Ferroptosis inhibitors: diarylamine paraacetamides

Abstract

Provided are compounds (including the corresponding sulfonamides) that inhibit ferroptosis activity or modulate or inhibit diseases associated with ferroptosis dysregulation, such as neurological disorders, ischemia-reperfusion injury, acute renal failure, and cancer, as well as pharmaceutically acceptable salts, hydrates, and stereoisomers thereof. The compounds of the present invention find use in pharmaceutical compositions and methods of use and manufacturing, including treating a person in need thereof with an effective amount of a compound or composition of the present invention and detecting a resulting improvement in the person's health or condition.

Description

[Background technology]

[0001] <Introduction>

[0002] Ferroptosis is an iron-dependent form of programmed cell death 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. Dysregulated ferroptosis is thought to be involved in numerous diseases, including neurological disorders, ischemia-reperfusion injury, acute renal failure, and cancer. Summary of the Invention

[0003] <Summary of the Invention>

[0004] The present invention provides compounds that modulate or inhibit ferroptosis activity or that modulate or inhibit diseases associated with ferroptosis dysregulation, such as neurological disorders, ischemia-reperfusion injury, acute renal failure, and cancer, and prodrugs thereof that are hydrolyzed, typically in the intestine or blood, to yield the corresponding compound / inhibitor.

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

[0006] TIFF0007807381000001.tif55127

[0007] (In the formula,

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

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

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

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

[0012] In embodiments:

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

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

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

[0016] R1 is NR'R'', where R' and R'' are independently substituted or unsubstituted hydrocarbyl or substituted or unsubstituted heterohydrocarbyl, which may be linked to form an optionally substituted C4-C9 heterocycle;

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

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

[0019] R2-R10 are independently H, halide, or substituted or unsubstituted lower alkyl, for example, F-substituted C1-C4 alkyl;

[0020] R2 to R10 are H;

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

[0022] R11 is H or OH;

[0023] R11 is H;

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

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

[0026] R12 is 1-ethyl-pyrrolidin-2-one-4-yl;

[0027] R11 and R12 are linked together to form a substituted or unsubstituted C3 to C10 heterocycle;

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

[0029] 0, 1, 2 or 3 of X1 to X4 and 0, 1, 2 or 3 of Y1 to Y4 are N;

[0030] 0, 1 or 2 of X1 to X4 and 0, 1 or 2 of Y1 to Y4 are N;

[0031] Only one of Y2 and X4, or Y2 and Y4, or X2 and Y2, or X2 and Y4, or X4 and X2, or X4 and Y4 is N; or

[0032] Only X2, X3, X4, Y2 or Y4 is N; or

[0033] Any combination of the above substituents.

[0034] In one aspect, the present invention provides a compound disclosed herein, or a salt, hydrate, or stereoisomer thereof:

[0035] In one aspect, the present invention provides pharmaceutical compositions 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.

[0036] In one aspect, the present invention provides the use of a compound or composition disclosed herein in the manufacture of a medicament for inhibiting ferroptosis activity or for modulating or inhibiting diseases associated with ferroptosis dysregulation, such as neurological disorders, ischemia-reperfusion injury, acute renal failure, and cancer, in a person in need thereof.

[0037] In certain aspects, the present invention provides a compound or composition as disclosed herein for inhibiting ferroptosis activity or modulating or inhibiting diseases associated with ferroptosis dysregulation, such as neurological disorders, ischemia-reperfusion injury, acute renal failure and cancer, in a person in need thereof, or in the manufacture of a medicament thereof in a person in need thereof.

[0038] In certain aspects, the present invention provides methods of using the compounds or compositions disclosed herein to inhibit ferroptosis activity or to modulate or inhibit diseases associated with ferroptosis dysregulation, such as neurological disorders, ischemia-reperfusion injury, acute renal failure, and cancer, in a person in need thereof, and optionally detecting the resulting improvement in the health or condition of the person.

[0039] The present invention includes all combinations of the specific embodiments described herein, each and every combination being contemplated as being fully described herein. DETAILED DESCRIPTION OF THE INVENTION

[0040] Description of Specific Embodiments of the Invention

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

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

[0043] The term "lower alkyl" refers to a group having 1 to 8 carbon atoms, preferably 1 to 6, and more preferably 1 to 4. The term "lower alkenyl" or "lower alkynyl" refers to a group having 2 to 8, 2 to 6, or 2 to 4 carbon atoms.

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

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

[0046] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups and partially unsaturated cyclic hydrocarbon groups, including monocyclic groups and polycyclic groups (e.g., bicyclic and tricyclic groups). For example, the cycloalkyl group may have 3 to 12, 3 to 8, or 3 to 6 carbon atoms. Also, for example, the cycloalkyl group may be a monocyclic group having 3 to 12, 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 groups having 7 to 12 ring atoms arranged as a bicyclic group selected from a [4,4], [4,5], [5,5], [5,6], and [6,6] ring system, and groups having 7 to 12 ring atoms arranged as a bridged bicyclic group selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. These rings may be saturated, may contain at least one double bond (i.e., may be partially unsaturated), but are not fully conjugated and are not aromatic as defined herein.

[0047] As used herein, the term "aryl" refers to a group selected from a 5- or 6-membered carbocyclic aromatic ring (such as phenyl); a bicyclic ring system (such as a 7- to 12-membered bicyclic ring system) in which at least one ring is carbocyclic aromatic (such as a bicyclic ring system selected from naphthalene, indane, and 1,2,3,4-tetrahydroquinoline); and a tricyclic ring system (such as a 10- to 15-membered tricyclic ring system) in which at least one ring is carbocyclic aromatic (such as fluorene).

[0048] For example, an aryl group may be selected from a 5- or 6-membered carbocyclic aromatic ring fused to a 5- to 7-membered cycloalkyl ring or heterocycle, optionally containing at least one heteroatom selected from N, O, and S. When the carbocyclic aromatic ring is fused to a heterocycle, the point of attachment is on the carbocyclic aromatic ring; when the carbocyclic aromatic ring is fused to a cycloalkyl group, the point of attachment may be on either the carbocyclic aromatic ring or the cycloalkyl group. Divalent radicals formed from substituted benzene derivatives and having free valences on ring atoms are called substituted phenylene radicals. In monovalent polycyclic hydrocarbon radicals whose names end in "yl," divalent radicals derived by removing one hydrogen atom from the carbon atom having the free valence are named by adding "idene" to the name of the corresponding monovalent radical; for example, a naphthyl group having two points of attachment is called naphthylidene.

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

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

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

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

[0053] an 8- to 12-membered bicyclic group containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0054] An 11- to 14-membered tricyclic group containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and the remaining ring atoms being carbon, in which at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0055] For example, heteroaryl groups include 5- to 7-membered heteroaromatic rings fused to 5- to 7-membered cycloalkyl rings. In such fused bicyclic heteroaryl ring systems, where only one ring contains at least one heteroatom, the point of attachment can be on either the heteroaromatic ring or the cycloalkyl ring.

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

[0057] Examples of heteroaryl groups (numbered from the position of attachment 1) include pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, thienyl, triazinyl, benzothienyl, furyl, benzofuryl, benzimidazolyl, indolyl, isoindolyl, indolinyl, phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridin-5-yl), and the like. benzo[d]thiazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (e.g., benzo[d]thiazol-6-yl), indazolyl (e.g., 1H-indazol-5-yl), and 5,6,7,8-tetrahydroisoquinoline.

[0058] The terms "heterocyclic," "heterocycle," or "heterocyclyl" refer to a 4-12-membered monocyclic, bicyclic, or tricyclic saturated or partially unsaturated ring containing 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 containing at least one heteroatom selected from N, O, and S fused to a 5-, 6-, and / or 7-membered cycloalkyl, carbocyclic, or heterocyclic aromatic ring; when the heterocycle is fused to a carbocyclic or heterocyclic aromatic ring, the point of attachment is on the heterocycle; when the heterocycle is fused to a cycloalkyl, the point of attachment can be on either the cycloalkyl or heterocycle.

[0059] Additionally, "heterocycle" also refers to an aliphatic spirocycle containing at least one heteroatom selected from N, O, and S, where the point of attachment is at the heterocycle. These rings may be saturated or have at least one double bond (i.e., may be partially unsaturated). The heterocycle may be substituted with oxo. The point of attachment may be at a carbon or a heteroatom of the heterocycle. A heterocycle is not a heteroaryl as defined herein.

[0060] Examples of heterocyclic rings (numbered starting from the bonding position) include 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, oxiranyl, aziridinyl, thiiranyl, azetidinyl, and oxetanyl. , thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxazepanyl, 1,4-dithiepanyl, 1,4- Thiazepanyl, 1,4-diazepane, 1,4-dithianyl, 1,4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl Substituted heterocycles include, but are not limited to, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, 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.

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

[0062] In an embodiment, the substituents are selected from optionally substituted heteroatoms and optionally substituted, heteroatom-containing, and cyclic C1-C18 hydrocarbyls. In particular, the optionally substituted, heteroatom-containing, and cyclic C1-C18 hydrocarbyl is optionally substituted, heteroatom-containing, and cyclic alkyl, alkenyl, or alkynyl, or optionally substituted, heteroatom-containing aryl, and / or the optionally substituted heteroatom is halogen, optionally substituted hydroxyl (alkoxy, aryloxy, etc.), optionally substituted acyl (formyl, alkanoyl, carbamoyl, carboxyl, amido, etc.), optionally substituted amino (amino, alkylamino, dialkylamino, amido, sulfamidyl, etc.), optionally substituted thiol (mercapto, alkylthiol, arylthiol, etc.), optionally substituted sulfinyl or sulfonyl (alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, etc.), nitro, or cyano.

[0063] In embodiments, the substituents are halogen, —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —COR′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR′—SONR′″, —NR″COR′, —NH—C( The number of substituents is 0 to 3, and groups having 0, 1, or 2 substituents are particularly preferred. R', R'', and R''' each independently represent hydrogen, unsubstituted (C1-C8) alkyl or heteroalkyl, (C1-C8) alkyl or heteroalkyl substituted with 1 to 3 halogen atoms, unsubstituted aryl, aryl substituted with 1 to 3 halogen atoms, unsubstituted alkyl group, unsubstituted alkoxy group, unsubstituted thioalkoxy group, or aryl-(C1-C4) alkyl group. When R' and R" are attached to the same nitrogen atom, R' and R" can be combined 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 -CH2CF3), and when the aryl group is 1,2,3,4-tetrahydronaphthalene, the aryl group can be optionally substituted with a substituted or unsubstituted (C3-C7) spirocycloalkyl group. The (C3-C7) spirocycloalkyl group can be optionally substituted as defined herein for "cycloalkyl."

[0064] Preferred substituents are selected from halogen, —R′, —OR′, ═O, —NR′R″, —SR′, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —COR′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR″COR′, —NR′-SONR″R′″, —S(O)R′, —SOR′, —SONR′R″, —NR″SOR, —CN, —NO, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl, where R′ and R″ are as defined above.

[0065] Preferred substituents are disclosed herein, specific examples of which are given in the tables, structures, examples, and claims, and may be applied to a variety of different compounds of the invention, i.e., the substituents of a given compound may be used in combination with another compound.

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

[0067] In more specific embodiments, each applicable substituent is independently aldehyde, aldimine, alkanoyloxy, alkoxy, alkoxycarbonyl, alkyloxy, alkyl, amine, azo, halogen, carbamoyl, carbonyl, carboxamide, carboxyl, cyanyl, ester, halo, haloformyl, hydroperoxyl, hydroxyl, imine, isocyanide, isocyanate, N-tert-butoxycarbonyl, nitrate, nitrite, nitro, nitroso, phosphate, phosphono, sulfide, sulfonyl, sulfo, sulfhydryl, thiol, thiocyanyl, trifluoromethyl, or trifluoromethyl ether (OCF3).

[0068] The compounds of the present invention may have asymmetric centers and therefore may exist as enantiomers. When the compounds of the present invention have two or more asymmetric centers, they may further exist as diastereomers. Enantiomers and diastereomers are included in the broader definition of stereoisomers. All possible stereoisomers, including substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers, are intended to be included in the present invention. Also, all possible stereoisomers of the compounds of the present invention and / or pharmaceutically acceptable salts thereof are intended to be included in the present invention. Unless otherwise specified herein, a reference to one isomer applies to all possible isomers. When the isomeric composition is not specified, all possible isomers are included.

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

[0070] Unless otherwise specified specifically herein, when compounds of the invention contain olefinic double bonds, such double bonds are meant to include both E and Z geometric isomers.

[0071] Some of the compounds of the present invention may have different points of attachment of hydrogen, and such compounds are called tautomers. For example, a compound having a carbonyl group (-CHC(O)-) (keto form) may form a hydroxyl group (-CH=C(OH)-) (enol form) through tautomerism. Where applicable, both the keto and enol forms, either individually, and mixtures of the keto and enol forms, are intended to be included.

[0072] It may be advantageous to separate reaction products from one another and / or from starting materials. The desired products from each step or series of steps are separated and / or purified (hereinafter "separated") to the desired degree of homogeneity by techniques common in the art. Typically, such separations include multiphase extraction, crystallization from a single solvent or a mixture of solvents, distillation, sublimation, or chromatography. Chromatography can include 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 devices; small-volume analytical chromatography; simulated moving bed ("SMB") chromatography; preparative thin-layer chromatography; preparative thick-layer chromatography; and small-volume thin-layer and flash chromatography techniques. One skilled in the art will be able to apply the technique most likely to achieve the desired separation.

[0073] Diastereomeric mixtures can be separated into individual diastereomers based on their physical chemical differences by methods known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomeric mixtures can be 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), separating the diastereomers, and converting each resulting diastereomer into its corresponding pure enantiomer (e.g., by hydrolysis). Enantiomers can also be separated using a chiral HPLC column.

[0074] Single stereoisomers (e.g., substantially pure enantiomers) may be obtained by resolving a racemic mixture, such as by forming diastereomers using an optically active resolving agent. Racemic mixtures of chiral compounds of the present invention can be separated and isolated by suitable methods, including, for example, (1) forming ionic diastereomeric salts with chiral compounds and separating them by methods such as fractional crystallization, (2) forming diastereomeric compounds with chiral derivatizing reagents, separating the diastereomers, and converting them to pure stereoisomers, and (3) directly isolating substantially pure or enriched stereoisomers under chiral conditions.

[0075] Examples of "pharmaceutically acceptable salts" include inorganic acid salts selected from hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfinates, and nitrates, as well as salts such as malates, maleates, fumarates, tartrates, succinates, citrates, lactates, methanesulfonates, p-toluenesulfonates, 2-hydroxyethylsulfonates, benzoates, salicylates, stearates, alkanoates (such as acetates), and HOOC-(CH2) n-COOH (n is selected from 0 to 4), and the like. Similarly, examples of pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.

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

[0077] "Treating," "treat," 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 identified in need thereof.

[0078] An "effective amount" refers to an amount of at least one compound, and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof, sufficient to be effective in "treating" a disease or disorder in a subject, e.g., when administered, to induce to some significant extent a desired biological or medical response in a tissue, system, animal, or human, and to prevent the development of, or alleviate to some extent, one or more 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 being treated.

[0079] The term "at least one substituent" includes, for example, 1 to 4 substituents, such as 1 to 3 substituents, and further, for example, 1 or 2 substituents. For example, as used herein, "at least one substituent R16 " is R 16 The group may contain 1 to 4 substituents, for example 1 to 3 substituents, further for example 1 or 2 substituents selected from the list of:

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

[0081] Additionally, there is provided a composition comprising a compound of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0082] Compositions containing the compounds of the present invention, their stereoisomers, or pharmaceutically acceptable salts thereof can be administered by a variety of known methods, including oral, topical, rectal, parenteral, inhalation spray, and implanted reservoirs; in each case, the most appropriate route will depend on the individual host and the nature and severity of the condition for which the active ingredient is being administered. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion. The compositions disclosed herein may be conveniently provided in unit dosage form and may be prepared by any method well known in the art.

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

[0084] Gelatin capsules containing the compounds disclosed herein and / or at least one pharmaceutically acceptable salt thereof and a powdered carrier such as lactose, starch, cellulose derivatives, magnesium stearate, or stearic acid can also be used. Similar diluents can also be used to prepare compressed tablets. Tablets and capsules can also be prepared as sustained-release formulations for continuous release of the drug over a period of time. Compressed tablets can be sugar-coated or film-coated to mask unpleasant tastes or protect the tablet from the atmosphere, or enteric-coated to selectively disintegrate in the digestive tract.

[0085] Liquid dosage forms for oral administration may further comprise at least one agent selected from coloring agents and flavoring agents to facilitate patient administration.

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

[0087] Pharmaceutically acceptable carriers are selected from carriers that are compatible with the active ingredients in the composition (and, in some embodiments, can stabilize the active ingredients) and are not harmful to the subject being treated. For example, solubilizing agents such as cyclodextrins (which can form specific, highly soluble complexes with at least one compound and / or at least one pharmaceutically acceptable salt disclosed herein) can be used as pharmaceutical excipients for delivery of the active ingredients. Other examples of carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments (such as D&C Yellow #10). Suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in the field.

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

[0089] For ocular administration, the ophthalmic preparation may be formulated as a suspension or solution containing the compound of the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof in an appropriate weight percentage in an appropriate ophthalmic solvent, thereby maintaining contact of the compound of the present invention, its stereoisomer, or at least one pharmaceutically acceptable salt thereof with the surface of the eye for a sufficient period of time to allow the compound to penetrate the cornea and the interior of the eye.

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

[0091] The dosage will depend on factors such as the recipient's age, health, and weight, the severity of the disease, the type of treatment, if any, the frequency of treatment, and the characteristics of the desired effect. Generally, the daily dosage of the active ingredient may vary, but may be, for example, 0.1 to 2,000 mg per day. For example, 10 to 500 mg administered once or multiple times daily may be effective to achieve the desired results.

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

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

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

[0095] In some embodiments, a parenteral composition suitable for administration by injection can be prepared by stirring 1.5% by weight of a compound disclosed herein and / or at least one enantiomer, diastereomer, or pharmaceutically acceptable salt thereof in 10% by volume propylene glycol. The solution is made up to volume with water for injection and sterilized.

[0096] In some embodiments, an aqueous suspension for oral administration can be prepared, for example, 5 ml of an aqueous suspension containing 100 mg of a micronized compound of the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof, 100 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution (USP), and 0.025 ml of vanillin.

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

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

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

[0100] The compounds of the present invention may be used as they are, or may be used in the form of a pharmaceutically acceptable salt such as hydrochloride, hydrobromide, acetate, sulfate, citrate, carbonate, trifluoroacetate, etc. When the compounds of the present invention have a relatively acidic functional group, a salt can be obtained by adding a desired base without a solvent or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium salt, potassium salt, calcium salt, ammonium salt, organic amino salt, magnesium salt, etc. When the compounds of the present invention have a relatively basic functional group, a salt can be obtained by adding a desired acid without a solvent or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, and phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0101] The neutral compound may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent compound may differ from the various salt forms in physical properties such as solubility in polar solvents, but for purposes of this invention, the salts are otherwise equivalent to the parent compound.

[0102] In addition to salt forms, the present invention provides compounds in prodrug forms. Prodrugs of the compounds described herein are compounds that are readily chemically altered under physiological conditions to provide the compounds of the present invention. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. In some situations, prodrugs are often useful because they are easier to administer than the parent drug. For example, prodrugs may have better oral bioavailability than the parent drug. Prodrugs may also have improved solubility in pharmacological compositions compared to the parent drug. Various prodrug derivatives are known in the art, including, for example, prodrugs that utilize hydrolysis or oxidative activation. Examples of prodrugs include, but are not limited to, compounds of the present invention that are administered as esters ("prodrugs") and then metabolically hydrolyzed to the active carboxylic acid.

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

[0104] Some of the compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; all of the racemates, diastereomers, geometric isomers and individual isomers thereof are intended to be encompassed within the scope of the present invention.

[0105] The compounds of the present invention may contain isotopes such as deuterium at one or more of the constituent atoms of the compound in proportions not found in nature, for example, -CD3, CD2H, or CDH2 in place of methyl. For example, the compounds of the present invention may contain isotopes such as tritium ( 3 H), iodine-125( 125 I), carbon-14 ( 14 The compounds of the present invention may be radiolabeled with a radioisotope such as C. All compounds of the present invention that contain isotopes, whether radioactive or non-radioactive, are intended to be encompassed within the scope of the present invention.

[0106] The compounds of the invention are typically administered in a "therapeutically effective amount," i.e., an amount of a compound of the invention that will induce in a tissue, system, animal, or human the biological or medical response desired by a researcher, veterinarian, physician, or other clinician. The term "therapeutically effective amount" encompasses that amount of compound sufficient, when administered, to prevent the development of, or alleviate to some extent, one or more 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 being treated.

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

[0108] The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined amount of active agent calculated to produce a desired therapeutic effect, together with suitable pharmaceutical excipients. Typical unit dosage forms include ampoules or syringes filled with premeasured amounts of liquid compositions, or pills, tablets, capsules, lozenges, and the like for solid compositions. In such compositions, the mimetic is typically present as a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being processing aids and various solvents or carriers to facilitate the formation of the desired dosage form. Unit dosage formulations are preferably about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 250 mg, about 500 mg, or about 1,000 mg per unit. In one particular embodiment, the unit dosage forms are packaged in a multi-pack package suitable for successive use, for example a blister pack containing sheets containing at least 6, 9 or 12 unit dosage forms.

[0109] The compositions of the present invention may be formulated and / or co-administered with different compounds to treat applicable indications, inhibit ferroptosis activity, or modulate or inhibit diseases associated with ferroptosis dysregulation, such as neurological disorders, ischemia-reperfusion injury, acute renal failure, and cancer. In embodiments, applicable indications include cancer, neurological disorders 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, cardiac disease, liver, gastrointestinal, or pancreatic disease, vascular necrosis, diabetes, cancer chemotherapy / radiotherapy-induced cell death, and poisoning.

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

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

[0112] Active compounds have been shown to inhibit ferroptosis.

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

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

[0115] Active Compound Group I: Representative Synthesis

[0116] N-(4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)-N-hydroxy-1-(trifluoromethyl)cyclobutane-1-carboxamide (1) TIFF0007807381000046.tif130170

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

[0118] Step 2.

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

[0120] Step 3.

[0121] 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 °C. The solution was stirred at room temperature for 3 h. The pH of the solution was adjusted to 8-9 with sodium carbonate solution. The mixture was then extracted with DCM (15 mL x 3). The combined organic layers were washed with water (20 mL x 3), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH / DCM = 1 / 40) to give the desired product as a yellow solid (242 mg, 25%). Mass (m / z): 289.3 [M+H] + .

[0122] Step 4.

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

[0124] Step 5.

[0125] 4-(tert-Butyl)-3-fluoro-N-(4-((hydroxyamino)methyl)phenyl)aniline (20 mg, 0.07 mmol) was dissolved in 1.0 mL of THF / HO (1:1, v / v) and 1.2 mL of saturated aqueous NaHCO. The solution was cooled to 0 °C, 1-(trifluoromethyl)cyclobutane-1-carbonyl chloride was added, and the mixture was stirred at room temperature for 16 h. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine, dried over (NaSO), and concentrated in vacuo to give the crude product. The residue was purified by prep-TLC (MeOH / DCM = 1 / 10) to give the desired product (13.9 mg, 45.9%) as a white solid. TIFF0007807381000047.tif28170

[0126] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxyadamantane-1-carboxamide (2) TIFF0007807381000048.tif3862

[0127] TIFF0007807381000049.tif27170

[0128] N-Hydroxy-N-(4-(pyridin-4-ylamino)benzyl)adamantane-1-carboxamide (3) TIFF0007807381000050.tif3555

[0129] TIFF0007807381000051.tif19170

[0130] N-(4-((4-fluorophenyl)amino)benzyl)-N-hydroxyadamantane-1-carboxamide (4) TIFF0007807381000052.tif3555

[0131] TIFF0007807381000053.tif19170

[0132] N-(4-((4-(N,N-diethylsulfamoyl)phenyl)amino)benzyl)-N-hydroxyadamantane-1-carboxamide (5) TIFF0007807381000054.tif3766

[0133] TIFF0007807381000055.tif36170

[0134] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxypivalamide (6) TIFF0007807381000056.tif3262

[0135] TIFF0007807381000057.tif27170

[0136] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxycyclopropanecarboxamide (7) TIFF0007807381000058.tif3357

[0137] TIFF0007807381000059.tif27170

[0138] N-Hydroxy-N-(4-((4-(trifluoromethyl)phenyl)amino)benzyl)adamantane-1-carboxamide (8) TIFF0007807381000060.tif3761

[0139] TIFF0007807381000061.tif28170

[0140] N-hydroxy-N-(4-(pyridin-4-ylamino)benzyl)pivalamide (9) TIFF0007807381000062.tif3158

[0141] TIFF0007807381000063.tif27170

[0142] N-(4-((4-fluorophenyl)amino)benzyl)-N-hydroxypivalamide (10) TIFF0007807381000064.tif3265

[0143] TIFF0007807381000065.tif18170

[0144] N-(4-((4-(N,N-diethylsulfamoyl)phenyl)amino)benzyl)-N-hydroxypivalamide (11) TIFF0007807381000066.tif3379

[0145] TIFF0007807381000067.tif36170

[0146] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxyacetamide (12) TIFF0007807381000068.tif3265

[0147] TIFF0007807381000069.tif27170

[0148] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2,2-dimethylbutanamide (13) TIFF0007807381000070.tif3074

[0149] TIFF0007807381000071.tif27170

[0150] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-1-methylcyclopropane-1-carboxamide (14) TIFF0007807381000072.tif3167

[0151] TIFF0007807381000073.tif36170

[0152] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-6-methoxy-2,2-dimethylhexanamide (15) TIFF0007807381000074.tif2991

[0153] TIFF0007807381000075.tif36170

[0154] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-2,2,2-trifluoro-N-hydroxyacetamide (16) TIFF0007807381000076.tif3269

[0155] TIFF0007807381000077.tif26170

[0156] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxycyclopentanecarboxamide (17) TIFF0007807381000078.tif3269

[0157] TIFF0007807381000079.tif26170

[0158] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxybenzamide (18) TIFF0007807381000080.tif3173

[0159] TIFF0007807381000081.tif27170

[0160] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-1-(trifluoromethyl)cyclobutane-1-carboxamide (19) TIFF0007807381000082.tif3075

[0161] TIFF0007807381000083.tif35170

[0162] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-methoxy-2-methylpropanamide (20) TIFF0007807381000084.tif3171

[0163] TIFF0007807381000085.tif26170

[0164] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-4-methoxy-2,2-dimethylbutanamide (21) TIFF0007807381000086.tif3181

[0165] TIFF0007807381000087.tif27170

[0166] N-Hydroxy-2,2-dimethyl-N-(4-((4-(trifluoromethyl)phenyl)amino)benzyl)butanamide (22) TIFF0007807381000088.tif3074

[0167] TIFF0007807381000089.tif36170

[0168] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxynicotinamide (23) TIFF0007807381000090.tif3170

[0169] TIFF0007807381000091.tif26170

[0170] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-4-methyltetrahydro-2H-pyran-4-carboxamide (24) TIFF0007807381000092.tif3075

[0171] TIFF0007807381000093.tif36170

[0172] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-3,3,3-trifluoro-N-hydroxy-2,2-dimethylpropanamide (25) TIFF0007807381000094.tif2873

[0173] TIFF0007807381000095.tif26170

[0174] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-1-methylcyclohexane-1-carboxamide (26) TIFF0007807381000096.tif3169

[0175] TIFF0007807381000097.tif35170

[0176] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-4,4-difluoro-N-hydroxycyclohexane-1-carboxamide (27) TIFF0007807381000098.tif3080

[0177] TIFF0007807381000099.tif27170

[0178] N-(4-((3-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-methoxy-2-methylpropanamide (28) TIFF0007807381000100.tif3968

[0179] TIFF0007807381000101.tif27170

[0180] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-1-(trifluoromethyl)cyclopropane-1-carboxamide (29) TIFF0007807381000102.tif3273

[0181] TIFF0007807381000103.tif26170

[0182] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-1-methylpiperidine-4-carboxamide (30) TIFF0007807381000104.tif3178

[0183] TIFF0007807381000105.tif28170

[0184] 1-Acetyl-N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxypiperidine-4-carboxamide (31) TIFF0007807381000106.tif3387

[0185] TIFF0007807381000107.tif35170

[0186] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-(2-methoxyethoxy)acetamide (32) TIFF0007807381000108.tif3083

[0187] TIFF0007807381000109.tif26170

[0188] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (33) TIFF0007807381000110.tif2979

[0189] TIFF0007807381000111.tif19170

[0190] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-4-(pyrrolidin-1-yl)benzamide (34) TIFF0007807381000112.tif3582

[0191] TIFF0007807381000113.tif36170

[0192] N-(4-((3-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-4-methyltetrahydro-2H-pyran-4-carboxamide (35) TIFF0007807381000114.tif3081

[0193] TIFF0007807381000115.tif36170

[0194] N-(4-((3-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-1-methylcyclopropane-1-carboxamide (36) TIFF0007807381000116.tif2973

[0195] TIFF0007807381000117.tif28170

[0196] N-(4-((3-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-1-(trifluoromethyl)cyclobutane-1-carboxamide (37) TIFF0007807381000118.tif3068

[0197] TIFF0007807381000119.tif30170

[0198] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)pivalamide (38) TIFF0007807381000120.tif3170

[0199] TIFF0007807381000121.tif27170

[0200] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)pivalamide (39) TIFF0007807381000122.tif3067

[0201] TIFF0007807381000123.tif35170

[0202] 1-Isopropyl-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)piperidine-4-carboxamide (40) TIFF0007807381000124.tif41168

[0203] The title compound 40 (13.0 mg) was prepared 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) as a pale blue powder in 41.01% yield. TIFF0007807381000125.tif37170

[0204] N-(4-((4-cyclohexylphenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (41) TIFF0007807381000126.tif3382

[0205] TIFF0007807381000127.tif38170

[0206] N-(4-((4-(diethylamino)phenyl)amino)benzyl)-4-(dimethylamino)-N-hydroxybutanamide (42) TIFF0007807381000128.tif3383

[0207] TIFF0007807381000129.tif29170

[0208] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((3-(pyrrolidin-1-yl)phenyl)amino)benzyl)acetamide (43) TIFF0007807381000130.tif3975

[0209] TIFF0007807381000131.tif38170

[0210] 1-Methyl-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)piperidine-4-carboxamide (44) TIFF0007807381000132.tif38167

[0211] The title compound 44 (13.0 mg) was prepared 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) as a pale yellow powder in 31.90% yield. TIFF0007807381000133.tif38170

[0212] N-Hydroxy-2,2-dimethyl-N-(4-(phenylamino)benzyl)butanamide (45) TIFF0007807381000134.tif3064

[0213] TIFF0007807381000135.tif26170

[0214] N-Hydroxy-N-(4-((4-(trifluoromethyl)phenyl)amino)benzyl)pivalamide (46) TIFF0007807381000136.tif3470

[0215] TIFF0007807381000137.tif27170

[0216] N-Hydroxy-N-(4-(pyridin-2-ylamino)benzyl)pivalamide (47) TIFF0007807381000138.tif102170

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

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

[0219] Step 3. Preparation of N-(4-((hydroxyamino)methyl)phenyl)pyridin-2-amine (47-5). The title compound 47-5 (105 mg) was prepared 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 of 9% HCl according to the procedure in 1 as a yellow solid in an overall yield of 65.4%.

