54, 40.00.LCMS R f (min)=3.65, MS m / z 513.0[M+H] + .

[0369] [ka]

[0370] N-Ethyl-N-((4-methoxybenzyl)oxy)-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide (0.20 g, 0.39 mmol) was dissolved in TFA (4.0 mL) and EtSiH (0.4 mL), and the mixture was stirred at room temperature for 5 h. The volatiles were then removed under reduced pressure, and the residue was directly subjected to preparative HPLC using 0.1% TFA in HO and 0.1% TFA in ACN as eluents to afford the title compound (0.14 g, 92%) as a golden yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.79 (s, 1H), 8.24 (dd, J = 8.6, 2.4 Hz, 1H), 7.80 (s, 4H), 7.76 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 3.71 (dd, J = 13.6, 6.7 Hz, 2H), 1.19 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 156.84, 143.66, 137.19, 131.94, 128.82, 128.72, 127.71, 127.39, 126.02, 125.77, 124.01, 123.51, 69.00, 40.89.LCMS R f(min)=3.68, MS m / z 393.9[M+H] + . HRMS(ESI) calculated value C 18 H 16 F3N4O3 + [M+H] + 393.1169, actual value 393.1172.

[0371] 33. N-Hydroxy-N-propyl-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide (Scheme 31)

[0372] [ka]

[0373] 5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinic acid (Intermediate B) (0.132 g, 0.38 mmol), HOBt (0.053 g, 0.45 mmol), and EDCl.HCl (0.080 g, 0.42 mmol) were added to a dry RBF and stirred with anhydrous DMF (6.5 mL) for 3 h with a steady stream of N. N-Propyl-O-(4-methoxybenzyl)hydroxylamine (0.089 g, 0.45 mmol) was then added to the reaction mixture, and stirring was continued for 16 h. After this period, the reaction was quenched with aq. NaHCO solution (10 mL) and diluted with EtOAc (10 mL). The organic layer was extracted with EtOAc (3 × 10 mL), and the combined organics were dried over MgSO. The mixture was filtered and concentrated under reduced pressure and the crude material (0.112 g) was used in the next step without further purification. LCMS R f (min)=3.69, MS m / z 527.0[M+H] + .

[0374] [ka]

[0375] TFA (2.5 mL) and EtSiH (0.3 mL) were combined with crude N-((4-methoxybenzyl)oxy)-N-propyl-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide (0.112 g), and the resulting mixture was stirred at room temperature for 6 h. The volatiles were removed under reduced pressure, and the residue was directly subjected to preparative HPLC using 0.1% TFA in HO and 0.1% TFA in ACN as eluents to give the title compound (0.082 g, 54% over two steps) as a golden yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.78 (d, J = 2.4 Hz, 1H), 8.23 ​​(dd, J = 8.6, 2.3 Hz, 1H), 7.80 (s, 4H), 7.77 (s, 1H), 7.68 (d, J = 7.5 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 1.73 - 1.54 (m, 2H), 0.86 (t, J = 8.0 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 156.88, 143.63, 137.28, 137.10, 132.15, 131.95, 127.70, 127.38, 126.03, 125.79, 123.50, 66.82, 11.44.LCMS R f (min)=3.39, MS m / z 407.0[M+H] + . HRMS(ESI) calculated value C 19 H 18 F3N4O3 + [M+H] + 407.1326, actual value 407.1336.

[0376] 34. N-Hydroxy-N-isopropyl-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide (Scheme 32)

[0377] [ka]

[0378] 5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinic acid (0.086 g) was converted to N-isopropyl-N-((4-methoxybenzyl)oxy)-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide as per Scheme 31 (step a). The crude product was used in the next step without further purification. LCMS R f (min)=3.51, MS m / z=527.0(M+H) + .

[0379] [ka]

[0380] TFA (2.0 mL) and EtSiH (0.2 mL) were added with crude N-isopropyl-N-((4-methoxybenzyl)oxy)-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide in a RBF, and the resulting mixture was stirred at room temperature for 6 h. The volatiles were removed under reduced pressure, and the residue was directly subjected to preparative HPLC using 0.1% TFA in HO and 0.1% TFA in ACN as eluents to give N-hydroxy-N-isopropyl-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide (0.064 g, 37% over two steps) as a golden yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.79 (s, 1H), 8.23 ​​(dd, J = 8.6, 2.4 Hz, 1H), 7.80 (s, 4H), 7.76 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 4.58 (s, 1H), 1.17 (d, J = 6.6 Hz, 6H). 13C NMR (100 MHz, DMSO) δ 156.70, 143.45, 131.78, 127.52, 127.20, 126.39, 126.35, 125.85, 125.61, 123.32, 123.15, 40.72, 39.52.LCMS R f (min)=3.37, MS m / z 407.0(M+H) + . HRMS(ESI) calculated value C 19 H 18 F3N4O3 + (M+H) + 407.1326, actual value 407.1338.

[0381] 35. 1-Hydroxy-1-methyl-3-(5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridin-2-yl)urea (Scheme 33)

[0382] [ka]

[0383] N 5 -(5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)pyridine-2,5-diamine (Intermediate H) (0.1 g, 0.312 mmol) was suspended in dry DCM (6 mL) and triphosgene (0.037 g, 0.124 mmol) and DIPEA (0.080 g, 0.624 mmol) were added. The resulting mixture was stirred at room temperature overnight. O-(4-Methoxybenzyl)-N-methylhydroxylamine and DIPEA (2 equivalents each) were added and the reaction was stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 (aq.) and extracted with EtOAc (3x). The organic solutions were combined, dried over MgSO4, and evaporated to dryness. The residue was chromatographed on silica gel using neat EtOAc to give 1-((4-methoxybenzyl)oxy)-1-methyl-3-(5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridin-2-yl)urea (34 mg, 21.2% yield). 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.12 (d, J = 8.9 Hz, 1H), 7.56 (s, 1H), 7.49 (s, 4H), 7.33 - 7.29 (m, 2H), 7.23 (d, J = 8.7 Hz, 1H), 6.75 (d, J = 8.2 Hz, 2H), 4.83 (s, 2H), 3.65 (s, 3H), 2.97 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 159.42, 156.39, 145.71, 143.18, 137.07, 136.92, 131.48, 130.80, 128.65, 128.25, 127.23, 126.91, 125.55, 125.31, 123.30, 123.03, 122.85, 113.69, 75.15, 55.06, 39.52, 33.23.LCMS R f (min)=4.09, MS m / z 514.1[M+H] + HRM S(ESI) calculated value C 25 H 23 F3N5O4 + [M+H] + 514.1697, actual value 514.1683.

[0384] [ka]

[0385] 1-((4-Methoxybenzyl)oxy)-1-methyl-3-(5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridin-2-yl)urea (0.034 g, 0.066 mmol) was dissolved in TFA (1.0 mL) and EtSiH (0.1 mL), and the mixture was stirred at room temperature for 5 h. The volatiles were then removed under reduced pressure, and the residue was directly subjected to preparative HPLC using 0.1% TFA in HO and 0.1% TFA in ACN as eluents to give the title product (24.14 mg, 93% yield) as a golden yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 10.13 (s, 1H), 9.20 (s, 1H), 8.57 ((d, J = 1.4 Hz, 1H), 8.07 (dd, J = 9.1, 2.5 Hz, 1H), 7.85 (d, J = 9.2 Hz, 1H), 7.72 (s, 4H), 7.66 (s, 1H), 3.07 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 156.80, 156.51, 145.47, 142.89, 131.65, 131.58, 127.06, 126.74, 126.06, 126.02, 125.57, 125.35, 122.87, 113.50, 66.35, 39.52, 37.38.LCMS R f (min)=3.62, MS m / z 393.9[M+H] + . HRMS(ESI) calculated value C 17 H 15 F3N5O3 + [M+H] + 394.1122, actual value 394.1141.

[0386] 36. (R)-N-(2,3-Dihydroxypropyl)-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide (Scheme 34)

[0387] [ka]

[0388] A resealable Schlenk tube was charged with Pd(dba) (0.02 equiv.), Xantphos (0.06 equiv.), 5-(4-(trifluoromethyl)phenyl)oxazol-2-amine (Intermediate D) (1.2 equiv.), KPO (fine powder, 1.4 equiv.), methyl 5-bromopicolinate (0.250 g, 1.152 mmol), and 1,4-dioxane (4 mL). After degassing the mixture, it was carefully subjected to three cycles of evacuation and filling with N. The reaction mixture was heated at 140 °C for 15 h under a N atmosphere. The reaction mixture was cooled, diluted with EtOAc (30 mL), and washed with HO (20 mL). The aq. layer was then back-extracted with EtOAc (2 × 15 mL). The combined organics were concentrated in vacuo to give the crude product. This was purified on a SiO2 column (EtOAc:toluene=1:1) to give methyl 5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinate (0.21 g, 49.8% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.90 (d, J = 2.5 Hz, 1H), 8.44 (s, 1H), 8.36 (dd, J = 8.7, 2.6 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 8.00 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 3.85 (s, 3H). 13 LCMS R f (minute )=3.907, MS m / z 363.8[M+H] + .

[0389] LiOH·HO (3 equiv.) in HO (2 mL) was added to a solution of methyl 5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinate (0.180 g, 0.495 mmol) in 1,4-dioxane (2 mL) and EtOH (2 mL), and the reaction mixture was refluxed for 3 h. The volatile solvents were removed in vacuo, and brine (2 mL) was added to the resulting suspension, followed by dropwise addition of 6 M HCl (2 mL) at 0 °C. The resulting precipitate was filtered and washed with HO (2 × 2 mL) to give 5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinic acid (0.240 g, 99.8% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.90 (d, J = 2.4 Hz, 1H), 8.46 (s, 1H), 8.34 (dd, J = 8.6, LCMS R f (min)=3.578, MS m / z 349.8[M+H] + .

[0390] [ka]

[0391] 5-((5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl)amino)picolinic acid (0.15 g) was suspended in DMF (3.0 mL) and EDCI (1.3 equiv.) and HOBt (1.4 equiv.) were added. The resulting mixture was stirred at room temperature for 1 hour. (R)-3-aminopropane-1,2-diol (2.0 equiv.) was then added to the reaction mixture and stirring was continued overnight. The reaction mixture was concentrated under reduced pressure to give a gummy solid, which was washed with DCM (2 × 2 mL) followed by MeOH (2 × 1 mL) to give the title compound (0.095 g, 52% yield) as a beige solid. 1 H NMR (400 MHz, DMSO-d₆) δ 11.1 (brs, 1H), 8.80 (d, J = 2.3 Hz, 1H), 8.45 (t, J = 5.8 Hz, 1H), 8.31 (dd, J = 8.6, 2.5 Hz, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.87–7.74 (m, 5H), 4.94 (brs, 1H), 4.65 (brs, 1H), 3.66–3.57 (m, 1H), 3.54–3.45 (m, 1H), (two proton resonances overlap with HO, not assigned), 3.26–3.17 (m, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 163.7, 156.2, 143.3, 142.7, 138.2, 137.1, 131.4, 127.3, 127.0, 126.0, 125.5, 125.3, 123.5, 123.1, 122.8, 122.6, 70.2, 64.0, 42.4.LCMS R f (minutes)=3.30. HRMS(ESI) calculated value C 19 H 18 F3 N4O4 + [M+H] + 423.1275, actual value 423.1289.

[0392] 37. (S)-N-(2,3-Dihydroxypropyl)-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide (Scheme 34)

[0393] [ka]

[0394] 5-((5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl)amino)picolinic acid (0.15 g) was suspended in DMF (3.0 mL) and EDCI (1.3 equiv.) and HOBt (1.4 equiv.) were added. The resulting mixture was stirred at room temperature for 1 hour. (S)-3-aminopropane-1,2-diol (2.0 equiv.) was then added to the reaction mixture and stirring was continued overnight. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a gummy solid, which was washed with DCM (2 × 2 mL) followed by MeOH (2 × 1 mL) to give the title compound (0.094 g, 52% yield) as a beige solid. 1 H NMR (401 MHz, DMSO-d6) δ 11.07 (brs, 1H), 8.80 (d, J = 2.2 Hz, 1H), 8.45 (t, J = 5.7 Hz, 1H), 8.30 (dd, J = 8.6, 2.3 Hz, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.94 - 7.64 (m, 5H), 4.94 (d, J = 4.2 Hz, 1H), 4.65 (brs, 1H), 3.61 (m, 1H), 3.56 - 3.44 (m, 1H), (two proton resonances overlap with H2O, not assigned), 3.27 - 3.12 (m, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 163.7, 156.2, 143.3, 142.7, 138.2, 137.1, 131.4, 127.3, 126.9, 126.0, 125.5, 125.3, 123.5, 123.0, 122.8, 122.5, 70.3, 64.0, 42.4.LCMS R f (minutes)=3.306. HRMS(ESI) calculated value C 19 H 18 F3N4O4 + [M+H] + 423.1275, actual value 423.1287.

