Ferroptosis inhibitors: Diarylamines and paraacetamides

Abstract

To provide compounds, etc., that inhibit ferroptosis activity or regulate or inhibit diseases related to ferroptosis dysregulation. [Solution] The present invention provides compounds (including corresponding sulfonamides) that inhibit ferroptosis activity or modulate or inhibit diseases associated with ferroptosis dysregulation, such as neurological disorders, ischemia-reperfusion injury, acute renal failure, and cancer, and pharmaceutically acceptable salts, hydrates, and stereoisomers thereof. The compounds of the present invention are used in pharmaceutical compositions, as well as in methods of use and methods of manufacture, which include treating a person in need with an effective amount of the compound or composition of the present invention and detecting the resulting improvement in the person's health or condition.

Description

[Background technology]

[0001] <Introduction>

[0002] Ferroptosis is a type of iron-dependent programmed cell death characterized by the accumulation of lipid peroxides, and is genetically and biochemically distinct from other forms of controlled cell death such as apoptosis, autophagy, and necrosis. Dysregulation of ferroptosis is thought to be involved in numerous diseases, including neuropathy, ischemia-reperfusion injury, acute renal failure, and cancer. [Overview of the Initiative]

[0003] <Summary of the Invention>

[0004] The present invention provides compounds that modulate or inhibit ferroptosis activity, or that modulate or inhibit diseases associated with ferroptosis dysregulation, such as neuropathy, ischemia-reperfusion injury, acute renal failure, and cancer, and prodrugs thereof, which are typically hydrolyzed in the intestines or blood to produce the corresponding compounds / inhibitors.

[0005] In one aspect, the present invention provides a compound of formula I, or a salt, hydrate, or stereoisomer thereof, or a corresponding sulfonamide:

[0006] JPEG2026063193000001.jpg66151

[0007] (In the formula,

[0008] R1 to R11 are, independently, H, a substituted or unsubstituted heteroatom, or a substituted or unsubstituted hydrocarbyl, a substituted or unsubstituted heterohydrocarbyl;

[0009] R12 is a substituted or unsubstituted heteroatom, or a substituted or unsubstituted hydrocarbyl, or a substituted or unsubstituted heterohydrocarbyl;

[0010] R11~R12 may be linked together to form a substituted or unsubstituted C3~C18, C3~C10, or C3~C6 heteroring; and

[0011] X1-X5 and Y1-Y5 are independently either C or N.

[0012] In an explicit manner:

[0013] R1 is H, a substituted or unsubstituted heteroatom, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;

[0014] R1 is a substituted or unsubstituted OH or NH2, a substituted or unsubstituted C1-C9 alkyl, or a substituted or unsubstituted C1-C9 heteroalkyl;

[0015] R1 is a substituted or unsubstituted OH or NH2;

[0016] R1 is NR'R'', where R' and R'' are independently substituted or unsubstituted hydrocarbyls, or substituted or unsubstituted heterohydrocarbyls, which may be linked together to form a substituted C4-C9 heterocycle;

[0017] R1 is NR'R'', forming a substituted or unsubstituted piperidine-1-yl such as 4-CF3-piperidine-1-yl;

[0018] R2 to R10 are independently H, a halide, a substituted or unsubstituted OH or NH2, a substituted or unsubstituted alkyl, or a substituted or unsubstituted heteroalkyl;

[0019] R2 to R10 are independently H, a halide, or a substituted or unsubstituted lower alkyl group, such as a fluorinated C1 to C4 alkyl group;

[0020] R2 to R10 are H;

[0021] R11 is H, OH, or a substituted or unsubstituted C1-C4 alkyl group;

[0022] R11 is either H or OH;

[0023] R11 is H;

[0024] R12 is a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;

[0025] R12 is a substituted or unsubstituted C3-C9 cycloalkyl, a substituted or unsubstituted C3-C9 heterocycloalkyl, a substituted or unsubstituted C5-C9 aryl, or a substituted or unsubstituted C5-C9 heteroaryl;

[0026] R12 is 1-ethyl-pyrrolidine-2-on-4-yl;

[0027] R11 to R12 are linked together to form a C3 to C10 heteroring with or without substitution;

[0028] R11-R12 are linked together to form a substituted or unsubstituted C5-C6 heterocycle such as piperazine-2-one, for example, with the 4-position substituted with methyl or ethyl;

[0029] The values ​​of X1-X4 (0, 1, 2, or 3) and Y1-Y4 (0, 1, 2, or 3) are N;

[0030] The values ​​of X1-X4 (0, 1, or 2) and Y1-Y4 (0, 1, or 2) are N;

[0031] Y2 and X4, or Y2 and Y4, or X2 and Y2, or X2 and Y4, or X4 and X2, or X4 and Y4 alone are N; or

[0032] X2, X3, X4, Y2 or Y4 alone are N; or

[0033] Any combination of the substituents mentioned above.

[0034] In one aspect, the present invention provides compounds disclosed herein, or salts, hydrates, or stereoisomers thereof:

[0035] In one aspect, the present invention provides a pharmaceutical composition comprising a predetermined unit dose form, a therapeutically effective amount of the compound of formula I (mentioned above), and one or more pharmaceutically acceptable excipients.

[0036] In one aspect, the present invention provides uses for compounds or compositions disclosed herein in the manufacture of pharmaceuticals that inhibit ferroptotic activity in persons who need it, or that modulate or inhibit diseases associated with ferroptotic dysregulation, such as neurological disorders, ischemia-reperfusion injury, acute renal failure, and cancer.

[0037] In some respects, the present invention provides compounds or compositions disclosed herein for inhibiting ferroptotic activity in persons who need it, or for modulating or inhibiting diseases associated with ferroptotic dysregulation such as neurological disorders, ischemia-reperfusion injury, acute renal failure, and cancer, or for use in the manufacture of such pharmaceuticals in persons who need it.

[0038] In one aspect, the present invention provides a method for using compounds or compositions disclosed herein to inhibit ferroptotic activity in a person who needs it, or to modulate or inhibit diseases associated with ferroptotic dysregulation, such as neurological disorders, ischemia-reperfusion injury, acute renal failure, and cancer, and for detecting, in some cases, the resulting improvement in the person's health or condition.

[0039] The present invention encompasses all combinations of the specific embodiments described herein, each of which is described herein. [Modes for carrying out the invention]

[0040] <Description of specific embodiments of the present invention>

[0041] It is understood that the examples and embodiments described herein are merely illustrative of the present invention, and that various modifications or changes may be proposed to the parties based on these examples and embodiments, and that such modifications or changes will fall within the spirit and scope of this application and the appended claims. All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety for all purposes.

[0042] The term "alkyl" refers to a hydrocarbon group selected from linear or branched saturated hydrocarbon groups having 1 to 18 carbon atoms, 1 to 12 carbon atoms, or 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), and 1,1-dimethylethyl or t-butyl ("t-Bu"). Other examples of alkyl groups include 1-pentyl group, 2-pentyl group, 3-pentyl group, 2-methyl-2-butyl group, 3-methyl-2-butyl group, 3-methyl-1-butyl group, 2-methyl-1-butyl group, 1-hexyl group, 2-hexyl group, 3-hexyl group, 2-methyl-2-pentyl group, 3-methyl-2-pentyl group, 4-methyl-2-pentyl group, 3-methyl-3-pentyl group, 2-methyl-3-pentyl group, 2,3-dimethyl-2-butyl group, and 3,3-dimethyl-2-butyl group.

[0043] Lower alkyl means having 1 to 8 carbon atoms, preferably 1 to 6, more preferably 1 to 4. Lower alkenyl or lower alkynyl means having 2 to 8, 2 to 6, or 2 to 4 carbon atoms.

[0044] The term "alkenyl" refers to a hydrocarbon group selected from linear or branched hydrocarbon groups having 2 to 18 carbon atoms, 2 to 12 carbon atoms, or 2 to 6 carbon atoms, and containing at least one C=C double bond. Examples of alkenyl groups may be selected from ethenyl or vinyl groups, propa-1-enyl group, propa-2-enyl group, 2-methylpropa-1-enyl group, buta-1-enyl group, buta-2-enyl group, buta-3-enyl group, buta-1,3-dienyl group, 2-methylbuta-1,3-diene group, hexa-1-enyl group, hexa-2-enyl group, hexa-3-enyl group, hexa-4-enyl group, and hexa-1,3-dienyl group.

[0045] The term "alkynyl" refers to a hydrocarbon group that contains at least one C≡C triple bond and is selected from straight-chain or branched hydrocarbon groups having 2 to 18 carbon atoms, 2 to 12 carbon atoms, or 2 to 6 carbon atoms. Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0046] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups and partially unsaturated cyclic hydrocarbon groups, including monocyclic and polycyclic groups (e.g., dicyclic and tricyclic groups). For example, the number of carbon atoms in a cycloalkyl group may be 3-12, 3-8, or 3-6. Alternatively, a cycloalkyl group may be a monocyclic group with 3-12, 3-8, or 3-6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopenta-1-enyl, 1-cyclopenta-2-enyl, 1-cyclopenta-3-enyl, cyclohexyl, 1-cyclohexa-1-enyl, 1-cyclohexa-2-enyl, 1-cyclohexa-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. Examples of bicyclic cycloalkyl groups include groups with 7 to 12 ring atoms arranged as bicyclic groups selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, as well as groups with 7 to 12 ring atoms arranged as bridging bicyclic groups selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. These rings may be saturated and may have at least one double bond (i.e., partially unsaturated), but are not fully conjugated and are not aromatic rings as defined herein.

[0047] In this specification, the term "aryl" refers to a group selected from five- or six-membered carbocyclic aromatic rings (e.g., phenyl); bicyclic systems (e.g., 7- to 12-membered bicyclic systems) in which at least one ring is carbocyclic aromatic (e.g., bicyclic systems selected from naphthalene, indane, and 1,2,3,4-tetrahydroquinoline); and tricyclic systems (e.g., 10- to 15-membered tricyclic systems) in which at least one ring is carbocyclic aromatic (e.g., fluorene).

[0048] For example, the aryl group is selected from a 5- to 7-membered cycloalkyl ring which may contain at least one heteroatom selected from N, O, and S, or a 5- or 6-membered carbocyclic aromatic ring fused with a heterocycle. When the carbocyclic aromatic ring is fused with a heterocycle, the bond site is on the carbocyclic aromatic ring, and when the carbocyclic aromatic ring is fused with a cycloalkyl group, the bond site may be on the carbocyclic aromatic ring or on the cycloalkyl group. A divalent radical formed from a substituted benzene derivative and having a free valence on the ring atom is called a substituted phenylene radical. In monovalent polycyclic hydrocarbon radicals whose names end in "yl", a divalent radical derived by removing one hydrogen atom from a carbon atom with a free valence is named by adding "idene" to the name of the corresponding monovalent radical. For example, a naphthyl group with two bond sites is called naphthylidene.

[0049] The term "halogen" refers to F, Cl, Br, or I.

[0050] The term "heteroalkyl" refers to an alkyl group that contains at least one heteroatom.

[0051] The term "heteroaryl" refers to a group selected from the following:

[0052] A 5-7 member aromatic monocyclic group comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon;

[0053] A bicyclic group comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, wherein the remaining ring atoms are carbon, and at least one ring is an aromatic ring, and at least one heteroatom is present in the aromatic ring; and,

[0054] A tricyclic group comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, wherein the remaining ring atoms are carbon, and at least one ring is an aromatic ring, and at least one heteroatom is present in the aromatic ring.

[0055] For example, a heteroaryl group includes a 5-7 membered heterocyclic aromatic ring fused with a 5-7 membered cycloalkyl ring. In such a fused bicyclic heteroaryl ring system, where only one ring contains at least one heteroatom, the bond site may be located on the heterocyclic aromatic ring or on the cycloalkyl ring.

[0056] In a heteroaryl group, if the total number of S atoms and O atoms exceeds 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S atoms and O atoms in a heteroaryl group is 2 or less. In some embodiments, the total number of S atoms and O atoms in an aromatic heterocycle is 1 or less.

[0057] Examples of heteroaryl groups include (numbered with the bond position as position 1) pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), synnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, thienyl, triazinyl, benzothienyl, furyl, benzofuryl, benzimidazolyl, indolyl, isoindolyl, indolinyl, phthalazinyl, pyrazinyl, pyridadinyl, pyrrolyl, triazolyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridinyl-5-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridyl Examples include, but are not limited to, benzo[d]thiazole-6-yl, benzoxazolyl (e.g., benzo[d]thiazole-6-yl), pteridinyl, prinyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, flazanil, benzoflazanil, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinil, quinoxalinil, naphthilidinil, phlopyridinil, benzothiazolyl (e.g., benzo[d]thiazole-6-yl), indazolyl (e.g., 1H-indazol-5-yl), and 5,6,7,8-tetrahydroisoquinoline.

[0058] The terms "heterocyclic," "heterocyclic," or "heterocyclyl" refer to a ring selected from 4- to 12 membered monocyclic, bicyclic, or tricyclic saturated or partially unsaturated rings, containing at least one carbon atom in addition to one, two, three, or four heteroatoms selected from oxygen, sulfur, and nitrogen. Furthermore, "heterocyclic" also refers to a group formed by the condensation of a 5- to 7 membered heterocyclic ring containing at least one heteroatom selected from N, O, and S with a 5-, 6-, and / or 7-membered cycloalkyl ring, carbocyclic aromatic ring, or heterocyclic aromatic ring, where the bond site is on the heterocyclic ring when the heterocyclic ring is condensed with a carbocyclic aromatic ring or heterocyclic aromatic ring, and where the bond site may be on the cycloalkyl ring or on the heterocyclic ring when the heterocyclic ring is condensed with a cycloalkyl ring.

[0059] Furthermore, “heterocycle” also refers to an aliphatic spirocycle containing at least one heteroatom selected from N, O, and S, in which case the bond site is located on the heterocycle. These rings may be saturated or may have at least one double bond (i.e., they may be partially unsaturated). The heterocycle may be substituted with an oxo. The bond site may be on the carbon of the heterocycle or on the heteroatom of the heterocycle. The heterocycle is not a heteroaryl as defined herein.

[0060] Examples of heterocycles include (numbered with bond position as position 1): 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranyl, 2-morpholinyl, 3-morpholinyl, oxylanyl, azilidinyl, thyranyl, azetidinyl, oxetanyl , thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanil, piperazinyl, homopiperazinyl, homopiperidinyl, azepanil, oxepanil, thiepanil, 1,4-oxathianil, 1,4-dioxepanil, 1,4-oxathiepanil, 1,4-oxazepanil, 1,4-dithiepanil, 1,4- Thiazepanyl, 1,4-diazepane, 1,4-dithianyl, 1,4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl Examples of substituted heterocycles include, but are not limited to, lanyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinol, 1,1-dioxo-thiomorpholinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, and azabicyclo[2.2.2]hexanyl. Substitutive heterocycles also include ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1,1-dioxo-1-thiomorpholinyl.

[0061] In this specification, the term "condensed ring" refers to a polycyclic system (e.g., a bicyclic or tricyclic system) in which two rings share only two ring atoms and one bond. Examples of condensed rings include condensed bicyclic cycloalkyl rings, such as groups in which 7 to 12 ring atoms are arranged as bicyclic groups selected from the aforementioned [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems; condensed bicyclic aryl rings, such as the aforementioned 7 to 12-membered bicyclic aryl ring systems; condensed tricyclic aryl rings, such as the aforementioned 10 to 15-membered tricyclic aryl ring systems; condensed bicyclic heteroaryl rings, such as the aforementioned 8 to 12-membered bicyclic heteroaryl rings; condensed tricyclic heteroaryl rings, such as the aforementioned 11 to 14-membered tricyclic heteroaryl rings; and the aforementioned condensed bicyclic heterocyclyl rings and condensed tricyclic heterocyclyl rings.

[0062] In embodiments, substituents are selected from optionally substituted heteroatoms and optionally substituted, heteroatom-containing, and cyclic C1-C18 hydrocarbyls. In particular, optionally substituted, heteroatom-containing, and cyclic C1-C18 hydrocarbyls are optionally substituted, heteroatom-containing, and cyclic alkyl, alkenyl, or alkynyl, or optionally substituted, heteroatom-containing, and / or substituted heteroatoms are halogens, optionally substituted hydroxyls (alkoxy, aryloxy, etc.), optionally substituted acyls (formyl, alkanoyl, carbamoyl, carboxyl, amide, etc.), optionally substituted aminos (amino, alkylamino, dialkylamino, amide, sulfamidyl, etc.), optionally substituted thiols (mercapto, alkylthiol, arylthiol, etc.), optionally substituted sulfinyl or sulfonyls (alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, etc.), nitro, or cyano.

[0063] In embodiments, substituents include halogen, -R', -OR', =O, =NR', =N-OR', -NR'R'', -SR', -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR'-SO2NR''', -NR''CO2R', -NH-C( The groups are selected from NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -SO2R', -SO2NR'R'', -NR''SO2R, -CN, -NO2, -N3, -CH(Ph)2, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, with 0 to 3 substituents, and groups having 0, 1 or 2 substituents are particularly preferred. R', R'' and R''' each independently refer to hydrogen, an unsubstituted (C1-C8)alkyl or heteroalkyl, a (C1-C8)alkyl or heteroalkyl substituted with 1 to 3 halogens, an unsubstituted aryl, an aryl substituted with 1 to 3 halogens, an unsubstituted alkyl group, an unsubstituted alkoxy group, an unsubstituted thioalkoxy group, or an aryl-(C1-C4)alkyl group. If R' and R'' are bonded to the same nitrogen atom, R' and R'' can join this nitrogen atom to form a five-membered, six-membered, or seven-membered ring. Thus, -NR'R'' includes 1-pyrrolidinyl and 4-morpholinyl, and "alkyl" includes a group such as a trihaloalkyl (e.g., CF3 and -CH2CF3), and if the aryl group is 1,2,3,4-tetrahydronaphthalene, this aryl group may be substituted with a substituted or unsubstituted (C3-C7) spirocycloalkyl group. This (C3-C7) spirocycloalkyl group may be substituted in the same manner as defined herein for "cycloalkyl".

[0064] Preferred substituents are selected from halogens, -R', -OR', =O, -NR'R'', -SR', -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR''CO2R', -NR'-SO2NR''R''', -S(O)R', -SO2R', -SO2NR'R'', -NR''SO2R, -CN, -NO2, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl (where R' and R'' are as defined above).

[0065] Preferred substituents are disclosed herein, with specific examples described in the table, structure, examples and claims, and may be applied to various different compounds of the present invention, i.e., substituents of a given compound may be used in combination with other compounds.

[0066] In certain embodiments, the applicable substituents are, independently, a substituted or unsubstituted heteroatom, a substituted or unsubstituted C1-C6 alkyl having 0-3 heteroatoms, a substituted or unsubstituted C2-C6 alkenyl having 0-3 heteroatoms, a substituted or unsubstituted C2-C6 alkynyl having 0-3 heteroatoms, or a substituted or unsubstituted C6-C14 aryl having 0-3 heteroatoms, where each heteroatom is independently oxygen, phosphorus, sulfur, or nitrogen.

[0067] In particular embodiments, the applicable substituents are, independently, aldehydes, aldimines, alkanoyloxys, alkoxys, alkoxycarbonyls, alkyloxys, alkyls, amines, azos, halogens, carbamoyls, carbonyls, carboxamides, carboxyls, cyanyls, esters, halos, halos, haloformyls, hydroperoxyls, hydroxyls, imines, isocyanides, isocyanates, N-tert-butoxycarbonyls, nitrates, nitriles, nitrites, nitrosos, phosphates, phosphonos, sulfides, sulfonyls, sulfo, sulfhydryls, thiols, thiocyanyls, trifluoromethyls, or trifluoromethyl ethers (OCF3).

[0068] The compounds of the present invention may have chiral centers and therefore may exist as enantiomers. If the compounds of the present invention have two or more chiral centers, they may also exist as diastereomers. Enantiomers and diastereomers are included in the broader definition of stereoisomers. It is intended that all possible stereoisomers, such as substantially purely divided enantiomers, their racemic mixtures, and mixtures of diastereomers, are included in the present invention. It is also intended that all stereoisomers and / or pharmaceutically acceptable salts of the compounds of the present invention are included in the present invention. Unless otherwise specified herein, a reference to one isomer shall also apply to all possible isomers. If the isomer composition is not specified, it shall include all possible isomers.

[0069] The term "substantially pure" means that the stereoisomer of interest contains no more than 35% by weight, for example, no more than 30% by weight, and further, for example, no more than 25% by weight, and further, for example, no more than 20% by weight, of other stereoisomers. In some embodiments, the term "substantially pure" means that the stereoisomer of interest contains no more than 10% by weight, for example, no more than 5% by weight, and further, for example, no more than 1% by weight, of other stereoisomers.

[0070] Unless otherwise specified herein, when a compound of the present invention has an olefinic double bond, such double bond means that it includes both E and Z geometric isomers.

[0071] Some of the compounds of the present invention may have different hydrogen bond sites, and such compounds are called tautomers. For example, a compound having a carbonyl group (-CH2C(O)-) (keto form) may form a hydroxyl group (-CH=C(OH)-) (enol form) through tautomerism. Where applicable, this includes either the keto form or the enol form individually, and mixtures of the keto form and the enol form.

[0072] It may be advantageous to separate reaction products from each other and / or from the starting materials. The desired products obtained in each step or series of steps are separated and / or purified (hereinafter referred to as "separation") by techniques common in the art until the desired degree of homogeneity is obtained. Typically, such separations include multiphase extraction, crystallization from a single solvent or mixed solvent, distillation, sublimation, or chromatography. Chromatography can include any number of methods, such as reversed-phase chromatography and normal-phase chromatography; size exclusion chromatography; ion exchange chromatography; liquid chromatography and chromatographic apparatus at high, medium, and low pressures; small-volume analytical chromatography; pseudo-moving-bed ("SMB") chromatography, preparative thin-layer chromatography, preparative thick-layer chromatography; and small-volume thin-layer chromatography techniques and flash chromatography techniques. Those skilled in the art will be able to apply the techniques that are most likely to achieve the desired separation.

[0073] A diastereomer mixture can be separated into individual diastereomers based on physicochemical differences by methods known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomer mixtures can be converted into diastereomer mixtures by reacting them with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or moscherate), separated, and then the enantiomers can be separated by converting each resulting diastereomer back into its corresponding pure enantiomer (e.g., by hydrolysis). Enantiomers can also be separated using a chiral HPLC column.

[0074] A single stereoisomer (e.g., a substantially pure enantiomer) may be obtained by splitting the racemic mixture, for example, by forming a diastereomer using an optically active resolving agent. The racemic mixture of the chiral compounds of the present invention can be separated and isolated by appropriate methods, such as (1) forming an ionic diastereomer salt using the chiral compound and separating it by methods such as fractional crystallization; (2) forming a diastereomer compound using a chiral derivatization reagent, separating the diastereomer and converting it to a pure stereoisomer; and (3) directly separating a substantially pure or enriched stereoisomer under chiral conditions.

[0075] "Pharmacologically acceptable salts" include, for example, inorganic salts selected from hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate, etc., and, for example, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, alkanate (such as acetate), HOOC-(CH2) nExamples of pharmaceutically acceptable cations include, but are not limited to, organic acid salts selected from salts with -COOH (where n is selected from 0 to 4). Similarly, examples of pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0076] Furthermore, if the compound is obtained as an acid addition salt, the free base can be obtained by making the solution of this acid addition salt basic. Conversely, if the product is a free base, the addition salt (such as a pharmaceutically acceptable addition salt) may be prepared by dissolving the free base in a suitable organic solvent and treating the resulting solution with acid, following conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will be able to prepare pharmaceutically acceptable and non-toxic addition salts by appropriately recognizing the various available synthesis methods without excessive experimentation.

[0077] "To treat," "to treat," or "treatment" means administering at least one compound, and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof, to a subject for whom such administration is deemed necessary.

[0078] The "effective dose" refers to the amount of at least one compound, and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof, that is effective in "treating" a disease or disorder in a subject and, for example when administered, induces a desired biological or medical response to a reasonably significant extent in a tissue, system, animal, or human, and prevents the progression of one or more symptoms of the condition or disorder being treated, or alleviates those symptoms to some extent. The therapeutic effective dose varies depending on the compound, the disease and its severity, and the age and weight of the mammal being treated.

[0079] The term "at least one substituent" includes, for example, 1 to 4 substituents, for example, 1 to 3 substituents, and further, for example, 1 or 2 substituents. For example, in this specification, "at least one substituent R16 " is R as described in this specification 16 It includes 1 to 4 substituents selected from the list, for example, 1 to 3 substituents, and further, for example, 1 or 2 substituents.

[0080] The compounds of the present invention, their stereoisomers, and their pharmaceutically acceptable salts may be used alone for treatment or in combination with at least one other therapeutic agent. In some embodiments, the compounds of the present invention, their stereoisomers, and their pharmaceutically acceptable salts may be used in combination with at least one further therapeutic agent. The compounds and / or one pharmaceutically acceptable salt disclosed herein may be administered together with at least one other therapeutic agent as a single unit dosage form, or as separate dosage forms. When administered as separate dosage forms, at least one other therapeutic agent may be administered before, simultaneously with, or after the administration of the compounds and / or one pharmaceutically acceptable salt disclosed herein.

[0081] Furthermore, the present invention provides a composition comprising the compound of the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0082] Compositions comprising the compounds of the present invention, their stereoisomers, or pharmaceutically acceptable salts thereof can be administered by a variety of known methods, including oral administration, topical administration, rectal administration, parenteral administration, administration by inhalation spray, and administration from an implanted reservoir, in which case the most appropriate route depends on the characteristics and severity of the disease in which the active ingredient is administered. In this specification, the term "parenteral" includes injection or infusion subcutaneously, intradermally, intravenously, intramuscularly, intra-articularly, intra-arterially, intra-bursally, intrasternally, intrathecally, intrafocally, and intracranially. The compositions disclosed herein may be provided in convenient unit dosage forms or prepared by any method well known in the art.

[0083] The compounds of the present invention, their stereoisomers, and their pharmaceutically acceptable salts can be administered orally in solid dosage forms such as capsules, tablets, lozenges, sugar-coated tablets, granules, and powders, or in liquid dosage forms such as elixirs, syrups, emulsions, dispersants, and suspensions. The compounds of the present invention disclosed herein, their stereoisomers, and their pharmaceutically acceptable salts can also be administered parenterally in sterile liquid dosage forms such as dispersants, suspensions, and solutions. The compounds of the present invention disclosed herein, their stereoisomers, and their pharmaceutically acceptable salts can also be administered using other dosage forms, including ointments, creams, intravenous infusions, transdermal patches, or powders for topical administration; ophthalmic solutions or ophthalmic suspensions (i.e., eye drops) for ophthalmic administration; aerosol sprays or powder compositions for inhalation or intranasal administration; and creams, ointments, sprays, or suppositories for rectal or vaginal administration.

[0084] Gelatin capsules may also be used, comprising the compounds disclosed herein and / or at least one pharmaceutically acceptable salt thereof, and a powder carrier such as lactose, starch, cellulose derivatives, magnesium stearate, or stearic acid. Compressed tablets may also be manufactured using similar diluents. Tablets and capsules may also be manufactured as sustained-release formulations for continuous release of the drug over a period of time. Compressed tablets may be coated with sugars or films to mask unpleasant tastes or protect the tablets from the air, or they may be selectively disintegrated in the gastrointestinal tract by enteric coating.

[0085] Liquid dosage forms for oral administration may further contain at least one agent selected from colorants and fragrances to facilitate patient administration.

[0086] Generally, suitable carriers for parenteral solutions include water, suitable oils, physiological saline, aqueous dextrose (glucose) solutions, related sugar solutions, and glycols (such as propylene glycol or polyethylene glycol). The parenteral solution may contain a water-soluble salt of at least one compound described herein, at least one suitable stabilizer, and, if necessary, at least one buffer. Examples of suitable stabilizers include antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid, which can be used alone or in combination. Citric acid and its salts, and sodium EDTA can also be used as examples of suitable stabilizers. Furthermore, the parenteral solution may contain at least one preservative selected from, for example, benzalkonium chloride, methylparaben, propylparaben, and chlorobutanol.

[0087] A pharmaceutically acceptable carrier is selected from carriers that are compatible with the active ingredient in the composition (and in some embodiments, can stabilize the active ingredient) and are not harmful to the patient receiving treatment. For example, solubilizers such as cyclodextrins (cyclodextrins can form certain highly soluble complexes with at least one of the compounds and / or at least one pharmaceutically acceptable salt disclosed herein) can be used as pharmaceutical excipients for the delivery of the active ingredient. Other examples of carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments (such as D&C Yellow #10). Suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference in the art.

[0088] When administered by inhalation, the compounds of the present invention, their stereoisomers, and pharmaceutically acceptable salts thereof may be conveniently delivered in the form of an aerosol spray from a pressurized container or inhaler. Alternatively, the compounds of the present invention, their stereoisomers, and pharmaceutically acceptable salts thereof may be delivered in powder form as a formulation, and such powder composition may be inhaled using a blown powder inhaler. An example of an inhalation delivery system is a metered-dose inhalation (MDI) aerosol, which may be formulated as a suspension or liquid containing the compounds of the present invention disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof in at least one suitable propellant selected from, for example, fluorocarbons and hydrocarbons.

[0089] When administered orally, the ophthalmic formulation may be prepared as a suspension or solution containing the compound of the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof in a suitable weight percent in a suitable ophthalmic solvent, thereby maintaining contact between the compound of the present invention, its stereoisomer, or at least one pharmaceutically acceptable salt thereof and the surface of the eye for a sufficient period of time, allowing the compound to penetrate the cornea and the interior of the eye.

[0090] Pharmaceutical dosage forms useful for administering the compounds of the present invention disclosed herein, their stereoisomers, and pharmaceutically acceptable salts thereof include, but are not limited to, hard gelatin capsules, soft gelatin capsules, tablets, parenteral injections, and oral suspensions.

[0091] The dosage depends on factors such as the recipient's age, health status and weight, the severity of the disease, the type of treatment currently being administered (if any), the frequency of treatment, and the characteristics of the desired effect. Generally, the daily dose of the active ingredient may vary, but may range from 0.1 to 2000 mg per day, for example. For instance, administering 10 to 500 mg once or multiple times a day may be effective in achieving the desired result.

[0092] In some embodiments, for example, a large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules with 100 mg of the powdered compounds of the present invention disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof, 150 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate.

[0093] In some embodiments, a mixture of the compound of the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof, with a digestible oil such as soybean oil, cottonseed oil, or olive oil can be prepared, and the mixture can be injected into gelatin using a volumetric pump to prepare soft gelatin capsules containing 100 mg of the active ingredient. These capsules are then washed and dried.

[0094] In some embodiments, for example, large quantities of tablets can be prepared by conventional methods so that a single dose contains, for example, 100 mg of the compound of the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg of lactose. Appropriate coatings may be applied to improve taste or slow absorption.

[0095] In some embodiments, parenteral compositions suitable for administration by injection can be prepared by stirring 1.5% by weight of the compounds disclosed herein and / or at least one of their enantiomers, diastereomers, or pharmaceutically acceptable salts in 10% by volume propylene glycol. This solution is then diluted to the desired volume with sterile water for injection and sterilized.

[0096] In some embodiments, aqueous suspensions for oral administration can be prepared. For example, 5 ml each of aqueous suspensions can be used, each containing 100 mg of the finely powdered compound of the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof, 100 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution (United States Pharmacopeia), and 0.025 ml of vanillin.

[0097] When the compounds of the present invention, their stereoisomers, or pharmaceutically acceptable salts thereof are administered stepwise or together with at least one other therapeutic agent, the same dosage form can usually be used. When drugs are administered in physical combination, the dosage form and route of administration should be selected according to the compatibility of the drugs being combined. Therefore, the term "simultaneous administration" is understood to include the simultaneous or sequential administration of at least two drugs, or the administration of a combination of fixed doses of at least two active ingredients.

[0098] The compounds disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof may be administered as a single active ingredient or in combination with at least one second active ingredient.

[0099] The compounds of the present invention are incorporated into pharmaceutical compositions or pharmaceutical formulations. These compositions include pharmaceutically acceptable diluents and / or carriers, i.e., diluents or carriers that are physiologically compatible and substantially free of pathogenic impurities. Suitable excipients or carriers and methods for preparing administerable compositions are known or obvious to those skilled in the art and are described in further detail in publications such as Remington's Pharmaceutical Science, Mack Publishing Co, NJ (1991). These compositions may also be in the form of controlled-release or sustained-release compositions known in the art. In many applications, the compounds of the present invention are administered in the morning / daytime with a rest period at night.

[0100] The compounds of the present invention may be used as is, or in the form of pharmaceutically acceptable salts such as hydrochloride, hydrobromide, acetate, sulfate, citrate, carbonate, and trifluoroacetate. If the compounds of the present invention have relatively acidic functional groups, salts can be obtained by adding a desired base in a solvent-free environment or a suitable inert solvent. Examples of pharmaceutically acceptable base-added salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, and magnesium salts. If the compounds of the present invention have relatively basic functional groups, salts can be obtained by adding a desired acid in a solvent-free environment or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, and phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. This also includes amino acid salts such as arginates, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0101] A neutral compound may be regenerated by contacting the salt with a base or acid using conventional methods and isolating the parent compound. The parent compound differs from the various salt forms in terms of physical properties such as solubility in polar solvents, but in other respects, the salt is equivalent to the parent compound for the purposes of the present invention.

[0102] The present invention provides compounds in the form of prodrugs in addition to salts. Prodrugs of the compounds described herein are compounds that readily undergo chemical transformation under physiological conditions to provide the compounds of the present invention. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be gradually converted to the compounds of the present invention when encapsulated in a transdermal patch reservoir with appropriate enzymes or chemical reagents. In some circumstances, prodrugs are often useful because they are easier to administer than the parent drug. For example, prodrugs may have better bioavailability by oral administration than the parent drug. Also, prodrugs may have improved solubility in pharmacological compositions than the parent drug. Various prodrug derivatives are known in the art, for example, prodrugs utilizing hydrolysis or oxidative activation. Examples of prodrugs include, but are not limited to, the compounds of the present invention that are administered as esters ("prodrugs") and metabolically hydrolyzed to the active carboxylic acid.

[0103] Certain compounds of the present invention may exist in an unsolvated form or in a solvated form, including a hydrated form. In general, the solvated form is equivalent to the unsolvated form and is intended to be within the scope of the present invention. Certain compounds of the present invention may exist in various crystalline forms or in an amorphous form. In general, all physical forms are equivalent for the applications envisioned in the present invention and are intended to be within the scope of the present invention.

[0104] Some of the compounds of the present invention have an asymmetric carbon atom (optical center) or a double bond, and their racemates, diastereomers, geometric isomers, and individual isomers are all intended to fall within the scope of the present invention.

[0105] The compounds of the present invention may contain one or more isotopic atoms such as deuterium in proportions not found in nature, and may contain, for example, -CD3, CD2H, or CDH2 instead of methyl. For example, the compounds of the present invention may contain, for example, tritium ( 3 H), Iodine-125 ( 125 I), carbon-14 ( 14 The compounds may be radioactively labeled with radioactive isotopes such as C). All compounds of the present invention containing isotopes, whether radioactive or non-radioactive, are intended to be included within the scope of the present invention.

[0106] The compounds of the present invention are typically administered in a “therapeutic dose,” that is, an amount of the compound that would induce a biological or medical response in a tissue, system, animal, or human, as desired by the researcher, veterinarian, physician, or other clinician. The term “therapeutic dose” encompasses an amount of the compound sufficient, when administered, to prevent the progression of one or more symptoms of the condition or disorder being treated, or to alleviate these symptoms to some extent. The therapeutic dose varies depending on the compound, the disease and its severity, and the age and weight of the mammal being treated.

[0107] The aforementioned contact is typically achieved by administering an effective amount of one or more compounds having general formula I (see above) to the target, and encompasses the various embodiments described above. Generally, the administration is adjusted to a therapeutic dose of about 0.1 to 50 mg / kg, preferably 0.5 to 10 mg / kg, more preferably 1 to 10 mg / kg, but the optimal dose is compound-specific and is generally determined empirically for each compound.

[0108] The term "unit dosage form" refers to a physically divided unit appropriate as a unit dose for human subjects and other mammals, each unit comprising a predetermined amount of the active substance calculated to produce the desired therapeutic effect, along with appropriate pharmaceutical excipients. Typical unit dosage forms include ampoules or syringes filled with pre-measured liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, lozenges, etc. In such compositions, the mimetic is usually included as a trace component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder consisting of processing aids to facilitate the formation of the desired dosage form and various solvents or carriers. Unit dosage form formulations are preferably about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 250 mg, about 500 mg, or about 1,000 mg per unit. In one particular embodiment, the unit dosage form is packaged in a multi-pack suitable for continuous use, for example, in a blister pack containing a sheet with at least 6, 9, or 12 unit dosage forms.

[0109] The compositions of the present invention may be formulated with and / or co-administered with different compounds to treat applicable indications, to inhibit ferroptotic activity, or to modulate or inhibit diseases associated with ferroptotic dysregulation, such as neuropathy, ischemia-reperfusion injury, acute renal failure, and cancer. In embodiments, applicable indications include cancer, neuropathy and neurodegenerative diseases of the central or peripheral nervous system, muscular dystrophy, ischemia and ischemia-reperfusion injury, kidney disease and failure, degenerative arthritis, retinal necrosis, heart disease, hepatic, gastrointestinal or pancreatic disease, vascular necrosis, diabetes mellitus, cancer chemotherapy / radiotherapy-induced cell death, and poisoning.

[0110] Table 1: Active compounds: Structure [Table 1-1] [Table 1-2] [Table 1-3] Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16

[0111] Table 2: Active Compounds: Structure Table 2-1 Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 2-20 [Table 2-21]

[0112] The active compound has been shown to inhibit ferroptosis.

[0113] Table 3: Bioactivity (RSL3-induced HT-1080 cell ferroptosis assay (10% FBS)): [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0114] Table 4: Bioactivity (RSL3-induced HT-1080 cell ferroptosis assay (10% FBS)): [Table 4-1] [Table 4-2] [Table 4-3]

[0115] Active Compounds Group I: Representative Synthesis

[0116] N-(4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)-N-hydroxy-1-(trifluoromethyl)cyclobutan-1-carboxamide (1) JPEG2026063193000046.jpg116151

[0117] Step 1. 4-(tert-butyl)-3-fluoroaniline (2.17 g, 13 mmol), 4-bromobenzaldehyde (1.85 g, 10 mmol), Pd(dppf)2Cl2 (147 mg, 0.2 mmol), xanthophos (231 mg, 0.4 mmol), and Cs2CO3 (4.89 g, 15 mmol) were dissolved in toluene under a nitrogen atmosphere and stirred overnight at 100°C. After the reaction was complete, the reaction product was cooled to room temperature, diluted with DCM, passed through a silica plug, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=5 / 1) to obtain the desired product as a yellow solid (1.8 g, 66%). Mass (m / z): 272.3 [M+H] + .

[0118] Step 2.

[0119] Hydroxylamine hydrochloride (261 mg, 3.8 mmol) was added to a solution of 4-((4-(tert-butyl)-3-fluorophenyl)amino)benzaldehyde (928 mg, 3.4 mmol) in THF / H2O / EtOH (2 / 1 / 5, 40 mL). The reaction mixture was then stirred overnight at room temperature. The reaction mixture was concentrated under vacuum. The crude product was used directly in the next step. (100%). Mass (m / z): 287.2 [M+H] + .

[0120] Step 3.

[0121] A solution of (Z)-4-((4-(tert-butyl)-3-fluorophenyl)amino)benzaldehyde oxime (972 mg, 3.4 mmol) in EtOH (40 mL) was added with borane-pyridine (632 mg, 6.8 mmol). Then 10% HCl (6.8 mL) was added dropwise at 0 °C. The solution was stirred at room temperature for 3 h. The pH of the solution was adjusted to 8 - 9 with sodium carbonate solution. Then the mixture was extracted with DCM (15 mL x 3). The combined organic layers were washed with water (20 mL x 3), dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography (MeOH / DCM = 1 / 40) to give the desired product as a yellow solid (242 mg, 25%). Mass (m / z): 289.3 [M+H] + .

[0122] Step 4.

[0123] 1-(Trifluoromethyl)cyclobutane-1-carboxylic acid (25.2 mg, 0.15 mmol) was dissolved in DCM (1 mL). The solution was cooled to 0 °C and then oxalyl chloride (0.0165 mL, 0.195 mmol) and DMF (0.05 mL) were added. The reaction mixture was stirred for 2 h, concentrated under reduced pressure and redissolved in anhydrous CH2Cl2. The solution was used as such in the next step.

[0124] Step 5.

[0125] 4-(tert-butyl)-3-fluoro-N-(4-((hydroxyamino)methyl)phenyl)aniline (20 mg, 0.07 mmol) was dissolved in 1.0 ml of THF / H2O (1:1, v / v) and 1.2 ml of saturated NaHCO3 aqueous solution. The solution was cooled to 0°C, 1-(trifluoromethyl)cyclobutane-1-carbonyl chloride was added, and the mixture was stirred at room temperature for 16 hours. The mixture was extracted with ethyl acetate, the bound organic layer was washed with brine, dried over (Na2SO4), and concentrated under vacuum to obtain the crude product. The residue was purified by prep-TLC (MeOH / DCM = 1 / 10) to obtain the desired product as a white solid (13.9 mg, 45.9%). 1 H NMR (400 MHz, Chloroform-d) δ 7.23 - 7.13 (m, 3H), 7.05 (d, J = 8.0 Hz, 2H), 6.81 - 6.70 (m, 2H), 4.76 (s, 2H), 2.79-2.70 (m, 2H), 2.51 (br m, 2H), 1.36 (m, 9H), 1.30 - 1.22 (m, 2H). Mass(m / z): 439.2 [M+H] + .

[0126] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxyadamantane-1-carboxamide (2) JPEG2026063193000047.jpg80130

[0127] 1 H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 7.02 (t, J = 8.1 Hz, 4H), 4.88 (s, 2H), 2.04 (s, 9H), 1.70 (s, 6H), 1.31 (s, 9H).LC-MS (ESI) m / z: 433.2, [M+H] + .

[0128] N-hydroxy-N-(4-(pyridine-4-ylamino)benzyl)adamantan-1-carboxamide (3) JPEG2026063193000048.jpg72116

[0129] 1 H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 7.9 Hz, 2H), 7.00 (m, 6H), 4.86 (s, 2H), 2.04 (s, 9H), 1.71 (m, 6H). LC-MS (ESI) m / z: 378.2, [M+H] + .

[0130] N-(4-((4-fluorophenyl)amino)benzyl)-N-hydroxyadamantane-1-carboxamide (4) JPEG2026063193000049.jpg73115

[0131] 1 H NMR (400 MHz, CDCl3) δ 7.13 (d, J = 7.8 Hz, 2H), 7.06-6.88 (m, 6H), 4.84 (s, 2H), 2.02 (s, 9H), 1.73 (m, 6H). LC-MS (ESI) m / z: 395.3, [M+H] + .

[0132] N-(4-((4-(N,N-diethylsulfamoyl)phenyl)amino)benzyl)-N-hydroxyadamantane-1-carboxamide (5) JPEG2026063193000050.jpg77138

[0133] 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.8 Hz, 2H), 7.27-7.22 (m, 2H), 7.14 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 4.93 (s, 2H), 3.21 (q, J = 7.2 Hz, 4H), 2.05 (s, 9H), 1.73 (s, 6H), 1.30-1.22 (m, 6H). LC-MS (ESI) m / z: 512.3, [M+H] + .

[0134] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxypivalamide (6) JPEG2026063193000051.jpg68129

[0135] 1 H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 7.04 (t, J = 8.1 Hz, 4H), 4.83 (s, 2H), 1.38 (s, 9H), 1.25 (s, 9H). LC-MS (ESI) m / z: 355.3, [M+H] + .

[0136] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxycyclopropanecarboxamide (7) JPEG2026063193000052.jpg70119

[0137] 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.3 Hz, 2H), 7.19 (d, J = 8.1 Hz, 2H), 7.02 (dd, J = 11.8, 8.4 Hz, 4H), 4.83 (s, 2H), 1.89-1.64 (m, 1H), 1.32 (s, 6H), 1.02 (m, 2H), 0.98-0.78 (m, 2H). LC-MS (ESI) m / z: 339.3, [M+H] + .

[0138] N-hydroxy-N-(4-((4-(trifluoromethyl)phenyl)amino)benzyl)adamantan-1-carboxamide (8) JPEG2026063193000053.jpg78127

[0139] 1 H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 7.12 (d, J = 8.2 Hz, 2H), 7.04 (d, J = 8.2 Hz, 2H), 4.91 (s, 2H), 2.05 (s, 9H), 1.70 (s, 6H). LC-MS (ESI) m / z: 445.3, [M+H] + .

[0140] N-hydroxy-N-(4-(pyridine-4-ylamino)benzyl)pivalamide (9) JPEG2026063193000054.jpg65121

[0141] 1 H NMR (400 MHz, CDCl3) δ 8.28-8.21 (m, 2H), 7.34 (d, J = 6.9 Hz, 2H), 7.17 (dd, J = 8.4, 1.6 Hz, 2H), 6.86-6.78 (m, 2H), 4.10 (s, 2H), 1.18 (s, 9H). LC-MS (ESI) m / z: 300.3, [M+H]+ .

[0142] N-(4-((4-fluorophenyl)amino)benzyl)-N-hydroxypivalamide (10) JPEG2026063193000055.jpg66136

[0143] 1 H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 5.8 Hz, 2H), 6.97 (m, 6H), 4.79 (s, 2H), 1.30 (s, 9H). LC-MS (ESI) m / z: 317.3, [M+H] + .

[0144] N-(4-((4-(N,N-diethylsulfamoyl)phenyl)amino)benzyl)-N-hydroxypivalamide (11) JPEG2026063193000056.jpg62151

[0145] 1 H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 7.8 Hz, 2H), 7.06 (d, J= 7.6 Hz, 2H), 6.95 (d, J = 7.8 Hz, 2H), 4.76 (s, 2H), 3.24-3.10 (m, 4H), 1.29 (s, 9H), 1.10 (t, J = 7.1 Hz, 6H). LC-MS (ESI) m / z: 434.3, [M+H] + .

[0146] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxyacetamide (12) JPEG2026063193000057.jpg68135

[0147] 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.2 Hz, 2H), 7.22-7.13 (m, 2H), 7.03 (m, 4H), 4.73 (s, 2H), 2.18 (s, 3H), 1.31 (s, 9H). LC-MS (ESI) m / z: 313.2. [M+H] + .

[0148] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2,2-dimethylbutanamide (13) JPEG2026063193000058.jpg62151

[0149] 1 H NMR (400 MHz, CDCl3) δ 7.33-7.28 (m, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.07-6.99 (m, 4H), 4.82 (s, 2H), 1.69 (q, J = 7.4 Hz, 2H), 1.31 (s, 9H), 1.27 (s, 6H), 0.86 (t, J= 7.6 Hz, 3H). LC-MS (ESI) m / z: 369.3, [M+H] + .

[0150] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-1-methylcyclopropane-1-carboxamide (14) JPEG2026063193000059.jpg65140

[0151] 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.2 Hz, 2H), 7.19 (d, J = 8.2 Hz, 2H), 7.03 (dd, J= 8.0, 6.2 Hz, 4H), 4.92 (s, 2H), 1.38 (s, 3H), 1.32 (s, 9H), 1.26 (m, 1H), 1.05 (t, J = 5.2 Hz, 2H), 0.68 (d, J = 5.0 Hz, 2H). LC-MS (ESI) m / z: 353.2, [M+H] + .

