HK40082404A - Ferroptosis inhibitors–diarylamine para-acetamides - Google Patents

Description

Iron death inhibitors diarylamine para-acetamides

Brief introduction to the drawings

Iron death is a type of programmed cell death that is iron dependent and characterized by the accumulation of lipid peroxides, and is genetically and biochemically distinct from other forms of regulated cell death such as apoptosis, autophagy, and necrosis. Disregulated iron death is associated with a number of diseases, including neuropathy, ischemia reperfusion injury, acute renal failure, and cancer.

Summary of The Invention

The present invention provides compounds and prodrugs thereof which modulate or inhibit iron death activity, or modulate or inhibit diseases associated with dysregulation of iron death, such as neuropathy, ischemia reperfusion injury, acute renal failure, and cancer, which hydrolyze, typically in the gut or blood, to produce the corresponding compounds/inhibitors.

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

wherein:

R1-R11 are independently H, a substituted or unsubstituted heteroatom or substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterohydrocarbyl;

r12 is a substituted or unsubstituted heteroatom, or a substituted or unsubstituted hydrocarbyl, or a substituted or unsubstituted heterohydrocarbyl;

R11-R-12 may be linked to form a substituted or unsubstituted C3-C18 or C3-C10 or C3-C6 heterocyclic ring; and is

X1-X5 and Y1-Y5 are independently C or N.

In an embodiment:

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;

r1 is substituted or unsubstituted OH or NH ₂ Substituted or unsubstituted C1-C9 alkyl, or substituted or unsubstituted C1-C9 heteroalkyl;

r1 is substituted or unsubstituted OH or NH ₂ ；

R1 is NR 'R ", wherein R' and R" are independently substituted or unsubstituted hydrocarbyl, or substituted or unsubstituted heterohydrocarbyl, which may be joined to form an optionally substituted C4-C9 heterocyclic ring;

R1 is NR ' R ' ' forming a substituted or unsubstituted piperidin-1-yl group, such as 4-CF ₃ Piperidin-1-yl;

R2-R10 are independently H, halide, substituted or unsubstituted OH or NH ₂ Or substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

R2-R10 are independently H, halide, or substituted or unsubstituted lower alkyl, such as F-substituted C1-C4 alkyl;

R2-R10 are H;

r11 is H, OH or substituted or unsubstituted C1-C4 alkyl;

r11 is H or OH;

r11 is H;

r12 is substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl, or substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

r12 is substituted or unsubstituted C3-C9 cycloalkyl, substituted or unsubstituted C3-C9 heterocycloalkyl, substituted or unsubstituted C5-C9 aryl, or substituted or unsubstituted C5-C9 heteroaryl;

r12 is 1-ethyl, pyrrolidin-2-on-4-yl;

R11-R12 are joined to form a substituted or unsubstituted C3-C10 heterocycle;

R11-R12 are joined to form a C5-C6 heterocyclic ring, such as a substituted or unsubstituted piperazin-2-one, such as wherein position 4 is substituted with methyl or ethyl;

0, 1, 2 or 3 of X1-X4, and 0, 1, 2 or 3 of Y1-Y4 are N;

0, 1 or 2 of X1-X4, and 0, 1 or 2 of Y1-Y4 are N;

only Y2 and X4, or Y2 and Y4, or X2 and Y2, or X2 and Y4, or X4 and X2, or X4 and Y4 are N; or

Only X2, X3, X4, Y2 or Y4 is N; or

Any combination of the foregoing substituents.

In one aspect, the present invention provides a compound disclosed herein, or a salt, hydrate, or stereoisomer thereof:

in one aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I (supra) and one or more pharmaceutically acceptable excipients in a predetermined unit dosage form.

In one aspect, the present invention provides the use of a compound or composition disclosed herein in the manufacture of a medicament for inhibiting iron death activity, or modulating or inhibiting diseases associated with dysregulation of iron death, such as neuropathy, ischemia reperfusion injury, acute renal failure, and cancer, in a human in need thereof.

In one aspect, the present invention provides a compound or composition disclosed herein for use in inhibiting iron death activity, or modulating or inhibiting diseases associated with dysregulation of iron death, such as neuropathy, ischemia reperfusion injury, acute renal failure and cancer, in a human in need thereof, or for use in the preparation of a medicament thereof for use in a human in need thereof.

In one aspect, the invention provides a method comprising inhibiting iron death activity, or modulating or inhibiting diseases associated with dysregulation of iron death, such as neuropathy, ischemia reperfusion injury, acute renal failure, and cancer, in a human in need thereof using a compound or composition disclosed herein, and optionally detecting an improvement in the health or condition of the human resulting therefrom.

The present invention includes all combinations of particular embodiments recited herein as if each combination had been laboriously recited.

Description of specific embodiments of the invention

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

The term "alkyl" refers to a hydrocarbon group selected from straight and branched chain saturated hydrocarbon groups having 1 to 18 or 1 to 12 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 sec-butyl ("s-Bu"), and 1,1-dimethylethyl or tert-butyl ("t-Bu"). Other examples of alkyl groups include 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl and 3,3-dimethyl-2-butyl groups.

Lower alkyl means 1 to 8, preferably 1 to 6, more preferably 1 to 4 carbon atoms; lower alkenyl or alkynyl means 2-8, 2-6 or 2-4 carbon atoms.

The term "alkenyl" refers to a hydrocarbon group selected from straight and branched chain hydrocarbon groups comprising at least one C = C double bond and 2-18 or 2-12 or 2-6 carbon atoms. Examples of alkenyl groups may be selected from vinyl (ethenyl) or vinyl (vinyl), prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-2-enyl, but-3-enyl, but-1,3-dienyl, 2-methylbut-1,3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hex-1,3-dienyl groups.

The term "alkynyl" refers to a hydrocarbon group selected from straight and branched chain hydrocarbon groups containing at least one C.ident.C triple bond and 2 to 18 or 2 to 12 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.

The term "cycloalkyl" refers to a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups containing monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups. For example, a cycloalkyl group may have 3 to 12 or 3 to 8 or 3 to 6 carbon atoms. Even further, for example, a cycloalkyl group can be a monocyclic group of 3 to 12 or 3 to 8 or 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl groups. Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged as a bicyclic ring selected from the group consisting of [4,4], [4,5], [5,5], [5,6] and [6,6] ring systems or as a bridged bicyclic ring selected from the group consisting of bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane and bicyclo [3.2.2] nonane. The ring may be saturated or have at least one double bond (i.e., partially unsaturated), but is not fully conjugated, and is not aromatic, as defined herein.

The term "aryl" refers herein to a group selected from: 5-and 6-membered carbocyclic aromatic rings, for example, phenyl; bicyclic ring systems such as 7-12 membered bicyclic ring systems, wherein at least one ring is carbocyclic and aromatic, selected from, for example, naphthalene, indane, and 1,2,3,4-tetrahydroquinoline; and tricyclic ring systems such as 10-15 membered tricyclic ring systems in which at least one ring is carbocyclic and aromatic, e.g., fluorene.

For example, the aryl group is selected from 5-and 6-membered carbocyclic aromatic rings fused to a 5-to 7-membered cycloalkyl or heterocyclic ring (optionally containing at least one heteroatom selected from N, O and S), provided that when the carbocyclic aromatic ring is fused to the heterocyclic ring, the point of attachment is at the carbocyclic aromatic ring, and when the carbocyclic aromatic ring is fused to the cycloalkyl group, the point of attachment may be at the carbocyclic aromatic ring or at the cycloalkyl group. A divalent group formed from a substituted benzene derivative and having a free valence at a ring atom is named a substituted phenylene group. Divalent groups derived from monovalent polycyclic hydrocarbon groups (whose name ends in a "-yl group") by removing one hydrogen atom from a carbon atom having a free valence are named by adding a "-ylidene (idene)" to the name of the corresponding monovalent group, for example, a naphthyl group having two points of attachment is called naphthylene.

The term "halogen" or "halo" refers to F, cl, br or I.

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

The term "heteroaryl" refers to a group selected from:

a 5-to 7-membered aromatic monocyclic ring comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon;

an 8-to 12-membered bicyclic ring comprising 1, 2, 3, or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

an 11-to 14-membered tricyclic ring comprising 1, 2, 3, or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

For example, heteroaryl groups include 5-to 7-membered heterocyclic aromatic rings fused to 5-to 7-membered cycloalkyl rings. For such fused bicyclic heteroaryl ring systems wherein only one ring contains at least one heteroatom, the point of attachment may be at the heteroaromatic ring or at the cycloalkyl ring.

When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In certain embodiments, the total number of S and O atoms in the heteroaryl group is no more than 2. In certain embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed 1.

Examples of heteroaryl groups include, but are not limited to (numbered from the attachment position of designated priority 1) pyridyl (such as 2-pyridyl, 3-pyridyl or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, thienyl, triazinyl, benzothienyl, furyl, benzofuryl, benzimidazolyl, indolyl, isoindolyl, indolinyl, phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl, quinolyl, isoquinolyl, pyrazolyl, pyrrolopyridinyl (such as 1H-pyrrolo [2,3-b ] pyridin-5-yl), pyrazolopyridyl (such as 1H-pyrazolo [3,4-b ] pyridin-5-yl), benzoxazolyl (such as benzo [ d ] oxazol-6-yl), pteridinyl, purinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl, quinolyl, isoquinolyl, pyrazolyl, pyrrolopyridinyl (such as 1H-pyrrolo [ 5283-b ] pyridin-5-yl), pyrazolopyridyl (such as 1H-pyrazolo [3,4-b ] pyridin-5-yl, benzoxazolyl (such as benzo [ d ] oxazol-6-yl), pteridinyl, and the like 1-oxa-2,3-oxadiazolyl, 1-oxa-2,4-oxadiazolyl, 1-oxa-2,5-oxadiazolyl, 1-oxa-3,4-oxadiazolyl, 1-thia-2,3-oxadiazolyl, 1-thia-2,4-oxadiazolyl, 1-thia-2,5-oxadiazolyl, 1-thia-3,4-oxadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (such as benzo [ d ] thiazol-6-yl), indazolyl (such as 1H-indazol-5-yl) and 5,6,7,8-tetrahydroisoquinoline.

The term "heterocyclic" or "heterocycle" or "heterocyclyl" refers to rings selected from 4-to 12-membered monocyclic, bicyclic, and tricyclic saturated and partially unsaturated rings, which contain at least one carbon atom in addition to 1,2, 3, or 4 heteroatoms selected from oxygen, sulfur, and nitrogen. "heterocycle" also refers to a 5-to 7-membered heterocycle fused to a 5-, 6-, and/or 7-membered cycloalkyl, carbocyclic aromatic or heteroaromatic ring comprising at least one heteroatom selected from N, O and S, provided that when the heterocycle is fused to a carbocyclic aromatic or heteroaromatic ring, the point of attachment is at the heterocycle, and when the heterocycle is fused to a cycloalkyl, the point of attachment can be at the cycloalkyl or the heterocycle.

"heterocycle" also refers to an aliphatic spirocycle containing at least one heteroatom selected from N, O and S, provided that the point of attachment is at the heterocycle. The ring may be saturated or have at least one double bond (i.e., partially unsaturated). The heterocyclic ring may be substituted by oxo. The point of attachment may be a carbon or heteroatom in a heterocycle. Heterocycles are not heteroaryl as defined herein.

Examples of heterocycles include, but are not limited to (numbered from the attachment position designating priority 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, oxetanyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithiocyclobutyl, 3524-dithiocyclobutyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, oxathietanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thietanyl, 1,4-oxathietanyl (4984-oxathianyl) 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxazepanyl, 1,4-dithiacycloheptyl, 1,4-thiazepanyl and 1,4-diazepanyl, 1,4-dithiacycloyl, 1,4-azathiepinyl, oxazepanyl, diazepitrienyl, thiazepanyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolyl, 2H-pyranyl, 564H-pyranyl, 5623 zzanyl, 5662 zzft 6223-dioxanyl, 62 zxft 626262626262-dioxanyl, pyrazolinyl, pyrazolidinyl, dithiacyclohexylyl, dithiacyclopentyl, pyrazolidinylimidazolinyl, pyrimidinonyl, 1,1-dioxo-thiomorpholinyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl, and azabicyclo [2.2.2] hexanyl. Substituted 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.

The term "fused ring" refers herein to a polycyclic ring system, e.g., a bicyclic or tricyclic ring system, wherein the two rings share only two ring atoms and one bond in common. Examples of fused rings may include: fused bicycloalkyl rings such as those described above having from 7 to 12 ring atoms arranged as a bicyclic ring selected from the group consisting of [4,4], [4,5], [5,5], [5,6] and [6,6] ring systems; a fused bicyclic aryl ring such as a 7-to 12-membered bicyclic aryl ring system as described above, a fused tricyclic aryl ring such as a 10-to 15-membered tricyclic aryl ring system as described above; a fused bicyclic heteroaryl ring such as an 8-to 12-membered bicyclic heteroaryl ring as described above, a fused tricyclic heteroaryl ring such as an 11-to 14-membered tricyclic heteroaryl ring as described above; and fused bicyclic or tricyclic heterocyclyl rings as described above.

In embodiments, the substituents are selected from optionally substituted heteroatoms and optionally substituted, optionally heteroj acked, optionally cyclic C1-C18 hydrocarbyl, in particular wherein optionally substituted, optionally heteroj acked, optionally cyclic C1-C18 hydrocarbyl is optionally substituted, optionally heteroj acked, optionally cyclic alkyl, alkenyl or alkynyl, or optionally substituted, optionally heteroj acked aryl; and/or the optionally substituted heteroatom is halogen, optionally substituted hydroxy (such as alkoxy, aryloxy), optionally substituted acyl (such as formyl, alkanoyl, carbamoyl, carboxy, acylamino), optionally substituted amino (such as amino, alkylamino, dialkylamino, acylamino, sulfonamido), optionally substituted thiol (such as mercapto, alkylthiol, arylthiol), optionally substituted sulfinyl or sulfonyl (such as alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl), nitro or cyano.

In embodiments, the substituents are selected from: 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 (NH 2) = NH, -NR ' C (NH 2) = NH, -NH-C (NH 2) = NR ', -S (O) R ', -SO2NR ' R ', -NR ' SO2R ', -CN ' and-NO 2, -N3, -CH (Ph 2), perfluoro (C1-C4) alkoxy and-C1-C4 alkyl, with a number of substitutions ranging from zero to preferably from zero, and NO2, and preferably from zero to zero. R ', R ", and R'" each independently refer to hydrogen, unsubstituted (C1-C8) alkyl and heteroalkyl, C1-C8 alkyl and heteroalkyl substituted with one to three halogens, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl- (C1-C4) alkyl groups. When R' and R "are attached to the same nitrogen atom, they may combine with the nitrogen atom to form a 5-, 6-, or 7-membered ring. Thus, -NR' R "includes 1-pyrrolidinyl and 4-morpholinyl," alkyl "includes groups such as trihaloalkyl (e.g., -CF3 and-CH 2CF 3), and when the aryl group is 1,2,3,4-tetrahydronaphthalene, it may be substituted with: a substituted or unsubstituted (C3-C7) spirocycloalkyl group. The (C3-C7) spirocycloalkyl group may be substituted in the same manner as defined herein for "cycloalkyl".

Preferred substituents are selected from: halogen, -R ', -OR ', = O, -NR ' R ', -SR ', -SiR ' 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 ', -SO2NR ' R ', -NR ' SO2R, -CN and-NO 2, perfluoro (C1-C4) alkoxy and perfluoro (C1-C4) alkyl, wherein R ' and R ' are as defined above.

Preferred substituents are disclosed herein and exemplified in the tables, structures, examples and claims, and can be applied to different compounds of the invention, i.e. the substituent of any given compound can be used in combination with other compounds.

In particular embodiments, suitable substituents are independently substituted or unsubstituted heteroatoms, substituted or unsubstituted 0-3 heteroatom C1-C6 alkyl, substituted or unsubstituted 0-3 heteroatom C2-C6 alkenyl, substituted or unsubstituted 0-3 heteroatom C2-C6 alkynyl, or substituted or unsubstituted 0-3 heteroatom C6-C14 aryl, wherein each heteroatom is independently oxygen, phosphorus, sulfur, or nitrogen.

In more specific embodiments, suitable substituents are independently aldehyde, aldimine, alkanoyloxy, alkoxy, alkoxycarbonyl, alkoxy, alkyl, amine, azo, halogen, carbamoyl, carbonyl, carboxamido, carboxyl, cyano (cyanoyl), ester, halo, haloformyl, hydroperoxy, hydroxyl, imine, isocyanide, isocyanate (isocyanide), N-t-butoxycarbonyl, nitrate, nitrile, nitrite, nitro, nitroso, phosphate, phosphonyl, sulfide, sulfonyl, sulfo, mercapto, thiol, thiocyano (thiocyanyl), trifluoromethyl, or trifluoromethyl ether (OCF 3).

The compounds may contain asymmetric centers and may therefore exist as enantiomers. Where the compounds have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. It is intended to include all such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers. All stereoisomers of the compounds and/or pharmaceutically acceptable salts thereof are intended to be included. Unless specifically mentioned otherwise, reference to one isomer applies to any possible isomer. Whenever the isomeric composition is not specified, all possible isomers are included.

The term "substantially pure" means that the stereoisomer of interest contains no more than 35%, such as no more than 30%, further such as no more than 25%, even further such as no more than 20% by weight of any other stereoisomer. In certain embodiments, the term "substantially pure" means that the stereoisomer of interest contains no more than 10%, e.g., no more than 5%, such as no more than 1%, by weight of any other stereoisomer.

When a compound contains an olefinic double bond, such double bond is intended to include both E and Z geometric isomers, unless otherwise specified.

Some compounds may have different points of attachment of hydrogen, known as tautomers. For example, containing carbonyl-CH ₂ Compounds of the C (O) -group (keto form) can undergo tautomerization to form a hydroxy-CH = C (OH) -group (enol form). Where applicable, the individual keto and enol forms as well as mixtures thereof are also intended to be included.

It may be advantageous to separate the reaction products from each other and/or from the starting materials. The desired product of each step or series of steps is isolated and/or purified (hereinafter referred to as isolated) to the desired degree of homogeneity by techniques commonly used in the art. Typically, such separation involves heterogeneous extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography may involve any number of methods, including, for example: reverse phase and normal phase chromatography; size exclusion chromatography; ion exchange chromatography; high, medium and low pressure liquid chromatography methods and apparatus; small-scale analytical chromatography; simulated moving bed ("SMB") chromatography, and preparative thin or thick layer chromatography, as well as small scale thin layer and flash chromatography. Those skilled in the art will apply the techniques most likely to achieve the desired separation.

Mixtures of diastereomers may be separated into their individual diastereomers on the basis of their physicochemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated as follows: the enantiomeric mixtures are converted into diastereomeric mixtures by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), the diastereomers are separated and the individual diastereomers are converted (e.g., hydrolyzed) into the corresponding pure enantiomers. Enantiomers can also be separated by using a chiral HPLC column.

Single stereoisomers, e.g. substantially pure enantiomers, may be obtained using methods such as diastereoisomeric resolution of racemic mixtures using optically active resolving agents. The racemic mixture of chiral compounds of the present invention can be separated and isolated by any suitable method, including: (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other means, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers and conversion to pure stereoisomers, and (3) separation of substantially pure or enriched stereoisomers directly under chiral conditions.

"pharmaceutically acceptable salts" include, but are not limited to, salts with inorganic acidsSalts formed with acids selected from, for example, hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfinates and nitrates; and salts with organic acids selected from, for example, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, alkanoates (such as acetate and with HOOC- (CH) ₂ ) n-COOH, wherein n is selected from 0-4). Similarly, examples of pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.

Alternatively, if the compound is obtained as an acid addition salt, the free base may be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, may be produced as follows: according to the conventional method for preparing an acid addition salt from a base compound, a free base is dissolved in a suitable organic solvent and the solution is treated with an acid. Those skilled in the art will recognize a variety of synthetic methods that may be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

"treating", "treatment" or "treatment" refers to administering at least one compound and/or at least one stereoisomer thereof and/or at least one pharmaceutically acceptable salt thereof to a subject considered in need thereof.

By "effective amount" is meant the amount of such at least one compound and/or at least one stereoisomer thereof and/or at least one pharmaceutically acceptable salt thereof: it is effective to "treat" a disease or disorder in a subject, and it will elicit, to some significant extent, the biological or medical response of a tissue, system, animal or human that is sought, such as sufficient to prevent the development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated when administered. The therapeutically effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

The term "at least one substituent" includes, for example, 1 to 4, substituentsSuch as 1 to 3, further 1 or 2 substituents. For example, "at least one substituent R ¹⁶ "herein comprises 1 to 4, such as 1 to 3, further 1 or 2, R selected from those described herein ¹⁶ Substituents of the list.

The subject compounds and stereoisomers thereof and pharmaceutically acceptable salts thereof may be used alone or in combination with at least one other therapeutic agent for treatment. In certain embodiments, the compounds, stereoisomers thereof, and pharmaceutically acceptable salts thereof, may be used in combination with at least one additional therapeutic agent. The compounds and/or one pharmaceutically acceptable salt disclosed herein may be administered with at least one other therapeutic agent in a single dosage form or as separate dosage forms. When administered as separate dosage forms, at least one other therapeutic agent can be administered prior to, concurrently with, or subsequent to the administration of the compound and/or one pharmaceutically acceptable salt disclosed herein.

Also provided is a composition comprising the subject compound and stereoisomers thereof and pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable carrier.

Compositions comprising the subject compounds and stereoisomers thereof and pharmaceutically acceptable salts thereof may be administered in various known ways, such as orally, topically, rectally, parenterally, by inhalation spray, or via implanted reservoirs, although the most suitable route in any given case will depend on the particular host, and the nature and severity of the condition for which the active ingredient is being administered. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The compositions disclosed herein may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art.

The subject compounds and stereoisomers thereof and pharmaceutically acceptable salts thereof may be administered orally in the following dosage forms: solid dosage forms such as capsules, tablets, troches, lozenges, granules and powders, or liquid dosage forms such as elixirs, syrups, emulsions, dispersions and suspensions. The subject compounds disclosed herein and stereoisomers thereof and pharmaceutically acceptable salts thereof may also be administered parenterally in sterile liquid dosage forms such as dispersions, suspensions or solutions. Other dosage forms that may also be used to administer the subject compounds disclosed herein and stereoisomers thereof and pharmaceutically acceptable salts thereof are: ointments, creams, drops, transdermal patches or powders for topical administration, ophthalmic solution or suspension formulations for ocular administration, i.e. eye drops, aerosol sprays or powder compositions for inhalation or intranasal administration, or creams, ointments, sprays or suppositories for rectal or vaginal administration.

Gelatin capsules containing a compound disclosed herein and/or at least one pharmaceutically acceptable salt thereof and a powdered carrier, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like, may also be used. Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be made into sustained release products to provide continuous release of the drug over a period of time. The compressed tablets may be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or may be enteric-coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration may further comprise at least one agent selected from coloring agents and flavoring agents to increase patient acceptance.

In general, water, suitable oils, saline, aqueous dextrose (glucose) and related sugar solutions, and glycols such as propylene glycol or polyethylene glycol may be examples of suitable carriers for parenteral solutions. Solutions for parenteral administration may comprise a water-soluble salt of at least one compound described herein, at least one suitable stabilizer, and, if necessary, at least one buffer substance. Antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid, alone or in combination, may be examples of suitable stabilizers. Citric acid and its salts and sodium EDTA may also be used as examples of suitable stabilizers. In addition, the parenteral solution may further comprise at least one preservative selected from, for example, benzalkonium chloride, methyl and propyl parabens, and chlorobutanol.

The pharmaceutically acceptable carrier is selected, for example, from carriers that are compatible with (and in certain embodiments capable of stabilizing) the active ingredients of the composition and not deleterious to the subject to be treated. For example, a solubilizing agent such as cyclodextrin (which may form a specific, more soluble complex with at least one compound and/or at least one pharmaceutically acceptable salt disclosed herein) may be used as a pharmaceutical excipient for delivery of the active ingredient. Examples of other 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 standard reference texts in the artRemington's Pharmaceutical SciencesOsol.

For administration by inhalation, the subject compounds and stereoisomers thereof and pharmaceutically acceptable salts thereof may be conveniently delivered in an aerosol spray delivery form from a pressurized pack or nebulizer. The subject compounds and stereoisomers thereof and pharmaceutically acceptable salts thereof may also be delivered as powders, which may be formulated and the powder compositions may be inhaled with the aid of an insufflation powder inhaler device. An exemplary delivery system for inhalation may be a Metered Dose Inhalation (MDI) aerosol, which may be formulated as a suspension or solution of the subject compounds disclosed herein and stereoisomers thereof, and pharmaceutically acceptable salts thereof, in at least one suitable propellant selected from, for example, fluorocarbons and hydrocarbons.

For ophthalmic administration, ophthalmic formulations can be formulated with solutions or suspensions of the subject compounds and stereoisomers thereof, and pharmaceutically acceptable salts thereof, in an appropriate ophthalmic vehicle, at appropriate weight percentages such that the subject compounds and stereoisomers thereof, and at least one pharmaceutically acceptable salt thereof, remain in contact with the ocular surface for a sufficient period of time to allow penetration of the compounds into the cornea and interior regions of the eye.

Useful pharmaceutical dosage forms for administering the subject compounds disclosed herein and stereoisomers and pharmaceutically acceptable salts thereof include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injections, and oral suspensions.

The dosage administered will depend on factors such as: age, health and weight of the recipient, extent of disease, type of concurrent treatment (if present), frequency of treatment, and nature of the desired effect. In general, the daily dosage of the active ingredient may vary, for example from 0.1 to 2000 mg per day. For example, 10-500 milligrams once or more times per day may be effective to achieve the desired results.

In certain embodiments, a large number of unit capsules can be prepared as follows: standard hard gelatin capsule halves are each filled with, for example, 100 mg of the subject compound disclosed herein and its stereoisomers in powder form, and pharmaceutically acceptable salts thereof, 150 mg lactose, 50 mg cellulose and 6 mg magnesium stearate.

In certain embodiments, mixtures of the compounds, their stereoisomers and pharmaceutically acceptable salts thereof, digestible oils such as soybean oil, cottonseed oil or olive oil may be prepared and injected by means of a volumetric pump into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried.

In certain embodiments, a large number of tablets may be prepared by conventional procedures such that a dosage unit contains, for example, 100 mg of the compound, its stereoisomers and pharmaceutically acceptable salts 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 increase palatability or delay absorption.

In certain embodiments, parenteral compositions suitable for administration by injection may be prepared as follows: 1.5% by weight of a compound disclosed herein and/or at least an enantiomer, diastereomer or pharmaceutically acceptable salt thereof is stirred in 10% by volume of propylene glycol. The solution was made up to the desired volume with water for injection and sterilized.

In certain embodiments, aqueous suspensions may be prepared for oral administration. For example, an aqueous suspension comprising 100 mg of finely pulverized compound, its stereoisomer, and pharmaceutically acceptable salts thereof, 100 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 gram of sorbitol solution (USP), and 0.025 ml of vanillin per 5 ml can be used.

When the compounds, stereoisomers thereof and pharmaceutically acceptable salts thereof are administered in steps or in combination with at least one other therapeutic agent, the same dosage forms may generally be used. When drugs are administered in a physical combination, the dosage form and route of administration should be selected according to the compatibility of the combined drugs. The term co-administration is therefore to be understood as including the simultaneous or sequential administration of at least two agents or alternatively the administration in the form of a fixed dose combination of at least two active ingredients.

The compounds disclosed herein, stereoisomers thereof and pharmaceutically acceptable salts thereof may be administered as the sole active ingredient or in combination with at least one second active ingredient.

The subject compounds are incorporated into pharmaceutical compositions or formulations. The compositions will contain a pharmaceutically acceptable diluent and/or carrier, i.e., a diluent or carrier that is physiologically compatible and substantially free of pathogenic impurities. Suitable excipients or carriers and methods for preparing administrable compositions are known or apparent to those skilled in the art and are described in more detail in publications such as Remington's Pharmaceutical Science, mack Publishing Co, NJ (1991), and the like. The composition may also be in the form of a controlled or sustained release composition as known in the art. For many applications, the subject compounds are administered for morning/day administration, with the evening being the drug off period.

The subject compounds may be used as such, or in the form of their pharmaceutically acceptable salts such as the hydrochloride, hydrobromide, acetate, sulfate, citrate, carbonate, trifluoroacetate and the like. When the compound contains relatively acidic functional groups, salts may be obtained by addition of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts and the like. When the compound contains a relatively basic functional group, a salt may be obtained by addition of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as salts derived from relatively nontoxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like. Also included are Salts of amino acids such as arginine, and the like, and Salts of organic acids such as glucuronic or galacturonic acids, and the like (see, e.g., berge et al, "Pharmaceutical Salts", journal of Pharmaceutical Science, 1977, 66, 1-19).

The neutral form of the compound may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties (such as solubility in polar solvents), but otherwise the salts are equivalent to the parent form of the compound for purposes of the present invention.

In addition to salt forms, the present invention provides compounds in prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. In addition, 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 slowly converted to compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical agent. Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. For example, they may be more bioavailable by oral administration than the parent drug. The prodrug may also have increased solubility in pharmacological compositions over the parent drug. A variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. One non-limiting example of a prodrug is a compound of the invention that is administered as an ester ("prodrug"), but which is subsequently metabolically hydrolyzed to the carboxylic acid, the active entity.

Certain compounds of the present invention may exist in unsolvated as well as solvated forms (including hydrated forms). In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in either polymorphic or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

Certain subject compounds have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers and various isomers are intended to be included within the scope of the present invention.

The compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds, such as deuterium (e.g., -CD) ₃ 、CD ₂ H or CDH ₂ ) Instead of methyl. For example, the compounds may be treated with radioactive isotopes such as, for example, tritium(s) ((iii)) ³ H) Iodine-125 ( ¹²⁵ I) Or carbon-14 ( ¹⁴ C) Is radiolabeled. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

The compounds are generally administered in a "therapeutically effective amount," i.e., that amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. The term "therapeutically effective amount" includes the amount of such compound: when administered, it is sufficient to prevent the development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated. The therapeutically effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

Contact is typically achieved by administering to the subject an effective amount of one or more compounds having the general formula I (supra), including the various embodiments described above. Administration is generally adjusted to achieve a therapeutic dose of about 0.1 to 50, preferably 0.5 to 10, more preferably 1 to 10 mg/kg, although the optimal dose is compound specific and is generally determined empirically for each compound.

The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in admixture with suitable pharmaceutical excipients. Typical unit dosage forms include pre-filled, pre-metered ampoules or syringes of liquid composition or, in the case of solid compositions, pills, tablets, capsules, lozenges and the like. In such compositions, the mimetic is typically a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight), the balance being various vehicles or carriers and processing aids that are helpful in forming the desired administration form. Preferably, the unit dosage formulation is about 5, 10, 25, 50, 100, 250, 500 or 1,000 mg per unit. In a particular embodiment, the unit dosage forms are packaged in a multi-pack suitable for sequential use, such as a blister pack comprising a sheet of at least 6, 9 or 12 unit dosage forms.

The subject compositions can also be co-formulated and/or co-administered with different compounds for the treatment of applicable indications, to inhibit iron death activity, or to modulate or inhibit diseases associated with dysregulation of iron death, such as neuropathy, ischemia reperfusion injury, acute renal failure, and cancer. In embodiments, suitable indications include cancer, neurological 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, liver, gastrointestinal or pancreatic diseases, avascular necrosis, diabetes, cancer-chemotherapy/radiotherapy-induced cell death and poisoning.

Table 1: active compound (b): structure of the device

Table 2: active compound (b): structure of the product

It was demonstrated that the active compounds inhibit iron death:

table 3: biological activity (RSL 3 induced HT-1080 cell iron death assay (10% FBS):

table 4: biological activity (RSL 3 induced HT-1080 cellular iron death assay (10% FBS):

active compound group I: representative Synthesis

N- (4- ((4- (tert-butyl) -3-fluorophenyl) amino) benzyl) -N-hydroxy-1- (trifluoromethyl) cyclobutane-1-carboxamide (1)

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

And 2. Step 2.

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

And 3. Step 3.

To a solution of (Z) -4- ((4- (tert-butyl) -3-fluorophenyl) amino) benzaldehyde oxime (972 mg, 3.4 mmol) in EtOH (40 mL) was added borane-pyridine (632 mg, 6.8 mmol). 10% HCl (6.8 mL) was then added dropwise at 0 ℃. 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). Will merge Washed with water (20 mL. Times.3) over Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by silica gel column chromatography (MeOH/DCM = 1/40) to yield the desired product (242 mg, 25%) as a yellow solid. Mass (m/z): 289.3 [ M + H ]] ⁺ 。

And 4. Step 4.

1- (trifluoromethyl) cyclobutane-1-carboxylic acid (25.2 mg, 0.15 mmol) was dissolved in DCM (1 mL). The solution was cooled to 0 ℃. Oxalyl chloride (0.0165 mL, 0.195 mmol) and DMF (0.05 mL) were then added. The reaction mixture was stirred for 2h, concentrated under reduced pressure and redissolved in anhydrous CH ₂ Cl ₂ In (1). The solution was used directly in the next step.

Step 5

4- (tert-butyl) -3-fluoro-N- (4- ((hydroxyamino) methyl) phenyl) aniline (20 mg, 0.07 mmol) was dissolved in 1.0 ml THF/H ₂ O (1:1, v/v) and 1.2 ml saturated NaHCO ₃ In aqueous solution. The solution was cooled to 0 ℃ and 1- (trifluoromethyl) cyclobutane-1-carbonyl chloride was added and the mixture was stirred at room temperature for 16 h. The mixture was extracted with EtOAc and the combined organic layers were washed with brine, washed with (Na) ₂ SO ₄ ) Dried and concentrated in vacuo to give the crude product. The residue was purified by preparative TLC (MeOH/DCM = 1/10) to yield 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 ]] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxyadamantane-1-carboxamide (2)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N-hydroxy-N- (4- (pyridin-4-ylamino) benzyl) adamantane-1-carboxamide (3)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N- (4- ((4-fluorophenyl) amino) benzyl) -N-hydroxyadamantane-1-carboxamide (4)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N- (4- ((4- (N, N-diethylsulfamoyl) phenyl) amino) benzyl) -N-hydroxyadamantane-1-carboxamide (5)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxypivalamide (6)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxycyclopropanecarboxamide (7)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N-hydroxy-N- (4- ((4- (trifluoromethyl) phenyl) amino) benzyl) adamantane-1-carboxamide (8)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N-hydroxy-N- (4- (pyridin-4-ylamino) benzyl) pivaloamide (9)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N- (4- ((4-fluorophenyl) amino) benzyl) -N-hydroxypivalamide (10)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N- (4- ((4- (N, N-diethylsulfamoyl) phenyl) amino) benzyl) -N-hydroxypivalamide (11)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxyacetamide (12)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-2,2-dimethylbutanamide (13)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-1-methylcyclopropane-1-carboxamide (14)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-6-methoxy-2,2-dimethylhexanamide (15)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -2,2,2-trifluoro-N-hydroxyacetamide (16)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxycyclopentanecarboxamide (17)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxybenzamide (18)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-1- (trifluoromethyl) cyclobutane-1-carboxamide (19)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-2-methoxy-2-methylpropanamide (20)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-4-methoxy-2,2-dimethylbutanamide (21)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N-hydroxy-2,2-dimethyl-N- (4- ((4- (trifluoromethyl) phenyl) amino) benzyl) butanamide (22)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxynicotinamide (23)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-4-methyltetrahydro-2H-pyran-4-carboxamide (24)

¹ H NMR (400 MHz, CDCl ₃ ) 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 = 9.6 Hz, 2H), 2.23 (d, J = 13.9 Hz, 2H), 1.65-1.48 (m, 2H), 1.31 (s, 12H)。LC-MS (ESI) m/z： 397.2, [M+H] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -3,3,3-trifluoro-N-hydroxy-2,2-dimethylpropionamide (25)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-1-methylcyclohexane-1-carboxamide (26)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -4,4-difluoro-N-hydroxycyclohexane-1-carboxamide (27)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N- (4- ((3- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-2-methoxy-2-methylpropanamide (28)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-1- (trifluoromethyl) cyclopropane-1-carboxamide (29)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-1-methylpiperidine-4-carboxamide (30)

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] ⁺ 。

1-acetyl-N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxypiperidine-4-carboxamide (31)

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] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-2- (2-methoxyethoxy) acetamide (32)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (33)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-4- (pyrrolidin-1-yl) benzamide (34)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺

N- (4- ((3- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-4-methyltetrahydro-2H-pyran-4-carboxamide (35)

¹ H NMR (400 MHz, CDCl ₃ ) 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, 2H), 3.68-3.57 (m, 2H), 2.24 (m, 2H), 1.63-1.53 (m, 2H), 1.31 (s, 9H), 1.25 (s, 3H)。LC-MS (ESI) m/z： 397.3, [M+H] ⁺

N- (4- ((3- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-1-methylcyclopropane-1-carboxamide (36)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺

N- (4- ((3- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-1- (trifluoromethyl) cyclobutane-1-carboxamide (37)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) pivaloamide (38)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) pivaloamide (39)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

1-isopropyl-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) piperidine-4-carboxamide (40)

From 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (30 mg, 0.09 mmol) and 1-isopropylpiperidine-4-carboxylic acid (16 mg, 0.09 mmol) the title compound 40 (13.0 mg) was prepared as a light blue powder in a yield of 41.01%. ¹ H NMR (400 MHz, methanol-d ₄ ) 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] ⁺ 。

N- (4- ((4-cyclohexylphenyl) amino) benzyl) -N-hydroxy-2- (4-methylpiperazin-1-yl) acetamide (41)

¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N- (4- ((4- (diethylamino) phenyl) amino) benzyl) -4- (dimethylamino) -N-hydroxybutyramide (42)

¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (4- ((3- (pyrrolidin-1-yl) phenyl) amino) benzyl) acetamide (43)

¹ H NMR (400 MHz, DMSO-d ₆ ) 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 ]] ⁺ 。

1-methyl-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) piperidine-4-carboxamide (44)

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) the title compound 44 (13.0 mg) was prepared in 31.90% yield as a pale yellow powder. ¹ H NMR (400 MHz, methanol-d ₄ ) 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] ⁺ 。

N-hydroxy-2,2-dimethyl-N- (4- (phenylamino) benzyl) butanamide (45)

¹ H 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 ]] ⁺ 。

N-hydroxy-N- (4- ((4- (trifluoromethyl) phenyl) amino) benzyl) pivaloamide (46)

¹ H 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 ]] ⁺ 。

N-hydroxy-N- (4- (pyridin-2-ylamino) benzyl) pivaloamide (47)

Step 1.4- (pyridin-2-ylamino) benzaldehyde (47-3) preparation: pyridine-2-amine (200 mg, 2.12 mmol), 4-bromobenzaldehyde (433 mg, 2.33 mmol), pd (dppf) ₂ Cl ₂ (264 mg, 0.36 mmol)、Xantphos (368 mg, 0.637 mmol)、Cs ₂ CO ₃ A mixture of (1.73 g, 5.31 mmol) in toluene (20 mL) was stirred at 100 deg.C overnight. After cooling to room temperature, 30 mL water was added. The solid was collected by filtration. The desired product (380 mg) was obtained as a yellow solid.

Step 2 preparation of (E) -4- (pyridin-2-ylamino) benzaldehyde oxime (47-4): the title compound 47-4 (406 mg) was prepared as a crude as a yellow solid in 100% overall yield from 4- (pyridin-2-ylamino) benzaldehyde (380 mg, 1.91 mmol), hydroxylamine hydrochloride (146 mg, 2.1 mmol) according to the procedure of 80-3.

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

Step 4. N-HydroxyPreparation of the group-N- (4- (pyridin-2-ylamino) benzyl) pivaloamide (47): starting from N- (4- ((hydroxyamino) methyl) phenyl) pyridin-2-amine (105 mg, 0.49 mmol), pivaloyl chloride (76 mg, 0.63 mmol), and NaHCO according to the procedure of 1 ₃ An aqueous solution (0.6 ml) prepared the title compound 47 (40 mg) as a white solid in 45% overall yield. ¹ H 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).

N- (4- ((2- (tert-butyl) phenyl) amino) benzyl) -N-hydroxypivalamide (48)

From 2- (tert-butyl) -N- (4- ((hydroxyamino) methyl) phenyl) aniline (94 mg, 0.35 mmol), pivaloyl chloride (55 mg, 0.45 mmol), and NaHCO according to the procedure of 1 ₃ The title compound 48 (50 mg) was prepared as a white solid in aqueous solution (0.42 ml) in 40% overall yield. ¹ H 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).

N- (4- ((3- (tert-butyl) phenyl) amino) benzyl) -N-hydroxypivalamide (49)

From 3- (tert-butyl) -N- (4- ((hydroxyamino) methyl) phenyl) aniline (69 mg, 0.256 mmol), pivaloyl chloride (40 mg, 0.332 mmol), and NaHCO according to the procedure of 1 ₃ The title compound 49 (50 mg) was prepared as a white solid in aqueous solution (0.3 ml) in 40% overall yield. ¹ H 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).

N- (4- ((4- (dimethylamino) phenyl) amino) benzyl) -N-hydroxypivalamide (50)

Step 1.4 preparation of- ((4- (dimethylamino) phenyl) amino) benzaldehyde (50-3): n1, N1-dimethylbenzene-1,4-diamine (100 mg, 0.73 mmol), 4-bromobenzaldehyde (149 mg, 0.8 mmol), pd (dppf) ₂ Cl ₂ (27 mg, 0.03 mmol)、Xantphos (42 mg, 0.07mmol)、Cs ₂ CO ₃ A mixture of (598 mg, 1.83 mmol) in toluene (15 mL) was stirred at 100 deg.C overnight. After cooling to room temperature, 30 ml of water was added. The solid was collected by filtration. The desired product (110 mg) was obtained as a yellow solid.

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

Step 3 the title compound 50-5 (28 mg) was prepared as a yellow solid in 65.4% overall yield 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 in 9% HCl according to the procedure of 1.

Step 4. Synthesis of N-substituted-N-1- (4- ((hydroxyamino) methyl) phenyl) -N4, N4-dimethylbenzene-1,4-diamine (28 mg, 0.11 mmol), pivaloyl chloride (17 mg, 0.14 mmol), and NaHCO according to the procedure of 1 ₃ The title compound 50 (14 mg) was prepared as a white solid in an aqueous solution (0.13 ml) in a total yield of 40%.

N- (4- ((2,4-difluorophenyl) amino) benzyl) -N-hydroxypivalic acid amide (51)

From 2,4-difluoro-N- (4- ((hydroxyamino) methyl) phenyl) aniline (58 mg, 0.23 mmol), pivaloyl chloride (36 mg, 0.3 mmol), and NaHCO according to the procedure of 1 ₃ Dissolving in waterLiquid (0.28 ml) the title compound 51 (28 mg) was prepared as a white solid in 40% overall yield. ¹ H 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).

N-hydroxy-N- (4- ((2,4,6-trifluorophenyl) amino) benzyl) pivaloamide (52)

From 2,4,6-trifluoro-N- (4- ((hydroxyamino) methyl) phenyl) aniline (56 mg, 0.207 mmol), pivaloyl chloride (33 mg, 0.27 mmol), and NaHCO according to the procedure of 1 ₃ The title compound 52 (42 mg) was prepared as a white solid in aqueous solution (0.25 ml) in 40% overall yield. ¹ H NMR (400 MHz, chloroform-d) delta 7.17-7.10 (m, 2H), 6.79-6.71 (m, 2H), 6.70-6.65 (m, 2H), 4.77 (s, 2H), 1.31-1.25 (m, 9H).

N-hydroxy-N- (4- (pyridin-3-ylamino) benzyl) pivaloamide (53)

Starting from N- (4- ((hydroxyamino) methyl) phenyl) pyridin-3-amine (93 mg, 0.43 mmol), pivaloyl chloride (68 mg, 0.56 mmol), and NaHCO according to the procedure of 1 ₃ An aqueous solution (0.51 ml) prepared the title compound 53 (35 mg) as a white solid in an overall yield of 45%. ¹ H 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)。

N-hydroxy-N- (4- ((4-methoxyphenyl) amino) benzyl) pivaloamide (54)

From 4- ((hydroxyamino) methyl) -N- (4-methoxyphenyl) aniline (95 mg, 0.39 mmol), pivaloyl chloride (61 mg, 0.15 mmol), and NaHCO according to the procedure of 1 ₃ The title compound 54 (23 mg) was prepared as a white solid in an aqueous solution (0.47 ml) in a total yield of 40%. ¹ H 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 ]] ⁺ 。

N-hydroxy-N- (4- (mesitylamino) benzyl) pivaloylamide (55)

From N- (4- ((hydroxyamino) methyl) phenyl) -2,4,6-trimethylaniline (108 mg, 0.42 mmol), pivaloyl chloride (66 mg, 0.55 mmol) and NaHCO according to the procedure of 1 ₃ An aqueous solution (0.5 ml) prepared the title compound 55 (50 mg) as a white solid in 40% overall yield. ¹ H NMR (400 MHz, chloroform-d) δ 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), 1.28 (d, J = 1.0 Hz, 9H).

N- (4- ((2,5-bis (trifluoromethyl) phenyl) amino) benzyl) -N-hydroxypivalamide (56)

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 NaHCO according to the procedure of 1 ₃ The title compound 56 (40 mg) was prepared as a white solid in aqueous solution (0.38 ml) in 40% overall yield. ¹ H NMR (400 MHz, chloroform-d) δ 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).

N- (4- ((4- (tert-butyl) -2,6-dimethylphenyl) amino) benzyl) -N-hydroxypivalamide (57)

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 NaHCO according to the procedure of 1 ₃ The title compound 57 (43 mg) was prepared as a white solid in aqueous solution (0.6 ml) in 40% overall yield. ¹ H NMR (400 MHz, chloroform-d) delta 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 ]] ⁺ 。

N-hydroxy-N- (4- (phenylamino) benzyl) pivaloyl amide (58)

A starting material was prepared according to the procedure of 1 from 4- ((hydroxyamino) methyl) -N-phenylaniline (38 mg, 0.18 mmol), pivaloyl chloride (0.028 ml, 0.23 mmol) and NaHCO ₃ The title compound 58 (7 mg) was prepared as a white solid in aqueous solution (0.2 ml) in 40% overall yield. ¹ H NMR (400 MHz, chloroform-d) δ 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).

N-hydroxy-N- (4- ((4- (pyrrolidin-1-yl) phenyl) amino) benzyl) pivaloamide (59)

From 4- ((hydroxyamino) methyl) -N- (4- (pyrrolidin-1-yl) phenyl) aniline (15 mg, 0.05 mmol), pivaloyl chloride (0.01 ml, 0.07 mmol) and NaHCO according to the procedure of 1 ₃ The title compound 59 (10 mg) was prepared as a white solid in aqueous solution (0.06 ml) in 40% overall yield.

N- (4- (phenylamino) benzyl) adamantane-1-carboxamide (60)

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 ]] ⁺ 。

N-hydroxy-N- (4- (phenylamino) benzyl) adamantane-1-carboxamide (61)

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ 。

N- (4- ((4- (tert-butyl) -3-fluorophenyl) amino) benzyl) -N-hydroxy-2-methoxy-2-methylpropanamide (62)

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 ]] ⁺ 。

N- (4- ((4- (tert-butyl) -3-fluorophenyl) amino) benzyl) -N-hydroxy-2- (2- (2-methoxyethoxy) ethoxy) acetamide (63)

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 ]] ⁺ 。

N- (4- ((4- (tert-butyl) -3-fluorophenyl) amino) benzyl) -N-hydroxypivalamide (64)

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 ]] ⁺ 。

3- ((4- ((4- (tert-butyl) -3-fluorophenyl) amino) benzyl) (hydroxy) carbamoyl) azetidine-1-carboxylic acid tert-butyl ester (65)

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 ]] ⁺ 。

4- ((4- ((4- (tert-butyl) -3-fluorophenyl) amino) benzyl) (hydroxy) carbamoyl) -4-methylpiperidine-1-carboxylic acid tert-butyl ester (66)

¹ H 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 ]] ⁺ 。

4- (2- ((4- ((4- (tert-butyl) phenyl) amino) benzyl) (hydroxy) amino) -2-oxoethyl) piperazine-1-carboxylic acid tert-butyl ester (67)

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 ]] ⁺ 。

N-hydroxy-2-methoxy-2-methyl-N- (4- ((4- (trifluoromethyl) phenyl) amino) benzyl) propanamide (68)

¹ H 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 ]] ⁺ 。

N-hydroxy-1-methyl-N- (4- ((4- (trifluoromethyl) phenyl) amino) benzyl) cyclohexane-1-carboxamide (69)

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 ]] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -4- (dimethylamino) -N-hydroxybutyramide (70)

¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-3-morpholinopropanamide (71)

¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

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

¹ H 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 ]] ⁺ 。

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

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 ]] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-1,4-dimethylpiperidine-4-carboxamide (74)

¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -2- (4-ethylpiperazin-1-yl) -N-hydroxyacetamide (75)

¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

2- (4-acetylpiperazin-1-yl) -N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxyacetamide (76)

¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-2- (4- (2,2,2-trifluoroacetyl) piperazin-1-yl) acetamide (77)

¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N- (4- ((4 '-fluoro- [1,1' -biphenyl ] -4-yl) amino) benzyl) -N-hydroxy-2- (4-methylpiperazin-1-yl) acetamide (78)

¹ H NMR (400 MHz, methanol-d ₄ ) 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 ] ] ⁺ 。

N-hydroxy-4-methyl-N- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) piperazine-1-carboxamide (79)

The title compound 79 (13.5 mg) was prepared as a white solid in an overall yield of 33.2%. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺

N- (4- ((4- (tert-butyl) -3-fluorophenyl) amino) benzyl) -N-hydroxy-1-methylcyclopropane-1-carboxamide (80)

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

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

Step 3. To a solution of (Z) -4- ((4- (tert-butyl) -3-fluorophenyl) amino) benzaldehyde oxime (972 mg, 3.4 mmol) in EtOH (40 mL) was added borane-pyridine (632 mg, 6.8 mmol). 10% HCl (6.8 mL) was then added dropwise at 0 ℃. 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 combined organic layers were washed with water (20 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by silica gel column chromatography (MeOH/DCM = 1/40) to yield the desired product (242 mg, 25%) as a yellow solid. Mass (m/z): 289.3 [ M + H ]] ⁺ 。

Step 4. Dissolving 4- (tert-butyl) -3-fluoro-N- (4- ((hydroxyamino) methyl) phenyl) aniline (20 mg, 0.07 mmol) in 1.0 ml THF/H ₂ O (1:1, v/v) and 1.2 ml saturated NaHCO ₃ In aqueous solution. The solution was cooled to 0 ℃ and 1-methylcyclopropane-1-carbonyl chloride (9.1 mg, 0.077 mmol) was added and the mixture was stirred at room temperature for 16 h. The mixture was extracted with EtOAc and the combined organic layers were washed with brine and dried (Na) ₂ SO ₄ ) And concentrated in vacuo to give the crude product. The residue was purified by preparative TLC (MeOH/DCM = 1/10) to yield the desired product as a white solid (8.0 mg, 30.9%). ¹ H NMR (400 MHz, chloroform-d) delta 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 ]] ⁺ 。

N- (4- ((4- (tert-butyl) -3-fluorophenyl) amino) benzyl) -N-hydroxy-4-methyltetrahydro-2H-pyran-4-carboxamide (81)

The title compound 81 (8.6 mg) was prepared as a white solid in 29.6% overall yield from 4- (tert-butyl) -3-fluoro-N- (4- ((hydroxyamino) methyl) phenyl) aniline (20 mg, 0.07 mmol), 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) delta 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 ]] ⁺ 。

N- (4- ((4- (tert-butyl) -3-fluorophenyl) amino) benzyl) -N-hydroxy-2-morpholinoacetamide (82)

The title compound 82 (11 mg) was prepared as a white solid in 37.8% overall yield from 4- (tert-butyl) -3-fluoro-N- (4- ((hydroxyamino) methyl) phenyl) aniline (20 mg, 0.07 mmol), 2-morpholinoacetyl chloride (12.6 mg, 0.077 mmol) according to the procedure for compound 1. ¹ H 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] ⁺ 。

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (4- ((4- (1-methylpiperidin-4-yl) phenyl) amino) benzyl) acetamide (83)

From N- (4- ((hydroxyamino) methyl) phenyl) - [1,1' -biphenyl according to the procedure of 1]-4-amine (30 mg, 0.1 mmol), pivaloyl chloride (16.2 mg, 0.13 mmol) and NaHCO ₃ The title compound 83 (16 mg) was prepared as a white solid in aqueous solution (0.13 ml) in 45% overall yield. ¹ H 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)。

N- (4- ((4- (tert-butyl) -3-fluorophenyl) amino) benzyl) -N-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carboxamide (84)

The title compound 84 (30 mg) was prepared as a yellow solid in 96% overall yield according to the procedure for compound 1 from 4- (tert-butyl) -3-fluoro-N- (4- ((hydroxyamino) methyl) phenyl) aniline (20 mg, 0.07 mmol), 5,6,7,8-tetrahydronaphthalene-2-carbonyl chloride (0.077 mmol). 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 ]] ⁺ 。

N- (4- ((4- (tert-butyl) -3-fluorophenyl) amino) benzyl) -4- (dimethylamino) -N-hydroxybutyramide (85)

Compound 1 was prepared according to the procedure for compound 1 from 4- (tert-butyl) -3-fluoro-N- (4- ((hydroxyamino) methyl) phenyl) aniline (20 mg, 0.07 mmol), 4- (dimethylamino) butyryl chloride (0). 077 mmol) the title compound 85 (2.4 mg) was prepared as a white solid in an overall yield of 8.5%. ¹ H NMR (400 MHz, chloroform-d) delta 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 ]] ⁺ 。

N- (4- ((4- (tert-butyl) -3-fluorophenyl) amino) benzyl) -N-hydroxy-2,3-dihydro-1H-indene-2-carboxamide (86)

The title compound 86 (32 mg) was prepared as a yellow solid in 90% overall yield from 4- (tert-butyl) -3-fluoro-N- (4- ((hydroxyamino) methyl) phenyl) aniline (20 mg, 0.07 mmol), 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 ]] ⁺ 。

N- (4- ((4- (tert-butyl) -3-fluorophenyl) amino) benzyl) -N-hydroxyazetidine-3-carboxamide (87)

The title compound 87 (4.0 mg) was prepared as a white solid in 15.4% overall yield according to the procedure for compound 1 from 4- (tert-butyl) -3-fluoro-N- (4- ((hydroxyamino) methyl) phenyl) aniline (20 mg, 0.07 mmol), 3- (chlorocarbonyl) azetidine-1-carboxylic acid tert-butyl ester (0.077 mmol). ¹ H 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 ] ] ⁺ 。

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

From 4- (tert-butyl) -N- (4- ((hydroxyamino) methyl) phenyl) aniline (20 mg, 0.074 mmol), benzo [ d ] according to the procedure for Compound 1]Thiazole-6-carbonyl chloride (0.077 mmol) the title compound 88 (4.2 mg) was prepared as a white solid in an overall yield of 13.9%. ¹ H NMR (400 MHz, chloroform-d) delta 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] ⁺ 。

N-hydroxy-4-methyl-N- (4- ((4- (trifluoromethyl) phenyl) amino) benzyl) tetrahydro-2H-pyran-4-carboxamide (89)

The title compound 89 (5.4 mg) was prepared as a yellow solid in 13.2% overall yield from 4- ((hydroxyamino) methyl) -N- (4- (trifluoromethyl) phenyl) aniline (28 mg, 0.1 mmol), 4-methyltetrahydro-2H-pyran-4-carbonyl chloride (0.11 mmol) according to the procedure for compound 1. ¹ H NMR (400 MHz, chloroform-d) delta 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 ]] ⁺ 。

N-hydroxy-N- (4- ((6-isopropylpyridin-3-yl) amino) benzyl) pivaloamide (90)

Starting from N- (4- ((hydroxyamino) methyl) phenyl) -6-isopropylpyridin-3-amine (20 mg, 0.08 mmol), pivaloyl chloride (12.3 mg, 0.1 mmol) and NaHCO according to the procedure of 1 ₃ The title compound 90 (12 mg) was prepared as a white solid in aqueous solution (0.1 ml) in 40% overall yield. ¹ H NMR (400 MHz, methanol-d 4) delta 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 ]] ⁺ 。

N-hydroxy-1- (trifluoromethyl) -N- (4- ((4- (trifluoromethyl) phenyl) amino) benzyl) cyclobutane-1-carboxamide (91)

The title compound 91 (7.2 mg) was prepared as a yellow solid in 23.8% overall yield according to the procedure for compound 80. ¹ H NMR (400 MHz, chloroform-d) delta ¹ H NMR (400 MHz, chloroform-d) delta 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 ]] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-2- (4-methylpiperazin-1-yl) acetamide (92)

The title compound 92 (10.8 mg) was prepared as a yellow solid in 26.3% overall yield 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 ] ] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-2-morpholinoacetamide (93)

Prepared according to the procedure for compound 80 in 50.3% overall yield as yellow solidThe title compound 93 (14.8 mg). 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 ]] ⁺

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-4-methylpiperidine-4-carboxamide (94)

The title compound 94 (3.0 mg) was prepared as a yellow solid in 20.3% overall yield 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 ]] ⁺

N- (4- ((4- (tert-butyl) phenyl) amino) -2-methylbenzyl) -N-hydroxypivalamide (95)

The title compound 95 (17.4 mg) was prepared as a yellow solid in 47.1% overall yield 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 ] ] ⁺

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

According to chemical combinationThe procedure of material 80 prepared the title compound 96 (26.5 mg) as a white solid in an overall yield of 61.8%. 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 ]] ⁺

N- (4- ((4- (tert-butyl) -2,6-dimethylphenyl) amino) benzyl) -N-hydroxy-4-methyltetrahydro-2H-pyran-4-carboxamide (97)

The title compound 97 (28 mg) was prepared as a white solid in 41.8% overall yield 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 ]] ⁺

N- (4- ((4- (tert-butyl) -2,6-dimethylphenyl) amino) benzyl) -N-hydroxy-2-methoxy-2-methylpropanamide (98)

The title compound 98 (21.4 mg) was prepared as a white solid in 53.8% overall yield according to 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 ] ] ⁺

N- (4- ((4- (tert-butyl) phenyl) amino) -3-fluorobenzyl) -N-hydroxypivalamide (99)

The title compound 99 (25.6 mg) was prepared as a white solid in 70.3% overall yield 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 ]] ⁺

N-hydroxy-N- (4- ((4-morpholinophenyl) amino) benzyl) pivaloamide (100)

Prepared according to the procedure of 80 from 4- ((hydroxyamino) methyl) -N- (4-morpholinophenyl) aniline (20 mg, 0.067 mmol), pivaloyl chloride (10 mg, 0.087 mmol) and NaHCO ₃ The title compound 100 (13 mg) was prepared as a white solid in aqueous solution (0.08 ml) in 40% overall yield.

N- (4- ([ 1,1' -biphenyl ] -4-ylamino) benzyl) -N-hydroxy-2- (4-methylpiperazin-1-yl) acetamide (101)

The title compound 101 (2.3 mg) was prepared as a white solid in 9.6% overall yield according to the procedure for compound 80. ¹ H 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 ]] ⁺

N- (4- ((4- (tert-butyl) -2,6-dimethylphenyl) amino) benzyl) -2,2,2-trifluoro-N-hydroxyacetamide (102)

The title compound was prepared according to the procedure for compound 80 in an overall yield of 76.1% as a white solid Compound 102 (30 mg). 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 ]] ⁺

N- (4- ((4- (tert-butyl) -2,6-dimethylphenyl) amino) benzyl) -N-hydroxy-1-methylpiperidine-4-carboxamide (103)

The title compound 103 (3.1 mg) was prepared as a white solid in 12.4% overall yield according to the procedure for compound 80. ¹ H 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 ]] ⁺

N- (4- ((4 '-fluoro- [1,1' -biphenyl ] -4-yl) amino) benzyl) -N-hydroxypivalamide (104)

The title compound 104 (19.2 mg) was prepared as a white solid in 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 ]] ⁺ 。

N- (4- ((4-cyclopropylphenyl) amino) benzyl) -N-hydroxypivalamide (105)

The title compound 105 (10.0 mg) was prepared as a white solid in 29.6% overall yield according to the procedure for compound 80. ¹ H NMR (400 MHz, chloroform-d) δ 7.16 (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 ] ] ⁺

N- (4- ((4- (1H-imidazol-1-yl) phenyl) amino) benzyl) -N-hydroxypivalamide (106)

The title compound 106 (13.7 mg) was prepared as a white solid in 37.6% overall yield 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 ]] ⁺

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (4- ((4- (trifluoromethyl) phenyl) amino) benzyl) acetamide (107)

The title compound 107 (13.3 mg) was prepared as a white solid in 35.8% overall yield according to the procedure for compound 80. ¹ H 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 ]] ⁺

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -2- (4-cyclopropylpiperazin-1-yl) -N-hydroxyacetamide (108)

Step 1-3 compound 108-4 (1.45 g) was prepared as a yellow solid in 27% overall yield according to the procedure for compound 80-4. Mass (m/z): 271.3 [ M + H ]] ⁺ 。

Step 4, adding 4- (tert-butyl) -N- (4- ((hydroxyamino) methyl) phenyl) To a solution of aniline (54 mg, 0.2 mmol) and 2- (4-cyclopropylpiperazin-1-yl) acetic acid (47.8 mg, 0.26 mmol) in DMF (1 ml) was added DIEA (0.045 mL, 0.26 mmol). DMT-MM (76.4 mg, 0.26 mmol) was then added and the reaction mixture was stirred at room temperature for 2 hours. 10 mL water was added. The mixture was then extracted with DCM (10 mL × 3). The combined organic layers were washed with water (10 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by preparative TLC (MeOH/DCM = 1/10) to yield the desired product as a white solid (27.2 mg, 31.1%). ¹ H 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 ]] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-2- (4-methyl-3-oxopiperazin-1-yl) acetamide (109)

The title compound 109 (5.0 mg) was prepared as a white solid in 16.3% overall yield according to 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 ]] ⁺

2- (4-benzoylpiperazin-1-yl) -N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxyacetamide (110)

The title compound 110 (7.4 mg) was prepared as a white solid in 49% overall yield according to the procedure for compound 80. ¹ H 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 ] ] ⁺

N-hydroxy-N- (4- ((4- (trifluoromethoxy) phenyl) amino) benzyl) pivaloamide (111)

The title compound 111 (28.2 mg) was prepared as a white solid in 73.6% overall yield 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 ]] ⁺

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

The title compound 112 (14.5 mg) was prepared as a white solid in total yield 33.7% according to the procedure for compound 80. ¹ H 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 ]] ⁺

N-hydroxy-N- (4- ((4 '- (trifluoromethyl) - [1,1' -biphenyl ] -4-yl) amino) benzyl) pivaloamide (113)

The title compound 113 (7.3 mg) was prepared as a white solid in 27.5% overall yield 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 ]] ⁺

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-2- (4-methyl-2-oxopiperazin-1-yl) acetamide (114)

The title compound 114 (5.7 mg) was prepared as a white solid in 13.4% overall yield according to the procedure for compound 108. ¹ H 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 ]] ⁺

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -2- (4- (cyclopropanecarbonyl) piperazin-1-yl) -N-hydroxyacetamide (115)

The title compound 115 (11.4 mg) was prepared as a white solid in 81.9% overall yield 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 ]] ⁺

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-2- (4- (methylsulfonyl) piperazin-1-yl) acetamide (116)

The title compound 116 (20.0 mg) was prepared as a white solid in 42.2% overall yield 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 ]] ⁺

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -2- (3,4-dimethylpiperazin-1-yl) -N-hydroxyacetamide (117)

The title compound 117 (17.7 mg) was prepared as a white solid in 42.0% overall yield 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 ]] ⁺

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -2- (4- (4-fluorophenyl) piperazin-1-yl) -N-hydroxyacetamide (118)

The title compound 118 (9.0 mg) was prepared as a white solid in 30.6% overall yield according to 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 ]] ⁺

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-4-methylpiperazine-1-carboxamide (119)

The title compound 119 (13.3 mg) was prepared as a white solid in 33.6% overall yield 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 ]] ⁺

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (4- ((4- ((tetrahydro-2H-pyran-4-yl) oxy) phenyl) amino) benzyl) acetamide (120)

The title compound 120 (13.4 mg) was prepared as a white solid in 6.6% overall yield 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 ]] ⁺

N- (4- ((4 '- (tert-butyl) - [1,1' -biphenyl ] -4-yl) amino) benzyl) -N-hydroxy-2- (4-methylpiperazin-1-yl) acetamide (121)

The title compound 121 (13.5 mg) was prepared as a white solid in 27.7% overall yield 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 ]] ⁺

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -2- (4- (6-fluoropyridin-3-yl) piperazin-1-yl) -N-hydroxyacetamide (122)

The title compound 122 (2.5 mg) was prepared as a white solid in 8.5% overall yield 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 ]] ⁺

4- (dimethylamino) -N-hydroxy-N- (4- ((4- ((tetrahydro-2H-pyran-4-yl) oxy) phenyl) amino) benzyl) butanamide (123)

¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

4- (dimethylamino) -N-hydroxy-N- (4- ((4- (N-methylacetamido) phenyl) amino) benzyl) butanamide (124)

¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N-hydroxy-N- (4- ((4- (2,2,2-trifluoroethoxy) phenyl) amino) benzyl) pivalamide (125)

The title compound 125 (35.0 mg) was prepared as a white solid in an overall yield of 88.4% according to 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 ]] ⁺

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-2- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) acetamide (126)

The title compound 126 (29.0 mg) was prepared as a white solid in 73.4% overall yield according to 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 ]] ⁺

N- (4- ((4-chlorophenyl) amino) benzyl) -N-hydroxypivalamide (127)

The title compound 127 (33.2 mg) was prepared as a white solid in 98.3% overall yield 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 ]] ⁺

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (4- ((4 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) amino) benzyl) acetamide (128)

The title compound 128 (23.4 mg) was prepared as a white solid in an overall yield of 45.5% according to the procedure for compound 108. ¹ H 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 ]] ⁺

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-2- ((3S, 5R) -3,4,5-trimethylpiperazin-1-yl) acetamide (129)

The title compound 129 (25.5 mg) was prepared as a white solid in 90.1% overall yield 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 ]] ⁺

N- (4- ((4-cyanophenyl) amino) benzyl) -N-hydroxypivalamide (130)

The title compound 130 (10.0 mg) was prepared as a white solid in 30.9% overall yield according to the procedure for compound 80. ¹ H 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 ]] ⁺

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)

The title compound 131 (10.6 mg) was prepared as a white solid in 39.4% overall yield 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 ]] ⁺

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-methoxy-pivaloyl amide (132)

The title compound 132 (32.0 mg) was prepared as a white solid in an overall yield of 86.9% according to the procedure for compound 80. ¹ H 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 ] ] ⁺

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -N-hydroxy-2- (4- (pyrimidin-2-yl) piperazin-1-yl) acetamide (133)

The title compound 133 (38.4 mg) was prepared as a white solid in an overall 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 ]] ⁺

1- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -3-cyclopropyl-1-hydroxyurea (134)

To a solution of 4- (tert-butyl) -N- (4- ((hydroxyamino) methyl) phenyl) aniline (27.1 mg, 0.1 mmol) in DCM (2 mL) was added triphosgene (29.7 mg, 0.1 mmol) and DIEA (39 mg, 0.3 mmol). After stirring the reaction mixture for 2 hours, DIEA (39 mg, 0.3 mmol) and cyclopropylamine (5.7 mg, 0.1 mmol) were added. The reaction mixture was then stirred for 1 hour. The reaction solution was washed with water (3X 5 mL) and Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by preparative TLC (MeOH/DCM = 1/10) to give 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 ] ] ⁺

N- (4- ((4- (6-fluoropyridin-3-yl) phenyl) amino) benzyl) -N-hydroxy-2- (4-methylpiperazin-1-yl) acetamide (135)

The title compound 135 (12.0 mg) was prepared as a white solid in 26.7% overall yield according to the procedure for compound 108. ¹ H 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 ]] ⁺

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (4- ((4- (pyrrolidin-1-yl) phenyl) amino) benzyl) acetamide (136)

Procedure according to compound 108 was 13.The title compound 136 (5.1 mg) was prepared as a white solid in 2% overall yield. ¹ H NMR (400 MHz, methanol-d ₄ ) Delta 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 ]] ⁺

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (4- ((4- (1-methylpiperidin-4-yl) phenyl) amino) benzyl) acetamide (137)

To a solution of 4- ((hydroxyamino) methyl) -N- (4- (1-methylpiperidin-4-yl) phenyl) aniline (130 mg, 0.42 mmol), 2- (4-methylpiperazin-1-yl) acetic acid (66 mg, 0.42 mmol), and DIEA (129 mg, 1 mmol) in DMF (1 ml) was added DMT-m (151 mg, 0.55 mmol). The mixture was then stirred at room temperature for 3 hours. The reaction was concentrated under vacuum. The residue was purified by preparative TLC to provide the desired product as a white solid (6 mg, 1.6%). ¹ H NMR (400 MHz, methanol-d 4) 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 ]] ⁺ 。

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (4- ((4-morpholinophenyl) amino) benzyl) acetamide (138)

The title compound 138 (38.1 mg) was prepared as a white solid in 86.5% overall yield according to the procedure for compound 108. ¹ H 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). Quality of foodAmount (m/z): 440.2 [ M + H ]] ⁺

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (4- ((4- (2-oxopyridin-1 (2H) -yl) phenyl) amino) benzyl) acetamide (139)

The title compound 139 (5 mg) was prepared as a yellow solid in 3.4% overall yield from 1- (4- ((4- ((hydroxyamino) methyl) phenyl) amino) phenyl) pyridin-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) according to the procedure of 137. ¹ H NMR (400 MHz, methanol-d 4) 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 (s, 2H), 3.69-3.64 (m, 2H), 3.38-3.32 (m, 4H), 3.08-2.94 (m, 4H), 2.88 (d, J = 1.1 Hz, 3H). 448.3 mass (m/z): [ M + H ]] ⁺

N-hydroxy-N- (4- ((4- (2-methoxyethoxy) phenyl) amino) benzyl) -2- (4-methylpiperazin-1-yl) acetamide (140)

The title compound 140 (16 mg) was prepared as a white solid in 18.0% total yield 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) according to the procedure of 137. ¹ H NMR (400 MHz, methanol-d 4). Delta.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 ]] ⁺ 。

N-hydroxy-N- (4- ((4- (N-methylacetamido) phenyl) amino) benzyl) -2- (4-methylpiperazin-1-yl) acetamide (141)

The title compound 141 (10.1 mg) was prepared as a white solid in 23.8% overall yield according to the procedure for compound 108. ¹ H 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 ]] ⁺

4- (dimethylamino) -N-hydroxy-N- (4- ((4- (piperidine-1-carbonyl) phenyl) amino) benzyl) butanamide (142)

The title compound 142 (8 mg) was prepared as a white solid in 18.32% overall yield from (4- ((4- ((hydroxyamino) methyl) phenyl) amino) phenyl) (piperidin-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) according to the procedure of 137. ¹ H NMR (400 MHz, methanol-d 4) 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 ] +.