[0395] 38. (R)-N-(2,3-Dihydroxypropyl)-5-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)amino)picolinamide (Scheme 35)

[0396] [ka]

[0397] A resealable Schlenk tube was charged with Pd(dba) (0.05 equiv.), Xantphos (0.1 equiv.), 1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-amine (Intermediate F) (0.3 g), CsCO (1.5 equiv.), and methyl 5-bromopicolinate (1.2 equiv.) in 1,4-dioxane (20 mL). The mixture was degassed, carefully subjected to three cycles of evacuation and filling with N, and heated at 100 °C overnight under a N atmosphere. Upon completion, the mixture was cooled, diluted (100 mL EtOAc), and washed with HO (2 × 30 mL). The organic layer was separated, dried (MgSO), filtered, and concentrated under reduced pressure to give the crude product. The crude product was washed with Et2O (3 x 2.0 mL) to give methyl 5-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)amino)picolinate (0.262 g, 55.5% yield) as a beige solid. 1H NMR (401 MHz, δ 10.40 (s, 1H), 9.34 (s, 1H), 8.88 (d, J = 2.4 Hz, 1H), 8.24 (dd, J = 8.7, 2.4 Hz, 1H), 8.12 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 8.7 Hz, 1H), 7.94 (d, J = 8.6 Hz, 2H), 3.84 (s, 3H). LiOH.HO (0.087 g) in HO (2.0 mL) was added to a solution of methyl 5-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)amino)picolinate in 1,4-dioxane (4 mL) and EtOH (4 mL). The resulting mixture was heated to 100 °C for 3 h. The volatiles were removed in vacuo, and the remaining suspension was acidified with 1 N HCl (pH ∼4). The resulting precipitate was filtered and washed with HO (3 × 2 mL) to give 5-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)amino)picolinic acid (0.180 g, 93% yield) as a yellow solid. 1 H NMR (401 MHz, DMSO-d6 ) δ 10.37 (s, 1H), 9.34 (s, 1H), 8.89 (d, J = 2.0 Hz, 1H), 8.24 (dd, J = 8.6, 2.2 Hz, 1H), 8.12 (d, J = 8.3 Hz, 2H), 8.04 (d, J = 8.6 Hz, 1H), 7.94 (d, J = 8.4 Hz, 2H).

[0398] [ka]

[0399] EDCI (1.3 equiv.) and HOBt (1.4 equiv.) were added to a suspension of 5-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)amino)picolinic acid (0.08 g) in DMF (5.0 mL). The reaction mixture was stirred at room temperature for 1 hour. (R)-3-aminopropane-1,2-diol (1.5 equiv.) was then added to the reaction mixture, and stirring was continued overnight. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give the crude material, which was washed with DCM (2 × 2 mL) followed by MeOH (2 × 1 mL) to give the title compound (0.055 g, 56.9% yield) as a beige solid. 1 H NMR (401 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.34 (s, 1H), 8.89 (d, J = 2.4 Hz, 1H), 8.42 (t, J = 5.8 Hz, 1H), 8.22 (dd, J = 8.6, 2.5 Hz, 1H), 8.12 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 8.6 Hz, 1H), 7.95 (d, J = 8.6 Hz, 2H), 4.94 (d, J = 5.0 Hz, 1H), 4.65 (t, J = 5.8 Hz, 1H), 3.64 - 3.58 (m, 1H), 3.53 - 3.47 (m, 1H), 3.42 - 3.27 (m, 2H), 3.25 - 3.16 (m, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 163.9, 160.2, 142.3, 141.3, 140.1, 139.5, 136.7, 127.1, 126.7, 125.4, 122.7, 122.5, 118.6, 70.3, 64.0, 42.3.LCMS R f (minutes)=3.135. HRMS(ESI) calculated value C 18 H 18 F3N6O3 + [M+H] + 423.1387, actual value 423.1395.

[0400] 39. N',3-Dihydroxy-5-((4-methyl-5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinimidamide (Scheme 36)

[0401] [ka]

[0402] Benzyltriethylammonium chloride (0.12 g, 0.51 mmol), iodomethane (0.72 g, 5.1 mmol), and NaOH (30% aqueous solution, 6 mL) were added to a solution of TosMIC (0.5 g, 2.55 mmol) in DCM (6 mL) at 0° C. The resulting mixture was stirred at 0° C. for 3 h, then diluted with DCM (10 mL), washed with water (10 mL × 2), dried over MgSO, filtered, and concentrated to give a brown oil, which was subjected to silica gel flash chromatography (20% EtOAc / hexane) to give 1-[(1-isocyanoethyl)sulfonyl]-4-methylbenzene (0.43 g, 80% yield) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2 H), 4.63 (q, J = 6.8 Hz, 1H), 2.42 (s, 3H), 1.64 (d, J = 6.8 Hz, 3H), MS m / z=207.9[MH] - .

[0403] 4-(Trifluoromethyl)benzaldehyde (1.25 g, 7.17 mmol) and K2CO3 (1.24 g, 8.96 mmol) were added to a solution of 1-((1-isocyanoethyl)sulfonyl)-4-methylbenzene (1.5 g, 7.17 mmol) in MeOH (35 mL) at room temperature. The resulting mixture was then refluxed under nitrogen for 5 h before being concentrated under reduced pressure. The residue was partitioned between Et2O and HO. The aqueous phase was extracted with Et2O (20 mL × 2), and the combined organic phases were dried over MgSO4, filtered, and concentrated to give a pale yellow oil, which was subjected to silica gel flash chromatography (10% EtOAc / hexane) to give 4-methyl-5-[4-(trifluoromethyl)phenyl]oxazole (1.4 g, 86% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.68-7.74 (m, 4H), 2.48 (s, 3H),MS m / z=228.0[M +H] + .

[0404] LiHMDS (1.0 M in THF, 0.53 mL, 0.53 mmol) was dissolved in dry THF To a solution of 4-methyl-5-[4-(trifluoromethyl)phenyl]oxazole (0.1 g, 0.44 mmol) in HCl (3 mL) was added at −78 °C under a nitrogen atmosphere. After an additional 0.5 h, a solution of C2Cl6 (0.16 g, 0.66 mmol) in THF (1 mL) was treated. The resulting reaction mixture was stirred at −78 °C for an additional 2 h and allowed to warm to room temperature over 14 h. The reaction was partitioned between saturated NaHCO3 (3 mL) and EtOAc (10 mL). The aqueous phase was extracted with EtOAc (8 mL × 2). The combined organic phase was dried over Na2SO4, filtered, and concentrated to a brown oil which was subjected to silica gel flash chromatography (5% EtOAc / hexanes) to afford 2-chloro-4-methyl-5-[4-(trifluoromethyl)phenyl]oxazole (0.11 g, 92% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.65-7.71 (m, 4H), 2.44 (s, 3H), MS m / z=261.9[M+H] + .

[0405] Ammonium hydroxide (28-30% aq., 2 mL) was added to a solution of 2-chloro-4-methyl-5-[4-(trifluoromethyl)phenyl]oxazole (0.11 g, 0.43 mmol) in THF (0.5 mL) at room temperature. The resulting reaction mixture was irradiated at 90 °C for 1 h under microwave conditions. The solid was filtered and washed with DCM (2 mL × 2) to give 4-methyl-5-[4-(trifluoromethyl)phenyl]oxazol-2-amine (0.1 g, 95% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 2.33 (s, 3H).MS m / z 243.0[M+H] + .

[0406] An oven-dried RBF was charged with Pd(dba) (0.028 g, 0.05 equiv.), Xantphos (0.036 g, 0.1 equiv.), 5-bromo-3-((4-methoxybenzyl)oxy)picolinonitrile (0.217 g, 0.681 mmol, 1.1 equiv.), CsCO (0.303 g, 1.5 equiv.), 4-methyl-5-(4-(trifluoromethyl)phenyl)oxazol-2-amine (0.15 g, 0.619 mmol), and 1,4-dioxane (7 mL). The reaction flask was briefly vacuumed and subsequently backfilled with N, and the procedure was repeated five times. The mixture was then heated to 100 °C and stirred for 5 h. LCMS indicated complete consumption of the starting material. The reaction mixture was then poured into water and extracted with EtOAc (5x). The combined organic solvents were dried over MgSO and evaporated to dryness. The residue was purified on silica gel using a mixture of DCM and EtOAc to give 3-((4-methoxybenzyl)oxy)-5-((4-methyl-5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinonitrile (0.15 g, 50.4% yield). 1 H NMR (401 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.33 (d, J = 2.0 Hz, 1H), 8.27 (d, J = 1.9 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 8.7 Hz, 2H), 5.26 (s, 2H), 3.76 (s, 3H), 2.45 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 159.88, 158.95, 154.46, 140.72, 138.31, 134.92, 133.08, 132.59, 130.35, 127.60, 127.25, 126.94, 126.45, 126.03, 124.75, 123.33, 116.53, 114.48, 113.88, 107.52, 55.59, 14.10.LCMS R f (minutes)= 4.20, MS m / z=480.9 [M+H] + .

[0407] 3-((4-Methoxybenzyl)oxy)-5-((4-methyl-5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinonitrile (0.15 g, 0.312 mmol) was suspended in EtOH (20 mL), then NHOH.HCl (0.109 g, 1.561 mmol) was added and approximately half of the EtOH was removed in vacuo. EtN (0.213 mL, 1.561 mol) was added and the resulting reaction mixture was stirred at reflux overnight. LCMS showed the reaction was complete. The volatile solvents were removed and the resulting solid was suspended in water, collected by filtration, and washed well with water. The solid was washed with EtO and then dried under high vacuum to give N'-hydroxy-3-((4-methoxybenzyl)oxy)-5-((4-methyl-5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinonitrile. )phenyl)oxazol-2-yl)amino)picolinimidamide (0.081 g, yield 50.5%) was obtained. 1 H NMR (401 MHz, DMSO-d6) δ 10.77 (s, 1H), 9.62 (s, 1H), 8.34 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 5.59 (s, 2H), 5.13 (s, 2H), 3.75 (d, J = 5.6 Hz, 3H), 2.08 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 159.39, 155.36, 153.54, 150.27, 137.64, 137.18, 135.11, 134.15, 132.89, 129.69, 129.57, 128.87, 126.88, 126.57, 126.47, 126.09, 124.46, 123.39, 114.26, 109.64, 55.54, 14.18.LCMS R f (min) = 3.236. HRMS(ESI ) Calculated value C 25 H 23 F3N5O4 + [M+H] + 514.1697, actual value 514.1687.

[0408] [ka]

[0409] N'-hydroxy-3-((4-methoxybenzyl)oxy)-5-((4-methyl-5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinimidamide (71.9 mg, 0.140 mmol) was stirred in a mixture of TFA (1.4 mL) and EtSiH (0.07 mL) at room temperature for 1 hour. The reaction mixture was evaporated to dryness. The residue was purified by preparative HPLC to give the title compound (40.9 mg, 74.26%) as a pale yellow solid. 1H NMR (401 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.79-10.21 (brs, 1H), 8.29 (d, J = 2.2 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.70-7.76 (brs, 1H), 2.41 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 154.8 (C), 154.6 (C), 137.5 (C), 134.6 (C), 132.3 (C), 129.9 (CH), 126.6 (C), 126.3 (C), 126.0 (CH), 125.6 (C), 124.2 (CH), 122.9 (C), 110.1 (CH), 13.7 (C), 13.6 (CH3).LCMS:Rf(min)=3.688, MS m / z=393.9[M+H] + . HRMS(ESI) calculated value C 17 H 15 F3N5O3 + [M+H] + 394.1122, actual value 394.1140.

[0410] 40. N',3-Dihydroxy-5-((5-(5-(trifluoromethyl)pyridin-2-yl)oxazol-2-yl)amino)picolinimidamide hydrochloride (Scheme 37)

[0411] [ka]

[0412] i-PrMgCl (2 M in THF, 10.0 mL, 20.0 mmol) was added over 5 min to a solution of 2-bromo-5-(trifluoromethyl)pyridine (4.0 g, 17.7 mmol) in DCM (550 mL) at 0 °C. After stirring for 40 min at 0-6 °C, the mixture was cooled to -20 °C and DMF (2.8 mL, 35.4 mmol) was added in one portion. The mixture was warmed to room temperature over 2 h and then quenched by the addition of saturated aqueous NaHCO (15 mL). After stirring for 10 min, the suspension was filtered through a Celite pad. The filtrate layers were separated. The Celite pad was washed with an additional 20 mL DCM, and the organic liquid was then re-extracted using the aqueous layer. The combined organic phases were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting crude material (approximately 3.6 g) was used in the next step without further characterization.

[0413] 5-(Trifluoromethyl)picolinaldehyde (0.65 g, 3.71 mmol) and K2CO3 (0.62 g, 4.45 mmol) were added to a solution of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (0.80 g, 4.08 mmol) in MeOH (10 mL) at room temperature. The resulting mixture was refluxed under nitrogen for 5 h and then concentrated under reduced pressure. The residue was partitioned between Et2O and HO. The aqueous phase was extracted with Et2O (20 mL × 2), and the combined organic phases were dried over MgSO4, filtered, and concentrated to give a pale yellow oil, which was subjected to silica gel flash chromatography (3% to 20%, EtOAc / hexane). Collection of appropriate fractions afforded 5-(5-(trifluoromethyl)pyridin-2-yl)oxazole as a white solid (0.65 g, 82% yield). 1 H NMR (400 MHz, CDCl3) δ 8.87 (m, 1H), 8.02 (s, 1H), 8.00 (m, 1H), 7.82 (s, 1H), 7.77 (d, J = 8.3 Hz, 1 H).MS m / z=215.0[M+H] + .

[0414] Intermediate J-2-chloro-5-(5-(trifluoromethyl)pyridin-2-yl)oxy Sasol LiHMDS (1.0 M in THF, 5.88 mL, 5.88 mmol) was added to a solution of 5-(5-(trifluoromethyl)pyridin-2-yl)oxazole (1.05 g, 4.90 mmol) in dry THF (10 mL) at −78 °C under a nitrogen atmosphere. After an additional 0.5 h, a solution of C2Cl6 (1.74 g, 7.35 mmol) in THF (5 mL) was treated. The resulting reaction mixture was stirred at −78 °C for an additional 2 h and allowed to warm to room temperature over 14 h. The reaction was quenched with saturated NaHCO3 (10 mL). The aqueous phase was extracted with EtOAc (30 mL × 2). The combined organic phase was dried over Na2SO4, filtered, and concentrated to give a brown oil, which was subjected to silica gel flash chromatography (2% to 10%, EtOAc / hexanes). Collection of appropriate fractions afforded 2-chloro-5-(5-(trifluoromethyl)pyridin-2-yl)oxazole (Intermediate J) (1.04 g, 85% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.86 (m, 1H), 8.00 (m, 1H), 7.75 (s, 1H), 7.71 (d, J = 8.0 Hz, 1 H).MS m / z=2 48.9[M+H] + .