[0152] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-6-methoxy-2,2-dimethylhexaneamide (15) JPEG2026063193000060.jpg48151

[0153] 1 H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 7.02 (m, 4H), 4.76 (s, 2H), 3.34 (t, J = 6.0 Hz, 2H), 3.07 (s, 3H), 1.76-1.64 (m, 2H), 1.59-1.45 (m, 2H), 1.43-1.33 (m, 2H), 1.31 (s, 9H), 1.27 (s, 6H). LC-MS (ESI) m / z: 427.2, [M+H] + .

[0154] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-2,2,2-trifluoro-N-hydroxyacetamide (16) JPEG2026063193000061.jpg66144

[0155] 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H), 7.05 (d, J= 8.6 Hz, 2H), 7.01 (d, J = 8.6 Hz, 2H), 4.83 (s, 2H), 1.32 (s, 9H). LC-MS (ESI) m / z: 367.3, [M+H] + .

[0156] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxycyclopentanecarboxamide (17) JPEG2026063193000062.jpg66145

[0157] 1 H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.2 Hz, 2H), 7.15 (m, 2H), 7.03 (m, Hz, 4H), 4.78 (s, 2H), 2.90 (m, 1H), 1.83 (m, 6H), 1.58 (m, 2H), 1.32 (s, 9H). LC-MS (ESI) m / z: 367.3, [M+H] + .

[0158] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxybenzamide (18) JPEG2026063193000063.jpg64151

[0159] 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 7.2 Hz, 2H), 7.48 (m, 3H), 7.36-7.29 (m, 2H), 7.12 (d, J= 8.3 Hz, 2H), 7.09- 6.97 (m, 4H), 4.77 (s, 2H), 1.31 (s, 9H). LC-MS (ESI) m / z: 375.2, [M+H] + .

[0160] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-1-(trifluoromethyl)cyclobutane-1-carboxamide (19) JPEG2026063193000064.jpg61151

[0161] 1 H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.03 (m, 4H), 4.74 (s, 2H), 2.75 (dd, J = 22.4, 10.2 Hz, 2H), 2.51 (m, 2H), 2.19-2.01 (m, 1H), 1.86 (m, 1H), 1.31 (s, 9H). LC-MS (ESI) m / z: 421.4, [M+H] + .

[0162] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-methoxy-2-methylpropanamide (20) JPEG2026063193000065.jpg64148

[0163] 1 H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 7.02 (m, 4H), 5.07 (s, 2H), 3.25 (s, 3H), 1.51 (s, 6H), 1.31 (m, 9H). LC-MS (ESI) m / z: 371.4 [M+H] + .

[0164] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-4-methoxy-2,2-dimethylbutanamide (21) JPEG2026063193000066.jpg58151

[0165] 1 H NMR (400 MHz, CDCl3) δ 7.30-7.25 (m, 4H), 7.04-6.97 (m, 4H), 4.67 (s, 2H), 3.43-3.34 (m, 2H), 2.89 (s, 3H), 1.31 (s, 9H), 1.29 (s, 6H), 1.26 (m, 2H).LC-MS (ESI) m / z: 399.3, [M+H] + .

[0166] N-hydroxy-2,2-dimethyl-N-(4-((4-(trifluoromethyl)phenyl)amino)benzyl)butanamide (22) JPEG2026063193000067.jpg61151

[0167] 1 H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 7.8 Hz, 2H), 7.27 (d, J = 7.6 Hz, 2H), 7.12 (d, J= 7.8 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 4.85 (s, 2H), 1.71 (q, J= 7.5 Hz, 2H), 1.28 (s, 6H), 0.87 (t, J = 7.4 Hz, 3H). LC-MS (ESI) m / z: 381.3, [M+H] + .

[0168] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxynicotinamide (23) JPEG2026063193000068.jpg66146

[0169] 1H NMR (400 MHz, CDCl3) δ 8.34 (br s, 1H), 7.96 (d, J = 7.2 Hz, 1H), 7.37-7.18 (m, 6H), 7.00 (dd, J = 15.2, 8.4 Hz, 4H), 4.83 (s, 2H), 1.31 (s, 9H). LC-MS (ESI) m / z: 376.3, [M+H] + .

[0170] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-4-methyltetrahydro-2H-pyran-4-carboxamide (24) JPEG2026063193000069.jpg62151

[0171] 1 H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 7.01 (m, 4H), 4.76 (s, 2H), 3.78-3.65 (m, 2H), 3.60 (t, J = LC-MS (ESI) m / z: 397.2, [M+H] + .

[0172] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-3,3,3-trifluoro-N-hydroxy-2,2-dimethylpropanamide (25) JPEG2026063193000070.jpg59151

[0173] 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H), 7.06 (m, 4H), 4.78 (s, 2H), 1.55 (s, 6H), 1.32 (m, 9H). LC-MS (ESI) m / z: 409.3, [M+H] + .

[0174] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-1-methylcyclohexane-1-carboxamide (26) JPEG2026063193000071.jpg65144

[0175] 1 H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 7.02 (m, 4H), 4.82 (s, 2H), 2.14 (dd, J = 13.4, 5.5 Hz, 2H), 1.59-1.43 (m, 5H), 1.43-1.33 (m, 3H), 1.32 (s, 9H), 1.25 (s, 3H). LC-MS (ESI) m / z: 395.3, [M+H] + .

[0176] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-4,4-difluoro-N-hydroxycyclohexane-1-carboxamide (27) JPEG2026063193000072.jpg58151

[0177] 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.03 (m, 4H), 4.76 (s, 2H), 2.56 (s, 1H), 2.17 (m, 2H), 1.73 (m, 6H), 1.32 (s, 9H). LC-MS (ESI) m / z: 317.3, [M+H] + .

[0178] N-(4-((3-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-methoxy-2-methylpropanamide (28) JPEG2026063193000073.jpg81142

[0179] 1 H NMR (400 MHz, CDCl3) δ 7.25-7.17 (m, 3H), 7.10 (s, 1H), 7.01 (m, 2H), 6.93 (m, 2H), 4.77 (s, 2H), 3.26 (s, 3H), 1.52 (s, 6H), 1.30 (s, 9H). LC-MS (ESI) m / z: 371.3, [M+H] + .

[0180] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-1-(trifluoromethyl)cyclopropane-1-carboxamide (29) JPEG2026063193000074.jpg67151

[0181] 1 H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 7.8 Hz, 2H), 7.16 (d, J = 7.2 Hz, 2H), 7.09 -6.95 (m, 4H), 4.91 (s, 2H), 1.37 (m, 2H), 1.32 (s, 9H), 1.29-1.23 (m, 2H). LC-MS (ESI) m / z: 407.3, [M+H] + .

[0182] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-1-methylpiperidine-4-carboxamide (30) JPEG2026063193000075.jpg60151

[0183] 1 H NMR (400 MHz, DMSO) δ 7.24 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 7.02 -6.92 (m, 4H), 4.58 (s, 2H), 3.55-3.22 (m, 2H), 3.01 (m, 3H), 2.70 (s, 3H), 2.07-1.72 (m, 4H), 1.25 (s, 9H). LC-MS (ESI) m / z: 396.3, [M+H] + .

[0184] 1-Acetyl-N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxypiperidine-4-carboxamide (31) JPEG2026063193000076.jpg58151

[0185] 1 H NMR (400 MHz, DMSO) δ 7.24 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 7.8 Hz, 2H), 7.01 -6.93 (m, 4H), 4.57 (s, 2H), 4.35 (m, 1H), 3.82 (m, 1H), 3.05 (m, 2H), 2.68-2.51 (m, 1H), 2.00 (s, 3H), 1.70 (m, 2H), 1.63-1.30 (m, 2H), 1.23 (s, 9H). LC-MS (ESI) m / z: 424.3, [M+H] + .

[0186] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-(2-methoxyethoxy)acetamide (32) JPEG2026063193000077.jpg54151

[0187] 1 H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H), 7.00 (m, 4H), 4.69 (s, 2H), 4.31 (s, 2H), 3.73-3.60 (m, 2H), 3.59-3.48 (m, 2H), 3.29 (s, 3H), 1.31 (s, 9H). LC-MS (ESI) m / z: 387.2, [M+H] +

[0188] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (33) JPEG2026063193000078.jpg56151

[0189] 1 H NMR (400 MHz, CDCl3) δ 7.26 (m, 6H), 6.99 (m, 4H), 6.63 (s, 1H), 4.81 (s, 2H), 3.41 (s, 3H), 1.31(s, 9H). LC-MS (ESI) m / z: 406.2, [M+H] +

[0190] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-4-(pyrrolidine-1-yl)benzamide (34) JPEG2026063193000079.jpg66151

[0191] 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 7.17 (d, J= 7.8 Hz, 2H), 7.08-6.96 (m, 4H), 6.54 (d, J = 7.7 Hz, 2H), 4.83 (s, 2H), 3.35 (m, 4H), 2.04 (m, 4H), 1.31 (s, 9H). LC-MS (ESI) m / z: 444.2, [M+H] +

[0192] N-(4-((3-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-4-methyltetrahydro-2H-pyran-4-carboxamide (35) JPEG2026063193000080.jpg56151

[0193] 1 H NMR (400 MHz, CDCl3) δ 7.25-7.15 (m, 3H), 7.11 (s, 1H), 7.04 (d, J = 8.2 Hz, 2H), 7.02-6.89 (m, 2H), 4.81 (s, 2H), 3.84-3.71 (m, LC-MS (ESI) m / z: 397.3, [M+H] +

[0194] N-(4-((3-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-1-methylcyclopropane-1-carboxamide (36) JPEG2026063193000081.jpg61151

[0195] 1H NMR (400 MHz, CDCl3) δ 7.22 (m, 3H), 7.11 (s, 1H), 7.03 (m, 2H), 6.94 (d, J = 7.8 Hz, 2H), 4.93 (s, 2H), 1.31 (s, 3H), 1.26 (m, 9H), 1.06 (m, 2H), 0.94-0.84 (m, 2H). LC-MS (ESI) m / z: 353.3, [M+H] +

[0196] N-(4-((3-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-1-(trifluoromethyl)cyclobutan-1-carboxamide (37) JPEG2026063193000082.jpg63142

[0197] 1 H NMR (400 MHz, CDCl3) δ 7.20 (m, 3H), 7.11 (s, 1H), 7.03 (t, J = 6.8 Hz, 2H), 6.94 (m, 2H), 4.75 (s, 2H), 2.75 (m, 2H), 2.52 (m, 2H), 2.17-2.03 (m, 1H), 1.86 (m, 1H), 1.31 (s, 9H). LC-MS (ESI) m / z: 421.3, [M+H] +

[0198] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)pivalamide (38) JPEG2026063193000083.jpg65146

[0199] 1H NMR (400 MHz, CDCl3) δ 7.31-7.28 (d, J = 8.6 Hz,, 2H), 7.14 (d, J= 8.4 Hz, 2H), 7.06-6.97 (m, 4H), 4.36 (d, J = 5.4 Hz, 2H), 1.32 (s, 9H), 1.23 (s, 9H). LC-MS (ESI) m / z: 339.4, [M+H] + .

[0200] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)pivalamide (39) JPEG2026063193000084.jpg63139

[0201] 1 H NMR (400 MHz, CDCl3) δ 7.31-7.28 (m, 2H), 7.15 (dd, J = 8.6, 2.4 Hz, 2H), 7.04 -6.97 (m, 4H), 4.35 (d, J = 5.6 Hz, 2H), 1.42-1.33 (m, 1H), 1.32 (s, 9H), 1.02-0.95 (m, 2H), 0.77-0.68 (m, 2H). LC-MS (ESI) m / z: 323.4, [M+H] + .

[0202] 1-Isopropyl-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)piperidine-4-carboxamide (40) JPEG2026063193000085.jpg37151

[0203] Compound 40 (13.0 mg) of the title compound was prepared from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (30 mg, 0.09 mmol) and 1-isopropylpiperidine-4-carboxylic acid (16 mg, 0.09 mmol) as a pale blue powder with a yield of 41.01%. 11H NMR (400 MHz, Methanol-d4) δ 7.25 - 6.74 (m, 8H), 4.26 (s, 2H), 3.55 - 3.44 (m, 3H), 3.05 (s, 2H), 2.67 (s, 2H), 2.54 (s, 1H), 2.36 - 2.18 (m, 1H), 2.16 - 1.87 (m, 7H), 1.72 (d, J = 13.0 Hz, 3H), 1.35 (d, J = 6.7 Hz, 6H). LC-MS (m / z) 503.4 [M+H] + .

[0204] N-(4-((4-Cyclohexylphenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (41) JPEG2026063193000086.jpg61151

[0205] 1 1H NMR (400 MHz, Methanol-d4) δ 8.63 (d, J = 6.4 Hz, 2H), 8.26 (d, J= 6.4 Hz, 2H), 7.93 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.22 (dd, J = 8.4, 4.0 Hz, 4H), 4.76 (s, 2H), 3.23 - 3.12 (m, 2H), 2.91 (s, 6H), 2.69 (t, J = 6.8 Hz, 2H), 2.09 - 1.93 (m, 2H).Mass(m / z): 405.3 [M+H] + .

[0206] N-(4-((4-(Diethylamino)phenyl)amino)benzyl)-4-(dimethylamino)-N-hydroxybutanamide (42) JPEG2026063193000087.jpg61151

[0207] 1H NMR (400 MHz, Methanol-d4) δ 7.34 - 6.57 (m, 8H), 4.64 (s, 2H), 3.01 - 2.93 (m, 2H), 2.86-2.80 (m, 4H), 2.72 (s, 6H), 2.63 (t, J = 6.8 Hz, 2H), 1.97 (m, 2H), 1.10 (t, J = 7.0 Hz, 6H). Mass(m / z): 399.3 [M+H] + .

[0208] N-hydroxy-2-(4-methylpiperazine-1-yl)-N-(4-((3-(pyrrolidine-1-yl)phenyl)amino)benzyl)acetamide (43) JPEG2026063193000088.jpg79151

[0209] 1 H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.20 - 6.92 (m, 5H), 6.37 -6.23 (m, 2H), 4.53 (s, 2H), 3.54 - 3.28 (m, 8H), 3.25 (s, 2H), 3.18 (br m, 4H), 2.29 (br s, 4H), 2.13 (s, 3H), 1.96 - 1.86 (m, 4H). Mass(m / z): 424.2 [M+H] + .

[0210] 1-Methyl-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)piperidine-4-carboxamide (44) JPEG2026063193000089.jpg35151

[0211] Compound 44 of the title (13.0 mg) was prepared as a pale yellow powder in a yield of 31.90% from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)aniline (30 mg, 0.09 mmol) and 1-methylpiperidine-4-carboxylic acid (14 mg, 0.09 mmol). 1 H NMR (400 MHz, Methanol-d4) δ 7.10 (s, 8H), 4.54 - 3.95 (br, 2H), 3.80 - 3.51 (m, 1H), 3.52 - 3.40 (m, 3H), 2.99 (td, J = 12.2, 3.6 Hz, 2H), 2.81 (s, 3H), 2.53 (tt, J = 10.8, 4.3 Hz, 1H), 2.39 - 2.16 (m, 1H), 2.13 - 1.85 (m, 7H), 1.72 (d, J = 12.7 Hz, 3H). LC-MS (m / z) 475.7 [M+H] + .

[0212] N-hydroxy-2,2-dimethyl-N-(4-(phenylamino)benzyl)butanamide (45) JPEG2026063193000090.jpg63134

[0213] 1H NMR (400 MHz, Chloroform-d) δ 7.29 - 7.12 (m, 4H), 7.07 - 6.88 (m, 5H), 4.74 (s, 2H), 1.71 (q, J = 7.4 Hz, 2H), 1.25 (s, 6H), 0.83 (t, J = 7.4 Hz, 3H). Mass(m / z): 313.2 [M+H] + .

[0214] N-hydroxy-N-(4-((4-(trifluoromethyl)phenyl)amino)benzyl)pivalamide (46) JPEG2026063193000091.jpg70147

[0215] 1H NMR (400 MHz, Chloroform-d) δ 7.45 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 7.8 Hz, 2H), 7.06 (dd, J = 27.4, 8.2 Hz, 4H), 4.82 (s, 2H), 1.31 (s, 9H).Mass(m / z): 367.3 [M+H] + .

[0216] N-hydroxy-N-(4-(pyridine-2-ylamino)benzyl)pivalamide (47) JPEG2026063193000092.jpg93151

[0217] Step 1. Preparation of 4-(pyridine-2-ylamino)benzaldehyde (47-3). A mixture of pyridine-2-amine (200 mg, 2.12 mmol), 4-bromobenzaldehyde (433 mg, 2.33 mmol), Pd(dppf)2Cl2 (264 mg, 0.36 mmol), xanthophos (368 mg, 0.637 mmol), and Cs2CO3 (1.73 g, 5.31 mmol) in toluene (20 mL) was stirred overnight at 100°C. After cooling to room temperature, 30 mL of water was added. The solid was recovered by filtration. The target product was obtained as a yellow solid (380 mg).

[0218] Step 2. Preparation of (E)-4-(pyridine-2-ylamino)benzaldehyde oxime (47-4). Compound 47-4 (406 mg) of the title was prepared as a crude product with a total yield of 100% as a yellow solid from 4-(pyridine-2-ylamino)benzaldehyde (380 mg, 1.91 mmol) and hydroxylamine hydrochloride (146 mg, 2.1 mmol) according to the procedure of 80-3.

[0219] Step 3. Preparation of N-(4-((hydroxyamino)methyl)phenyl)pyridine-2-amine (47-5). Compound 47-5 (105 mg) of the title compound was prepared according to the procedure in step 1 from (E)-4-(pyridine-2-ylamino)benzaldehyde oxime (406 mg, 1.91 mmol), borane-pyridine complex (1.15 ml, 2.1 mmol), and 0.64 mL of 9% HCl as a yellow solid with a total yield of 65.4%.

[0220] Step 4. Preparation of N-hydroxy-N-(4-(pyridine-2-ylamino)benzyl)pivalamide (47). Compound 47 (40 mg) of the title was prepared as a white solid with a total yield of 45% from N-(4-((hydroxyamino)methyl)phenyl)pyridine-2-amine (105 mg, 0.49 mmol), pivaloyl chloride (76 mg, 0.63 mmol), and NaHCO3 aq. (0.6 ml) according to the procedure in step 1. 1H NMR (400 MHz, Chloroform-d) δ 11.71 (s, 1H), 7.84 - 7.73 (m, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.23 - 7.18 (m, 2H), 7.07 (d, J = 9.2 Hz, 1H), 6.83 (t, J = 6.6 Hz, 1H), 4.72 (s, 2H), 1.25 (d, J = 1.0 Hz, 9H).

[0221] N-(4-((2-(tert-butyl)phenyl)amino)benzyl)-N-hydroxypivalamide (48) JPEG2026063193000093.jpg81124

[0222] Compound 48 (50 mg) of the title was prepared as a white solid with a total yield of 40% from 2-(tert-butyl)-N-(4-((hydroxyamino)methyl)phenyl)aniline (94 mg, 0.35 mmol), pivaloyl chloride (55 mg, 0.45 mmol), and NaHCO3 aq. (0.42 ml) according to the procedure in 1. 1H NMR (400 MHz, Chloroform-d) δ 7.41 (dd, J = 8.0, 1.6 Hz, 1H), 7.24 (dd, J = 8.0, 1.6 Hz, 1H), 7.18 - 7.04 (m, 4H), 6.77 - 6.72 (m, 2H), 4.78 (s, 2H), 1.40 (d, J = 0.6 Hz, 9H), 1.29 (d, J = 0.6 Hz, 9H.

[0223] N-(4-((3-(tert-butyl)phenyl)amino)benzyl)-N-hydroxypivalamide (49) JPEG2026063193000094.jpg77149

[0224] Compound 49 (50 mg) of the title compound was prepared according to the procedure in 1 from 3-(tert-butyl)-N-(4-((hydroxyamino)methyl)phenyl)aniline (69 mg, 0.256 mmol), pivaloyl chloride (40 mg, 0.332 mmol), and NaHCO3 aq. (0.3 ml) as a white solid with a total yield of 40%. ¹H NMR (400 MHz, Chloroform-d) δ 7.21 - 7.10 (m, 4H), 7.03 (dd, J = 14.4, 8.0 Hz, 3H), 6.94 (ddd, J = 7.8, 2.4, 1.0 Hz, 1H), 4.79 (s, 2H), 1.29 (d, J = 2.6 Hz, 18H).

[0225] N-(4-((4-(dimethylaminophenyl)amino)benzyl)-N-hydroxypivalamide (50) JPEG2026063193000095.jpg91151

[0226] Step 1. Preparation of 4-((4-(dimethylamino)phenyl)amino)benzaldehyde (50-3). A mixture of N1,N1-dimethylbenzene-1,4-diamine (100 mg, 0.73 mmol), 4-bromobenzaldehyde (149 mg, 0.8 mmol), Pd(dppf)2Cl2 (27 mg, 0.03 mmol), xanthophos (42 mg, 0.07 mmol), and Cs2CO3 (598 mg, 1.83 mmol) in toluene (15 mL) was stirred overnight at 100°C. After cooling to room temperature, 30 mL of water was added. The solid was recovered by filtration. The target product was obtained as a yellow solid (110 mg).

[0227] Step 2. Compound 50-4 (130 mg) of the title compound was prepared as a crude product with a total yield of 100% as a yellow solid from 4-((4-(dimethylamino)phenyl)amino)benzaldehyde (110 mg, 0.46 mmol) and hydroxylamine hydrochloride (35 mg, 0.5 mmol) according to the procedure in Step 1.

[0228] Step 3. 50-5 (28 mg) of the title compound was prepared according to the procedure in 1 from (E)-4-((4-(dimethylamino)phenyl)amino)benzaldehyde oxime (130 mg, 0.5 mmol), borane-pyridine complex (0.3 ml, 2.8 mmol), and 0.93 mL of 9% HCl as a yellow solid with a total yield of 65.4%.

[0229] Step 4. 50 (14 mg) of the title compound was prepared as a white solid with a total yield of 40% from N1-(4-((hydroxyamino)methyl)phenyl)-N4,N4-dimethylbenzene-1,4-diamine (28 mg, 0.11 mmol), pivaloyl chloride (17 mg, 0.14 mmol), and NaHCO3 aq. (0.13 ml) according to the procedure in 1.

[0230] N-(4-((2,4-difluorophenyl)amino)benzyl)-N-hydroxypivalamide (51) JPEG2026063193000096.jpg80135

[0231] Compound 51 (28 mg) was prepared as a white solid with a total yield of 40% from 2,4-difluoro-N-(4-((hydroxyamino)methyl)phenyl)aniline (58 mg, 0.23 mmol), pivaloyl chloride (36 mg, 0.3 mmol), and NaHCO3 aq. (0.28 ml) according to the procedure in 1. 1H NMR (400 MHz, Chloroform-d) δ 7.23 - 7.16 (m, 3H), 6.99 - 6.94 (m, 2H), 6.87 (ddd, J = 11.0, 8.4, 2.8 Hz, 1H), 6.78 (dddd, J = 8.8, 7.8, 2.8, 1.6 Hz, 1H), 4.82 (s, 2H), 1.29 (s, 9H).

[0232] N-hydroxy-N-(4-((2,4,6-trifluorophenyl)amino)benzyl)pivalamide (52) JPEG2026063193000097.jpg74136

[0233] Compound 52 (42 mg) of the title compound was prepared as a white solid with a total yield of 40% from 2,4,6-trifluoro-N-(4-((hydroxyamino)methyl)phenyl)aniline (56 mg, 0.207 mmol), pivaloyl chloride (33 mg, 0.27 mmol), and NaHCO3 aq. (0.25 ml) according to the procedure in 1. ¹H NMR (400 MHz, Chloroform-d) showed δ values ​​of 7.17 - 7.10 (m, 2H), 6.79 - 6.71 (m, 2H), 6.70 - 6.65 (m, 2H), 4.77 (s, 2H), and 1.31 - 1.25 (m, 9H).

[0234] N-hydroxy-N-(4-(pyridine-3-ylamino)benzyl)pivalamide (53) JPEG2026063193000098.jpg92146

[0235] Compound 53 (35 mg) of the title was prepared as a white solid with a total yield of 45% from N-(4-((hydroxyamino)methyl)phenyl)pyridine-3-amine (93 mg, 0.43 mmol), pivaloyl chloride (68 mg, 0.56 mmol), and NaHCO3 aq. (0.51 ml) according to the procedure in 1. . 1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 9.06 (s, 1H), 8.35 (s, 1H), 8.15 (s, 1H), 7.86 (dd, J = 8.8, 2.4 Hz, 1H), 7.65 (dd, J = 8.8, 5.2 Hz, 1H), 7.23 - 7.12 (m, 4H), 4.62 (s, 2H), 1.18 (d, J = 1.0 Hz, 9H).

[0236] N-hydroxy-N-(4-((4-methoxyphenyl)amino)benzyl)pivalamide (54) JPEG2026063193000099.jpg80141

[0237] Compound 54 (23 mg) of the title compound was prepared as a white solid with a total yield of 40% according to the procedure in 1, from 4-((hydroxyamino)methyl)-N-(4-methoxyphenyl)aniline (95 mg, 0.39 mmol), pivaloyl chloride (61 mg, 0.15 mmol), and NaHCO3 aq. (0.47 ml). ¹H NMR (400 MHz, Chloroform-d) δ 7.12 (s, 4H), 6.86 (t, J = 10.0 Hz, 4H), 4.79 (s, 2H), 3.78 (s, 3H), 1.29 (d, J = 1.6 Hz, 9H). Mass (m / z): 329.4 [M+H] + .

[0238] N-hydroxy-N-(4-(mesitylamino)benzyl)pivalamide (55) JPEG2026063193000100.jpg78128

[0239] Compound 55 (50 mg) of the title compound was prepared as a white solid with a total yield of 40% from N-(4-((hydroxyamino)methyl)phenyl)-2,4,6-trimethylaniline (108 mg, 0.42 mmol), pivaloyl chloride (66 mg, 0.55 mmol), and NaHCO3 aq. (0.5 ml) according to the procedure in 1. ¹H NMR (400 MHz, Chloroform-d) showed δ values ​​of 7.05 (d, J = 8.2 Hz, 2H), 6.92 (s, 2H), 6.48 - 6.42 (m, 2H), 4.76 (s, 2H), 2.28 (s, 3H), 2.14 (s, 6H), and 1.28 (d, J = 1.0 Hz, 9H).

[0240] N-(4-((2,5-bis(trifluoromethyl)phenyl)amino)benzyl)-N-hydroxypivalamide (56) JPEG2026063193000101.jpg91124

[0241] Compound 56 (40 mg) of the title compound was prepared as a white solid with a total yield of 40% from N-(4-((hydroxyamino)methyl)phenyl)-2,5-bis(trifluoromethyl)aniline (110 mg, 0.31 mmol), pivaloyl chloride (0.05 ml, 0.41 mmol), and NaHCO3 aq. (0.38 ml) according to the procedure in 1. ¹H NMR (400 MHz, Chloroform-d) δ values ​​were 7.64 (d, J = 8.2 Hz, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.31 - 7.27 (m, 2H), 7.15 - 7.10 (m, 3H), 4.87 (s, 2H), 1.31 (d, J = 0.6 Hz, 9H).

[0242] N-(4-((4-(tert-butyl)-2,6-dimethylphenyl)amino)benzyl)-N-hydroxypivalamide (57) JPEG2026063193000102.jpg78141

[0243] Compound 57 (43 mg) of the title compound was prepared according to the procedure in 1 from 4-(tert-butyl)-N-(4-((hydroxyamino)methyl)phenyl)-2,6-dimethylaniline (150 mg, 0.5 mmol), pivaloyl chloride (0.08 ml, 0.65 mmol), and NaHCO3 aq. (0.6 ml) as a white solid with a total yield of 40%. ¹H NMR (400 MHz, Chloroform-d) δ 7.11 - 7.03 (m, 4H), 6.50 - 6.43 (m, 2H), 4.78 - 4.75 (m, 2H), 2.20 - 2.16 (m, 6H), 1.31 - 1.27 (m, 18H). Mass (m / z): 383.6 [M+H] + .

[0244] N-hydroxy-N-(4-(phenylamino)benzyl)pivalamide (58) JPEG2026063193000103.jpg78121

[0245] Compound 58 (7 mg) of the title compound was prepared as a white solid with a total yield of 40% from 4-((hydroxyamino)methyl)-N-phenylaniline (38 mg, 0.18 mmol), pivaloyl chloride (0.028 ml, 0.23 mmol), and NaHCO3 aq. (0.2 ml) according to the procedure in 1. ¹H NMR (400 MHz, Chloroform-d) δ values ​​were 7.28 - 7.22 (m, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.07 - 7.00 (m, 4H), 6.93 (tt, J = 7.4, 1.0 Hz, 1H), 4.81 (s, 2H), 1.31 - 1.28 (s, 9H).

[0246] N-hydroxy-N-(4-((4-(pyrrolidin-1-yl)phenyl)aminobenzyl)pivalamide (59) JPEG2026063193000104.jpg82151

[0247] Compound 59 (10 mg) of the title compound was prepared according to the procedure in 1 from 4-((hydroxyamino)methyl)-N-(4-(pyrrolidine-1-yl)phenyl)aniline (15 mg, 0.05 mmol), pivaloyl chloride (0.01 ml, 0.07 mmol), and NaHCO3 aq. (0.06 ml) as a white solid with a total yield of 40%.

[0248] N-(4-(phenylamino)benzyl)adamantan-1-carboxamide (60) JPEG2026063193000105.jpg85123

[0249] 1 H NMR (400 MHz, Chloroform-d) δ 7.28 - 7.21 (m, 2H), 7.13 (d, J = 8.4 Hz, 2H), 7.06-7.00 (m, 4H), 6.91 (t, J = 7.4 Hz, 1H), 4.34 (s, 2H), 2.03 (s, 3H), 1.86 (d, J = 2.8 Hz, 6H). Mass(m / z): 361.3 [M+H] + .

[0250] N-hydroxy-N-(4-(phenylamino)benzyl)adamantane-1-carboxamide (61) JPEG2026063193000106.jpg80112

[0251] 1 H NMR (400 MHz, CDCl3) δ 7.30-7.25 (m, 2H), 7.18 (d, J = 8.6 Hz, 2H), 7.10-7.03 (m, 4H), 6.95 (m, 1H), 4.91 (s, 2H), 2.05 (s, 9H), 1.71 (s, 6H). LC-MS (ESI) m / z: 377.3, [M+H] + .

[0252] N-(4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)-N-hydroxy-2-methoxy-2-methylpropanamide (62) JPEG2026063193000107.jpg70136

[0253] 1 H NMR (400 MHz, Chloroform-d) δ 7.31-7.15 (m, 3H), 7.04 (d, J = 7.8 Hz, 2H), 6.80 - 6.69 (m, 2H), 4.75 (s, 2H), 3.26 (s, 3H), 1.51 (s, 6H), 1.35 (s, 9H).Mass(m / z): 389.2 [M+H] + .

[0254] N-(4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)-N-hydroxy-2-(2-(2-methoxyethoxy)ethoxy)acetamide (63) JPEG2026063193000108.jpg53151

[0255] 1 H NMR (400 MHz, Chloroform-d) δ 7.25 - 7.21 (m, 2H), 7.18 - 7.11 (m, 1H), 7.06 - 7.00 (m, 2H), 6.80 - 6.64 (m, 2H), 4.73 (s, 2H), 4.36 (s, 2H), 3.80 - 3.41 (m, 8H), 3.24 (s, 3H), 1.35 (s, 9H). Mass(m / z): 449.2 [M+H] + .

[0256] N-(4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)-N-hydroxypivalamide (64) JPEG2026063193000109.jpg69128

[0257] 1 H NMR (400 MHz, Chloroform-d) δ 7.23 - 7.11 (m, 3H), 7.09 - 7.01 (m, 2H), 6.80 - 6.70 (m, 2H), 4.82 (s, 2H), 1.35 (s, 9H), 1.31 (s, 9H). Mass(m / z): 373.2 [M+H] + .

[0258] tert-butyl3-((4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)(hydroxy)carbamoyl)azetidine-1-carboxylate (65) JPEG2026063193000110.jpg62151

[0259] 1 H NMR (400 MHz, Chloroform-d) δ 7.24 - 7.09 (m, 3H), 6.99 (d, J = 7.8 Hz, 2H), 6.78 - 6.67 (m, 2H), 4.71 (s, 2H), 4.22 - 3.91 (m, 4H), 3.77 - 3.61 (m, 1H), 1.40 (s, 9H), 1.35 (s, 9H). Mass(m / z): 472.3 [M+H] + .

[0260] tert-butyl 4-((4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)(hydroxy)carbamoyl)-4-methylpiperidine-1-carboxylate (66) JPEG2026063193000111.jpg58151

[0261] 1H NMR (400 MHz, Chloroform-d) δ 7.23 - 7.12 (m, 3H), 7.06 - 7.00 (m, 2H), 6.79 - 6.71 (m, 2H), 4.79 (s, 2H), 3.76 -3.61 (m, 2H), 3.18-3.04 (m, 2H), 2.28-2.21 (m, 2H), 2.14 - 2.00 (m, 2H), 1.44 (s, 9H), 1.35 (s, 9H), 1.30 (s, 3H). Mass(m / z): 514.3 [M+H] + .

[0262] tert-butyl4-(2-((4-((4-(tert-butyl)phenyl)amino)benzyl)(hydroxy)amino)-2-oxoethyl)piperazine-1-carboxylate (67) JPEG2026063193000112.jpg56151

[0263] 1 H NMR (400 MHz, Chloroform-d) δ 7.31 - 7.15 (m, 4H), 7.06 - 6.92 (m, 4H), 4.69 (s, 2H), 4.06(s, 2H), 3.95-2.91 (m, 8H), 1.46 (s, 9H), 1.31 (s, 9H).Mass(m / z): 497.3 [M+H] + .

[0264] N-hydroxy-2-methoxy-2-methyl-N-(4-((4-(trifluoromethyl)phenyl)amino)benzyl)propanamide (68) JPEG2026063193000113.jpg60151

[0265] 1H NMR (400 MHz, Chloroform-d) δ 7.47 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 7.8 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H), 4.80 (s, 2H), 3.27 (s, 3H), 1.52 (s, 6H).Mass(m / z): 383.3 [M+H] + .

[0266] N-hydroxy-1-methyl-N-(4-((4-(trifluoromethyl)phenyl)amino)benzyl)cyclohexane-1-carboxamide (69) JPEG2026063193000114.jpg62150

[0267] 1 H NMR (400 MHz, Chloroform-d) δ 7.47 (d, J = 8.4 Hz, 2H), 7.30 - 7.23 (m, 2H), 7.13 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 4.89 (s, 2H), 2.16-2.11 (m, 2H), 1.64 - 1.29 (m, 8H), 1.26 (s, 3H). Mass(m / z): 407.3 [M+H] + .

[0268] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-4-(dimethylamino)-N-hydroxybutanamide (70) JPEG2026063193000115.jpg57151

[0269] 1H NMR (400 MHz, Methanol-d4) δ 7.27 (d, J = 8.8 Hz, 2H), 7.18 (d, J= 8.4 Hz, 2H), 7.03-6.99 (m, 4H), 4.67 (s, 2H), 3.10-3.06 (m, 2H), 2.82 (s, 6H), 2.67-2.64 (m, 2H), 2.03-1.96 (m, 2H), 1.30 (s, 9H).Mass(m / z): 384.3 [M+H] + .

[0270] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-3-morpholinopropanamide (71) JPEG2026063193000116.jpg61151

[0271] 1 H NMR (400 MHz, Methanol-d4) δ 7.27 (d, J = 8.8 Hz, 2H), 7.18 (d, J= 8.4 Hz, 2H), 7.03-6.99 (m, 4H), 4.66 (s, 2H), 3.73 - 3.55 (m, 4H), 2.84 - 2.65 (m, 4H), 2.56-2.43 (m, 4H), 1.30 (s, 9H).Mass(m / z): 412.2 [M+H] + .

[0272] N-(4-([1,1'-biphenyl]-4-ylamino)benzyl)-N-hydroxy-4-methyltetrahydro-2H-pyran-4-carboxamide (72) JPEG2026063193000117.jpg67151

[0273] 1H NMR (400 MHz, Chloroform-d) δ 7.60 - 7.47 (m, 4H), 7.45 - 7.39 (m, 2H), 7.34 - 7.28 (m, 1H), 7.3-7.11 (m, 6H), 4.83 (s, 2H), 3.83 - 3.56 (m, 4H), 2.34 - 2.14 (m, 2H), 1.62-1.55 (m, 2H), 1.33 (s, 3H).Mass(m / z): 417.3 [M+H] + .

[0274] N-(4-([1,1'-biphenyl]-4-ylamino)benzyl)-2,2,2-trifluoro-N-hydroxyacetamide (73) JPEG2026063193000118.jpg70151

[0275] 1 H NMR (400 MHz, Chloroform-d) δ 7.59-7.52 (m, 4H), 7.46 - 7.28 (m, 3H), 7.22 - 7.05 (m, 6H), 4.83 (m, 2H). Mass(m / z): 387.3 [M+H] + .

[0276] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-1,4-dimethylpiperidine-4-carboxamide (74) JPEG2026063193000119.jpg64151

[0277] 1H NMR (400 MHz, Methanol-d4) δ 7.29 - 7.25 (m, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.08 - 6.99 (m, 4H), 4.69 (s, 2H), 3.49 - 3.36 (m, 2H), 3.13-3.02 (d, J= 3.8 Hz, 2H), 2.82 (s, 3H), 2.24 - 2.12 (m, 4H), 1.34(s, 3H), 1.30 (s, 9H). Mass(m / z): 410.3 [M+H] + .

[0278] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-2-(4-ethylpiperazine-1-yl)-N-hydroxyacetamide (75) JPEG2026063193000120.jpg62151

[0279] 1 H NMR (400 MHz, Methanol-d4) δ 7.27 (d, J = 8.8 Hz, 2H), 7.18 (d, J= 8.4 Hz, 2H), 7.03-6.99 (m, 4H), 4.68 (s, 2H), 4.12 (s, 2H), 3.54 (br s, 8H), 3.26 (t, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H), 1.30 (s, 9H). Mass(m / z): 425.2 [M+H] + .

[0280] 2-(4-acetylpiperazine-1-yl)-N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxyacetamide (76) JPEG2026063193000121.jpg72151

[0281] 1H NMR (400 MHz, Methanol-d4) δ 7.31 - 7.24 (m, 2H), 7.22 - 7.15 (m, 2H), 7.03-6.98 (m, 4H), 4.70 (s, 2H), 4.30 (s, 2H), 3.88 (br s, 4H), 3.44 (br s, 4H), 2.15 (s, 3H), 1.30 (s, 9H).Mass(m / z): 439.3 [M+H] + .

[0282] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-(4-(2,2,2-trifluoroacetyl)piperazine-1-yl)acetamide (77) JPEG2026063193000122.jpg71151

[0283] 1 H NMR (400 MHz, Methanol-d4) δ 7.27 (d, J = 8.4 Hz, 2H), 7.19 (d, J= 8.4 Hz, 2H), 7.01 (dd, J = 8.4, 4.0 Hz, 4H), 4.70 (s, 2H), 4.33 (s, 2H), 4.00 (br s, 4H), 3.54 (br s, 4H), 1.30 (s, 9H). Mass(m / z): 493.2 [M+H] + .

[0284] N-(4-((4'-fluoro-[1,1'-biphenyl]-4-yl)aminobenzyl)-N-hydroxy-2-(4-methylpiperazine-1-yl)acetamide (78) JPEG2026063193000123.jpg61151

[0285] 1H NMR (400 MHz, Methanol-d4) δ 7.57 (dd, J = 8.8, 5.2 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 7.16 - 7.07 (m, 6H), 4.70 (s, 2H), 3.81 (s, 2H), 3.39 (br s, 4H), 3.16 (br s, 4H), 2.90 (s, 3H). Mass(m / z): 449.2 [M+H] + .

[0286] N-hydroxy-4-methyl-N-(4-((4-(piperidine-1-yl)phenyl)amino)benzyl)piperazine-1-carboxamide (79) JPEG2026063193000124.jpg64151

[0287] Compound 79 (13.5 mg) was prepared as a white solid with a total yield of 33.2%. 1 H NMR (400 MHz, Methanol-d4) δ 7.35 - 6.67 (m, 8H), 4.60 (s, 2H), 3.73 (br s, 4H), 3.22-3.01 (m, 8H), 2.78 (s, 3H), 2.04-1.77 (m, 4H), 1.75-1.51 (m, 2H).Mass(m / z): 424.3 [M+H] +

[0288] N-(4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)-N-hydroxy-1-methylcyclopropane-1-carboxamide (80) JPEG2026063193000125.jpg98151

[0289] Step 1. 4-(tert-butyl)-3-fluoroaniline (2.17 g, 13 mmol), 4-bromobenzaldehyde (1.85 g, 10 mmol), Pd(dppf)2Cl2 (147 mg, 0.2 mmol), xanthophos (231 mg, 0.4 mmol), and Cs2CO3 (4.89 g, 15 mmol) were dissolved in toluene under a nitrogen atmosphere and stirred overnight at 100°C. After the reaction was complete, the reaction product was cooled to room temperature, diluted with DCM, passed through a silica plug, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=5 / 1) to obtain the desired product as a yellow solid (1.8 g, 66%). Mass (m / z): 272.3 [M+H] + .

[0290] Step 2. Hydroxylamine hydrochloride (261 mg, 3.8 mmol) was added to a solution of 4-((4-(tert-butyl)-3-fluorophenyl)amino)benzaldehyde (928 mg, 3.4 mmol) in THF / H2O / EtOH (2 / 1 / 5, 40 mL). The reaction mixture was then stirred overnight at room temperature. The reaction mixture was concentrated under vacuum. The crude product was used directly in the next step (100%). Mass (m / z): 287.2 [M+H] + .

[0291] Step 3. Boran-pyridine (632 mg, 6.8 mmol) was added to a solution of (Z)-4-((4-(tert-butyl)-3-fluorophenyl)amino)benzaldehyde oxime (972 mg, 3.4 mmol) in EtOH (40 mL). Then 10% HCl (6.8 mL) was added dropwise at 0°C. The solution was stirred at room temperature for 3 hours. The pH of the solution was adjusted to 8-9 with sodium carbonate solution. The mixture was then extracted with DCM (15 mL x 3). The bound organic layer was washed with water (20 mL x 3), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (MeOH / DCM = 1 / 40) to obtain the desired product as a yellow solid (242 mg, 25%). Mass (m / z): 289.3 [M+H] + .

[0292] Step 4. 4-(tert-butyl)-3-fluoro-N-(4-((hydroxyamino)methyl)phenyl)aniline (20 mg, 0.07 mmol) was dissolved in 1.0 mL of THF / H2O (1:1, v / v) and 1.2 mL of saturated NaHCO3 aqueous solution. The solution was cooled to 0°C, 1-methylcyclopropane-1-carbonyl chloride (9.1 mg, 0.077 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was extracted with ethyl acetate, the bound organic layer was washed with brine, dried over (Na2SO4), and concentrated under vacuum to obtain the crude product. The residue was purified by prep-TLC (MeOH / DCM = 1 / 10) to obtain the desired product as a white solid (8.0 mg, 30.9%). 1 H NMR (400 MHz, Chloroform-d) δ 7.23-7.14 (m, 3H), 7.07 (d, J = 8.0 Hz, 2H), 6.78-6.73 (m, 2H), 4.96 (s, 2H), 1.38 (s, 3H), 1.36 (s, 9H), 1.09-1.01 (m, 2H), 0.74-0.66 (m, 1H). Mass(m / z): 371.2 [M+H] + .

[0293] N-(4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)-N-hydroxy-4-methyltetrahydro-2H-pyran-4-carboxamide (81) JPEG2026063193000126.jpg74145

[0294] Compound 81 (8.6 mg) was prepared as a white solid with a total yield of 29.6% from 4-(tert-butyl)-3-fluoro-N-(4-((hydroxyamino)methyl)phenyl)aniline (20 mg, 0.07 mmol) and 4-methyltetrahydro-2H-pyran-4-carbonyl chloride (12.5 mg, 0.077 mmol) according to the procedure for compound 80. 1 H NMR (400 MHz, Chloroform-d) δ 7.21-7.13 (m, 3H), 7.04 (d, J = 8.0 Hz, 2H), 6.77-6.72 (m, 2H), 4.81 (s, 2H), 3.81-3.49(m, 4H), 2.26-2. 21(m, 2H), 1.61-1.53(m, 2H), 1.35 (s, 9H), 1.32 (s, 3H). Mass(m / z): 415.6 [M+H] + .

[0295] N-(4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)-N-hydroxy-2-morpholinoacetamide (82) JPEG2026063193000127.jpg61151

[0296] Compound 82 (11 mg) was prepared as a white solid with a total yield of 37.8% from 4-(tert-butyl)-3-fluoro-N-(4-((hydroxyamino)methyl)phenyl)aniline (20 mg, 0.07 mmol) and 2-morpholinoacetyl chloride (12.6 mg, 0.077 mmol) according to the procedure for Compound 1. 1H NMR (400 MHz, Chloroform-d) 7.21-7.09 (m, 3H), 7.04 (d, J = 8.0 Hz, 2H), 6.79-6.66 (m, 2H), 4.68 (s, 2H), 4.16 (s, 2H), 4.07-3.87 (m, 4H), 3.76-3.47(m, 2H), 3.21-2.93(m, 2H), 1.35 (s, 9H) Mass(m / z): 416.6 [M+H] + .

[0297] N-hydroxy-2-(4-methylpiperazine-1-yl)-N-(4-((4-(1-methylpiperidine-4-yl)phenyl)amino)benzyl)acetamide (83) JPEG2026063193000128.jpg75151

[0298] Compound 83 (16 mg) of the title was prepared as a white solid with a total yield of 45% from N-(4-((hydroxyamino)methyl)phenyl)-[1,1'-biphenyl]-4-amine (30 mg, 0.1 mmol), pivaloyl chloride (16.2 mg, 0.13 mmol), and NaHCO3 aq. (0.13 ml) according to the procedure in 1. 1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.30 (s, 1H), 7.63 - 7.52 (m, 4H), 7.41 (t, J = 7.6 Hz, 2H), 7.31 - 7.23 (m, 1H), 7.17 - 7.04 (m, 6H), 4.61 (s, 2H), 1.22 (s, 9H).

[0299] N-(4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)-N-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carboxamide (84) JPEG2026063193000129.jpg66151

[0300] Compound 84 (30 mg) was prepared as a yellow solid with a total yield of 96% from 4-(tert-butyl)-3-fluoro-N-(4-((hydroxyamino)methyl)phenyl)aniline (20 mg, 0.07 mmol) and 5,6,7,8-tetrahydronaphthalene-2-carbonyl chloride (0.077 mmol) according to the procedure for Compound 1. 1 H NMR (400 MHz, Chloroform-d) δ 7.85-7.74 (m, 3H), 7.38-6.96 (m, 6H), 6.79-6.65 (m, 1H), 4.80 (s, 2H), 2.91-2.69 (m, 4H), 1.89-1.71(m, 4H), 1.35 (s, 9H) Mass(m / z): 447.7 [M+H] + .