N- (4- ((4-butoxyphenyl) amino) benzyl) -4- (dimethylamino) -N-hydroxybutyramide (143)

The title compound 143 (5.2 mg) was prepared as a white solid in 13.8% overall yield 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 ]] ⁺

N-hydroxy-2- (piperazin-1-yl) -N- (4- ((4- (pyrrolidin-1-ylmethyl) phenyl) amino) benzyl) acetamide (144)

The title compound 144 (19 mg) was prepared as a white solid in 22.5% overall yield from 4- ((hydroxyamino) methyl) -N- (4- (pyrrolidin-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) according to the procedure of 137. ¹ H NMR (400 MHz, methanol-d 4) 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 ]] ⁺ 。

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (4- ((3-morpholinophenyl) amino) benzyl) acetamide (145)

The title compound 145 (14.3 mg) was prepared as a white solid in 16.3% overall yield 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) according to the procedure of 137. ¹ H NMR (400 MHz, methanol-d 4) 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] ⁺ 。

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) acetamide (146)

The title compound 146 (5.4 mg) was prepared as a white solid in 24.7% overall yield 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, 8H), 3.63-3.55 (m, 4H), 3.05 (s, 3H), 2.13-2.00 (m, 4H), 1.98-1.88 (m, 2H). Mass (m/z): 438.2 [ M + H ]] ⁺

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (4- ((4- (tetrahydro-2H-pyran-4-yl) phenyl) amino) benzyl) acetamide (147)

The title compound 147 (13.0 mg) was prepared as a white solid in 29.6% total yield 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 of 137. ¹ H NMR (400 MHz, methanol-d 4) 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, 2H), 3.58-3.46 (m, 4H), 2.94-2.64 (m, 9H), 2.56 (s, 3H), 1.79-1.65 (m, 4H). Mass (m/z): 439.3 [ M + H ]] ⁺ 。

N-hydroxy-N- (4- ((4- (4-hydroxypiperidin-1-yl) phenyl) amino) benzyl) -2- (4-methylpiperazin-1-yl) acetamide (148)

The title compound 148 (2.9 mg) was prepared as a white solid in 16.0% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺

N- (4- ((4- (6-fluoropyridin-3-yl) phenyl) amino) benzyl) -N-hydroxy-1-methylpiperidine-4-carboxamide (149)

The title compound 149 (5.3 mg) was prepared as a white solid in 24.4% overall yield 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 ] ] ⁺

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (4- ((4-pentylphenyl) amino) benzyl) acetamide (150)

The title compound 150 (20.0 mg) was prepared as a white solid in 23.8% overall yield 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) according to the procedure of 137. ¹ H NMR (400 MHz, methanol-d 4) 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, 8H), 2.57-2.44 (m, 5H), 1.63-1.54 (m, 2H), 1.40-1.29 (m, 4H), 0.94-0.85 (m, 3H). Mass (m/z): 425.3 [ M + H ]] ⁺ 。

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (4- ((4-phenoxyphenyl) amino) benzyl) acetamide (151)

The title compound 151 (30.0 mg) was prepared as a white solid in 42.0% overall yield 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) according to the procedure of 137. ¹ H NMR (400 MHz, methanol-d 4) 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 ] ] ⁺ 。

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (4- ((4- (pyridin-4-yl) phenyl) amino) benzyl) acetamide (152)

The title compound 152 (5.8 mg) was prepared as a white solid in 23.2% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺

N- (4- ((4-cyclohexylphenyl) amino) benzyl) -4- (dimethylamino) -N-hydroxybutyramide (153)

Procedure according to compound 108 with a total yield of 29.3%Yield the title compound 153 (12.1 mg) was prepared as a white solid. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺

N- (4- ((4- (cyclohexyloxy) phenyl) amino) benzyl) -N-hydroxy-2- (4-methylpiperazin-1-yl) acetamide (154)

The title compound 154 (14.3 mg) was prepared as a yellow solid in 19.7% overall yield 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) according to the procedure of 137. ¹ H NMR (400 MHz, methanol-d 4) delta 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 ]] ⁺ 。

N- (4- ((4- (tert-butylamino) phenyl) amino) benzyl) -N-hydroxy-2- (4-methylpiperazin-1-yl) acetamide (155)

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 ℃ for 18 hours. After cooling to room temperature, 20 mL water was added. The resulting solution was extracted with 3X50 mL of ethyl acetate. Combining the organic layers and using water(3x100 mL), dried and concentrated in vacuo. The residue was applied to a silica gel column and eluted with ethyl acetate/hexane (1/20-1/5) to give the desired product (3.0 g, 72.6%) as a yellow solid. Mass (m/z): 195.2 [ M + H ]] ⁺ 。

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

Step 3.4 preparation of- ((4- (tert-butylamino) phenyl) amino) benzaldehyde (155-6): from N according to the procedure of 137-3 ¹ - (tert-butyl) benzene-1,4-diamine (1.11 g, 6.0 mmol), 4-bromobenzaldehyde (740 mg, 4.0 mmol), pd (dppf) ₂ Cl ₂ (59 mg, 0.08 mmol)、Xantphos (93 mg, 0.16 mmol)、Cs ₂ CO ₃ (1.96 g, 6.0 mmol) the title compound 155-6 (620 mg) was prepared as a yellow solid in 59.2% overall yield. Mass (m/z): 269.2 [ M + H ]] ⁺ 。

Step 4 preparation of (E) -4- ((4- (tert-butylamino) phenyl) amino) benzaldehyde oxime (155-7): the title compound 155-7 (425 mg) was prepared as a crude as a yellow solid in 100% overall yield from 4- ((4- (tert-butylamino) phenyl) amino) benzaldehyde (404 mg, 1.5 mmol), hydroxylamine hydrochloride (155 mg, 2.25 mmol) according to the procedure of 137-4. Mass (m/z): 284.2[ 2 ] M + H] ⁺ 。

Step 5. N ¹ - (tert-butyl) -N ⁴ Preparation of- (4- ((hydroxyamino) methyl) phenyl) benzene-1,4-diamine (155-8): the title compound 155-8 (130 mg) was prepared as a yellow solid in 30.6% overall yield 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 in 10% HCl according to the procedure of 137-5. Mass (m/z): 307.2 [ M + H ]] ⁺ 。

Step 6 preparation of N- (4- ((4- (tert-butylamino) phenyl) amino) benzyl) -N-hydroxy-2- (4-methylpiperazin-1-yl) acetamide (155) : from N according to the procedure of 137 ¹ - (tert-butyl) -N ⁴ - (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) the title compound 155 (20.0 mg) was prepared as a yellow solid in an overall yield of 20.0%. ¹ H NMR (400 MHz, methanol-d 4). Delta.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 ]] ⁺ 。

N- (4- ((4- (diethylamino) phenyl) amino) benzyl) -N-hydroxy-2- (4-methylpiperazin-1-yl) acetamide (156)

The title compound 156 (15.9 mg) was prepared as a white solid in 37.4% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺

4- (dimethylamino) -N-hydroxy-N- (4- ((4-isopropoxyphenyl) amino) benzyl) butanamide (157)

The title compound 157 (10.3 mg) was prepared as a yellow solid in 13.4% overall yield from 4- ((hydroxyamino) methyl) -N- (4-isopropoxyphenyl) aniline (54 mg, 0.2 mmol), 4- (dimethylamino) butyric 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 of 137. ¹ H NMR (400 MHz, methanol-d 4) 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 ]] ⁺ 。

4- (dimethylamino) -N-hydroxy-N- (4- ((4-propoxyphenyl) amino) benzyl) butanamide (158)

The title compound 158 (23.5 mg) was prepared as a white solid in 60.9% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺

N- (4- ((4- (heptyloxy) phenyl) amino) benzyl) -N-hydroxy-2- (4-methylpiperazin-1-yl) acetamide (159)

The title compound 159 (11.6 mg) was prepared as a white solid in 24.8% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺

N- (4- ((4- (2,6-dimethylmorpholino) phenyl) amino) benzyl) -N-hydroxy-2- (4-methylpiperazin-1-yl) acetamide (160)

The title compound 160 (9.1 mg) was prepared as a white solid in 19.4% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 ]] ⁺

2- (4-methylpiperazin-1-yl) -N- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) acetamide (161)

The title compound 161 (4.1 mg) was prepared as a white solid in 19.5% overall yield according to the procedure for compound 163. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺

N-hydroxy-N- (4- ((4- (2-methylmorpholino) phenyl) amino) benzyl) -2- (4-methylpiperazin-1-yl) acetamide (162)

The title compound 162 (37.6 mg) was prepared as a white solid in 41.5% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺

2- (4-methylpiperazin-1-yl) -N- (4- ((4-pentylphenyl) amino) benzyl) acetamide (163)

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) was added 10% Pd/C (16 mg, 0.015 ml) and AcOH (0.5 mL). The reaction was then stirred under hydrogen atmosphere at room temperature overnight. The 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 × 3). The combined organic layers were washed with brine (20 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated to yield the desired product as a yellow solid. (190 mg, 47.3%). 252.3 [ M-NH2] ⁺ 。

Step 2.2 preparation of 2- (4-methylpiperazin-1-yl) -N- (4- ((4-pentylphenyl) amino) benzyl) acetamide (163): to a solution of 4- (aminomethyl) -N- (4-pentylphenyl) aniline (53.4 mg, 0.2 mmol) and 2- (4-methylpiperazin-1-yl) acetic acid (34.8 mg, 0.22 mmol) in DMF (1 ml) was added DIEA (77.4 mg, 0.6 mmol). HATU (83.6 mg, 0.22 mmol) was then added and the reaction mixture was stirred at room temperature for 2 hours. 10 mL water was added. The mixture was then extracted with DCM (10 mL × 3). The combined organic layers were washed with water (10 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by preparative TLC (MeOH/DCM = 1/10) to yield the desired product as a white solid (38.1 mg, 46.7%). ¹ H NMR (400 MHz, methanol-d 4) 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, 4H), 2.73-2.59 (m, 4H), 2.55-2.50 (m, 5H), 1.63-1.55 (m, 2H), 1.38-1.28 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H). Mass (m/z): 409.4 [ M + H ]] ⁺ 。

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (1- (4- ((4- (piperidin-1-yl) phenyl) amino) phenyl) ethyl) acetamide (164)

The title compound 164 (6.4 mg) was prepared as a yellow solid in 8.8% overall yield from 4- (1- (hydroxyamino) ethyl) -N- (4- (piperidin-1-yl) phenyl) aniline (50 mg, 0.16 mmol), 4- (dimethylamino) butyric 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) according to the procedure of 137. ¹ H NMR (400 MHz, methanol-d 4) 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] ⁺ 。

N- (4- ((4- (2-oxa-6-azaspiro [3.3] heptan-6-yl) phenyl) amino) benzyl) -4- (dimethylamino) -N-hydroxybutyramide (165)

The title compound 165 (15.1 mg) was prepared as a white solid in 52.3% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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, 4H), 4.61 (s, 2H), 3.95 (s, 4H), 2.53 (t, J = 6.8 Hz, 2H), 2.32 (t, J = 6.8 Hz, 2H), 2.08 (s, 6H), 1.87 (p, J= 6.8 Hz, 2H). Mass (m/z): 425.3 [ M + H ]] ⁺

N-hydroxy-4- (4-methylpiperazin-1-yl) -N- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) butanamide (166)

The title compound 166 (7.4 mg) was prepared as a white solid in 31.8% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ] ] ⁺

2- (dimethylamino) -N-hydroxy-N- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) acetamide (167)

The title compound 167 (11.1 mg) was prepared as a white solid in 58.1% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺

N- (4- ((4- (4,4-difluoropiperidin-1-yl) phenyl) amino) benzyl) -N-hydroxy-2- (4-methylpiperazin-1-yl) acetamide

The title compound 168 (15.0 mg) was prepared as a white solid in 35.5% overall yield from 4- (4,4-difluoropiperidin-1-yl) -N- (4- ((hydroxyamino) methyl) phenyl) aniline (30 mg, 0.090 mmol) and 2- (4-methylpiperazin-1-yl) acetic acid (18 mg, 0.117 mmol) according to the procedure of 174. ¹ H NMR (400 MHz, methanol-d 4). Delta ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N-hydroxy-2- (1-methylpiperidin-4-yl) -N- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) acetamide (169)

The title compound 169 (12.0 mg) was prepared as a white solid in 55.0% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol- d ₄ ) 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 ]] ⁺

N- (4- ((4-butoxyphenyl) amino) benzyl) -N-hydroxy-2- (4-methylpiperazin-1-yl) acetamide (170)

¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N-hydroxy-N- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) quinuclidine-4-carboxamide (171)

The title compound 171 (15.4 mg) was prepared as a white solid in 25.2% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺

N-hydroxy-1-methyl-5-oxo-N- (4- ((4- (piperidin-1-yl) phenyl) amino) -2- (trifluoromethyl) benzyl) pyrrolidine-3-carboxamide (172)

To a solution of 4- ((hydroxyamino) methyl) -N- (4- (piperidin-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) was added DMT-MM (33.1 mg, 0.12 mmol), and the reaction mixture was stirred at room temperature for 3 hours. 5 mL water was added. The mixture was then extracted with DCM (5 mL × 3). The combined organic layers were washed with water (10 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by preparative TLC (MeOH/DCM = 1/10) to yield the desired product as a yellow solid (16.4 mg, 33.5%). ¹ H NMR (400 MHz, methanol-d 4) 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 3262 zxf3262, 2H), 1.79-1.71 (m, 4H), 1.62-1.55 (m, 2H). Mass (m/z): 491.3 [ M + H ]] ⁺

5- (dimethylamino) -N-hydroxy-N- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) pentanamide (173)

The title compound 173 (21.1 mg) was prepared as a white solid in 51.2% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) acetamide (174)

To 4- ((hydroxyamino)) Methyl) -N- (4- (4-methylpiperidin-1-yl) phenyl) aniline (30 mg, 0.096 mmol) and 2- (4-methylpiperazin-1-yl) acetic acid (20 mg, 0.125 mmol) in solution 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 h. The mixture was extracted with EA (25 mL x 3). The combined organic layers were washed with brine (15 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated to give the crude product, which was purified by TLC (MeOH/DCM = 1:8) to give the desired product as a white solid (13.2 mg, 30.0%). ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) acetamide (175)

The title compound 175 (16.3 mg) was prepared as a white solid in 39.2% total yield from 4- ((hydroxyamino) methyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (30 mg, 0.082 mmol) and 2- (4-methylpiperazin-1-yl) acetic acid (17 mg, 0.107 mmol) according to the procedure of 174. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

2- (4-methylpiperazin-1-yl) -N- (2,2,2-trifluoro-1- (4- ((4- (piperidin-1-yl) phenyl) amino) phenyl) ethyl) acetamide (176)

Procedure according to 163 from 4-, (C1)1-amino-2,2,2-trifluoroethyl) -N- (4- (piperidin-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) the title compound 176 (8.0 mg) was prepared as a yellow solid in a total yield of 23.5%. ¹ H NMR (400 MHz, methanol-d 4). Delta.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 ]] ⁺ 。

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (4- ((4- (3-methylpiperidin-1-yl) phenyl) amino) benzyl) acetamide (177)

The title compound 177 (28.3 mg) was prepared as a white solid in an overall yield of 61.9% according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (4- ((4- (2-methylpiperidin-1-yl) phenyl) amino) benzyl) acetamide (178)

The title compound 178 (34.2 mg) was prepared as a white solid in 75.7% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺

2- (4-methyl-3-oxopiperazin-1-yl) -N- (4- ((4- (piperidin-1-yl) -3- (trifluoromethyl) phenyl) amino) benzyl) acetamide (179)

To a solution of N- (4- (aminomethyl) phenyl) -4- (piperidin-1-yl) -3- (trifluoromethyl) aniline (30 mg, 0.086 mmol) and 2- (4-methyl-3-oxopiperazin-1-yl) acetate salt (20 mg, 0.112 mmol) in DMF (3 mL) was added DMT-MM (33 mg, 0.112 mmol) and DIPEA (15 mg, 0.112 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was extracted with EA (25 mL x 3). The combined organic layers were washed with brine (15 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated to give the crude product, which was purified by TLC (MeOH/DCM = 1 10) to give the desired product as a white solid (41.2 mg, 89.1%). ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N- (4- ((4- (azacyclooctane-1-yl) phenyl) amino) benzyl) -N-hydroxy-2- (4-methylpiperazin-1-yl) acetamide (180)

The title compound 180 (16.1 mg) was prepared as a white solid in 34.6% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) Delta 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 ]] ⁺

N- (4- ((4- (azetidin-1-yl) phenyl) amino) benzyl) -N-hydroxy-2- (4-methylpiperazin-1-yl) acetamide (181)

The title compound 181 (9.1 mg) was prepared as a yellow solid in 20.0% overall yield from 4- (azetidin-1-yl) -N- (4- ((hydroxyamino) methyl) phenyl) aniline (26.9 mg, 0.1 mmol), 4- (dimethylamino) butyric 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) according to the procedure of 137. ¹ H NMR (400 MHz, methanol-d 4) 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 ] ] ⁺ 。

N- (4- ((4- (4-fluoropiperidin-1-yl) phenyl) amino) benzyl) -N-hydroxy-2- (4-methylpiperazin-1-yl) acetamide (182)

To a solution of 4- (4-fluoropiperidin-1-yl) -N- (4- ((hydroxyamino) methyl) phenyl) aniline (30 mg, 0.095 mmol) and 2- (4-methylpiperazin-1-yl) acetic acid (20 mg, 0.124 mmol) in DMF (3 mL) were added DMT-MM (37 mg, 0.125 mmol) and DIPEA (16 mg, 0.125 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was extracted with EA (25 mL x 3). The combined organic layers were washed with brine (15 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated to give the crude product, which was purified by TLC (MeOH/DCM = 1:8) to give the desired product as a white solid (8.1 mg, 29%). ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (4- ((4- (3- (trifluoromethyl) pyrrolidin-1-yl) phenyl) amino) benzyl) acetamide (183)

The title compound 183 (25.1 mg) was prepared as white green in 60% overall yield from 4- ((hydroxyamino) methyl) -N- (4- (3- (trifluoromethyl) pyrrolidin-1-yl) phenyl) aniline (30 mg, 0.086 mmol) and 2- (4-methylpiperazin-1-yl) acetic acid (18 mg, 0.111 mmol) according to the procedure of 182. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N- (4- ((4- (3,3-difluoropiperidin-1-yl) phenyl) amino) benzyl) -N-hydroxy-2- (4-methylpiperazin-1-yl) acetamide (184)

The title compound 184 (10.0 mg) was prepared as a yellow solid in 21.1% total yield from 4- (3,3-difluoropiperidin-1-yl) -N- (4- ((hydroxyamino) methyl) phenyl) aniline (33.3 mg, 0.1 mmol), 4- (dimethylamino) butyric 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) according to the procedure of 137. ¹ H NMR (400 MHz, methanol-d 4) 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 Hz, 2H), 2.03-1.95 (m, 6H), 2.92-2.80 (m, 4H), 2.74 (s, 3H), 2.03-1.95 (m, 2H), 1.92-1.83 (m, 2H). Mass (m/z): 237.7 [ M/2+H] ⁺ 。

N-hydroxy-1-isopropyl-N- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) piperidine-4-carboxamide (185)

According to the formationThe procedure for compound 108 prepared the title compound 185 (12.3 mg) as a white solid in 40.7% overall yield. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺

1-isopropyl-N- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) piperidine-4-carboxamide (186)

The title compound 186 (16.1 mg) was prepared as a white solid in 43.1% overall yield according to the procedure for compound 163. ¹ H NMR (400 MHz, methanol-d ₄ ) 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, 4H), 1.74 (br s, 4H), 1.59 (br s, 2H), 1.35 (d, J= 6.8 Hz, 6H). Mass (m/z): 435.3 [ M + H ]] ⁺

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (4- ((4- (3- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) acetamide (187)

The title compound 187 (16.5 mg) was prepared as a white solid in 32.7% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (4- ((4- (pyrrolidin-1-yl) -3- (trifluoromethyl) phenyl) amino) benzyl) acetamide (188)

The title compound 188 (13.5 mg) was prepared as a white solid in 22.1% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ] ] ⁺

1-methyl-6-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) piperidine-3-carboxamide (189)

Step 1 from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (30 mg, 0.09 mmol) and 1-methyl-6-oxopiperidine-3-carboxylic acid (15 mg, 0.09 mmol) the title compound 189 (18.3 mg) was prepared as a light yellow powder in a yield of 43.63%. ¹ H NMR (400 MHz, methanol-d ₄ ) 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] ⁺ 。

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (4- ((6- (piperidin-1-yl) pyridin-3-yl) amino) benzyl) acetamide (190)

The title compound 190 (22.1 mg) was prepared as a white solid in 50.4% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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, 2H), 3.45-3.38 (m, 4H), 2.86 (br s, 4H), 2.76 (br s, 4H), 2.54 (s, 3H), 1.72-1.65 (m, 6H). Mass (m/z): 439.3 [ M + H ]] ⁺

N- (4- ((4- (2,6-dimethylmorpholino) phenyl) amino) benzyl) -2- (4-methylpiperazin-1-yl) acetamide (191)

The title compound 191 (31.4 mg) was prepared as a white solid in 72.3% overall yield according to the procedure for compound 163. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ] ] ⁺

N-hydroxy-N- (4- ((2-methyl-4- (piperidin-1-yl) phenyl) amino) benzyl) -2- (4-methylpiperazin-1-yl) acetamide (192)

The title compound 192 (20.1 mg) was prepared as a white solid in 56.3% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺

N-hydroxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) -N- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) acetamide (193)

The title compound 193 (10.4 mg) was prepared as a white solid in 21.7% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺

N-hydroxy-N- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) -2- (pyrazin-2-yl) acetamide (194)

The title compound 194 (15.9 mg) was prepared as a white solid in 31.8% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺

4- (hydroxy (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) amino) -4-oxobutanoic acid (195)

To a solution of 4- ((hydroxyamino) methyl) -N- (4- (piperidin-1-yl) phenyl) aniline (59.4 mg, 0.2 mmol) in toluene (1 ml) was added dihydrofuran-2,5-dione (20.0 mg, 0.2 mmol) at 0 ℃. The reaction was then stirred for 3 hours. After completion, the reaction solution was concentrated and purified by preparative TLC (MeOH/DCM = 1/10) to yield the desired product as a white solid (18.2 mg, 23.1%). ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺

N-hydroxy-N- (3-methyl-4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) -2- (4-methylpiperazin-1-yl) acetamide (196)

The title compound 196 (26.5 mg) was prepared as a white solid in 52.5% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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[ 2 ] M + H ] ⁺

N- (3-fluoro-4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) -N-hydroxy-2- (4-methylpiperazin-1-yl) acetamide (197)

The title compound 197 (20.6 mg) was prepared as a white solid in 41.7% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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[ 2 ] M + H] ⁺

N-hydroxy-N- (3-methyl-4- ((2-methyl-4- (piperidin-1-yl) phenyl) amino) benzyl) -2- (4-methylpiperazin-1-yl) acetamide (198)

The title compound 198 (10.2 mg) was prepared as a yellow solid in 21.9% overall yield from 4- ((hydroxyamino) methyl) -2-methyl-N- (2-methyl-4- (piperidin-1-yl) phenyl) aniline (32.5 mg, 0.1 mmol), 4- (dimethylamino) butyric 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) according to the procedure of 137. ¹ H NMR(400 MHz, methanol-d 4) 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 ]+。

N-hydroxy-N- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) oxazole-4-carboxamide (199)

The title compound 199 (12.5 mg) was prepared as a white solid in 37.4% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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] ⁺

2- (3,5-dimethyl-1H-1,2,4-triazol-1-yl) -N-hydroxy-N- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) acetamide (200)

The title compound 200 (10.2 mg) was prepared as a white solid in 25.1% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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] ⁺

N1-diethyl-5-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (201)

Step 1. Preparation of 1-ethyl-5-oxopyrrolidine according to intermediate procedure-3-carboxylic acid (367 mg, 2.34 mmol) andN- (4-bromobenzyl) ethylamine (500 mg, 2.34 mmol) was prepared as intermediate as a brown oil in a yield of 56.61% N- (4-bromobenzyl) -N1-diethyl-5-oxopyrrolidine-3-carboxamide (467 mg). LC-MS (M/z) 353.2, 355.1 [ M + H] ⁺ 。

Step 2 from 4- (4- (trifluoromethyl) piperidin-1-yl) aniline (50 mg, 0.20 mmol) andN- (4-bromobenzyl) -N1-diethyl-5-oxopyrrolidine-3-carboxamide (72 mg, 0.20 mmol) the title compound 201 (5.9 mg) was prepared in 5.58% yield as a light yellow powder. ¹ H NMR (400 MHz, methanol-d ₄ ) 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] ⁺ 。

1- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) piperazin-2-one (202)

Step 1.preparation of tert-butyl 4- (4-bromobenzyl) -3-oxopiperazine-1-carboxylate (202-2): to a solution of 1-bromo-4- (bromomethyl) benzene (992 mg, 4.0 mmol) and 3-oxopiperazine-1-carboxylic acid tert-butyl ester (800 mg, 4.0 mmol) in DMSO (10.0 mL) was added KOH (828 mg, 6.0 mmol). The mixture was then stirred at room temperature overnight. After cooling to room temperature, 20 mL water was added. The resulting solution was extracted with 3X20 mL of ethyl acetate. The organic layers were combined, washed with water (3xf 30 mL), dried and concentrated under vacuum to afford the desired product as a yellow oil (500 mg, 34.0%). Mass (m/z): 313.1[ M ] +H] ⁺ 。

Step 2.preparation of 3-oxo-4- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) piperazine-1-carboxylic acid tert-butyl ester (202-3): from 4- (piperidin-1-yl) aniline (310 mg, 1.77 mmol), 4- (4-bromobenzyl) -3-oxopiperazine-1-carboxylic acid tert-butyl ester (500 mg, 1.36 mmol), pd (dppf) according to the procedure of 137-3 ₂ Cl ₂ (20 mg, 0.03 mmol)、Xantphos (32 mg, 0.05 mmol)、Cs ₂ CO ₃ (665 mg, 2.04 mmol) at 27.6%Total yield the title compound 202-3 (173 mg) was prepared as a yellow oil. Mass (m/z): 465.4 [ M + H ]] ⁺ 。

Step 3.1 preparation of- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) piperazin-2-one (202): to a solution of 3-oxo-4- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) piperazine-1-carboxylic acid tert-butyl ester (162 mg, 0.35 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction was then stirred at room temperature for 30min. The reaction solution was concentrated under vacuum. 10 ml water was added. With Na ₂ CO ₃ The pH of the solution was adjusted to 8. The resulting solution was extracted with 3 × 10 mL of ethyl DCM. The organic layers were combined, washed with water (3x10 mL), dried and concentrated in vacuo. The residue was purified by preparative TLC (MeOH/DCM = 1/5) to provide the desired product as a yellow solid (74.0 mg, 61.2%). ¹ H NMR (400 MHz, methanol-d 4) 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] ⁺ 。

5-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (203)

To a solution of 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-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 added DMT-MM (89 mg, 0.302 mmol) and DIPEA (39 mg, 0.302 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was extracted with EA (25 mL x 3). The combined organic layers were washed with brine (15 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated to give the crude product, which was purified by TLC (MeOH/DCM = 1 10) to give the desired product as a white solid (56.7 mg, 53.0%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 ]] ⁺ 。

1- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) pyrrolidin-2-one (204)

Step 1.1 preparation of- (4-bromobenzyl) pyrrolidin-2-one (204-2): to a solution of 1-bromo-4- (bromomethyl) benzene (992 mg, 4.0 mmol) and pyrrolidin-2-one (744 mg, 4.0 mmol) in DMSO (10.0 mL) was added KOH (828 mg, 6.0 mmol). The mixture was then stirred at room temperature overnight. After cooling to room temperature, 20 mL water was added. The resulting solution was extracted with 3X20 mL of ethyl acetate. The organic layers were combined, washed with water (3xf 30 mL), dried and concentrated under vacuum to afford the desired product as a yellow oil (460 mg, 45.5%). Mass (m/z): 254.1[ 2 ] M + H ] ⁺ 。

Step 2.1 preparation of- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) pyrrolidin-2-one (204): from 4- (piperidin-1-yl) aniline (176 mg, 1.0 mmol), 1- (4-bromobenzyl) pyrrolidin-2-one (121 mg, 0.5 mmol), pd (dppf) according to the procedure of 137-3 ₂ Cl ₂ (7.3 mg, 0.01 mmol)、Xantphos (11.6 mg, 0.02 mmol)、Cs ₂ CO ₃ (244 mg, 0.75 mmol) the title compound 304 (40.1 mg) was prepared in 22.9% overall yield as a yellow oil. 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 ]] ⁺ 。

1-ethyl-N-isopropyl-5-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (205)

Step 1. Procedure according to intermediate from 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (69 mg, 0.44 mmol) andN- (4-bromobenzyl) cyclopropylamine (100 mg, 0.44 mmol) was prepared in 93.17% yield as intermediate as a brown oilN- (4-bromobenzyl) -1-ethyl-N-isopropyl-5-oxopyrrolidine-3-carboxamide (150 mg). LC-MS (M/z) 367.2, 369.2 [ M + H] ⁺ 。

Step 2 from 4- (4- (trifluoromethyl) piperidin-1-yl) aniline (100 mg, 0.41 mmol) andN- (4-bromobenzyl) -1-ethyl- N-isopropyl-5-oxopyrrolidine-3-carboxamide (150 mg, 0.41 mmol) the title compound 205 (14 mg) was prepared in 6.44% yield as a blue powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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, 4.1 Hz, 2H), 1.09 (dd, J = 6.6, 1.7 Hz, 3H), 1.07 - 1.00 (m, 5H), 0.96 (t, J = 7.2 Hz, 2H)。LC-MS (m/z) 531.5 [M+H] ⁺ 。

N-hydroxy-2- (4-methyl-3-oxopiperazin-1-yl) -N- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) acetamide (206)

The title compound 206 (5.6 mg) was prepared as a white solid in 21.6% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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[ deg. ] M + H] ⁺ 。

N- (4- ((4- (2-oxa-6-azaspiro [3.3] heptan-6-yl) phenyl) amino) benzyl) -2- (4-methylpiperazin-1-yl) acetamide (207)

The title compound 207 (21.8 mg) was prepared as a white solid in 50.7% overall yield according to the procedure for compound 163. ¹ H NMR (400 MHz, methanol-d ₄ ) 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[ mu ] M + H] ⁺ 。

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (4- ((4- (piperidin-1-yl) phenyl) amino) -2- (trifluoromethyl) benzyl) acetamide (208)

The title compound 208 (28.2 mg) was prepared as a white solid in 58.4% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 2 [ M ] +H] ⁺ 。

1-Ethyl-N- (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (209)

Step 1. Mixing 1,4-dioxane 4- (4-methylpiperidin-1-yl) aniline (375 mg, 2.0 mmol), 4-bromobenzaldehyde (281 mg, 1.5 mmol), pd (dppf) ₂ Cl ₂ A mixture of (22 mg, 0.03 mmol), xantphos (35 mg, 0.06 mmol), cs2CO3 (734 mg, 2.3 mmol) (5 mL) was stirred at 110 deg.C overnight. After cooling to room temperature, 5 mL water was added. The mixture was then extracted with DCM (5 mL × 3). To be combined withThe organic layer was washed with water (10 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by preparative TLC (MeOH/DCM = 1/10) to yield the desired product as a yellow solid (490 mg, 86.0%). Mass (m/z): 295.3 [ M + H ]] ⁺

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

Step 3. To a solution of (E) -4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) benzaldoxime (516 mg, 1.67 mmol) in EtOH (20 mL) was added 10% Pd/C (18 mg, 16.7 ummol) and AcOH (0.5 mL). The reaction was then stirred under hydrogen atmosphere at room temperature overnight. The 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 × 3). The combined organic layers were washed with brine (20 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated to yield the desired product as a yellow solid. (120 mg, 24.3%). 296.3 [ M + H ]] ⁺ 。

Step 4. To a solution of 4- (aminomethyl) -N- (4- (4-methylpiperidin-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) was added DIEA (38.7 mg, 0.3 mmol). HATU (38 mg, 0.1 mmol) was then added and the reaction mixture was stirred at room temperature for 2 hours. 5 mL water was added. The mixture was then extracted with DCM (5 mL × 3). The combined organic layers were washed with water (10 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by preparative TLC (MeOH/DCM = 1/5) to yield the desired product as a white solid (16.9 mg, 28.9%). ¹ H NMR (400 MHz, methanol-d 4) 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, 2H) 6H). Mass (m/z): 435.4[ 2 ] M + H] ⁺ 。

N- (4- ((4- (4,4-dimethylpiperidin-1-yl) phenyl) amino) benzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (210)

The title compound 210 (26.4 mg) was prepared as a yellow solid in 58.9% overall yield from 4- (aminomethyl) -N- (4- (4,4-dimethylpiperidin-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), HATU (38 mg, 0.1 mmol) according to the procedure of 209. ¹ H NMR (400 MHz, methanol-d 4) 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 ]] ⁺ 。

N- (4- ((4- (3,3-dimethylazetidin-1-yl) phenyl) amino) benzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (211)

The title compound 211 (5.7 mg) was prepared as a yellow solid in 6.8% overall yield from 4- (aminomethyl) -N- (4- (3,3-dimethylazetidin-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), HATU (76 mg, 0.2 mmol) according to the procedure of 209. ¹ H NMR (400 MHz, methanol-d 4) 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 ]] ⁺ 。

N- (4- ((4- (4,4-difluoropiperidin-1-yl) phenyl) amino) benzyl) -N-hydroxy-1-isopropylpiperidine-4-carboxamide (212)

The title compound 212 (21.8 mg) was prepared according to the procedure of 174 as a white solid in 49.8% overall yield from 4- (4,4-difluoropiperidin-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). ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N-cyclopropyl-1-ethyl-5-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (213)

Step 1, in argon atmosphere at room temperatureN- (4-bromobenzyl) cyclopropylamine (200 mg, 0.88 mmol, 1.0 equiv.) and 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (139 mg, 0.89 mmol, 1.1 equiv.) in the super-dried stateN,NAdding 2- (1) to a solution of-dimethylformamide (10 mL) H-benzo [ d ]][1,2,3]Triazol-1-yl) -1,1,3,3-tetramethylisouronium tetrafluoroborate (340 mg, 1.06 mmol, 1.5 equiv.) andN-ethyl-N-isopropylpropan-2-amine (438 mmL, 2.65 mmol, 3.0 equiv.) and stirred overnight. The reaction was diluted with water (10 mL) and extracted 3 times with dichloromethane (5 mL). The organic layers were combined and separately washed with water and saturated NH ₄ Cl (aq) and brine. Then over MgSO ₄ Dried, filtered and concentrated under reduced pressure. Mixing the residueN- (4-bromobenzyl) -N-cyclopropyl-1-ethyl-5-oxopyrrolidine-3-carboxamide (275 mg) was used in the next step after concentration and drying in vacuo without further purification. LC-MS (m/z) 365.2, 367.1 [M+H] ⁺ 。

Step 2 Add 4- (4- (trifluoromethyl) piperidin-1-yl) aniline (100 mg, 0.41 mmol, 1.0 equiv.) andN- (4-bromobenzyl) -NTo a solution of-cyclopropyl-1-ethyl-5-oxopyrrolidine-3-carboxamide (150 mg, 0.41 mmol, 1.0 equiv.) in 1,4-dioxane (10 mL) was added (9,9-dimethyl-9 respectivelyH-xanthene-4,5-diyl) bis (diphenylphosphine) (18.95 mg, 0.032 mmol, 0.08 equiv.) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (11.98 mg, 0.016 mmol, 0.04 eq) and cesium carbonate (200.0 mg, 0.64mmol, 1.5 eq). The resulting mixture was heated to 100 ℃ and stirred at the same temperature overnight. The reaction was diluted with water (10 mL) and extracted 3 times with ethyl acetate (5 mL). The organic layers were combined and washed with water and saturated NaHCO, respectively ₃ (aqueous solution) and brine wash. Then over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/AcOEt, 1/6) to give 108.2 mg as a blue solidN-cyclopropyl-1-ethyl-5-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide 299 in a yield of 50.00%. ¹ H NMR (400 MHz, methanol-d ₄ ) 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] ⁺ 。

1-methyl-5-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (214)

From 4- (aminomethyl) -N-(4-The title compound 214 (14.2 mg) was prepared in 26.14% yield as a light blue solid in (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (40 mg, 0.11 mmol) and 1-methyl-5-oxopyrrolidine-3-carboxylate (31 mg, 0.17 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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] ⁺ 。

N-hydroxy-1-isopropyl-N- (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) piperidine-4-carboxamide (215)

The title compound 215 (23.2 mg) was prepared as a white solid in 51.9% overall yield from 4- ((hydroxyamino) methyl) -N- (4- (4-methylpiperidin-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 of 174. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N- (cyclopropylmethyl) -1-ethyl-5-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (216)

¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

2- (4-methylpiperazin-1-yl) -N- (4- ((4- (piperidin-1-yl) phenyl) amino) -2- (trifluoromethyl) benzyl) acetamide (217)

The title compound 217 (20.2 mg) was prepared as a white solid in 35.4% overall yield according to the procedure for compound 163. ¹ H NMR (400 MHz, methanol-d ₄ ) 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[ deg. ] M + H] ⁺ 。

N-hydroxy-N- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) nicotinamide (218)

The title compound 218 (15.2 mg) was prepared as a white solid in 41.7% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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[ 2 ] M + H ] ⁺ 。

N- (4- ((2,6-dimethyl-4- (piperidin-1-yl) phenyl) amino) -3-methylbenzyl) -N-hydroxy-2- (4-methylpiperazin-1-yl) acetamide (219)

The title compound 219 (16.8 mg) was prepared as a white solid in 43.9% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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[ deg. ] M + H] ⁺ 。

N- (2-fluoro-4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) -N-hydroxy-2- (4-methylpiperazin-1-yl) acetamide (220)

The title compound 220 (20.1 mg) was prepared as a white solid in 48.7% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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[ 2 ] M + H] ⁺ 。

4-acetyl-1- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) piperazin-2-one (221)

Acetyl chloride (15.7 mg, 0.2 mmol) was added dropwise to a solution of 1- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) piperazin-2-one (36.5 mg, 0.1 mmol) and DIEA (38.7 mg, 0.3 mmol) in DCM (2 mL) at 0 ℃. The reaction was then stirred at 0 ℃ for 2 hours. The reaction solution was washed with water (3X 5 mL) and Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by preparative TLC (MeOH/DCM = 1/10) to provide the desired product as a yellow solid. ¹ H NMR (400 MHz, methanol-d 4). Delta.7.27-6.72 (m, 8H), 4.52 (s, 2)H) 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[ 2 ] M + H] ⁺

4- (cyclopropylmethyl) -1- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) piperazin-2-one (222)

To 1- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) piperazin-2-one (18.2 mg, 0.05 mmol) and K ₂ CO ₃ (10.4 mg, 0.75 mmol) to a mixture in ACN (2.0 mL) was added (bromomethyl) cyclopropane (8.1 mg, 0.6 mmol). The reaction was then stirred at room temperature overnight. 10 mL water was added. The resulting solution was extracted with 3 × 10 mL of ethyl DCM. The organic layers were combined, washed with water (3x10 mL), dried and concentrated in vacuo. The residue was purified by preparative TLC (MeOH/DCM = 1/20) to provide the desired product as a yellow solid (7.0 mg, 33.4%). ¹ H NMR (400 MHz, methanol-d 4) 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 ]+。

1-Ethyl-5-oxo-N-propyl-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (223)

¹ H NMR (400 MHz, methanol-d ₄ ) 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, J = 12.7 Hz, 2H), 1.80 - 1.46 (m, 4H), 1.09 (dt, J = 17.6, 7.4 Hz, 3H), 0.87 (dt, J= 9.8, 7.4 Hz, 3H). Mass (m/z): 531.2 [ M + H ]] ⁺ 。

2- (4-methyl-3-oxopiperazin-1-yl) -N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) acetamide (224)

From 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (100 mg, 0.29 mmol) and 2- (4-methyl-3-oxopiperazin-1-yl) acetic acid (66 mg, 0.31 mmol) the title compound 224 (18.4 mg) was prepared in 12.77% yield as a light blue solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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] ⁺ 。

1-ethyl-N-methyl-5-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (225)

¹ H NMR (400 MHz, methanol-d ₄ ) 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, 3H), 2.21 (br m, 1H), 1.93 (br m, 2H), 1.68 (br m, 2H), 1.08 (t, J= 7.4 Hz, 3H). Mass (m/z): 503.3 [ M + H ]] ⁺ 。

N-hydroxy-N- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) hexanamide (226)

Prepared according to the procedure for compound 108 in an overall yield of 38.4%The title compound 226 (11.3 mg) as a white solid. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ] C + H] ⁺ 。

2- (4-methylpiperazin-1-yl) -N- (4- ((4- (piperidin-1-yl) phenyl) amino) -3- (trifluoromethyl) benzyl) acetamide (227)

The title compound 227 (15.9 mg) was prepared as a white solid in 56.9% overall yield 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[ deg. ] M + H] ⁺ 。

1-methyl-2-oxo-N- (4- ((4- (piperidin-1-yl) phenyl) amino) -2- (trifluoromethyl) benzyl) piperidine-4-carboxamide (228)

The title compound 228 (21.2 mg) was prepared as a white solid in 47.5% overall yield according to the procedure for compound 163. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 2[ M ] +H] ⁺ 。

N- (4- ((3,5-difluoro-4- (piperidin-1-yl) phenyl) amino) benzyl) -N-hydroxy-2- (4-methylpiperazin-1-yl) acetamide (229)

The title compound 229 (11.9 mg) was prepared as a white solid in 27.1% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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[ 2 ] M + H ] ⁺ 。

1-methyl-2-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) piperidine-4-carboxamide (230)

4- (aminomethyl) at room temperatureN- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (100 mg, 0.29 mmol, 1.0 equiv.) and 1-methyl-2-oxopiperidine-4-carboxylic acid (49 mg, 0.31 mmol, 1.1 equiv.) in the ultra-dried stateN,NTo the solution in dimethylformamide (5 mL) was added 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholin-4-ium chloride (87 mg, 0.31 mmol, 1.1 equiv.) andN-ethyl-NIsopropylpropan-2-amine (142 mmL, 0.86 mmol, 3.0 equiv.). The resulting solution was stirred at room temperature overnight. The reaction mixture was added dropwise to water (25 mL) with stirring. The precipitate was filtered, the filter cake was washed 3 times with water and dried in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/AcOEt, 1/5) to give 1-methyl-2-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) piperidine-4-carboxamide 296 in a yield of 31.32%. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 = 12.1, 10.1 Hz, 2H), 1.88 (d, J = 12.4 Hz, 2H), 1.57 (d, J = 12.8 Hz, 2H)。LC-MS (m/z) 489.4 [M+H] ⁺ 。

N- (tert-butyl) -1-ethyl-5-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (231)

¹ H NMR (400 MHz, methanol- d ₄ ) 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 ]] ⁺ 。

1- (4- ((4- (4,4-difluoropiperidin-1-yl) phenyl) amino) benzyl) -4-ethylpiperazin-2-one (232)

A mixture of 1- (4-bromobenzyl) -4-ethylpiperazin-2-one (91 mg, 0.307 mmol), 4- (4,4-difluoropiperidin-1-yl) aniline (50 mg, 0.236 mmol), pd2 (dppf) 2Cl2 (4 mg, 0.005 mmol), xantphos (6 mg, 0.010 mmol), cs2CO3 (116 mg, 0.354 mmol) and Tol (5 mL) was stirred at 100 ℃ for 16 h. The mixture was concentrated and purified by preparative HPLC to give the desired product as a white solid (10.0 mg, 9.9%). ¹ H NMR (400 MHz, methanol-d ₄ ) 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 = 7.4, 1.4 Hz, 2H), 2.87 (s, 2H), 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): 429.3 [ M + H ]] ⁺ 。

N- (2,6-difluoro-4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) -2- (4-methylpiperazin-1-yl) acetamide (233)

The title compound 233 (20.7 mg) was prepared as a white solid in 46.1% overall yield according to the procedure for compound 163. ¹ H NMR (400 MHz, methanol-d ₄ ) 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] ⁺ 。

3- (2-oxopyrrolidin-1-yl) -N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) propionamide (234)

¹ H NMR (400 MHz, methanol- d ₄ ) 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 ]] ⁺ 。

1-acetyl-N- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) piperidine-4-carboxamide (235)

The title compound 235 (4.2 mg) was prepared as a white solid in 30.8% overall yield according to the procedure for compound 163. ¹ H NMR (400 MHz, methanol-d ₄ ) 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] ⁺

1- (cyclopropanecarbonyl) -N- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) piperidine-4-carboxamide (236)

The title compound 236 (5.1 mg) was prepared as a white solid in 35.1% overall yield according to the procedure for compound 163. ¹ H NMR (400 MHz, methanol-d ₄ ) Delta 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] ⁺

N- (4- ((3-chloro-4- (piperidin-1-yl) phenyl) amino) benzyl) -2- (4-methylpiperazin-1-yl) acetamide (237)

The title compound 237 (20.7 mg) was prepared as a white solid in 48.3% overall yield according to the procedure for compound 163. ¹ H NMR (400 MHz, methanol-d ₄ ) 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[ 2 ] M + H] ⁺

1- (4- ((4- (2,6-dimethylmorpholino) phenyl) amino) benzyl) -4-ethylpiperazin-2-one (238)

The title compound 238 (11.3 mg) was prepared as a white solid in 26.7% overall yield according to the procedure for compound 202. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 = 7.2 Hz, 2H), 1.22 (d, J = 6.2 Hz, 6H), 1.12 (t, J= 7.2 Hz, 3H). Mass (m/z): 423.3[ M ] +H] ⁺

2- (4-methylpiperazin-1-yl) -N- (4- ((4- (piperidin-1-yl) -3- (trifluoromethyl) phenyl) amino) benzyl) acetamide (239)

The title compound 239 (12.5 mg) was prepared as a yellow solid in 25.5% total yield from N- (4- (aminomethyl) phenyl) -4- (piperidin-1-yl) -3- (trifluoromethyl) aniline (34.9 mg, 0.1 mmol), 4- (dimethylamino) butyric 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 of 163. ¹ H NMR (400 MHz, methanol-d 4) 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 = 6.3425 zxft 3H). Mass (m/z): 490.4 [ M + H ] ] ⁺ 。

4-Ethyl-1- (4- ((4- (piperidin-1-yl) phenyl) amino) -2- (trifluoromethyl) benzyl) piperazin-2-one (240)

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

Step 2 the title compound 240 (40.1 mg) was prepared as a light yellow solid in 63.6% yield from 1- (4-bromo-2- (trifluoromethyl) benzyl) -4-ethylpiperazin-2-one (240-1) (50 mg, 0.14 mmol) and 4- (piperidin-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] ⁺ 。

4- (dimethylamino) -N- (4- ((4- (piperidin-1-yl) -3- (trifluoromethyl) phenyl) amino) benzyl) butanamide (241)

The title compound 241 (32.0 mg) was prepared as a white solid in 76.1% total yield from N- (4- (aminomethyl) phenyl) -4- (piperidin-1-yl) -3- (trifluoromethyl) aniline (30 mg, 0.086 mmol) and 4- (dimethylamino) butyric acid hydrochloride (19 mg, 0.122 mmol) according to the procedure of 179. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

1- (tert-butyl) -5-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (242)

From 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (100 mg, 0.29 mmol) and 1- (tert-butyl) -5-oxopyrrolidine-3-carboxylic acid (58 mg, 0.31 mmol) the title compound 242 (97.2 mg) was prepared as a white solid in a yield of 69.74%. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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] ⁺ 。

1-Ethyl-N- (2-hydroxyethyl) -5-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (243)

¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N-hydroxy-2- (4-methylpiperazin-1-yl) -N- (4- ((4- (3- (trifluoromethyl) pyrrolidin-1-yl) phenyl) amino) benzyl) acetamide (244)

The title compound 244 (24.6 mg) was prepared as a white solid in 57.1% overall yield from 4- ((hydroxyamino) methyl) -N- (4- (3- (trifluoromethyl) pyrrolidin-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 of 179. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N-ethyl-2- (4-methylpiperazin-1-yl) - N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) acetamide (245)

Step 1. According toN- (4-bromobenzyl) -NProcedure for (E) -Ethyl-2- (4-methyl-3-oxopiperazin-1-yl) acetamide (289-1)N- (4-bromobenzyl) ethylamine (500 mg, 2.34 mmol) and 2- (4-methylpiperazin-1-yl) acetic acid (406 mg, 2.57 mmol) were prepared as colorless oilN- (4-bromobenzyl) -N-ethyl-2- (4-methylpiperazin-1-yl) acetamide (245-1). The residue was concentrated in vacuo and dried and used in the next step without further purification. LC-MS (M/z) 354.2, 356.1 [ M + H ]] ⁺ 。

Step 2 from 4- (4- (trifluoromethyl) piperidin-1-yl) aniline (100 mg, 0.41 mmol) andN- (4-bromobenzyl) -N-Ethyl-2- (4-methylpiperazin-1-yl) acetamide (145 mg, 0.41 mmol) the title compound 245 (56.2 mg) was prepared as a blue solid in 26.52% yield. ¹ H NMR (400 MHz, methanol-d ₄ ) 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] ⁺ 。

N-hydroxy-N- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) -2- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) acetamide (246)

Step 1. To a solution of 1- (2,2,2-trifluoroethyl) piperazine dihydrochloride (300 mg, 1.24 mmol, 1.0 equiv) in water (5 mL) was added 2-bromoacetic acid (190 mg, 1.37 mmol, 1.1 equiv) and potassium carbonate (516 mg, 3.73 mmol, 3.0 equiv), respectively, slowly in a 0 ℃ ice-water bath. The reactants are warmed Warm to room temperature and stir overnight. The reaction mixture was acidified with 1N hydrochloric acid to pH =4 and then extracted 3 times with dichloromethane (5 mL). The organic layers were combined and MgSO ₄ Dried, filtered and concentrated under reduced pressure. The residue 2- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) acetic acid (246-1) was used in the next step without further purification after concentration in vacuo and drying. LC-MS (M/z) 227.4 [ M + H] ⁺ 。

Step 2. Synthesis of 2- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) acetic acid (246-1) (46 mg, 0.16 mmol) and 4- ((hydroxyamino) methyl) -N- (4- (piperidin-1-yl) phenyl) aniline (50 mg, 0.17 mmol) the title compound 246 (14.9 mg) was prepared in 17.53% yield as a brown solid. 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, 3H), 2.95 (q, J = 9.5 Hz, 3H), 2.76-2.51 (m, 8H), 1.82-1.61 (m, 4H), 1.57 (s, 2H)。LC-MS (m/z) 506.7 [M+H] ⁺ 。

N- (2-chloro-4- ((5- (piperidin-1-yl) pyridin-2-yl) amino) benzyl) -N-hydroxy-2- (4-methylpiperazin-1-yl) acetamide (247)

The title compound 247 (17.9 mg) was prepared as a white solid in 42.3% overall yield from N- (3-chloro-4- ((hydroxyamino) methyl) phenyl) -5- (piperidin-1-yl) pyridin-2-amine (30 mg, 0.090 mmol) and 2- (4-methylpiperazin-1-yl) acetic acid (19 mg, 0.117 mmol) according to the procedure of 179. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ] ] ⁺ 。

N- (4- ((5-fluoro-6- (piperidin-1-yl) pyridin-3-yl) amino) benzyl) -2- (4-methyl-3-oxopiperazin-1-yl) acetamide (248)

The title compound 248 (16.9 mg) was prepared as a white solid in 41.2% overall yield according to the procedure for compound 163. ¹ H NMR (400 MHz, methanol-d ₄ ) 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] ⁺

N- (4- ((4- (4,4-difluoropiperidin-1-yl) phenyl) amino) benzyl) -N-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (249)

The title compound 249 (10.1 mg) was prepared as a white solid in 33.4% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 2[ M ] +H] ⁺

1- (4- ((4- (4,4-difluoropiperidin-1-yl) phenyl) amino) benzyl) -4-fluoropyridin-2 (1H) -one (250)

The title compound 250 (20.1 mg) was prepared as a white solid in 48.4% overall yield according to the procedure for compound 202. ¹ H NMR (400 MHz, methanol-d ₄ ) 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[ mu ] M + H ] ⁺

N- (4- ((4- (4,4-difluoropiperidin-1-yl) phenyl) amino) benzyl) -N-hydroxy-1-methyl-6-oxopiperidine-3-carboxamide (251)

The title compound 251 (9.9 mg) was prepared as a white solid in 23.5% overall yield from 4- (4,4-difluoropiperidin-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 of 174. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N- (4- ((4- (4,4-difluoropiperidin-1-yl) phenyl) amino) benzyl) -1-ethyl-N-hydroxy-5-oxopyrrolidine-3-carboxamide (252)

The title compound 251 (7.0 mg) was prepared as a white solid in 17% overall yield from 4- (4,4-difluoropiperidin-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 of 174. ¹ H NMR (400 MHz, methanol-d ₄ ) 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, J0.4 Hz, 2H), 2.00-1.91 (m, 2H). Mass (m/z): 473.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4,4-difluoropiperidin-1-yl) phenyl) amino) benzyl) -N-hydroxy-2- (2-methoxyethoxy) acetamide (253)

From 4- (4,4-difluoropiperidin-1-yl) -The title compound 253 (8.2 mg) was prepared as a white solid in 10.2% overall yield from N- (4- ((hydroxyamino) methyl) phenyl) aniline (30 mg, 0.090 mmol) and 2- (2-methoxyethoxy) acetic acid (16 mg, 0.117 mmol). ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

1- (cyclopropylmethyl) -N-hydroxy-2-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) piperidine-4-carboxamide (254)

The title compound 254 (11.6 mg) was prepared according to the procedure of 179 from 4- ((hydroxyamino) methyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (30 mg, 0.082 mmol) and 1- (cyclopropylmethyl) -2-oxopiperidine-4-carboxylic acid (21 mg, 0.107 mmol) in 26.4% overall yield as a white solid. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

3- (4- ((4- ((N-hydroxy-2- (4-methylpiperazin-1-yl) acetylamino) methyl) phenyl) amino) phenyl) -N, N-dimethylpropionamide (255)

¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

4- (dimethylamino) -N- (4- ((4- (6-fluoropyridin-3-yl) phenyl) amino) benzyl) -N-hydroxybutyramide (256)

¹ H NMR (400 MHz, methanol-d ₄ ) 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, 2H), 2.82 (t, J= 7.4 Hz, 2H), 2.68-2.59 (m, 2H), 2.56 (s, 6H), 2.06-1.88 (m, 2H). Mass (m/z): 423.3 [ M + H ]] ⁺ 。

N-hydroxy-1-methyl-6-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) piperidine-3-carboxamide (257)

Step 1. Preparation of a mixture of 4- ((hydroxyamino) methyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (20 mg, 0.054 mmol) and 1-methyl-6-oxopiperidine-3-carboxylic acid (10.3 mg, 0.066 mmol) the title compound 257 (10.5 mg) was prepared as a light yellow powder in 38.02% yield. ¹ H NMR (400 MHz, methanol-d ₄ ) 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] ⁺ 。

N-hydroxy-1-methyl-6-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) piperidine-3-carboxamide (258)

From 4- ((hydroxyamino) methyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (20 mg, 0.054 mmol) and 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (9.4 mg, 0.066 mmol) the title compound 258 (19.9 mg) was prepared as a light yellow solid in a yield of 72.06%. ¹ H NMR (400 MHz, methanol-d ₄ ) 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, 1H), 2.06-1.86 (m, J = 24.3 Hz, 3H), 1.84 - 1.55 (m, 2H), 1.34-1.27 (m, 1H), 1.10 (t, J = 7.2 Hz, 3H)。LC-MS (m/z) 491.2 [M+H] ⁺ 。

3- (hydroxy (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) carbamoyl) azetidine-1-carboxylic acid tert-butyl ester (259)

The title compound 259 (164.1 mg) was prepared as a white solid in 46.9% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.27-6.79 (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 ] ⁺

N-hydroxy-1-methyl-2-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) piperidine-4-carboxamide (260)

The procedure was followed 137 from 4- ((hydroxyamino) methyl) -N- (4- (4- (trifluoromethyl) piperidin-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) to affordTotal yield of 40.4% the title compound 260 (36.6 mg) was prepared as a yellow solid. ¹ H NMR (400 MHz, methanol-d 4) 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] ⁺ 。

1-Ethyl-5-oxo-N- (4- ((4- (3- (trifluoromethyl) pyrrolidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (261)

The title compound 261 (9.4 mg) was prepared as a blue solid in total yield of 32.9% from 4- (aminomethyl) -N- (4- (3- (trifluoromethyl) pyrrolidin-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), HATU (30.4 mg, 0.08 mmol) according to the procedure of 209. ¹ H NMR (400 MHz, methanol-d 4) 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 ]] ⁺ 。

N-hydroxy-2- (4-methyl-3-oxopiperazin-1-yl) -N- (4- ((4- (piperidin-1-yl) phenyl) amino) -2- (trifluoromethyl) benzyl) acetamide (262)

Step 1. Synthesis of a mixture of 4- (piperidin-1-yl) aniline (1.76 g, 10.0 mmol), 4-bromo-2- (trifluoromethyl) benzaldehyde (2.53 g, 10.0 mmol), pd (dppf) according to the procedure 137-3 ₂ Cl ₂ (73.1 mg, 0.2 mmol)、Xantphos (231.6 mg, 0.4 mmol)、Cs ₂ CO ₃ (4.89 g, 15 mmol) the title compound 262-3 (2.1 g) was prepared as a yellow oil in 60.3% overall yield. Mass (m/z): 349.3 [ M + H ]] ⁺ 。

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

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

Step 4 the title compound 262 (30.0 mg) was prepared as a yellow solid in 38.5% overall yield from 4- ((hydroxyamino) methyl) -N- (4- (piperidin-1-yl) phenyl) -3- (trifluoromethyl) aniline (55 mg, 0.15 mmol), 2- (4-methyl-3-oxopiperazin-1-yl) acetate salt (41 mg, 0.20 mmol), DMT-MM (65 mg, 0.23 mmol), DIEA (58 mg, 0.45 mmol), and DMF (1.0 mL) according to the procedure of 137. ¹ H NMR (400 MHz, methanol-d 4) 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, 4H), 2.81 (t, J = 5.5 Hz, 2H), 2.39 (s, 3H), 1.78 (p, J = 5.9 Hz, 4H), 1.64-1.54 (m, 7H). Mass (m/z): 520.3 [ M + H ]] ⁺ 。

N-hydroxy-2- (4-methyl-2-oxopiperazin-1-yl) -N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) acetamide (263)

The title compound 263 (19.0 mg) was prepared as a yellow solid in 24.4% overall yield from 4- ((hydroxyamino) methyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (55 mg, 0.15 mmol), 2- (4-methyl-3-oxopiperazin-1-yl) acetate hydrochloride (41 mg, 0.20 mmol), DMT-MM (65 mg, 0.23 mmol), DIEA (58 mg, 0.45 mmol), and DMF (1.0 mL) according to the procedure of 137. ¹ H NMR (400 MHz, methanol-d 4). Delta.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] ⁺ 。

1-Ethyl-5-oxo-N- ((5- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) pyridin-2-yl) methyl) pyrrolidine-3-carboxamide (264)

The title compound 264 (23.6 mg) was prepared as a blue solid in 48.2% total yield from 6- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) pyridin-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), HATU (38.0 mg, 0.1 mmol) according to the procedure of 209. ¹ H NMR (400 MHz, methanol-d 4) 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 ] ] ⁺ 。

2- (4-methylpiperazin-1-yl) -N- (4- (pyrimidin-5-ylamino) benzyl) acetamide (265)

The title compound 265 (6.7 mg) was prepared as a white solid in 12.9% overall yield from N- (4-bromobenzyl) -2- (4-methylpiperazin-1-yl) acetamide (50 mg, 0.153 mmol) and pyrimidin-5-amine (22 mg, 0.230 mmol) according to the procedure of 232. ¹ H NMR (400 MHz, methanol-d ₄ ) 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] ⁺ 。

1-methyl-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -1H-imidazole-5-carboxamide (266)

The title compound 266 (12.8 mg) was prepared as a white solid in 32.6% overall yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-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 of 203. ¹ H NMR(400 MHz, DMSO-d ₆ ) 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 ]]+。

6-chloro-N- (4- ((4- (4,4-difluoropiperidin-1-yl) phenyl) amino) benzyl) -N-hydroxypyrazine-2-carboxamide (267)

From 4- (4,4-difluoropiperidin-1-yl) -NThe title compound 267 (11.4 mg) was prepared in 4.01% yield as a pink powder in (4- ((hydroxyamino) methyl) phenyl) aniline (200 mg, 0.60 mmol) and 6-chloropyrazine-2-carboxylic acid (105 mg, 0.66 mmol). ¹ H NMR (400 MHz, methanol-d ₄ ) 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-d ₄ ) δ -99.35。 LC-MS (m/z) 474.2 [M+H] ⁺ 。

N- (4- ((4- (4,4-difluoropiperidin-1-yl) benzene)Group) amino) benzyl) -N-hydroxy-2- (3- (trifluoromethyl) piperazin-1-yl) acetamide (268)

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) according to the procedure for 2- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) acetic acid (246-1). The residue was concentrated in vacuo and dried and used in the next step without further purification. LC-MS (M/z) 213.4 [ M + H] ⁺ 。

Step 2. Preparation of 4- (4,4-difluoropiperidin-1-yl) -propanoic acid according to the procedure for Compound 290N- (4- ((hydroxyamino) methyl) phenyl) aniline (40 mg, 0.12 mmol) and 2- (3- (trifluoromethyl) piperazin-1-yl) acetic acid (268-1) (31 mg, 0.14 mmol) the title compound 268 (22.0 mg) was prepared as a white powder in 34.26% yield. ¹ H NMR (400 MHz, methanol-d ₄ ) 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] ⁺ 。

4- (dimethylamino) -N-hydroxy-N- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) butanamide (269)

¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N- (4- ((4- (6-fluoropyridin-3-yl) phenyl) amino) benzyl) -N-hydroxy-2-morpholinoacetamide (270)

¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N- (4- ((4-cyclohexylphenyl) amino) benzyl) -N-hydroxy-2- (4-methylpiperazin-1-yl) acetamide (271)

¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N-hydroxy-1-methyl-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -1H-imidazole-5-carboxamide (272)

The title compound 272 (20.1 mg) was prepared according to the procedure of 174 as a white solid in 51.7% overall yield from 4- ((hydroxyamino) methyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (30 mg, 0.082 mmol) and 1-methyl-1H-imidazole-5-carboxylic acid (14 mg, 0.107 mmol). ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

1-Ethyl-N-hydroxy-2-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) piperidine-4-carboxamide (273)

The title compound 273 (14.5 mg) was prepared as a white solid in 34.0% total yield from 4- ((hydroxyamino) methyl) -N- (4- (4- (trifluoromethyl) piperidin-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 174. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N- ((5- ((4- (4,4-difluoropiperidin-1-yl) phenyl) amino) -3-fluoropyridin-2-yl) methyl) -N-hydroxy-2- (4-methyl-3-oxopiperazin-1-yl) acetamide (274)

The title compound 274 (11.6 mg) was prepared according to the procedure of 174 from N- (4- (4,4-difluoropiperidin-1-yl) phenyl) -5-fluoro-6- ((hydroxyamino) methyl) pyridin-3-amine (30 mg, 0.085 mmol) and 2- (4-methyl-3-oxopiperazin-1-yl) acetate salt (23 mg, 0.111 mmol) as a white solid in an overall yield of 26.9%. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

1- (cyclopropanecarbonyl) -N-hydroxy-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (275)

The title compound 275 (13.1 mg) was prepared as a white solid in 22.3% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 2 [ M ] +H ] ⁺

N-hydroxy-1-isopropyl-N- (4- ((4- (2-methylpiperidin-1-yl) phenyl) amino) benzyl) piperidine-4-carboxamide (276)

The title compound 276 (13.5 mg) was prepared as a white solid in 30.3% overall yield from 4- ((hydroxyamino) methyl) -N- (4- (2-methylpiperidin-1-yl) phenyl) aniline (30 mg, 0.096 mmol) and 1-isopropylpiperidine-4-carboxylic acid (26 mg, 0.125 mmol) according to the procedure of 179. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N-hydroxy-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) azetidine-3-carboxamide (277)

The title compound 277 (86.1 mg) was prepared as a white solid in 42.8% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺

N-hydroxy-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (278)

The title compound 278 (90.1 mg) was prepared as a white solid in 44.5% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ] ] ⁺

1-acetyl-N-hydroxy-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) azetidine-3-carboxamide (279)

The title compound 279 (15.1 mg) was prepared as a white solid in 31.6% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺

1- (cyclopropanecarbonyl) -N-hydroxy-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) azetidine-3-carboxamide (280)

The title compound 280 (17.5 mg) was prepared as a white solid in 32.7% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺

N-hydroxy-1-isopropyl-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) piperidine-4-carboxamide (281)

The title compound 281 (14.0 mg) was prepared according to the procedure of 179 as a white solid in a total yield of 32.9% from 4- ((hydroxyamino) methyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (30 mg, 0.082 mmol) and 1-isopropylpiperidine-4-carboxylic acid hydrochloride (22 mg, 0.107 mmol). ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N-hydroxy-1-isopropyl-N- (4- ((4- (3- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) piperidine-4-carboxamide (282)

From 4- ((hydroxyamino) methyl) -N- (4- (3- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (30 mg) according to procedure 1790.082 mmol) and 1-isopropylpiperidine-4-carboxylic acid hydrochloride (22 mg, 0.107 mmol) the title compound 282 (19.6 mg) was prepared as a white solid in an overall yield of 45.7%. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

4-Ethyl-1- (4- ((3-fluoro-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) -2- (trifluoromethyl) benzyl) piperazin-2-one (283)

The title compound 283 (6.1 mg) was prepared as a white solid in 12% overall yield from 1- (4-bromo-2- (trifluoromethyl) benzyl) -4-ethylpiperazin-2-one (50 mg, 0.137 mmol) and 3-fluoro-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (47 mg, 0.178 mmol) according to the procedure of 232. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

4-Ethyl-1- (4- ((3-fluoro-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) piperazin-2-one (284)

Prepared according to the procedure of 232 from 1- (4-bromobenzyl) -4-ethylpiperazin-2-one (50 mg, 0.168 mmol) and 3-fluoro-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (57 mg, 0.218 mmol) in a total yield of 3.7% as a white solidTitle compound 284 (2.9 mg) of (1). ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N-hydroxy-1-methyl-2-oxo-N- (4- ((4- (piperidin-1-yl) phenyl) amino) -2- (trifluoromethyl) benzyl) piperidine-4-carboxamide (285)

The title compound 285 (13.4 mg) was prepared as a yellow solid in 17.7% overall yield from 4- ((hydroxyamino) methyl) -N- (4- (piperidin-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) according to the procedure of 137. ¹ H NMR (400 MHz, methanol-d 4) 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 ]] ⁺ 。

N-hydroxy-2- (4-methyl-3-oxopiperazin-1-yl) -N- (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) acetamide (286)

The titled solid was prepared as a yellow solid in 31.0% overall yield from 4- ((hydroxyamino) methyl) -N- (4- (4-methylpiperidin-1-yl) phenyl) aniline (54 mg, 0.17 mmol), 2- (4-methyl-3-oxopiperazin-1-yl) acetate salt (42 mg, 0.20 mmol), DMT-MM (55 mg, 0.20 mmol), DIEA (66 mg, 0.51 mmol), and DMF (1.0 mL) according to the procedure of 137Compound 286 (24.5 mg). ¹ H NMR (400 MHz, methanol-d 4) 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 ]] ⁺ 。

N-hydroxy-2,4-dimethyl-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) oxazole-5-carboxamide (287)

The title compound 287 (15.0 mg) was prepared as a white solid in 37.4% overall yield from 4- ((hydroxyamino) methyl) -N- (4- (4- (trifluoromethyl) piperidin-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 of 174. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ] ] ⁺ 。

2,4-dimethyl-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) oxazole-5-carboxamide (288)

The title compound 288 (8.8 mg) was prepared as a white solid in 21.7% overall yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-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 of 203. ¹ H NMR(400 MHz, DMSO-d ₆ ) 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 ]]+。

N-ethyl-2- (4-methyl-3-oxopiperazin-1-yl) -N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) acetamide (289)

Step 1. In argon atmosphere at room temperatureN- (4-bromobenzyl) ethylamine (200 mg, 0.93 mmol, 1.0 equiv.) and 2- (4-methyl-3-oxopiperazin-1-yl) acetic acid (177 mg, 1.03 mmol, 1.1 equiv.) in the super-dried stateN,NAdding 2- (1) to a solution of-dimethylformamide (5 mL)H-benzo [ d ]][1,2,3]Triazol-1-yl) -1,1,3,3-tetramethylisouronium tetrafluoroborate (390 mg, 1.21 mmol, 1.3 equivalents) andN-ethyl-N-isopropylpropan-2-amine (463 mmL, 2.80 mmol, 3.0 equiv.) and stirred overnight. The reaction was diluted with water (10 mL) and extracted 3 times with dichloromethane (5 mL). The organic layers were combined and separately washed with water and saturated NH ₄ Cl (aq) and brine. Then over MgSO ₄ Dried, filtered and concentrated under reduced pressure. Mixing the residueN- (4-bromobenzyl) -N-ethyl-2- (4-methyl-3-oxopiperazin-1-yl) acetamide (289-1) was used in the next step without further purification after concentration and drying in vacuo. LC-MS (M/z) 368.2, 370.1 [ M + H [ ]] ⁺ 。

Step 2. Preparation of 4- (4- (trifluoromethyl) piperidin-1-yl) aniline (100 mg, 0.41 mmol) andN- (4-bromobenzyl) -N-ethyl-2- (4-methyl-3-oxopiperazin-1-yl) acetamide (151 mg, 0.41 mmol) the title compound 289 (38.2 mg) was prepared as a white powder in a yield of 17.55%. ¹ H 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] ⁺ 。

1-ethyl-5-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (290)

Step 1, in an argon atmosphere, (A) and (B)E) To a solution of-4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzaldoxime (900 mg, 2.48 mmol) in methanol (100 mL) was added palladium on activated carbon (100 mg, 10%). Acetic acid (1.5 mL) was added dropwise. The flask was evacuated and flushed 3 times with hydrogen. The mixture was stirred at room temperature under hydrogen (balloon) atmosphere overnight. The reaction-completed mixture was filtered through celite, the filtrate was concentrated and the residue was 4- (aminomethyl) - N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (290-1) was used in the next step without further purification after concentration and drying in vacuo. LC-MS (M/z) 350.2 [ M + H] ⁺ 。

Step 2, adding 4- (aminomethyl) at room temperatureN- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (290-1) (100 mg, 0.29 mmol, 1.0 equiv.) and 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (49 mg, 0.31 mmol, 1.1 equiv.) in the super-dried stateN,NTo a solution of-dimethylformamide (5 mL) were added 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholin-4-ium chloride (87 mg, 0.31 mmol, 1.1 equiv.), andN-ethyl-NIsopropylpropan-2-amine (142 mmL, 0.86 mmol, 3.0 equiv.). The resulting solution was stirred at room temperature overnight. The reaction mixture was added dropwise to water (25 mL) with stirring. The precipitate was filtered, the filter cake was washed 3 times with water and dried in vacuo. 1-Ethyl-5-oxo-substituted ketone as a pale white solid was obtainedN- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (290) in 79.38% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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] ⁺ 。

2- (2,6-dimethylmorpholino) -N-hydroxy-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) acetamide (291)

The title compound 291 (31.4 mg) was prepared as a white solid in 55.9% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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, 2H), 2.71-2.58 (m, 2H), 2.23 (m, 1H), 2.00-1.71 (m, 4H), 1.10 (d, J= 6.4 Hz, 6H). Mass (m/z): 521.3 [ M + H ]] ⁺

N-hydroxy-2,2-dimethyl-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) tetrahydro-2H-pyran-4-carboxamide (292)

The title compound 292 (10.1 mg) was prepared as a white solid in 21.8% overall yield according to the procedure for compound 108. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺

N- (4- ((4- (3,3-difluoropiperidin-1-yl) phenyl) amino) benzyl) -N-hydroxy-1-isopropylpiperidine-4-carboxamide (293)

The title compound 293 (19.0 mg) was prepared as a white solid in 43.2% total yield according to the procedure of 179 from 4- (3,3-difluoropiperidin-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). ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

Compounds 294-302 were prepared according to the procedure of scheme 1.

Scheme 1

Compounds 303-314 were prepared according to the procedure of scheme 2.

Scheme 2

Compounds 315-326 were prepared according to the procedure of scheme 3.

Scheme 3

Compounds 327-338 were prepared according to the procedure of scheme 4.

Scheme 4

Compounds 339-350 were prepared according to the procedure of scheme 5.

Scheme 5

Compounds 351-362 were prepared according to the procedure of scheme 6.

Scheme 6.

