HK1227394B - Novel compounds as histone deacetylase 6 inhibitors and pharmaceutical compositions comprising the same - Google Patents

Description

Novel compounds as histone deacetylase 6 inhibitors and pharmaceutical compositions containing the same

Technical Field

The present invention relates to novel compounds having histone deacetylase 6 (HDAC6) inhibitory activity, their isomers, their pharmaceutically acceptable salts, their use in preparing therapeutic drugs, pharmaceutical compositions containing them, methods for treating diseases using the compositions, and methods for preparing the novel compounds.

Background Art

Post-translational modifications such as acetylation are very critical regulatory modules at the core of biological processes in cells and are tightly regulated by a large number of enzymes. Histones are the main protein components of chromatin and serve as the spools around which DNA chains are woven. Moreover, the balance between histone acetylation and deacetylation is a key player in regulating gene expression.

Histone deacetylase (HDAC) is an enzyme that removes acetyl groups from the lysine residues on the histone of chromatin, and is known to be relevant to gene silencing and induces cell cycle arrest, angiogenesis inhibition, immunomodulation, cell death etc. (Hassig etc., Curr.Opin.Chem.Biol.1997,1,300-308).In addition, it is reported that the inhibition of the enzymatic function of HDAC induces the apoptosis of cancer cells in vivo by reducing the activity of cancer cell survival-related factors and activating cancer cell apoptosis-related factors (Warrell etc., J.Natl.Cancer Inst.1998,90,1621-1625).

In humans, 18 HDACs have been identified and subdivided into four classes based on their homology to yeast HDACs. Among them, 11 HDACs utilize zinc as a cofactor and can be divided into three groups: Class I (HDACs 2, 3, and 8), Class II (IIa: HDACs 4, 5, 7, and 9; IIb: HDACs 6 and 10), Class IV (HDACs 11). Additionally, 7 HDACs of Class III (SIRT1-7) require NAD ⁺ instead of zinc as an additional cofactor (Bolden et al., Nat. Rev. Drug Discov. 2006, 5 (9), 769-784).

Multiple HDAC inhibitors are in preclinical or clinical development, but to date, only non-selective HDAC inhibitors have been identified as anticancer agents, and only vorinostat (SAHA) and romidepsin (FK228) have been approved for the treatment of cutaneous T-cell lymphoma. However, known non-selective HDAC inhibitors cause side effects such as fatigue and nausea, usually in high doses (Piekarz et al., Pharmaceuticals 2010, 3, 2751-2767). Such side effects have been reported to be due to the inhibition of category I HDAC. Due to such side effects, the use of non-selective HDAC inhibitors in the medicine different from anticancer drugs is restricted (Witt et al., Cancer Letters, 2009, 277, 8-21).

Meanwhile, it is reported that the selective inhibition of class II HDAC will not show the toxicity shown in the inhibition of class I HDAC. Moreover, when developing selective HDAC inhibitors, side effects such as toxicity (which is caused by non-selective HDAC inhibition) can be overcome. Therefore, selective HDAC inhibitors have the potential to be developed as a therapeutic agent effectively for treating various diseases (Matthias et al., Mol.Cell.Biol.2008,28,1688-1701).

It is known that HDAC6 (a member of class IIb HDAC) is mainly present in the cytoplasm and is involved in a large number of non-histone substrates (HSP90, cortical proteins, etc.), including the deacetylation of tubulin (Yao et al., Mol. Cell 2005, 18, 601-607). HDAC6 has two catalytic domains, and the zinc finger domain at the C-terminus can bind to ubiquitinated proteins. It is known that HDAC6 has a large number of non-histone proteins as substrates and therefore plays an important role in a variety of diseases, including cancer, inflammatory diseases, autoimmune diseases, neurological diseases and neurodegenerative disorders (Santo et al., Blood 2012119: 2579-258; Vishwakarma et al., International Immunopharmacology 2013, 16, 72-78; Hu et al., J. Neurol. Sci. 2011, 304, 1-8).

Therefore, there is a need to develop selective HDAC 6 inhibitors for the treatment of cancer, inflammatory diseases, autoimmune diseases, neurological diseases and neurodegenerative disorders that do not cause side effects, unlike non-selective inhibitors.

Summary of the Invention

Technical issues

One object of the present invention is to provide novel compounds, isomers thereof or pharmaceutically acceptable salts thereof having selective HDAC6 inhibitory activity.

Another object of the present invention is to provide a pharmaceutical composition comprising a novel compound having selective HDAC6 inhibitory activity, an isomer thereof, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for preparing the novel compound.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating diseases related to HDAC6 activity, including cancer, inflammatory diseases, autoimmune diseases, neurological diseases and neurodegenerative disorders, wherein the pharmaceutical composition contains the above-mentioned compound.

Another object of the present invention is to provide use of the compound for preparing therapeutic drugs for diseases related to HDAC6 activity.

Another object of the present invention is to provide a method for treating diseases related to HDAC6 activity, comprising administering a therapeutically effective amount of a pharmaceutical composition containing the compound.

Technical Solution

The present inventors have discovered novel dimethylpiperazine derivative compounds, particularly dimethylpiperazine hydroxamic acid derivative compounds, which have histone deacetylase 6 (HDAC6) inhibitory activity, and have found that these compounds can be used to inhibit or treat diseases related to histone deacetylase 6 (HDAC6) activity, thereby completing the present invention.

Novel HDAC6 inhibitors

In order to achieve the above object, the present invention provides a compound represented by the following formula I, an isomer thereof or a pharmaceutically acceptable salt thereof:

Formula I

in

*R ₁ is hydrogen or -CH ₃ ,

*R ₂ is hydrogen or -CH ₃ , provided that when R ₁ is hydrogen R ₂ is -CH ₃ , and when R ₁ is -CH ₃ R ₂ is hydrogen,

*L is -(C ₄ -C ₅ alkyl)-; -(C ₁ -C ₃ alkyl)-L ₁ -; -C(═O)-L ₁ - or -S(═O) ₂ -L ₁ -,

wherein -(C ₄ -C ₅ alkyl)- and -(C ₁ -C ₃ alkyl)- may be unsubstituted or substituted with -CH ₃ ,

L ₁ is -(C ₃ -C ₆ )cycloalkyl-; or

_A1 and _A2 are each independently -N- or _-CR3- , provided that _A1 and _A2 cannot both be -N-,

_R3 is hydrogen; -F, -Cl, -Br, -I or -OH, and

_A3 is -NH- or -O-,

*Q is selected from the group consisting of: -(C ₁ -C ₆ )alkyl-; -(C ₂ -C ₆ )alkenyl-; -C(═O)-; -C(═S)-; -S(═O) ₂ - or

wherein -(C ₁ -C ₆ )alkyl- and -(C ₂ -C ₆ )alkenyl- may be unsubstituted or each independently substituted by 1 to 3 -CH ₃ groups or halogen atoms,