[0220] Step 4. Preparation of N-hydroxy-N-(4-(pyridin-2-ylamino)benzyl)pivalamide (47). The title compound 47 (40 mg) was prepared from N-(4-((hydroxyamino)methyl)phenyl)pyridin-2-amine (105 mg, 0.49 mmol), pivaloyl chloride (76 mg, 0.63 mmol), and NaHCO3 aqueous solution (0.6 ml) according to the procedure in 1 in an overall yield of 45% as a white solid. TIFF0007807381000139.tif28170

[0221] N-(4-((2-(tert-butyl)phenyl)amino)benzyl)-N-hydroxypivalamide (48) TIFF0007807381000140.tif3959

[0222] The title compound 48 (50 mg) was prepared from 2-(tert-butyl)-N-(4-((hydroxyamino)methyl)phenyl)aniline (94 mg, 0.35 mmol), pivaloyl chloride (55 mg, 0.45 mmol) and NaHCO3 aq. (0.42 ml) according to the procedure in 1 as a white solid in 40% overall yield. TIFF0007807381000141.tif28170

[0223] N-(4-((3-(tert-butyl)phenyl)amino)benzyl)-N-hydroxypivalamide (49) TIFF0007807381000142.tif3771

[0224] The title compound 49 (50 mg) was prepared from 3-(tert-butyl)-N-(4-((hydroxyamino)methyl)phenyl)aniline (69 mg, 0.256 mmol), pivaloyl chloride (40 mg, 0.332 mmol) and NaHCO3 aq. (0.3 ml) according to the procedure in 1 as a white solid in 40% overall yield. TIFF0007807381000143.tif27170

[0225] N-(4-((4-(dimethylamino)phenyl)amino)benzyl)-N-hydroxypivalamide (50) TIFF0007807381000144.tif101170

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

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

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

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

[0230] N-(4-((2,4-difluorophenyl)amino)benzyl)-N-hydroxypivalamide (51) TIFF0007807381000145.tif3865

[0231] The title compound 51 (28 mg) was prepared from 2,4-difluoro-N-(4-((hydroxyamino)methyl)phenyl)aniline (58 mg, 0.23 mmol), pivaloyl chloride (36 mg, 0.3 mmol) and NaHCO3 aq. (0.28 ml) according to the procedure in 1 as a white solid in 40% overall yield. TIFF0007807381000146.tif27170

[0232] N-hydroxy-N-(4-((2,4,6-trifluorophenyl)amino)benzyl)pivalamide (52) TIFF0007807381000147.tif3565

[0233] The title compound 52 (42 mg) was prepared from 2,4,6-trifluoro-N-(4-((hydroxyamino)methyl)phenyl)aniline (56 mg, 0.207 mmol), pivaloyl chloride (33 mg, 0.27 mmol) and NaHCO3 aq. (0.25 ml) according to the procedure in 1 as a white solid in 40% overall yield. TIFF0007807381000148.tif18170

[0234] N-Hydroxy-N-(4-(pyridin-3-ylamino)benzyl)pivalamide (53) TIFF0007807381000149.tif4470

[0235] The title compound 53 (35 mg) was prepared from N-(4-((hydroxyamino)methyl)phenyl)pyridin-3-amine (93 mg, 0.43 mmol), pivaloyl chloride (68 mg, 0.56 mmol) and NaHCO3 aq. (0.51 ml) according to the procedure in 1 as a white solid in 45% overall yield. TIFF0007807381000150.tif28170

[0236] N-hydroxy-N-(4-((4-methoxyphenyl)amino)benzyl)pivalamide (54) TIFF0007807381000151.tif3868

[0237] The title compound 54 (23 mg) was prepared from 4-((hydroxyamino)methyl)-N-(4-methoxyphenyl)aniline (95 mg, 0.39 mmol), pivaloyl chloride (61 mg, 0.15 mmol) and NaHCO3 aq. (0.47 ml) according to the procedure in 1 as a white solid in 40% overall yield. TIFF0007807381000152.tif27170

[0238] N-Hydroxy-N-(4-(mesitylamino)benzyl)pivalamide (55) TIFF0007807381000153.tif3761

[0239] The title compound 55 (50 mg) was prepared from N-(4-((hydroxyamino)methyl)phenyl)-2,4,6-trimethylaniline (108 mg, 0.42 mmol), pivaloyl chloride (66 mg, 0.55 mmol) and NaHCO3 aq. (0.5 ml) according to the procedure in 1 as a white solid in 40% overall yield. TIFF0007807381000154.tif26170

[0240] N-(4-((2,5-bis(trifluoromethyl)phenyl)amino)benzyl)-N-hydroxypivalamide (56) TIFF0007807381000155.tif4359

[0241] The title compound 56 (40 mg) was prepared from N-(4-((hydroxyamino)methyl)phenyl)-2,5-bis(trifluoromethyl)aniline (110 mg, 0.31 mmol), pivaloyl chloride (0.05 ml, 0.41 mmol) and NaHCO3 aq. (0.38 ml) according to the procedure in 1 as a white solid in 40% overall yield. TIFF0007807381000156.tif27170

[0242] N-(4-((4-(tert-butyl)-2,6-dimethylphenyl)amino)benzyl)-N-hydroxypivalamide (57) TIFF0007807381000157.tif3767

[0243] The title compound 57 (43 mg) was prepared from 4-(tert-butyl)-N-(4-((hydroxyamino)methyl)phenyl)-2,6-dimethylaniline (150 mg, 0.5 mmol), pivaloyl chloride (0.08 ml, 0.65 mmol) and NaHCO3 aq. (0.6 ml) according to the procedure in 1 as a white solid in 40% overall yield. TIFF0007807381000158.tif29170

[0244] N-Hydroxy-N-(4-(phenylamino)benzyl)pivalamide (58) TIFF0007807381000159.tif3758

[0245] The title compound 58 (7 mg) was prepared from 4-((hydroxyamino)methyl)-N-phenylaniline (38 mg, 0.18 mmol), pivaloyl chloride (0.028 ml, 0.23 mmol) and NaHCO3 aq. (0.2 ml) according to the procedure in 1 as a white solid in 40% overall yield. TIFF0007807381000160.tif27170

[0246] N-Hydroxy-N-(4-((4-(pyrrolidin-1-yl)phenyl)amino)benzyl)pivalamide (59) TIFF0007807381000161.tif3973

[0247] The title compound 59 (10 mg) was prepared 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 NaHCO3 aq. (0.06 ml) according to the procedure in 1 as a white solid in 40% overall yield.

[0248] N-(4-(phenylamino)benzyl)adamantane-1-carboxamide (60) TIFF0007807381000162.tif4159

[0249] TIFF0007807381000163.tif27170

[0250] N-Hydroxy-N-(4-(phenylamino)benzyl)adamantane-1-carboxamide (61) TIFF0007807381000164.tif3853

[0251] TIFF0007807381000165.tif28170

[0252] N-(4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)-N-hydroxy-2-methoxy-2-methylpropanamide (62) TIFF0007807381000166.tif3365

[0253] TIFF0007807381000167.tif26170

[0254] N-(4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)-N-hydroxy-2-(2-(2-methoxyethoxy)ethoxy)acetamide (63) TIFF0007807381000168.tif3190

[0255] TIFF0007807381000169.tif29170

[0256] N-(4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)-N-hydroxypivalamide (64) TIFF0007807381000170.tif3361

[0257] TIFF0007807381000171.tif27170

[0258] tert-Butyl 3-((4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)(hydroxy)carbamoyl)azetidine-1-carboxylate (65) TIFF0007807381000172.tif3278

[0259] TIFF0007807381000173.tif26170

[0260] tert-Butyl 4-((4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)(hydroxy)carbamoyl)-4-methylpiperidine-1-carboxylate (66) TIFF0007807381000174.tif3183

[0261] TIFF0007807381000175.tif36170

[0262] tert-Butyl 4-(2-((4-((4-(tert-butyl)phenyl)amino)benzyl)(hydroxy)amino)-2-oxoethyl)piperazine-1-carboxylate (67) TIFF0007807381000176.tif3289

[0263] TIFF0007807381000177.tif27170

[0264] N-Hydroxy-2-methoxy-2-methyl-N-(4-((4-(trifluoromethyl)phenyl)amino)benzyl)propanamide (68) TIFF0007807381000178.tif3077

[0265] TIFF0007807381000179.tif27170

[0266] N-Hydroxy-1-methyl-N-(4-((4-(trifluoromethyl)phenyl)amino)benzyl)cyclohexane-1-carboxamide (69) TIFF0007807381000180.tif2971

[0267] TIFF0007807381000181.tif36170

[0268] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-4-(dimethylamino)-N-hydroxybutanamide (70) TIFF0007807381000182.tif3285

[0269] TIFF0007807381000183.tif39170

[0270] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-3-morpholinopropanamide (71) TIFF0007807381000184.tif3278

[0271] TIFF0007807381000185.tif28170

[0272] N-(4-([1,1'-biphenyl]-4-ylamino)benzyl)-N-hydroxy-4-methyltetrahydro-2H-pyran-4-carboxamide (72) TIFF0007807381000186.tif3579

[0273] TIFF0007807381000187.tif36170

[0274] N-(4-([1,1'-biphenyl]-4-ylamino)benzyl)-2,2,2-trifluoro-N-hydroxyacetamide (73) TIFF0007807381000188.tif3475

[0275] TIFF0007807381000189.tif19170

[0276] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-1,4-dimethylpiperidine-4-carboxamide (74) TIFF0007807381000190.tif3276

[0277] TIFF0007807381000191.tif37170

[0278] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-2-(4-ethylpiperazin-1-yl)-N-hydroxyacetamide (75) TIFF0007807381000192.tif3381

[0279] TIFF0007807381000193.tif39170

[0280] 2-(4-acetylpiperazin-1-yl)-N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxyacetamide (76) TIFF0007807381000194.tif3881

[0281] TIFF0007807381000195.tif28170

[0282] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)acetamide (77) TIFF0007807381000196.tif4493

[0283] TIFF0007807381000197.tif27170

[0284] N-(4-((4'-fluoro-[1,1'-biphenyl]-4-yl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (78) TIFF0007807381000198.tif3485

[0285] TIFF0007807381000199.tif36170

[0286] N-hydroxy-4-methyl-N-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)piperazine-1-carboxamide (79) TIFF0007807381000200.tif3378

[0287] The title compound 79 (13.5 mg) was prepared as a white solid in 33.2% overall yield. TIFF0007807381000201.tif28170

[0288] N-(4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)-N-hydroxy-1-methylcyclopropane-1-carboxamide (80) TIFF0007807381000202.tif108170

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

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

[0291] 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 °C. The solution was stirred at room temperature for 3 h. The pH of the solution was adjusted to 8-9 with sodium carbonate solution. The mixture was then extracted with DCM (15 mL x 3). The combined organic layers were washed with water (20 mL x 3), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH / DCM = 1 / 40) to give the desired product as a yellow solid (242 mg, 25%). Mass (m / z): 289.3 [M+H] + .

[0292] Step 4. 4-(tert-Butyl)-3-fluoro-N-(4-((hydroxyamino)methyl)phenyl)aniline (20 mg, 0.07 mmol) was dissolved in 1.0 mL of THF / HO (1:1, v / v) and 1.2 mL of saturated aqueous NaHCO. The solution was cooled to 0 °C, and 1-methylcyclopropane-1-carbonyl chloride (9.1 mg, 0.077 mmol) was added. 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, dried over (NaSO), and concentrated in vacuo to give the crude product. The residue was purified by prep-TLC (MeOH / DCM = 1 / 10) to give the desired product (8.0 mg, 30.9%) as a white solid. TIFF0007807381000203.tif28170

[0293] N-(4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)-N-hydroxy-4-methyltetrahydro-2H-pyran-4-carboxamide (81) TIFF0007807381000204.tif3569

[0294] The title compound 81 (8.6 mg) was prepared 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 in an overall yield of 29.6% as a white solid. TIFF0007807381000205.tif37170

[0295] N-(4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)-N-hydroxy-2-morpholinoacetamide (82) TIFF0007807381000206.tif3280

[0296] The title compound 82 (11 mg) was prepared 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 in an overall yield of 37.8% as a white solid. TIFF0007807381000207.tif27170

[0297] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((4-(1-methylpiperidin-4-yl)phenyl)amino)benzyl)acetamide (83) TIFF0007807381000208.tif3876

[0298] The title compound 83 (16 mg) was prepared from N-(4-((hydroxyamino)methyl)phenyl)-[1,1′-biphenyl]-4-amine (30 mg, 0.1 mmol), pivaloyl chloride (16.2 mg, 0.13 mmol) and NaHCO 3 aq. (0.13 ml) according to the procedure in 1 as a white solid in 45% overall yield. TIFF0007807381000209.tif27170

[0299] N-(4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)-N-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carboxamide (84) TIFF0007807381000210.tif3376

[0300] The title compound 84 (30 mg) was prepared 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) according to the procedure for compound 1 as a yellow solid in 96% overall yield. TIFF0007807381000211.tif27170

[0301] N-(4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)-4-(dimethylamino)-N-hydroxybutanamide (85) TIFF0007807381000212.tif3080

[0302] The title compound 85 (2.4 mg) was prepared from 4-(tert-butyl)-3-fluoro-N-(4-((hydroxyamino)methyl)phenyl)aniline (20 mg, 0.07 mmol), 4-(dimethylamino)butanoyl chloride (0.077 mmol) according to the procedure for compound 1 in an overall yield of 8.5% as a white solid. TIFF0007807381000213.tif37170

[0303] N-(4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)-N-hydroxy-2,3-dihydro-1H-indene-2-carboxamide (86) TIFF0007807381000214.tif3380

[0304] The title compound 86 (32 mg) was prepared 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 as a yellow solid in 90% overall yield. TIFF0007807381000215.tif18170

[0305] N-(4-((4-(tert-butyl)-3-fluorophenyl)amino)benzyl)-N-hydroxyazetidine-3-carboxamide (87) TIFF0007807381000216.tif3371

[0306] The title compound 87 (4.0 mg) was prepared from 4-(tert-butyl)-3-fluoro-N-(4-((hydroxyamino)methyl)phenyl)aniline (20 mg, 0.07 mmol), tert-butyl 3-(chlorocarbonyl)azetidine-1-carboxylate (0.077 mmol) according to the procedure for compound 1 as a white solid in an overall yield of 15.4%. TIFF0007807381000217.tif27170

[0307] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxybenzo[d]thiazole-6-carboxamide (88) TIFF0007807381000218.tif3282

[0308] The title compound 88 (4.2 mg) was prepared from 4-(tert-butyl)-N-(4-((hydroxyamino)methyl)phenyl)aniline (20 mg, 0.074 mmol), benzo[d]thiazole-6-carbonyl chloride (0.077 mmol) according to the procedure for compound 1 as a white solid in 13.9% overall yield. TIFF0007807381000219.tif29170

[0309] N-Hydroxy-4-methyl-N-(4-((4-(trifluoromethyl)phenyl)amino)benzyl)tetrahydro-2H-pyran-4-carboxamide (89) TIFF0007807381000220.tif3176

[0310] The title compound 89 (5.4 mg) was prepared 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 in an overall yield of 13.2% as a yellow solid. TIFF0007807381000221.tif29170

[0311] N-Hydroxy-N-(4-((6-isopropylpyridin-3-yl)amino)benzyl)pivalamide (90) TIFF0007807381000222.tif3770

[0312] The title compound 90 (12 mg) was prepared from N-(4-((hydroxyamino)methyl)phenyl)-6-isopropylpyridin-3-amine (20 mg, 0.08 mmol), pivaloyl chloride (12.3 mg, 0.1 mmol) and NaHCO3 aq. (0.1 ml) according to the procedure in 1 as a white solid in 40% overall yield. TIFF0007807381000223.tif36170

[0313] N-Hydroxy-1-(trifluoromethyl)-N-(4-((4-(trifluoromethyl)phenyl)amino)benzyl)cyclobutane-1-carboxamide (91) TIFF0007807381000224.tif3174

[0314] The title compound 91 (7.2 mg) was prepared according to the procedure for compound 80 as a yellow solid in 23.8% overall yield. TIFF0007807381000225.tif39170

[0315] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (92) TIFF0007807381000226.tif3685

[0316] The title compound 92 (10.8 mg) was prepared according to the procedure for compound 80 as a yellow solid in 26.3% overall yield. TIFF0007807381000227.tif26170

[0317] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-morpholinoacetamide (93) TIFF0007807381000228.tif3577

[0318] The title compound 93 (14.8 mg) was prepared according to the procedure for compound 80 as a yellow solid in 50.3% overall yield. TIFF0007807381000229.tif37170

[0319] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-4-methylpiperidine-4-carboxamide (94) TIFF0007807381000230.tif3477

[0320] The title compound 94 (3.0 mg) was prepared according to the procedure for compound 80 as a yellow solid in 20.3% overall yield. TIFF0007807381000231.tif38170

[0321] N-(4-((4-(tert-butyl)phenyl)amino)-2-methylbenzyl)-N-hydroxypivalamide (95) TIFF0007807381000232.tif3065

[0322] The title compound 95 (17.4 mg) was prepared according to the procedure for compound 80 as a yellow solid in 47.1% overall yield. TIFF0007807381000233.tif28170

[0323] N-(4-([1,1'-biphenyl]-4-ylamino)benzyl)-N-hydroxy-2-methoxy-2-methylpropanamide (96) TIFF0007807381000234.tif3679

[0324] The title compound 96 (26.5 mg) was prepared according to the procedure for compound 80 as a white solid in 61.8% overall yield. TIFF0007807381000235.tif29170

[0325] N-(4-((4-(tert-butyl)-2,6-dimethylphenyl)amino)benzyl)-N-hydroxy-4-methyltetrahydro-2H-pyran-4-carboxamide (97) TIFF0007807381000236.tif3370

[0326] The title compound 97 (28 mg) was prepared according to the procedure for compound 80 as a white solid in 41.8% overall yield. TIFF0007807381000237.tif36170

[0327] N-(4-((4-(tert-butyl)-2,6-dimethylphenyl)amino)benzyl)-N-hydroxy-2-methoxy-2-methylpropanamide (98) TIFF0007807381000238.tif3675

[0328] The title compound 98 (21.4 mg) was prepared according to the procedure for compound 80 as a white solid in 53.8% overall yield. TIFF0007807381000239.tif27170

[0329] N-(4-((4-(tert-butyl)phenyl)amino)-3-fluorobenzyl)-N-hydroxypivalamide (99) TIFF0007807381000240.tif3266

[0330] The title compound 99 (25.6 mg) was prepared according to the procedure for compound 80 as a white solid in 70.3% overall yield. TIFF0007807381000241.tif28170

[0331] N-hydroxy-N-(4-((4-morpholinophenyl)amino)benzyl)pivalamide (100) TIFF0007807381000242.tif4278

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

[0333] N-(4-([1,1'-biphenyl]-4-ylamino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (101) TIFF0007807381000243.tif3690

[0334] The title compound 101 (2.3 mg) was prepared according to the procedure for compound 80 as a white solid in 9.6% overall yield. TIFF0007807381000244.tif37170

[0335] N-(4-((4-(tert-butyl)-2,6-dimethylphenyl)amino)benzyl)-2,2,2-trifluoro-N-hydroxyacetamide (102) TIFF0007807381000245.tif3569

[0336] The title compound 102 (30 mg) was prepared according to the procedure for compound 80 as a white solid in 76.1% overall yield. TIFF0007807381000246.tif20170

[0337] N-(4-((4-(tert-butyl)-2,6-dimethylphenyl)amino)benzyl)-N-hydroxy-1-methylpiperidine-4-carboxamide (103) TIFF0007807381000247.tif3477

[0338] The title compound 103 (3.1 mg) was prepared according to the procedure for compound 80 as a white solid in 12.4% overall yield. TIFF0007807381000248.tif37170

[0339] N-(4-((4'-fluoro-[1,1'-biphenyl]-4-yl)amino)benzyl)-N-hydroxypivalamide (104) TIFF0007807381000249.tif3981

[0340] The title compound 104 (19.2 mg) was prepared according to the procedure for compound 80 as a white solid in 48.9% overall yield. TIFF0007807381000250.tif28170

[0341] N-(4-((4-cyclopropylphenyl)amino)benzyl)-N-hydroxypivalamide (105) TIFF0007807381000251.tif3467

[0342] The title compound 105 (10.0 mg) was prepared according to the procedure for compound 80 as a white solid in 29.6% overall yield. TIFF0007807381000252.tif29170

[0343] N-(4-((4-(1H-imidazol-1-yl)phenyl)amino)benzyl)-N-hydroxypivalamide (106) TIFF0007807381000253.tif3373

[0344] The title compound 106 (13.7 mg) was prepared according to the procedure for compound 80 as a white solid in 37.6% overall yield. TIFF0007807381000254.tif18170

[0345] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((4-(trifluoromethyl)phenyl)amino)benzyl)acetamide (107) TIFF0007807381000255.tif3582

[0346] The title compound 107 (13.3 mg) was prepared according to the procedure for compound 80 as a white solid in 35.8% overall yield. TIFF0007807381000256.tif26170

[0347] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-2-(4-cyclopropylpiperazin-1-yl)-N-hydroxyacetamide (108) TIFF0007807381000257.tif108170

[0348] Steps 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] + .