Active compound group II: representative Synthesis

N- (4- ((4- (tert-butyl (ethyl) amino) phenyl) amino) benzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (363)

Step 1 preparation of tert-butyl (4- ((4- (tert-butyl (ethyl) amino) phenyl) amino) benzyl) carbamate (363-3): n1- (tert-butyl) -N1-ethylbenzene-1,4-diamine (192 mg, 1.0 mmol), (4-bromobenzyl) carbamic acid tert-butyl ester (220 mg, 0.77 mmol), pd (dppf) ₂ Cl ₂ (14.6 mg, 0.02 umol)、Xantphos (23.2 mg, 0.04 mmol)、Cs ₂ CO ₃ (489 mg, 1.5 mmol) in 1,4-dioxane (10 mL) was stirred at 100 ℃ overnight. After cooling to room temperature, 15 mL water was added. The mixture was then extracted with DCM (15 mL x 3). The combined organic layers were washed with water (20 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by preparative TLC (EA) to give the desired product as a yellow solid (204 mg, 67.8%). Mass (m/z): 398.4 [ M + H ]] ⁺

And 2. Step 2.N ¹ Preparation of- (4- (aminomethyl) phenyl) -N4- (tert-butyl) -N4-ethylbenzene-1,4-diamine (363-4): reacting tert-butyl (4- ((4- (tert-butyl (ethyl) amino) phenyl) amino) benzyl) carbamate (204 mg, 0.51 mmol) in 10 mL A solution in 1,4-dioxane in HCl was stirred at room temperature for 30 minutes and concentrated. 5 ml 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 × 3). The combined organic layers were washed with water (10 mL) and Na ₂ SO ₄ Dried and concentrated. The residue was purified by preparative TLC (MeOH/DCM = 1/5) to provide the desired product as a yellow solid. Mass (m/z): 298.3 [ M + H ]] ⁺

And 3. Step 3.NPreparation of- (4- ((4- (tert-butyl (ethyl) amino) phenyl) amino) benzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (363): to a solution of 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (31.4 mg, 0.2 mmol) in DCM (5 ml) was added HATU (76.0 mg, 0.2 mmol). The reaction mixture was then stirred at room temperature for 1 hour. Adding intoN 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). The reaction mixture was then stirred at room temperature for 3 hours. 5 mL water was added. The mixture was then extracted with DCM (5 mL × 3). The combined organic layers were washed with water (10 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by preparative TLC (MeOH/DCM = 1/15) to yield the desired product as a white solid (13.2 mg, 15.0%). ¹ H NMR (300 MHz, methanol-d ₄ ) 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] ⁺ 。

N- (4- ((4- (dimethylamino) phenyl) amino) benzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (364)

Step 1 preparation of tert-butyl (4- ((4- (dimethylamino) phenyl) amino) benzyl) carbamate (364-3): programmed according to 363N ¹ ,N ¹ -dimethylbenzene-1,4-diamine (204 mg, 1.5 mmol), (4-bromobenzyl) carbamic acid tert-butyl ester (286 mg, 1.0 mmol), pd (dppf) ₂ Cl ₂ (14.6 mg, 0.02 mmol)、Xantphos (23.2 mg, 0.04 mmol)、Cs ₂ CO ₃ (489 mg, 1.5 mmol) the title compound 364-3 (160 mg) was prepared as a yellow solid in 46.9% overall yield. Mass (m/z): 342.3 [ M + H ]] ⁺ 。

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

And 3. Step 3.NPreparation of- (4- ((4- (dimethylamino) phenyl) amino) benzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (364): programmed according to 363N ¹ - (4- (aminomethyl) phenyl) -N ⁴ ,N ⁴ -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) the title compound 364 (21.6 mg) was prepared as a yellow solid in 28.4% overall yield. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

1-ethyl-N- (1- (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) phenyl) ethyl) -5-oxopyrrolidine-3-carboxamide (365)

And (1).NPreparation of- (1- (4-bromophenyl) ethyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (365-2): program according to 363The title compound (365-2 (560 mg) was prepared as a white solid in 82.8% total yield from 1- (4-bromophenyl) ethan-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) in mass (M/z): 339.1 [ M + H ] with a total yield of 82.8%] ⁺ 。

Step 2.1-Ethyl-NPreparation of- (1- (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) phenyl) ethyl) -5-oxopyrrolidine-3-carboxamide (365): program according to 363-3 fromN- (1- (4-bromophenyl) ethyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (84.5 mg, 0.25 mmol), 4- (4-methylpiperidin-1-yl) aniline (63 mg, 0.33 mmol), pd ₂ (dba) ₃ (2.3 mg, 2.5 umol), X-Phos (5.9 mg, 12.5 umol), t-BuONa (36 mg, 0.38 mmol) the title compound 365 (4.2 mg) was prepared as a gray solid in total yield of 3.8%. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ] ] ⁺ 。

N- (2-chloro-4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (366)

Step 1 preparation of tert-butyl (4-bromo-2-chlorobenzyl) carbamate: to a solution of compound 366-1 (600 mg, 2.72 mmol) in DCM (20 mL) was added Boc at 25 deg.C ₂ O (891 mg, 4.08 mmol) and TEA (551 mg, 5.44 mmol). The mixture was then stirred at room temperature overnight. Pouring the mixture into H ₂ O, and extracted with DCM (50 ml × 3). The organic layer was washed with brine, over Na ₂ SO ₄ Dried, filtered and concentrated, the residue was purified by silica gel chromatography with EA/PE (20Yield). MS (ESI) M/z 264.0, 266.0 [ M + H] ⁺ 。

Preparation of tert-butyl (2-chloro-4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) benzyl) carbamate: to a solution of a mixture 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 was added Cs ₂ CO ₃ (610 mg, 1.87 mmol) and tris (dibenzylideneacetone) dipalladium (114 mg, 0.12 mmol). The reaction mixture was stirred at 90 ℃ for 16 hours. The mixture was then filtered and concentrated. The residue was purified by preparative TLC to give tert-butyl (2-chloro-4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) benzyl) carbamate 366-4 (351 mg, 61% yield) as a yellow solid. MS (ESI) M/z 460.2 [ M + H ] ] ⁺ 。

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

Step 4. Preparation of N- (2-chloro-4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (SIR-00005284): to a stirred solution of compound 366-5 (253 mg,0.70 mmol), 5-oxopyrrolidine-3-carboxylic acid 366-6 (91 mg,0.70 mmol) in DMF (10 mL) under nitrogen was added N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) uronium (321 mg, 0.84 mmol) and DIEA (136 mg, 1.05 mmol). The reaction mixture was stirred at room temperature for 16 hours. Pouring the mixture into H ₂ O (10 mL) and extracted with EA (20 mL x 3), the organic layer was washed with brine and Na ₂ SO ₄ Dried, filtered and concentrated, and the residue was purified by preparative HPLC to yield 366 (93 mg) as a white solid. MS ( ESI) m/z 471.2 [M+H] ⁺ 。 ¹ H NMR (400 MHz, CD ₃ OD) 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)。

1-ethyl-5-oxo-N- (1- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) phenyl) ethyl) pyrrolidine-3-carboxamide (367)

Programmed according to 363-3N- (1- (4-bromophenyl) ethyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (42.3 mg, 0.125 mmol), 4- (4- (trifluoromethyl) piperidin-1-yl) aniline (40 mg, 0.16 mmol), pd ₂ (dba) ₃ (1.1 mg, 1.6 umol), X-Phos (3.0 mg, 6.2 umol), t-BuONa (18 mg, 0.19 mmol) the title compound 367 (4.1 mg) was prepared as a yellow solid in total yield of 6.5%. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N ¹ - (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) succinamide (368)

From 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperazine)Pyridin-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) was prepared in 16.7% total yield as the light yellow solid, the title compound 368 (11.2 mg). ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

1-cyclopropyl-5-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (369)

The title compound 369 (10.6 mg) was prepared as a yellow solid in 14.1% overall yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-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 at 363. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N ¹ - (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) oxamide (370)

From 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-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 tu) according to the procedure of 363mg, 0.15 mmol) the title compound 370 (10.3 mg) was prepared as a yellow solid in 16.3% overall yield. ¹ H NMR (400 MHz, methanol-d ₄ ) Delta 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 ]] ⁺ 。

N ¹ ,N ¹ -dimethyl-N ² - (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) oxamide (371)

The title compound (16.4 mg) was prepared as a light yellow solid in 24.4% total yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-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) according to the procedure of 363. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

4-oxo-4- (pyrrolidin-1-yl) -N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) butanamide (372)

From 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (70.0 mg, 0.2 mmol), 4-oxo-4- (pyrrolidin-1-yl) butyric acid (41.0 mg, 0.24 mmol), DIEA (77.4 mg, 0.6 mmol) and HATU (91.2 mmol)mg, 0.24 mmol) the title compound 372 (16.4 mg) was prepared as a pale yellow solid in 24.4% overall yield. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N- (4- ((2-methoxy-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (373)

Programmed according to 363-3N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 2-methoxy-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (89 mg, 0.33 mmol), pd ₂ (dba) ₃ (2.0 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), t-BuONa (36.0 mg, 0.38 mmol) the title compound 373 (4.2 mg) was prepared as a yellow solid in a total yield of 3.4%. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ] ] ⁺ 。

N- (4- ((2,6-dimethyl-4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (374)

Programmed according to 363-3N- (4-bromobenzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (81.0 mg, 0.25 mmol), 2,6-dimethyl-4- (4-methylpiperidin-1-yl) aniline (72 mg, 0.33 mmol), pd ₂ (dba) ₃ (2.0 mg, 2.5 umol)、X-Phos (6.0 mg, 12.5 umol), t-BuONa (36.0 mg, 0.38 mmol) the title compound 374 (35.1 mg) was prepared as a white solid in an overall yield of 30.4%. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

1- (2-ethoxyethyl) -5-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (375)

From 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline hydrochloride (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) the title compound 375 (11.0 mg) was prepared as a light yellow solid in 11.4% overall yield. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N ¹ ,N ¹ -dimethyl-N ⁴ - (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) succinimide (376)

From 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline hydrochloride (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) the title compound 376 (15.9 mg) was prepared as a light yellow solid in a total yield of 22.3%. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N ¹ - (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) glutaramide (377)

Step 1.preparation of 5-oxo-5- ((4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) amino) pentanoic acid (377-2): to 4- (aminomethyl) -NTo a solution of- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline hydrochloride (115 mg, 3.0 mmol) in DCM (10.0 mL) was added DIEA (1.16 g, 9 mmol). dihydro-2H-pyran-2,6 (3H) -dione (410.8 mg, 3.6 mmol) was then added and the reaction was stirred at room temperature for 2 hours. The solution was washed with 2x10 mL of water and Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by preparative TLC (MeOH/DCM = 1/10) to provide the desired product (42 mg, 30.2%) as a yellow solid. Mass (m/z): 464.3 [ M + H ] ] ⁺ 。

And 2. Step 2.N ¹ Preparation of- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) glutaramide (377): to a solution of 5-oxo-5- ((4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) amino) pentanoic acid (42 mg, 0.09 mmol) in DMF (1.0 mL) was added HATU (41 mg, 0.11 mmo)l). The reaction was then stirred at room temperature for 5 hours. Addition of NH ₃ .H ₂ O (0.2 mL). The mixture was then stirred at room temperature overnight. 5 ml water was added. The resulting solution was extracted with 3 × 5 mL EA. The organic layers were combined, washed with 3X10 mL of water, and washed with Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by preparative TLC (MeOH/DCM = 1/20) to provide the desired product as a yellow solid (6.5 mg, 15.5%). ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N ¹ - (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) malonamide (378)

The title compound 378 (5.3 mg) was prepared as a light yellow solid in 6.1% total yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline hydrochloride (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) according to the procedure of 363. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

5-oxo-5- (pyrrolidin-1-yl) -N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pentanamide (379)

Procedure according to 363 from 4- (aminomethyl) -N- (4- (4- (tris)Fluoromethyl) piperidin-1-yl) phenyl) aniline hydrochloride (77.1 mg, 0.2 mmol), 5-oxo-5- (pyrrolidin-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) the title compound 379 (17.7 mg) was prepared as a pale yellow solid in a total yield of 17.2%. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

3-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) piperazine-1-carboxamide (380)

To a solution of 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (34.9 mg, 0.1 mmol) in DCM (10 mL) was added CDI (17.8 mg, 0.11 mmol). The reaction was then stirred at room temperature for 1 hour. Piperazin-2-one (11.0 mg, 0.11 mmol) and DIEA (38.7 mg, 0.3 mmol) were added. The reaction was then stirred at room temperature for 3 hours. The solution was then washed with 3X10 mL of water and Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by preparative TLC (MeOH/DCM = 1/15) to provide the desired product as a light yellow solid (26.7 mg, 56.2%). ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

4-methyl-3-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) piperazine-1-carboxamide (381)

From 4- (amino) according to the procedure of 380Methyl) one-step reactionN- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (34.9 mg, 0.1 mmol), 1-methylpiperazin-2-one (12.5 mg, 0.11 mmol), CDI (17.8 mg, 0.11 mmol) and DIEA (38.7 mg, 0.3 mmol) the title compound 381 (9.8 mg) was prepared as a blue solid in an overall yield of 20.0%. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

2- (1-ethyl-5-oxopyrrolidin-3-yl) -N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) acetamide (382)

From 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (34.9 mg, 0.1 mmol), 2- (1-ethyl-5-oxopyrrolidin-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) the title compound 382 (20.6 mg) was prepared as a pale yellow solid in an overall yield of 41.0%. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

1-methyl-2-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) imidazolidine-4-carboxamide (383)

From 4- (aminomethyl) according to the procedure of 363) -N- (4- (4- (trifluoromethyl) piperidin-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) the title compound 383 (15.6 mg) was prepared as a white solid in a total yield of 32.8%. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

1-ethyl-N- (2-methyl-4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (384)

Step 1.2-preparation of methyl-4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzaldehyde (384-3): from 4-bromo-2-methylbenzaldehyde (995 mg, 5 mmol), 4- (4- (trifluoromethyl) piperidin-1-yl) aniline (1.06 g, 4.34 mmol), pd according to the procedure at 363-3 ₂ (dba) ₃ (46 mg, 50 umol)、X-Phos (119 mg, 0.25 mol)、Cs ₂ CO ₃ (2.72 g, 7.5 mmol) the title compound 384-3 (1.22 g) was prepared as a yellow oil in 77.7% overall yield. Mass (m/z): 363.3 [ M + H ]] ⁺ 。

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

Step 3.4- (aminomethyl) -3-methyl-NPreparation of- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (384-5): to a solution of (E) -2-methyl-4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzaldoxime (500 mg, 1.32 mmol) in EtOH (20 mL) was added 10% Pd/C (16 mg, 0.015 ml) and AcOH (0. 0.5 mL). The reaction was then stirred under hydrogen atmosphere at room temperature overnight. The 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 × 3). The combined organic layers were washed with brine (20 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated to yield the desired product as a yellow solid. (190 mg, 40.0%). 364.2 [ M + H ]] ⁺ 。

Step 4.1 preparation of ethyl-N- (2-methyl-4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (384): the title compound 384 (17.9 mg) was prepared as a white powder in 35.7% overall yield from 4- (aminomethyl) -3-methyl-N- (4- (4- (trifluoromethyl) piperidin-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) according to the procedure at 363. ¹ H NMR (400 MHz, methanol- d ₄ ) 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 ]] ⁺ 。

N- (2-methyl-4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (385)

From 4- (aminomethyl) -3-methyl-N- (4- (4- (trifluoromethyl) piperidin-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) andHATU (38.0 mg, 0.1 mmol) prepared the title compound 385 (17.7 mg) as a white powder in 37.3% overall yield. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

5-oxo-N- (4- ((4- (3- (trifluoromethyl) azetidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (386)

Step 1.1 preparation of- (4-nitrophenyl) -3- (trifluoromethyl) azetidine (386-3): 1-fluoro-4-nitrobenzene (241 mg, 1.71 mmol), 3- (trifluoromethyl) azetidine hydrochloride (250 mg, 1.55 mmol) and K ₂ CO ₃ A solution of (320 mg, 2.32 mmol) in DMSO (5 mL) was stirred at 80 ℃ for 18 hours. After cooling to room temperature, 10 mL water was added. The resulting solution was extracted with 3X10 mL of ethyl acetate. The organic layers were combined, washed with water (3x15 mL), dried and concentrated in vacuo. The residue was purified by preparative TLC (EA/PE = 1/10) to provide the desired product as a yellow solid (275 mg, 72.2%). Mass (m/z): 247.1 [ M + H ] ] ⁺ 。

Step 2.4- (3- (trifluoromethyl) azetidin-1-yl) aniline (386-4) preparation: to a solution of 1- (4-nitrophenyl) -3- (trifluoromethyl) azetidine (135 mg, 0.55 mmol) in EtOH (10 mL) was added 10% Pd/C (5.8 mg, 5.5 umol). The reaction was then stirred under hydrogen atmosphere at room temperature overnight. The Pd/C was filtered off. The filtrate was concentrated in vacuo to afford the desired product (99 mg, 83.2%) as a yellow oil. Mass (m/z): 217.2 [ M + H ]] ⁺ 。

Step 3 preparation of tert-butyl (4- ((4- (3- (trifluoromethyl) azetidin-1-yl) phenyl) amino) benzyl) carbamate (386-5): from tert-butyl (4-bromobenzyl) carbamate (109 mg, 0.38 mmol), 4- (3- (trifluoromethyl) nitrogen according to the procedure 363-3Azetidin-1-yl) aniline (99 mg, 0.46 mmol), pd ₂ (dba) ₃ (3.5 mg, 3.8 umol)、X-Phos (9.0 mg, 19 umol)、Cs ₂ CO ₃ (206 mg, 0.57 mmol) the title compound 386-5 (116 mg) was prepared as a yellow solid in an overall yield of 72.5%. Mass (m/z): 422.3 [ M + H ]] ⁺ 。

Step 4.4 preparation of 4- (aminomethyl) -N- (4- (3- (trifluoromethyl) azetidin-1-yl) phenyl) aniline hydrochloride (386-6): the title compound 386-6 (98 mg) was prepared as a yellow solid in 100% overall yield from tert-butyl (4- ((4- (3- (trifluoromethyl) azetidin-1-yl) phenyl) amino) benzyl) carbamate (116 mg, 0.28 mmol), HCl in 1,4-dioxane (5.0 mL) according to the procedure of 363-4. Mass (m/z): 322.3 [ M + H ] ] ⁺ 。

Step 5.5-oxo-NPreparation of- (4- ((4- (3- (trifluoromethyl) azetidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (386): the title compound 386 (3.0 mg) was prepared as a dark blue powder in 5.0% total yield from 4- (aminomethyl) -N- (4- (3- (trifluoromethyl) azetidin-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) according to the procedure of 363. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

1-ethyl-5-oxo-N- (4- ((4- (3- (trifluoromethyl) azetidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (387)

From 4- (aminomethyl) -N- (4- (3- (trifluoromethyl) azetidin-1-yl) phenyl) aniline hydrochloride (49 mg, 0.14 mmol), 1-ethyl-5-oxopyrazinePyrrolidine-3-carboxylic acid (21.8 mg, 0.14 mmol), DIEA (53.4 mg, 0.41 mmol) and HATU (52 mg, 0.14 mmol) produced the title compound 387 (4.1 mg) as a dark blue powder in a total yield of 6.5%. ¹ H NMR (400 MHz, methanol-d ₄ ) 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 ]] ⁺ 。

N ¹ - (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) malonamide (388)

The title compound 388 (15.3 mg) was prepared as a dark blue powder in 20.1% overall yield from 4- (aminomethyl) -N- (4- (4-methylpiperidin-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) according to the procedure at 363. ¹ H NMR (400 MHz, methanol-d ₄ ) 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, 4H), 3.23 (s, 2H), 2.01 - 1.92 (m, 2H), 1.86 - 1.74 (m, 1H), 1.64 - 1.49 (m, 2H), 1.01 (d, J= 6.4 Hz, 3H). Mass (m/z): 381.3 [ M + H ]] ⁺ 。

N ¹ - (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) glutaramide (389)

From 4- (aminomethyl) -N- (4- (4-methylpiperidin-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) the title compound 389 (15.3 mg) was prepared as a dark blue powder in 20.1% overall yield. ¹ H NMR (400 MHz, methanol-d 4) delta 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, 4H), 2.22-2.13 (m, 4H), 1.99-1.91 (m, 4H), 1.88-1.71 (m, 3H), 1.65-1.51 (m, 2H), 1.01 (d, J = 6.4 Hz, 3H). Mass (m/z): 409.3 [ M + H ] ] ⁺ 。

N- (2-chloro-4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (390)

Step 1.preparation of 2-chloro-4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzonitrile (390-2): from 4-bromo-2-chlorobenzonitrile (860 mg, 4 mmol), 4- (4- (trifluoromethyl) piperidin-1-yl) aniline (1.27 g, 5.2 mmol), pd according to the procedure of 363-3 ₂ (dba) ₃ (36.6 mg, 0.04 mmol)、X-Phos (95.4 mg, 0.2 mmol)、Cs ₂ CO ₃ (1.96 g, 6 mmol) the title compound 390-2 (1.26 g) was prepared as a gray solid in an overall yield of 82.9%. Mass (m/z): 380.2 [ M + H ]] ⁺ 。

Step 2.4- (aminomethyl) -3-chloro-NPreparation of- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (390-3): to a solution of 2-chloro-4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzonitrile (379 mg, 1 mmol) in THF (20 mL) was added LiAlH ₄ (380 mg, 10 mmol). The reaction was then refluxed at room temperature overnight. 20 mL water was added at 0 ℃. The resulting solution was extracted with 3X20 mL of ethyl acetate. The organic layers were combined, washed with water (3x50 mL), dried and concentrated in vacuo. The residue was purified by preparative TLC (MeOH/DCM = 1/15) to provide the desired product as a yellow solid (50 mg, 13.0%). Mass (m/z): 384.2 [ M + H ]] ⁺ 。

Step 3. Preparation of N- (2-chloro-4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (390): root of herbaceous plants The title compound 390 (40.9 mg) was prepared as a dark blue powder in 63.9% overall yield from 4- (aminomethyl) -3-chloro-N- (4- (4- (trifluoromethyl) piperidin-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) according to the procedure of 363. ¹ H NMR (400 MHz, methanol-d 4) delta 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 ]] ⁺ 。

N- (3-methoxy-4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (391)

The title compound 391 (12.8 mg) was prepared as a white powder in 26.1% total yield from 4- (aminomethyl) -2-methoxy-N- (4- (4- (trifluoromethyl) piperidin-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 363. ¹ H NMR (400 MHz, methanol-d ₄ ) Delta 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, 1H), 2.79-2.35 (m, 4H), 2.25-2.16 (m, 1H), 2.00-1.79 (m, 2H), 1.73-1.55 (m, 2H). Mass (m/z): 491.3 [ M + H ] ] ⁺ 。

N- (4- ((4-cyclohexylphenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (392)

Programmed according to 363-3N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 4-cyclohexylaniline (58 mg, 0.33 mmol), pd ₂ (dba) ₃ (2.3 mg, 2.5 umol)、X-Phos (6.0 mg, 12.5 umol)、Cs ₂ CO ₃ (122 mg, 0.38 mmol) the title compound 392 (9.3 mg) was prepared as a pale yellow solid in 9.5% total yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) 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 ]] ⁺ 。

N- (3-fluoro-4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (393)

Step 1.preparation of 3-fluoro-4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzonitrile (393-2): from 4-bromo-3-fluorobenzonitrile (1.0 g, 5 mmol), 4- (4- (trifluoromethyl) piperidin-1-yl) aniline (1.59 g, 6.5 mmol), pd according to the procedure of 363-3 ₂ (dba) ₃ (46 mg, 0.05 mmol)、X-Phos (119 mg, 0.25 mmol)、Cs ₂ CO ₃ (2.45 g, 7.5 mmol) the title compound 393-2 (1.56 g) was prepared as a gray solid in an overall yield of 85.7%. Mass (m/z): 364.2 [ M + H ]] ⁺ 。

Step 2.preparation of 4- (aminomethyl) -2-fluoro-N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (393-3): to a solution of 3-fluoro-4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzonitrile (363 mg, 1 mmol) in EtOH (10 mL) was added raney nickel. The reaction was then stirred at room temperature under a hydrogen atmosphere overnight. The raney nickel is filtered off. The filtrate was concentrated in vacuo. The residue was purified by preparative TLC (MeOH/DCM = 1/5) to provide the target product as a yellow solid (220 mg, 60.0%). Mass (m/z): 368.1 [ M + H ] ] ⁺ 。

Step 3. Preparation of N- (3-fluoro-4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (393): according to the equation of 363The title compound 393 (28.0 mg) was prepared as a white powder in 43.1% overall yield from 4- (aminomethyl) -2-fluoro-N- (4- (4- (trifluoromethyl) piperidin-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). ¹ H NMR(400 MHz, DMSO-d ₆ ) 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 ]] ⁺ 。

N- (4- ((4-fluoro-3- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (394)

Step 1.1 preparation of- (2-fluoro-5-nitrophenyl) -4- (trifluoromethyl) piperidine (394-3): from 2-bromo-1-fluoro-4-nitrobenzene (1.1 g, 5 mmol), 4- (trifluoromethyl) piperidine (995 mg, 6.5 mmol), pd according to the procedure of 363-3 ₂ (dba) ₃ (46 mg, 0.05 mmol)、X-Phos (119 mg, 0.25 mmol)、Cs ₂ CO ₃ (2.45 g, 7.5 mmol) the title compound 394-3 (570 mg) was prepared as a yellow solid in an overall yield of 39.0%.

Step 2.preparation of 4-fluoro-3- (4- (trifluoromethyl) piperidin-1-yl) aniline (394-4): to a solution of 1- (2-fluoro-5-nitrophenyl) -4- (trifluoromethyl) piperidine (570 mg, 1.92 mmol) in EtOH (10 mL) was added 10% Pd/C (20.6 mg, 20 umol). The reaction was then stirred under hydrogen atmosphere at room temperature overnight. The Pd/C was filtered off. The filtrate was concentrated in vacuo. The residue was purified by preparative TLC (MeOH/DCM = 1/5) to provide the target product as a yellow oil (390 mg, 76.3%). Mass (m/z): 263.2 [ M + H ] ] ⁺ 。

Step 3. N- (4- ((4-fluoro-3- (4- (trifluoromethyl) piperidin-1-yl) phenyl)Preparation of amino) benzyl) -5-oxopyrrolidine-3-carboxamide (394): 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), pd according to the procedure of 363-3 ₂ (dba) ₃ (2.3 mg, 2.5 umol)、X-Phos (6.0 mg, 12.5 umol)、Cs ₂ CO ₃ (122 mg, 0.38 mmol) the title compound 394 (5.0 mg) was prepared as a white powder in 5.0% overall yield. ¹ H 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 ]] ⁺ 。

N- (4- ((3-chloro-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (395)

And (1).NPreparation of- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (395-2): from 2-chloro-1-fluoro-4-nitrobenzene (700 mg, 4.0 mmol), 4- (trifluoromethyl) piperidine (612 mg, 4.0 mmol) and K according to the procedure of 386-3 ₂ CO ₃ (828 mg, 6.0 mmol) the title compound 395-2 (616 mg) was prepared as a yellow solid in 50.0% overall yield.

Step 2.3-chloro-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (395-3) preparation: the title compound 395-3 (500 mg) was prepared as a yellow solid in 89.9% total yield 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 of 386-4. Mass (m/z): 279.3 [ M + H ] ] ⁺ 。

And 3. Step 3.N- (4- ((3-chloro-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (395)The preparation of (1): from N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 3-chloro-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (92 mg, 0.33 mmol), pd according to the procedure of 363-3 ₂ (dba) ₃ (2.5 mg, 2.5 umol)、X-Phos (6.0 mg, 12.5 umol)、Cs ₂ CO ₃ (122 mg, 0.38 mmol) the title compound 395 (30.0 mg) was prepared as a white powder in 24.3% overall yield. 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 ]] ⁺ 。

N- (4- ((4- (4,4-difluoropiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (396)

From N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 4- (4,4-difluoropiperidin-1-yl) aniline (70 mg, 0.33 mmol), pd according to the procedure of 363-3 ₂ (dba) ₃ (2.3 mg, 2.5 umol)、X-Phos (6.0 mg, 12.5 umol)、Cs ₂ CO ₃ (122 mg, 0.38 mmol) the title compound 396 (36.2 mg) was prepared as a white powder in an overall yield of 33.8%. ¹ H NMR(400 MHz, DMSO-d ₆ ) 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 ]] ⁺ 。

N- (4- ((3-bromo-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (397)

Step 1.1 preparation of- (2-bromo-4-nitrophenyl) -4- (trifluoromethyl) piperidine (397-2): from 2-bromo-1-fluoro-4-nitrobenzene (2.19 g, 10 mmol), 4- (trifluoromethyl) piperidine (1.53 g, 10 mmol) and K according to the procedure of 386-3 ₂ CO ₃ (2.07 g, 15 mmol) the title compound 397-2 (2.38 g) was prepared as a yellow solid in 67.6% overall yield.

Step 2.3-bromo-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (397-3) preparation: the title compound 397-3 (315 mg) was prepared as a yellow solid in 48.9% overall yield 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 of 386-4. Mass (m/z): 323.1 [ M + H ]] ⁺ 。

Step 3 preparation of tert-butyl (4- ((3-bromo-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) carbamate (397-4): from tert-butyl (4-bromobenzyl) carbamate (143 mg, 0.5 mmol), 3-bromo-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (209 mg, 0.65 mmol), pd according to the procedure of 363-3 ₂ (dba) ₃ (4.6 mg, 5.0 umol)、X-Phos (11.9 mg, 25 umol)、Cs ₂ CO ₃ (245 mg, 0.75 mmol) the title compound 397-4 (102 mg) was prepared as a yellow solid in an overall yield of 38.6%. Mass (m/z): 528.3 [ M + H ]] ⁺ 。

And 4. Step 4.NPreparation of- (4- (aminomethyl) phenyl) -3-bromo-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (397-5): the title compound 397-5 (32.9 mg) was prepared as a yellow solid in 39.8% overall yield from tert-butyl (4- ((3-bromo-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) carbamate (102 mg, 0.19 mmol), HCl in 1,4-dioxane (5.0 mL), according to the procedure of 363-4. Mass (m/z): 428.1 [ M + H ] ] ⁺ 。

And 5. Step 5.NPreparation of- (4- ((3-bromo-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (397): from N- (4- (aminomethyl) phenyl) -3-Bromo-4- (4- (trifluoromethyl) piperidin-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) the title compound 397 (9.0 mg) was prepared in a total yield of 27.3% as a pale yellow solid. ¹ H NMR(400 MHz, DMSO-d ₆ ) 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 ]] ⁺ 。

N- (4- ((5-fluoro-2-methyl-4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (398)

Step 1.1 preparation of 1- (2-fluoro-5-methyl-4-nitrophenyl) -4-methylpiperidine (398-3): the title compound 398-3 (1.27 g) was prepared as a yellow solid in 88.2% overall yield from 1,2-difluoro-4-methyl-5-nitrobenzene (1.0 g, 5.7 mmol), 4-methylpiperidine (1.72 g, 17.3 mmol) according to the procedure of 386-3.

Step 2.5-fluoro-2-methyl-4- (4-methylpiperidin-1-yl) aniline (398-4) preparation: the title compound 398-4 (1.16 g) was prepared as a yellow solid in 100% overall yield 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 ] ] ⁺ 。

And 3. Step 3.NPreparation of- (4- ((5-fluoro-2-methyl-4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (398): from N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 5-fluoro-2-methyl-4- (4-methylpiperidin-1-yl) aniline (74 mg, 0.33 mmol), pd according to the procedure of 363-3 ₂ (dba) ₃ (2.5 mg, 2.5 umol)、X-Phos (6.0 mg, 12.5 umol)、Cs ₂ CO ₃ (122 mg, 0.38 mmol) the title compound 398 (22.1 mg) was prepared as a white powder in 20.2% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) 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 ]] ⁺ 。

N- (4- ((5-chloro-2-methyl-4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (399)

Step 1.1 preparation of- (2-chloro-5-methyl-4-nitrophenyl) -4-methylpiperidine (399-2): the title compound 399-2 (1.35 g) was prepared as a yellow solid in overall yield of 88.2% from 1-chloro-2-fluoro-4-methyl-5-nitrobenzene (1.08 g, 5.7 mmol), 4-methylpiperidine (1.72 g, 17.3 mmol) according to the procedure of 386-3.

Step 2.5-chloro-2-methyl-4- (4-methylpiperidin-1-yl) aniline (399-3) preparation: the title compound 399-3 (1.19 g) was prepared as a yellow solid in 100% total yield 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 of 386-4. Mass (m/z): 239.2 [ M + H ] ] ⁺ 。

Step 3. Preparation of N- (4- ((5-chloro-2-methyl-4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (399): from N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 5-chloro-2-methyl-4- (4-methylpiperidin-1-yl) aniline (79 mg, 0.33 mmol), pd according to the procedure of 363-3 ₂ (dba) ₃ (2.5 mg, 2.5 umol)、X-Phos (6.0 mg, 12.5 umol)、Cs ₂ CO ₃ (122 mg, 0.38 mmol) was prepared as white in 18.5% overall yieldTitle compound of powder 399 (21.0 mg). ¹ H NMR(400 MHz, DMSO-d ₆ ) 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 ]] ⁺ 。

N- (4- ((2-fluoro-3-methyl-4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (400)

Step 1.1 preparation of- (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), 4-methylpiperidine (1.72 g, 17.3 mmol) in DMSO (10 mL) was stirred at room temperature overnight. 10 mL water was added dropwise. The precipitate was collected by filtration to afford the desired product as a yellow solid (1.20 g, 83.3%). Mass (m/z): 253.2 [ M + H ]] ⁺ 。

Step 2.5-chloro-2-methyl-4- (4-methylpiperidin-1-yl) aniline (400-3): the title compound 400-3 (1.1 g) was prepared as a yellow solid in 100% total yield from 2-fluoro-3-methyl-4- (4-methylpiperidin-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 of 386-4. Mass (m/z): 239.2 [ M + H ] ] ⁺ 。

And 3. Step 3.NPreparation of- (4- ((2-fluoro-3-methyl-4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (400): from N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 2-fluoro-3-methyl-4- (4-methylpiperidin-1-yl) aniline (74 mg, 0.33 mmol), pd according to the procedure of 363-3 ₂ (dba) ₃ (2.5 mg, 2.5 umol)、X-Phos (6.0 mg, 12.5 umol)、Cs ₂ CO ₃ (122 mg, 0.38 mmol) at 15.7%Total yield the title compound 400 (17.2 mg) was prepared as a white powder. ¹ H NMR(400 MHz, DMSO-d ₆ ) 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 ]] ⁺ 。

N- (4- ((3-fluoro-2-methyl-4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (401)

From N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 3-fluoro-2-methyl-4- (4-methylpiperidin-1-yl) aniline (74 mg, 0.33 mmol), pd according to the procedure of 398 ₂ (dba) ₃ (2.5 mg, 2.5 umol)、X-Phos (6.0 mg, 12.5 umol)、Cs ₂ CO ₃ (122 mg, 0.38 mmol) the title compound 401 (11.7 mg) was prepared as a white powder in 10.7% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) 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 ]] ⁺ 。

N- (4- ((2,3-dimethyl-4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (402)

From N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 2,3-dimethyl-4- (4-methylpiperidin-1-yl) aniline (73 mg, 0.33 mmol), pd according to the procedure of 398 ₂ (dba) ₃ (2.5 mg, 2.5 umol)、X-Phos (6.0 mg, 12.5 umol)、Cs ₂ CO ₃ (122 mg, 0.38 mmol) the title compound 402 (11.1 mg) was prepared as a yellow powder in 10.2% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) 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 ]] ⁺ 。

N- (4- ((5-methyl-6- (4- (trifluoromethyl) piperidin-1-yl) pyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (403)

Step 1.preparation of 4- (trifluoromethyl) piperidine (403-2): from 2-fluoro-3-methyl-5-nitropyridine (624 mg, 4 mmol), 4- (trifluoromethyl) piperidine (734 mg, 4.8 mmol) and K according to the procedure of 386-3 ₂ CO ₃ (828 mg, 6 mmol) the title compound 403-2 (959 mg) was prepared as a yellow solid in 83.1% overall yield.

Step 2.5-methyl-6- (4- (trifluoromethyl) piperidin-1-yl) pyridin-3-amine (403-3) preparation: the title compound 403-3 (390 mg) was prepared as a purple solid in 72.5% total yield from 3-methyl-5-nitro-2- (4- (trifluoromethyl) piperidin-1-yl) pyridine (578 mg, 2 mmol) and 10% Pd/C (22 mg, 0.02 mmol) in EtOH (20 mL) according to the procedure of 386-4. Mass (m/z): 260.3 [ M + H ]] ⁺ 。

And 3. Step 3.N- (4- ((5-methyl)Preparation of-6- (4- (trifluoromethyl) piperidin-1-yl) pyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (403): program according to 363-3 fromN- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 5-methyl-6- (4- (trifluoromethyl) piperidin-1-yl) pyridin-3-amine (86 mg, 0.33 mmol), pd ₂ (dba) ₃ (2.5 mg, 2.5 umol)、X-Phos (6.0 mg, 12.5 umol)、Cs ₂ CO ₃ (122 mg, 0.38 mmol) the title compound 403 (25.2 mg) was prepared as a pale yellow powder in 21.2% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) 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 ]] ⁺ 。

N- (4- ((2-methyl-6- (4- (trifluoromethyl) piperidin-1-yl) pyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (404)

Step 1.2-methyl-3-nitro-6- (4- (trifluoromethyl) piperidin-1-yl) pyridine (404-2) preparation: from 6-fluoro-2-methyl-3-nitropyridine (624 mg, 4 mmol), 4- (trifluoromethyl) piperidine (734 mg, 4.8 mmol) and K according to the procedure of 386-3 ₂ CO ₃ (828 mg, 6 mmol) the title compound 404-2 (1.03 g) was prepared as a yellow solid in 89.0% overall yield.

Step 2.2 preparation of 2-methyl-6- (4- (trifluoromethyl) piperidin-1-yl) pyridin-3-amine (404-3): the title compound 404-3 (406 mg) was prepared as a yellow oil in 78.3% total yield from 2-methyl-3-nitro-6- (4- (trifluoromethyl) piperidin-1-yl) pyridine (578 mg, 2 mmol) and 10% Pd/C (21 mg, 0.02 mmol) in EtOH (20 mL) according to the procedure of 386-4. Mass (m/z): 260.2 [ M + H ]] ⁺ 。

And (3) performing step (b).NPreparation of- (4- ((2-methyl-6- (4- (trifluoromethyl) piperidin-1-yl) pyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (404): from N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 2-methyl-6- (4- (trifluoromethyl) piperidin-1-yl) pyridin-3-amine (86 mg, 0.33 mmol), pd according to the procedure of 363-3 ₂ (dba) ₃ (2.5 mg, 2.5 umol)、X-Phos (6.0 mg, 12.5 umol)、Cs ₂ CO ₃ (122 mg, 0.38 mmol) the title compound 404 (18.6 mg) was prepared as a pale yellow powder in an overall yield of 15.6%. ¹ H NMR(400 MHz, DMSO-d ₆ ) 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 ]] ⁺ 。

5-oxo-N- (4- ((3- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (405)

From N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (30 mg, 0.10 mmol), 3- (4- (trifluoromethyl) piperidin-1-yl) aniline (30 mg, 0.12 mmol), pd according to the procedure of 363-3 ₂ (dba) ₃ (0.9 mg, 1.0 umol)、X-Phos (2.4 mg, 5.0 umol)、Cs ₂ CO ₃ (50 mg, 0.15 mmol) the title compound 405 (4.6 mg) was prepared as a pale yellow powder in an overall yield of 9.8%. ¹ H NMR(400 MHz, DMSO-d ₆ ) 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 ]] ⁺ 。

5-oxo-N- (4- ((6- (4- (trifluoromethyl) piperidin-1-yl) pyridin-3-yl) amino) benzyl) pyrrolidine-3-carboxamide (406)

From N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 2,3-dimethyl-4- (4-methylpiperidin-1-yl) aniline (73 mg, 0.33 mmol), pd according to the procedure of 363-3 ₂ (dba) ₃ (2.5 mg, 2.5 umol)、X-Phos (6.0 mg, 12.5 umol)、Cs ₂ CO ₃ (122 mg, 0.38 mmol) the title compound 406 (72.4 mg) was prepared as a purple powder in 31.5% overall yield. ¹ H NMR(300 MHz, DMSO-d ₆ ) 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 ] ] ⁺ 。

N- (4- ((2,6-dimethyl-4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (407)

From N- (4- (aminomethyl) phenyl) -2,6-dimethyl-4- (4-methylpiperidin-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) according to the procedure of 397 with a total yield of 13.7%The title compound 407 (8.6 mg) was prepared as a pale yellow solid. ¹ H NMR(400 MHz, DMSO-d ₆ ) 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 ]] ⁺ 。

N- (4- ((5-chloro-2-methyl-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (408)

According to the program of 404N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (99 mg, 0.33 mmol), 5-chloro-2-methyl-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (126 mg, 0.43 mmol), pd ₂ (dba) ₃ (3.0 mg, 3.3 umol)、X-Phos (7.9 mg, 16.5 umol)、Cs ₂ CO ₃ (163 mg, 0.50 mmol) the title compound 408 (30.8 mg) was prepared as a yellow powder in 18.2% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) 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 ]] ⁺ 。

N- (4- ((3-fluoro-2-methyl-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (409)

From N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (99 mg, 0.33 mmol), 3-fluoro-2-methyl-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (119 mg, 0.43 mmol), pd according to the procedure of 404 ₂ (dba) ₃ (3.0 mg, 3.3 umol)、X-Phos (7.9 mg, 16.5 umol)、Cs ₂ CO ₃ (163 mg, 0.50 mmol) the title compound 409 (13.1 mg) was prepared as a yellow powder in 8.0% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) 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, 2H), 2.06 (d, J = 2.5 Hz, 3H), 1.93 - 1.86 (m, 2H), 1.61 (qd, J= 12.5, 4.2 Hz, 2H). Mass (m/z): 493.3 [ M + H ]] ⁺ 。

N- (4- ((5-fluoro-2-methyl-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (410)

According to the program of 404N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (99 mg, 0.33 mmol), 5-fluoro-2-methyl-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (119 mg, 0.43 mmol), pd ₂ (dba) ₃ (3.0 mg, 3.3 umol)、X-Phos (7.9 mg, 16.5 umol)、Cs ₂ CO ₃ (163 mg, 0.50 mmol) the title compound 410 (28.9 mg) was prepared as a yellow powder in an overall yield of 17.6%. ¹ H NMR(400 MHz, DMSO-d ₆ ) 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 ]] ⁺ 。

N- (4- ((2-fluoro-3-methyl-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (411)

From N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (99 mg, 0.33 mmol), 2-fluoro-3-methyl-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (119 mg, 0.43 mmol), pd according to the procedure of 404 ₂ (dba) ₃ (3.0 mg, 3.3 umol)、X-Phos (7.9 mg, 16.5 umol)、Cs ₂ CO ₃ (163 mg, 0.50 mmol) the title compound 411 (38.5 mg) was prepared as a white powder in an overall yield of 23.8%. ¹ H NMR(400 MHz, DMSO-d ₆ ) 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 ]] ⁺ 。

N- (4- ((2,3-dimethyl-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (412)

From N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (99 mg, 0.33 mmol), 2,3-dimethyl-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (107 mg, 0.40 mmol), pd according to the procedure of 404 ₂ (dba) ₃ (3.0 mg, 3.3 umol)、X-Phos (7.9 mg, 16.5 umol)、Cs ₂ CO ₃ (163 mg, 0.50 mmol) the title compound was prepared as a white powder in 6.6% overall yieldItem 412 (10.6 mg). ¹ H NMR(400 MHz, DMSO-d ₆ ) 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 ]] ⁺ 。

N- (4- ((4- (4,4-dimethylcyclohexyl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (413)

Step 3236 preparation of zxft 3236-dimethyl-4 '-nitro-2,3,4,5-tetrahydro-1,1' -biphenyl (413-3): to 1-bromo-4-nitrobenzene (6.06 g, 30 mmol), 2- (4,4-dimethylcyclohex-1-en-1-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.52 g, 36 mmol) and Pd (PPh) ₃ ) ₄ (690 mg, 0.6 mmol) to a mixture of 1,4-dioxane of 100 mL and 20 mL water was added K ₂ CO ₃ (6.24 g, 45 mmol). After stirring overnight at 110 ℃ under argon, the reaction was cooled to Room Temperature (RT). The mixture was treated with EtOAc (100 mL) with H ₂ O (3x200 mL) and brine (200 mL). The organic layer was dried (Na) ₂ SO ₄ ) And concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-10% EtOAc/hexanes) to give the desired product as a pale yellow oil (6.5 g, 94.0%).

Step 2.4- (4,4-dimethylcyclohexyl) aniline (413-4) preparation: 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) was added 10% Pd/C (114.7 mg, 0.11 ml) and 1.0 mL concentrated HCl. The reaction was then stirred overnight at 60 ℃ under a hydrogen atmosphere. The reaction was cooled to Room Temperature (RT). The Pd/C was filtered off. The filtrate was concentrated in vacuo. Adding 50 ml water and adding carbonThe pH of the solution was adjusted to 8-9 with sodium acid solution. The mixture was then extracted with DCM (50 mL × 3). The combined organic layers were washed with water (100 mL) and over Na ₂ SO ₄ Dried and concentrated to provide the desired product as a yellow solid (1.8 g, 81.8%). Mass (m/z): 204.3 [ M + H ]] ⁺ 。

And 3. Step 3.NPreparation of- (4- ((4- (4,4-dimethylcyclohexyl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (413): from N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (73.5 mg, 0.25 mmol), 4- (4,4-dimethylcyclohexyl) aniline (58 mg, 0.29 mmol), pd according to the procedure of 404 ₂ (dba) ₃ (2.3 mg, 2.5 umol)、X-Phos (5.9 mg, 12.4 umol)、Cs ₂ CO ₃ (121 mg, 0.37 mmol) the title compound 413 (33.5 mg) was prepared as a white powder in an overall yield of 32.2%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.39 (t, J = 5.7 Hz, 1H), 8.00 (s, 1H), 7.59 (s, 1H), 7.11 - 7.04 (m, 4H), 7.06 - 6.92 (m, 4H), 4.17 (d, J = 5.7 Hz, 2H), 3.40 (t, J = 8.8 Hz, 1H), 3.25 - 3.12 (m, 2H), 2.32 - 2.28 (m, 2H), 1.63 - 1.53 (m, 4H), 1.47 - 1.41 (m, 2H), 1.34 - 1.24 (m, 2H), 0.95 (d, J= 10.0 Hz, 6H). Mass (m/z): 420.4 [ M + H ]] ⁺ 。

N- (4- ((4-fluoro-3- (piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (414)

From N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (112 mg, 0.38 mmol), 4-fluoro-3- (piperidin-1-yl) aniline (90 mg, 0.46 mmol), pd according to the procedure of 404 ₂ (dba) ₃ (3.5 mg, 3.8 umol)、X-Phos (9.1 mg, 19 umol)、Cs ₂ CO ₃ (186 mg, 0.57 mmol) the title compound 414 (57.8 mg) was prepared as a yellow powder in 37.1% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.39 (t, J = 5.7 Hz, 1H), 7.99 (s, 1H), 7.59 (s, 1H), 7.12 - 7.06 (m, 2H), 6.99 - 6.91 (m, 3H), 6.61 - 6.55 (m, 1H), 6.58 (ddt, J = 7.8, 3.7, 2.7 Hz, 1H), 4.17 (d, J = 5.7 Hz, 2H), 3.40 (t, J= 8.7 Hz, 1H), 3.27-3.15 (m, 2H), 2.95-2.87 (m, 4H), 2.33-2.25 (m, 2H), 1.67-1.60 (m, 4H), 1.54-1.47 (m, 2H). Mass (m/z): 411.3 [ M + H ]] ⁺ 。

N- (4- ((4- (azacyclooctan-1-yl) -3- (trifluoromethyl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (415)

From N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (99 mg, 0.33 mmol), 4- (azacyclooctan-1-yl) -3- (trifluoromethyl) aniline (117 mg, 0.43 mmol), pd according to the procedure of 404 ₂ (dba) ₃ (3.0 mg, 3.3 umol)、X-Phos (7.9 mg, 16.5 umol)、Cs ₂ CO ₃ (163 mg, 0.5 mmol) the title compound 415 (63.6 mg) was prepared as a yellow powder in an overall yield of 39.1%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.43 (t, J = 5.8 Hz, 1H), 8.36 (s, 1H), 7.59 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.28 (dd, J = 8.7, 2.7 Hz, 1H), 7.19 (d, J = 2.7 Hz, 1H), 7.16 - 7.12 (m, 2H), 7.07 - 7.01 (m, 2H), 4.20 (d, J = 5.7 Hz, 2H), 3.41 (t, J= 8.8 Hz, 1H), 3.27-3.16 (m, 2H), 3.00-2.85 (m, 4H), 2.34-2.26 (m, 2H), 1.72-1.55 (m, 10H). Mass (m/z): 489.3 [ M + H ] ] ⁺ 。

N- (4- ((4- (4,4-dimethylpiperidin-1-yl) -3- (trifluoromethyl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (416)

From N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (99 mg, 0.33 mmol), 4- (4,4-dimethylpiperidin-1-yl) -3- (trifluoromethyl) aniline (117 mg, 0.43 mmol), pd according to the procedure of 404 ₂ (dba) ₃ (3.0 mg, 3.3 umol)、X-Phos (7.9 mg, 16.5 umol)、Cs ₂ CO ₃ (163 mg, 0.5 mmol) the title compound 416 (54.1 mg) was prepared as a white powder in 33.3% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.42 (t, J = 5.8 Hz, 1H), 8.34 (s, 1H), 7.59 (s, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.26 (dd, J = 8.6, 2.7 Hz, 1H), 7.21 (d, J = 2.7 Hz, 1H), 7.18 - 7.10 (m, 2H), 7.05 - 7.00 (m, 2H), 4.20 (d, J = 5.7 Hz, 2H), 3.44 - 3.38 (m, 1H), 3.27 - 3.16 (m, 2H), 2.80 - 2.69 (m, 4H), 2.30 (dd, J= 8.4, 3.4 Hz, 2H), 1.46-1.36 (m, 4H), 0.98 (s, 6H). Mass (m/z): 489.3 [ M + H ]] ⁺ 。

5-oxo-N- (4- ((4- (4- (trifluoromethyl) cyclohexyl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (417)

From N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 4- (4- (trifluoromethyl) cyclohexyl) aniline (73 mg, 0.30 mmol), pd according to the procedure of 413 ₂ (dba) ₃ (2.3 mg, 2.5 umol)、X-Phos (5.9 mg, 12.4 umol)、Cs ₂ CO ₃ (121 mg, 0.37 mmol) the title compound 417 (9.6 mg) was prepared as a white powder in an overall yield of 8.4%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.39 (t, J = 5.7 Hz, 1H), 8.04 (s, 1H), 7.59 (s, 1H), 7.16 - 7.05 (m, 4H), 7.03 - 6.92 (m, 4H), 4.17 (d, J = 5.6 Hz, 2H), 3.40 (t, J= 8.8 Hz, 1H), 3.27-3.15 (m, 2H), 2.69-2.64 (m, 1H), 2.35-2.26 (m, 2H), 1.87-1.67 (m, 8H). Mass (m/z): 460.3 [ M + H ]] ⁺ 。

N- (4- ((3- (diethylamino) -4-fluorophenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (418)

From N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (99 mg, 0.33 mmol), 4- (4- (trifluoromethyl) cyclohexyl) aniline (73 mg, 0.30 mmol), pd according to the procedure of 404 ₂ (dba) ₃ (3.0 mg, 3.3 umol)、X-Phos (7.9 mg, 16.5 umol)、Cs ₂ CO ₃ (163 mg, 0.50 mmol) the title compound 418 (9.0 mg) was prepared as a white solid in 6.8% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.41 (t, J = 5.9 Hz, 1H), 8.11 (s, 1H), 7.59 (s, 1H), 7.15 - 6.94 (m, 5H), 6.83 - 6.56 (m, 2H), 4.18 (d, J = 5.7 Hz, 2H), 3.41 (t, J = 8.8 Hz, 1H), 3.32 - 3.16 (m, 6H), 2.34 - 2.25 (m, 2H), 1.04 (t, J= 7.0 Hz, 6H). Mass (m/z): 399.3 [ M + H ]] ⁺ 。

N- (4- ((6- (azepan-1-yl) -2-methylpyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (419)

From N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (99 mg, 0.33 mmol), 6- (azepan-1-yl) -2-methylpyridin-3-amine (88 mg, 0.43 mmol), pd according to the procedure of 404 ₂ (dba) ₃ (3.0 mg, 3.3 umol)、X-Phos (7.9 mg, 16.5 umol)、Cs ₂ CO ₃ (163 mg, 0.50 mmol) the title compound 419 (16.1 mg) was prepared as a yellow powder in 11.5% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.35 (s, 1H), 7.58 (s, 1H), 7.27 - 7.08 (m, 2H), 7.04 - 6.93 (m, 2H), 6.56 - 6.28 (m, 3H), 4.12 (d, J5.7 Hz, 2H), 3.71-3.50 (m, 4H), 3.41-3.37 (m, 1H), 3.25-3.13 (m, 2H), 2.32-2.24 (m, 2H), 2.22-2.13 (m, 2H), 1.80-1.67 (m, 4H), 1.56-1.45 (m, 4H). Mass (m/z): 422.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4,4-dimethylpiperidin-1-yl) -2- (trifluoromethyl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (420)

The title compound 420 (9.2 mg) was prepared according to the procedure of 397 from N- (4- (aminomethyl) phenyl) -4- (4,4-dimethylpiperidin-1-yl) -2- (trifluoromethyl) aniline (37.7 mg, 0.1 mmol), 5-oxopyrrolidine-3-carboxylic acid (15.5 mg, 0.12 mmol), DIEA (38.7 mg, 0.3 mmol) and HATU (45.6 mg, 0.12 mmol) as a pale yellow solid in 18.8% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.34 (t, J = 5.7 Hz, 1H), 7.57 (s, 1H), 7.21 - 7.11 (m, 4H), 7.02 - 6.97 (m, 2H), 6.67 - 6.61 (m, 2H), 4.13 (d, J = 5.6 Hz, 2H), 3.39 (t, J= 8.9 Hz, 1H), 3.25-3.13 (m, 6H), 2.34-2.25 (m, 2H), 1.48-1.40 (m, 4H), 0.96 (s, 6H). Mass (m/z): 489.3 [ M + H ]] ⁺ 。

N- (4- ((2,5-dimethyl-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (421)

From N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (99 mg, 0.33 mmol), 2,5-dimethyl-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (117 mg, 0.43 mmol), pd according to the procedure of 394 ₂ (dba) ₃ (3.3 mg, 3.3 umol)、X-Phos (7.9 mg, 16.5 umol)、Cs ₂ CO ₃ (163 mg, 0.50 mmol) the title compound 421 (17.0 mg) was prepared as a pale yellow powder in a total yield of 10.4%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.34 (t, J = 5.7 Hz, 1H), 7.57 (s, 1H), 7.20 (s, 1H), 7.05 - 6.98 (m, 2H), 6.92 (s, 1H), 6.86 (s, 1H), 6.71 - 6.64 (m, 2H), 4.14 (d, J = 5.7 Hz, 2H), 3.44 - 3.36 (m, 1H), 3.27 - 3.14 (m, 2H), 3.10 - 3.00 (m, 2H), 2.67 - 2.59 (m, 2H), 2.47 - 2.37 (m, 1H), 2.33 - 2.25 (m, 2H), 2.14 (s, 3H), 2.10 (s, 3H), 1.93 - 1.83 (m, 2H), 1.61 (qd, J= 12.3, 4.0 Hz, 2H). Mass (m/z): 489.3 [ M + H ]] ⁺ 。

N- (4- ((2-chloro-5-fluoro-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (422)

The title compound 422 (10.1 mg) was prepared as a pale yellow solid in 24.5% total yield from N- (4- (aminomethyl) phenyl) -2-chloro-5-fluoro-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (31 mg, 0.1 mmol), 5-oxopyrrolidine-3-carboxylic acid (12.9 mg, 0.1 mmol), DIEA (31.2 mg, 0.24 mmol), and HATU (38 mg, 0.1 mmol) according to the procedure of 397. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.41 (t, J = 5.8 Hz, 1H), 7.62 (s, 1H), 7.58 (s, 1H), 7.15 - 7.07 (m, 3H), 6.99 - 6.92 (m, 3H), 4.19 (d, J = 5.7 Hz, 2H), 3.41 (t, J = 8.8 Hz, 1H), 3.27 - 3.14 (m, 2H), 2.74 - 2.64 (m, 2H), 2.46 - 2.39 (m, 1H), 2.33 - 2.26 (m, 2H), 1.93 - 1.85 (m, 2H), 1.59 (qd, J= 12.3, 3.7 Hz, 2H). Mass (m/z): 513.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4-methylcyclohexyl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (423)

From 4- (aminomethyl) -N- (4- (4-methylcyclohexyl) phenyl) aniline (21.6 mg, 74 umol), 5-oxopyrrolidine-3-carboxylic acid (11.4 mg, 88 umol), DIEA (28.6 mg, 0.22 mmol) and HATU (33.4 mg, 88 umol) the title compound 423 (4.1 mg) was prepared as a white solid in a total yield of 10.0%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.38 (t, J = 5.8 Hz, 1H), 7.99 (s, 1H), 7.58 (s, 1H), 7.13 - 7.07 (m, 4H), 7.01 - 6.94 (m, 4H), 4.17 (d, J = 5.8 Hz, 2H), 3.40 (t, J = 8.8 Hz, 1H), 3.26 - 3.16 (m, 2H), 2.46 - 2.40 (m, 1H), 2.33 - 2.27 (m, 2H), 1.93 - 1.85 (m, 1H), 1.69 - 1.45 (m, 9H), 1.00 (d, J= 7.1 Hz, 3H). Mass (m/z): 406.3 [ M + H ]] ⁺ 。

N ¹ - (4- ((4-cyclohexylphenyl) amino) benzyl) succinamide (424)

The title compound 424 (17.1 mg) was prepared as a white powder in 45.1% total yield from 4- (aminomethyl) -N- (4-cyclohexylphenyl) aniline (28.0 mg, 0.1 mmol), 4-amino-4-oxobutanoic acid (14 mg, 0.2 mmol), DIEA (38.7 mg, 0.3 mmol), and HATU (38.7 mg, 0.3 mmol) according to the procedure of 413. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.21 (t, J = 5.8 Hz, 1H), 7.96 (s, 1H), 7.28 (s, 1H), 7.11 - 7.04 (m, 4H), 6.98 - 6.91 (m, 4H), 6.74 (s, 1H), 4.14 (d, J= 5.8 Hz, 2H), 2.45-2.24 (m, 6H), 1.83-1.66 (m, 6H), 1.39-1.29 (m, 4H). Mass (m/z): 380.3 [ M + H ]] ⁺ 。

(R)-N- (4- ((4-cyclohexylphenyl) amino) benzyl) -2-oxoimidazolidine-4-carboxamide (425)

The title compound 425 (9.9 mg) was prepared as a white solid in 15.3% total yield from 4- (aminomethyl) -N- (4-cyclohexylphenyl) aniline (28.0 mg, 0.1 mmol), (R) -2-oxoimidazolidine-4-carboxylic acid (15.6 mg, 0.12 mmol), DIEA (38.7 mg, 0.3 mmol), and HATU (45.6 mg, 0.12 mmol) according to the procedure of 413. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.29 (t, J5.9 Hz, 1H), 7.98 (s, 1H), 7.13-7.03 (m, 4H), 7.01-6.91 (m, 4H), 6.54 (s, 1H), 6.32 (s, 1H), 4.21-4.16 (m, 2H), 4.13-4.05 (m, 1H), 3.59-3.52 (m, 1H), 3.24-3.19 (m, 1H), 2.44-2.34 (m, 1H), 1.82-1.65 (m, 5H), 1.41-1.09 (m, 6H). Mass (m/z): 393.3 [ M + H ]] ⁺ 。

N- (4- ((3,5-bis (diethyl)Amino) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (426)

Procedure according to 397 fromN ¹ - (4- (aminomethyl) phenyl) -N ³ ,N ³ ,N ⁵ ,N ⁵ -tetraethylbenzene-1,3,5-triamine (60.6 mg, 0.18 mmol), 5-oxopyrrolidine-3-carboxylic acid (27.6 mg, 0.21 mmol), DIEA (69 mg, 0.53 mmol) and HATU (81.3 mg, 0.21 mmol) the title compound 426 (15.7 mg) was prepared as a green solid in a total yield of 20.0%. Mass (m/z): 452.3 [ M + H ]] ⁺ 。

N- (4- ((3-chloro-2-methyl-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (427)

Step 1. Preparation of N- (4-bromo-3-chloro-2-methylphenyl) pivaloamide (427-2): pivaloyl chloride (2.88 g, 24 mmol) was added dropwise at 0 ℃ to a solution of 4-bromo-3-chloro-2-methylaniline (4.36 g, 20 mmol) and DIEA (3.87 g, 30 mmol) in DCM (30 mL). The mixture was then stirred at room temperature overnight. Subjecting the solution to H ₂ O (3x50 mL) and brine (50 mL). The organic layer was dried (Na) ₂ SO ₄ ) And concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-10% EtOAc/hexanes) to give the desired product as a pale yellow oil (5.6 g, 92.4%). Mass (m/z): 304.2 [ M + H ]] ⁺ 。

And 2. Step 2.NPreparation of- (3-chloro-2-methyl-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) pivaloamide (427-3): from N- (4-bromo-3-chloro-2-methylphenyl) pivaloamide (1.52 g, 5 mmol), 4- (trifluoromethyl) piperidine (765 mg, 5.0 mmol), pd according to the procedure of 394-3 ₂ (dba) ₃ (91.5 mg, 0.05 mmol)、X-Phos (119 mg, 0.25 mmol)、Cs ₂ CO ₃ (2.45 g, 7.5 mmol) the title compound 427-3 (545 mg) was prepared as a yellow solid in an overall yield of 29.0%.

Step 3.3-chloro-2-methyl-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (427-4) preparation: a solution of N- (3-chloro-2-methyl-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) pivaloamide (545 mg, 1.45 mmol) in 10 mL concentrated HCl was stirred in pressure tube at 100 deg.C overnight. The solution was then concentrated. 10 ml water was added. The pH of the filtrate was adjusted to 8-9 with sodium carbonate solution. The mixture was then extracted with DCM (10 mL × 3). The combined organic layers were washed with water (15 mL) and Na ₂ SO ₄ Dried and concentrated. The residue was purified by preparative TLC (EA/PE = 1/2) to provide the desired product as a yellow solid (87.6 mg, 20.7%). Mass (m/z): 293.3 [ M + H ] ] ⁺ 。

And 3. Step 3.NPreparation of- (4- ((3-chloro-2-methyl-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (427): from N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 3-chloro-2-methyl-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (87.6 mg, 0.3 mmol), pd according to the procedure of 404 ₂ (dba) ₃ (2.3 mg, 2.5 umol)、X-Phos (6.0 mg, 12.5 umol)、Cs ₂ CO ₃ (122 mg, 0.38 mmol) the title compound 427 (19.3 mg) was prepared as a white solid in 15.2% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.38 (t, J = 5.7 Hz, 1H), 7.58 (s, 1H), 7.52 (s, 1H), 7.09 - 6.96 (m, 4H), 6.71 - 6.64 (m, 2H), 4.15 (d, J = 5.7 Hz, 2H), 3.42 - 3.36 (m, 1H), 3.28 - 3.14 (m, 4H), 2.69 - 2.61 (m, 2H), 2.47 - 2.39 (m, 1H), 2.34 - 2.25 (m, 2H), 2.21 (s, 3H), 1.95 - 1.87 (m, 2H), 1.63 (qd, J= 12.4, 4.0 Hz, 2H). Mass (m/z): 509.3 [ M + H ]] ⁺ 。

N- (4- ((4-chloro-3- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (428)

The title compound 428 (4.6 mg) was prepared as a white solid in 10.3% overall yield from N- (4- (aminomethyl) phenyl) -4-chloro-3- (4- (trifluoromethyl) piperidin-1-yl) aniline (35 mg, 0.09 mmol), 5-oxopyrrolidine-3-carboxylic acid (14.0 mg, 0.11 mmol), DIEA (34.8 mg, 0.27 mmol), and HATU (41.8 mg, 0.11 mmol) according to the procedure of 397. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.42 (t, J = 5.8 Hz, 1H), 8.26 (s, 1H), 7.59 (s, 1H), 7.20 (d, J = 8.6 Hz, 1H), 7.16 - 7.10 (m, 2H), 7.06 - 6.99 (m, 2H), 6.77 (d, J = 2.6 Hz, 1H), 6.70 (dd, J = 8.6, 2.6 Hz, 1H), 4.20 (d, J= 5.7 Hz, 2H), 3.44 - 3.39 (m, 1H), 3.26 - 3.17 (m, 2H), 2.65 - 2.57 (m, 2H), 2.47 - 2.40 (m, 1H), 2.34 - 2.27 (m, 2H), 1.94 - 1.88 (m, 2H), 1.61 (qd, J= 12.1, 3.6 Hz, 2H). Mass (m/z): 495.2 [ M + H ]] ⁺ 。

N- (4- ((2-fluoro-5-methyl-4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (429)

According to the program of 404N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (111 mg, 0.38 mmol), 2-fluoro-5-methyl-4- (4-methylpiperidin-1-yl) aniline (100 mg, 0.45 mmol), pd ₂ (dba) ₃ (3.5 mg, 3.8 umol)、X-Phos (9.7 mg, 19 umol)、Cs ₂ CO ₃ (186 mg, 0.57 mmol) the title compound 429 (19.3 mg) was prepared in 15.2% overall yield as a white solid. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.36 (t, J = 5.7 Hz, 1H), 7.60 (s, 1H), 7.58 (s, 1H), 7.06 - 6.99 (m, 3H), 6.86 (d, J = 13.1 Hz, 1H), 6.80 - 6.75 (m, 2H), 4.15 (d, J = 5.7 Hz, 2H), 3.43 - 3.36 (m, 1H), 3.26 - 3.15 (m, 2H), 3.02 - 2.94 (m, 2H), 2.57 - 2.52 (m, 2H), 2.32 - 2.24 (m, 2H), 2.15 (s, 3H), 1.69 (d, J = 12.4 Hz, 2H), 1.51 - 1.41 (m, 1H), 1.33 - 1.23 (m, 2H), 0.96 (d, J= 6.5 Hz, 3H). Mass (m/z): 439.3 [M+H] ⁺ 。

N- (4- ((6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (430)

According to the program of 404N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (98 mg, 0.33 mmol), 6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-amine (92 mg, 0.40 mmol), pd ₂ (dba) ₃ (3.0 mg, 3.3 umol)、X-Phos (7.9 mg, 16.5 umol)、Cs ₂ CO ₃ (163 mg, 0.50 mmol) the title compound 430 (19.3 mg) was prepared as a white solid in 15.2% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.31 (t, J = 5.7 Hz, 1H), 7.57 (s, 1H), 7.25 (d, J = 8.7 Hz, 1H), 7.19 (s, 1H), 7.01 - 6.93 (m, 2H), 6.63 (d, J = 8.8 Hz, 1H), 6.54 - 6.46 (m, 2H), 4.32 - 4.23 (m, 2H), 4.11 (d, J = 5.7 Hz, 2H), 3.40 - 3.34 (m, 1H), 3.25 - 3.12 (m, 2H), 2.70 - 2.60 (m, 2H), 2.34 - 2.21 (m, 2H), 2.19 (s, 3H), 1.74 - 1.65 (m, 2H), 1.48 - 1.38 (m, 1H), 1.27 - 1.10 (m, 4H), 0.88 (d, J= 6.7 Hz, 6H). Mass (m/z): 450.3 [ M + H ]] ⁺ 。

N- (4- ((6- (4-butylpiperidin-1-yl) -2-methylpyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (431)

According to the program of 404N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (98 mg, 0.33 mmol), 6- (4-butylpiperidin-1-yl) -2-methylpyridin-3-amine (99 mg, 0.40 mmol), pd ₂ (dba) ₃ (3.0 mg, 3.3 umol)、X-Phos (7.9 mg, 16.5 umol)、Cs ₂ CO ₃ (163 mg, 0.50 mmol) the title compound 431 (22.9 mg) was prepared as a white solid in 14.9% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.31 (t, J = 5.6 Hz, 1H), 7.57 (s, 1H), 7.24 (d, J = 8.7 Hz, 1H), 7.19 (s, 1H), 7.01 - 6.94 (m, 2H), 6.63 (d, J8.8 Hz, 1H), 6.52-6.47 (m, 2H), 4.26-4.18 (m, 2H), 4.13-4.08 (m, 2H), 3.41-3.37 (m, 1H), 3.24-3.15 (m, 2H), 2.72-2.63 (m, 2H), 2.57-2.52 (m, 1H), 2.33-2.26 (m, 2H), 2.19 (s, 3H), 1.74-1.68 (m, 2H), 1.45-1.38 (m, 1H), 1.31-1.21 (m, 6H), 1.14-1.05 (m, 2H), 0.90-0.85 (m, 3H). Mass (m/z): 4564.4 [ M + H ] ] ⁺ 。

4-amino-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) butanamide (432)

Step 1 preparation of tert-butyl (4-oxo-4- ((4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) amino) butyl) carbamate (432-2): the title compound 432-2 (110 mg) was prepared as a blue solid in 68.8% overall yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (116 mg, 0.3 mmol), 4- ((tert-butoxycarbonyl) amino) butyric acid (73 mg, 0.0.36 mmol), DIEA (116 mg, 0.3 mmol), and HATU (137 mg, 0.36 mmol) according to the procedure of 397. Mass (m/z): 535.4 [ M + H ]] ⁺ 。

Step 2.preparation of 4-amino-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) butanamide (432): the title compound 432 (45.2 mg) was prepared as a gray solid in 52.0% overall yield from tert-butyl (4-oxo-4- ((4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) amino) butyl) carbamate (110 mg, 0.20 mmol), HCl in 1,4-dioxane (10.0 mL). ¹ H NMR(300 MHz, DMSO-d ₆ ) δ 8.33 (t, J = 5.8 Hz, 1H), 7.92 (s, 1H), 7.42 (s, 1H), 7.24 - 6.83 (m, 8H), 4.26 - 4.06 (m, 2H), 3.70 - 3.51 (m, 2H), 2.83 - 2.73 (m, 2H), 2.70 - 2.54 (m, 2H), 2.45 - 2.35 (m, 1H), 2.22 (t, J = 7.2 Hz, 2H), 1.95 - 1.74 (m, 4H),1.65-1.51 (m, 2H). Mass (m/z): 435.2 [ M + H ]] ⁺ 。

5-oxo-N- (2- (trifluoromethyl) -4- ((2- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-5-yl) amino) benzyl) pyrrolidine-3-carboxamide (433)

Procedure according to 397 fromN- (4- (aminomethyl) -3- (trifluoromethyl) phenyl) -2- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-5-amine (31 mg, 0.07 mmol), 5-oxopyrrolidine-3-carboxylic acid (11.5 mg, 0.09 mmol), DIEA (28.6 mg, 0.22 mmol), and HATU (33.7 mg, 0.09 mmol) the title compound 433 (6.2 mg) was prepared as a white solid in a total yield of 16.7%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.41 (t, J = 5.5 Hz, 1H), 8.29 (s, 2H), 8.07 (s, 1H), 7.59 (s, 1H), 7.24 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 2.5 Hz, 1H), 6.97 (dd, J = 8.3, 2.4 Hz, 1H), 4.72 (d, J = 13.4 Hz, 2H), 4.30 (d, J5.6 Hz, 2H), 3.44-3.37 (m, 2H), 3.25-3.20 (m, 2H), 2.96-2.87 (m, 3H), 2.31-2.27 (m, 2H), 1.91-1.85 (m, 2H), 1.43-1.35 (m, 3H). Mass (m/z): 531.3 [ M + H ]] ⁺ 。

(S)-N- (4- ((4- (4,4-dimethylcyclohexyl) phenyl) amino) benzyl) -2,6-dioxohexahydropyrimidine-4-carboxamide (434)

The title compound 434 (6.1 mg) was prepared as a white solid in 13.6% overall yield from 4- (aminomethyl) -N- (4- (4,4-dimethylcyclohexyl) phenyl) aniline (25 mg, 0.08 mmol), (S) -2,6-dioxohexahydropyrimidine-4-carboxylic acid (15.8 mg, 0.1 mmol), DIEA (38.7 mg, 0.3 mmol), and HATU (38.0 mg, 0.1 mmol) according to the procedure of 413. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 10.03 (s, 1H), 8.47 (t, J = 5.7 Hz, 1H), 8.02 (s, 1H), 7.63 (s, 1H), 7.15 - 7.05 (m, 4H), 6.99 - 6.92 (m, 4H), 4.20 - 4.12 (m, 2H), 4.01 (dt, J = 7.3, 3.5 Hz, 1H), 2.85 (dd, J = 16.6, 7.2 Hz, 1H), 2.38 - 2.27 (m, 2H), 1.64 - 1.52 (m, 2H), 1.46 - 1.40 (m, 2H), 1.34 - 1.24 (m, 2H), 0.95 (d, J= 10.0 Hz, 6H). Mass (m/z): 449.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4,4-dimethylcyclohexyl) phenyl) amino) benzyl) -2,6-dioxopiperidine-4-carboxamide (435)

The title compound 435 (19.6 mg) was prepared as a pale yellow solid in 54.7% total yield from 4- (aminomethyl) -N- (4- (4,4-dimethylcyclohexyl) phenyl) aniline (25 mg, 0.08 mmol), 2,6-dioxopiperidine-4-carboxylic acid (15.7 mg, 0.1 mmol), DIEA (38.7 mg, 0.3 mmol), and HATU (38.0 mg, 0.1 mmol) according to the procedure of 413. ¹ H NMR(300 MHz, DMSO-d ₆ ) δ 10.66 (s, 1H), 8.43 (t, J = 5.7 Hz, 1H), 7.98 (s, 1H), 7.13 - 7.02 (m, 4H), 6.98 - 6.92 (m, 4H), 4.15 (d, J = 5.7 Hz, 2H), 2.89 - 3.10 (m, 1H), 2.63 - 2.53 (m, 4H), 2.36 - 2.27 (m, 1H), 1.62 - 1.51 (m, 4H), 1.47 - 1.40 (m, 2H), 1.34 - 1.27 (m, 2H), 0.94 (d, J= 7.5 Hz, 6H). Mass (m/z): 448.3 [ M + H ]] ⁺ 。

(R)-N- (4- ((4- (4,4-dimethylcyclohexyl) phenyl) amino) benzyl) -2-oxoimidazolidine-4-carboxamide (436)

From 4- (aminomethyl) -N- (4- (4,4-dimethylcyclohexyl) phenyl) aniline (25 mg, 0.08 mmol),(R)-2-oxoimidazolidine-4-carboxylic acid (13.0 mg, 0.1 mmol), DIEA (38.7 mg, 0.3 mmol) and HATU (38.0 mg, 0.1 mmol) the title compound 436 (12.6 mg) was prepared as a light yellow solid in a total yield of 37.5%. ¹ H NMR(300 MHz, DMSO-d ₆ ) δ 8.28 (t, J = 5.7 Hz, 1H), 7.97 (s, 1H), 7.12 - 7.05 (m, 4H), 6.99 - 6.92 (m, 4H), 6.53 (s, 1H), 6.30 (s, 1H), 4.18 (d, J = 5.8 Hz, 2H), 4.09 (dd, J = 9.7, 6.1 Hz, 2H), 3.54 (t, J = 9.3 Hz, 1H), 3.27 - 3.18 (m, 2H), 1.58 - 1.35 (m, 8H), 0.94 (d, J= 7.5 Hz, 6H). Mass (m/z): 421.3 [ M + H ]] ⁺ 。

4-guanidino-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) butanamide (437)

To a solution of 4-amino-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) butanamide (33.6 mg, 7.7 umol) and DIEA (29.8 mg, 23.1 ummol) in MeCN (3.0 mL) was added 1H-pyrrole-1-carboxamidine (10.1 mg, 9.3 ummol). The mixture was then stirred at 60 ℃ for 16 hours. After cooling to room temperature, the solid was collected by filtration and washed with 5 mL MeCN to provide the desired product as a white solid (16.5 mg, 45.1%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (t, J = 5.8 Hz, 1H), 7.80 (s, 1H), 7.70 (s, 1H), 7.35 (s, 3H), 7.07 - 7.02 (m, 2H), 6.99 - 6.94 (m, 2H), 6.91 - 6.85 (m, 4H), 4.14 (d, J = 5.7 Hz, 2H), 3.66 - 3.57 (m, 2H), 3.10 (q, J = 6.7 Hz, 2H), 2.62 (td, J = 12.2, 2.4 Hz, 2H), 2.45 - 2.37 (m, 1H), 2.18 (t, J = 7.3 Hz, 2H), 1.92 - 1.83 (m, 2H), 1.71 (p, J = 7.3 Hz, 2H), 1.57 (qd, J= 12.4, 4.1 Hz, 2H). Mass (m/z): 477.3 [ M + H ]] ⁺ 。

N- (4- ((2-fluoro-6-methyl-4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (438)

From N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (99 mg, 0.33 mmol), 2-fluoro-6-methyl-4- (4-methylpiperidin-1-yl) aniline (95 mg, 0.43 mmol), pd ₂ (dba) ₃ (3.0 mg, 3.3 umol)、X-Phos (7.9 mg, 16.5 umol)、Cs ₂ CO ₃ (163 mg, 0.50 mmol) the title compound 438 (5.9 mg) was prepared as a white solid in 4.0% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.30 (t, J = 5.6 Hz, 1H), 7.56 (s, 1H), 7.10 (s, 1H), 7.00 - 6.91 (m, 2H), 6.67 (d, J = 2.9 Hz, 1H), 6.63 (dd, J = 13.5, 2.7 Hz, 1H), 6.43 - 6.35 (m, 2H), 4.10 (d, J= 5.6 Hz, 2H), 3.73 - 3.61 (m, 2H), 3.38 (t, J = 8.9 Hz, 1H), 3.24 - 3.14 (m, 2H), 2.69 - 2.62 (m, 2H), 2.30 - 2.22 (m, 2H), 2.10 (s, 3H), 1.71 - 1.65 (m, 2H), 1.54 - 1.47 (m, 1H), 1.25 - 1.18 (m, 2H), 0.94 (d, J= 6.5 Hz, 3H). Mass (m/z): 439.4 [ M + H ]] ⁺ 。

4- (methylamino) -N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) butanamide (439)

The title compound 439 (4.0 mg) was prepared as a gray solid in 31.5% overall yield according to the procedure of 363-4 from tert-butyl methyl (4-oxo-4- ((4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) amino) butyl) carbamate (15.6 mg, 2.8 umol), HCl in 1,4-dioxane (3.0 mL). ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.59 (s, 2H), 8.34 (s, 1H), 7.80 (s, 1H), 7.10 - 6.79 (m, 8H), 4.21 - 4.08 (m, 2H), 3.67 - 3.55 (m, 2H), 2.90 - 2.83 (m, 2H), 2.65 - 2.58 (m, 1H), 2.54 (t, J = 4.6 Hz, 2H), 2.23 (t, J= 7.2 Hz, 2H), 1.92-1.77 (m, 4H), 1.63-1.49 (m, 2H). Mass (m/z): 449.3 [ M + H ]] ⁺ 。

5-oxo-N- (4- ((4- (pentan-3-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (440)

Step 1.1-Nitro-4- (Pentane-3-yl) benzene (440-2): pentane-3-ylbenzene (444 mg, 3.0 mol) in acetic anhydride (2.0 mL) and CHCl at-5 deg.C ₃ (5.0 mL) to the stirred solution was slowly added concentrated HNO ₃ (0.3 mL). The reaction was maintained at 0 ℃ for 1 hour, then at room temperature for 18 hours. Water (10 mL) was added. The reaction was extracted with EtOAc (3x10 mL) over Na ₂ SO ₄ Dried and concentrated in vacuo. The residue was purified by preparative TLC (DCM/PE = 1/10) to provide the title compound (482 mg, 83.2%).