_Q1 is hydrogen; -F, -Cl, -Br or I,

*n is an integer of 0, 1 or 2, provided that n is 0 when Q is, n is 1 when Q is -C(=O)-, -C(=S)- or -S(=O) ₂ -, and n is 1 or 2 when Q is -(C ₁ -C ₆ )alkyl- or -(C ₂ -C ₆ )alkenyl-, and

*X may be selected from the group consisting of: -C ₁ -C ₆ alkyl; -C ₃ -C ₆ cycloalkyl; -C ₂ -C ₆ alkenyl; -C ₃ -C ₆ cycloalkenyl; -(C ₀ -C ₂ alkyl)Ar; -OAr; -(C ₀ -C ₂ alkyl)Het; naphthyl and the following groups:

wherein R ₄ is H or -C ₁ -C ₄ alkyl,

-C ₀ -C ₂ alkyl, -C ₂ -C ₆ alkenyl and -C ₁ -C ₆ alkyl may be unsubstituted or substituted with 1 to 2 -CH ₃ groups; 1 to 3 -F groups, or a combination thereof,

Ar is a C ₆ monocyclic aromatic compound which may be unsubstituted or substituted by one or more of the following groups: a halogen atom; -OH; -NH ₂ ; -C ₁ -C ₆ alkyl; -O(C ₁ -C ₆ )alkyl; -C _{3 -C 6} cycloalkenyl; -NH(C ₁ -C ₆ alkyl); -N(C ₁ -C ₃ alkyl) ₂ ; -CH ₂ N(C ₁ -C ₃ alkyl) ₂ ; -S(═O) ₂ -(C ₁ -C ₃ alkyl) or a phenyl group, wherein -C ₁ -C ₃ alkyl; -C ₁ -C ₆ alkyl and -C ₃ -C ₆ cycloalkenyl may each independently be substituted by 1 to 5 -F or -CH ₃ groups, and

Het is a 4- to 6-membered heteroaromatic or non-aromatic ring compound which contains 1 to 3 elements selected from the group consisting of N, O and S while having 0 to 3 double bonds, and may be unsubstituted or substituted by one or more of the following groups: a halogen atom; -C ₁ -C ₆ alkyl; -C(=O)(C ₁ -C ₃ alkyl); -S(=O) ₂ (C ₁ -C ₃ alkyl) or a benzyl group, wherein -C ₁ -C ₃ alkyl and -C ₁ -C ₆ alkyl may each independently be substituted by: -OH; 1 to 5 -F or -CH ₃ groups.

As used herein, " _C0 alkyl" means no carbon and thus represents a bond. For example, "-( _C0 alkyl)Ar" means -Ar.

The compound represented by Formula I according to the present invention may be a compound represented by the following Formula II or Formula III:

Formula II

Formula III

in

*L is -(C ₅ alkyl)-; -(C ₁ -C ₂ alkyl)-L ₁ -; -C(═O)-L ₁ - or -S(═O) ₂ -L ₁ -,

wherein -(C ₅ alkyl)- and -(C ₁ -C ₂ alkyl)- are linear and may be unsubstituted or substituted with -CH ₃ ,

L ₁ is -(C ₃ -C ₆ )cycloalkyl-;

_A1 and _A2 are each independently -N- or _-CR3- , provided that _A1 and _A2 cannot both be -N-,

_R3 is hydrogen; -F or -OH, and

_A3 is -NH- or -O-,

*Q is selected from the group consisting of: -(C1-C3)alkyl-; -C(=O)-; -C(=S)-; -S(=O) ₂ - or

wherein -(C ₁ -C ₃ )alkyl- may be unsubstituted or substituted by 1 to 3 -CH ₃ groups or halogen atoms,

_Q1 is hydrogen; -F or -Cl,

*n is an integer of 0 or 1, provided that n is 0 when Q is, and n is 1 when Q is -C(=O)-, -C(=S)-, -S(=O) ₂ -, or -(C ₁ -C ₃ )alkyl-, and

*X may be selected from the group consisting of: -C ₁ -C ₆ alkyl; -C ₃ -C ₆ cycloalkyl; -C ₂ -C ₆ alkenyl; -C ₃ -C ₆ cycloalkenyl; -(C ₀ -C ₂ alkyl)Ar; -OAr; -(C ₀ -C ₂ alkyl)Het; naphthyl; and the following groups:

wherein R ₄ is H or -C ₁ -C ₄ alkyl,

-C ₀ -C ₂ alkyl; -C ₂ -C ₆ alkenyl and -C ₁ -C ₆ alkyl may be unsubstituted or substituted by 1 or 2 -CH ₃ groups or 1 to 3 F groups,

Ar is a C ₆ monocyclic aromatic compound which may be unsubstituted or substituted by one or more of the following groups: a halogen atom; -OH; -NH ₂ ; -C ₁ -C ₆ alkyl; -O(C ₁ -C ₆ )alkyl; -C _{3 -C 6} cycloalkenyl; -NH(C ₁ -C ₆ alkyl); -N(C ₁ -C ₃ alkyl) ₂ ; -CH ₂ N(C ₁ -C ₃ alkyl) ₂ ; -S(═O) ₂ -(C ₁ -C ₃ alkyl) or a phenyl group, wherein -C ₁ -C ₃ alkyl; -C ₁ -C ₆ alkyl and -C ₃ -C ₆ cycloalkenyl may each independently be substituted by 1 to 5 -F or -CH ₃ groups, and

Het is a 4- to 6-membered heteroaromatic or non-aromatic ring compound which contains 1 to 3 elements selected from the group consisting of N, O and S while having 0 to 3 double bonds, and may be unsubstituted or substituted by one or more of the following groups: a halogen atom; -C ₁ -C ₆ alkyl; -C(=O)(C ₁ -C ₃ alkyl); -S(=O) ₂ (C ₁ -C ₃ alkyl) or a benzyl group, wherein -C ₁ -C ₃ alkyl and -C ₁ -C ₆ alkyl may each independently be substituted by -OH; or 1 to 5 -F or -CH ₃ groups.

In a preferred embodiment of the present invention, L, Q and X in Formulas I, II and III can be defined as follows:

*L is -CH ₂ -L ₁ -,

in

_L1 is

_A1 and _A2 are each independently -N- or _-CR3- , provided that _A1 and _A2 cannot both be -N-,

_R3 is hydrogen; -F or -OH, and

_A3 is -NH- or -O-,

*Q is _-CH2- , -C(=O)-, or -S(=O) _2- , and

*X may be selected from the group consisting of: -C ₁ -C ₆ alkyl; -(C ₀ -C ₂ alkyl)Ar; -(C ₀ -C ₂ alkyl)Het; -OAr; or the following groups:

wherein R ₄ is H or -C ₁ -C ₄ alkyl,

-C ₀ -C ₂ alkyl and -C ₁ -C ₆ alkyl may be unsubstituted or substituted by 1 or 2 -CH ₃ groups and/or 1 to 3 -F groups, and

Ar and Het are each independently as defined in Formula I to Formula III.