[0415] Intermediate K-5-(5-(trifluoromethyl)pyridin-2-yl)oxazol-2-amine Ammonium hydroxide (28-30% aqueous solution, 10 mL) was added to a solution of 2-chloro-5-(5-(trifluoromethyl)pyridin-2-yl)oxazole (0.60 g, 2.41 mmol) in THF (1.5 mL) at room temperature. The resulting reaction mixture was irradiated in a microwave at 90 °C for 1 h. The solid was filtered and washed with DCM (5 mL × 2) to give 5-(5-(trifluoromethyl)pyridin-2-yl)oxazol-2-amine (0.52 g, 95% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.81 (t, J = 1.5 Hz, 1 H), 8.13 (dd, J = 8.4, 1.5 Hz, 1 H), 7.60 (s, 1H), 7.57 (d, J = 8.4 Hz, 1 H), 7.33 (s, 2H).MS m / z=230.0[M+H] + .

[0416] An oven-dried RBF was charged with Pd(dba) (0.030 g, 0.05 equiv.), Xantphos (0.038 g, 0.1 equiv.), 5-bromo-3-((4-methoxybenzyl)oxy)picolinonitrile (0.209 g, 0.681 mmol, 1.0 equiv.), CsCO (0.320 g, 1.5 equiv.), 5-(5-(trifluoromethyl)pyridin-2-yl)oxazol-2-amine (0.15 g, 0.654 mmol), and 1,4-dioxane (7 mL). The reaction flask was briefly vacuumed and subsequently backfilled with N, and the procedure was repeated five times. The mixture was then heated to 110 °C and stirred for 18 h. LCMS indicated complete consumption of the starting material. The reaction mixture was poured into water and extracted with EtOAc (5x). The combined organic solvents were dried over MgSO and evaporated to dryness. The residue was purified on silica gel using a mixture of DCM and EtOAc to give 3-((4-methoxybenzyl)oxy)-5-((5-(5-(trifluoromethyl)pyridin-2-yl)oxazol-2-yl)amino)picolinonitrile (0.215 g, 70.3% yield). 1 H NMR (401 MHz, DMSO-d6) δ 11.65 (s, 1H), 8.95 (s, 1H), 8.36 (d, J = 1.9 Hz, 1H), 8.28 (m, 2H), 7.98 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.52 - 7.43 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H), 5.22 (s, 2H), 3.79 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 159.91, 158.99, 156.98, 150.22, 144.34, 140.59, 135.26, 133.21, 130.48, 129.28, 127.54, 118.43, 116.45, 114.48, 114.27, 107.77, 70.71, 55.61.LCMS R f (min)=3.626, MS m / z=467.9[M+H] + .

[0417] 3-((4-Methoxybenzyl)oxy)-5-((5-(5-(trifluoromethyl)pyridin-2-yl)oxazol-2-yl)amino)picolinonitrile (0.20 g, 0.427 mmol) was suspended in EtOH (30 mL), then NH2OH.HCl (0.238 g, 3.423 mmol) was added and approximately half of the EtOH was removed in vacuo. Et3N (0.467 mL, 3.423 mol) was added and the resulting reaction The mixture was stirred at reflux overnight. LCMS showed the reaction was complete. The volatile solvent was removed, and the resulting solid was suspended in water, filtered, and washed thoroughly with water. The solid was washed with EtO and dried under high vacuum to give N'-hydroxy-3-((4-methoxybenzyl)oxy)-5-((5-(5-(trifluoromethyl)pyridin-2-yl)oxazol-2-yl)amino)picolinimidamide (0.183 g, 85.75% yield). 1 H NMR (401 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.61 (s, 1H), 8.93 (s, 1H), 8.36 (s, 1H), 8.26 (d, J = 7.7 Hz, 1H), 8.01 (s, 1H), 7.92 (s, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.47 (d, J = 7.7 Hz, 2H), 6.94 (d, J = 7.8 Hz, 2H), 5.60 (s, 2H), 5.12 (s, 2H), 3.75 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ159.41, 157.87, 153.61, 150.43, 150.23, 147.04, 143.79, 136.96, 135.21, 134.62, 129.87, 129.72, 129.57, 128.79, 125.62, 123.17, 122.85, 118.08, 114.25, 109.80, 70.07, 55.54.LCMS R f (min)=3.082, MS m / z=500.9[M+H] + .

[0418] [ka]

[0419] N'-hydroxy-3-((4-methoxybenzyl)oxy)-5-((5-(5-(trifluoromethyl)pyridin-2-yl)oxazol-2-yl)amino)-picolinimidamide (170 mg, 0.339 mmol) was stirred in a mixture of TFA (3 mL) and EtSiH (0.15 mL) at room temperature for 4 hours. The reaction mixture was evaporated to dryness. The residue was purified by preparative HPLC and then freeze-dried from 4 N HCl in dioxane to give N',3-dihydroxy-5-((5-(5-(trifluoromethyl)pyridin-2-yl)oxazol-2-yl)amino)picolinimidamide hydrogen chloride (104 mg, 66.43% yield, corrected for the presence of the HCl salt and 0.5 molar equivalents of dioxane). 1 H NMR (401 MHz, DMSO-d6) δ 12.30 - 12.03 (br, 1H), 11.54 (s, 1H), 10.90 (brs, 1H), 8.94 (d, J = 0.9 Hz, 1H), 8.50 (br, 1H), 8.37 (d, J = 2.1 Hz, 1H), 8.28 (dd, J = 8.5, 2.0 Hz, 1H), 8.12 (s, 1H), 7.95 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 157.32, 155.51, 150.30, 147.06, 144.20, 140.12, 135.26, 131.19, 129.37, 125.58, 123.39, 118.32, 110.89.LCMS R f (minute ) = 3.682, MS m / z = 380.9 [M + H] + . HRMS(ESI) calculated value C 15 H 12 F3N6O3 + [M+H] + 381.0917, actual value 381.0928.

[0420] 41. (R)-N-(2,3-Dihydroxypropyl)-6-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)-pyridazine-3-carboxamide (Scheme 38)

[0421] [ka]

[0422] 6-Chloropyridazine-3-carboxylic acid (0.57 g, 3.595 mmol) was dissolved in DCM (18 mL) with a catalytic amount of DMF. Oxalyl chloride (0.617 mL, 4.19 mmol, 2 equiv.) was added dropwise, and the resulting solution was stirred at room temperature overnight. Volatile solvents were removed in vacuo, and the residue was dried under high vacuum. (R)-3-aminopropane-1,2-diol (0.982 g, 10.78 mmol, 3 equiv.) and EtN (1.45 mL, 10.78 mmol, 3 equiv.) were added to the reaction mixture. iThe crude acid chloride was dissolved in a mixture of PrOH (5 mL) and EtOH (5 mL). The amine solution was slowly added to the solid residue, and the resulting reaction mixture was stirred overnight at room temperature. All volatile solvents were removed in vacuo, and the residue was freeze-dried from water. The crude product was dissolved in MeOH and treated with IR120 ion exchange resin to remove excess amine and EtN. The resin was washed thoroughly with MeOH, and the combined MeOH washing solutions were evaporated to dryness. The solid residue was purified on silica gel using a DCM and MeOH mixture as the eluent to give (R)-6-chloro-N-(2,3-dihydroxypropyl)pyridazine-3-carboxamide (0.477 g, 57.27%). 1 H NMR (401 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.24 (d, J = 8.7 Hz, 1H), 8.10 (d, J = 8.7 Hz, 1H), 4.92 (br, 1H), 4.65 (br, 1H), 3.68 (br, 1H), 3.55 - 3.46 (m, 1H), 3.29 (m, 3H). 13 C NMR (101 MHz, DMSO-d6) δ162.12, 158.66, 152.91, 130.75, 129.27, 70.38, 64.43, 43.28.LCMS R f (min)=1.393, MS m / z=231.9[M+H] + .

[0423] [ka]

[0424] An oven-dried RBF was charged with Pd2(dba)3 (0.020 g, 0.05 equiv.), Xantphos (0.025 g, 0.1 equiv.), (R)-6-chloro-N-(2,3-dihydroxypropyl)pyridazine-3-carboxamide (0.101 g, 0.438 mmol, 1.0 equiv.), Cs2CO3 (0.214 g, 1.5 equiv.), 5-(4-(trifluoromethyl)-phenyl)oxazol-2-amine (0.1 g, 0.438 mmol), and 1 ,4-Dioxane (8 mL) was charged. The reaction flask was briefly vacuumed and then backfilled with N2, and the procedure was repeated five times. The mixture was then heated to 110 °C and stirred for 18 h. LCMS indicated complete consumption of the starting material. The volatile solvents were removed in vacuo, and the residue was triturated with water. The solid precipitate was collected by filtration and washed with 5% aqueous potassium xanthate (2x), 10% aqueous citric acid, and water. The remaining solid was purified by preparative HPLC to give (R)-N-(2,3-dihydroxypropyl)-6-((5-(4-(trifluoromethyl)-phenyl)oxazol-2-yl)amino)pyridazine-3-carboxamide (0.072 g, 38.8% yield). 1 H NMR (401 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.74 (s, 1H), 8.46 (s, 1H), 8.20 (d, J = 9.2 Hz, 1H), 7.82 (s, 4H), 7.815 (s, 1H), 4.94 (d, J = 5.0 Hz, 1H), 4.65 (t, J = 5.6 Hz, 1H), 3.66 (m, 1H), 3.52 (m, 1H), 3.38 (m, 2H), 3.27 (m, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 162.90, 144.38, 131.79, 128.16, 128.01, 127.69, 126.58, 126.54, 126.00, 123.76, 123.30, 70.56, 64.44, 43.02.LCMS R f (minutes)=4.032. HRMS(ESI) calculated value C 18 H 17 F3N5O4 + [M+H] + 424.1227, actual value 424.1225.

[0425] 42. N',4-Dihydroxy-6-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridazine-3-carboximidamide (Scheme 39)

[0426] [ka]

[0427] p-Methoxybenzyl alcohol (0.121 g, 0.879 mmol, 1.0 equiv.) was dissolved in dry THF (5 mL) and NaH (60%, 0.021 g, 0.879 mmol, 1.0 equiv.) was added under N2. After 10 min of stirring, the solution was transferred to a flask containing 4,6-dichloropyridazine-3-carbonitrile (0.153 g, 0.879 mmol) in dry THF (5 mL). The resulting reaction mixture was stirred at room temperature for 1 h. LCMS indicated that all starting material had been consumed. The reaction mixture was poured into saturated aqueous NaHCO3 solution and the product was extracted with DCM (5x). The combined organic solution was dried over MgSO4 and evaporated to dryness. The residue was eluted with a mixture of petroleum distillate and EtOAc. The liquid was used and purified on silica gel to give 6-chloro-4-((4-methoxybenzyl)oxy)pyridazine-3-carbonitrile (0.127 g, 52.38%). 1 H NMR (401 MHz, CDCl3) δ 7.35 (d, J = 8.6 Hz, 2H), 7.16 (s, 1H), 6.95 (d, J = 8.6 Hz, 2H), 5.24 (s, 2H), 3.82 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.55, 159.42, 158.49, 132.41, 129.59, 124.34, 114.64, 112.29, 110.58, 72.15, 55.41.LCMS Rf(min)=3.298, MS m / z=297.9[M+Na] + .

[0428] An oven-dried RBF was charged with Pd(dba) (0.021 g, 0.05 equiv.), Xantphos (0.026 g, 0.1 equiv.), 5-(4-(trifluoromethyl)phenyl)oxazol-2-amine (0.119 g, 0.544 mmol, 1.2 equiv.), CsCO (0.221 g, 1.5 equiv.), 6-chloro-4-((4-methoxybenzyl)oxy)pyridazine-3-carbonitrile (0.125 g, 0.453 mmol), and 1,4-dioxane (8 mL). The reaction flask was briefly vacuumed and subsequently backfilled with N, and the procedure was repeated five times. The mixture was then heated to 110 °C and stirred for 18 h. LCMS indicated complete consumption of the starting material. The reaction mixture was then poured into water and extracted with EtOAc (5x). The combined organic solvents were dried over MgSO4 and evaporated to dryness. The residue was purified on silica gel using a mixture of DCM, EtOAc and MeOH to give 4-((4-methoxybenzyl)oxy)-6-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)-pyridazine-3-carbonitrile (0.046 g, 21.7% yield). The purity was about 80%, and the product was used in the next step without further purification. LCMS Rf(min)=4.47, MS m / z=467.9 [M+H] + .

[0429] 4-((4-Methoxybenzyl)oxy)-6-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridazine-3-carbonitrile (0.046 g, 0.098 mmol) was suspended in EtOH (10 mL), then NHOH·HCl (0.055 g, 0.787 mmol) was added, and approximately half of the EtOH was removed in vacuo. EtN (0.107 mL, 0.787 mmol) was added, and the resulting reaction mixture was stirred at reflux overnight. LCMS indicated the reaction was complete. The volatile solvents were removed, and the resulting solid was suspended in water, collected by filtration, and then washed well with water. The solid was washed with EtO and then dried under high vacuum to give N'-hydroxy-4-((4-methoxybenzyl)oxy)-6-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridazine-3-carboximidamide (0.037 g, 75.12% yield). The product was used in the next step without further purification. LCMS Rf (min) = 3.717, MS m / z = 500.9 [M+H] + .