[0349] Step 4. To a solution of 4-(tert-butyl)-N-(4-((hydroxyamino)methyl)phenyl)aniline (54 mg, 0.2 mmol) and 2-(4-cyclopropylpiperazin-1-yl)acetic acid (47.8 mg, 0.26 mmol) in DMF (1 ml) was added DIEA (0.045 mL, 0.26 mmol). Subsequently, DMT-MM (76.4 mg, 0.26 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. 10 mL of water was added. The mixture was then extracted with DCM (10 mL x 3). The combined organic layers were washed with water (10 mL x 3), dried over Na2SO4, and concentrated in vacuo. The residue was purified by prep-TLC (MeOH / DCM = 1 / 10) to give the desired product as a white solid (27.2 mg, 31.1%). TIFF0007807381000258.tif36170

[0350] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-(4-methyl-3-oxopiperazin-1-yl)acetamide (109) TIFF0007807381000259.tif4079

[0351] The title compound 109 (5.0 mg) was prepared according to the procedure for compound 108 as a white solid in 16.3% overall yield. TIFF0007807381000260.tif29170

[0352] 2-(4-benzoylpiperazin-1-yl)-N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxyacetamide (110) TIFF0007807381000261.tif4099

[0353] The title compound 110 (7.4 mg) was prepared according to the procedure for compound 80 as a white solid in 49% overall yield. TIFF0007807381000262.tif28170

[0354] N-hydroxy-N-(4-((4-(trifluoromethoxy)phenyl)amino)benzyl)pivalamide (111) TIFF0007807381000263.tif3175

[0355] The title compound 111 (28.2 mg) was prepared according to the procedure for compound 80 as a white solid in 73.6% overall yield. TIFF0007807381000264.tif28170

[0356] N-(4-((4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)amino)benzyl)-N-hydroxypivalamide (112) TIFF0007807381000265.tif4179

[0357] The title compound 112 (14.5 mg) was prepared according to the procedure for compound 80 as a white solid in 33.7% overall yield. TIFF0007807381000266.tif28170

[0358] N-hydroxy-N-(4-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)amino)benzyl)pivalamide (113) TIFF0007807381000267.tif4383

[0359] The title compound 113 (7.3 mg) was prepared according to the procedure for compound 80 as a white solid in 27.5% overall yield. TIFF0007807381000268.tif30170

[0360] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-(4-methyl-2-oxopiperazin-1-yl)acetamide (114) TIFF0007807381000269.tif3474

[0361] The title compound 114 (5.7 mg) was prepared according to the procedure for compound 108 as a white solid in 13.4% overall yield. TIFF0007807381000270.tif36170

[0362] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-2-(4-(cyclopropanecarbonyl)piperazin-1-yl)-N-hydroxyacetamide (115) TIFF0007807381000271.tif3785

[0363] The title compound 115 (11.4 mg) was prepared according to the procedure for compound 108 as a white solid in 81.9% overall yield. TIFF0007807381000272.tif37170

[0364] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-(4-(methylsulfonyl)piperazin-1-yl)acetamide (116) TIFF0007807381000273.tif3785

[0365] The title compound 116 (20.0 mg) was prepared according to the procedure for compound 108 as a white solid in 42.2% overall yield. TIFF0007807381000274.tif28170

[0366] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-2-(3,4-dimethylpiperazin-1-yl)-N-hydroxyacetamide (117) TIFF0007807381000275.tif3473

[0367] The title compound 117 (17.7 mg) was prepared according to the procedure for compound 108 as a white solid in 42.0% overall yield. TIFF0007807381000276.tif37170

[0368] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-2-(4-(4-fluorophenyl)piperazin-1-yl)-N-hydroxyacetamide (118) TIFF0007807381000277.tif3983

[0369] The title compound 118 (9.0 mg) was prepared according to the procedure for compound 108 as a white solid in 30.6% overall yield. TIFF0007807381000278.tif29170

[0370] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-4-methylpiperazine-1-carboxamide (119) TIFF0007807381000279.tif3070

[0371] The title compound 119 (13.3 mg) was prepared according to the procedure for compound 134 as a white solid in 33.6% overall yield. TIFF0007807381000280.tif28170

[0372] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)benzyl)acetamide (120) TIFF0007807381000281.tif3084

[0373] The title compound 120 (13.4 mg) was prepared according to the procedure for compound 108 as a white solid in 6.6% overall yield. TIFF0007807381000282.tif38170

[0374] N-(4-((4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (121) TIFF0007807381000283.tif3888

[0375] The title compound 121 (13.5 mg) was prepared according to the procedure for compound 108 as a white solid in 27.7% overall yield. TIFF0007807381000284.tif38170

[0376] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-2-(4-(6-fluoropyridin-3-yl)piperazin-1-yl)-N-hydroxyacetamide (122) TIFF0007807381000285.tif3787

[0377] The title compound 122 (2.5 mg) was prepared according to the procedure for compound 108 as a white solid in 8.5% overall yield. TIFF0007807381000286.tif28170

[0378] 4-(Dimethylamino)-N-hydroxy-N-(4-((4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)benzyl)butanamide (123) TIFF0007807381000287.tif3087

[0379] TIFF0007807381000288.tif37170

[0380] 4-(Dimethylamino)-N-hydroxy-N-(4-((4-(N-methylacetamido)phenyl)amino)benzyl)butanamide (124) TIFF0007807381000289.tif4078

[0381] TIFF0007807381000290.tif31170

[0382] N-hydroxy-N-(4-((4-(2,2,2-trifluoroethoxy)phenyl)amino)benzyl)pivalamide (125) TIFF0007807381000291.tif3369

[0383] The title compound 125 (35.0 mg) was prepared according to the procedure for compound 80 as a white solid in 88.4% overall yield. TIFF0007807381000292.tif28170

[0384] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)acetamide (126) TIFF0007807381000293.tif3783

[0385] The title compound 126 (29.0 mg) was prepared according to the procedure for compound 108 as a white solid in 73.4% overall yield. TIFF0007807381000294.tif29170

[0386] N-(4-((4-chlorophenyl)amino)benzyl)-N-hydroxypivalamide (127) TIFF0007807381000295.tif3264

[0387] The title compound 127 (33.2 mg) was prepared according to the procedure for compound 80 as a white solid in 98.3% overall yield. TIFF0007807381000296.tif19170

[0388] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)amino)benzyl)acetamide (128) TIFF0007807381000297.tif3192

[0389] The title compound 128 (23.4 mg) was prepared according to the procedure for compound 108 as a white solid in 45.5% overall yield. TIFF0007807381000298.tif37170

[0390] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)acetamide (129) TIFF0007807381000299.tif3783

[0391] The title compound 129 (25.5 mg) was prepared according to the procedure for compound 108 as a white solid in 90.1% overall yield. TIFF0007807381000300.tif36170

[0392] N-(4-((4-cyanophenyl)amino)benzyl)-N-hydroxypivalamide (130) TIFF0007807381000301.tif3169

[0393] The title compound 130 (10.0 mg) was prepared according to the procedure for compound 80 as a white solid in 30.9% overall yield. TIFF0007807381000302.tif30170

[0394] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)acetamide (131) TIFF0007807381000303.tif3281

[0395] The title compound 131 (10.6 mg) was prepared according to the procedure for compound 108 as a white solid in 39.4% overall yield. TIFF0007807381000304.tif28170

[0396] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-methoxypivalamide (132) TIFF0007807381000305.tif3368

[0397] The title compound 132 (32.0 mg) was prepared according to the procedure for compound 80 as a white solid in 86.9% overall yield. TIFF0007807381000306.tif28170

[0398] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-N-hydroxy-2-(4-(pyrimidin-2-yl)piperazin-1-yl)acetamide (133) TIFF0007807381000307.tif3887

[0399] The title compound 133 (38.4 mg) was prepared according to the procedure for compound 108 as a white solid in 45.3% overall yield. TIFF0007807381000308.tif30170

[0400] 1-(4-((4-(tert-butyl)phenyl)amino)benzyl)-3-cyclopropyl-1-hydroxyurea (134) TIFF0007807381000309.tif32162

[0401] 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). The reaction mixture was stirred for 2 h, and then DIEA (39 mg, 0.3 mmol) and cyclopropanamine (5.7 mg, 0.1 mmol) were added. The reaction mixture was then stirred for 1 h. The reaction solution was washed with water (3x 5 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by prep-TLC (MeOH / DCM = 1 / 10) to give the desired product as a yellow solid (21.5 mg, 65.7%). TIFF0007807381000310.tif28170

[0402] N-(4-((4-(6-fluoropyridin-3-yl)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (135) TIFF0007807381000311.tif3991

[0403] The title compound 135 (12.0 mg) was prepared according to the procedure for compound 108 as a white solid in 26.7% overall yield. TIFF0007807381000312.tif37170

[0404] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((4-(pyrrolidin-1-yl)phenyl)amino)benzyl)acetamide (136) TIFF0007807381000313.tif3286

[0405] The title compound 136 (5.1 mg) was prepared according to the procedure for compound 108 as a white solid in 13.2% overall yield. TIFF0007807381000314.tif27170

[0406] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((4-(1-methylpiperidin-4-yl)phenyl)amino)benzyl)acetamide (137) TIFF0007807381000315.tif3894

[0407] 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-MM (151 mg, 0.55 mmol). The mixture was then stirred at room temperature for 3 hours. The reaction was concentrated in vacuo. The residue was purified by perp-TLC to give the desired product as a white solid (6 mg, 1.6%). TIFF0007807381000316.tif47170

[0408] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((4-morpholinophenyl)amino)benzyl)acetamide (138) TIFF0007807381000317.tif3590

[0409] The title compound 138 (38.1 mg) was prepared according to the procedure for compound 108 as a white solid in 86.5% overall yield. TIFF0007807381000318.tif38170

[0410] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((4-(2-oxopyridin-1(2H)-yl)phenyl)amino)benzyl)acetamide (139) TIFF0007807381000319.tif4286

[0411] The title compound 139 (5 ​​mg) was prepared 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 in 137 as a yellow solid in 3.4% overall yield. TIFF0007807381000320.tif36170

[0412] N-hydroxy-N-(4-((4-(2-methoxyethoxy)phenyl)amino)benzyl)-2-(4-methylpiperazin-1-yl)acetamide (140) TIFF0007807381000321.tif4097

[0413] N-Hydroxy The title compound 140 (16 mg) was prepared 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 in 137 as a white solid in an overall yield of 18.0%. TIFF0007807381000322.tif37170

[0414] N-Hydroxy-N-(4-((4-(N-methylacetamido)phenyl)amino)benzyl)-2-(4-methylpiperazin-1-yl)acetamide (141) TIFF0007807381000323.tif3587

[0415] The title compound 141 (10.1 mg) was prepared according to the procedure for compound 108 as a white solid in 23.8% overall yield. TIFF0007807381000324.tif28170

[0416] 4-(Dimethylamino)-N-hydroxy-N-(4-((4-(piperidine-1-carbonyl)phenyl)amino)benzyl)butanamide (142) TIFF0007807381000325.tif4283

[0417] The title compound 142 (8 mg) was prepared according to the procedure in 137 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) as a white solid in 18.32% overall yield. TIFF0007807381000326.tif37170

[0418] N-(4-((4-butoxyphenyl)amino)benzyl)-4-(dimethylamino)-N-hydroxybutanamide (143) TIFF0007807381000327.tif33104

[0419] The title compound 143 (5.2 mg) was prepared according to the procedure for compound 108 as a white solid in 13.8% overall yield. TIFF0007807381000328.tif38170

[0420] N-hydroxy-2-(piperazin-1-yl)-N-(4-((4-(pyrrolidin-1-ylmethyl)phenyl)amino)benzyl)acetamide (144) TIFF0007807381000329.tif4284

[0421] The title compound 144 (19 mg) was prepared 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 in 137 as a white solid in 22.5% overall yield. TIFF0007807381000330.tif37170

[0422] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((3-morpholinophenyl)amino)benzyl)acetamide (145) TIFF0007807381000331.tif3991

[0423] The title compound 145 (14.3 mg) was prepared 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 in 137 as a white solid in 16.3% overall yield. TIFF0007807381000332.tif48170

[0424] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)acetamide (146) TIFF0007807381000333.tif3391

[0425] The title compound 146 (5.4 mg) was prepared according to the procedure for compound 108 as a white solid in 24.7% overall yield. TIFF0007807381000334.tif38170

[0426] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)benzyl)acetamide (147) TIFF0007807381000335.tif3579

[0427] The title compound 147 (13.0 mg) was prepared 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 in 137 as a white solid in 29.6% overall yield. TIFF0007807381000336.tif37170

[0428] N-Hydroxy-N-(4-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)benzyl)-2-(4-methylpiperazin-1-yl)acetamide (148) TIFF0007807381000337.tif3387

[0429] The title compound 148 (2.9 mg) was prepared according to the procedure for compound 108 as a white solid in 16.0% overall yield. TIFF0007807381000338.tif36170

[0430] N-(4-((4-(6-fluoropyridin-3-yl)phenyl)amino)benzyl)-N-hydroxy-1-methylpiperidine-4-carboxamide (149) TIFF0007807381000339.tif3380

[0431] The title compound 149 (5.3 mg) was prepared according to the procedure for compound 108 as a white solid in 24.4% overall yield. TIFF0007807381000340.tif35170

[0432] N-Hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((4-pentylphenyl)amino)benzyl)acetamide (150) TIFF0007807381000341.tif3787

[0433] The title compound 150 (20.0 mg) was prepared 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 in 137 as a white solid in 23.8% overall yield. TIFF0007807381000342.tif36170

[0434] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((4-phenoxyphenyl)amino)benzyl)acetamide (151) TIFF0007807381000343.tif3384

[0435] The title compound 151 (30.0 mg) was prepared 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 in 137 as a white solid in 42.0% overall yield. TIFF0007807381000344.tif37170

[0436] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((4-(pyridin-4-yl)phenyl)amino)benzyl)acetamide (152) TIFF0007807381000345.tif3486

[0437] The title compound 152 (5.8 mg) was prepared according to the procedure for compound 108 as a white solid in 23.2% overall yield. TIFF0007807381000346.tif36170

[0438] N-(4-((4-cyclohexylphenyl)amino)benzyl)-4-(dimethylamino)-N-hydroxybutanamide (153) TIFF0007807381000347.tif3686

[0439] The title compound 153 (12.1 mg) was prepared according to the procedure for compound 108 as a white solid in 29.3% overall yield. TIFF0007807381000348.tif45170

[0440] N-(4-((4-(cyclohexyloxy)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (154) TIFF0007807381000349.tif3382

[0441] The title compound 154 (14.3 mg) was prepared 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 in 137 as a yellow solid in 19.7% overall yield. TIFF0007807381000350.tif37170

[0442] N-(4-((4-(tert-butylamino)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (155) JPEG0007807381000351.jpg107170

[0443] Step 1. Preparation of N-(tert-butyl)-4-nitroaniline (155-3). A solution of 1-fluoro-4-nitrobenzene (3 g, 21.3 mg) and 2-methylpropan-2-amine (4.66 g, 63.9 mmol) in DMSO (15 mL) was stirred at 80 °C for 18 h. After cooling to room temperature, 20 mL of water was added. The resulting solution was extracted with 3 x 50 mL of ethyl acetate. The organic layers were combined, washed with water (3 x 100 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 as a yellow solid (3.0 g, 72.6%). Mass (m / z): 195.2 [M+H] + .

[0444] Step 2. Preparation of N1-(tert-butyl)benzene-1,4-diamine (155-4). 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 overnight at room temperature under a hydrogen atmosphere. The Pd / C was removed by filtration. The filtrate was concentrated in vacuo to give the desired product as a black oil (1.11 g, 87.4%). Mass (m / z): 165.2 [M+H] + .

[0445] Step 3. Preparation of 4-((4-(tert-butylamino)phenyl)amino)benzaldehyde (155-6). The title compound 155-6 (620 mg) was prepared by N 1Prepared from -(tert-butyl)benzene-1,4-diamine (1.11 g, 6.0 mmol), 4-bromobenzaldehyde (740 mg, 4.0 mmol), Pd(dppf)2Cl2 (59 mg, 0.08 mmol), Xantphos (93 mg, 0.16 mmol), and Cs2CO3 (1.96 g, 6.0 mmol) as a yellow solid in 59.2% overall yield. Mass (m / z): 269.2 [M+H] + .

[0446] Step 4. Preparation of (E)-4-((4-(tert-butylamino)phenyl)amino)benzaldehyde oxime (155-7). The title compound 155-7 (425 mg) was prepared crude 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 as a yellow solid in 100% overall yield. Mass (m / z): 284.2 [M+H] + .

[0447] 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 according to the procedure of 137-5 from (E)-4-((4-(tert-butylamino)phenyl)amino)benzaldehyde oxime (425 mg, 1.5 mmol), borane-pyridine complex (279 mg, 3.0 mmol) and 5 mL of 10% HCl as a yellow solid in an overall yield of 30.6%. Mass (m / z): 307.2 [M+H] + .

[0448] Step 6. Preparation of N-(4-((4-(tert-butylamino)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (155). The title compound 155 (20.0 mg) was prepared according to the procedure in 137. 1-(tert-butyl)-N 4 Prepared from -(4-((hydroxyamino)methyl)phenyl)benzene-1,4-diamine (69 mg, 0.24 mmol), 2-(4-methylpiperazin-1-yl)acetic acid (38 mg, 0.24 mmol), DMT-MM (73 mg, 0.26 mmol), DIEA (93 mg, 0.72 mmol) and DMF (1.0 mL) as a yellow solid in 20.0% overall yield. TIFF0007807381000352.tif28170

[0449] N-(4-((4-(diethylamino)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (156) TIFF0007807381000353.tif3586

[0450] The title compound 156 (15.9 mg) was prepared according to the procedure for compound 108 as a white solid in 37.4% overall yield. TIFF0007807381000354.tif29170

[0451] 4-(Dimethylamino)-N-hydroxy-N-(4-((4-isopropoxyphenyl)amino)benzyl)butanamide (157) TIFF0007807381000355.tif3786

[0452] The title compound 157 (10.3 mg) was prepared from 4-((hydroxyamino)methyl)-N-(4-isopropoxyphenyl)aniline (54 mg, 0.2 mmol), 4-(dimethylamino)butanoic acid hydrochloride (37 mg, 0.22 mmol), DMT-MM (66 mg, 0.24 mmol), DIEA (77 mg, 0.6 mmol) and DMF (1.0 mL) according to the procedure in 137 as a yellow solid in 13.4% overall yield. TIFF0007807381000356.tif36170

[0453] 4-(Dimethylamino)-N-hydroxy-N-(4-((4-propoxyphenyl)amino)benzyl)butanamide (158) TIFF0007807381000357.tif2891

[0454] The title compound 158 (23.5 mg) was prepared according to the procedure for compound 108 as a white solid in 60.9% overall yield. TIFF0007807381000358.tif46170

[0455] N-(4-((4-(heptyloxy)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (159) TIFF0007807381000359.tif33102

[0456] The title compound 159 (11.6 mg) was prepared according to the procedure for compound 108 as a white solid in 24.8% overall yield. TIFF0007807381000360.tif46170

[0457] N-(4-((4-(2,6-dimethylmorpholino)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (160) TIFF0007807381000361.tif3786

[0458] The title compound 160 (9.1 mg) was prepared according to the procedure for compound 108 as a white solid in 19.4% overall yield. TIFF0007807381000362.tif37170

[0459] 2-(4-methylpiperazin-1-yl)-N-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)acetamide (161) TIFF0007807381000363.tif3382

[0460] The title compound 161 (4.1 mg) was prepared according to the procedure for compound 163 as a white solid in 19.5% overall yield. TIFF0007807381000364.tif29170

[0461] N-hydroxy-N-(4-((4-(2-methylmorpholino)phenyl)amino)benzyl)-2-(4-methylpiperazin-1-yl)acetamide (162) TIFF0007807381000365.tif3683

[0462] The title compound 162 (37.6 mg) was prepared according to the procedure for compound 108 as a white solid in 41.5% overall yield. TIFF0007807381000366.tif37170

[0463] 2-(4-methylpiperazin-1-yl)-N-(4-((4-pentylphenyl)amino)benzyl)acetamide (163) TIFF0007807381000367.tif70170

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

[0465] Step 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). Subsequently, HATU (83.6 mg, 0.22 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. 10 mL of water was added. The mixture was then extracted with DCM (10 mL x 3). The combined organic layers were washed with water (10 mL x 3), dried over Na2SO4, and concentrated in vacuo. The residue was purified by prep-TLC (MeOH / DCM=1 / 10) to give the desired product as a white solid (38.1 mg, 46.7%). TIFF0007807381000368.tif37170

[0466] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(1-(4-((4-(piperidin-1-yl)phenyl)amino)phenyl)ethyl)acetamide (164) TIFF0007807381000369.tif3477

[0467] The title compound 164 (6.4 mg) was prepared from 4-(1-(hydroxyamino)ethyl)-N-(4-(piperidin-1-yl)phenyl)aniline (50 mg, 0.16 mmol), 4-(dimethylamino)butanoic acid hydrochloride (25 mg, 0.16 mmol), DMT-MM (44 mg, 0.16 mmol), DIEA (62 mg, 0.48 mmol) and DMF (1.0 mL) according to the procedure in 137 as a yellow solid in an overall yield of 8.8%. TIFF0007807381000370.tif29170

[0468] N-(4-((4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)amino)benzyl)-4-(dimethylamino)-N-hydroxybutanamide (165) TIFF0007807381000371.tif3186

[0469] The title compound 165 (15.1 mg) was prepared according to the procedure for compound 108 as a white solid in 52.3% overall yield. TIFF0007807381000372.tif37170

[0470] N-hydroxy-4-(4-methylpiperazin-1-yl)-N-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)butanamide (166) TIFF0007807381000373.tif3287

[0471] The title compound 166 (7.4 mg) was prepared according to the procedure for compound 108 as a white solid in 31.8% overall yield. TIFF0007807381000374.tif29170

[0472] 2-(Dimethylamino)-N-hydroxy-N-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)acetamide (167) TIFF0007807381000375.tif3375

[0473] The title compound 167 (11.1 mg) was prepared according to the procedure for compound 108 as a white solid in 58.1% overall yield. TIFF0007807381000376.tif28170

[0474] N-(4-((4-(4,4-difluoropiperidin-1-yl)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide TIFF0007807381000377.tif3778

[0475] The title compound 168 (15.0 mg) was prepared 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 in 174 as a white solid in 35.5% overall yield. TIFF0007807381000378.tif36170

[0476] N-hydroxy-2-(1-methylpiperidin-4-yl)-N-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)acetamide (169) TIFF0007807381000379.tif3479

[0477] The title compound 169 (12.0 mg) was prepared according to the procedure for compound 108 as a white solid in 55.0% overall yield. TIFF0007807381000380.tif28170

[0478] N-(4-((4-butoxyphenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (170) TIFF0007807381000381.tif3289

[0479] TIFF0007807381000382.tif38170

[0480] N-Hydroxy-N-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)quinuclidine-4-carboxamide (171) TIFF0007807381000383.tif3374

[0481] The title compound 171 (15.4 mg) was prepared according to the procedure for compound 108 as a white solid in 25.2% overall yield. TIFF0007807381000384.tif26170

[0482] N-Hydroxy-1-methyl-5-oxo-N-(4-((4-(piperidin-1-yl)phenyl)amino)-2-(trifluoromethyl)benzyl)pyrrolidine-3-carboxamide (172) TIFF0007807381000385.tif3680

[0483] 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 h. 5 mL of water was added. The mixture was then extracted with DCM (5 mL x 3). The combined organic layers were washed with water (10 mL x 3), dried over NaSO, and concentrated in vacuo. The residue was purified by prep-TLC (MeOH / DCM = 1 / 10) to give the desired product as a yellow solid (16.4 mg, 33.5%). TIFF0007807381000386.tif38170

[0484] 5-(Dimethylamino)-N-hydroxy-N-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)pentanamide (173) TIFF0007807381000387.tif3085

[0485] The title compound 173 (21.1 mg) was prepared according to the procedure for compound 108 as a white solid in 51.2% overall yield. TIFF0007807381000388.tif28170

[0486] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((4-(4-methylpiperidin-1-yl)phenyl)amino)benzyl)acetamide (174) TIFF0007807381000389.tif28169

[0487] To a solution of 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 DMF (3 mL) was 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 x 3), dried over NaSO, 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%). TIFF0007807381000390.tif27170

[0488] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)acetamide (175) TIFF0007807381000391.tif3690

[0489] The title compound 175 (16.3 mg) was prepared 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 in 174 as a white solid in 39.2% overall yield. TIFF0007807381000392.tif36170

[0490] 2-(4-methylpiperazin-1-yl)-N-(2,2,2-trifluoro-1-(4-((4-(piperidin-1-yl)phenyl)amino)phenyl)ethyl)acetamide (176) TIFF0007807381000393.tif3682

[0491] The title compound 176 (8.0 mg) was prepared from 4-(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) according to the procedure in 163 as a yellow solid in 23.5% overall yield. TIFF0007807381000394.tif28170

[0492] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((4-(3-methylpiperidin-1-yl)phenyl)amino)benzyl)acetamide (177) TIFF0007807381000395.tif4188

[0493] The title compound 177 (28.3 mg) was prepared according to the procedure for compound 108 as a white solid in 61.9% overall yield. TIFF0007807381000396.tif27170

[0494] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((4-(2-methylpiperidin-1-yl)phenyl)amino)benzyl)acetamide (178) TIFF0007807381000397.tif3282

[0495] The title compound 178 (34.2 mg) was prepared according to the procedure for compound 108 as a white solid in 75.7% overall yield. TIFF0007807381000398.tif28170

[0496] 2-(4-methyl-3-oxopiperazin-1-yl)-N-(4-((4-(piperidin-1-yl)-3-(trifluoromethyl)phenyl)amino)benzyl)acetamide (179) TIFF0007807381000399.tif27169

[0497] 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)acetic acid hydrochloride (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 x 3), dried over Na2SO4, 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%). TIFF0007807381000400.tif45170

[0498] N-(4-((4-(azocan-1-yl)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (180) TIFF0007807381000401.tif3583

[0499] The title compound 180 (16.1 mg) was prepared according to the procedure for compound 108 as a white solid in 34.6% overall yield. TIFF0007807381000402.tif27170

[0500] N-(4-((4-(azetidin-1-yl)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (181) TIFF0007807381000403.tif3481

[0501] The title compound 181 (9.1 mg) was prepared from 4-(azetidin-1-yl)-N-(4-((hydroxyamino)methyl)phenyl)aniline (26.9 mg, 0.1 mmol), 4-(dimethylamino)butanoic acid hydrochloride (15.8 mg, 0.1 mmol), DMT-MM (26.7 mg, 0.1 mmol), DIEA (38.7 mg, 0.3 mmol) and DMF (1.0 mL) according to the procedure in 137 as a yellow solid in 20.0% overall yield. TIFF0007807381000404.tif28170

[0502] N-(4-((4-(4-fluoropiperidin-1-yl)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (182) TIFF0007807381000405.tif3687

[0503] 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) was 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 x 3), dried over Na2SO4, 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%). TIFF0007807381000406.tif36170

[0504] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((4-(3-(trifluoromethyl)pyrrolidin-1-yl)phenyl)amino)benzyl)acetamide (183) TIFF0007807381000407.tif3879

[0505] The title compound 183 (25.1 mg) was prepared 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 for 182 as a white-green material in 60% overall yield. TIFF0007807381000408.tif28170

[0506] N-(4-((4-(3,3-difluoropiperidin-1-yl)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (184) TIFF0007807381000409.tif3977

[0507] The title compound 184 (10.0 mg) was prepared from 4-(3,3-difluoropiperidin-1-yl)-N-(4-((hydroxyamino)methyl)phenyl)aniline (33.3 mg, 0.1 mmol), 4-(dimethylamino)butanoic acid hydrochloride (15.8 mg, 0.1 mmol), DMT-MM (26.7 mg, 0.1 mmol), DIEA (38.7 mg, 0.3 mmol) and DMF (1.0 mL) according to the procedure in 137 as a yellow solid in 21.1% overall yield. TIFF0007807381000410.tif38170

[0508] N-Hydroxy-1-isopropyl-N-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)piperidine-4-carboxamide (185) TIFF0007807381000411.tif3384

[0509] The title compound 185 (12.3 mg) was prepared according to the procedure for compound 108 as a white solid in 40.7% overall yield. TIFF0007807381000412.tif37170

[0510] 1-Isopropyl-N-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)piperidine-4-carboxamide (186) TIFF0007807381000413.tif3687

[0511] The title compound 186 (16.1 mg) was prepared according to the procedure for compound 163 as a white solid in 43.1% overall yield. TIFF0007807381000414.tif38170

[0512] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((4-(3-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)acetamide (187) TIFF0007807381000415.tif4191

[0513] The title compound 187 (16.5 mg) was prepared according to the procedure for compound 108 as a white solid in 32.7% overall yield. TIFF0007807381000416.tif37170

[0514] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((4-(pyrrolidin-1-yl)-3-(trifluoromethyl)phenyl)amino)benzyl)acetamide (188) TIFF0007807381000417.tif3787

[0515] The title compound 188 (13.5 mg) was prepared according to the procedure for compound 108 as a white solid in 22.1% overall yield. TIFF0007807381000418.tif28170

[0516] 1-Methyl-6-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)piperidine-3-carboxamide (189) TIFF0007807381000419.tif39164

[0517] Step 1. The title compound 189 (18.3 mg) was prepared 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) as a pale yellow powder in 43.63% yield. TIFF0007807381000420.tif36170

[0518] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((6-(piperidin-1-yl)pyridin-3-yl)amino)benzyl)acetamide (190) TIFF0007807381000421.tif3077