Step 2.4 preparation of 4- (Pentane-3-yl) aniline (440-3): the title compound 440-3 (390 mg) was prepared as a purple solid in 72.5% overall yield from 1-nitro-4- (pentan-3-yl) benzene (578 mg, 2 mmol) and 10% Pd/C (22 mg, 0.02 mmol) in EtOH (20 mL) according to the procedure of 386-4. Mass (m/z): 164.2 [ M + H ]] ⁺ 。

Step 3.5-oxo-NPreparation of- (4- ((4- (pentan-3-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (440): from N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (99 mg, 0.33 mmol), 4- (pentan-3-yl) aniline (70 mg, 0.43 mmol), pd according to the procedure of 427 ₂ (dba) ₃ (3.0 mg, 3.3 umol)、X-Phos (7.9 mg, 16.5 umol)、Cs ₂ CO ₃ (163 mg, 0.50 mmol) the title compound 440 (29.5 mg) was prepared as a light yellow solid in an overall yield of 23.4%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.39 (t, J = 5.8 Hz, 1H), 8.00 (s, 1H), 7.58 (s, 1H), 7.11 - 7.06 (m, 2H), 7.04 - 6.95 (m, 6H), 4.18 (d, J = 5.7 Hz, 2H), 3.40 (t, J = 8.7 Hz, 1H), 3.26 - 3.11 (m, 2H), 2.31 (td, J = 8.9, 4.4 Hz, 2H), 2.20 (dt, J = 9.6, 5.1 Hz, 1H), 1.68 - 1.55 (m, 2H), 1.51 - 1.40 (m, 2H), 0.72 (t, J= 7.3 Hz, 6H). Mass (m/z): 439.4 [ M + H ]] ⁺ 。

N- (4- ((4-cyclopentylphenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (441)

The title compound 441 (20.5 mg) was prepared as a white solid in 27.2% total yield from 4- (aminomethyl) -N- (4-cyclopentylphenyl) aniline hydrochloride (60 mg, 0.2 mmol), 5-oxopyrrolidine-3-carboxylic acid (31 mg, 0.24 mmol), DIEA (77.4 mg, 0.6 mmol), and HATU (91.2 mg, 0.24 mmol) according to the procedure of 413. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.39 (t, J = 5.8 Hz, 1H), 8.00 (s, 1H), 7.58 (s, 1H), 7.13 - 7.06 (m, 4H), 7.00 - 6.93 (m, 4H), 4.17 (d, J = 5.7 Hz, 2H), 3.40 (t, J= 8.9 Hz, 1H), 3.26-3.14 (m, 2H), 2.90-2.80 (m, 1H), 2.33-2.25 (m, 2H), 2.02-1.92 (m, 2H), 1.79-1.69 (m, 2H), 1.67-1.57 (m, 2H), 1.53-1.41 (m, 2H). Mass (m/z): 378.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4,4-dimethylcyclohexyl) phenyl) amino) phenethyl) -5-oxopyrrolidine-3-carboxamide (442)

And (1).NPreparation of- (4-bromophenylethyl) -5-oxopyrrolidine-3-carboxamide (442-2): to a solution of 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (568 mg, 4.4 mmol) in DCM (20 ml) was added HATU (1.67 mg, 4.4 mmol). The reaction mixture was then stirred at room temperature for 1 hour. 2- (4-bromophenyl) ethan-1-amine (800 mg, 4.0 mmol) and DIEA (1.55 mg, 12.0 mmol) were added. The reaction mixture was then stirred at room temperature for 3 hours. 5 mL water was added. The mixture was then extracted with DCM (5 mL × 3). The precipitate was collected by filtration to provide the desired product as a white solid (1.14 g, 91.9%). Mass (m/z): 311.1 [ M + H ]] ⁺ 。

And (2).NPreparation of- (4- ((4- (4,4-dimethylcyclohexyl) phenyl) amino) phenethyl) -5-oxopyrrolidine-3-carboxamide (442): from N- (4-bromophenylethyl) -5-oxopyrrolidine-3-carboxamide (78 mg, 0.25 mmol), 4- (4,4-dimethylcyclohexyl) aniline (61 mg, 0.3 mmol), pd according to the procedure of 427 ₂ (dba) ₃ (2.3 mg, 2.5 umol)、X-Phos (6.0 mg, 12.5 umol)、Cs ₂ CO ₃ (122 mg, 0.40 mmol) the title compound 442 (14.0 mg) was prepared as a white solid in 12.9% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.05 (t, J = 5.6 Hz, 1H), 7.92 (s, 1H), 7.56 (s, 1H), 7.11 - 7.07 (m, 2H), 7.04 - 7.01 (m, 2H), 6.98 - 6.92 (m, 4H), 3.38 - 3.35 (m, 1H), 3.27 - 3.10 (m, 4H), 2.61 (t, J = 7.3 Hz, 2H), 2.46 (s, 1H), 2.34 - 2.21 (m, 4H), 1.62 - 1.50 (m, 4H), 1.47 - 1.39 (m, 2H), 1.34 - 1.24 (m, 2H), 0.95 (d, J= 10.1 Hz, 6H). Mass (m/z): 434.3 [ M + H ]] ⁺ 。

N- (4- ((2-fluoro-6- (4- (trifluoromethyl) piperidin-1-yl) pyridin-3-yl) amino) benzyl) -2-oxoimidazolidine-4-carboxamide (443)

Procedure according to 397 fromN- (4- (aminomethyl) phenyl) -2-fluoro-6- (4- (trifluoromethyl) piperidin-1-yl) pyridin-3-amine hydrochloride (50 mg, 0.12 mmol), 2-oxoimidazolidine-4-carboxylic acid (18.6 mg, 0.14 mmol), DIEA (46.0 mg, 0.36 mmol), and HATU (55.0 mg, 0.14 mmol) the title compound 443 (4.8 mg) was prepared in a total yield of 8.3% as an off-white solid. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.25 (t, J = 5.9 Hz, 1H), 7.55 (dd, J = 10.7, 8.5 Hz, 1H), 7.46 (s, 1H), 7.06 - 7.01 (m, 2H), 6.73 (dd, J = 7.9, 1.5 Hz, 1H), 6.64 - 6.59 (m, 2H), 6.55 - 6.49 (m, 1H), 6.31 (s, 1H), 4.28 - 4.20 (m, 2H), 4.18 - 4.11 (m, 2H), 4.08 (dd, J = 9.7, 6.2 Hz, 1H), 3.55 (d, J = 9.3 Hz, 1H), 3.20 (dd, J = 8.9, 6.2 Hz, 1H), 2.84 (td, J = 12.8, 2.1 Hz, 2H), 2.64 - 2.58 (m, 1H), 1.92 - 1.81 (m, 2H), 1.43 (qd, J= 13.0, 12.2, 3.5 Hz, 2H). Mass (m/z): 481.3 [ M + H ]] ⁺ 。

N- (4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) benzyl) -5-oxopyrrolidine-3-methylAmide (444)

Programmed according to 427N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 2- (4-isopropylpiperidin-1-yl) pyrimidin-5-amine (73 mg, 0.33 mmol), pd ₂ (dba) ₃ (2.3 mg, 2.5 umol)、X-Phos (6.0 mg, 12.5 umol)、Cs ₂ CO ₃ (122 mg, 0.38 mmol) the title compound 444 (40.0 mg) was prepared as a white solid in 36.7% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.37 (t, J = 5.8 Hz, 1H), 8.21 (s, 2H), 7.62 (s, 1H), 7.58 (s, 1H), 7.06 - 7.00 (m, 2H), 6.74 - 6.68 (m, 2H), 4.67 - 4.59 (m, 2H), 4.13 (d, J = 5.7 Hz, 2H), 3.39 (t, J = 8.6 Hz, 1H), 3.25 - 3.11 (m, 2H), 2.75 (td, J = 12.8, 2.5 Hz, 2H), 2.32 - 2.20 (m, 2H), 1.73 - 1.62 (m, 2H), 1.47 - 1.36 (m, 1H), 1.31 - 1.22 (m, 1H), 1.10 (qd, J = 12.4, 4.1 Hz, 2H), 0.87 (d, J= 6.7 Hz, 6H). Mass (m/z): 437.4 [ M + H ]] ⁺ 。

N- (4- ((2- (4-ethylpiperidin-1-yl) pyrimidin-5-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (445)

From N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 2- (4-ethylpiperidin-1-yl) pyrimidin-5-amine (68 mg, 0.33 mmol), pd according to the procedure of 427 ₂ (dba) ₃ (2.3 mg, 2.5 umol)、X-Phos (6.0 mg, 12.5 umol)、Cs ₂ CO ₃ (122 mg, 0.38 mmol) the title compound 445 (23.2 mg) was prepared as a pale yellow solid in 22.0% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.35 (t, J = 5.8 Hz, 1H), 8.21 (s, 2H), 7.61 (s, 1H), 7.58 (s, 1H), 7.06 - 6.98 (m, 2H), 6.76 - 6.67 (m, 2H), 4.64 - 4.54 (m, 2H), 4.13 (d, J = 5.7 Hz, 2H), 3.42 - 3.36 (m, 1H), 3.24 - 3.13 (m, 2H), 2.81 (td, J = 12.8, 2.7 Hz, 2H), 2.32 - 2.22 (m, 2H), 1.75 - 1.69 (m, 2H), 1.40 (s, 1H), 1.25 (p, J = 7.3 Hz, 2H), 1.08 - 0.99 (m, 2H), 0.89 (t, J= 7.4 Hz, 3H). Mass (m/z): 423.4 [ M + H ]] ⁺ 。

N- (4- ((4-methyl-2- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-5-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (446)

The title compound 446 (4.1 mg) was prepared as a white powder in 15.1% total yield from N- (4- (aminomethyl) phenyl) -4-methyl-2- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-5-amine (21 mg, 57 umol), 5-oxopyrrolidine-3-carboxylic acid (8.9 mg, 69 umol), DIEA (22.0 mg, 0.17 mmol), and HATU (26 mg, 69 umol) according to the procedure of 413. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.33 (t, J = 5.6 Hz, 1H), 8.09 (s, 1H), 7.57 (s, 1H), 7.29 (s, 1H), 7.03 - 6.96 (m, 2H), 6.52 - 6.46 (m, 2H), 4.80 - 4.68 (m, 2H), 4.12 (d, J = 5.7 Hz, 2H), 3.43 - 3.36 (m, 1H), 3.23 - 3.12 (m, 2H), 2.92 - 2.84 (m, 2H), 2.65 - 2.56 (m, 1H), 2.32 - 2.26 (m, 2H), 2.18 (s, 3H), 1.92 - 1.83 (m, 2H), 1.38 (qd, J= 12.6, 4.3 Hz, 2H). Mass (m/z): 477.3 [ M + H ]] ⁺ 。

N- (3- (4- ((4- (4,4-dimethylcyclohexyl) phenyl) amino) phenyl) propyl) -5-oxopyrrolidine-3-carboxamide (447)

From N- (3- (4-bromophenyl) propyl) -5-oxopyrrolidine-3-carboxamide (32.4 mg, 0.1 mmol), 4- (4,4-dimethylcyclohexyl) aniline (24.5 mg, 0.12 mmol), pd according to the procedure of 442 ₂ (dba) ₃ (1.8 mg, 2 umol)、X-Phos (4.8 mg, 10 umol)、Cs ₂ CO ₃ (99 mg, 0.3 mmol) the title compound 447 (6.8 mg) was prepared as a white solid in 16.3% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.01 (t, J = 5.5 Hz, 1H), 7.90 (s, 1H), 7.57 (s, 1H), 7.11 - 7.06 (m, 2H), 7.06 - 7.00 (m, 2H), 6.98 - 6.91 (m, 4H), 3.41 - 3.37 (m, 1H), 3.23 - 3.04 (m, 4H), 2.49 - 2.44 (m, 2H), 2.35 - 2.23 (m, 3H), 1.68 - 1.39 (m, 8H), 1.33 - 1.21 (m, 2H), 0.95 (d, J= 10.1 Hz, 6H). Mass (m/z): 448.4 [ M + H ]] ⁺ 。

N- (4- ((3- (4-methoxybutoxy) -4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (448)

Step 1.2- (tert-butyl) -5-nitrophenol (448-2) preparation: 15% H at 0 ℃ to 2-tert-butyl-5-nitroaniline (582 g, 3.0 mmol) at 10 mL ₂ SO ₄ Adding NaNO dropwise into the mixture ₂ (217 mg, 3.15 mmol) in water (3 mL). The resulting mixture was stirred at 0-5 ℃ for 20 min. The solution was then added dropwise to 5 mL in H, stirred at 100 deg.C ₂ SO ₄ -H ₂ O (V/V = 1/2) solution. The resulting mixture was stirred at 100 ℃ for 20 min. After cooling to room temperature, extract with DCM (20 mL × 3). The combined organic layers were washed with water (20 mL) and Na ₂ SO ₄ Dried and concentrated. The residue was purified by preparative TLC (DCM/PE = 1/3) to provide the title compound (300 mg, 51.5%) as a yellow oil. Mass (m/z): 194.0 [ M-H ]] ⁺ 。

Step 2.1 preparation of- (tert-butyl) -2- (4-methoxybutoxy) -4-nitrobenzene (448-3): to 2- (tert-butyl) -5-nitrophenol (150 mg, 0.77 mmol), KI (12.8 mg, 77 ummol) and K ₂ CO ₃ (212 mg, 1.54 mmol) to a mixture in DMSO (2.0 mL) was added 1-bromo-4-methoxybutane (190 mg, 1.15 mmol). The mixture was then stirred at 80 ℃ overnight. After cooling to room temperature, 5 mL water was added and extracted with DCM (10 mL x 3). The combined organic layers are washed with Washed with water (10 mL. Times.3) over Na ₂ SO ₄ Dried and concentrated to provide the title compound as a crude as a yellow oil (216 mg, 100%).

Step 3.4- (tert-butyl) -3- (4-methoxybutoxy) aniline (448-4) preparation: the title compound 448-4 (193 mg) was prepared as a yellow solid in 100% overall yield from 1- (tert-butyl) -2- (4-methoxybutoxy) -4-nitrobenzene (216 mg, 0.77 mmol) and 10% Pd/C (81.6 mg, 77 umol) according to the procedure of 386-4. Mass (m/z): 252.4 [ M + H ]] ⁺ 。

And 4. Step 4.NPreparation of- (4- ((3- (4-methoxybutoxy) -4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (448): programmed according to 442N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (59.2 mg, 0.2 mmol), 4- (tert-butyl) -3- (4-methoxybutoxy) aniline (83 mg, 0.24 mmol), pd ₂ (dba) ₃ (1.8 mg, 2 umol)、X-Phos (4.8 mg, 10 umol)、Cs ₂ CO ₃ (99 mg, 0.3 mmol) the title compound 448 (9.2 mg) was prepared as a white solid in 8.2% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 7.60 (s, 1H), 7.22 - 6.92 (m, 5H), 6.73 - 6.60 (m, 2H), 4.19 (d, J = 4.8 Hz, 2H), 4.02 - 3.96 (m, 2H), 3.85 - 3.67 (m, 4H), 3.56 - 3.45 (m, 2H), 3.41 - 3.36 (m, 3H), 3.29 - 3.17 (m, 5H), 2.62 - 2.54 (m, 1H), 2.33 - 2.28 (m, 2H), 2.08 - 1.93 (m, 2H), 1.86 - 1.79 (m, 2H), 1.72 - 1.64 (m, 2H)。

N- (4- ((2- (4-isopropylpiperidin-1-yl) -4-methylpyrimidin-5-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (449)

Step 1.5-bromo-2- (4-isopropylpiperidin-1-yl) -4-methylpyrimidine (449-3) preparation: a solution of 4-isopropylpiperidine (254 mg, 2.0 mmol), 5-bromo-2-chloro-4-methylpyrimidine (414 mg, 2.0 mmol) and DIEA (774 mg, 6.0 mmol) in EtOH (10 mL) was stirred at 100 ℃ for 18 hours. After cooling to room temperature, add 20 mL water. The precipitate was collected by filtration to afford the desired product as a white solid (414 mg, 69.5%). Mass (m/z): 298.1 [ M + H ]] ⁺ 。

And 2. Step 2.NPreparation of- (4- (aminomethyl) phenyl) -2- (4-isopropylpiperidin-1-yl) -4-methylpyrimidin-5-amine (449-5): from 5-bromo-2- (4-isopropylpiperidin-1-yl) -4-methylpyrimidine (100 mg, 0.33 mmol), (4-aminobenzyl) carbamic acid tert-butyl ester (111 mg, 0.50 mmol), pd according to the procedure of 427 ₂ (dba) ₃ (3.0 mg, 3.3 umol), X-Phos (7.9 mg, 16.5 umol), t-BuOK (56 mg, 0.50 mmol) the title compound 449-5 (16.3 mg) was prepared as a yellow solid in an overall yield of 14.4%. Mass (m/z): 340.3 [ M + H ]] ⁺ 。

And (3) performing step (b).NPreparation of- (4- ((2- (4-isopropylpiperidin-1-yl) -4-methylpyrimidin-5-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (449): programmed according to 413 fromN- (4- (aminomethyl) phenyl) -2- (4-isopropylpiperidin-1-yl) -4-methylpyrimidin-5-amine (16.3 mg, 0.05 mmol), 5-oxopyrrolidine-3-carboxylic acid (7.8 mg, 0.06 mmol), DIEA (19.4 mg, 0.15 mmol), and HATU (20.9 mg, 0.06 mmol) prepared the title compound 449 (3.4 mg) as a gray solid in a total yield of 15.2%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.30 (t, J = 5.7 Hz, 1H), 8.01 (s, 1H), 7.54 (s, 1H), 7.22 (s, 1H), 6.97 - 6.93 (m, 2H), 6.46 - 6.40 (m, 2H), 4.70 - 4.64 (m, 2H), 4.08 (d, J = 5.7 Hz, 2H), 3.37 - 3.33 (m, 1H), 3.20 - 3.09 (m, 2H), 2.75 - 2.67 (m, 2H), 2.27 - 2.20 (m, 2H), 2.12 (s, 3H), 1.69 - 1.63 (m, 2H), 1.44 - 1.36 (m, 1H), 1.24 (d, J = 6.1 Hz, 1H), 1.14 - 0.99 (m, 2H), 0.84 (d, J= 6.8 Hz, 6H). Mass (m/z): 451.1 [ M + H ] ] ⁺ 。

5-oxo-N- (4- ((5- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-2-yl) amino) benzyl) pyrrolidine-3-carboxamide (450)

From N- (4- (aminomethyl) according to the procedure of 413) Phenyl) -5- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-2-amine (53.7 mg, 0.15 mmol), 5-oxopyrrolidine-3-carboxylic acid (23.2 mg, 0.18 mmol), DIEA (58 mg, 0.45 mmol) and HATU (57 mg, 0.15 mmol) the title compound 450 (10.2 mg) was prepared as a white powder in a total yield of 12.3%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.33 (t, J = 5.8 Hz, 1H), 8.22 (s, 2H), 7.65 (s, 1H), 7.54 (s, 1H), 7.03 - 6.98 (m, 2H), 6.73 - 6.69 (m, 2H), 4.69 - 4.61 (m, 2H), 4.10 (d, J = 5.8 Hz, 2H), 3.35 (t, J = 8.7 Hz, 1H), 3.20 - 3.09 (m, 2H), 2.85 (td, J = 12.9, 2.6 Hz, 2H), 2.61 - 2.55 (m, 1H), 2.25 (dd, J= 8.4, 3.4 Hz, 2H), 1.88-1.77 (m, 2H), 1.39-1.28 (m, 2H). Mass (m/z): 463.3 [ M + H ]] ⁺ 。

N- (4- ((2-Ethyl-6- (4-methylpiperidin-1-yl) pyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (451)

Step 1.6-chloro-2-ethylpyridin-3-amine (451-2) preparation: to a solution of 2,6-dichloropyridin-3-amine (1.63 g, 10 mmol) in 1,4-dioxane (25 ml) was added tetrakis (triphenylphosphine) palladium (0) (231 mg, 0.2 mmol) and triethylaluminum (2.2 mL, 2M in hexane, 10.4 mmol) at room temperature and the mixture was stirred at 100 ℃ for 3 hours. The mixture was quenched after cooling with 2M aqueous HCl and then separated between aqueous and organic phases. The aqueous phase was extracted with EtOAc. The combined organic phases were dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography on silica eluting with hexane/EtOAc (2:1) to give the title compound (25 mg, 16.0%). 157.3 [ M + H ] ] ⁺ 。

And 2. Step 2.NPreparation of (6-chloro-2-ethylpyridin-3-yl) pivaloamide (451-3): pivaloyl chloride (289 mg, 2.39 mmol) was added dropwise to a solution of 6-chloro-2-ethylpyridin-3-amine (250 mg, 1.59 mmol) and DIEA (410 mg, 3.18 mmol) in DCM (20 mL) at 0 deg.C. The mixture was then stirred at room temperature overnight. Subjecting the solution to H ₂ O (3x20 mL) and brine (20 mL). The organic layer was dried (Na) ₂ SO ₄ ) And concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-10% EtOAc/hexanes) to give the desired product as a pale yellow oil (300 mg, 78.9%). Mass (m/z): 241.2 [ M + H ]] ⁺ 。

And 3. Step 3.NPreparation of (2-ethyl-6- (4-methylpiperidin-1-yl) pyridin-3-yl) pivaloamide (451-4): program according to 394-3 fromN- (6-chloro-2-ethylpyridin-3-yl) pivaloamide (300 mg, 1.25 mmol), 4-methylpiperidine (186 mg, 1.9 mmol), pd ₂ (dba) ₃ (11.4 mg, 12.5 umol)、X-Phos (29.8 mg, 62.5 mmol)、Cs ₂ CO ₃ (611 mg, 1.08 mmol) the title compound 451-4 (330 mg) was prepared as a yellow solid in overall yield of 87.3%.

Step 4.2-Ethyl-6- (4-methylpiperidin-1-yl) pyridin-3-amine (451-5) preparation: in a pressure pipe, willNA solution of (2-ethyl-6- (4-methylpiperidin-1-yl) pyridin-3-yl) pivaloamide (330 mg, 1.09 mmol) in 10 mL concentrated HCl was stirred at 100 deg.C overnight. The solution was then concentrated. 10 ml water was added. The pH of the filtrate was adjusted to 8-9 with sodium carbonate solution. The mixture was then extracted with DCM (10 mL × 3). The combined organic layers were washed with water (15 mL) and Na ₂ SO ₄ Dried and concentrated. The residue was purified by preparative TLC (EA/PE = 1/2) to provide the desired product as a yellow solid (230 mg, 98.2%). Mass (m/z): 220.3 [ M + H ]] ⁺ 。

And 5. Step 5.NPreparation of- (4- ((2-ethyl-6- (4-methylpiperidin-1-yl) pyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (451): from N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (97 mg, 0.33 mmol), 2-ethyl-6- (4-methylpiperidin-1-yl) pyridin-3-amine (87 mg, 0.4 mmol), pd according to the procedure of 404 ₂ (dba) ₃ (3.0 mg, 3.3 umol)、X-Phos (7.9 mg, 16.5 umol)、Cs ₂ CO ₃ (163 mg, 0.50 mmol) the title compound 451 (15.5 mg) was prepared as a white solid in 10.7% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.33 (t, J = 5.7 Hz, 1H), 7.57 (s, 1H), 7.33 (s, 1H), 7.07 (s, 1H), 7.01 - 6.91 (m, 2H), 6.64 (s, 1H), 6.52 - 6.46 (m, 2H), 4.28 - 4.20 (m, 2H), 4.11 (d, J = 5.7 Hz, 2H), 3.41 - 3.35 (m, 2H), 3.25 - 3.14 (m, 2H), 2.78 - 2.67 (m, 2H), 2.58 - 2.53 (m, 2H), 2.28 (dd, J = 8.4, 5.2 Hz, 2H), 1.71 - 1.63 (m, 2H), 1.61 - 1.51 (m, 1H), 1.17 - 1.07 (m, 5H), 0.93 (d, J= 6.5 Hz, 3H). Mass (m/z): 436.4 [ M + H ]] ⁺ 。

5-oxo-N- (4- ((2-propoxypyrimidin-5-yl) amino) benzyl) pyrrolidine-3-carboxamide (452)

Step 1.5-Nitro-2-propoxypyrimidine (452-2) preparation: to a solution of 2-chloro-5-nitropyrimidine (474 mg, 3 mmol) in 1-propane (10 mL) was added sodium propylalkoxide (492 mg, 6 mmol). The mixture was then stirred at 80 ℃ for 2 hours. After cooling to room temperature, 15 mL water was added. The mixture was then extracted with DCM (15 mL x 3). The combined organic layers were washed with water (20 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by preparative TLC (EA/PE = 1/10) to yield the desired product as a yellow solid (80 mg, 14.6%). Mass (m/z): 184.1 [ M + H ] ] ⁺

Step 2.2 preparation of 2-propoxypyrimidin-5-amine (452-3): the title compound 452-3 (60 mg) was prepared as a yellow solid in 92.3% overall yield from 5-nitro-2-propoxypyrimidine (80 mg, 0.43 mmol) and 10% Pd/C (4.6 mg, 4.3 umol) according to the procedure of 386-4. Mass (m/z): 154.1 [ M + H ]] ⁺ 。

Step 3.preparation of 5-oxo-N- (4- ((2-propoxypyrimidin-5-yl) amino) benzyl) pyrrolidine-3-carboxamide (452): from N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (107 mg, 0.36 mmol), 2-propoxypyrimidin-5-amine (60 mg, 0.4 mmol), pd according to the procedure of 442 ₂ (dba) ₃ (3.3 mg, 3.6 umol)、X-Phos (8.6 mg, 18 umol)、Cs ₂ CO ₃ (176 mg, 0.54 mmol) the title compound 452 (23.3 mg) was prepared as a white solid in 17.5% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 7.60 (s, 1H), 7.22 - 6.92 (m, 5H), 6.73 - 6.60 (m, 2H), 4.19 (d, J4.8 Hz, 2H), 4.02-3.96 (m, 2H), 3.85-3.67 (m, 4H), 3.56-3.45 (m, 2H), 3.41-3.36 (m, 3H), 3.29-3.17 (m, 5H), 2.62-2.54 (m, 1H), 2.33-2.28 (m, 2H), 2.08-1.93 (m, 2H), 1.86-1.79 (m, 2H), 1.72-1.64 (m, 2H). Mass (m/z): 370.2 [ M + H ]] ⁺ 。

5-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) phenethyl) pyrrolidine-3-carboxamide (453)

From N- (4-bromophenylethyl) -5-oxopyrrolidine-3-carboxamide (62 mg, 0.2 mmol), 4- (4- (trifluoromethyl) piperidin-1-yl) aniline (63 mg, 0.26 mmol), pd according to the procedure of 442 ₂ (dba) ₃ (1.8 mg, 2.0 umol)、X-Phos (4.8 mg, 10 umol)、Cs ₂ CO ₃ (98 mg, 0.3 mmol) the title compound 453 (17.5 mg) was prepared as a white solid in 18.5% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 7.98 (t, J = 5.6 Hz, 1H), 7.66 (s, 1H), 7.51 (s, 1H), 6.97 - 6.90 (m, 4H), 6.87 - 6.80 (m, 4H), 3.60 - 3.54 (m, 2H), 3.34 - 3.29 (m, 1H), 3.21 - 3.13 (m, 3H), 3.10 - 3.03 (m, 1H), 2.56 (td, J = 7.6, 6.7, 3.4 Hz, 4H), 2.42 - 2.33 (m, 1H), 2.21 (dd, J = 8.5, 3.1 Hz, 2H), 1.88 - 1.81 (m, 2H), 1.54 (qd, J= 12.4, 4.0 Hz, 2H). Mass (m/z): 475.2 [ M + H ]] ⁺ 。

5-oxo-N- (3- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) phenyl) propyl) pyrrolidine-3-carboxamide (454)

From N- (3- (4-bromophenyl) propyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.15 mmol), 4- (4- (trifluoromethyl) piperidine-1-carboxylic acid) according to the procedure of 442Phenyl) aniline (41.1 mg, 0.17 mmol), pd ₂ (dba) ₃ (1.8 mg, 2.0 umol)、X-Phos (4.8 mg, 10 umol)、Cs ₂ CO ₃ (83 mg, 0.26 mmol) the title compound 454 (8.8 mg) was prepared as a white solid in 10.6% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 7.95 (t, J = 5.6 Hz, 1H), 7.65 (s, 1H), 7.53 (s, 1H), 6.97 - 6.89 (m, 4H), 6.86 - 6.80 (m, 4H), 3.60 - 3.53 (m, 2H), 3.35 (t, J= 8.7 Hz, 1H), 3.20-3.15 (m, 1H), 3.11-2.99 (m, 3H), 2.62-2.54 (m, 3H), 2.44-2.37 (m, 4H), 2.26-2.21 (m, 2H), 1.88-1.82 (m, 2H), 1.65-1.46 (m, 4H). Mass (m/z): 489.2 [ M + H ]] ⁺ 。

N- (3- (4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) phenyl) propyl) -5-oxopyrrolidine-3-carboxamide (455)

From N- (3- (4-bromophenyl) propyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.15 mmol), 2- (4-isopropylpiperidin-1-yl) pyrimidin-5-amine (37.4 mg, 0.17 mmol), pd according to the procedure of 442 ₂ (dba) ₃ (1.8 mg, 2.0 umol)、X-Phos (4.8 mg, 10 umol)、Cs ₂ CO ₃ (83 mg, 0.26 mmol) the title compound 455 (7.8 mg) was prepared as a white solid in 9.9% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 7.95 (t, J = 5.6 Hz, 1H), 7.65 (s, 1H), 7.53 (s, 1H), 6.97 - 6.89 (m, 4H), 6.86 - 6.80 (m, 4H), 3.60 - 3.53 (m, 2H), 3.35 (t, J= 8.7 Hz, 1H), 3.20-3.15 (m, 1H), 3.11-2.99 (m, 3H), 2.62-2.54 (m, 3H), 2.44-2.37 (m, 4H), 2.26-2.21 (m, 2H), 1.88-1.82 (m, 2H), 1.65-1.46 (m, 4H). Mass (m/z): 465.2 [ M + H ]] ⁺ 。

N- (4- ((6- (4- (2-methoxypropan-2-yl) piperidin-1-yl) -2-methylpyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (456)

From N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 6- (4- (2-methoxypropan-2-yl) piperidin-1-yl) -2-methylpyridin-3-amine (87 mg, 0.33 mmol), pd according to the procedure of 427 ₂ (dba) ₃ (2.3 mg, 2.5 umol)、X-Phos (6.0 mg, 12.5 umol)、Cs ₂ CO ₃ (122 mg, 0.38 mmol) the title compound 456 (22.0 mg) was prepared as a pale yellow solid in 18.3% total yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.27 (t, J = 5.7 Hz, 1H), 7.52 (s, 1H), 7.21 (d, J = 8.7 Hz, 1H), 7.14 (s, 1H), 6.97 - 6.90 (m, 2H), 6.59 (d, J = 8.8 Hz, 1H), 6.49 - 6.44 (m, 2H), 4.32 - 4.23 (m, 2H), 4.08 (d, J = 5.6 Hz, 2H), 3.39 - 3.31 (m, 1H), 3.23 - 3.10 (m, 2H), 3.06 (s, 3H), 2.62 - 2.54 (m, 2H), 2.24 (dd, J = 8.4, 5.2 Hz, 2H), 2.16 (s, 3H), 1.69 - 1.62 (m, 2H), 1.60 - 1.52 (m, 2H), 1.20 (td, J= 12.9, 4.3 Hz, 2H), 1.02 (s, 6H). Mass (m/z): 480.3 [ M + H ]] ⁺ 。

N- (4- ((3-fluoro-2-methyl-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -2-oxoimidazolidine-4-carboxamide (457)

The title compound 457 (31.0 mg) was prepared as a light blue solid in 31.4% total yield from N- (4- (aminomethyl) phenyl) -3-fluoro-2-methyl-4- (4- (trifluoromethyl) piperidin-1-yl) aniline hydrochloride (81.4 mg, 0.2 mmol), 2-oxoimidazolidine-4-carboxylic acid (52 mg, 0.4 mmol), DIEA (77.4 mg, 0.6 mmol), and HATU (91.2 mg, 0.24 mmol) according to the procedure of 413. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.26 (t, J = 5.8 Hz, 1H), 7.40 (s, 1H), 7.05 (d, J = 8.5 Hz, 2H), 6.90 - 6.80 (m, 2H), 6.75 - 6.68 (m, 2H), 6.53 (s, 1H), 6.30 (s, 1H), 4.16 (s, 2H), 4.11 - 4.04 (m, 2H), 3.57 - 3.49 (m, 1H), 3.35 (s, 2H), 3.24 - 3.17 (m, 2H), 2.71 - 2.63 (m, 2H), 2.45 (s, 1H), 2.05 (d, J = 2.7 Hz, 3H), 1.93 - 1.87 (m, 2H), 1.61 (qd, J= 12.3, 4.1 Hz, 2H). Mass (m/z): 494.2 [ M + H ]] ⁺ 。

1-Ethyl-5-oxo-N- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (458)

Step 1.preparation of 1-ethyl-5-oxo-N- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (458): to a mixture of 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (39 mg, 0.25 mmol) and DMT-MM (69 mg, 0.25 mmol) in the super-dried stateN,N-dimethylformamide (5 mL) to a solution4- (aminomethyl) -N- (4- (piperidin-1-yl) phenyl) aniline (70 mmL, 0.25 mmol) andN-ethyl-N-isopropylpropan-2-amine (75 mg, 0.75 mmol), and the resulting solution was stirred at room temperature overnight. The reaction mixture was added dropwise to water (15 mL) with stirring. The precipitate was filtered, the filter cake was washed 3 times with water and dried in vacuo. The residue was purified by preparative TLC to give the desired product 458 (36.2 mg) as a light blue powder in 34.60% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.89 (s, 1H), 8.49 (t, J = 6.0 Hz, 1H), 7.47 (s, 2H), 7.12 (dd, J = 28.8, 10.1 Hz, 6H), 4.21 (s, 3H), 3.51 (t, J = 9.2 Hz, 4H), 3.37 (dd, J = 9.5, 6.3 Hz, 1H), 3.25 - 3.06 (m, 3H), 2.41 (dd, J = 8.5, 4.0 Hz, 2H), 1.87 (s, 4H), 1.54 (s, 2H), 1.00 (t, J= 7.2 Hz, 3H). Mass (m/z): 421.4 [ M + H ]] ⁺ 。

1-Ethyl-5-oxo-N- (4- ((4- (pyrrolidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (459)

From 4- (aminomethyl) -N- (4- (pyrrolidin-1-yl) phenyl) aniline (70 mg, 0.26 mm) according to the procedure of 458 ol) and 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (41 mg, 0.26 mmol) the title compound 459 (30.0 mg) was prepared in 28.19% yield as a light blue powder. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 7.56-6.45 (m, 7H), 4.79 (s, 3H), 3.51 (t, J = 9.2 Hz, 1H), 3.36 (dd, J = 9.5, 6.3 Hz, 2H), 3.19 (qd, J = 7.3, 1.6 Hz, 4H), 3.16 - 3.07 (m, 2H), 2.41 (dd, J = 8.5, 1.7 Hz, 2H), 2.25-1.82 (br, 3H), 1.00 (t, J= 7.2 Hz, 3H). Mass (m/z): 407.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (460)

The title compound 460 (25.7 mg) was prepared as a light gray powder in 19.66% yield from 4- (aminomethyl) -N- (4- (4-methylpiperidin-1-yl) phenyl) aniline (95 mg, 0.32 mmol) and 5-oxopyrrolidine-3-carboxylic acid (46 mg, 0.35 mmol) according to the procedure of 458. ¹ H NMR (400 MHz, DMSO-d 6) δ 8.37 (s, 1H), 7.58 (s, 1H), 7.34-6.45 (m, 6H), 4.16 (s, 2H), 3.64-3.36 (m, 4H), 3.20 (ddt, J = 23.6, 15.6, 7.2 Hz, 2H), 2.29 (dd, J = 8.4, 4.3 Hz, 2H), 1.69 (s, 2H), 1.44 (s, 2H), 1.19 (d, J = 35.5 Hz, 2H), 0.94 (d, J = 6.1 Hz, 3H). Mass (m/z): 407.3 [ M + H ]] ⁺ 。

1-Ethyl-N- (4- ((4- (4-hydroxy-4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (461)

To a solution of 1- (4-aminophenyl) -4- (trifluoromethyl) piperidin-4-ol (50 mg, 0.15 mmol, 1.0 equivalent) and N- (4-bromobenzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (40 mg, 0.15 mmol, 1.0 equivalent) in ultra-dried 1,4-dioxane (5 mL) under argon atmosphere was added dicyclohexyl (2 ',4',6' -triisopropyl-, "respectively 1,1' -biphenyl]-2-yl) phosphane (7.12 mg, 0.012 mmol, 0.08 equiv.) and tris (dibenzylideneacetone) palladium (O) (4.5 mg, 0.006 mmol, 0.04 equiv.) and cesium carbonate (75 mg, 0.23 mmol, 1.5 equiv.). The resulting mixture was heated to 110 ℃ and stirred at the same temperature overnight. The reaction was diluted with water (20 mL) and extracted 3 times with ethyl acetate (5 mL). The organic layers were combined and washed with water and saturated NaHCO, respectively ₃ (aqueous solution) and brine wash. Then over MgSO ₄ Dried, filtered and the filtrate concentrated under reduced pressure. The residue was purified by preparative TLC to give the desired product 461 (9.5 mg) as a pale white powder in 12.25% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.35 (t, J = 6.2 Hz, 1H), 7.77 (s, 1H), 7.11 (d, J = 8.3 Hz, 2H), 7.01 - 6.93 (m, 2H), 6.93 - 6.83 (m, 4H), 5.93 (s, 1H), 5.76 (s, 1H), 4.35 (d, J = 5.9 Hz, 2H), 3.82 (d, J = 10.3 Hz, 6H), 3.44 (d, J = 12.1 Hz, 2H), 2.86 (td, J = 12.2, 2.9 Hz, 2H), 1.77 (ddd, J= 23.5, 15.3, 12.3 Hz, 4H). Mass (m/z): 505.3 [ M + H ]] ⁺ 。

N- (4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) -2-methylbenzyl) -5-oxopyrrolidine-3-carboxamide (462)

Step 1 preparation of tert-butyl (4-bromo-2-methylbenzyl) carbamate: to a solution of compound 462-1 (600 mg, 3.00 mmol) in DCM (20 mL) was added Boc at 25 deg.C ₂ O (982 mg, 4.50 mmol) and TEA (607 mg, 6.00 mmol). The mixture was then stirred at room temperature overnight. Pouring the mixture into H ₂ O, and extracted with DCM (50 ml × 3). The organic layer was washed with brine, over Na ₂ SO ₄ Dried, filtered and concentrated, the residue was purified by silica gel chromatography with EA/PE (20). MS (ESI) M/z 322.0, 324.1 [ M + H ]] ⁺ 。

Step 2 (4- ((2- (4)Preparation of-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) -2-methylbenzyl) carbamic acid tert-butyl ester: to a solution of a mixture of compound 462-2 (300 mg, 1.00 mmol), compound 462-3 (220 mg, 1.00 mmol) and dicyclohexyl (2 ',6' -diisopropoxybiphenyl-2-yl) phosphine (93 mg, 0.20 mmol) in dioxane (15 mL) under nitrogen was added Cs ₂ CO ₃ (488 mg, 1.50 mmol) and tris (dibenzylideneacetone) dipalladium (92 mg, 0.10 mmol). The reaction mixture was stirred at 90 ℃ for 16 hours. The mixture was then filtered and concentrated. The residue was purified by preparative TLC to provide tert-butyl (4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) -2-methylbenzyl) carbamate 462-4 (283 mg, 64% yield) as a yellow solid. MS (ESI) M/z 440.1 [ M + H ]] ⁺ 。

Step 3. Preparation of N- (4- (aminomethyl) -3-methylphenyl) -2- (4-isopropylpiperidin-1-yl) pyrimidin-5-amine: to a solution of compound 462-4 (283 mg, 0.64 mmol) in DCM (5 mL) was added 4N HCl in dioxane (5 mL) at room temperature. The mixture was then stirred at room temperature overnight. LCMS indicated the reaction was complete. The mixture was filtered and dried to give N- (4- (aminomethyl) -3-methylphenyl) -2- (4-isopropylpiperidin-1-yl) pyrimidin-5-amine 462-5 (165 mg, 76% yield) as a brown solid. MS (ESI) M/z 340.2 [ M + H ] ] ⁺ 。

Step 4. Preparation of N- (4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) -2-methylbenzyl) -5-oxopyrrolidine-3-carboxamide (462): to a stirred solution of compound 462-5 (165 mg,0.49 mmol), 5-oxopyrrolidine-3-carboxylic acid 462-6 (63 mg,0.49 mmol) in DMF (5 mL) under nitrogen was added N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) uronium (222 mg, 0.58 mmol) and DIEA (94 mg, 0.73 mmol). The reaction mixture was stirred at room temperature for 16 hours. Pouring the mixture into H ₂ O (10 mL) and extracted with EA (20 mL x 3), the organic layer was washed with brine and Na ₂ SO ₄ Dried, filtered and concentrated, and the residue was purified by preparative HPLC to yield 462 (10 mg) as a white solid. MS (ESI) M/z 451.3 [ M + H ]] ⁺ 。 ¹ H NMR (400 MHz, CD ₃ OD) δ 8.28 (s, 2H), 7.12 (d, J = 8.1 Hz, 1H), 6.83 - 6.71 (m, 2H), 4.55 (d, J = 12.7 Hz, 2H), 4.38 - 4.24 (m, 2H), 3.57 (dd, J = 9.8, 8.9 Hz, 1H), 3.49 (dd, J = 9.9, 6.4 Hz, 1H), 3.13 - 2.97 (m, 2H), 2.61-2.46 (m, 2H), 2.27 (s, 3H), 1.86 (d, J = 13.0 Hz, 2H), 1.55-1.45 (m, 1H), 1.46 - 1.24 (m, 5H), 0.94 (d, J= 6.7 Hz, 6H)。

2-ethyl-5-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (463)

The title compound 463 (6.5 mg) was prepared according to the procedure of 458 as a light gray powder in 4.65% yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (100 mg, 0.29 mmol) and 2-ethyl-5-oxopyrrolidine-3-carboxylic acid (49 mg, 0.31 mmol). ¹ H NMR (400 MHz, DMSO-d 6) δ 8.47 (s, 1H), 7.84 (s, 1H), 7.35-6.84 (m, 7H), 4.18 (s, 2H), 3.72 (s, 1H), 3.49 (q, J = 6.0 Hz, 2H), 2.81-2.68 (m, 1H), 2.40-2.21 (m, 3H), 2.04 (d, J = 26.4 Hz, 2H), 1.76 (s, 2H), 1.53-1.36 (m, 2H), 1.25 (dd, J = 10.7, 4.6 Hz, 2H), 0.85 (t, J = 7.4 Hz, 3H). Mass (m/z): 489.4 [ M + H ] ] ⁺ 。

1-ethyl-N- (4- ((2-methyl-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (464)

The title compound 464 (31.1 mg) was prepared as a white powder in 31.97% yield from 2-methyl-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (50 mg, 0.19 mmol) and N- (4-bromobenzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (63 mg, 0.19 mmol) according to the procedure of 461. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.30 (t, J= 6.3 Hz, 1H), 7.14 (s, 1H), 7.09 - 7.02 (m, 2H), 6.97 (d, J = 8.6 Hz, 1H), 6.84 (d, J = 2.8 Hz, 1H), 6.74 (dd, J = 8.7, 2.9 Hz, 1H), 6.63 - 6.54 (m, 2H), 4.32 (d, J = 6.1 Hz, 2H), 3.81 (d, J = 10.9 Hz, 6H), 3.76 - 3.59 (m, 2H), 3.30 (s, 3H), 2.70 - 2.58 (m, 2H), 2.49 - 2.37 (m, 2H), 2.11 (s, 3H), 1.88 (d, J = 12.6 Hz, 2H), 1.56 (qd, J= 12.5, 4.1 Hz, 2H). Mass (m/z): 503.3 [ M + H ]] ⁺ 。

1-ethyl-N- (4- ((2-methoxy-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (465)

The title compound 465 (29.5 mg) was prepared according to the procedure of 461 as a white powder in 31.2% yield from 2-methoxy-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (50 mg, 0.18 mmol) and N- (4-bromobenzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (59 mg, 0.18 mmol). ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.32 (t, J = 6.3 Hz, 1H), 7.10 - 6.97 (m, 4H), 6.74 (dd, J = 8.6, 1.9 Hz, 2H), 6.65 (d, J = 2.6 Hz, 1H), 6.46 (dd, J = 8.6, 2.6 Hz, 1H), 4.33 (d, J = 5.8 Hz, 2H), 3.82 (d, J = 10.7 Hz, 6H), 3.76 (s, 3H), 3.70 (d, J = 12.3 Hz, 2H), 3.34-3.31 (m, 3H), 2.66 (td, J = 12.3, 2.4 Hz, 2H), 2.44 (ddd, J = 12.3, 8.4, 3.7 Hz, 2H), 1.95 - 1.83 (m, 2H), 1.58 (qd, J= 12.5, 4.1 Hz, 2H). Mass (m/z): 519.3 [ M + H ]] ⁺ 。

1-Ethyl-2-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (466)

Following the procedure of 458 from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (50 mg, 0.14 mmol) and 1-ethyl-2-oxopyrrolidine-3-carboxylic acid (27 mg, 0.17 mmol) at 17.The title compound 466 (12.3 mg) was prepared as a white powder in 6% yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.01 - 7.90 (m, 1H), 7.77 (s, 1H), 7.04 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.9 Hz, 2H), 6.93 - 6.80 (m, 4H), 4.22 - 4.09 (m, 2H), 3.62 (d, J = 12.3 Hz, 2H), 3.34 (s, 2H), 3.20 - 3.08 (m, 2H), 2.70 - 2.57 (m, 2H), 2.41 (td, J = 8.6, 4.1 Hz, 1H), 1.89 (ddd, J = 12.4, 7.5, 5.3 Hz, 3H), 1.81 (dd, J = 13.8, 7.2 Hz, 1H), 1.69 - 1.48 (m, 3H), 0.80 (t, J= 7.4 Hz, 3H). Mass (m/z): 489.3 [ M + H ]] ⁺ 。

N- (4- ((2-cyano-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (467)

The title compound 467 (60.2 mg) was prepared as a white powder according to the procedure of 461 from 2-amino-5- (4- (trifluoromethyl) piperidin-1-yl) benzonitrile (50 mg, 0.18 mmol) and N- (4-bromobenzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (60 mg, 0.18 mmol) in a yield of 63.13%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.44 (t, J= 5.8 Hz, 1H), 8.04 (s, 1H), 7.24 (d, J = 8.2 Hz, 2H), 7.19 - 7.13 (m, 1H), 7.11 - 7.06 (m, 2H), 6.90 - 6.82 (m, 2H), 4.23 - 4.11 (m, 2H), 3.73 (d, J = 12.2 Hz, 2H), 3.50 (t, J = 9.2 Hz, 1H), 3.39 - 3.34 (m, 1H), 3.30 (s, 1H), 3.18 (qd, J = 7.2, 1.6 Hz, 2H), 3.14 - 3.06 (m, 1H), 2.69 (td, J = 12.4, 2.5 Hz, 2H), 2.43 - 2.36 (m, 2H), 1.91 - 1.80 (m, 2H), 1.54 (qd, J = 12.6, 4.1 Hz, 2H), 1.00 (t, J= 7.2 Hz, 3H). Mass (m/z): 514.3 [ M + H ]] ⁺ 。

4-methyl-3-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) piperazine-1-carboxamide (468)

The title compound 468 (9.0 mg) was prepared as a light pink powder in 7.09% yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (100 mg, 0.49 mmol) and 4-methyl-3-oxopiperazine-1-carboxylic acid (49 mg, 0.53 mmol) according to the procedure of 458. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.16 (s, 3H), 6.93 (s, 5H), 4.48 (s, 2H), 3.60 (s, 1H), 3.54 (t, J = 6.7 Hz, 2H), 2.66 (s, 2H), 2.33-2.20 (m, 2H), 2.15 - 2.07 (m, 2H), 1.97 (d, J = 12.6 Hz, 2H), 1.72 (d, J = 12.7 Hz, 2H), 1.52 (q, J= 7.0 Hz, 2H), 1.49-1.37 (m, 1H), 0.97-0.83 (m, 3H). Mass (m/z): 489.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -2-ureidoacetamide (469)

The title compound 469 (2.3 mg) was prepared according to the procedure of 458 as a light gray powder in 3.58% yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (50 mg, 0.14 mmol) and carbamoylglycine (18 mg, 0.15 mmol). ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.16 (t, J = 5.9 Hz, 1H), 7.77 (s, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.9 Hz, 2H), 6.87 (t, J = 8.6 Hz, 4H), 6.16 (s, 1H), 5.64 (s, 2H), 5.32 (t, J = 4.8 Hz, 1H), 4.15 (d, J = 5.9 Hz, 2H), 3.62 (d, J = 5.7 Hz, 4H), 2.62 (t, J = 11.9 Hz, 2H), 2.00 (q, J = 7.0, 6.5 Hz, 1H), 1.88 (d, J= 12.6 Hz, 2H), 1.63-1.54 (m, 2H). Mass (m/z): 450.2 [ M + H ]] ⁺ 。

1-ethyl-N- (4- ((2-fluoro-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (470)

The title compound 470 (45.4 mg) was prepared as a light gray powder in 46.60% yield from 2-fluoro-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (50 mg, 0.19 mmol) and N- (4-bromobenzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (68 mg, 0.21 mmol) according to the procedure of 461. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.39 (t, J= 5.7 Hz, 1H), 7.50 (s, 1H), 7.09 (dd, J = 9.8, 8.8 Hz, 1H), 7.05 - 6.99 (m, 2H), 6.85 (dd, J = 14.3, 2.7 Hz, 1H), 6.76 - 6.71 (m, 1H), 6.71 - 6.66 (m, 2H), 4.14 (d, J = 5.6 Hz, 2H), 3.73 (d, J = 12.3 Hz, 2H), 3.49 (t, J = 9.2 Hz, 1H), 3.38 - 3.33 (m, 2H), 3.18 (qd, J = 7.2, 1.4 Hz, 2H), 3.13 - 3.04 (m, 1H), 2.68 (td, J = 12.5, 2.6 Hz, 2H), 2.42 - 2.37 (m, 2H), 1.92 - 1.79 (m, 2H), 1.54 (qd, J = 12.5, 4.2 Hz, 2H), 0.99 (t, J= 7.2 Hz, 3H). Mass (m/z): 507.3 [ M + H ]] ⁺ 。

N- (4- ((3,5-difluoro-4- (piperidin-1-yl) phenyl) amino) benzyl) -3,5-dioxopiperazine-1-carboxamide (471)

Preparation of N- (4- ((3,5-difluoro-4- (piperidin-1-yl) phenyl) amino) benzyl) -3,5-dioxopiperazine-1-carboxamide (471): a solution of a mixture of N- (4- (aminomethyl) phenyl) -3,5-difluoro-4- (piperidin-1-yl) aniline (50 mg, 0.14 mmol), CDI (46 mg, 0.28 mmol) and TEA (43 mg, 0.42 mmol) in MeCN (10 mL) was stirred at room temperature for 2 hours. Piperazine-2,6-dione (19 mg, 0.17 mmol) was then added to the mixture and stirred at room temperature overnight. The solvent was removed in vacuo, the residue diluted with EA (20 mL), washed with water (10 mL X3), and Na ₂ SO ₄ Dried, filtered and evaporated. The residue was purified by preparative HPLC to give 471 (6.3 mg, 11.96%). Mass (m/z): 457.7 [ M + H ]] ⁺ 。 ¹ H NMR (400 MHz, CD ₃ OD) δ 7.20 - 7.16 (m, 2H), 7.03 - 6.98 (m, 2H), 6.52 - 6.44 (m, 2H), 4.27 (s, 2H), 3.28 (dt, J = 3.3, 1.6 Hz, 4H), 3.02 - 2.96 (m, 4H), 1.66 - 1.58 (m, 4H), 1.56 - 1.48 (m, 2H)。

N- (4- ((4- (azepan-1-yl) phenyl) amino) benzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (472)

The title compound 472 (86.3 mg) was prepared as a light olive solid in 75.58% yield from 4- (azepan-1-yl) aniline (50 mg, 0.26 mmol) and N- (4-bromobenzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (94 mg, 0.28 mmol) according to the procedure of 461. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.40 (s, 2H), 7.42-6.56 (m, 6H), 4.12 (s, 3H), 3.50 (t, J = 9.2 Hz, 1H), 3.17 (s, 10H), 2.40 (d, J = 8.5 Hz, 2H), 1.58 (d, J = 85.1 Hz, 5H), 1.00 (t, J= 7.2 Hz, 3H). Mass (m/z): 435.4 [ M + H ]] ⁺ 。

N- (4- ((4- (tert-butyl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (473)

The title compound 473 (15.5 mg) was prepared as a dark gray powder in 12.60% yield from 4- (tert-butyl) aniline (50 mg, 0.34 mmol) and N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (100 mg, 0.34 mmol) according to the procedure of 461. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.39 (t, J = 5.8 Hz, 1H), 8.01 (s, 1H), 7.58 (s, 1H), 7.30 - 7.18 (m, 2H), 7.09 (d, J = 8.5 Hz, 2H), 7.04 - 6.93 (m, 4H), 4.17 (d, J = 5.7 Hz, 2H), 3.17 (dd, J = 15.4, 8.1 Hz, 1H), 2.30 (dd, J = 8.4, 4.2 Hz, 3H), 2.00 (q, J= 7.0, 6.5 Hz, 1H), 1.25 (s, 9H). Mass (m/z): 366.3 [ M + H ]] ⁺ 。

5-oxo-N- (4- ((4- (2,2,2-trifluoroethyl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (474)

The title compound 474 (34.5 mg) was prepared as a light yellow powder in 26.19% yield from 4- (2,2,2-trifluoroethyl) aniline (59 mg, 0.34 mmol) and N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (100 mg, 0.34 mmol) according to the procedure of 461. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 8.22 (s, 1H), 7.58 (s, 1H), 7.17 (d, J = 8.2 Hz, 2H), 7.14 - 7.09 (m, 2H), 7.06 - 6.99 (m, 4H), 4.19 (d, J = 5.8 Hz, 2H), 3.49 (q, J = 11.6 Hz, 2H), 3.40 (t, J = 8.7 Hz, 1H), 3.21 (ddt, J= 23.4, 15.5, 7.2 Hz, 2H), 2.35-2.25 (m, 2H). Mass (m/z): 366.3 [ M + H ]] ⁺ . Mass (m/z): 392.2 [ M + H ]] ⁺ 。

N- (4- ((4- (azacyclooctan-1-yl) phenyl) amino) benzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (475)

The title compound 475 (143.7 mg) was prepared according to the procedure of 461 as a gray solid from 4- (azocycloctan-1-yl) aniline (100 mg, 0.49 mmol) and N- (4-bromobenzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (191 mg, 0.59 mmol) in 65.45% yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.36 (t, J = 5.6 Hz, 1H), 7.59 - 6.35 (m, 8H), 4.12 (s, 2H), 3.49 (t, J = 9.2 Hz, 2H), 3.43 - 3.33 (m, 4H), 3.17 (qd, J = 7.2, 1.5 Hz, 2H), 3.13 - 3.05 (m, 1H), 2.39 (d, J = 8.6 Hz, 2H), 1.66 (s, 5H), 1.49 (s, 5H), 0.99 (t, J= 7.2 Hz, 3H). Mass (m/z): 449.3 [ M + H ]] ⁺ 。

(R) -N- (4- ((4- (azepan-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (476)

The title compound 476 (23.7 mg) was prepared as a gray powder in 16.59% yield from 4- (azepan-1-yl) aniline (64 mg, 0.34 mmol) and N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (100 mg, 0.34 mmol) according to the procedure of 461. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.33 (s, 1H), 7.57 (s, 1H), 7.54 - 7.47 (m, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.90 (s, 5H), 4.23 (t, J5.8 Hz, 1H), 3.29-3.03 (m, 5H), 2.33-2.25 (m, 3H), 2.03-1.92 (m, 2H), 1.88-1.33 (m, 7H), 0.88-0.78 (m, 1H). Mass (m/z): 407.3 [ M + H ]] ⁺ 。

N- (4- ((4- (Azacyclooctan-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (477)

The title compound 477 (28.3 mg) was prepared as a gray powder in 20.00% yield from 4- (azocyclooctan-1-yl) aniline (69 mg, 0.34 mmol) and N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (100 mg, 0.34 mmol) according to the procedure of 461. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.32 (s, 1H), 7.56 (s, 1H), 6.99 (s, 7H), 4.25-4.10 (m, 2H), 3.30 - 3.05 (m, 2H), 2.27 (dd, J = 8.4, 5.2 Hz, 3H), 1.99 (q, J= 7.2 Hz, 1H), 1.84-1.33 (m, 11H), 0.89-0.76 (m, 2H). Mass (m/z): 421.3 [ M + H ]] ⁺ 。

(R) -5-oxo-N- (4- ((4- (piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (478)

The title compound was prepared according to the procedure of 461 as a dark gray powder from 4- (piperidin-1-yl) aniline (59 mg, 0.34 mmol) and (R) -N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (100 mg, 0.34 mmol) in 20.82% yieldCompound 478 (27.5 mg). ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.36 (s, 1H), 7.74 (s, 1H), 7.57 (s, 1H), 7.03 (s, 2H), 6.95 (s, 2H), 6.86 (s, 3H), 4.14 (s, 2H), 3.39 (t, J = 8.8 Hz, 2H), 3.27 - 3.11 (m, 3H), 3.00 (s, 4H), 2.32 - 2.24 (m, 2H), 1.98 (p, J= 7.0, 6.5 Hz, 1H), 1.50 (s, 3H). Mass (m/z): 393.3 [ M + H ]] ⁺ 。

(R) -N- (4- ((4- (4,4-dimethylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (479)

The title compound 479 (16.8 mg) was prepared as a gray powder in 11.87% yield from 4- (4,4-dimethylpiperidin-1-yl) aniline (69 mg, 0.34 mmol) and (R) -N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (100 mg, 0.34 mmol) according to the procedure of 461. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.35 (s, 1H), 7.72 (s, 1H), 7.57 (s, 1H), 7.02 (s, 2H), 6.94 (s, 2H), 6.86 (s, 4H), 4.14 (s, 2H), 3.40 (d, J = 7.6 Hz, 2H), 3.27 - 3.11 (m, 2H), 3.02 (s, 3H), 2.34 - 2.25 (m, 4H), 1.99 (q, J= 7.0, 6.4 Hz, 2H), 0.94 (s, 6H). Mass (m/z): 421.3 [ M + H ]] ⁺ 。

N- (4- ((3-methyl-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (480)

The title compound 480 (30.2 mg) was prepared as a white powder in 16.44% yield from 3-methyl-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (115 mg, 0.39 mmol) and N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (100 mg, 0.39 mmol) according to the procedure of 461. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.37 (t, J= 5.7 Hz, 1H), 7.88 (s, 1H), 7.58 (s, 1H), 7.13 - 7.02 (m, 2H), 6.99 - 6.90 (m, 3H), 6.90 - 6.81 (m, 2H), 4.16 (d, J = 5.7 Hz, 2H), 3.03 (d, J = 11.3 Hz, 2H), 2.72 - 2.56 (m, 3H), 2.45 - 2.25 (m, 3H), 2.19 (s, 3H), 2.06 - 1.93 (m, 1H), 1.95 - 1.84 (m, 2H), 1.60 (d, J= 12.5 Hz, 2H), 1.45 (s, 1H). Mass (m/z): 476.3 [ M + H ]] ⁺ 。

1- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (481)

The title compound 481 (3.8 mg) was prepared as a white powder in 5.74% yield from 4- (4- (trifluoromethyl) piperidin-1-yl) aniline (36 mg, 0.15 mmol) and 1- (4-bromobenzyl) pyrrolidine-3-carboxamide (42 mg, 0.15 mmol) according to the procedure of 461. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.39 (s, 4H), 7.19 (d, J = 24.9 Hz, 4H), 4.31 (d, J = 33.8 Hz, 2H), 3.73 (s, 2H), 3.62 (s, 2H), 3.45 (d, J = 11.3 Hz, 3H), 2.59 (d, J= 48.1 Hz, 2H), 2.31 (s, 1H), 2.12 (s, 3H), 2.09-1.90 (m, 3H). Mass (m/z): 447.4 [ M + H ]] ⁺ 。

N- (4- ((4- (2-fluoroethyl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (482)

The title compound 482 (8.4 mg) was prepared as a white powder in 3.29% yield from 4- (2-fluoroethyl) aniline (100 mg, 0.72 mmol) and N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (213 mg, 0.72 mmol) according to the procedure of 461. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.17 - 7.07 (m, 4H), 7.05 - 6.97 (m, 4H), 4.61 (t, J = 6.6 Hz, 1H), 4.49 (t, J = 6.6 Hz, 1H), 4.28 (s, 2H), 3.58 (dd, J = 9.9, 8.8 Hz, 1H), 3.49 (dd, J = 9.9, 6.5 Hz, 1H), 2.94 (t, J = 6.6 Hz, 1H), 2.88 (t, J = 6.6 Hz, 1H), 2.54 (qd, J = 17.0, 8.6 Hz, 2H), 1.31 (dt, J = 7.4,3.3 Hz, 1H). Mass (m/z): 356.2 [ M + H ]] ⁺ 。

5-oxo-N- (2- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) phenyl) propan-2-yl) pyrrolidine-3-carboxamide (483)

The title compound 483 (9.7 mg) as a light blue powder was prepared in 9.7% yield from 4- (4- (trifluoromethyl) piperidin-1-yl) aniline (67 mg, 0.20 mmol) and N- (2- (4-bromophenyl) propan-2-yl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.20 mmol) according to the procedure of 461. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.20 - 7.99 (m, 1H), 7.53 (s, 1H), 7.31 - 6.70 (m, 7H), 3.42 (d, J= 8.5 Hz, 3H), 3.29-3.12 (m, 3H), 2.55 (s, 2H), 2.28-2.20 (m, 2H), 1.71 (s, 2H), 1.53 (s, 6H). Mass (m/z): 489.3 [ M + H ]] ⁺ 。

N- (4- ((2-fluoro-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (484)

The title compound 484 (6.4 mg) was prepared as a gray powder in 7.95% yield from 2-fluoro-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (50 mg, 0.17 mmol) and N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (44 mg, 0.17 mmol) according to the procedure of 461. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.35 (t, J = 5.7 Hz, 1H), 7.58 (s, 2H), 7.11 (t, J = 9.2 Hz, 1H), 7.03 (d, J = 8.3 Hz, 2H), 6.88 (d, J = 14.2 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 6.71 (d, J = 8.1 Hz, 2H), 4.15 (d, J = 5.6 Hz, 2H), 3.39 (d, J = 8.8 Hz, 2H), 3.31 - 3.08 (m, 2H), 2.72 (t, J = 12.6 Hz, 3H), 2.36 - 2.22 (m, 3H), 1.89 (d, J = 12.6 Hz, 2H), 1.55 (tt, J= 12.4, 6.4 Hz, 2H). Mass (m/z): 479.3 [ M + H ]] ⁺ 。

N- (4- ((2-methyl-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (485)

The title compound 485 (4.5 mg) was prepared as a gray powder in 5.64% yield from 2-methyl-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (50 mg, 0.17 mmol) and N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (43 mg, 0.17 mmol) according to the procedure of 461. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.35 (s, 1H), 7.58 (s, 1H), 7.22 (s, 1H), 7.15 - 6.78 (m, 5H), 6.67 (s, 2H), 4.14 (d, J = 5.5 Hz, 2H), 3.40 (t, J = 8.8 Hz, 2H), 3.28 - 3.04 (m, 3H), 2.29 (dd, J = 8.4, 4.1 Hz, 2H), 2.15 (s, 3H), 2.00 (p, J = 7.1 Hz, 3H), 1.64 (s, 2H), 1.47 (d, J= 8.0 Hz, 1H), 1.18 (t, J= 7.3 Hz, 1H), 0.90-0.82 (m, 2H). Mass (m/z): 475.3 [ M + H ]] ⁺ 。

N- (4- ((2-chloro-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (486)

The title compound 486 (9.5 mg) was prepared as a gray powder in 5.70% yield from 2-chloro-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (100 mg, 0.34 mmol) and N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (93 mg, 0.34 mmol) according to the procedure of 461. ¹ H NMR (400 MHz, pyridine-d ₅ ) δ 9.27 (d, J = 6.1 Hz, 1H), 8.53 (d, J = 9.4 Hz, 1H), 8.06 (s, 1H), 7.49 - 7.37 (m, 3H), 7.24 (d, J= 2.8 Hz, 1H), 7.20 - 7.16 (m, 2H), 6.96 (dd, J = 8.9, 2.8 Hz, 1H), 4.76 - 4.62 (m, 2H), 3.93 (dd, J = 9.3, 6.5 Hz, 1H), 3.74 - 3.48 (m, 4H), 3.15 (dd, J = 16.5, 7.8 Hz, 1H), 2.72 (dd, J = 16.5, 9.5 Hz, 1H), 2.56 (td, J = 12.3, 2.5 Hz, 2H), 2.19 (dtt, J = 12.6, 8.2, 4.2 Hz, 1H), 1.83 (d, J = 12.9 Hz, 2H), 1.65 (qd, J= 12.5, 4.2 Hz, 2H). Mass (m/z): 495.6 [ M + H ]] ⁺ 。

N- (2,6-difluoro-4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (487)

The title compound 487 (9.3 mg) as a light blue powder was prepared according to the procedure of 458 from 4- (aminomethyl) -3,5-difluoro-N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (100 mg, 0.26 mmol) and 5-oxopyrrolidine-3-carboxylic acid (40 mg, 0.31 mmol) in 7.22% yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.51 (s, 1H), 8.26 (t, J = 5.1 Hz, 1H), 7.56 (s, 1H), 7.09 (s, 4H), 6.50 (d, J = 10.1 Hz, 2H), 4.23 - 4.14 (m, 2H), 3.68 (d, J = 12.0 Hz, 2H), 3.35 (t, J = 8.8 Hz, 1H), 3.23 - 3.01 (m, 3H), 2.95 (s, 2H), 2.30 - 2.11 (m, 2H), 1.96 (d, J = 13.1 Hz, 2H), 1.67 (d, J= 12.8 Hz, 2H). Mass (m/z): 497.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) -2- (trifluoromethyl) benzyl) -5-oxopyrrolidine-3-carboxamide (488)

The title compound 488 (52.0 mg) was prepared according to the procedure of 458 as an off-white powder in 79.65% yield from 4- (aminomethyl) -N- (4- (4-methylpiperidin-1-yl) phenyl) -3- (trifluoromethyl) aniline (50 mg, 0.14 mmol) and 5-oxopyrrolidine-3-carboxylic acid (35 mg, 0.27 mmol). ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.41 (t, J = 5.6 Hz, 1H), 8.16 (s, 1H), 7.60 (s, 1H), 7.24 (d, J = 8.5 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 7.09 (dd, J = 8.4, 2.4 Hz, 1H), 6.99 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 4.30 (d, J = 5.4 Hz, 2H), 3.55 (dt, J = 12.5, 3.5 Hz, 2H), 3.40 (q, J = 6.5, 5.2 Hz, 1H), 3.28 - 3.14 (m, 2H), 2.67 - 2.52 (m, 2H), 2.37 - 2.21 (m, 2H), 1.73 - 1.61 (m, 2H), 1.57 - 1.37 (m, 1H), 1.34 - 1.13 (m, 2H), 0.93 (d, J= 6.5 Hz, 3H). Mass (m/z): 475.3 [ M + H ]] ⁺ 。

N1- (4- ((3,5-difluoro-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) oxamide (489)

Step 1.2 preparation of ethyl- ((4- ((3,5-difluoro-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) amino) -2-oxoacetate (489-3): n- (4- (aminomethyl) phenyl) -3,5-difluoro-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (0.2 g, 0.52 mmol) and Et ₃ A mixture of N (0.16 g, 1.56 mmol) was stirred in DCM (10 mL) at 0 deg.C for 0.5 h. Ethyl 2-chloro-2-oxoacetate was dissolved in DCM (5 mL), and then dropped into the stirred mixture solution at 25 ℃, followed by stirring at room temperature overnight. The mixture was diluted with DCM (100 mL) and washed with water (100 mL x 3). The organic phase was concentrated and evaporated to give ethyl 2- ((4- ((3,5-difluoro-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) amino) -2-oxoacetate 489-3 (0.2 g, 78.8%) as a colorless oil. Mass (m/z): 486.1 [ M + H ]] ⁺ 。

Step 2. Preparation of N1- (4- ((3,5-difluoro-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) oxamide (489): 2- ((4- ((3,5-difluoro-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) amino) -2-oxoacetate (0.2 g, 0.41 mmol) and NH ₄ A solution of OH (0.5 mL, 13 mmol) in THF (10 mL) was stirred at 25 deg.C for 2 hours. The mixture was diluted with EA (100 mL) and washed with water (100 mL x 2), the organic phase was removed in vacuo and the residue was purified by preparative HPLC (column-Xbridge-C18 x 21.2 mm, 5um; mobile phase: ACN-H ₂ O (0.1% fa), 40% -60%) to provide 489 (38.3 mg, 18.5%) as a white solid. Quality (a) m/z)： 456.6 [M+H] ⁺ 。 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.16 (t, J = 8.0 Hz, 1H), 8.40 (s, 1H), 8.07 (s, 1H), 7.80 (s, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H), 6.58 (d, J = 11.6 Hz, 2H), 4.24 (d, J = 4.0 Hz, 2H), 3.05 (s, 4H), 2.43 - 2.37 (m, 1H), 1.83 (d, J = 10.8 Hz, 2H), 1.59-1.49 (m, 2H)。

5-oxo-N- (4- ((3-pentylphenyl) amino) benzyl) pyrrolidine-3-carboxamide (490)

The title compound 490 (9.5 mg) was prepared according to the procedure of 461 as a white powder in 16.83% yield from 3-pentylaniline (55 mg, 0.34 mmol) and N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (100 mg, 0.34 mmol). ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.39 (t, J = 5.8 Hz, 1H), 8.05 (s, 1H), 7.58 (s, 1H), 7.10 (dt, J = 8.6, 3.8 Hz, 3H), 7.04 - 6.95 (m, 2H), 6.84 (dq, J = 4.2, 1.6 Hz, 2H), 6.62 (dt, J = 7.5, 1.3 Hz, 1H), 4.18 (d, J = 5.7 Hz, 2H), 3.45 - 3.36 (m, 1H), 3.28 - 3.11 (m, 2H), 2.47 (d, J = 7.7 Hz, 2H), 2.37 - 2.22 (m, 2H), 1.54 (p, J = 7.4 Hz, 2H), 1.28 (qdt, J= 12.0, 7.8, 4.5 Hz, 4H), 0.93-0.79 (m, 3H). Mass (m/z): 380.5 [ M + H ]] ⁺ 。

N- (2-fluoro-3-methyl-4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (491)

The title compound 491 (49.6 m) as a rose brown powder was prepared according to the procedure of 458 from 4- (aminomethyl) -3-fluoro-2-methyl-N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (100 mg, 0.26 mmol) and 5-oxopyrrolidine-3-carboxylic acid (37 mg, 0.29 mmol) in 37.95% yieldg)。 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.36 (s, 1H), 7.69 (d, J = 18.6 Hz, 1H), 7.58 (s, 1H), 7.19 (s, 1H), 6.90 (s, 4H), 6.71 (d, J = 8.0 Hz, 1H), 4.20 (s, 2H), 3.63 (d, J = 11.8 Hz, 2H), 3.20 (s, 2H), 2.62 (t, J = 12.3 Hz, 2H), 2.27 (d, J = 8.3 Hz, 2H), 2.09 (s, 2H), 1.88 (d, J = 12.3 Hz, 2H), 1.56 (d, J= 13.0 Hz, 2H), 1.37 (s, 1H), 1.23 (s, 1H), 0.91 (s, 1H). Mass (m/z): 493.6 [ M + H ]] ⁺ 。

N- (2-fluoro-5-methyl-4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (492)

The title compound 492 (23.5 mg) was prepared according to the procedure of 458 as a dark gray powder in 18.20% yield from 4- (aminomethyl) -5-fluoro-2-methyl-N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (100 mg, 0.26 mmol) and 5-oxopyrrolidine-3-carboxylic acid (37 mg, 0.29 mmol). ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.33 (t, J = 5.5 Hz, 1H), 7.57 (s, 1H), 7.12 (s, 1H), 7.04 - 6.85 (m, 5H), 6.56 (d, J = 12.7 Hz, 1H), 4.15 (d, J = 5.5 Hz, 2H), 3.66 (d, J = 12.1 Hz, 2H), 3.38 (t, J = 8.5 Hz, 2H), 3.26 - 3.08 (m, 2H), 2.64 (td, J = 12.4, 2.5 Hz, 2H), 2.43 (tt, J = 8.6, 3.7 Hz, 2H), 2.27 (dd, J = 8.4, 2.4 Hz, 2H), 1.88 (d, J = 12.6 Hz, 2H), 1.58 (pd, J= 13.6, 12.5, 5.6 Hz, 3H). Mass (m/z): 493.3 [ M + H ]] ⁺ 。

N- (3-methyl-4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (493)

From 4- (4- (trifluoromethyl) piperidin-1-yl) aniline (13) according to the procedure of 4614 mg, 0.55 mmol) and N- (4-bromo-3-methylbenzyl) -5-oxopyrrolidine-3-carboxamide (180 mg, 0.58 mmol) the title compound 493 (28.8 mg) was prepared as a gray powder in 11.02% yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.41 (s, 1H), 7.58 (s, 1H), 7.27 - 6.91 (m, 5H), 6.84 (d, J = 8.4 Hz, 2H), 4.30 - 4.13 (m, 2H), 3.67-3.56 (m, 2H), 3.40 (t, J = 8.7 Hz, 2H), 3.30 - 3.12 (m, 3H), 2.72-2.51 (br, 1H), 2.29 (dd, J= 8.4, 1.7 Hz, 2H), 2.15 (s, 3H), 2.00 (s, 2H), 1.76 (s, 2H). Mass (m/z): 475.6 [ M + H ]] ⁺ 。

(S) -N- (4- ((4-cyclohexylphenyl) amino) benzyl) -2,6-dioxohexahydropyrimidine-4-carboxamide (494)

The title compound 494 (31.1 mg) was prepared according to the procedure of 458 as an off-white powder from 4- (aminomethyl) -N- (4-cyclohexylphenyl) aniline (30 mg, 0.11 mmol) and (S) -2,6-dioxohexahydropyrimidine-4-carboxylic acid (61 mg, 0.16 mmol) in 69.13% yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 10.03 (d, J = 1.8 Hz, 1H), 8.43 (t, J = 5.7 Hz, 1H), 8.00 (s, 1H), 7.62 (d, J = 3.4 Hz, 1H), 7.12 - 7.02 (m, 4H), 7.00 - 6.88 (m, 4H), 4.25 - 4.09 (m, 2H), 4.00 (dt, J = 7.1, 3.5 Hz, 1H), 3.61 (s, 1H), 3.13 (s, 1H), 2.96 - 2.78 (m, 1H), 2.42 (d, J = 23.3 Hz, 1H), 1.76 (d, J = 8.8 Hz, 4H), 1.69 (d, J = 12.8 Hz, 1H), 1.35 (dd, J= 11.5, 8.5 Hz, 4H). Mass (m/z): 421.5 [ M + H ]] ⁺ 。

N- (2,5-dimethyl-4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (495)

From 4- (aminomethyl) -2,5-dimethyl-N- (4- (4- (trifluoromethyl) according to the procedure of 458) Piperidin-1-yl) phenyl) aniline (66 mg, 0.17 mmol) and 5-oxopyrrolidine-3-carboxylic acid (34 mg, 0.26 mmol) the title compound 495 (37.2 mg) was prepared as a light gray powder in a yield of 43.55%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.26 (t, J = 5.4 Hz, 1H), 7.58 (s, 1H), 6.93 (d, J = 1.6 Hz, 2H), 6.89 - 6.82 (m, 4H), 6.79 (s, 1H), 4.13 (d, J = 5.4 Hz, 2H), 3.59 (d, J = 12.3 Hz, 2H), 3.29 - 3.14 (m, 2H), 2.60 (td, J = 12.3, 2.5 Hz, 2H), 2.40 (dq, J = 12.4, 3.8 Hz, 1H), 2.35 - 2.20 (m, 3H), 2.11 (d, J = 5.3 Hz, 6H), 1.87 (d, J = 12.6 Hz, 2H), 1.56 (qd, J= 12.5, 4.1 Hz, 2H). Mass (m/z): 489.4 [ M + H ]] ⁺ 。

4-oxo-4- ((4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) amino) butanoic acid (496)

To a solution of 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline hydrochloride (100 mg, 0.26 mmol) in toluene (5 mL) were added dihydrofuran-2,5-dione (26 mg, 0.26 mmol) and triethylamine (26 mg, 0.26 mmol), and the resulting solution was stirred at room temperature overnight. The reaction mixture was added dropwise to water (15 mL) with stirring. The precipitate was filtered, the filter cake was washed 3 times with water and dried in vacuo. The residue was purified by preparative TLC to give the desired product 496 (36.2 mg) as a light grey powder in 31.25% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.22-12.33 (br, 1H), 8.24 (t, J = 5.8 Hz, 1H), 7.77 (s, 1H), 7.09 - 7.00 (m, 2H), 7.00 - 6.93 (m, 2H), 6.92 - 6.81 (m, 4H), 4.13 (d, J = 5.8 Hz, 2H), 3.61 (d, J = 11.9 Hz, 2H), 2.62 (td, J = 12.4, 2.5 Hz, 2H), 2.48 - 2.40 (m, 3H), 2.35 (td, J = 6.7, 1.3 Hz, 2H), 1.94 - 1.83 (m, 2H), 1.57 (qd, J= 12.5, 4.1 Hz, 2H). Mass (m/z): 450.3 [ M + H ]] ⁺ 。

N- (2,3-dimethyl-4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (497)

The title compound 497 (11.2 mg) was prepared according to the procedure of 458 from 4- (aminomethyl) -2,3-dimethyl-N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (30 mg, 0.08 mmol) and 5-oxopyrrolidine-3-carboxylic acid (16 mg, 0.12 mmol) in a yield of 43.55% as an off-white powder. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.23 (d, J = 5.3 Hz, 1H), 7.56 (d, J = 10.9 Hz, 1H), 7.22 (s, 1H), 7.04 (s, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.87 - 6.80 (m, 2H), 6.74 (d, J = 8.9 Hz, 1H), 6.67 (s, 1H), 4.20 (d, J = 5.8 Hz, 2H), 3.55 (d, J = 11.4 Hz, 1H), 3.30 - 3.09 (m, 2H), 2.28 (dd, J = 8.4, 5.9 Hz, 2H), 2.04 - 1.93 (m, 5H), 1.92 - 1.81 (m, 2H), 1.64 - 1.51 (m, 2H), 1.45 (d, J = 7.0 Hz, 3H), 0.84 (t, J= 6.7 Hz, 4H). Mass (m/z): 489.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4-ethylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (498)

The title compound 498 (41.4 mg) was prepared as a white powder in 20.11% yield from 4- (4-ethylpiperidin-1-yl) aniline (152 mg, 0.51 mmol) and N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (100 mg, 0.49 mmol) according to the procedure of 461. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.35 (t, J = 5.7 Hz, 1H), 7.74 (s, 1H), 7.58 (s, 1H), 7.08 - 6.99 (m, 2H), 6.99 - 6.91 (m, 2H), 6.90 - 6.81 (m, 4H), 4.14 (d, J = 5.7 Hz, 2H), 3.52 (d, J = 11.5 Hz, 2H), 3.43 - 3.36 (m, 1H), 3.28 - 3.20 (m, 1H), 3.20 - 3.12 (m, 1H), 2.35 - 2.22 (m, 2H), 1.74 (d, J = 8.9 Hz, 2H), 1.25 (d, J = 15.1 Hz, 7H), 0.89 (t, J= 7.2 Hz, 3H). Mass (m/z): 421.4 [ M + H ]] ⁺ 。

4-oxo-4- ((4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) amino) butyric acid methyl ester (499)

The title compound 499 (45.3 mg) was prepared as an off-white powder in 37.71% yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline hydrochloride (100 mg, 0.26 mmol) and 4-methoxy-4-oxobutanoic acid (41 mg, 0.31 mmol) according to the procedure of 458. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.26 (t, J = 5.8 Hz, 1H), 7.78 (s, 1H), 7.08 - 7.00 (m, 2H), 7.00 - 6.94 (m, 2H), 6.88 (ddd, J = 8.6, 6.0, 2.5 Hz, 4H), 4.13 (d, J = 5.8 Hz, 2H), 3.65 - 3.58 (m, 2H), 3.57 (s, 3H), 2.67 - 2.56 (m, 2H), 2.54 (s, 2H), 2.40 (t, J = 6.7 Hz, 3H), 1.87 (d, J = 12.6 Hz, 2H), 1.57 (qd, J= 12.5, 4.1 Hz, 2H). Mass (m/z): 464.4 [ M + H ]] ⁺ 。

N- (4- ((3-methoxy-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (500)

The title compound 500 (53.2 mg) was prepared according to the procedure of 461 as a light gray powder from 3-methoxy-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (100 mg, 0.36 mmol) and N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (113 mg, 0.38 mmol) in 66.86% yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.46 (t, J= 5.8 Hz, 1H), 7.60 (s, 1H), 7.32 (d, J = 8.7 Hz, 1H), 7.16 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 8.1 Hz, 2H), 6.84 - 6.73 (m, 1H), 6.68 (d, J = 8.5 Hz, 1H), 4.21 (d, J = 5.9 Hz, 2H), 3.87 (s, 3H), 3.51 (d, J = 25.7 Hz, 3H), 3.47 - 3.36 (m, 2H), 3.32 - 3.12 (m, 2H), 2.30 (dd, J = 8.4, 1.7 Hz, 2H), 2.01 (d, J= 23.0 Hz, 4H). Mass (m/z): 491.4 [ M + H ]] ⁺ 。

N-hydroxy-N- (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -2,6-dioxopiperidine-4-carboxamide (501)

The title compound 501 (29.8 mg) was prepared according to the procedure of 458 as a light blue powder from 4- ((hydroxyamino) methyl) -N- (4- (4-methylpiperidin-1-yl) phenyl) aniline (100 mg, 0.32 mmol) and 2,6-dioxopiperidine-4-carboxylic acid (60 mg, 0.39 mmol) in a yield of 20.60%. ¹ H NMR(300 MHz, DMSO-d ₆ ) δ 10.66 (s, 1H), 10.04 (s, 1H), 8.53 (s, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.08 (dt, J = 16.0, 8.7 Hz, 5H), 4.59 (s, 2H), 3.95 (s, 2H), 3.64 - 3.37 (m, 4H), 2.62 (qd, J = 16.7, 5.7 Hz, 3H), 1.89 (d, J = 14.1 Hz, 2H), 1.55 (s, 2H), 0.98 (d, J= 6.2 Hz, 3H). Mass (m/z): 451.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (502)

Step 1.preparation of tert-butyl 3- ((4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) carbamoyl) pyrrolidine-1-carboxylate: the intermediate 3- ((4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) carbamoyl) pyrrolidine-1-carboxylic acid tert-butyl ester (151 mg) was prepared as a light gray powder in 47.94% yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (200 mg, 0.57 mmol) and 1- (tert-butoxycarbonyl) pyrrolidine-3-carboxylic acid (123 mg, 0.57 mmol) according to the procedure 458.