In one embodiment of the present invention, the heterocyclic compound (Het) mentioned as X or substituent in the above formula I to formula III may have a structure selected from the following groups:

in

R ₅ is each independently hydrogen; -F; -Cl; -C ₁ -C ₆ alkyl; -C(=O)(C ₁ -C ₃ alkyl); -S(=O) ₂ (C ₁ -C ₃ alkyl) or benzyl, wherein -C ₁ -C ₃ alkyl and -C ₁ -C ₆ alkyl may each independently be substituted by: -OH; 1 to 5 -F or -CH ₃ groups,

m is an integer of 0, 1, 2 or 3, and

When m is 0, Het is unsubstituted, and when m is 1, 2, or 3, Het may be substituted by independently R ₅ .

The compound represented by Formula I according to the present invention may be a compound represented by Formula I-1:

Formula I-1

in

A is -C(=O)-; -CH ₂ -; -NH(C=O)-; -C(=S)- or -S(=O) ₂ -, and

R ₁ is a straight chain or branched C ₁ -C ₄ alkyl group; a straight chain or branched C ₁ -C ₄ alkenyl group; a C ₃ -C ₅ cycloalkyl group; -OC ₆ C ₅ ; -(C ₀ -C ₂ alkyl)CF ₃ ; a phenyl group (which may be unsubstituted or substituted by the following groups: C ₁ -C ₃ alkyl group; pyrrole; -OCH ₃ ; -CF ₃ ; -F; -Cl or -OH); a pyridyl group; a furyl group; a thienyl group; a benzyl group (which may be unsubstituted or substituted by one or more of the following groups: C ₁ -C ₃ alkyl group; pyrrole; -OCH ₃ ; -CF ₃ ; -F; -Cl or -OH group); a phenethyl group; a naphthyl group; an oxazolyl group; a pyrimidinyl group; a pyrazolyl group or a pyrazinyl group.

The compound represented by formula I-1 is preferably compound 82, 83, 84, 98, 99, 100, 120, 121, 122, 123, 125, 126, 127, 128, 145, 146, 147, 148, 149, 159, 160, 161, 177, 184, 188, 204, 211, 212, 213, 214, 222, 223, 224, 225, 232, 255, 265, 266, 267, 270, 272, 275, 290, 291, 292, 293, 294, 295, 296, 297, 354, 355, 403, 404 and 405 as disclosed herein.

The compound represented by Formula I may be a compound represented by Formula I-2:

Formula I-2

wherein R ₂ , R ₃ or R ₄ may each independently be hydrogen or any one of the following groups:

The compound represented by formula 1-2 is preferably compound 309, 327, 328, 329, 330, 331, 332, 342, 343, 344, 345, 346 and 347 as disclosed herein.

The compound represented by Formula I according to the present invention may be a compound represented by Formula I-3:

Formula I-3

wherein R ₅ may be selected from the group consisting of: a linear or branched C ₁ -C ₄ alkyl group; —COCH ₃ ; —CH ₂ CF ₃ and —SO ₂ CH ₃ .

The compound represented by formula 1-3 is preferably compound 481, 482, 483, 484 and 485 as disclosed herein.

The compound represented by Formula I according to the present invention may be a compound represented by Formula I-4:

Formula I-4

wherein n is an integer of 0, 1 or 2, and R ₆ , R ₇ or R ₈ may each independently be hydrogen or any one selected from the group consisting of:

The compound represented by formula 1-4 is preferably compound 234, 242, 243, 244, 245, 246, 247, 283, 284, 285, 286, 288, 326 and 340 as disclosed herein.

The compound represented by formula I according to the present invention may be a compound represented by formula I-5:

Formula I-5

wherein R ₉ may be selected from the following: morpholine; piperidine; pyrrolidine; azetidine; piperazine; -C ₁ -C ₂ primary or secondary alkylamine; or wherein pyrrolidine may be unsubstituted or substituted with one or more -F or -Cl groups, azetidine may be unsubstituted or substituted with one or more -F or -Cl groups, and piperazine may be unsubstituted or substituted with one or more of the following groups: linear or branched C ₁ -C ₅ alkyl; benzyl; -COCH ₃ ; -CH ₂ CF ₃ or -SO ₂ CH ₃ groups.

The compound represented by formula 1-5 is preferably compound 356, 376, 382, 383, 384, 385, 411, 412, 413, 426, 427, 428, 429, 430, 431, 452, 453, 454, 455, 456, 457, 466, 467, 468 and 486 as disclosed herein.

The compound represented by Formula I according to the present invention may be a compound represented by Formula I-6 _A or Formula I-6 _B :

Formula I-6 _A

Formula I-6 _B

wherein R ₁₀ may be selected from the following: pyrrolidine; piperidine; C ₁ -C ₂ primary or secondary alkylamine; piperazine; morpholine; or wherein pyrrolidine may be unsubstituted or substituted with one or more -F or -Cl groups, and piperazine may be unsubstituted or substituted with one or more of the following groups: linear or branched C ₁ -C ₅ alkyl; -COCH ₃ ; -CH ₂ CF ₃ or -SO ₂ CH ₃ groups.

The compound represented by formula I-6 _A is preferably compound 423, 424, 425, 432, 433, 434, 435, 439, 440, 441, 442, 443, 444, 458, 459, 460, 461, 462, and 463 as disclosed herein. In addition, the compound represented by formula I-6 _B is preferably compound 446 as disclosed herein.

The compound represented by Formula I according to the present invention may be a compound represented by Formula I-7:

Formula I-7

Wherein X may be selected from -OH; -F; -Cl or -Br.

The compound represented by formula 1-7 is preferably compound 386 and 387 as disclosed herein.

The compound represented by Formula I according to the present invention may be a compound represented by Formula I-8:

Formula I-8

Wherein B can be selected from the following:

wherein w is hydrogen or may be substituted by: -F; -Cl or -OH.

The compound represented by formula 1-8 is preferably compounds 154, 171, 172, 173, 194, 218, 219, 520, 571, 574, 652, 812, 813, 814, 818, 820, 822, 823 and 824 as disclosed herein.

The compound represented by Formula I according to the present invention may be a compound represented by Formula I-9:

Formula I-9

wherein A is -C(=O)-; -CH ₂ -; -NH(C=O)-; -C(=S)- or -S(=O) ₂ -, and R ₁₁ may be selected from the following: furyl; benzyl; pyrrole-substituted phenyl or pyrrole-substituted anilino.

The compound represented by formula 1-9 is preferably compound 321, 322 and 323 as disclosed herein.