[0430] [ka]

[0431] N'-hydroxy-4-((4-methoxybenzyl)oxy)-6-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridazine-3-carboxylate Carboximidamide (37 mg, 0.069 mmol) was stirred in a mixture of TFA (2 mL) and EtSiH (0.1 mL) at room temperature for 4 hours. The reaction mixture was evaporated to dryness. The residue was purified by preparative HPLC to give N',4-dihydroxy-6-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridazine-3-carboximidamide (5.3 mg, 19.96% yield). 1H NMR (401 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.87 (s, 1H), 7.81 (m, 4H), 7.59 (br, 3H).LCMS Rf(min)=3.615, MS m / z=380.9[M+H] + . HRMS(ESI) calculated value C 15 H 12 F3N6O3 + [M+H] + 381.0917, actual value 381.0912.

[0432] 43. 5-((5-(3-Fluoro-4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)-N',3-dihydroxypicolinimidamide (Scheme 40)

[0433] [ka]

[0434] 3-Fluoro-4-(trifluoromethyl)benzaldehyde (2.5 g, 13.01 mmol), p-toluenesulfonylmethyl isocyanide (2.723 g, 13.01 mmol), and K2CO3 (2.158 g, 15.61 mmol) were added to a dry RBF and refluxed with MeOH (7 mL) for 2.5 h. After this period, the solvent was evaporated and aq. NaHCO3 solution (20 mL) was added. The suspension was extracted with DCM (3 x 25 mL). The combined organic fractions were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 50% EtOAc in hexane to give 5-(3-fluoro-4-(trifluoromethyl)phenyl)oxazone. The zole (2.808 g, 94%) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.93 (s, 1H), 7.78 (dd, J = 10.0, 5.4 Hz, 2H), 7.65 (d, J = 8.3 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 160.51, 157.99, 153.09, 148.09, 133.70, 128.21, 125.42, 120.01, 112.33, 112.10.LCMS R f (min)=3.461, MS m / z=232.0[M+H] + .

[0435] LiHMDS (1.00 M in THF, 14.75 mL, 14.02 mmol) was added to a solution of 5-(3-fluoro-4-(trifluoromethyl)phenyl)oxazole (2.70 g, 11.68 mmol) in THF (90 mL) at −78 °C. The mixture was stirred at −78 °C for 1 h. After this period, a solution of C2Cl6 (4.15 g, 17.52 mmol) in THF (6 mL) was added at −78 °C, and the resulting mixture was stirred at −78 °C for 2 h. The mixture was then warmed to room temperature and stirred for an additional 14 h. The reaction was quenched with HO (15 mL) and diluted with EtOAc (20 mL). The organic layer was extracted with EtOAc (3 × 20 mL). The combined organics were washed with brine (20 mL), dried over MgSO4, filtered, and evaporated to dryness. The resulting white crystalline solid was used in the next step without further purification (2.825 g, 94%). 1 H NMR (400 MHz, CDCl3) δ 7.65 (t, J = 7.7 Hz, 1H), 7.49 - 7.37 (m, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 160.53, 158.02, 153.09, 148.12, 133.70, 128.21, 128.15, 125.42, 120.05, 112.10.LCMS R f (min)=3.745, MS m / z=265.8[M+H] + .

[0436] NH4OH (aq)The solution (28-30% NH3 based, 35 mL) was added to a microwave vial containing 2-chloro-5-(3-fluoro-4-(trifluoromethyl)phenyl)oxazole (0.577 g, 2.173 mmol) in THF (4 mL), and the mixture was subjected to microwave irradiation for 1 h at 90 °C. The resulting suspension was filtered, washed with Et2O, and dried under vacuum to give 5-(3-fluoro-4-(trifluoromethyl)phenyl)oxazol-2-amine (0.494 g, 92%) as a yellow solid. 1 H NMR (400 MHz, MeOH-d4) δ 7.61 (t, J = 7.8 Hz, 1H), 7.41 (t, J = 10.5 Hz, 2H), 7.31 (s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 162.21, 158.42, 140.69, 134.82, 134.72, 128.21, 127.14, 117.59, 109.58, 109.35. 13 C NMR (101 MHz, DMSO-d6) δ 162.66, 161.14, 158.85, 141.14, 135.16, 128.65, 127.58, 121.86, 118.02, 110.02.LCMS R f (min)=3.273, MS m / z=246.9[M+H] + .

[0437] 5-(3-Fluoro-4-(trifluoromethyl)phenyl)oxazol-2-amine (0.300 g, 1.219 mmol), 5-bromo-3-((4-methoxybenzyl)oxy)picolinonitrile (0.466 g, 1.462 mmol), CsCO (0.596 g, 1.828 mmol), Pd(dba) (0.056 g, 0.0609 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.0705 g, 0.122 mmol), and anhydrous 1,4-dioxane (16 mL) were added to a dry RBF. The mixture was degassed and purged with N 2(g) (x5) refill and N for 8 hours 2(g)The mixture was refluxed under reduced pressure. The reaction mixture was quenched with aq. NaHCO3 solution (10 mL) and diluted with EtOAc (15 mL). The organic layer was extracted with EtOAc (4 x 15 mL). The combined organic fractions were dried over MgSO4, filtered and evaporated to dryness. The residue (0.426 g) was carried on to the next step without further purification. LCMS R f (min)=3.732, MS m / z=484.9[M+H] + .

[0438] 5-((5-(3-Fluoro-4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)-3-((4-methoxybenzyl)oxy)picolinonitrile (0.426 g) was suspended in EtOH (12 mL), and NHOH·HCl (0.148 g, 2.132 mmol) was added to the mixture with stirring at room temperature. The EtOH volume was then reduced to half in vacuo (approximately 6 mL), and EtN (0.30 mL, 2.132 mmol) was added. The mixture was stirred at reflux for 24 hours. After this period, the volatiles were evaporated to dryness. The residue was washed with HO (15 mL) and EtO (20 mL) to give 5-((5-(3-fluoro-4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)-N'-hydroxy-3-((4-methoxybenzyl)oxy)picolinimidamide (0.325 g, 76%) as a bright orange solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.11 - 8.06 (m, 1H), 7.83 (q, J = 5.3, 3.4 Hz, 3H), 7.67 (d, J = 11.8 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.35 (s, 1H), 6.97 (d, J = 8.5 Hz, 2H), 5.14 (s, 2H), 3.76 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 159.79, 157.89, 155.06, 142.14, 141.84, 140.88, 140.59, 138.85, 138.79, 138.68, 133.23, 131.03, 130.47, 130.00, 128.11, 127.65, 125.91, 118.71, 114.38, 114.30, 110.33, 70.35, 55.58.LCMS R f (min)=3.350, MS m / z=517.9[M+H] + .

[0439] [ka]

[0440] TFA (2.0 mL) and EtSiH (0.2 mL) were added along with 5-((5-(3-fluoro-4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)-N'-hydroxy-3-((4-methoxybenzyl)oxy)picolinimidamide (0.1124 g, 0.217 mmol) in a RBF, and the resulting mixture was stirred at room temperature for 4 h. The volatiles were removed under reduced pressure, and the residue was directly subjected to preparative HPLC to give 5-((5-(3-fluoro-4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)-N',3-dihydroxypicolinimidamide (0.069 g, 80%, 100% pure) as an orange solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 10.5 (brs, 1H), 8.30 (d, J = 2.1 Hz, 1H), 7.96 - 7.88 (m, 3H), 7.73 (d, J = 12.0 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 158.25, 158.10, 156.55, 154.67, 142.26, 134.11, 129.86, 128.49, 128.47, 126.98, 123.99, 118.58, 118.55, 110.72, 110.38.LCMS R f (min)=3.341, MS m / z=397.9[M+H] + . HRMS(ESI) calculated value C 16 H 12 F4N5O3 + [M+H] + 398.0871, actual value 398.0877.

[0441] 44. (R)-N-(2,3-Dihydroxypropyl)-5-((5-(3-fluoro-4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide (Scheme 41)

[0442] [ka]

[0443] 5-(3-Fluoro-4-(trifluoromethyl)phenyl)oxazol-2-amine (0.198 g, 0.804 mmol), methyl 5-bromopicolinate (0.208 g, 0.964 mmol), CsCO (0.393 g, 1.205 mmol), Pd(dba) (0.037 g, 0.0402 mmol), Xantphos (0.0465 g, 0.0803 mmol), and anhydrous 1,4-dioxane (10 mL) were added to a dry RBF. The mixture was degassed and purged with N 2(g) (х5) and N for 24 hours 2(g)The mixture was refluxed under reduced pressure. The reaction mixture was quenched with aq. NaHCO3 solution (8 mL) and diluted with EtOAc (10 mL). The organic layer was extracted with EtOAc (3 x 10 mL). The combined organic fractions were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 50% EtOAc in DCM to give methyl 5-((5-(3-fluoro-4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinate (0.227 g, 74%) as a light brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.83 (d, J = 2.6 Hz, 1H), 8.31 (dd, J = 8.7, 2.6 Hz, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.89 (s, 1H), 7.86 (t, J = 8.1 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 3.85 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 166.97, 164.82, 156.41, 139.87, 138.60, 136.99, 132.37, 131.71, 131.59, 128.66, 126.94, 125.97, 122.85, 118.66, 52.07.LCMS R f (min)=3.794, MS m / z=381.9[M+H] + .

[0444] A solution of LiOH.HO (0.0387 g, 0.922 mmol) in HO (1 mL) was added dropwise to a solution of methyl 5-((5-(3-fluoro-4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinate (0.352 g, 0.922 mmol) in 1,4-dioxane (2 mL) and EtOH (2 mL). The mixture was stirred at 80 °C for 1 h. After this period, the contents were evaporated to dryness. The residue was washed with EtO (15 mL), filtered off, and dried under vacuum to give the title compound (0.258 g, 76%) as a white solid, which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 2.5 Hz, 1H), 8.14 (dd, J = 8.5, 2.6 Hz, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.81 - 7.74 (m, 2H), 7.60 (d, J = 12.2 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 168.60, 156.61, 142.90, 142.22, 137.98, 137.23, 134.11, 128.40, 126.97, 123.99, 123.72, 122.56, 121.29, 118.56, 110.47.LCMS R f (min)=4.702, MS m / z=367.9[M+H] + .

[0445] [ka]

[0446] 5-((5-(3-fluoro-4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinic acid (0.12 g, 0.327 mmol), HOBt (0.046 g, 0.392 mmol), and EDCl.HCl (0.069 g, 0.360 mmol) were added to a dry RBF and heated with anhydrous DMF (6.5 mL) under N 2(g) The mixture was stirred with a steady stream of HCl. (R)-3-aminopropane-1,2-diol (0.036 g, 0.392 mmol) was then added, and stirring was continued for 16 h. After this period, the reaction was quenched with aq. NaHCO solution (8 mL) and diluted with EtOAc (10 mL). The organic layer was extracted with EtOAc (3 × 10 mL), and the combined organics were dried over MgSO. The volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC using 0.1% TFA in HO and 0.1% TFA in ACN as eluents to give (R)-N-(2,3-dihydroxypropyl)-5-((5-(3-fluoro-4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide (0.086 g, 60%, 100% pure) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.80 (d, J = 2.6 Hz, 1H), 8.46 (t, J = 5.9 Hz, 1H), 8.30 (dd, J = 8.6, 2.6 Hz, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.88 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 12.0 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 4.95 (d, J = 4.9 Hz, 1H), 4.66 (t, J = 5.8 Hz, 1H), 3.63 (m, , 1H), 3.50 (m, 1H), (two proton resonances overlap with H2O, not assigned), 3.23 (m, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 163.60, 156.61, 142.90, 142.22, 137.98, 137.23, 134.11, 128.40, 126.97, 123.99, 123.72, 122.56, 121.29, 118.56, 110.71, 110.47, 70.20, 63.94, 42.34.LCMS R f (minutes)=3.266, MS m / z=440.9[M+H] + . HRMS(ESI) calculated value C 19 H 17 F4N4O4 + [M+H] + 441.118, actual value 441.1197.

[0447] 45. 5-((5-(3-Fluoro-4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)-N'-hydroxypicolinimidamide (Scheme 42)

[0448] [ka]

[0449] 5-((5-(3-Fluoro-4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinic acid (0.093 g, 0.253 mmol) was suspended in DMF (3.0 mL), then EDCI (1.3 equiv.) and HOBt (1.4 equiv.) were added. The resulting mixture was stirred at room temperature for 3 h. Concentrated aqueous ammonia (1 mL) was added and stirring was continued overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give (5-((5-(3-fluoro-4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinamide (LCMS R f (min)=3.723, MS m / z=366.9[M+H] +), which was suspended in anhydrous THF. EtN (3 equiv.) was added, followed by TFAA (1.5 equiv.). The resulting solution was stirred at room temperature for 2 h, and the volatile solvents were removed in vacuo. The crude 5-((5-(3-fluoro-4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)picolinonitrile was dried under high vacuum and then redissolved in anhydrous EtOH. NHOH·HCl (5 equiv.) and EtN (5 equiv.) were added, and the resulting reaction mixture was stirred at reflux overnight. All volatile solvents were removed, and the residue was purified by preparative HPLC to give 5-((5-(3-fluoro-4-(trifluoromethyl)-phenyl)oxazol-2-yl)amino)-N'-hydroxypicolinimidamide (0.023 g over three steps; 21.35% yield, corrected for the suggested 0.5 molar equivalent of dioxane). 1 H NMR (401 MHz, DMSO-d6) δ 11.36 (s, 1H), 10.92 - 10.88 (br, 1H), 8.87 (s, 1H), 8.30 (d, J = 8.7 Hz, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.87 (s, 1H), 7.84 (t, J = 8.0 Hz, 1H), 7.70 (d, J = 12.0 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 161.09, 158.56, 156.88, 142.85, 138.85, 138.75, 134.51, 134.41, 128.85, 127.37, 127.14, 124.44, 123.88, 123.16, 121.75, 119.08, 119.04, 115.15, 115.03, 114.83, 114.71, 111.22, 110.99.LCMS R f (min)=3.782, MS m / z=381.9[M+H] + . HRMS(ESI) calculated value C 16 H 12 F4N5O2+ [M+H] + 382.0922, actual value 382.0907.