[0301] N-(4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)-4-(dimethylamino)-N-hydroxybutanamide (85) JPEG2026063193000130.jpg57151

[0302] Compound 85 (2.4 mg) was prepared as a white solid with a total yield of 8.5% from 4-(tert-butyl)-3-fluoro-N-(4-((hydroxyamino)methyl)phenyl)aniline (20 mg, 0.07 mmol) and 4-(dimethylamino)butanoyl chloride (0.077 mmol) according to the procedure for Compound 1. 1 H NMR (400 MHz, Chloroform-d) δ 7.20-7.07 (m, 3H), 7.03 (d, J = 8.0 Hz, 2H), 6.77-6.64 (m, 2H), 4.73 (s, 2H), 2.54 (t, J = 8.0 Hz, 2H), 2.38 (t, J = 8.0 Hz, 2H), 2.14 (s, 6H), 1.90 - 1.63 (m, 2H), 1.35 (s, 9H) Mass(m / z): 402.6 [M+H] + .

[0303] N-(4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)-N-hydroxy-2,3-dihydro-1H-inden-2-carboxamide (86) JPEG2026063193000131.jpg63151

[0304] Compound 86 (32 mg) was prepared as a yellow solid with a total yield of 90% from 4-(tert-butyl)-3-fluoro-N-(4-((hydroxyamino)methyl)phenyl)aniline (20 mg, 0.07 mmol) and 2,3-dihydro-1H-indene-2-carbonyl chloride (0.077 mmol) according to the procedure for Compound 1. 1 H NMR (400 MHz, Chloroform-d)δ 7.22-6.90 (m, 9H), 6.77-6.64 (m, 2H), 4.81 (s, 2H), 3.42-2.98 (m, 5H), 1.35 (s, 9H) Mass(m / z): 433.4 [M+H] + .

[0305] N-(4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)-N-hydroxyazetidine-3-carboxamide (87) JPEG2026063193000132.jpg69148

[0306] Compound 87 (4.0 mg) was prepared as a white solid with a total yield of 15.4% from 4-(tert-butyl)-3-fluoro-N-(4-((hydroxyamino)methyl)phenyl)aniline (20 mg, 0.07 mmol) and tert-butyl 3-(chlorocarbonyl)azetidine-1-carboxylate (0.077 mmol) according to the procedure for Compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.22-7.08 (m, 3H), 7.04-6.93 (m, 3H), 6.79-6.69 (m, 2H), 4.62 (s, 2H), 4.39 (m, 1H), 4.23-3.75 (m, 4H), 1.35 (s, 9H) Mass(m / z): 372.4 [M+H] + .

[0307] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxybenzo[d]thiazole-6-carboxamide (88) JPEG2026063193000133.jpg61151

[0308] Compound 88 (4.2 mg) was prepared as a white solid with a total yield of 13.9% from 4-(tert-butyl)-N-(4-((hydroxyamino)methyl)phenyl)aniline (20 mg, 0.074 mmol) and benzo[d]thiazole-6-carbonyl chloride (0.077 mmol) according to the procedure for Compound 1. 1 H NMR (400 MHz, Chloroform-d)δ 9.00 (s, 1H), 8.21 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.15 (d, J= 8.0 Hz, 2H), 7.06-6.96 (m, 4H), 4.81 (s, 2H), 1.30 (s, 9H). 432.3 [M+H] + .

[0309] N-hydroxy-4-methyl-N-(4-((4-(trifluoromethyl)phenyl)amino)benzyl)tetrahydro-2H-pyran-4-carboxamide (89) JPEG2026063193000134.jpg62151

[0310] Compound 89 (5.4 mg) was prepared as a yellow solid with a total yield of 13.2% from 4-((hydroxyamino)methyl)-N-(4-(trifluoromethyl)phenyl)aniline (28 mg, 0.1 mmol) and 4-methyltetrahydro-2H-pyran-4-carbonyl chloride (0.11 mmol) according to the procedure for Compound 1. 1 H NMR (400 MHz, Chloroform-d) δ 7.53-7.42 (m, 3H), 7.18-6.99 (m, 5H), 4.86 (s, 2H), 3.82-3.58(m, 4H), 2.29-2. 17(m, 2H), 1.65-1.53(m, 2H), 1.34 (s, 3H). Mass(m / z): 408.3 [M+H] + .

[0311] N-hydroxy-N-(4-((6-isopropylpyridine-3-yl)amino)benzyl)pivalamide (90) JPEG2026063193000135.jpg76146

[0312] Compound 90 (12 mg) of the title compound was prepared as a white solid with a total yield of 40% from N-(4-((hydroxyamino)methyl)phenyl)-6-isopropylpyridine-3-amine (20 mg, 0.08 mmol), pivaloyl chloride (12.3 mg, 0.1 mmol), and NaHCO3 aq. (0.1 ml) according to the procedure in 1. 1H NMR (400 MHz, Methanol-d4) δ 8.08 (s, 1H), 7.98 (dd, J = 8.8, 2.4 Hz, 1H), 7.70 (d, J = 9.2 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.22 - 7.12 (m, 2H), 5.47 (d, J = 0.8 Hz, 1H), 4.72 (s, 2H), 1.36 (dd, J = 6.8, 0.8 Hz, 6H), 1.27 (s, 9H). Mass(m / z): 342.5 [M+H] + .

[0313] N-hydroxy-1-(trifluoromethyl)-N-(4-((4-(trifluoromethyl)phenyl)amino)benzyl)cyclobutan-1-carboxamide (91) JPEG2026063193000136.jpg65151

[0314] Compound 91 (7.2 mg) was prepared as a yellow solid with a total yield of 23.8% according to the procedure for compound 80. 1 H NMR (400 MHz, Chloroform-d) δ 1H NMR (400 MHz, Chloroform-d) δ 7.50-7.44 (m, 2H), 7.27 - 7.22 (m, 2H), 7.17 - 7.01 (m, 4H), 4.78 (s, 2H), 2.82-2.66 (m, 2H), 2.57-2.45 (m, 2H), 2.17-2.06 (m, 2H). Mass(m / z): 433.2 [M+H] + .

[0315] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazine-1-yl)acetamide (92) JPEG2026063193000137.jpg65151

[0316] Compound 92 (10.8 mg) was prepared as a yellow solid with a total yield of 26.3% according to the procedure for compound 80. 1 H NMR (400 MHz, Methanol-d4) δ 7.20 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 6.97-6.91 (m, 4H), 4.61 (s, 2H), 3.91 (s, 2H), 3.52 - 3.11 (m, 8H), 2.87 (s, 3H), 1.23 (s, 9H). Mass(m / z): 411.3 [M+H] + .

[0317] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-morpholinoacetamide (93) JPEG2026063193000138.jpg69151

[0318] Compound 93 (14.8 mg) was prepared as a yellow solid with a total yield of 50.3% according to the procedure for compound 80. 1 H NMR (400 MHz, Methanol-d4) δ 7.27 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.03-6.99 (m, 4H), 4.69 (s, 2H), 4.28 (s, 2H), 4.08-3.78 (m, 4H), 3.66-3.47 (m, 2H), 3.26-3.13 (m, 2H),1.30 (s, 9H). Mass(m / z): 398.2 [M+H] +

[0319] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-4-methylpiperidine-4-carboxamide (94) JPEG2026063193000139.jpg67151

[0320] Compound 94 (3.0 mg) was prepared as a yellow solid with a total yield of 20.3% according to the procedure for compound 80. 1 H NMR (400 MHz, Methanol-d4) δ 7.26 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 6.99-6.93 (m, 4H), 4.68 (s, 2H), 3.29-2.92 (m, 4H), 2.64-2.46 (m, 2H), 1.75-1.56 (m, 2H),1.27 (s, 9H), 1.25 (s, 3H). Mass(m / z): 396.3 [M+H] +

[0321] N-(4-((4-(tert-butyl)phenyl)amino)-2-methylbenzyl)-N-hydroxypivalamide (95) JPEG2026063193000140.jpg63136

[0322] Compound 95 (17.4 mg) was prepared as a yellow solid with a total yield of 47.1% according to the procedure for compound 80. 1 H NMR (400 MHz, Methanol-d4) δ 7.30 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 8.0 Hz, 2H), 6.88-6.83 (m, 2H), 4.82 (s, 2H), 2.25 (s, 3H), 1.32 (s, 9H), 1.30 (s, 9H). Mass(m / z): 369.2 [M+H] +

[0323] N-(4-([1,1'-biphenyl]-4-ylamino)benzyl)-N-hydroxy-2-methoxy-2-methylpropanamide (96) JPEG2026063193000141.jpg68151

[0324] Compound 96 (26.5 mg) was prepared as a white solid with a total yield of 61.8% following the procedure for compound 80. 1 H NMR (400 MHz, Chloroform -d) δ 7.51 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.38-7.34 (m, 2H), 7.25-7.20 (m, 3H), 7.09-7.02 (m, 4H), 4.72 (s, 2H), 3.20 (s, 3H), 1.46 (s, 6H). Mass(m / z): 391.4 [M+H] +

[0325] N-(4-((4-(tert-butyl)-2,6-dimethylphenyl)amino)benzyl)-N-hydroxy-4-methyltetrahydro-2H-pyran-4-carboxamide (97) JPEG2026063193000142.jpg69147

[0326] Compound 97 (28 mg) was prepared as a white solid with a total yield of 41.8% according to the procedure for compound 80. 1 H NMR (400 MHz, Chloroform -d) δ 7.12 (s, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.46 (d, J = 8.0 Hz, 2H), 4.74 (s, 2H), 3.80-3.52 (m, 4H), 2.37-2.10 (m, 8H), 1.58-1.52 (m, 2H), 1.33 (s, 9H), 1.30 (s, 3H). Mass(m / z): 425.2 [M+H] +

[0327] N-(4-((4-(tert-butyl)-2,6-dimethylphenyl)amino)benzyl)-N-hydroxy-2-methoxy-2-methylpropanamide (98) JPEG2026063193000143.jpg73151

[0328] Compound 98 (21.4 mg) was prepared as a white solid with a total yield of 53.8% following the procedure for compound 80. 1 H NMR (400 MHz, Chloroform -d) δ 7.14 - 7.08 (m, 4H), 6.46 (d, J = 8.0 Hz, 2H), 4.64 (s, 2H), 3.23 (s, 3H), 2.19 (s, 6H), 1.49 (s, 6H), 1.32 (s, 9H). Mass(m / z): 399.4 [M+H] +

[0329] N-(4-((4-(tert-butyl)phenyl)amino)-3-fluorobenzyl)-N-hydroxypivalamide (99) JPEG2026063193000144.jpg68137

[0330] Compound 99 (25.6 mg) was prepared as a white solid with a total yield of 70.3% according to the procedure for compound 80. 1 H NMR (400 MHz, Chloroform -d) δ 7.31 (d, J = 8.0 Hz, 2H), 7.25- 7.20 (m, 1H), 7.06- 7.00 (m, 3H), 6.91 (d, J = 8.0 Hz, 2H), 4.75 (s, 2H), 1.31 (s, 9H), 1.29 (s, 9H). Mass(m / z): 373.2 [M+H] +

[0331] N-hydroxy-N-(4-((4-morpholinophenyl)amino)benzyl)pivalamide (100) JPEG2026063193000145.jpg83151

[0332] Compound 100 (13 mg) of the title compound was prepared according to procedure 80 from 4-((hydroxyamino)methyl)-N-(4-morpholinophenyl)aniline (20 mg, 0.067 mmol), pivaloyl chloride (10 mg, 0.087 mmol), and NaHCO3 aq. (0.08 ml) as a white solid with a total yield of 40%.

[0333] N-(4-([1,1'-biphenyl]-4-ylamino)benzyl)-N-hydroxy-2-(4-methylpiperazine-1-yl)acetamide (101) JPEG2026063193000146.jpg60151

[0334] Compound 101 (2.3 mg) was prepared as a white solid with a total yield of 9.6% according to the procedure for compound 80. 1H NMR (400 MHz, Methanol-d4) δ 7.56 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.39 (t, J = 7.6 Hz, 2H), 7.28-7.21 (m, 3H), 7.16-7.09 (m, 4H), 4.69 (s, 2H), 3.66 (s, 2H), 3.36-3.15 (m, 8H), 2.88 (s, 3H). Mass(m / z): 431.4 [M+H] +

[0335] N-(4-((4-(tert-butyl)-2,6-dimethylphenyl)amino)benzyl)-2,2,2-trifluoro-N-hydroxyacetamide (102) JPEG2026063193000147.jpg73143

[0336] Compound 102 (30 mg) was prepared as a white solid with a total yield of 76.1% according to the procedure for compound 80. 1 H NMR (400 MHz, Chloroform-d) δ 7.15-7.08 (m, 4H), 6.48 (d, J = 8.4 Hz, 2H), 4.73 (s, 2H), 2.20 (s, 6H), 1.33 (s, 9H). Mass(m / z): 395.3 [M+H] +

[0337] N-(4-((4-(tert-butyl)-2,6-dimethylphenyl)amino)benzyl)-N-hydroxy-1-methylpiperidine-4-carboxamide (103) JPEG2026063193000148.jpg68151

[0338] Compound 103 (3.1 mg) was prepared as a white solid with a total yield of 12.4% according to the procedure for compound 80. 1H NMR (400 MHz, Methanol-d4) δ 7.12 (m, 2H), 7.03 (d, J = 8.4 Hz, 2H), 6.39 (d, J = 8.4 Hz, 2H), 4.61 (s, 2H), 3.56-3.53 (m, 2H), 3.06-3.00 (m, 3H), 2.86 (s, 3H), 2.1 (s, 6H), 2.10-1.85 (m, 4H),1.31 (s, 9H). Mass(m / z): 424.4 [M+H] +

[0339] N-(4-((4'-Fluoro-[1,1'-biphenyl]-4-yl)aminobenzyl)-N-hydroxypivalamide (104) JPEG2026063193000149.jpg73151

[0340] Compound 104 (19.2 mg) was prepared as a white solid with a total yield of 48.9% according to the procedure for compound 80. 1 H NMR (400 MHz, Chloroform-d) δ 7.56 - 7.41 (m, 4H), 7.22 (d, J = 8.4 Hz, 2H), 7.14 - 7.08 (m, 6H), 4.86 (s, 2H), 1.32 (s, 9H). Mass(m / z): 393.1 [M+H] + .

[0341] N-(4-((4-cyclopropylphenyl)amino)benzyl)-N-hydroxypivalamide (105) JPEG2026063193000150.jpg71140

[0342] Compound 105 (10.0 mg) was prepared as a white solid with a total yield of 29.6% according to the procedure for compound 80. 1H NMR (400 MHz, Chloroform-d) δ7.16 (d, J = 8.0 Hz, 2H), 7.03-6.93 (m, 6H), 4.81 (s, 2H), 1.89-1.83 (m, 1H), 1.31 (s, 9H), 0.98-0.88 (m, 2H), 0.65-0.63 (m, 2H). Mass(m / z): 339.4 [M+H] +

[0343] N-(4-((4-(1H-imidazole-1-yl)phenyl)aminobenzyl)-N-hydroxypivalamide (106) JPEG2026063193000151.jpg68151

[0344] Compound 106 (13.7 mg) was prepared as a white solid with a total yield of 37.6% according to the procedure for compound 80. 1 H NMR (400 MHz, Chloroform-d)δ 7.85-7.95 (m, 1H), 7.32-7.18 (m, 6H), 7.14 -7.07 (m, 4H), 4.08 (s, 2H), 1.20 (s, 9H). Mass(m / z): 365.4 [M+H] +

[0345] N-hydroxy-2-(4-methylpiperazine-1-yl)-N-(4-((4-(trifluoromethyl)phenyl)amino)benzyl)acetamide (107) JPEG2026063193000152.jpg66151

[0346] Compound 107 (13.3 mg) was prepared as a white solid with a total yield of 35.8% according to the procedure for compound 80. 1H NMR (400 MHz, Methanol-d4) δ 7.45 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.16-7.10 (m, 4H), 4.73 (s, 2H), 3.92 (s, 2H), 3.51-3.39(m, 4H), 3.37 - 3.22 (m, 4H), 2.93 (s, 3H). Mass(m / z): 423.3 [M+H] +

[0347] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-2-(4-cyclopropylpiperazine-1-yl)-N-hydroxyacetamide (108) JPEG2026063193000153.jpg97151

[0348] Steps 1-3. Compound 108-4 (1.45 g) was prepared as a yellow solid at a total yield of 27% according to the procedure for compound 80-4. Mass (m / z): 271.3 [M+H] + .

[0349] Step 4. DIEA (0.045 mL, 0.26 mmol) was added to a solution of 4-(tert-butyl)-N-(4-((hydroxyamino)methyl)phenyl)aniline (54 mg, 0.2 mmol) and 2-(4-cyclopropylpiperazin-1-yl)acetic acid (47.8 mg, 0.26 mmol) in DMF (1 ml). Subsequently, DMT-MM (76.4 mg, 0.26 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. 10 mL of water was added. The mixture was then extracted with DCM (10 mL x 3). The bound organic layer was washed with water (10 mL x 3), dried over Na2SO4, and concentrated under vacuum. The residue was purified by prep-TLC (MeOH / DCM = 1 / 10) to obtain the desired product as a white solid (27.2 mg, 31.1%). 1H NMR (400 MHz, Methanol-d4) δ 7.27 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.03-6.99 (m, 4H), 4.68 (s, 2H), 4.11 (s, 2H), 3.42 - 3.30 (m, 4H), 3.23 - 3.17 (m, 4H), 2.24 (m, 1H), 1.30 (s, 9H), 0.74 - 0.63 (m, 4H). Mass(m / z): 437.3 [M+H] + .

[0350] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-(4-methyl-3-oxopiperazin-1-yl)acetamide (109) JPEG2026063193000154.jpg78151

[0351] Compound 109 (5.0 mg) was prepared as a white solid with a total yield of 16.3% following the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.29-7.24 (m, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.07-7.00 (m, 4H), 4.69 (s, 2H), 4.21 (s, 2H), 3.90 (s, 2H), 3.70-3.48 (m, 4H), 3.02 (s, 3H), 1.31 (s, 9H). Mass(m / z): 425.4 [M+H] +

[0352] 2-(4-benzoylpiperazine-1-yl)-N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxyacetamide (110) JPEG2026063193000155.jpg62151

[0353] Compound 110 (7.4 mg) was prepared as a white solid with a total yield of 49% according to the procedure for compound 80. 1H NMR (400 MHz, Methanol-d4) δ 7.53 - 7.43 (m, 5H), 7.27 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.03-6.99 (m, 4H), 4.69 (s, 2H), 4.31 (s, 2H), 4.08-3.4 (m, 8H), 1.30 (m, 9H).Mass(m / z): 501.4 [M+H] +

[0354] N-hydroxy-N-(4-((4-(trifluoromethoxy)phenyl)amino)benzyl)pivalamide (111) JPEG2026063193000156.jpg64151

[0355] Compound 111 (28.2 mg) was prepared as a white solid with a total yield of 73.6% according to the procedure for compound 80. 1 H NMR (400 MHz, Chloroform-d) δ 7.20 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 7.06-7.00 (m, 4H), 4.83 (s, 2H), 1.31 (s, 9H).Mass(m / z): 383.1 [M+H] +

[0356] N-(4-((4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)amino)benzyl)-N-hydroxypivalamide (112) JPEG2026063193000157.jpg80151

[0357] Compound 112 (14.5 mg) was prepared as a white solid with a total yield of 33.7% according to the procedure for compound 80. 1H NMR (400 MHz, Chloroform-d) δ 7.58-7.41 (m, 6H), 7.21 (d, J = 8.4 Hz, 2H), 7.16-7.05 (m, 4H), 4.84 (s, 2H), 1.37 (s, 9H), 1.32 (s, 9H).Mass(m / z): 431.4 [M+H] +

[0358] N-hydroxy-N-(4-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)aminobenzyl)pivalamide (113) JPEG2026063193000158.jpg80151

[0359] Compound 113 (7.3 mg) was prepared as a white solid with a total yield of 27.5% according to the procedure for compound 80. 1 H NMR (400 MHz, Chloroform-d) δ 7.67-7.74 (m, 4H), 7.53 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 7.17-7.09 (m, 4H), 4.87 (s, 2H), 1.33 (s, 9H). Mass(m / z): 443.2 [M+H] +

[0360] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-(4-methyl-2-oxopiperazine-1-yl)acetamide (114) JPEG2026063193000159.jpg70151

[0361] Compound 114 (5.7 mg) was prepared as a white solid with a total yield of 13.4% according to the procedure for compound 108. 1H NMR (400 MHz, Methanol-d4) δ 7.31 - 7.24 (m, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.03-7.00 (m, 4H), 4.69 (s, 2H), 4.31 (s, 2H), 4.03 - 3.90 (m, 2H), 3.84 - 3.57 (m, 2H), 3.68-3.59 (m, 2H), 3.48 (s, 3H),1.30 (s, 9H). Mass(m / z): 425.4 [M+H] +

[0362] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-2-(4-(cyclopropanecarbonyl)piperazin-1-yl)-N-hydroxyacetamide (115) JPEG2026063193000160.jpg66151

[0363] Compound 115 (11.4 mg) was prepared as a white solid with a total yield of 81.9% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.27 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.03-7.00 (m, 4H), 4.70 (s, 2H), 4.31 (s, 2H), 4.05 (br s, 4H), 3.48 (br s, 4H), 2.04-1.95 (m, 1H), 1.30 (s, 9H), 0.92 - 0.87 (m, 4H).Mass(m / z): 465.3 [M+H] +

[0364] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-(4-(methylsulfonyl)piperazin-1-yl)acetamide (116) JPEG2026063193000161.jpg67151

[0365] Compound 116 (20.0 mg) was prepared as a white solid with a total yield of 42.2% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.27 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.03-7.00 (m, 4H), 4.69 (s, 2H), 4.33 (s, 2H), 3.54 (br s, 8H), 2.97 (s, 3H), 1.30 (s, 9H).Mass(m / z): 475.4 [M+H] +

[0366] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-2-(3,4-dimethylpiperazine-1-yl)-N-hydroxyacetamide (117) JPEG2026063193000162.jpg71151

[0367] Compound 117 (17.7 mg) was prepared as a white solid with a total yield of 42.0% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.27 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 7.08-6.95 (m, 4H), 4.67 (s, 2H), 3.82 (s, 2H), 3.66-3.33 (m, 7H), 2.91 (s, 3H), 1.38 (d, J = 5.6 Hz, 3H), 1.30 (s, 9H).Mass(m / z): 425.3 [M+H] +

[0368] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-2-(4-(4-fluorophenyl)piperazin-1-yl)-N-hydroxyacetamide (118) JPEG2026063193000163.jpg72151

[0369] Compound 118 (9.0 mg) was prepared as a white solid with a total yield of 30.6% following the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.27 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.07-6.97 (m, 8H), 4.71 (s, 2H), 4.33 (s, 2H), 3.95-2.94 (m, 8H), 1.30 (s, 9H). Mass(m / z): 491.2 [M+H] +

[0370] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-4-methylpiperazine-1-carboxamide (119) JPEG2026063193000164.jpg63146

[0371] Compound 119 (13.3 mg) was prepared as a white solid with a total yield of 33.6% according to the procedure for compound 134. 1 H NMR (400 MHz, Methanol-d4) δ 7.26 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.03-6.99 (m, 4H), 4.44 (s, 2H), 3.60 - 3.39 (m, 4H), 3.29 - 3.16 (m, 4H), 2.91 (s, 3H), 1.30 (s, 9H). Mass(m / z): 397.3 [M+H] +

[0372] N-hydroxy-2-(4-methylpiperazine-1-yl)-N-(4-((4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)benzyl)acetamide (120) JPEG2026063193000165.jpg56151

[0373] Compound 120 (13.4 mg) was prepared as a white solid with a total yield of 6.6% according to the procedure for compound 108.1 H NMR (400 MHz, Methanol-d4) δ 7.15 (d, J = 8.0 Hz, 2H), 7.03(d, J = 8.0 Hz, 2H), 6.97 - 6.85 (m, 4H), 4.65 (s, 2H), 4.45 (m, 1H), 4.00-3.89 (m, 2H), 3.81 (s, 2H), 3.62-3.53 (m, 2H), 3.39 (br s, 4H), 3.17 (br s, 4H), 2.91 (s, 3H), 2.08-1.94 (m, 2H), 1.77-1.65 (m, 2H). Mass(m / z): 455.3 [M+H] +

[0374] N-(4-((4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)aminobenzyl)-N-hydroxy-2-(4-methylpiperazine-1-yl)acetamide (121) JPEG2026063193000166.jpg65151

[0375] Compound 121 (13.5 mg) was prepared as a white solid with a total yield of 27.7% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.53-7.46 (m, 6H), 7.22 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 4.69 (s, 2H), 3.84 (s, 2H), 3.40 (br s, 4H), 3.20 (br s, 4H), 2.90 (s, 3H), 1.34 (s, 9H). Mass(m / z): 487.3 [M+H] +

[0376] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-2-(4-(6-fluoropyridine-3-yl)piperazine-1-yl)-N-hydroxyacetamide (122) JPEG2026063193000167.jpg67151

[0377] Compound 122 (2.5 mg) was prepared as a white solid with a total yield of 8.5% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.89 (s, 1H), 7.70-7.65 (m, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.03-7.00 (m, 4H), 4.71 (s, 2H), 4.35 (s, 2H), 3.58 (br s, 8H), 1.30 (s, 9H). Mass(m / z): 492.2 [M+H] +

[0378] 4-(dimethylamino)-N-hydroxy-N-(4-((4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)benzyl)butanamide (123) JPEG2026063193000168.jpg53151

[0379] 1 H NMR (400 MHz, Methanol-d4) δ 7.17 (d, J = 8.4 Hz, 2H), 7.02 (d, J= 8.8 Hz, 2H), 6.90 (dd, J = 13.6, 8.8 Hz, 4H), 4.63 (s, 2H), 4.44 (m, 1H), 4.02 - 3.88 (m, 2H), 3.59-3.53 (m, 2H), 2.62-2.55 (m, 4H), 2.35 (s, 6H), 2.06 - 1.85 (m, 4H), 1.77 - 1.63 (m, 2H). Mass(m / z): 428.2 [M+H] + .

[0380] 4-(dimethylamino)-N-hydroxy-N-(4-((4-(N-methylacetamide)phenyl)amino)benzyl)butanamide (124) JPEG2026063193000169.jpg79151

[0381] 1 H NMR (400 MHz, Methanol-d4) δ 7.29 - 7.20 (m, 2H), 7.14-7.04 (m, 6H), 4.69 (s, 2H), 3.20 (s, 3H), 2.85 - 2.74 (m, 2H), 2.67 - 2.57 (m, 2H), 2.53 (s, 6H), 2.02 - 1.89 (m, 2H), 1.86 (s, 3H). Mass(m / z): 399.2 [M+H] + .

[0382] N-hydroxy-N-(4-((4-(2,2,2-trifluoroethoxy)phenyl)amino)benzyl)pivalamide (125) JPEG2026063193000170.jpg68143

[0383] Compound 125 (35.0 mg) was prepared as a white solid with a total yield of 88.4% following the procedure for compound 80. 1 H NMR (400 MHz, Chloroform-d) δ 7.16 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 6.93-6.89 (m, 4H), 4.82 (s, 2H), 4.32 (q, J = 8.4 Hz,, 2H), 1.31 (s, 9H).Mass(m / z): 397.3 [M+H] +

[0384] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)acetamide (126) JPEG2026063193000171.jpg68151

[0385] Compound 126 (29.0 mg) was prepared as a white solid with a total yield of 73.4% following the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.26 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 7.03-6.98 (m, 4H), 4.65 (s, 2H), 3.44 (s, 2H), 3.05 (m, 2H), 2.80-2.57 (m, 8H), 1.30 (s, 9H). Mass(m / z): 479.3 [M+H] +

[0386] N-(4-((4-chlorophenyl)amino)benzyl)-N-hydroxypivalamide (127) JPEG2026063193000172.jpg66133

[0387] Compound 127 (33.2 mg) was prepared as a white solid with a total yield of 98.3% according to the procedure for compound 80. 1 H NMR (400 MHz, Chloroform-d) δ 7.20-7.16 (m, 4H), 6.99-6.94 (m, 4H), 4.78 (s, 2H), 1.30 (s, 9H). Mass(m / z): 333.2 [M+H] +

[0388] N-hydroxy-2-(4-methylpiperazine-1-yl)-N-(4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)aminobenzyl)acetamide (128) JPEG2026063193000173.jpg51151

[0389] Compound 128 (23.4 mg) was prepared as a white solid with a total yield of 45.5% following the procedure for compound 108. 1H NMR (400 MHz, Methanol-d4) δ 7.65 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.34-7.20 (m, 4H), 7.16-7.09 (m, 4H), 4.70 (s, 2H), 3.92 (s, 2H), 3.45 (br s, 4H), 3.29 (br s, 4H), 2.92 (s, 3H). Mass(m / z): 515.3 [M+H] +

[0390] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-((3S,5R)-3,4,5-trimethylpiperazine-1-yl)acetamide (129) JPEG2026063193000174.jpg67151

[0391] Compound 129 (25.5 mg) was prepared as a white solid with a total yield of 90.1% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.30-7.24 (m, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.04-6.99 (m, 4H), 4.67 (s, 2H), 3.82 (s, 2H), 3.55 (br s, 2H), 3.38 (m, 2H), 2.91 (s, 3H), 2.86 (m, 2H), 1.40 (d, J = 6.4 Hz, 6H), 1.30 (s, 9H). Mass(m / z): 439.4 [M+H] +

[0392] N-(4-((4-cyanophenyl)amino)benzyl)-N-hydroxypivalamide (130) JPEG2026063193000175.jpg64144

[0393] Compound 130 (10.0 mg) was prepared as a white solid with a total yield of 30.9% following the procedure for compound 80. 1H NMR (400 MHz, Chloroform-d) δ 7.52-7.41 (m, 2H), 7.33-7.22 (m, 2H), 7.18-7.11 (m, 2H), 7.02-6.91 (m, 2H), 4.88 (s, 2H), 1.32 (s, 9H). Mass(m / z): 324.3 [M+H] +

[0394] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)acetamide (131) JPEG2026063193000176.jpg62151

[0395] Compound 131 (10.6 mg) was prepared as a white solid with a total yield of 39.4% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.27 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.03-6.99 (m, 4H), 4.68 (s, 2H), 4.27 (s, 2H),4.04-3.44 (m, 6H), 3.01 (s, 3H), 2.50 (br s, 2H), 1.30 (s, 9H). Mass(m / z): 423.3 [M+H] +

[0396] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-methoxypivalamide (132) JPEG2026063193000177.jpg69142

[0397] Compound 132 (32.0 mg) was prepared as a white solid with a total yield of 86.9% according to the procedure for compound 80. 1H NMR (400 MHz, Chloroform-d) δ 7.34-7.27 (m, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.04-6.98 (m, 4H), 4.75 (s, 2H), 3.68 (s, 3H), 1.32 (s, 9H), 1.27 (s, 9H). Mass(m / z): 369.3 [M+H] +

[0398] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-(4-(pyrimidine-2-yl)piperazin-1-yl)acetamide (133) JPEG2026063193000178.jpg67151

[0399] Compound 133 (38.4 mg) was prepared as a white solid with a total yield of 45.3% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 8.31 (d, J = 4.4 Hz, 2H), 7.32 - 7.08 (m, 4H), 7.08 - 6.89 (m, 4H), 6.59 (t, J = 4.4 Hz, 1H), 4.67 (s, 2H), 3.91 (br s, 4H), 3.69 (s, 2H), 2.86 (br s, 4H), 1.28 (s, 9H).Mass(m / z): 475.2 [M+H] +

[0400] 1-(4-((4-(tert-butyl)phenyl)amino)benzyl)-3-cyclopropyl-1-hydroxyurea (134) JPEG2026063193000179.jpg30151

[0401] To a solution of 4-(tert-butyl)-N-(4-((hydroxyamino)methyl)phenyl)aniline (27.1 mg, 0.1 mmol) in DCM (2 mL), triphosgene (29.7 mg, 0.1 mmol) and DIEA (39 mg, 0.3 mmol) were added. After stirring the reaction mixture for 2 hours, DIEA (39 mg, 0.3 mmol) and cyclopropanamine (5.7 mg, 0.1 mmol) were added. The reaction mixture was then stirred for 1 hour. The reaction solution was washed with water (3 x 5 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by prep-TLC (MeOH / DCM = 1 / 10) to obtain the desired product as a yellow solid (21.5 mg, 65.7%). 1 H NMR (400 MHz, Chloroform-d) δ 7.32-7.27 (m, 2H), 7.22 (d, J = 8.4 Hz, 2H), 7.05-6.95 (m, 4H), 4.57 (s, 2H), 2.63 (m, 1H), 1.31 (s, 9H), 0.76-0.71 (m, 2H), 0.60-0.44 (m, 2H).Mass(m / z): 354.2 [M+H] +

[0402] N-(4-((4-(6-fluoropyridine-3-yl)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazine-1-yl)acetamide (135) JPEG2026063193000180.jpg65151

[0403] Compound 135 (12.0 mg) was prepared as a white solid with a total yield of 26.7% according to the procedure for compound 108. 1H NMR (400 MHz, Methanol-d4) δ 8.37 (d, J = 2.8 Hz, 1H), 8.13 (ddd, J = 8.4, 7.6, 2.8 Hz, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.29 - 7.21 (m, 2H), 7.20 - 7.14 (m, 2H), 7.13-7.08 (m, 3H), 4.71 (s, 2H), 3.94 (s, 2H), 3.45 (br s, 4H), 3.29 (br s, 4H), 2.93 (s, 3H). Mass(m / z): 450.2 [M+H] +

[0404] N-hydroxy-2-(4-methylpiperazine-1-yl)-N-(4-((4-(pyrrolidine-1-yl)phenyl)aminobenzyl)acetamide (136) JPEG2026063193000181.jpg57151

[0405] Compound 136 (5.1 mg) was prepared as a white solid with a total yield of 13.2% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.38-6.68 (m, 8H), 4.65 (s, 2H), 3.55 (s, 2H), 3.27 - 3.15 (m, 4H), 2.89 (br s, 8H), 2.80 (s, 3H), 2.09 - 1.85 (m, 4H). Mass(m / z): 424.3 [M+H] +

[0406] N-hydroxy-2-(4-methylpiperazine-1-yl)-N-(4-((4-(1-methylpiperidine-4-yl)phenyl)aminobenzyl)acetamide (137) JPEG2026063193000182.jpg62151

[0407] DMT-MM (151 mg, 0.55 mmol) was added to a solution of 4-((hydroxyamino)methyl)-N-(4-(1-methylpiperidine-4-yl)phenyl)aniline (130 mg, 0.42 mmol), 2-(4-methylpiperazine-1-yl)acetic acid (66 mg, 0.42 mmol), and DIEA (129 mg, 1 mmol) in DMF (1 ml). The mixture was then stirred at room temperature for 3 hours. The reaction product was concentrated under vacuum. The residue was purified by perp-TLC to obtain the desired product as a white solid (6 mg, 1.6%). 1 H NMR (400 MHz, Methanol-d4) δ 7.20 - 7.16 (m, 2H), 7.15 - 7.10 (m, 2H), 7.06 - 6.99 (m, 4H), 4.67 (s, 2H), 3.77 (s, 2H), 3.62 - 3.56 (m, 2H), 3.41 - 3.32 (m, 4H), 3.19 - 3.07 (m, 6H), 2.90 (d, J = 5.1 Hz, 6H), 2.82 - 2.75 (m, 1H), 2.12 - 2.05 (m, 2H), 1.99 - 1.86 (m, 2H). Mass(m / z): 452.3 [M+H] + .

[0408] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((4-morpholinophenyl)amino)benzyl)acetamide (138) JPEG2026063193000183.jpg59151

[0409] Compound 138 (38.1 mg) was prepared as a white solid with a total yield of 86.5% following the procedure for compound 108. 1H NMR (400 MHz, Methanol-d4) δ 7.13 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 6.93-6.86 (m, 4H), 4.63 (s, 2H), 3.84 - 3.69 (m, 4H), 3.39 (s, 2H), 3.07 - 2.91 (m, 4H), 2.75-2.46 (m, 8H), 2.29 (s, 3H). Mass(m / z): 440.2 [M+H] +

[0410] N-hydroxy-2-(4-methylpiperazine-1-yl)-N-(4-((4-(2-oxopyridine-1(2H)-yl)phenyl)aminobenzyl)acetamide (139) JPEG2026063193000184.jpg74151

[0411] Compound 139 (5 ​​mg) was prepared according to the procedure for compound 137 from 1-(4-((4-((hydroxyamino)methyl)phenyl)amino)phenyl)pyridine-2(1H)-one (100 mg, 0.33 mmol), 2-(4-methylpiperazin-1-yl)acetic acid (52 mg, 0.33 mmol), and DMT-MM (118 mg, 0.43 mmol) as a yellow solid with a total yield of 3.4%. 1 H NMR (400 MHz, Methanol-d4) δ 7.64 - 7.57 (m, 2H), 7.27 - 7.10 (m, 8H), 6.63 (dd, J = 10.0, 1.4 Hz, 1H), 6.48 (td, J = 6.8, 1.4 Hz, 1H), 4.70 448.3 Mass(m / z): [M+H] +

[0412] N-hydroxy-N-(4-((4-(2-methoxyethoxy)phenyl)amino)benzyl)-2-(4-methylpiperazine-1-yl)acetamide (140) JPEG2026063193000185.jpg62151

[0413] Compound 140 (16 mg) of the title compound was prepared according to the procedure in 137 from 4-((hydroxyamino)methyl)-N-(4-(2-methoxyethoxy)phenyl)aniline (60 mg, 0.21 mmol), 2-(4-methylpiperazin-1-yl)acetic acid (33 mg, 0.21 mmol), and DMT-MM (63 mg, 0.23 mmol) as a white solid with a total yield of 18.0%. 1H NMR (400 MHz, Methanol-d4) δ 7.16 - 7.10 (m, 2H), 7.06 - 7.01 (m, 2H), 6.92 - 6.82 (m, 4H), 4.63 (s, 2H), 4.09 - 4.04 (m, 2H), 3.74 - 3.70 (m, 2H), 3.55 (s, 2H), 3.42 (s, 3H), 3.24 - 3.08 (m, 4H), 2.98 - 2.82 (m, 4H), 2.78 (s, 3H). Mass(m / z):429.4 [M+H] + .

[0414] N-hydroxy-N-(4-((4-(N-methylacetamide)phenyl)amino)benzyl)-2-(4-methylpiperazine-1-yl)acetamide (141) JPEG2026063193000186.jpg62151

[0415] Compound 141 (10.1 mg) was prepared as a white solid with a total yield of 23.8% according to the procedure for compound 108. 1H NMR (400 MHz, Methanol-d4) δ 7.38-7.32 (m, 2H), 7.24-7.17 (m, 6H), 4.80 (s, 2H), 3.92 (s, 2H), 3.50 (br s, 4H), 3.44 - 3.38 (m, 3H), 3.35 - 3.18 (br s, 4H), 3.01 (s, 3H), 1.97 (s, 3H). Mass(m / z): 426.3 [M+H] +

[0416] 4-(dimethylamino)-N-hydroxy-N-(4-((4-(piperidine-1-carbonyl)phenyl)amino)benzyl)butanamide (142) JPEG2026063193000187.jpg78151

[0417] Compound 142 (8 mg) was prepared according to the procedure in 137 from (4-((4-((hydroxyamino)methyl)phenyl)amino)phenyl)(piperidine-1-yl)methanone (32.5 mg, 0.1 mmol), 4-(dimethylamino)butanoic acid hydrochloride (16.7 mg, 0.1 mmol), DMT-MM (63 mg, 0.23 mmol), DIEA (38.7 mg, 0.3 mmol), and DMF (1 mL) as a white solid with a total yield of 18.32%. 1H NMR (400 MHz, Methanol-d4) δ 7.30 - 7.23 (m, 4H), 7.15 - 7.05 (m, 4H), 4.71 (s, 2H), 3.65 - 3.46 (m, 4H), 3.15 - 3.06 (m, 2H), 2.85 (s, 6H), 2.67 (t, J = 6.9 Hz, 2H), 2.05 - 1.93 (m, 2H), 1.74 - 1.56 (m, 6H). Mass (m / z): 439.3 [M+H]+.

[0418] N-(4-((4-butoxyphenyl)amino)benzyl)-4-(dimethylamino)-N-hydroxybutanamide (143) JPEG2026063193000188.jpg48151

[0419] Compound 143 (5.2 mg) was prepared as a white solid with a total yield of 13.8% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.14 (d, J = 8.4 Hz, 2H), 7.06 - 7.00 (m, 2H), 6.92 - 6.80 (m, 4H), 4.65 (s, 2H), 3.94 (m, 2H), 3.13 - 3.05 (m, 2H), 2.83 (s, 6H), 2.65 (t, J = 6.8 Hz, 2H), 2.07 - 1.92 (m, 2H), 1.74 (m, 2H), 1.61 - 1.40 (m, 2H), 0.99 (t, J = 7.6, 3H). Mass(m / z): 400.3 [M+H] +

[0420] N-hydroxy-2-(piperazine-1-yl)-N-(4-((4-(pyrrolidine-1-ylmethyl)phenyl)aminobenzyl)acetamide (144) JPEG2026063193000189.jpg75151

[0421] Compound 144 (19 mg) was prepared according to the procedure in 137 from 4-((hydroxyamino)methyl)-N-(4-(pyrrolidine-1-ylmethyl)phenyl)aniline (52 mg, 0.18 mmol), 2-(4-methylpiperazin-1-yl)acetic acid (28 mg, 0.18 mmol), DMT-MM (53 mg, 0.19 mmol), DIEA (113 mg, 0.88 mmol), and DMF (1 mL) as a white solid with a total yield of 22.5%. 1H NMR (400 MHz, Methanol-d4) δ 7.37 - 7.31 (m, 2H), 7.26 - 7.21 (m, 2H), 7.13 - 7.08 (m, 4H), 4.69 (s, 2H), 4.26 (s, 2H), 3.57 (s, 2H), 3.53 - 3.40 (m, 4H), 3.24 - 3.07 (m, 6H), 2.87 (s, 3H), 2.77 - 2.63 (m, 2H), 2.19 - 2.11 (m, 2H), 2.06 - 1.96 (m, 2H). Mass(m / z): 439.3 [M+H] + .

[0422] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((3-morpholinophenyl)amino)benzyl)acetamide (145) JPEG2026063193000190.jpg65151

[0423] Compound 145 (14.3 mg) was prepared according to the procedure in 137 from N-(4-((hydroxyamino)methyl)phenyl)-3-morpholinoaniline (60 mg, 0.2 mmol), 2-(4-methylpiperazin-1-yl)acetic acid (32 mg, 0.2 mmol), DMT-MM (61 mg, 0.22 mmol), DIEA (78 mg, 0.6 mmol), and DMF (2 mL) as a white solid with a total yield of 16.3%. 1H NMR (400 MHz, Methanol-d4) δ 7.20 - 7.16 (m, 2H), 7.10 (t, J = 8.1 Hz, 1H), 7.05 - 7.01 (m, 2H), 6.66 (t, J = 2.2 Hz, 1H), 6.63 - 6.60 (m, 1H), 6.53 - 6.49 (m, 1H), 4.66 (s, 2H), 3.85 - 3.78 (m, 4H), 3.57 (s, 2H), 3.27 - 3.11 (m, 4H), 3.11 - 3.07 (m, 4H), 2.95 - 2.69 (m, 7H). Mass(m / z):440.3 [M+H] + .

[0424] N-hydroxy-2-(4-methylpiperazine-1-yl)-N-(4-((4-(piperidine-1-yl)phenyl)aminobenzyl)acetamide (146) JPEG2026063193000191.jpg57151

[0425] Compound 146 (5.4 mg) was prepared as a white solid with a total yield of 24.7% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.51 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.18-7.13 (m, 4H), 4.76 (s, 2H), 4.51 (s, 2H), 3.80 (br s, Mass(m / z): 438.2 [M+H] +

[0426] N-hydroxy-2-(4-methylpiperazine-1-yl)-N-(4-((4-(tetrahydro-2H-pyran-4-yl)phenyl)aminobenzyl)acetamide (147) JPEG2026063193000192.jpg67151

[0427] Compound 147 (13.0 mg) was prepared as a white solid with a total yield of 29.6% from 4-((hydroxyamino)methyl)-N-(4-(tetrahydro-2H-pyran-4-yl)phenyl)aniline (29.8 mg, 0.1 mmol), 2-(4-methylpiperazin-1-yl)acetic acid (15.8 mg, 0.1 mmol), DMT-MM (27.6 mg, 0.1 mmol), DIEA (38.7 mg, 0.3 mmol), and DMF (1 mL) according to the procedure for compound 137. 1 H NMR (400 MHz, Methanol-d4) δ 7.17 (d, J = 8.2 Hz, 2H), 7.12 - 7.07 (m, 2H), 7.04 - 6.97 (m, 4H), 4.65 (s, 2H), 4.02 (dt, J = 11.1, 3.0 Hz, Mass(m / z):439.3 [M+H] + .

[0428] N-hydroxy-N-(4-((4-(4-hydroxypiperidine-1-yl)phenyl)amino)benzyl)-2-(4-methylpiperazine-1-yl)acetamide (148) JPEG2026063193000193.jpg58151

[0429] Compound 148 (2.9 mg) was prepared as a white solid with a total yield of 16.0% following the procedure for compound 108. 1H NMR (400 MHz, Methanol-d4) δ 7.51 - 6.54 (m, 8H), 4.62 (s, 2H), 3.91 (m, 1H), 3.56 (s, 2H), 3.35 (br s, 8H), 3.28-3.21 (m, 2H), 2.99 - 2.86 (m, 2H), 2.83 (s, 3H), 2.04-1.99 (m, 2H), 1.79-1.68 (m, 2H). Mass(m / z): 454.3 [M+H] +

[0430] N-(4-((4-(6-fluoropyridine-3-yl)phenyl)amino)benzyl)-N-hydroxy-1-methylpiperidine-4-carboxamide (149) JPEG2026063193000194.jpg62151

[0431] Compound 149 (5.3 mg) was prepared as a white solid with a total yield of 24.4% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 8.38 (d, J = 2.8 Hz, 1H), 8.14 (ddd, J = 8.3, 7.6, 2.8 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.27 - 7.07 (m, 7H), 4.70 (s, 2H), 3.57-3.48 (m, 2H), 3.29-3.20 (m, 1H), 3.17-3.04 (m, 2H), 2.86 (s, 3H), 2.18 - 1.85 (m, 4H).. Mass(m / z): 435.3 [M+H] +

[0432] N-hydroxy-2-(4-methylpiperazine-1-yl)-N-(4-((4-pentylphenyl)amino)benzyl)acetamide (150) JPEG2026063193000195.jpg66151

[0433] Compound 150 (20.0 mg) of the title compound was prepared according to the procedure in 137 from 4-((hydroxyamino)methyl)-N-(4-pentylphenyl)aniline (56.8 mg, 0.2 mmol), 2-(4-methylpiperazin-1-yl)acetic acid (31.6 mg, 0.2 mmol), DMT-MM (60.0 mg, 0.22 mmol), DIEA (76.0 mg, 0.6 mmol), and DMF (1.5 mL) as a white solid with a total yield of 23.8%. 1H NMR (400 MHz, Methanol-d4) δ 7.18 - 7.13 (m, 2H), 7.06 - 7.01 (m, 2H), 7.01 - 6.92 (m, 4H), 4.65 (s, 2H), 3.48 (s, 2H), 2.94 - 2.66 (m, Mass(m / z):425.3 [M+H] + .