The compound represented by Formula I according to the present invention may be a compound represented by Formula I-10:

Formula I-10

A preferred compound represented by formula 1-10 is compound 472 as disclosed herein.

The compound represented by Formula I according to the present invention may be a compound represented by Formula I-11:

Formula I-11

A preferred compound represented by formula 1-11 is compound 402 as disclosed herein.

The compound represented by Formula I according to the present invention may be a compound represented by Formula I-12:

Formula I-12

The compound represented by formula 1-12 is preferably compounds 380 and 388 as disclosed herein.

The compound represented by Formula I according to the present invention may be a compound represented by Formula I-13:

Formula I-13

wherein A is -C(=O)-; -CH ₂ -; -CH(CH ₃ )-; -NH(C=O)-; -NCH ₃ (C=O)-; -C(=S)- or -S(=O) ₂ -, and R ₁₂ may be selected from the following: linear or branched C ₁ -C ₄ alkyl; phenyl (which may be unsubstituted or substituted with one or more of the following groups: linear or branched C ₁ -C ₃ alkyl; -F; -Cl; CF ₃ ; -OCH ₃ ; -C ₁ -C ₂ primary or secondary alkylamine; -SO ₂ CH ₃ ; thienyl; pyrrole; pyrazole; furyl; triazolyl or imidazolyl); pyridyl; thienyl; furyl; benzyl (which may be unsubstituted or substituted with -F, -Cl or -OCH ₃ ); indole (which may be unsubstituted or substituted with one or more linear or branched C ₁ -C ₃ alkyl groups), dihydrobenzofuranyl; aniline (which may be unsubstituted or substituted by a straight-chain or branched C ₁ -C ₃ alkyl group); indoline or naphthyl.

The compound represented by formula 1-13 is preferably compound 80, 81, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 118, 162, 163, 164, 165, 166, 167, 168, 183, 185, 186, 187, 189, 196, 197, 215, 220, 230, 231, 233, 256, 268, 271, 273, 274, 298, 299, 300, 301, 302, 303, 304 and 305 as disclosed herein.

The compound represented by Formula I according to the present invention may be a compound represented by Formula I-14:

Formula I-14

wherein R ₂ , R ₃ and R ₄ can each independently be hydrogen or any one selected from the following groups:

The compound represented by formula 1-14 is preferably compound 348, 349, 350, 351, 352, 396, 400 and 401 as disclosed herein.

The compound represented by Formula I according to the present invention may be a compound represented by Formula I-15:

Formula I-15

wherein n is an integer of 0, 1 or 2, and R ₆ , R ₇ and R ₈ may each independently be hydrogen or any one selected from the following groups:

The compound represented by formula 1-15 is preferably compound 250, 251, 252, 253, 257, 258, 259, 260, 261, 262, 263, 276, 277, 278, 279 and 280 as disclosed herein.

The compound represented by Formula I according to the present invention may be a compound represented by Formula I-16:

Formula I-16

Wherein B can be selected from the following:

Wherein w can be substituted by -F or -Cl.

The compound represented by formula 1-16 is preferably compounds 174, 175, 176 and 195 as disclosed herein.

The compound represented by Formula I according to the present invention may be a compound represented by Formula I-17:

Formula I-17

wherein A is -C(=O)-; _-CH2- ; -NH(C=O)-; -C(=S)- or -S(=O) _2- , and B may be selected from the following: Furthermore, _R13 may be selected from the following: pyrrolidine and _-C1 -C2 _primary or secondary alkylamine.

The compound represented by formula 1-17 is preferably compound 475, 476, 478, 479, 480 and 487 as disclosed herein.

The compound represented by Formula I according to the present invention may be a compound represented by Formula I-18:

Formula I-18

A preferred compound represented by formula 1-18 is compound 477 as disclosed herein.

The compound represented by Formula I according to the present invention may be a compound represented by Formula I-19:

Formula I-19

Wherein R ₁₄ can be selected from the following:

The compound represented by formula 1-19 is preferably compounds 119 and 193 as disclosed herein.

The compound represented by Formula I according to the present invention may be a compound represented by Formula I-20:

Formula I-20

A preferred compound represented by formula 1-20 is compound 198 as disclosed herein.

The compound represented by Formula I according to the present invention may be a compound represented by Formula I-21:

Formula I-21

Wherein R ₁₅ can be selected from the following:

The compound represented by formula 1-21 is preferably compounds 248 and 249 as disclosed herein.

The compound represented by Formula I according to the present invention may be a compound represented by Formula I-22:

Formula I-22

The compound represented by formula 1-22 is preferably compounds 569 and 573 as disclosed herein.

The compound represented by Formula I according to the present invention may be a compound represented by Formula I-23:

Formula I-23

Wherein B can be selected from the following:

wherein w is hydrogen; -F; -Cl or -OH.

Preferred compounds represented by formula 1-23 are compounds 609, 653 and 696 as disclosed herein.

The compounds represented by Formula I, Formula II, Formula III, and Formulas I-1 to I-23 are shown in Table 1 below.

Table 1: Names of dimethylpiperazine derivative compounds

Preferably, the compound represented by formula I according to the present invention or a pharmaceutically acceptable salt thereof can be selected from the group consisting of compounds 081, 082, 083, 084, 098, 099, 100, 106, 107, 108, 109, 110, 112, 120, 121, 122, 123, 125, 126, 127, 128, 145, 146, 147, 148, 149, 159, 160, 161, 171, 173, 174, 175, 177, 186, 188, 193, 194, 195, 196, 198, 211, 214, 219, 248, 249, 250, 251, 252, 255, 265, 266, 267 , 272, 283, 284, 285, 286, 292, 295, 297, 305, 326, 328, 329, 330, 332, 342, 343, 344, 345, 346, 349, 354, 356, 376, 380, 382, 383, 384, 385, 386, 387, 388, 4 03, 411, 413, 430, 431, 432, 433, 434, 435, 439, 440, 441, 442, 443, 444, 452, 453, 454, 455, 456, 467, 468, 481, 482, 483, 484, 485, 486, 569, 696, 813, and 823. More preferably, the compound represented by formula I according to the present invention or a pharmaceutically acceptable salt thereof can be selected from the group consisting of compounds 082, 083, 084, 098, 100, 120, 121, 122, 123, 125, 126, 127, 128, 145, 146, 148, 149, 159, 160, 161, 171, 174, 177, 194, 211, 249, 255, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 301, 302, 303, 304, 305, 306, 307, 308 83, 305, 326, 328, 329, 330, 332, 342, 343, 344, 345, 346, 349, 354, 356, 376, 382, 383, 387, 388, 411, 413, 431, 439, 441, 444, 452, 453, 454, 467, 468, 481, 482, 483, 484, 485, 696, and 813.