[0450] 46. ​​N'-Hydroxy-5-((5-(5-(trifluoromethyl)pyridin-2-yl)oxazol-2-yl)amino)-picolinimidamide (Scheme 43)

[0451] [ka]

[0452] Intermediate L-2-bromo-5-(5-(trifluoromethyl)pyridin-2-yl)oxazole BrCFCFBr (1.71 g, 6.6 mmol) and t BuOLi (0.53 g, 6.6 mmol) was added to a solution of 5-(5-(trifluoromethyl)pyridin-2-yl)oxazole (0.70 g, 3.3 mmol) in DMF / m-xylene (5 / 5 mL). The resulting mixture was stirred at 60 °C for 3 h and quenched with saturated NaHCO (10 mL). The aqueous phase was extracted with EtOAc (20 mL × 2). The combined organic phases were dried over NaSO, filtered, and concentrated to give a brown oil, which was subjected to silica gel flash chromatography (3% to 10%, EtOAc / hexane). Collection of appropriate fractions afforded 2-bromo-5-(5-(trifluoromethyl)pyridin-2-yl)oxazole as a white solid (0.68 g, 70% yield). 1 H NMR (400 MHz, CDCl3) δ 8.86 (m, 1H), 8.00 (dd, J = 8.3, 1.7 Hz, 1H), 7.75 (s, 1H), 7.72 (d, J = 8.3 Hz, 1 H).MS m / z=292.9[M+H] + .

[0453] An oven-dried RBF was charged with Pd2(dba)3 (0.025 g, 0.04 equiv.), Xantphos (0.031 g, 0.08 equiv.), 2-bromo-5-(5-(trifluoromethyl)pyridin-2-yl)oxazole (Intermediate L) (0.2 g, 0.68 mmol), Cs2CO3 (0.332 g, 1.5 equiv.), 5-aminopicolinonitrile (0.405 g, 3.4 mmol, 5 equiv.), and 1,4-dioxane (10 mL). The reaction flask was briefly vacuumed and then backfilled with N2, and the procedure was repeated five times. The mixture was then heated to 110 °C and stirred for 18 h. The reaction mixture was poured into water and extracted with EtOAc (5x). The combined organic solvents were dried over MgSO4 and evaporated to dryness. The residue was purified on silica gel using a mixture of DCM and EtOAc to give 5-((5-(5-(trifluoromethyl)pyridin-2-yl)oxazol-2-yl)amino)picolinonitrile (0.127 g, 56.36% yield). 1 H NMR (401 MHz, DMSO-d6) δ 11.59 (s, 1H), 8.93 (d, J = 1.0 Hz, 1H), 8.85 (d, J = 2.4 Hz, 1H), 8.32 (dd, J = 8.7, 2.6 Hz, 1H), 8.26 (dd, J = 8.6, 2.1 Hz, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.93 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 157.07, 150.25, 147.07, 144.32, 140.75, 139.28, 135.28, 130.30, 129.31, 125.56, 124.60, 123.47, 123.14, 118.42, 118.38.LCMS R f (min)=2.978, MS m / z=332.1[M +H] + .

[0454] [ka]

[0455] 5-((5-(5-(trifluoromethyl)pyridin-2-yl)oxazol-2-yl)amino)picolinonitrile (0.127 g, 0.383 mmol) was suspended in EtOH (10 mL), then NHOH·HCl (0.213 g, 3.067 mmol, 8 equiv.) was added, and approximately half of the EtOH was removed in vacuo. EtN (0.42 mL, 3.067 mmol, 8 equiv.) was added, and the resulting reaction mixture was stirred at reflux overnight. The volatile solvents were removed, and the resulting solid was suspended in water, collected by filtration, and then washed thoroughly with water. The crude solid was purified by preparative HPLC to give N-hydroxy-5-((5-(5-(trifluoromethyl)pyridin-2-yl)oxazol-2-yl)amino)picolinimidamide (0.106 g; 75.9%). 1 H NMR (401 MHz, DMSO-d6) δ 11.50 (s, 1H), 10.97 - 10.88 (brs, 1H), 8.95 - 8.93 (m, 1H), 8.89 (d, J = 2.5 Hz, 1H), 8.6-8.2 (br, 1H), 8.32 (dd, J = 8.8, 2.6 Hz, 1H), 8.27 (dd, J = 8.7, 2.1 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.94 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 158.42, 157.39, 154.87, 150.31, 147.06, 144.17, 138.92, 138.84, 135.26, 129.41, 125.57, 123.96, 123.38, 123.33, 123.06, 122.87, 118.28.LCMS R f (min)=2.865, MS m / z=365.1[M+H] + . HRMS(ESI) calculated value C 15 H 12 F3N6O2+ [M+H] + 365.0968, actual value 365.0974.

[0456] 47. 6-((5-(4-Fluorophenyl)oxazol-2-yl)amino)-N'-hydroxypyridazine-3-carboximidamide (Scheme 44)

[0457] [ka]

[0458] 4-Fluorobenzaldehyde (2.00 g, 16.11 mmol) and K2CO3 (2.67 g, 19.33 mmol) were added to a solution of p-toluenesulfonylmethyl isocyanide (3.46 g, 17.73 mmol) in MeOH (30 mL) at room temperature. The resulting mixture was then refluxed under nitrogen for 5 h before being concentrated under reduced pressure. The residue was partitioned between Et2O and HO. The aqueous phase was extracted with Et2O (50 mL × 2), and the combined organic phases were dried over MgSO4, filtered, and concentrated to give a pale yellow oil, which was subjected to silica gel flash chromatography (3% to 20%, EtOAc / hexanes). Collection of appropriate fractions afforded 5-(4-fluorophenyl)oxazole as a white solid (2.16 g, 82% yield). 1 H NMR (400 MHz, CDCl3) δ ) δ 7.90 (s, 1H), 7.58-7.63 (m, 2H), 7.28 (s, 1H), 7.07-7.13 (m, 2H).MS m / z=164 .1[M+H] + .

[0459] LiHMDS (1.0 M in THF, 6.58 mL, 6.58 mmol) was added to a solution of 5-(4-fluorophenyl)oxazole (0.98 g, 5.98 mmol) in dry THF (6 mL) at −78 °C under a nitrogen atmosphere. After an additional 0.5 h, a solution of C2Cl6 (2.12 g, 8.97 mmol) in THF (5 mL) was treated. The resulting reaction mixture was stirred at −78 °C for an additional 2 h and allowed to warm to room temperature over 14 h. The reaction was quenched with saturated NaHCO3 (10 mL). The aqueous phase was extracted with EtOAc (30 mL × 2). The combined organic phase was dried over Na2SO4, filtered, and concentrated to give a brown oil, which was subjected to silica gel flash chromatography (2% to 10%, EtOAc / hexanes). Collection of appropriate fractions gave 2-chloro-5-(4-fluorophenyl)oxazole (1.06 g, 90% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.55-7.60 (m, 2H), 7.23 (s, 1H), 7.10-7.15 (m, 2 H).MS m / z= 198.0[M+H] + .

[0460] NHOH (28-30% NH based aqueous solution, 8 mL) was added to a solution of 2-chloro-5-(4-fluorophenyl)oxazole (0.60 g, 3.04 mmol) in THF (1.5 mL) at room temperature. The resulting reaction mixture was heated in a microwave oven for 1 h. Irradiated at 90° C. The solid was filtered and washed with DCM (5 mL×2) to give 5-(4-fluorophenyl)oxazol-2-amine (0.52 g, 96% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.47-7.50 (m, 2H), 7.18-7.23 (m, 2H), 7.15 (s, 1H), 6.82 (s, 2H).MS m / z=179.0[M+H] + .

[0461] An oven-dried RBF was charged with Pd(dba) (0.044 g, 0.05 equiv.), Xantphos (0.055 g, 0.10 equiv.), 5-(4-fluorophenyl)oxazol-2-amine (0.17 g, 0.954 mmol), CsCO (0.466 g, 1.5 equiv.), 6-chloropyridazine-3-carbonitrile (0.146 g, 1.05 mmol, 1.1 equiv.), and 1,4-dioxane (5 mL). The reaction flask was briefly vacuumed and subsequently backfilled with N, and the procedure was repeated five times. The mixture was then heated to 110 °C and stirred for 18 h. The reaction mixture was poured into water and extracted with EtOAc (5x). The combined organic solvents were dried over MgSO and evaporated to dryness. The residue was purified on silica gel using a mixture of DCM and EtOAc to give 6-((5-(4-fluorophenyl)oxazol-2-yl)amino)pyridazine-3-carbonitrile (0.181 g, 67.44% yield). 1 H NMR (401 MHz, DMSO-d6) δ 12.37 (br, 1H), 8.41 (s, 1H), 8.22 (d, J = 9.4 Hz, 1H), 7.67 (dd, J = 8.7, 5.4 Hz, 2H), 7.59 (s, 1H), 7.32 (t, J = 8.9 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 163.26, 160.82, 133.39, 125.81, 125.73, 124.53, 124.50, 117.07, 116.75, 116.53.LCMS R f (minutes)=3.185. MS m / z=282.1[M+H] + .

[0462] [ka]

[0463] 6-((5-(4-fluorophenyl)oxazol-2-yl)amino)pyridazine-3-carbonitrile (0.152 g, 0.54 mmol) in EtOH (12 mL) The mixture was suspended in water, then NHOH.HCl (0.301 g, 4.323 mmol, 8 equiv.) was added, and approximately half of the EtOH was removed in vacuo. EtN (0.59 mL, 4.323 mmol, 8 equiv.) was added, and the resulting reaction mixture was stirred at reflux overnight. The volatile solvents were removed, and the resulting solid was suspended in water, collected by filtration, and then washed thoroughly with water. The crude solid was purified by preparative HPLC to give 6-((5-(4-fluorophenyl)oxazol-2-yl)amino)-N-hydroxypyridazine-3-carboximidamide (0.075 g; 43.4%). 1 H NMR (401 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.28 (d, J = 8.9 Hz, 1H), 8.08 (d, J = 9.5 Hz, 1H), 7.68 (dd, J = 8.7, 5.4 Hz, 2H), 7.59 (s, 1H), 7.32 (t, J = 8.9 Hz, 2H), 13 C NMR (101 MHz, DMSO-d6) δ 163.19, 160.75, 158.51, 156.23, 144.92, 127.54, 125.71, 125.63, 124.69, 121.95, 116.73, 116.51.LCMS R f (min)=2.935, MS m / z=315.1[M+H ] + . HRMS(ESI) calculated value C 14 H 12 FN6O2 + [M+H] + 315.1, actual value 315.0991.

[0464] 48. 6-((5-(3,4-Difluorophenyl)oxazol-2-yl)amino)-N'-hydroxypyridazine-3-carboximidamide (Scheme 45)

[0465] [ka]

[0466] 3,4-Difluorobenzaldehyde (2.00 g, 14.1 mmol) and K2CO3 (2.33 g, 16.9 mmol) were added to a solution of TosMIC (3.02 g, 15.5 mmol) in MeOH (30 mL) at room temperature. The resulting mixture was then refluxed under nitrogen for 5 h before being concentrated under reduced pressure. The residue was partitioned between Et2O and H2O. The aqueous phase was extracted with Et2O (50 mL × 2), and the combined organic phase was washed with MgSO4. Drying, filtration, and concentration gave a pale yellow oil which was subjected to silica gel flash chromatography (3% to 20%, EtOAc / hexanes). Collection of appropriate fractions afforded 5-(3,4-difluorophenyl)oxazole) as a white solid (2.25 g, 88% yield). 1 H NMR (400 MHz, CDCl3) δ ) δ 7.55-7.60 (m, 2H), 7.23 (s, 1H), 7.09-7.15 (m, 2 H),MS m / z=182.0[M+H] + .

[0467] LiHMDS (1.0 M in THF, 8.46 mL, 8.46 mmol) was added to a solution of 5-(3,4-difluorophenyl)oxazole (1.40 g, 7.69 mmol) in dry THF (10 mL) at −78 °C under a nitrogen atmosphere. After an additional 0.5 h, a solution of C2Cl6 (2.73 g, 11.5 mmol) in THF (5 mL) was treated. The resulting reaction mixture was stirred at −78 °C for an additional 2 h and allowed to warm to room temperature over 14 h. The reaction was quenched with saturated NaHCO3 (10 mL). The aqueous phase was extracted with EtOAc (40 mL × 2). The combined organic phase was dried over Na2SO4, filtered, and concentrated to give a brown oil, which was subjected to silica gel flash chromatography (2% to 10%, EtOAc / hexanes). Collection of appropriate fractions gave 2-chloro-5-(3,4-difluorophenyl)oxazole (1.41 g, 85% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.47 (m, 1H), 7.39 (m, 1H), 7.32 (s, 1H), 7.31 (m, 1 H).MS m / z=216.0[M+H] + .

[0468] NHOH (28-30% NH3 based aqueous solution, 12 mL) was added to a solution of 2-chloro-5-(3,4-difluorophenyl)oxazole (1.10 g, 4.42 mmol) in THF (2.0 mL) at room temperature. The resulting reaction mixture was irradiated in a microwave at 90 °C for 1 h. The solid was filtered and washed with DCM (5 mL × 2) to give 5-(3,4-difluorophenyl)oxazol-2-amine (0.82 g, 95% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.38-7.49 (m, 2H), 7.25 (s, 2H), 6.93 (s, 2H).MS m / z=197.0[M+H] + .