[0519] The title compound 190 (22.1 mg) was prepared according to the procedure for compound 108 as a white solid in 50.4% overall yield. TIFF0007807381000422.tif36170

[0520] N-(4-((4-(2,6-dimethylmorpholino)phenyl)amino)benzyl)-2-(4-methylpiperazin-1-yl)acetamide (191) TIFF0007807381000423.tif3685

[0521] The title compound 191 (31.4 mg) was prepared according to the procedure for compound 163 as a white solid in 72.3% overall yield. TIFF0007807381000424.tif38170

[0522] N-Hydroxy-N-(4-((2-methyl-4-(piperidin-1-yl)phenyl)amino)benzyl)-2-(4-methylpiperazin-1-yl)acetamide (192) TIFF0007807381000425.tif3787

[0523] The title compound 192 (20.1 mg) was prepared according to the procedure for compound 108 as a white solid in 56.3% overall yield. TIFF0007807381000426.tif28170

[0524] N-hydroxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-N-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)acetamide (193) TIFF0007807381000427.tif3995

[0525] The title compound 193 (10.4 mg) was prepared according to the procedure for compound 108 as a white solid in 21.7% overall yield. TIFF0007807381000428.tif28170

[0526] N-Hydroxy-N-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)-2-(pyrazin-2-yl)acetamide (194) TIFF0007807381000429.tif3379

[0527] The title compound 194 (15.9 mg) was prepared according to the procedure for compound 108 as a white solid in 31.8% overall yield. TIFF0007807381000430.tif28170

[0528] 4-(hydroxy(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)amino)-4-oxobutanoic acid (195) TIFF0007807381000431.tif33163

[0529] 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° C. The reaction was then stirred for 3 hours. After completion, the reaction solution was concentrated and purified by prep-TLC (MeOH / DCM=1 / 10) to give the desired product as a white solid (18.2 mg, 23.1%). TIFF0007807381000432.tif27170

[0530] N-Hydroxy-N-(3-methyl-4-((4-(piperidin-1-yl)phenyl)amino)benzyl)-2-(4-methylpiperazin-1-yl)acetamide (196) TIFF0007807381000433.tif3484

[0531] Title compound 196 (26.5 mg) was prepared according to the procedure for compound 108 as a white solid in 52.5% overall yield. TIFF0007807381000434.tif28170

[0532] N-(3-fluoro-4-((4-(piperidin-1-yl)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (197) TIFF0007807381000435.tif3688

[0533] The title compound 197 (20.6 mg) was prepared according to the procedure for compound 108 as a white solid in 41.7% overall yield. TIFF0007807381000436.tif27170

[0534] N-Hydroxy-N-(3-methyl-4-((2-methyl-4-(piperidin-1-yl)phenyl)amino)benzyl)-2-(4-methylpiperazin-1-yl)acetamide (198) TIFF0007807381000437.tif3882

[0535] The title compound 198 (10.2 mg) was prepared from 4-((hydroxyamino)methyl)-2-methyl-N-(2-methyl-4-(piperidin-1-yl)phenyl)aniline (32.5 mg, 0.1 mmol), 4-(dimethylamino)butanoic acid hydrochloride (15.8 mg, 0.1 mmol), DMT-MM (26.7 mg, 0.1 mmol), DIEA (38.7 mg, 0.3 mmol) and DMF (1.0 mL) according to the procedure in 137 as a yellow solid in 21.9% overall yield. TIFF0007807381000438.tif36170

[0536] N-Hydroxy-N-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)oxazole-4-carboxamide (199) TIFF0007807381000439.tif3475

[0537] The title compound 199 (12.5 mg) was prepared according to the procedure for compound 108 as a white solid in 37.4% overall yield. TIFF0007807381000440.tif27170

[0538] 2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-N-hydroxy-N-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)acetamide (200) TIFF0007807381000441.tif3882

[0539] Title compound 200 (10.2 mg) was prepared according to the procedure for compound 108 as a white solid in 25.1% overall yield. TIFF0007807381000442.tif28170

[0540] N,1-Diethyl-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (201) TIFF0007807381000443.tif90170

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

[0542] Step 2. The title compound 201 (5.9 mg) was prepared from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (50 mg, 0.20 mmol) and N-(4-bromobenzyl)-N,1-diethyl-5-oxopyrrolidine-3-carboxamide (72 mg, 0.20 mmol) as a pale yellow powder in 5.58% yield. TIFF0007807381000444.tif28170

[0543] 1-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)piperazin-2-one (202) TIFF0007807381000445.tif78170

[0544] 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 tert-butyl 3-oxopiperazine-1-carboxylate (800 mg, 4.0 mmol) in DMSO (10.0 mL) was added KOH (828 mg, 6.0 mmol). The mixture was then stirred overnight at room temperature. After cooling to room temperature, 20 mL of water was added. The resulting solution was extracted with 3 x 20 mL of ethyl acetate. The organic layers were combined, washed with water (3 x 30 mL), dried, and concentrated in vacuo to give the desired product as a yellow oil (500 mg, 34.0%). Mass (m / z): 313.1 [M+H] + .

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

[0546] Step 3. Preparation of 1-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)piperazin-2-one (202). To a solution of tert-butyl tert-butyl 3-oxo-4-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)piperazine-1-carboxylate (162 mg, 0.35 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction was then stirred at room temperature for 30 minutes. The reaction solution was concentrated under vacuum. 10 ml of HCl was added. The pH value of the solution was adjusted to 8 with Na2CO3. The resulting solution was extracted with 3x10 mL of ethyl acetate DCM. The organic layers were combined, washed with water (3x10 mL), dried, and concentrated under vacuum. The residue was purified by perp-TLC (MeOH / DCM=1 / 5) to give the desired product as a yellow solid. (74.0 mg, 61.2%). TIFF0007807381000446.tif27170

[0547] 5-Oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (203) TIFF0007807381000447.tif30168

[0548] 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) were 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 x 3), dried over Na2SO4, 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%). TIFF0007807381000448.tif55170

[0549] 1-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)pyrrolidin-2-one (204) TIFF0007807381000449.tif79170

[0550] Step 1. Preparation of 1-(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 of water was added. The resulting solution was extracted with 3 x 20 mL of ethyl acetate. The organic layers were combined, washed with water (3 x 30 mL), dried, and concentrated in vacuo to give the desired product as a yellow oil. (460 mg, 45.5%). Mass (m / z): 254.1 [M+H] + .

[0551] Step 2. Preparation of 1-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)pyrrolidin-2-one (204). The title compound 304 (40.1 mg) was prepared from 4-(piperidin-1-yl)aniline (176 mg, 1.0 mmol), 1-(4-bromobenzyl)pyrrolidin-2-one (121 mg, 0.5 mmol), Pd(dppf)Cl (7.3 mg, 0.01 mmol), Xantphos (11.6 mg, 0.02 mmol), and CsCO (244 mg, 0.75 mmol) according to the procedure in 137-3 as a yellow oil in 22.9% overall yield. TIFF0007807381000450.tif27170

[0552] 1-Ethyl-N-isopropyl-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (205) TIFF0007807381000451.tif90170

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

[0554] Step 2. The title compound 205 (14 mg) was prepared from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (100 mg, 0.41 mmol) and N-(4-bromobenzyl)-1-ethyl-N-isopropyl-5-oxopyrrolidine-3-carboxamide (150 mg, 0.41 mmol) as a blue powder in 6.44% yield. TIFF0007807381000452.tif55170

[0555] N-hydroxy-2-(4-methyl-3-oxopiperazin-1-yl)-N-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)acetamide (206) TIFF0007807381000453.tif3984

[0556] The title compound 206 (5.6 mg) was prepared according to the procedure for compound 108 as a white solid in 21.6% overall yield. TIFF0007807381000454.tif27170

[0557] N-(4-((4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)amino)benzyl)-2-(4-methylpiperazin-1-yl)acetamide (207) TIFF0007807381000455.tif3686

[0558] The title compound 207 (21.8 mg) was prepared according to the procedure for compound 163 as a white solid in 50.7% overall yield. TIFF0007807381000456.tif26170

[0559] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((4-(piperidin-1-yl)phenyl)amino)-2-(trifluoromethyl)benzyl)acetamide (208) TIFF0007807381000457.tif3586

[0560] The title compound 208 (28.2 mg) was prepared according to the procedure for compound 108 as a white solid in 58.4% overall yield. TIFF0007807381000458.tif29170

[0561] 1-Ethyl-N-(4-((4-(4-methylpiperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (209) JPEG0007807381000459.jpg129170

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

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

[0564] Step 3. To a solution of (E)-4-((4-(4-methylpiperidin-1-yl)phenyl)amino)benzaldehyde oxime (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 overnight at room temperature under a hydrogen atmosphere. 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 x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, and concentrated to give the desired product as a yellow solid. (120 mg, 24.3%). 296.3 [M+H] + .

[0565] 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). Subsequently, HATU (38 mg, 0.1 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. 5 mL of water was added. The mixture was then extracted with DCM (5 mL x 3). The combined organic layers were washed with water (10 mL x 3), dried over Na2SO4, and concentrated in vacuo. The residue was purified by prep-TLC (MeOH / DCM = 1 / 5) to give the desired product as a white solid (16.9 mg, 28.9%). TIFF0007807381000460.tif48170

[0566] N-(4-((4-(4,4-dimethylpiperidin-1-yl)phenyl)amino)benzyl)-1-ethyl-5-oxopyrrolidine-3-carboxamide (210) TIFF0007807381000461.tif3783

[0567] The title compound 210 (26.4 mg) was prepared 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), and HATU (38 mg, 0.1 mmol) according to the procedure in 209 as a yellow solid in 58.9% overall yield. TIFF0007807381000462.tif39170

[0568] N-(4-((4-(3,3-dimethylazetidin-1-yl)phenyl)amino)benzyl)-1-ethyl-5-oxopyrrolidine-3-carboxamide (211) TIFF0007807381000463.tif3381

[0569] The title compound 211 (5.7 mg) was prepared 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), and HATU (76 mg, 0.2 mmol) according to the procedure in 209 as a yellow solid in 6.8% overall yield. TIFF0007807381000464.tif39170

[0570] N-(4-((4-(4,4-difluoropiperidin-1-yl)phenyl)amino)benzyl)-N-hydroxy-1-isopropylpiperidine-4-carboxamide (212) TIFF0007807381000465.tif3681

[0571] The title compound 212 (21.8 mg) was prepared 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) according to the procedure in 174 as a white solid in 49.8% overall yield. TIFF0007807381000466.tif28170

[0572] N-Cyclopropyl-1-ethyl-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (213) TIFF0007807381000467.tif92170

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

[0574] Step 2. To a solution of 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (100 mg, 0.41 mmol, 1.0 equivs) and N-(4-bromobenzyl)-N-cyclopropyl-1-ethyl-5-oxopyrrolidine-3-carboxamide (150 mg, 0.41 mmol, 1.0 equivs) in 1,4-dioxane (10 mL) was added (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (18.95 mg, 0.032 mmol, 0.08 equivs), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11.98 mg, 0.016 mmol, 0.04 equivs), and cesium carbonate (200.0 mg, 0.64 mmol, 1.5 equiv) was added to each under an argon atmosphere. The resulting mixture was heated to 100 °C and stirred at the same temperature overnight. The reaction was diluted with water (10 mL) and extracted three times with ethyl acetate (5 mL). The organic layers were combined and washed with water, saturated NaHCO3 (aq), and brine, respectively. Then, it was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / AcOEt, 1 / 6) to afford 108.2 mg of N-cyclopropyl-1-ethyl-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide 299 as a blue solid in a 50.00% yield. TIFF0007807381000468.tif56170

[0575] 1-Methyl-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (214) TIFF0007807381000469.tif35163

[0576] The title compound 214 (14.2 mg) was prepared from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)aniline (40 mg, 0.11 mmol) and 1-methyl-5-oxopyrrolidine-3-carboxylic acid hydrochloride (31 mg, 0.17 mmol) according to the procedure for compound 276 in 26.14% yield as a pale blue solid. TIFF0007807381000470.tif65170

[0577] N-Hydroxy-1-isopropyl-N-(4-((4-(4-methylpiperidin-1-yl)phenyl)amino)benzyl)piperidine-4-carboxamide (215) TIFF0007807381000471.tif40100

[0578] The title compound 215 (23.2 mg) was prepared 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 in 174 as a white solid in 51.9% overall yield. TIFF0007807381000472.tif35170

[0579] N-(cyclopropylmethyl)-1-ethyl-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (216) TIFF0007807381000473.tif3987

[0580] TIFF0007807381000474.tif36170

[0581] 2-(4-methylpiperazin-1-yl)-N-(4-((4-(piperidin-1-yl)phenyl)amino)-2-(trifluoromethyl)benzyl)acetamide (217) TIFF0007807381000475.tif3675

[0582] The title compound 217 (20.2 mg) was prepared according to the procedure for compound 163 as a white solid in 35.4% overall yield. TIFF0007807381000476.tif29170

[0583] N-Hydroxy-N-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)nicotinamide (218) TIFF0007807381000477.tif3175

[0584] The title compound 218 (15.2 mg) was prepared according to the procedure for compound 108 as a white solid in 41.7% overall yield. TIFF0007807381000478.tif36170

[0585] N-(4-((2,6-dimethyl-4-(piperidin-1-yl)phenyl)amino)-3-methylbenzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (219) TIFF0007807381000479.tif3671

[0586] The title compound 219 (16.8 mg) was prepared according to the procedure for compound 108 as a white solid in 43.9% overall yield. TIFF0007807381000480.tif37170

[0587] N-(2-fluoro-4-((4-(piperidin-1-yl)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (220) TIFF0007807381000481.tif3473

[0588] The title compound 220 (20.1 mg) was prepared according to the procedure for compound 108 as a white solid in 48.7% overall yield. TIFF0007807381000482.tif28170

[0589] 4-Acetyl-1-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)piperazin-2-one (221) TIFF0007807381000483.tif34156

[0590] 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) was added acetyl chloride (15.7 mg, 0.2 mmol) dropwise at 0 °C. The reaction was then stirred at 0 °C for 2 h. The reaction solution was washed with water (3 × 5 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by prep-TLC (MeOH / DCM = 1 / 10) to give the desired product as a yellow solid. TIFF0007807381000484.tif37170

[0591] 4-(Cyclopropylmethyl)-1-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)piperazin-2-one (222) TIFF0007807381000485.tif29163

[0592] To a mixture of 1-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)piperazin-2-one (18.2 mg, 0.05 mmol) and K2CO3 (10.4 mg, 0.75 mmol) 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 of water was added. The resulting solution was extracted with 3 x 10 mL of ethyl acetate (DCM). The organic layers were combined, washed with water (3 x 10 mL), dried, and concentrated in vacuo. The residue was purified by perp-TLC (MeOH / DCM = 1 / 20) to give the desired product as a yellow solid (7.0 mg, 33.4%). TIFF0007807381000486.tif45170

[0593] 1-Ethyl-5-oxo-N-propyl-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (223) TIFF0007807381000487.tif3690

[0594] TIFF0007807381000488.tif35170

[0595] 2-(4-methyl-3-oxopiperazin-1-yl)-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)acetamide (224) TIFF0007807381000489.tif27163

[0596] The title compound 224 (18.4 mg) was prepared 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) as a light blue solid in 12.77% yield. TIFF0007807381000490.tif45170

[0597] 1-Ethyl-N-methyl-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (225) TIFF0007807381000491.tif3686

[0598] TIFF0007807381000492.tif36170

[0599] N-Hydroxy-N-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)hexanamide (226) TIFF0007807381000493.tif3181

[0600] The title compound 226 (11.3 mg) was prepared according to the procedure for compound 108 as a white solid in 38.4% overall yield. TIFF0007807381000494.tif28170

[0601] 2-(4-methylpiperazin-1-yl)-N-(4-((4-(piperidin-1-yl)phenyl)amino)-3-(trifluoromethyl)benzyl)acetamide (227) TIFF0007807381000495.tif4697

[0602] The title compound 227 (15.9 mg) was prepared according to the procedure for compound 163 as a white solid in 56.9% overall yield. TIFF0007807381000496.tif27170

[0603] 1-Methyl-2-oxo-N-(4-((4-(piperidin-1-yl)phenyl)amino)-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (228) TIFF0007807381000497.tif3181

[0604] Title compound 228 (21.2 mg) was prepared according to the procedure for compound 163 as a white solid in 47.5% overall yield. TIFF0007807381000498.tif36170

[0605] N-(4-((3,5-difluoro-4-(piperidin-1-yl)phenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (229) TIFF0007807381000499.tif3682

[0606] The title compound 229 (11.9 mg) was prepared according to the procedure for compound 108 as a white solid in 27.1% overall yield. TIFF0007807381000500.tif37170

[0607] 1-Methyl-2-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)piperidine-4-carboxamide (230) TIFF0007807381000501.tif43168

[0608] To a solution of 1-methyl-2-oxopiperidine-4-carboxylic acid (49 mg, 0.31 mmol, 1.1 equivs) and 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)aniline (100 mg, 0.29 mmol, 1.0 equivs) in ultra-dry N,N-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 equivs) and N-ethyl-N-isopropylpropan-2-amine (142 mmL, 0.86 mmol, 3.0 equivs), respectively, at room temperature. 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, and the filter cake was washed with water three times 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 as a pale blue solid in 31.32% yield. TIFF0007807381000502.tif54170

[0609] N-(tert-butyl)-1-ethyl-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (231) TIFF0007807381000503.tif3688

[0610] TIFF0007807381000504.tif36170

[0611] 1-(4-((4-(4,4-difluoropiperidin-1-yl)phenyl)amino)benzyl)-4-ethylpiperazin-2-one (232) TIFF0007807381000505.tif31166

[0612] 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), Pd(dppf)Cl (4 mg, 0.005 mmol), Xantphos (6 mg, 0.010 mmol), CsCO (116 mg, 0.354 mmol), and Tol (5 mL) was stirred at 100 °C for 16 h. The mixture was concentrated and purified by prep-HPLC to give the desired product as a white solid (10.0 mg, 9.9%). TIFF0007807381000506.tif35170

[0613] N-(2,6-difluoro-4-((4-(piperidin-1-yl)phenyl)amino)benzyl)-2-(4-methylpiperazin-1-yl)acetamide (233) TIFF0007807381000507.tif3582

[0614] The title compound 233 (20.7 mg) was prepared according to the procedure for compound 163 as a white solid in 46.1% overall yield. TIFF0007807381000508.tif36170

[0615] 3-(2-oxopyrrolidin-1-yl)-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)propanamide (234) TIFF0007807381000509.tif3493

[0616] TIFF0007807381000510.tif38170

[0617] 1-Acetyl-N-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)piperidine-4-carboxamide (235) TIFF0007807381000511.tif3080

[0618] The title compound 235 (4.2 mg) was prepared according to the procedure for compound 163 as a white solid in 30.8% overall yield. TIFF0007807381000512.tif29170

[0619] 1-(Cyclopropanecarbonyl)-N-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)piperidine-4-carboxamide (236) TIFF0007807381000513.tif2982

[0620] The title compound 236 (5.1 mg) was prepared according to the procedure for compound 163 as a white solid in 35.1% overall yield. TIFF0007807381000514.tif28170

[0621] N-(4-((3-chloro-4-(piperidin-1-yl)phenyl)amino)benzyl)-2-(4-methylpiperazin-1-yl)acetamide (237) TIFF0007807381000515.tif3379

[0622] The title compound 237 (20.7 mg) was prepared according to the procedure for compound 163 as a white solid in 48.3% overall yield. TIFF0007807381000516.tif37170

[0623] 1-(4-((4-(2,6-dimethylmorpholino)phenyl)amino)benzyl)-4-ethylpiperazin-2-one (238) TIFF0007807381000517.tif3477

[0624] The title compound 238 (11.3 mg) was prepared according to the procedure for compound 202 as a white solid in 26.7% overall yield. TIFF0007807381000518.tif36170

[0625] 2-(4-Methylpiperazin-1-yl)-N-(4-((4-(piperidin-1-yl)-3-(trifluoromethyl)phenyl) amino)benzyl)acetamide (239) TIFF0007807381000519.tif3584

[0626] The title compound 239 (12.5 mg) was prepared from N-(4-(aminomethyl)phenyl)-4-(piperidin-1-yl)-3-(trifluoromethyl)aniline (34.9 mg, 0.1 mmol), 4-(dimethylamino)butanoic acid hydrochloride (19.0 mg, 0.12 mmol), HATU (45.6 mg, 0.12 mmol), DIEA (38.7 mg, 0.3 mmol) and DMF (1.0 mL) according to the procedure in 163 as a yellow solid in 25.5% overall yield. TIFF0007807381000520.tif47170

[0627] 4-Ethyl-1-(4-((4-(piperidin-1-yl)phenyl)amino)-2-(trifluoromethyl)benzyl)piperazin-2-one (240) TIFF0007807381000521.tif72170

[0628] 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 compound 1-(3-bromo-5-fluorobenzyl)-4-ethylpiperazin-2-one (241-1). LC-MS (m / z) 365.2, 367.2 [M+H] + .

[0629] Step 2. The title compound 240 (40.1 mg) was prepared 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 in 63.6% yield as a pale yellow solid. TIFF0007807381000522.tif46170

[0630] 4-(Dimethylamino)-N-(4-((4-(piperidin-1-yl)-3-(trifluoromethyl)phenyl)amino)benzyl)butanamide (241) JPEG0007807381000523.jpg26166

[0631] The title compound 241 (32.0 mg) was prepared from N-(4-(aminomethyl)phenyl)-4-(piperidin-1-yl)-3-(trifluoromethyl)aniline (30 mg, 0.086 mmol) and 4-(dimethylamino)butanoic acid hydrochloride (19 mg, 0.122 mmol) according to the procedure in 179 as a white solid in 76.1% overall yield. TIFF0007807381000524.tif37170

[0632] 1-(tert-butyl)-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (242) TIFF0007807381000525.tif38162

[0633] The title compound 242 (97.2 mg) was prepared 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) as a white solid in 69.74% yield. TIFF0007807381000526.tif56170

[0634] 1-Ethyl-N-(2-hydroxyethyl)-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (243) TIFF0007807381000527.tif3786

[0635] TIFF0007807381000528.tif29170

[0636] N-hydroxy-2-(4-methylpiperazin-1-yl)-N-(4-((4-(3-(trifluoromethyl)pyrrolidin-1-yl)phenyl)amino)benzyl)acetamide (244) TIFF0007807381000529.tif29166

[0637] The title compound 244 (24.6 mg) was prepared 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 in 179 as a white solid in 57.1% overall yield. TIFF0007807381000530.tif27170

[0638] N-ethyl-2-(4-methylpiperazin-1-yl)-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)acetamide (245) TIFF0007807381000531.tif82170

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

[0640] Step 2. The title compound 245 (56.2 mg) was prepared from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (100 mg, 0.41 mmol) and N-(4-bromobenzyl)-N-ethyl-2-(4-methylpiperazin-1-yl)acetamide (145 mg, 0.41 mmol) as a blue solid in 26.52% yield. TIFF0007807381000532.tif55170

[0641] N-Hydroxy-N-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)acetamide (246) JPEG0007807381000533.jpg80170

[0642] 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 slowly added 2-bromoacetic acid (190 mg, 1.37 mmol, 1.1 equiv) and potassium carbonate (516 mg, 3.73 mmol, 3.0 equiv) at 0 °C using an ice-water bath. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was acidified to pH = 4 with 1 N hydrochloric acid and then extracted three times with dichloromethane (5 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue, 2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)acetic acid (246-1), was used directly in the next step without further purification after concentration and drying in vacuo. LC-MS (m / z) 227.4 [M+H] + .

[0643] Step 2. The title compound 246 (14.9 mg) was prepared from 2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)acetic acid (246-1) (46 mg, 0.16 mmol) and 4-((hydroxyamino)methyl)-N-(4-(piperidin-1-yl)phenyl)aniline (50 mg, 0.17 mmol) according to the procedure for compound 290 in 17.53% yield as a brown solid. TIFF0007807381000534.tif38170

[0644] N-(2-chloro-4-((5-(piperidin-1-yl)pyridin-2-yl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (247) TIFF0007807381000535.tif29167

[0645] The title compound 247 (17.9 mg) was prepared 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 in 179 as a white solid in 42.3% overall yield. TIFF0007807381000536.tif27170

[0646] N-(4-((5-fluoro-6-(piperidin-1-yl)pyridin-3-yl)amino)benzyl)-2-(4-methyl-3-oxopiperazin-1-yl)acetamide (248) TIFF0007807381000537.tif3473

[0647] Title compound 248 (16.9 mg) was prepared according to the procedure for compound 163 as a white solid in 41.2% overall yield. TIFF0007807381000538.tif37170

[0648] N-(4-((4-(4,4-difluoropiperidin-1-yl)phenyl)amino)benzyl)-N-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (249) TIFF0007807381000539.tif3883

[0649] The title compound 249 (10.1 mg) was prepared according to the procedure for compound 108 as a white solid in 33.4% overall yield. TIFF0007807381000540.tif29170

[0650] 1-(4-((4-(4,4-difluoropiperidin-1-yl)phenyl)amino)benzyl)-4-fluoropyridin-2(1H)-one (250) TIFF0007807381000541.tif3855

[0651] Title compound 250 (20.1 mg) was prepared according to the procedure for compound 202 as a white solid in 48.4% overall yield. TIFF0007807381000542.tif30170

[0652] N-(4-((4-(4,4-difluoropiperidin-1-yl)phenyl)amino)benzyl)-N-hydroxy-1-methyl-6-oxopiperidine-3-carboxamide (251) TIFF0007807381000543.tif3481

[0653] The title compound 251 (9.9 mg) was prepared 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 in 174 as a white solid in 23.5% overall yield. TIFF0007807381000544.tif36170

[0654] N-(4-((4-(4,4-difluoropiperidin-1-yl)phenyl)amino)benzyl)-1-ethyl-N-hydroxy-5-oxopyrrolidine-3-carboxamide (252) TIFF0007807381000545.tif3681

[0655] The title compound 251 (7.0 mg) was prepared 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 in 174 as a white solid in 17% overall yield. TIFF0007807381000546.tif28170

[0656] N-(4-((4-(4,4-difluoropiperidin-1-yl)phenyl)amino)benzyl)-N-hydroxy-2-(2-methoxyethoxy)acetamide (253) TIFF0007807381000547.tif27170

[0657] The title compound 253 (8.2 mg) was prepared from 4-(4,4-difluoropiperidin-1-yl)-N-(4-((hydroxyamino)methyl)phenyl)aniline (30 mg, 0.090 mmol) and 2-(2-methoxyethoxy)acetic acid (16 mg, 0.117 mmol) according to the procedure in 179 as a white solid in 10.2% overall yield. TIFF0007807381000548.tif28170

[0658] 1-(Cyclopropylmethyl)-N-hydroxy-2-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)piperidine-4-carboxamide (254) TIFF0007807381000549.tif27169

[0659] The title compound 254 (11.6 mg) was prepared 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) according to the procedure in 179 as a white solid in 26.4% overall yield. TIFF0007807381000550.tif54170

[0660] 3-(4-((4-((N-hydroxy-2-(4-methylpiperazin-1-yl)acetamido)methyl)phenyl)amino)phenyl)-N,N-dimethylpropanamide (255) TIFF0007807381000551.tif3291

[0661] TIFF0007807381000552.tif35170

[0662] 4-(Dimethylamino)-N-(4-((4-(6-fluoropyridin-3-yl)phenyl)amino)benzyl)-N-hydroxybutanamide (256) TIFF0007807381000553.tif3586

[0663] TIFF0007807381000554.tif37170

[0664] N-Hydroxy-1-methyl-6-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)piperidine-3-carboxamide (257) TIFF0007807381000555.tif30166

[0665] Step 1. The title compound 257 (10.5 mg) was prepared from 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) according to the procedure for compound 290 in 38.02% yield as a pale yellow powder. TIFF0007807381000556.tif27170

[0666] N-Hydroxy-1-methyl-6-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)piperidine-3-carboxamide (258) TIFF0007807381000557.tif30165

[0667] The title compound 258 (19.9 mg) was prepared 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) according to the procedure for compound 290 in 72.06% yield as a pale yellow solid. TIFF0007807381000558.tif37170

[0668] tert-Butyl 3-(hydroxy(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)carbamoyl)azetidine-1-carboxylate (259) TIFF0007807381000559.tif3482

[0669] The title compound 259 (164.1 mg) was prepared according to the procedure for compound 108 as a white solid in 46.9% overall yield. TIFF0007807381000560.tif30170

[0670] N-hydroxy-1-methyl-2-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)piperidine-4-carboxamide (260) TIFF0007807381000561.tif3386

[0671] The title compound 260 (36.6 mg) was prepared 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) according to the procedure in 137 as a yellow solid in 40.4% overall yield. TIFF0007807381000562.tif28170

[0672] 1-Ethyl-5-oxo-N-(4-((4-(3-(trifluoromethyl)pyrrolidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (261) TIFF0007807381000563.tif3792

[0673] The title compound 261 (9.4 mg) was prepared 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), and HATU (30.4 mg, 0.08 mmol) according to the procedure in 209 as a blue solid in 32.9% overall yield. TIFF0007807381000564.tif36170

[0674] N-hydroxy-2-(4-methyl-3-oxopiperazin-1-yl)-N-(4-((4-(piperidin-1-yl)phenyl)amino)-2-(trifluoromethyl)benzyl)acetamide (262) TIFF0007807381000565.tif118170

[0675] Step 1. The title compound 262-3 (2.1 g) was prepared from 4-(piperidin-1-yl)aniline (1.76 g, 10.0 mmol), 4-bromo-2-(trifluoromethyl)benzaldehyde (2.53 g, 10.0 mmol), Pd(dppf)Cl (73.1 mg, 0.2 mmol), Xantphos (231.6 mg, 0.4 mmol), and CsCO (4.89 g, 15 mmol) according to the procedure for 137-3 in an overall yield of 60.3% as a yellow oil. Mass (m / z): 349.3 [M+H] + .