[0434] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((4-phenoxyphenyl)amino)benzyl)acetamide (151) JPEG2026063193000196.jpg59151

[0435] Compound 151 (30.0 mg) was prepared according to the procedure in 137 from 4-((hydroxyamino)methyl)-N-(4-phenoxyphenyl)aniline (50.0 mg, 0.16 mmol), 2-(4-methylpiperazin-1-yl)acetic acid (25 mg, 0.16 mmol), DMT-MM (49.0 mg, 0.18 mmol), DIEA (62.0 mg, 0.48 mmol), and DMF (2.0 mL) as a white solid with a total yield of 42.0%. 1H NMR (400 MHz, Methanol-d4) δ 7.33 - 7.27 (m, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.11 - 7.06 (m, 2H), 7.05 - 6.98 (m, 3H), 6.95 - 6.89 (m, 4H), 4.65 (s, 2H), 3.48 (s, 2H), 2.96 - 2.72 (m, 2H), 2.55 (s, 3H). Mass(m / z):447.3 [M+H] + .

[0436] N-hydroxy-2-(4-methylpiperazine-1-yl)-N-(4-((4-(pyridine-4-yl)phenyl)aminobenzyl)acetamide (152) JPEG2026063193000197.jpg59151

[0437] Compound 152 (5.8 mg) was prepared as a white solid with a total yield of 23.2% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 8.63 (d, J = 6.8 Hz, 2H), 8.26 (d, J = 7.2 Hz, 2H), 7.94 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.24-7.19 (m, 4H), 4.75 (s, 2H), 3.73 (s, 2H), 3.45-3.27 (m, 4H), 3.18-2.97 (m, 4H), 2.90 (s, 3H).Mass(m / z): 432.2 [M+H] +

[0438] N-(4-((4-cyclohexylphenyl)amino)benzyl)-4-(dimethylamino)-N-hydroxybutanamide (153) JPEG2026063193000198.jpg63151

[0439] Compound 153 (12.1 mg) was prepared as a white solid with a total yield of 29.3% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.17 (d, J = 8.4 Hz, 2H), 7.07 (d, J= 8.4 Hz, 2H), 7.03 - 6.97 (m, 4H), 4.67 (s, 2H), 3.23 - 3.08 (m, 2H), 2.87 (s, 6H), 2.67 (t, J = 6.8 Hz, 2H), 2.50 - 2.37 (m, 1H), 2.07 - 1.92 (m, 2H), 1.90 - 1.78 (m, 4H), 1.49 - 1.35 (m, 4H), 1.35 - 1.21 (m, 2H). Mass(m / z): 410.3 [M+H] +

[0440] N-(4-((4-(cyclohexyloxy)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazine-1-yl)acetamide (154) JPEG2026063193000199.jpg61151

[0441] Compound 154 (14.3 mg) was prepared according to the procedure in 137 from 4-(cyclohexyloxy)-N-(4-((hydroxyamino)methyl)phenyl)aniline (50.0 mg, 0.16 mmol), 2-(4-methylpiperazin-1-yl)acetic acid (28 mg, 0.18 mmol), DMT-MM (53 mg, 0.19 mmol), DIEA (62.0 mg, 0.48 mmol), and DMF (1 mL) as a yellow solid with a total yield of 19.7%. 1H NMR (400 MHz, Methanol-d4) δ 7.15 - 7.10 (m, 2H), 7.04 - 6.98 (m, 2H), 6.91 - 6.87 (m, 2H), 6.86 - 6.81 (m, 2H), 4.63 (s, 2H), 4.22 - 4.16 (m, 2H), 3.56 (s, 2H), 3.28 - 3.14 (m, 4H), 2.99 - 2.78 (m, 7H), 2.02 - 1.92 (m, 2H), 1.86 - 1.75 (m, 2H), 1.60 - 1.33 (m, 6H).Mass(m / z):453.2 [M+H] + .

[0442] N-(4-((4-(tert-butylamino)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazine-1-yl)acetamide (155) JPEG2026063193000200.jpg96151

[0443] Step 1. Preparation of N-(tert-butyl)-4-nitroaniline (155-3). A solution of 1-fluoro-4-nitrobenzene (3 g, 21.3 mg) and 2-methylpropan-2-amine (4.66 g, 63.9 mmol) in DMSO (15 mL) was stirred at 80°C for 18 hours. After cooling to room temperature, 20 mL of water was added. The resulting solution was extracted with 3 x 50 mL of ethyl acetate. The organic layer was bonded, washed with water (3 x 100 mL), dried, and concentrated under vacuum. The residue was passed through a silica gel column and eluted with ethyl acetate / hexane (1 / 20-1 / 5) to obtain the desired product as a yellow solid (3.0 g, 72.6%). Mass (m / z): 195.2 [M+H] + .

[0444] Step 2. Preparation of N1-(tert-butyl)benzene-1,4-diamine (155-4). 10% Pd / C (81.6 mg, 0.08 ml) was added to a solution of N-(tert-butyl)-4-nitroaniline (1.5 g, 7.7 mmol) in EtOH (100 mL). The reaction was then stirred overnight at room temperature under a hydrogen atmosphere. Pd / C was filtered off. The filtrate was concentrated under vacuum to obtain the target product as black oil (1.11 g, 87.4%). Mass (m / z): 165.2 [M+H] + .

[0445] Step 3. Preparation of 4-((4-(tert-butylamino)phenyl)amino)benzaldehyde (155-6). Prepare compound 155-6 (620 mg) according to the procedure in 137-3. 1 A yellow solid was prepared from (tert-butyl)benzene-1,4-diamine (1.11 g, 6.0 mmol), 4-bromobenzaldehyde (740 mg, 4.0 mmol), Pd(dppf)2Cl2 (59 mg, 0.08 mmol), xanthophos (93 mg, 0.16 mmol), and Cs2CO3 (1.96 g, 6.0 mmol) with a total yield of 59.2%. Mass (m / z): 269.2 [M+H] + .

[0446] Step 4. Preparation of (E)-4-((4-(tert-butylamino)phenyl)amino)benzaldehyde oxime (155-7). Compound 155-7 (425 mg) of the title compound was prepared as a crude product with a total yield of 100% as a yellow solid from 4-((4-(tert-butylamino)phenyl)amino)benzaldehyde (404 mg, 1.5 mmol) and hydroxylamine hydrochloride (155 mg, 2.25 mmol) according to the procedure in 137-4. Mass (m / z): 284.2 [M+H] + .

[0447] Step 5. N 1 -(tert-butyl)-N 4Preparation of -(4-((hydroxyamino)methyl)phenyl)benzene-1,4-diamine (155-8). Compound 155-8 (130 mg) was prepared as a yellow solid with a total yield of 30.6% from (E)-4-((4-(tert-butylamino)phenyl)amino)benzaldehyde oxime (425 mg, 1.5 mmol), borane-pyridine complex (279 mg, 3.0 mmol), and 5 mL of 10% HCl, according to the procedure in 137-5. Mass (m / z): 307.2 [M+H] + .

[0448] Step 6. Preparation of N-(4-((4-(tert-butylamino)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (155). Prepare compound 155 (20.0 mg) of the title compound according to procedure 137. 1 -(tert-butyl)-N 4 A yellow solid was prepared from -(4-((hydroxyamino)methyl)phenyl)benzene-1,4-diamine (69 mg, 0.24 mmol), 2-(4-methylpiperazin-1-yl)acetic acid (38 mg, 0.24 mmol), DMT-MM (73 mg, 0.26 mmol), DIEA (93 mg, 0.72 mmol), and DMF (1.0 mL) with a total yield of 20.0%. 1 H NMR (400 MHz, Methanol-d4) δ 7.24 - 7.16 (m, 2H), 7.09 - 6.96 (m, 6H), 4.66 (s, 2H), 3.47 (s, 2H), 2.86 - 2.64 (m, 8H), 2.50 (s, 3H), 1.27 (s, 9H). Mass(m / z):426.3 [M+H] + .

[0449] N-(4-((4-(diethylamino)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (156) JPEG2026063193000201.jpg62151

[0450] Compound 156 (15.9 mg) was prepared as a white solid with a total yield of 37.4% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.34-6.58 (m, 8H), 4.64 (s, 2H), 3.40 (s, 2H), 3.35 (m, 4H), 2.81-2.44 (m, 8H), 2.33 (s, 3H), 1.10 (t, J = 6.8 Hz, 6H). Mass(m / z): 426.3 [M+H] +

[0451] 4-(dimethylamino)-N-hydroxy-N-(4-((4-isopropoxyphenyl)amino)benzyl)butanamide (157) JPEG2026063193000202.jpg67151

[0452] Compound 157 (10.3 mg) was prepared as a yellow solid with a total yield of 13.4% from 4-((hydroxyamino)methyl)-N-(4-isopropoxyphenyl)aniline (54 mg, 0.2 mmol), 4-(dimethylamino)butanoic acid hydrochloride (37 mg, 0.22 mmol), DMT-MM (66 mg, 0.24 mmol), DIEA (77 mg, 0.6 mmol), and DMF (1.0 mL) according to the procedure for compound 137. 1 H NMR (400 MHz, Methanol-d4) δ 7.20 - 7.10 (m, 2H), 7.06 - 6.98 (m, 2H), 6.94 - 6.80 (m, 4H), 4.65 (s, 2H), 4.48 (p, J = 6.2 Hz, 1H), 3.09 - 3.01 (m, 2H), 2.79 (s, 6H), 2.64 (t, J = 7.0 Hz, 2H), 2.03 - 1.95 (m, 2H), 1.28 (d, J = 6.0 Hz, 6H). Mass(m / z):386.3 [M+H] + .

[0453] 4-(dimethylamino)-N-hydroxy-N-(4-((4-propoxyphenyl)amino)benzyl)butanamide (158) JPEG2026063193000203.jpg48151

[0454] Compound 158 (23.5 mg) was prepared as a white solid with a total yield of 60.9% following the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.17 (d, J = 8.4 Hz, 2H), 7.01 (d, J= 8.8 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 4.62 (s, 2H), 3.88 (t, J = 6.4 Hz, 2H), 2.54 (t, J = 7.2 Hz, 2H), 2.38 (t, J = 7. 2 Hz, 2H), 2.14 (s, 6H), 1.91- 1.72 (m, 4H), 1.03 (t, J = 7.2 Hz, 3H). Mass(m / z): 386.1 [M+H] +

[0455] N-(4-((4-(heptyloxy)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazine-1-yl)acetamide (159) JPEG2026063193000204.jpg51151

[0456] Compound 159 (11.6 mg) was prepared as a white solid with a total yield of 24.8% according to the procedure for compound 108. 1H NMR (400 MHz, Methanol-d4) δ 7.13 (d, J = 8.4 Hz, 2H), 7.03 (d, J= 8.8 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 4.64 (s, 2H), 3.93 (t, J = 6.4 Hz, 2H), 3.57 (s, 2H), 3.26 (br s, 4H), 2.92 (br s, 4H), 2.84 (s, 3H), 1.81-1.69 (m, 2H), 1.57-1.18 (m, 8H), 0.96-0.84 (m, 3H). Mass(m / z): 469.3 [M+H] +

[0457] N-(4-((4-(2,6-dimethylmorpholino)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (160) JPEG2026063193000205.jpg66151

[0458] Compound 160 (9.1 mg) was prepared as a white solid with a total yield of 19.4% according to the procedure for compound 108. 1 H NMR (400 MHz, DMSO-d6) δ 7.05 (d, J = 8.0 Hz, 2H), 6.97 (d, J= 8.8 Hz, 2H), 6.86 (m, 4H), 4.52 (s, 2H), 3.68 (m, 2H), 3.51 - 3.21 (m, 6H), 2.94 - 2.61 (m, 8H), 2.49 (s, 3H), 1.13 (d, J = 6.4 Hz, 6H). Mass(m / z): 468.2 [M+H] +

[0459] 2-(4-methylpiperazine-1-yl)-N-(4-((4-(piperidine-1-yl)phenyl)aminobenzyl)acetamide (161) JPEG2026063193000206.jpg61151

[0460] Compound 161 (4.1 mg) was prepared as a white solid with a total yield of 19.5% according to the procedure for compound 163. 1 H NMR (400 MHz, Methanol-d4) δ 7.25 - 6.91 (m, 8H), 4.30 (s, 2H), 3.07 (s, 2H), 3.04 (br s, 4H), 2.59 (br s, 8H), 2.35 (s, 3H), 1.77-1.71 (m, 4H), 1.64 - 1.51 (m, 2H).Mass(m / z): 422.2 [M+H] +

[0461] N-hydroxy-N-(4-((4-(2-methylmorpholino)phenyl)amino)benzyl)-2-(4-methylpiperazin-1-yl)acetamide (162) JPEG2026063193000207.jpg67151

[0462] Compound 162 (37.6 mg) was prepared as a white solid with a total yield of 41.5% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.13 (d, J = 8.0 Hz, 2H), 7.03 (d, J= 8.4 Hz, 2H), 6.97-6.84 (m, 4H), 4.63 (s, 2H), 3.93 (m, 1H), 3.82 - 3.66 (m, 2H), 3.47 (s, 2H), 3.39 -3.28 (m, 4H), 2.80 (br m, 8H), 2.53 (s, 3H), 1.19 (d, J= 6.4 Hz, 3H). Mass(m / z): 454.1 [M+H] +

[0463] 2-(4-methylpiperazine-1-yl)-N-(4-((4-pentylphenyl)amino)benzyl)acetamide (163) JPEG2026063193000208.jpg63151

[0464] Step 1. Preparation of 4-(aminomethyl)-N-(4-pentylphenyl)aniline (163-1): To a solution of (E)-4-((4-pentylphenyl)amino)benzaldehyde oxime (423 mg, 1.5 mmol) in EtOH (20 mL), 10% Pd / C (16 mg, 0.015 ml) and AcOH (0.5 mL) were added. The reaction mixture was then stirred overnight at room temperature under a hydrogen atmosphere. Pd / C was filtered off. The pH of the filtrate was adjusted to 8-9 with sodium carbonate solution. The mixture was then extracted with DCM (20 mL x 3). The combined organic layer was washed with brine (20 mL x 3), dried over Na2SO4, and concentrated to obtain the desired product as a yellow solid (190 mg, 47.3%). 252.3 [M-NH2] + .

[0465] Step 2. Preparation of 2-(4-methylpiperazine-1-yl)-N-(4-((4-pentylphenyl)amino)benzyl)acetamide (163). DIEA (77.4 mg, 0.6 mmol) was added to a solution of 4-(aminomethyl)-N-(4-pentylphenyl)aniline (53.4 mg, 0.2 mmol) and 2-(4-methylpiperazine-1-yl)acetic acid (34.8 mg, 0.22 mmol) in DMF (1 ml). Subsequently, HATU (83.6 mg, 0.22 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. 10 mL of water was added. The mixture was then extracted with DCM (10 mL x 3). The bound organic layer was washed with water (10 mL x 3), dried over Na2SO4, and concentrated under vacuum. The residue was purified by TLC (MeOH / DCM = 1 / 10) to obtain the desired product as a white solid (38.1 mg, 46.7%). 1H NMR (400 MHz, Methanol-d4) δ 7.14 - 7.11 (m, 2H), 7.05 - 7.01 (m, 2H), 7.00 - 6.95 (m, 4H), 4.31 (s, 2H), 3.11 (s, 2H), 2.91 - 2.77 (m, Mass(m / z): 409.4 [M+H] + .

[0466] N-hydroxy-2-(4-methylpiperazine-1-yl)-N-(1-(4-((4-(piperidine-1-yl)phenyl)amino)phenyl)ethyl)acetamide (164) JPEG2026063193000209.jpg69151

[0467] Compound 164 (6.4 mg) was prepared according to the procedure in 137 from 4-(1-(hydroxyamino)ethyl)-N-(4-(piperidine-1-yl)phenyl)aniline (50 mg, 0.16 mmol), 4-(dimethylamino)butanoic acid hydrochloride (25 mg, 0.16 mmol), DMT-MM (44 mg, 0.16 mmol), DIEA (62 mg, 0.48 mmol), and DMF (1.0 mL) as a yellow solid with a total yield of 8.8%. 1 H NMR (400 MHz, Methanol-d4) δ 8.25 - 5.75 (m, 8H), 4.64 - 4.52 (m, 1H), 3.52 (s, 2H), 3.29 - 3.09 (m, 6H), 3.01 - 2.75 (m, 9H), 1.99 - 1.56 (m, 6H), 1.52 (d, J = 7.0 Hz, 3H). Mass(m / z):226.7 [M / 2+H] + .

[0468] N-(4-((4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)amino)benzyl)-4-(dimethylamino)-N-hydroxybutanamide (165) JPEG2026063193000210.jpg57151

[0469] Compound 165 (15.1 mg) was prepared as a white solid with a total yield of 52.3% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.15 (d, J = 8.4 Hz, 2H), 6.98 (d, J= 8.4 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 6.49 (d, J = 8.8 Hz, 2H), 4.83 (s, Mass(m / z): 425.3 [M+H] +

[0470] N-hydroxy-4-(4-methylpiperazine-1-yl)-N-(4-((4-(piperidine-1-yl)phenyl)amino)benzyl)butanamide (166) JPEG2026063193000211.jpg57151

[0471] Compound 166 (7.4 mg) was prepared as a white solid with a total yield of 31.8% according to the procedure for compound 108. 1H NMR (400 MHz, Methanol-d4) δ 7.19 (d, J = 8.0 Hz, 2H), 7.07-6.86 (m, 6H), 4.63 (s, 2H), 3.21 - 2.88 (m, 4H), 2.75 - 2.01 (m, 15H), 1.95-1.85 (m, 2H), 1.81-1.69 (m, 4H), 1.63-1.54 (m, 2H). Mass(m / z): 466.2 [M+H] +

[0472] 2-(dimethylamino)-N-hydroxy-N-(4-((4-(piperidine-1-yl)phenyl)amino)benzyl)acetamide (167) JPEG2026063193000212.jpg68151

[0473] Compound 167 (11.1 mg) was prepared as a white solid with a total yield of 58.1% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.15 (d, J = 8.0 Hz, 2H), 7.02-6.74 (m, 6H), 4.67 (s, 2H), 3.94 (s, 2H), 3.05 (br s, 4H), 2.75 (s, 6H), 1.77-1.72 (m, 4H), 1.63-1.54 (m, 2H). Mass(m / z): 383.2 [M+H] +

[0474] N-(4-((4-(4,4-difluoropiperidine-1-yl)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazine-1-yl)acetamide JPEG2026063193000213.jpg71151

[0475] Compound 168 (15.0 mg) was prepared as a white solid with a total yield of 35.5% from 4-(4,4-difluoropiperidine-1-yl)-N-(4-((hydroxyamino)methyl)phenyl)aniline (30 mg, 0.090 mmol) and 2-(4-methylpiperazine-1-yl)acetic acid (18 mg, 0.117 mmol) according to the procedure of 174. ¹H NMR (400 MHz, Methanol-d4) δ 1 H NMR (400 MHz, Methanol-d4) δ 7.13 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 6.93 (t, J= 10.0 Hz, 4H), 4.63 (s, 2H), 3.47 (s, 2H), 3.22 (s, 4H), 2.80 (d, J = 36.8 Hz, 8H), 2.53 (s, 3H), 2.08 (tt, J = 13.6, 5.7 Hz, 5H).Mass(m / z): 574.3 [M+H] + .

[0476] N-hydroxy-2-(1-methylpiperidine-4-yl)-N-(4-((4-(piperidine-1-yl)phenyl)aminobenzyl)acetamide (169) JPEG2026063193000214.jpg64151

[0477] Compound 169 (12.0 mg) was prepared as a white solid with a total yield of 55.0% following the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.31-6.77 (m, 8H), 4.63 (s, 2H), 3.56 - 3.39 (m, 4H), 3.11-2.93 (m, 4H), 2.84 (s, 3H), 2.52 (d, J = 6.8 Hz, 2H), 2.11 (br s, 1H), 1.99-1.55 (m, 10H).Mass(m / z): 437.2 [M+H] +

[0478] N-(4-((4-butoxyphenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazine-1-yl)acetamide (170) JPEG2026063193000215.jpg55151

[0479] 1 H NMR (400 MHz, Methanol-d4) δ 7.13 (d, J = 8.4 Hz, 2H), 7.03 (d, J= 8.8 Hz, 2H), 6.93 - 6.79 (m, 4H), 4.64 (s, 2H), 3.94 (t, J = 6.4Hz, 2H), 3.57 (s, 2H), 3.24 (br s, 4H), 2.90 (br s, 4H), 2.83 (s, 3H), 1.82 - 1.66 (m, 2H), 1.57 - 1.42 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H).Mass(m / z): 427.3 [M+H] + .

[0480] N-hydroxy-N-(4-((4-(piperidine-1-yl)phenyl)aminobenzyl)quinuclidine-4-carboxamide (171) JPEG2026063193000216.jpg67151

[0481] Compound 171 (15.4 mg) was prepared as a white solid with a total yield of 25.2% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.37 - 6.73 (m, 8H), 4.64 (s, 2H), 3.49 - 3.34 (m, 6H), 3.26 - 3.07 (m, 4H), 2.37-2.25 (m, 6H), 2.04 - 1.51 (m, 6H). Mass(m / z): 435.3 [M+H] +

[0482] N-hydroxy-1-methyl-5-oxo-N-(4-((4-(piperidine-1-yl)phenyl)amino)-2-(trifluoromethyl)benzyl)pyrrolidine-3-carboxamide (172) JPEG2026063193000217.jpg67151

[0483] DMT-MM (33.1 mg, 0.12 mmol) was added to a solution of 4-((hydroxyamino)methyl)-N-(4-(piperidine-1-yl)phenyl)-3-(trifluoromethyl)aniline (36.5 mg, 0.1 mmol), 1-methyl-5-oxopyrrolidine-3-carboxylic acid (21.6 mg, 0.15 mmol), and DIEA (38.7 mg, 0.3 mmol) in DMF (1 ml), and the reaction mixture was stirred at room temperature for 3 hours. 5 mL of water was added. The mixture was then extracted with DCM (5 mL x 3). The bound organic layer was washed with water (10 mL x 3), dried over Na2SO4, and concentrated under vacuum. The residue was purified by prep-TLC (MeOH / DCM = 1 / 10) to obtain the desired product as a yellow solid (16.4 mg, 33.5%). 1 H NMR (400 MHz, Methanol-d4) δ 7.25 - 7.18 (m, 2H), 7.13 - 6.99 (m, 5H), 4.86 (s, 2H), 3.86 - 3.78 (m, 1H), 3.70 (t, J = 9.6 Hz, 1H), 3.62 - 3.55 (m, 1H), 3.14 - 3.06 (m, 4H), 2.84 (s, 3H), 2.66 (t, J = 7.7 Hz, 2H), 1.79 - 1.71 (m, 4H), 1.62 - 1.55 (m, 2H). Mass(m / z): 491.3 [M+H] +

[0484] 5-(dimethylamino)-N-hydroxy-N-(4-((4-(piperidine-1-yl)phenyl)amino)benzyl)pentanamide (173) JPEG2026063193000218.jpg54151

[0485] Compound 173 (21.1 mg) was prepared as a white solid with a total yield of 51.2% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.37 - 6.65 (m, 8H), 4.67 (s, 2H), 3.19-3.03 (m, 4H), 2.87 (m, 2H), 2.84 (s, 6H), 2.70 - 2.50 (m, 2H), 1.90 - 1.42 (m, 10H). Mass(m / z): 425.2 [M+H] +

[0486] N-hydroxy-2-(4-methylpiperazine-1-yl)-N-(4-((4-(4-methylpiperidine-1-yl)phenyl)aminobenzyl)acetamide (174) JPEG2026063193000219.jpg27151

[0487] To a solution of 4-((hydroxyamino)methyl)-N-(4-(4-methylpiperidine-1-yl)phenyl)aniline (30 mg, 0.096 mmol) and 2-(4-methylpiperazine-1-yl)acetic acid (20 mg, 0.125 mmol) in DMF (3 mL), DMT-MM (37 mg, 0.125 mmol) and DIPEA (16 mg, 0.125 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The mixture was extracted with EA (25 mL x 3). The bound organic layer was washed with brine (15 mL x 3), dried over Na2SO4, and concentrated to obtain the crude product, which was purified by TLC (MeOH / DCM = 1:8) to obtain the desired product as a white solid (13.2 mg, 30.0%). 1H NMR (400 MHz, Methanol-d4) δ 7.20 - 6.81 (m, 8H), 4.64 (s, 2H), 3.46 (s, 2H), 2.80 (d, J = 36.0 Hz, 9H), 2.52 (s, 3H), 1.76 (s, 2H), 1.55 - 1.26 (m, 5H), 0.99 (d, J = 6.4 Hz, 3H).Mass(m / z): 452.3 [M+H] + .

[0488] N-hydroxy-2-(4-methylpiperazine-1-yl)-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)acetamide (175) JPEG2026063193000220.jpg63151

[0489] Compound 175 (16.3 mg) was prepared as a white solid with a total yield of 39.2% from 4-((hydroxyamino)methyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (30 mg, 0.082 mmol) and 2-(4-methylpiperazine-1-yl)acetic acid (17 mg, 0.107 mmol) according to the procedure for compound 174. 1 H NMR (400 MHz, Methanol-d4) δ 7.43 - 6.70 (m, 8H), 4.65 (s, 2H), 3.58 - 3.50 (m, 2H), 3.28 - 3.12 (m, 4H), 2.96 - 2.83 (m, 3H), 2.80 (d, J = 2.0 Hz, 3H), 2.35 - 2.14 (m, 2H), 2.01 (s, 2H), 1.72 (s, 3H).Mass(m / z): 506.3 [M+H] + .

[0490] 2-(4-methylpiperazine-1-yl)-N-(2,2,2-trifluoro-1-(4-((4-(piperidine-1-yl)phenyl)amino)phenyl)ethyl)acetamide (176) JPEG2026063193000221.jpg68151

[0491] Compound 176 (8.0 mg) was prepared as a yellow solid with a total yield of 23.5% from 4-(1-amino-2,2,2-trifluoroethyl)-N-(4-(piperidine-1-yl)phenyl)aniline (25 mg, 0.07 mmol), 2-(4-methylpiperazin-1-yl)acetic acid (12.5 mg, 0.08 mmol), DIEA (27 mg, 0.21 mmol), and HATU (30.4 mg, 0.08 mmol) according to the procedure of compound 163. 1H NMR (400 MHz, Methanol-d4) δ 7.31 - 7.20 (m, 2H), 7.15 - 6.88 (m, 6H), 5.63 - 5.54 (m, 1H), 3.34 (s, 2H), 3.23 - 3.05 (m, 8H), 2.87 - 2.70 (m, 7H), 1.81 - 1.72 (m, 4H), 1.64 - 1.56 (m, 2H). Mass(m / z): 490.3 [M+H] + .

[0492] N-hydroxy-2-(4-methylpiperazine-1-yl)-N-(4-((4-(3-methylpiperidine-1-yl)phenyl)aminobenzyl)acetamide (177) JPEG2026063193000222.jpg73151

[0493] Compound 177 (28.3 mg) was prepared as a white solid with a total yield of 61.9% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.26-6.77 (m, 8H), 4.64 (s, 2H), 3.54-3.39 (m, 6H), 2.78 (br s, 8H), 2.49 (s, 3H), 1.88-1.54 (m, 5H), 0.96 (d, J = 6.8 Hz,, 3H). Mass(m / z): 452.4 [M+H] +

[0494] N-hydroxy-2-(4-methylpiperazine-1-yl)-N-(4-((4-(2-methylpiperidine-1-yl)phenyl)aminobenzyl)acetamide (178) JPEG2026063193000223.jpg62151

[0495] Compound 178 (34.2 mg) was prepared as a white solid with a total yield of 75.7% following the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.12 (d, J = 8.0 Hz, 2H), 7.04-6.89 (m, 6H), 4.61 (s, 2H), 3.38 (s, 2H), 3.06 - 2.80 (m, 3H), 2.60 (br s, 8H), 2.30 (s, 3H), 1.88-1.42 (m, 6H), 0.86 (d, J = 6.4 Hz, 3H). Mass(m / z): 452.4 [M+H] +

[0496] 2-(4-methyl-3-oxopiperazine-1-yl)-N-(4-((4-(piperidine-1-yl)-3-(trifluoromethyl)phenyl)amino)benzyl)acetamide (179) JPEG2026063193000224.jpg25151

[0497] To a solution of N-(4-(aminomethyl)phenyl)-4-(piperidine-1-yl)-3-(trifluoromethyl)aniline (30 mg, 0.086 mmol) and 2-(4-methyl-3-oxopiperazine-1-yl)acetic acid hydrochloride (20 mg, 0.112 mmol) in DMF (3 mL), DMT-MM (33 mg, 0.112 mmol) and DIPEA (15 mg, 0.112 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The mixture was extracted with EA (25 mL x 3). The bound organic layer was washed with brine (15 mL x 3), dried over Na2SO4, and concentrated to obtain the crude product, which was purified by TLC (MeOH / DCM = 1:10) to obtain the desired product as a white solid (41.2 mg, 89.1%). 1 H NMR (400 MHz, Methanol-d4) δ 7.30 (d, J = 8.5 Hz, 1H), 7.25 - 7.16 (m, 4H), 7.04 - 6.99 (m, 2H), 4.33 (s, 2H), 3.38 (dd, J = 6.3, 4.7 Hz, 2H), 3.19 (s, 2H), 3.15 (s, 2H), 2.92 (s, 3H), 2.77 (q, J = 5.4 Hz, 6H), 1.65 (p, J = 5.6 Hz, 4H), 1.58 - 1.49 (m, 2H). Mass (m / z): 504.3 [M+H] + .

[0498] N-(4-((4-(azocan-1-yl)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazine-1-yl)acetamide (180) JPEG2026063193000225.jpg63151

[0499] Compound 180 (16.1 mg) was prepared as a white solid with a total yield of 34.6% following the procedure for compound 108. 1H NMR (400 MHz, Methanol-d4) δ 7.35 - 6.49 (m, 8H), 4.62 (s, 2H), 3.47 (s, 2H), 3.25 - 3.17 (m, 4H),2.95 (br s, 4H), 2.78 (br s, 4H), 2.60 (s, 3H), 1.81-1.66 (m, 4H), 1.64-1.49 (m, 6H). Mass(m / z): 466.2 [M+H] +

[0500] N-(4-((4-(azetidine-1-yl)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazine-1-yl)acetamide (181) JPEG2026063193000226.jpg64151

[0501] Compound 181 (9.1 mg) was prepared according to the procedure in 137 from 4-(azetidine-1-yl)-N-(4-((hydroxyamino)methyl)phenyl)aniline (26.9 mg, 0.1 mmol), 4-(dimethylamino)butanoic acid hydrochloride (15.8 mg, 0.1 mmol), DMT-MM (26.7 mg, 0.1 mmol), DIEA (38.7 mg, 0.3 mmol), and DMF (1.0 mL) as a yellow solid with a total yield of 20.0%. 1 H NMR (400 MHz, Methanol-d4) δ 6.99 - 6.94 (m, 8H), 4.63 (s, 2H), 3.54 (s, 2H), 3.28 - 3.01 (m, 6H), 2.99 - 2.61 (m, 7H), 2.38 - 2.27 (m, 2H).Mass(m / z):410.3 [M+H] + .

[0502] N-(4-((4-(4-fluoropiperidine-1-yl)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazine-1-yl)acetamide (182) JPEG2026063193000227.jpg62151

[0503] To a solution of 4-(4-fluoropiperidine-1-yl)-N-(4-((hydroxyamino)methyl)phenyl)aniline (30 mg, 0.095 mmol) and 2-(4-methylpiperazine-1-yl)acetic acid (20 mg, 0.124 mmol) in DMF (3 mL), DMT-MM (37 mg, 0.125 mmol) and DIPEA (16 mg, 0.125 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The mixture was extracted with EA (25 mL x 3). The bound organic layer was washed with brine (15 mL x 3), dried over Na2SO4, and concentrated to obtain the crude product, which was purified by TLC (MeOH / DCM = 1:8) to obtain the desired product as a white solid (8.1 mg, 29%). 1 H NMR (400 MHz, Methanol-d4) δ 7.14 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 34.2 Hz, 6H), 4.64 (s, 2H), 3.51 - 3.45 (m, 2H), 3.29 - 3.19 (m, 2H), 3.06 (d, J = 8.6 Hz, 2H), 2.83 (d, J = 45.6 Hz, 10H), 2.55 (s, 3H), 2.12 - 1.87 (m, 6H).Mass(m / z): 456.3 [M+H] + .

[0504] N-hydroxy-2-(4-methylpiperazine-1-yl)-N-(4-((4-(3-(trifluoromethyl)pyrrolidine-1-yl)phenyl)amino)benzyl)acetamide (183) JPEG2026063193000228.jpg73151

[0505] Compound 183 (25.1 mg) was prepared according to the procedure for compound 182 from 4-((hydroxyamino)methyl)-N-(4-(3-(trifluoromethyl)pyrrolidine-1-yl)phenyl)aniline (30 mg, 0.086 mmol) and 2-(4-methylpiperazine-1-yl)acetic acid (18 mg, 0.111 mmol) as a greenish-white substance with a total yield of 60%. 1 H NMR (400 MHz, Methanol-d4) δ 7.54 - 6.58 (m, 8H),4.63(s, 2H), 3.77 - 3.57 (m, 2H), 3.55 - 3.47 (m, 2H), 3.02 (s, 4H), 2.83 (s, 4H), 2.66 (s, 3H), 2.36 - 2.06 (m, 3H), 1.35 - 1.23 (m, 2H).Mass(m / z): 492.3 [M+H] + .

[0506] N-(4-((4-(3,3-difluoropiperidine-1-yl)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazine-1-yl)acetamide (184) JPEG2026063193000229.jpg76151

[0507] Compound 184 (10.0 mg) was prepared according to the procedure in 137 from 4-(3,3-difluoropiperidine-1-yl)-N-(4-((hydroxyamino)methyl)phenyl)aniline (33.3 mg, 0.1 mmol), 4-(dimethylamino)butanoic acid hydrochloride (15.8 mg, 0.1 mmol), DMT-MM (26.7 mg, 0.1 mmol), DIEA (38.7 mg, 0.3 mmol), and DMF (1.0 mL) as a yellow solid with a total yield of 21.1%. 1H NMR (400 MHz, Methanol-d4) δ 7.16 - 7.11 (m, 2H), 7.06 - 6.94 (m, 2H), 6.98 - 6.89 (m, 4H), 4.64 (s, 2H), 3.54 (s, 2H), 3.25 (t, J = 11.4 Mass(m / z):237.7 [M / 2+H] + .

[0508] N-hydroxy-1-isopropyl-N-(4-((4-(piperidine-1-yl)phenyl)amino)benzyl)piperidine-4-carboxamide (185) JPEG2026063193000230.jpg59151

[0509] Compound 185 (12.3 mg) was prepared as a white solid with a total yield of 40.7% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.28-6.77 (m, 8H), 4.66 (s, 2H), 3.55-3.43 (m, 4H), 3.30-3.20 (m, 1H), 3.18-3.04 (m, 4H), 2.22 - 1.88 (m, 5H), 1.87-1.71 (m, 4H), 1.67-1.52 (m, 2H), 1.35 (d, J = 6.8 Hz, 6H). Mass(m / z): 451.3 [M+H] +

[0510] 1-Isopropyl-N-(4-((4-(piperidine-1-yl)phenyl)amino)benzyl)piperidine-4-carboxamide (186) JPEG2026063193000231.jpg63151

[0511] Compound 186 (16.1 mg) was prepared as a white solid with a total yield of 43.1% according to the procedure for compound 163. 1 H NMR (400 MHz, Methanol-d4) δ 7.26 - 6.78 (m, 8H), 4.26 (s, 2H), 3.61 - 3.40 (m, 4H), 3.23 - 2.87 (m, 5H), 2.57 (m, 1H), 2.16 - 1.91 (m, Mass(m / z): 435.3 [M+H] +

[0512] N-hydroxy-2-(4-methylpiperazine-1-yl)-N-(4-((4-(3-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)acetamide (187) JPEG2026063193000232.jpg68151

[0513] Compound 187 (16.5 mg) was prepared as a white solid with a total yield of 32.7% following the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.14 (d, J = 8.4 Hz, 2H), 7.03 (d, J= 8.4 Hz, 2H), 6.93 (d, J = 8.0 Hz, 4H), 4.64 (s, 2H), 3.63 (m, 1H), 3.55 - 3.38 (s, 2H), 2.97 - 2.49 (m, 12H), 2.45 (s, 3H), 2.08-1.82 (m, 2H), 1.79-1.36 (m, 2H).Mass(m / z): 506.3 [M+H] +

[0514] N-hydroxy-2-(4-methylpiperazine-1-yl)-N-(4-((4-(pyrrolidine-1-yl)-3-(trifluoromethyl)phenyl)amino)benzyl)acetamide (188) JPEG2026063193000233.jpg65151

[0515] Compound 188 (13.5 mg) was prepared as a white solid with a total yield of 22.1% following the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.28 - 7.17 (m, 5H), 6.98 (d, J = 8.4 Hz, 2H), 4.67 (s, 2H), 3.51 (s, 2H), 3.17 - 3.05 (m, 4H), 2.98 (br s, 4H), 2.82 (br s, 4H), 2.63 (s, 3H), 1.96 - 1.87 (m, 4H).Mass(m / z): 492.2 [M+H] +

[0516] 1-Methyl-6-oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)piperidine-3-carboxamide (189) JPEG2026063193000234.jpg37151

[0517] Step 1. Compound 189 (18.3 mg) of the title compound was prepared from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (30 mg, 0.09 mmol) and 1-methyl-6-oxopiperidine-3-carboxylic acid (15 mg, 0.09 mmol) as a pale yellow powder with a yield of 43.63%. 1H NMR (400 MHz, Methanol-d4) δ 7.02 (d, J = 63.1 Hz, 8H), 4.27 (s, 2H), 3.54 (dd, J = 12.4, 9.7 Hz, 3H), 3.40 (ddd, J = 12.4, 5.4, 1.3 Hz, 1H), 2.93 (s, 3H), 2.77 (tdd, J = 9.7, 5.4, 4.3 Hz, 1H), 2.49 - 2.16 (m, 4H), 2.07 - 1.90 (m, 4H), 1.72 (d, J = 13.5 Hz, 2H). LC-MS (m / z) 489.3 [M+H] + .

[0518] N-hydroxy-2-(4-methylpiperazine-1-yl)-N-(4-((6-(piperidine-1-yl)pyridine-3-yl)amino)benzyl)acetamide (190) JPEG2026063193000235.jpg60151

[0519] Compound 190 (22.1 mg) was prepared as a white solid with a total yield of 50.4% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.93 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 8.4 Hz, 2H), 6.86-6.79 (m, 3H), 4.63 (s, 2H), 3.47 (s, Mass(m / z): 439.3 [M+H] +

[0520] N-(4-((4-(2,6-dimethylmorpholino)phenyl)amino)benzyl)-2-(4-methylpiperazin-1-yl)acetamide (191) JPEG2026063193000236.jpg64151

[0521] Compound 191 (31.4 mg) was prepared as a white solid with a total yield of 72.3% according to the procedure for compound 163. 1 H NMR (400 MHz, Methanol-d4) δ 7.09 (d, J = 8.4 Hz, 2H), 7.02 (d, J= 8.4 Hz, 2H), 6.96 - 6.79 (m, 4H), 4.29 (s, 2H), 3.84-3.73 (m, 2H), 3.43-3.33 (m, 2H), 3.06 (s, 2H), 2.77-2.48 (m, 10H), 2.36 (s, 3H), 1.20 (d, J = 6.4 Hz, 6H). Mass(m / z): 452.3 [M+H] +

[0522] N-hydroxy-N-(4-((2-methyl-4-(piperidine-1-yl)phenyl)amino)benzyl)-2-(4-methylpiperazine-1-yl)acetamide (192) JPEG2026063193000237.jpg65151

[0523] Compound 192 (20.1 mg) was prepared as a white solid with a total yield of 56.3% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.19 - 6.52 (m, 7H), 4.61 (s, 2H), 3.41 (s, 2H), 3.07 (br s, 4H), 2.63 (br s, 8H), 2.36 (s, 3H), 2.17 (s, 3H), 1.79-1.68 (m, 4H), 1.63-1.52 (m, 2H).Mass(m / z): 452.3 [M+H] +

[0524] N-hydroxy-2-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-N-(4-((4-(piperidine-1-yl)phenyl)amino)benzyl)acetamide (193) JPEG2026063193000238.jpg63151

[0525] Compound 193 (10.4 mg) was prepared as a white solid with a total yield of 21.7% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.30-6.69 (m, 8H), 4.65 (s, 2H), 3.64 (s, 2H), 3.29-3.19 (m, 4H),3.15-2.69 (m, 13H), 2.56 (s, 3H), 2.01-1.91 (m, 2H), 1.81-1.67 (m, 6H), 1.59 (s, 2H).Mass(m / z): 521.4 [M+H] +

[0526] N-hydroxy-N-(4-((4-(piperidine-1-yl)phenyl)amino)benzyl)-2-(pyrazine-2-yl)acetamide (194) JPEG2026063193000239.jpg64151

[0527] Compound 194 (15.9 mg) was prepared as a white solid with a total yield of 31.8% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 8.58-8.53 (m, 2H), 8.48-8.46 (m, 1H), 7.48-6.78 (m, 8H), 4.73 (s, 2H), 4.09 (s, 2H), 3.29-3.19 (m, 4H),1.80 (br s, 4H), 1.63 (br s, 2H).Mass(m / z): 418.3 [M+H] +

[0528] 4-(hydroxy(4-((4-(piperidine-1-yl)phenyl)amino)benzyl)amino)-4-oxobutanoic acid (195) JPEG2026063193000240.jpg31151

[0529] Dihydrofuran-2,5-dione (20.0 mg, 0.2 mmol) was added at 0°C to a solution of 4-((hydroxyamino)methyl)-N-(4-(piperidine-1-yl)phenyl)aniline (59.4 mg, 0.2 mmol) in toluene (1 ml). The reaction mixture was then stirred for 3 hours. After completion, the reaction solution was concentrated and purified by prep-TLC (MeOH / DCM = 1 / 10) to obtain the desired product as a white solid (18.2 mg, 23.1%). 1 H NMR (400 MHz, Methanol-d4) δ 7.32-6.77 (m, 8H), 4.66 (s, 2H), 3.28 - 2.91 (m, 4H), 2.77 (t, J = 6.8 Hz, 2H), 2.58 (t, J = 6.8 Hz, 2H), 1.89-1.70 (m, 4H), 1.61 (br s, 2H).Mass(m / z): 398.3 [M+H] +

[0530] N-hydroxy-N-(3-methyl-4-((4-(piperidine-1-yl)phenyl)amino)benzyl)-2-(4-methylpiperazine-1-yl)acetamide (196) JPEG2026063193000241.jpg62151

[0531] Compound 196 (26.5 mg) was prepared as a white solid with a total yield of 52.5% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.15 - 6.85 (m, 7H), 4.63 (s, 2H), 3.40 (s, 2H), 3.00 (br s, 4H), 2.60 (br s, 8H), 2.31 (s, 3H), 2.21 (s, 3H), 1.79-1.68 (m, 4H), 1.63-1.52 (m, 2H).Mass(m / z): 452.3[M+H] +

[0532] N-(3-fluoro-4-((4-(piperidine-1-yl)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazine-1-yl)acetamide (197) JPEG2026063193000242.jpg62151

[0533] Compound 197 (20.6 mg) was prepared as a white solid with a total yield of 41.7% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.12 - 6.88 (m, 7H), 4.65 (s, 2H), 3.47 (s, 2H), 3.13-3.02 (m, 4H), 2.77 (br s, 8H), 2.49 (s, 3H), 1.76-1.69 (m, 4H), 1.60-1.54 (m, 2H).Mass(m / z): 456.2[M+H] +

[0534] N-hydroxy-N-(3-methyl-4-((2-methyl-4-(piperidine-1-yl)phenyl)amino)benzyl)-2-(4-methylpiperazine-1-yl)acetamide (198) JPEG2026063193000243.jpg72151

[0535] Compound 198 (10.2 mg) was prepared according to the procedure in 137 from 4-((hydroxyamino)methyl)-2-methyl-N-(2-methyl-4-(piperidine-1-yl)phenyl)aniline (32.5 mg, 0.1 mmol), 4-(dimethylamino)butanoic acid hydrochloride (15.8 mg, 0.1 mmol), DMT-MM (26.7 mg, 0.1 mmol), DIEA (38.7 mg, 0.3 mmol), and DMF (1.0 mL) as a yellow solid with a total yield of 21.9%. 1H NMR (400 MHz, Methanol-d4) δ 7.07 (s, 1H), 6.96- 6.81 (m, 4H), 6.41 (d, J = 8.2 Hz, 1H), 4.62 (s, 2H), 3.52 (s, 2H), 3.14 - 2.99 (m, 8H), 2.90 - 2.76 (m, 4H), 2.69 (s, 3H), 2.22 (s, 3H), 2.15 (s, 3H), 1.78 - 1.69 (m, 4H), 1.62 - 1.54 (m, 4H). Mass(m / z):233.7 [M / 2+H]+.

[0536] N-hydroxy-N-(4-((4-(piperidine-1-yl)phenyl)aminobenzyl)oxazole-4-carboxamide (199) JPEG2026063193000244.jpg70151

[0537] Compound 199 (12.5 mg) was prepared as a white solid with a total yield of 37.4% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 8.25 (s, 1H), 7.47-6.77 (m, 8H), 4.62 (s, 2H), 3.25 - 2.90 (m, 4H), 1.77 (br s, 4H), 1.60 (br s, 2H). Mass(m / z): 393.2[M+H] +

[0538] 2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-N-hydroxy-N-(4-((4-(piperidine-1-yl)phenyl)amino)benzyl)acetamide (200) JPEG2026063193000245.jpg71151

[0539] Compound 200 (10.2 mg) was prepared as a white solid with a total yield of 25.1% according to the procedure for compound 108. 1H NMR (400 MHz, Methanol-d4) δ 7.44-6.78 (m, 8H), 5.12 (s, 2H), 4.67 (s, 2H), 3.26 - 2.87 (m, 4H), 2.35 (s, 3H), 2.28 (s, 3H), 1.79 (br s, 4H), 1.62 (br s, 2H). Mass(m / z): 435.3[M+H] +

[0540] N,1-Diethyl-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (201) JPEG2026063193000246.jpg81151

[0541] Step 1. The intermediate N-(4-bromobenzyl)-N,1-diethyl-5-oxopyrrolidine-3-carboxamide (467 mg) was prepared as brown oil in a yield of 56.61% from 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (367 mg, 2.34 mmol) and N-(4-bromobenzyl)ethaneamine (500 mg, 2.34 mmol) according to the procedure for the intermediate. LC-MS (m / z) 353.2, 355.1 [M+H] + .

[0542] Step 2. Compound 201 (5.9 mg) of the title compound was prepared from 4-(4-(trifluoromethyl)piperidine-1-yl)aniline (50 mg, 0.20 mmol) and N-(4-bromobenzyl)-N,1-diethyl-5-oxopyrrolidine-3-carboxamide (72 mg, 0.20 mmol) as a pale yellow powder with a yield of 5.58%. 1H NMR (400 MHz, Methanol-d4) δ 7.67 - 6.72 (m, 8H), 3.81 - 3.51 (m, 6H), 3.51 - 3.34 (m, 5H), 2.77 - 2.44 (m, 4H), 1.30 (d, J = 3.8 Hz, 2H), 1.25 - 1.05 (m, 9H). LC-MS (m / z) 517.6 [M+H] + .