Step 2. Preparation of N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (502) Preparation: to a solution of tert-butyl 3- ((4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) carbamoyl) pyrrolidine-1-carboxylate (100 mg, 0.18 mmol) in DCM (5 mL) was added TFAOH (2 mL) and the resulting solution was stirred at room temperature overnight. The reaction mixture was added to water (15 mL) and extracted 3 times with ethyl acetate (5 mL). The organic layers were combined and washed with water and saturated NaHCO, respectively ₃ (aqueous solution) and brine wash. Then over MgSO ₄ Dried, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by preparative TLC to give the desired product 502 (35.2 mg) as an off-white powder in 40.09% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.17 (s, 2H), 8.59 (t, J = 5.8 Hz, 1H), 7.82 (s, 1H), 7.10 - 7.02 (m, 2H), 7.00 - 6.94 (m, 2H), 6.88 (dd, J = 8.8, 3.3 Hz, 4H), 4.16 (d, J = 5.6 Hz, 2H), 3.61 (d, J = 11.7 Hz, 2H), 3.33 - 3.28 (m, 1H), 3.27 - 3.02 (m, 4H), 2.62 (td, J = 12.3, 2.4 Hz, 2H), 2.42 (ddt, J = 12.4, 8.7, 4.3 Hz, 1H), 2.21 - 2.08 (m, 1H), 2.02 - 1.92 (m, 1H), 1.91 - 1.83 (m, 2H), 1.57 (qd, J= 12.4, 4.0 Hz, 2H). Mass (m/z): 447.6 [ M + H ]] ⁺ 。

1-methyl-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (503)

The title compound 503 (22.4 mg) was prepared according to the procedure of 458 as a white powder in 18.77% yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline hydrochloride (100 mg, 0.26 mmol) and 1-methylpyrrolidine-3-carboxylic acid (40 mg, 0.31 mmol). ¹ H NMR(300 MHz, DMSO-d ₆ ) δ 8.57 (t, J= 5.7 Hz, 1H), 7.80 (s, 1H), 7.04 (d, J = 8.4 Hz, 2H), 7.00 - 6.92 (m, 2H), 6.87 (dd, J = 8.9, 3.1 Hz, 4H), 4.16 (d, J = 5.6 Hz, 2H), 3.61 (d, J = 12.0 Hz, 2H), 3.29 - 3.11 (m, 3H), 2.80 (s, 3H), 2.62 (t, J = 12.1 Hz, 2H), 2.42 (dd, J = 8.4, 4.0 Hz, 1H), 2.22 (d, J = 9.3 Hz, 1H), 2.03 (d, J = 16.5 Hz, 2H), 1.88 (d, J = 12.6 Hz, 2H), 1.57 (qd, J= 12.4, 4.0 Hz, 3H). Mass (m/z): 461.2 [ M + H ]] ⁺ 。

N- (4- ((2-methyl-6- (4-methylpiperidin-1-yl) pyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (504)

The title compound 504 (40.3 mg) was prepared according to the procedure of 461 as a light yellow powder in 39.25% yield from 2-methyl-6- (4-methylpiperidin-1-yl) pyridin-3-amine (50 mg, 0.24 mmol) and N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (70 mg, 0.24 mmol). ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.32 (t, J = 5.7 Hz, 1H), 7.57 (s, 1H), 7.29 - 7.16 (m, 2H), 7.01 - 6.93 (m, 2H), 6.64 (d, J = 8.8 Hz, 1H), 6.54 - 6.45 (m, 2H), 4.27 - 4.17 (m, 2H), 4.11 (d, J = 5.7 Hz, 2H), 3.44 - 3.35 (m, 1H), 3.26 - 3.14 (m, 2H), 2.71 (t, J = 12.5 Hz, 2H), 2.36 - 2.24 (m, 2H), 2.19 (s, 3H), 1.67 (d, J = 12.9 Hz, 2H), 1.61 - 1.49 (m, 1H), 1.11 (qd, J = 12.4, 4.1 Hz, 2H), 0.93 (d, J= 6.5 Hz, 3H). Mass (m/z): 422.4 [ M + H ]] ⁺ 。

N- (4- ((6- (4-ethylpiperidin-1-yl) -2-methylpyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (505)

The title compound 505 (41.0 mg) was prepared according to the procedure of 461 as a light yellow powder in 41.29% yield from 6- (4-ethylpiperidin-1-yl) -2-methylpyridin-3-amine (50 mg, 0.23 mmol) and N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (68 mg, 0.23 mmol). ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.33 (t, J = 5.7 Hz, 1H), 7.57 (s, 1H), 7.26 (d, J = 8.6 Hz, 1H), 7.21 (s, 1H), 7.03 - 6.94 (m, 2H), 6.64 (d, J = 8.9 Hz, 1H), 6.54 - 6.46 (m, 2H), 4.30 - 4.18 (m, 2H), 4.11 (d, J = 5.7 Hz, 2H), 3.38 (t, J = 8.6 Hz, 1H), 3.26 - 3.08 (m, 2H), 2.69 (t, J = 12.2 Hz, 2H), 2.34 - 2.23 (m, 2H), 2.20 (s, 3H), 1.77 - 1.66 (m, 2H), 1.33 (s, 1H), 1.25 (p, J = 7.2 Hz, 2H), 1.09 (qd, J = 12.2, 3.9 Hz, 2H), 0.89 (t, J= 7.4 Hz, 3H). Mass (m/z): 436.4 [ M + H ]] ⁺ 。

N- (4- ((6- ((1R, 4S) -2-azabicyclo [2.2.1] heptan-2-yl) -2-methylpyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (506)

Procedure from 6- ((1R,4S) -2-azabicyclo [2.2.1] according to 461]Heptane-2-yl) -2-methylpyridin-3-amine (51 mg, 0.25 mmol) and N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (75 mg, 0.25 mmol) was prepared in 8.78% yield as a light yellow powder of the title compound 506 (9.0 mg). ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 12.26 (s, 1H), 8.38 (t, J = 5.8 Hz, 1H), 7.71 (s, 1H), 7.60 (s, 1H), 7.54 (s, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.93 (s, 1H), 6.58 (d, J = 8.4 Hz, 2H), 4.69 (s, 1H), 4.15 (dd, J = 5.9, 3.6 Hz, 2H), 3.56 (s, 1H), 3.39 (d, J = 8.8 Hz, 1H), 3.26 - 3.11 (m, 3H), 2.76 (s, 1H), 2.35 (s, 3H), 2.32 - 2.27 (m, 2H), 1.76 (d, J= 8.8 Hz, 3H), 1.69-1.58 (m, 2H), 1.46 (s, 1H). Mass (m/z): 420.3 [ M + H ] ] ⁺ 。

N- (4- ((6- (3,3-dimethylazetidin-1-yl) -2-methylpyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (507)

From 6- (3,3-dimethyl azetidin-1-yl) -2-methylpyridin-3-amine (4) according to procedure 4618 mg, 0.25 mmol) and N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (75 mg, 0.25 mmol) the title compound 507 (15.0 mg) was prepared in 14.58% yield as a light yellow powder. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.32 (t, J = 5.7 Hz, 1H), 7.56 (s, 1H), 7.24 (d, J = 8.5 Hz, 1H), 7.19 (s, 1H), 7.00 - 6.93 (m, 2H), 6.50 - 6.42 (m, 2H), 6.20 (d, J = 8.5 Hz, 1H), 4.10 (d, J = 5.7 Hz, 2H), 3.59 (s, 4H), 3.24 - 3.12 (m, 3H), 2.27 (dd, J= 8.4, 4.9 Hz, 2H), 2.17 (s, 3H), 1.26 (s, 6H). Mass (m/z): 408.2 [ M + H ]] ⁺ 。

N- (4- ((6- (4-isopropylpiperidin-1-yl) pyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (508)

The title compound 508 (50.3 mg) was prepared according to the procedure of 461 as a light yellow powder from 6- (4-isopropylpiperidin-1-yl) pyridin-3-amine (37 mg, 0.17 mmol) and N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.17 mmol) in a yield of 68.63%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.35 (t, J = 5.7 Hz, 1H), 7.93 (d, J = 2.8 Hz, 1H), 7.67 (s, 1H), 7.57 (s, 1H), 7.33 (dd, J = 9.0, 2.8 Hz, 1H), 7.07 - 6.97 (m, 2H), 6.83 - 6.71 (m, 3H), 4.20 (d, J = 12.9 Hz, 2H), 4.13 (d, J = 5.7 Hz, 2H), 3.41 - 3.36 (m, 1H), 3.26 - 3.12 (m, 2H), 2.63 (t, J = 11.8 Hz, 2H), 2.34 - 2.22 (m, 2H), 1.69 (d, J = 10.4 Hz, 2H), 1.49 - 1.35 (m, 1H), 1.29 - 1.10 (m, 4H), 0.87 (d, J= 6.8 Hz, 6H). Mass (m/z): 436.7 [ M + H ]] ⁺ 。

N- (4- ((6- (4-ethylpiperidin-1-yl) pyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (509)

Procedure according to 461The title compound 509 (17.9 mg) was prepared from 6- (4-ethylpiperidin-1-yl) pyridin-3-amine (35 mg, 0.17 mmol) and N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.17 mmol) in 25.24% yield as a light yellow powder. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.36 (t, J = 5.8 Hz, 1H), 7.94 (d, J = 2.8 Hz, 1H), 7.67 (s, 1H), 7.58 (s, 1H), 7.33 (dd, J = 9.0, 2.9 Hz, 1H), 7.06 - 7.00 (m, 2H), 6.82 - 6.74 (m, 3H), 4.23 - 4.09 (m, 4H), 3.39 (t, J = 8.9 Hz, 1H), 3.27 - 3.11 (m, 2H), 2.68 (td, J = 12.5, 2.5 Hz, 2H), 2.33 - 2.24 (m, 2H), 2.00 (q, J = 6.9, 6.5 Hz, 1H), 1.72 (d, J = 12.5 Hz, 2H), 1.17 - 1.02 (m, 3H), 0.89 (t, J= 7.4 Hz, 4H). Mass (m/z): 422.6 [ M + H ]] ⁺ 。

N- (4- ((2-methyl-6- (4-propylpiperidin-1-yl) pyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (510)

The title compound 510 (28.5 mg) was prepared as a white powder in 29.59% yield from 2-methyl-6- (4-propylpiperidin-1-yl) pyridin-3-amine (63 mg, 0.21 mmol) and N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.21 mmol) according to the procedure of 461. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.32 (t, J = 5.6 Hz, 1H), 7.57 (s, 1H), 7.24 (d, J = 8.7 Hz, 1H), 7.19 (s, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 8.8 Hz, 1H), 6.53 - 6.46 (m, 2H), 4.22 (d, J = 12.8 Hz, 2H), 4.11 (d, J = 5.6 Hz, 2H), 3.39 (d, J = 8.7 Hz, 2H), 3.26 - 3.10 (m, 3H), 2.74 - 2.62 (m, 2H), 2.36 - 2.21 (m, 3H), 1.99 (dt, J = 13.2, 7.3 Hz, 1H), 1.71 (d, J = 12.3 Hz, 2H), 1.51 - 1.37 (m, 1H), 1.32 (p, J = 7.3 Hz, 3H), 1.09 (qd, J = 12.5, 4.0 Hz, 2H), 0.88 (t, J= 7.2 Hz, 4H). Mass (m/z): 450.4 [ M + H ]] ⁺ 。

5-oxo-N- (4- ((2- (3-propylazetidin-1-yl) pyrimidin-5-yl) amino) benzyl) pyrrolidine-3-carboxamide (511)

The title compound 511 (14.7 mg) was prepared as a yellow powder in 11.53% yield from 2- (3-propylazetidin-1-yl) pyrimidin-5-amine (60 mg, 0.31 mmol) and N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (97 mg, 0.32 mmol) according to the procedure of 461. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.37 (t, J = 5.7 Hz, 1H), 7.67 - 7.55 (m, 2H), 7.35 - 7.25 (m, 2H), 7.08 - 7.02 (m, 2H), 6.76 - 6.66 (m, 2H), 4.14 (d, J = 5.8 Hz, 2H), 3.63 (dd, J= 8.5, 5.7 Hz, 2H), 2.70-2.62 (m, 1H), 2.37-2.25 (m, 3H), 1.66-1.48 (m, 3H), 0.98-0.81 (m, 5H). Mass (m/z): 409.3 [ M + H ]] ⁺ 。

N- (4- ((2- ((1R, 4S) -2-azabicyclo [2.2.1] heptan-2-yl) pyrimidin-5-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (512)

Procedure from 2- ((1R,4S) -2-azabicyclo [2.2.1] according to 461 ]Heptane-2-yl) pyrimidin-5-amine (50 mg, 0.26 mmol) and N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (78 mg, 0.26 mmol) the title compound 512 (34.8 mg) was prepared as a yellow powder in a yield of 32.57%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.34 (t, J = 5.8 Hz, 1H), 8.16 (s, 2H), 7.57 (s, 1H), 7.53 (s, 1H), 7.06 - 6.97 (m, 2H), 6.71 - 6.64 (m, 2H), 4.54 (s, 1H), 4.12 (d, J = 5.7 Hz, 2H), 3.41 - 3.36 (m, 2H), 3.25 - 3.08 (m, 3H), 2.60 (s, 1H), 2.33 - 2.19 (m, 2H), 1.73 - 1.60 (m, 3H), 1.59 - 1.52 (m, 1H), 1.46 (dq, J = 9.3, 1.5 Hz, 1H), 1.36 (ddd, J= 9.4, 7.3, 2.2 Hz, 1H). Mass (m/z): 407.2 [ M + H ]] ⁺

N- (4- ((6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-yl) amino) phenethyl) -5-oxopyrrolidine-3-carboxamide (513)

The title compound 513 (18.5 mg) was prepared as a yellow powder in 22.65% yield from 6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-amine (40 mg, 0.17 mmol) and N- (4-bromophenylethyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.17 mmol) according to the procedure of 461. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.09 - 7.98 (m, 2H), 7.55 (s, 2H), 6.92 (d, J = 8.4 Hz, 2H), 6.63 (d, J = 8.7 Hz, 1H), 6.50 (d, J = 8.4 Hz, 2H), 4.28 (d, J = 12.6 Hz, 2H), 3.24 - 3.15 (m, 4H), 2.70 (d, J = 6.9 Hz, 3H), 2.28 - 2.22 (m, 4H), 2.21 (s, 3H), 2.01 (dd, J = 14.6, 6.9 Hz, 1H), 1.71 (d, J = 11.2 Hz, 2H), 1.52 - 1.39 (m, 2H), 0.89 (d, J= 6.8 Hz, 7H). Mass (m/z): 464.3 [ M + H ]] ⁺

N- (3- (4- ((6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-yl) amino) phenyl) propyl) -5-oxopyrrolidine-3-carboxamide (514)

The title compound 514 (16 mg) was prepared as a yellow powder in 19.54% yield from 6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-amine (40 mg, 0.17 mmol) and N- (3- (4-bromophenyl) propyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.17 mmol) according to the procedure of 461. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 7.97 (t, J = 5.5 Hz, 1H), 7.55 (s, 1H), 7.26 (d, J = 8.7 Hz, 1H), 7.05 (s, 1H), 6.95 - 6.89 (m, 2H), 6.62 (d, J = 8.8 Hz, 1H), 6.53 - 6.46 (m, 2H), 4.27 (d, J = 12.8 Hz, 2H), 3.42 - 3.35 (m, 1H), 3.20 (dd, J = 9.3, 6.5 Hz, 1H), 3.16 - 3.09 (m, 1H), 3.04 (q, J = 6.7 Hz, 2H), 2.63 (t, J = 12.1 Hz, 2H), 2.42 (t, J= 7.6 Hz, 2H), 2.26 (dd, J = 8.5, 2.0 Hz, 2H), 2.20 (s, 3H), 1.70 (d, J = 11.1 Hz, 2H), 1.63 (p, J = 7.2 Hz, 2H), 1.42 (dt, J = 13.0, 6.5 Hz, 1H), 1.26 - 1.10 (m, 3H), 0.88 (d, J= 6.8 Hz, 6H). Mass (m/z): 478.6 [ M + H ]] ⁺

1- (4- ((6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-yl) amino) benzyl) urea (515)

To a solution of N- (4- (aminomethyl) phenyl) -6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-amine (30 mg, 0.09 mmol) in DMSO (5 mL) was added phenyl carbamate (24 mg, 0.18 mmol), and the resulting solution was stirred at room temperature overnight. The reaction mixture was added to water (15 mL) and extracted 3 times with ethyl acetate (5 mL). The organic layers were combined and washed with water and saturated NaHCO, respectively ₃ (aqueous solution) and brine wash. Then over MgSO ₄ Dried, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by preparative TLC to give the desired product 515 (9.4 mg) as an off-white powder in 27.80% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.24 (d, J = 8.8 Hz, 1H), 7.13 (s, 1H), 7.00 - 6.94 (m, 2H), 6.62 (d, J = 8.8 Hz, 1H), 6.53 - 6.44 (m, 2H), 6.17 (t, J = 5.8 Hz, 1H), 4.27 (d, J = 12.8 Hz, 2H), 3.99 (d, J = 5.8 Hz, 2H), 2.61 (d, J = 12.0 Hz, 2H), 2.19 (s, 3H), 1.69 (d, J = 11.2 Hz, 2H), 1.42 (dq, J = 13.1, 6.8 Hz, 1H), 1.26 - 1.07 (m, 3H), 0.87 (d, J= 6.8 Hz, 6H). Mass (m/z): 381.2 [ M + H ]] ⁺

N1- (4- ((6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-yl) amino) benzyl) oxamide (516)

Prepared from N- (4- (aminomethyl) phenyl) -6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-amine (b) according to the procedure of 45830 mg, 0.09 mmol) and 2-amino-2-oxoacetic acid (50 mg, 0.15 mmol) the title compound 516 (7.1 mg) was prepared as a yellow powder in 19.56% yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 9.00 (s, 1H), 8.04 (s, 1H), 7.76 (s, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.16 (d, J = 6.7 Hz, 1H), 6.98 (dd, J = 11.7, 8.5 Hz, 2H), 6.61 (d, J = 9.0 Hz, 1H), 6.48 (dd, J = 8.5, 3.2 Hz, 2H), 4.27 (d, J = 13.2 Hz, 2H), 4.13 (d, J = 6.5 Hz, 1H), 2.61 (d, J = 11.9 Hz, 3H), 1.99 (q, J = 6.8, 6.1 Hz, 3H), 1.69 (d, J = 11.2 Hz, 3H), 1.42 (dd, J = 13.2, 6.7 Hz, 3H), 0.87 (d, J= 6.7 Hz, 6H). Mass (m/z): 410.5 [ M + H ]] ⁺

(S) -N- (4- ((6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-yl) amino) benzyl) -2,6 dioxohexahydropyrimidine-4-carboxamide (517)

The title compound 517 (6.5 mg) was prepared as a yellow powder in 15.32% yield from N- (4- (aminomethyl) phenyl) -6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-amine (30 mg, 0.09 mmol) and (S) -2,6-dioxohexahydropyrimidine-4-carboxylic acid (21 mg, 0.15 mmol) according to the procedure of 458. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 10.01 (s, 1H), 8.35 (t, J = 5.6 Hz, 1H), 7.59 (s, 1H), 7.26 (d, J = 8.7 Hz, 1H), 7.20 (s, 1H), 6.98 (d, J = 8.5 Hz, 2H), 6.64 (d, J = 8.8 Hz, 1H), 6.50 (d, J = 8.5 Hz, 2H), 4.29 (d, J = 13.0 Hz, 2H), 4.12 (d, J = 5.6 Hz, 2H), 3.99 (dt, J = 7.1, 3.4 Hz, 1H), 2.88 - 2.81 (m, 1H), 2.63 (d, J = 11.9 Hz, 2H), 2.20 (s, 3H), 1.71 (d, J = 11.4 Hz, 2H), 1.48 - 1.39 (m, 1H), 1.22 - 1.12 (m, 4H), 0.89 (d, J= 6.8 Hz, 6H). Mass (m/z): 479.3 [ M + H ]] ⁺

N- (4- ((6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-yl) amino) benzyl) -2-oxopyrrolidine-3-carboxamide (518)

The title compound 518 (11.5 mg) was prepared as a yellow powder in 28.86% yield from N- (4- (aminomethyl) phenyl) -6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-amine (30 mg, 0.09 mmol) and 2-oxopyrrolidine-3-carboxylic acid (17 mg, 0.15 mmol) according to the procedure of 458. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.31 (s, 1H), 7.79 (s, 1H), 7.23 (d, J = 34.0 Hz, 2H), 7.01 (d, J = 8.2 Hz, 2H), 6.65 (s, 1H), 6.50 (d, J = 8.1 Hz, 2H), 4.26 (d, J = 12.9 Hz, 2H), 4.16 - 4.05 (m, 2H), 3.61 (dtd, J = 13.2, 6.6, 4.1 Hz, 2H), 3.24 (td, J = 8.9, 4.0 Hz, 2H), 3.13 (qd, J = 7.3, 4.2 Hz, 3H), 2.28 - 2.09 (m, 5H), 1.70 (d, J = 11.4 Hz, 2H), 1.48 - 1.36 (m, 2H), 0.87 (d, J= 6.8 Hz, 6H). Mass (m/z): 450.3 [ M + H ]] ⁺

(R) -N- (4- ((6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-yl) amino) benzyl) pyrrolidine-2-carboxamide (519)

The title compound 519 (6.8 mg) was prepared as a yellow powder in 17.61% yield from N- (4- (aminomethyl) phenyl) -6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-amine (30 mg, 0.09 mmol) and (R) -2-oxopyrrolidine-3-carboxylic acid (15 mg, 0.15 mmol) according to the procedure of 458. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.02 (s, 1H), 7.35 (s, 1H), 7.26 (d, J = 8.9 Hz, 1H), 7.09 (d, J = 8.3 Hz, 2H), 6.65 (d, J = 8.8 Hz, 1H), 6.55 (d, J = 8.3 Hz, 2H), 4.30 (d, J = 12.9 Hz, 2H), 4.18 (d, J = 5.4 Hz, 2H), 2.64 (d, J = 11.8 Hz, 2H), 2.19 (s, 3H), 2.04 - 1.95 (m, 1H), 1.71 (d, J = 11.6 Hz, 2H), 1.51 - 1.39 (m, 1H), 1.33 - 1.23 (m, 6H), 1.23 - 1.10 (m, 3H), 0.89 (d, J = 6.8 Hz, 6H). Mass (m/z): 436.4 [ M + H ] ] ⁺

(S) -N- (4- ((6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-yl) amino) benzyl) -6-oxopiperidine-2-carboxamide (520)

The title compound 520 (12.4 mg) was prepared as a yellow powder in 30.18% yield from N- (4- (aminomethyl) phenyl) -6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-amine (30 mg, 0.09 mmol) and (S) -2-oxopyrrolidine-3-carboxylic acid (19 mg, 0.15 mmol) according to the procedure of 458. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.25 (t, J = 5.9 Hz, 1H), 7.47 (d, J = 2.6 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.16 (s, 1H), 7.02 - 6.96 (m, 2H), 6.62 (d, J = 8.8 Hz, 1H), 6.51 - 6.45 (m, 2H), 4.27 (d, J = 12.8 Hz, 2H), 4.12 (qd, J = 14.6, 5.8 Hz, 2H), 3.86 (td, J = 5.6, 2.7 Hz, 1H), 2.61 (d, J = 11.9 Hz, 2H), 2.18 (s, 3H), 2.11 (t, J = 6.5 Hz, 2H), 1.84 (dq, J = 9.5, 5.1, 4.7 Hz, 1H), 1.68 (ddd, J = 12.9, 8.6, 4.8 Hz, 4H), 1.63 - 1.51 (m, 1H), 1.46 - 1.36 (m, 1H), 1.20 - 1.07 (m, 3H), 0.87 (d, J= 6.7 Hz, 6H). Mass (m/z): 464.5 [ M + H ]] ⁺

N- (4- ((3,5-dimethyl-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (521)

Step 1.1 preparation of- (2,6-dimethyl-4-nitrophenyl) -4- (trifluoromethyl) piperidine: to a solution of 4- (trifluoromethyl) piperidine (2.0 g, 13.06 mmol) and 2-fluoro-1,3-dimethyl-5-nitrobenzene (2.21 g, 13.06 mmol) in DMF (30 mL) was added K ₂ CO ₃ (5.11 g, 15.67 mmol) and the resulting solution was stirred with a microwave at 165 ℃ overnight. The reaction mixture was added dropwise to water (150 mL) with stirring. The precipitate is filteredFiltration and the filter cake was washed 3 times with water and dried in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/AcOEt, 10/1) to give 1.3g of 1- (2,6-dimethyl-4-nitrophenyl) -4- (trifluoromethyl) piperidine as a pale yellow solid in 32.93% yield. Mass (m/z): 303.5 [ M + H ] ] ⁺

Step 8978 preparation of zxft 8978-dimethyl-4- (4- (trifluoromethyl) piperidin-1-yl) aniline: to a solution of 1- (2,6-dimethyl-4-nitrophenyl) -4- (trifluoromethyl) piperidine (1.3 g, 4.3 mmol) in ethanol (50 mL) under argon was added a suspension of palladium on charcoal (130 mg, 0.1 equiv). Bubbling with hydrogen gas for 10 min. The resulting mixture was stirred at the same temperature under hydrogen atmosphere overnight. The completed reaction mixture was bubbled with argon using a balloon, then celite was added, filtration was performed with celite, and the filter cake was washed with ethanol. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/AcOEt, 1/1 to 0/1) to give 920 mg as a brown oil 3,5-dimethyl-4- (4- (trifluoromethyl) piperidin-1-yl) aniline, yield 78.56%. Mass (m/z): 273.3 [ M + H ]] ⁺

Step 3. Preparation of N- (4- ((3,5-dimethyl-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (521): the title compound 521 (7.4 mg) was prepared as a white powder in 5.89% yield from 3,5-dimethyl-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (70 mg, 0.26 mmol) and N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (84 mg, 0.28 mmol) according to the procedure of 461. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.37 (t, J = 5.8 Hz, 1H), 7.86 (s, 1H), 7.58 (s, 1H), 7.09 (d, J = 8.6 Hz, 2H), 7.01 - 6.94 (m, 2H), 6.72 (d, J = 2.6 Hz, 1H), 6.61 (d, J = 2.7 Hz, 1H), 4.18 (d, J = 5.7 Hz, 2H), 3.44 - 3.38 (m, 1H), 3.30 - 3.22 (m, 2H), 3.21 - 3.12 (m, 3H), 2.90 (d, J = 11.7 Hz, 2H), 2.31 (dd, J = 8.4, 4.3 Hz, 2H), 2.20 (d, J = 10.3 Hz, 6H), 1.82 (d, J = 12.1 Hz, 2H), 1.56 (qd, J= 12.0, 4.2 Hz, 2H). Mass (m/z): 489.3 [ M + H ]] ⁺

N- (4- ((6- (4-ethoxypiperidin-1-yl) -2-methylpyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (522)

The title compound 522 (18.5 mg) was prepared as a yellow powder in 18.84% yield from 6- (4-ethoxypiperidin-1-yl) -2-methylpyridin-3-amine (70 mg, 0.30 mmol) and N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (88 mg, 0.30 mmol) according to the procedure of 461. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.31 (t, J = 5.7 Hz, 1H), 7.57 (s, 1H), 7.26 (d, J = 8.7 Hz, 1H), 7.20 (s, 1H), 7.01 - 6.93 (m, 2H), 6.66 (d, J = 8.7 Hz, 1H), 6.54 - 6.47 (m, 2H), 4.12 (d, J = 5.7 Hz, 2H), 3.95 (dt, J = 12.8, 4.3 Hz, 2H), 3.49 (q, J = 7.0 Hz, 3H), 3.39 (t, J = 9.0 Hz, 1H), 3.26 - 3.19 (m, 1H), 3.18 - 3.13 (m, 1H), 3.02 (ddd, J = 13.1, 10.1, 3.0 Hz, 2H), 2.28 (dd, J = 8.4, 5.2 Hz, 2H), 2.20 (s, 3H), 1.94 - 1.83 (m, 2H), 1.41 (dtd, J = 13.0, 9.4, 3.9 Hz, 2H), 1.12 (t, J= 7.0 Hz, 3H). Mass (m/z): 452.4 [ M + H ]] ⁺

2-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) piperidine-4-carboxamide (523)

To a solution of 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline hydrochloride (50 mg, 0.145 mmol) and 2-oxopiperidine-4-carboxylic acid (27 mg, 0.188 mmol) in DMF (3 mL) was added HATU (72 mg, 0.188 mmol) and DIEA (25 mg, 0.188 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was extracted with EA (25 mL x 3). The combined organic layers were washed with brine (15 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated to give the crude product, which was purified by preparative HPLC to give the desired product as a white solid (32.8 mg, 47.7%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.29 (t, J = 5.6 Hz, 1H), 7.76 (s, 1H), 7.41 (s, 1H), 6.97 (d, J = 8.4 Hz, 2H), 6.93 - 6.88 (m, 2H), 6.82 (dd, J = 8.8, 2.4 Hz, 4H), 4.15 - 4.00 (m, 2H), 3.54 (d, J = 12.0 Hz, 2H), 3.05 (tdd, J = 16.4, 9.5, 4.2 Hz, 2H), 2.65 - 2.50 (m, 4H), 2.36 (dtd, J = 12.4, 8.4, 3.6 Hz, 1H), 2.24 - 2.10 (m, 2H), 1.80 (td, J = 11.1, 8.4, 3.5 Hz, 3H), 1.53 (tdd, J= 25.2, 12.8, 4.8 Hz, 3H). Mass (m/z): 475.3 [ M + H ] ] ⁺ 。

6-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) piperidine-3-carboxamide (524)

The title compound 524 (24.6 mg) was prepared as a white solid in 35.8% overall yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline hydrochloride (50 mg, 0.145 mmol), 6-oxopiperidine-3-carboxylic acid (27 mg, 0.188 mmol), HATU (72 mg, 0.188 mmol), DIEA (25 mg, 0.188 mmol), and DMF (3 mL) according to the procedure of 523. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.37 (t, J = 5.6 Hz, 1H), 7.80 (s, 1H), 7.45 (d, J = 10.0 Hz, 1H), 7.04 (d, J = 8.4 Hz, 2H), 7.00 - 6.94 (m, 2H), 6.92 - 6.85 (m, 4H), 4.21 - 4.09 (m, 2H), 3.62 (d, J = 12.4 Hz, 2H), 3.25 - 3.19 (m, 2H), 2.68 - 2.57 (m, 3H), 2.43 (dd, J = 8.4, 4.0 Hz, 1H), 2.17 (ddd, J = 13.2, 10.4, 6.4 Hz, 2H), 1.88 (dd, J = 11.2, 5.2 Hz, 3H), 1.84 - 1.77 (m, 1H), 1.57 (qd, J= 12.4, 4.0 Hz, 2H). Mass (m/z): 475.3 [ M + H ]] ⁺ 。

N- (4- ((4- (diethylamino) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (525)

To the N1, N1-diethylbenzene-1,to a solution of 4-diamine (33 mg, 0.202 mmol) and N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol) in 1,4-dioxane (5 mL) were added Pd2 (dba) 3 (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs2CO3 (83 mg, 0.252 mmol), and the mixture was stirred at 110 ℃ for 16 h. The mixture was extracted with EA (25 mL x 3). The combined organic layers were washed with brine (15 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated to give the crude product, which was purified by TLC (MeOH/DCM = 1/15) to give the desired product as a pale green solid (11.7 mg, 18.3%). ¹ H NMR (400 MHz, DMSO-d 6) δ 8.34 (t, J = 5.6 Hz, 1H), 7.57 (d, J = 5.6 Hz, 2H), 7.01 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.0 Hz, 2H), 6.65 (d, J = 8.4 Hz, 2H), 4.13 (d, J = 5.6 Hz, 2H), 3.40 (s, 1H), 3.31-3.12 (m, 6H), 2.29 (dd, J = 428.4, 5.0 zxft 34, 2H 5306, 1H = 5364, J = 4264). Mass (m/z): 381.3 [ M + H ]]+。

N- (4- ((4- (4-fluoropiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (526)

Step 1.4-fluoro-1- (4-nitrophenyl) piperidine: (526-1). To a solution of 4-fluoropiperidine (357 mg, 2.55 mmol) and 1-fluoro-4-nitrobenzene (300 mg, 2.13 mmol) in DMSO (5 mL) was added K2CO3 (440 mg, 3.20 mmol). The reaction was then stirred at 80 ℃ overnight. The mixture was extracted with EA (25 mL x 3). The combined organic layers were washed with brine (15 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated to give the crude product, which was purified by silica gel chromatography (EA/PE = 1:3) to give the desired product as a yellow solid (454 mg, 95%). Mass (m/z): 225.2 [ M + H ]] ⁺ 。

Step 2.4- (4-fluoropiperidin-1-yl) aniline: (526-2). To a solution of 4-fluoro-1- (4-nitrophenyl) piperidine (454 mg, 2.03 mmol) in MeOH (10 mL) was added Pd/C (50 mg). The solution is added in H ₂ The mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and concentrated under vacuum to afford as violetDesired product as a colored solid (310 mg, 79%). Mass (m/z): 195.3 [ M + H ]] ⁺ 。

Step 3. N- (4- ((4- (4-fluoropiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide: (526). From 4- (4-fluoropiperidin-1-yl) aniline (39 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 526 (18.9 mg) was prepared as a white solid in 27.4% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.45 (dt, J = 71.2, 5.6 Hz, 1H), 7.59 (d, J = 5.6 Hz, 1H), 7.55 - 7.49 (m, 1H), 7.24 - 7.18 (m, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.99 - 6.94 (m, 1H), 6.93 - 6.83 (m, 2H), 4.81 (dtt, J = 49.2, 7.2, 3.6 Hz, 1H), 4.25 (d, J = 5.6 Hz, 1H), 4.15 (d, J = 5.6 Hz, 1H), 3.45 - 3.37 (m, 1H), 3.29 - 3.12 (m, 3H), 3.00 (ddd, J = 12.0, 7.6, 3.6 Hz, 1H), 2.37 - 2.26 (m, 2H), 2.04 - 1.92 (m, 1H), 1.81 (dqd, J= 14.8, 7.6, 4.0 Hz, 1H). Mass (m/z): 411.3 [ M + H ]] ⁺ 。

1-Ethyl-N- (4- ((4- (4-fluoropiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (527)

From 4- (4-fluoropiperidin-1-yl) aniline (36 mg, 0.185 mmol), N- (4-bromobenzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (50 mg, 0.154 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (76 mg, 0.231 mmol) and 1,4-dioxane (5 mL) the title compound 527 (43.1 mg) was prepared as a light green solid in 63.8% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.46 (t, J = 5.6 Hz, 1H), 7.81 (s, 1H), 7.09 - 7.02 (m, 2H), 6.99 - 6.95 (m, 2H), 6.92 - 6.86 (m, 4H), 4.81 (dtt, J = 49.2, 7.2, 3.6 Hz, 1H), 4.16 (d, J = 5.6 Hz, 2H), 3.51 (t, J = 9.2 Hz, 1H), 3.34 (d, J = 4.0 Hz, 1H), 3.26 - 3.10 (m, 5H), 2.99 (ddd, J = 12.0, 7.6, 3.6 Hz, 2H), 2.41 (d, J = 8.4 Hz, 2H), 2.06 - 1.89 (m, 2H), 1.87 - 1.73 (m, 2H), 1.00 (t, J= 7.2 Hz, 3H). Mass (m/z): 439.3 [ M + H ]] ⁺ 。

1-isopropyl-5-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (528)

The title compound 528 (17.3 mg) was prepared as a blue solid in 22.0% total yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline hydrochloride (50 mg, 0.145 mmol), 1-isopropyl-5-oxopyrrolidine-3-carboxylic acid (32 mg, 0.188 mmol), HATU (72 mg, 0.188 mmol), DIEA (25 mg, 0.188 mmol), and DMF (3 mL) according to the procedure of 523. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.41 (t, J = 5.6 Hz, 1H), 7.83 (s, 1H), 7.17 -6.63 (m, 8H), 4.12 (p, J = 6.8 Hz, 2H), 3.62 (s, 2H), 3.47 (t, J = 9.2 Hz, 3H), 3.30 (dd, J = 9.6, 6.4 Hz, 3H), 3.08 (td, J = 8.4, 6.4 Hz, 1H), 2.41 (d, J = 8.4 Hz, 2H), 2.01 - 1.81 (m, 2H), 1.66 - 1.44 (m, 2H), 1.05 (t, J= 6.4 Hz, 6H). Mass (m/z): 503.3 [ M + H ]] ⁺ 。

N- (4- ((4- (diethylamino) phenyl) amino) benzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (529)

From N1, N1-diethylbenzene-1,4-diamine (30 mg, 0.185 mmol), N- (4-bromobenzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (50 mg, 0.154 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol)、x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (76 mg, 0.231 mmol) and 1,4-dioxane (5 mL) the title compound 529 (23.4 mg) was prepared as a blue solid in 37.3% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 11.47 (s, 1H), 8.52 (s, 2H), 7.57 - 6.93 (m, 8H), 4.22 (s, 2H), 3.53 (t, J = 9.2 Hz, 3H), 3.38 (dd, J = 9.6, 6.3 Hz, 2H), 3.26 - 3.08 (m, 4H), 2.42 (dd, J = 8.4, 2.4 Hz, 2H), 1.01 (t, J= 7.2 Hz, 9H). Mass (m/z): 409.3 [ M + H ]] ⁺ 。

N- (4- ((4- (2-azaspiro [3.3] heptan-2-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (530)

Step 1.2- (4-Nitrophenyl) -2-azaspiro [3.3]Heptane: (530-1). From 2-azaspiro [3.3] according to the procedure 526-1]Heptane hemioxalate (800 mg, 2.817 mmol) and 1-fluoro-4-nitrobenzene (662 mg, 4.695 mmol) produced the title compound 530-1 (1 g) as a yellow solid in an overall yield of 97.7%. Mass (m/z): 219.2 [ M + H ]] ⁺ 。

Step 2.4- (2-azaspiro [3.3]]Heptane-2-yl) aniline: (530-2). From 2- (4-Nitrophenyl) -2-azaspiro [3.3] according to the procedure 526-2]Heptane (1 g, 4.587 mmol) prepared the title compound 530-2 (836 mg) as a purple solid in an overall yield of 96%. Mass (m/z): 189.3 [ M + H ]] ⁺ 。

Step 3.4- ((4- ((1R, 4S) -2-azabicyclo [ 2.2.1)]Heptane-2-yl) phenyl) amino) benzaldehyde (530). The procedure according to 525 was followed from 4- (2-azaspiro [3.3]]Heptane-2-yl) aniline (38 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 530 (10.1 mg) was prepared as a white solid in a total yield of 14.9%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.34 (t, J = 5.6 Hz, 1H), 7.59 (d, J = 13.6 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 6.97 - 6.88 (m, 2H), 6.78 (d, J = 8.4 Hz, 2H), 6.42 - 6.30 (m, 2H), 4.13 (d, J = 5.6 Hz, 2H), 3.70 (s, 4H), 3.41 (d, J = 9.2 Hz, 1H), 3.26 - 3.17 (m, 2H), 2.29 (dd, J = 8.4, 4.4 Hz, 2H), 2.16 (t, J = 7.6 Hz, 4H), 1.82 (p, J= 7.6 Hz, 2H). Mass (m/z): 405.3 [ M + H ]] ⁺ 。

N- (4- ((4- (2-azaspiro [3.3] heptan-2-yl) phenyl) amino) benzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (531)

The procedure according to 525 was followed from 4- (2-azaspiro [3.3 ]]Heptane-2-yl) aniline (38 mg, 0.185 mmol), N- (4-bromobenzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (50 mg, 0.154 mmol), pd ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (76 mg, 0.231 mmol) and 1,4-dioxane (5 mL) the title compound 531 (52.4 mg) was prepared in 78.8% total yield as a brown solid. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.39 (t, J = 5.6 Hz, 1H), 7.62 (s, 1H), 7.04 - 6.98 (m, 2H), 6.96 - 6.90 (m, 2H), 6.82 - 6.76 (m, 2H), 6.40 - 6.34 (m, 2H), 4.14 (d, J = 5.6 Hz, 2H), 3.70 (s, 4H), 3.50 (t, J = 9.2 Hz, 1H), 3.37 (d, J = 6.4 Hz, 1H), 3.23 - 3.05 (m, 3H), 2.44 - 2.36 (m, 2H), 2.16 (t, J = 7.6 Hz, 4H), 1.87 - 1.77 (m, 2H), 1.00 (t, J= 7.2 Hz, 3H). Mass (m/z): 433.3 [ M + H ]] ⁺ 。

N- (4- ((4- (azetidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (532)

Step 1.1- (4-nitrophenyl) azetidine: (532-1). From 1-fluoro according to the procedure 526-1-4-Nitrobenzene (1 g, 7.09 mmol) and azetidine (445 mg, 7.80 mmol) the title compound 532-1 (995 mg) was prepared as a yellow solid in an overall yield of 79%. Mass (m/z): 279.2 [ M + H ]] ⁺ 。

Step 2.4- (azetidin-1-yl) aniline: (532-2). The title compound 532-2 (788 mg) was prepared as a purple solid in 95% overall yield from 1- (4-nitrophenyl) azetidine (995 g, 5.59 mmol) according to the procedure of 526-2. Mass (m/z): 149.3 [ M + H ]] ⁺ 。

Step3.N- (4- ((4- (azetidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide: (532). From 4- (azetidin-1-yl) aniline (30 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 532 (12.7 mg) was prepared as a brown solid in a total yield of 20.8%. ¹ H NMR(300 MHz, DMSO-d ₆ ) δ 8.33 (d, J = 5.7 Hz, 1H), 7.57 (s, 2H), 7.09 - 6.64 (m, 8H), 6.36 (s, 1H), 4.12 (s, 2H), 3.72 (s, 3H), 3.40 (d, J= 8.4 Hz, 2H), 3.27-3.10 (m, 3H), 2.33-2.23 (m, 3H). Mass (m/z): 365.3 [ M + H ]] ⁺ 。

N- (4- ((4- (azetidin-1-yl) phenyl) amino) benzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (533)

From 4- (azetidin-1-yl) aniline (27 mg, 0.185 mmol), N- (4-bromobenzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (50 mg, 0.154 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (76 mg, 0.231 mmol) and 1,4-dioxane (5 mL) the title compound 533 (26.6 mg) was prepared as a blue solid in 44.0% overall yield. ¹ H NMR(300 MHz, DMSO-d ₆ ) δ 8.33 (d, J = 5.7 Hz, 1H), 7.57 (s, 2H), 7.09 - 6.64 (m, 8H),4.24 (s, 3H), 3.51 (td, J = 9.0, 1.8 Hz, 2H), 3.41 - 3.32 (m, 2H), 3.23 - 3.09 (m, 5H), 2.44 - 2.37 (m, 3H), 1.00 (t, J= 7.2 Hz, 3H). Mass (m/z): 393.3 [ M + H ]] ⁺ 。

N- (4- ((4-butoxyphenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (534)

From 4-butoxyaniline (33 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 534 (3.7 mg) was prepared as a white solid in 5.8% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.41 (d, J = 6.0 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.59 (s, 1H), 7.07 - 7.03 (m, 2H), 7.02 - 6.96 (m, 2H), 6.90 - 6.81 (m, 4H), 4.15 (d, J = 5.6 Hz, 2H), 3.90 (t, J = 6.4 Hz, 2H), 3.40 (t, J = 8.4 Hz, 1H), 3.27 - 3.14 (m, 2H), 2.35 - 2.24 (m, 2H), 1.67 (dq, J = 8.4, 6.4 Hz, 2H), 1.48 - 1.38 (m, 2H), 0.93 (t, J= 7.4 Hz, 3H). Mass (m/z): 382.3 [ M + H ]] ⁺ 。

N- (4- ((4- (cyclohexyloxy) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (535)

From 4- (cyclohexyloxy) aniline (39 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxoHeterocyclohexane (5 mL) prepared the title compound 535 (37.7 mg) as a white solid in 55.1% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.53 (d, J = 5.6 Hz, 1H), 7.92 (t, J = 2.0 Hz, 1H), 7.61 (s, 1H), 7.08 - 7.02 (m, 2H), 7.02 - 6.95 (m, 2H), 6.93 - 6.86 (m, 2H), 6.86 - 6.79 (m, 2H), 4.16 (dd, J = 12.8, 4.8 Hz, 3H), 3.27 - 3.16 (m, 2H), 2.33 - 2.25 (m, 2H), 1.90 (dt, J= 8.4, 4.0 Hz, 2H), 1.70 (dd, J= 10.4, 6.0 Hz, 2H), 1.55-1.48 (m, 1H), 1.43-1.21 (m, 6H). Mass (m/z): 408.3 [ M + H ]] ⁺ 。

N- (4- ((4-butoxyphenyl) amino) benzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (536)

From 4-butoxyaniline (31 mg, 0.185 mmol), N- (4-bromobenzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (50 mg, 0.154 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (76 mg, 0.231 mmol) and 1,4-dioxane (5 mL) the title compound 536 (12.0 mg) was prepared as a white solid in a total yield of 19.0%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.43 (t, J = 5.6 Hz, 1H), 7.81 (s, 1H), 7.08 - 7.03 (m, 2H), 7.02 - 6.97 (m, 2H), 6.90 - 6.82 (m, 4H), 4.16 (d, J = 5.6 Hz, 2H), 3.90 (t, J = 6.4 Hz, 2H), 3.51 (t, J = 9.2 Hz, 1H), 3.36 (dd, J = 9.6, 6.4 Hz, 1H), 3.19 (qd, J = 7.2, 1.6 Hz, 2H), 3.15 - 3.08 (m, 1H), 2.41 (d, J = 8.4 Hz, 2H), 1.67 (dq, J= 8.4, 6.4 Hz, 2H), 1.49-1.37 (m, 2H), 1.03-0.90 (m, 8H). Mass (m/z): 410.3 [ M + H ]] ⁺ 。

N- (4- ((4- (cyclohexyloxy) phenyl) amino) benzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (537)

From 4- (cyclohexyloxy) aniline (35 mg, 0.185 mmol), N- (4-bromobenzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (50 mg, 0.154 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (76 mg, 0.231 mmol) and 1,4-dioxane (5 mL) the title compound 537 (17.6 mg) was prepared as a white solid in a total yield of 26.3%. ¹ H NMR(300 MHz, DMSO-d ₆ ) δ 8.40 (t, J = 5.7 Hz, 1H), 7.80 (s, 1H), 7.04 (d, J = 8.4 Hz, 2H), 7.00 - 6.93 (m, 2H), 6.90 - 6.79 (m, 4H), 4.16 (t, J = 5.4 Hz, 3H), 3.50 (t, J = 9.3 Hz, 1H), 3.36 (dd, J = 9.6, 6.3 Hz, 1H), 3.22 - 3.08 (m, 3H), 2.40 (d, J= 8.4 Hz, 2H), 1.90 (d, J = 8.1 Hz, 2H), 1.71 (d, J = 6.9 Hz, 2H), 1.56 - 1.48 (m, 1H), 1.46 - 1.22 (m, 6H), 1.00 (t, J= 7.2 Hz, 3H). Mass (m/z): 436.3 [ M + H ]] ⁺ 。

1-Ethyl-N- (4- ((4- (ethyl (pentyl) amino) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (538)

From N1-Ethyl-N1-pentylbenzene-1,4-diamine (38 mg, 0.185 mmol), N- (4-bromobenzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (50 mg, 0.154 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (76 mg, 0.231 mmol) and 1,4-dioxane (5 mL) the title compound 538 (44.2 mg) was prepared as a blue solid in 63.8% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.51 (t, J = 6.0 Hz, 2H), 7.43 (s, 2H), 7.12 (s, 6H), 4.22 (s, 2H), 3.53 (t, J = 9.2 Hz, 2H), 3.41 - 3.36 (m, 1H), 3.17 (ddd, J = 16.4, 8.0, 2.0 Hz, 3H), 2.42 (dd, J = 8.4, 2.4 Hz, 2H), 1.48 (s, 1H), 1.26 - 1.19 (m, 4H), 1.01 (t, J= 7.2 Hz, 6H), 0.84-0.77 (m, 3H). Mass (m/z): 451.3 [ M + H ]] ⁺ 。

1-Ethyl-N- (4- ((4- (ethyl (3-methoxypropyl) amino) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (539)

From N1-Ethyl-N1- (3-methoxypropyl) benzene-1,4-diamine (39 mg, 0.185 mmol), N- (4-bromobenzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (50 mg, 0.154 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (76 mg, 0.231 mmol) and 1,4-dioxane (5 mL) the title compound 539 (49.2 mg) was prepared as a blue solid in a total yield of 70.7%. ¹ H NMR(300 MHz, DMSO-d ₆ ) δ 8.49 (s, 2H), 7.50 - 6.97 (m, 8H), 4.13 (s, 4H), 3.52 (t, J = 9.3 Hz, 3H), 3.37 (dd, J = 9.6, 6.3 Hz, 2H), 3.20 (s, 1H), 3.18 (s, 3H), 3.18 - 3.10 (m, 3H), 2.42 (dd, J = 8.4, 1.2 Hz, 2H), 1.01 (t, J= 7.2 Hz, 6H). Mass (m/z): 453.3 [ M + H ]] ⁺ 。

N- (4- ((4- (ethyl (3-methoxypropyl) amino) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (540)

From N1-ethyl-N1- (3-methoxypropyl) benzene-1,4-diamine (42 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 540 (10.7 mg) was prepared as a black solid in a total yield of 15.0%. ¹ H NMR(300 MHz, DMSO-d ₆ ) δ 8.49 (s, 2H), 7.50 - 6.97 (m, 8H), 4.13 (s, 2H), 3.52 (t, J = 9.3 Hz, 3H), 3.37 (dd, J = 9.6, 6.3 Hz, 2H), 3.20 (s, 1H), 3.18 (s, 3H), 3.18 - 3.10 (m, 3H), 2.42 (dd, J= 8.4, 1.2 Hz, 2H). Mass (m/z): 425.3 [ M + H ]] ⁺ 。

1-Ethyl-N- (4- ((3-methoxy-4- (pentyloxy) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (541)

From 3-methoxy-4- (pentyloxy) aniline (39 mg, 0.185 mmol), N- (4-bromobenzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (50 mg, 0.154 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (76 mg, 0.231 mmol) and 1,4-dioxane (5 mL) the title compound 541 (45.3 mg) was prepared as a white solid in a total yield of 64.9%. ¹ H NMR(300 MHz, DMSO-d ₆ ) δ 8.40 (t, J = 5.7 Hz, 1H), 7.84 (s, 1H), 7.09 - 7.02 (m, 2H), 6.95 - 6.89 (m, 2H), 6.82 (d, J = 8.7 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 6.56 (dd, J = 8.4, 2.4 Hz, 1H), 4.16 (d, J = 5.7 Hz, 2H), 3.86 (t, J = 6.6 Hz, 2H), 3.71 (s, 3H), 3.51 (t, J = 9.3 Hz, 1H), 3.35 (d, J = 6.3 Hz, 1H), 3.23 - 3.08 (m, 3H), 2.41 (d, J = 8.6 Hz, 2H), 1.74 - 1.61 (m, 2H), 1.46 - 1.28 (m, 4H), 1.01 (t, J= 7.2 Hz, 3H), 0.93-0.85 (m, 3H). Mass (m/z): 454.3 [ M + H ]] ⁺ 。

N- (4- ((3-methoxy-4- (pentyloxy) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (542)

From 3-methoxy-4- (pentyloxy) aniline (42 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 542 (25.1 mg) was prepared as a white solid in a total yield of 35.2%. ¹ H NMR(300 MHz, DMSO-d ₆ ) δ 8.35 (t, J = 5.7 Hz, 1H), 7.84 (s, 1H), 7.56 (s, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.94 - 6.88 (m, 2H), 6.82 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 6.56 (dd, J = 8.4, 2.4 Hz, 1H), 4.16 (d, J = 5.7 Hz, 2H), 3.86 (t, J = 6.6 Hz, 2H), 3.71 (s, 3H), 3.38 (d, J = 8.4 Hz, 1H), 3.28 - 3.14 (m, 2H), 2.30 (dd, J = 8.4, 2.6 Hz, 2H), 1.66 (q, J = 6.9 Hz, 2H), 1.37 (ddt, J= 12.0, 8.7, 4.5 Hz, 4H), 0.94-0.85 (m, 3H). Mass (m/z): 426.3 [ M + H ]] ⁺ 。

N- (4- ((4- (ethyl (pentyl) amino) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (543)

From N1-Ethyl-N1-pentylbenzene-1,4-diamine (43 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 543 (6.5 mg) was prepared as a blue solid in a total yield of 9.2%. ¹ H NMR(300 MHz, DMSO-d ₆ ) δ 8.32 (t, J = 5.7 Hz, 1H), 7.54 (d, J = 6.3 Hz, 2H), 6.95 (dd, J = 21.3, 8.2 Hz, 4H), 6.76 (d, J = 8.1 Hz, 2H), 6.61 (d, J = 8.6 Hz, 2H), 4.12 (d, J = 5.7 Hz, 2H), 3.28 - 3.12 (m, 6H), 2.29 (dd, J = 8.4, 3.2 Hz, 2H), 1.49 (s, 3H), 1.30 (d, J = 3.3 Hz, 3H), 1.05 (t, J= 6.9 Hz, 3H), 0.90-0.86 (m, 3H). Mass (m/z): 423.3 [ M + H ]] ⁺ 。

N- (4- ((2- (diethylamino) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (544)

From N1, N1-diethylbenzene-1,2-diamine (33 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 544 (15.0 mg) was prepared as an orange solid in a total yield of 23.5%. ¹ H NMR(300 MHz, DMSO-d ₆ ) δ 8.40 (t, J = 5.7 Hz, 1H), 7.56 (s, 1H), 7.21 (s, 2H), 7.10 (d, J = 8.4 Hz, 2H), 7.02 (s, 3H), 4.18 (d, J = 5.7 Hz, 2H), 3.44 - 3.36 (m, 3H), 3.29 - 3.13 (m, 4H), 2.30 (dd, J = 8.4, 2.3 Hz, 2H), 0.94 (t, J= 7.2 Hz, 6H). Mass (m/z): 381.3 [ M + H ]] ⁺ 。

N- (4- ((2- (diethylamino) phenyl) amino) benzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (545)

From N1, N1-diethylbenzene-1,2-diamine (30 mg, 0.185 mmol), N- (4-bromobenzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (50 mg, 0.154 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (76 mg, 0.231 mmol) and 1,4-dioxane (5 mL) the title compound 545 (46.1 mg) was prepared as a yellow solid in an overall yield of 73.4%. ¹ H NMR(300 MHz, DMSO-d ₆ ) δ 8.46 (t, J = 5.7 Hz, 1H), 7.60 (s, 1H), 7.32 (s, 2H), 7.22 (s, 1H), 7.13 - 7.06 (m, 2H), 6.85 (d, J = 8.1 Hz, 2H), 4.19 (d, J = 5.7 Hz, 2H), 3.51 (t, J = 9.3 Hz, 2H), 3.36 (dd, J = 9.6, 6.3 Hz, 3H), 3.16 (ddt, J = 12.9, 8.7, 6.3 Hz, 4H), 2.41 (dd, J = 8.4, 1.3 Hz, 2H), 0.99 (td, J= 7.1, 5.7 Hz, 9H). Mass (m/z): 409.3 [ M + H ]] ⁺ 。

5-oxo-1- (2- (2-oxopyrrolidin-1-yl) ethyl) -N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (546)

The title compound 546 (16.2 mg) was prepared as a blue solid in 19.6% overall yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline hydrochloride (50 mg, 0.145 mmol), 5-oxo-1- (2- (2-oxopyrrolidin-1-yl) ethyl) pyrrolidine-3-carboxylic acid (45 mg, 0.188 mmol), HATU (72 mg, 0.188 mmol), DIEA (25 mg, 0.188 mmol), and DMF (3 mL) according to the procedure of 523. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.41 (d, J = 6.0 Hz, 1H), 7.05 (s, 8H), 4.17 (s, 2H), 3.75 - 3.68(m, 4H), 3.58 (s, 2H), 3.45 - 3.34 (m, 5H), 3.33 - 3.25 (m, 2H), 3.21 (qd, J = 8.8, 8.0, 3.6 Hz, 2H), 3.10 - 3.03 (m, 1H), 2.38 (dd, J = 8.4, 3.2 Hz, 2H), 2.15 (td, J = 7.6, 2.8 Hz, 2H), 1.86 (td, J= 8.0, 6.0 Hz, 2H). Mass (m/z): 572.3 [ M + H ]] ⁺ 。

5-oxo-N- (4- ((4-pentylphenyl) amino) benzyl) pyrrolidine-3-carboxamide (547)

From 4-pentylaniline (33 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 547 (9.0 mg) was prepared as a white solid in a total yield of 14.1%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.40 (t, J = 5.6 Hz, 1H), 8.00 (s, 1H), 7.59 (s, 1H), 7.09 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 6.97 (dd, J = 8.0, 5.2 Hz, 4H), 4.17 (d, J = 5.6 Hz, 2H), 3.39 (d, J = 8.8 Hz, 1H), 3.28 - 3.15 (m, 2H), 2.46 (d, J = 7.6 Hz, 1H), 2.30 (dd, J = 8.4, 4.4 Hz, 2H), 1.53 (p, J = 7.6 Hz, 2H), 1.32 - 1.22 (m, 5H), 0.86 (t, J= 6.8 Hz, 3H). Mass (m/z): 380.3 [ M + H ]] ⁺ 。

1-Ethyl-5-oxo-N- (4- ((4-pentylphenyl) amino) benzyl) pyrrolidine-3-carboxamide (548)

From 4-pentylaniline (30 mg, 0.185 mmol), N- (4-bromobenzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (50 mg, 0.154 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (76 mg, 0.231 mmol) and 1,4-dioxane (5 mL) the title compound 548 (12.4 mg) was prepared as a white solid in a total yield of 19.8%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.45 (t, J = 5.6 Hz, 1H), 8.00 (s, 1H), 7.09 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H), 6.97 (dd, J = 8.4, 5.6 Hz, 4H), 4.18 (d, J = 5.6 Hz, 2H), 3.51 (t, J= 9.2 Hz, 1H), 3.38 (d, J = 6.4 Hz, 1H), 3.22 - 3.09 (m, 3H), 2.48 (s, 1H), 2.41 (d, J = 8.4 Hz, 2H), 1.53 (p, J = 7.2 Hz, 2H), 1.28 (ddt, J = 14.4, 9.2, 5.2 Hz, 5H), 1.00 (t, J = 7.2 Hz, 3H), 0.86 (t, J= 6.8 Hz, 3H). Mass (m/z): 408.3 [ M + H ]] ⁺ 。

5-oxo-N- (4- ((3-propoxy-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (549)

From 3-propoxy-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (61 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 549 (12.4 mg) was prepared as a white solid in a total yield of 14.3%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.54 (s, 1H), 7.97 (s, 1H), 7.08 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 1H), 6.66 - 6.57 (m, 2H), 4.17 (d, J = 5.6 Hz, 2H), 3.85 (t, J = 6.0 Hz, 2H), 3.52 (t, J = 9.2 Hz, 1H), 3.18 (tt, J = 10.4, 5.2 Hz, 3H), 2.54 (s, 1H), 2.41 (d, J = 8.4 Hz, 3H), 1.87 (d, J = 12.4 Hz, 2H), 1.59 (qd, J= 12.4, 4.0 Hz, 2H). Mass (m/z): 520.3 [ M + H ]] ⁺ 。

1-Ethyl-5-oxo-N- (4- ((3-propoxy-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (550)

From 3-propoxy-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (56 mg, 0.185 mmol), N- (4-bromobenzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (50 mg, 0.154 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (76 mg, 0.231 mmol) and 1,4-dioxane (5 mL) the title compound 550 (35.1 mg) was prepared as a brown solid in 41.7% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.54 (s, 1H), 7.97 (s, 1H), 7.08 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H), 6.59 (dd, J = 8.4, 2.4 Hz, 1H), 4.17 (d, J = 5.6 Hz, 2H), 3.85 (t, J = 6.0 Hz, 2H), 3.52 (t, J = 9.2 Hz, 1H), 3.18 (tt, J = 10.4, 5.2 Hz, 3H), 2.54 (s, 1H), 2.41 (d, J = 8.4 Hz, 3H), 1.87 (d, J = 12.4 Hz, 2H), 1.75 (q, J = 6.8 Hz, 2H), 1.58 (tt, J = 12.4, 6.1 Hz, 2H), 1.01 (td, J= 7.2, 5.2 Hz, 6H). Mass (m/z): 547.3 [ M + H ]] ⁺ 。

5-oxo-N- (4- ((2-propoxy-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (551)

From 2-propoxy-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (61 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 551 (15.4 mg) was prepared as a blue solid in a total yield of 17.7%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.38 (s, 1H), 7.58 (s, 1H), 7.23 - 6.56 (m, 7H), 4.10 (d, J = 5.6 Hz, 5H), 3.40 (t, J = 8.8 Hz, 2H), 3.27 - 3.13 (m, 3H), 2.89 (s, 1H), 2.29 (dd, J = 8.4, 3.6 Hz, 2H), 2.00 (dd, J = 16.0, 8.4 Hz, 2H), 1.69 (s, 3H), 0.92 (t, J= 7.4 Hz, 3H). Mass (m/z): 519.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) isobutyramide (552)

The title compound 552 (28.6 mg) was prepared as a white solid in 47.0% total yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline hydrochloride (50 mg, 0.145 mmol), isobutyric acid (17 mg, 0.188 mmol), HATU (72 mg, 0.188 mmol), DIEA (25 mg, 0.188 mmol), and DMF (3 mL) according to the procedure of 523. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.13 (t, J = 5.6 Hz, 1H), 7.79 (s, 1H), 7.06 - 7.00 (m, 2H), 6.99 - 6.94 (m, 2H), 6.91 - 6.84 (m, 4H), 4.12 (d, J = 5.6 Hz, 2H), 3.61 (d, J = 12.4 Hz, 2H), 2.67 - 2.57 (m, 2H), 2.42 - 2.37 (m, 1H), 1.88 (d, J = 12.8 Hz, 2H), 1.57 (qd, J = 12.8, 4.2 Hz, 3H), 1.01 (d, J= 6.8 Hz, 6H). Mass (m/z): 420.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) acetamide (553)

To a solution of 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline hydrochloride (50 mg, 0.145 mmol) and phenyl carbamate (26 mg, 0.188 mmol) in DMSO (3 mL) was added Et ₃ N (43 mg, 0.435 mmol), the mixture was then stirred at room temperature for 2 h. The mixture was extracted with EA (25 mL x 3). The combined organic layers were washed with brine (15 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated to give the crude product, which was purified by preparative HPLC to give the desired product as a white solid (29.0 mg, 51.1%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.20 (t, J = 5.6 Hz, 1H), 7.78 (s, 1H), 7.07 - 7.02 (m, 2H), 7.00 - 6.94 (m, 2H), 6.91 - 6.85 (m, 4H), 4.11 (d, J = 5.6 Hz, 2H), 3.61 (d, J = 12.0 Hz, 2H), 2.62 (td, J = 12.4, 2.4 Hz, 2H), 2.42 (dp, J = 12.4, 4.4, 3.6 Hz, 1H), 1.88 (d, J = 12.8 Hz, 2H), 1.84 (s, 3H), 1.57 (qd, J= 12.4, 4.0 Hz, 3H). Mass (m/z): 392.3 [ M + H ]] ⁺ 。

1-Ethyl-N- (4- ((4- (4-methoxy-4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (554)

Following 525 procedures from 4- (4-methoxy-4- (trifluoromethyl) piperidin-1-yl) aniline (51 mg, 0.185 mmol), N- (4-bromobenzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (50 mg, 0.154 mmol), pd ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (76 mg, 0.231 mmol) and 1,4-dioxane (5 mL) the title compound 554 (31.3 mg) was prepared as a blue solid in 39.2% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.46 (t, J = 5.9 Hz, 1H), 7.08 (s, 8H), 3.52 (t, J = 9.2 Hz, 2H), 3.87 - 3.82(m, 3H), 3.46 - 3.32 (m, 5H), 3.22 - 3.07 (m, 4H), 3.00 (s, 1H), 2.41 (dd, J = 8.5, 1.4 Hz, 2H), 2.17 - 1.86 (m, 3H), 1.00 (t, J= 7.2 Hz, 3H). Mass (m/z): 519.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4-hydroxy-4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (555)

Following the procedure of 525 from 1- (4-aminophenyl) -4- (trifluoromethyl) piperidin-4-ol (55 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 555 (14.7 mg) was prepared as a blue solid in a total yield of 17.9%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.42 (t, J = 5.8 Hz, 1H), 7.59 (s, 1H), 7.21 - 6.84 (m, 8H), 4.17 (s, 2H), 3.87 - 3.82(m, 3H), 3.49 (s, 2H), 3.28 - 3.13 (m, 3H), 2.99 (s, 2H), 2.30 (dd, J = 8.3, 3.9 Hz, 2H), 2.03 (dd, J= 25.4, 9.2 Hz, 4H). Mass (m/z): 491.3 [ M + H ] ] ⁺ 。

1-Ethyl-5-oxo-N- (4- (phenylamino) benzyl) pyrrolidine-3-carboxamide (556)

The procedure was followed 525 from aniline (17 mg, 0.185 mmol), N- (4-bromobenzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (50 mg, 0.154 mmol), pd ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (76 mg, 0.231 mmol) and 1,4-dioxane (5 mL) the title compound 556 (34.1 mg) was prepared as a white solid in an overall yield of 62.1%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.46 (t, J = 5.6 Hz, 1H), 8.13 (s, 1H), 7.25 - 7.17 (m, 2H), 7.15 - 7.09 (m, 2H), 7.06 - 7.00 (m, 4H), 6.79 (tt, J = 7.2, 1.1 Hz, 1H), 4.20 (d, J = 5.6 Hz, 2H), 3.52 (t, J = 9.2 Hz, 1H), 3.40 - 3.36 (m, 1H), 3.25 - 3.08 (m, 3H), 2.45 - 2.38 (m, 2H), 1.01 (t, J= 7.2 Hz, 3H). Mass (m/z): 338.3 [ M + H ]] ⁺ 。

2- (4-methylpiperazin-1-yl) -N- (4- (phenylamino) benzyl) acetamide (557)