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

[0677] Step 3. The title compound 262-5 (720 mg) was prepared 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 15 mL of 10% HCl according to the procedure of 137-5 as a yellow solid in an overall yield of 50.0%. Mass (m / z): 366.2 [M+H] + .

[0678] Step 4. The title compound 262 (30.0 mg) was prepared 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)acetic acid hydrochloride (41 mg, 0.20 mmol), DMT-MM (65 mg, 0.23 mmol), DIEA (58 mg, 0.45 mmol), and DMF (1.0 mL) according to the procedure in 137 as a yellow solid in 38.5% overall yield. TIFF0007807381000566.tif39170

[0679] N-hydroxy-2-(4-methyl-2-oxopiperazin-1-yl)-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)acetamide (263) TIFF0007807381000567.tif3486

[0680] The title compound 263 (19.0 mg) was prepared 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)acetic acid hydrochloride (41 mg, 0.20 mmol), DMT-MM (65 mg, 0.23 mmol), DIEA (58 mg, 0.45 mmol) and DMF (1.0 mL) according to the procedure in 137 as a yellow solid in 24.4% overall yield. TIFF0007807381000568.tif46170

[0681] 1-Ethyl-5-oxo-N-((5-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)pyridin-2-yl)methyl)pyrrolidine-3-carboxamide (264) TIFF0007807381000569.tif3588

[0682] The title compound 264 (23.6 mg) was prepared 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), and HATU (38.0 mg, 0.1 mmol) according to the procedure in 209 as a blue solid in 48.2% overall yield. TIFF0007807381000570.tif46170

[0683] 2-(4-methylpiperazin-1-yl)-N-(4-(pyrimidin-5-ylamino)benzyl)acetamide (265) TIFF0007807381000571.tif28169

[0684] The title compound 265 (6.7 mg) was prepared 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 in 232 as a white solid in 12.9% overall yield. TIFF0007807381000572.tif27170

[0685] 1-Methyl-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-1H-imidazole-5-carboxamide (266) TIFF0007807381000573.tif3571

[0686] The title compound 266 (12.8 mg) was prepared 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 in 203 as a white solid in 32.6% overall yield. TIFF0007807381000574.tif46170

[0687] 6-chloro-N-(4-((4-(4,4-difluoropiperidin-1-yl)phenyl)amino)benzyl)-N-hydroxypyrazine-2-carboxamide (267) TIFF0007807381000575.tif35165

[0688] The title compound 267 (11.4 mg) was prepared from 4-(4,4-difluoropiperidin-1-yl)-N-(4-((hydroxyamino)methyl)phenyl)aniline (200 mg, 0.60 mmol) and 6-chloropyrazine-2-carboxylic acid (105 mg, 0.66 mmol) according to the procedure for compound 290 in 4.01% yield as a pink powder. TIFF0007807381000576.tif37170

[0689] N-(4-((4-(4,4-difluoropiperidin-1-yl)phenyl)amino)benzyl)-N-hydroxy-2-(3-(trifluoromethyl)piperazin-1-yl)acetamide (268) TIFF0007807381000577.tif90170

[0690] Step 1. 2-(3-(trifluoromethyl)piperazin-1-yl)acetic acid (268-1) (190 mg) was prepared 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) as a yellow powder. The residue was used directly in the next step without further purification after concentration and drying in vacuo. LC-MS (m / z) 213.4 [M+H] + .

[0691] Step 2. The title compound 268 (22.0 mg) was prepared as a white powder in 34.26% yield from 4-(4,4-difluoropiperidin-1-yl)-N-(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) according to the procedure for compound 290. TIFF0007807381000578.tif45170

[0692] 4-(Dimethylamino)-N-hydroxy-N-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)butanamide (269) TIFF0007807381000579.tif3490

[0693] TIFF0007807381000580.tif28170

[0694] N-(4-((4-(6-fluoropyridin-3-yl)phenyl)amino)benzyl)-N-hydroxy-2-morpholinoacetamide (270) TIFF0007807381000581.tif3590

[0695] TIFF0007807381000582.tif28170

[0696] N-(4-((4-cyclohexylphenyl)amino)benzyl)-N-hydroxy-2-(4-methylpiperazin-1-yl)acetamide (271) TIFF0007807381000583.tif3588

[0697] TIFF0007807381000584.tif36170

[0698] N-Hydroxy-1-methyl-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-1H-imidazole-5-carboxamide (272) TIFF0007807381000585.tif3573

[0699] The title compound 272 (20.1 mg) was prepared 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) according to the procedure in 174 as a white solid in 51.7% overall yield. TIFF0007807381000586.tif38170

[0700] 1-Ethyl-N-hydroxy-2-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)piperidine-4-carboxamide (273) TIFF0007807381000587.tif3280

[0701] The title compound 273 (14.5 mg) was prepared 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 in 174 as a white solid in 34.0% overall yield. TIFF0007807381000588.tif47170

[0702] 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) TIFF0007807381000589.tif3585

[0703] The title compound 274 (11.6 mg) was prepared 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)acetic acid hydrochloride (23 mg, 0.111 mmol) according to the procedure for 174 as a white solid in 26.9% overall yield. TIFF0007807381000590.tif38170

[0704] 1-(Cyclopropanecarbonyl)-N-hydroxy-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (275) TIFF0007807381000591.tif3876

[0705] The title compound 275 (13.1 mg) was prepared according to the procedure for compound 108 as a white solid in 22.3% overall yield. TIFF0007807381000592.tif38170

[0706] N-Hydroxy-1-isopropyl-N-(4-((4-(2-methylpiperidin-1-yl)phenyl)amino)benzyl) piperidine-4-carboxamide (276) TIFF0007807381000593.tif28166

[0707] The title compound 276 (13.5 mg) was prepared 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 in 179 as a white solid in 30.3% overall yield. TIFF0007807381000594.tif36170

[0708] N-Hydroxy-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)azetidine-3-carboxamide (277) TIFF0007807381000595.tif3079

[0709] The title compound 277 (86.1 mg) was prepared according to the procedure for compound 108 as a white solid in 42.8% overall yield. TIFF0007807381000596.tif26170

[0710] N-Hydroxy-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (278) TIFF0007807381000597.tif3177

[0711] The title compound 278 (90.1 mg) was prepared according to the procedure for compound 108 as a white solid in 44.5% overall yield. TIFF0007807381000598.tif28170

[0712] 1-Acetyl-N-hydroxy-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)azetidine-3-carboxamide (279) TIFF0007807381000599.tif3178

[0713] The title compound 279 (15.1 mg) was prepared according to the procedure for compound 108 as a white solid in 31.6% overall yield. TIFF0007807381000600.tif36170

[0714] 1-(Cyclopropanecarbonyl)-N-hydroxy-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)azetidine-3-carboxamide (280) TIFF0007807381000601.tif3482

[0715] Title compound 280 (17.5 mg) was prepared according to the procedure for compound 108 as a white solid in 32.7% overall yield. TIFF0007807381000602.tif37170

[0716] N-Hydroxy-1-isopropyl-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)piperidine-4-carboxamide (281) TIFF0007807381000603.tif27170

[0717] The title compound 281 (14.0 mg) was prepared 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) according to the procedure in 179 as a white solid in 32.9% overall yield. TIFF0007807381000604.tif46170

[0718] N-Hydroxy-1-isopropyl-N-(4-((4-(3-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)piperidine-4-carboxamide (282) TIFF0007807381000605.tif31166

[0719] The title compound 282 (19.6 mg) was prepared from 4-((hydroxyamino)methyl)-N-(4-(3-(trifluoromethyl)piperidin-1-yl)phenyl)aniline (30 mg, 0.082 mmol) and 1-isopropylpiperidine-4-carboxylic acid hydrochloride (22 mg, 0.107 mmol) according to the procedure in 179 as a white solid in 45.7% overall yield. TIFF0007807381000606.tif38170

[0720] 4-Ethyl-1-(4-((3-fluoro-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)-2-(trifluoromethyl)benzyl)piperazin-2-one (283) TIFF0007807381000607.tif26166

[0721] The title compound 283 (6.1 mg) was prepared 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 in 232 as a white solid in 12% overall yield. TIFF0007807381000608.tif46170

[0722] 4-Ethyl-1-(4-((3-fluoro-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)piperazin-2-one (284) TIFF0007807381000609.tif30166

[0723] The title compound 284 (2.9 mg) was prepared 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) according to the procedure in 232 as a white solid in 3.7% overall yield. TIFF0007807381000610.tif45170

[0724] N-Hydroxy-1-methyl-2-oxo-N-(4-((4-(piperidin-1-yl)phenyl)amino)-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (285) TIFF0007807381000611.tif3683

[0725] The title compound 285 (13.4 mg) was prepared 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 in 137 as a yellow solid in 17.7% overall yield. TIFF0007807381000612.tif37170

[0726] N-hydroxy-2-(4-methyl-3-oxopiperazin-1-yl)-N-(4-((4-(4-methylpiperidin-1-yl)phenyl)amino)benzyl)acetamide (286) TIFF0007807381000613.tif3693

[0727] The title compound 286 (24.5 mg) was prepared from 4-((hydroxyamino)methyl)-N-(4-(4-methylpiperidin-1-yl)phenyl)aniline (54 mg, 0.17 mmol), 2-(4-methyl-3-oxopiperazin-1-yl)acetic acid hydrochloride (42 mg, 0.20 mmol), DMT-MM (55 mg, 0.20 mmol), DIEA (66 mg, 0.51 mmol) and DMF (1.0 mL) according to the procedure in 137 as a yellow solid in 31.0% overall yield. TIFF0007807381000614.tif46170

[0728] N-Hydroxy-2,4-dimethyl-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)oxazole-5-carboxamide (287) TIFF0007807381000615.tif3477

[0729] The title compound 287 (15.0 mg) was prepared 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 in 174 as a white solid in 37.4% overall yield. TIFF0007807381000616.tif37170

[0730] 2,4-Dimethyl-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl) oxazole-5-carboxamide (288) TIFF0007807381000617.tif3476

[0731] The title compound 288 (8.8 mg) was prepared 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 in 203 as a white solid in 21.7% overall yield. TIFF0007807381000618.tif46170

[0732] N-ethyl-2-(4-methyl-3-oxopiperazin-1-yl)-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)acetamide (289) TIFF0007807381000619.tif66170

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

[0734] Step 2. The title compound 289 (38.2 mg) was prepared from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (100 mg, 0.41 mmol) and N-(4-bromobenzyl)-N-ethyl-2-(4-methyl-3-oxopiperazin-1-yl)acetamide (151 mg, 0.41 mmol) according to the procedure for compound 253 in 17.55% yield as a white powder. TIFF0007807381000620.tif47170

[0735] 1-Ethyl-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (290) TIFF0007807381000621.tif71170

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

[0737] Step 2. To a solution of 4-(aminomethyl)-N-(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 ultra-dry N,N-dimethylformamide (5 mL), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (87 mg, 0.31 mmol, 1.1 equiv.) and N-ethyl-N-isopropylpropan-2-amine (142 mmL, 0.86 mmol, 3.0 equiv.) were added at room temperature. 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, and the filter cake was washed with water three times and dried in vacuo to give 1-ethyl-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (290) as a pale white solid in 79.38% yield. TIFF0007807381000622.tif63170

[0738] 2-(2,6-dimethylmorpholino)-N-hydroxy-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)acetamide (291) TIFF0007807381000623.tif3483

[0739] The title compound 291 (31.4 mg) was prepared according to the procedure for compound 108 as a white solid in 55.9% overall yield. TIFF0007807381000624.tif37170

[0740] N-Hydroxy-2,2-dimethyl-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)tetrahydro-2H-pyran-4-carboxamide (292) TIFF0007807381000625.tif3281

[0741] The title compound 292 (10.1 mg) was prepared according to the procedure for compound 108 as a white solid in 21.8% overall yield. TIFF0007807381000626.tif35170

[0742] N-(4-((4-(3,3-difluoropiperidin-1-yl)phenyl)amino)benzyl)-N-hydroxy-1-isopropylpiperidine-4-carboxamide (293) TIFF0007807381000627.tif30166

[0743] The title compound 293 (19.0 mg) was prepared 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) according to the procedure in 179 as a white solid in 43.2% overall yield. TIFF0007807381000628.tif26170

[0744] Compounds 294-302 were prepared according to the method in Scheme 1. JPEG0007807381000629.jpg133170

[0745] Compounds 303-314 were prepared according to the method in Scheme 2. JPEG0007807381000630.jpg149170

[0746] Compounds 315-326 were prepared according to the method in Scheme 3. JPEG0007807381000631.jpg153170

[0747] Compounds 327-338 were prepared according to the method in Scheme 4. JPEG0007807381000632.jpg146170

[0748] Compounds 339-350 were prepared according to the method in Scheme 5. JPEG0007807381000633.jpg144170

[0749] Compounds 351-362 were prepared according to the method in Scheme 6. JPEG0007807381000634.jpg143170

[0750] Active Compound Group II: Representative Synthesis

[0751] N-(4-((4-(tert-butyl(ethyl)amino)phenyl)amino)benzyl)-1-ethyl-5-oxopyrrolidine-3-carboxamide (363) TIFF0007807381000635.tif124170

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

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

[0754] Step 3. Preparation of N-(4-((4-(tert-butyl(ethyl)amino)phenyl)amino)benzyl)-1-ethyl-5-oxopyrrolidine-3-carboxamide (363). 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 h. N 1 -(4-(aminomethyl)phenyl)-N4-(tert-butyl)-N4-ethylbenzene-1,4-diamine (59.4 mg, 0.2 mmol) and DIEA (77.4 mg, 0.6 mmol) were added. The reaction mixture was then stirred at room temperature for 3 hours. 5 mL of water was added. The mixture was then extracted with DCM (5 mL x 3). The combined organic layers were washed with water (10 mL x 3), dried over Na2SO4, and concentrated in vacuo. The residue was purified by prep-TLC (MeOH / DCM = 1 / 15) to give the desired product as a white solid (13.2 mg, 15.0%). TIFF0007807381000636.tif36170

[0755] N-(4-((4-(dimethylamino)phenyl)amino)benzyl)-1-ethyl-5-oxopyrrolidine-3-carboxamide (364) TIFF0007807381000637.tif140170

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

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

[0758] Step 3. Preparation of N-(4-((4-(dimethylamino)phenyl)amino)benzyl)-1-ethyl-5-oxopyrrolidine-3-carboxamide (364). The title compound 364 (21.6 mg) was prepared by the procedure for 363 using N 1 -(4-(aminomethyl)phenyl)-N 4 ,N 4 Prepared from -dimethylbenzene-1,4-diamine (48.4 mg, 0.2 mmol), 1-methylpiperazine (31.4 mg, 0.2 mmol), DIEA (77.4 mg, 0.6 mmol) and HATU (76.0 mg, 0.02 mmol) as a yellow solid in 28.4% overall yield. TIFF0007807381000638.tif27170

[0759] 1-Ethyl-N-(1-(4-((4-(4-methylpiperidin-1-yl)phenyl)amino)phenyl)ethyl)-5-oxopyrrolidine-3-carboxamide (365) JPEG0007807381000639.jpg104170

[0760] Step 1. Preparation of N-(1-(4-bromophenyl)ethyl)-1-ethyl-5-oxopyrrolidine-3-carboxamide (365-2). The title compound 365-2 (560 mg) was prepared 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) according to the procedure in 363 as a white solid in an overall yield of 82.8%. Mass (m / z): 339.1 [M+H] + .

[0761] Step 2. Preparation of 1-ethyl-N-(1-(4-((4-(4-methylpiperidin-1-yl)phenyl)amino)phenyl)ethyl)-5-oxopyrrolidine-3-carboxamide (365). The title compound 365 (4.2 mg) was prepared from N-(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(dba) (2.3 mg, 2.5 umol), X-Phos (5.9 mg, 12.5 umol), and t-BuONa (36 mg, 0.38 mmol) according to the procedure in 363-3 as a gray solid in 3.8% overall yield. TIFF0007807381000640.tif46170

[0762] N-(2-chloro-4-((2-(4-isopropylpiperidin-1-yl)pyrimidin-5-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (366) JPEG0007807381000641.jpg148170

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

[0764] Step 2. Preparation of tert-butyl (2-chloro-4-((2-(4-isopropylpiperidin-1-yl)pyrimidin-5-yl)amino)benzyl)carbamate. To 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, Cs2CO3 (610 mg, 1.87 mmol) and tris(dibenzylideneacetone)dipalladium (114 mg, 0.12 mmol) were added. The reaction mixture was stirred at 90 °C for 16 h. The mixture was then filtered and concentrated. The residue was purified by pre-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] + .

[0765] 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 4N HCl in dioxane (5 mL) at room temperature. The mixture was then stirred at room temperature overnight. LCMS showed 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] + .

[0766] 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, N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium (321 mg, 0.84 mmol) and DIEA (136 mg, 1.05 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into H2O (10 mL) and extracted with EA (20 mL*3), the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated, and the residue was purified by prep-HPLC to give 366 (93 mg) as a white solid. TIFF0007807381000642.tif46170

[0767] 1-Ethyl-5-oxo-N-(1-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)phenyl)ethyl)pyrrolidine-3-carboxamide (367) TIFF0007807381000643.tif4292

[0768] The title compound 367 (4.1 mg) was prepared from N-(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(dba) (1.1 mg, 1.6 umol), X-Phos (3.0 mg, 6.2 umol), and t-BuONa (18 mg, 0.19 mmol) according to the procedure in 363-3 as a yellow solid in 6.5% overall yield. TIFF0007807381000644.tif46170

[0769] N 1 -(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)succinamide (368) TIFF0007807381000645.tif34165

[0770] The title compound 368 (11.2 mg) was prepared from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidin-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) according to the procedure for 363 as a pale yellow solid in 16.7% overall yield. TIFF0007807381000646.tif37170

[0771] 1-Cyclopropyl-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (369) TIFF0007807381000647.tif38144

[0772] The title compound 369 (10.6 mg) was prepared 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 for 363 as a yellow solid in 14.1% overall yield. TIFF0007807381000648.tif37170

[0773] N 1 -(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)oxalamide (370) TIFF0007807381000649.tif4586

[0774] The title compound 370 (10.3 mg) was prepared 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 mg, 0.15 mmol) according to the procedure in 363 as a yellow solid in 16.3% overall yield. TIFF0007807381000650.tif28170

[0775] N 1 ,N 1 -Dimethyl-N 2 -(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)oxalamide (371) TIFF0007807381000651.tif4185

[0776] The title compound 371 (16.4 mg) was prepared 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 in 363 as a pale yellow solid in 24.4% overall yield. TIFF0007807381000652.tif46170

[0777] 4-Oxo-4-(pyrrolidin-1-yl)-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)butanamide (372) TIFF0007807381000653.tif40103

[0778] The title compound 372 (16.4 mg) was prepared from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)aniline (70.0 mg, 0.2 mmol), 4-oxo-4-(pyrrolidin-1-yl)butanoic acid (41.0 mg, 0.24 mmol), DIEA (77.4 mg, 0.6 mmol) and HATU (91.2 mg, 0.24 mmol) according to the procedure in 363 as a pale yellow solid in 24.4% overall yield. TIFF0007807381000654.tif37170

[0779] N-(4-((2-methoxy-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (373) TIFF0007807381000655.tif28166

[0780] The title compound 373 (4.2 mg) was prepared from N-(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(dba) (2.0 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and t-BuONa (36.0 mg, 0.38 mmol) according to the procedure in 363-3 as a yellow solid in 3.4% overall yield. TIFF0007807381000656.tif28170

[0781] N-(4-((2,6-dimethyl-4-(4-methylpiperidin-1-yl)phenyl)amino)benzyl)-1-ethyl-5-oxopyrrolidine-3-carboxamide (374) TIFF0007807381000657.tif28166

[0782] The title compound 374 (35.1 mg) was prepared from N-(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(dba) (2.0 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and t-BuONa (36.0 mg, 0.38 mmol) according to the procedure in 363-3 as a white solid in 30.4% overall yield. TIFF0007807381000658.tif46170

[0783] 1-(2-ethoxyethyl)-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (375) TIFF0007807381000659.tif4994

[0784] The title compound 375 (11.0 mg) was prepared from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)aniline hydrochloride salt (77.0 mg, 0.2 mmol), 1-(2-ethoxyethyl)-5-oxopyrrolidine-3-carboxylic acid (40.2 mg, 0.2 mmol), DIEA (77.9 mg, 0.6 mmol) and HATU (76.0 mg, 0.2 mmol) according to the procedure in 363 as a pale yellow solid in an overall yield of 11.4%. TIFF0007807381000660.tif38170

[0785] N 1 ,N 1 -Dimethyl-N 4 -(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)succinimide (376) TIFF0007807381000661.tif4396

[0786] The title compound 376 (15.9 mg) was prepared from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)aniline hydrochloride salt (60.3 mg, 0.15 mmol), 4-(dimethylamino)-4-oxobutanoic acid (21.8 mg, 0.15 mmol), DIEA (58.0 mg, 0.45 mmol) and HATU (57 mg, 0.15 mmol) according to the procedure in 363 as a pale yellow solid in 22.3% overall yield. TIFF0007807381000662.tif37170

[0787] N 1 -(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)glutaramide (377) TIFF0007807381000663.tif82170

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

[0789] Step 2. N 1 Preparation of -(4-((4-(4-(trifluoromethyl)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 mmol). The reaction was then stirred at room temperature for 5 h. NH3.HO (0.2 mL) was added. The mixture was then stirred at room temperature overnight. 5 mL of water was added. The resulting solution was extracted with 3 x 5 mL of EA. The organic layers were combined, washed with 3 x 10 mL of water, dried over Na2SO4, and concentrated in vacuo. The residue was purified by prep-TLC (MeOH / DCM=1 / 20) to give the desired product as a yellow solid (6.5 mg, 15.5%). TIFF0007807381000664.tif28170

[0790] N 1 -(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)malonamide (378) TIFF0007807381000665.tif4191

[0791] The title compound 378 (5.3 mg) was prepared from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)aniline hydrochloride salt (77.1 mg, 0.2 mmol), 3-amino-3-oxopropanoic acid (33.8 mg, 0.24 mmol), DIEA (77.4 mg, 0.6 mmol) and HATU (91.2 mg, 0.24 mmol) according to the procedure in 363 as a pale yellow solid in 6.1% overall yield. TIFF0007807381000666.tif37170

[0792] 5-Oxo-5-(pyrrolidin-1-yl)-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pentanamide (379) TIFF0007807381000667.tif43107

[0793] The title compound 379 (17.7 mg) was prepared from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)aniline hydrochloride salt (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) according to the procedure in 363 as a pale yellow solid in 17.2% overall yield. TIFF0007807381000668.tif29170

[0794] 3-Oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)piperazine-1-carboxamide (380) TIFF0007807381000669.tif40168

[0795] 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 h. 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 h. The solution was then washed with 3×10 mL of water, dried over NaSO, and concentrated in vacuo. The residue was purified by prep-TLC (MeOH / DCM=1 / 15) to give the desired product as a pale yellow solid (26.7 mg, 56.2%). TIFF0007807381000670.tif37170

[0796] 4-Methyl-3-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)piperazine-1-carboxamide (381) TIFF0007807381000671.tif3993

[0797] The title compound 381 (9.8 mg) was prepared from 4-(aminomethyl)-N-(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) according to the procedure for 380 as a blue solid in 20.0% overall yield. TIFF0007807381000672.tif28170

[0798] 2-(1-ethyl-5-oxopyrrolidin-3-yl)-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)acetamide (382) TIFF0007807381000673.tif42100

[0799] The title compound 382 (20.6 mg) was prepared 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) according to the procedure in 363 as a pale yellow solid in 41.0% overall yield. TIFF0007807381000674.tif56170

[0800] 1-Methyl-2-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)imidazolidine-4-carboxamide (383) TIFF0007807381000675.tif3991

[0801] The title compound 383 (15.6 mg) was prepared from 4-(aminomethyl)-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) according to the procedure for 363 as a white solid in 32.8% overall yield. TIFF0007807381000676.tif47170

[0802] 1-Ethyl-N-(2-methyl-4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (384) TIFF0007807381000677.tif134170

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

[0804] 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 in vacuo. The residue was applied to a silica gel column and eluted with ethyl acetate / hexane (0-1 / 1) to give the crude product as a yellow oil (1.01 g, 79.5%). Mass(m / z): 378.2 [M+H] + .

[0805] Step 3. Preparation of 4-(aminomethyl)-3-methyl-N-(4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)aniline (384-5). To a solution of (E)-2-methyl-4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzaldehyde oxime (500 mg, 1.32 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 a 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 x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, and concentrated to give the desired product as a yellow solid. (190 mg, 40.0%). 364.2 [M+H] + .