[0543] 1-(4-((4-(piperidine-1-yl)phenyl)aminobenzyl)piperazine-2-one (202) JPEG2026063193000247.jpg70151

[0544] Step 1. Preparation of tert-butyl 4-(4-bromobenzyl)-3-oxopiperazine-1-carboxylate (202-2). KOH (828 mg, 6.0 mmol) was added to a solution of 1-bromo-4-(bromomethyl)benzene (992 mg, 4.0 mmol) and tert-butyl 3-oxopiperazine-1-carboxylate (800 mg, 4.0 mmol) in DMSO (10.0 mL). The mixture was then stirred overnight at room temperature. After cooling to room temperature, 20 mL of water was added. The resulting solution was extracted with 3 x 20 mL of ethyl acetate. The organic layer was bound, washed with water (3 x 30 mL), dried, and concentrated under vacuum to obtain the desired product as yellow oil (500 mg, 34.0%). Mass (m / z): 313.1 [M+H] + .

[0545] Step 2. Preparation of tert-butyl 3-oxo-4-(4-((4-(piperidine-1-yl)phenyl)amino)benzyl)piperazine-1-carboxylate (202-3). Compound 202-3 (173 mg) of the title was prepared according to the procedure of 137-3 from 4-(piperidine-1-yl)aniline (310 mg, 1.77 mmol), tert-butyl 4-(4-bromobenzyl)-3-oxopiperazine-1-carboxylate (500 mg, 1.36 mmol), Pd(dppf)2Cl2 (20 mg, 0.03 mmol), xanthophos (32 mg, 0.05 mmol), and Cs2CO3 (665 mg, 2.04 mmol) as a yellow oil with a total yield of 27.6%. Mass (m / z): 465.4 [M+H] + .

[0546] Step 3. Preparation of 1-(4-((4-(piperidine-1-yl)phenyl)amino)benzyl)piperazine-2-one (202). To a solution of tert-butyl tert-butyl 3-oxo-4-(4-((4-(piperidine-1-yl)phenyl)amino)benzyl)piperazine-1-carboxylate (162 mg, 0.35 mmol) in DCM (2 mL), TFA (2 mL) was added. The reaction mixture was then stirred at room temperature for 30 minutes. The reaction solution was concentrated under vacuum. 10 mL was added. The pH of the solution was adjusted to 8 with Na2CO3. The resulting solution was extracted with 3 x 10 mL of ethyl DCM. The organic layer was attached, washed with water (3 x 10 mL), dried, and concentrated under vacuum. The residue was purified by perp-TLC (MeOH / DCM = 1 / 5) to obtain the desired product as a yellow solid. (74.0 mg, 61.2%). 1 H NMR (400 MHz, Methanol-d4) δ 7.11 (d, J = 8.1 Hz, 2H), 7.05 - 6.84 (m, 6H), 4.50 (s, 2H), 3.50 (s, 2H), 3.30 - 3.28 (m, 3H), 3.15 - 2.89 (m, 6H), 1.79 - 1.70 (m, 4H), 1.63 - 1.53 (m, 2H). Mass(m / z): 365.3[M+H]+ .

[0547] 5-Oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (203) JPEG2026063193000248.jpg30151

[0548] A solution of 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (105 mg, 0.302 mmol) and 5-oxopyrrolidine-3-carboxylic acid (30 mg, 0.233 mmol) in DMF (3 mL) was mixed with DMT-MM (89 mg, 0.302 mmol) and DIPEA (39 mg, 0.302 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was extracted with EA (25 mL x 3). The bound organic layer was washed with brine (15 mL x 3), dried over Na2SO4, and concentrated to obtain the crude product, which was purified by TLC (MeOH / DCM = 1:10) to obtain the desired product as a white solid (56.7 mg, 53.0%). 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (t, J = 5.6 Hz, 1H), 7.76 (s, 1H), 7.56 (s, 1H), 7.04 - 7.00 (m, 2H), 6.97 - 6.92 (m, 2H), 6.90 - 6.84 (m, 4H), 4.13 (d, J = 5.6 Hz, 2H), 3.59 (d, J = 12.0 Hz, 2H), 3.25 - 3.10 (m, 2H), 2.60 (td, J = 12.4, 2.4 Hz, 2H), 2.45 - 2.36 (m, 1H), 2.27 (dd, J = 8.4, 5.0 Hz, 2H), 1.91 - 1.80 (m, 2H), 1.55 (qd, J = 12.4, 4.0 Hz, 2H).Mass(m / z): 461.3 [M+H] + .

[0549] 1-(4-((4-(piperidine-1-yl)phenyl)aminobenzyl)pyrrolidine-2-one (204) JPEG2026063193000249.jpg73151

[0550] Step 1. Preparation of 1-(4-bromobenzyl)pyrrolidine-2-one (204-2). KOH (828 mg, 6.0 mmol) was added to a solution of 1-bromo-4-(bromomethyl)benzene (992 mg, 4.0 mmol) and pyrrolidine-2-one (744 mg, 4.0 mmol) in DMSO (10.0 mL). The mixture was then stirred overnight at room temperature. After cooling to room temperature, 20 mL of water was added. The resulting solution was extracted with 3 x 20 mL of ethyl acetate. The organic layer was bonded, washed with water (3 x 30 mL), dried, and concentrated under vacuum to obtain the desired product as a yellow oil (460 mg, 45.5%). Mass (m / z): 254.1 [M+H] + .

[0551] Step 2. Preparation of 1-(4-((4-(piperidine-1-yl)phenyl)amino)benzyl)pyrrolidine-2-one (204). Compound 304 (40.1 mg) of the title compound was prepared according to the procedure in 137-3 from 4-(piperidine-1-yl)aniline (176 mg, 1.0 mmol), 1-(4-bromobenzyl)pyrrolidine-2-one (121 mg, 0.5 mmol), Pd(dppf)2Cl2 (7.3 mg, 0.01 mmol), xanthophos (11.6 mg, 0.02 mmol), and Cs2CO3 (244 mg, 0.75 mmol) as a yellow oil with a total yield of 22.9%. 1 H NMR (400 MHz, Chloroform-d) δ 7.65 - 6.32 (brm, 8H), 4.70 - 4.10 (brs, 2H), 3.28 - 3.23 (m, 2H), 2.42 (t, J = 8.0 Hz, 2H), 2.02 - 1.92 (m, 2H), 1.89 - 1.65 (m, 4H), 1.62- 1.53 (m, 2H). Mass(m / z): 350.3 [M+H]+ .

[0552] 1-Ethyl-N-isopropyl-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (205) JPEG2026063193000250.jpg81151

[0553] Step 1. The intermediate N-(4-bromobenzyl)-1-ethyl-N-isopropyl-5-oxopyrrolidine-3-carboxamide (150 mg) was prepared as brown oil in a yield of 93.17% from 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (69 mg, 0.44 mmol) and N-(4-bromobenzyl)cyclopropanamine (100 mg, 0.44 mmol) according to the procedure for the intermediate. LC-MS (m / z) 367.2, 369.2 [M+H] + .

[0554] Step 2. Compound 205 (14 mg) of the title compound was prepared from 4-(4-(trifluoromethyl)piperidine-1-yl)aniline (100 mg, 0.41 mmol) and N-(4-bromobenzyl)-1-ethyl-N-isopropyl-5-oxopyrrolidine-3-carboxamide (150 mg, 0.41 mmol) as a blue powder with a yield of 6.44%. 1H NMR (400 MHz, DMSO-d6) δ 7.06 - 6.78 (m, 8H), 4.54 (q, J = 6.8 Hz, 1H), 4.42 (s, 1H), 4.36 (d, J = 6.4 Hz, 1H), 4.28 - 4.15 (m, 1H), 3.66 - 3.55 (m, 3H), 3.47 (q, J = 4.3 Hz, 1H), 3.26 - 3.10 (m, 3H), 2.62 (t, J= 12.4 Hz, 2H), 2.36 - 2.28 (m, 1H), 1.88 (d, J = 12.7 Hz, 2H), 1.57 (qd, J = 12.5, LC-MS (m / z) 531.5 [M+H] + .

[0555] N-hydroxy-2-(4-methyl-3-oxopiperazine-1-yl)-N-(4-((4-(piperidine-1-yl)phenyl)aminobenzyl)acetamide (206) JPEG2026063193000251.jpg71151

[0556] Compound 206 (5.6 mg) was prepared as a white solid with a total yield of 21.6% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.52 - 6.55 (m, 8H), 4.65 (s, 2H), 3.50 (s, 2H), 3.39-3.23(m, 8H), 2.94 (s, 3H), 2.88 (m, 2H), 1.75 (br s, 4H), 1.59 ((br s, 2H).Mass(m / z): 452.3[M+H] + .

[0557] N-(4-((4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)amino)benzyl)-2-(4-methylpiperazine-1-yl)acetamide (207) JPEG2026063193000252.jpg63151

[0558] Compound 207 (21.8 mg) was prepared as a white solid with a total yield of 50.7% according to the procedure for compound 163. 1 H NMR (400 MHz, Methanol-d4) δ 7.12 -6.40 (m, 8H), 4.81 (s, 4H), 4.28 (s, 2H), 3.95 (s, 4H), 3.08 (s, 2H), 2.66 (br s, 8H), 2.43 (s, 3H). Mass(m / z): 436.2[M+H] + .

[0559] N-hydroxy-2-(4-methylpiperazine-1-yl)-N-(4-((4-(piperidine-1-yl)phenyl)amino)-2-(trifluoromethyl)benzyl)acetamide (208) JPEG2026063193000253.jpg63151

[0560] Compound 208 (28.2 mg) was prepared as a white solid with a total yield of 58.4% following the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.27 - 7.17 (m, 2H), 7.15 - 6.94 (m, 5H), 4.85 (s, 2H), 3.52 (s, 2H), 3.12 - 3.02 (m, 4H), 2.93-2.64 (m, 8H), 2.52 (s, 3H), 1.77-1.69 (m, 4H), 1.65-1.51 (m, 2H). Mass(m / z): 506.3[M+H] + .

[0561] 1-Ethyl-N-(4-((4-(4-methylpiperidine-1-yl)phenyl)aminobenzyl)-5-oxopyrrolidine-3-carboxamide (209) JPEG2026063193000254.jpg115151

[0562] Step 1. A mixture (5 mL) of 1,4-dioxane-4-(4-methylpiperidine-1-yl)aniline (375 mg, 2.0 mmol), 4-bromobenzaldehyde (281 mg, 1.5 mmol), Pd(dppf)2Cl2 (22 mg, 0.03 mmol), xanthophos (35 mg, 0.06 mmol), and Cs2CO3 (734 mg, 2.3 mmol) was stirred overnight at 110°C. After cooling to room temperature, 5 mL of water was added. The mixture was then extracted with DCM (5 mL x 3). The combined organic layer was washed with water (10 mL x 3), dried over Na2SO4, and concentrated under vacuum. The residue was purified by prep-TLC (MeOH / DCM = 1 / 10) to obtain the desired product as a yellow solid (490 mg, 86.0%). Mass (m / z): 295.3 [M+H] +

[0563] Step 2. Hydroxylamine hydrochloride (230 mg, 3.34) was added to a solution of 4-((4-(4-methylpiperidine-1-yl)phenyl)amino)benzaldehyde (490 mg, 5 mmol) in EtOH (20 mL). The reaction mixture was then stirred overnight at room temperature. The reaction mixture was concentrated under vacuum. The crude product was used directly in the next step (100%). Mass (m / z): 310.3 [M+H] + .

[0564] Step 3. To a solution of (E)-4-((4-(4-methylpiperidine-1-yl)phenyl)amino)benzaldehyde oxime (516 mg, 1.67 mmol) in EtOH (20 mL), 10% Pd / C (18 mg, 16.7 mmol) and AcOH (0.5 mL) were added. The reaction mixture was then stirred overnight at room temperature under a hydrogen atmosphere. Pd / C was filtered off. The pH of the filtrate was adjusted to 8-9 with sodium carbonate solution. The mixture was then extracted with DCM (20 mL x 3). The combined organic layer was washed with brine (20 mL x 3), dried over Na2SO4, and concentrated to obtain the desired product as a yellow solid (120 mg, 24.3%). 296.3 [M+H] + .

[0565] Step 4. DIEA (38.7 mg, 0.3 mmol) was added to a solution of 4-(aminomethyl)-N-(4-(4-methylpiperidine-1-yl)phenyl)aniline (29.6 mg, 0.1 mmol) and 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (15.7 mg, 0.1 mmol) in DCM (1 ml). Subsequently, HATU (38 mg, 0.1 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. 5 mL of water was added. The mixture was then extracted with DCM (5 mL x 3). The bound organic layer was washed with water (10 mL x 3), dried over Na2SO4, and concentrated under vacuum. The residue was purified by prep-TLC (MeOH / DCM = 1 / 5) to obtain the desired product as a white solid (16.9 mg, 28.9%). 1H NMR (400 MHz, Methanol-d4) δ 7.45 - 7.38 (m, 2H), 7.25 - 7.19 (m, 2H), 7.16 - 7.07 (m, 4H), 4.87 (s, 1H) 4.39 - 4.26 (m, 2H), 3.69 - 3.52 (m, 4H), 3.34 - 3.32 (m, 2H), 3.28 - 3.16 (m, 2H), 2.61 (d, J = 8.5 Hz, 2H), 2.08 - 2.00 (m, 2H), 1.92 - 1.82 (m, 1H), 1.71 - 1.61 (m, 2H), 1.18 - 1.02 (m, 6H). Mass (m / z): 435.4[M+H] + .

[0566] N-(4-((4-(4,4-dimethylpiperidine-1-yl)phenyl)amino)benzyl)-1-ethyl-5-oxopyrrolidine-3-carboxamide (210) JPEG2026063193000255.jpg67151

[0567] Compound 210 (26.4 mg) was prepared according to the procedure for compound 209 from 4-(aminomethyl)-N-(4-(4,4-dimethylpiperidine-1-yl)phenyl)aniline (31 mg, 0.1 mmol), 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (15.7 mg, 0.1 mmol), DIEA (38.7 mg, 0.3 mmol), and HATU (38 mg, 0.1 mmol) as a yellow solid with a total yield of 58.9%. 1H NMR (400 MHz, Methanol-d4) δ 7.49 - 7.43 (m, 2H), 7.26 - 7.19 (m, 2H), 7.18 - 7.09 (m, 4H), 4.87 (s, 1H), 4.39 - 4.27 (m, 2H), 3.69 - 3.49 (m, 4H), 3.36 - 3.32 (m, 1H), 3.27 - 3.16 (m, 2H), 2.61 (d, J = 8.5 Hz, 2H), 1.91 - 1.75 (m, 4H), 1.23 - 1.06 (m, 9H). Mass(m / z): 449.4 [M+H] + .

[0568] N-(4-((4-(3,3-dimethylazetidine-1-yl)phenyl)amino)benzyl)-1-ethyl-5-oxopyrrolidine-3-carboxamide (211) JPEG2026063193000256.jpg61151

[0569] Compound 211 (5.7 mg) was prepared according to the procedure in 209 from 4-(aminomethyl)-N-(4-(3,3-dimethylazetidine-1-yl)phenyl)aniline (56.2 mg, 0.2 mmol), 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (31.4 mg, 0.2 mmol), DIEA (77.4 mg, 0.6 mmol), and HATU (76 mg, 0.2 mmol) as a yellow solid with a total yield of 6.8%. 1 H NMR NMR (400 MHz, Methanol-d4) δ 7.49 - 7.43 (m, 2H), 7.26 - 7.19 (m, 2H), 7.18 - 7.09 (m, 4H), 4.87 (s, 1H), δ 3.69 - 3.51 (m, 3H), 3.37 - 3.31 (m, 4H), 3.27 - 3.16 (m, 2H), 2.61 (d, J = 8.4 Hz, 2H), 1.47 (s, 6H), 1.11 (d, J = 7.2 Hz, 3H). Mass(m / z): 421.4 [M+H] + .

[0570] N-(4-((4-(4,4-difluoropiperidine-1-yl)phenyl)amino)benzyl)-N-hydroxy-1-isopropylpiperidine-4-carboxamide (212) JPEG2026063193000257.jpg67151

[0571] Compound 212 (21.8 mg) was prepared as a white solid with a total yield of 49.8% from 4-(4,4-difluoropiperidine-1-yl)-N-(4-((hydroxyamino)methyl)phenyl)aniline (30 mg, 0.090 mmol) and 1-isopropylpiperidine-4-carboxylic acid hydrochloride (25 mg, 0.117 mmol) according to the procedure in 174. 1 H NMR (400 MHz, Methanol-d4) δ 7.20 - 6.85 (m, 8H), 4.65 (s, 2H), 3.55 - 3.43 (m, 4H), 3.14 (d, J = 31.6 Hz, 4H), 2.09 (tt, J = 13.6, 5.7 Hz, 7H), 1.96 (s, 2H), 1.36 (s, 3H), 1.34 (s, 3H).Mass(m / z): 487.4 [M+H] + .

[0572] N-Cyclopropyl-1-ethyl-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (213) JPEG2026063193000258.jpg82151

[0573] Step 1. To a solution of 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (139 mg, 0.89 mmol, 1.1 equivs) and N-(4-bromobenzyl)cyclopropanamine (200 mg, 0.88 mmol, 1.0 equivs) in superdried N,N-dimethylformamide (10 mL), 2-(1H-benzo[d][1,2,3]triazole-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (340 mg, 1.06 mmol, 1.5 equivs) and N-ethyl-N-isopropylpropan-2-amine (438 mL, 2.65 mmol, 3.0 equivs) were added at room temperature under an argon atmosphere and stirred overnight. The reaction mixture was diluted with water (10 mL) and extracted three times with dichloromethane (5 mL). The organic layers were bonded and washed with water, saturated NH4Cl(aq), and brine, respectively. They were then dried over MgSO4, filtered, and concentrated under reduced pressure. The residue N-(4-bromobenzyl)-N-cyclopropyl-1-ethyl-5-oxopyrrolidine-3-carboxamide (275 mg) was used directly in the next step without further purification after concentration and drying under vacuum. LC-MS (m / z) 365.2, 367.1 [M+H] + .

[0574] Step 2. In 1,4-dioxane (10 mL), a solution of 4-(4-(trifluoromethyl)piperidine-1-yl)aniline (100 mg, 0.41 mmol, 1.0 equivs) and N-(4-bromobenzyl)-N-cyclopropyl-1-ethyl-5-oxopyrrolidine-3-carboxamide (150 mg, 0.41 mmol, 1.0 equivs) is prepared, and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (18.95 mg, 0.032 mmol, 0.08 equivs) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11.98 mg, 0.016 mmol, 0.04 equivs) and cesium carbonate (200.0 mg, 0.64 mmol) is added. Each of the 1.5 equivs) was added under an argon atmosphere. The resulting mixture was heated to 100°C and stirred overnight at the same temperature. The reaction product was diluted with water (10 mL) and extracted three times with ethyl acetate (5 mL). The organic layer was combined and washed with water, saturated NaHCO3 (aq), and brine, respectively. The mixture was then dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / AcOEt, 1 / 6) to obtain 108.2 mg of N-cyclopropyl-1-ethyl-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aminobenzyl)pyrrolidine-3-carboxamide 299 as a blue solid with a yield of 50.00%. 1H NMR (400 MHz, Methanol-d4) δ 7.48 - 7.41 (m, 2H), 7.14 (d, J = 8.3 Hz, 2H), 7.11 - 6.80 (m, 4H), 4.58 (s, 2H), 4.08 (dtt, J = 12.8, 9.1, 6.8 Hz, 2H), 3.67 (q, J = 9.3 Hz, 2H), 3.55 (ddd, J = 9.7, 5.7, 4.0 Hz, 2H), 2.75 - 2.50 (m, 5H), 2.23 (dtd, J = 15.9, 7.8, 3.8 Hz, 1H), 1.97 - 1.84 (m, 1H), 1.70 (td, J = 12.9, 12.5, 4.2 Hz, 1H), 1.10 (td, J= 7.2, 1.7 Hz, 4H), 0.96 - 0.74 (m, 6H). LC-MS (m / z) 529.4 [M+H] + .

[0575] 1-Methyl-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (214) JPEG2026063193000259.jpg35151

[0576] Compound 214 (14.2 mg) was prepared as a pale blue solid in a yield of 26.14% from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (40 mg, 0.11 mmol) and 1-methyl-5-oxopyrrolidine-3-carboxylic acid hydrochloride (31 mg, 0.17 mmol) according to the procedure for compound 276. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (t, J = 5.7 Hz, 1H), 7.78 (s, 1H), 7.10 - 7.01 (m, 2H), 7.00 - 6.94 (m, 2H), 6.93 - 6.83 (m, 4H), 4.15 (d, J= 5.6 Hz, 2H), 3.61 (d, J = 12.1 Hz, 2H), 3.49 (dd, J = 9.6, 9.0 Hz, 1H), 3.36 (dd, J = 6.6, 3.0 Hz, 1H), 3.31 (s, 1H), 3.21 - 3.05 (m, 1H), 2.69 (d, J = 0.8 Hz, 3H), 2.62 (td, J = 13.8, 12.3, 3.3 Hz, 2H), 2.43 - 2.37 (m, 2H), 1.88 (d, J = 12.7 Hz, 2H), 1.58 (td, J= 12.5, 4.0 Hz, 2H). LC-MS (m / z) 475.4 [M+H] + .

[0577] N-hydroxy-1-isopropyl-N-(4-((4-(4-methylpiperidine-1-yl)phenyl)amino)benzyl)piperidine-4-carboxamide (215) JPEG2026063193000260.jpg61151

[0578] Compound 215 (23.2 mg) was prepared as a white solid with a total yield of 51.9% from 4-((hydroxyamino)methyl)-N-(4-(4-methylpiperidine-1-yl)phenyl)aniline (30 mg, 0.096 mmol) and 1-isopropylpiperidine-4-carboxylic acid hydrochloride (26 mg, 0.125 mmol) according to the procedure in 174. 1H NMR (400 MHz, Methanol-d4) δ 7.37 - 6.85 (m, 8H), 4.65 (s, 2H), 3.53 - 3.41 (m, 4H), 3.27 - 3.19 (m, 1H), 3.10 (t, J = 12.4 Hz, 3H), 2.15 - 1.93 (m, 5H), 1.77 (s, 3H), 1.57 - 1.44 (m, 2H), 1.35 (s, 3H), 1.33 (s, 3H), 0.99 (d, J= 6.4 Hz, 3H).Mass(m / z): 465.4 [M+H] + .

[0579] N-(cyclopropylmethyl)-1-ethyl-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (216) JPEG2026063193000261.jpg68151

[0580] 1 H NMR (400 MHz, Methanol-d4) δ 7.23 - 6.68 (m, 8H), 4.61 (s, 2H), 3.77 - 3.12 (m, 10H), 2.72 - 2.40 (m, 3H), 2.31 - 2.13 (m, 1H), 1.98-1.87 (m, 2H), 1.74-1.63 (m, 2H), 1.09 (dt, J = 18.2, 7.4 Hz, 3H), 0.99-0.87 (m, 1H), 0.57-0.43 (m, 2H), 0.23-0.17 (m, 2H). Mass(m / z): 543.3 [M+H] + .

[0581] 2-(4-methylpiperazine-1-yl)-N-(4-((4-(piperidine-1-yl)phenyl)amino)-2-(trifluoromethyl)benzyl)acetamide (217) JPEG2026063193000262.jpg72151

[0582] Compound 217 (20.2 mg) was prepared as a white solid with a total yield of 35.4% according to the procedure for compound 163. 1 H NMR (400 MHz, Methanol-d4) δ 7.52-6.99 (m, 7H), 4.61 (s, 2H), 3.44 (s, 2H), 3.27 - 3.12 (m, 4H), 3.05 - 2.74 (m, 8H), 2.52 (s, 3H), 1.87 (br s, 4H), 1.72 (br s, 2H).Mass(m / z): 490.3[M+H] + .

[0583] N-hydroxy-N-(4-((4-(piperidine-1-yl)phenyl)aminobenzyl)nicotinamide (218) JPEG2026063193000263.jpg62151

[0584] Compound 218 (15.2 mg) was prepared as a white solid with a total yield of 41.7% following the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 8.83 (s, 1H), 8.66-8.51 (m, 1H), 8.13 (d, J= 8.0 Hz, 1H), 7.50 (dd, J = 8.0, 4.8 Hz, 1H), 7.40-6.77 (m, 8H), 4.72 (s, 2H), 3.29 - 2.97 (m, 4H), 1.86 (br s, 4H), 1.67 (br s, 2H). Mass(m / z): 403.2[M+H] + .

[0585] N-(4-((2,6-dimethyl-4-(piperidine-1-yl)phenyl)amino)-3-methylbenzyl)-N-hydroxy-2-(4-methylpiperazine-1-yl)acetamide (219) JPEG2026063193000264.jpg74149

[0586] Compound 219 (16.8 mg) was prepared as a white solid with a total yield of 43.9% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.04 (s, 1H), 6.92 - 6.75 (m, 3H), 5.92 (d, J= 8.0, 1H), 4.58 (s, 2H), 3.53 (s, 2H), 3.27 -2.88 (br m, 12H), 2.77 (s, 3H), 2.29 (s, 3H), 2.11 (s, 6H), 1.86 - 1.68 (m, 4H), 1.67 - 1.53 (m, 2H). Mass(m / z): 480.2[M+H] + .

[0587] N-(2-fluoro-4-((4-(piperidine-1-yl)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazine-1-yl)acetamide (220) JPEG2026063193000265.jpg71151

[0588] Compound 220 (20.1 mg) was prepared as a white solid with a total yield of 48.7% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.22 - 6.86 (m, 5H), 6.72-6.58 (m, 2H), 4.70 (s, 2H), 3.47 (s, 2H), 3.06 (br s, 4H), 2.83 (br m, 8H), 2.56 (s, 3H), 1.81 - 1.67 (m, 4H), 1.64 - 1.51 (m, 2H). Mass(m / z): 456.3[M+H] + .

[0589] 4-acetyl-1-(4-((4-(piperidine-1-yl)phenyl)aminobenzyl)piperazine-2-one (221) JPEG2026063193000266.jpg34151

[0590] To a solution of 1-(4-((4-(piperidine-1-yl)phenyl)amino)benzyl)piperazine-2-one (36.5 mg, 0.1 mmol) and DIEA (38.7 mg, 0.3 mmol) in DCM (2 mL), acetyl chloride (15.7 mg, 0.2 mmol) was added dropwise at 0°C. The reaction mixture was then stirred at 0°C for 2 hours. The reaction solution was washed with water (3 x 5 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by prep-TLC (MeOH / DCM = 1 / 10) to obtain the desired product as a yellow solid. 1 H NMR (400 MHz, Methanol-d4) δ 7.27 - 6.72 (m, 8H), 4.52 (s, 2H), 4.22 (d, J = 15.0 Hz, 2H), 3.71 (q, J = 5.2 Hz, 2H), 3.41 - 3.32 (m, 2H), 3.25 - 2.82 (m, 4H), 2.10 (s, 3H), 1.76 (p, J = 5.6 Hz, 4H), 1.65 - 1.51 (m, 2H).Mass(m / z): 407.3[M+H] +

[0591] 4-(cyclopropylmethyl)-1-(4-((4-(piperidine-1-yl)phenyl)aminobenzyl)piperazine-2-one (222) JPEG2026063193000267.jpg27151

[0592] (Bromomethyl)cyclopropane (8.1 mg, 0.6 mmol) was added to a mixture of 1-(4-((4-(piperidine-1-yl)phenyl)amino)benzyl)piperazine-2-one (18.2 mg, 0.05 mmol) and K2CO3 (10.4 mg, 0.75 mmol) in ACN (2.0 mL). The reaction mixture was then stirred overnight at room temperature. 10 mL of water was added. The resulting solution was extracted with 3 x 10 mL of ethyl DCM. The organic layer was bonded, washed with water (3 x 10 mL), dried, and concentrated under vacuum. The residue was purified by perp-TLC (MeOH / DCM = 1 / 20) to obtain the desired product as a yellow solid (7.0 mg, 33.4%). 1 H NMR (400 MHz, Methanol-d4) δ 7.37 - 6.56 (m, 8H), 4.52 (s, 2H), 3.34 - 3.31 (m, 2H), 3.28 - 2.90 (m, 4H), 2.84 - 2.76 (m, 2H), 2.35 (d, J = 6.8 Hz, 2H), 1.86 - 1.74 (m, 4H), 1.69 - 1.52 (m, 2H), 0.97 - 0.86 (m, 1H), 0.56 (d, J = 8.1 Hz, 2H), 0.17 (q, J = 4.7 Hz, 2H). Mass(m / z): 419.3[M+H]+.

[0593] 1-Ethyl-5-oxo-N-propyl-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (223) JPEG2026063193000268.jpg61151

[0594] 1H NMR (400 MHz, Methanol-d4) δ 7.04-6.97 (m, 8H), 4.51 (s, 2H), 3.77 - 3.12 (m, 10H), 2.70 - 2.40 (m, 3H), 2.35 - 2.09 (m, 1H), 1.92 (d, Mass(m / z): 531.2 [M+H] + .

[0595] 2-(4-methyl-3-oxopiperazine-1-yl)-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)acetamide (224) JPEG2026063193000269.jpg26151

[0596] Compound 224 (18.4 mg) was prepared from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (100 mg, 0.29 mmol) and 2-(4-methyl-3-oxopiperazine-1-yl)acetic acid (66 mg, 0.31 mmol) as a pale blue solid with a yield of 12.77%. 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (t, J = 5.8 Hz, 1H), 7.78 (s, 1H), 7.25 - 6.63 (m, 8H), 4.14 (s, 2H), 3.61 (s, 2H), 3.28 - 3.21 (m, 2H), 2.79 (s, 3H), 2.73 - 2.56 (m, 4H), 2.34 - 2.26 (m, 2H), 1.92 (ddd, J = 13.1, 5.8, 2.8 Hz, 3H), 1.77 (dddd, J = 13.3, 10.5, 8.4, 7.2 Hz, 1H), 1.57 (s, 2H). LC-MS (m / z) 504.4 [M+H] + .

[0597] 1-Ethyl-N-methyl-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (225) JPEG2026063193000270.jpg64151

[0598] 1 H NMR (400 MHz, Methanol-d4) δ 7.41 - 6.55 (m, 8H), 4.48 (s, 2H), 3.75 - 3.43 (m, 4H), 3.39 - 3.17 (m, 4H), 2.92 (s, 3H), 2.68 - 2.45 (m, Mass(m / z): 503.3 [M+H] + .

[0599] N-hydroxy-N-(4-((4-(piperidine-1-yl)phenyl)aminobenzyl)hexanamide (226) JPEG2026063193000271.jpg59151

[0600] Compound 226 (11.3 mg) was prepared as a white solid with a total yield of 38.4% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.43-6.64 (m, 8H), 4.75 (s, 2H), 3.03 (br s, 4H), 2.38 (t, J = 7.4 Hz, 2H), 1.73 (br , 4H), 1.60- 1.16 (m, 8H), 1.04 - 0.81 (m, 3H).Mass(m / z): 396.3[M+H] + .

[0601] 2-(4-methylpiperazine-1-yl)-N-(4-((4-(piperidine-1-yl)phenyl)amino)-3-(trifluoromethyl)benzyl)acetamide (227) JPEG2026063193000272.jpg72151

[0602] Compound 227 (15.9 mg) was prepared as a white solid with a total yield of 56.9% according to the procedure for compound 163. 1 H NMR (400 MHz, Methanol-d4) δ 7.47 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.05-6.89 (m, 5H), 4.34 (s, 2H), 3.15 (s, 2H), 3.10-2.75 (br m, 12H), 2.66 (s, 3H), 1.74 (br s, 4H), 1.60 (br s, 2H). Mass(m / z): 490.3[M+H] +

[0603] 1-Methyl-2-oxo-N-(4-((4-(piperidine-1-yl)phenyl)amino)-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (228) JPEG2026063193000273.jpg58151

[0604] Compound 228 (21.2 mg) was prepared as a white solid with a total yield of 47.5% according to the procedure for compound 163. 1 H NMR (400 MHz, Methanol-d4) δ 7.46 - 6.87 (m, 7H), 4.44 (s, 2H), 3.39-3.37 (m, 2H), 3.19 (br s, 4H), 2.93 (s, 3H), 2.81 (m, 1H), 2.57 - 2.40 (m, 2H), 2.11 - 1.89 (m, 2H), 1.81 (br s, 4H), 1.64 (br s, 2H). Mass(m / z): 489.3[M+H] + .

[0605] N-(4-((3,5-difluoro-4-(piperidine-1-yl)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazine-1-yl)acetamide (229) JPEG2026063193000274.jpg66151

[0606] Compound 229 (11.9 mg) was prepared as a white solid with a total yield of 27.1% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.23 (d, J = 8.4 Hz, 2H), 7.05 (d, J= 8.4 Hz, 2H), 6.53 (d, J = 11.6 Hz, 2H), 4.68 (s, 2H), 3.45 (s, 2H), 3.07 - 2.95 (m, 4H), 2.72 (br s, 8H), 2.43 (s, 3H), 1.69-1.62 (m, 4H), 1.57-1.50 (m, 2H).Mass(m / z): 474.2[M+H] + .

[0607] 1-Methyl-2-oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)piperidine-4-carboxamide (230) JPEG2026063193000275.jpg41151

[0608] To a solution of 1-methyl-2-oxopiperidine-4-carboxylic acid (49 mg, 0.31 mmol, 1.1 equivs) and 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (100 mg, 0.29 mmol, 1.0 equivs) in superdried N,N-dimethylformamide (5 mL), 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine-4-ium chloride (87 mg, 0.31 mmol, 1.1 equivs) and N-ethyl-N-isopropylpropan-2-amine (142 mL, 0.86 mmol, 3.0 equivs) were added at room temperature. The resulting solutions were stirred overnight at room temperature. The reaction mixture was added dropwise to water (25 mL) with stirring. The precipitate was filtered, the filtrate was washed three times with water, and dried in a vacuum. The residue was purified by silica gel column chromatography (petroleum ether / AcOEt, 1 / 5) to obtain 1-methyl-2-oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aminobenzyl)piperidine-4-carboxamide 296 as a pale blue solid in yield of 31.32%. 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 6.8 Hz, 1H), 7.77 (s, 1H), 7.05 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.2 Hz, 2H), 6.89 (d, J= 9.7 Hz, 4H), 4.16 (d, J = 5.8 Hz, 2H), 3.61 (d, J = 12.1 Hz, 2H), 3.28 (t, J = 5.5 Hz, 2H), 3.06 (d, J = 8.5 Hz, 4H), 2.81 (s, 3H), 2.71 (t, J = 5.5 Hz, 2H), 2.63 (q, J = LC-MS (m / z) 489.4 [M+H] + .

[0609] N-(tert-butyl)-1-ethyl-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (231) JPEG2026063193000276.jpg63151

[0610] 1 H NMR (400 MHz, Methanol-d4) δ 7.25-6.72 (m, 8H), 4.62 (s, 2H), 3.79 - 3.37 (m, 5H), 3.27 - 3.13 (m, 3H), 2.55 (m, 3H), 2.38 - 2.19 (m, 1H), 1.99 (br m, 2H), 1.73 (br m, 2H), 1.46 (s, 9H), 1.10 (t, J = 7.3 Hz, 3H).Mass(m / z): 545.3 [M+H] + .

[0611] 1-(4-((4-(4,4-difluoropiperidine-1-yl)phenyl)amino)benzyl)-4-ethylpiperazine-2-one (232) JPEG2026063193000277.jpg30151

[0612] A mixture of 1-(4-bromobenzyl)-4-ethylpiperazine-2-one (91 mg, 0.307 mmol), 4-(4,4-difluoropiperidine-1-yl)aniline (50 mg, 0.236 mmol), Pd2(dppf)2Cl2 (4 mg, 0.005 mmol), xanthophos (6 mg, 0.010 mmol), Cs2CO3 (116 mg, 0.354 mmol), and Tol (5 mL) was stirred at 100°C for 16 hours. The mixture was concentrated and purified by prep-HPLC to obtain the desired product as a white solid (10.0 mg, 9.9%). 1H NMR (400 MHz, Methanol-d4) δ 7.29 - 7.11 (m, 8H), 4.82 - 4.75 (m, 2H), 4.07 (s, 2H), 3.55 (td, J = 21.4, 20.6, 10.4 Hz, 6H), 3.34 (td, J = Mass(m / z): 429.3 [M+H] + .

[0613] N-(2,6-difluoro-4-((4-(piperidine-1-yl)phenyl)amino)benzyl)-2-(4-methylpiperazine-1-yl)acetamide (233) JPEG2026063193000278.jpg65151

[0614] Compound 233 (20.7 mg) was prepared as a white solid with a total yield of 46.1% according to the procedure for compound 163. 1 H NMR (400 MHz, Methanol-d4) δ 7.55 (d, J = 8.8 Hz, 2H), 7.27 (d, J= 8.8 Hz, 2H), 6.69 (d, J = 9.6 Hz, 2H), 4.42 (s, 2H), 3.45 (s, 2H), 3.21 (br s, 4H), 2.89 (br m, 8H), 2.41 (s, 3H), 1.74 - 1.48 (m, 6H). Mass(m / z): 458.3[M+H] + .

[0615] 3-(2-oxopyrrolidine-1-yl)-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)propanamide (234) JPEG2026063193000279.jpg56151

[0616] 1H NMR (400 MHz, Methanol-d4) δ 7.12-6.93 (m, 8H), 4.23 (s, 2H), 3.66-3.52 (m, 4H), 3.38 (t, J = 6.8 Hz, 2H), 2.70 (br m, 2H), 2.43 (t, J = 6.8 Hz, 2H), 2.31-2.26 (m, 3H), 2.07 - 1.82 (m, 4H), 1.79-1.68 (m, 2H). Mass(m / z): 490.2 [M+H] + .

[0617] 1-Acetyl-N-(4-((4-(piperidine-1-yl)phenyl)aminobenzyl)piperidine-4-carboxamide (235) JPEG2026063193000280.jpg57151

[0618] Compound 235 (4.2 mg) was prepared as a white solid with a total yield of 30.8% according to the procedure for compound 163. 1 H NMR (400 MHz, Methanol-d4) δ 7.45 - 6.85 (m, 8H), 4.26 (s, 2H), 3.60 - 3.39 (m, 4H), 3.25 - 2.87 (m, 4H), 2.49 (m, 1H), 2.10 (s, 3H), 1.98 - 1.47 (m, 10H). Mass(m / z): 435.3[M+H] +

[0619] 1-(cyclopropanecarbonyl)-N-(4-((4-(piperidine-1-yl)phenyl)aminobenzyl)piperidine-4-carboxamide (236) JPEG2026063193000281.jpg54151

[0620] Compound 236 (5.1 mg) was prepared as a white solid with a total yield of 35.1% according to the procedure for compound 163. 1H NMR (400 MHz, Methanol-d4) δ 7.47 - 6.76 (m, 8H), 4.27 (s, 2H), 3.35 (br s, 4H), 3.26- 2.62 (m, 4H), 2.52 (m, 1H), 1.98 - 1.47 (m, 11H), 0.94 - 0.74 (m, 4H). Mass(m / z): 461.3[M+H] +

[0621] N-(4-((3-chloro-4-(piperidine-1-yl)phenyl)amino)benzyl)-2-(4-methylpiperazine-1-yl)acetamide (237) JPEG2026063193000282.jpg63151

[0622] Compound 237 (20.7 mg) was prepared as a white solid with a total yield of 48.3% according to the procedure for compound 163. 1 H NMR (400 MHz, Methanol-d4) δ 7.16 (d, J = 8.4 Hz, 2H), 7.07 (s, 1H), 7.03 - 6.93 (m, 4H), 4.32 (s, 2H), 3.11 (s, 2H), 2.88 (br m, 4H), 2.73 (br m, 8H), 2.50 (s, 3H), 1.81 - 1.64 (m, 4H), 1.57 (br s, 2H). Mass(m / z): 456.2[M+H] +

[0623] 1-(4-((4-(2,6-dimethylmorpholino)phenyl)amino)benzyl)-4-ethylpiperazine-2-one (238) JPEG2026063193000283.jpg68151

[0624] Compound 238 (11.3 mg) was prepared as a white solid with a total yield of 26.7% according to the procedure for compound 202. 1H NMR (400 MHz, Methanol-d4) δ 7.46-6.65 (m, 8H), 4.53 (s, 2H), 3.79 (m, 2H), 3.24 (s, 2H), 3.05 (br m, 4H), 2.78-2.71 (m, 4H), 2.55 (q, J = Mass(m / z): 423.3[M+H] +

[0625] 2-(4-methylpiperazine-1-yl)-N-(4-((4-(piperidine-1-yl)-3-(trifluoromethyl)phenyl)amino)benzyl)acetamide (239) JPEG2026063193000284.jpg63151

[0626] Compound 239 (12.5 mg) was prepared as a yellow solid with a total yield of 25.5% from N-(4-(aminomethyl)phenyl)-4-(piperidine-1-yl)-3-(trifluoromethyl)aniline (34.9 mg, 0.1 mmol), 4-(dimethylamino)butanoic acid hydrochloride (19.0 mg, 0.12 mmol), HATU (45.6 mg, 0.12 mmol), DIEA (38.7 mg, 0.3 mmol), and DMF (1.0 mL) according to the procedure in 163. 1H NMR (400 MHz, Methanol-d4) δ 7.79 - 7.72 (m, 2H), 7.14 - 7.02 (m, 2H), 6.71 - 6.62 (m, 2H), 4.17 - 4.09 (m, 1H), 3.55 - 3.45 (m, 2H), 3.18 - 3.09 (m, 2H), 3.05 (d, J = 7.9 Hz, 4H), 2.85 (s, 3H), 2.18 (d, J = 12.2 Hz, 2H), 1.96 (q, J = 12.8 Hz, 2H), 1.70 - 1.61 (m, 2H), 1.51 - 1.40 (m, 1H), 1.38 - 1.26 (m, 2H), 0.97 (d, J = 6.4 Hz, 3H). Mass(m / z):490.4 [M+H] + .

[0627] 4-Ethyl-1-(4-((4-(piperidine-1-yl)phenyl)amino)-2-(trifluoromethyl)benzyl)piperazine-2-one (240) JPEG2026063193000285.jpg65151

[0628] Step 1. 1-(4-bromo-2-(trifluoromethyl)benzyl)-4-ethylpiperazine-2-one (240-1) (530 mg) was prepared as a pale yellow oil with a yield of 92.28% from 4-bromo-1-(bromomethyl)-2-(trifluoromethyl)benzene (500 mg, 1.57 mmol) and 4-ethylpiperazine-2-one hydrochloride (259 mg, 1.57 mmol) following the procedure for compound 1-(3-bromo-5-fluorobenzyl)-4-ethylpiperazine-2-one (241-1). LC-MS (m / z) 365.2, 367.2 [M+H] + .

[0629] Step 2. Compound 240 (40.1 mg) was prepared as a pale yellow solid in a yield of 63.6% from 1-(4-bromo-2-(trifluoromethyl)benzyl)-4-ethylpiperazine-2-one (240-1) (50 mg, 0.14 mmol) and 4-(piperidine-1-yl)aniline (29 mg, 0.16 mmol) according to the procedure for compound 253. 1 H NMR (400 MHz, Chloroform-d) δ 7.17 (d, J = 8.5 Hz, 1H), 7.10 (s, 1H), 7.02 (s, 2H), 6.95 (d, J = 18.1 Hz, 3H), 5.69 (s, 1H), 4.70 (s, 2H), 3.24 (s, 2H), 3.23 - 3.19 (m, 2H), 3.11 (s, 4H), 2.66 - 2.60 (m, 2H), 2.47 (q, J= 7.2 Hz, 2H), 1.72 (p, J = 5.5 Hz, 4H), 1.57 (p, J = 5.8 Hz, 2H), 1.10 (t, J = 7.2 Hz, 3H). LC-MS (m / z) 461.4 [M+H] + .

[0630] 4-(dimethylamino)-N-(4-((4-(piperidine-1-yl)-3-(trifluoromethyl)phenyl)amino)benzyl)butanamide (241) JPEG2026063193000286.jpg26151

[0631] Compound 241 (32.0 mg) was prepared as a white solid with a total yield of 76.1% from N-(4-(aminomethyl)phenyl)-4-(piperidine-1-yl)-3-(trifluoromethyl)aniline (30 mg, 0.086 mmol) and 4-(dimethylamino)butanoic acid hydrochloride (19 mg, 0.122 mmol) according to the procedure in 179. 1H NMR (400 MHz, Methanol-d4) δ 7.30 (d, J = 8.6 Hz, 1H), 7.26 - 7.15 (m, 4H), 7.06 - 6.98 (m, 2H), 4.28 (s, 2H), 2.85 - 2.74 (m, 6H), 2.61 (d, J= 1.0 Hz, 6H), 2.38 - 2.31 (m, 2H), 1.92 (p, J = 7.2 Hz, 2H), 1.65 (p, J= 5.6 Hz, 4H), 1.53 (q, J = 6.1 Hz, 2H).Mass(m / z): 463.3 [M+H] + .

[0632] 1-(tert-butyl)-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (242) JPEG2026063193000287.jpg36151

[0633] Compound 242 (97.2 mg) was prepared as a white solid with a yield of 69.74% from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (100 mg, 0.29 mmol) and 1-(tert-butyl)-5-oxopyrrolidine-3-carboxylic acid (58 mg, 0.31 mmol). 1H NMR (400 MHz, DMSO-d6) δ 8.37 (t, J = 5.8 Hz, 1H), 7.78 (s, 1H), 7.04 (d, J = 8.5 Hz, 2H), 6.99 - 6.94 (m, 2H), 6.91 - 6.84 (m, 4H), 4.15 (d, J = 5.7 Hz, 2H), 3.60 (t, J = 9.3 Hz, 3H), 3.45-3.40 (m, 2H), 3.07 - 2.96 (m, 1H), 2.66 - 2.57 (m, 2H), 2.38 (dd, J = 8.9, 3.8 Hz, 2H), 1.87 (d, J = 12.6 Hz, 2H), 1.56 (qd, J = 12.5, 4.1 Hz, 2H), 1.30 (s, 9H). LC-MS (m / z) 517.4 [M+H] + .

[0634] 1-Ethyl-N-(2-hydroxyethyl)-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (243) JPEG2026063193000288.jpg65151

[0635] 1 H NMR (400 MHz, Methanol-d4) δ 7.32 - 6.68 (m, 8H), 4.64 (s, 2H), 3.81 - 3.17 (m, 12H), 2.73 - 2.44 (m, 3H), 2.26 (br m, 1H), 1.96 (br m, 2H), 1.71 (br m, 2H), 1.10 (dt, J = 15.0, 7.4 Hz, 3H).Mass(m / z): 533.4 [M+H] + .

[0636] N-hydroxy-2-(4-methylpiperazine-1-yl)-N-(4-((4-(3-(trifluoromethyl)pyrrolidine-1-yl)phenyl)amino)benzyl)acetamide (244) JPEG2026063193000289.jpg27151

[0637] Compound 244 (24.6 mg) was prepared as a white solid with a total yield of 57.1% from 4-((hydroxyamino)methyl)-N-(4-(3-(trifluoromethyl)pyrrolidine-1-yl)phenyl)aniline (30 mg, 0.094 mmol) and 2-(4-methylpiperazin-1-yl)acetic acid (19 mg, 0.122 mmol) according to the procedure in 179. 1 H NMR (400 MHz, Methanol-d4) δ 7.48 - 7.36 (m, 1H), 7.10 (s, 2H), 6.91 - 6.55 (m, 5H), 4.63 (s, 2H), 3.54 (s, 2H), 3.17 (d, J = 10.4 Hz, 4H), 2.88 (s, 3H), 2.77 (s, 4H), 2.46 (d, J = 16.1 Hz, 3H).Mass(m / z): 460.3 [M+H] + .