As used herein, the term "pharmaceutically acceptable salt" means any salt commonly used in the pharmaceutical field. Examples of pharmaceutically acceptable salts include, but are not limited to, salts with inorganic ions such as calcium, potassium, sodium or magnesium ions, salts with inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, tartaric acid or sulfuric acid, salts with organic acids such as acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc., salts with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid, salts with amino acids such as glycine, arginine or lysine, and salts with amines such as trimethylamine, triethylamine, ammonia water, pyridine or picoline.

In the present invention, preferred salts include salts with hydrochloric acid, trifluoroacetic acid, citric acid, bromic acid, maleic acid, phosphoric acid, sulfuric acid, tartaric acid and the like, and preferred examples of such compounds include compounds 230, 245, 250, 251, 253, 266, 270, 271, 273, 274, 275, 290, 291, 292, 293, 294, 295, 296, 297, 478 and 486 as disclosed herein.

The compound represented by formula I can contain one or more asymmetric carbon atoms, and therefore can exist in the form of racemate, racemic mixture, single enantiomer, diastereomeric mixture and individual diastereoisomer.The compound of formula I can be separated into such isomer by methods known in the art, such as column chromatography or HPLC.Alternatively, the stereoisomer of the compound of formula I can be synthesized by stereospecific synthesis using optically pure starting materials and/or reagents of known configuration.

Method for preparing novel HDAC6 inhibitors

The present invention provides a method for preparing a novel compound of formula I, an isomer thereof or a pharmaceutically acceptable salt thereof.

Preferred methods for preparing the novel compounds of Formula I, isomers thereof, or pharmaceutically acceptable salts thereof are shown in the following reaction schemes 1 to 23, and also include modifications that will be apparent to those skilled in the art.

Reaction Scheme 1

Conditions: a) R ₁ -CH ₂ -Br (or -I, -Cl, -OTf, -OMs), K ₂ CO ₃ (or Cs ₂ CO ₃ )/CH ₃ CN (or DMF); b) R ₁ -CHO, Na(CN)BH ₃ , AcOH/THF; c) R ₁ -COCl, TEA/CH ₂ Cl ₂ ; d) R ₁ CO ₂ H, HOBt, EDCI, DIPEA/CH ₂ Cl ₂ ; e) R ₁ -NCO, TEA/CH ₂ Cl ₂ ; f) 4-nitrophenyl 3-fluorobenzylcarbamate, TEA/DMF; g) Ac ₂ O, TEA/CH ₂ Cl ₂ ; h) R ₁ -SO ₂ Cl, TEA/CH ₂ Cl ₂ ; i) R ₁ CO ₂ H, HATU, DIPEA/DMF.

Table 2

As shown in the above reaction scheme 1, the amine of (2S,6R)-2,6-dimethylpiperazine is subjected to an alkylation reaction with methyl (4-bromomethyl)benzoate to prepare compound 1-2, which is then subjected to an alkylation reaction, an acylation reaction or a reductive amination reaction under conditions a) to i) to thereby prepare compound 1-3. Finally, the prepared compounds 1-3 were reacted with aqueous hydroxylamine solution and potassium hydroxide to prepare compounds 82, 83, 84, 98, 99, 100, 120, 121, 122, 123, 125, 126, 127, 128, 145, 146, 147, 148, 149, 159, 160, 161, 177, 184, 188, 204, 211, 212, 213, 214, 222, 223, 224, 225, 232, 255, 265, 266, 267, 270, 272, 275, 290, 291, 292, 293, 294, 295, 296, 297, 354, 355, 403, 404 and 405.

Reaction Scheme 2

Table 3

Compound 309 H H Y-2 327 Y-1 H H 328 Y-2 H H 329 Y-3 H H 330 Y-4 H H 331 Y-5 H H 332 Y-6 H H 342 H Y-1 H 343 H Y-2 H 344 H Y-4 H 345 H Y-3 H 346 H Y-6 H 347 H Y-5 H

As shown in the above reaction scheme 2, compound 1-2 is alkylated to prepare compound 2-1, which is then subjected to a Suzuki reaction with a boronic acid or boronic acid ester containing each of compounds Y-1 to Y-6, thereby preparing compound 2-2. Finally, the prepared compound 2-2 is reacted with an aqueous hydroxylamine solution and potassium hydroxide to prepare compounds 309, 327, 328, 329, 330, 331, 332, 342, 343, 344, 345, 346 and 347.

Reaction Scheme 3

Conditions: a) MsCl, TEA/CH ₂ Cl ₂ ; b) Ac ₂ O, TEA/CH ₂ Cl ₂ ; c) R ₅ -OTf, K ₂ CO ₃ /CH ₃ CN; d) R ₅ -X, TEA/CH ₂ Cl ₂ .

Table 4

Compound condition 481 Methylsulfonyl a 482 Acetyl b 483 2,2,2-trifluoroethyl c 484 Isopropyl d 485 Ethyl d

As shown in the above reaction scheme 3, compound 2-1 is subjected to a Suzuki reaction with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate to prepare compound 3-1, which is then deprotected under acidic conditions to prepare compound 3-2. The prepared compound 3-2 is subjected to a substitution reaction under the above conditions a) to d) to prepare compound 3-3, which is then reacted with an aqueous hydroxylamine solution and potassium hydroxide to prepare compounds 481, 482, 483, 484, and 485.

Reaction Scheme 4

Conditions: a) (iodine, chloride or bromide)benzoyl chloride, TEA/CH ₂ Cl ₂ ; b) 2-([1,1′-biphenyl]-3-yl)acetic acid, HOBt, EDCI, DIPEA/CH ₂ Cl ₂ .

Table 5

As shown in the above reaction scheme 4, compound 1-2 is reacted with benzoyl chloride or benzoyl bromide to prepare compound 4-1, which is then subjected to a Suzuki reaction with a boronic acid or boronic acid ester containing each of compounds Y-1 to Y-8, thereby preparing compound 4-2. Alternatively, compound 1-2 is subjected to an amide coupling reaction with 2-([1,1′-biphenyl]-3-yl)acetic acid, thereby preparing compound 4-2. The prepared compound 4-2 is reacted with an aqueous hydroxylamine solution and potassium hydroxide, thereby preparing compounds 234, 242, 243, 244, 245, 246, 247, 283, 284, 285, 286, 288, 326, and 340.

Reaction Scheme 5

Table 6

As shown in the above reaction scheme 5, compound 1-2 is subjected to a substitution reaction with o-, m- or p-(bromomethyl)benzaldehyde to prepare compound 5-1, which is then subjected to a reductive amination reaction with an amine compound to prepare compound 5-2. Finally, the prepared amine compound 5-2 is reacted with an aqueous hydroxylamine solution and potassium hydroxide to prepare compounds 356, 376, 382, 383, 384, 385, 411, 412, 413, 426, 427, 428, 429, 430, 431, 452, 453, 454, 455, 456, 457, 466, 467, 468 and 486.