[0806] Step 4. Preparation of 1-ethyl-N-(2-methyl-4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (384). The title compound 384 (17.9 mg) was prepared 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 in 363 as a white powder in an overall yield of 35.7%. TIFF0007807381000678.tif37170

[0807] N-(2-methyl-4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (385) TIFF0007807381000679.tif3793

[0808] The title compound 385 (17.7 mg) was prepared 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) and HATU (38.0 mg, 0.1 mmol) according to the procedure in 363 as a white powder in an overall yield of 37.3%. TIFF0007807381000680.tif36170

[0809] 5-Oxo-N-(4-((4-(3-(trifluoromethyl)azetidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (386) TIFF0007807381000681.tif135170

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

[0811] Step 2. Preparation of 4-(3-(trifluoromethyl)azetidin-1-yl)aniline (386-4). 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 a hydrogen atmosphere at room temperature overnight. The Pd / C was removed by filtration. The filtrate was concentrated in vacuo to give the desired product as a yellow oil (99 mg, 83.2%). Mass(m / z): 217.2 [M+H] + .

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

[0813] Step 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 from HCl (5.0 mL), tert-butyl (4-((4-(3-(trifluoromethyl)azetidin-1-yl)phenyl)amino)benzyl)carbamate (116 mg, 0.28 mmol) in 1,4-dioxane according to the procedure of 363-4 as a yellow solid in 100% overall yield. Mass (m / z): 322.3 [M+H] + .

[0814] Step 5. Preparation of 5-oxo-N-(4-((4-(3-(trifluoromethyl)azetidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (386). The title compound 386 (3.0 mg) was prepared 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 in 363 as a dark blue powder in an overall yield of 5.0%. TIFF0007807381000682.tif36170

[0815] 1-Ethyl-5-oxo-N-(4-((4-(3-(trifluoromethyl)azetidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (387) TIFF0007807381000683.tif3791

[0816] The title compound 387 (4.1 mg) was prepared from 4-(aminomethyl)-N-(4-(3-(trifluoromethyl)azetidin-1-yl)phenyl)aniline hydrochloride (49 mg, 0.14 mmol), 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (21.8 mg, 0.14 mmol), DIEA (53.4 mg, 0.41 mmol), and HATU (52 mg, 0.14 mmol) according to the procedure in 363 as a dark blue powder in 6.5% overall yield. TIFF0007807381000684.tif38170

[0817] N 1 -(4-((4-(4-methylpiperidin-1-yl)phenyl)amino)benzyl)malonamide (388) TIFF0007807381000685.tif3986

[0818] The title compound 388 (15.3 mg) was prepared 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 in 363 as a dark blue powder in an overall yield of 20.1%. TIFF0007807381000686.tif37170

[0819] N 1 -(4-((4-(4-methylpiperidin-1-yl)phenyl)amino)benzyl)glutaramide (389) TIFF0007807381000687.tif3795

[0820] The title compound 389 (15.3 mg) was prepared 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) according to the procedure in 363 as a dark blue powder in an overall yield of 20.1%. TIFF0007807381000688.tif38170

[0821] N-(2-chloro-4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (390) TIFF0007807381000689.tif73170

[0822] Step 1. Preparation of 2-chloro-4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzonitrile (390-2). The title compound 390-2 (1.26 g) was prepared from 4-bromo-2-chlorobenzonitrile (860 mg, 4 mmol), 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (1.27 g, 5.2 mmol), Pd2(dba)3 (36.6 mg, 0.04 mmol), X-Phos (95.4 mg, 0.2 mmol), and Cs2CO3 (1.96 g, 6 mmol) according to the procedure in 363-3 in an overall yield of 82.9% as a gray solid. Mass (m / z): 380.2 [M+H] + .

[0823] Step 2. Preparation of 4-(aminomethyl)-3-chloro-N-(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 LiAlH4 (380 mg, 10 mmol). The reaction was then refluxed at room temperature overnight. 20 mL of water was added at 0 °C. The resulting solution was extracted with 3 x 20 mL of ethyl acetate. The organic layers were combined, washed with water (3 x 50 mL), dried, and concentrated in vacuo. The residue was purified by prep-TLC (MeOH / DCM = 1 / 15) to give the desired product as a yellow solid (50 mg, 13.0%). Mass (m / z): 384.2 [M+H] + .

[0824] Step 3. Preparation of N-(2-chloro-4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (390). The title compound 390 (40.9 mg) was prepared 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 in 363 as a dark blue powder in an overall yield of 63.9%. TIFF0007807381000690.tif28170

[0825] N-(3-Methoxy-4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (391) TIFF0007807381000691.tif4290

[0826] The title compound 391 (12.8 mg) was prepared 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 in 363 as a white powder in an overall yield of 26.1%. TIFF0007807381000692.tif37170

[0827] N-(4-((4-cyclohexylphenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (392) TIFF0007807381000693.tif3883

[0828] The title compound 392 (9.3 mg) was prepared from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 4-cyclohexylaniline (58 mg, 0.33 mmol), Pd(dba) (2.3 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and CsCO (122 mg, 0.38 mmol) according to the procedure in 363-3 as a pale yellow solid in 9.5% overall yield. TIFF0007807381000694.tif46170

[0829] N-(3-fluoro-4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (393) JPEG0007807381000695.jpg71170

[0830] Step 1. Preparation of 3-fluoro-4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzonitrile (393-2). The title compound 393-2 (1.56 g) was prepared from 4-bromo-3-fluorobenzonitrile (1.0 g, 5 mmol), 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (1.59 g, 6.5 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), X-Phos (119 mg, 0.25 mmol), and Cs2CO3 (2.45 g, 7.5 mmol) according to the procedure of 363-3 in an overall yield of 85.7% as a gray solid. Mass (m / z): 364.2 [M+H] + .

[0831] 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 Ni. The reaction was then stirred overnight at room temperature under a hydrogen atmosphere. The Raney Ni was filtered off. The filtrate was concentrated in vacuo. The residue was purified by prep-TLC (MeOH / DCM=1 / 5) to give the desired product as a yellow solid (220 mg, 60.0%). Mass (m / z): 368.1 [M+H] + .

[0832] Step 3. Preparation of N-(3-fluoro-4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (393). The title compound 393 (28.0 mg) was prepared 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) according to the procedure for 363 in an overall yield of 43.1% as a white powder. TIFF0007807381000696.tif47170

[0833] N-(4-((4-fluoro-3-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (394) TIFF0007807381000697.tif153170

[0834] Step 1. Preparation of 1-(2-fluoro-5-nitrophenyl)-4-(trifluoromethyl)piperidine (394-3). The title compound 394-3 (570 mg) was prepared from 2-bromo-1-fluoro-4-nitrobenzene (1.1 g, 5 mmol), 4-(trifluoromethyl)piperidine (995 mg, 6.5 mmol), Pd(dba) (46 mg, 0.05 mmol), X-Phos (119 mg, 0.25 mmol), and CsCO (2.45 g, 7.5 mmol) according to the procedure for 363-3 in an overall yield of 39.0% as a yellow solid.

[0835] 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 overnight at room temperature under a hydrogen atmosphere. The Pd / C was removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by prep-TLC (MeOH / DCM=1 / 5) to give the desired product as a yellow oil (390 mg, 76.3%). Mass (m / z): 263.2 [M+H] + .

[0836] Step 3. Preparation of N-(4-((4-fluoro-3-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (394). The title compound 394 (5.0 mg) was prepared 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(dba) (2.3 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and CsCO (122 mg, 0.38 mmol) according to the procedure in 363-3 as a white powder in a 5.0% overall yield. TIFF0007807381000698.tif48170

[0837] N-(4-((3-chloro-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (395) TIFF0007807381000699.tif160170

[0838] Step 1. Preparation of N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (395-2). The title compound 395-2 (616 mg) was prepared from 2-chloro-1-fluoro-4-nitrobenzene (700 mg, 4.0 mmol), 4-(trifluoromethyl)piperidine (612 mg, 4.0 mmol), and KCO (828 mg, 6.0 mmol) according to the procedure of 386-3 in an overall yield of 50.0% as a yellow solid.

[0839] Step 2. Preparation of 3-chloro-4-(4-(trifluoromethyl)piperidin-1-yl)aniline (395-3). The title compound 395-3 (500 mg) was prepared 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 in an overall yield of 89.9% as a yellow solid. Mass (m / z): 279.3 [M+H] + .

[0840] Step 3. Preparation of N-(4-((3-chloro-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (395). The title compound 395 (30.0 mg) was prepared 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(dba) (2.5 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and CsCO (122 mg, 0.38 mmol) according to the procedure in 363-3 as a white powder in 24.3% overall yield. TIFF0007807381000700.tif47170

[0841] N-(4-((4-(4,4-difluoropiperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (396) TIFF0007807381000701.tif4288

[0842] The title compound 396 (36.2 mg) was prepared 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(dba) (2.3 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and CsCO (122 mg, 0.38 mmol) according to the procedure in 363-3 as a white powder in 33.8% overall yield. TIFF0007807381000702.tif47170

[0843] N-(4-((3-bromo-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (397) TIFF0007807381000703.tif119170

[0844] Step 1. Preparation of 1-(2-bromo-4-nitrophenyl)-4-(trifluoromethyl)piperidine (397-2). The title compound 397-2 (2.38 g) was prepared from 2-bromo-1-fluoro-4-nitrobenzene (2.19 g, 10 mmol), 4-(trifluoromethyl)piperidine (1.53 g, 10 mmol), and K2CO3 (2.07 g, 15 mmol) according to the procedure of 386-3 in an overall yield of 67.6% as a yellow solid.

[0845] Step 2. Preparation of 3-bromo-4-(4-(trifluoromethyl)piperidin-1-yl)aniline (397-3). The title compound 397-3 (315 mg) was prepared 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 in an overall yield of 48.9% as a yellow solid. Mass (m / z): 323.1 [M+H] + .

[0846] Step 3. Preparation of tert-butyl (4-((3-bromo-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)carbamate (397-4). The title compound 397-4 (102 mg) was prepared 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), Pd2(dba)3 (4.6 mg, 5.0 umol), X-Phos (11.9 mg, 25 umol), and Cs2CO3 (245 mg, 0.75 mmol) according to the procedure in 363-3 in an overall yield of 38.6% as a yellow solid. Mass (m / z): 528.3 [M+H] + .

[0847] Step 4. Preparation of N-(4-(aminomethyl)phenyl)-3-bromo-4-(4-(trifluoromethyl)piperidin-1-yl)aniline (397-5). The title compound 397-5 (32.9 mg) was prepared from HCl (5.0 mL), tert-butyl (4-((3-bromo-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)carbamate (102 mg, 0.19 mmol) in 1,4-dioxane according to the procedure of 363-4 as a yellow solid in 39.8% overall yield. Mass (m / z): 428.1 [M+H] + .

[0848] Step 5. Preparation of N-(4-((3-bromo-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (397). The title compound 397 (9.0 mg) was prepared 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) according to the procedure in 363 in an overall yield of 27.3% as a pale yellow solid. TIFF0007807381000704.tif46170

[0849] N-(4-((5-fluoro-2-methyl-4-(4-methylpiperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (398) TIFF0007807381000705.tif177170

[0850] Step 1. Preparation of 1-(2-fluoro-5-methyl-4-nitrophenyl)-4-methylpiperidine (398-3). The title compound 398-3 (1.27 g) was prepared from 1,2-difluoro-4-methyl-5-nitrobenzene (1.0 g, 5.7 mmol) and 4-methylpiperidine (1.72 g, 17.3 mmol) according to the procedure for 386-3 in an overall yield of 88.2% as a yellow solid.

[0851] Step 2. Preparation of 5-fluoro-2-methyl-4-(4-methylpiperidin-1-yl)aniline (398-4). The title compound 398-4 (1.16 g) was prepared 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 for 386-4 in a total yield of 100% as a yellow solid. Mass (m / z): 223.2 [M+H] + .

[0852] Step 3. Preparation of N-(4-((5-fluoro-2-methyl-4-(4-methylpiperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (398). The title compound 398 (22.1 mg) was prepared 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(dba) (2.5 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and CsCO (122 mg, 0.38 mmol) according to the procedure in 363-3 as a white powder in 20.2% overall yield. TIFF0007807381000706.tif46170

[0853] N-(4-((5-chloro-2-methyl-4-(4-methylpiperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (399) TIFF0007807381000707.tif171170

[0854] Step 1. Preparation of 1-(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 88.2% overall yield from 1-chloro-2-fluoro-4-methyl-5-nitrobenzene (1.08 g, 5.7 mmol) and 4-methylpiperidine (1.72 g, 17.3 mmol) according to the procedure of 386-3.

[0855] Step 2. Preparation of 5-chloro-2-methyl-4-(4-methylpiperidin-1-yl)aniline (399-3). The title compound 399-3 (1.19 g) was prepared 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 as a yellow solid in 100% overall yield. Mass (m / z): 239.2 [M+H] + .

[0856] Step 3. Preparation of N-(4-((5-chloro-2-methyl-4-(4-methylpiperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (399). The title compound 399 (21.0 mg) was prepared 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(dba) (2.5 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and CsCO (122 mg, 0.38 mmol) according to the procedure in 363-3 as a white powder in an overall yield of 18.5%. TIFF0007807381000708.tif46170

[0857] N-(4-((2-fluoro-3-methyl-4-(4-methylpiperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (400) TIFF0007807381000709.tif166170

[0858] Step 1. Preparation of 1-(3-fluoro-2-methyl-4-nitrophenyl)-4-methylpiperidine (400-2). A solution of 1,3-difluoro-2-methyl-4-nitrobenzene (1 g, 5.7 mmol) and 4-methylpiperidine (1.72 g, 17.3 mmol) in DMSO (10 mL) was stirred overnight at room temperature. 10 mL of water was added dropwise. The precipitate was collected by filtration to give the desired product as a yellow solid (1.20 g, 83.3%). Mass (m / z): 253.2 [M+H] + .

[0859] Step 2. Preparation of 5-chloro-2-methyl-4-(4-methylpiperidin-1-yl)aniline (400-3). The title compound 400-3 (1.1 g) was prepared 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 as a yellow solid in 100% overall yield. Mass (m / z): 239.2 [M+H] + .

[0860] Step 3. Preparation of N-(4-((2-fluoro-3-methyl-4-(4-methylpiperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (400). The title compound 400 (17.2 mg) was prepared 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(dba) (2.5 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and CsCO (122 mg, 0.38 mmol) according to the procedure in 363-3 as a white powder in 15.7% overall yield. TIFF0007807381000710.tif46170

[0861] N-(4-((3-fluoro-2-methyl-4-(4-methylpiperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (401) TIFF0007807381000711.tif3376

[0862] The title compound 401 (11.7 mg) was prepared 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(dba) (2.5 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and CsCO (122 mg, 0.38 mmol) according to the procedure in 398 as a white powder in 10.7% overall yield. TIFF0007807381000712.tif55170

[0863] N-(4-((2,3-dimethyl-4-(4-methylpiperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (402) TIFF0007807381000713.tif3071

[0864] The title compound 402 (11.1 mg) was prepared 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), Pd2(dba)3 (2.5 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and Cs2CO3 (122 mg, 0.38 mmol) as a yellow powder according to the procedure in 398 in an overall yield of 10.2%. TIFF0007807381000714.tif63170

[0865] N-(4-((5-methyl-6-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (403) TIFF0007807381000715.tif167170

[0866] Step 1. Preparation of 4-(trifluoromethyl)piperidine (403-2). The title compound 403-2 (959 mg) was prepared from 2-fluoro-3-methyl-5-nitropyridine (624 mg, 4 mmol), 4-(trifluoromethyl)piperidine (734 mg, 4.8 mmol), and KCO (828 mg, 6 mmol) according to the procedure of 386-3 in an overall yield of 83.1% as a yellow solid.

[0867] Step 2. Preparation of 5-methyl-6-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-amine (403-3). The title compound 403-3 (390 mg) was prepared 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 in an overall yield of 72.5% as a purple solid. Mass (m / z): 260.3 [M+H] + .

[0868] Step 3. Preparation of N-(4-((5-methyl-6-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (403). The title compound 403 (25.2 mg) was prepared from N-(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(dba) (2.5 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and CsCO (122 mg, 0.38 mmol) as a pale yellow powder in 21.2% overall yield according to the procedure in 363-3. TIFF0007807381000716.tif54170

[0869] N-(4-((2-methyl-6-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (404) TIFF0007807381000717.tif167170

[0870] Step 1. Preparation of 2-methyl-3-nitro-6-(4-(trifluoromethyl)piperidin-1-yl)pyridine (404-2). The title compound 404-2 (1.03 g) was prepared from 6-fluoro-2-methyl-3-nitropyridine (624 mg, 4 mmol), 4-(trifluoromethyl)piperidine (734 mg, 4.8 mmol) and K2CO3 (828 mg, 6 mmol) according to the procedure of 386-3 in an overall yield of 89.0% as a yellow solid.

[0871] Step 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 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 in an overall yield of 78.3% as a yellow oil. Mass (m / z): 260.2 [M+H] + .

[0872] Step 3. Preparation of N-(4-((2-methyl-6-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (404). The title compound 404 (18.6 mg) was prepared 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(dba) (2.5 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and CsCO (122 mg, 0.38 mmol) according to the procedure in 363-3 as a pale yellow powder in an overall yield of 15.6%. TIFF0007807381000718.tif57170

[0873] 5-Oxo-N-(4-((3-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (405) TIFF0007807381000719.tif38162

[0874] The title compound 405 (4.6 mg) was prepared 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(dba) (0.9 mg, 1.0 umol), X-Phos (2.4 mg, 5.0 umol), and CsCO (50 mg, 0.15 mmol) as a pale yellow powder in 9.8% overall yield according to the procedure in 363-3. TIFF0007807381000720.tif46170

[0875] 5-Oxo-N-(4-((6-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)amino)benzyl)pyrrolidine-3-carboxamide (406) TIFF0007807381000721.tif33166

[0876] The title compound 406 (72.4 mg) was prepared 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(dba) (2.5 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and CsCO (122 mg, 0.38 mmol) according to the procedure in 363-3 as a purple powder in 31.5% overall yield. TIFF0007807381000722.tif65170

[0877] N-(4-((2,6-dimethyl-4-(4-methylpiperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (407) TIFF0007807381000723.tif4974

[0878] The title compound 407 (8.6 mg) was prepared 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 in 397 as a pale yellow solid in 13.7% overall yield. TIFF0007807381000724.tif55170

[0879] N-(4-((5-chloro-2-methyl-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (408) TIFF0007807381000725.tif5276

[0880] The title compound 408 (30.8 mg) was prepared from N-(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), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.9 mg, 16.5 umol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure for 404 as a yellow powder in an overall yield of 18.2%. TIFF0007807381000726.tif46170

[0881] N-(4-((3-fluoro-2-methyl-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (409) TIFF0007807381000727.tif4878

[0882] The title compound 409 (13.1 mg) was prepared 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(dba) (3.0 mg, 3.3 umol), X-Phos (7.9 mg, 16.5 umol), and CsCO (163 mg, 0.50 mmol) as a yellow powder according to the procedure for 404 in an overall yield of 8.0%. TIFF0007807381000728.tif53170

[0883] N-(4-((5-fluoro-2-methyl-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (410) TIFF0007807381000729.tif5578

[0884] The title compound 410 (28.9 mg) was prepared from N-(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), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.9 mg, 16.5 umol), and Cs2CO3 (163 mg, 0.50 mmol) as a yellow powder according to the procedure in 404 in an overall yield of 17.6%. TIFF0007807381000730.tif55170

[0885] N-(4-((2-fluoro-3-methyl-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (411) TIFF0007807381000731.tif4879

[0886] The title compound 411 (38.5 mg) was prepared 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(dba) (3.0 mg, 3.3 umol), X-Phos (7.9 mg, 16.5 umol), and CsCO (163 mg, 0.50 mmol) according to the procedure in 404 as a white powder in 23.8% overall yield. TIFF0007807381000732.tif46170

[0887] N-(4-((2,3-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (412) TIFF0007807381000733.tif5178

[0888] The title compound 412 (10.6 mg) was prepared 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), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.9 mg, 16.5 umol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure for 404 as a white powder in 6.6% overall yield. TIFF0007807381000734.tif54170

[0889] N-(4-((4-(4,4-dimethylcyclohexyl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (413) TIFF0007807381000735.tif188170

[0890] Step 1. Preparation of 4,4-dimethyl-4'-nitro-2,3,4,5-tetrahydro-1,1'-biphenyl (413-3). To a mixture of 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(PPh3)4 (690 mg, 0.6 mmol) in 100 mL of 1,4-dioxane and 20 mL of water was added K2CO3 (6.24 g, 45 mmol). After stirring overnight at 110 °C under Ar, the reaction was cooled to room temperature (RT). The mixture was treated with EtOAc (100 mL) and washed with HO (3 x 200 mL) and brine (200 mL). The organic layer was dried (Na2SO4) 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%).

[0891] Step 2. Preparation of 4-(4,4-dimethylcyclohexyl)aniline (413-4). 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 of concentrated HCl. The reaction was then stirred under a hydrogen atmosphere at 60 °C overnight. The reaction was cooled to room temperature (RT). The Pd / C was filtered off. The filtrate was concentrated in vacuo. 50 mL of water was added, and the pH of the solution was adjusted to 8-9 with sodium carbonate solution. The mixture was then extracted with DCM (50 mL x 3). The combined organic layers were washed with water (100 mL), dried over Na2SO4, and concentrated to give the desired product as a yellow solid (1.8 g, 81.8%). Mass (m / z): 204.3 [M + H] + .

[0892] Step 3. Preparation of N-(4-((4-(4,4-dimethylcyclohexyl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (413). The title compound 413 (33.5 mg) was prepared 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(dba) (2.3 mg, 2.5 umol), X-Phos (5.9 mg, 12.4 umol), and CsCO (121 mg, 0.37 mmol) according to the procedure in 404 as a white powder in 32.2% overall yield. TIFF0007807381000736.tif47170

[0893] N-(4-((4-fluoro-3-(piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (414) TIFF0007807381000737.tif5168

[0894] The title compound 414 (57.8 mg) was prepared 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(dba) (3.5 mg, 3.8 umol), X-Phos (9.1 mg, 19 umol), and CsCO (186 mg, 0.57 mmol) as a yellow powder according to the procedure for 404 in an overall yield of 37.1%. TIFF0007807381000738.tif46170

[0895] N-(4-((4-(azocan-1-yl)-3-(trifluoromethyl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (415) TIFF0007807381000739.tif4574

[0896] The title compound 415 (63.6 mg) was prepared from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (99 mg, 0.33 mmol), 4-(azocan-1-yl)-3-(trifluoromethyl)aniline (117 mg, 0.43 mmol), Pd(dba) (3.0 mg, 3.3 umol), X-Phos (7.9 mg, 16.5 umol), and CsCO (163 mg, 0.5 mmol) as a yellow powder according to the procedure in 404 in an overall yield of 39.1%. TIFF0007807381000740.tif46170

[0897] N-(4-((4-(4,4-dimethylpiperidin-1-yl)-3-(trifluoromethyl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (416) TIFF0007807381000741.tif4773

[0898] The title compound 416 (54.1 mg) was prepared 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(dba) (3.0 mg, 3.3 umol), X-Phos (7.9 mg, 16.5 umol), and CsCO (163 mg, 0.5 mmol) according to the procedure in 404 as a white powder in 33.3% overall yield. TIFF0007807381000742.tif53170

[0899] 5-Oxo-N-(4-((4-(4-(trifluoromethyl)cyclohexyl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (417) TIFF0007807381000743.tif4879

[0900] The title compound 417 (9.6 mg) was prepared from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 4-(4-(trifluoromethyl)cyclohexyl)aniline (73 mg, 0.30 mmol), Pd2(dba)3 (2.3 mg, 2.5 umol), X-Phos (5.9 mg, 12.4 umol), and Cs2CO3 (121 mg, 0.37 mmol) according to the procedure in 413 as a white powder in an overall yield of 8.4%. TIFF0007807381000744.tif36170

[0901] N-(4-((3-(diethylamino)-4-fluorophenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (418) TIFF0007807381000745.tif4768

[0902] The title compound 418 (9.0 mg) was prepared from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (99 mg, 0.33 mmol), 4-(4-(trifluoromethyl)cyclohexyl)aniline (73 mg, 0.30 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.9 mg, 16.5 umol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure in 404 as a white solid in 6.8% overall yield. TIFF0007807381000746.tif37170

[0903] N-(4-((6-(azepan-1-yl)-2-methylpyridin-3-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (419) TIFF0007807381000747.tif4769

[0904] The title compound 419 (16.1 mg) was prepared 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(dba) (3.0 mg, 3.3 umol), X-Phos (7.9 mg, 16.5 umol), and CsCO (163 mg, 0.50 mmol) as a yellow powder according to the procedure in 404 in an overall yield of 11.5%. TIFF0007807381000748.tif46170

[0905] N-(4-((4-(4,4-dimethylpiperidin-1-yl)-2-(trifluoromethyl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (420) TIFF0007807381000749.tif4773

[0906] The title compound 420 (9.2 mg) was prepared 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) according to the procedure in 397 as a pale yellow solid in 18.8% overall yield. TIFF0007807381000750.tif38170

[0907] N-(4-((2,5-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (421) TIFF0007807381000751.tif4192

[0908] The title compound 421 (17.0 mg) was prepared 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), Pd2(dba)3 (3.3 mg, 3.3 umol), X-Phos (7.9 mg, 16.5 umol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure in 394 as a pale yellow powder in an overall yield of 10.4%. TIFF0007807381000752.tif57170

[0909] N-(4-((2-chloro-5-fluoro-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (422) TIFF0007807381000753.tif5078

[0910] The title compound 422 (10.1 mg) was prepared 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 in 397 as a pale yellow solid in 24.5% overall yield. TIFF0007807381000754.tif46170

[0911] N-(4-((4-(4-methylcyclohexyl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (423) TIFF0007807381000755.tif4773

[0912] The title compound 423 (4.1 mg) was prepared from 4-(aminomethyl)-N-(4-(4-methyldicyclohexyl)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) according to the procedure for 413 as a white solid in 10.0% overall yield. TIFF0007807381000756.tif46170

[0913] N 1 -(4-((4-cyclohexylphenyl)amino)benzyl)succinamide (424) TIFF0007807381000757.tif3486

[0914] The title compound 424 (17.1 mg) was prepared 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 in 413 as a white powder in an overall yield of 45.1%. TIFF0007807381000758.tif39170

[0915] (R)-N-(4-((4-cyclohexylphenyl)amino)benzyl)-2-oxoimidazolidine-4-carboxamide (425) TIFF0007807381000759.tif4568

[0916] The title compound 425 (9.9 mg) was prepared 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 in 413 as a white solid in 15.3% overall yield. TIFF0007807381000760.tif46170

[0917] N-(4-((3,5-bis(diethylamino)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (426) TIFF0007807381000761.tif4969

[0918] The title compound 426 (15.7 mg) was prepared according to the procedure of 397. 1 -(4-(aminomethyl)phenyl)-N 3 ,N 3 ,N 5 ,N 5Prepared from 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) as a green solid in 20.0% overall yield. Mass (m / z): 452.3 [M+H] + .

[0919] N-(4-((3-chloro-2-methyl-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (427) TIFF0007807381000762.tif162170

[0920] Step 1. Preparation of N-(4-bromo-3-chloro-2-methylphenyl)pivalamide (427-2). 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) was added pivaloyl chloride (2.88 g, 24 mmol) dropwise at 0 °C. The mixture was then stirred at room temperature overnight. The solution was washed with HO (3 × 50 mL) and brine (50 mL). The organic layer was dried (NaSO) 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] + .

[0921] Step 2. Preparation of N-(3-chloro-2-methyl-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)pivalamide (427-3). The title compound 427-3 (545 mg) was prepared from N-(4-bromo-3-chloro-2-methylphenyl)pivalamide (1.52 g, 5 mmol), 4-(trifluoromethyl)piperidine (765 mg, 5.0 mmol), Pd(dba) (91.5 mg, 0.05 mmol), X-Phos (119 mg, 0.25 mmol), and CsCO (2.45 g, 7.5 mmol) according to the procedure for 394-3 in an overall yield of 29.0% as a yellow solid.