[0638] N-ethyl-2-(4-methylpiperazine-1-yl)-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)acetamide (245) JPEG2026063193000290.jpg74151

[0639] Step 1. N-(4-bromobenzyl)-N-ethyl-2-(4-methylpiperazin-1-yl)acetamide (245-1) was prepared as a colorless oil from N-(4-bromobenzyl)ethanamine (500 mg, 2.34 mmol) and 2-(4-methylpiperazin-1-yl)acetic acid (406 mg, 2.57 mmol) according to the procedure for N-(4-bromobenzyl)-N-ethyl-2-(4-methyl-3-oxopiperazin-1-yl)acetamide (289-1). The residue was concentrated and dried under vacuum, and used directly in the next step without further purification. LC-MS (m / z) 354.2, 356.1 [M+H] + .

[0640] Step 2. Compound 245 (56.2 mg) of the title compound was prepared from 4-(4-(trifluoromethyl)piperidine-1-yl)aniline (100 mg, 0.41 mmol) and N-(4-bromobenzyl)-N-ethyl-2-(4-methylpiperazin-1-yl)acetamide (145 mg, 0.41 mmol) as a blue solid with a yield of 26.52%. 1 H NMR (400 MHz, Methanol-d4) δ 7.56 - 7.51 (m, 1H), 7.49 - 7.44 (m, 1H), 7.22 - 7.16 (m, 2H), 7.05 (dt, J = 13.2, 7.2 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 4.55 (s, 2H), 3.62 (d, J = 12.0 Hz, 2H), 3.44 - 3.34 (m, 6H), 2.66 (s, 2H), 2.40 (d, J = 1.9 Hz, 4H), 2.01 - 1.94 (m, 2H), 1.73 (qd, J= 12.5, 4.1 Hz, 2H), 1.24 (t, J = 7.1 Hz, 2H), 1.21 - 1.15 (m, 4H), 1.08 (td, J = 7.0, 4.3 Hz, 3H). LC-MS (m / z) 518.4 [M+H] + .

[0641] N-hydroxy-N-(4-((4-(piperidine-1-yl)phenyl)amino)benzyl)-2-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)acetamide (246) JPEG2026063193000291.jpg74151

[0642] Step 1. To a solution of 1-(2,2,2-trifluoroethyl)piperazine dihydrochloride (300 mg, 1.24 mmol, 1.0 equivs) in water (5 mL), 2-bromoacetic acid (190 mg, 1.37 mmol, 1.1 equivs) and potassium carbonate (516 mg, 3.73 mmol, 3.0 equivs) were slowly added at 0°C using an ice bath. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was acidified to pH=4 with 1N hydrochloric acid and then extracted three times with dichloromethane (5 mL). The organic layer was bonded, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue 2-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)acetic acid (246-1) was concentrated, dried under vacuum, and used directly in the next step without further purification. LC-MS (m / z) 227.4 [M+H] + .

[0643] Step 2. Compound 246 (14.9 mg) was prepared as a brown solid in a yield of 17.53% from 2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)acetic acid (246-1) (46 mg, 0.16 mmol) and 4-((hydroxyamino)methyl)-N-(4-(piperidine-1-yl)phenyl)aniline (50 mg, 0.17 mmol) according to the procedure for compound 290. 1 H NMR (400 MHz, Chloroform-d) δ 7.35-7.11 (br, 2H), 7.10-6.65 (br, 6H), 5.89 - 5.17 (br, 1H), 4.70 (s, 2H), 3.35 (s, 2H), 3.29 - 3.00 (br, LC-MS (m / z) 506.7 [M+H] + .

[0644] N-(2-chloro-4-((5-(piperidine-1-yl)pyridine-2-yl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazine-1-yl)acetamide (247) JPEG2026063193000292.jpg27151

[0645] Compound 247 (17.9 mg) was prepared as a white solid with a total yield of 42.3% from N-(3-chloro-4-((hydroxyamino)methyl)phenyl)-5-(piperidine-1-yl)pyridine-2-amine (30 mg, 0.090 mmol) and 2-(4-methylpiperazine-1-yl)acetic acid (19 mg, 0.117 mmol) according to the procedure in 179. 1 H NMR (400 MHz, Methanol-d4) δ 7.18 - 6.90 (m, 7H), 4.78 (s, 2H), 3.56 (s, 2H), 3.11 (d, J = 22.2 Hz, 8H), 2.88 (s, 3H), 2.75 (s, 3H), 1.75 (p, J= 5.6 Hz, 4H), 1.59 (s, 3H).Mass(m / z): 473.3 [M+H] + .

[0646] N-(4-((5-fluoro-6-(piperidine-1-yl)pyridine-3-yl)amino)benzyl)-2-(4-methyl-3-oxopiperazine-1-yl)acetamide (248) JPEG2026063193000293.jpg70151

[0647] Compound 248 (16.9 mg) was prepared as a white solid with a total yield of 41.2% according to the procedure for compound 163. 1H NMR (400 MHz, Methanol-d4) δ 7.80 (s, 1H), 7.24 - 7.13 (m, 3H), 6.95 (d, J = 8.4 Hz, 2H), 4.32 (s, 2H), 3.38 (m, 2H), 3.25 - 3.17 (m, 6H), 3.15 (s, 2H), 2.93 (s, 3H), 2.82 - 2.76 (m, 2H), 1.78 - 1.55 (m, 6H). Mass(m / z): 455.2[M+H] +

[0648] N-(4-((4-(4,4-difluoropiperidine-1-yl)phenyl)amino)benzyl)-N-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (249) JPEG2026063193000294.jpg69151

[0649] Compound 249 (10.1 mg) was prepared as a white solid with a total yield of 33.4% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.65 (d, J = 6.4 Hz, 1H), 7.31 - 6.82 (m, 8H), 6.67 (s, 1H), 6.55 - 6.38 (m, 1H), 4.74 (s, 2H), 3.55 (s, 3H), 3.30 - 3.06 (m, 4H), 2.13-2.03 (m, 4H). Mass(m / z): 469.3[M+H] +

[0650] 1-(4-((4-(4,4-difluoropiperidine-1-yl)phenyl)aminobenzyl)-4-fluoropyridine-2(1H)-one (250) JPEG2026063193000295.jpg80116

[0651] Compound 250 (20.1 mg) was prepared as a white solid with a total yield of 48.4% according to the procedure for compound 202. 1H NMR (400 MHz, Methanol-d4) δ 7.86 - 7.68 (m, 1H), 7.28 - 6.56 (m, 8H), 6.35 - 6.17 (m, 2H), 4.15 (s, 2H), 3.27 - 3.06 (m, 4H), 2.14-2.03 (m, 4H). Mass(m / z): 414.3[M+H] +

[0652] N-(4-((4-(4,4-difluoropiperidine-1-yl)phenyl)amino)benzyl)-N-hydroxy-1-methyl-6-oxopiperidine-3-carboxamide (251) JPEG2026063193000296.jpg63151

[0653] Compound 251 (9.9 mg) was prepared as a white solid with a total yield of 23.5% from 4-(4,4-difluoropiperidine-1-yl)-N-(4-((hydroxyamino)methyl)phenyl)aniline (30 mg, 0.090 mmol) and 1-methyl-6-oxopiperidine-3-carboxylic acid (18.5 mg, 0.117 mmol) according to the procedure in 174. 1 H NMR (400 MHz, Methanol-d4) δ 7.83 - 6.43(m,8H), 4.65 (s, 2H),3.80 - 3.74 (m, 1H), 3.73 - 3.66 (m, 1H), 3.56 (dd, J = 9.8, 5.2 Hz, 1H), 3.30 (dq, J= 3.2, 1.6 Hz, 7H), 2.67 - 2.60 (m, 2H), 2.40 (s, 4H), 1.11 (td, J = 7.2, 0.6 Hz, 3H).Mass(m / z): 473.3 [M+H] +

[0654] N-(4-((4-(4,4-difluoropiperidine-1-yl)phenyl)amino)benzyl)-1-ethyl-N-hydroxy-5-oxopyrrolidine-3-carboxamide (252) JPEG2026063193000297.jpg68151

[0655] Compound 251 (7.0 mg) was prepared as a white solid with a total yield of 17% from 4-(4,4-difluoropiperidine-1-yl)-N-(4-((hydroxyamino)methyl)phenyl)aniline (30 mg, 0.090 mmol) and 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (18.5 mg, 0.117 mmol) according to the procedure in 174. 1 H NMR (400 MHz, Methanol-d4) δ 7.74 - 6.73(m,8H), 4.65 (s, 2H),3.49 (ddd, J= 22.8, 13.5, 9.6 Hz, 5H), 2.94 (s, 4H), 2.42 - 2.34 (m, 4H), 2.03 (d, J= 0.4 Hz, 2H), 2.00 - 1.91 (m, 2H).Mass(m / z): 473.3 [M+H] + .

[0656] N-(4-((4-(4,4-difluoropiperidine-1-yl)phenyl)amino)benzyl)-N-hydroxy-2-(2-methoxyethoxy)acetamide (253) JPEG2026063193000298.jpg25151

[0657] Compound 253 (8.2 mg) was prepared as a white solid with a total yield of 10.2% from 4-(4,4-difluoropiperidine-1-yl)-N-(4-((hydroxyamino)methyl)phenyl)aniline (30 mg, 0.090 mmol) and 2-(2-methoxyethoxy)acetic acid (16 mg, 0.117 mmol) according to the procedure in 179. 1H NMR (400 MHz, Methanol-d4) δ 7.29 - 7.11 (m, 8H), 4.37 (s, 2H), 3.72 - 3.67 (m, 2H), 3.60 - 3.55 (m, 2H), 3.36 (d, J = 0.5 Hz, 3H), 2.41 (s, 4H), 1.78 - 1.55(m, 6).Mass(m / z): 450.3 [M+H] + .

[0658] 1-(cyclopropylmethyl)-N-hydroxy-2-oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)piperidine-4-carboxamide (254) JPEG2026063193000299.jpg25151

[0659] Compound 254 (11.6 mg) was prepared as a white solid with a total yield of 26.4% from 4-((hydroxyamino)methyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (30 mg, 0.082 mmol) and 1-(cyclopropylmethyl)-2-oxopiperidine-4-carboxylic acid (21 mg, 0.107 mmol) according to the procedure in 179. 1H NMR (400 MHz, Methanol-d4) δ 7.18 - 6.81 (m, 8H), 4.65 (q, J = 16.0, 15.4 Hz, 2H), 3.68 - 3.38 (m, 5H), 3.22 (dd, J = 13.8, 6.9 Hz, 1H), 2.65 (s, 2H), 2.49 (d, J = 7.3 Hz, 2H), 2.25 (dtt, J = 16.1, 7.7, 4.0 Hz, 1H), 2.05 (t, J = 7.4 Hz, 1H), 2.01 - 1.89 (m, 3H), 1.71 (qd, J= 12.6, 3.9 Hz, 2H), 1.29 (d, J = 3.9 Hz, 1H), 1.05 - 0.98 (m, 1H), 0.50 (ddd, J = 8.2, 4.1, 2.3 Hz, 2H), 0.29 - 0.17 (m, 2H).Mass(m / z): 545.3 [M+H] + .

[0660] 3-(4-((4-((N-hydroxy-2-(4-methylpiperazine-1-yl)acetamide)methyl)phenyl)amino)phenyl)N,N-dimethylpropanamide (255) JPEG2026063193000300.jpg54151

[0661] 1H NMR (400 MHz, Methanol-d4) δ 7.17 (d, J = 8.4 Hz, 2H), 7.09 (d, J= 8.4 Hz, 2H), 7.00 (d, J = 8.4 Hz, 4H), 4.65 (s, 2H), 3.48 (s, 2H), 2.96 (s, 3H), 2.91 (s, 3H), 2.89 - 2.68 (m, 10H), 2.63 (t, J = 8.4 Hz, 2H), 2.53 (s, 3H). Mass(m / z): 454.3 [M+H] + .

[0662] 4-(dimethylamino)-N-(4-((4-(6-fluoropyridine-3-yl)phenyl)amino)benzyl)-N-hydroxybutanamide (256) JPEG2026063193000301.jpg62151

[0663] 1H NMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H), 8.13 (m, 1H), 7.50 (d, J= 8.8 Hz, 2H), 7.30 - 7.22 (m, 2H), 7.20 - 7.06 (m, 5H), 4.70 (s, Mass(m / z): 423.3 [M+H] + .

[0664] N-hydroxy-1-methyl-6-oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)piperidine-3-carboxamide (257) JPEG2026063193000302.jpg28151

[0665] Step 1. Compound 257 (10.5 mg) was prepared as a pale yellow powder with a yield of 38.02% from 4-((hydroxyamino)methyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (20 mg, 0.054 mmol) and 1-methyl-6-oxopiperidine-3-carboxylic acid (10.3 mg, 0.066 mmol) according to the procedure for compound 290. 1H NMR (400 MHz, Methanol-d4) δ 7.81 - 6.16 (m, 8H), 4.81 - 4.42 (br, 2H), 3.55 - 3.38 (m, 4H), 2.93 (s, 3H), 2.42 - 2.20 (m, 4H), 2.12 - 1.85 (m, 5H), 1.72 (s, 3H). LC-MS (m / z) 505.4 [M+H] + .

[0666] N-hydroxy-1-methyl-6-oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)piperidine-3-carboxamide (258) JPEG2026063193000303.jpg29151

[0667] Compound 258 (19.9 mg) was prepared as a pale yellow solid in a yield of 72.06% from 4-((hydroxyamino)methyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (20 mg, 0.054 mmol) and 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (9.4 mg, 0.066 mmol) according to the procedure for compound 290. 1 H NMR (400 MHz, Methanol-d4) δ 7.37-7.10 (br, 3H), 7.076.55 (br, 5H), 4.66 (s, 2H), 3.81 - 3.47 (m, 5H), 2.83 - 2.42 (m, 4H), 2.34-2.20(m, LC-MS (m / z) 491.2 [M+H] + .

[0668] tert-butyl3-(hydroxy(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aminobenzyl)carbamoyl)azetidine-1-carboxylate (259) JPEG2026063193000304.jpg63151

[0669] Compound 259 (164.1 mg) was prepared as a white solid with a total yield of 46.9% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ7.27 - 6.79 (m, 8H), 4.67 (s, 2H), 4.05 (br m, 4H), 3.25-3.16 (m, 4H), 2.31 - 2.17 (m, 2H), 2.02 - 1.85 (m, 2H), 1.76-1.72 (m, 2H), 1.45 (s, 9H). Mass(m / z): 549.3[M+H] +

[0670] N-hydroxy-1-methyl-2-oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)piperidine-4-carboxamide (260) JPEG2026063193000305.jpg59151

[0671] Compound 260 (36.6 mg) of the title compound was prepared according to the procedure in 137 from 4-((hydroxyamino)methyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (55.0 mg, 0.15 mmol), 1-methyl-2-oxopiperidine-4-carboxylic acid (28.0 mg, 0.18 mmol), DMT-MM (48.0 mg, 0.18 mmol), DIEA (58.0 mg, 0.45 mmol), and DMF (1.0 mL) as a yellow solid with a total yield of 40.4%. 1H NMR (400 MHz, Methanol-d4) δ 7.34 - 6.41 (m, 8H), 4.64 (s, 2H), 3.74 - 3.31 (m, 6H), 2.92 (s, 3H), 2.47 (d, J = 7.3 Hz, 2H), 2.32 - 2.19 (m, 1H), 2.09 - 1.88 (m, 4H), 1.79 - 1.64(m, 2H). Mass(m / z):505.3 [M / 2+H] + .

[0672] 1-Ethyl-5-oxo-N-(4-((4-(3-(trifluoromethyl)pyrrolidine-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (261) JPEG2026063193000306.jpg62151

[0673] Compound 261 (9.4 mg) was prepared according to the procedure in 209 from 4-(aminomethyl)-N-(4-(3-(trifluoromethyl)pyrrolidine-1-yl)phenyl)aniline (20 mg, 0.06 mmol), 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (11.8 mg, 0.08 mmol), DIEA (23.2 mg, 0.18 mmol), and HATU (30.4 mg, 0.08 mmol) as a blue solid with a total yield of 32.9%. 1 H NMR (400 MHz, Methanol-d4) δ 7.49 - 7.43 (m, 2H), 7.26 - 7.19 (m, 2H), 7.18 - 7.09 (m, 4H), 4.87 (s, 1H), 4.39 - 4.27 (m, 2H), 3.71 - 3.49 (m, 3H), 3.46 - 3.32 (m, 4H), 3.22 - 3.11 (m, 2H), 2.60 (d, J = 8.1 Hz, 2H), 1.41 - 1.25 (m, 3H), 1.16 - 1.07 (m, 3H). Mass(m / z): 475.3 [M+H] + .

[0674] N-hydroxy-2-(4-methyl-3-oxopiperazine-1-yl)-N-(4-((4-(piperidine-1-yl)phenyl)amino)-2-(trifluoromethyl)benzyl)acetamide (262) JPEG2026063193000307.jpg105151

[0675] Step 1. Compound 262-3 (2.1 g) was prepared as a yellow oil with a total yield of 60.3% from 4-(piperidine-1-yl)aniline (1.76 g, 10.0 mmol), 4-bromo-2-(trifluoromethyl)benzaldehyde (2.53 g, 10.0 mmol), Pd(dppf)2Cl2 (73.1 mg, 0.2 mmol), xanthophos (231.6 mg, 0.4 mmol), and Cs2CO3 (4.89 g, 15 mmol) according to the procedure in 137-3. Mass (m / z): 349.3 [M+H] + .

[0676] Step 2. Compound 262-4 (1.4 g) was prepared as a yellow solid with a total yield of 64.0% from 4-((4-(piperidine-1-yl)phenyl)amino)-2-(trifluoromethyl)benzaldehyde (2.1 g, 6.03 mmol) and hydroxylamine hydrochloride (625 mg, 9.05 mmol) according to the procedure in 137-4. Mass (m / z): 364.2 [M+H] + .

[0677] Step 3. Compound 262-5 (720 mg) of the title compound was prepared according to the procedure in 137-5 from (E)-4-((4-(piperidine-1-yl)phenyl)amino)-2-(trifluoromethyl)benzaldehyde oxime (720 mg, 2.0 mmol), borane-pyridine complex (370 mg, 0.4 mmol), and 15 mL of 10% HCl as a yellow solid with a total yield of 50.0%. Mass (m / z): 366.2 [M+H] + .

[0678] Step 4. Compound 262 (30.0 mg) of the title compound was prepared according to the procedure in 137 from 4-((hydroxyamino)methyl)-N-(4-(piperidine-1-yl)phenyl)-3-(trifluoromethyl)aniline (55 mg, 0.15 mmol), 2-(4-methyl-3-oxopiperazine-1-yl)acetic acid hydrochloride (41 mg, 0.20 mmol), DMT-MM (65 mg, 0.23 mmol), DIEA (58 mg, 0.45 mmol), and DMF (1.0 mL) as a yellow solid with a total yield of 38.5%. 1 H NMR (400 MHz, Methanol-d4) δ 7.30 - 7.03 (m, 7H), 4.88 - 4.85 (m, 7H), 4.41 (s, 2H), 3.49 - 3.43 (m, 2H), 3.19 (s, 2H), 3.17 - 3.09 (m, Mass(m / z):520.3 [M+H] + .

[0679] N-hydroxy-2-(4-methyl-2-oxopiperazine-1-yl)-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)acetamide (263) JPEG2026063193000308.jpg60151

[0680] Compound 263 (19.0 mg) was prepared according to the procedure in 137 from 4-((hydroxyamino)methyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (55 mg, 0.15 mmol), 2-(4-methyl-3-oxopiperazine-1-yl)acetic acid hydrochloride (41 mg, 0.20 mmol), DMT-MM (65 mg, 0.23 mmol), DIEA (58 mg, 0.45 mmol), and DMF (1.0 mL) as a yellow solid with a total yield of 24.4%. 1H NMR (400 MHz, Methanol-d4) δ 7.17 - 6.87 (m, 8H), 4.64 (s, 2H), 4.35 (s, 2H), 3.66 - 3.52 (m, 2H), 3.47 - 3.38 (m, 2H), 3.20 - 3.15 (m, 2H), 2.80 (t, J = 5.4 Hz, 2H), 2.73 - 2.57 (m, 2H), 2.39 (d, J = s, 3H), 2.31 - 2.21 (m, 1H), 2.00 - 1.90 (m, 2H), 1.78 - 1.66 (m, 2H).Mass(m / z):260.7 [M / 2+H] + .

[0681] 1-Ethyl-5-oxo-N-((5-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)pyridine-2-yl)methyl)pyrrolidine-3-carboxamide (264) JPEG2026063193000309.jpg61151

[0682] Compound 264 (23.6 mg) was prepared according to the procedure in 209 from 6-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)pyridine-3-amine (35 mg, 0.1 mmol), 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (15.7 mg, 0.1 mmol), DIEA (38.7 mg, 0.3 mmol), and HATU (38.0 mg, 0.1 mmol) as a blue solid with a total yield of 48.2%. 1H NMR (400 MHz, Methanol-d4) δ 8.27 - 8.09 (m, 1H), 7.99 - 7.86 (m, 1H), 7.71 - 7.54 (m, 1H), 7.46 - 7.13 (m, 4H), 4.81 (s, 2H), 4.60 - 4.43 (m, 2H), 3.83 - 3.55 (m, 4H), 3.29 - 3.19 (m, 4H), 2.67 - 2.48 (m, 3H), 2.22 - 2.07 (m, 2H), 1.98 - 1.81 (m, 2H), 1.11 (t, J = 7.3 Hz, 3H). Mass(m / z): 490.3 [M+H] + .

[0683] 2-(4-methylpiperazine-1-yl)-N-(4-(pyrimidine-5-ylamino)benzyl)acetamide (265) JPEG2026063193000310.jpg26151

[0684] Compound 265 (6.7 mg) was prepared as a white solid with a total yield of 12.9% from N-(4-bromobenzyl)-2-(4-methylpiperazin-1-yl)acetamide (50 mg, 0.153 mmol) and pyrimidine-5-amine (22 mg, 0.230 mmol) according to the procedure in 232. 1 H NMR (400 MHz, Methanol-d4) δ 8.55 (d, J = 0.5 Hz, 1H), 8.51 - 8.47 (m, 2H), 7.31 - 7.24 (m, 2H), 7.16 - 7.08 (m, 2H), 4.37 (s, 2H), 3.10 (s, 2H), 2.64 (d, J = 15.7 Hz, 8H), 2.39 (s, 3H).Mass(m / z): 341.3 [M+H] + .

[0685] 1-Methyl-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)-1H-imidazole-5-carboxamide (266) JPEG2026063193000311.jpg72149

[0686] Compound 266 (12.8 mg) was prepared as a white solid with a total yield of 32.6% from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (30 mg, 0.086 mmol) and 1-methyl-1H-imidazole-5-carboxylic acid (14 mg, 0.112 mmol) according to the procedure in 203. 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (t, J = 6.0 Hz, 1H), 7.78 (s, 1H), 7.71 (s, 1H), 7.59 (d, J = 1.2 Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H), 6.98 - 6.93 (m, 2H), 6.89 - 6.83 (m, 4H), 4.27 (d, J = 6.0 Hz, 2H), 3.80 (s, 3H), 3.61 - 3.55 (m, 2H), 2.59 (td, J = 12.4, 2.4 Hz, 2H),1.88 - 1.82 (m, 2H), 1.54 (qd, J = 12.6, 4.0 Hz, 3H).Mass(m / z): 458.3 [M+H]+.

[0687] 6-Chloro-N-(4-((4-(4,4-difluoropiperidine-1-yl)phenyl)aminobenzyl)-N-hydroxypyrazine-2-carboxamide (267) JPEG2026063193000312.jpg35151

[0688] Compound 267 (11.4 mg) was prepared as a pink powder with a yield of 4.01% from 4-(4,4-difluoropiperidine-1-yl)-N-(4-((hydroxyamino)methyl)phenyl)aniline (200 mg, 0.60 mmol) and 6-chloropyrazine-2-carboxylic acid (105 mg, 0.66 mmol) according to the procedure for compound 290. 1H NMR (400 MHz, Methanol-d4) δ 7.38 - 7.24 (m, 2H), 7.11 (d, J = 8.4 Hz, 3H), 7.02 (t, J = 9.0 Hz, 5H), 5.01 (s, 2H), 4.11 - 3.97 (m, 4H), 2.18 (q, J = 14.2, 11.8 Hz, 4H). 19 F NMR (376 MHz, Methanol-d4) δ -99.35. LC-MS (m / z) 474.2 [M+H] + .

[0689] N-(4-((4-(4,4-difluoropiperidine-1-yl)phenyl)amino)benzyl)-N-hydroxy-2-(3-(trifluoromethyl)piperazine-1-yl)acetamide (268) JPEG2026063193000313.jpg80151

[0690] Step 1. 2-(3-(trifluoromethyl)piperazin-1-yl)acetic acid (268-1) (190 mg) was prepared as a yellow powder from 2-(trifluoromethyl)piperazine (150 mg, 0.97 mmol) and 2-bromoacetic acid (162 mg, 1.17 mmol) following the procedure for 2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)acetic acid (246-1). The residue was concentrated, dried under vacuum, and used directly in the next step without further purification. LC-MS (m / z) 213.4 [M+H] + .

[0691] Step 2. Compound 268 (22.0 mg) was prepared as a white powder with a yield of 34.26% from 4-(4,4-difluoropiperidine-1-yl)-N-(4-((hydroxyamino)methyl)phenyl)aniline (40 mg, 0.12 mmol) and 2-(3-(trifluoromethyl)piperazine-1-yl)acetic acid (268-1) (31 mg, 0.14 mmol) according to the procedure for compound 290. 1H NMR (400 MHz, Methanol-d4) δ 7.23 (d, J = 7.8 Hz, 2H), 7.12 (d, J= 8.3 Hz, 2H), 7.03 (t, J = 8.9 Hz, 4H), 4.73 (s, 2H), 3.58 (d, J= 17.6 Hz, 3H), 3.20 (d, J = 11.1 Hz, 1H), 3.07 (d, J = 2.6 Hz, 2H), 3.05-2.97 (d, J = 24.0 Hz, 2H), 2.94 (d, J = 2.6 Hz, 2H), 2.44-2.26 (m, 2H), 2.24-2.09 (m, 4H).LC-MS (m / z) 578.4 [M+H] + .

[0692] 4-(dimethylamino)-N-hydroxy-N-(4-((4-(piperidine-1-yl)phenyl)amino)benzyl)butanamide (269) JPEG2026063193000314.jpg58151

[0693] 1 H NMR (400 MHz, Methanol-d4) δ 7.30-6.79 (m, 8H), 4.66 (s, 2H), 3.06 (br m, 4H), 3.04 - 2.96 (m, 2H), 2.75 (s, 6H), 2.64 (t, J = 6.8 Hz, 2H), 2.04-1.94 (m, 2H), 1.74 (br s, 4H), 1.59 (br s, 2H). Mass(m / z): 411.3 [M+H] + .

[0694] N-(4-((4-(6-fluoropyridine-3-yl)phenyl)amino)benzyl)-N-hydroxy-2-morpholinoacetamide (270) JPEG2026063193000315.jpg62151

[0695] 1H NMR (400 MHz, Methanol-d4) δ 8.39 (s, 1H), 8.14 (m, 1H), 7.51 (d, J= 8.6 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 7.21 - 7.08 (m, 5H), 4.73 (s, 2H), 4.29 (s, 2H), 3.96 (br s, 4H), 3.41 (br s, 4H). Mass(m / z): 437.3 [M+H] + .

[0696] N-(4-((4-cyclohexylphenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazine-1-yl)acetamide (271) JPEG2026063193000316.jpg61151

[0697] 1 H NMR (400 MHz, Methanol-d4) δ 7.16 (d, J = 8.4 Hz, 2H), 7.08 (d, J= 8.4 Hz, 2H), 6.99 (dd, J = 8.4, 3.2 Hz, 4H), 4.65 (s, 2H), 3.56 (s, 2H), 3.19 (br s, 4H), 2.89 (br s, 4H), 2.79 (s, 3H), 2.52 - 2.34 (m, 1H), 1.91 - 1.67 (m, 6H), 1.49 - 1.34 (m, 4H).Mass(m / z): 437.3 [M+H] + .

[0698] N-hydroxy-1-methyl-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)-1H-imidazole-5-carboxamide (272) JPEG2026063193000317.jpg73151

[0699] Compound 272 (20.1 mg) was prepared as a white solid with a total yield of 51.7% from 4-((hydroxyamino)methyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (30 mg, 0.082 mmol) and 1-methyl-1H-imidazole-5-carboxylic acid (14 mg, 0.107 mmol) according to the procedure of compound 174. 1 H NMR (400 MHz, Methanol-d4) δ 7.70 (d, J = 10.0 Hz, 2H), 7.18 (d, J= 8.0 Hz, 2H), 7.04 - 6.89 (m, 6H), 4.77 (s, 2H), 3.89 (s, 3H), 3.57 (d, J= 11.2 Hz, 2H), 2.70 - 2.54 (m, 2H), 2.24 (ddd, J = 12.4, 8.2, 4.0 Hz, 1H), 1.98 - 1.91 (m, 2H), 1.69 (dd, J = 12.4, 4.0 Hz, 2H).Mass(m / z): 474.3 [M+H] + .

[0700] 1-Ethyl-N-hydroxy-2-oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)piperidine-4-carboxamide (273) JPEG2026063193000318.jpg62151

[0701] Compound 273 (14.5 mg) was prepared as a white solid with a total yield of 34.0% from 4-((hydroxyamino)methyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (30 mg, 0.082 mmol) and 1-ethyl-2-oxopiperidine-4-carboxylic acid (14 mg, 0.107 mmol) according to the procedure of compound 174. 1H NMR (400 MHz, Methanol-d4) δ 7.16 - 6.88 (m, 8H), 4.73 - 4.52 (m, 2H), 3.61 (s, 2H), 3.46 - 3.33 (m, 5H), 2.70 (d, J = 29.6 Hz, 2H), 2.47 (d, J = 8.0 Hz, 1H), 2.27 (dtd, J = 12.4, 8.4, 4.0 Hz, 1H), 2.06 - 1.90 (m, 4H), 1.75 - 1.65 (m, 2H), 1.11 (td, J = 7.2, 1.6 Hz, 3H).Mass(m / z): 519.4 [M+H] + .

[0702] N-((5-((4-(4,4-difluoropiperidine-1-yl)phenyl)amino)-3-fluoropyridine-2-yl)methyl)-N-hydroxy-2-(4-methyl-3-oxopiperazine-1-yl)acetamide (274) JPEG2026063193000319.jpg62151

[0703] Compound 274 (11.6 mg) was prepared as a white solid with a total yield of 26.9% from N-(4-(4,4-difluoropiperidine-1-yl)phenyl)-5-fluoro-6-((hydroxyamino)methyl)pyridine-3-amine (30 mg, 0.085 mmol) and 2-(4-methyl-3-oxopiperazine-1-yl)acetic acid hydrochloride (23 mg, 0.111 mmol) according to the procedure for compound 174. 1 H NMR (400 MHz, Methanol-d4) δ 7.13 - 6.98 (m, 6H), 4.54 (d, J = 17.2 Hz, 2H), 3.54 (d, J = 2.6 Hz, 2H), 3.40 (s, 2H), 3.35 (d, J = 2.6 Hz, 3H), 2.95 (d, J = 2.6 Hz, 3H), 2.92 - 2.85 (m, 2H), 2.15 - 2.02 (m, 5H), 1.35 - 1.27 (m, 2H).Mass(m / z): 507.3 [M+H]+ .

[0704] 1-(cyclopropanecarbonyl)-N-hydroxy-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (275) JPEG2026063193000320.jpg78151

[0705] Compound 275 (13.1 mg) was prepared as a white solid with a total yield of 22.3% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.47-6.58 (m, 8H), 4.67 (s, 2H), 3.96-3.79 (m, 2H), 3.75-3.66 (m, 2H), 3.65-3.50 (m, 4H), 3.41 (m, 1H), 2.40 - 2.11 (m, 3H), 2.11 - 1.88 (m, 2H), 1.84-1.65 (m, 3H), 0.99 - 0.73 (m, 4H). Mass(m / z): 531.3[M+H] +

[0706] N-hydroxy-1-isopropyl-N-(4-((4-(2-methylpiperidine-1-yl)phenyl)amino)benzyl)piperidine-4-carboxamide (276) JPEG2026063193000321.jpg26151

[0707] Compound 276 (13.5 mg) was prepared as a white solid with a total yield of 30.3% from 4-((hydroxyamino)methyl)-N-(4-(2-methylpiperidine-1-yl)phenyl)aniline (30 mg, 0.096 mmol) and 1-isopropylpiperidine-4-carboxylic acid (26 mg, 0.125 mmol) according to the procedure in 179. 1H NMR (400 MHz, Methanol-d4) δ 7.17 (s, 8H), 4.67 (s, 2H), 3.48 (dd, J= 11.5, 5.3 Hz, 3H), 3.25 (dd, J = 9.3, 5.2 Hz, 1H), 3.14 - 3.00 (m, 3H), 2.17 - 1.71 (m, 10H), 1.59 (s, 2H), 1.34 (d, J = 6.6 Hz, 6H), 0.95 (d, J = 6.2 Hz, 3H).Mass(m / z): 465.3 [M+H] + .

[0708] N-hydroxy-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)azetidine-3-carboxamide (277) JPEG2026063193000322.jpg57151

[0709] Compound 277 (86.1 mg) was prepared as a white solid with a total yield of 42.8% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.21 - 6.86 (m, 8H), 4.63 (s, 2H), 4.32 - 4.13 (m, 4H), 3.27 - 3.18 (m, 4H), 2.37 - 2.19 (m, 2H), 2.03-1.91 (m, 2H), 1.81-1.63 (m, 2H). Mass(m / z): 449.3 [M+H] +

[0710] N-hydroxy-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (278) JPEG2026063193000323.jpg61151

[0711] Compound 278 (90.1 mg) was prepared as a white solid with a total yield of 44.5% following the procedure for compound 108. 1H NMR (400 MHz, Methanol-d4) δ 7.23 - 6.81 (m, 8H), 4.64 (s, 2H), 3.88 - 3.70 (m, 2H), 3.70 - 3.38 (m, 6H), 2.43 - 2.19 (m, 3H), 2.19 - 2.07 (m, 1H), 1.99-1.93 (m, 2H), 1.78-1.65 (m, 2H). Mass(m / z): 463.2 [M+H] +

[0712] 1-Acetyl-N-hydroxy-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)azetidine-3-carboxamide (279) JPEG2026063193000324.jpg60151

[0713] Compound 279 (15.1 mg) was prepared as a white solid with a total yield of 31.6% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.33-6.68 (m, 8H), 4.67 (s, 2H), 4.40 - 4.27 (m, 2H), 4.18 - 3.99 (m, 2H), 3.83-3.46 (m, 4H), 2.39-2.20 (m, 2H), 2.10-1.91 (m, 2H), 1.85 (s, 3H), 1.81-1.64 (m, 2H).Mass(m / z): 491.3 [M+H] +

[0714] 1-(cyclopropanecarbonyl)-N-hydroxy-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)azetidine-3-carboxamide (280) JPEG2026063193000325.jpg64151

[0715] Compound 280 (17.5 mg) was prepared as a white solid with a total yield of 32.7% according to the procedure for compound 108.1 H NMR (400 MHz, Methanol-d4) δ 7.51 - 6.47 (m, 8H), 4.66 (s, 2H), 4.50 - 4.38 (m, 2H), 4.16-4.02 (m, 2H), 3.90- 3.81 (m, 4H), 2.39 - 2.18 (m, 2H), 1.98 (br s, 2H), 1.72 (br s, 2H), 1.60 - 1.50 (m, 1H), 0.91 - 0.74 (m, 4H).Mass(m / z): 517.3 [M+H] +

[0716] N-hydroxy-1-isopropyl-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)piperidine-4-carboxamide (281) JPEG2026063193000326.jpg25151

[0717] Compound 281 (14.0 mg) was prepared as a white solid with a total yield of 32.9% from 4-((hydroxyamino)methyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (30 mg, 0.082 mmol) and 1-isopropylpiperidine-4-carboxylic acid hydrochloride (22 mg, 0.107 mmol) according to the procedure in 179. 1 H NMR (400 MHz, Methanol-d4) δ 7.12 (s, 8H), 4.65 (s, 2H), 4.26 (s, 1H), 3.53 - 3.44 (m, 3H), 3.17 - 3.04 (m, 2H), 2.66 (d, J = 63.8 Hz, 2H), 2.27 (dq, J = 8.4, 5.0, 4.4 Hz, 1H), 2.04 (dd, J = 54.4, 9.9 Hz, 6H), 1.71 (d, J = 12.0 Hz, 2H), 1.40 - 1.37 (m, 2H), 1.37 - 1.34 (m, 6H).Mass(m / z): 519.3 [M+H] + .

[0718] N-hydroxy-1-isopropyl-N-(4-((4-(3-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)piperidine-4-carboxamide (282) JPEG2026063193000327.jpg30151

[0719] Compound 282 (19.6 mg) was prepared as a white solid with a total yield of 45.7% from 4-((hydroxyamino)methyl)-N-(4-(3-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (30 mg, 0.082 mmol) and 1-isopropylpiperidine-4-carboxylic acid hydrochloride (22 mg, 0.107 mmol) according to the procedure in 179. 1 H NMR (400 MHz, Methanol-d4) δ 7.17 - 6.81 (m, 8H), 4.65 (s, 2H), 3.50 - 3.43 (m, 3H), 3.10 (t, J = 13.0 Hz, 2H), 2.52 (d, J = 9.7 Hz, 4H), 2.00 (ddd, J = 51.6, 24.7, 13.0 Hz, 7H), 1.72 (tdd, J = 12.9, 8.7, 4.0 Hz, 1H), 1.38 - 1.36 (m, 2H), 1.34 (d, J = 6.7 Hz, 6H).Mass(m / z): 519.3 [M+H] + .

[0720] 4-Ethyl-1-(4-((3-Fluoro-4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)-2-(trifluoromethyl)benzyl)piperazine-2-one (283) JPEG2026063193000328.jpg26151

[0721] Compound 283 (6.1 mg) was prepared as a white solid with a total yield of 12% from 1-(4-bromo-2-(trifluoromethyl)benzyl)-4-ethylpiperazine-2-one (50 mg, 0.137 mmol) and 3-fluoro-4-(4-(trifluoromethyl)piperidine-1-yl)aniline (47 mg, 0.178 mmol) according to the procedure in 232. 1 H NMR (400 MHz, Methanol-d4) δ 7.29 (d, J = 10.1 Hz, 3H), 7.11 (s, 1H), 6.89 (s, 2H), 4.82 - 4.75 (m, 2H), 4.07 (s, 2H), 3.55 (td, J = 21.4, 20.6, 10.4 Hz, 6H), 3.34 (td, J = 7.4, 1.4 Hz, 2H), 2.87 (s, 2H), 2.40 - 2.32 (m, 1H), 2.07 - 1.94 (m, 2H), 1.88 - 1.74 (m, 2H), 1.38 (td, J= 7.3, 1.4 Hz, 3H). Mass (m / z): 547.3 [M+H] + .

[0722] 4-Ethyl-1-(4-((3-Fluoro-4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)piperazine-2-one (284) JPEG2026063193000329.jpg30151

[0723] Compound 284 (2.9 mg) was prepared as a white solid with a total yield of 3.7% from 1-(4-bromobenzyl)-4-ethylpiperazine-2-one (50 mg, 0.168 mmol) and 3-fluoro-4-(4-(trifluoromethyl)piperidine-1-yl)aniline (57 mg, 0.218 mmol) according to the procedure in 232. 1H NMR (400 MHz, Methanol-d4) δ 7.29 (d, J = 10.1 Hz, 3H), 7.11 (s, 2H), 6.89 (s, 2H), 4.82 - 4.75 (m, 2H), 4.07 (s, 2H), 3.55 (td, J = 21.4, 20.6, 10.4 Hz, 6H), 3.34 (td, J = 7.4, 1.4 Hz, 2H), 2.87 (s, 2H), 2.40 - 2.32 (m, 1H), 2.07 - 1.94 (m, 2H), 1.88 - 1.74 (m, 2H), 1.38 (td, J= 7.3, 1.4 Hz, 3H). Mass (m / z): 479.3 [M+H] + .

[0724] N-hydroxy-1-methyl-2-oxo-N-(4-((4-(piperidine-1-yl)phenyl)amino)-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (285) JPEG2026063193000330.jpg66151

[0725] Compound 285 (13.4 mg) of the title compound was prepared according to the procedure in 137 from 4-((hydroxyamino)methyl)-N-(4-(piperidine-1-yl)phenyl)-3-(trifluoromethyl)aniline (55 mg, 0.15 mmol), 1-methyl-2-oxopiperidine-4-carboxylic acid (28 mg, 0.18 mmol), DMT-MM (48 mg, 0.18 mmol), DIEA (58 mg, 0.45 mmol), and DMF (1.0 mL) as a yellow solid with a total yield of 17.7%. 1H NMR (400 MHz, Methanol-d4) δ 7.53 - 7.47 (m, 2H), 7.41 - 7.32 (m, 3H), 7.27 - 7.19 (m, 2H), 4.86 (s, 2H), 3.64 - 3.57 (m, 4H), 3.42 - 3.38 (m, 1H), 3.28 - 3.22 (m, 2H), 2.94 (s, 3H), 2.53 - 2.50 (m, 2H), 2.11 - 1.97 (m, 6H). Mass(m / z):505.3 [M+H] + .

[0726] N-hydroxy-2-(4-methyl-3-oxopiperazine-1-yl)-N-(4-((4-(4-methylpiperidine-1-yl)phenyl)aminobenzyl)acetamide (286) JPEG2026063193000331.jpg58151

[0727] Compound 286 (24.5 mg) was prepared according to the procedure in 137 from 4-((hydroxyamino)methyl)-N-(4-(4-methylpiperidine-1-yl)phenyl)aniline (54 mg, 0.17 mmol), 2-(4-methyl-3-oxopiperazine-1-yl)acetic acid hydrochloride (42 mg, 0.20 mmol), DMT-MM (55 mg, 0.20 mmol), DIEA (66 mg, 0.51 mmol), and DMF (1.0 mL) as a yellow solid with a total yield of 31.0%. 1H NMR (400 MHz, Methanol-d4) δ 7.21 - 6.87 (m, 8H), 4.63 (s, 2H), 3.56 - 3.43 (m, 4H), 3.39 (t, J = 5.3 Hz, 2H), 3.29 - 3.26 (m, 2H), 2.94 (s, 3H), 2.87 (t, J = 5.2 Hz, 2H), 2.79 - 2.54 (m, 2H), 1.84 - 1.73 (m, 2H), 1.56 - 1.47 (m, 1H), 1.44 - 1.32 (m, 2H), 0.99 (d, J = 6.4 Hz, 3H). Mass(m / z):466.2 [M+H] + .

[0728] N-hydroxy-2,4-dimethyl-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)oxazole-5-carboxamide (287) JPEG2026063193000332.jpg67151

[0729] Compound 287 (15.0 mg) was prepared as a white solid with a total yield of 37.4% from 4-((hydroxyamino)methyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (30 mg, 0.082 mmol) and 2,4-dimethyloxazole-5-carboxylic acid (15 mg, 0.107 mmol) according to the procedure in 174. 1H NMR (400 MHz, Methanol-d4) δ 7.06 (d, J = 89.8 Hz, 8H), 3.99 (d, J= 2.6 Hz, 2H), 2.48 (d, J = 2.6 Hz, 2H), 2.39 (dd, J = 6.4, 2.7 Hz, 3H), 2.29 (dd, J = 10.8, 2.6 Hz, 5H), 1.98 (d, J = 20.6 Hz, 3H), 1.75 - 1.64 (m, 2H).Mass(m / z): 489.3 [M+H] + .

[0730] 2,4-dimethyl-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)oxazole-5-carboxamide (288) JPEG2026063193000333.jpg67151

[0731] Compound 288 (8.8 mg) was prepared as a white solid with a total yield of 21.7% from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (30 mg, 0.086 mmol) and 2,4-dimethyloxazole-5-carboxylic acid (16 mg, 0.112 mmol) according to the procedure in 203. 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (t, J = 6.0 Hz, 1H), 7.78 (s, 1H), 7.08 (d, J = 8.4 Hz, 2H), 6.98 - 6.93 (m, 2H), 6.89 - 6.83 (m, 4H), 4.27 (d, J = 6.0 Hz, 2H), 3.61 - 3.55 (m, 2H), 2.59 (td, J = 12.4, 2.4 Hz, 2H),2.40(s, 3H), 2.29(s, 3H), 1.88 - 1.82 (m, 2H), 1.54 (qd, J = 12.6, 4.0 Hz, 3H).Mass(m / z): 473.3 [M+H]+.

[0732] N-ethyl-2-(4-methyl-3-oxopiperazine-1-yl)-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)acetamide (289) JPEG2026063193000334.jpg59151

[0733] Step 1. To a solution of N-(4-bromobenzyl)ethaneamine (200 mg, 0.93 mmol, 1.0 equivs) and 2-(4-methyl-3-oxopiperazin-1-yl)acetic acid (177 mg, 1.03 mmol, 1.1 equivs) in superdried N,N-dimethylformamide (5 mL), 2-(1H-benzo[d][1,2,3]triazole-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (390 mg, 1.21 mmol, 1.3 equivs) and N-ethyl-N-isopropylpropan-2-amine (463 mL, 2.80 mmol, 3.0 equivs) were added at room temperature under an argon atmosphere and stirred overnight. The reaction mixture was diluted with water (10 mL) and extracted three times with dichloromethane (5 mL). The organic layers were bonded and washed with water, saturated NH4Cl(aq), and brine, respectively. They were then dried over MgSO4, filtered, and concentrated under reduced pressure. The residue, N-(4-bromobenzyl)-N-ethyl-2-(4-methyl-3-oxopiperazin-1-yl)acetamide (289-1), was used directly in the next step without further purification after concentration and drying under vacuum. LC-MS (m / z) 368.2, 370.1 [M+H] + .

[0734] Step 2. Compound 289 (38.2 mg) was prepared as a white powder with a yield of 17.55% from 4-(4-(trifluoromethyl)piperidine-1-yl)aniline (100 mg, 0.41 mmol) and N-(4-bromobenzyl)-N-ethyl-2-(4-methyl-3-oxopiperazine-1-yl)acetamide (151 mg, 0.41 mmol) according to the procedure for compound 253. 1H NMR (400 MHz, Chloroform-d) δ 7.30 - 6.37 (br, 8H), 4.76 (s, 3H), 4.65 - 4.19 (br, 3H), 3.75 - 3.32 (m, 3H), 2.75 (dd, J = 6.3, 4.8 Hz, 2H), 2.69 (dd, J= 6.2, 4.8 Hz, 2H), 2.24-2.09 (m, 2H), 1.94-1.78 (m, 3H), 1.60 (d, J = 13.1 Hz, 3H), 1.09 - 1.02 (m, 3H), 0.97 (t, J = 7.1 Hz, 3H).LC-MS (m / z) 532.5 [M+H] + .

[0735] 1-Ethyl-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (290) JPEG2026063193000335.jpg63151

[0736] Step 1. To a solution of (E)-4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzaldehyde oxime (900 mg, 2.48 mmol) in methanol (100 mL), palladium (100 mg, 10%) on activated carbon was added under an argon atmosphere. Acetic acid (1.5 mL) was added dropwise. The flask was evacuated and flushed three times with hydrogen. The mixture was stirred overnight at room temperature under a hydrogen (balloon) atmosphere. The completed reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the residue 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (290-1), which was used directly in the next step without further purification after concentration and drying under vacuum. LC-MS (m / z) 350.2 [M+H] + .