The procedure was followed 525 from aniline (17 mg, 0.184 mmol), N- (4-bromobenzyl) -2- (4-methylpiperazin-1-yl) acetamide (50 mg, 0.153 mmol), pd ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (75 mg, 0.229 mmol) and 1,4-dioxane (5 mL) the title compound 557 (40.5 mg) was prepared as a white solid in an overall yield of 78.3%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.31 - 8.19 (m, 2H), 7.24 - 7.17 (m, 2H), 7.16 - 7.09 (m, 2H), 7.04 (td, J = 6.8, 1.6 Hz, 4H), 6.79 (tt, J = 7.2, 1.2 Hz, 1H), 4.21 (d, J= 6.0 Hz, 2H), 3.02 (s, 2H), 2.81-2.53 (m, 8H), 2.41 (s, 3H). Mass (m/z): 339.3 [ M + H ]] ⁺ 。

N- (4- ((3-fluoro-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (558)

Step 1.1- (2-fluoro-4-nitrophenyl) -4- (trifluoromethyl) piperidine: (558-1). The title compound 558-1 (3.4 g) was prepared as a yellow solid in 93% overall yield according to the procedure of 526-1 from 4- (trifluoromethyl) piperidine (1.9 g, 12.5 mmol) and 1,2-difluoro-4-nitrobenzene (1.8 g, 11.3 mmol). Mass (m/z): 293.2 [ M + H ] ] ⁺ 。

Step 2.3-fluoro-4- (4- (trifluoromethyl) piperidin-1-yl) aniline: (558-2). The title compound 558-2 (2.9 g) was prepared as a purple solid in 92% overall yield from 1- (2-fluoro-4-nitrophenyl) -4- (trifluoromethyl) piperidine (3.4 g, 12.0 mmol) according to the procedure of 526-2. Mass (m/z): 263.3 [ M + H ]] ⁺ 。

Step3. N- (4- ((3-fluoro-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide: (558). From 3-fluoro-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (53 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 558 (53.7 mg) was prepared as a white solid in a total yield of 66.9%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.52 (s, 1H), 8.21 (d, J = 2.4 Hz, 1H), 7.60 (s, 1H), 7.14 - 7.08 (m, 2H), 7.02 - 6.91 (m, 3H), 6.83 - 6.76 (m, 2H), 4.18 (d, J = 5.6 Hz, 2H), 3.31 - 3.17 (m, 4H), 2.70 - 2.59 (m, 2H), 2.47 - 2.37 (m, 1H), 2.33 - 2.27 (m, 2H), 1.93 - 1.84 (m, 2H), 1.60 (qd, J= 12.4, 4.0 Hz, 2H). Mass (m/z): 479.3 [ M + H ]] ⁺ 。

N- (4- ((3,5-difluoro-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (559)

Step 1.1- (2,6-difluoro-4-nitrophenyl) -4- (trifluoromethyl) piperidine: (559-1). The title compound 559-1 (1.5 g) was prepared as a yellow solid in 96.4% overall yield from 4- (trifluoromethyl) piperidine (0.95 g, 5.6 mmol) and 1,2,3-trifluoro-5-nitrobenzene (1 g, 6.2 mmol) according to the procedure of 526-1. Mass (m/z): 311.2 [ M + H ] ] ⁺ 。

Step 2.3,5-difluoro-4- (4- (trifluoromethyl) piperidin-1-yl) aniline: (559-2). The title compound 559-2 (1.3 g) was prepared as a purple solid in 96% overall yield from 1- (2,6-difluoro-4-nitrophenyl) -4- (trifluoromethyl) piperidine (1.5 g, 4.8 mmol) according to the procedure of 526-2. Mass (m/z): 281.3 [ M + H ]] ⁺ 。

Step3. N- (4- ((3,5-difluoro-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide: (559). From 3,5-difluoro-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (57 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 559 (24.9 mg) was prepared as a white solid in 29.9% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.44 (d, J = 4.8 Hz, 2H), 7.59 (s, 1H), 7.19 - 7.14 (m, 2H), 7.08 - 7.01 (m, 2H), 6.62 - 6.53 (m, 2H), 4.21 (d, J = 5.6 Hz, 2H), 3.45 - 3.38 (m, 1H), 3.29 - 3.14 (m, 2H), 3.03 (d, J = 14.0 Hz, 4H), 2.41 (dq, J = 8.4, 4.8, 4.4 Hz, 1H), 2.31 (dd, J = 8.4, 3.2 Hz, 2H), 1.88 - 1.78 (m, 2H), 1.54 (qd, J= 12.0, 5.2 Hz, 2H). Mass (m/z): 497.3 [ M + H ]] ⁺ 。

N- (4- ((4- ((1R, 4S) -2-azabicyclo [2.2.1] heptan-2-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (560)

Step 1. (1R, 4S) -2- (4-nitrophenyl) -2-azabicyclo [2.2.1]Heptane: (560-1). From (1R,4S) -2-azabicyclo [2.2.1] according to the procedure of 526-1]Heptane (500 mg, 5.155 mmol) and 4-bromobenzaldehyde (606 mg, 4.296 mmol) produced the title compound 560-1 (970 mg) as a yellow solid in a total yield of 92%. Mass (m/z): 219.2 [ M + H ] ] ⁺ 。

Step 2.4- ((1R, 4S) -2-azabicyclo [2.2.1]Heptane-2-yl) aniline: (560-2). From (1R, 4S) -2- (4-nitrophenyl) -2-azabicyclo [2.2.1 according to the procedure 526-2]Heptane (970 mg, 4.450 mmol) prepared the title compound 560-2 (906 mg) as a purple solid in 90% overall yield. Mass (m/z): 189.3 [ M + H ]] ⁺ 。

Step 3N- (4- ((4- ((1R, 4S) -2-azabicyclo [ 2.2.1)]Heptane-2-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (560-3). The procedure was followed 525 from 4- ((1R, 4S) -2-azabicyclo [2.2.1]Heptane-2-yl) aniline (38 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 560 (4.2 mg) was prepared in a total yield of 6.2% as a blue solid. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.51 (s, 1H), 8.35 (s, 2H), 7.58 (s, 3H), 7.35 - 7.30 (m, 2H), 7.25 (dd, J = 7.2, 2.8 Hz, 3H), 4.28 (d, J = 6.0 Hz, 2H), 2.33 - 2.26 (m, 6H), 2.00 (q, J= 6.8, 6.4 Hz, 2H), 1.65 (s, 4H). Mass (m/z): 405.3 [ M + H ]] ⁺ 。

N- (4- ((4- (3,3-Dimethylazetidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (561)

From 4- (3,3-dimethylazetidin-1-yl) aniline (36 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 561 (10.0 mg) was prepared as a blue solid in a total yield of 15.2%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.38 (s, 2H), 7.59 (s, 2H), 7.41 - 6.75 (m, 8H), 4.27 - 4.16 (m, 2H), 3.40 (t, J = 8.8 Hz, 2H), 3.27 - 3.12 (m, 4H), 2.30 (dd, J = 8.4, 3.6 Hz, 3H), 1.31 (d, J= 2.0 Hz, 6H). Mass (m/z): 393.3 [ M + H ]] ⁺ 。

N- (4- ((4- (3-methylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (562)

From 4- (3-methylpiperidin-1-yl) aniline (39 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 562 (14.7 mg) was prepared as a green solid in a total yield of 21.6%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.44 (t, J = 5.6 Hz, 2H), 7.60 (s, 2H), 7.22 - 6.98 (m, 8H), 3.42 (d, J= 8.8 Hz, 4H), 3.23 (dt, J = 15.2, 7.2 Hz, 4H), 2.30 (dd, J= 8.4, 3.2 Hz, 3H), 1.95-1.77 (m, 3H), 0.92 (s, 3H). Mass (m/z): 407.3 [ M + H ]] ⁺ 。

N- (4- ((4- (2-methylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (563)

From 4- (2-methylpiperidin-1-yl) aniline (39 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 563 (19.1 mg) was prepared as a white solid in 27.9% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 10.67 (s, 1H), 8.57 - 8.42 (m, 2H), 7.60 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.20 - 7.05 (m, 6H), 4.22 (dd, J = 6.0, 2.0 Hz, 2H), 3.57 - 3.38 (m, 4H), 3.30 - 3.17 (m, 2H), 2.34 - 2.28 (m, 2H), 2.02 (t, J = 6.8 Hz, 1H), 1.93 - 1.77 (m, 3H), 1.73 - 1.62 (m, 2H), 0.97 (d, J= 6.4 Hz, 3H). Mass (m/z): 407.3 [ M + H ]] ⁺ 。

5-oxo-N- (3- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (564)

From 4- (4- (trifluoromethyl) piperidin-1-yl) aniline (49 mg, 0.202 mmol), N- (3-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 564 (22.5 mg) was prepared as a brown solid in a total yield of 29.1%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.60 (s, 1H), 7.95 (s, 1H), 7.68 (s, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 6.90 - 6.82 (m, 2H), 6.64 (d, J = 7.6 Hz, 1H), 4.24 (d, J = 5.6 Hz, 2H), 3.70 (d, J = 12.0 Hz, 2H), 3.47 (d, J = 16.8 Hz, 1H), 3.35 - 3.25 (m, 2H), 2.69 (t, J = 12.0 Hz, 2H), 2.50 (d, J = 8.4 Hz, 1H), 2.40 - 2.34 (m, 2H), 1.95 (d, J= 12.4 Hz, 2H), 1.73-1.55 (m, 2H). Mass (m/z): 461.3 [ M + H ]] ⁺ 。

N- (4- ((4- (2-azaspiro [3.4] octan-2-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (565)

Step 1.2- (4-Nitrophenyl) -2-azaspiro [3.4]Octane: (565-1). Synthesis of 2-azaspiro [3.4] compounds according to the procedure of 526-1]Octane (250 mg, 2.252 mmol) and 1-fluoro-4-nitrobenzene (265 mg, 1.877 mmol) produced the title compound 565-1 (510 mg) as a yellow solid in 98% overall yield. Mass (m/z): 233.2 [ M + H ]] ⁺ 。

Step 2.4- (2-azaspiro [3.4]]Octane-2-yl) aniline: (565-2). From 2- (4-Nitrophenyl) -2-azaspiro [3.4] according to the procedure 526-2]Octane (510 mg, 2.198 mmol) the title compound 565-2 (290 mg) was prepared as a purple solid in 65% overall yield. Mass (m/z): 203.3 [ M + H ] ] ⁺ 。

Step 3. N- (4- ((4- (2-azaspiro [3.4 ]))]Octane-2-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (565). The procedure according to 525 was followed from 4- (2-azaspiro [3.4 ]]Octane-2-yl) aniline (41 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 565 (21.5 mg) was prepared as a white solid in a total yield of 30.6%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.33 (s, 1H), 7.54 (d, J = 18.8 Hz, 2H), 6.90 (dd, J = 31.2, 8.4 Hz, 4H), 6.72 (d, J = 8.0 Hz, 2H), 6.31 (d, J = 8.0 Hz, 2H), 4.06 (d, J = 5.6 Hz, 2H), 3.53 (s, 4H), 3.21 - 3.06 (m, 3H), 2.22 (dd, J = 8.4, 5.2 Hz, 2H), 1.71 (td, J= 6.0, 4.8, 2.8 Hz, 4H), 1.55-1.47 (m, 4H). Mass (m/z): 419.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4- (difluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (566)

From 4- (4- (difluoromethyl) piperidin-1-yl) aniline (46 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 566 (20.1 mg) was prepared as a brown solid in 27.1% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.36 (s, 1H), 7.75 (s, 1H), 7.53 (s, 1H), 7.05 - 6.69 (m, 8H), 4.08 (d, J = 5.6 Hz, 2H), 3.52 (d, J = 11.6 Hz, 2H), 3.33 (t, J = 8.4 Hz, 1H), 3.20 - 3.09 (m, 2H), 2.50 (d, J = 11.6 Hz, 2H), 2.27 - 2.19 (m, 2H), 1.84 (s, 1H), 1.69 (d, J = 12.4 Hz, 2H), 1.41 (d, J= 12.4 Hz, 2H). Mass (m/z): 443.3 [ M + H ]] ⁺ 。

5-oxo-N- (4- ((4- (piperidin-1-yl) -3- (trifluoromethyl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (567)

From 4- (piperidin-1-yl) -3- (trifluoromethyl) aniline (50 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 567 (26.5 mg) was prepared as a white solid in 34.3% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.51 (t, J = 5.6 Hz, 1H), 8.44 (s, 1H), 7.61 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.27 (dd, J = 8.8, 2.8 Hz, 1H), 7.23 (d, J = 2.8 Hz, 1H), 7.17 - 7.12 (m, 2H), 7.06 - 7.00 (m, 2H), 4.20 (d, J = 5.6 Hz, 2H), 3.46 - 3.39 (m, 1H), 3.30 - 3.16 (m, 2H), 2.73 (t, J = 5.2 Hz, 4H), 2.31 (dd, J = 8.4, 4.4 Hz, 2H), 1.59 (p, J = 5.2 Hz, 4H), 1.49 (s, 2H). Mass (m/z): 461.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4-methylpiperidin-1-yl) -3- (trifluoromethyl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (568)

From 4- (4-methylpiperidin-1-yl) -3- (trifluoromethyl) aniline (52 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 568 (13.3 mg) was prepared as a white solid in a total yield of 16.7%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.42 (t, J = 5.6 Hz, 1H), 8.34 (s, 1H), 7.59 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.26 (dd, J = 8.8, 2.8 Hz, 1H), 7.21 (d, J = 2.8 Hz, 1H), 7.18 - 7.12 (m, 2H), 7.06 - 7.00 (m, 2H), 4.20 (d, J = 5.6 Hz, 2H), 3.41 (t, J = 8.8 Hz, 3H), 3.30 - 3.12 (m, 3H), 2.82 (d, J = 11.2 Hz, 2H), 2.67 (td, J = 11.6, 2.0 Hz, 2H), 2.30 (dd, J = 8.4, 3.2 Hz, 2H), 1.70 - 1.60 (m, 2H), 1.44 (q, J = 7.2, 6.4 Hz, 1H), 1.30 - 1.19 (m, 3H), 0.95 (d, J= 6.4 Hz, 3H). Mass (m/z): 475.3 [ M + H ]] ⁺ 。

N1- (4- ((4- (4,4-dimethylpiperidin-1-yl) phenyl) amino) benzyl) glutaramide (569)

The title compound 569 (19.9 mg) was prepared as a blue solid in 29.1% total yield from 4- (aminomethyl) -N- (4- (4,4-dimethylpiperidin-1-yl) phenyl) aniline (50 mg, 0.162 mmol), 5-amino-5-oxopentanoic acid (28 mg, 0.210 mmol), HATU (80 mg, 0.210 mmol), DIEA (27 mg, 0.210 mmol), and DMF (3 mL) according to the procedure of 523. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.46 (s, 1H), 8.27 (t, J = 6.0 Hz, 1H), 7.53 (s, 2H), 7.27 (s, 1H), 7.16 (d, J = 8.0 Hz, 2H), 7.07 (dd, J = 15.6, 8.0 Hz, 4H), 6.74 (s, 1H), 4.19 (d, J = 5.6 Hz, 4H), 2.13 (t, J = 7.6 Hz, 2H), 2.05 (t, J = 7.6 Hz, 2H), 1.72 (p, J= 7.6 Hz, 4H), 1.07 (s, 6H). Mass (m/z): 423.3 [ M + H ]] ⁺ 。

5-oxo-N- (4- ((2- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-5-yl) amino) benzyl) pyrrolidine-3-carboxamide (570)

Step 1.5-nitro-2- (4- (trifluoromethyl) piperidin-1-yl) pyrimidine: (570-1). The title compound 570-1 (1.6 g) was prepared as a yellow solid in 86.4% total yield from 4- (trifluoromethyl) piperidine (1.1 g, 7.382 mmol) and 2-chloro-5-nitropyrimidine (1 g, 6.711 mmol) according to the procedure of 526-1. Mass (m/z): 277.2 [ M + H ]] ⁺ 。

Step 2.2- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-5-amine: (570-2). The title compound 570-2 (1.2 g) was prepared as a purple solid in 84% overall yield from 5-nitro-2- (4- (trifluoromethyl) piperidin-1-yl) pyrimidine (1.6 g, 5.80 mmol) according to the procedure of 526-2. Mass (m/z): 247.3 [ M + H ]] ⁺ 。

Step 3.5-oxo-N- (4- ((2- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-5-yl) amino) benzyl) pyrrolidine-3-carboxamide (570). From 2- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-5-amine (52 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 570 (18.6 mg) was prepared as a yellow solid in a total yield of 24.0%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.37 (t, J = 6.0 Hz, 1H), 8.26 (s, 2H), 7.58 (s, 1H), 7.07 - 7.00 (m, 2H), 6.78 - 6.71 (m, 2H), 4.69 (d, J = 13.2 Hz, 2H), 4.14 (d, J = 5.6 Hz, 2H), 3.39 (t, J = 8.8 Hz, 1H), 3.28 - 3.10 (m, 2H), 2.89 (td, J = 12.8, 2.6 Hz, 2H), 2.62 (ddd, J = 12.4, 8.4, 3.6 Hz, 1H), 2.29 (dd, J = 8.4, 3.42 Hz, 2H), 1.95 - 1.79 (m, 2H), 1.38 (qd, J= 12.4, 4.4 Hz, 2H). Mass (m/z): 463.3 [ M + H ]] ⁺ 。

(S) -N- (4- ((4- (4,4-dimethylpiperidin-1-yl) phenyl) amino) benzyl) -2,6-dioxohexahydropyrimidine-4-carboxamide (571)

The title compound 571 (7.1 mg) was prepared as a blue solid in 9.8% overall yield from 4- (aminomethyl) -N- (4- (4,4-dimethylpiperidin-1-yl) phenyl) aniline (50 mg, 0.162 mmol), (S) -2,6-dioxohexahydropyrimidine-4-carboxylic acid (33 mg, 0.210 mmol), HATU (80 mg, 0.210 mmol), DIEA (27 mg, 0.210 mmol), and DMF (3 mL) according to the procedure of 523 in 9.8%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 10.05 (d, J = 1.6 Hz, 1H), 8.50 (s, 2H), 7.64 (t, J = 2.4 Hz, 1H), 7.52 (s, 1H), 7.29 - 6.92 (m, 7H), 4.21 (s, 2H), 4.01 (dt, J = 7.2, 3.6 Hz, 2H), 3.54 - 3.35(m, 3H), 3.10 (qd, J= 7.2, 4.8 Hz, 1H), 2.87 (dd, J= 16.4, 7.2 Hz, 1H), 1.66 (s, 4H), 1.14-0.99 (m, 6H). Mass (m/z): 450.3 [ M + H ]] ⁺ 。

(R) -N- (4- ((4- (4,4-dimethylpiperidin-1-yl) phenyl) amino) benzyl) -2-oxoimidazolidine-4-carboxamide (572)

Prepared as a blue solid in 63.3% overall yield from 4- (aminomethyl) -N- (4- (4,4-dimethylpiperidin-1-yl) phenyl) aniline (50 mg, 0.162 mmol), (R) -2-oxoimidazolidine-4-carboxylic acid (27 mg, 0.210 mmol), HATU (80 mg, 0.210 mmol), DIEA (27 mg, 0.210 mmol), and DMF (3 mL) according to the procedure of 523The title compound 572 (43.2 mg). ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.47 (s, 1H), 8.38 (t, J = 6.0 Hz, 1H), 7.53 (s, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.08 (dd, J = 16.0, 8.4 Hz, 4H), 6.57 (s, 1H), 6.35 (s, 1H), 4.23 (d, J = 5.4 Hz, 2H), 4.11 (dd, J = 9.6, 6.2 Hz, 2H), 3.56 (t, J = 9.6 Hz, 2H), 3.22 (dd, J = 889, 6.2 Hz, 1H), 3.10 (qd, J= 7.2, 4.8 Hz, 3H), 1.69 (s, 3H), 1.07 (s, 6H). Mass (m/z): 422.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4,4-dimethylpiperidin-1-yl) phenyl) amino) benzyl) -2,6-dioxopiperidine-4-carboxamide (573)

The title compound 573 (7.0 mg) as a blue solid was prepared according to the procedure of 523 in 9.6% total yield from 4- (aminomethyl) -N- (4- (4,4-dimethylpiperidin-1-yl) phenyl) aniline (50 mg, 0.162 mmol), 2,6-dioxopiperidine-4-carboxylic acid (33 mg, 0.210 mmol), HATU (80 mg, 0.210 mmol), DIEA (27 mg, 0.210 mmol), and DMF (3 mL) according to 523. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.50 (s, 1H), 7.52 (s, 1H), 7.10 (d, J = 19.6 Hz, 8H), 4.19 (s, 2H), 3.47 - 3.27(m, 5H), 3.03 - 2.95 (m, 1H), 2.61 (qd, J= 16.8, 6.2 Hz, 5H), 1.62 (s, 3H), 1.05 (s, 6H). Mass (m/z): 449.3 [ M + H ]] ⁺ 。

N- (4- ((5-fluoro-6- (4- (trifluoromethyl) piperidin-1-yl) pyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (574)

From 5-fluoro-6- (4- (trifluoromethyl) piperidin-1-yl) pyridin-3-amine (53 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 574 (8.1 mg) was prepared as a white solid in 10.1% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.45 (t, J = 5.6 Hz, 1H), 8.20 (s, 1H), 7.87 (dd, J = 2.4, 1.0 Hz, 1H), 7.59 (s, 1H), 7.28 (dd, J = 14.4, 2.4 Hz, 1H), 7.14 - 7.08 (m, 2H), 6.98 - 6.92 (m, 2H), 4.18 (d, J = 5.6 Hz, 2H), 3.77 (d, J = 12.4 Hz, 2H), 3.28 - 3.12 (m, 2H), 2.81 (td, J = 12.8, 2.4 Hz, 2H), 2.30 (dd, J = 8.4, 3.6 Hz, 2H), 1.95 - 1.81 (m, 2H), 1.57 (qd, J= 12.4, 4.0 Hz, 2H). Mass (m/z): 480.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4-isopropylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (575)

Step 1.4-isopropyl-1- (4-nitrophenyl) piperidine: (575-1). The title compound 575-1 (485 mg) was prepared as a yellow solid in 92% overall yield from 4-isopropylpiperidine (297 mg, 2.340 mmol) and 1-fluoro-4-nitrobenzene (300 mg, 2.128 mmol) according to the procedure of 526-1. Mass (m/z): 249.2 [ M + H ] ] ⁺ 。

Step 2.4- (4-isopropylpiperidin-1-yl) aniline: (575-2). The title compound 575-2 (405 mg) was prepared as a purple solid in 95.1% overall yield from 4-isopropyl-1- (4-nitrophenyl) piperidine (485 mg, 1.956 mmol) according to the procedure of 526-2. Mass (m/z): 219.3 [ M + H ]] ⁺ 。

Step 3. N- (4- ((4- (4-isopropylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (575): from 4- (4-isopropylpiperidin-1-yl) aniline (44 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) were prepared in 19.9% overall yieldThe title compound 575 (14.5 mg) as a brown solid. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.83 (s, 1H), 8.39 (t, J = 5.6 Hz, 1H), 7.88 (dd, J = 9.6, 1.6 Hz, 2H), 7.58 (s, 1H), 7.50 - 7.37 (m, 4H), 7.13 - 7.07 (m, 2H), 4.18 (d, J = 5.6 Hz, 2H), 4.15 - 4.08 (m, 2H), 3.40 (t, J = 8.4 Hz, 1H), 3.28 - 3.15 (m, 2H), 2.62 (d, J = 12.0 Hz, 2H), 2.34 - 2.26 (m, 2H), 1.77 - 1.67 (m, 2H), 1.48 - 1.37 (m, 1H), 0.87 (d, J= 6.8 Hz, 6H). Mass (m/z): 435.3 [ M + H ]] ⁺ 。

5-oxo-N- (4- ((4- (4-propylpiperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (576)

Step 1.1- (4-nitrophenyl) -4-propylpiperidine: (576-1). The title compound 576-1 (410 mg) was prepared as a yellow solid in 93% overall yield from 4-propylpiperidine (247 mg, 1.950 mmol) and 1-fluoro-4-nitrobenzene (250 mg, 1.773 mmol) according to the procedure of 526-1. Mass (m/z): 249.2 [ M + H ] ] ⁺ 。

Step 2.4- (4-propylpiperidin-1-yl) aniline: (576-2). The title compound 576-2 (350 mg) was prepared as a purple solid in 95.1% overall yield from 1- (4-nitrophenyl) -4-propylpiperidine (410 mg, 1.653 mmol) according to the procedure of 526-2. Mass (m/z): 219.3 [ M + H ]] ⁺ 。

Step 3.5-oxo-N- (4- ((4- (4-propylpiperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (576). From 4- (4-Propylpiperidin-1-yl) aniline (44 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 576 (27.9 mg) was prepared in a total yield of 38.3% as a brown solid. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.39 (s, 1H), 7.76 (s, 1H), 7.59 (s, 1H), 7.12 - 6.79 (m, 8H), 4.15 (s, 2H), 3.50 (s, 2H), 3.40 (t, J = 8.6 Hz, 1H), 3.26 - 3.17 (m, 2H), 2.29 (dd, J= 8.4, 4.8 Hz, 2H), 1.73 (s, 2H), 1.39 - 1.28 (m, 3H), 1.23 (t, J = 7.2 Hz, 4H), 0.89 (t, J= 7.2 Hz, 3H). Mass (m/z): 435.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4-butylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (577)

Step 1.4-butyl-1- (4-nitrophenyl) piperidine: (577-1). The title compound 577-1 (620 mg) was prepared as a yellow solid in 92.7% overall yield from 4-butylpiperidine hydrochloride (500 mg, 2.809 mmol) and 1-fluoro-4-nitrobenzene (360 mg, 2.554 mmol) according to the procedure of 526-1. Mass (m/z): 263.2 [ M + H ] ] ⁺ 。

Step 2.4-butyl-1- (4-nitrophenyl) piperidine: (577-2). The title compound 577-2 (505 mg) was prepared as a purple solid in 92% overall yield from 4-butyl-1- (4-nitrophenyl) piperidine (620 mg, 2.366 mmol) according to the procedure of 526-2. Mass (m/z): 233.3 [ M + H ]] ⁺ 。

Step 3. N- (4- ((4- (4-butylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (577). From 4- (4-butylpiperidin-1-yl) aniline (45 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 577 (33.9 mg) was prepared as a brown solid in a total yield of 44.5%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.46 (s, 1H), 7.83 (d, J = 27.0 Hz, 1H), 7.60 (s, 1H), 7.14 - 6.75 (m, 8H), 4.15 (s, 2H), 3.40 (d, J = 16.8 Hz, 1H), 3.26 - 3.16 (m, 2H), 2.29 (dd, J= 8.4, 5.5 Hz, 2H), 1.74 (s, 2H), 1.36-1.20 (m, 9H), 0.91-0.86 (m, 3H). Mass (m/z): 449.3 [ M + H ]] ⁺ 。

N- (4- ((6- (4-methylpiperidin-1-yl) -5- (trifluoromethyl) pyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (578)

From 6- (4-methylpiperidin-1-yl) -5- (trifluoromethyl) pyridin-3-amine (52 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 578 (20.5 mg) was prepared as an off-white solid in an overall yield of 25.7%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.44 (d, J = 4.4 Hz, 2H), 8.34 (d, J = 2.8 Hz, 1H), 7.62 - 7.55 (m, 2H), 7.19 - 7.14 (m, 2H), 7.07 - 7.00 (m, 2H), 4.21 (d, J = 5.6 Hz, 2H), 3.45 - 3.37 (m, 1H), 3.28 - 3.15 (m, 2H), 3.08 (d, J = 11.6 Hz, 2H), 2.85 - 2.74 (m, 2H), 2.30 (dd, J = 8.4, 3.2 Hz, 2H), 1.68 (d, J = 12.4 Hz, 2H), 1.47 (dt, J = 10.8, 5.2 Hz, 1H), 1.25 (qd, J = 12.4, 3.6 Hz, 2H), 0.95 (d, J= 6.4 Hz, 3H). Mass (m/z): 476.3 [ M + H ]] ⁺ 。

N- (4- ((2-fluoro-6- (4- (trifluoromethyl) piperidin-1-yl) pyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (579)

From 2-fluoro-6- (4- (trifluoromethyl) piperidin-1-yl) pyridin-3-amine (52 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) were prepared in 4.2% overall yield as off-white solidThing 579 (3.4 mg). ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.34 (t, J = 5.6 Hz, 1H), 7.59 - 7.50 (m, 2H), 7.46 (s, 1H), 7.05 - 6.98 (m, 2H), 6.73 (dd, J = 8.4, 1.2 Hz, 1H), 6.66 - 6.60 (m, 2H), 4.29 - 4.19 (m, 2H), 4.14 (d, J = 5.6 Hz, 2H), 3.39 (t, J = 9.2 Hz, 1H), 3.26 - 3.13 (m, 2H), 2.88 - 2.78 (m, 2H), 2.65 - 2.55 (m, 1H), 2.30 (td, J = 8.8, 4.4 Hz, 2H), 1.88 (d, J = 12.8 Hz, 2H), 1.43 (qd, J= 12.4, 4.0 Hz, 2H). Mass (m/z): 480.3 [ M + H ]] ⁺ 。

N- (4- ((4-methyl-6- (4- (trifluoromethyl) piperidin-1-yl) pyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (580)

From 4-methyl-6- (4- (trifluoromethyl) piperidin-1-yl) pyridin-3-amine (52 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 580 (10.5 mg) was prepared as a yellow solid in a total yield of 13.2%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.40 (t, J = 5.6 Hz, 1H), 7.73 (s, 1H), 7.59 (s, 2H), 7.27 (s, 1H), 7.10 - 7.02 (m, 2H), 6.75 - 6.63 (m, 2H), 4.24 (d, J = 13.6 Hz, 3H), 4.16 (dd, J = 5.6, 1.6 Hz, 2H), 3.27 - 3.15 (m, 2H), 3.09 (t, J = 12.8 Hz, 2H), 2.69 (dq, J = 16.4, 6.8, 5.2 Hz, 1H), 2.31 - 2.27 (m, 2H), 2.23 (s, 3H), 1.93 (dd, J = 13.6, 3.6 Hz, 2H), 1.53 (qd, J= 12.8, 4.0 Hz, 2H). Mass (m/z): 476.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4-ethoxy-4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (581)

Following the procedure of 525 from 4- (4-ethoxy-4- (trifluoromethyl) piperidin-1-yl) aniline (58 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 581 (6.1 mg) was prepared as a blue solid in 7.2% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.39 (s, 1H), 7.59 (s, 1H), 7.22 - 6.82 (m, 8H), 4.17 (s, 2H), 3.65 (d, J = 7.2 Hz, 3H), 3.50 (s, 1H), 3.40 (t, J = 8.8 Hz, 1H), 3.26 - 3.12 (m, 3H), 2.98 (s, 1H), 2.30 (dd, J = 8.4, 3.2 Hz, 2H), 2.15 -1.89 (m, 4H), 1.18 (t, J= 6.8 Hz, 3H). Mass (m/z): 505.3 [ M + H ]] ⁺ 。

(R) -2-oxo-N- (4- ((4- (4-propylpiperidin-1-yl) phenyl) amino) benzyl) imidazolidine-4-carboxamide (582)

The title compound 582 (35.2 mg) was prepared as a white solid in 52.3% overall yield from 4- (aminomethyl) -N- (4- (4-propylpiperidin-1-yl) phenyl) aniline (50 mg, 0.155 mmol), (R) -2-oxoimidazolidine-4-carboxylic acid (26 mg, 0.201 mmol), HATU (76 mg, 0.201 mmol), DIEA (26 mg, 0.201 mmol), and DMF (3 mL) according to the procedure of 523 in 52.3%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.40 (s, 1H), 7.81 (s, 1H), 7.23 - 6.76 (m, 8H), 6.60 (s, 1H), 6.33 (s, 1H), 4.24 - 4.08 (m, 3H), 3.54 (t, J = 9.2 Hz, 3H), 3.23 (dd, J = 8.8, 6.4 Hz, 1H), 1.73 (s, 3H), 1.37 - 1.18 (m, 7H), 0.89 (t, J= 7.2 Hz, 3H). Mass (m/z): 436.3 [ M + H ]] ⁺ 。

(S) -2,6 dioxo-N- (4- ((4- (4-propylpiperidin-1-yl) phenyl) amino) benzyl) hexahydropyrimidine-4-carboxamide (583)

The title compound 583 (2.0 mg) was prepared as a white solid in 2.8% overall yield from 4- (aminomethyl) -N- (4- (4-propylpiperidin-1-yl) phenyl) aniline (50 mg, 0.155 mmol), (S) -2,6-dioxohexahydropyrimidine-4-carboxylic acid (32 mg, 0.201 mmol), HATU (76 mg, 0.201 mmol), DIEA (26 mg, 0.201 mmol), and DMF (3 mL) according to the procedure of 523 in 2.8%. ¹ H NMR(400 MHz, DMSO-d6) δ 10.04 (d, J = 1.4 Hz, 1H), 8.47 (s, 1H), 7.63 (d, J = 3.2 Hz, 1H), 7.28 - 6.91 (m, 8H), 4.20 (s, 2H), 4.01 (dt, J = 7.2, 3.6 Hz, 1H), 3.51 (s, 3H), 2.86 (dd, J = 16.4, 7.2 Hz, 2H), 2.03 - 1.83 (m, 4H), 1.33 (dd, J = 9.2, 5.6 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H)。 ¹ H NMR (400 MHz, DMSO-d 6) δ 8.29 (t, J = 5.6 Hz, 1H), 7.76 (s, 1H), 7.41 (s, 1H), 6.97 (d, J = 8.4 Hz, 2H), 6.93-6.88 (m, 2H), 6.82 (dd, J = 8.8, 2.4 Hz, 4H), 4.15-4.00 (m, 2H), 3.54 (d, J = 12.0 Hz, 2H), 3.05 (tdd, J = 16.4, 9.5, 4.2 Hz, 2H), 2.65-2.50 (m, 4H), 2.36 (dtd, J = 12.4, 8.4, 3.6 Hz, 1H), 2.24-2.10 (m, 2H), 1.80 (td, J = 11.1, 8.4, 3.5 Hz, 3H), 1.53 (tdd, J = 25.2, 12.8, 4.8 Hz, 3H). Mass (m/z): 464.3 [ M + H ]] ⁺ 。

2,6 dioxo-N- (4- ((4- (4-propylpiperidin-1-yl) phenyl) amino) benzyl) piperidine-4-carboxamide (584)

The title compound 584 (18.5 mg) as a red solid was prepared according to the procedure of 523 from 4- (aminomethyl) -N- (4- (4-propylpiperidin-1-yl) phenyl) aniline (50 mg, 0.155 mmol), 2,6-dioxopiperidine-4-carboxylic acid (32 mg, 0.201 mmol), HATU (76 mg, 0.201 mmol), DIEA (26 mg, 0.201 mmol), and DMF (3 mL) in 25.8% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 10.69 (s, 1H), 8.64 (s, 2H), 7.73 (s, 2H), 7.12 (dd, J = 16.0, 9.2 Hz, 6H), 4.19 (d, J = 5.6 Hz, 2H), 3.03 (ddd, J = 7.2, 5.2, 2.0 Hz, 1H), 2.69 - 2.55 (m, 4H), 1.85 (s, 4H), 1.66 (s, 1H), 1.43 - 1.16 (m, 7H), 0.90 (t, J= 7.2 Hz, 3H). Mass (m/z): 463.3 [ M + H ]] ⁺ 。

N1- (4- ((4- (4-propylpiperidin-1-yl) phenyl) amino) benzyl) oxamide (585)

The title compound 585 (19.7 mg) was prepared as a white solid in 32.2% overall yield from 4- (aminomethyl) -N- (4- (4-propylpiperidin-1-yl) phenyl) aniline (50 mg, 0.155 mmol), 2-amino-2-oxoacetic acid (18 mg, 0.201 mmol), HATU (76 mg, 0.201 mmol), DIEA (26 mg, 0.201 mmol), and DMF (3 mL) according to the procedure of 523 in 32.2%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 9.17 (s, 1H), 8.57 (s, 1H), 8.09 (s, 1H), 7.84 - 7.80 (m, 1H), 7.70 (s, 1H), 7.13 (d, J = 36.4 Hz, 7H), 4.23 (d, J = 6.4 Hz, 2H), 3.59 - 3.48 (m, 3H), 1.95 - 1.56 (m, 6H), 1.33 (td, J = 8.8, 7.2, 5.2 Hz, 4H), 0.90 (t, J= 7.2 Hz, 3H). Mass (m/z): 395.3 [ M + H ]] ⁺ 。

1- (4- ((4- (4-propylpiperidin-1-yl) phenyl) amino) benzyl) urea (586)

From 4- (aminomethyl) -N- (4- (4-propylpiperidin-1-yl) phenyl) aniline (50 mg, 0.155 mmol), phenyl carbamate (28 mg, 0.201 mmol), et according to the procedure of 553 ₃ N (46 mg, 0.465 mmol) and DMSO (3 mL) the title compound 586 (12.9 mg) was prepared in 22.7% overall yield as a white solid. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 7.74 (s, 1H), 7.23 - 6.70 (m, 8H), 6.58 - 6.38 (m, 1H), 5.56 (s, 2H), 4.09 (s, 2H), 3.51 (s, 3H), 1.83 (s, 3H), 1.40 - 1.17 (m, 6H), 0.89 (t, J= 7.2 Hz, 3H). Mass (m/z): 367.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4,4-dimethylcyclohexyl) phenyl) amino) benzyl) acetamide (587)

From 4- (aminomethyl) -N- (4- (4,4-dimethylcyclohexyl) phenyl) aniline (50 mg, 0.162 mmol), phenyl carbamate (29 mg, 0.210 mmol), et according to the procedure of 553 ₃ N (48 mg, 0.486 mmol) and DMSO (3 mL) the title compound 587 (13.0 mg) was prepared as a yellow solid in 22.8% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.01 (d, J = 2.0 Hz, 1H), 7.09 (dd, J = 8.4, 1.6 Hz, 4H), 6.97 (dq, J = 9.2, 2.4 Hz, 4H), 6.49 - 6.32 (m, 1H), 5.52 (s, 2H), 4.06 (d, J = 6.0 Hz, 2H), 2.31 (tt, J = 10.0, 50 Hz, 1H), 1.60 - 1.54 (m, 3H), 1.43 (dd, J= 8.8, 6.0 Hz, 2H), 1.30 (td, J = 12.4, 5.6 Hz, 2H), 0.94 (d, J= 10.0 Hz, 6H). Mass (m/z): 352.3 [ M + H ]] ⁺ 。

N1- (4- ((4- (4,4-dimethylcyclohexyl) phenyl) amino) benzyl) oxamide (588)

The title compound 588 (6.9 mg) was prepared as a white solid in 11.2% total yield from 4- (aminomethyl) -N- (4- (4,4-dimethylcyclohexyl) phenyl) aniline (50 mg, 0.162 mmol), 2-amino-2-oxoacetic acid (19 mg, 0.210 mmol), HATU (80 mg, 0.210 mmol), DIEA (27 mg, 0.210 mmol), and DMF (3 mL) according to the procedure of 523 in 11.2%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 9.10 (t, J = 6.4 Hz, 1H), 8.07 (s, 1H), 7.99 (s, 1H), 7.79 (s, 1H), 7.10 (dd, J = 8.4, 6.0 Hz, 4H), 6.96 (dd, J = 8.4, 4.0 Hz, 4H), 4.20 (d, J = 6.4 Hz, 2H), 2.31 (tt, J = 10.4, 5.2 Hz, 1H), 1.61 - 1.54 (m, 3H), 1.44 (d, J = 12.8 Hz, 2H), 1.30 (td, J = 12.4, 5.2 Hz, 2H), 0.94 (d, J= 10.0 Hz, 6H). Mass (m/z): 380.3 [ M + H ]] ⁺ 。

N- (4- ((4- (3,5-dimethylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (589)

From 4- (3,5-dimethylpiperidin-1-yl) aniline (41 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 589 (6.8 mg) was prepared as a white solid in a total yield of 9.6%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.45 (d, J = 7.2 Hz, 1H), 7.60 (s, 1H), 7.47 (s, 1H), 7.12 (d, J = 33.2 Hz, 5H), 4.21 (s, 2H), 3.42 (t, J= 8.8 Hz, 3H), 3.30-3.13 (m, 3H), 3.02 (s, 2H), 2.36-2.27 (m, 2H), 2.13-1.96 (m, 2H), 1.79 (s, 1H), 0.93 (s, 6H). Mass (m/z): 421.3 [ M + H ]] ⁺ 。

N- (4- ((6- (4,4-dimethylpiperidin-1-yl) -2-methylpyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (590)

From 6- (4,4-dimethylpiperidin-1-yl) -2-methylpyridin-3-amine (44 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 590 (4.5 mg) was prepared as a blue solid in 6.2% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.35 (t, J = 5.6 Hz, 1H), 7.59 (s, 1H), 7.41 (d, J = 35.2 Hz, 2H), 7.01 (d, J = 8.0 Hz, 2H), 6.92 - 6.81 (m, 1H), 6.55 (d, J = 8.0 Hz, 2H), 4.13 (d, J = 5.6 Hz, 2H), 3.52 (s, 5H), 3.26 - 3.13 (m, 3H), 2.28 (qd, J = 8.0, 7.6, 2.4 Hz, 5H), 1.41 (t, J= 5.6 Hz, 4H), 0.98 (s, 6H). Mass (m/z): 436.3 [ M + H ]] ⁺ 。

(R) -N- (4- ((4-methyl-6- (4- (trifluoromethyl) piperidin-1-yl) pyridin-3-yl) amino) benzyl) -2-oxoimidazolidine-4-carboxamide (591)

The title compound 591 (7.0 mg) was prepared as a white solid in total yield from N- (4- (aminomethyl) phenyl) -4-methyl-6- (4- (trifluoromethyl) piperidin-1-yl) pyridin-3-amine (50 mg, 0.137 mmol), (R) -2-oxoimidazolidine-4-carboxylic acid (23 mg, 0.179 mmol), HATU (68 mg, 0.179 mmol), DIEA (23 mg, 0.179 mmol), and DMF (3 mL) according to the procedure of 523 in 10.7%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.25 (t, J = 5.6 Hz, 1H), 7.87 (s, 1H), 7.26 (s, 1H), 7.04 - 6.97 (m, 2H), 6.81 (s, 1H), 6.54 (s, 1H), 6.52 - 6.47 (m, 2H), 6.31 (s, 1H), 4.35 (d, J = 13.2 Hz, 2H), 4.13 (d, J = 5.6 Hz, 2H), 4.08 (ddd, J = 9.6, 6.0, 1.6 Hz, 1H), 3.21 (ddd, J = 8.8, 6.0, 1.2 Hz, 1H), 2.79 (t, J = 12.0 Hz, 2H), 2.57 (dt, J = 7.6, 3.6 Hz, 1H), 2.08 (s, 3H), 1.86 (d, J = 12.8 Hz, 2H), 1.43 (qd, J = 12.4, 4.0 Hz, 2H), 1.28 (dd, J= 12.0, 6.8 Hz, 1H). Mass (m/z): 477.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4-hydroxy-4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (592)

From 1- (4-aminophenyl) -4- (trifluoromethyl) piperidin-4-ol (53 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg,0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 592 (15.3 mg) was prepared as a blue solid in a total yield of 19.1%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.41 (t, J = 5.6 Hz, 1H), 7.60 (s, 1H), 7.09 (s, 8H), 4.18 (s, 2H), 3.40 (d, J = 8.8 Hz, 2H), 3.28 - 3.13 (m, 4H), 2.30 (dd, J = 8.4, 2.4 Hz, 2H), 2.00 (q, J= 7.2, 6.4 Hz, 2H), 1.87 (s, 2H). Mass (m/z): 477.3 [ M + H ]] ⁺ 。

(R) -N- (4- ((6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-yl) amino) benzyl) -2-oxoimidazolidine-4-carboxamide (593)

The title compound 593 (19.8 mg) was prepared as a white solid in 29.7% overall yield from N- (4- (aminomethyl) phenyl) -6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-amine (50 mg, 0.148 mmol), (R) -2-oxoimidazolidine-4-carboxylic acid (25 mg, 0.192 mmol), HATU (73 mg, 0.192 mmol), DIEA (25 mg, 0.192 mmol), and DMF (3 mL) according to the procedure of 523 in 29.7%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.23 (t, J = 6.0 Hz, 1H), 7.33 - 7.18 (m, 2H), 7.01 (d, J = 8.0 Hz, 2H), 6.51 (d, J = 10.0 Hz, 3H), 6.31 (s, 1H), 4.27 (d, J = 12.8 Hz, 2H), 4.13 (d, J = 5.6 Hz, 2H), 4.08 (dd, J = 9.6, 6.0 Hz, 1H), 3.53 (t, J = 9.2 Hz, 1H), 3.20 (dd, J = 8.8, 6.0 Hz, 1H), 2.21 (s, 2H), 1.71 (d, J = 11.2 Hz, 2H), 1.46 - 1.40 (m, 1H), 1.31 - 1.21 (m, 5H), 0.88 (d, J= 6.8 Hz, 6H). Mass (m/z): 451.3 [ M + H ]] ⁺ 。

N- (4- ((6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-yl) amino) benzyl) -2,6-dioxopiperidine-4-carboxamide (594)

The title compound 594 (4.9 mg) was prepared as a yellow solid in 6.9% total yield from N- (4- (aminomethyl) phenyl) -6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-amine (50 mg, 0.148 mmol), 2,6-dioxopiperidine-4-carboxylic acid (30 mg, 0.192 mmol), HATU (73 mg, 0.192 mmol), DIEA (25 mg, 0.192 mmol) and DMF (3 mL) according to the procedure of 523 in 6.9%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 10.68 (s, 1H), 8.42 (t, J = 5.6 Hz, 1H), 7.50 (d, J = 40.8 Hz, 2H), 7.01 (d, J = 8.0 Hz, 2H), 6.58 (d, J = 8.0 Hz, 2H), 4.23 (d, J = 13.2 Hz, 2H), 4.12 (d, J = 5.6 Hz, 2H), 3.01 - 2.84 (m, 3H), 2.68 - 2.53 (m, 4H), 2.30 (s, 3H), 1.75 (d, J = 12.4 Hz, 2H), 1.45 (dq, J = 13.2, 6.4 Hz, 1H), 1.33 - 1.17 (m, 3H), 0.88 (d, J= 6.8 Hz, 6H). Mass (m/z): 478.3 [ M + H ]] ⁺ 。

N1- (4- ((6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-yl) amino) benzyl) malonamide (595)

The title compound 595 (10.2 mg) was prepared as a yellow solid in 16.3% overall yield from N- (4- (aminomethyl) phenyl) -6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-amine (50 mg, 0.148 mmol), 3-amino-3-oxopropanoic acid (20 mg, 0.192 mmol), HATU (73 mg, 0.192 mmol), DIEA (25 mg, 0.192 mmol), and DMF (3 mL) according to the procedure of 523 in 16.3%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.34 (t, J = 5.6 Hz, 1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.06 (d, J = 8.4 Hz, 4H), 6.60 (d, J = 8.0 Hz, 2H), 4.22 (d, J = 13.2 Hz, 2H), 4.15 (d, J = 5.6 Hz, 2H), 2.92 (s, 2H), 2.32 (s, 3H), 1.76 (d, J = 12.4 Hz, 2H), 1.46 (dt, J = 13.2, 6.5 Hz, 1H), 1.34 - 1.17 (m, 5H), 0.88 (d, J= 6.8 Hz, 6H). Mass (m/z): 424.3 [ M + H ]] ⁺ 。

N1- (4- ((6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-yl) amino) benzyl) glutaramide (596)

The title compound 596 (13.8 mg) was prepared as a yellow solid in 20.7% overall yield from N- (4- (aminomethyl) phenyl) -6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-amine (50 mg, 0.148 mmol), 5-amino-5-oxopentanoic acid (25 mg, 0.192 mmol), HATU (73 mg, 0.192 mmol), DIEA (25 mg, 0.192 mmol), and DMF (3 mL) according to the procedure of 523 in 20.7%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.19 (t, J = 6.0 Hz, 1H), 7.74 - 7.41 (m, 2H), 7.26 (s, 1H), 7.04 (d, J = 8.4 Hz, 3H), 6.73 (s, 1H), 6.61 (d, J = 8.0 Hz, 2H), 4.21 (d, J = 13.2 Hz, 2H), 4.12 (d, J = 5.6 Hz, 2H), 2.98 (q, J = 12.0, 11.2 Hz, 2H), 2.34 (s, 3H), 2.07 (dt, J = 24.4, 7.6 Hz, 4H), 1.72 (ddd, J = 22.4, 15.6, 9.6 Hz, 4H), 1.46 (dq, J = 13.2, 6.4 Hz, 1H), 1.37 - 1.16 (m, 4H), 0.89 (d, J= 6.8 Hz, 6H). Mass (m/z): 452.3 [ M + H ]] ⁺ 。

N1- (4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) benzyl) malonamide (597)

The title compound 597 (9.7 mg) was prepared as a white solid in 20.7% overall yield from N- (4- (aminomethyl) phenyl) -2- (4-isopropylpiperidin-1-yl) pyrimidin-5-amine (50 mg, 0.154 mmol), 3-amino-3-oxopropanoic acid (21 mg, 0.200 mmol), HATU (76 mg, 0.200 mmol), DIEA (26 mg, 0.200 mmol), and DMF (3 mL) according to the procedure of 523 in 20.7%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.58 - 8.29 (m, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 7.50 - 7.45 (m, 2H), 7.22 - 7.19 (m, 1H), 7.05 - 6.97 (m, 3H), 6.69 - 6.66 (m, 1H), 4.60 (d, J = 13.2 Hz, 2H), 4.24 - 4.06 (m, 3H), 3.01 (d, J = 14.0 Hz, 3H), 2.75 - 2.69 (m, 1H), 1.66 (d, J = 12.4 Hz, 2H), 1.43 - 1.35 (m, 1H), 1.08 (td, J = 12.0, 4.0 Hz, 2H), 0.83 (d, J= 6.8 Hz, 6H). Mass (m/z): 411.3 [ M + H ]] ⁺ 。

(R) -N- (4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) benzyl) -2-oxoimidazolidine-4-carboxamide (598)

The title compound 598 (21.5 mg) was prepared as a yellow solid in 31.9% total yield from N- (4- (aminomethyl) phenyl) -2- (4-isopropylpiperidin-1-yl) pyrimidin-5-amine (50 mg, 0.154 mmol), (R) -2-oxoimidazolidine-4-carboxylic acid (26 mg, 0.200 mmol), HATU (76 mg, 0.200 mmol), DIEA (26 mg, 0.200 mmol), and DMF (3 mL) according to the procedure of 523. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.18 (s, 1H), 7.50 - 7.45 (m, 1H), 7.06 - 6.93 (m, 2H), 6.70 - 6.65 (m, 1H), 6.57 (d, J = 17.6 Hz, 1H), 6.30 (d, J = 12.4 Hz, 1H), 4.60 (d, J = 13.2 Hz, 2H), 4.21 (d, J = 6.0 Hz, 1H), 4.14 - 4.01 (m, 3H), 3.52 - 3.48 (m, 1H), 3.17 (ddt, J = 7.4, 6.0, 3.2 Hz, 1H), 2.71 (td, J = 12.8, 2.4 Hz, 2H), 1.65 (d, J = 12.4 Hz, 2H), 1.42 - 1.36 (m, 1H), 1.12 - 1.02 (m, 2H), 0.83 (d, J= 6.8 Hz, 6H). Mass (m/z): 438.3 [ M + H ]] ⁺ 。

N- (4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) benzyl) -1-methylpyrrolidine-3-carboxamide (599)

The title compound 599 (16.3 mg) was prepared as a yellow solid in 24.3% total yield from N- (4- (aminomethyl) phenyl) -2- (4-isopropylpiperidin-1-yl) pyrimidin-5-amine (50 mg, 0.154 mmol), 1-methylpyrrolidine-3-carboxylic acid (26 mg, 0.200 mmol), HATU (76 mg, 0.200 mmol), DIEA (26 mg, 0.200 mmol), and DMF (3 mL) according to the procedure of 523. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.76 - 8.48 (m, 2H), 8.18 (s, 2H), 7.51 - 7.43 (m, 2H), 7.19 - 7.15 (m, 2H), 7.02 - 6.96 (m, 2H), 6.71 - 6.63 (m, 2H), 4.66 - 4.58 (m, 2H), 4.20 (d, J = 6.0 Hz, 2H), 4.10 (d, J = 6.0 Hz, 2H), 3.10 (d, J = 18.4 Hz, 4H), 2.99 (d, J = 8.0 Hz, 2H), 2.90 (s, 2H), 2.71 (td, J = 12.8, 2.4 Hz, 2H), 2.59 (d, J = 7.6 Hz, 6H), 2.09 (dq, J= 13.2, 7.2, 6.4 Hz, 2H), 2.01-1.91 (m, 3H), 1.69-1.63 (m, 2H), 1.42-1.35 (m, 1H), 1.28-1.21 (m, 2H), 1.12-1.01 (m, 3H), 0.84 (s, 3H), 0.82 (s, 3H). Mass (m/z): 437.3 [ M + H ] ] ⁺ 。

N- (4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) benzyl) -2,6-dioxopiperidine-4-carboxamide (600)

The title compound 600 (2.7 mg) was prepared as a yellow solid in 3.8% total yield from N- (4- (aminomethyl) phenyl) -2- (4-isopropylpiperidin-1-yl) pyrimidin-5-amine (50 mg, 0.154 mmol), 2,6-dioxopiperidine-4-carboxylic acid (31 mg, 0.200 mmol), HATU (76 mg, 0.200 mmol), DIEA (26 mg, 0.200 mmol), and DMF (3 mL) according to the procedure of 523 in 3.8%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 10.68 (s, 1H), 8.42 (t, J = 6.0 Hz, 1H), 8.21 (s, 2H), 7.05 - 6.98 (m, 2H), 6.75 - 6.67 (m, 2H), 4.64 (d, J = 12.8 Hz, 2H), 4.12 (d, J = 5.6 Hz, 2H), 2.96 (dt, J = 7.2, 5.2 Hz, 1H), 2.81 - 2.71 (m, 2H), 2.59 (dd, J = 12.8, 6.0 Hz, 3H), 1.99 (p, J = 7.2, 6.4 Hz, 2H), 1.69 (d, J = 12.8 Hz, 2H), 1.43 (dq, J = 13.2, 6.6 Hz, 2H), 1.27 (d, J = 11.6 Hz, 2H), 1.10 (qd, J = 12.0, 4.0 Hz, 3H), 0.87 (d, J= 6.8 Hz, 6H). Mass (m/z): 465.3 [ M + H ]] ⁺ 。

N- (4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) benzyl) -2,6-dioxopiperidine-4-carboxamide (601)

The title compound 601 (3.2 mg) was prepared as a yellow solid in 4.5% total yield from N- (4- (aminomethyl) phenyl) -2- (4-isopropylpiperidin-1-yl) pyrimidin-5-amine (50 mg, 0.154 mmol), 2,6-dioxopiperidine-4-carboxylic acid (31 mg, 0.200 mmol), HATU (76 mg, 0.200 mmol), DIEA (26 mg, 0.200 mmol), and DMF (3 mL) according to the procedure of 523 in 4.5%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.17 (s, 2H), 7.38 (s, 1H), 7.08 - 6.96 (m, 2H), 6.92 - 6.83 (m, 1H), 6.68 - 6.58 (m, 2H), 4.60 (dt, J = 13.2, 2.4 Hz, 2H), 4.43 - 4.29 (m, 2H), 3.05 - 2.96 (m, 1H), 2.75 - 2.66 (m, 2H), 2.53 - 2.49 (m, 2H), 2.39 (dd, J = 17.6, 5.1 Hz, 1H), 1.96 (q, J = 6.8, 6.4 Hz, 1H), 1.70 - 1.62 (m, 2H), 1.43 - 1.35 (m, 1H), 1.25 (d, J = 6.8 Hz, 1H), 1.06 (qd, J = 12.8, 12.4, 4.4 Hz, 2H), 0.83 (d, J= 6.8 Hz, 6H). Mass (m/z): 465.3 [ M + H ]] ⁺ 。

N, N-dimethyl-3- (4- ((4- ((2- (4-methylpiperazin-1-yl) acetylamino) methyl) phenyl) amino) phenyl) propanamide (602)

The title compound 602 (16.1 mg) was prepared as a yellow solid in 21.9% overall yield from 3- (4- ((4- (aminomethyl) phenyl) amino) phenyl) -N, N-dimethylpropanamide (50 mg, 0.168 mmol), 2- (4-methylpiperazin-1-yl) acetic acid (31 mg, 0.218 mmol), HATU (83 mg, 0.218 mmol), DIEA (28 mg, 0.218 mmol), and DMF (3 mL) according to the procedure of 523. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.18 (t, J = 6.0 Hz, 1H), 8.09 - 8.04 (m, 1H), 7.08 - 7.01 (m, 4H), 6.93 (dd, J = 8.8, 2.7 Hz, 4H), 4.15 (d, J = 6.0 Hz, 2H), 2.96 (s, 2H), 2.89 (s, 3H), 2.77 (s, 3H), 2.65 (q, J= 5.6, 4.0 Hz, 4H), 2.56-2.49 (m, 4H), 2.33 (s, 3H). Mass (m/z): 438.3 [ M + H ]] ⁺ 。

5-oxo-N- (4- ((2- (4-propylpiperidin-1-yl) pyrimidin-5-yl) amino) benzyl) pyrrolidine-3-carboxamide (603)

From 2- (4-Propylpiperidin-1-yl) pyrimidin-5-amine (44 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 603 (28.7 mg) was prepared in 39.2% total yield as a white solid. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.38 (t, J = 6.0 Hz, 1H), 8.17 (s, 2H), 7.63 (s, 1H), 7.55 (s, 1H), 7.01 - 6.96 (m, 2H), 6.71 - 6.64 (m, 2H), 4.59 - 4.47 (m, 2H), 4.09 (d, J = 5.6 Hz, 2H), 3.39 - 3.32 (m, 1H), 3.23 - 3.13 (m, 2H), 2.77 (td, J = 12.8, 2.8 Hz, 2H), 2.28 - 2.22 (m, 2H), 1.66 (dd, J = 13.6, 3.2 Hz, 2H), 1.46 (ddp, J = 11.2, 6.8, 3.6 Hz, 1H), 1.33 - 1.23 (m, 2H), 1.22 - 1.13 (m, 2H), 1.06 - 0.92 (m, 2H), 0.84 (t, J= 7.2 Hz, 3H). Mass (m/z): 437.3 [ M + H ]] ⁺ 。

N- (4- ((2- (3,3-dimethylazetidin-1-yl) pyrimidin-5-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (604)

From 2- (3,3-dimethylcyclobutyl) pyrimidin-5-amine (36 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 604 (21.4 mg) was prepared as a yellow solid in a total yield of 32.4%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.42 (d, J = 6.2 Hz, 1H), 8.17 (s, 2H), 7.71 (s, 1H), 7.56 (s, 1H), 7.02 - 6.96 (m, 2H), 6.71 - 6.66 (m, 2H), 4.09 (d, J= 5.8 Hz, 2H), 3.66 (s, 4H), 3.22-3.12 (m, 2H), 2.50-2.47 (m, 1H), 2.28-2.20 (m, 2H), 1.24 (s, 6H). Mass (m/z): 395.3 [ M + H ] ] ⁺ 。

N- (4- ((2- (4,4-dimethylpiperidin-1-yl) pyrimidin-5-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (605)

From 2- (4,4-dimethylpiperidin-1-yl) pyrimidin-5-amine (42 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 605 (2.1 mg) was prepared as a yellow solid in a total yield of 2.9%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.32 (t, J = 6.0 Hz, 1H), 8.18 (s, 2H), 7.54 (s, 1H), 7.02 - 6.97 (m, 2H), 6.71 - 6.64 (m, 2H), 4.10 (d, J = 5.6 Hz, 2H), 3.68 - 3.64 (m, 4H), 3.35 (t, J = 9.2 Hz, 2H), 3.22 - 3.06 (m, 3H), 2.26 (td, J = 9.2, 3.6 Hz, 3H), 1.95 (p, J= 7.2, 6.4 Hz, 1H), 1.32-1.27 (m, 4H), 0.94 (s, 6H). Mass (m/z): 423.3 [ M + H ]] ⁺ 。

N- (4- ((2- (4-methylpiperidin-1-yl) pyrimidin-5-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (606)

From 2- (4-methylpiperidin-1-yl) pyrimidin-5-amine (39 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 606 (11.9 mg) was prepared as a yellow solid in a total yield of 17.4%. ¹ H NMR (400 MHz, ethanol-d ₆ ) δ 8.35 (t, J = 6.0 Hz, 1H), 8.21 (s, 2H), 7.57 (s, 1H), 7.05 - 6.99 (m, 2H), 6.74 - 6.69 (m, 2H), 4.55 (dq, J = 12.4, 2.6, 2.4 Hz, 2H), 4.13 (d, J = 5.6 Hz, 4H), 3.44 - 3.33 (m, 1H), 3.25 - 3.11 (m, 2H), 2.89 - 2.77 (m, 2H), 2.28 (dd, J = 8.4, 3.6 Hz, 2H), 1.63 (ddt, J = 14.4, 10.4, 3.9 Hz, 3H), 1.11 - 1.00 (m, 2H), 0.92 (d, J= 6.4 Hz, 3H). Mass (m/z): 409.3 [ M + H ]] ⁺ 。

1- (4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) benzyl) urea (607)

From N- (4- (aminomethyl) phenyl) -2- (4-isopropylpiperidin-1-yl) pyrimidin-5-amine (50 mg, 0.154 mmol) phenyl carbamate (27 mg, 0.200 mmol), et according to the procedure of 553 ₃ N (46 mg, 0.462 mmol) and DMSO (3 mL) the title compound 607 (15.9 mg) was prepared as a yellow solid in 28.1% overall yield. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.21 (s, 2H), 7.61 (s, 1H), 7.06 - 7.00 (m, 2H), 6.75 - 6.69 (m, 2H), 6.28 (t, J = 6.0 Hz, 1H), 5.46 (s, 2H), 4.64 (dt, J = 12.8, 2.5 Hz, 2H), 4.03 (d, J = 6.0 Hz, 2H), 2.75 (td, J = 12.8, 2.4 Hz, 2H), 1.74 - 1.64 (m, 2H), 1.44 (dt, J = 13.2, 6.7 Hz, 1H), 1.28 (dq, J = 5.6, 3.2 Hz, 1H), 1.12 (td, J = 12.4, 4.4 Hz, 2H), 0.87 (d, J= 6.8 Hz, 6H). Mass (m/z): 369.3 [ M + H ]] ⁺ 。

N1- (4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) benzyl) oxamide (608)

According to 523The procedure prepared the title compound 608 (31.5 mg) as a yellow solid in 57.6% total yield from N- (4- (aminomethyl) phenyl) -2- (4-isopropylpiperidin-1-yl) pyrimidin-5-amine (50 mg, 0.154 mmol), 2-amino-2-oxoacetic acid (18 mg, 0.200 mmol), HATU (76 mg, 0.200 mmol), DIEA (26 mg, 0.200 mmol), and DMF (3 mL) in 57.6%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 9.06 (t, J = 6.4 Hz, 1H), 8.22 (s, 2H), 8.05 (s, 1H), 7.78 (d, J = 16.0 Hz, 2H), 7.09 - 7.02 (m, 2H), 6.75 - 6.68 (m, 2H), 4.69 - 4.60 (m, 2H), 4.17 (d, J = 6.4 Hz, 2H), 2.75 (td, J = 12.8, 2.4 Hz, 2H), 1.74 - 1.64 (m, 2H), 1.46 - 1.39 (m, 1H), 1.10 (qd, J = 12.4, 4.0 Hz, 3H), 0.87 (d, J= 6.8 Hz, 6H). Mass (m/z): 397.3 [ M + H ]] ⁺ 。

(S) -N- (4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) benzyl) -2,6 dioxohexahydropyrimidine-4-carboxamide (609)

The title compound 609 (20.9 mg) was prepared as a yellow solid in 29.2% total yield from N- (4- (aminomethyl) phenyl) -2- (4-isopropylpiperidin-1-yl) pyrimidin-5-amine (50 mg, 0.154 mmol), (S) -2,6-dioxohexahydropyrimidine-4-carboxylic acid (32 mg, 0.200 mmol), HATU (76 mg, 0.200 mmol), DIEA (26 mg, 0.200 mmol), and DMF (3 mL) according to the procedure of 523. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 10.00 (s, 1H), 8.45 (t, J = 5.6 Hz, 1H), 8.22 (s, 2H), 7.66 (s, 1H), 7.62 (d, J = 3.6 Hz, 1H), 7.06 - 6.98 (m, 2H), 6.75 - 6.68 (m, 2H), 4.64 (d, J = 13.2 Hz, 2H), 4.13 (d, J = 5.6 Hz, 2H), 4.00 (dt, J = 7.2, 3.6 Hz, 1H), 2.83 (dd, J = 16.8, 7.2 Hz, 1H), 2.75 (td, J = 12.8, 2.4 Hz, 2H), 1.69 (d, J = 12.8 Hz, 2H), 1.42 (dt, J = 13.2, 6.6 Hz, 1H), 1.30 - 1.27 (m, 1H), 1.11 (qd, J = 12.4, 4.2 Hz, 3H), 0.87 (d, J= 6.8 Hz, 6H). Mass (m/z): 466.3 [ M + H ]] ⁺ 。

(R) -N- (4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) benzyl) pyrrolidine-2-carboxamide (610)

The title compound 610 (24.3 mg) was prepared as a yellow solid in 37.4% total yield from N- (4- (aminomethyl) phenyl) -2- (4-isopropylpiperidin-1-yl) pyrimidin-5-amine (50 mg, 0.154 mmol), D-proline (23 mg, 0.200 mmol), HATU (76 mg, 0.200 mmol), DIEA (26 mg, 0.200 mmol), and DMF (3 mL) according to the procedure of 523. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.33 (s, 1H), 8.23 (d, J = 6.8 Hz, 2H), 7.92 (s, 1H), 7.17 - 7.10 (m, 2H), 6.75 (dd, J = 21.2, 8.4 Hz, 2H), 4.64 (d, J = 12.8 Hz, 2H), 4.19 (s, 2H), 2.80 - 2.72 (m, 3H), 2.69 (s, 2H), 1.69 (d, J= 12.4 Hz, 2H), 1.43 (td, J = 12.8, 6.0 Hz, 2H), 1.29 (s, 1H), 1.11 (tt, J = 12.4, 6.0 Hz, 3H), 0.87 (d, J= 6.8 Hz, 6H). Mass (m/z): 423.3 [ M + H ]] ⁺ 。

(S) -N- (4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) benzyl) -6-oxopiperidine-2-carboxamide (611)

The title compound 611 (40.3 mg) was prepared as a yellow solid in 58.2% overall yield from N- (4- (aminomethyl) phenyl) -2- (4-isopropylpiperidin-1-yl) pyrimidin-5-amine (50 mg, 0.154 mmol), (S) -6-oxopiperidine-2-carboxylic acid (29 mg, 0.200 mmol), HATU (76 mg, 0.200 mmol), DIEA (26 mg, 0.200 mmol), and DMF (3 mL) according to the procedure of 523. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.36 (t, J = 6.0 Hz, 1H), 8.22 (s, 2H), 7.68 (s, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.08 - 7.01 (m, 2H), 6.75 - 6.68 (m, 2H), 4.64 (d, J = 13.2 Hz, 2H), 4.15 (qd, J = 14.4, 5.6 Hz, 2H), 3.89 (td, J = 5.6, 2.8 Hz, 1H), 2.75 (td, J = 11.6, 10.4, 2.8 Hz, 2H), 2.12 (t, J = 6.4 Hz, 2H), 1.85 (ddd, J = 13.2, 6.0, 3.6 Hz, 1H), 1.75 - 1.64 (m, 4H), 1.60 (td, J = 6.8, 6.0, 3.6 Hz, 1H), 1.42 (dt, J = 11.6, 6.0 Hz, 1H), 1.34 - 1.26 (m, 2H), 1.10 (qd, J = 12.4, 4.0 Hz, 2H), 0.87 (d, J= 6.8 Hz, 6H). Mass (m/z): 451.3 [ M + H ]] ⁺ 。

N- (4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) phenethyl) -5-oxopyrrolidine-3-carboxamide (612)

Following the procedure of 525 from 2- (4-isopropylpiperidin-1-yl) pyrimidin-5-amine (42 mg, 0.193 mmol), N- (4-bromophenylethyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.161 mmol), pd ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (79 mg, 0.242 mmol) and 1,4-dioxane (5 mL) the title compound 612 (24.4 mg) was prepared as a yellow solid in a total yield of 33.7%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.21 (s, 2H), 8.07 (t, J = 5.6 Hz, 1H), 7.58 (s, 1H), 7.55 (s, 1H), 6.99 - 6.94 (m, 2H), 6.72 - 6.68 (m, 2H), 4.69 - 4.59 (m, 2H), 3.19 (h, J = 6.8 Hz, 3H), 3.14 - 3.08 (m, 1H), 2.75 (td, J = 13.2, 2.8 Hz, 2H), 2.57 (t, J = 7.6 Hz, 2H), 2.27 - 2.21 (m, 2H), 1.73 - 1.65 (m, 2H), 1.44 (dt, J = 13.2, 6.8 Hz, 1H), 1.12 (td, J = 12.4, 4.0 Hz, 2H), 0.87 (d, J= 6.8 Hz, 6H). Mass (m/z): 451.3 [ M + H ]] ⁺ 。

N- (4- ((3,5-difluoro-4- (4-isopropylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (613)

From 3,5-difluoro-4- (4-isopropylpiperidin-1-yl) aniline (51 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxo according to the procedure of 525Pyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 613 (7.0 mg) was prepared as a white solid in a total yield of 8.9%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.39 (t, J = 5.6 Hz, 1H), 8.34 (s, 1H), 7.55 (s, 1H), 7.15 - 7.10 (m, 2H), 7.03 - 6.98 (m, 2H), 6.56 - 6.49 (m, 2H), 4.17 (d, J = 5.6 Hz, 2H), 3.40 - 3.33 (m, 1H), 3.24 - 3.13 (m, 2H), 3.01 - 2.86 (m, 4H), 2.27 (dd, J = 8.4, 3.2 Hz, 2H), 1.60 (d, J = 12.4 Hz, 2H), 1.41 (dt, J = 13.2, 6.4 Hz, 1H), 1.30 - 1.20 (m, 3H), 1.12 - 0.99 (m, 1H), 0.84 (d, J= 6.8 Hz, 6H). Mass (m/z): 471.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4,4-dimethylpiperidin-1-yl) -3,5-difluorophenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (614)

From 3,4- (4,4-dimethylpiperidin-1-yl) -3,5-difluoroaniline (48 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 614 (6.8 mg) was prepared as a white solid in an overall yield of 8.9%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.38 (t, J = 5.6 Hz, 1H), 8.33 (s, 1H), 7.54 (s, 1H), 7.13 (d, J = 8.4 Hz, 2H), 7.03 - 6.98 (m, 2H), 6.57 - 6.48 (m, 2H), 4.17 (d, J = 5.8 Hz, 2H), 3.37 (d, J = 17.6 Hz, 1H), 3.25 - 3.11 (m, 2H), 2.91 (t, J = 5.6 Hz, 4H), 2.27 (dd, J= 8.4, 3.6 Hz, 2H), 1.41-1.34 (m, 4H), 0.92 (s, 6H). Mass (m/z): 457.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4-ethylpiperidin-1-yl) -3,5-difluorophenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (615)

From 4- (4-ethylpiperidin-1-yl) -3,5-difluoroaniline (48 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 625 (3.2 mg) was prepared as a white solid in a total yield of 4.2%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.39 (t, J = 6.0 Hz, 1H), 8.33 (s, 1H), 7.55 (s, 1H), 7.15 - 7.09 (m, 2H), 7.04 - 6.97 (m, 2H), 6.57 - 6.48 (m, 2H), 4.17 (d, J = 6.0 Hz, 2H), 3.42 - 3.35 (m, 1H), 3.24 - 3.12 (m, 2H), 2.92 (d, J = 14.0 Hz, 4H), 2.52 - 2.48 (m, 2H), 2.27 (dd, J = 8.4, 3.2 Hz, 2H), 1.64 (d, J = 8.4 Hz, 2H), 1.23 (d, J = 7.2 Hz, 3H), 0.84 (t, J= 7.2 Hz, 3H). Mass (m/z): 457.3 [ M + H ]] ⁺ 。

N- (4- ((6- (4- (ethoxymethyl) piperidin-1-yl) -2-methylpyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (616)

From 6- (4- (ethoxymethyl) piperidin-1-yl) -2-methylpyridin-3-amine (50 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 616 (6.7 mg) was prepared as a white solid in an overall yield of 8.6%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.31 (t, J = 5.6 Hz, 1H), 7.57 (s, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.19 (s, 1H), 7.01 - 6.95 (m, 2H), 6.63 (d, J = 8.8 Hz, 1H), 6.53 - 6.47 (m, 2H), 4.23 (d, J = 12.8 Hz, 2H), 4.11 (d, J = 5.6 Hz, 2H), 3.46 - 3.37 (m, 3H), 3.28 - 3.12 (m, 4H), 2.72 (dd, J = 12.8, 2.4 Hz, 2H), 2.28 (dd, J = 8.4, 5.2 Hz, 2H), 2.19 (s, 3H), 1.72 (dd, J = 12.0, 3.2 Hz, 3H), 1.22 - 1.13 (m, 2H), 1.11 (t, J= 7.2 Hz, 3H). Mass (m/z): 466.3 [ M + H ] ] ⁺ 。

N- (4- ((5- (4-isopropylpiperidin-1-yl) pyrazin-2-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (617)

From 5- (4-isopropylpiperidin-1-yl) pyrazin-2-amine (44 mg, 0.202 mmol), N- (4-bromobenzyl) -5-oxopyrrolidine-3-carboxamide (50 mg, 0.168 mmol), pd according to the procedure of 525 ₂ (dba) ₃ (2 mg, 0.002 mmol), x-phos (6 mg, 0.01 mmol) and Cs ₂ CO ₃ (83 mg, 0.252 mmol) and 1,4-dioxane (5 mL) the title compound 617 (9.2 mg) was prepared as a yellow solid in a total yield of 12.6%. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.83 (s, 1H), 8.39 (t, J = 5.6 Hz, 1H), 7.88 (dd, J = 9.6, 1.6 Hz, 2H), 7.58 (s, 1H), 7.48 - 7.41 (m, 2H), 7.13 - 7.07 (m, 2H), 4.18 (d, J = 5.6 Hz, 2H), 4.15 - 4.08 (m, 2H), 3.40 (t, J = 8.4 Hz, 1H), 3.28 - 3.15 (m, 2H), 2.62 (d, J = 12.0 Hz, 2H), 2.34 - 2.26 (m, 2H), 1.77 - 1.67 (m, 2H), 1.48 - 1.37 (m, 1H), 0.87 (d, J= 6.8 Hz, 6H). Mass (m/z): 437.3 [ M + H ]] ⁺ 。