Reaction Scheme 6

Table 7

As shown in the above reaction scheme 6, compound 6-1 is prepared and subjected to an acylation reaction with compound 1-2 to prepare compound 6-2. The prepared compound 6-2 is subjected to a substitution reaction with an amine compound to prepare compound 6-3, which is then reacted with an aqueous hydroxylamine solution and potassium hydroxide to prepare compounds 423, 424, 425, 432, 433, 434, 435, 439, 440, 441, 442, 443, 444, 458, 459, 460, 461, 462 and 463.

Alternatively, compound 6-1 is reacted with morpholine to prepare compound 6-4. The prepared compound 6-4 and compound 1-2 are subjected to a substitution reaction and then reacted with a hydroxylamine aqueous solution and potassium hydroxide, thereby preparing compound 446.

Reaction Scheme 7

As shown in the above reaction scheme 7, compound 5-1 is subjected to a reductive amination reaction with 4-tert-butyl piperazine-1-carboxylate, followed by deprotection under acidic conditions to produce compound 7-2. The prepared compound 7-2 is reacted with 2,2-dimethyloxirane to produce compound 7-3, which is then reacted with an aqueous hydroxylamine solution and potassium hydroxide to produce compound 386. In addition, compound 7-3 is reacted with DAST to replace the hydroxyl group with fluorine, thereby producing compound 7-4. The prepared compound 7-4 is reacted with an aqueous hydroxylamine solution and potassium hydroxide to produce compound 387.

Reaction Scheme 8

Conditions: a) base/CH ₃ CN or DCM; b) reducing agent/CH ₂ Cl ₂ .c) EDC, HOBt, DIPEA/CH ₂ Cl ₂

Table 8

As shown in the above reaction scheme 8, (2S, 6R) -2,6-dimethylpiperazine is protected with Boc and reacted with benzyl bromide, which is then deprotected under acidic conditions to prepare compound (8-3). The prepared compound 8-3 is subjected to an alkylation reaction or a reductive amination reaction with compound 8-4 as shown in conditions a) to c) to prepare compound 8-5. The prepared compound 8-5 is reacted with an aqueous hydroxylamine solution and potassium hydroxide to prepare compounds 154, 171, 172, 173, 194, 218, 219, 520, 571, 574, 652, 812, 813, 814, 818, 820, 822, 823 and 824.

Reaction Scheme 9

Table 9

Compound A 321 NH(C=O) 3-(1H-pyrrol-1-yl)phenyl 322 C＝O 2-Furyl 323 C＝O benzyl

As shown in the above reaction scheme 9, compound 8-4 is reacted with (2S,6R)-2,6-dimethylpiperazine to prepare compound 9-1, which is then subjected to a substitution reaction with an isocyanate or a carbonyl chloride containing a substituent represented by R ₁₁ , thereby preparing compound 9-2. The prepared compound 9-2 is reacted with an aqueous hydroxylamine solution and potassium hydroxide, thereby preparing compounds 321, 322, and 323.

Reaction Scheme 10

As shown in the above reaction scheme 10, compound 9-1 is subjected to an alkylation reaction with 3-(bromomethyl)benzaldehyde to prepare compound 10-1. The prepared compound 10-1 is subjected to a reductive amination reaction with morpholine to prepare compound 10-2, which is then reacted with an aqueous hydroxylamine solution and potassium hydroxide to prepare compound 472.

Reaction Scheme 11

As shown in the above reaction scheme 11, compound 8-1 is reacted with furan-2-carbonyl chloride to prepare compound 11-1. The prepared compound 11-1 is hydrogenated to prepare compound 11-2, which is then Boc-deprotected under acidic conditions to prepare compound 11-3. The prepared compound 11-3 is reacted with compound 1-1, and then reacted with aqueous hydroxylamine and potassium hydroxide to prepare compound 402.

Reaction Scheme 12

As shown in the above reaction scheme 12, 3-hydroxybenzyl alcohol and 4-hydroxybenzyl alcohol are subjected to a substitution reaction with compound 12-1 to produce compound 12-2, which is then reacted with MsCl to produce compound 12-3. Compound 12-3 is reacted with compound 1-2 to produce compound 12-4, which is deprotected under acidic conditions and reacted with 2,2-dimethyloxirane to produce compound 12-6. The resulting compound 12-6 is reacted with DAST to replace the hydroxyl group with fluorine, thereby producing compound 12-7. Finally, the resulting compound 12-7 is reacted with an aqueous hydroxylamine solution and potassium hydroxide to produce compounds 380 and 388.

Reaction Scheme 13

Conditions: a) _R12 - _CH2 -Br(I _or -Cl), _{K2CO3 (} or _Cs2CO3 )/ _CH3CN (or DMF); b) _R12 -CHO, _NaCNBH3 , AcOH/THF or AcOH _{/ CH2ClCH2Cl} ; c) _R12 -COX, TEA/ _CH2Cl2 ; d) _R12CO2H , _HOBt , EDCI _{, DIPEA} / _CH2Cl2 ; e) _R12 -NCO, TEA/ _CH2Cl2 ; f) _{R12 -} NCS, TEA/ _{CH2Cl2 ;} g) DMF; h) _R12 - _SO2Cl , TEA/ _{CH2Cl2 .}

Table 10

As shown in the above reaction scheme 13, compound 8-1 and compound 1-1 are subjected to an alkylation reaction to prepare compound 13-1, which is then deprotected under acidic conditions to prepare compound 13-2. The prepared compound 13-2 is subjected to an alkylation reaction, an acylation reaction, or a reductive amination reaction under conditions a) to h) to prepare compound 13-3. Finally, the prepared compound 13-3 was reacted with an aqueous hydroxylamine solution and potassium hydroxide to prepare compounds 80, 81, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 118, 162, 163, 164, 165, 166, 167, 168, 183, 185, 186, 187, 189, 196, 197, 215, 220, 230, 231, 233, 256, 268, 271, 273, 274, 298, 299, 300, 301, 302, 303, 304 and 305.

Reaction Scheme 14

Table 11

As shown in the above reaction scheme 14, compound 13-2 is subjected to an alkylation reaction to prepare compound 14-1, which is then subjected to a Suzuki reaction with a boronic acid or boronic acid ester containing each of Y-2 to Y-6, thereby preparing compound 14-2. Finally, the prepared compound 14-2 is reacted with an aqueous hydroxylamine solution and potassium hydroxide, thereby preparing compounds 348, 349, 350, 351, 352, 396, 400 and 401.

Reaction Scheme 15

Table 12

As shown in the above reaction scheme 15, compound 13-2 is subjected to an amide coupling reaction with 2-, 3-, or 4-iodobenzoic acid or 2-(3-bromophenyl)acetic acid to prepare compound 15-1, which is then subjected to a Suzuki reaction with a boronic acid or boronic acid ester containing each of Y-1 to Y-8 to prepare compound 15-2. Finally, the prepared compound 15-2 is reacted with an aqueous hydroxylamine solution and potassium hydroxide to prepare compounds 250, 251, 252, 253, 257, 258, 259, 260, 261, 262, 263, 276, 277, 278, 279, and 280.