[0737] Step 2. To a solution of 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (290-1) (100 mg, 0.29 mmol, 1.0 equivs) and 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (49 mg, 0.31 mmol, 1.1 equivs) in superdried N,N-dimethylformamide (5 mL), 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine-4-ium chloride (87 mg, 0.31 mmol, 1.1 equivs) and N-ethyl-N-isopropylpropan-2-amine (142 mL, 0.86 mmol, 3.0 equivs) were added at room temperature. The resulting solutions were stirred overnight at room temperature. The reaction mixture was added dropwise to water (25 mL) with stirring. The precipitate was filtered, the filtrate was washed three times with water, and dried in a vacuum. 1-Ethyl-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (290) was obtained as a pale white solid in a yield of 79.38%. 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (t, J = 5.8 Hz, 1H), 7.79 (s, 1H), 7.08 - 7.02 (m, 2H), 6.99 - 6.94 (m, 2H), 6.92 - 6.85 (m, 4H), 4.16 (d, J= 5.7 Hz, 2H), 3.62 (d, J = 12.3 Hz, 2H), 3.51 (dd, J = 9.6, 8.9 Hz, 1H), 3.34 (d, J = 3.7 Hz, 2H), 3.19 (qd, J = 7.3, 1.7 Hz, 2H), 3.15 - 3.08 (m, 1H), 2.62 (td, J = 12.1, 2.3 Hz, 2H), 2.41 (dt, J= 8.2, 2.4 Hz, 2H), 1.88 (d, J = 12.8 Hz, 2H), 1.59 (td, J = 12.5, 4.1 Hz, 2H), 1.00 (t, J = 7.2 Hz, 3H). LC-MS (m / z) 389.3 [M+H] +.

[0738] 2-(2,6-dimethylmorpholino)-N-hydroxy-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)acetamide (291) JPEG2026063193000336.jpg63151

[0739] Compound 291 (31.4 mg) was prepared as a white solid with a total yield of 55.9% according to the procedure for compound 108. 1 H NMR (400 MHz, Methanol-d4) δ 7.25 - 6.82 (m, 8H), 4.63 (s, 2H), 3.80 - 3.51 (m, 4H), 3.38 (s, 2H), 3.22-3.15 (m, 2H), 2.89-2.83 (m, Mass(m / z): 521.3 [M+H] +

[0740] N-hydroxy-2,2-dimethyl-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)tetrahydro-2H-pyran-4-carboxamide (292) JPEG2026063193000337.jpg61151

[0741] Compound 292 (10.1 mg) was prepared as a white solid with a total yield of 21.8% according to the procedure for compound 108. 1H NMR (400 MHz, Methanol-d4) δ 7.49 - 6.56 (m, 8H), 4.63 (s, 2H), 3.80 - 3.66 (m, 2H), 3.46 - 3.34 (m, 2H), 2.99-2.86 (m, 2H), 2.39 - 2.15 (m, 2H), 2.03-1.91 (m, 2H), 1.83-1.57 (m, 6H), 1.24 (s, 3H), 1.21 (s, 3H). Mass(m / z): 506.2 [M+H] +

[0742] N-(4-((4-(3,3-difluoropiperidine-1-yl)phenyl)amino)benzyl)-N-hydroxy-1-isopropylpiperidine-4-carboxamide (293) JPEG2026063193000338.jpg30151

[0743] Compound 293 (19.0 mg) was prepared as a white solid with a total yield of 43.2% from 4-(3,3-difluoropiperidine-1-yl)-N-(4-((hydroxyamino)methyl)phenyl)aniline (30 mg, 0.090 mmol) and 1-isopropylpiperidine-4-carboxylic acid hydrochloride (24 mg, 0.117 mmol) according to the procedure in 179. 1 H NMR (400 MHz, Methanol-d4) δ 7.17 - 6.87 (m, 8H), 4.65 (s, 2H), 3.50 - 3.43 (m, 3H), 3.28 - 3.00 (m, 7H), 2.16 - 1.82 (m, 9H), 1.34 (d, J = 6.6 Hz, 6H).Mass(m / z): 487.3 [M+H] + .

[0744] Compounds 294-302 were prepared according to the method in Scheme 1. JPEG2026063193000339.jpg120151

[0745] Compounds 303-314 were prepared according to the method in Scheme 2. JPEG2026063193000340.jpg133151

[0746] Compounds 315-326 were prepared according to the method of Scheme 3. JPEG2026063193000341.jpg138151

[0747] Compounds 327-338 were prepared according to the method of Scheme 4. JPEG2026063193000342.jpg130151

[0748] Compounds 339-350 were prepared according to the method of Scheme 5. JPEG2026063193000343.jpg128151

[0749] Compounds 351-362 were prepared according to the method of Scheme 6. JPEG2026063193000344.jpg127151

[0750] Active Compounds Group II: Representative Synthesis

[0751] N-(4-((4-(tert-butyl(ethyl)amino)phenyl)amino)benzyl)-1-ethyl-5-oxopyrrolidine-3-carboxamide (363) JPEG2026063193000345.jpg111151

[0752] Step 1. Preparation of tert-butyl(4-((4-(tert-butyl(ethyl)amino)phenyl)amino)benzyl)carbamate (363-3). A mixture of N1-(tert-butyl)-N1-ethylbenzene-1,4-diamine (192 mg, 1.0 mmol), tert-butyl(4-bromobenzyl)carbamate (220 mg, 0.77 mmol), Pd(dppf)2Cl2 (14.6 mg, 0.02 mmol), xanthophos (23.2 mg, 0.04 mmol), and Cs2CO3 (489 mg, 1.5 mmol) in 1,4-dioxane (10 mL) was stirred overnight at 100°C. After cooling to room temperature, 15 mL of water was added. The mixture was then extracted with DCM (15 mL x 3). The combined organic layer was washed with water (20 mL x 3), dried over Na2SO4, and concentrated under vacuum. The residue was purified by prep-TLC(EA) to obtain the desired product as a yellow solid (204 mg, 67.8%). Mass (m / z): 398.4 [M+H] +

[0753] Step 2. N 1 Preparation of -(4-(aminomethyl)phenyl)-N4-(tert-butyl)-N4-ethylbenzene-1,4-diamine (363-4). A solution of tert-butyl(4-((4-(tert-butyl(ethyl)amino)phenyl)amino)benzyl)carbamate (204 mg, 0.51 mmol) in 10 mL of HCl solution in 1,4-dioxane was stirred at room temperature for 30 minutes and concentrated. 5 mL of water was added. The pH of the filtrate was adjusted to 8-9 with sodium carbonate solution. The mixture was then extracted with DCM (5 mL x 3). The bound organic layer was washed with water (10 mL), dried over Na2SO4, and concentrated. The residue was purified by perp-TLC (MeOH / DCM=1 / 5) to obtain the desired product as a yellow solid. Mass(m / z):298.3 [M+H] +

[0754] Step 3. Preparation of N-(4-((4-(tert-butyl(ethyl)amino)phenyl)amino)benzyl)-1-ethyl-5-oxopyrrolidine-3-carboxamide (363). HATU (76.0 mg, 0.2 mmol) was added to a solution of 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (31.4 mg, 0.2 mmol) in DCM (5 ml). The reaction mixture was then stirred at room temperature for 1 hour. N 1 -(4-(aminomethyl)phenyl)-N4-(tert-butyl)-N4-ethylbenzene-1,4-diamine (59.4 mg, 0.2 mmol) and DIEA (77.4 mg, 0.6 mmol) were added. The reaction mixture was then stirred at room temperature for 3 hours. 5 mL of water was added. The mixture was then extracted with DCM (5 mL x 3). The bound organic layer was washed with water (10 mL x 3), dried over Na2SO4, and concentrated under vacuum. The residue was purified by prep-TLC (MeOH / DCM = 1 / 15) to obtain the desired product as a white solid (13.2 mg, 15.0%). 1 H NMR (300 MHz, Methanol-d4) δ 7.33 - 7.04 (m, 9H), 4.33 (d, J = 5.0 Hz, 2H), 3.77 - 3.54 (m, 5H), 3.27 - 3.18 (m, 2H), 2.62 (d, J = 8.2 Hz, 2H), 1.41 (s, 9H), 1.13 (t, J= 7.2 Hz, 3H), 1.07 (t, J = 7.0 Hz, 3H). Mass(m / z): 437.4[M+H] + .

[0755] N-(4-((4-(dimethylamino)phenyl)amino)benzyl)-1-ethyl-5-oxopyrrolidine-3-carboxamide (364) JPEG2026063193000346.jpg125151

[0756] Step 1. Preparation of tert-butyl(4-((4-(dimethylamino)phenyl)amino)benzyl)carbamate (364-3). Prepare compound 364-3 (160 mg) according to the procedure for 363. 1 ,N 1 A yellow solid was prepared from dimethylbenzene-1,4-diamine (204 mg, 1.5 mmol), tert-butyl(4-bromobenzyl)carbamate (286 mg, 1.0 mmol), Pd(dppf)2Cl2 (14.6 mg, 0.02 mmol), xanthophos (23.2 mg, 0.04 mmol), and Cs2CO3 (489 mg, 1.5 mmol) with a total yield of 46.9%. Mass (m / z): 342.3 [M+H] + .

[0757] Step 2. N 1 Preparation of -(4-(aminomethyl)phenyl)-N4,N4-dimethylbenzene-1,4-diamine (364-4). Compound 364-4 (147 mg) was prepared as a yellow solid with a total yield of 100% from 1,4-dioxane, HCl (5.0 mL), and tert-butyl (4-((4-(dimethylamino)phenyl)amino)benzyl)carbamate (160 mg, 0.47 mmol) according to the procedure for 363-4. Mass (m / z): 242.3 [M+H] + .

[0758] Step 3. Preparation of N-(4-((4-(dimethylamino)phenyl)amino)benzyl)-1-ethyl-5-oxopyrrolidine-3-carboxamide (364). Compound 364 (21.6 mg) of the title compound was prepared according to the procedure of 363. 1 -(4-(aminomethyl)phenyl)-N 4 ,N 4 A yellow solid was prepared from -dimethylbenzene-1,4-diamine (48.4 mg, 0.2 mmol), 1-methylpiperazine (31.4 mg, 0.2 mmol), DIEA (77.4 mg, 0.6 mmol), and HATU (76.0 mg, 0.02 mmol) with a total yield of 28.4%. 1H NMR (400 MHz, Methanol-d4) 7.51 - 6.83 (m, 8H), 4.41 (d, J = 5.0 Hz, 2H), 3.78 - 3.52 (m, 4H), 3.30 (s, 6H), 3.28 - 3.15 (m, 2H), 2.60 (d, J= 8.4 Hz, 2H), 1.13 (t, J = 7.2 Hz, 3H). Mass(m / z): 381.3 [M+H] + .

[0759] 1-Ethyl-N-(1-(4-((4-(4-methylpiperidine-1-yl)phenyl)amino)phenyl)ethyl)-5-oxopyrrolidine-3-carboxamide (365) JPEG2026063193000347.jpg94151

[0760] Step 1. Preparation of N-(1-(4-bromophenyl)ethyl)-1-ethyl-5-oxopyrrolidine-3-carboxamide (365-2). Compound 365-2 (560 mg) was prepared as a white solid with a total yield of 82.8% from 1-(4-bromophenyl)ethane-1-amine (400 mg, 2.0 mmol), 1-methylpiperazine (345 mg, 2.2 mmol), DIEA (774 mg, 6.0 mmol), and HATU (836 mg, 2.2 mmol) according to the procedure of 363. Mass (m / z): 339.1 [M+H] + .

[0761] Step 2. Preparation of 1-ethyl-N-(1-(4-((4-(4-methylpiperidine-1-yl)phenyl)amino)phenyl)ethyl)-5-oxopyrrolidine-3-carboxamide (365). Compound 365 (4.2 mg) of the title was prepared as a gray solid with a total yield of 3.8% from N-(1-(4-bromophenyl)ethyl)-1-ethyl-5-oxopyrrolidine-3-carboxamide (84.5 mg, 0.25 mmol), 4-(4-methylpiperidine-1-yl)aniline (63 mg, 0.33 mmol), Pd2(dba)3 (2.3 mg, 2.5 mmol), X-Phos (5.9 mg, 12.5 mmol), and t-BuONa (36 mg, 0.38 mmol) according to the procedure of 363-3. 1 H NMR (400 MHz, Methanol-d4) δ 7.24 - 6.84 (m, 8H), 4.99 - 4.92 (m, 1H), 3.71 - 3.44 (m, 4H), 3.37 - 3.34 (m, 2H), 3.25 - 3.17 (m, 1H), 2.73 - 2.50 (m, 4H), 1.86 - 1.73 (m, 2H), 1.56 - 1.48 (m, 1H), 1.47 - 1.36 (m, 5H), 1.13 (dt, J= 13.0, 7.3 Hz, 3H), 1.02 (d, J = 6.2 Hz, 3H). Mass(m / z): 449.4 [M+H] + .

[0762] N-(2-chloro-4-((2-(4-isopropylpiperidine-1-yl)pyrimidine-5-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (366) JPEG2026063193000348.jpg133151

[0763] Step 1. Preparation of tert-butyl(4-bromo-2-chlorobenzyl)carbamate. Boc2O (891 mg, 4.08 mmol) and TEA (551 mg, 5.44 mmol) were added to a solution of compound 366-1 (600 mg, 2.72 mmol) in DCM (20 mL) at 25°C. The mixture was then stirred overnight at room temperature. The mixture was poured into H2O and extracted with DCM (50 mL x 3). The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated, and the residue was purified by silica gel chromatography using EA / PE (20:1) to obtain tert-butyl(4-bromo-2-chlorobenzyl)carbamate 366-2 (854 mg, 97% yield) as a yellow oil. MS (ESI) m / z 264.0, 266.0 [M+H] + .

[0764] Step 2. Preparation of tert-butyl(2-chloro-4-((2-(4-isopropylpiperidine-1-yl)pyrimidine-5-yl)amino)benzyl)carbamate. Cs2CO3 (610 mg, 1.87 mmol) and tris(dibenzylideneacetone)dipalladium (114 mg, 0.12 mmol) were added to a mixed solution of compound 366-2 (400 mg, 1.25 mmol), compound 366-3 (275 mg, 1.25 mmol), and dicyclohexyl(2',6'-diisopropoxybiphenyl-2-yl)phosphine (116 mg, 0.25 mmol) in dioxane (20 mL) under nitrogen. The reaction mixture was stirred at 90°C for 16 hours. The mixture was then filtered and concentrated. The residue was purified by pre-TLC to obtain tert-butyl(2-chloro-4-((2-(4-isopropylpiperidine-1-yl)pyrimidine-5-yl)aminobenzyl)carbamate 366-4 (351 mg, 61% yield) as a yellow solid. MS (ESI) m / z 460.2 [M+H] + .

[0765] Step 3. Preparation of N-(4-(aminomethyl)-3-chlorophenyl)-2-(4-isopropylpiperidine-1-yl)pyrimidine-5-amine. To a solution of compound 366-4 (351 mg, 0.76 mmol) in DCM (5 mL), 4N HCl (5 mL) in dioxane was added at room temperature. The mixture was then stirred overnight at room temperature. LC-MS indicated that the reaction was complete. The mixture was filtered and dried to obtain N-(4-(aminomethyl)-3-chlorophenyl)-2-(4-isopropylpiperidine-1-yl)pyrimidine-5-amine 366-5 (253 mg, 92% yield) as a brown solid. MS (ESI) m / z 360.2 [M+H] + .

[0766] Step 4. Preparation of N-(2-chloro-4-((2-(4-isopropylpiperidine-1-yl)pyrimidine-5-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (SIR-00005284). Compound 366-5 (253 mg, 0.70 mmol) and 5-oxopyrrolidine-3-carboxylic acid 366-6 (91 mg, 0.70 mmol) were stirred in DMF (10 mL) under nitrogen. N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium (321 mg, 0.84 mmol) and DIEA (136 mg, 1.05 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into H2O (10 mL), extracted with EA (20 mL x 3), washed with brine, dried over Na2SO4, filtered, concentrated, and the residue was purified by prep-HPLC to obtain 366 (93 mg) as a white solid. MS (ESI) m / z 471.2 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 8.19 (s, 2H), 7.15 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H), 6.66 (dd, J = 8.4, 2.4 Hz, 1H), 4.76 - 4.65 (m, 2H), 4.35 (s, 2H), 3.62 - 3.53 (m, 1H), 3.51-3.45 (m, 1H), 2.88-2.77 (m, 2H), 2.61-2.44 (m, 2H), 1.81 - 1.70 (m, 2H), 1.53-1.43 (m, 1H), 1.38-1.28 (m, 2H), 1.27-1.14 (m, 2H), 0.93 (d, J = 6.8 Hz, 6H).

[0767] 1-Ethyl-5-oxo-N-(1-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)phenyl)ethyl)pyrrolidine-3-carboxamide (367) JPEG2026063193000349.jpg70151

[0768] Compound 367 (4.1 mg) was prepared as a yellow solid with a total yield of 6.5% from N-(1-(4-bromophenyl)ethyl)-1-ethyl-5-oxopyrrolidine-3-carboxamide (42.3 mg, 0.125 mmol), 4-(4-(trifluoromethyl)piperidine-1-yl)aniline (40 mg, 0.16 mmol), Pd2(dba)3 (1.1 mg, 1.6 mmol), X-Phos (3.0 mg, 6.2 mmol), and t-BuONa (18 mg, 0.19 mmol) according to the procedure in 363-3. 1H NMR (400 MHz, Methanol-d4) δ 7.16 (d, J = 8.2 Hz, 2H), 7.04 (d, J = 8.5 Hz, 2H), 7.00 - 6.89 (m, 4H), 4.97 - 4.92 (m, 1H), 3.66 - 3.61 (m, 2H), 3.53 - 3.44 (m, 1H), 3.30 - 3.14 (m, 2H), 2.75 - 2.59 (m, 4H), 2.34 - 2.24 (m, 1H), 2.03 - 1.94 (m, 2H), 1.75 (qd, J = 12.5, 4.0 Hz, 2H), 1.49 - 1.40 (m, 3H), 1.11 (t, J = 7.3 Hz, 3H). Mass(m / z): 503.3 [M+H] + .

[0769] N 1 -(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)succinamide (368) JPEG2026063193000350.jpg32151

[0770] Compound 368 (11.2 mg) was prepared according to the procedure for compound 363 from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (52 mg, 0.15 mmol), 4-amino-4-oxobutanoic acid (18 mg, 0.15 mmol), DIEA (58 mg, 0.45 mmol), and HATU (57 mg, 0.15 mmol) as a pale yellow solid with a total yield of 16.7%. 1H NMR (400 MHz, Methanol-d4) δ 7.09 - 6.76 (m, 8H), 4.16 (s, 2H), 3.58 - 3.45 (m, 2H), 2.64 - 2.49 (m, 2H), 2.45 - 2.38 (m, 4H), 2.24 - 2.12 (m, 2H), 1.92 - 1.83 (m, 2H), 1.64 (qd, J = 12.9, 3.7 Hz, 2H). Mass(m / z): 449.3 [M+H] + .

[0771] 1-Cyclopropyl-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (369) JPEG2026063193000351.jpg40151

[0772] Compound 369 (10.6 mg) was prepared as a yellow solid with a total yield of 14.1% from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (52 mg, 0.15 mmol), 1-cyclopropyl-5-oxopyrrolidine-3-carboxylic acid (25 mg, 0.15 mmol), DIEA (58 mg, 0.45 mmol), and HATU (57 mg, 0.15 mmol) according to the procedure for compound 363. 1 H NMR (400 MHz, Methanol-d4) δ 7.07 - 6.74 (m, 8H), 4.15 (s, 2H), 3.55 - 3.36 (m, 4H), 3.10 - 2.99 (m, 1H), 2.61 - 2.44 (m, 5H), 2.26 - 2.12 (m, 1H), 1.91 - 1.81 (m, 2H), 1.62 (qd, J = 12.5, 4.1 Hz, 2H), 0.67 - 0.60 (m, 4H). Mass(m / z): 501.3 [M+H] + .

[0773] N 1-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)oxalamide (370) JPEG2026063193000352.jpg81151

[0774] Compound 370 (10.3 mg) was prepared according to the procedure for compound 363 from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (52 mg, 0.15 mmol), 2-amino-2-oxoacetic acid (13.4 mg, 0.15 mmol), DIEA (58 mg, 0.45 mmol), and HATU (57 mg, 0.15 mmol) as a yellow solid with a total yield of 16.3%. 1 H NMR (400 MHz, Methanol-d4) δ 7.63 - 6.47 (m, 8H), 4.34 (s, 2H), 3.79 - 3.33 (m, 2H), 2.85 - 2.42 (m, 2H), 2.34 - 2.24 (m, 1H), 2.05 - 1.91 (m, 2H), 1.78 - 1.63 (m, 2H). Mass(m / z): 421.3 [M+H] + .

[0775] N 1 ,N 1 -dimethyl-N 2 -(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)oxalamide (371) JPEG2026063193000353.jpg73151

[0776] Compound 371 (16.4 mg) was prepared according to the procedure for compound 363 from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (52.0 mg, 0.15 mmol), 2-(dimethylamino)-2-oxoacetic acid (17.6 mg, 0.15 mmol), DIEA (58 mg, 0.45 mmol), and HATU (57 mg, 0.15 mmol) as a pale yellow solid with a total yield of 24.4%. 1 H NMR (400 MHz, Methanol-d4) δ 7.05 (d, J = 8.3 Hz, 2H), 6.94 (d, J= 8.8 Hz, 2H), 6.85 (dd, J = 11.4, 8.5 Hz, 4H), 4.24 (s, 2H), 3.55 - 3.49 (m, 2H), 2.98 (s, 3H), 2.87 (s, 3H), 2.61 - 2.54 (m, 2H), 2.22 - 2.14 (m, 1H), 1.91 - 1.85 (m, 2H), 1.63 (qd, J = 12.5, 4.1 Hz, 2H). Mass(m / z): 449.3 [M+H] + .

[0777] 4-Oxo-4-(pyrrolidine-1-yl)-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)butanamide (372) JPEG2026063193000354.jpg61151

[0778] Compound 372 (16.4 mg) was prepared according to the procedure for compound 363 from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (70.0 mg, 0.2 mmol), 4-oxo-4-(pyrrolidine-1-yl)butanoic acid (41.0 mg, 0.24 mmol), DIEA (77.4 mg, 0.6 mmol), and HATU (91.2 mg, 0.24 mmol) as a pale yellow solid with a total yield of 24.4%. 1H NMR (400 MHz, Methanol-d4) δ 7.03 - 6.80 (m, 8H), 4.15 (s, 2H), 3.55 - 3.46 (m, 2H), 3.41 (t, J = 6.8 Hz, 2H), 3.29 (t, J = 6.9 Hz, 2H), 2.59 - 2.39 (m, 6H), 2.21 - 2.13 (m, 1H), 1.90 - 1.83 (m, 4H), 1.81 - 1.75 (m, 2H), 1.63 (qd, J = 12.5, 4.0 Hz, 2H). Mass(m / z): 503.4 [M+H] + .

[0779] N-(4-((2-Methoxy-4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (373) JPEG2026063193000355.jpg27151

[0780] Compound 373 (4.2 mg) was prepared as a yellow solid with a total yield of 3.4% from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 2-methoxy-4-(4-(trifluoromethyl)piperidine-1-yl)aniline (89 mg, 0.33 mmol), Pd2(dba)3 (2.0 mg, 2.5 mmol), X-Phos (6.0 mg, 12.5 mmol), and t-BuONa (36.0 mg, 0.38 mmol) according to the procedure in 363-3. 1 H NMR (400 MHz, Methanol-d4) δ 7.48 - 6.01 (m, 7H), 4.18 (s, 2H), 3.73 (s, 3H), 3.64 - 3.29 (m, 5H), 2.80 - 2.30 (m, 4H), 2.25 - 2.12 (m, 1H), 1.96 - 1.82 (m, 2H), 1.72 - 1.57 (m, 2H). Mass(m / z): 591.3 [M+H] + .

[0781] N-(4-((2,6-dimethyl-4-(4-methylpiperidine-1-yl)phenyl)amino)benzyl)-1-ethyl-5-oxopyrrolidine-3-carboxamide (374) JPEG2026063193000356.jpg26151

[0782] Compound 374 (35.1 mg) was prepared as a white solid with a total yield of 30.4% from N-(4-bromobenzyl)-1-ethyl-5-oxopyrrolidine-3-carboxamide (81.0 mg, 0.25 mmol), 2,6-dimethyl-4-(4-methylpiperidine-1-yl)aniline (72 mg, 0.33 mmol), Pd2(dba)3 (2.0 mg, 2.5 mmol), X-Phos (6.0 mg, 12.5 mmol), and t-BuONa (36.0 mg, 0.38 mmol) according to the procedure in 363-3. 1 H NMR (400 MHz, Methanol-d4) δ 7.02 (d, J = 8.4 Hz, 2H), 6.81 (s, 2H), 6.39 (d, J = 8.4 Hz, 2H), 4.23 (s, 2H), 3.68 - 3.52 (m, 4H), 3.39 - 3.33 (m, 2H), 3.24 - 3.13 (m, 2H), 2.78 - 2.56 (m, 4H), 2.15 (s, 6H), 1.84 - 1.73 (m, 2H), 1.60 - 1.49 (m, 1H), 1.44 - 1.34 (m, 2H), 1.13 (t, J = 7.3 Hz, 3H), 1.02 (d, J = 6.4 Hz, 3H). Mass(m / z): 463.4 [M+H] + .

[0783] 1-(2-ethoxyethyl)-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (375) JPEG2026063193000357.jpg79151

[0784] Compound 375 (11.0 mg) was prepared according to the procedure for compound 363 from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline hydrochloride salt (77.0 mg, 0.2 mmol), 1-(2-ethoxyethyl)-5-oxopyrrolidine-3-carboxylic acid (40.2 mg, 0.2 mmol), DIEA (77.9 mg, 0.6 mmol), and HATU (76.0 mg, 0.2 mmol) as a pale yellow solid with a total yield of 11.4%. 1 H NMR (400 MHz, Methanol-d4) δ 7.93 - 5.89 (m, 8H), 4.30 (s, 2H), 3.67 - 3.59 (m, 2H), 3.53 (dd, J = 10.0, 6.3 Hz, 1H), 3.47 - 3.29 (m, 8H), 3.15 - 3.07 (m, 2H), 2.57 - 2.46 (m, 2H), 2.27 - 2.10 (m, 1H), 2.04 - 1.80 (m, 2H), 1.72 - 1.51 (m, 2H), 1.06 (t, J = 7.0 Hz, 3H). Mass(m / z): 533.4 [M+H] + .

[0785] N 1 ,N 1 -dimethyl-N 4 -(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)succinimide (376) JPEG2026063193000358.jpg69151

[0786] Compound 376 (15.9 mg) was prepared according to the procedure for compound 363 from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline hydrochloride salt (60.3 mg, 0.15 mmol), 4-(dimethylamino)-4-oxobutanoic acid (21.8 mg, 0.15 mmol), DIEA (58.0 mg, 0.45 mmol), and HATU (57 mg, 0.15 mmol) as a pale yellow solid with a total yield of 22.3%. 1 H NMR (400 MHz, Methanol-d4) δ 7.13 (d, J = 7.9 Hz, 2H), 7.07 - 6.88 (m, 6H), 4.27 (s, 2H), 3.68 - 3.56 (m, 2H), 3.09 (s, 3H), 2.94 (s, 3H), 2.78 - 2.63 (m, 4H), 2.53 (t, J = 6.9 Hz, 2H), 2.34 - 2.21 (m, 1H), 2.03 - 1.95 (m, 2H), 1.75 (qd, J = 12.6, 4.1 Hz, 2H). Mass(m / z): 477.4 [M+H] + .

[0787] N 1 -(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)glutaramide (377) JPEG2026063193000359.jpg74151

[0788] Step 1. Preparation of 5-oxo-5-((4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)amino)pentanoic acid (377-2). DIEA (1.16 g, 9 mmol) was added to a solution of 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline hydrochloride salt (115 mg, 3.0 mmol) in DCM (10.0 mL). Subsequently, dihydro-2H-pyran-2,6(3H)-dione (410.8 mg, 3.6 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The solution was washed with 2 x 10 mL of water, dried over Na2SO4, and concentrated under vacuum. The residue was purified by prep-TLC (MeOH / DCM = 1 / 10) to obtain the desired product as a yellow solid (42 mg, 30.2%). Mass (m / z): 464.3 [M+H] + .

[0789] Step 2. N 1 Preparation of -(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)glutaramide (377). HATU (41 mg, 0.11 mmol) was added to a solution of 5-oxo-5-((4-((4-(4-((trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)amino)pentanoic acid (42 mg, 0.09 mmol) in DMF (1.0 mL). The reaction mixture was then stirred at room temperature for 5 hours. NH3.H2O (0.2 mL) was added. The mixture was then stirred at room temperature overnight. 5 mL of water was added. The resulting solution was extracted with 3 x 5 mL of EA. The organic layer was bound, washed with 3 x 10 mL of water, dried over Na2SO4, and concentrated under vacuum. The residue was purified by prep-TLC (MeOH / DCM = 1 / 20) to obtain the desired product as a yellow solid (6.5 mg, 15.5%). 1H NMR (400 MHz, Methanol-d4) δ 7.22 - 6.86 (m, 8H), 4.27 (s, 2H), 3.72 - 3.55 (m, 2H), 2.77 - 2.61 (m, 2H), 2.30 - 2.24 (m, 4H), 2.08 - 1.86 (m, 5H), 1.80 - 1.69 (m, 2H). Mass(m / z): 463.3 [M+H] + .

[0790] N 1 -(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)malonamide (378) JPEG2026063193000360.jpg68151

[0791] Compound 378 (5.3 mg) was prepared according to the procedure for compound 363 from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline hydrochloride salt (77.1 mg, 0.2 mmol), 3-amino-3-oxopropanoic acid (33.8 mg, 0.24 mmol), DIEA (77.4 mg, 0.6 mmol), and HATU (91.2 mg, 0.24 mmol) as a pale yellow solid with a total yield of 6.1%. 1 H NMR (400 MHz, Methanol-d4) δ 7.12 - 6.69 (m, 8H), 4.20 (s, 2H), 3.67 - 359 (m, 1H), 3.57 - 3.43 (m, 2H), 3.17 - 3.10 (m, 1H), 2.65 - 2.44 (m, 2H), 2.23 - 2.12 (m, 1H), 1.94 - 1.84 (m, 2H), 1.70 - 1.60 (m, 2H). Mass(m / z): 435.3 [M+H] + .

[0792] 5-Oxo-5-(pyrrolidine-1-yl)-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)pentanamide (379) JPEG2026063193000361.jpg62151

[0793] Compound 379 (17.7 mg) was prepared according to the procedure for compound 363 from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline hydrochloride salt (77.1 mg, 0.2 mmol), 5-oxo-5-(pyrrolidine-1-yl)pentanoic acid (37.0 mg, 0.2 mmol), DIEA (77.4 mg, 0.6 mmol), and HATU (76.0 mg, 0.2 mmol) as a pale yellow solid with a total yield of 17.2%. 1 H NMR (400 MHz, Methanol-d4) δ 8.09 - 5.94 (m, 8H),, 4.16 (s, 2H), 3.26 (q, J = 7.1 Hz, 4H), 2.23 - 2.09 (m, 5H), 1.94 - 1.69 (m, 8H), 1.68 - 1.53 (m, 2H). Mass(m / z): 517.4 [M+H] + .

[0794] 3-Oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)piperazine-1-carboxamide (380) JPEG2026063193000362.jpg36151

[0795] To a solution of 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (34.9 mg, 0.1 mmol) in DCM (10 mL), CDI (17.8 mg, 0.11 mmol) was added. The reaction mixture was then stirred at room temperature for 1 hour. Piperazine-2-one (11.0 mg, 0.11 mmol) and DIEA (38.7 mg, 0.3 mmol) were added. The reaction mixture was then stirred at room temperature for 3 hours. The solution was then washed with 3 x 10 mL of water, dried over Na2SO4, and concentrated under vacuum. The residue was purified by prep-TLC (MeOH / DCM = 1 / 15) to obtain the desired product as a pale yellow solid (26.7 mg, 56.2%). 1 H NMR (400 MHz, Methanol-d4) δ 7.50 - 6.40 (m, 8H), 4.30 (s, 2H), 4.05 (s, 2H), 3.84 - 3.47 (m, 4H), 3.36 (d, J = 5.6 Hz, 2H), 2.99 - 2.45 (m, 2H), 2.36 - 2.22 (m, 1H), 2.09 - 1.89 (m, 2H), 1.83 - 1.66 (m, 2H). Mass(m / z): 476.3 [M+H] + .

[0796] 4-methyl-3-oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)piperazine-1-carboxamide (381) JPEG2026063193000363.jpg64151

[0797] Compound 381 (9.8 mg) was prepared according to the procedure for compound 380 from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (34.9 mg, 0.1 mmol), 1-methylpiperazine-2-one (12.5 mg, 0.11 mmol), CDI (17.8 mg, 0.11 mmol), and DIEA (38.7 mg, 0.3 mmol) as a blue solid with a total yield of 20.0%. 1H NMR (400 MHz, Methanol-d4) δ 7.77 - 6.65 (m, 8H), 4.37 (s, 2H), 4.06 (s, 2H), 3.99 - 3.36 (m, 8H), 3.03 - 2.97 (m, 3H), 2.88 - 2.69 (m, 1H), 2.42 - 1.74 (m, 4H). Mass(m / z): 490.3 [M+H] + .

[0798] 2-(1-ethyl-5-oxopyrrolidine-3-yl)-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)acetamide (382) JPEG2026063193000364.jpg64151

[0799] Compound 382 (20.6 mg) was prepared according to the procedure for compound 363 from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (34.9 mg, 0.1 mmol), 2-(1-ethyl-5-oxopyrrolidine-3-yl)acetic acid (17.1 mg, 0.1 mmol), DIEA (38.7 mg, 0.3 mmol), and HATU (38.0 mg, 0.1 mmol) as a pale yellow solid with a total yield of 41.0%. 1H NMR (400 MHz, Methanol-d4) δ 7.17 - 7.09 (m, 2H), 7.08 - 6.87 (m, 6H), 4.27 (s, 2H), 3.68 - 3.57 (m, 3H), 3.32 - 3.27 (m, 2H), 3.19 (dd, J = 10.1, 6.0 Hz, 1H), 2.83 - 2.75 (m, 1H), 2.73 - 2.61 (m, 2H), 2.56 (dd, J = 16.9, 8.8 Hz, 1H), 2.39 (d, J = 7.5 Hz, 2H), 2.32- 2.23 (m, 1H), 2.18 - 2.10 (m, 1H), 2.04 - 1.91 (m, 2H), 1.81 - 1.70 (m, 2H), 1.12 (t, J = 7.3 Hz, 3H). Mass(m / z): 503.3 [M+H] + .

[0800] 1-Methyl-2-oxo-N-(4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)imidazolidined-4-carboxamide (383) JPEG2026063193000365.jpg66151

[0801] Compound 383 (15.6 mg) was prepared as a white solid with a total yield of 32.8% from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (34.9 mg, 0.1 mmol), 1-methyl-2-oxoimidazolidine-4-carboxylic acid (14.3 mg, 0.1 mmol), DIEA (38.7 mg, 0.3 mmol), and HATU (38.0 mg, 0.1 mmol) according to the procedure for compound 363. 1H NMR (400 MHz, Methanol-d4) δ 7.03 (d, J = 8.4 Hz, 2H), 6.94 (d, J= 8.9 Hz, 2H), 6.86 (dd, J = 12.0, 8.6 Hz, 4H), 4.22 (s, 2H), 4.04 (dd, J = 9.9, 7.2 Hz, 1H), 3.58 - 3.49 (m, 3H), 2.64 (s, 3H), 2.58 (t, J = 12.1 Hz, 2H), 2.25 - 2.16 (m, 1H), 1.92 - 1.86 (m, 2H), 1.64 (qd, J = 12.5, 4.1 Hz, 2H). Mass (m / z): 476.3 [M+H] + .

[0802] 1-Ethyl-N-(2-methyl-4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (384) JPEG2026063193000366.jpg120151

[0803] Step 1. Preparation of 2-methyl-4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzaldehyde (384-3). Compound 384-3 (1.22 g) was prepared as a yellow oil with a total yield of 77.7% from 4-bromo-2-methylbenzaldehyde (995 mg, 5 mmol), 4-(4-(trifluoromethyl)piperidine-1-yl)aniline (1.06 g, 4.34 mmol), Pd2(dba)3 (46 mg, 50 umol), X-Phos (119 mg, 0.25 mol), and Cs2CO3 (2.72 g, 7.5 mmol) according to the procedure of 363-3. Mass (m / z): 363.3 [M+H] + .

[0804] Step 2. Preparation of (E)-2-methyl-4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzaldehyde oxime (384-4). Hydroxylamine hydrochloride (318 mg, 5 mmol) was added to a solution of 2-methyl-4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzaldehyde (1.22 g, 3.36 mmol) in EtOH solution (20 mL). The reaction mixture was then stirred overnight at room temperature. The reaction mixture was concentrated under vacuum. The residue was passed through a silica gel column and eluted with ethyl acetate / hexane (0-1 / 1) to obtain the crude product as yellow oil (1.01 g, 79.5%). Mass (m / z): 378.2 [M+H] + .

[0805] Step 3. Preparation of 4-(aminomethyl)-3-methyl-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (384-5). 10% Pd / C (16 mg, 0.015 ml) and AcOH (0.5 mL) were added to a solution of (E)-2-methyl-4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzaldehyde oxime (500 mg, 1.32 mmol) in EtOH (20 mL). The reaction mixture was then stirred overnight at room temperature under a hydrogen atmosphere. Pd / C was filtered off. The pH of the filtrate was adjusted to 8-9 with sodium carbonate solution. The mixture was then extracted with DCM (20 mL x 3). The combined organic layer was washed with brine (20 mL x 3), dried over Na2SO4, and concentrated to obtain the desired product as a yellow solid. (190 mg, 40.0%). 364.2 [M+H] + .

[0806] Step 4. Preparation of 1-ethyl-N-(2-methyl-4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (384). Compound 384 (17.9 mg) of the title was prepared according to the procedure of 363 from 4-(aminomethyl)-3-methyl-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (36.3 mg, 0.1 mmol), 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (15.7 mg, 0.1 mmol), DIEA (38.7 mg, 0.3 mmol), and HATU (38.0 mg, 0.1 mmol) as a white powder with a total yield of 35.7%. 1 H NMR (400 MHz, Methanol-d4) δ 7.09 - 6.56 (m, 8H), 4.21 (s, 2H), 3.59 - 3.45 (m, 4H), 3.29 - 3.23 (m, 4H), 3.16 - 3.08 (m, 1H), 2.67 - 2.47 (m, 4H), 2.22 - 2.12 (m, 4H), 1.93 - 1.84 (m, 2H), 1.70 - 1.60 (m, 2H), 1.04 (t, J = 7.3 Hz, 3H). Mass(m / z): 503.3 [M+H] + .

[0807] N-(2-methyl-4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (385) JPEG2026063193000367.jpg61151

[0808] Compound 385 (17.7 mg) was prepared as a white powder with a total yield of 37.3% from 4-(aminomethyl)-3-methyl-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (36.3 mg, 0.1 mmol), 5-oxopyrrolidine-3-carboxylic acid (12.8 mg, 0.1 mmol), DIEA (38.7 mg, 0.3 mmol), and HATU (38.0 mg, 0.1 mmol) according to the procedure of compound 363. 1 H NMR (400 MHz, Methanol-d4) δ 6.98 - 6.91 (m, 3H), 6.89 - 6.84 (m, 2H), 6.73 - 6.67 (m, 2H), 4.21 (s, 2H), 3.57 - 3.37 (m, 5H), 2.65 - 2.35 (m, 6H), 2.23 - 2.12 (m, 4H), 1.93 - 1.84 (m, 2H), 1.70 - 1.58 (m, 2H). Mass(m / z): 475.3 [M+H] + .

[0809] 5-Oxo-N-(4-((4-(3-(trifluoromethyl)azetidine-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (386) JPEG2026063193000368.jpg120151

[0810] Step 1. Preparation of 1-(4-nitrophenyl)-3-(trifluoromethyl)azetidine (386-3). A solution of 1-fluoro-4-nitrobenzene (241 mg, 1.71 mmol), 3-(trifluoromethyl)azetidine hydrochloride (250 mg, 1.55 mmol), and K2CO3 (320 mg, 2.32 mmol) in DMSO (5 mL) was stirred at 80°C for 18 hours. After cooling to room temperature, 10 mL of water was added. The resulting solution was extracted with 3 x 10 mL of ethyl acetate. The organic layer was bonded, washed with water (3 x 15 mL), dried, and concentrated under vacuum. The residue was purified by prep-TLC (EA / PE = 1 / 10) to obtain the desired product as a yellow solid (275 mg, 72.2%). Mass (m / z): 247.1 [M+H] + .

[0811] Step 2. Preparation of 4-(3-(trifluoromethyl)azetidine-1-yl)aniline (386-4). 10% Pd / C (5.8 mg, 5.5 mmol) was added to a solution of 1-(4-nitrophenyl)-3-(trifluoromethyl)azetidine (135 mg, 0.55 mmol) in EtOH (10 mL). The reaction was then stirred overnight at room temperature under a hydrogen atmosphere. Pd / C was filtered off. The filtrate was concentrated under vacuum to obtain the target product as a yellow oil (99 mg, 83.2%). Mass (m / z): 217.2 [M+H] + .

[0812] Step 3. Preparation of tert-butyl(4-((4-(3-(trifluoromethyl)azetidine-1-yl)phenyl)amino)benzyl)carbamate (386-5). Compound 386-5 (116 mg) was prepared as a yellow solid with a total yield of 72.5% from tert-butyl(4-bromobenzyl)carbamate (109 mg, 0.38 mmol), 4-(3-(trifluoromethyl)azetidine-1-yl)aniline (99 mg, 0.46 mmol), Pd2(dba)3 (3.5 mg, 3.8 mmol), X-Phos (9.0 mg, 19 mmol), and Cs2CO3 (206 mg, 0.57 mmol) according to the procedure in 363-3. Mass (m / z): 422.3 [M+H] + .

[0813] Step 4. Preparation of 4-(aminomethyl)-N-(4-(3-(trifluoromethyl)azetidine-1-yl)phenyl)aniline hydrochloride (386-6). Compound 386-6 (98 mg) was prepared as a yellow solid with a total yield of 100% from HCl (5.0 mL) in 1,4-dioxane and tert-butyl(4-((4-(3-(trifluoromethyl)azetidine-1-yl)phenyl)aminobenzyl) carbamate (116 mg, 0.28 mmol) according to the procedure in 363-4. Mass (m / z): 322.3 [M+H] + .

[0814] Step 5. Preparation of 5-oxo-N-(4-((4-(3-(trifluoromethyl)azetidine-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (386). Compound 386 (3.0 mg) of the title compound was prepared according to the procedure of 363 from 4-(aminomethyl)-N-(4-(3-(trifluoromethyl)azetidine-1-yl)phenyl)aniline hydrochloride (49 mg, 0.14 mmol), 5-oxopyrrolidine-3-carboxylic acid (18 mg, 0.14 mmol), DIEA (53.4 mg, 0.41 mmol), and HATU (52 mg, 0.14 mmol) as a dark blue powder with a total yield of 5.0%. 1H NMR (400 MHz, Methanol-d4) δ 8.16 - 6.48 (m, 8H), 4.87 (s, 2H), 3.62 - 3.56 (m, 1H), 3.53 - 3.46 (m, 1H), 3.37 - 3.34 (m, 2H), 3.27 - 3.19 (m, 1H), 2.64 - 2.46 (m, 2H), 2.25 - 2.17 (m, 1H), 2.07 - 2.02 (m, 1H), 1.66 - 1.57 (m, 1H). Mass(m / z): 433.3 [M+H] + .

[0815] 1-Ethyl-5-oxo-N-(4-((4-(3-(trifluoromethyl)azetidine-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (387) JPEG2026063193000369.jpg62151

[0816] Compound 387 (4.1 mg) was prepared according to the procedure in 363 from 4-(aminomethyl)-N-(4-(3-(trifluoromethyl)azetidine-1-yl)phenyl)aniline hydrochloride (49 mg, 0.14 mmol), 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (21.8 mg, 0.14 mmol), DIEA (53.4 mg, 0.41 mmol), and HATU (52 mg, 0.14 mmol) as a dark blue powder with a total yield of 6.5%.1 H NMR (400 MHz, Methanol-d4) δ 7.79 - 6.15 (m, 8H), 4.77 (s, 2H), 3.59 - 3.45 (m, 2H), 3.29 - 3.23 (m, 4H), 3.14 - 3.05 (m, 1H), 2.52 (d, J = 8.4 Hz, 2H), 2.01 - 1.83 (m, 1H), 1.04 (t, J = 7.3 Hz, 3H). Mass(m / z): 461.3 [M+H] + .

[0817] N 1 -(4-((4-(4-methylpiperidine-1-yl)phenyl)amino)benzyl)malonamide (388) JPEG2026063193000370.jpg68151

[0818] Compound 388 (15.3 mg) was prepared according to the procedure for compound 363 from 4-(aminomethyl)-N-(4-(4-methylpiperidine-1-yl)phenyl)aniline (59 mg, 0.2 mmol), 3-amino-3-oxopropanoic acid (30.9 mg, 0.3 mmol), DIEA (77.4 mg, 0.6 mmol), and HATU (91.2 mg, 0.24 mmol) as a dark blue powder with a total yield of 20.1%. 1 H NMR (400 MHz, Methanol-d4) δ 7.35 (d, J = 8.6 Hz, 2H), 7.18 (d, J= 8.0 Hz, 2H), 7.04 (dd, J = 13.4, 8.3 Hz, 4H), 4.27 (s, 2H), 3.57 - 3.43 (m, Mass(m / z): 381.3 [M+H] + .

[0819] N 1-(4-((4-(4-methylpiperidine-1-yl)phenyl)amino)benzyl)glutaramide (389) JPEG2026063193000371.jpg59151

[0820] Compound 389 (15.3 mg) was prepared according to the procedure for compound 363 from 4-(aminomethyl)-N-(4-(4-methylpiperidine-1-yl)phenyl)aniline (59 mg, 0.2 mmol), 3-amino-3-oxopropanoic acid (39.3 mg, 0.3 mmol), DIEA (77.4 mg, 0.6 mmol), and HATU (91.2 mg, 0.24 mmol) as a dark blue powder with a total yield of 20.1%. 1 H NMR (400 MHz, Methanol-d4) δ 7.36 (d, J = 8.6 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 7.04 (dd, J = 12.6, 8.4 Hz, 4H), 4.23 (s, 2H), 3.58 - 3.45 (m, Mass(m / z): 409.3 [M+H] + .

[0821] N-(2-chloro-4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (390) JPEG2026063193000372.jpg65151

[0822] Step 1. Preparation of 2-chloro-4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzonitrile (390-2). Compound 390-2 (1.26 g) was prepared as a gray solid with a total yield of 82.9% from 4-bromo-2-chlorobenzonitrile (860 mg, 4 mmol), 4-(4-(trifluoromethyl)piperidine-1-yl)aniline (1.27 g, 5.2 mmol), Pd2(dba)3 (36.6 mg, 0.04 mmol), X-Phos (95.4 mg, 0.2 mmol), and Cs2CO3 (1.96 g, 6 mmol) according to the procedure in 363-3. Mass (m / z): 380.2 [M+H] + .