5-oxo-N- (4- ((4- (tert-amyl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (618)

Step 1. (4- ((4- (tert-amyl) phenyl) amino) benzyl) carbamic acid tert-butyl ester(618-2): to a solution of 4- (tert-amyl) aniline (600 mg, 3.68 mmol) and tert-butyl (4-bromobenzyl) carbamate (1.05 g, 3.68 mmol) in dioxane (15 mL) was added Pd under nitrogen atmosphere ₂ (dba) ₃ (168 mg, 0.184 mmol), X-phos (176 mg, 0.368 mmol) and Cs ₂ CO ₃ (1.8 g, 5.52 mmol). The mixture was then stirred at 100 ℃ overnight. The mixture was extracted with EA (25 mL x 3). The combined organic layers were washed with brine (15 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated to give the crude product, which was purified by column chromatography (PE/EA = 4:1) to give the desired product as a white solid (800 mg, 59.1%). Mass (m/z): 369.3 [ M + H ] ] ⁺ 。

Step 2.4- (aminomethyl) -N- (4- (tert-amyl) phenyl) aniline (618-3): to a solution of tert-butyl (4- ((4- (tert-amyl) phenyl) amino) benzyl) carbamate (800 mg, 2.17 mmol) in DCM (15 mL) was added 2,2,2-trifluoroacetic acid (5 mL). The mixture was then stirred at room temperature for 0.5 h. The mixture was extracted with EA (25 mL x 3). The combined organic layers were washed with brine (15 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated to yield the crude product as a yellow oil. Mass (m/z): 269.3 [ M + H ]] ⁺ 。

Step 3.5-oxo-N- (4- ((4- (tert-amyl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (618): to a solution of 5-oxopyrrolidine-3-carboxylic acid (29 mg, 0.223 mmol), HATU (102 mg, 0.268 mmol) and DIPEA (58 mg, 0.446 mmol) in DMF (3 mL) was added 618-3 (60 mg, 0.223 mmol). The mixture was stirred at room temperature overnight. The mixture was then extracted with EA (25 mL x 3). The combined organic layers were washed with brine (15 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated to give the crude product, which was purified by preparative HPLC to give the desired product as a white solid (20.3 mg, 24.0%). ¹ H NMR (400 MHz, DMSO-d 6) δ 8.35 (t, J = 5.7 Hz, 1H), 7.97 (s, 1H), 7.55 (s, 1H), 7.18-7.10 (m, 2H), 7.08-7.03 (m, 2H), 7.00-6.90 (m, 4H), 4.14 (d, J = 5.7 Hz, 2H), 3.23-3.17 (m, 1H), 2.35-2.20 (m, 2H), 1.53 (q, J = 7.5 Hz, 2H), 1.17 (s, 6H), 0.60 (t, J = 7.894 Hz, 3H). Mass (m/z): 380.2 [ M + H ] ] ⁺ 。

(R) -2-oxo-N- (4- ((4- (tert-amyl) phenyl) amino) benzyl) imidazolidine-4-carboxamide (619)

The title compound 619 (17.7 mg) was prepared as a white solid in 20.8% total yield from (R) -2-oxoimidazolidine-4-carboxylic acid (29 mg, 0.223 mmol), HATU (102 mg, 0.268 mmol), and DIPEA (58 mg, 0.446 mmol) according to the procedure of SIR-00004702. ¹ H NMR (400 MHz, DMSO-d 6) δ 8.26 (t, J = 5.9 Hz, 1H), 7.97 (s, 1H), 7.20-7.02 (m, 4H), 6.99-6.88 (m, 4H), 6.51 (s, 1H), 6.28 (s, 1H), 4.15 (d, J = 5.8 Hz, 2H), 4.06 (ddd, J = 9.8, 6.2, 1.8 Hz, 1H), 3.51 (ddd, J = 9.8, 8.9, 1.1 Hz, 1H), 3.19 (ddd, J = 8.9, 6.2, 1.3 Hz, 1H), 1.53 (q, J = 7.4 Hz, 2H), 1.17 (s, 6H), 0.60 (t, J = 7.4 Hz, 3H). Mass (m/z): 381.2 [ M + H ]] ⁺ 。

N ¹ - (4- ((4- (tert-amyl) phenyl) amino) benzyl) succinamide (620)

The title compound 620 (6.5 mg) was prepared as a white solid in a total yield of 7.1% from 4-amino-4-oxobutanoic acid (26.1 mg, 0.223 mmol), HATU (102 mg, 0.268 mmol), and DIPEA (58 mg, 0.446 mmol) according to the procedure of SIR-00004702. ¹ H NMR (400 MHz, DMSO-d 6) δ 8.18 (t, J = 5.9 Hz, 1H), 7.95 (s, 1H), 7.25 (s, 1H), 7.18-7.10 (m, 2H), 7.08-7.01 (m, 2H), 6.98-6.88 (m, 4H), 6.71 (s, 1H), 4.11 (d, J = 5.8 Hz, 2H), 2.30-2.27 (m, 4H), 1.53 (q, J = 7.4 Hz, 2H), 1.17 (s, 6H), 0.60 (t, J = 7.4 Hz, 3H). Mass (m/z): 368.3 [ M + H ] ] ⁺ 。

(S) -2,6 dioxo-N- (4- ((4- (tert-amyl) phenyl) amino) benzyl) hexahydropyrimidine-4-carboxamide (621)

The title compound 621 (20.5 mg) was prepared as a white solid in 22.5% total yield from (S) -2,6-dioxohexahydropyrimidine-4-carboxylic acid (35.2 mg, 0.223 mmol), HATU (102 mg, 0.268 mmol), and DIPEA (58 mg, 0.446 mmol) according to the procedure of SIR-00004702. ¹ H NMR (400 MHz, DMSO-d 6) δ 10.02 (d, J = 1.8 zxft 3528, 1H), 8.42 (t, J = 5.7 Hz, 1H), 8.01 (s, 1H), 7.61 (d, J = 3.0 Hz, 1H), 7.25-7.13 (m, 2H), 7.12-7.06 (m, 2H), 7.03-6.92 (m, 4H), 4.17 (dd, J = 6.1, 1.7 Hz, 2H), 4.00 (dt, J = 7.2, 3.5 Hz, 1H), 2.85 (dd, J = 16.6, 7.2 Hz, 1H), 1.57 (q, J = 7.25 zxft 5725, 345725 zxft 5732, 3432, 347.2 zxft 5732, 3432H). Mass (m/z): 409.2 [ M + H ]] ⁺ 。

2,6 dioxo-N- (4- ((4- (tert-amyl) phenyl) amino) benzyl) piperidine-4-carboxamide (622)

The title compound 622 (25.7 mg) was prepared as a white solid in 28.3% total yield from 2,6-dioxopiperidine-4-carboxylic acid (35 mg, 0.223 mmol), HATU (102 mg, 0.268 mmol), and DIPEA (58 mg, 0.446 mmol) according to the procedure of SIR-00004702. ¹ H NMR (400 MHz, DMSO-d 6) δ 7.98 (s, 1H), 7.38 (s, 1H), 7.16-7.12 (m, 2H), 7.10-7.06 (m, 2H), 6.97-6.93 (m, 2H), 6.93-6.87 (m, 3H), 4.48-4.32 (m, 2H), 3.08-2.98 (m, 1H), 2.78 (dd, J = 17.8, 9.2 Hz, 1H), 2.53-2.50 (m, 2H), 2.43 (d, J = 4.9 3252 zxft 52, 1H), 1.53 (q, J = 7.4 Hz, 2H), 1.17 (s, 6H), 0.59 (t, J = 7.4 zxft 3225, 343H). Mass (m/z): 408.3 [ M + H ] ] ⁺ 。

N- (4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) -3-methylbenzyl) -5-oxopyrrolidine-3-carboxamide (623)

Step 1. (4-bromo-3-methylbenzyl) ammoniaPreparation of tert-butyl benzoate (623-2): mixing (4-bromo-3-methylphenyl) methylamine (0.2 g, 1.0 mmol) and Boc ₂ A solution of a mixture of O (0.26 g, 1.2 mmol), triethylamine (0.30 g, 3.0 mmol) in DCM (20 mL) was stirred at 25 deg.C for 3 hours. The mixture was diluted with DCM (100 mL) and washed with water (100 mL x 3). The organic phase was concentrated and purified by flash chromatography with PE/EA = 10:1 to yield tert-butyl (4-bromo-3-methylbenzyl) carbamate (0.26 g, 87.8%) as a yellow oil. Mass (m/z): 243.8 [ M + H ]] ⁺ 。

Step 2 preparation of tert-butyl (4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) -3-methylbenzyl) carbamate (623-4): tert-butyl (4-bromo-3-methylbenzyl) carbamate (0.26 g, 0.87 mmol), 2- (4-isopropylpiperidin-1-yl) pyrimidin-5-amine (3) (0.23 g, 1.04 mmol), ruphos (81 mg, 0.17 mmol), pd2 (dba) 3 (80 mg, 0.34 mmol), and Cs ₂ CO ₃ (0.85 g, 2.60 mmol) in 1,4-dioxane (20 mL)) in N ₂ Stirred at 100 ℃ for 12 hours under an atmosphere. The mixture was concentrated and purified by combiflash, eluting with PE/EA = 10:1 to 1:1 to give tert-butyl (4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) -3-methylbenzyl) carbamate as a yellow solid (0.45 g, 88.7%). Mass (m/z): 440.3 [ M + H ] ] ⁺ 。

Step 3. Preparation of N- (4- (aminomethyl) -2-methylphenyl) -2- (4-isopropylpiperidin-1-yl) pyrimidin-5-amine (623-5): a solution of tert-butyl (4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) -3-methylbenzyl) carbamate (0.45 g, 0.92 mmol) in 4N HCl in dioxane (10 mL) was stirred at 25 ℃ for 2 hours. With saturated NaHCO ₃ (30 mL), extracted with EA (50 ml x 3) and the organic phase concentrated under vacuum to provide N- (4- (aminomethyl) -2-methylphenyl) -2- (4-isopropylpiperidin-1-yl) pyrimidin-5-amine 623-5 (0.35 g, 94.5%) as a yellow oil. Mass (m/z): 339.2 [ M + H ]] ⁺ 。

Step 4. Preparation of N- (4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) -3-methylbenzyl) -5-oxopyrrolidine-3-carboxamide (623): reacting N- (4- (aminomethyl) -2-methylphenyl) -2- (4-isopropylpiperidin-1-yl)A solution of a mixture of pyrimidin-5-amine (0.1 g, 0.3 mmol), 5-oxopyrrolidine-3-carboxylic acid (6) (0.04 g, 0.33 mmol), DIEA (0.12 g, 0.9 mmol), HATU (0.13 g, 0.33 mmol) in DMF (10 mL) was stirred at 25 ℃ for 3 hours. The mixture was removed in vacuo and the residue was purified by preparative HPLC (column-Xbridge-C18X 21.2 mm, 5um; mobile phase: ACN-H ₂ O (0.1% FA), 40% -60%) to provide 623 (106.5 mg, 74.9%) as a yellow solid. Mass (m/z): 451.2 [ M + H ]] ⁺ 。 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.33 (t, J = 5.6 Hz, 1H), 8.16 (s, 2H), 7.57 (s, 1H), 6.97 (d, J = 1.4 Hz, 1H), 6.87 (dd, J = 8.3, 1.7 Hz, 1H), 6.81 (s, 1H), 6.60 (d, J = 8.2 Hz, 1H), 4.64 (d, J= 13.0 Hz, 2H), 4.13 (d, J = 5.7 Hz, 2H), 3.39 (t, J = 8.8 Hz, 1H), 3.27 - 3.12 (m, 2H), 2.89 (s, 2H), 2.77 (dd, J = 12.7, 2.0 Hz, 1H), 2.32 - 2.27 (m, 1H), 2.19 (s, 3H), 1.69 (d, J = 11.4 Hz, 2H), 1.42 (dt, J = 13.2, 6.6 Hz, 1H), 1.31 - 1.22 (m, 1H), 1.19 - 1.04 (m, 2H), 0.87 (d, J = 6.8 Hz, 6H)。

5-oxo-N- (3- (4- ((4- (tert-amyl) phenyl) amino) phenyl) propyl) pyrrolidine-3-carboxamide (624)

Step 1.3- (4-bromophenyl) propanamide (624-2): to a solution of 3- (4-bromophenyl) propionic acid (1.2 g, 5.26 mmol) in DMF (5 mL) was added CDI (1.7 g, 10.52 mmol) and stirred under nitrogen at 80 deg.C overnight. After cooling to room temperature, the reaction mixture was slowly poured into 28% aqueous ammonium hydroxide (30 ml) at 0 ℃. The mixture was extracted with ethyl acetate, washed with water and brine and over Na ₂ SO ₄ And (5) drying. Filtration followed by evaporation under reduced pressure gave 3- (4-bromophenyl) propan-1-amine (1.1 g, 92%) as a white solid. Mass (m/z): 227.9 [ M + H ]] ⁺ 。

Step 2.3- (4-bromophenyl) propan-1-amine (624-3): to 3- (4-bromophenyl) propan-1-amine (1.1 g, 4.84 mmol)) To a solution in THF (15 mL) was added LAH (276 mg, 7.26 mmol) and stirred under nitrogen at 0 deg.C for 4 h. The reaction mixture was poured into 1N aqueous sodium hydroxide solution (100 ml). The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine and dried over magnesium sulfate. Filtration, followed by evaporation under reduced pressure, followed by purification by flash chromatography gave 3- (4-bromophenyl) propan-1-amine (180 mg, 17%) as a white solid. Mass (m/z): 214.0 [ M + H ] ] ⁺ 。

Step 3. N- (3- (4-bromophenyl) propyl) -5-oxopyrrolidine-3-carboxamide (624-4): to a solution of 3- (4-bromophenyl) propan-1-amine (180 mg, 0.84 mmol), 5-oxopyrrolidine-3-carboxylic acid (163 mg, 1.26 mmol) in DMF (2 mL) was added 3-DIEA (327 mg, 2.53 mmol) and HATU (481 mg, 1.26 mmol). The mixture was then stirred under nitrogen at 0 ℃ for 1 h. The mixture was purified by flash chromatography to give N- (3- (4-bromophenyl) propyl) -5-oxopyrrolidine-3-carboxamide (138 mg, 50%) as a white solid. Mass (m/z): 325.0 [ M + H ]] ⁺ 。

Step 4.5-oxo-N- (3- (4- ((4- (tert-amyl) phenyl) amino) phenyl) propyl) pyrrolidine-3-carboxamide (624): to a solution of 4- (tert-amyl) aniline (83 mg, 0.51 mmol) and N- (3- (4-bromophenyl) propyl) -5-oxopyrrolidine-3-carboxamide (138 mg, 3.68 mmol) in dioxane (1.5 mL) was added Pd under a nitrogen atmosphere ₂ (dba) ₃ (39 mg, 0.04 mmol), xphos (40 mg, 0.08 mmol) and Cs ₂ CO ₃ (277 mg, 0.85 mmol). The mixture was then purified by preparative TLC and then by preparative HPLC to give 5-oxo-N- (3- (4- ((4- (tert-amyl) phenyl) amino) phenyl) propyl) pyrrolidine-3-carboxamide (20.8 mg, 12%) as a white solid. Mass (m/z): 408.2 [ M + H ] ] ⁺ 。 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.00 (t, J = 5.5 Hz, 1H), 7.90 (br, 1H), 7.56 (s, 1H), 7.20 - 7.12 (m, 2H), 7.07 - 6.99 (m, 2H), 7.02 - 6.91 (m, 4H), 3.40 (d, J = 8.7 Hz, 1H), 3.21 (dd, J = 9.3, 6.5 Hz, 1H), 3.18 - 3.05 (m, 2H), 3.05 (d, J = 6.6 Hz, 1H), 2.49 - 2.44 (m, 2H), 2.27 (dd, J = 8.5, 1.9 Hz, 2H), 1.72 - 1.61 (m, 2H), 1.57 (q, J = 7.4 Hz, 2H), 1.20 (s, 6H), 0.63 (t, J = 7.4 Hz, 3H)。

(S) -5-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (625)

Step 1.1 preparation of- (4-nitrophenyl) -4- (trifluoromethyl) piperidine (625-3): 1-fluoro-4-nitrobenzene (1.41 g, 10.0 mmol), 4- (trifluoromethyl) piperidine (1.99 g, 13.0 mmol) and Cs ₂ CO ₃ A solution of (6.51 g, 20.0 mmol) in DMSO (50 mL) was stirred at room temperature for 18 hours. After cooling to room temperature, 200 mL water was added dropwise. The resulting solution was extracted with 3X100 mL of ethyl acetate. The organic layers were combined, washed with water (3x150 mL), dried and concentrated in vacuo. The residue was purified by flash column chromatography (EA/PE = 1/10) to provide the desired product as a yellow solid (2.10 g, 76.6%). Mass (m/z): 275.1 [ M + H ]] ⁺ 。

Step 2.4- (4- (trifluoromethyl) piperidin-1-yl) aniline (625-4) preparation: to a solution of 1- (4-nitrophenyl) -4- (trifluoromethyl) piperidine (1.37 g, 5.0 mmol) in EtOH (50 mL) was added 10% Pd/C (53 mg, 5.0 umol). The reaction was then stirred under hydrogen atmosphere at room temperature overnight. The 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 (100 mL x 3). The combined organic layers were washed with brine (100 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated to give the desired product as a yellow solid (1.04 g, 85.2%). Mass (m/z): 245.2 [ M + H ]] ⁺ 。

Step 3 preparation of tert-butyl (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) carbamate (625-6): 4- (4- (trifluoromethyl) piperidin-1-yl) aniline (878 mg, 3.6 mmol), (4-bromobenzyl) carbamic acid tert-butyl ester (858 mg, 3.0 mmol), pd2 (dba) 3 (27.5 mg, 0.03 mmol), X-Phos (71.55 mg, 0.15 mmol), cs ₂ CO ₃ (1.47 g, 4.5 mmol) in 1,4-dioxane (30 mL) was stirred at 100 ℃ overnight. ColdAfter cooling to room temperature, 100 mL water was added. The mixture was then extracted with DCM (100 mL x 3). The combined organic layers were washed with water (100 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by flash column chromatography (EA/PE = 1/2) to yield the desired product as a yellow solid (1.03 g, 76.3%). Mass (m/z): 450.3 [ M + H ]] ⁺ 。

Step 4.4 preparation of 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (625-7): a solution of tert-butyl (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) carbamate (1.03 g, 2.28 mmol) in a solution of 10 mL HCl in 1,4-dioxane was stirred at room temperature for 30 minutes and concentrated. 5 ml water was added. The pH of the filtrate was adjusted to 8-9 with sodium carbonate solution. The mixture was then extracted with DCM (10 mL × 3). The combined organic layers were washed with water (20 mL) and Na ₂ SO ₄ Dried and concentrated. The residue was purified by preparative TLC (MeOH/DCM = 1/10) to provide the desired product as a yellow solid. Mass (m/z): 350.2 [ M + H ]] ⁺ 。

Step 5 preparation of (S) -5-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (625): to a solution of 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (146.6 mg, 0.42 mmol) and 2- (4-methylpiperazin-1-yl) acetic acid (64.5 mg, 0.5 mmol) in DMF (2 mL) was added DIEA (0.023 mL, 1.26 mmol). DMT-MM (147.4 mg, 0.5 mmol) was then added and the reaction mixture was stirred at room temperature for 3 hours. 20 mL water was added. The mixture was then extracted with DCM (10 mL × 3). The combined organic layers were washed with water (10 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by preparative TLC (MeOH/DCM = 1/10) to yield the desired product as a yellow solid (135 mg, 70.0%). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.11 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 6.99-6.88 (m, 4H), 4.26 (s, 2H), 3.68-3.43 (m, 4H), 3.28 (m, 1H), 2.73-2.43 (m, 4H), 2.31 (m, 1H), 2.01-1.92 (m, 2H), 1.79-1.65 (m, 2H). Mass (m/z): 461.2 [ M + H ] ] ⁺ 。

N- (2- (dimethylamino) ethyl) -1-ethyl-N- (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (626)

Step 1. Preparation of N- (4-bromobenzyl) -N- (2- (dimethylamino) ethyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (626-3): the title compound (626-3) was prepared as a white solid in 82.8% overall yield from N1- (4-bromobenzyl) -N2, N2-dimethylethane-1,2-diamine (288 mg, 1.12 mmol), 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (229 mg, 1.46 mmol), DIEA (0.293 mL, 1.68 mmol), and HATU (554 mg, 1.46 mmol) according to the procedure of 625. Mass (m/z): 396.1 [ M + H ] +.

Step 2. Preparation of N- (2- (dimethylamino) ethyl) -1-ethyl-N- (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (626): from N- (4-bromobenzyl) -N- (2- (dimethylamino) ethyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (39.6 mg, 0.1 mmol), 4- (4-methylpiperidin-1-yl) aniline (25 mg, 0.13 mmol), pd2 (dba) 3 (1.83 mg, 2 umol), X-Phos (1.91 mg, 4 umol), cs according to the procedure of 625-3 ₂ CO ₃ (48.8 mg, 0.15 mmol) the title compound 626 (16.4 mg) was prepared as a white solid in 32.4% overall yield. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.28 - 6.91 (m, 8H), 4.60 (s, 2H), 3.78 - 3.44 (m, 6H), 3.37 (m, 1H), 3.25- 3.08 (m, 4H), 2.97 (s, 6H), 2.70 - 2.58 (m, 2H), 2.39 - 2.28 (m, 2H), 1.96 - 1.83 (m, 2H), 1.78 (m, 1H), 1.65 - 1.50 (m, 2H), 0.99 (d, J = 6.4 Hz, 3H), 0.87 (t, J= 6.8 Hz, 3H). Mass (m/z): 506.3 [ M + H ]] ⁺ 。

1-acetyl-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (627)

The title compound 627 (12.8 mg) as a wheat-colored powder was prepared according to the procedure for compound 625 from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), 1-acetylpyrrolidine-3-carboxylic acid (10.2 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) in 52.1% overall yield. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.14-6.91 (m, 8H), 4.26 (s, 2H), 4.03-3.83 (m, 2H), 3.79-3.66 (m, 2H), 3.57-3.43 (m, 2H), 3.36 (m, 1H), 2.99-2.78 (m, 2H), 2.26 (s, 3H), 2.41 (m, 1H), 1.97-1.71 (m, 4H), 1.66-1.51 (m, 2H). Mass (m/z): 489.3 [ M + H ]] ⁺ 。

1- (cyclopropanecarbonyl) -N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (628)

The title compound 628 (12.3 mg) was prepared as a wheat-colored powder in 47.6% overall yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), 1- (cyclopropanecarbonyl) pyrrolidine-3-carboxylic acid (11.9 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.15-6.88 (m, 8H), 4.28 (s, 2H), 4.05-3.69 (m, 4H), 3.59-3.44 (m, 2H), 3.35 (m, 1H), 2.97-2.78 (m, 2H), 2.42 (m, 1H), 2.11-1.98 (m, 2H), 1.97-1.71 (m, 4H), 1.66-1.51 (m, 2H), 0.89-0.75 (m, 4H). Mass (m/z): 515.2 [ M + H ]] ⁺ 。

1-acetyl-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) azetidine-3-carboxamide (629)

Synthesis of 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) N-butyl) according to the procedure for Compound 625) Piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), 1-acetoacetidine-3-carboxylic acid (9.3 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) the title compound 629 (12.0 mg) was prepared as a wheat colored powder in 50.5% overall yield. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.14-6.87 (m, 8H), 4.39-4.23 (m, 4H), 4.17-3.99 (m, 2H), 3.54-3.67 (m, 2H), 3.39 (m, 1H), 2.76-2.54 (m, 2H), 2.27 (m, 1H), 2.04-1.94 (m, 2H), 1.86 (s, 3H), 1.79-1.65 (m, 2H). Mass (m/z): 475.2 [ M + H ]] ⁺ 。

1- (cyclopropanecarbonyl) -N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) azetidine-3-carboxamide (630)

The title compound 630 (14.4 mg) was prepared according to the procedure for compound 625 from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), 1- (cyclopropanecarbonyl) azetidine-3-carboxylic acid (11.0 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) as a wheat-colored powder in an overall yield of 57.5%. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.14-7.06 (m, 8H), 4.23 (s, 2H), 4.13-4.04 (m, 4H), 3.51-3.41 (m, 2H), 2.79-2.55 (m, 2H), 2.21 (m, 1H), 2.13-2.03 (m, 2H), 1.97-1.71 (m, 2H), 1.64-1.46 (m, 2H), 0.89-0.78 (m, 4H). Mass (m/z): 501.3 [ M + H ]] ⁺ 。

1,1-dimethyl-3- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) urea (631)

To a solution of 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (34.9 mg, 0.1 mmol) and DIEA (39.0 mg, 0.3 mmol) in DCM (2 ml) was added dimethylcarbamoyl chloride (12.8 mg, 0.12 mmol) dropwise at 0 deg.Cmmol). The reaction was then stirred at room temperature for 2 hours. The reaction solution was concentrated and purified by preparative TLC (MeOH/DCM = 1/10) to yield the desired product as a yellow solid (21.0 mg, 49.9%). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.15-7.08 (d, J = 8.1 Hz, 2H), 7.06-6.82 (m, 6H), 4.24 (s, 2H), 3.70-3.52 (m, 2H), 2.91 (s, 6H), 2.56-2.78 (m, 2H), 2.27 (m, 1H), 2.03-1.93 (m, 2H), 1.79-1.64 (m, 2H). Mass (m/z): 421.3 [ M + H ]] ⁺ 。

1-acetyl-N- (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (632)

The title compound 632 (7.0 mg) was prepared as a wheat-colored powder in 32.1% overall yield from 4- (aminomethyl) -N- (4- (4-methylpiperidin-1-yl) phenyl) aniline (14.8 mg, 0.05 mmol), 1-acetylpyrrolidine-3-carboxylic acid (10.2 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.43 - 6.87 (m, 8H), 4.34 (s, 2H), 4.01 - 3.68 (m, 4H), 3.58 - 3.43 (m, 2H), 3.38 (m, 1H), 3.20 - 2.98 (m, 2H), 2.21 (s, 3H), 2.11 - 1.99 (m, 2H), 1.91 - 1.58 (m, 5H), 1.04 (d, J = 6.4 Hz, 3H). Mass (m/z): 435.3 [ M + H ]] ⁺ 。

1- (cyclopropanecarbonyl) -N- (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (633)

The title compound 633 (12.2 mg) as a pale sky blue solid was prepared according to the procedure for compound 625 in 52.9% overall yield from 4- (aminomethyl) -N- (4- (4-methylpiperidin-1-yl) phenyl) aniline (14.8 mg, 0.05 mmol), 1- (cyclopropanecarbonyl) pyrrolidine-3-carboxylic acid (11.9 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol) and HATU (25 mg, 0.065 mmol). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.46 (d, J = 8.0 Hz, 2H), 7.32 - 7.04 (m, 6H), 4.33 (s, 2H), 4.01 - 3.79 (m, 2H), 3.75 - 3.50 (m, 6H), 3.20 - 2.98 (m, 2H), 2.28 - 2.16 (m, 1H), 2.10 - 1.98 (m, 2H), 1.90 - 1.59 (m, 4H), 1.09 (d, J = 6.4 Hz, 3H), 0.91-0.76 (m, 4H). Mass (m/z): 461.3 [ M + H ]] ⁺ 。

1-acetyl-N- (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) azetidine-3-carboxamide (634)

The title compound 634 (8.1 mg) was prepared as a dark gray solid r in 38.5% total yield from 4- (aminomethyl) -N- (4- (4-methylpiperidin-1-yl) phenyl) aniline (14.8 mg, 0.05 mmol), 1-acetylazetidine-3-carboxylic acid (9.3 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.46 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.17 - 7.08 (m, 4H), 4.43 - 4.26 (m, 4H), 4.18 - 3.99 (m, 2H), 3.61 (m, 1H), 3.59 (s, 3H), 2.10-2.00 (m, 2H), 1.93 -1.83 (m, 3H), 1.74 - 1.62 (m, 2H), 1.09 (d, J = 6.4 Hz, 3H). Mass (m/z): 421.3 [ M + H ]] ⁺ 。

1- (cyclopropanecarbonyl) -N- (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) azetidine-3-carboxamide (635)

The title compound 635 (15.4 mg) was prepared as a dark gray solid r in 68.9% overall yield according to the procedure for compound 625 from 4- (aminomethyl) -N- (4- (4-methylpiperidin-1-yl) phenyl) aniline (14.8 mg, 0.05 mmol), 1- (cyclopropanecarbonyl) azetidine-3-carboxylic acid (11.0 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol). ¹ H NMR (400 MHz,Methanol-d ₄ ) δ 7.46 (d, J = 8.0 Hz, 2H), 7.35 - 7.06 (m, 6H), 4.51 - 4.40 (m, 4H), 4.13 - 4.04 (m, 6H), 3.51 - 3.41 (m, 2H), 2.21 (m, 1H), 2.11 - 2.01 (m, 2H), 1.64 - 1.48 (m, 2H), 1.07 (d, J = 6.4 Hz, 3H), 0.89-0.78 (m, 4H). Mass (m/z): 447.3 [ M + H ] ] ⁺ 。

4-oxo-4- (pyrrolidin-1-yl) -N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) butanamide (636)

The title compound (8.0 mg) was prepared according to the procedure for compound 625 from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), 1-ethyl-2-oxoimidazolidine-4-carboxylic acid (10.3 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) as a white solid in a total yield of 32.7%. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.38 - 6.64 (m, 8H), 4.38 - 4.21 (m, 3H), 3.66 - 3.38 (m, 6H), 3.07 - 2.88 (m, 2H), 2.26 (m, 1H), 2.04 - 1.92 (m, 2H), 1.78 - 1.65 (m, 2H), 1.05 (t, J= 7.2 Hz, 3H). Mass (m/z): 490.3 [ M + H ]] ⁺ 。

5-oxo-1-propyl-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (637)

The title compound 637 (12.8 mg) as a dark gray solid was prepared in 49.3% overall yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), 5-oxo-1-propylpyrrolidine-3-carboxylic acid (11.1 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.45 - 6.65 (m, 8H), 4.26 (s, 2H), 3.79 - 3.49 (m, 4H), 3.28 - 3.12 (m, 5H), 2.65 - 2.52 (m, 2H), 2.25 (s, 2H), 2.05-1.87 (m, 2H), 1.79 - 1.63 (m, 2H), 1.55 (m, 2H), 0.89 (t, J= 7.2 Hz, 3H). Mass (m/z): 503.2 [ M + H ]] ⁺ 。

N- (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxo-1-propylpyrrolidine-3-carboxamide (638)

The title compound 638 (10.2 mg) was prepared as a solid as a crude wood color in a total yield of 45.4% according to the procedure for compound 625 from 4- (aminomethyl) -N- (4- (4-methylpiperidin-1-yl) phenyl) aniline (14.8 mg, 0.05 mmol), 5-oxo-1-propylpyrrolidine-3-carboxylic acid (11.1 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.46 - 6.71 (m, 8H), 4.28 (s, 2H), 3.76 - 3.47 (m, 4H), 3.28 - 3.13 (m, 5H), 2.65 - 2.54 (m, 2H), 1.78 (m, 2H), 1.62 - 1.48 (m, 3H), 1.38 - 1.33 (m, 2H), 0.99 (d, J = 6.0 Hz, 3H), 0.89 (t, J= 7.2 Hz, 3H). Mass (m/z): 449.3 [ M + H ]] ⁺ 。

1-Ethyl-N- (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -2-oxoimidazolidine-4-carboxamide (639)

The title compound 639 (18.1 mg) was prepared according to the procedure for compound 625 from 4- (aminomethyl) -N- (4- (4-methylpiperidin-1-yl) phenyl) aniline (14.8 mg, 0.05 mmol), 1-ethyl-2-oxoimidazolidine-4-carboxylic acid (10.3 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) as a white solid in a total yield of 82.9%. ¹ H NMR (400 MHz, chloroform-d) δ 7.48 - 6.67 (m, 8H), 4.14 (s, 2H), 3.70 - 3.62 (m, 2H), 3.32 - 3.22 (m, 2H), 3.06 (m, 1H), 2.96 - 2.84 (m, 4H), 1.58 - 1.27 (m, 5H), 1.00 (d, J = 6.0 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H). Mass (m/z): 436.4 [M+H] ⁺ 。

1-methyl-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) azetidine-3-carboxamide (640)

The title compound 640 (9.6 mg) was prepared as a white solid in 43.0% overall yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), 1-methylazetidine-3-carboxylic acid (7.5 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.50-6.70 (m, 8H), 4.37-4.15 (m, 6H), 3.65-3.52 (m, 5H), 2.93 (s, 3H), 2.29 (m, 1H), 2.12-1.90 (m, 2H), 1.82-1.62 (m, 2H). Mass (m/z): 447.2 [ M + H ]] ⁺ 。

1-methyl-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (641)

The title compound 641 (10.5 mg) was prepared as a light gray solid in 45.6% overall yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), 1-methylpyrrolidine-3-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.55-6.75 (m, 8H), 4.29 (s, 2H), 3.80-3.55 (m, 3H), 3.51-3.35 (m, 4H), 3.29-3.20 (m, 2H), 2.95 (s, 3H), 2.44 (m, 1H), 2.30 (m, 1H), 2.18 (m, 1H), 2.10-1.86 (m, 2H), 1.79-1.58 (m, 2H). Mass (m/z): 461.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (642)

The title compound 642 (13.1 mg) was prepared according to the procedure for compound 625 from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), pyrrolidine-3-carboxylic acid (7.5 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) as a light gray solid in 58.6% overall yield. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.65 - 7.53 (m, 2H), 7.24 (d, J = 8.4 Hz, 2H), 7.19-7.04 (m, 4H), 4.33 (s, 2H), 3.86-3.62 (m, 4H), 3.54-3.21 (m, 5H), 2.70 (m, 1H), 2.41-2.09 (m, 6H). Mass (m/z): 447.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) azetidine-3-carboxamide (643)

The title compound 643 (6.2 mg) as a sand-brown solid was prepared according to the procedure for compound 625 from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), azetidine-3-carboxylic acid (6.5 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) in 28.6% overall yield. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.58 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 4.34 (s, 2H), 4.25 (m, 4H), 3.81-3.68 (m, 5H), 2.83 (m, 1H), 2.32-2.15 (m, 4H). Mass (m/z): 433.2 [ M + H ]] ⁺ 。

N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) nicotinamide (644)

From 4- (aminomethyl) according to the procedure for Compound 625Phenyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), nicotinic acid (8.0 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol) and HATU (25 mg, 0.065 mmol) the title compound 644 (16.8 mg) was prepared as a light green solid in a total yield of 73.8%. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.98 (s, 1H), 8.67 (m, 1H), 8.25 (m, 1H), 7.59-7.50 (m, 1H), 7.28-6.84 (m, 8H), 4.48 (s, 2H), 3.84-3.45 (m, 2H), 2.91-2.41 (m, 2H), 2.26 (m, 1H), 2.10-1.91 (m, 2H), 1.80-1.63 (m, 2H). Mass (m/z): 455.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-1-carboxamide (645)

The title compound 645 (9.2 mg) was prepared as a white powder in 41.2% overall yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), pyrrolidine-1-carbonyl chloride (8.0 mg, 0.06 mmol), and DIEA (19 mg, 0.15 mmol) according to the procedure for compound 631. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.45-6.65 (m, 8H), 4.24 (s, 2H), 3.83-3.45 (m, 2H), 3.39-3.32 (m, 4H), 2.83-2.54 (m, 2H), 2.27 (m, 1H), 2.06-1.84 (m, 6H), 1.78-1.65 (m, 2H). Mass (m/z): 447.2 [ M + H ]] ⁺ 。

6-chloro-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrazine-2-carboxamide (646)

The title compound 646 (23.1 mg) was prepared as a white solid in 95.5% overall yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), 6-chloropyrazine-2-carboxylic acid (10.3 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400MHz, methanol-d ₄ ) δ 9.16 (s, 1H), 8.83 (s, 1H), 7.32-6.67 (m, 8H), 4.48 (s, 2H), 3.81-3.46 (m, 2H), 2.91-2.42 (m, 2H), 2.25 (m, 1H), 2.02-1.88 (m, 2H), 1.78-1.62 (m, 2H). Mass (m/z): 490.2 [ M + H ]] ⁺ 。

2-methyl-5-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (647)

The title compound 647 (14.3 mg) as a wheat-colored powder was prepared according to the procedure for compound 625 from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), 2-methyl-5-oxopyrrolidine-3-carboxylic acid (9.3 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) in 60.2% overall yield. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.56 - 6.65 (m, 8H), 4.27 (s, 2H), 3.93 - 3.77 (m, 2H), 3.72 (m, 1H), 3.22 (m, 1H), 2.77 (m, 1H), 2.73 - 2.44 (m, 2H), 2.27 (m, 1H), 2.07 - 1.85 (m, 2H), 1.81 - 1.65(m, 2H), 1.25 (d, J= 6.4 Hz, 3H). Mass (m/z): 475.3 [ M + H ]] ⁺ 。

2-methyl-5-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (648)

The title compound 648 (9.2 mg) was prepared as a wheat-colored powder in 38.7% overall yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), 2-methyl-5-oxopyrrolidine-3-carboxylic acid (9.3 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.51 - 6.64 (m, 8H), 4.27 (s, 2H), 4.02 - 3.95 (m, 2H), 3.77 - 3.68 (m, 1H), 3.23 (m, 1H), 2.74 (m, 1H), 2.42 - 2.33 (m, 2H), 2.30 (m, 1H), 2.08 - 1.87 (m, 2H), 1.83 - 1.71(m, 2H), 1.09 (d, J = 6.4 Hz, 3H). Mass (m/z): 475.3 [ M + H ]] ⁺ 。

3-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) tetrahydro-1H-pyrrolizine-7 a (5H) -carboxamide (649)

The title compound 649 (16.1 mg) was prepared as a white powder in 64.2% total yield according to the procedure for compound 625 from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), 3-oxotetrahydro-1H-pyrrolizine-7 a (5H) -carboxylic acid (10.9 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol). ¹ H NMR (400 MHz, methanol-d ₄ ) Delta 7.52-6.71 (m, 8H), 4.31 (s, 2H), 3.63-3.53 (m, 2H), 3.19-3.06 (m, 2H), 2.82-2.62 (m, 2H), 2.51-2.32 (m, 6H), 2.18 (m, 1H), 2.12-2.01 (m, 2H), 1.93-1.83 (m, 2H), 1.74-1.65 (m, 2H). Mass (m/z): 501.2 [ M + H ]] ⁺ 。

2-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) imidazolidine-4-carboxamide (650)

The title compound 650 (10.1 mg) was prepared as a white powder in 43.8% total yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), 2-oxoimidazolidine-4-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.35-6.66 (m, 8H), 4.17 (s, 2H), 4.12-4.06 (m, 1H), 3.82-3.46 (m, 2H), 3.26-3.05 (m, 2H), 2.78-2.54 (m, 2H), 2.42 (m, 1H), 1.94-1.76 (m, 2H), 1.67-1.47 (m, 2H). Mass (m/z): 462.2 [ M + H ]] ⁺ 。

2-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (651)

The title compound 651 (13 mg) was prepared as a white powder in 56.4% overall yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), 2-oxopyrrolidine-3-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.23-6.72 (m, 8H), 4.18 (s, 2H), 3.72-3.51 (m, 2H), 3.31-3.12 (m, 3H), 2.73-2.52 (m, 2H), 2.42 (m, 1H), 2.32-2.08 (m, 2H), 1.95-1.80 (m, 2H), 1.66-1.48 (m, 2H). Mass (m/z): 461.2 [ M + H ]] ⁺ 。

(S) -5-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-2-carboxamide (652)

The title compound 652 (9.3 mg) was prepared as a white powder in 40.4% overall yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), (S) -5-oxopyrrolidine-2-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.31-6.68 (m, 8H), 4.31 (s, 2H), 4.20 (m, 1H), 3.78-3.38 (m, 2H), 2.53-2.12 (m, 4H), 2.12-1.82 (m, 3H), 1.78-1.62 (m, 2H). Mass (m/z): 461.2 [ M + H ]] ⁺ 。

(R) -5-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-2-carboxamide (653)

The title compound 653 (9.8 mg) was prepared as a white powder in 42.5% overall yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), (R) -5-oxopyrrolidine-2-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.42-6.65 (m, 8H), 4.29 (s, 2H), 4.17 (m, 1H), 3.82-3.55 (m, 2H), 2.48-2.19 (m, 4H), 2.14-1.88 (m, 3H), 1.84-1.57 (m, 2H). Mass (m/z): 461.2 [ M + H ]] ⁺ 。

N- (4- ((4- (tert-butylamino) phenyl) amino) benzyl) -1-ethyl-5-oxopyrrolidine-3-carboxamide (654)

The title compound 654 (7.2 mg) was prepared according to the procedure for compound 625 from N1- (4- (aminomethyl) phenyl) -N4- (tert-butyl) benzene-1,4-diamine (13.5 mg, 0.05 mmol), 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (10.2 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) as a white powder in an overall yield of 35.2%. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.37 - 7.00 (m, 8H), 4.32 (s, 2H), 3.82 - 3.66 (m, 4H), 3.52 (m, 1H), 2.61 (d, J = 8.4 Hz, 2H), 1.39 (s, 9H), 1.12 (t, J = 7.2 Hz, 3H). Mass (m/z): 409.3 [ M + H ]] ⁺ 。

(S) -N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-2-carboxamide (655)

From 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), L-proline (7.5 mg, 0.065 mmol), DI-proline (7.5 mg, 0.065 mmol) according to the procedure for compound 625EA (19 mg, 0.15 mmol) and HATU (25 mg, 0.065 mmol) prepared the title compound 655 (8.8 mg) as a white powder in a total yield of 39.4%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.11-6.81 (m, 8H), 4.20 (s, 2H), 4.12 (m, 1H), 3.68-3.54 (m, 2H), 3.26-3.12 (m, 2H), 2.68-2.55 (m, 2H), 2.41 (m, 1H), 1.95-1.76 (m, 4H), 1.71-1.44 (m, 4H). Mass (m/z): 447.3 [ M + H ]] ⁺ 。

(R) -N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-2-carboxamide (656)

Starting from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol) according to the procedure for compound 625,DProline (7.5 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol) and HATU (25 mg, 0.065 mmol) the title compound 656 (8.0 mg) was prepared as a white powder in a total yield of 35.8%. ¹ H NMR (400 MHz, DMSO-d ₆ ) Delta 7.12-6.82 (m, 8H), 4.22 (s, 2H), 4.14 (m, 1H), 3.66-3.55 (m, 2H), 3.25-3.03 (m, 2H), 2.68-2.55 (m, 2H), 2.40 (m, 1H), 1.98-1.76 (m, 4H), 1.73-1.48 (m, 4H). Mass (m/z): 447.3 [ M + H ] ] ⁺ 。

(S) -6-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) piperidine-2-carboxamide (657)

The title compound 657 (14.6 mg) was prepared as a white powder in 61.5% overall yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), (S) -6-oxopiperidine-2-carboxylic acid (9.3 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.35 - 6.55 (m, 8H), 4.19 (s, 2H), 3.70 (m, 1H), 3.63 - 3.55 (m, 2H), 2.72 - 2.58 (m, 2H), 2.42 (m, 1H), 2.13 (t, J = 6.4 Hz, 2H), 1.97-1.82 (m, 2H), 1.78-1.50 (m, 6H). Mass (m/z): 475.2 [ M + H ]] ⁺ 。

(S) -2,6-dioxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) hexahydropyrimidine-4-carboxamide (658)

The title compound 658 (13.1 mg) was prepared as a white powder in 53.6% overall yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), (S) -2,6-dioxohexahydropyrimidine-4-carboxylic acid (10.3 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.17-6.65 (m, 8H), 4.16 (s, 2H), 4.00 (m, 1H), 3.73-3.50 (m, 2H), 2.90-2.77 (m, 1H), 2.75-2.56 (m, 2H), 2.48-2.35 (m, 2H), 2.02-1.82 (m, 2H), 1.68-1.52 (m, 2H). Mass (m/z): 490.2 [ M + H ] ] ⁺ 。

(S) -1-methyl-2,6-dioxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) hexahydropyrimidine-4-carboxamide (659)

The title compound 659 (19.4 mg) was prepared as a white powder in 77.0% total yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), (S) -1-methyl-2,6-dioxohexahydropyrimidine-4-carboxylic acid (11.2 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.21-6.65 (m, 8H), 4.14 (s, 2H), 3.97 (m, 1H), 3.75-3.46 (m, 2H), 3.00 (m, 1H), 2.95 (s, 3H), 2.78-2.54 (m, 3H), 2.44 (m, 1H), 1.97-1.76 (m, 2H), 1.68-1.47 (m, 2H). Quality (m/z)： 504.3 [M+H] ⁺ 。

4-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) imidazolidine-1-carboxamide (660)

To a solution of 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (34.9 mg, 0.1 mmol) in DMF (10 mL) was added CDI (17.8 mg, 0.11 mmol). The reaction mixture was stirred at room temperature for 1 hour, then imidazolidin-4-one (9.5 mg, 0.11 mmol) and DIEA (38.7 mg, 0.3 mmol) were added and the reaction was stirred for an additional 3 hours. The solution was then washed with 3X10 mL of water and Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by preparative TLC (MeOH/DCM = 1/15) to provide the desired product as a light yellow solid (10.1 mg, 21.9%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.25-6.57 (m, 8H), 4.61 (s, 2H), 4.14 (s, 2H), 3.72 (s, 2H), 3.68-3.42 (m, 2H), 2.78-2.55 (m, 2H), 2.41 (m, 1H), 1.98-1.77 (m, 2H), 1.68-1.45 (m, 2H). Mass (m/z): 462.2 [ M + H ]] ⁺ 。

(R) -5-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (661)

The title compound 661 (122 mg) as a wheat-colored solid was prepared in 63.1% total yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (146.6 mg, 0.42 mmol) and 2- (4-methylpiperazin-1-yl) acetic acid (64.5 mg, 0.5 mmol) in DMF (2 mL) according to the procedure for compound 625, adding DIEA (0.023 mL, 1.26 mmol). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.10 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 6.99 - 6.88 (m, 4H), 4.26 (s, 2H), 3.69 - 3.42 (m, 4H), 3.27 (m, 1H), 2.75 - 2.44 (m, 4H), 2.27 (m, 1H), 2.02-1.93 (m, 2H), 1.79-1.66 (m, 2H). Mass (m/z): 461.2 [ M + H ]] ⁺ 。

1- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) urea (662)

To a solution of 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (34.9 mg, 0.1 mmol) in DMSO (2 mL) was added DIEA (39.0 mg, 0.3 mmol) and phenyl carbamate (16.4 mg, 0.12 mmol) at 0 ℃. The reaction was then stirred at room temperature for 2 hours. The solution was then washed with 3X10 mL of water and Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by preparative TLC (MeOH/DCM = 1/15) to provide the desired product as a light yellow solid (30.1 mg, 77.2%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.05 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 6.91-6.85 (m, 4H), 4.04 (s, 2H), 3.65-3.56 (m, 2H), 2.68-2.55 (m, 2H), 2.41 (m, 1H), 1.95-1.81 (m, 2H), 1.63-1.50 (m, 2H). Mass (m/z): 393.2 [ M + H ]] ⁺ 。

(R) -2,6-dioxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) hexahydropyrimidine-4-carboxamide (663)

The title compound 663 (15.4 mg) as a white powder was prepared according to the procedure for compound 625 from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), (R) -2,6-dioxohexahydropyrimidine-4-carboxylic acid (10.3 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) in 63.0% overall yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.05 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 6.92 - 6.86 (m, 4H), 4.15 (s, 2H), 4.01 (m, 1H), 3.66 - 3.57 (m, 2H), 2.85 (m, 1H), 2.67-2.56 (m, 2H), 2.48-2.34 (m, 2H), 1.94-1.78 (m, 2H), 1.63-1.51 (m, 2H). Mass (m/z): 490.2 [ M + H ]] ⁺ 。

(R) -6-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) piperidine-2-carboxamide (664)

The title compound 664 (14.8 mg) was prepared as a white powder in 62.3% overall yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), (R) -6-oxopiperidine-2-carboxylic acid (9.3 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.30 - 6.68 (m, 8H), 4.17 (s, 2H), 3.89 (m, 1H), 3.72 - 3.53 (m, 2H), 2.79 - 2.56 (m, 2H), 2.42 (m, 1H), 2.13 (t, J= 6.4 Hz, 2H), 1.93-1.82 (m, 2H), 1.76-1.67 (m, 2H), 1.64-1.53 (m, 2H), 1.31-1.22 (m, 2H). Mass (m/z): 475.2 [ M + H ]] ⁺ 。

N3- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) azetidine-1,3-dicarboxamide (665)

The title compound 665 (12.4 mg) was prepared as a white solid in 52.2% overall yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), 1-carbamoylazetidine-3-carboxylic acid (9.3 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.20-6.68 (m, 8H), 4.16 (s, 2H), 3.92-3.73 (m, 4H), 3.69-3.53 (m, 2H), 3.26 (m, 1H), 2.72-2.54 (m, 2H), 2.41 (m, 1H), 1.95-1.80 (m, 2H), 1.65-1.51 (m, 2H). Mass (m/z): 476.2 [ M + H ]] ⁺ 。

N- (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -3-oxopiperazine-1-carboxamide (666)

From 4- (aminomethyl) -N- (4- (4-methylpiperidin-1-yl) phenyl) aniline (29 mg, 0.1 mmol), piperazin-2-one (11.0 mg, 0.11 mmol), CDI (17.8 mg, 0.11 mmol) and DIEA (38.7 mg, 0.3 mmol) the title compound 666 (8.2 mg) was prepared as a white solid in a total yield of 38.9%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.28 - 6.64 (m, 8H), 4.15 (s, 2H), 3.86 (s, 2H), 3.65 - 3.45 (m, 4H), 3.23 - 3.13 (m, 2H), 2.80 - 2.55 (m, 2H), 1.83 -1.60 (m, 2H), 1.46 (m, 1H), 1.38 - 1.16 (m, 2H), 0.93 (d, J= 6.4 Hz, 3H). Mass (m/z): 422.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -2-oxoimidazolidine-4-carboxamide (667)

The title compound 667 (14.0 mg) as a wheat-colored powder was prepared in 68.5% total yield according to the procedure for compound 625 from 4- (aminomethyl) -N- (4- (4-methylpiperidin-1-yl) phenyl) aniline (14.8 mg, 0.05 mmol), 2-oxoimidazolidine-4-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol) and HATU (25 mg, 0.065 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.30 - 6.69 (m, 8H), 4.17 (s, 2H), 4.09 (m, 1H), 3.65 - 3.43 (m, 3H), 3.22 (m, 1H), 2.72 - 2.54 (m, 2H), 1.82 - 1.58 (m, 2H), 1.46 (m, 1H), 1.37 - 1.10 (m, 2H), 0.94 (d, J = 6.4 Hz, 3H). Mass (m/z): 408.2 [ M + H ]] ⁺ 。

(S) -N- (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -2,6-dioxohexahydropyrimidine-4-carboxamide (668)

The title compound 668 (7.4 mg) was prepared as a wheat-colored powder in 33.9% total yield from 4- (aminomethyl) -N- (4- (4-methylpiperidin-1-yl) phenyl) aniline (14.8 mg, 0.05 mmol), (S) -2,6-dioxohexahydropyrimidine-4-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.31 - 6.63 (m, 8H), 4.15 (s, 2H), 4.01 (m, 1H), 3.67 - 3.42 (m, 3H), 2.84 (m, 1H), 2.68 - 2.54 (m, 2H), 1.87 - 1.62 (m, 2H), 1.46 (m, 1H), 1.39 - 1.15 (m, 2H), 0.94 (d, J= 6.4 Hz, 3H). Mass (m/z): 436.2 [ M + H ]] ⁺ 。

N- (2-methoxy-4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (669)

The title compound 669 (8.2 mg) was prepared as a wheat-colored powder in 33.4% total yield from 4- (aminomethyl) -3-methoxy-N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (19.5 mg, 0.05 mmol), 5-oxopyrrolidine-3-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.06-6.85 (m, 5H), 6.58-6.44 (m, 2H), 4.12 (s, 2H), 3.71 (s, 3H), 3.67-3.55 (m, 2H), 3.41 (m, 1H), 3.28-3.11 (m, 2H), 2.68-2.54 (m, 2H), 2.43 (m, 1H), 2.32-2.23 (m, 2H), 1.95-1.80 (m, 2H), 1.65-1.48 (m, 2H). Mass (m/z): 491.2 [ M + H ]] ⁺ 。

N- (2-fluoro-4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (670)

The title compound 670 (10.9 mg) was prepared as a wheat-colored solid in 45.5% overall yield from 4- (aminomethyl) -3-fluoro-N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (18.3 mg, 0.05 mmol), 5-oxopyrrolidine-3-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.12-6.86 (m, 5H), 6.72-6.56 (m, 2H), 4.17 (s, 2H), 3.74-3.58 (m, 2H), 3.39 (m, 1H), 3.28-3.06 (m, 2H), 2.71-2.58 (m, 2H), 2.43 (m, 1H), 2.32-2.25 (m, 2H), 1.92-1.83 (m, 2H), 1.63-1.50 (m, 2H). Mass (m/z): 479.2 [ M + H ]] ⁺ 。

1-ethyl-3- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) urea (671)

The title compound 671 (14.0 mg) was prepared as a white solid in 33.3% overall yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (34.9 mg, 0.1 mmol), ethylamine (4.9 mg, 0.11 mmol), CDI (17.8 mg, 0.11 mmol), and DIEA (38.7 mg, 0.3 mmol) according to the procedure for compound 660. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.25 - 6.70 (m, 8H), 4.06 (s, 2H), 3.75 - 3.47 (m, 2H), 3.02 (q, J = 7.2 Hz, 2H), 2.75 - 2.54 (m, 2H), 2.42 (m, 1H), 1.97 - 1.75 (m, 2H), 1.68 - 1.45 (m, 2H), 0.98 (t, J= 7.2 Hz, 3H). Mass (m/z): 421.3 [ M + H ]] ⁺ 。

1- (tert-butyl) -3- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) urea (672)

The procedure for compound 660 was followed from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (34.9 mg, 0.1 mmol), 2-methylpropan-2-amine (10.3 mg, 0.11 mmol), CDI (178 mg, 0.11 mmol) and DIEA (38.7 mg, 0.3 mmol) the title compound 672 (8.0 mg) was prepared as a white solid in a total yield of 35.3%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.09-6.82 (m, 8H), 4.02 (s, 2H), 3.68-3.55 (m, 2H), 2.69-2.55 (m, 2H), 2.42 (m, 1H), 1.95-1.82 (m, 2H), 1.63-1.51 (m, 2H), 1.22 (s, 9H). Mass (m/z): 449.3 [ M + H ]] ⁺ 。

(S) -2-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) imidazolidine-4-carboxamide (673)

The title compound 673 (12.2 mg) as a wheat-colored solid was prepared according to the procedure for compound 625 from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), (S) -2-oxoimidazolidine-4-carboxylic acid (8.5 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) in 52.8% overall yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.43-6.67 (m, 8H), 4.18 (s, 2H), 4.09 (m, 1H), 3.78-3.47 (m, 3H), 3.22 (m, 1H), 2.71-2.54 (m, 2H), 2.41 (m, 1H), 2.05-1.77 (m, 2H), 1.69-1.44 (m, 2H). Mass (m/z): 462.2 [ M + H ] ] ⁺ 。

(R) -2-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) imidazolidine-4-carboxamide (674)

The title compound 674 (8.2 mg) as a wheat-colored solid was prepared according to the procedure for compound 625 from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), (R) -2-oxoimidazolidine-4-carboxylic acid (8.5 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) in a total yield of 36.0%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.31 - 6.72 (m, 8H), 4.18 (s, 2H), 4.12 (m, 1H),3.73-3.50 (m, 3H), 3.24 (m, 1H), 2.78-2.54 (m, 2H), 2.40 (m, 1H), 1.97-1.77 (m, 2H), 1.67-1.44 (m, 2H). Mass (m/z): 462.2 [ M + H ]] ⁺ 。

1-ethyl-5-imino-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (675)

The title compound 675 (8.0 mg) was prepared as a wheat-colored solid in 32.7% overall yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), 1-ethyl-5-iminopyrrolidine-3-carboxylic acid (10.1 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.32 - 6.70 (m, 8H), 4.35 (s, 2H), 3.85 - 3.78 (m, 6H), 3.73 (m, 1H), 3.67 - 3.55 (m, 2H), 2.71 - 2.55 (m, 2H), 2.41 (m, 1H), 1.95 - 1.79 (m, 2H), 1.65 - 1.46 (m, 2H), 0.85 (t, J= 6.8 Hz, 3H). Mass (m/z): 488.3 [ M + H ]] ⁺ 。

3,5 dioxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) piperazine-1-carboxamide (676)

The title compound 676 (18.0 mg) as a light gray solid was prepared in 36.8% overall yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (34.9 mg, 0.1 mmol), DIEA (39.0 mg, 0.3 mmol), CDI (17.8 mg, 0.11 mmol), and piperazine-2,6-dione (12.1 mg, 0.11 mmol) according to the procedure for compound 660. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.23-6.75 (m, 8H), 4.40 (s, 2H), 3.98 (s, 2H), 3.87 (s, 2H), 3.65-3.44 (m, 2H), 2.67-2.54 (m, 2H), 2.43 (m, 1H), 1.91-1.81 (m, 2H), 1.63-1.47 (m, 2H). Mass (m/z): 490.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -3,5-dioxopiperazine-1-carboxamide (677)

From 4- (aminomethyl) -N- (4- (4-methylpiperidin-1-yl) phenyl) aniline (29 mg, 0.1 mmol), piperazine-2,6-dione (12.1 mg, 0.11 mmol), CDI (17.8 mg, 0.11 mmol) and DIEA (38.7 mg, 0.3 mmol) the title compound 677 (13.0 mg) was prepared as a white solid in a total yield of 29.8%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.31 - 6.67 (m, 8H), 4.42 (s, 2H), 4.00 (s, 2H), 3.89 (s, 2H), 3.68 - 3.42 (m, 2H), 2.71 - 2.54 (m, 2H), 1.83 - 1.57(m, 2H), 1.46 (m, 1H), 1.35 - 1.14 (m, 2H), 0.94 (d, J= 6.0 Hz, 3H). Mass (m/z): 436.2 [ M + H ]] ⁺ 。

2,6 dioxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) piperidine-4-carboxamide (678)

The title compound 678 (12.0 mg) was prepared as a gray solid in 49.1% total yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (17.5 mg, 0.05 mmol), 2,6-dioxopiperidine-4-carboxylic acid (10.2 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.15-6.79 (m, 8H), 4.15 (s, 2H), 3.70-3.53 (m, 2H), 2.99 (m, 1H), 2.74-2.52 (m, 6H), 2.40 (m, 1H), 1.94-1.80 (m, 2H), 1.67-1.48 (m, 2H). Mass (m/z): 489.2 [ M + H ]] ⁺ 。

5-oxo-N- (4- ((4-propyl-3,4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) amino) benzyl) pyrrolidine-3-carboxamide (679)

From N- (4- (aminomethyl) phenyl) -4-propyl-3,4-dihydro-2H-benzo [ b ] according to the procedure for Compound 625][1,4]Oxazin-7-amine (14.9 mg, 0.05 mmol), 5-oxopyrrolidine-3-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol) and HATU (25 mg, 0.065 mmol) the title compound 679 (8.6 mg) was prepared as a gray solid in a total yield of 42.1%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.25-6.35 (m, 7H), 4.14 (s, 2H), 3.27-3.12 (m, 5H), 2.54-2.51 (m, 4H), 2.36-2.21 (m, 2H), 1.62-1.45 (m, 2H), 0.98-0.76 (m, 3H). Mass (m/z): 409.2 [ M + H ]] ⁺ 。

2,4 dioxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) imidazolidine-1-carboxamide (680)

The title compound 680 (10.1 mg) was prepared as a white solid in 43.8% total yield from 4- (aminomethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (34.9 mg, 0.1 mmol), CDI (17.8 mg, 0.11 mmol), DIEA (39.0 mg, 0.3 mmol), and imidazolidine-2,4-dione (11.0 mg, 0.11 mmol) according to the procedure for compound 660. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.43-6.71 (m, 8H), 4.38 (s, 2H), 4.19 (s, 2H), 3.66-3.47 (m, 2H), 2.73-2.54 (m, 2H), 2.41 (m, 1H), 1.92-1.82 (m, 2H), 1.64-1.51 (m, 2H). Mass (m/z): 476.2 [ M + H ]] ⁺ 。

5-oxo-N- (4- ((2- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (681)

From N- (4- (aminomethyl) phenyl) -2- (4- (trifluoromethyl) piperidin-1-yl) aniline (17.5 mg, 0.05 mmol), 5-oxopyrrolidine-3-Formic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol) and HATU (25 mg, 0.065 mmol) prepared the title compound 681 (8.4 mg) as a white powder in a total yield of 36.4%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.21-6.76 (m, 8H), 4.19 (s, 2H), 3.75-3.64 (m, 2H), 3.42 (m, 1H), 3.26-3.17 (m, 2H), 2.74-2.66 (m, 2H), 2.34-2.27 (m, 3H), 1.91-1.83 (m, 2H), 1.59-1.52 (m, 2H). Mass (m/z): 461.2 [ M + H ]] ⁺ 。

N- (4- ((4- (diethylamino) -3-fluorophenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (682)

The title compound 682 (8.4 mg) was prepared according to the procedure for compound 625 from N4- (4- (aminomethyl) phenyl) -N1, N1-diethyl-2-fluorobenzene-1,4-diamine (14.5 mg, 0.05 mmol), 5-oxopyrrolidine-3-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) as a white powder in a total yield of 42.1%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.46 - 6.68 (m, 7H), 4.21 (s, 2H), 3.54 - 3.31 (m, 5H), 3.28 - 3.10 (m, 2H), 2.42 - 2.28 (m, 2H), 0.99 (t, J = 7.2 Hz, 6H). Mass (m/z): 399.2 [ M + H ]] ⁺ 。

N- (4- ((3-chloro-4- (diethylamino) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (683)

The title compound 683 (13.2 mg) was prepared according to the procedure for compound 625 from N4- (4- (aminomethyl) phenyl) -2-chloro-N1, N1-diethylbenzene-1,4-diamine (15.2 mg, 0.05 mmol), 5-oxopyrrolidine-3-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) as a white powder in 63.6% overall yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.53 (s, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.14 - 7.03 (m, 4H), 4.23 (s, 2H), 3.55 - 3.35 (m, 5H), 3.27 - 3.11 (m, 2H), 2.34 - 2.28 (m, 2H), 0.98 (t, J = 7.2 Hz, 6H). Mass (m/z): 415.2 [ M + H ]] ⁺ 。

N- (4- ((4- (diethylamino) -3-methylphenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (684)

The title compound 684 (4.2 mg) was prepared as a white powder in 21.3% overall yield from N4- (4- (aminomethyl) phenyl) -N1, N1-diethyl-2-methylbenzene-1,4-diamine (14.1 mg, 0.05 mmol), 5-oxopyrrolidine-3-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol) and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.26 - 6.67 (m, 7H), 4.18 (s, 2H), 3.62 - 3.45 (m, 2H), 3.44 - 3.36 (m, 2H), 3.29 - 3.11 (m, 3H), 2.41 - 2.25 (m, 2H), 2.17 (s, 3H), 0.87 (t, J = 7.2 Hz, 6H). Mass (m/z): 395.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -2,6-dioxopiperidine-4-carboxamide (685)

The title compound 685 (12.6 mg) was prepared as a wheat-colored powder in 29.7% total yield from 4- (aminomethyl) -N- (4- (4-methylpiperidin-1-yl) phenyl) aniline (14.8 mg, 0.05 mmol), 2,6-dioxopiperidine-4-carboxylic acid (10.2 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.25 - 6.73 (m, 8H), 4.14 (s, 2H), 3.65 - 3.36 (m, 2H), 2.99 (m, 1H), 2.70 - 2.52 (m, 6H), 1.87 - 1.58 (m, 2H), 1.55 - 1.17 (m, 3H), 0.94 (d, J = 6.4 Hz, 3H). Mass (m/z): 435.2 [ M + H ]] ⁺ 。

N- (4- ((2- (Azacyclooctan-1-yl) pyrimidin-5-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (686)

The title compound 686 (12.1 mg) as a wheat-colored powder was prepared according to the procedure for compound 625 from N- (4- (aminomethyl) phenyl) -2- (azacyclooctan-1-yl) pyrimidin-5-amine (15.7 mg, 0.05 mmol), 5-oxopyrrolidine-3-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) in 56.9% overall yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.21 (s, 2H), 7.07-6.96 (m, 2H), 6.74-6.62 (m, 2H), 4.13 (s, 2H), 3.75-3.57 (m, 4H), 3.46-3.36 (m, 1H), 3.27-3.09 (m, 2H), 2.34-2.21 (m, 2H), 1.78-1.65 (m, 4H), 1.55-1.38 (m, 6H). Mass (m/z): 423.2 [ M + H ]] ⁺ 。

N- (4- ((5-chloro-2-fluoro-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (687)

The title compound 687 (10.1 mg) was prepared as a wheat-colored powder in 38.9% overall yield from N- (4- (aminomethyl) phenyl) -5-chloro-2-fluoro-4- (4- (trifluoromethyl) piperidin-1-yl) aniline (25.2 mg, 0.05 mmol), 5-oxopyrrolidine-3-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.25-7.17 (m, 2H), 7.13 (m, 1H), 7.06-6.93 (m, 3H), 4.32 (s, 2H), 3.66-3.46 (m, 2H), 3.26 (m, 1H), 2.70-2.46 (m, 4H), 2.32-2.16 (m, 2H), 2.08-1.98 (m, 1H), 1.94-1.85 (m, 2H), 1.77-1.63 (m, 2H). Mass (m/z): 513.2 [ M + H ]] ⁺ 。

N-hydroxy-5-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (688)

The title compound 688 (10.5 mg) was prepared as a light yellow powder in total yield of 41.9% according to the procedure for compound 625 from 4- ((hydroxyamino) methyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (18.2 mg, 0.05 mmol), 5-oxopyrrolidine-3-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol) and HATU (25 mg, 0.065 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.06 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 6.94-6.84 (m, 4H), 4.57 (s, 2H), 3.75-3.55 (m, 3H), 3.46 (m, 1H), 3.24 (m, 1H), 2.70-2.55 (m, 2H), 2.41 (m, 1H), 2.37-2.24 (m, 2H), 1.94-1.82 (m, 2H), 1.65-1.50 (m, 2H). Mass (m/z): 477.2 [ M + H ]] ⁺ 。

N-hydroxy-2,6 dioxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) piperidine-4-carboxamide (689)

The title compound 689 (10.5 mg) was prepared as a light yellow powder in 41.9% total yield from 4- ((hydroxyamino) methyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (18.2 mg, 0.05 mmol), 2,6-dioxopiperidine-4-carboxylic acid (10.2 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.03 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 6.93 - 6.84 (m, 4H), 4.54 (s, 2H), 3.67 - 3.58 (m, 2H), 3.52 (p, J= 6.0 Hz, 1H), 2.75-2.53 (m, 6H), 2.42 (m, 1H), 1.93-1.82 (m, 2H), 1.64-1.51 (m, 2H). Mass (m/z): 505.3 [ M + H ]] ⁺ 。

1-acetyl-N- (4- ((4-cyclohexylphenyl) amino) benzyl) azetidine-3-carboxamide (690)

The title compound 690 (7.2 mg) was prepared as a yellow powder in 35.6% overall yield from 4- (aminomethyl) -N- (4-cyclohexylphenyl) aniline (14.0 mg, 0.05 mmol), 1-acetoacetidine-3-carboxylic acid (9.3 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.17-6.88 (m, 8H), 4.19 (s, 2H), 4.17-4.06 (m, 2H), 3.95-3.79 (m, 2H), 3.33-3.28 (m, 1H), 2.39 (m, 1H), 1.87-1.65 (m, 5H), 1.73 (s, 3H), 1.39-1.13 (m, 5H). Mass (m/z): 406.3 [ M + H ]] ⁺ 。

N- (4- ((4-cyclohexylphenyl) amino) benzyl) -2,6-dioxopiperidine-4-carboxamide (691)

The title compound 691 (8.7 mg) was prepared as a yellow powder in 41.4% overall yield from 4- (aminomethyl) -N- (4-cyclohexylphenyl) aniline (14.0 mg, 0.05 mmol), 2,6-dioxopiperidine-4-carboxylic acid (10.2 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.12-6.91 (m, 8H), 4.15 (s, 2H), 2.99 (m, 1H), 2.72-2.52 (m, 4H), 2.39 (m, 1H), 1.83-1.63 (m, 5H), 1.43-1.13 (m, 5H). Mass (m/z): 420.2 [ M + H ]] ⁺ 。

N- (4- ((4-cyclohexylphenyl) amino) benzyl) azetidine-3-carboxamide (692)

Prepared according to the procedure for compound 625 from 4- (aminomethyl) -N- (4-cyclohexylphenyl) aniline (14.0 mg, 0.05 mmol), azetidine-3-carboxylic acid (5.1 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol) and HATU (25 mg, 0.065 mmol) as a yellow powder in 64.3% overall yieldThe final title compound 692 (11.7 mg). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.18 - 6.88 (m, 8H), 4.18 (s, 2H), 4.03 - 3.85 (m, 4H), 3.59 (p, J= 8.4 Hz, 1H), 2.38 (m, 1H), 1.83-1.61 (m, 5H), 1.42-1.15 (m, 5H). Mass (m/z): 364.2 [ M + H ]] ⁺ 。

(S) -N-hydroxy-2-oxo-N- (4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) imidazolidine-4-carboxamide (693)

The title compound 693 (9.7 mg) was prepared as a sky blue powder in total yield of 40.1% according to the procedure for compound 625 from 4- ((hydroxyamino) methyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (18.2 mg, 0.05 mmol), (S) -2-oxoimidazolidine-4-carboxylic acid (8.5 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) Delta 7.31-6.86 (m, 8H), 4.59 (s, 2H), 4.52 (m, 1H), 3.73-3.51 (m, 4H), 3.29-3.02 (m, 2H), 2.61 (m, 1H), 2.10-1.91 (m, 2H), 1.85-1.65 (m, 2H). Mass (m/z): 478.1 [ M + H ] ] ⁺ 。

N- (3-fluoro-4- ((2- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-5-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (694)

The title compound 694 (10.7 mg) was prepared as a wheat-colored solid in 44.5% overall yield from N- (4- (aminomethyl) -2-fluorophenyl) -2- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-5-amine (18.5 mg, 0.05 mmol), 5-oxopyrrolidine-3-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.63 - 7.50 (m, 2H), 7.03 (m, 1H), 6.91 - 6.69 (m, 2H), 4.69 (s, 2H), 4.22 - 4.12 (m, 2H), 3.46 - 3.37 (m, 1H), 3.26 - 313 (m, 2H), 2.95-2.83 (m, 2H), 2.62 (m, 1H), 2.34-2.25 (m, 2H), 1.93-1.82 (m, 2H), 1.45-1.30 (m, 2H). Mass (m/z): 481.2 [ M + H ]] ⁺ 。

N- (4- ((4-cyclohexylphenyl) amino) benzyl) -N-hydroxy-5-oxopyrrolidine-3-carboxamide (695)

The title compound 695 (8.8 mg) was prepared according to the procedure for compound 625 from 4-cyclohexyl-N- (4- ((hydroxyamino) methyl) phenyl) aniline (14.8 mg, 0.05 mmol), 5-oxopyrrolidine-3-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) as a light yellow powder in a total yield of 43.2%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.16-6.91 (m, 8H), 4.59 (s, 2H), 3.76-3.57 (m, 1H), 3.46 (m, 1H), 3.25 (m, 1H), 2.45-2.24 (m, 3H), 1.83-1.65 (m, 5H), 1.43-1.27 (m, 5H). Mass (m/z): 408.1 [ M + H ] ] ⁺ 。

N1- (4- ((4- (4,4-dimethylpiperidin-1-yl) phenyl) amino) benzyl) oxamide (696)

The title compound 696 (9.0 mg) was prepared according to the procedure for compound 625 from 4- (aminomethyl) -N- (4- (4,4-dimethylpiperidin-1-yl) phenyl) aniline (15.4 mg, 0.05 mmol), 2-amino-2-oxoacetic acid (4.5 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) as a light yellow powder in a total yield of 47.2%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.06 (d, J = 8.4 Hz, 2H), 6.95 (d, J= 8.4 Hz, 2H), 6.90-6.80 (m, 4H), 4.17 (s, 2H), 3.08-2.94 (m, 4H), 1.52-1.36 (m, 4H), 0.94 (s, 6H). Mass (m/z): 381.3 [ M + H ]] ⁺ 。

1- (4- ((4- (4,4-dimethylpiperidin-1-yl) phenyl) amino) benzyl) urea (697)

The title compound 697 (10.9 mg) was prepared according to the procedure for compound 662 as a light yellow powder in a total yield of 61.9% from 4- (aminomethyl) -N- (4- (4,4-dimethylpiperidin-1-yl) phenyl) aniline (15.4 mg, 0.05 mmol), phenyl carbamate (8.2 mg, 0.06 mmol), and DIEA (19 mg, 0.15 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.35-6.67 (m, 8H), 4.04 (s, 2H), 3.31-2.69 (m, 4H), 1.55-1.37 (m, 4H), 0.95 (s, 6H). Mass (m/z): 353.2 [ M + H ]] ⁺ 。

3,5 dioxo-N- (4- ((4- (4-propylpiperidin-1-yl) phenyl) amino) benzyl) piperazine-1-carboxamide (698)

The title compound 698 (10.1 mg) was prepared as a white solid in 21.5% total yield from 4- (aminomethyl) -N- (4- (4-propylpiperidin-1-yl) phenyl) aniline (32.3 mg, 0.1 mmol), piperazine-2,6-dione (12.1 mg, 0.11 mmol), CDI (17.8 mg, 0.11 mmol), and DIEA (38.7 mg, 0.3 mmol) according to the procedure for compound 660. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.56 - 6.98 (m, 8H), 4.61 (s, 2H), 4.07 (s, 4H), 3.80 - 3.51 (m, 2H), 2.23 - 1.94 (m, 3H), 1.86 - 1.53 (m, 4H), 1.48 - 1.36 (m, 4H), 0.97 (t, J = 7.2 Hz, 3H). Mass (m/z): 464.3 [ M + H ]] ⁺ 。

2,4 dioxo-N- (4- ((4- (4-propylpiperidin-1-yl) phenyl) amino) benzyl) imidazolidine-1-carboxamide (699)