Reaction Scheme 16

Table 13

As shown in the above reaction scheme 16, (2S, 6R) -2,6-dimethylpiperazine is reacted with benzyl bromide to introduce a benzyl group therein, thereby preparing compound 16-1, which is then subjected to an alkylation reaction with compound 8-4, thereby preparing compound 16-2. Finally, the prepared compound 16-2 is reacted with an aqueous hydroxylamine solution and potassium hydroxide, thereby preparing compounds 174, 175, 176 and 195.

Reaction Scheme 17

Conditions: a) (3-bromomethyl)benzaldehyde, Cs ₂ CO ₃ /CH ₃ CN; b) 3-formylbenzoic acid, HOBt, EDCI, DIPEA/CH ₂ Cl ₂ .

Table 14

As shown in the above reaction scheme 17, compound 8-1 is subjected to an alkylation reaction with compound 8-4 and deprotected under acidic conditions to prepare compound 17-1. The prepared compound 17-1 is subjected to an alkylation reaction or an amide coupling reaction under conditions a) or b) to prepare compound 17-2, which is then subjected to a reductive amination reaction with pyrrolidine or diethylamine to prepare compound 17-3. Finally, the prepared compound 17-3 is reacted with an aqueous hydroxylamine solution and potassium hydroxide to prepare compounds 475, 476, 478, 479, 480, and 487.

Reaction Scheme 18

As shown in the above reaction scheme 18, compound 17-1 is subjected to an alkylation reaction with 4-bromobenzyl bromide to prepare compound 18-1, which is then subjected to a Suzuki reaction with furan-2-ylboronic acid to prepare compound 18-2. Finally, the prepared compound 18-2 is reacted with an aqueous hydroxylamine solution and potassium hydroxide to prepare compound 477.

Reaction Scheme 19

As shown in Reaction Scheme 19 above, compound 13-2 is subjected to a Buchwald reaction with 1-bromo-4-fluorobenzene to produce compound 19-1, which is then reacted with aqueous hydroxylamine and potassium hydroxide to produce compound 119.

Alternatively, compound 13-2 is reacted with 2,2-dimethyloxirane to produce compound 19-2, which is then reacted with DAST to replace the hydroxyl group with fluorine, and then reacted with an aqueous hydroxylamine solution and potassium hydroxide, thereby producing compound 193.

Reaction Scheme 20

As shown in the above reaction scheme 20, compound 13-3 is subjected to an alkylation reaction with butyl iodide to prepare compound 20-1, which is then reacted with aqueous hydroxylamine and potassium hydroxide to prepare compound 198.

Reaction Scheme 21

As shown in the above reaction scheme 21, (2R, 6R) -2,6-dimethylpiperazine is subjected to an alkylation reaction with compound 1-1 to prepare compound 21-1, which is then subjected to an alkylation reaction or an acylation reaction to prepare compound 21-2 or compound 21-3. Finally, the prepared compound 21-2 or compound 21-3 is reacted with an aqueous hydroxylamine solution and potassium hydroxide to prepare compounds 248 and 249.

Reaction Scheme 22

As shown in the above reaction scheme 22, (2S, 6R) -1-benzyl-2,6-dimethylpiperazine is subjected to an alkylation reaction with compound 8-3 and compound 22-1 to prepare compound 22-2, which is then deprotected to remove the tert-butyloxycarbonyl group, thereby preparing compound 22-3. Finally, compound 22-3 is reacted with aqueous hydroxylamine solution and potassium hydroxide to prepare compounds 569 and 573.

Reaction Scheme 23

Conditions: a) TEA/CH ₃ CN; b) reducing agent/CH ₂ Cl ₂ .

Table 15

As shown in the above reaction scheme 23, compound 8-1 is subjected to an alkylation reaction to prepare compound 23-1, which is then subjected to a reductive amination reaction with morpholine to prepare compound 23-2, which is then deprotected to remove the tert-butyloxycarbonyl group, thereby preparing compound 23-3. Compound 23-3 is subjected to an alkylation reaction with compound 8-4 to prepare compound 23-4. Finally, the prepared compound 23-4 is reacted with an aqueous hydroxylamine solution and potassium hydroxide to prepare compounds 609, 653, and 696.

Compositions comprising novel compounds having HDAC6 inhibitory activity, uses thereof, and methods for treating diseases

The present invention provides a pharmaceutical composition for preventing or treating histone deacetylase 6 (HDAC6) activity-related diseases, which contains a compound represented by the following formula I, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient:

Formula I

wherein L, R ₁ , R ₂ , Q, X and n are as defined above.

The pharmaceutical composition according to the present invention exhibits a significant effect on the prevention or treatment of histone deacetylase 6 (HDAC6) activity-related diseases by selectively inhibiting histone deacetylase 6 (HDAC6).

Histone deacetylase 6 (HDAC6) activity-associated diseases include cancer, inflammatory diseases, autoimmune diseases, neurological diseases, and neurodegenerative disorders. Specifically, these histone deacetylase 6 (HDAC6) activity-related diseases include lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, brain cancer, ovarian cancer, stomach cancer, skin cancer, pancreatic cancer, glioma, glioblastoma, leukemia, lymphoma, multiple myeloma, solid cancer, Wilson's disease, spinocerebellar ataxia, prion disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, amyloidosis, Alzheimer's disease, alcoholic liver disease, spinal muscular atrophy, atrophy), rheumatoid arthritis and osteoarthritis, as well as conditions or diseases associated with abnormal histone deacetylase function.

In one embodiment, the compound represented by formula I according to the present invention can be a compound represented by formula II or formula III. In another embodiment, the compound represented by formula I according to the present invention can be any one of the compounds represented by formula I-1 to I-23. In yet another embodiment, the compound represented by formula I according to the present invention can be any one of compounds 080 to 824.

The pharmaceutically acceptable salts are as described above with respect to the pharmaceutically acceptable salts of the compounds represented by formula I according to the present invention.

For administration, in addition to the compound of formula I, its isomer or its pharmaceutically acceptable salt, the pharmaceutical composition according to the present invention can also contain at least one pharmaceutical carrier. The pharmaceutical carrier used in the present invention can be at least one of the following: physiological saline, sterile water, Ringer's solution (Ringer solution), buffered saline, glucose solution, maltodextrin solution, glycerol, ethanol, and a mixture of two or more thereof. If necessary, the composition can contain other conventional additives such as antioxidants, buffers or antibacterial agents. In addition, the composition can be formulated into injection preparations such as solutions, suspensions, turbid fluids, etc., pills, capsules, granules and tablets using diluents, dispersants, surfactants, adhesives and lubricants. Therefore, the composition of the present invention can be in the form of patches, liquids, pills, capsules, granules, tablets, suppositories, etc. These preparations can be prepared by conventional methods for preparation in the art or by the method disclosed in Remington's Pharmaceutical Science (Remington's Pharmaceutical Science) (latest edition), Mack Publishing Company, Easton PA. In addition, the composition of the present invention can be prepared into various preparations according to disease or component.