[0823] Step 2. Preparation of 4-(aminomethyl)-3-chloro-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (390-3). LiAlH4 (380 mg, 10 mmol) was added to a solution of 2-chloro-4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzonitrile (379 mg, 1 mmol) in THF (20 mL). The reaction was then refluxed overnight at room temperature. 20 mL of water was added at 0°C. The resulting solution was extracted with 3 x 20 mL of ethyl acetate. The organic layer was bonded, washed with water (3 x 50 mL), dried, and concentrated under vacuum. The residue was purified by prep-TLC (MeOH / DCM = 1 / 15) to obtain the desired product as a yellow solid (50 mg, 13.0%). Mass (m / z): 384.2 [M+H] + .

[0824] Step 3. Preparation of N-(2-chloro-4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (390). Compound 390 (40.9 mg) of the title was prepared according to the procedure of 363 from 4-(aminomethyl)-3-chloro-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (50 mg, 0.13 mmol), 5-oxopyrrolidine-3-carboxylic acid (33.0 mg, 0.26 mmol), DIEA (50.0 mg, 0.40 mmol), and HATU (59 mg, 0.16 mmol) as a dark blue powder with a total yield of 63.9%. 1 H NMR (400 MHz, Methanol-d4) δ 7.98 - 6.52 (m, 7H), 4.33 (s, 2H), 3.88 - 3.37 (m, 4H), 3.31 - 3.25 (m, 1H), 2.78 - 2.37 (m, 4H), 2.35 - 1.43 (m, 5H). Mass(m / z): 495.3 [M+H] + .

[0825] N-(3-Methoxy-4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (391) JPEG2026063193000373.jpg70151

[0826] Compound 391 (12.8 mg) was prepared as a white powder with a total yield of 26.1% from 4-(aminomethyl)-2-methoxy-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (37.9 mg, 0.1 mmol), 5-oxopyrrolidine-3-carboxylic acid (12.8 mg, 0.1 mmol), DIEA (38.7 mg, 0.1 mmol), and HATU (38.0 mg, 0.1 mmol) according to the procedure of compound 363. 1H NMR (400 MHz, Methanol-d4) δ 7.52 - 6.34 (m, 7H), 4.23 (s, 2H), 3.80 (s, 3H), 3.61 - 3.38 (m, 3H), 3.26 - 3.23 (m, 1H), 3.22 - 3.20 (m, Mass(m / z): 491.3 [M+H] + .

[0827] N-(4-((4-cyclohexylphenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (392) JPEG2026063193000374.jpg71151

[0828] Compound 392 (9.3 mg) was prepared according to the procedure in 363-3 from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 4-cyclohexylaniline (58 mg, 0.33 mmol), Pd2(dba)3 (2.3 mg, 2.5 mmol), X-Phos (6.0 mg, 12.5 mmol), and Cs2CO3 (122 mg, 0.38 mmol) as a pale yellow solid with a total yield of 9.5%. 1H NMR (400 MHz, DMSO-d6) δ 8.33 (t, J = 5.6 Hz, 1H), 7.93 (s, 1H), 7.52 (s, 1H), 7.04 - 6.97 (m, 4H), 6.93 - 6.87 (m, 4H), 4.10 (d, J = 5.6 Hz, 2H), 3.33 (t, J = 8.8 Hz, 1H), 3.20 - 3.10 (m, 2H), 2.37 - 2.29 (m, 1H), 2.23 (dd, J = 8.4, 4.2 Hz, 2H), 1.74 - 1.67 (m, 4H), 1.66 - 1.58 (m, 4H), 1.33 - 1.24 (m, 4H). Mass(m / z): 392.3 [M+H] + .

[0829] N-(3-fluoro-4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (393) JPEG2026063193000375.jpg64151

[0830] Step 1. Preparation of 3-fluoro-4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzonitrile (393-2). Compound 393-2 (1.56 g) was prepared as a gray solid with a total yield of 85.7% from 4-bromo-3-fluorobenzonitrile (1.0 g, 5 mmol), 4-(4-(trifluoromethyl)piperidine-1-yl)aniline (1.59 g, 6.5 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), X-Phos (119 mg, 0.25 mmol), and Cs2CO3 (2.45 g, 7.5 mmol) according to the procedure of 363-3. Mass (m / z): 364.2 [M+H] + .

[0831] Step 2. Preparation of 4-(aminomethyl)-2-fluoro-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (393-3). Raney Ni was added to a solution of 3-fluoro-4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzonitrile (363 mg, 1 mmol) in EtOH (10 mL). The reaction was then stirred overnight at room temperature under a hydrogen atmosphere. Raney Ni was filtered off. The filtrate was concentrated under vacuum. The residue was purified by prep-TLC (MeOH / DCM=1 / 5) to obtain the target product as a yellow solid (220 mg, 60.0%). Mass (m / z): 368.1 [M+H] + .

[0832] Step 3. Preparation of N-(3-fluoro-4-((4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (393). Compound 393 (28.0 mg) was prepared as a white powder with a total yield of 43.1% from 4-(aminomethyl)-2-fluoro-N-(4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aniline (50 mg, 0.14 mmol), 5-oxopyrrolidine-3-carboxylic acid (35.0 mg, 0.27 mmol), DIEA (52.6 mg, 0.41 mmol), and HATU (62 mg, 0.16 mmol) according to the procedure for 363. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (t, J = 5.8 Hz, 1H), 7.59 (s, 1H), 7.55 (s, 1H), 7.08 - 7.00 (m, 2H), 6.97 - 6.88 (m, 5H), 4.19 (d, J = 5.6 Hz, 2H), 3.66- 3.60 (m, 2H), 3.42 - 3.39 (m, 1H), 3.28 - 3.17 (m, 2H), 2.63 (t, J = 12.1 Hz, 2H), 2.47 - 2.37 (m, 1H), 2.33 - 2.28 (m, 2H), 1.91- 1.85 (m, 2H), 1.62 - 1.52 (m, 2H). Mass(m / z): 479.3 [M+H] + .

[0833] N-(4-((4-fluoro-3-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (394) JPEG2026063193000376.jpg136151

[0834] Step 1. Preparation of 1-(2-fluoro-5-nitrophenyl)-4-(trifluoromethyl)piperidine (394-3). Compound 394-3 (570 mg) was prepared as a yellow solid with a total yield of 39.0% from 2-bromo-1-fluoro-4-nitrobenzene (1.1 g, 5 mmol), 4-(trifluoromethyl)piperidine (995 mg, 6.5 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), X-Phos (119 mg, 0.25 mmol), and Cs2CO3 (2.45 g, 7.5 mmol) according to the procedure of 363-3.

[0835] Step 2. Preparation of 4-fluoro-3-(4-(trifluoromethyl)piperidine-1-yl)aniline (394-4). 10% Pd / C (20.6 mg, 20 umol) was added to a solution of 1-(2-fluoro-5-nitrophenyl)-4-(trifluoromethyl)piperidine (570 mg, 1.92 mmol) in EtOH (10 mL). The reaction was then stirred overnight at room temperature under a hydrogen atmosphere. Pd / C was filtered off. The filtrate was concentrated under vacuum. The residue was purified by prep-TLC (MeOH / DCM=1 / 5) to obtain the target product as yellow oil (390 mg, 76.3%). Mass (m / z): 263.2 [M+H] + .

[0836] Step 3. Preparation of N-(4-((4-fluoro-3-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (394). Compound 394 (5.0 mg) of the title was prepared as a white powder with a total yield of 5.0% from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 1-(2-fluoro-5-nitrophenyl)-4-(trifluoromethyl)piperidine (87 mg, 0.33 mmol), Pd2(dba)3 (2.3 mg, 2.5 mmol), X-Phos (6.0 mg, 12.5 mmol), and Cs2CO3 (122 mg, 0.38 mmol) according to the procedure in 363-3. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (t, J = 5.8 Hz, 1H), 8.03 (s, 1H), 7.59 (s, 1H), 7.10 (d, J = 8.5 Hz, 2H), 7.03 - 6.93 (m, 3H), 6.71 - 6.58 (m, 2H), 4.18 (d, J = 5.7 Hz, 2H), 3.45 - 3.37 (m, 3H), 3.27 - 3.15 (m, 2H), 2.70 - 2.62 (m, 2H), 2.48- 2.41 (m, 2H), 2.34 - 2.28 (m, 2H), 1.94 - 1.84 (m, 2H), 1.60 (qd, J = 12.6, 4.0 Hz, 2H). Mass(m / z): 479.3 [M+H] + .

[0837] N-(4-((3-chloro-4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (395) JPEG2026063193000377.jpg142151

[0838] Step 1. Preparation of N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (395-2). Compound 395-2 (616 mg) was prepared as a yellow solid with a total yield of 50.0% from 2-chloro-1-fluoro-4-nitrobenzene (700 mg, 4.0 mmol), 4-(trifluoromethyl)piperidine (612 mg, 4.0 mmol), and K2CO3 (828 mg, 6.0 mmol) according to the procedure of 386-3.

[0839] Step 2. Preparation of 3-chloro-4-(4-(trifluoromethyl)piperidine-1-yl)aniline (395-3). Compound 395-3 (500 mg) was prepared as a yellow solid with a total yield of 89.9% from 1-(2-chloro-4-nitrophenyl)-4-(trifluoromethyl)piperidine (616 mg, 2.0 mmol) and 10% Pd / C (21.2 mg, 0.02 mmol) in EtOH (20 mL) according to the procedure in 386-4. Mass (m / z): 279.3 [M+H] + .

[0840] Step 3. Preparation of N-(4-((3-chloro-4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (395). Compound 395 (30.0 mg) of the title compound was prepared as a white powder with a total yield of 24.3% from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 3-chloro-4-(4-(trifluoromethyl)piperidine-1-yl)aniline (92 mg, 0.33 mmol), Pd2(dba)3 (2.5 mg, 2.5 mmol), X-Phos (6.0 mg, 12.5 mmol), and Cs2CO3 (122 mg, 0.38 mmol) according to the procedure in 363-3. 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (t, J = 5.8 Hz, 1H), 8.13 (s, 1H), 7.59 (s, 1H), 7.15 - 7.10 (m, 2H), 7.08 - 7.03 (m, 2H), 7.00 - 6.95 (m, 3H), 4.19 (d, J = 5.7 Hz, 2H), 3.29 - 3.15 (m, 5H), 2.70 - 2.60 (m, 2H), 2.47 - 2.38 (m, 1H), 2.31 (dd, J = 8.4, 3.4 Hz, 2H), 1.95 - 1.86 (m, 2H), 1.61 (qd, J= 12.3, 4.0 Hz, 2H). Mass(m / z): 495.3 [M+H] + .

[0841] N-(4-((4-(4,4-difluoropiperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (396) JPEG2026063193000378.jpg71151

[0842] Compound 396 (36.2 mg) was prepared as a white powder with a total yield of 33.8% from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 4-(4,4-difluoropiperidine-1-yl)aniline (70 mg, 0.33 mmol), Pd2(dba)3 (2.3 mg, 2.5 mmol), X-Phos (6.0 mg, 12.5 mmol), and Cs2CO3 (122 mg, 0.38 mmol) according to the procedure in 363-3. 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (t, J = 5.8 Hz, 1H), 7.82 (s, 1H), 7.58 (s, 1H), 7.06 (d, J = 8.1 Hz, 2H), 6.96 (q, J = 8.8 Hz, 4H), 6.89 (d, J = 8.1 Hz, 2H), 4.16 (d, J = 5.6 Hz, 2H), 3.40 (t, J= 8.7 Hz, 1H), 3.28 - 3.13 (m, 6H), 2.35 - 2.24 (m, 2H), 2.13 - 2.00 (m, 4H). Mass(m / z): 429.3 [M+H] + .

[0843] N-(4-((3-bromo-4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (397) JPEG2026063193000379.jpg106151

[0844] Step 1. Preparation of 1-(2-bromo-4-nitrophenyl)-4-(trifluoromethyl)piperidine (397-2). Compound 397-2 (2.38 g) was prepared as a yellow solid with a total yield of 67.6% from 2-bromo-1-fluoro-4-nitrobenzene (2.19 g, 10 mmol), 4-(trifluoromethyl)piperidine (1.53 g, 10 mmol), and K2CO3 (2.07 g, 15 mmol) according to the procedure in 386-3.

[0845] Step 2. Preparation of 3-bromo-4-(4-(trifluoromethyl)piperidine-1-yl)aniline (397-3). Compound 397-3 (315 mg) was prepared as a yellow solid with a total yield of 48.9% from 4-(trifluoromethyl)piperidine (704 mg, 2.0 mmol) and 10% Pd / C (21.2 mg, 0.02 mmol) in EtOH (20 mL) according to the procedure in 386-4. Mass (m / z): 323.1 [M+H] + .

[0846] Step 3. Preparation of tert-butyl(4-((3-bromo-4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)carbamate (397-4). Compound 397-4 (102 mg) was prepared as a yellow solid with a total yield of 38.6% from tert-butyl(4-bromobenzyl)carbamate (143 mg, 0.5 mmol), 3-bromo-4-(4-(trifluoromethyl)piperidine-1-yl)aniline (209 mg, 0.65 mmol), Pd2(dba)3 (4.6 mg, 5.0 mmol), X-Phos (11.9 mg, 25 mmol), and Cs2CO3 (245 mg, 0.75 mmol) according to the procedure in 363-3. Mass (m / z): 528.3 [M+H] + .

[0847] Step 4. Preparation of N-(4-(aminomethyl)phenyl)-3-bromo-4-(4-(trifluoromethyl)piperidine-1-yl)aniline (397-5). Compound 397-5 (32.9 mg) was prepared as a yellow solid with a total yield of 39.8% from 1,4-dioxane, HCl (5.0 mL), and tert-butyl(4-((3-bromo-4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)aminobenzyl)carbamate (102 mg, 0.19 mmol) according to the procedure in 363-4. Mass (m / z): 428.1 [M+H] + .

[0848] Step 5. Preparation of N-(4-((3-bromo-4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (397). Compound 397 (9.0 mg) of the title compound was prepared according to the procedure in 363 from N-(4-(aminomethyl)phenyl)-3-bromo-4-(4-(trifluoromethyl)piperidine-1-yl)aniline (32.9 mg, 77 umol), 5-oxopyrrolidine-3-carboxylic acid (11.9 mg, 92 umol), DIEA (30.0 mg, 0.23 mmol), and HATU (35.1 mg, 92 umol) as a pale yellow solid with a total yield of 27.3%. 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (t, J = 5.8 Hz, 1H), 8.07 (s, 1H), 7.52 (s, 1H), 7.16 (d, J = 2.4 Hz, 1H), 7.09 - 7.02 (m, 2H), 7.01 - 6.89 (m, 4H), 4.12 (d, J = 5.7 Hz, 2H), 3.24 - 3.08 (m, 5H), 2.61 - 2.52 (m, 2H), 2.37 - 2.26 (m, 1H), 2.24 (dd, J = 8.4, 3.2 Hz, 2H), 1.86 - 1.80 (m, 2H), 1.54 (qd, J = 12.4, 4.0 Hz, 2H). Mass(m / z): 539.3 [M+H] + .

[0849] N-(4-((5-fluoro-2-methyl-4-(4-methylpiperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (398) JPEG2026063193000380.jpg158151

[0850] Step 1. Preparation of 1-(2-fluoro-5-methyl-4-nitrophenyl)-4-methylpiperidine (398-3). Compound 398-3 (1.27 g) was prepared as a yellow solid with a total yield of 88.2% from 1,2-difluoro-4-methyl-5-nitrobenzene (1.0 g, 5.7 mmol) and 4-methylpiperidine (1.72 g, 17.3 mmol) according to the procedure of 386-3.

[0851] Step 2. Preparation of 5-fluoro-2-methyl-4-(4-methylpiperidine-1-yl)aniline (398-4). Compound 398-4 (1.16 g) was prepared as a yellow solid with a total yield of 100% from 1-(2-fluoro-5-methyl-4-nitrophenyl)-4-methylpiperidine (1.27 g, 5.0 mmol) and 10% Pd / C (53 mg, 0.05 mmol) in EtOH (20 mL) according to the procedure of 386-4. Mass (m / z): 223.2 [M+H] + .

[0852] Step 3. Preparation of N-(4-((5-fluoro-2-methyl-4-(4-methylpiperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (398). Compound 398 (22.1 mg) was prepared as a white powder with a total yield of 20.2% from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 5-fluoro-2-methyl-4-(4-methylpiperidine-1-yl)aniline (74 mg, 0.33 mmol), Pd2(dba)3 (2.5 mg, 2.5 mmol), X-Phos (6.0 mg, 12.5 mmol), and Cs2CO3 (122 mg, 0.38 mmol) according to the procedure in 363-3. 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (t, J = 5.8 Hz, 1H), 7.59 (s, 1H), 7.45 (s, 1H), 7.18 - 7.02 (m, 3H), 6.94 - 6.77 (m, 3H), 4.19 (d, J = 5.6 Hz, 2H), 3.44 - 3.14 (m, 5H), 3.03 - 2.73 (m, 2H), 2.33 - 2.26 (m, 2H), 2.15 (s, 3H), 1.80 - 1.69 (m, 2H), 1.60 - 1.50 (m, 1H), 1.46 - 1.34 (m, 2H), 0.96 (d, J = 6.4 Hz, 3H). Mass(m / z): 439.4 [M+H] + .

[0853] N-(4-((5-chloro-2-methyl-4-(4-methylpiperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (399) JPEG2026063193000381.jpg152151

[0854] Step 1. Preparation of 1-(2-chloro-5-methyl-4-nitrophenyl)-4-methylpiperidine (399-2). Compound 399-2 (1.35 g) was prepared as a yellow solid with a total yield of 88.2% from 1-chloro-2-fluoro-4-methyl-5-nitrobenzene (1.08 g, 5.7 mmol) and 4-methylpiperidine (1.72 g, 17.3 mmol) according to the procedure in 386-3.

[0855] Step 2. Preparation of 5-chloro-2-methyl-4-(4-methylpiperidine-1-yl)aniline (399-3). Compound 399-3 (1.19 g) was prepared as a yellow solid with a total yield of 100% from 1-(2-chloro-5-methyl-4-nitrophenyl)-4-methylpiperidine (1.35 g, 5.0 mmol) and 10% Pd / C (53 mg, 0.05 mmol) in EtOH (20 mL) according to the procedure in 386-4. Mass (m / z): 239.2 [M+H] + .

[0856] Step 3. Preparation of N-(4-((5-chloro-2-methyl-4-(4-methylpiperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (399). Compound 399 (21.0 mg) of the title was prepared as a white powder with a total yield of 18.5% from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 5-chloro-2-methyl-4-(4-methylpiperidine-1-yl)aniline (79 mg, 0.33 mmol), Pd2(dba)3 (2.5 mg, 2.5 mmol), X-Phos (6.0 mg, 12.5 mmol), and Cs2CO3 (122 mg, 0.38 mmol) according to the procedure in 363-3. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (t, J = 5.8 Hz, 1H), 7.59 (s, 1H), 7.36 (s, 1H), 7.13 - 6.98 (m, 4H), 6.83 - 6.73 (m, 2H), 4.17 (d, J = 5.6 Hz, 2H), 3.40 (t, J = 8.9 Hz, 1H), 3.28 - 3.14 (m, 4H), 2.70 - 2.57 (m, 2H), 2.35 - 2.25 (m, 2H), 2.15 (s, 3H), 1.76 - 1.67 (m, 1H), 1.54 - 1.45 (m, 1H), 1.37 - 1.26 (m, 2H), 0.97 (d, J = 6.4 Hz, 3H). Mass(m / z): 455.4 [M+H] + .

[0857] N-(4-((2-fluoro-3-methyl-4-(4-methylpiperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (400) JPEG2026063193000382.jpg148151

[0858] Step 1. Preparation of 1-(3-fluoro-2-methyl-4-nitrophenyl)-4-methylpiperidine (400-2). A solution of 1,3-difluoro-2-methyl-4-nitrobenzene (1 g, 5.7 mmol) and 4-methylpiperidine (1.72 g, 17.3 mmol) in DMSO (10 mL) was stirred overnight at room temperature. 10 mL of water was added dropwise. The precipitate was collected by filtration, and the desired product was obtained as a yellow solid (1.20 g, 83.3%). Mass (m / z): 253.2 [M+H] + .

[0859] Step 2. Preparation of 5-chloro-2-methyl-4-(4-methylpiperidine-1-yl)aniline (400-3). Compound 400-3 (1.1 g) was prepared as a yellow solid with a total yield of 100% from 2-fluoro-3-methyl-4-(4-methylpiperidine-1-yl)aniline (1.20 g, 4.8 mmol) and 10% Pd / C (53 mg, 0.05 mmol) in EtOH (20 mL) according to the procedure in 386-4. Mass (m / z): 239.2 [M+H] + .

[0860] Step 3. Preparation of N-(4-((2-fluoro-3-methyl-4-(4-methylpiperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (400). Compound 400 (17.2 mg) of the title compound was prepared as a white powder with a total yield of 15.7% from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 2-fluoro-3-methyl-4-(4-methylpiperidine-1-yl)aniline (74 mg, 0.33 mmol), Pd2(dba)3 (2.5 mg, 2.5 mmol), X-Phos (6.0 mg, 12.5 mmol), and Cs2CO3 (122 mg, 0.38 mmol) according to the procedure in 363-3. 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (t, J = 5.8 Hz, 1H), 7.59 (s, 1H), 7.10 - 7.00 (m, 3H), 6.92 - 6.80 (m, 3H), 4.17 (d, J = 5.6 Hz, 2H), 3.40 (t, J = 8.8 Hz, 1H), 3.29 - 2.93 (m, 6H), 2.33 - 2.28 (m, 2H), 2.23 - 2.15 (m, 3H), 1.78 - 1.70 (m, 2H), 1.56 - 1.47 (m, 1H), 1.42 - 1.30 (m, 2H), 0.97 (d, J = 6.4 Hz, 3H). Mass(m / z): 439.3 [M+H] + .

[0861] N-(4-((3-fluoro-2-methyl-4-(4-methylpiperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (401) JPEG2026063193000383.jpg66151

[0862] Compound 401 (11.7 mg) was prepared as a white powder with a total yield of 10.7% from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 3-fluoro-2-methyl-4-(4-methylpiperidine-1-yl)aniline (74 mg, 0.33 mmol), Pd2(dba)3 (2.5 mg, 2.5 mmol), X-Phos (6.0 mg, 12.5 mmol), and Cs2CO3 (122 mg, 0.38 mmol) according to the procedure in 398. 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (t, J = 5.8 Hz, 1H), 7.59 (s, 1H), 7.51 (s, 1H), 7.08 (d, J = 8.2 Hz, 2H), 7.04 - 6.95 (m, 1H), 6.89 (d, J= 8.6 Hz, 1H), 6.83 - 6.72 (m, 2H), 4.17 (d, J = 5.6 Hz, 2H), 3.41 - 3.11 (m, 5H), 3.00 - 2.73 (m, 2H), 2.33 - 2.27 (m, 2H), 2.08 (s, 3H), 1.79 - 1.69 (m, 2H), 1.60 - 1.50 (m, 1H), 1.46 - 1.32 (m, 2H), 0.97 (d, J = 6.4 Hz, 3H). Mass(m / z): 439.3 [M+H] + .

[0863] N-(4-((2,3-dimethyl-4-(4-methylpiperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (402) JPEG2026063193000384.jpg62148

[0864] Compound 402 (11.1 mg) was prepared as a yellow powder with a total yield of 10.2% from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 2,3-dimethyl-4-(4-methylpiperidine-1-yl)aniline (73 mg, 0.33 mmol), Pd2(dba)3 (2.5 mg, 2.5 mmol), X-Phos (6.0 mg, 12.5 mmol), and Cs2CO3 (122 mg, 0.38 mmol) according to the procedure in 398. 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (t, J = 5.7 Hz, 1H), 7.58 (s, 1H), 7.30 (s, 1H), 7.01 - 6.96 (m, 2H), 6.92 (d, J = 8.5 Hz, 1H), 6.87 (d, J= 8.6 Hz, 1H), 6.63 - 6.53 (m, 2H), 4.13 (d, J = 5.4 Hz, 2H), 3.39 (t, J= 8.9 Hz, 1H), 3.25 - 3.16 (m, 2H), 2.96 - 2.89 (m, 2H), 2.59 - 2.52 (m, 2H), 2.29 (dd, J = 8.4, 5.1 Hz, 2H), 2.19 (s, 3H), 2.05 (s, 3H), 1.74 - 1.67 (m, 2H), 1.50 - 1.43 (m, 1H), 1.28 - 1.36 (m, 2H), 0.97 (d, J = 6.4 Hz, 3H). Mass(m / z): 435.4 [M+H] + .

[0865] N-(4-((5-methyl-6-(4-(trifluoromethyl)piperidine-1-yl)pyridine-3-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (403) JPEG2026063193000385.jpg149151

[0866] Step 1. Preparation of 4-(trifluoromethyl)piperidine (403-2). Compound 403-2 (959 mg) was prepared as a yellow solid with a total yield of 83.1% from 2-fluoro-3-methyl-5-nitropyridine (624 mg, 4 mmol), 4-(trifluoromethyl)piperidine (734 mg, 4.8 mmol), and K2CO3 (828 mg, 6 mmol) according to the procedure in 386-3.

[0867] Step 2. Preparation of 5-methyl-6-(4-(trifluoromethyl)piperidine-1-yl)pyridine-3-amine (403-3). Compound 403-3 (390 mg) was prepared as a purple solid with a total yield of 72.5% from 3-methyl-5-nitro-2-(4-(trifluoromethyl)piperidine-1-yl)pyridine (578 mg, 2 mmol) and 10% Pd / C (22 mg, 0.02 mmol) in EtOH (20 mL) according to the procedure in 386-4. Mass (m / z): 260.3 [M+H] + .

[0868] Step 3. Preparation of N-(4-((5-methyl-6-(4-(trifluoromethyl)piperidine-1-yl)pyridine-3-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (403). Compound 403 (25.2 mg) was prepared according to the procedure in 363-3 from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 5-methyl-6-(4-(trifluoromethyl)piperidine-1-yl)pyridine-3-amine (86 mg, 0.33 mmol), Pd2(dba)3 (2.5 mg, 2.5 mmol), X-Phos (6.0 mg, 12.5 mmol), and Cs2CO3 (122 mg, 0.38 mmol) as a pale yellow powder with a total yield of 21.2%. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.10 (s, 1H), 7.98 (d, J = 2.7 Hz, 1H), 7.66 (s, 1H), 7.36 (d, J = 2.7 Hz, 1H), 7.20 - 7.13 (m, 2H), 7.04 - 6.97 (m, 2H), 4.24 (d, J = 5.7 Hz, 2H), 3.49 (d, J = 8.6 Hz, 1H), 3.39 - 3.19 (m, 4H), 2.79 (t, J = 12.2 Hz, 2H), 2.55 - 2.45 (m, 1H), 2.39 - 2.32 (m, 2H), 1.99 - 1.91 (m, 2H), 1.67 (qd, J = 12.4, 4.0 Hz, 2H). Mass(m / z): 476.3 [M+H] + .

[0869] N-(4-((2-methyl-6-(4-(trifluoromethyl)piperidine-1-yl)pyridine-3-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (404) JPEG2026063193000386.jpg149151

[0870] Step 1. Preparation of 2-methyl-3-nitro-6-(4-(trifluoromethyl)piperidine-1-yl)pyridine (404-2). Compound 404-2 (1.03 g) was prepared as a yellow solid with a total yield of 89.0% from 6-fluoro-2-methyl-3-nitropyridine (624 mg, 4 mmol), 4-(trifluoromethyl)piperidine (734 mg, 4.8 mmol), and K2CO3 (828 mg, 6 mmol) according to the procedure of 386-3.

[0871] Step 2. Preparation of 2-methyl-6-(4-(trifluoromethyl)piperidine-1-yl)pyridine-3-amine (404-3). Compound 404-3 (406 mg) was prepared as yellow oil with a total yield of 78.3% from 2-methyl-3-nitro-6-(4-(trifluoromethyl)piperidine-1-yl)pyridine (578 mg, 2 mmol) and 10% Pd / C (21 mg, 0.02 mmol) in EtOH (20 mL) according to the procedure in 386-4. Mass (m / z): 260.2 [M+H] + .

[0872] Step 3. Preparation of N-(4-((2-methyl-6-(4-(trifluoromethyl)piperidine-1-yl)pyridine-3-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (404). Compound 404 (18.6 mg) was prepared according to the procedure in 363-3 from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 2-methyl-6-(4-(trifluoromethyl)piperidine-1-yl)pyridine-3-amine (86 mg, 0.33 mmol), Pd2(dba)3 (2.5 mg, 2.5 mmol), X-Phos (6.0 mg, 12.5 mmol), and Cs2CO3 (122 mg, 0.38 mmol) as a pale yellow powder with a total yield of 15.6%. 1H NMR (400 MHz, DMSO-d6) δ 8.33 (t, J = 5.7 Hz, 1H), 7.58 (s, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.25 (s, 1H), 7.02 - 6.95 (m, 2H), 6.72 (d, J= 8.1 Hz, 1H), 6.57 - 6.49 (m, 2H), 4.38 - 4.30 (m, 2H), 4.13 (d, J = 5.7 Hz, 2H), 3.39 (t, J = 8.8 Hz, 3H), 3.25 - 3.15 (m, 2H), 2.83 - 2.74 (m, 2H), 2.61 - 2.53 (m, 1H), 2.29 (dd, J = 8.5, 4.5 Hz, 2H), 2.23 (s, 3H), 1.91 - 1.83 (m, 2H), 1.45 (qd, J = 12.4, 3.9 Hz, 2H). Mass(m / z): 476.4 [M+H] + .

[0873] 5-Oxo-N-(4-((3-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (405) JPEG2026063193000387.jpg36151

[0874] Compound 405 (4.6 mg) was prepared according to the procedure in 363-3 from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (30 mg, 0.10 mmol), 3-(4-(trifluoromethyl)piperidine-1-yl)aniline (30 mg, 0.12 mmol), Pd2(dba)3 (0.9 mg, 1.0 umol), X-Phos (2.4 mg, 5.0 umol), and Cs2CO3 (50 mg, 0.15 mmol) as a pale yellow powder with a total yield of 9.8%. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (t, J = 5.6 Hz, 1H), 8.01 (s, 1H), 7.59 (s, 1H), 7.12 - 7.00 (m, 4H), 6.59 (s, 1H), 6.54 - 6.50 (m, 1H), 6.47 - 6.43 (m, 1H), 4.19 (d, J = 5.7 Hz, 2H), 3.73 - 3.67 (m, 2H), 3.41 (t, J= 8.8 Hz, 1H), 3.26 - 3.19 (m, 2H), 2.74 - 2.66 (m, 2H), 2.34 - 2.27 (m, 2H), 1.90 - 1.84 (m, 2H), 1.59 - 1.52 (m, 2H). Mass(m / z): 461.3 [M+H] + .

[0875] 5-Oxo-N-(4-((6-(4-(trifluoromethyl)piperidine-1-yl)pyridine-3-yl)amino)benzyl)pyrrolidine-3-carboxamide (406) JPEG2026063193000388.jpg31151

[0876] Compound 406 (72.4 mg) was prepared according to the procedure in 363-3 from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 2,3-dimethyl-4-(4-methylpiperidine-1-yl)aniline (73 mg, 0.33 mmol), Pd2(dba)3 (2.5 mg, 2.5 mmol), X-Phos (6.0 mg, 12.5 mmol), and Cs2CO3 (122 mg, 0.38 mmol) as a purple powder with a total yield of 31.5%. 1H NMR (300 MHz, DMSO-d6) δ 8.33 (t, J = 5.8 Hz, 1H), 7.94 (d, J= 2.8 Hz, 1H), 7.71 (s, 1H), 7.56 (s, 1H), 7.35 (dd, J = 8.9, 2.8 Hz, 1H), 7.06 - 6.97 (m, 2H), 6.84 (d, J = 9.0 Hz, 1H), 6.80 - 6.73 (m, 2H), 4.32 - 4.21 (m, 2H), 4.13 (d, J = 5.7 Hz, 2H), 3.39 (t, J = 8.6 Hz, 1H), 3.26 - 3.14 (m, 2H), 2.76 (td, J = 12.5, 2.2 Hz, 2H), 2.61 - 2.52 (m, 1H), 2.33 - 2.21 (m, 2H), 1.90 - 1.80 (m, 2H), 1.44 (qd, J = 12.5, 4.2 Hz, 2H). Mass(m / z): 435.4 [M+H] +

[0877] N-(4-((2,6-dimethyl-4-(4-methylpiperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (407) JPEG2026063193000389.jpg99151

[0878] Compound 407 (8.6 mg) was prepared according to the procedure for compound 397 from N-(4-(aminomethyl)phenyl)-2,6-dimethyl-4-(4-methylpiperidine-1-yl)aniline (53 mg, 0.16 mmol), 5-oxopyrrolidine-3-carboxylic acid (25.4 mg, 0.20 mmol), DIEA (62 mg, 0.48 mmol), and HATU (76 mg, 0.20 mmol) as a pale yellow solid with a total yield of 13.7%. 1H NMR (400 MHz, DMSO-d6) δ 8.32 (t, J = 5.5 Hz, 1H), 7.58 (s, 1H), 7.35 - 7.10 (m, 3H), 6.97 (d, J = 8.4 Hz, 2H), 6.34 (d, J = 8.2 Hz, 2H), 4.13 - 4.09 (m, 2H), 3.63 - 3.58 (m, 2H), 3.37 (d, J = 8.9 Hz, 1H), 3.24 - 3.16 (m, 2H), 2.28 (dd, J = 8.5, 4.2 Hz, 2H), 2.11 (s, 6H), 1.86 - 1.77 (m, 2H), 1.68 - 1.60 (m, 1H), 1.47 - 1.33 (m, 2H), 0.98 (d, J= 6.4 Hz, 3H). Mass(m / z): 435.3 [M+H] + .

[0879] N-(4-((5-chloro-2-methyl-4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (408) JPEG2026063193000390.jpg103151

[0880] Compound 408 (30.8 mg) was prepared as a yellow powder with a total yield of 18.2% from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (99 mg, 0.33 mmol), 5-chloro-2-methyl-4-(4-(trifluoromethyl)piperidine-1-yl)aniline (126 mg, 0.43 mmol), Pd2(dba)3 (3.0 mg, 3.3 mmol), X-Phos (7.9 mg, 16.5 mmol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure for compound 404. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (t, J = 5.8 Hz, 1H), 7.59 (s, 1H), 7.37 (s, 1H), 7.12 - 7.05 (m, 3H), 7.01 (s, 1H), 6.82 - 6.76 (m, 2H), 4.17 (d, J= 5.6 Hz, 2H), 3.40 (t, J = 8.8 Hz, 1H), 3.28 - 3.13 (m, 4H), 2.70 - 2.63 (m, 2H), 2.32 - 2.26 (m, 2H), 2.15 (s, 3H), 1.94 - 1.87 (m, 2H), 1.67 - 1.57 (m, 2H). Mass(m / z): 509.3 [M+H] + .

[0881] N-(4-((3-fluoro-2-methyl-4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (409) JPEG2026063193000391.jpg95151

[0882] Compound 409 (13.1 mg) was prepared as a yellow powder with a total yield of 8.0% from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (99 mg, 0.33 mmol), 3-fluoro-2-methyl-4-(4-(trifluoromethyl)piperidine-1-yl)aniline (119 mg, 0.43 mmol), Pd2(dba)3 (3.0 mg, 3.3 mmol), X-Phos (7.9 mg, 16.5 mmol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure for compound 404. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (t, J = 5.8 Hz, 1H), 7.59 (s, 1H), 7.43 (s, 1H), 7.08 - 7.01 (m, 2H), 6.91 - 6.81 (m, 2H), 6.75 - 6.68 (m, 2H), 4.15 (d, J = 5.7 Hz, 2H), 3.43 - 3.39 (m, 1H), 3.34 - 3.30 (m, 2H), 3.26 - 3.14 (m, 2H), 2.70 - 2.61 (m, 2H), 2.48 - 2.40 (m, 1H), 2.33 - 2.24 (m, Mass(m / z): 493.3 [M+H] + .

[0883] N-(4-((5-fluoro-2-methyl-4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (410) JPEG2026063193000392.jpg108151

[0884] Compound 410 (28.9 mg) was prepared as a yellow powder with a total yield of 17.6% from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (99 mg, 0.33 mmol), 5-fluoro-2-methyl-4-(4-(trifluoromethyl)piperidine-1-yl)aniline (119 mg, 0.43 mmol), Pd2(dba)3 (3.0 mg, 3.3 mmol), X-Phos (7.9 mg, 16.5 mmol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure for compound 404. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (t, J = 5.8 Hz, 1H), 7.59 (s, 1H), 7.34 (s, 1H), 7.09 - 7.03 (m, 2H), 6.90 (d, J = 9.8 Hz, 1H), 6.83 (d, J= 14.0 Hz, 1H), 6.79 - 6.76 (m, 2H), 4.16 (d, J = 5.7 Hz, 2H), 3.40 (t, J= 8.9 Hz, 1H), 3.34 - 3.30 (m, 2H), 3.25 - 3.13 (m, 2H), 2.72 - 2.63 (m, 2H), 2.43 (dp, J = 12.2, 4.2, 3.8 Hz, 1H), 2.34 - 2.23 (m, 2H), 2.13 (s, 3H), 1.94 - 1.86 (m, 2H), 1.61 (qd, J = 12.4, 4.0 Hz, 2H). Mass(m / z): 493.3 [M+H] + .

[0885] N-(4-((2-fluoro-3-methyl-4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (411) JPEG2026063193000393.jpg93151

[0886] Compound 411 (38.5 mg) was prepared according to the procedure for compound 404 from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (99 mg, 0.33 mmol), 2-fluoro-3-methyl-4-(4-(trifluoromethyl)piperidine-1-yl)aniline (119 mg, 0.43 mmol), Pd2(dba)3 (3.0 mg, 3.3 mmol), X-Phos (7.9 mg, 16.5 mmol), and Cs2CO3 (163 mg, 0.50 mmol) as a white powder with a total yield of 23.8%. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (t, J = 5.7 Hz, 1H), 7.65 (s, 1H), 7.58 (s, 1H), 7.08 - 7.02 (m, 3H), 6.86 - 6.77 (m, 3H), 4.16 (d, J = 5.7 Hz, 2H), 3.40 (t, J = 8.8 Hz, 1H), 3.25 - 3.04 (m, 4H), 2.67 - 2.58 (m, 2H), 2.46 - 2.36 (m, 1H), 2.32 - 2.24 (m, 2H), 2.16 (d, J = 2.7 Hz, 3H), 1.94 - 1.86 (m, 2H), 1.63 (qd, J = 12.4, 3.9 Hz, 2H). Mass(m / z): 493.3 [M+H] + .

[0887] N-(4-((2,3-dimethyl-4-(4-(trifluoromethyl)piperidine-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (412) JPEG2026063193000394.jpg99151

[0888] Compound 412 (10.6 mg) was prepared as a white powder with a total yield of 6.6% from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (99 mg, 0.33 mmol), 2,3-dimethyl-4-(4-(trifluoromethyl)piperidine-1-yl)aniline (107 mg, 0.40 mmol), Pd2(dba)3 (3.0 mg, 3.3 mmol), X-Phos (7.9 mg, 16.5 mmol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure for compound 404. 1H NMR (400 MHz, DMSO-d6) δ 8.34 (t, J = 5.7 Hz, 1H), 7.58 (s, 1H), 7.34 (s, 1H), 7.01 - 6.97 (m, 2H), 6.95 (d, J = 8.2 Hz, 1H), 6.89 (d, J= 8.8 Hz, 1H), 6.64 - 6.57 (m, 2H), 4.13 (d, J = 5.7 Hz, 2H), 3.39 (t, J= 8.8 Hz, 1H), 3.25 - 3.15 (m, 2H), 3.10 - 3.02 (m, 2H), 2.69 - 2.59 (m, 3H), 2.48 - 2.36 (m, 1H), 2.33 - 2.25 (m, 2H), 2.20 (s, 3H), 2.06 (s, 3H), 1.94 - 1.86 (m, 2H), 1.71 - 1.60 (m, 2H). Mass(m / z): 489.4 [M+H] + .

[0889] N-(4-((4-(4,4-dimethylcyclohexyl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (413) JPEG2026063193000395.jpg167151

[0890] Step 1. Preparation of 4,4-dimethyl-4'-nitro-2,3,4,5-tetrahydro-1,1'-biphenyl (413-3). K2CO3 (6.24 g, 45 mmol) was added to a mixture of 1,4-dioxane and 1,4-dioxane, 1-bromo-4-nitrobenzene (6.06 g, 30 mmol), 2-(4,4-dimethylcyclohexa-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.52 g, 36 mmol), and Pd(PPh3)4 (690 mg, 0.6 mmol) in 100 mL of water. The mixture was stirred overnight at 110°C under Ar, and then the reaction was cooled to room temperature (RT). The mixture was treated with ELISA (100 mL) and washed with H2O (3 x 200 mL) and brine (200 mL). The organic layer was dried (Na2SO4) and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-10% Âxane) to obtain the desired product as a pale yellow oil (6.5 g, 94.0%).

[0891] Step 2. Preparation of 4-(4,4-dimethylcyclohexyl)aniline (413-4). 10% Pd / C (114.7 mg, 0.11 ml) and 1.0 mL of concentrated HCl were added to a solution of 4,4-dimethyl-4'-nitro-2,3,4,5-tetrahydro-1,1'-biphenyl (2.5 g, 10.8 mmol) in THF (50 mL). The reaction mixture was then stirred overnight at 60°C under a hydrogen atmosphere. The reaction mixture was cooled to room temperature (RT). Pd / C was filtered off. The filtrate was concentrated under vacuum. 50 mL of water was added, and the pH of the solution was adjusted to 8-9 with sod...

Claims

1. A compound of formula I, or its salt, hydrate, or stereoisomer. 【Chemistry 1】 (In the formula, R1 is OH, NH ２ , or NR'R'', where R' and R'' are independently substituted or unsubstituted C1-C9 alkyl groups or substituted or unsubstituted aryl groups, and optionally they may be linked together to form substituted or unsubstituted C4-C9 heterocycles; R2 to R9 are independently H, halogen, C1-C6 alkoxy, amino, C1-C6 alkylamino, di(C1-C6 alkyl)amino, or substituted or unsubstituted C1-C6 alkyl; R10 is H, halogen, C1-C6 alkoxy, amino, C1-C6 alkylamino, di(C1-C6 alkyl)amino, or unsubstituted C1-C6 alkyl; R11 is either H or OH; R12 is C1-C6 alkoxy, amino, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C1-C6 alkanoyl, carbamoyl, carboxyl, -C(O)-NR''' (wherein R''' is H or CH ３ It is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C9 cycloalkyl, or a substituted or unsubstituted C3-C9 heterocycloalkyl; and, X1-X5 and Y1-Y5 are independently either C or N.

2. R1 is NR'R'', where R' and R'' are linked to form a substituted or unsubstituted piperidine-1-yl; R2 to R9 are independently H, halogen, or substituted or unsubstituted C1 to C4 alkyl; R10 is H, a halogen, or an unsubstituted C1-C4 alkyl; R11 is either H or OH; R12 is 1-ethyl-pyrrolidine-2-on-4-yl; or, The above X1 to X5 and Y1 to Y5 are as follows: The values ​​of X1 to X4 (0, 1, 2, or 3) and Y1 to Y4 (0, 1, 2, or 3) are N; The values ​​of X1 to X4 (0, 1, or 2) and Y1 to Y4 (0, 1, or 2) are N; Y2 and X4, or Y2 and Y4, or X2 and Y2, or X2 and Y4, or X4 and X2, or X4 and Y4 alone are N; or X2, X3, X4, Y2 or Y4 are defined as N, The compound according to claim 1.

3. The compound according to claim 1, wherein R1 is NR'R'', where R' and R'' are linked to form a substituted or unsubstituted piperidine-1-yl.

4. R1 is NR'R'', where R' and R'' are linked together to form piperidine-1-yl, 4-methylpiperidine-1-yl, or 4-CF ３ The compound according to claim 1, which forms piperidine-1-yl.

5. The compound according to claim 3, wherein R2 to R9 are independently H, a halogen, or a substituted or unsubstituted lower alkyl group; and R10 is H, a halogen, or an unsubstituted C1 to C4 alkyl group.

6. The compound according to claim 5, wherein R2 to R9 are independently H, halogen, C1 to C4 alkyl, or F-substituted C1 to C4 alkyl; and R10 is H, halogen, or unsubstituted C1 to C4 alkyl.

7. The compound according to claim 3, wherein R2 to R10 are H.

8. The compound according to any one of claims 3 to 7, wherein R11 is H.

9. The compound according to any one of claims 3 to 7, wherein R12 is a substituted or unsubstituted C3-C9 cycloalkyl group, or a substituted or unsubstituted C3-C9 heterocycloalkyl group.

10. The compound according to any one of claims 3 to 7, wherein R12 is pyrrolidine-2-on-4-yl, 1-methyl-pyrrolidine-2-on-4-yl, or 1-ethyl-pyrrolidine-2-on-4-yl.

11. The compound according to any one of claims 3 to 7, wherein 0, 1, 2, or 3 of X1 to X4 and 0, 1, 2, or 3 of Y1 to Y4 are N.

12. The compound according to any one of claims 3 to 7, wherein 0, 1, or 2 of X1 to X4 and 0, 1, or 2 of Y1 to Y4 are N.

13. The compound according to any one of claims 3 to 7, wherein zero of X1 to X4 and zero of Y1 to Y4 are N.

14. The compound according to any one of claims 3 to 7, wherein Y2 and X4, or Y2 and Y4, or X2 and Y2, or X2 and Y4, or X4 and X2, or X4 and Y4 is N.

15. The compound according to any one of claims 3 to 7, wherein only X2, X3, X4, Y2, or Y4 is N.

16. Compounds having a structure selected from the following: Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14

17. The compound according to claim 16, having a structure selected from the following: Table 2

18. Compounds having a structure selected from the following: Table 3-1 Table 3-2 Table 3-3 Table 3-4 Table 3-5 Table 3-6 Table 3-7 Table 3-8 Table 3-9 Table 3-10 Table 3-11 Table 3-12 Table 3-13 Table 3-14 Table 3-15 Table 3-16 Table 3-17 Table 3-18

19. The compound according to claim 18, having a structure selected from the following: Table 4

20. The compound according to claim 18, having a structure selected from the following: Table 5

21. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1, 2, and 16 to 20, and one or more pharmaceutically acceptable excipients, in a predetermined unit dosage form.

22. Use of a composition comprising the compounds according to claims 1, 2 and 21-26 or the compounds according to claims 1, 2 and 16-20 in the manufacture of a pharmacopoeia for inhibiting ferroptosis activity or for modulating or inhibiting a disease associated with ferroptosis dysregulation in persons who require it.

23. The use according to claim 22, wherein the disease associated with ferroptosis dysregulation is selected from neuropathy, ischemia-reperfusion injury, acute renal failure, and cancer.

24. A composition comprising the compounds according to claims 1, 2 and 16-20 or the compounds according to claims 1, 2 and 21-26, for inhibiting ferroptosis activity in persons who need it, or for modulating or inhibiting diseases associated with ferroptosis dysregulation, or for the manufacture of such a medicament in persons who need it.

25. The compound or composition according to claim 24, wherein the disease associated with ferroptosis dysregulation is selected from neuropathy, ischemia-reperfusion injury, acute renal failure, and cancer.

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