[0469] An oven-dried RBF was charged with Pd(dba) (0.058 g, 0.05 equiv.), Xantphos (0.074 g, 0.10 equiv.), 5-(3,4-difluorophenyl)oxazol-2-amine (0.25 g, 1.274 mmol), CsCO (0.622 g, 1.5 equiv.), 6-chloropyridazine-3-carbonitrile (0.196 g, 1.40 mmol, 1.1 equiv.), and 1,4-dioxane (7 mL). The reaction flask was briefly vacuumed and subsequently backfilled with N, and the procedure was repeated five times. The mixture was then heated to 110 °C and stirred for 18 h. The reaction mixture was poured into water and extracted with EtOAc (5x). The combined organic solvents were dried over MgSO and evaporated to dryness. The residue was purified on silica gel using a mixture of DCM and EtOAc to give 6-((5-(3,4-difluorophenyl)oxazol-2-yl)amino)pyridazine-3-carbonitrile (0.194 g, 50.9% yield). 1H NMR (401 MHz, DMSO-d6) δ 12.44 - 12.38 (br s, 1H), 8.41 (d, J = 8.9 Hz, 1H), 8.23 ​​(d, J = 9.4 Hz, 1H), 7.74 - 7.69 (m, 1H), 7.68 (s, 1H), 7.56 (dt, J = 10.5, 8.5 Hz, 1H), 7.48 - 7.43 (m, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 156.61, 154.90, 151.62, 151.49, 150.43, 149.18, 149.05, 148.10, 133.42, 125.44, 120.44, 119.13, 118.95, 117.04, 112.84, 112.65.LCMS R f (minute ) = 3.061, MS m / z = 300.0 [M + H] + .

[0470] [ka]

[0471] 6-((5-(3,4-Difluorophenyl)oxazol-2-yl)amino)pyridazine-3-carbonitrile (0.095 g, 0.317 mmol) was suspended in EtOH (12 mL), then NHOH·HCl (0.177 g, 2.54 mmol, 8 equiv.) was added, and approximately half of the EtOH was removed in vacuo. EtN (0.347 mL, 2.54 mmol, 8 equiv.) was added, and the resulting reaction mixture was stirred at reflux overnight. The volatile solvents were removed, and the resulting solid was suspended in water, collected by filtration, and then washed thoroughly with water. The crude solid was purified by preparative HPLC to give 6-((5-(3,4-difluorophenyl)oxazol-2-yl)amino)-N-hydroxypyridazine-3-carboximidamide (0.083 g; 78.67%). 1H NMR (401 MHz, DMSO-d6) δ 11.85 (brs, 1H), 10.16 (brs, 1H), 8.31-7.47 (m, 6H), 5.97 (s, 2H).LCMS R f (min)=2.848, MS m / z=333.1[M+H] + . HRMS(ESI) calculated value C 14 H 11 F2N6O2 + [M+H] + 333.0906, actual value 333.0908.

[0472] 49. 6-((5-(5-fluoropyridin-2-yl)oxazol-2-yl)amino)-N'-hydroxypyridazine-3-carboximidamide (Scheme 46)

[0473] [ka]

[0474] 5-Fluoropicolinaldehyde (1.20 g, 9.60 mmol) and K2CO3 (1.60 g, 11.5 mmol) were added to a solution of p-toluenesulfonylmethyl isocyanide (2.06 g, 10.6 mmol) in MeOH (20 mL) at room temperature. The resulting mixture was then refluxed under nitrogen for 5 h before being concentrated under reduced pressure. The residue was partitioned between Et2O and HO. The aqueous phase was extracted with Et2O (20 mL × 2), and the combined organic phases were dried over MgSO4, filtered, and concentrated to give a pale yellow oil, which was subjected to silica gel flash chromatography (3% to 20%, EtOAc / hexane). Collection of appropriate fractions afforded 5-(5-fluoropyridin-2-yl)oxazole as a white solid (1.39 g, 88% yield). 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 2.8 Hz, 1 H, resolved by F), 7.95 (s, 1 H), 7.66-7.69 (m, 1 H), 7.64 (s, 1 H), 7.48 (td, J = 8.3, 2.8 Hz, 1 H). MS m / z = 165.1 [M+H]. + .

[0475] LiHMDS (1.0 M in THF, 5.18 mL, 5.18 mmol) was added to a solution of 5-(5-fluoropyridin-2-yl)oxazole (0.80 g, 4.93 mmol) in dry THF (5 mL) at −78 °C under a nitrogen atmosphere. After an additional 0.5 h, a solution of C2Cl6 (1.52 g, 6.41 mmol) in THF (5 mL) was treated. The resulting reaction mixture was stirred at −78 °C for an additional 2 h and allowed to warm to room temperature over 14 h. The reaction was quenched with saturated NaHCO3 (10 mL). The aqueous phase was extracted with EtOAc (30 mL × 2). The combined organic phase was dried over Na2SO4, filtered, and concentrated to give a brown oil, which was subjected to silica gel flash chromatography (2% to 10%, EtOAc / hexanes). Collection of appropriate fractions gave 2-chloro-5-(5-fluoropyridin-2-yl)oxazole (0.82 g, 84% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 2.8 Hz, 1H, resolved by F), 7.59-7.6 3 (m, 1H), 7.56 (s, 1H), 7.48 (td, J = 8.0 and 2.8 Hz, 1H). MS m / z = 19 8.9[M+H] + .

[0476] NHOH (28-30% NH3 based aqueous solution, 4 mL) was added to a solution of 2-chloro-5-(5-fluoropyridin-2-yl)oxazole (0.20 g, 1.02 mmol) in THF (0.5 mL) at room temperature. The resulting reaction mixture was irradiated in a microwave oven at 90 °C for 1 h. The solid was filtered and washed with DCM (3 mL × 2) to give 5-(5-fluoropyridin-2-yl)oxazol-2-amine (0.18 g, 97% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1 H), 7.72 (m, 1 H), 7.47 (m, 1H), 7.30 (s 1 H), 7.05 (s, 2H).MS m / z=180.1[M+H] + .

[0477] An oven-dried RBF was charged with Pd(dba) (0.044 g, 0.05 equiv.), Xantphos (0.055 g, 0.10 equiv.), 5-(5-fluoropyridin-2-yl)oxazol-2-amine (0.17 g, 0.948 mmol), CsCO (0.464 g, 1.5 equiv.), 6-chloropyridazine-3-carbonitrile (0.146 g, 1.04 mmol, 1.1 equiv.), and 1,4-dioxane (5 mL). The reaction flask was briefly vacuumed and subsequently backfilled with N, and the procedure was repeated five times. The mixture was then heated to 110 °C and stirred for 18 h. The reaction mixture was poured into water and extracted with EtOAc (5x). The combined organic solvents were dried over MgSO and evaporated to dryness. The residue was purified on silica gel using a mixture of DCM and EtOAc to give 6-((5-(5-fluoropyridin-2-yl)oxazol-2-yl)amino)pyridazine-3-carbonitrile (0.053 g, 19.78% yield). 1 H NMR (401 MHz, DMSO-d6) δ 12.51 (s, 1H), 8.61 (d, J = 2.8 Hz, 1H), 8.46 (d, J = 9.0 Hz, 1H), 8.25 (d, J = 9.4 Hz, 1H), 7.86 (td, J = 8.7, 2.9 Hz, 1H), 7.72 (m, J = 4.1 Hz, 2H).13 C NMR (101 MHz, DMSO-d6) δ159.74, 157.21, 156.60, 145.29, 143.53, 138.57, 138.33, 133.46, 125.05, 124.86, 120.38, 120.34, 117.04.LCMS R f (min)=2.892, MS m / z=283.1[M+H] + .

[0478] [ka]

[0479] 6-((5-(5-fluoropyridin-2-yl)oxazol-2-yl)amino)pyridazine-3-carbonitrile (0.05 g, 0.177 mmol) was suspended in EtOH (7 mL), then NHOH·HCl (0.099 g, 1.417 mmol, 8 equiv.) was added, and approximately half of the EtOH was removed in vacuo. EtN (0.193 mL, 1.417 mmol, 8 equiv.) was added, and the resulting reaction mixture was stirred at reflux overnight. The volatile solvents were removed, and the resulting solid was suspended in water, collected by filtration, and then washed thoroughly with water, EtOH, and EtO to give 6-((5-(5-fluoropyridin-2-yl)oxazol-2-yl)amino)-N'-hydroxypyridazine-3-carboximidamide (0.041 g; 73.4%). 1 H NMR (401 MHz, DMSO-d6) δ 11.97 - 11.87 (br, 1H), 10.17 (s, 1H), 8.60 (d, J = 2.7 Hz, 1H), 8.29 (br, 1H), 8.02 (d, J = 8.9 Hz, 1H), 7.85 (td, J = 8.7, 2.8 Hz, 1H), 7.72 - 7.69 (m, 1H), 7. 67 (s, 1H), 5.98 (s, 2H). 13C NMR (101MHz, DMSO-d6) δ 159.58, 157.07, 144.72, 143.85, 138.50, 138.26, 124.99, 124.79, 120.06, 120.02.LCMS f (minutes)=2 .439, MS m / z=316.1 [M+H] + . HRMS(ESI) calculated value C 13 H 11 FN7O2 + [M+H] + 316.0953, actual value 316.0954.

[0480] 50. N,5-Dihydroxy-2-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)isonicotinimide-amide (Scheme 47)

[0481] [ka]

[0482] 4-Methoxybenzyl alcohol (0.687 g, 4.975 mmol, 1.0 equiv) was dissolved in dry DMF (12 mL), and then NaH (60%, 0.119 g, 4.975 mmol, 1.0 equiv) was added under a nitrogen atmosphere at 0 °C. After 15 min of stirring, the solution was transferred to a flask containing 2-bromo-5-fluoroisonicotinonitrile (1.0 g, 0.495 mmol) in dry DMF (12 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 h. LCMS indicated that all starting material had been consumed. The reaction mixture was poured into saturated aqueous NaHCO3 solution, and the product was extracted with DCM (5x). The combined organic solution was dried over MgSO4 and evaporated to dryness. The residue was purified on silica gel using neat toluene as the eluent to give 2-bromo-5-((4-methoxybenzyl)oxy)isonicotinonitrile (1.37 g, 86.27%). 1H NMR (401 MHz, CDCl3) δ 8.25 (s, 1H), 7.59 (d, J = 0.4 Hz, 1H), 7.36 - 7.33 (m, 2H), 6.94 - 6.89 (m, 2H), 5.23 (s, 2H), 3.81 (d, J = 3.3 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.10, 154.31, 136.57, 131.84, 130.35, 129.26, 126.22, 114.38, 112.86, 112.73, 71.87, 55.36.LCMS Rf(min)=3.691, MS m / z=316.9 / 318.9(MH) - .

[0483] An oven-dried RBF was charged with Pd2(dba)3 (0.108 g, 0.15 equiv.), Xantphos (0.09 g, 0.2 equiv.), 5-(4-(trifluoromethyl)phenyl)oxazol-2-amine (Intermediate D) (0.215 g, 0.939 mmol, 1.2 equiv.), Cs2CO3 (0.383 g, 1.5 equiv.), 2-bromo-5-((4-methoxybenzyl)oxy)isonicotinonitrile (0.25 g, 0.783 mmol), and 1,4-dioxane (15 mL). The reaction flask was briefly vacuumed and subsequently backfilled with N2, and the procedure was repeated five times. The mixture was then heated to 110 °C and stirred for 18 h. LC MS showed that the starting material was completely consumed. The reaction mixture was then poured into water and extracted with EtOAc (5x). The combined organic solvents were dried over MgSO4 and evaporated to dryness. The residue was purified on silica gel using a mixture of DCM and EtOAc to give 5-((4-methoxybenzyl)oxy)-2-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)isonicotinonitrile (0.051 g, 13.95% yield). 1H NMR (401 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.63 - 8.42 (s, 1H), 8.31 (s, 1H), 7.80 (s, 4H), 7.74 (s, 1H), 7.43 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.5 Hz, 2H), 5.28 (s, 2H), 3.77 (s, 3H).LCMS Rf(min)=3.93, MS m / z=467.1[M+H] + .

[0484] 5-((4-Methoxybenzyl)oxy)-2-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)isonicotinonitrile (0.043 g, 0.092 mmol) was suspended in EtOH (10 mL), then NHOH.HCl (0.051 g, 0.737 mmol) was added and approximately half of the EtOH was removed in vacuo. EtN (0.101 mL, 0.737 mmol) was added and the resulting reaction mixture was stirred at reflux overnight. LCMS showed the reaction was complete. The volatile solvents were removed and the resulting solid was suspended in water, collected by filtration, and then washed well with water. The solid was washed with EtO and then dried under high vacuum to give N-hydroxy-5-((4-methoxybenzyl)oxy)-2-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)isonicotinimide amide (0.033 g, 71.66% yield). The product was used in the next step without further purification. LCMS Rf (min) = 4.733, MS m / z = 499.9 [M+H] + .

[0485] [ka]

[0486] (N-Hydroxy-5-((4-methoxybenzyl)oxy)-2-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)isonicotinimide amide (33 mg, 0.066 mmol) was stirred in a mixture of TFA (2 mL) and EtSiH (0.1 mL) at room temperature for 4 hours. The reaction mixture was evaporated to dryness. The residue was purified by preparative HPLC to give N,5-dihydroxy-2-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)isonicotinimide amide (5.0 mg, 19.95% yield). 1 H NMR (401 MHz, DMSO-d6) δ 10.68 (s, 1H), 10.48 (s, 1H), 8.42 (s, 1H), 8.12 (s, 1H), 7.99 (s, 1H), 7.77 (s, 4H), 7.71 (s, 1H), 6.43 (s, 2H). 13 C NMR (101 MHz, DMSO) δ 158.83, 158.52, 157.53, 152.33, 148.30, 144.76, 143.21, 136.99, 132.23, 128.77, 127.69, 127.37, 127.06, 126.74, 126.48, 126.44, 126.07, 125.77, 124.37, 123.26, 108.41.LCMS Rf(min)=3.62, MS m / z=380.1[M+H] + . HRMS(ESI) calculated value C 16 H 13 F3N5O3 + [M+H] + 380.0965, actual value 380.0967.