[0922] Step 3. Preparation of 3-chloro-2-methyl-4-(4-(trifluoromethyl)piperidin-1-yl)aniline (427-4). In a pressure tube, a solution of N-(3-chloro-2-methyl-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)pivalamide (545 mg, 1.45 mmol) in 10 mL of concentrated HCl was stirred at 100 °C overnight. The solution was then concentrated. 10 mL of water was added. The pH of the filtrate was adjusted to 8-9 with sodium carbonate solution. The mixture was then extracted with DCM (10 mL x 3). The combined organic layers were washed with water (15 mL), dried over Na2SO4, and concentrated. The residue was purified by perp-TLC (EA / PE=1 / 2) to give the desired product as a yellow solid (87.6 mg, 20.7%). Mass (m / z): 293.3 [M+H] + .

[0923] Step 3. Preparation of N-(4-((3-chloro-2-methyl-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (427). The title compound 427 (19.3 mg) was prepared 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(dba) (2.3 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and CsCO (122 mg, 0.38 mmol) according to the procedure in 404 as a white solid in 15.2% overall yield. TIFF0007807381000763.tif47170

[0924] N-(4-((4-chloro-3-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (428) TIFF0007807381000764.tif4981

[0925] The title compound 428 (4.6 mg) was prepared 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 in 397 as a white solid in 10.3% overall yield. TIFF0007807381000765.tif57170

[0926] N-(4-((2-fluoro-5-methyl-4-(4-methylpiperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (429) TIFF0007807381000766.tif5276

[0927] The title compound 429 (19.3 mg) was prepared from N-(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(dba) (3.5 mg, 3.8 umol), X-Phos (9.7 mg, 19 umol), and CsCO (186 mg, 0.57 mmol) according to the procedure in 404 as a white solid in 15.2% overall yield. TIFF0007807381000767.tif55170

[0928] N-(4-((6-(4-isopropylpiperidin-1-yl)-2-methylpyridin-3-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (430) TIFF0007807381000768.tif4677

[0929] The title compound 430 (19.3 mg) was prepared from N-(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), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.9 mg, 16.5 umol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure in 404 as a white solid in 15.2% overall yield. TIFF0007807381000769.tif56170

[0930] N-(4-((6-(4-butylpiperidin-1-yl)-2-methylpyridin-3-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (431) TIFF0007807381000770.tif5087

[0931] The title compound 431 (22.9 mg) was prepared from N-(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(dba) (3.0 mg, 3.3 umol), X-Phos (7.9 mg, 16.5 umol), and CsCO (163 mg, 0.50 mmol) according to the procedure in 404 as a white solid in 14.9% overall yield. TIFF0007807381000771.tif65170

[0932] 4-Amino-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)butanamide (432) JPEG0007807381000772.jpg65170

[0933] 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 from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)aniline (116 mg, 0.3 mmol), 4-((tert-butoxycarbonyl)amino)butanoic acid (73 mg, 0.0.36 mmol), DIEA (116 mg, 0.3 mmol), and HATU (137 mg, 0.36 mmol) according to the procedure in 397 as a blue solid in 68.8% overall yield. Mass (m / z): 535.4 [M+H] + .

[0934] 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 from HCl (10.0 mL), tert-butyl (4-oxo-4-((4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)amino)butyl)carbamate (110 mg, 0.20 mmol) in 1,4-dioxane according to the procedure in 363-4 as a gray solid in 52.0% overall yield. TIFF0007807381000773.tif49170

[0935] 5-Oxo-N-(2-(trifluoromethyl)-4-((2-(4-(trifluoromethyl)piperidin-1-yl)pyrimidin-5-yl)amino)benzyl)pyrrolidine-3-carboxamide (433) TIFF0007807381000774.tif4780

[0936] The title compound 433 (6.2 mg) was prepared from N-(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) according to the procedure in 397 as a white solid in 16.7% overall yield. TIFF0007807381000775.tif54170

[0937] (S)-N-(4-((4-(4,4-dimethylcyclohexyl)phenyl)amino)benzyl)-2,6-dioxohexahydropyrimidine-4-carboxamide (434) TIFF0007807381000776.tif5278

[0938] The title compound 434 (6.1 mg) was prepared 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 in 413 as a white solid in 13.6% overall yield. TIFF0007807381000777.tif47170

[0939] N-(4-((4-(4,4-dimethylcyclohexyl)phenyl)amino)benzyl)-2,6-dioxopiperidine-4-carboxamide (435) TIFF0007807381000778.tif5477

[0940] The title compound 435 (19.6 mg) was prepared 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 in 413 as a pale yellow solid in 54.7% overall yield. TIFF0007807381000779.tif46170

[0941] (R)-N-(4-((4-(4,4-dimethylcyclohexyl)phenyl)amino)benzyl)-2-oxoimidazolidine-4-carboxamide (436) TIFF0007807381000780.tif4573

[0942] The title compound 436 (12.6 mg) was prepared 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) according to the procedure in 413 as a pale yellow solid in 37.5% overall yield. TIFF0007807381000781.tif47170

[0943] 4-Guanidino-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)butanamide (437) TIFF0007807381000782.tif30166

[0944] 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-carboximidamide (10.1 mg, 9.3 ummol). The mixture was then stirred at 60° C. for 16 hours. After cooling to room temperature, the solid was collected by filtration and washed with 5 mL of MeCN to give the desired product as a white solid (16.5 mg, 45.1%). TIFF0007807381000783.tif57170

[0945] N-(4-((2-fluoro-6-methyl-4-(4-methylpiperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (438) TIFF0007807381000784.tif5072

[0946] The title compound 438 (5.9 mg) was prepared 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), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.9 mg, 16.5 umol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure in 427 as a white solid in 4.0% overall yield. TIFF0007807381000785.tif56170

[0947] 4-(Methylamino)-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)butanamide (439) TIFF0007807381000786.tif4095

[0948] The title compound 439 (4.0 mg) was prepared from HCl (3.0 mL), 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) in 1,4-dioxane according to the procedure in 363-4 as a gray solid in 31.5% overall yield. TIFF0007807381000787.tif39170

[0949] 5-Oxo-N-(4-((4-(pentan-3-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (440) TIFF0007807381000788.tif194170

[0950] Step 1. 1-Nitro-4-(pentan-3-yl)benzene (440-2). To a stirred solution of pentan-3-ylbenzene (444 mg, 3.0 mol) in acetic anhydride (2.0 mL) and CHCl (5.0 mL) at −5° C., concentrated HNO (0.3 mL) was added slowly. The reaction was kept at 0° C. for 1 h and then at room temperature for 18 h. Water (10 mL) was added. The reaction was extracted with EtOAc (3×10 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by prep-TLC (DCM / PE=1 / 10) to give the title compound (482 mg, 83.2%).

[0951] Step 2. Preparation of 4-(pentan-3-yl)aniline (440-3). The title compound 440-3 (390 mg) was prepared 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 in 386-4 as a purple solid in 72.5% overall yield. Mass (m / z): 164.2 [M+H] + .

[0952] Step 3. Preparation of 5-oxo-N-(4-((4-(pentan-3-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (440). The title compound 440 (29.5 mg) was prepared from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (99 mg, 0.33 mmol), 4-(pentan-3-yl)aniline (70 mg, 0.43 mmol), Pd(dba) (3.0 mg, 3.3 umol), X-Phos (7.9 mg, 16.5 umol), and CsCO (163 mg, 0.50 mmol) according to the procedure in 427 in an overall yield of 23.4% as a pale yellow solid. TIFF0007807381000789.tif46170

[0953] N-(4-((4-cyclopentylphenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (441) TIFF0007807381000790.tif4870

[0954] The title compound 441 (20.5 mg) was prepared 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 in 413 as a white solid in 27.2% overall yield. TIFF0007807381000791.tif46170

[0955] N-(4-((4-(4,4-dimethylcyclohexyl)phenyl)amino)phenethyl)-5-oxopyrrolidine-3-carboxamide (442) TIFF0007807381000792.tif100170

[0956] Step 1. Preparation of N-(4-bromophenethyl)-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 of water was added. The mixture was then extracted with DCM (5 mL x 3). The precipitate was collected by filtration to give the desired product as a white solid (1.14 g, 91.9%). Mass (m / z): 311.1 [M+H] + .

[0957] Step 2. Preparation of N-(4-((4-(4,4-dimethylcyclohexyl)phenyl)amino)phenethyl)-5-oxopyrrolidine-3-carboxamide (442). The title compound 442 (14.0 mg) was prepared from N-(4-bromophenethyl)-5-oxopyrrolidine-3-carboxamide (78 mg, 0.25 mmol), 4-(4,4-dimethylcyclohexyl)aniline (61 mg, 0.3 mmol), Pd(dba) (2.3 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and CsCO (122 mg, 0.40 mmol) according to the procedure in 427 as a white solid in 12.9% overall yield. TIFF0007807381000793.tif47170

[0958] N-(4-((2-fluoro-6-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)amino)benzyl)-2-oxoimidazolidine-4-carboxamide (443) TIFF0007807381000794.tif5077

[0959] The title compound 443 (4.8 mg) was prepared from N-(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) according to the procedure in 397 as an off-white solid in an overall yield of 8.3%. TIFF0007807381000795.tif64170

[0960] N-(4-((2-(4-isopropylpiperidin-1-yl)pyrimidin-5-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (444) TIFF0007807381000796.tif4978

[0961] The title compound 444 (40.0 mg) was prepared from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (74 mg, 0.25 mmol), 2-(4-isopropylpiperidin-1-yl)pyrimidin-5-amine (73 mg, 0.33 mmol), Pd2(dba)3 (2.3 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and Cs2CO3 (122 mg, 0.38 mmol) according to the procedure in 427 as a white solid in 36.7% overall yield. TIFF0007807381000797.tif55170

[0962] N-(4-((2-(4-ethylpiperidin-1-yl)pyrimidin-5-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (445) TIFF0007807381000798.tif4677

[0963] The title compound 445 (23.2 mg) was prepared 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), Pd2(dba)3 (2.3 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and Cs2CO3 (122 mg, 0.38 mmol) according to the procedure in 427 as a pale yellow solid in 22.0% overall yield. TIFF0007807381000799.tif55170

[0964] N-(4-((4-methyl-2-(4-(trifluoromethyl)piperidin-1-yl)pyrimidin-5-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (446) TIFF0007807381000800.tif4880

[0965] The title compound 446 (4.1 mg) was prepared 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 in 413 as a white powder in 15.1% overall yield. TIFF0007807381000801.tif55170

[0966] N-(3-(4-((4-(4,4-dimethylcyclohexyl)phenyl)amino)phenyl)propyl)-5-oxopyrrolidine-3-carboxamide (447) TIFF0007807381000802.tif5380

[0967] The title compound 447 (6.8 mg) was prepared 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(dba) (1.8 mg, 2 umol), X-Phos (4.8 mg, 10 umol), and CsCO (99 mg, 0.3 mmol) according to the procedure for 442 as a white solid in 16.3% overall yield. TIFF0007807381000803.tif45170

[0968] N-(4-((3-(4-methoxybutoxy)-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (448) TIFF0007807381000804.tif189170

[0969] Step 1. Preparation of 2-(tert-butyl)-5-nitrophenol (448-2). To a mixture of 2-tert-butyl-5-nitroaniline (582 g, 3.0 mmol) in 10 mL of 15% H2SO4 was added dropwise a solution of NaNO2 (217 mg, 3.15 mmol) in water (3 mL) at 0 °C. The resulting mixture was stirred at 0-5 °C for 20 min. The solution was then added dropwise to a solution of 5 mL of H2SO4-H2O (V / V = 1 / 2) stirred at 100 °C. The resulting mixture was stirred at 100 °C for 20 min. After cooling to room temperature, it was extracted with DCM (20 mL x 3). The combined organic layers were washed with water (20 mL), then dried over Na2SO4, and concentrated. The residue was purified by prep-TLC (DCM / PE=1 / 3) to give the title compound as a yellow oil (300 mg, 51.5%). Mass (m / z): 194.0 [MH] + .

[0970] Step 2. Preparation of 1-(tert-butyl)-2-(4-methoxybutoxy)-4-nitrobenzene (448-3). To a mixture of 2-(tert-butyl)-5-nitrophenol (150 mg, 0.77 mmol), KI (12.8 mg, 77 ummol), and K2CO3 (212 mg, 1.54 mmol) in DMSO (2.0 mL) was added 1-bromo-4-methoxybutane (190 mg, 1.15 mmol). The mixture was then stirred at 80 °C overnight. After cooling to room temperature, 5 mL of DCM was added and extracted with DCM (10 mL x 3). The combined organic layers were washed with water (10 mL x 3), dried over Na2SO4, and concentrated to give the crude title compound as a yellow oil. (216 mg, 100%)

[0971] Step 3. Preparation of 4-(tert-butyl)-3-(4-methoxybutoxy)aniline (448-4). 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 for 386-4. Mass (m / z): 252.4 [M+H] + .

[0972] Step 4. Preparation of N-(4-((3-(4-methoxybutoxy)-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (448). The title compound 448 (9.2 mg) was prepared from N-(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(dba) (1.8 mg, 2 umol), X-Phos (4.8 mg, 10 umol), and CsCO (99 mg, 0.3 mmol) according to the procedure for 442 as a white solid in an overall yield of 8.2%. TIFF0007807381000805.tif45170

[0973] N-(4-((2-(4-isopropylpiperidin-1-yl)-4-methylpyrimidin-5-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (449) TIFF0007807381000806.tif154170

[0974] Step 1. Preparation of 5-bromo-2-(4-isopropylpiperidin-1-yl)-4-methylpyrimidine (449-3). 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 °C for 18 h. After cooling to room temperature, 20 mL of water was added. The precipitate was collected by filtration to give the desired product as a white solid (414 mg, 69.5%). Mass (m / z): 298.1 [M+H] + .

[0975] Step 2. Preparation of N-(4-(aminomethyl)phenyl)-2-(4-isopropylpiperidin-1-yl)-4-methylpyrimidin-5-amine (449-5). The title compound 449-5 (16.3 mg) was prepared from 5-bromo-2-(4-isopropylpiperidin-1-yl)-4-methylpyrimidine (100 mg, 0.33 mmol), tert-butyl(4-aminobenzyl)carbamate (111 mg, 0.50 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.9 mg, 16.5 umol), and t-BuOK (56 mg, 0.50 mmol) according to the procedure in 427 in a total yield of 14.4% as a yellow solid. Mass (m / z): 340.3 [M+H] + .

[0976] Step 3. Preparation of N-(4-((2-(4-isopropylpiperidin-1-yl)-4-methylpyrimidin-5-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (449). The title compound 449 (3.4 mg) was prepared from N-(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) according to the procedure in 413 as a gray solid in 15.2% overall yield. TIFF0007807381000807.tif55170

[0977] 5-Oxo-N-(4-((5-(4-(trifluoromethyl)piperidin-1-yl)pyrimidin-2-yl)amino)benzyl)pyrrolidine-3-carboxamide (450) TIFF0007807381000808.tif4780

[0978] The title compound 450 (10.2 mg) was prepared from N-(4-(aminomethyl)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) according to the procedure in 413 as a white powder in an overall yield of 12.3%. TIFF0007807381000809.tif55170

[0979] N-(4-((2-ethyl-6-(4-methylpiperidin-1-yl)pyridin-3-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (451) TIFF0007807381000810.tif140170

[0980] Step 1. Preparation of 6-chloro-2-ethylpyridin-3-amine (451-2). To a solution of 2,6-dichloropyridin-3-amine (1.63 g, 10 mmol) in 1,4-dioxane (25 ml), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol) and triethylaluminum (2.2 mL, 2M in hexane, 10.4 mmol) were added at room temperature, and the mixture was stirred at 100 °C for 3 h. After cooling, the mixture was quenched with 2M aqueous HCl and then separated into aqueous and organic phases. The aqueous phase was extracted with EtOAc. The combined organic phase was dried over magnesium sulfate and concentrated. The crude product was purified by silica gel column chromatography eluting with hexane / EtOAc (2:1) to give the title compound (25 mg, 16.0%). 157.3 [M+H] + .

[0981] Step 2. Preparation of N-(6-chloro-2-ethylpyridin-3-yl)pivalamide (451-3). 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) was added pivaloyl chloride (289 mg, 2.39 mmol) dropwise at 0 °C. The mixture was then stirred at room temperature overnight. The solution was washed with HO (3 × 20 mL) and brine (20 mL). The organic layer was dried (NaSO) 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] + .

[0982] Step 3. Preparation of N-(2-ethyl-6-(4-methylpiperidin-1-yl)pyridin-3-yl)pivalamide (451-4). The title compound 451-4 (330 mg) was prepared from N-(6-chloro-2-ethylpyridin-3-yl)pivalamide (300 mg, 1.25 mmol), 4-methylpiperidine (186 mg, 1.9 mmol), Pd(dba) (11.4 mg, 12.5 umol), X-Phos (29.8 mg, 62.5 mmol), and CsCO (611 mg, 1.08 mmol) according to the procedure in 394-3 in an overall yield of 87.3% as a yellow solid.

[0983] Step 4. Preparation of 2-ethyl-6-(4-methylpiperidin-1-yl)pyridin-3-amine (451-5). In a pressure tube, a solution of N-(2-ethyl-6-(4-methylpiperidin-1-yl)pyridin-3-yl)pivalamide (330 mg, 1.09 mmol) in 10 mL of concentrated HCl was stirred at 100 °C overnight. The solution was then concentrated. 10 mL of water was added. The pH of the filtrate was adjusted to 8-9 with sodium carbonate solution. The mixture was then extracted with DCM (10 mL x 3). The combined organic layers were washed with water (15 mL), dried over Na2SO4, and concentrated. The residue was purified by perp-TLC (EA / PE=1 / 2) to give the desired product as a yellow solid (230 mg, 98.2%). Mass (m / z): 220.3 [M+H] + .

[0984] Step 5. Preparation of N-(4-((2-ethyl-6-(4-methylpiperidin-1-yl)pyridin-3-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (451). The title compound 451 (15.5 mg) was prepared 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(dba) (3.0 mg, 3.3 umol), X-Phos (7.9 mg, 16.5 umol), and CsCO (163 mg, 0.50 mmol) according to the procedure in 404 as a white solid in 10.7% overall yield. TIFF0007807381000811.tif56170

[0985] 5-Oxo-N-(4-((2-propoxypyrimidin-5-yl)amino)benzyl)pyrrolidine-3-carboxamide (452) TIFF0007807381000812.tif163170

[0986] Step 1. Preparation of 5-nitro-2-propoxypyrimidine (452-2). To a solution of 2-chloro-5-nitropyrimidine (474 ​​mg, 3 mmol) in 1-propanoic acid (10 mL) was added sodium propanolate (492 mg, 6 mmol). The mixture was then stirred at 80 °C for 2 h. After cooling to room temperature, 15 mL of water was added. The mixture was then extracted with DCM (15 mL x 3). The combined organic layers were washed with water (20 mL x 3), dried over Na2SO4, and concentrated in vacuo. The residue was purified by prep-TLC (EA / PE=1 / 10) to give the desired product as a yellow solid (80 mg, 14.6%). Mass (m / z): 184.1 [M+H] +

[0987] Step 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 in 386-4. Mass (m / z): 154.1 [M+H] + .

[0988] Step 3. Preparation of 5-oxo-N-(4-((2-propoxypyrimidin-5-yl)amino)benzyl)pyrrolidine-3-carboxamide (452). The title compound 452 (23.3 mg) was prepared from N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (107 mg, 0.36 mmol), 2-propoxypyrimidin-5-amine (60 mg, 0.4 mmol), Pd(dba) (3.3 mg, 3.6 umol), X-Phos (8.6 mg, 18 umol), and CsCO (176 mg, 0.54 mmol) according to the procedure for 442 in an overall yield of 17.5% as a white solid. TIFF0007807381000813.tif46170

[0989] 5-Oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)phenethyl)pyrrolidine-3-carboxamide (453) TIFF0007807381000814.tif4390

[0990] The title compound 453 (17.5 mg) was prepared from N-(4-bromophenethyl)-5-oxopyrrolidine-3-carboxamide (62 mg, 0.2 mmol), 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (63 mg, 0.26 mmol), Pd(dba) (1.8 mg, 2.0 umol), X-Phos (4.8 mg, 10 umol), and CsCO (98 mg, 0.3 mmol) according to the procedure for 442 as a white solid in 18.5% overall yield. TIFF0007807381000815.tif55170

[0991] 5-Oxo-N-(3-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)phenyl)propyl)pyrrolidine-3-carboxamide (454) TIFF0007807381000816.tif5379

[0992] The title compound 454 (8.8 mg) was prepared from N-(3-(4-bromophenyl)propyl)-5-oxopyrrolidine-3-carboxamide (50 mg, 0.15 mmol), 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (41.1 mg, 0.17 mmol), Pd(dba) (1.8 mg, 2.0 umol), X-Phos (4.8 mg, 10 umol), and CsCO (83 mg, 0.26 mmol) according to the procedure for 442 in an overall yield of 10.6% as a white solid. TIFF0007807381000817.tif46170

[0993] N-(3-(4-((2-(4-isopropylpiperidin-1-yl)pyrimidin-5-yl)amino)phenyl)propyl)-5-oxopyrrolidine-3-carboxamide (455) TIFF0007807381000818.tif5383

[0994] The title compound 455 (7.8 mg) was prepared 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(dba) (1.8 mg, 2.0 umol), X-Phos (4.8 mg, 10 umol), and CsCO (83 mg, 0.26 mmol) according to the procedure for 442 in an overall yield of 9.9% as a white solid. TIFF0007807381000819.tif46170

[0995] N-(4-((6-(4-(2-methoxypropan-2-yl)piperidin-1-yl)-2-methylpyridin-3-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (456) TIFF0007807381000820.tif4591

[0996] The title compound 456 (22.0 mg) was prepared 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(dba) (2.3 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and CsCO (122 mg, 0.38 mmol) according to the procedure in 427 as a pale yellow solid in 18.3% overall yield. TIFF0007807381000821.tif64170

[0997] N-(4-((3-fluoro-2-methyl-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-2-oxoimidazolidine-4-carboxamide (457) TIFF0007807381000822.tif3890

[0998] The title compound 457 (31.0 mg) was prepared 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 in 413 as a pale blue solid in 31.4% overall yield. TIFF0007807381000823.tif55170

[0999] 1-Ethyl-5-oxo-N-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (458) TIFF0007807381000824.tif49167

[1000] Step 1. Preparation of 1-ethyl-5-oxo-N-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (458). To a solution of 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (39 mg, 0.25 mmol) and DMT-MM (69 mg, 0.25 mmol) in ultra-dry N,N-dimethylformamide (5 mL) was added 4-(aminomethyl)-N-(4-(piperidin-1-yl)phenyl)aniline (70 mmL, 0.25 mmol) and N-ethyl-N-isopropylpropan-2-amine (75 mg, 0.75 mmol). 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, and the filter cake was washed three times with water and dried in vacuo. The residue was purified by perp-TLC to give the desired product 458 (36.2 mg) as a light blue powder in 34.60% yield. TIFF0007807381000825.tif46170

[1001] 1-Ethyl-5-oxo-N-(4-((4-(pyrrolidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (459) TIFF0007807381000826.tif5068

[1002] The title compound 459 (30.0 mg) was prepared from 4-(aminomethyl)-N-(4-(pyrrolidin-1-yl)phenyl)aniline (70 mg, 0.26 mmol) and 1-ethyl-5-oxopyrrolidine-3-carboxylic acid (41 mg, 0.26 mmol) according to the procedure of 458 as a pale blue powder in 28.19% yield. TIFF0007807381000827.tif38170

[1003] N-(4-((4-(4-methylpiperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (460) TIFF0007807381000828.tif5569

[1004] The title compound 460 (25.7 mg) was prepared 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 as a pale gray powder in 19.66% yield. TIFF0007807381000829.tif35170

[1005] 1-Ethyl-N-(4-((4-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (461) TIFF0007807381000830.tif49166

[1006] A solution of 1-(4-aminophenyl)-4-(trifluoromethyl)piperidin-4-ol (50 mg, 0.15 mmol, 1.0 equivs) and N-(4-bromobenzyl)-1-ethyl-5-oxopyrrolidine-3-carboxamide (40 mg, 0.15 mmol, 1.0 equivs) in ultra-dry 1,4-dioxane (5 mL) was added with dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane (7.12 mg, 0.012 mmol, 0.08 equivs), tris(dibenzylideneacetone)palladium(O) (4.5 mg, 0.006 mmol, 0.04 equivs), and cesium carbonate (75 mg, 0.23 mmol, 1.5 equivs). Equiv) were added to each under an argon atmosphere. The resulting mixture was heated to 110 °C and stirred at the same temperature overnight. The reaction was diluted with water (20 mL) and extracted three times with ethyl acetate (5 mL). The organic layers were combined and washed with water, saturated NaHCO3(aq), and brine, respectively. It was then dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by perp-TLC to give the desired product 461 (9.5 mg) as a pale floral white powder in 12.25% yield. TIFF0007807381000831.tif47170

[1007] N-(4-((2-(4-isopropylpiperidin-1-yl)pyrimidin-5-yl)amino)-2-methylbenzyl)-5-oxopyrrolidine-3-carboxamide (462) TIFF0007807381000832.tif148170

[1008] 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 BocO (982 mg, 4.50 mmol) and TEA (607 mg, 6.00 mmol) at 25 °C. The mixture was then stirred at room temperature overnight. The mixture was poured into H2O and extracted with DCM (50 mL*3). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography with EA / PE (20:1) to give tert-butyl (4-bromo-2-methylbenzyl)carbamate 462-2 (745 mg, 83% yield) as a yellow oil. MS (ESI) m / z 322.0, 324.1 [M+H] + .

[1009] Step 2. Preparation of tert-butyl (4-((2-(4-isopropylpiperidin-1-yl)pyrimidin-5-yl)amino)-2-methylbenzyl)carbamate. Under nitrogen, to 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) was added Cs2CO3 (488 mg, 1.50 mmol) and tris(dibenzylideneacetone)dipalladium (92 mg, 0.10 mmol). The reaction mixture was stirred at 90 °C for 16 h. The mixture was then filtered and concentrated. The residue was purified by pre-TLC to give 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] + .

[1010] 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 showed 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] + .