The procedure was followed for compound 660 from 4- (aminomethyl) -N- (4- (4-propylpiperidin-1-yl) phenyl) aniline (32.3 mg, 0.1 mmol), imidazolidine-2,4-dione (11.0 mg, 0.11 mmol), CDI (17.8 mg, 0.11 mmol), and DIEA (38.7 mg, 0).3 mmol) the title compound 699 (9.3 mg) was prepared as a white solid in 20.9% overall yield. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.55 - 6.85 (m, 8H), 4.41 (s, 2H), 4.28 (s, 2H), 3.78 - 3.45 (m, 2H), 2.19 - 1.95 (m, 3H), 1.86 - 1.53 (m, 4H), 1.48 - 1.36 (m, 4H), 0.93 (t, J = 7.2 Hz, 3H). Mass (m/z): 450.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4,4-dimethylcyclohexyl) phenyl) amino) benzyl) -1-methylpyrrolidine-3-carboxamide (700)

The title compound 700 (11.2 mg) was prepared as a light gray solid in 53.3% total yield from 4- (aminomethyl) -N- (4- (4,4-dimethylcyclohexyl) phenyl) aniline (15.4 mg, 0.05 mmol), 1-methylpyrrolidine-3-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.16-6.90 (m, 8H), 4.18 (s, 2H), 3.29-3.12 (m, 3H), 2.80 (s, 3H), 2.39-2.13 (m, 2H), 2.11-1.95 (m 1H), 1.65-1.20 (m, 10H), 0.95 (s, 6H). Mass (m/z): 420.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4,4-dimethylcyclohexyl) phenyl) amino) benzyl) pyrrolidine-3-carboxamide (701)

The title compound 701 (9.1 mg) was prepared according to the procedure for compound 625 as a light gray solid in 44.3% overall yield from 4- (aminomethyl) -N- (4- (4,4-dimethylcyclohexyl) phenyl) aniline (15.4 mg, 0.05 mmol), pyrrolidine-3-carboxylic acid (7.5 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.08 (d, J = 8.4 Hz, 4H), 7.01 - 6.94 (m, 4H), 4.17 (s, 2H), 3.31 (m, 1H), 3.22 - 3.04 (m, 2H), 2.29 (m, 1H), 2.13 (m, 1H), 1.93 (m1H), 1.62-1.48 (m, 4H), 1.47-1.39 (m, 2H), 1.37-1.16 (m, 4H), 0.94 (s, 6H). Mass (m/z): 406.3 [ M + H ]] ⁺ 。

N1- (4- ((4- (4-ethylpiperidin-1-yl) phenyl) amino) benzyl) oxamide (702)

The title compound 702 (9.0 mg) was prepared as a light yellow powder in 47.2% total yield from 4- (aminomethyl) -N- (4- (4-ethylpiperidin-1-yl) phenyl) aniline (15.4 mg, 0.05 mmol), 2-amino-2-oxoacetic acid (4.5 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.40 - 6.58 (m, 8H), 4.18 (s, 2H), 3.67 - 3.44 (m, 2H), 2.69 - 2.55 (m, 2H), 2.06 - 1.55 (m, 2H), 1.33 - 1.10 (m, 5H), 0.89 (t, J = 7.2 Hz, 3H). Mass (m/z): 381.2 [ M + H ] ] ⁺ 。

N1- (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) oxamide (703)

The title compound 703 (8.3 mg) was prepared according to the procedure for compound 625 from 4- (aminomethyl) -N- (4- (4-methylpiperidin-1-yl) phenyl) aniline (14.8 mg, 0.05 mmol), 2-amino-2-oxoacetic acid (4.5 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) as a light yellow powder in a total yield of 45.2%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.28 - 6.64 (m, 8H), 4.18 (s, 2H), 3.70 - 3.41 (m, 2H), 2.71 - 2.53 (m, 2H), 1.83 - 1.54 (m, 2H), 1.45 (m, 1H), 1.34 - 1.13 (m, 2H), 0.93 (d, J= 6.4 Hz, 3H). Mass (m/z): 367.2 [ M + H ]] ⁺ 。

1- (4- ((4- (4-ethylpiperidin-1-yl) phenyl) amino) benzyl) urea (704)

The title compound 704 (8.9 mg) was prepared according to the procedure for compound 662 as a light yellow powder from 4- (aminomethyl) -N- (4- (4-ethylpiperidin-1-yl) phenyl) aniline (15.4 mg, 0.05 mmol), phenyl carbamate (8.2 mg, 0.06 mmol), and DIEA (19 mg, 0.15 mmol) in a total yield of 50.9%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.30 - 6.66 (m, 8H), 4.04 (s, 2H), 3.65 - 3.43 (m, 2H), 2.65 - 2.53 (m, 2H), 1.86 - 1.63 (m, 2H), 1.33 - 1.11 (m, 5H), 0.89 (t, J = 7.2 Hz, 3H). Mass (m/z): 353.3 [ M + H ]] ⁺ 。

1- (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) urea (705)

The title compound 705 (15.5 mg) was prepared according to the procedure for compound 662 as a white powder from 4- (aminomethyl) -N- (4- (4-methylpiperidin-1-yl) phenyl) aniline (14.8 mg, 0.05 mmol), phenyl carbamate (8.2 mg, 0.06 mmol), and DIEA (19 mg, 0.15 mmol) in a total yield of 91.4%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.24 - 6.60 (m, 8H), 4.04 (s, 2H), 3.65 - 3.41 (m, 2H), 2.71 - 2.52 (m, 2H), 1.80 - 1.61 (m, 2H), 1.44 (m, 1H), 1.34 - 1.14 (m, 2H), 0.93 (d, J= 6.4 Hz, 3H). Mass (m/z): 339.2 [ M + H ]] ⁺ 。

N- (4- ((4- (4,4-dimethylcyclohexyl) phenyl) amino) benzyl) -3,5-dioxopiperazine-1-carboxamide (706)

Prepared according to the procedure for compound 660 from 4- (aminomethyl) -N- (4- (4,4-dimethylcyclohexyl) phenyl) aniline (30.8 mg, 0.1 mmol), piperazine-2,6-dione (12.1 mg, 0.11 mmol), CDI (17.8 mg, 0.11 mmol), and DIEA (38.7 mg, 0.3 mmol) in total yield of 70.5% as whiteThe title compound 706 (8.1 mg) as a solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.13-7.03 (m, 4H), 7.00-6.91 (m, 4H), 4.19 (s, 4H), 4.13 (s, 2H), 2.29 (m, 1H), 1.63-1.20 (m, 8H), 0.95 (s, 3H), 0.93 (s, 3H). Mass (m/z): 449.3 [ M + H ]] ⁺ 。

N- (4- ((3- (azepan-1-yl) -4-fluorophenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (707)

The title compound 707 (7.8 mg) was prepared as a yellow powder in 36.7% overall yield from N- (4- (aminomethyl) phenyl) -3- (azepan-1-yl) -4-fluoroaniline (15.6 mg, 0.05 mmol), 5-oxopyrrolidine-3-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.06 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 6.90-6.77 (m, 1H), 6.40-6.31 (m, 1H), 6.20 (m, 1H), 4.15 (s, 2H), 3.45-3.13 (m, 4H), 2.97-2.84 (m, 2H), 2.36-2.24 (m, 2H), 2.24-2.15 (m, 1H), 1.78-1.65 (m, 2H), 1.63-1.45 (m, 4H), 1.28-1.18 (m, 2H). Mass (m/z): 425.2 [ M + H ] ] ⁺ 。

N- (4- ((4-fluoro-3- (pyrrolidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (708)

The title compound 708 (14.1 mg) was prepared as a yellow powder in 71.0% overall yield from N- (4- (aminomethyl) phenyl) -4-fluoro-3- (pyrrolidin-1-yl) aniline (14.2 mg, 0.05 mmol), 5-oxopyrrolidine-3-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.08 (d, J = 8.4 Hz, 2H), 7.00 - 6.81 (m, 3H), 6.42 - 6.28 (m, 2H), 4.17 (s, 2H), 3.41 (m, 1H), 3.31-3.12 (m, 6H), 2.35-2.26 (m, 2H), 1.95-1.79 (m, 4H). Mass (m/z): 397.2 [ M + H ]] ⁺ 。

N-hydroxy-N- (4- ((4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (709)

The title compound 709 (12.1 mg) was prepared as a white solid in 56.7% overall yield from 4- ((hydroxyamino) methyl) -N- (4- (4-methylpiperidin-1-yl) phenyl) aniline (15.5 mg, 0.05 mmol), 5-oxopyrrolidine-3-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.30 - 6.99 (m, 8H), 4.63 (s, 2H), 3.74 - 3.62 (m, 2H), 3.56- 3.41 (m, 4H), 3.26 (m, 1H), 2.39 - 2.28 (m, 2H), 1.95 - 1.84 (m, 2H), 1.77 (m, 1H), 1.62 - 1.49 (m, 2H), 0.99 (d, J= 6.4 Hz, 3H). Mass (m/z): 423.3 [ M + H ]] ⁺ 。

N- (4- ((2-methyl-6- (4- (trifluoromethyl) cyclohexyl) pyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (710)

The title compound 710 (10.3 mg) was prepared as a white solid in 43.5% total yield from N- (4- (aminomethyl) phenyl) -2-methyl-6- (4- (trifluoromethyl) cyclohexyl) pyridin-3-amine (18.2 mg, 0.05 mmol), 5-oxopyrrolidine-3-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) Δ 7.53-7.36 (m, 2H), 7.15-7.00 (m, 2H), 6.93-6.73 (m, 2H), 4.18 (s, 2H), 3.30-3.11 (m, 2H), 2.87 (m, 1H), 2.38 (s, 3H), 2.34-2.19 (m, 3H), 2.15-1.86 (m, 2H), 1.82-1.50 (m, 6H). Mass (m/z): 475.2 [ M + H ]] ⁺ 。

N- (4- ((4- (4-hydroxy-4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -1-methylpyrrolidine-3-carboxamide (711)

The title compound 711 (9.6 mg) was prepared as a light yellow solid in total yield of 40.2% from 1- (4- ((4- (aminomethyl) phenyl) amino) phenyl) -4- (trifluoromethyl) piperidin-4-ol (15.4 mg, 0.05 mmol), 1-methylpyrrolidine-3-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.14-6.82 (m, 8H), 4.16 (s, 2H), 3.33-3.09 (m, 6H), 2.92-2.82 (m, 2H), 2.77 (s, 3H), 2.23 (m, 1H), 2.05 (m, 1H), 1.85-1.66 (m, 4H). Mass (m/z): 477.3 [ M + H ] ] ⁺ 。

N- (4- ((4-fluoro-6- (4- (trifluoromethyl) piperidin-1-yl) pyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (712)

The title compound 712 (10.5 mg) was prepared as a white solid in 42.9% overall yield from N- (4- (aminomethyl) phenyl) -4-fluoro-6- (4- (trifluoromethyl) piperidin-1-yl) pyridin-3-amine (18.4 mg, 0.05 mmol), 5-oxopyrrolidine-3-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.50 (s, 1H), 7.00 (d, J = 8.4 Hz, 2H), 6.85 (m, 1H), 6.59 (d, J = 8.4 Hz, 2H), 4.35 (s, 2H), 4.15-4.09 (m, 2H), 3.41 (m, 1H), 3.25-3.11 (m, 2H), 2.90-2.76 (m, 2H), 2.63 (m, 1H), 2.31-2.23 (m, 2H), 1.91-1.80 (m, 2H), 1.49-1.34 (m, 2H). Mass (m/z): 480.2 [ M + H ]] ⁺ 。

N- (4- ((2- (2-azaspiro [3.3] heptan-2-yl) pyrimidin-5-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (713)

Synthesis of N- (4- (aminomethyl) phenyl) -2- (2-azaspiro [3.3] according to the procedure for Compound 625]Heptane-2-yl) pyrimidin-5-amine (14.8 mg, 0.05 mmol), 5-oxopyrrolidine-3-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol) and HATU (25 mg, 0.065 mmol) the title compound 713 (4.5 mg) was prepared as a white solid in 22.1% total yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.66 (s, 1H), 7.58 (s, 1H), 7.03 (d, J = 8.4 Hz, 2H), 6.71 (d, J = 8.4 Hz, 2H), 4.13 (s, 2H), 3.96 (s, 4H), 3.38 (m, 1H), 3.27 - 3.11 (m, 2H), 2.31 - 2.25 (m, 2H), 2.17 (t, J = 7.6 Hz, 4H), 1.86-1.76 (m, 2H). Mass (m/z): 407.2 [ M + H ]] ⁺ 。

N- (4- ((2- (2-azaspiro [3.4] octan-2-yl) pyrimidin-5-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (714)

Synthesis of N- (4- (aminomethyl) phenyl) -2- (2-azaspiro [3.4] from the procedure of Compound 625]Octane-2-yl) pyrimidin-5-amine (15.5 mg, 0.05 mmol), 5-oxopyrrolidine-3-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol) and HATU (25 mg, 0.065 mmol) the title compound 714 (7.2 mg) was prepared as a white solid in a total yield of 34.2%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.66 (s, 1H), 7.58 (s, 1H), 7.03 (d, J = 8.4 Hz, 2H), 6.71 (d, J = 8.4 Hz, 2H), 4.13 (s, 2H), 3.84 (s, 4H), 3.40 (m, 1H), 3.26 - 3.08 (m, 2H), 2.34 - 2.25 (m, 2H), 1.79 (t, J = 6.8, 4H), 1.63-1.53 (m, 4H). Mass (m/z): 421.3 [ M + H ]] ⁺ 。

N- (2- (2- (dimethylamino) ethyl) -4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (715)

The title compound 715 (6.7 mg) was prepared according to the procedure for compound 625 from 4- (aminomethyl) -3- (2- (dimethylamino) ethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (21.0 mg, 0.05 mmol), 5-oxopyrrolidine-3-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) as a white solid in an overall yield of 25.2%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.21 (s, 1H), 7.15-6.73 (m, 6H), 4.21 (s, 2H), 3.70-3.55 (m, 2H), 3.42 (m, 1H), 3.30-3.19 (m, 2H), 3.17-3.11 (m, 2H), 3.02-2.91 (m, 2H), 2.80 (s, 6H), 2.70-2.56 (m, 2H), 2.35-2.23 (m, 2H), 2.01 (m, 1H), 1.95-1.81 (m, 2H), 1.68-1.51 (m, 2H). Mass (m/z): 532.3 [ M + H ] ] ⁺ 。

N- (2- (2-methoxyethyl) -4- ((4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (716)

The title compound 716 (7.0 mg) was prepared as a white solid in 26.9% overall yield from 4- (aminomethyl) -3- (2-methoxyethyl) -N- (4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) aniline (20.3 mg, 0.05 mmol), 5-oxopyrrolidine-3-carboxylic acid (8.4 mg, 0.065 mmol), DIEA (19 mg, 0.15 mmol), and HATU (25 mg, 0.065 mmol) according to the procedure for compound 625. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.05 - 6.66 (m, 7H), 4.18 (s, 2H), 3.68 - 3.55 (m, 2H), 3.47 (t, J = 6.8 Hz, 2H), 3.40 (m, 1H), 3.24 (s, 3H), 3.22-3.11 (m, 2H), 2.79-2.54 (m, 4H), 2.42 (m, 1H), 2.36-2.21 (m, 2H), 1.94-1.78 (m, 2H), 1.65-1.49 (m, 2H). Mass (m/z): 519.3 [ M + H ]] ⁺ 。

N- (4- ((6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-yl) amino) benzyl) -2,4-dioxoimidazolidine-1-carboxamide (717)

The title compound 717 (4.2 mg) as a white solid was prepared in 18.1% overall yield from N- (4- (aminomethyl) phenyl) -6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-amine (16.9 mg, 0.05 mmol), imidazolidine-2,4-dione (5.5 mg, 0.055 mmol), CDI (8.9 mg, 0.055 mmol) and DIEA (19.4 mg, 0.15 mmol) according to the procedure for compound 660. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.26 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 8.8 Hz, 1H), 6.51 (d, J = 8.4 Hz, 2H), 4.28 (s, 2H), 4.22 - 4.19 (m, 2H), 4.16 (s, 2H), 2.68 - 2.56 (m, 2H), 2.20 (s, 3H), 1.75 - 1.65 (m, 2H), 1.49 -1.37 (m, 1H), 1.21 - 1.13 (m, 3H), 0.88 (d, J= 6.8 Hz, 6H). Mass (m/z): 465.3 [ M + H ]] ⁺ 。

N- (4- ((6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-yl) amino) benzyl) -3,5-dioxopiperazine-1-carboxamide (718)

The title compound 718 (10.4 mg) was prepared as a white solid in 43.4% overall yield from N- (4- (aminomethyl) phenyl) -6- (4-isopropylpiperidin-1-yl) -2-methylpyridin-3-amine (16.9 mg, 0.05 mmol), piperazine-2,6-dione (6.1 mg, 0.055 mmol), CDI (8.9 mg, 0.055 mmol), and DIEA (19.4 mg, 0.15 mmol) according to the procedure for compound 660. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.25 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 8.4 Hz, 2H), 6.63 (d, J = 8.8 Hz, 1H), 6.49 (d, J = 8.4 Hz, 2H), 4.27 (s, 2H), 4.18 (s, 4H), 4.11 - 4.06 (m, 2H), 2.68 - 2.58 (m, 2H), 2.20 (s, 3H), 1.75 - 1.66 (m, 2H), 1.46 - 1.36 (m, 1H), 1.27 - 1.05 (m, 3H), 0.88 (d, J = 6.8 Hz, 6H). Mass (m/z): 479.3 [ M + H ]] ⁺ 。

N- (4- ((4- (4- (2-methoxypropan-2-yl) piperidin-1-yl) -2-methylphenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (719)

The title compound 719 (30.2 mg) as a sand-brown solid was prepared according to the procedure for compound 625 from N- (4- (aminomethyl) phenyl) -4- (4- (2-methoxypropan-2-yl) piperidin-1-yl) -2-methylaniline (36.7 mg, 0.1 mmol), 5-oxopyrrolidine-3-carboxylic acid (12.8 mg, 0.13 mmol), DIEA (39.0 mg, 0.3 mmol), and HATU (49.4 mg, 0.13 mmol) in 63.0% overall yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.23-7.12 (m, 2H), 7.01-6.92 (m, 5H), 4.25 (s, 2H), 4.15-4.08 (m, 2H), 3.71-3.62 (m, 2H), 3.41 (m, 1H), 3.10 (s, 3H), 2.36-2.23 (m, 4H), 2.10 (s, 3H), 1.75-1.62 (m, 2H), 1.50 (m, 1H), 1.43-1.30 (m, 2H), 1.06 (s, 6H). Mass (m/z): 479.3 [ M + H ] ] ⁺ 。

N- (4- (aminomethyl) phenyl) -2- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-5-amine (720)

Step 1.5-Nitro-2- (4- (trifluoromethyl) piperidin-1-yl) pyrimidine preparation: to a solution of compound 720-1 (2 g, 12.6 mmol) in DMF (40 mL) at room temperature was added K ₂ CO ₃ (3.5 g, 25.2 mmol) and compound 720-2 (1.93 g, 12.6 mmol), then the mixture was stirred at 70 ℃ for 2 hours. TLC indicated the reaction was complete. Pouring the mixture into H ₂ O (150 mL). The mixture was filtered, the solid collected and dried under reduced pressure to give 5-nitro-2- (4- (trifluoromethyl) piperidin-1-yl) pyrimidine 720-3 (2.2 g, 63% yield) as a yellow solid. MS (ESI) M/z 276.1 [ M + H ]] ⁺ 。

Step 2.2- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-5-amine preparation: to a solution of compound 720-3 (0.1 g, 0.4 mmol) in EtOH (5 mL) was added Pd/C (20 mg) followed by H at 1 atm ₂ Stirring was continued for 2 hours at 25 ℃. The mixture was then filtered and concentrated to give 2- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-5-amine 720-4 (0.1 g, 100% yield) as a brown solid. MS (ESI) M/z 246.1 [ M + H ]] ⁺ 。

Step 3 preparation of tert-butyl (4- ((2- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-5-yl) amino) benzyl) carbamate: to a stirred solution of compound 720-4 (0.1 g, 0.4 mmol) and compound 720-5 (0.12 g, 0.4 mmol) in dioxane under nitrogen was added Cs ₂ CO ₃ (0.39 g, 1.2 mmol), tris (dibenzylideneacetone) dipalladium (0.037 g, 0.04 mmol) and Ruphos (38 mg, 0.08 mmol), followed by stirring at 90 ℃ for 16 hours. The mixture was then filtered and concentrated, and the residue was purified by combi-flash with EA/PE (1:1) to afford tert-butyl (4- ((2- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-5-yl) amino) benzyl) carbamate 720-6 (0.07 g, 38.5% yield) as a yellow solid. MS (ESI) M/z 452.3 [ M + H ]] ⁺ 。

Step 4. Preparation of N- (4- (aminomethyl) phenyl) -2- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-5-amine: to a solution of compound 720-6 (0.07 g, 0.15 mmol) in DCM (2 mL) was added 4N HCl in dioxane (2 mL) at room temperature. The mixture was then stirred at room temperature for 1 h. LCMS indicated the reaction was complete. The mixture was filtered and the solid was collected and dried to give N- (4- (aminomethyl) phenyl) -2- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-5-amine 720-7 (50 mg,% yield) as a brown solid. MS (ESI) M/z 352.2 [ M + H ]] ⁺ 。

Step 5.5-oxo-N- (4- ((2- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-5-yl) amino) benzyl) pyrrolidine-3-carboxamide (720) preparation: to a solution of compound 720-7 (0.05 g, 0.14 mmol), 5-oxopyrrolidine-3-carboxylic acid (22.1 mg, 0.17 mmol) in DMF (3 mL) stirred under nitrogen was added N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) uronium (53.2 mg, 0.14 mmol) and DIEA (54 mg, 0.42 mmol). The reaction mixture was stirred at room temperature for 16 hours. Pouring the mixture into H ₂ O (10 mL) and extracted with EA (10 mL x 3), the organic layer was washed with brine and Na ₂ SO ₄ Drying, filtering and concentrating. The residue was purified by preparative HPLC to provide 720 (29 mg, 45% yield) as a yellow solid. MS (ESI) M/z 462.7 [ M + H ]] ^{+ 1} H NMR (400 MHz, CD ₃ OD) δ 8.21 (s, 2H), 7.08 (d, J = 8.0 Hz, 2H), 6.75 (d, J = 8.0 Hz, 2H), 4.91 - 4.74 (m, 2H), 4.24 (s, 2H), 3.46 - 3.30 (m, 1H), 2.91 - 2.80 (m, 2H), 2.60 - 2.30 (m, 3H), 1.91 - 1.88 (m, 2H), 1.50 - 1.45 (m, 2H)。

N- (4- ((6-butylpyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (721)

Step 1.2-butyl-5-nitropyridine (721-3) preparation: to n-butylboronic acid (1004 mg, 9.85 mmol), 2-bromo-5-nitropyridine (1000 mg, 4.93 mmol), K ₂ CO ₃ (1361 mg, 9.85 mmol) in toluene/H ₂ O = 10:1 (20 mL) to a solution of palladium diacetate (110 mg, 0.49 mmol), tricyclohexylphosphine (138 mg, 0.49 mmol) was added and the mixture was stirred in N ₂ Then, the mixture was heated and stirred at 100 ℃ for 16 hours. After cooling to ambient temperature, concentrate under reduced pressure. The residue was purified by silica gel column to provide 2-butyl-5-nitropyridine 721-3 (520 mg, 58.58% yield) as a yellow solid. MS (ESI) M/z 181.2 [ M + H ]] ⁺ 。

Step 2.6-preparation of butylpyridin-3-amine (721-4): to a solution of 2-butyl-5-nitropyridine (520 mg, 2.88 mmol) in MeOH (10 mL) was added Pd/C (200 mg, 10%) followed by H at 1 atm ₂ Stirred at room temperature for 16 hours then filtered and the filtrate concentrated in vacuo to give 6-butylpyridin-3-amine 721-4 as a yellow solid (420 mg, 96.89% yield). MS (ESI) M/z 151.0 [ M + H ] ] ⁺ 。

Step 3 preparation of tert-butyl (4- ((6-butylpyridin-3-yl) amino) benzyl) carbamate (721-6): to compound 721-4 (420 mg, 2.79 mmol), compound 721-5 (1200 mg, 4.19 mmol), cs ₂ CO ₃ (1821 mg, 5.59 mmol) to a solution of 1,4-dioxane (20 mL) RuPhos (130 mg, 0.28 mmol) was added mmol)、Pd ₂ (dba) ₃ (256 mg, 0.28 mmol) and then in N ₂ The mixture was heated and stirred at 90 ℃ for 16 hours. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column to provide tert-butyl (4- ((6-butylpyridin-3-yl) amino) benzyl) carbamate 721-6 (640 mg, 64.39% yield) as a yellow solid. MS (ESI) M/z 355.9 [ M + H ]] ⁺ 。

Step 4. Preparation of N- (4- (aminomethyl) phenyl) -6-butylpyridin-3-amine (721-7): a solution of compound 721-6 (640 mg, 1.80 mmol) in HCl (10 mL, 4N) in 1,4-dioxane was stirred at room temperature for 16 hours. The solution was then concentrated to dryness to give N- (4- (aminomethyl) phenyl) -6-butylpyridin-3-amine 721-7 (450 mg, 97.88% yield) as a white solid. MS (ESI) M/z 256.2 [ M + H ]] ⁺ 。

Step 5. Preparation of N- (4- ((6-butylpyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (721): to a stirred solution of compound 721-7 (0.2 g, 0.78 mmol), 5-oxopyrrolidine-3-carboxylic acid (151 mg, 1.17 mmol) in DMF (3 mL) was added N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) uronium (446 mg, 1.17 mmol) and TEA (237 mg, 2.35 mmol). The reaction mixture was stirred at 25 ℃ for 16 hours. Pouring the mixture into H ₂ O (20 mL), extracted with EA (20 mL. Multidot.2), and the organic layer was washed with brine and Na ₂ SO ₄ Dried, filtered and concentrated. The residue was purified by preparative HPLC to provide 721 (72 mg, 25% yield) as a yellow solid. MS (ESI) M/z 367.2 [ M + H] ⁺ 。 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 8.26 - 8.20 (m, 2H), 7.59 (s, 1H), 7.40 (dd, J = 8.4, 2.8 Hz, 1H), 7.12 (dd, J = 8.4, 4.8 Hz, 3H), 7.00 (d, J = 8.5 Hz, 2H), 4.19 (d, J = 5.8 Hz, 2H), 3.41 (s, 1H), 3.27 - 3.17 (m, 2H), 2.67 - 2.61 (m, 2H), 2.30 (dd, J = 8.4, 3.3 Hz, 2H), 1.61 (dd, J = 8.7, 6.5 Hz, 2H), 1.31 (dd, J = 14.9, 7.4 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H)。

N- (4- ((3- (2-aminoethoxy) -4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (722)

Step 1 preparation of benzyl (4-bromobenzyl) carbamate (722-7): cbzCl (920 mg, 5.4 mmol) was added to a solution of (4-bromophenyl) methylamine hydrochloride (100 mg, 4.5 mmol), triethylamine (910 mg, 9.0 mmol) in DCM (50 mL), the mixture was reacted at 25 ℃ for 16 hours, then the solvent was removed under vacuum to give benzyl (4-bromobenzyl) carbamate 7 as a yellow solid (900 mg, 62.22% yield). MS (ESI) M/z 341.6 [ M + H ]] ⁺ 。

Step 2 preparation of tert-butyl (2- (2-fluoro-5-nitrophenoxy) ethyl) carbamate (722-3): adding 722-1 (3 g, 19.09 mmol) and 722-2 (4.28 g, 19.09 mmol) in CH ₃ Adding K into CN (50 mL) ₂ CO ₃ (7.9 g, 57.29 mmol) and then stirred at 80 ℃ for 16 hours. After cooling to ambient temperature, filtered and concentrated, the residue was purified by combi-flash with EA/PE (1:3) to provide tert-butyl (2- (2-fluoro-5-nitrophenoxy) ethyl) carbamate 722-3 (5.3 g, 92.43% yield) as a yellow solid. MS (ESI) M/z 322.8 [ M + Na ] ] ⁺ 。

Step 3 preparation of tert-butyl (2- (5-nitro-2- (4- (trifluoromethyl) piperidin-1-yl) phenoxy) ethyl) carbamate (722-5): to solutions of 722-3 (5300 mg, 17.65 mmol), 722-4 (2703 mg, 17.65 mmol) in DMSO (50 mL) and water (2 mL) was added K ₂ CO ₃ (7307 mg, 52.95 mmol) and then stirred at 100 ℃ for 3 hours. After cooling to ambient temperature, poured into water (150 mL) and extracted with EA (50 ml × 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column to provide tert-butyl (2- (5-nitro-2- (4- (trifluoromethyl) piperidin-1-yl) phenoxy) ethyl) carbamate 722-5 (5100 mg, 66.67% yield) as a yellow solid. MS (ESI) M/z 434.1 [ M + H ]] ⁺ 。

Step 4. (2- (5-amino-2- (4- (trifluoromethyl) piperidine-1-carboxylic acid)Preparation of-yl) phenoxy) ethyl) carbamic acid tert-butyl ester (722-6): to a solution of 722-5 (5000 mg, 11.54 mmol) in MeOH (50 mL) was added Pd/C (1000 mg, 10%) followed by H at 1 atm ₂ Stirring was continued for 16 hours, then filtration was performed, and the filtrate was concentrated to dryness to give tert-butyl (2- (5-amino-2- (4- (trifluoromethyl) piperidin-1-yl) phenoxy) ethyl) carbamate 722-6 (5000 mg, 100% yield) as a yellow solid. MS (ESI) M/z 404.2 [ M + H ] ] ⁺ 。

Step 5 preparation of tert-butyl (2- (5- ((4- ((((benzyloxy) carbonyl) amino) methyl) phenyl) amino) -2- (4- (trifluoromethyl) piperidin-1-yl) phenoxy) ethyl) carbamate (722-8): to compound 722-6 (190.46 mg,0.59 mmol), compound 722-7 (200 mg, 0.4957 mmol), cs ₂ CO ₃ (323.02 mg, 0.99 mmol) to a solution of 1,4-dioxane (20 mL) was added RuPhos (23 mg, 0.04957 mmol), pd ₂ (dba) ₃ (45.39 mg, 0.04957 mmol) and then in N ₂ The mixture was heated and stirred at 90 ℃ for 16 hours. After cooling to ambient temperature, concentrate under reduced pressure. The residue was purified by silica gel column to provide tert-butyl (2- (5- ((4- ((((benzyloxy) carbonyl) amino) methyl) phenyl) amino) -2- (4- (trifluoromethyl) piperidin-1-yl) phenoxy) ethyl) carbamate 722-8 (300 mg, 94.17% yield) as a yellow solid. MS (ESI) M/z 642.6 [ M + H ]] ⁺ 。

Step 6 preparation of tert-butyl (2- (5- ((4- (aminomethyl) phenyl) amino) -2- (4- (trifluoromethyl) piperidin-1-yl) phenoxy) ethyl) carbamate (722-9): to a solution of 722-8 (220 mg, 0.34 mmol) in MeOH (20 mL) was added Pd/C (50 mg, 10%) followed by H at 1 atm ₂ Stirring was continued for 16 hours then filtration and the filtrate was concentrated to dryness to give tert-butyl (2- (5- ((4- (aminomethyl) phenyl) amino) -2- (4- (trifluoromethyl) piperidin-1-yl) phenoxy) ethyl) carbamate 722-9 (175 mg, 100% yield) as a yellow solid. MS (ESI) M/z 509.3 [ M + H ] ] ⁺ . Preparation of tert-butyl (2- (5- ((4- ((5-oxopyrrolidine-3-carboxamido) methyl) phenyl) amino) -2- (4- (trifluoromethyl) piperidin-1-yl) phenoxy) ethyl) carbamate (722-11): to compound 722-9 (0.175 g, 0.3441 m)mol), 5-oxopyrrolidine-3-carboxylic acid (53.31 mg, 0.41 mmol) in DMF (3 mL) to a stirred solution N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) uronium (196 mg,0.516 mmol) and TEA (104.26 mg, 1.032 mmol) were added. The reaction mixture was stirred at 25 ℃ for 16 hours. Pouring the mixture into H ₂ O (15 mL) and extracted with EA (15 mL x 3), the organic layer was washed with brine and Na ₂ SO ₄ Dried, filtered and concentrated. The residue was purified by silica gel column to provide tert-butyl (2- (5- ((4- ((5-oxopyrrolidine-3-carboxamido) methyl) phenyl) amino) -2- (4- (trifluoromethyl) piperidin-1-yl) phenoxy) ethyl) carbamate 722-11 (160 mg, 74.92% yield) as a yellow solid. MS (ESI) M/z 620.3 [ M + H ]] ⁺ 。

Step 8. Preparation of N- (4- ((6-butylpyridin-3-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (722): a solution of compound 722-11 (160 mg, 1.80 mmol) in HCl (5 mL, 4N) in 1,4-dioxane was stirred at 25 ℃ for 2 hours. Then concentrated and the residue purified by preparative HPLC to provide 722 as a yellow solid (7.7 mg, 5.74% yield). MS (ESI) M/z 520.3 [ M + H ] ] ⁺ 。 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (t, J = 5.8 Hz, 1H), 8.05 (s, 3H), 7.61 (s, 1H), 7.14 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H), 6.76 (d, J = 2.3 Hz, 1H), 6.71 (dd, J = 8.7, 2.3 Hz, 1H), 4.20 (d, J = 3.2 Hz, 5H), 3.51 (s, 2H), 3.40 (d, J = 8.7 Hz, 1H), 3.31 - 3.16 (m, 5H), 2.63 (s, 1H), 2.31 (d, J = 8.5 Hz, 2H), 2.00 (d, J= 10.5 Hz, 2H), 1.88 (s, 2H)。

(4- ((5- (4- (trifluoromethyl) piperidin-1-yl) pyrazin-2-yl) amino) benzyl) carbamic acid tert-butyl ester (723)

Step 1 preparation of tert-butyl (4- ((5- (4- (trifluoromethyl) piperidin-1-yl) pyrazin-2-yl) amino) benzyl) carbamate: to compound 723-1 (3 g, 12.6 mmol) in DMSO (40 mL) at 25 deg.CAdding Cs to the solution ₂ CO ₃ (6.16 g, 18.9 mmol) and compound 723-2 (1.93 g, 12.6 mmol). The mixture was then stirred at 100 ℃ for 2 hours. LCMS indicated the reaction was complete. Pouring the mixture into H ₂ O (120 mL). The mixture was filtered and the solid was collected and dried to give tert-butyl (4- ((5- (4- (trifluoromethyl) piperidin-1-yl) pyrazin-2-yl) amino) benzyl) carbamate 723-3 (4 g, 100% yield) as a yellow solid. MS (ESI) M/z 310.0 [ M + H ]] ⁺ 。

Step 2 preparation of tert-butyl (4- ((5- (4- (trifluoromethyl) piperidin-1-yl) pyrazin-2-yl) amino) benzyl) carbamate: to a mixture solution of compound 723-3 (0.5 g, 1.6 mmol), compound 723-4 (0.39 g, 1.76 mmol) and dicyclohexyl (2 ',6' -diisopropoxybiphenyl-2-yl) phosphine (0.15 g, 0.32 mmol) in dioxane was added Cs under nitrogen ₂ CO ₃ (1.04 g, 3.2 mmol) and tris (dibenzylideneacetone) dipalladium (0.15 g, 0.16 mmol). The reaction mixture was stirred at 90 ℃ for 16 hours. The mixture was then filtered and concentrated. The residue was purified by combi-flash with EA/PE (1:1) to afford tert-butyl (4- ((5- (4- (trifluoromethyl) piperidin-1-yl) pyrazin-2-yl) amino) benzyl) carbamate 723-5 (0.3 g, 69.8% yield) as a yellow solid. MS (ESI) M/z 452.3 [ M + H ] ] ⁺ 。

Step 3. Preparation of N- (4- (aminomethyl) phenyl) -5- (4- (trifluoromethyl) piperidin-1-yl) pyrazin-2-amine: to a solution of compound 723-5 (0.1 g, 0.22 mmol) in DCM (2 mL) was added 4N HCl in dioxane (2 mL) at room temperature. The mixture was then stirred at room temperature for 1 h. LCMS indicated the reaction was complete. The mixture was filtered and dried to give N- (4- (aminomethyl) phenyl) -5- (4- (trifluoromethyl) piperidin-1-yl) pyrazin-2-amine 723-6 (70 mg, 89.7% yield) as a brown solid. MS (ESI) M/z 351.8 [ M + H ]] ⁺ 。

Step 4.5-oxo-N- (4- ((5- (4- (trifluoromethyl) piperidin-1-yl) pyrazin-2-yl) amino) benzyl) pyrrolidine-3-carboxamide (723): to a stirred solution of compound 723-6 (0.1 g,0.3 mmol), 5-oxopyrrolidine-3-carboxylic acid 723-7 (40 mg, 0.3 mmol) in DMF (3 mL) was added N, N, N ', N' -tetramethyl-O- (R) (N, N, N ', N' -tetramethyl-O-) (R) under nitrogen7-Azabenzotriazol-1-yl) uronium (110 mg, 0.3 mmol) and DIEA (0.06 g, 0.45 mmol). The reaction mixture was stirred at room temperature for 16 hours. Pouring the mixture into H ₂ O (10 mL) and extracted with EA (10 mL x 3), the organic layer was washed with brine and Na ₂ SO ₄ Dried, filtered and concentrated, and the residue was purified by preparative HPLC to give 723 (40 mg) as a yellow solid. MS (ESI) M/z 463.2 [ M + H ] ] ^+。1 H NMR (300 MHz, CD ₃ OD) δ 7.88 - 7.75 (m, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 4.25 (s, 2H), 4.14 (d, J = 12.6 Hz, 2H), 3.50 - 3.40 (m, 2H), 2.74 (t, J = 12.6 Hz, 2H), 2.61 - 2.30 (m, 4H), 1.91 (d, J = 12.6 Hz, 2H), 1.66 - 1.52 (m, 2H)。

N- (4- ((2,2-dimethyl-2,3-dihydro-1H-inden-5-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (724)

Step 1.5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-one preparation: to a solution of compound 724-1 (3 g, 14.2 mmol) in DMF (40 mL) was added NaH (0.78 g, 32.6 mmol) at 0 ℃. The mixture was then stirred at 25 ℃ for 30 minutes. MeI (4.44 g, 31.2 mmol) was then added. TLC indicated the reaction was complete. The mixture is poured into H ₂ O (120 mL) and extracted with EA (50 mL x 3), the organic layer was washed with brine and Na ₂ SO ₄ Dried, filtered and concentrated to dryness to give 5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-one 724-2 as a yellow oil (2.4 g, 70.6% yield).

Step 2.5-bromo-2,2-dimethyl-2,3-dihydro-1H-indene preparation: to a solution of compound 724-2 (2.4 g, 10 mmol) in TFA (10 mL) was added Et ₃ SiH (10 mL). The reaction mixture was stirred at 70 ℃ for 2 hours. The mixture was then poured into H ₂ O (50 mL) and extracted with EA (30 ml x 2), the organic layer was washed with brine and Na ₂ SO ₄ Dried, filtered and concentrated. The residue was purified by passing through a combi-flash column with EA/PE (1:4)To provide 5-bromo-2,2-dimethyl-2,3-dihydro-1H-indene 724-3 (2 g, 80% yield) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.28 (s, 1H), 7.24 - 7.20 (m, 1H), 7.01 (d, J = 7.9 Hz, 1H), 2.69 (s, 2H), 2.64 (s, 2H), 1.13 (s, 6H)。

Step 3 preparation of tert-butyl (4- ((2,2-dimethyl-2,3-dihydro-1H-inden-5-yl) amino) benzyl) carbamate (724-4): tert-butyl 5-bromo-2,2-dimethyl-2,3-dihydro-1H-indene (1 g, 4.4 mmol), (4- ((2,2-dimethyl-2,3-dihydro-1H-inden-5-yl) amino) benzyl) carbamate (1.08 g, 4.8 mmol), cs ₂ CO ₃ (4.3 g, 13.2 mmol), ruphos (410 mg, 0.8 mmol) and Pd ₂ (dba) ₃ (400 mg, 0.4 mmol)) in dioxane (50 mL) in N ₂ The mixture was stirred at 100 ℃ for 16 hours. The solvent was then removed under reduced pressure and the residue diluted with EA (50 mL), washed with water (50 mL X3) and Na ₂ SO ₄ Dried, filtered and evaporated. The residue was purified by column chromatography to give tert-butyl (4- ((2,2-dimethyl-2,3-dihydro-1H-inden-5-yl) amino) benzyl) carbamate 724-4 (900 mg, 52.27%). Mass (m/z): 366.7 [ M + H ]] ⁺ 。

Step 4. Preparation of N- (4- ((2,2-dimethyl-2,3-dihydro-1H-inden-5-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (724-5): a solution of tert-butyl (4- ((2,2-dimethyl-2,3-dihydro-1H-inden-5-yl) amino) benzyl) carbamate (900 mg, 2.45 mmol) in 4N HCl in dioxane was stirred at room temperature for 2 hours. The solvent was then removed under vacuum to give N- (4- ((2,2-dimethyl-2,3-dihydro-1H-inden-5-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide 724-5 (800 mg, 98.7%). Mass (m/z): 366.7 [ M + H ] ] ⁺ 。

Step 5. Preparation of N- (4- ((2,2-dimethyl-2,3-dihydro-1H-inden-5-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (724): a mixture solution of N- (4- ((2,2-dimethyl-2,3-dihydro-1H-inden-5-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (200 mg, 0.66 mmol), 5-oxopyrrolidine-3-carboxylic acid (103 mg, 0.8 mmol), TEA (258 mg, 1.99 mmol) and HATU (506 mg, 1.33 mmol) in DCM (20 mL) was taken at room temperatureStirred for 2 hours. The solvent was then removed in vacuo, the residue diluted with EA (20 mL), washed with water (20 mL X3), and Na ₂ SO ₄ Dried, filtered and evaporated. The residue was purified by column chromatography to give 724 (90 mg). Mass (m/z): 377.8 [ M + H ]] ⁺ 。 ¹ H NMR (400 MHz, CD ₃ OD) δ 7.13 - 7.08 (m, 2H), 7.01 - 6.94 (m, 3H), 6.88 (s, 1H), 6.82 (dd, J = 8.0, 2.1 Hz, 1H), 4.27 (s, 2H), 3.57 (dd, J = 9.9, 8.9 Hz, 1H), 3.48 (dd, J = 9.9, 6.5 Hz, 1H), 2.65 (dd, J = 5.8, 2.9 Hz, 4H), 2.53 (qd, J = 16.9, 8.6 Hz, 2H), 1.14 (s, 6H)。

(S) -N- (4- ((2,2-dimethyl-2,3-dihydro-1H-inden-5-yl) amino) benzyl) -2-oxoimidazolidine-4-carboxamide (725)

Step 1 preparation of tert-butyl (4- ((2,2-dimethyl-2,3-dihydro-1H-inden-5-yl) amino) benzyl) carbamate (725): a solution of a mixture of N- (4- ((2,2-dimethyl-2,3-dihydro-1H-inden-5-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (200 mg, 0.66 mmol), (S) -2-oxoimidazolidine-4-carboxylic acid (103 mg, 0.8 mmol), TEA (258 mg, 1.99 mmol) and HATU (506 mg, 1.33 mmol) in DCM (20 mL) was stirred at room temperature for 2 hours. The solvent was then removed in vacuo, the residue diluted with EA (20 mL), washed with water (10 mL X3), and Na ₂ SO ₄ Dried, filtered and evaporated. The residue was purified by preparative HPLC to give 725 (61 mg, 21.47%). Mass (m/z): 378.8 [ M + H ]] ⁺ 。 ¹ H NMR (400 MHz, CD ₃ OD) δ 7.15 - 7.10 (m, 2H), 7.01 - 6.94 (m, 3H), 6.88 (s, 1H), 6.82 (dd, J = 8.0, 2.1 Hz, 1H), 4.31 (s, 2H), 4.29 - 4.26 (m, 1H), 3.78 (dd, J = 10.1, 9.4 Hz, 1H), 3.43 (dd, J = 9.3, 6.5 Hz, 1H), 2.66 - 2.62 (m, 4H), 1.14 (s, 6H)。

N- (4- ((3,5-difluoro-4- (piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (726)

Step 1.1 preparation of- (2,6-difluoro-4-nitrophenyl) piperidine (726-2): 1,2,3-trifluoro-5-nitrobenzene (1 g, 5.65 mmol), piperidine (962 mg, 11.3 mmol) and K ₂ CO ₃ A solution of a mixture of (2.36 g, 16.8 mmol) in acetonitrile (50 mL) was stirred at 60 ℃ for 2 hours. The residue was then diluted with EA (200 mL), washed with water (100 mL X3) and washed with Na ₂ SO ₄ Dried, filtered and evaporated. The residue was purified by column chromatography to provide 1- (2,6-difluoro-4-nitrophenyl) piperidine 726-2 (1.5 g, 100%).

Step 8978 preparation of zxft 8978-difluoro-4- (piperidin-1-yl) aniline (726-3): to a solution of 1- (2,6-difluoro-4-nitrophenyl) piperidine (1.5 g, 5.6 mmol) in THF was added Pd/C (200 mg), and the mixture was then brought to 1 atmosphere of H ₂ 16 h was stirred at room temperature. Then filtered and the filtrate concentrated under vacuum to provide 3,5-difluoro-4- (piperidin-1-yl) aniline 726-3 (1.3 g, 98.39%). Mass (m/z): 212.9 [ M + H ]] ⁺ 。

Step 3 preparation of tert-butyl (4- ((3,5-difluoro-4- (piperidin-1-yl) phenyl) amino) benzyl) carbamate (726-5): 3,5-difluoro-4- (piperidin-1-yl) aniline (500 mg, 2.36 mmol), (4-bromobenzyl) tert-butyl carbamate (809 g, 2.83 mmol), cs ₂ CO ₃ (2.3 g, 7.07 mmol), ruphos (220 mg, 0.47 mmol) and Pd ₂ (dba) ₃ (216 mg, 0.24 mmol)) in dioxane (50 mL) in N ₂ 16 h was stirred at 100 ℃. The solvent was then removed in vacuo, the residue diluted with EA (50 mL), washed with water (50 mL X3), and Na ₂ SO ₄ Dried, filtered and evaporated. The residue was purified by column chromatography to give tert-butyl (4- ((3,5-difluoro-4- (piperidin-1-yl) phenyl) amino) benzyl) carbamate 726-5 (1.2 g, 97.6%). Mass (m/z): 417.8 [ M + H ]] ⁺ 。

Step 4. Preparation of N- (4- (aminomethyl) phenyl) -3,5-difluoro-4- (piperidin-1-yl) aniline (726-6): mixing (4- ((3,5-difluoro-4- (piperazine)Pyridin-1-yl) phenyl) amino) benzyl) carbamic acid tert-butyl ester (1.2 g, 2.3 mmol) in 4N HCl in dioxane (50 mL) was stirred at room temperature for 2 hours. The solvent was then removed under vacuum to give N- (4- (aminomethyl) phenyl) -3,5-difluoro-4- (piperidin-1-yl) aniline 726-6 (1 g, 96.55%). Mass (m/z): 317.8 [ M + H ]] ⁺ 。

Step 5. Preparation of N- (4- ((3,5-difluoro-4- (piperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (726): a mixture solution of N- (4- (aminomethyl) phenyl) -3,5-difluoro-4- (piperidin-1-yl) aniline (100 mg, 0.28 mmol), 5-oxopyrrolidine-3-carboxylic acid (44 mg, 0.34 mmol), TEA (86 mg, 0.85 mmol), and HATU (216 mg, 0.57 mmol) in DCM (20 mL) was stirred at room temperature for 2 hours. The solvent was then removed in vacuo, the residue diluted with EA (20 mL), washed with water (10 mL X3), and Na ₂ SO ₄ Dried, filtered and evaporated. The residue was purified by preparative HPLC to give 726 (45.6 mg, 37.44%). Mass (m/z): 429.2 [ M + H ]] ⁺ 。 ¹ H NMR (400 MHz, CD ₃ OD) δ 7.21 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.1 Hz, 2H), 6.54 (d, J = 11.6 Hz, 2H), 4.31 (s, 2H), 3.58 (dd, J = 9.8, 8.9 Hz, 1H), 3.49 (dd, J = 9.9, 6.4 Hz, 1H), 3.12 (br, 4H), 2.58-2.47 (m, 2H), 1.70 (br, 4H), 1.58 (br, 2H)。

(R) -N- (4- ((3,5-difluoro-4- (piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-2-carboxamide (727)

Step 1 preparation of (R) -2- ((4- ((3,5-difluoro-4- (piperidin-1-yl) phenyl) amino) benzyl) carbamoyl) pyrrolidine-1-carboxylic acid tert-butyl ester (727-3): to a stirred solution of compound 727-1 (0.1 g, 0.3151 mmol), compound 727-2 (68.14 mg, 0.3151 mmol) in DMF (3 mL) was added N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) uronium (119.8 mg, 0.3151 mmol) and TEA (95.6 mg, 0.9453 mmol). The reaction mixture was stirred at 25 ℃ for 2 hours. The mixture is poured into H ₂ O (10 mL) and extracted with EA (15 mL. Multidot.2), the organic layer was washed with brine and Na ₂ SO ₄ Dried, filtered and concentrated. The residue was purified by silica gel column to provide (R) -2- ((4- ((3,5-difluoro-4- (piperidin-1-yl) phenyl) amino) benzyl) carbamoyl) pyrrolidine-1-carboxylic acid tert-butyl ester 727-3 (90 mg, 55.38% yield) as a yellow solid. MS (ESI) M/z 620.3 [ M + H ]] ⁺ 。

Step 2: (R) Preparation of (E) -N- (4- ((3,5-difluoro-4- (piperidin-1-yl) phenyl) amino) benzyl) pyrrolidine-2-carboxamide (727): a solution of compound 727-3 (160 mg, 1.80 mmol) in HCl (5 mL, 4N) in 1,4-dioxane was stirred at 25 ℃ for 2 hours. Then concentrated and the residue purified by preparative HPLC to provide 727 (16.7 mg, 23.09% yield) as a yellow solid. MS (ESI) M/z 414.7 [ M + H ] ] ⁺ 。 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.49 (s, 1H), 8.37 (s, 1H), 8.19 (s, 1H), 7.16 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.5 Hz, 2H), 6.56 (d, J = 11.7 Hz, 2H), 4.22 (d, J = 5.9 Hz, 2H), 3.71 (d, J = 6.6 Hz, 2H), 2.93 (d, J = 5.0 Hz, 6H), 2.54 (d, J = 5.0 Hz, 1H), 2.06 (d, J = 11.1 Hz, 1H), 1.68 (dd, J = 11.4, 5.3 Hz, 4H), 1.60 - 1.45 (m, 6H)。

N- (2-fluoro-4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (728)

Step 1 preparation of tert-butyl (4-bromo-2-fluorobenzyl) carbamate (728-5): (Boc) 2O (427.9 mg, 1.96 mmol) was added to a solution of (4-bromo-2-fluorophenyl) methylamine (200 mg, 0.98 mmol), DIEA (380 mg, 2.94 mmol) in THF (10 mL), then stirred at room temperature for 16 hours, the solvent was removed under vacuum, and the residue was purified by combi-flash with EA/PE (1:3) to provide tert-butyl (4-bromo-2-fluorobenzyl) carbamate 728-5 (0.18 g, 60.17% yield) as a yellow solid. MS (ESI) M/z 326 [ M + Na ]] ⁺ 。

Step 2.2- (4-isopropylpiperidin-1-yl) -5-nitropyrimidine (728-3) preparation: to a solution of compound 728-1 (3 g, 18.8 mmol), compound 728-2 (2.39 g, 18.8 mmol) in 1,4-dioxane (50 mL) was added Cs ₂ CO ₃ (12.25 g, 37.61 mmol) and then stirred at 100 ℃ for 2 hours. After cooling to ambient temperature, filtered and concentrated. The residue was purified by combi-flash with EA/PE (1:3) to afford 2- (4-isopropylpiperidin-1-yl) -5-nitropyrimidine 728-3 as a yellow solid (3.6 g, 76.48% yield). MS (ESI) M/z 251.2 [ M + H ]] ⁺ 。

Step 3.2- (4-isopropylpiperidin-1-yl) pyrimidin-5-amine (728-4) preparation: to a solution of compound 728-3 (3600 mg, 14.4 mmol) in EtOAc (50 mL) was added Pd/C (360 mg, 10%) followed by H at 1 atm ₂ Stirring was continued for 16 hours, then filtered and the solvent removed under vacuum to give 2- (4-isopropylpiperidin-1-yl) pyrimidin-5-amine 728-4 as a yellow solid (3000 mg, 94.44% yield). MS (ESI) M/z 221.0 [ M + H ]] ⁺ 。

Preparation of tert-butyl (2-fluoro-4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) benzyl) carbamate (728-6): to compound 728-4 (100 mg,0.45 mmol), compound 728-5 (138.5 mg,0.45 mmol), cs ₂ CO ₃ (295.8 mg, 0.90 mmol) in toluene (20 mL) RuPhos (42 mg, 0.091 mmol), pd were added to a solution of RuPhos (42 mg, 0.091 mmol) ₂ (dba) ₃ (41.5 mg, 0.04539 mmol) and then in N ₂ The mixture was heated and stirred at 80 ℃ for 16 hours. After cooling to ambient temperature, concentrate under reduced pressure. The residue was purified by silica gel column to provide tert-butyl (2-fluoro-4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) benzyl) carbamate 728-6 as a yellow solid (110 mg, 54.64% yield). MS (ESI) M/z 443.8 [ M + H ]] ⁺ 。

Step 5. Preparation of N- (4- (aminomethyl) -3-fluorophenyl) -2- (4-isopropylpiperidin-1-yl) pyrimidin-5-amine (728-7): a solution of compound 728-6 (110 mg, 0.25 mmol) in HCl (10 mL, 4N) in 1,4-dioxane was stirred at 25 ℃ for 1 h. Then concentrated to dryness to give N- (4- (aminomethyl) -3-fluorophenyl) as a white solid ) -2- (4-isopropylpiperidin-1-yl) pyrimidin-5-amine 728-7 (95 mg, 100% yield). MS (ESI) M/z 343.8 [ M + H ]] ⁺ 。

Step 6. Preparation of N- (2-fluoro-4- ((2- (4-isopropylpiperidin-1-yl) pyrimidin-5-yl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (728): to a stirred solution of compound 728-7 (95 mg, 0.25 mmol), 5-oxopyrrolidine-3-carboxylic acid (32 mg, 0.25 mmol) in DMF (3 mL) were added N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) uronium (95 mg, 0.25 mmol) and TEA (75.9 mg, 0.75 mmol). The reaction mixture was stirred at 25 ℃ for 16 hours. Pouring the mixture into H ₂ O (10 mL) and extracted with EA (10 mL x 3), the organic layer was washed with brine and Na ₂ SO ₄ Dried, filtered and concentrated. The residue was purified by preparative HPLC to provide 728 (35.3 mg, 31% yield) as a yellow solid. MS (ESI) M/z 455.2 [ M + H ]] ⁺ 。 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.29 (t, J = 5.6 Hz, 1H), 8.19 (s, 2H), 7.81 (s, 1H), 7.53 (s, 1H), 7.03 (t, J = 8.6 Hz, 1H), 6.48 (dd, J = 8.3, 2.2 Hz, 1H), 6.40 (dd, J = 12.6, 2.2 Hz, 1H), 4.62 (d, J = 13.1 Hz, 2H), 4.12 (d, J = 5.5 Hz, 2H), 3.34 (t, J = 8.5 Hz, 1H), 3.19 - 3.11 (m, 2H), 2.73 (td, J = 12.8, 2.4 Hz, 2H), 2.23 (dd, J = 8.5, 1.9 Hz, 2H), 1.66 (d, J = 10.7 Hz, 2H), 1.39 (dd, J = 13.2, 6.6 Hz, 1H), 1.24 - 1.04 (m, 3H), 0.83 (d, J = 6.8 Hz, 6H)。

N- (4- ((3,5-difluoro-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -2-oxopyrrolidine-3-carboxamide (729)

Step 1.1 preparation of- (2,6-difluoro-4-nitrophenyl) -4- (trifluoro (fleoro) methyl) piperidine: to a solution of compound 729-1 (4.75 g, 31 mmol) in DMSO (50 mL) at room temperature was added K ₂ CO ₃ (5.8 g, 42.3 mmol) and 1,2,3-trifluoro-5-nitrobenzene 729-2 (5 g, 28.2 mmol). Then mixing the mixture Stirred at room temperature for 4 hours. TLC indicated the reaction was complete. The mixture was filtered and dried to give 1- (2,6-difluoro-4-nitrophenyl) -4- (trifluoromethyl) piperidine 729-3 (6 g, 68.5% yield) as a yellow solid. MS (ESI) M/z 310.07 [ M + H ]] ⁺ 。

Step 8978 preparation of zxft 8978-difluoro-4- (4- (trifluoromethyl) piperidin-1-yl) aniline: to a solution of compound 729-3 (6 g, 19.3 mmol) in THF (100 mL) was added Pd/C (1 g) at 25 ℃. The mixture was then brought to 1 atmosphere of H ₂ Stirring was continued overnight at 25 ℃. The mixture was then filtered and concentrated. The residue was purified by combi-flash with EA/PE (1:0) to afford 3,5-difluoro-4- (4- (trifluoromethyl) piperidin-1-yl) aniline 729-4 (3.5 g, 64% yield) as a brown solid. MS (ESI) M/z 281.2 [ M + H ]] ⁺ 。

Step 3 preparation of tert-butyl (4- ((3,5-difluoro-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) carbamate: to a stirred solution of compound 729-4 (3.5 g, 12.5 mmol), (4-bromobenzyl) carbamic acid tert-butyl ester (3.59 g, 12.5 mmol) and dicyclohexyl (2 ',6' -diisopropoxybiphenyl-2-yl) phosphine (1.17 g, 2.5 mmol) in dioxane under nitrogen was added Cs ₂ CO ₃ (8.15 g, 25 mmol) and tris (dibenzylideneacetone) dipalladium (1.14 g, 1.25 mmol). The reaction mixture was stirred at 90 ℃ for 16 hours. The mixture was then filtered and concentrated. The residue was purified by combi-flash with EA/PE (1:1) to afford tert-butyl (4- ((3,5-difluoro-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) carbamate 729-5 (1.2 g, 19.8% yield) as a yellow solid. MS (ESI) M/z 485.6 [ M + H ] ] ⁺ 。

Step 4. Preparation of N- (4- (aminomethyl) phenyl) -3,5-difluoro-4- (4- (trifluoromethyl) piperidin-1-yl) aniline: to a solution of compound 729-5 (1.2 g, 2.5 mmol) in DCM (5 mL) was added 4N HCl in dioxane (5 mL) at 25 ℃. The mixture was then stirred at 25 ℃ for 1 h. LCMS indicated the reaction was complete. The mixture was concentrated to give N- (4- (aminomethyl) phenyl) -3,5-difluoro-4- (4- (trifluoromethyl) piperidin-1-yl) aniline 729-6 (1 g, 100% yield) as a brown solid. MS (ESI) M/z 385.7 [ M + H ]] ⁺

Step 5. Preparation of N- (4- ((3,5-difluoro-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -2-oxopyrrolidine-3-carboxamide (729): to a solution of a mixture of compound 729-6 (0.1 g, 0.3 mmol), 2-oxopyrrolidine-3-carboxylic acid (0.04 g, 0.3 mmol) and HATU (0.11 g, 0.3 mmol) in DMF (3 mL) was added DIEA (0.06 g, 0.45 mmol). The reaction mixture was stirred at 25 ℃ for 6 hours. Pouring the mixture into H ₂ O (10 mL) and extracted with EA (10 mL x 3), the organic layer was washed with brine and Na ₂ SO ₄ Dried, filtered and concentrated, and the residue was purified by combi-flash with EA/PE (1:1) to provide 729 (0.0782 g, 60.7% yield) as a yellow solid. MS (ESI) M/z 496.2 [ M + H ] ] ^{+ 1} H NMR (400 MHz, CD ₃ OD) δ 7.25 - 7.19 (m, 2H), 7.05 - 7.00 (m, 2H), 6.55 - 6.46 (m, 2H), 4.40 - 4.27 (m, 2H), 3.46 - 3.26 (m, 2H), 3.15 - 3.00 (m, 4H), 2.46 - 2.13 (m, 3H), 1.90 - 1.79 (m, 2H), 1.71 - 1.61 (m, 2H)。

(S) -N- (4- ((3,5-difluoro-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -2,6-dioxohexahydropyrimidine-4-carboxamide (730)

To 730-1 (100 mg, 0.26 mmol) and (S) -2,6-dioxohexahydropyrimidine-4-carboxylic acid (49.24 mg, 0.31 mmol) in DMF (5 mL) HATU (148 mg, 0.39 mmol), DIEA (134.15 mg, 1.04 mmol) were added. The reaction mixture was then stirred at room temperature for 16 hours. 10 mL water was added to the mixture and extracted with EA (10 mL x 3). The combined organic layers were washed with brine (10 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by preparative TLC to provide the desired product 730 (30.8 mg) as a white solid. Mass (m/z): 526.2 [ M ] +H] ⁺ 。 ¹ H NMR (400 MHz, CD ₃ OD) δ 7.20 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H), 6.53 (d, J = 11.6 Hz, 2H), 4.36 - 4.30 (m, 2H), 4.15 (dd, J = 6.8, 4.4 Hz, 1H), 3.10 (d, J = 12.0 Hz, 4H), 2.92 (dd, J = 16.8, 7.0 Hz, 1H), 2.73 (dd, J = 16.8, 4.4 Hz, 1H), 2.26 - 2.18 (m, 1H), 1.88 (d, J = 12.2 Hz, 2H), 1.75-1.65 (m, 2H)。

(S) -N- (4- ((3,5-difluoro-4- (4- (trifluoromethyl) piperidin-1-yl) phenyl) amino) benzyl) -2,6-dioxohexahydropyrimidine-4-carboxamide (731)

To a solution of 731-1 (100 mg, 0.26 mmol) and TMSNCO (29.89 mg, 0.26 mmol) in DCM (5 mL) was added TEA (105 mg, 1.04 mmol), DMAP (6.3 mg, 0.05 mmol). The reaction mixture was then stirred at room temperature for 16 hours. 10 mL water was added to the mixture and extracted with EA (10 mL x 3). The combined organic layers were washed with brine (10 mL. Times.3) and Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by preparative TLC to provide 731 (40.8 mg) as a white solid. Mass (m/z): 429.2 [ M ] +H] ⁺ 。 ¹ H NMR (400 MHz, CD ₃ OD) δ 7.21 (d, J = 8.6 Hz, 2H), 7.07 - 7.00 (m, 2H), 6.56 - 6.48 (m, 2H), 4.23 (s, 2H), 3.15 - 3.03 (m, 4H), 2.30-2.20 (m, 1H), 1.87 (d, J = 13.6 Hz, 2H), 1.70 (d, J = 4.8 Hz, 2H)。

(S) -N- (4- ((3,5-difluoro-4- (piperidin-1-yl) phenyl) amino) benzyl) -6-oxopiperidine-2-carboxamide (732)

Step 1: (S) Preparation of (E) -N- (4- ((3,5-difluoro-4- (piperidin-1-yl) phenyl) amino) benzyl) -6-oxopiperidine-2-carboxamide (732): to a solution of compound 732-1 (0.1 g,0.315 mmol), compound 732-2 (45 mg,0.315 mmol) in DMF (3 mL) was added N, N' -tetramethyl-O- (7-azabenzotriazol-1-yl) uronium (120 mg,0.315 mmol) and TEA (96 mg, 0.94 mmol) under nitrogen. The reaction mixture was stirred at 25 ℃ for 2 hours. Pouring the mixture into H ₂ O (10 mL) and extracted with EA (10 ml x 3), the organic layer was washed with brine and washed with Na ₂ SO ₄ Dried, filtered and concentrated. The residue was purified by preparative HPLC to provide 732 (45.2 mg, 32.4% yield) as a yellow solid. MS (ESI) M/z 443.2 [ M + H ]] ⁺ 。 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.38 (dd, J = 11.5, 5.4 Hz, 2H), 7.52 (d, J = 2.5 Hz, 1H), 7.18 (d, J = 8.5 Hz, 2H), 7.03 (d, J = 8.5 Hz, 2H), 6.55 (d, J = 11.7 Hz, 2H), 4.22 (dd, J = 10.2, 5.9 Hz, 2H), 3.91 - 3.88 (m, 1H), 2.94 (d, J = 5.3 Hz, 4H), 2.13 (t, J = 6.5 Hz, 2H), 1.90 - 1.85 (m, 1H), 1.71 (dd, J = 11.0, 4.3 Hz,2H), 1.57 (s, 5H), 1.49 (d, J= 4.0 Hz,2H)。

N- (4- ((3,5-difluoro-4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (733)

Step 1 preparation of tert-butyl (4- ((3,5-difluoro-4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) carbamate (733-3): to the mixture was added 733-1 (150 mg, 0.66 mmol), 733-2 (190 mg, 0.66 mmol), cs ₂ CO ₃ (431 mg, 1.33 mmol) in toluene (20 mL) RuPhos (61 mg, 0.13 mmol), pd was added to a solution of RuPhos (61 mg, 0.13 mmol) ₂ (dba) ₃ (61 mg, 0.066 mmol) then in N ₂ The mixture was heated and stirred at 90 ℃ for 16 hours. After cooling to ambient temperature, concentrate under reduced pressure. The residue was purified by silica gel column to provide tert-butyl (4- ((3,5-difluoro-4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) carbamate 733-3 (200 mg, 69.92% yield) as a yellow solid. MS (ESI) M/z 432.3 [ M + H ]] ⁺ 。

Step 2. Preparation of N- (4- (aminomethyl) phenyl) -3,5-difluoro-4- (4-methylpiperidin-1-yl) aniline (733-4): a solution of compound 733-3 (200 mg, 0.46 mmol) in HCl (5 mL, 4N) in 1,4-dioxane was stirred at 25 ℃ for 16 hours. Concentrating to dryness to give whiteN- (4- (aminomethyl) phenyl) -3,5-difluoro-4- (4-methylpiperidin-1-yl) aniline 733-4 (150 mg, 97.65% yield) as a colored solid. MS (ESI) M/z 332.2 [ M + H ]] ⁺ 。

Step 3. Preparation of N- (4- ((3,5-difluoro-4- (4-methylpiperidin-1-yl) phenyl) amino) benzyl) -5-oxopyrrolidine-3-carboxamide (733): to a stirred solution of compound 733-4 (0.15 g, 0.45 mmol), 5-oxopyrrolidine-3-carboxylic acid (58 mg, 0.45 mmol) in DMF (3 mL) was added N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) uronium (172 mg, 0.45 mmol) and TEA (137 mg, 1.35 mmol) under nitrogen. The reaction mixture was stirred at 25 ℃ for 2 hours. The mixture is poured into H ₂ O (10 mL) and extracted with EA (10 mL x 3), the organic layer was washed with brine and Na ₂ SO ₄ Dried, filtered and concentrated. The residue was purified by preparative HPLC to provide 733 (81.6 mg, 40.4% yield) as a yellow solid. MS (ESI) M/z 443.2 [ M + H ]] ⁺ 。 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 8.36 (s, 1H), 7.58 (s, 1H), 7.16 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 8.5 Hz, 2H), 6.56 (d, J = 11.7 Hz, 2H), 4.21 (d, J = 5.8 Hz, 2H), 3.41 (t, J = 8.6 Hz, 1H), 3.27 - 3.17 (m, 2H), 2.95 (d, J = 7.7 Hz, 4H), 2.30 (dd, J = 8.4, 3.4 Hz, 2H), 1.62 (d, J = 12.1 Hz, 2H), 1.46 - 1.39 (m, 1H), 1.24 (dd, J = 17.2, 10.5 Hz, 2H), 0.94 (d, J = 6.5 Hz, 3H)。

Claims (35)

1. A compound of formula I, or a salt, hydrate, or stereoisomer thereof:

wherein:

R1-R11 are independently 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;

r12 is a substituted or unsubstituted heteroatom, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R11-R-12 may be linked to form a substituted or unsubstituted C3-C18 or C3-C10 or C3-C6 heterocyclic ring; and is

X1-X5 and Y1-Y5 are independently C or N.

2. The compound of claim 1, wherein:

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;

R1 is substituted or unsubstituted OH or substituted or unsubstituted NH ₂ Substituted or unsubstituted C1-C9 alkyl, or substituted or unsubstituted C1-C9 heteroalkyl;

r1 is substituted or unsubstituted OH or substituted or unsubstituted NH ₂ ；

R1 is NR 'R ", wherein R' and R" are independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, which may be joined to form a substituted or unsubstituted C4-C9 heterocyclic ring;

r1 is NR ' R ' ' forming a substituted or unsubstituted piperidin-1-yl group, such as 4-CF ₃ Piperidin-1-yl;

R2-R10 are independently H, halide, substituted or unsubstituted OH, or substituted or unsubstituted NH ₂ Or substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;

R2-R10 are independently H, halide, or substituted or unsubstituted lower alkyl, such as F-substituted C1-C4 alkyl;

R2-R10 are H;

r11 is H, OH or substituted or unsubstituted C1-C4 alkyl;

r11 is H or OH;

r11 is H;

r12 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R12 is substituted or unsubstituted C3-C9 cycloalkyl, substituted or unsubstituted C3-C9 heterocycloalkyl, substituted or unsubstituted C5-C9 aryl, or substituted or unsubstituted C5-C9 heteroaryl;

r12 is 1-ethyl-pyrrolidin-2-one-4-yl;

R11-R12 are joined to form a substituted or unsubstituted C3-C10 heterocycle;

R11-R12 are joined to form a C5-C6 heterocyclic ring, such as a substituted or unsubstituted piperazin-2-one, such as wherein position 4 is substituted with methyl or ethyl;

0, 1, 2 or 3 of X1-X4, and 0, 1, 2 or 3 of Y1-Y4 are N;

0, 1 or 2 of X1-X4, and 0, 1 or 2 of Y1-Y4 are N;

only Y2 and X4, or Y2 and Y4, or X2 and Y2, or X2 and Y4, or X4 and X2, or X4 and Y4 are N; or

Only X2, X3, X4, Y2 or Y4 is N; or

Any combination of the foregoing substituents.

3. The compound of claim 1, wherein:

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.

4. The compound of claim 1, wherein:

R1 is substituted or unsubstituted OH or substituted or unsubstituted NH ₂ Substituted or unsubstitutedOr a substituted or unsubstituted C1-C9 heteroalkyl group.

5. The compound of claim 1, wherein:

r1 is substituted or unsubstituted OH or substituted or unsubstituted NH ₂ 。

6. The compound of claim 1, wherein:

r1 is NR 'R ", wherein R' and R" are independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, which may be joined to form a substituted or unsubstituted C4-C9 heterocyclic ring.

7. The compound of claim 1, wherein:

r1 is NR 'R ", wherein R' and R" are independently substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl, and are joined to form a substituted or unsubstituted C4-C9 heterocyclic ring.

8. The compound of claim 1, wherein:

r1 is NR 'R' forming a substituted or unsubstituted piperidin-1-yl group.

9. The compound of claim 1, wherein:

r1 is NR 'R', forming piperidin-1-yl, 4-methylpiperidin-1-yl or 4-CF ₃ Piperidin-1-yl.

10. The compound of claim 3, 4, 5, 6, 7, 8, or 9, wherein:

R2-R10 are independently H, halide, substituted or unsubstituted OH, or substituted or unsubstituted NH ₂ Substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

11. The compound of claim 3, 4, 5, 6, 7, 8, or 9, wherein:

R2-R10 are independently H, halide, or substituted or unsubstituted lower alkyl.

12. The compound of claim 3, 4, 5, 6, 7, 8, or 9, wherein:

R2-R10 are H.

13. The compound of claim 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, wherein:

r11 is H, OH or substituted or unsubstituted C1-C4 alkyl.

14. The compound of claim 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, wherein:

r11 is H or OH.

15. The compound of claim 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, wherein:

r11 is H.

16. The compound of claim 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein:

r12 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

17. The compound of claim 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein:

r12 is substituted or unsubstituted C3-C9 cycloalkyl, substituted or unsubstituted C3-C9 heterocycloalkyl, substituted or unsubstituted C5-C9 aryl, or substituted or unsubstituted C5-C9 heteroaryl.

18. The compound of claim 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein:

r12 is substituted or unsubstituted C3-C9 cycloalkyl, or substituted or unsubstituted C3-C9 heterocycloalkyl.

19. The compound of claim 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein:

r12 is pyrrolidin-2-one-4-yl, 1-methyl-pyrrolidin-2-one-4-yl or 1-ethyl-pyrrolidin-2-one-4-yl.

20. The compound of claim 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein:

R11-R12 are joined to form a substituted or unsubstituted C3-C10 heterocyclic ring.

21. The compound of claim 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein:

R11-R12 are joined to form a C5-C6 heterocyclic ring, such as a substituted or unsubstituted piperazin-2-one, such as wherein position 4 is substituted with methyl or ethyl.

22. The compound of claim 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21, wherein:

0, 1, 2 or 3 of X1 to X4 and 0, 1, 2 or 3 of Y1 to Y4 are N.

23. The compound of claim 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21, wherein:

0, 1 or 2 of X1 to X4, and 0, 1 or 2 of Y1 to Y4 are N.

24. The compound of claim 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21, wherein:

0 of X1-X4, and 0 of Y1-Y4 is N.

25. The compound of claim 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21, wherein:

only Y2 and X4, or Y2 and Y4, or X2 and Y2, or X2 and Y4, or X4 and X2, or X4 and Y4 are N.

26. The compound of claim 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21, wherein:

only X2, X3, X4, Y2 or Y4 is N.

27. The compound of claim 1 having the structure of table 1.

28. The compound of claim 1 having a structure selected from:

。

29. The compound of claim 1 having the structure of table 2.

30. The compound of claim 1 having a structure selected from:

。

31. the compound of claim 1 having a structure selected from:

。

32. a pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 and one or more pharmaceutically acceptable excipients in a predetermined unit dosage form.

33. Use of a compound or composition of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 in the manufacture of a medicament for inhibiting iron death activity, or modulating or inhibiting a disease associated with dysregulation of iron death, such as neuropathy, ischemia reperfusion injury, acute renal failure, and cancer, in a human in need thereof.

34. A compound or composition as claimed in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31 for use in inhibiting iron death activity, or modulating or inhibiting diseases associated with dysregulation of iron death, such as neuropathy, ischemia reperfusion injury, acute renal failure and cancer, or for use in the manufacture of a medicament thereof for use in a human in need thereof.

35. A method of inhibiting iron death activity, or modulating or inhibiting diseases associated with dysregulation of iron death such as neuropathy, ischemia reperfusion injury, acute renal failure and cancer, and optionally detecting an improvement in the health or condition of a human resulting therefrom, using a compound or composition according to claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31.