[0487] 51. 5-((5-(4-(difluoromethoxy)phenyl)oxazol-2-yl)amino)-N'-hydroxypicolinimidamide (Scheme 48)

[0488] [ka]

[0489] 4-(Difluoromethoxy)benzaldehyde (3.0 g, 17.4 mmol) and K2CO3 (2.89 g, 20.9 mmol) were added to a solution of TosMIC (3.74 g, 19.2 mmol) in MeOH (40 mL) at room temperature. The resulting mixture was refluxed under nitrogen for 5 h and then concentrated under reduced pressure. The residue was partitioned between Et2O and HO. The aqueous phase was extracted with Et2O (40 mL × 2), and the combined organic phases were dried over MgSO4, filtered, and concentrated to give a pale yellow oil, which was subjected to silica gel flash chromatography (3% to 10%, EtOAc / hexane). Collection of appropriate fractions afforded 5-(4-(difluoromethoxy)phenyl)oxazole (3.23 g, 88% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.31 (s, 1H), 7.17 (d, J = 8.0 Hz, 2 H), 6.54 (t, J = 72 Hz, 1 H, MS m / z = 212.1 [M+H] + .

[0490] LiHMDS (1.0 M in THF, 8.86 mL, 8.86 mmol) was added to a solution of 5-(4-(difluoromethoxy)phenyl)oxazole (1.70 g, 8.05 mmol) in dry THF (15 mL) at −78° C. under a nitrogen atmosphere. After an additional 0.5 h, a solution of C2Cl6 (2.86 g, 12.1 mmol) in THF (5 mL) was treated. The resulting reaction mixture was stirred at −78° C. for an additional 2 h, warmed to room temperature over 14 h, and then quenched with saturated NaHCO3 (10 mL). The aqueous phase was extracted with EtOAc (30 mL × 3). The combined organic phases were dried over Na2SO4, filtered, and concentrated to give a brown oil which was subjected to silica gel flash chromatography (5%, EtOAc / hexanes) and collection of appropriate fractions afforded 2-chloro-5-(4-(difluoromethoxy)phenyl)oxazole (1.78 g, 90% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.0 Hz, 2H), 7.25 (s, 1H), 7.17 (d, J = 8.0 Hz, 2 H), 6.55 (t, J = 72 Hz, 1 H, resolved by F). MS m / z = 246.0 [M+H] + .

[0491] NHOH (28-30% NH based aqueous solution, 10 mL) was added to a solution of 2-chloro-5-(4-(difluoromethoxy)phenyl)oxazole (1.2 g, 4.89 mmol) in THF (1.5 mL) at room temperature. The resulting reaction mixture was irradiated in a microwave at 90 °C for 1 h. The solid was filtered and washed with DCM (5 mL × 2) to give 5-(4-(difluoromethoxy)phenyl)oxazol-2-amine (1.05 g, 95% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.20 (t, J = 72 Hz, 1H, resolved by F), 6.86 (s, 2H). MS m / z = 227.1 [M+H] + .

[0492] A degassed solution of 5-(4-(difluoromethoxy)phenyl)oxazol-2-amine (200 mg, 0.88 mmol), 5-bromopicolinonitrile (178 mg, 0.97 mmol), CsCO (430 mg, 1.32 mmol), Pd(dba) (40 mg, 0.044 mmol), and Xantphos (51 mg, 0.088 mmol) in 1,4-dioxane (10 mL) was stirred for 5 h at 110 °C. The volatile solvents were removed in vacuo. The residue was partitioned between EtOAc and HO. The aqueous phase was extracted with EtOAc (20 mL × 3). The combined organic phases were dried over MgSO, filtered, and concentrated to give a yellow residue, which was subjected to silica gel flash chromatography (5% to 50%, EtOAc / DCM). Collection of appropriate fractions gave 5-((5-(4-(difluoromethoxy)phenyl)oxazol-2-yl)amino)picolinonitrile (0.26 g, 89% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 8.83 (d, J = 2.5 Hz, 1H), 8.32 (dd, J = 8.6, 2.5 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.66 (d, J = MS m / z=329.1[M+H] + .

[0493] [ka]

[0494] EtN (0.81 mL, 5.85 mmol) and NHOH.HCl (406 mg, 5.85 mmol) were added to a suspension of 5-((5-(4-(difluoromethoxy)phenyl)oxazol-2-yl)amino)picolinonitrile (240 mg, 0.73 mmol) in EtOH (10 mL) at room temperature. The reaction mixture was stirred at reflux overnight. Volatile solvents were removed and the crude material was purified using preparative HPLC to give 5-((5-(4-(difluoromethoxy)phenyl)oxazol-2-yl)amino)-N'-hydroxypicolinimideamide (0.022 g, 8.3% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 10.79 (brs, 1H), 8.87 (d, J = 2.5 Hz, 1H), 8.30 (dd, J = 8.8, 2.5 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.28 (t, J = 74 Hz, 1H, resolved by F). 13 C NMR (101 MHz, DMSO-d6) δ 150.0, 143.8, 138.8, 138.0, 124.8, 124.6, 123.0, 122.5, 119.5, 116.3.LCMS R f (min)=2.54, MS m / z=362.1[M +H] + . HRMS(ESI) calculated value C 16 H 14 F2N5O3 + [M+H] + 362.1065, actual value 362.1045.

[0495] 52.5-((5-(4-(difluoromethyl)phenyl)oxazol-2-yl) Amino)-N'-hydroxypicolinimidamide (Scheme 49)

[0496] [ka]

[0497] 4-(Difluoromethyl)benzaldehyde (1.38 g, 8.84 mmol) and K2CO3 (1.47 g, 10.6 mmol) were added to a solution of TosMIC (1.90 g, 9.72 mmol) in MeOH (20 mL) at room temperature. The resulting mixture was then refluxed under nitrogen for 5 h before being concentrated under reduced pressure. The residue was partitioned between Et2O and HO. The aqueous phase was extracted with Et2O (30 mL × 2), and the combined organic phases were dried over MgSO4, filtered, and concentrated to give a pale yellow oil, which was subjected to silica gel flash chromatography (3% to 20%, EtOAc / hexanes). Collection of appropriate fractions afforded 5-(4-(difluoromethyl)phenyl)oxazole as a white solid (1.40 g, 81% yield). 1 H NMR (400 MHz, CDCl3) δ ) δ 7.94 (s, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2 H), 7.42 (s, 1H), 6.66 (t, J = 56 Hz, 1 H, F). MS m / z = 196.0 [M+H] + .

[0498] LiHMDS (1.0 M in THF, 4.22 mL, 4.22 mmol) was added to a solution of 5-(4-(difluoromethyl)phenyl)oxazole (0.75 g, 3.84 mmol) in dry THF (10 mL) at −78 °C under a nitrogen atmosphere. After an additional 0.5 h, a solution of C2Cl6 (1.36 g, 5.76 mmol) in THF (5 mL) was treated. The resulting reaction mixture was stirred at −78 °C for an additional 2 h and allowed to warm to room temperature over 14 h. The reaction was quenched with saturated NaHCO3 (10 mL). The aqueous phase was extracted with EtOAc (30 mL × 2). The combined organic phase was dried over Na2SO4, filtered, and concentrated to give a brown oil, which was subjected to silica gel flash chromatography (2% to 10%, EtOAc / hexanes). Collection of appropriate fractions afforded 2-chloro-5-(4- (Difluoromethyl)phenyl)oxazole (0.73 g, 83% yield) was obtained as a white solid. 1 H NMR (400 MHz, CDCl) δ 7.77 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.35 (s, 1H), 6.66 (t, J = 56 Hz, 1H, resolved by F). MS m / z = 230.0 [M+H] + .

[0499] NHOH (28-30% NH3 based aqueous solution, 10 mL) was added to a solution of 2-chloro-5-(4-(difluoromethyl)phenyl)oxazole) (0.75 g, 3.27 mmol) in THF (1.5 mL) at room temperature. The resulting reaction mixture was irradiated in a microwave at 90 °C for 1 h. The solid was filtered and washed with DCM (5 mL × 2) to give 5-(4-(difluoromethyl)phenyl)oxazol-2-amine (0.66 g, 96% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO) δ 7.52-7.61 (m, 4H), 7.33 (s, 1H), 7.14-6.86 (m, 3H).MS m / z=211.0[M+H] + .

[0500] A degassed solution of 5-(4-(difluoromethyl)phenyl)oxazol-2-amine (152 mg, 0.72 mmol), 5-bromopicolinonitrile (199 mg, 1.08 mmol), CsCO (469 mg, 1.44 mmol), Pd(dba) (53 mg, 0.058 mmol), and Xantphos (42 mg, 0.072 mmol) in 1,4-dioxane (10 mL) was stirred for 5 h at 110 °C. The volatile solvents were removed in vacuo. The residue was partitioned between EtOAc and HO. The aqueous phase was extracted with EtOAc (20 mL × 3). The combined organic phases were dried over MgSO, filtered, and concentrated to give a gray residue, which was subjected to flash chromatography using EtOAc / DCM (5% to 50%). Collection of appropriate fractions gave 5-((5-(4-(difluoromethyl)phenyl)oxazol-2-yl)amino)picolinonitrile (0.20 g, 90% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.85 (d, J = 2.5 Hz, 1H), 8.32 (dd, J = 8.6, 2.5 Hz, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.71 (s, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.05 (t, J = 56 Hz, 1 H, F split). MS m / z = 313.1 [M+H] + .

[0501] [ka]

[0502] EtN (0.57 mL, 4.10 mmol) and NHOH.HCl (284 mg, 4.10 mmol) were added to a suspension of 5-((5-(4-(difluoromethyl)phenyl)oxazol-2-yl)amino)picolinonitrile (160 mg, 0.51 mmol) in EtOH (8 mL) at room temperature. The reaction mixture was stirred at reflux overnight. Volatile solvents were removed and the crude material was purified using preparative HPLC to give 5-((5-(4-(difluoromethyl)phenyl)oxazol-2-yl)amino)-N'-hydroxypicolinimideamide (0.016 g, 9.1% yield) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 10.70 (brs, 1H), 8.87 (d, J = 2.3 Hz, 1H), 8.29 (dd, J = 8.7, 2.3 Hz, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.75 (d, J = 8.2 Hz, 2H), 7.70 (s, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.05 (t, J = 56 Hz, 1 H, F Split). 13 C NMR (101 MHz, DMSO-d6) δ 155.8, 143.9, 138.0, 132.9, 132.7, 132.5, 1 30.0, 126.6(4), 126.5(8), 126.5(2), 124.2, 123.3, 123.0, 122.4, 117.1, 114.8, 112.4.LCMS Rf(min)=2.65, MS m / z=346.1[M+H] + . HRMS(ESI) calculated value C 16 H 14 F2N5O2+[M+H] + 346.1116, actual value 346.1107.

[0503] 53. N'-Hydroxy-6-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridazine-3-carboximidamide (Scheme 50)

[0504] [ka]

[0505] A resealable Schlenk tube was charged with Pd(dba) (0.05 equiv.), Xantphos (0.1 equiv.), 6-chloropyridazine-3-carbonitrile (1.1 equiv.), CsCO (1.3 equiv.), and 5-(4-(trifluoromethyl)phenyl)oxazol-2-amine (Intermediate D) (0.2 g, 0.88 mmol) in 1,4-dioxane (8 mL). The mixture was degassed, carefully subjected to three cycles of evacuation and filling with N, and heated at 100 °C overnight. Upon completion, the mixture was cooled and the solvent evaporated to give the crude product, which was stirred with a 5% aqueous solution of potassium xanthate (10 mL) for 5 min, filtered, and washed with water (2 × 10 mL), MeOH (3 × 5 mL), and EtO (3 × 5 mL) to give the pure product (210 mg, 72.3%) as a yellow solid. 1 H NMR (401 MHz, DMSO-d6) δ 8.44 (d, J = 7.9 Hz, 1H), 8.24 (d, J = 9.3 Hz, 1H), 7.82 (s, 5H).LCMS Rf(min)=3.604. MS m / z=332.1[M+H] + .

[0506] [ka]

[0507] 6-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyridazine-3-carbonitrile (0.15 g) was suspended in EtOH (15 mL), followed by the addition of NHOH.HCl (8.0 equiv.) and EtN (8 equiv.). The resulting mixture was refluxed overnight. Upon completion, the mixture was cooled and the solid was filtered and washed with water (2 × 10 mL), MeOH (3 × 5 mL), and EtO (2 × 5 mL) to give the pure product (90 mg, 54.6%) as a beige solid. 1H NMR (401 MHz, DMSO-d6) δ 11.98 (s, 1H), 10.16 (s, 1H), 8.25 (s, 1H), 8.02 (s, 1H), 7.82 (s, 5H), 5.97 (s, 2H).LCMS Rf(min)=3.463. HRMS(ESI) calculated value C 15 H 12 F3N6O2 + [M+H] + 365.0968, actual value 365.0975.

[0508] 54. N'-Hydroxy-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyrazine-2-carboximidamide (Scheme 51)

[0509] [ka]

[0510] A resealable Schlenk tube was charged with Pd(dba) (0.05 equiv.), Xantphos (0.1 equiv.), 5-bromopyrazine-2-carbonitrile (1.1 equiv.), CsCO (1.3 equiv.), and 5-(4-(trifluoromethyl)phenyl)oxazol-2-amine (Intermediate D) (0.2 g, 0.877 mmol) in 1,4-dioxane. The mixture was carefully subjected to three cycles of evacuation and filling with N and heated at 100 °C overnight. Upon completion, the mixture was cooled and the solvent evaporated to give the crude product, which was stirred with a 5% aqueous solution of potassium xanthate (10 mL) for 5 min, filtered, and washed with water (3 × 10 mL), MeOH (3 × 5 mL), and EtO (2 × 5 mL) to give the pure product (200 mg, 69%) as a yellow solid. 1 H NMR (401 MHz, DMSO-d6) δ 12.24 (s, 1H), 9.25 (s, 1H), 8.87 (s, 1H), 7.86 (s, 1H), 7.83 (m, 4H).LCMS Rf(min)=3.551, M S m / z=332.0[M+H]+ .