[1011] 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, N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium (222 mg, 0.58 mmol) and DIEA (94 mg, 0.73 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. The mixture was poured into H2O (10 mL) and extracted with EA (20 mL*3), the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated, and the residue was purified by prep-HPLC to give 462 (10 mg) as a white solid. TIFF0007807381000833.tif46170

[1012] 2-Ethyl-5-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (463) TIFF0007807381000834.tif4779

[1013] The title compound 463 (6.5 mg) was prepared 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) according to the procedure of 458 as a light gray powder in 4.65% yield. TIFF0007807381000835.tif45170

[1014] 1-Ethyl-N-(4-((2-methyl-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (464) TIFF0007807381000836.tif5080

[1015] The title compound 464 (31.1 mg) was prepared 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 for 461 as a white powder in an overall yield of 31.97%. TIFF0007807381000837.tif54170

[1016] 1-Ethyl-N-(4-((2-methoxy-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (465) TIFF0007807381000838.tif4981

[1017] The title compound 465 (29.5 mg) was prepared 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) according to the procedure for 461 as a white powder in 31.2% yield. TIFF0007807381000839.tif54170

[1018] 1-Ethyl-2-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (466) TIFF0007807381000840.tif5079

[1019] The title compound 466 (12.3 mg) was prepared 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) according to the procedure in 458 as a white powder in 17.6% yield. TIFF0007807381000841.tif53170

[1020] N-(4-((2-cyano-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-1-ethyl-5-oxopyrrolidine-3-carboxamide (467) TIFF0007807381000842.tif5181

[1021] The title compound 467 (60.2 mg) was prepared 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) according to the procedure for 461 as a white powder in 63.13% yield. TIFF0007807381000843.tif66170

[1022] 4-Methyl-3-oxo-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)piperazine-1-carboxamide (468) TIFF0007807381000844.tif5184

[1023] The title compound 468 (9.0 mg) was prepared 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 for 458 as a pale pink powder in 7.09% yield. TIFF0007807381000845.tif44170

[1024] N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-2-ureidoacetamide (469) TIFF0007807381000846.tif3799

[1025] The title compound 469 (2.3 mg) was prepared from 4-(aminomethyl)-N-(4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)aniline (50 mg, 0.14 mmol) and carbamoylglycine (18 mg, 0.15 mmol) according to the procedure in 458 as a light gray powder in 3.58% yield. TIFF0007807381000847.tif55170

[1026] 1-Ethyl-N-(4-((2-fluoro-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (470) TIFF0007807381000848.tif5282

[1027] The title compound 470 (45.4 mg) was prepared 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 in 461 as a light gray powder in 46.60% yield. TIFF0007807381000849.tif64170

[1028] N-(4-((3,5-difluoro-4-(piperidin-1-yl)phenyl)amino)benzyl)-3,5-dioxopiperazine-1-carboxamide (471) TIFF0007807381000850.tif41154

[1029] Preparation of N-(4-((3,5-difluoro-4-(piperidin-1-yl)phenyl)amino)benzyl)-3,5-dioxopiperazine-1-carboxamide (471). 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. Then, piperazine-2,6-dione (19 mg, 0.17 mmol) was added to the mixture, and the mixture was stirred at room temperature overnight. The solvent was then removed in vacuo, and the residue was diluted with EA (20 mL), washed with water (10 mL × 3), dried over NaSO, filtered, and evaporated. The residue was purified by prep-HPLC to give 471 (6.3 mg, 11.96%). TIFF0007807381000851.tif28170

[1030] N-(4-((4-(azepan-1-yl)phenyl)amino)benzyl)-1-ethyl-5-oxopyrrolidine-3-carboxamide (472) JPEG0007807381000852.jpg5170

[1031] The title compound 472 (86.3 mg) was prepared 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 in 461 as a light olive solid in 75.58% yield. TIFF0007807381000853.tif29170

[1032] N-(4-((4-(tert-butyl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (473) TIFF0007807381000854.tif4764

[1033] The title compound 473 (15.5 mg) was prepared 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 for 461 as a dim gray powder in 12.60% yield. TIFF0007807381000855.tif45170

[1034] 5-Oxo-N-(4-((4-(2,2,2-trifluoroethyl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (474) TIFF0007807381000856.tif4871

[1035] The title compound 474 (34.5 mg) was prepared 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 in 461 as a pale yellow powder in 26.19% yield. TIFF0007807381000857.tif46170

[1036] N-(4-((4-(azocan-1-yl)phenyl)amino)benzyl)-1-ethyl-5-oxopyrrolidine-3-carboxamide (475) TIFF0007807381000858.tif5072

[1037] The title compound 475 (143.7 mg) was prepared from 4-(azocan-1-yl)aniline (100 mg, 0.49 mmol) and N-(4-bromobenzyl)-1-ethyl-5-oxopyrrolidine-3-carboxamide (191 mg, 0.59 mmol) according to the procedure in 461 as a gray solid in 65.45% yield. TIFF0007807381000859.tif39170

[1038] (R)-N-(4-((4-(azepan-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (476) TIFF0007807381000860.tif39152

[1039] The title compound 476 (23.7 mg) was prepared 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 in 461 as a gray powder in 16.59% yield. TIFF0007807381000861.tif37170

[1040] N-(4-((4-(azocan-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (477) TIFF0007807381000862.tif4772

[1041] The title compound 477 (28.3 mg) was prepared from 4-(azocan-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 in 461 as a gray powder in 20.00% yield. TIFF0007807381000863.tif38170

[1042] (R)-5-Oxo-N-(4-((4-(piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (478) TIFF0007807381000864.tif4770

[1043] The title compound 478 (27.5 mg) was prepared 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) according to the procedure in 461 as a dim gray powder in 20.82% yield. TIFF0007807381000865.tif38170

[1044] (R)-N-(4-((4-(4,4-dimethylpiperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (479) TIFF0007807381000866.tif4373

[1045] The title compound 479 (16.8 mg) was prepared 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 in 461 as a gray powder in 11.87% yield. TIFF0007807381000867.tif36170

[1046] N-(4-((3-methyl-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (480) TIFF0007807381000868.tif4678

[1047] The title compound 480 (30.2 mg) was prepared 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 for 461 as a white powder in 16.44% yield. TIFF0007807381000869.tif49170

[1048] 1-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (481) TIFF0007807381000870.tif4191

[1049] The title compound 481 (3.8 mg) was prepared 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 for 461 as a white powder in 5.74% yield. TIFF0007807381000871.tif37170

[1050] N-(4-((4-(2-fluoroethyl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (482) TIFF0007807381000872.tif4570

[1051] The title compound 482 (8.4 mg) was prepared 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 for 461 as a white powder in 3.29% yield. TIFF0007807381000873.tif45170

[1052] 5-Oxo-N-(2-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)phenyl)propan-2-yl)pyrrolidine-3-carboxamide (483) TIFF0007807381000874.tif4880

[1053] The title compound 483 (9.7 mg) was prepared 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 in 461 as a pale blue powder in 9.7% yield. TIFF0007807381000875.tif29170

[1054] N-(4-((2-fluoro-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (484) TIFF0007807381000876.tif4679

[1055] The title compound 484 (6.4 mg) was prepared 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 in 461 as a gray powder in 7.95% yield. TIFF0007807381000877.tif55170

[1056] N-(4-((2-methyl-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (485) TIFF0007807381000878.tif4879

[1057] The title compound 485 (4.5 mg) was prepared 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 for 461 as a gray powder in 5.64% yield. TIFF0007807381000879.tif48170

[1058] N-(4-((2-chloro-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (486) TIFF0007807381000880.tif5080

[1059] The title compound 486 (9.5 mg) was prepared 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 in 461 as a gray powder in 5.70% yield. TIFF0007807381000881.tif62170

[1060] N-(2,6-difluoro-4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (487) TIFF0007807381000882.tif4977

[1061] The title compound 487 (9.3 mg) was prepared 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) according to the procedure of 458 as a pale blue powder in 7.22% yield. TIFF0007807381000883.tif46170

[1062] N-(4-((4-(4-methylpiperidin-1-yl)phenyl)amino)-2-(trifluoromethyl)benzyl)-5-oxopyrrolidine-3-carboxamide (488) TIFF0007807381000884.tif4573

[1063] The title compound 488 (52.0 mg) was prepared 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) according to the procedure for 458 as an off-white powder in 79.65% yield. TIFF0007807381000885.tif64170

[1064] N1-(4-((3,5-difluoro-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)oxalamide (489) TIFF0007807381000886.tif79170

[1065] Step 1. Preparation of ethyl 2-((4-((3,5-difluoro-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)amino)-2-oxoacetate (489-3): A mixture of N-(4-(aminomethyl)phenyl)-3,5-difluoro-4-(4-(trifluoromethyl)piperidin-1-yl)aniline (0.2 g, 0.52 mmol) and EtN (0.16 g, 1.56 mmol) in DCM (10 mL) was stirred at 0 °C for 0.5 h. Ethyl 2-chloro-2-oxoacetate was dissolved in DCM (5 mL) and then added dropwise to the stirred mixture at 25 °C, 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 as a colorless oil (0.2 g, 78.8%). Mass(m / z): 486.1 [M+H] + .

[1066] Step 2. Preparation of N1-(4-((3,5-difluoro-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)oxalamide (489): A solution of 2-((4-((3,5-difluoro-4-(4-(trifluoromethyl)piperidin-1-yl) phenyl)amino)benzyl)amino)-2-oxoacetate (0.2 g, 0.41 mmol) and NH4OH (0.5 mL, 13 mmol) in THF (10 mL) was stirred at 25 °C for 2 h. The mixture was diluted with EA (100 mL) and washed with water (100 mL × 2). The organic phase was removed under vacuum, and the residue was purified by perp-HPLC (column-Xbridge-C18 150 × 21.2 mm, 5 μm; mobile phase: ACN-HO (0.1% FA), 40%-60%) to give 489 as a white solid. TIFF0007807381000887.tif46170

[1067] 5-Oxo-N-(4-((3-pentylphenyl)amino)benzyl)pyrrolidine-3-carboxamide (490) TIFF0007807381000888.tif4960

[1068] The title compound 490 (9.5 mg) was prepared from 3-pentylaniline (55 mg, 0.34 mmol) and N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (100 mg, 0.34 mmol) according to the procedure in 461 as a white powder in 16.83% yield. TIFF0007807381000889.tif55170

[1069] N-(2-fluoro-3-methyl-4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (491) TIFF0007807381000890.tif4980

[1070] The title compound 491 (49.6 mg) was prepared 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) according to the procedure for 458 as a rosy-brown powder in 37.95% yield. TIFF0007807381000891.tif47170

[1071] N-(2-fluoro-5-methyl-4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (492) TIFF0007807381000892.tif5079

[1072] The title compound 492 (23.5 mg) was prepared 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) according to the procedure for 458 as a dim gray powder in 18.20% yield. TIFF0007807381000893.tif56170

[1073] N-(3-methyl-4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (493) TIFF0007807381000894.tif4979

[1074] The title compound 493 (28.8 mg) was prepared from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (134 mg, 0.55 mmol) and N-(4-bromo-3-methylbenzyl)-5-oxopyrrolidine-3-carboxamide (180 mg, 0.58 mmol) according to the procedure in 461 as a gray powder in 11.02% yield. TIFF0007807381000895.tif46170

[1075] (S)-N-(4-((4-cyclohexylphenyl)amino)benzyl)-2,6-dioxohexahydropyrimidine-4-carboxamide (494) TIFF0007807381000896.tif5274

[1076] The title compound 494 (31.1 mg) was prepared 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) according to the procedure for 458 as an off-white powder in 69.13% yield. TIFF0007807381000897.tif55170

[1077] N-(2,5-dimethyl-4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (495) TIFF0007807381000898.tif4982

[1078] The title compound 495 (37.2 mg) was prepared from 4-(aminomethyl)-2,5-dimethyl-N-(4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)aniline (66 mg, 0.17 mmol) and 5-oxopyrrolidine-3-carboxylic acid (34 mg, 0.26 mmol) according to the procedure of 458 as a light gray powder in 43.55% yield. TIFF0007807381000899.tif57170

[1079] 4-Oxo-4-((4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)amino)butanoic acid (496) TIFF0007807381000900.tif3994

[1080] 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) was added dihydrofuran-2,5-dione (26 mg, 0.26 mmol) and triethylamine (26 mg, 0.26 mmol). 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, and the filter cake was washed three times with water and dried in vacuo. The residue was purified by perp-TLC to give the desired product 496 (36.2 mg) as a light gray powder in 31.25% yield. TIFF0007807381000901.tif49170

[1081] N-(2,3-dimethyl-4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (497) TIFF0007807381000902.tif4783

[1082] The title compound 497 (11.2 mg) was prepared 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) according to the procedure for 458 as an off-white powder in 43.55% yield. TIFF0007807381000903.tif57170

[1083] N-(4-((4-(4-ethylpiperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (498) TIFF0007807381000904.tif4677

[1084] The title compound 498 (41.4 mg) was prepared 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 in 461 as a white powder in 20.11% yield. TIFF0007807381000905.tif56170

[1085] Methyl 4-oxo-4-((4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)amino)butanoate (499) TIFF0007807381000906.tif3894

[1086] The title compound 499 (45.3 mg) was prepared 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 for 458 as an off-white powder in 37.71% yield. TIFF0007807381000907.tif47170

[1087] N-(4-((3-methoxy-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (500) TIFF0007807381000908.tif4580

[1088] The title compound 500 (53.2 mg) was prepared 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) according to the procedure in 461 as a light gray powder in 66.86% yield. TIFF0007807381000909.tif55170

[1089] N-Hydroxy-N-(4-((4-(4-methylpiperidin-1-yl)phenyl)amino)benzyl)-2,6-dioxopiperidine-4-carboxamide (501) TIFF0007807381000910.tif44160

[1090] The title compound 501 (29.8 mg) was prepared 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) according to the procedure in 458 as a light blue powder in 20.60% yield. TIFF0007807381000911.tif46170

[1091] N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (502) TIFF0007807381000912.tif89170

[1092] Step 1. Preparation of tert-butyl 3-((4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)carbamoyl)pyrrolidine-1-carboxylate. The intermediate tert-butyl 3-((4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)carbamoyl)pyrrolidine-1-carboxylate (151 mg) was prepared 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 in 458 as a light gray powder in 47.94% yield.

[1093] Step 2. Preparation of N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (502). 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). The resulting solution was stirred at room temperature overnight. The reaction mixture was added to water (15 mL). Extraction was performed three times with ethyl acetate (5 mL). The organic layers were combined and washed with water, saturated NaHCO3(aq), and brine, respectively. It was then dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by perp-TLC to give the desired product 502 (35.2 mg) as a pale white powder in 40.09% yield. TIFF0007807381000913.tif54170

[1094] 1-Methyl-N-(4-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)pyrrolidine-3-carboxamide (503) TIFF0007807381000914.tif4978

[1095] The title compound 503 (22.4 mg) was prepared 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) according to the procedure in 458 as a white powder in 18.77% yield. TIFF0007807381000915.tif55170

[1096] N-(4-((2-methyl-6-(4-methylpiperidin-1-yl)pyridin-3-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (504) TIFF0007807381000916.tif4675

[1097] The title compound 504 (40.3 mg) was prepared 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) according to the procedure in 461 as a pale yellow powder in 39.25% yield. TIFF0007807381000917.tif57170

[1098] N-(4-((6-(4-ethylpiperidin-1-yl)-2-methylpyridin-3-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (505) TIFF0007807381000918.tif4578

[1099] The title compound 505 (41.0 mg) was prepared 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) according to the procedure in 461 as a pale yellow powder in 41.29% yield. TIFF0007807381000919.tif64170

[1100] N-(4-((6-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)-2-methylpyridin-3-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (506) TIFF0007807381000920.tif4871

[1101] The title compound 506 (9.0 mg) was prepared from 6-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)-2-methylpyridin-3-amine (51 mg, 0.25 mmol) and N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (75 mg, 0.25 mmol) according to the procedure in 461 as a pale yellow powder in 8.78% yield. TIFF0007807381000921.tif55170

[1102] N-(4-((6-(3,3-dimethylazetidin-1-yl)-2-methylpyridin-3-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (507) TIFF0007807381000922.tif4871

[1103] The title compound 507 (15.0 mg) was prepared from 6-(3,3-dimethylazetidin-1-yl)-2-methylpyridin-3-amine (48 mg, 0.25 mmol) and N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (75 mg, 0.25 mmol) according to the procedure in 461 as a pale yellow powder in 14.58% yield. TIFF0007807381000923.tif47170

[1104] N-(4-((6-(4-isopropylpiperidin-1-yl)pyridin-3-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (508) TIFF0007807381000924.tif4979

[1105] The title compound 508 (50.3 mg) was prepared 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) according to the procedure in 461 as a pale yellow powder in 68.63% yield. TIFF0007807381000925.tif56170

[1106] N-(4-((6-(4-ethylpiperidin-1-yl)pyridin-3-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (509) TIFF0007807381000926.tif4680

[1107] The 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) according to the procedure in 461 as a pale yellow powder in 25.24% yield. TIFF0007807381000927.tif56170

[1108] N-(4-((2-methyl-6-(4-propylpiperidin-1-yl)pyridin-3-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (510) TIFF0007807381000928.tif4784

[1109] The title compound 510 (28.5 mg) was prepared 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 in 461 as a white powder in 29.59% yield. TIFF0007807381000929.tif64170

[1110] 5-Oxo-N-(4-((2-(3-propylazetidin-1-yl)pyrimidin-5-yl)amino)benzyl)pyrrolidine-3-carboxamide (511) TIFF0007807381000930.tif4779

[1111] The title compound 511 (14.7 mg) was prepared 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 in 461 as a yellow powder in 11.53% yield. TIFF0007807381000931.tif46170

[1112] N-(4-((2-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)pyrimidin-5-yl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (512) TIFF0007807381000932.tif4778

[1113] The title compound 512 (34.8 mg) was prepared from 2-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)pyrimidin-5-amine (50 mg, 0.26 mmol) and N-(4-bromobenzyl)-5-oxopyrrolidine-3-carboxamide (78 mg, 0.26 mmol) according to the procedure in 461 as a yellow powder in 32.57% yield. TIFF0007807381000933.tif55170

[1114] N-(4-((6-(4-isopropylpiperidin-1-yl)-2-methylpyridin-3-yl)amino)phenethyl)-5-oxopyrrolidine-3-carboxamide (513) TIFF0007807381000934.tif5091

[1115] The title compound 513 (18.5 mg) was prepared from 6-(4-isopropylpiperidin-1-yl)-2-methylpyridin-3-amine (40 mg, 0.17 mmol) and N-(4-bromophenethyl)-5-oxopyrrolidine-3-carboxamide (50 mg, 0.17 mmol) according to the procedure in 461 as a yellow powder in 22.65% yield. TIFF0007807381000935.tif56170

[1116] N-(3-(4-((6-(4-isopropylpiperidin-1-yl)-2-methylpyridin-3-yl)amino)phenyl)propyl)-5-oxopyrrolidine-3-carboxamide (514) TIFF0007807381000936.tif5474

[1117] The title compound 514 (16 mg) was prepared 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 in 461 as a yellow powder in 19.54% yield. TIFF0007807381000937.tif74170

[1118] 1-(4-((6-(4-isopropylpiperidin-1-yl)-2-methylpyridin-3-yl)amino)benzyl)urea (515) TIFF0007807381000938.tif41163

[1119] 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 phenylcarbamate (24 mg, 0.18 mmol). The resulting solution was stirred at room temperature overnight. The reaction mixture was added to water (15 mL) and extracted three times with ethyl acetate (5 mL). The organic layers were combined and washed with water, saturated NaHCO3(aq), and brine, respectively. It was then dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by perp-TLC to give the desired product 515 (9.4 mg) as a pale white powder in 27.80% yield. TIFF0007807381000939.tif54170

[1120] N1-(4-((6-(4-isopropylpiperidin-1-yl)-2-methylpyridin-3-yl)amino)benzyl)oxalamide (516) TIFF0007807381000940.tif4389

[1121] The title compound 516 (7.1 mg) was prepared from N-(4-(aminomethyl)phenyl)-6-(4-isopropylpiperidin-1-yl)-2-methylpyridin-3-amine (30 mg, 0.09 mmol) and 2-amino-2-oxoacetic acid (50 mg, 0.15 mmol) according to the procedure in 458 as a yellow powder in 19.56% yield. TIFF0007807381000941.tif56170

[1122] (S)-N-(4-((6-(4-isopropylpiperidin-1-yl)-2-methylpyridin-3-yl)amino)benzyl)-2,6-dioxohexahydropyrimidine-4-carboxamide (517) TIFF0007807381000942.tif5083

[1123] The title compound 517 (6.5 mg) was prepared 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 in 458 as a yellow powder in 15.32% yield. TIFF0007807381000943.tif65170

[1124] N-(4-((6-(4-isopropylpiperidin-1-yl)-2-methylpyridin-3-yl)amino)benzyl)-2-oxopyrrolidine-3-carboxamide (518) TIFF0007807381000944.tif4290

[1125] The title compound 518 (11.5 mg) was prepared 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 in 458 as a yellow powder in 28.86% yield. TIFF0007807381000945.tif57170

[1126] (R)-N-(4-((6-(4-isopropylpiperidin-1-yl)-2-methylpyridin-3-yl)amino)benzyl)pyrrolidine-2-carboxamide (519) TIFF0007807381000946.tif4085

[1127] The title compound 519 (6.8 mg) was prepared 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 in 458 as a yellow powder in 17.61% yield. TIFF0007807381000947.tif56170

[1128] (S)-N-(4-((6-(4-isopropylpiperidin-1-yl)-2-methylpyridin-3-yl)amino)benzyl)-6-oxopiperidine-2-carboxamide (520) TIFF0007807381000948.tif4580

[1129] The title compound 520 (12.4 mg) was prepared 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 in 458 as a yellow powder in 30.18% yield. TIFF0007807381000949.tif72170

[1130] N-(4-((3,5-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzyl)-5-oxopyrrolidine-3-carboxamide (521) JPEG0007807381000950.jpg97170

[1131] Step 1. Preparation of 1-(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 K2CO3 (5.11 g, 15.67 mmol). The resulting solution was stirred overnight at 165 °C using a microwave. The reaction mixture was added dropwise to water (150 mL) with stirring. The precipitate was filtered, and the filter cake was washed three times with water and dried in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / AcOEt, 10 / 1) to give 1.3 g 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] +

[1132] Step 2. Preparation of 3,5-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) was added a suspension of palladium on carbon (130 mg, 0.1 equiv.) under an argon atmosphere. Hydrogen was bubbled through the mixture using a balloon for 10 minutes. The resulting mixture was stirred overnight at the same temperature under a hydrogen atmosphere. Argon was bubbled through the completed reaction mixture using a balloon, after which Celite was added, and the Celite was filtered 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 obtain 920 mg of 3,5-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)aniline as a brown oil in a yield of 78...

Claims

1. A compound of formula I, or a salt, hydrate or stereoisomer thereof. 【Chemistry 1】 (In the formula, R1 is OH, NH ２ or NR'R'', where R' and R'' are independently substituted or unsubstituted C1-C9 alkyl or substituted or unsubstituted aryl, and optionally linked to form a substituted or unsubstituted C4-C9 heterocycle; R2 to R9 are independently H, halogen, C1 to C6 alkoxy, amino, C1 to C6 alkylamino, di(C1 to C6 alkyl)amino, or substituted or unsubstituted C1 to C6 alkyl; R10 is H, halogen, C1-C6 alkoxy, amino, C1-C6 alkylamino, di(C1-C6 alkyl)amino, or unsubstituted C1-C6 alkyl; R11 is H or OH; R12 is C1-C6 alkoxy, amino, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C1-C6 alkanoyl, carbamoyl, carboxyl, —C(O)—NR″ (wherein R″ is H or CH 3 ), substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C9 cycloalkyl, or substituted or unsubstituted C3-C9 heterocycloalkyl; and, X1 to X5 and Y1 to Y5 are independently C or N.

2. R1 is NR'R'' where R' and R'' are linked to form a substituted or unsubstituted piperidin-1-yl; R2-R9 are independently H, halogen, or substituted or unsubstituted C1-C4 alkyl; R10 is H, halogen, or unsubstituted C1-C4 alkyl; R11 is H or OH; R12 is 1-ethyl-pyrrolidin-2-one-4-yl; or The X1 to X5 and Y1 to Y5 are as follows: 0, 1, 2 or 3 of X1 to X4 and 0, 1, 2 or 3 of Y1 to Y4 are N; 0, 1 or 2 of X1 to X4 and 0, 1 or 2 of Y1 to Y4 are N; Only one of Y2 and X4, or Y2 and Y4, or X2 and Y2, or X2 and Y4, or X4 and X2, or X4 and Y4 is N; or Only X2, X3, X4, Y2 or Y4 is defined as N; The compound of claim 1.

3. The compound of claim 1, wherein R1 is NR'R'', wherein R' and R'' are linked to form a substituted or unsubstituted piperidin-1-yl.

4. R1 is NR'R'', where R' and R'' are linked to form piperidin-1-yl, 4-methylpiperidin-1-yl, or 4-CF ３ The compound of claim 1, which forms piperidin-1-yl.

5. 4. The compound of claim 3, wherein R2 to R9 are independently H, halogen, or substituted or unsubstituted lower alkyl; and R10 is H, halogen, or unsubstituted C1 to C4 alkyl.

6. 6. The compound of claim 5, wherein R2 to R9 are independently H, halogen, C1-C4 alkyl, or F-substituted C1-C4 alkyl; and R10 is H, halogen, or unsubstituted C1-C4 alkyl.

7. The compound of claim 3, wherein R2 to R10 are H.

8. The compound of any one of claims 3 to 7, wherein R11 is H.

9. The compound according to any one of claims 3 to 7, wherein R12 is a substituted or unsubstituted C3 to C9 cycloalkyl or a substituted or unsubstituted C3 to C9 heterocycloalkyl.

10. The compound of any one of claims 3 to 7, wherein R12 is pyrrolidin-2-one-4-yl, 1-methyl-pyrrolidin-2-one-4-yl or 1-ethyl-pyrrolidin-2-one-4-yl.

11. The compound according to any one of claims 3 to 7, wherein 0, 1, 2 or 3 of X1 to X4 and 0, 1, 2 or 3 of Y1 to Y4 are N.

12. The compound according to any one of claims 3 to 7, wherein 0, 1 or 2 of X1 to X4 and 0, 1 or 2 of Y1 to Y4 are N.

13. The compound according to any one of claims 3 to 7, wherein zero of X1 to X4 and zero of Y1 to Y4 are N.

14. The compound according to any one of claims 3 to 7, wherein only one of Y2 and X4, or Y2 and Y4, or X2 and Y2, or X2 and Y4, or X4 and X2, or X4 and Y4 is N.

15. The compound of any one of claims 3 to 7, wherein only X2, X3, X4, Y2 or Y4 is N.

16. A compound having a structure selected from: Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14

17. 17. The compound of claim 16, having a structure selected from: Table 2

18. A compound having a structure selected from: Table 3-1 Table 3-2 Table 3-3 Table 3-4 Table 3-5 Table 3-6 Table 3-7 Table 3-8 Table 3-9 Table 3-10 Table 3-11 Table 3-12 Table 3-13 Table 3-14 Table 3-15 Table 3-16 Table 3-17 Table 3-18

19. 19. The compound of claim 18, having a structure selected from: Table 4

20. 19. The compound of claim 18, having a structure selected from: Table 5

21. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1, 2 and 16-20 and one or more pharmaceutically acceptable excipients, in a predetermined unit dosage form.

22. 26. Use of a compound according to claims 1, 2 and 21-26 or a composition comprising a compound according to claims 1, 2 and 16-20 in the manufacture of a medicament for inhibiting ferroptosis activity or for regulating or inhibiting a disease associated with ferroptosis dysregulation in a person in need thereof.

23. The use according to claim 22, wherein the disease associated with ferroptosis dysregulation is selected from neurological disorders, ischemia-reperfusion injury, acute renal failure and cancer.

24. 27. A composition comprising a compound according to claims 1, 2 and 16-20 or a compound according to claims 1, 2 and 21-26 for inhibiting ferroptosis activity, or for regulating or inhibiting a disease associated with ferroptosis dysregulation, in a person in need thereof, or in the manufacture of a medicament thereof in a person in need thereof.

25. 25. The compound or composition according to claim 24, wherein the disease associated with ferroptosis dysregulation is selected from neurological disorders, ischemia-reperfusion injury, acute renal failure and cancer.

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