[0511] [ka]

[0512] 5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyrazine-2-carbonitrile (0.15 g) was suspended in EtOH (15 mL), followed by the addition of NHOH.HCl (8.0 equiv.) and EtN (8.0 equiv.). The resulting mixture was refluxed overnight. Upon completion, the mixture was cooled, and the solid was filtered and washed with water (2 × 10 mL), MeOH (3 × 5 mL), 1,4-dioxane:EtO (1:1, 3 × 5 mL), and EtO (2 × 5 mL) to afford N'-hydroxy-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyrazine-2-carboximidamide (70 mg, 42%) as a beige solid. 1 H NMR (401 MHz, DMSO-d6) δ 11.59 (s, 1H), 9.94 (s, 1H), 9.23 (s, 1H), 8.75 (s, 1H), 7.82 (br s, 5H), 5.85 (s, 2H).LCMS Rf(min)=3.697. HRMS(ESI) calculated value C 15 H 12 F3N6O2 + [M+H] + 365.0968, actual value 365.0984.

[0513] 55. N'-Hydroxy-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyrimidine-2-carboximidamide (Scheme 52)

[0514] [ka]

[0515] A resealable Schlenk tube was charged with Pd(dba) (0.05 equiv.), Xantphos (0.1 equiv.), 5-bromopyrimidine-2-carbonitrile (1.1 equiv.), CsCO (1.3 equiv.), and 5-(4-(trifluoromethyl)phenyl)oxazol-2-amine (Intermediate D) (0.2 g, 0.877 mmol) in 1,4-dioxane (8 mL). The mixture was degassed and carefully subjected to three cycles of evacuation-filling with N and heated at 100 °C overnight. After completion, the mixture was cooled and the solvent was evaporated to give the crude product, which was stirred with a 5% aqueous solution of potassium xanthate (10 mL) for 5 min, filtered, and washed with water (3 × 10 mL), MeOH (3 × 5 mL), and EtO (2 × 5 mL) to give 5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyrimidine-2-carbonitrile (200 mg, 69%) as a beige solid. The compound was used as is without further purification.

[0516] [ka]

[0517] 5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyrimidine-2-carbonitrile (0.11 g) was suspended in EtOH (10 mL), followed by the addition of NHOH.HCl (8.0 equiv.) and EtN (8.0 equiv.). The resulting mixture was refluxed overnight. Upon completion, the mixture was cooled, the solid was filtered, and the resulting solution was diluted with water (2 × 10 mL), MeOH (2 × 5 mL), 1,4-dioxane:EtO (1:1, 3 × 5 mL) and EtO (2 × 5 mL) to give N'-hydroxy-5-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)pyrimidine-2-carboximidamide (50 mg, 41.3%) as a beige solid. 1H NMR (401 MHz, DMSO-d6) δ 11.28 (s, 1H), 9.79 (s, 1H), 8.80 (s, 2H), 7.82 (m, 5H), 6.01 (s, 2H).LCMS Rf(min)=3.597. HRMS(ESI) calculation value C 15 H 12 F3N6O2 + [M+H] + 365.0968, actual value 365.0982.

[0518] 56. 3-Fluoro-N'-hydroxy-5-((5-(5-(trifluoromethyl)pyridin-2-yl)oxazol-2-yl)amino)picolinimidamide (Scheme 53)

[0519] [ka]

[0520] Intermediate K (5-(5-(trifluoromethyl)pyridin-2-yl)oxazol-2-amine) (0.2 g, 0.872 mmol) was reacted with 5-bromo-3-fluoropicolinonitrile (0.175 g, 0.872 mmol) according to General Procedure 4, Method 1. The crude product was purified on silica gel using a mixture of DCM and EtOAc (0-30%) as eluent to afford the desired 3-fluoro-5-((5-(5-(trifluoromethyl)pyridin-2-yl)oxazol-2-yl)amino)picolinonitrile in 73.16% yield (0.223 g). 1 H NMR (401 MHz, DMSO-d6) δ 11.99 (br s, 1H), 8.95 (s, 1H), 8.60 (s, 1H), 8.35 (d, J = 11.5 Hz, 1H), 8.29 (d, J = 8.3 Hz, 1H), 7.97 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H).LCMS R f (min)=3.351, MS m / z=350.1[M+H] + .

[0521] [ka]

[0522] 3-Fluoro-5-((5-(5-(trifluoromethyl)pyridin-2-yl)oxazol-2-yl)amino)picolinonitrile (0.21 g, 0.6 mmol) was subjected to amidoxime formation in EtOH as per General Procedure 1 Method 2, filtered with water, then washed with water, EtOH and Et2O to give 3-fluoro-N'-hydroxy-5-((5-(5-(trifluoromethyl)pyridin-2-yl)oxazol-2-yl)amino)picolinonitrile (0.21 g, 0.6 mmol) To this end, 211 mg of (methyl)amino)picolinimidamide (91.8%, 211 mg) was obtained. 1 H NMR (401 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.94 (s, 1H), 8.58 (s, 1H), 8.27 (d, J = 6.7 Hz, 1H), 8.14 (dd, J = 13.1, 1.8 Hz, 1H), 7.92 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 5.76 (s, 2H).LCMS R f (min)=3.027, MS m / z=383.1[M+H] + . HRMS(ESI) calculated value C 15 H 11 F4N6O2 + [M+H] + 383.0874, actual value 383.0871.

[0523] 57. N'-Hydroxy-5-((5-(5-(trifluoromethyl)pyridin-2-yl)oxazol-2-yl)amino)pyrazine-2-carboximidamide (Scheme 54)

[0524] [ka]

[0525] Intermediate K (5-(5-(trifluoromethyl)pyridin-2-yl)oxazol-2-amine) (0.156 g, 0.68 mmol) was reacted with 5-bromopyrazine-2-carbonitrile (0.125 g, 0.68 mmol) according to General Procedure 4, Method 1. The crude product was purified on silica gel using a mixture of DCM and EtOAc (0–70%) as eluent to afford the desired 5-((5-(5-(trifluoromethyl)pyridin-2-yl)oxazol-2-yl)amino)pyrazine-2-carbonitrile in 32.34% yield (0.073 g). 1 H NMR (401 MHz, DMSO-d6) δ 12.36 (br s, 1H), 9.29 (s, 1H), 8.94 (s, 1H), 8.88 (d, J = ...

Claims

1. Formula (I') 【Chemical 1】 (In the formula, A １ ~A ５ is C-R ａ and N, １ ~A ５ any 0, 1, 2, 3 or 4 of may be N; Each R ａ are independently H or R ａａ and R ａａ is selected from halo, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, cycloamino, halocycloamino, alkoxylalkyl, and alkoxyalkoxy; Q is a 5-membered aromatic heterocycle having two, three, or four ring heteroatoms, at least one of which must be N, the remainder being independently selected from N, O, and S, and the ring carbon atom bearing a hydrogen atom or the ring nitrogen atom bearing a hydrogen atom, when present, is optionally selected from halo, haloalkyl, and alkyl. ａ may be substituted with W is 【Chemistry 2】 is a 6-membered N-containing heterocycle selected from R ｂ teeth, -OH (where R ｂ provided that if is OH, then W is (E) or (I); -K-NR ｃ -Y, or a tautomer thereof, - (CH ２ ) ｐ —NH—OH, and 【Chemistry 3】 is selected from K is SO, SO ２ , C(=X') or NHC(=X'), where X' is O or NH; R ｃ is H, C １～６ Alkyl or hydroxy C １～６ is alkyl, Y is OH, NHR ｅ (R ｅ is H, C １～６ Alkyl, —(C═O)H or —(C═O)C １～６ alkyl), hydroxy C １～６ Alkyl or (SC １～６ alkyl) C １～６ is alkyl, p is 0 or 1; R ｄ H, OH, halo, C １～６ Alkyl and C １～６ alkoxy) provided that the compound has the formula 【Chemistry 4】 provided that the A １ ~A ５ Any four of these are C—H, and the rest are C—R ａ and R ａ is H, halo, CH ３ or OCH ３ or a pharmaceutically acceptable salt or solvate thereof.

2. Q is optionally, if permitted, Q ａ Heterocyclic (a) to (kk) optionally substituted with a group (wherein the bond marked with # is attached to NH, ＊ The bond labeled A １ ~A ５ attached to an aryl ring defined by 【Chemistry 5】 2. The compound of claim 1 selected from:

3. Q ａ But, Halo, C １～６ Alkyl and HaloC １～６ 3. The compound of claim 1 or 2, wherein the alkyl is selected from the group consisting of aryl, aryl, arylsulfonyl ...

4. A １ ~A ５ Each of these is C-R ａ The compound according to any one of claims 1 to 3,

5. A １ , A ２ , A ４ and A ５ The compound according to any one of claims 1 to 3, wherein one, two, three or four of are N.

6. A ５ Or A １ is N, or A ２ Or A ４ is N, or A １ and A ５ are both N, or A ２ and A ４ are both N, A １ and A ４ , or A ２ and A ５ are both N, or A １ and A ２、 Or A ４ and A ５ The compound of claim 5 , wherein both are N.

7. A ３ is C-R ａａ The compound according to any one of claims 1 to 6,

8. R ａａ The compound of claim 7, wherein is halo, haloalkyl, or haloalkoxy.

9. R ａａ is Cl, CF ３ or OCF ３ 9. The compound of claim 8, wherein:

10. 10. The compound of any one of claims 1 to 9, wherein W is selected from (A), (B), (C), (D), (F), (G), (H) and (J).

11. R ｄ H, OH, Cl, F, Br, I, CH ３ or OCH ３ The compound according to any one of claims 1 to 10,

12. Q, if necessary Q ａ The compound according to any one of claims 1 to 11, wherein (f) is substituted with

13. The compound of any one of claims 1 to 12, wherein W is (A).

14. R ｂ But K-NR ｃ -Y or its tautomer, or -(CH ２ ) ｐ The compound of any one of claims 1 to 13, which is -NH-OH.

15. R ｂ But K-NR ｃ The compound of any one of claims 1 to 14, which is -Y or a tautomer thereof.

16. R ｂ But -K-NR ｃ -Y or a tautomer thereof, K is SO ２ , C(=O), C(=NH) or NHC(=O), R ｃ is H, C １～６ Alkyl (e.g., C １～３ Alkyl, e.g. CH ３ , C.H. ２ CH ３ or (CH ２ ) ２ CH ３ ), or hydroxy C １～６ Alkyl (e.g., hydroxy C １～３ Alkyl, for example -(CH ２ )OH, -(CH ２ ) ２ OH, -CH(OH)CH ２ OH, CH(OH)CH ３ , -(CH ２ ) ３ OH, -CH(OH)(CH ２ ) ２ OH, -CH ２ CH(OH)CH ２ OH, -(CH(OH)) ２ CH ３ and -(CH(OH)) ２ CH ２ OH), Y is OH, NH ２ , N.H.C. １～３ Alkyl, NHC(=O)H, NH(C=O)C １～３ Alkyl, hydroxy C １～６ Alkyl (e.g., hydroxy C １～３ Alkyl, for example -(CH ２ )OH, -(CH ２ ) ２ OH, -CH(OH)CH ２ OH, CH(OH)CH ３ , -(CH ２ ) ３ OH, -CH(OH)(CH ２ ) ２ OH, -CH ２ CH(OH)CH ２ OH, -(CH(OH)) ２ CH ３ and -(CH(OH)) ２ CH ２ OH), or (SC １～６ alkyl) C １～６ Alkyl (e.g., (SC １～３ alkyl) C １～３ Alkyl, for example -(CH ２ ) SCH ３ , -(CH ２ ) ２ SCH ３ , -CH(SCH ３ ) CH ２ SCH ３ , CH(SCH ３ ) CH ３ , -(CH ２ ) ３ SCH ３ , -CH(SCH ３ ) (CH ２ ) ２ SCH ３ , -CH ２ CH (SCH ３ ) CH ２ SCH ３ , -(CH(SCH ３ )) ２ CH ３ and -(CH(SCH ３ )) ２ CH ２ SCH ３ 15. The compound according to any one of claims 1 to 14, wherein

17. R ｂ but, 【Chemistry 6】 (In the formula, X' is O or NH; R ｃ is H or C １～６ Alkyl or hydroxy C １～６ is alkyl, Y is OH or NHR ｅ is) 16. The compound of any one of claims 1 to 15, which is:

18. R ｂ but, 【Chemistry 7】 18. The compound of any one of claims 1 to 17, selected from:

19. R ｂ but, 【Chemistry 8】 The compound according to any one of claims 1 to 17,

20. R ｂ is OH and W is (E) or (I), The compound described.

21. 2. The compound of claim 1, which is any one of compounds 1-120 described in the claims or specification.

22. A composition comprising the compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

23. 23. A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, or a composition according to claim 22, for use as an agent for inhibiting or otherwise interacting with Des1, or for use as an agent in the treatment of fibrosis or a fibrotic disease.

24. A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, or a composition according to claim 22, for use in therapy.

25. 22. A method of treating a disease or condition in a subject in need thereof in which Des1 inhibition is beneficial, comprising administering to the subject a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof.

26. 22. Use of a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating a disease in which Des1 inhibition is beneficial.

27. 22. A method of treating fibrosis or a fibrotic disease in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof.

28. 22. Use of a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating fibrosis or a fibrotic disease.

Images