The compositions of the present invention can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically), depending on the intended use. The dosage of the pharmaceutical composition varies depending on the patient's weight, age, sex, health status, diet, time of administration, mode of administration, excretion rate, severity of disease, etc.

In addition to the compound of formula I, its isomers or pharmaceutically acceptable salts thereof, the pharmaceutical composition of the present invention may further contain one or more active ingredients that exhibit the same or similar medical effects as those thereof.

The present invention provides a method for preventing or treating a histone deacetylase 6 activity-related disease, comprising administering a therapeutically effective amount of a compound of formula I, an isomer thereof, or a pharmaceutically acceptable salt thereof.

As used herein, the term "therapeutically effective amount" refers to an amount of the compound represented by Formula I that is effective for preventing or treating a histone deacetylase 6 activity-related disease.

The present invention also provides a method for selectively inhibiting HDAC6, comprising administering a compound of formula I, an isomer thereof, or a pharmaceutically acceptable salt thereof to a mammal including a human.

The method for preventing or treating histone deacetylase 6 activity-related diseases according to the present invention includes suppressing or preventing the disease and solving the disease itself before the onset of symptoms by using a compound represented by Formula I. In the management of the disease, the amplitude of the prevention or treatment dose of a specific active ingredient will vary with the nature and severity of the disease or condition, and can also vary according to the approach of administering the active ingredient. Dosage and dosage frequency will also vary according to the age, body weight and response of the individual patient. Suitable medication regimens can be easily selected by those skilled in the art with due consideration of such factors. In addition, the method for preventing or treating histone deacetylase 6 activity-related diseases according to the present invention can also include administering a therapeutically effective amount of an additional active agent that helps treat the disease together with the compound represented by Formula I, wherein the additional active agent can show synergy or auxiliary action with the compound of Formula I.

The present invention also intends to provide the use of a compound represented by Formula I, an isomer thereof, or a pharmaceutically acceptable salt thereof for preparing a medicament for treating a disease associated with histone deacetylase 6 activity. For the preparation of the medicament, the compound represented by Formula I can be mixed with a pharmaceutical adjuvant, diluent, carrier, etc., and combined with other active pharmaceutical ingredients to achieve a synergistic effect of the active ingredients.

The details mentioned in the uses, compositions and methods of treatment of the present invention may be combined appropriately unless they contradict each other.

Beneficial effects

The compound represented by Formula I, its isomer or a pharmaceutically acceptable salt thereof can selectively inhibit HDAC6, and thus exhibit excellent effects on the prevention or treatment of histone deacetylase 6 activity-related diseases.

Embodiments of the invention

Hereinafter, the present invention will be described in more detail with reference to Examples, Preparation Examples and Experimental Examples. However, it should be understood that these Examples are only for illustrative purposes and are not intended to limit the scope of the present invention.

Preparation of new dimethylpiperazine derivatives

The specific method for preparing the compound of formula I is as follows.

Example 1: Synthesis of Compound 80 (4-(((2S,6R)-4-benzoyl-2,6-dimethylpiperazin-1-yl)methyl (4-Hydroxybenzamide)

Step 1: Synthesis of methyl 4-(((2S,6R)-4-benzoyl-2,6-dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((2S, 6R)-2,6-dimethylpiperazine-1-yl)methyl)benzoate (Formula 13-2, 0.100 g, 0.381 mmol) was dissolved in dichloromethane (3 mL), and benzoyl chloride (0.049 mL, 0.420 mmol) and TEA (0.106 mL, 0.763 mmol) were then added thereto. The mixture was stirred at 0 ° C for 1 hour, and saturated sodium bicarbonate was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was separated and concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; methanol / dichloromethane = 5%) and concentrated to give the desired compound (0.124 g, 88.7%) as a light yellow oil.

Step 2: Synthesis of compound 80

4-(((2S, 6R)-4-benzoyl-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.060g, 0.164mmol) was dissolved in methanol (1mL), and hydroxylamine (0.2mL, 3.275mmol, 50.00% aqueous solution) and potassium hydroxide (0.091g, 1.637mmol) were then added thereto. The mixture was stirred at room temperature for 20 minutes, and saturated sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain compound 80 (0.045g, 74.8%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.68 (d, 2H, J=8.2Hz), 7.46-7.39 (m, 5H), 7.34 (d, 2H, J=8.8Hz), 3.67 (s, 2H), 3.17 (s, 2H), 2.69-2.61 (m, 2H), 2.60-2.57 (m, 2H), 1.82-1.76 (m, 2H), 0.83 (d, 6H, J=6.12Hz); LRMS (ES) m/z 368.0(M ⁺ +1).

Example 2: Synthesis of Compound 81 (4-(((2S,6R)-4-benzyl-2,6-dimethylpiperazin-1-yl)methyl)-N- Hydroxybenzamide)

Step 1: Synthesis of methyl 4-(((2S,6R)-4-benzyl-2,6-dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.050 g, 0.191 mmol) was dissolved in acetonitrile (2 mL), and then benzyl bromide ₍ 0.023 mL, 0.210 mmol) and _K₂CO₃ (0.053 g, 0.381 mmol) were added. The mixture was heated and stirred at 80°C for 1 hour, then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = 30%) and concentrated to give the desired compound (0.022 g, 32.8%) as a colorless oil.

Step 2: Synthesis of compound 81

4-(((2S, 6R)-4-benzyl-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.022g, 0.062mmol) was dissolved in methanol (2mL), and hydroxylamine (0.023mL, 0.210mmol, 50.00% aqueous solution) and potassium hydroxide (0.053g, 0.381mmol) were then added thereto. The mixture was stirred at room temperature for 20 minutes, and water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Compound 81 (0.003g, 13.6%) was obtained as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.65 (d, 2H, J=8.1Hz), 7.34-7.23 (m, 7H), 3.73 (s, 2H), 3.39 (s, 2H), 2.64 (d, 2H, J=1 0.4Hz), 2.56-2.54 (m, 2H), 1.79 (t, 2H, J=10.6Hz), 0.88 (d, 6H, J=6.1Hz); LRMS (ES) m/z 354.2(M ⁺ +1).

Example 3: Synthesis of Compound 82 (4-(((3R,5S)-4-acetyl-3,5-dimethylpiperazin-1-yl)methyl)- N-hydroxybenzamide)

Step 1: Synthesis of methyl 4-(((3R,5S)-4-acetyl-3,5-dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol) was dissolved in dichloromethane (2 mL), and acetic anhydride (0.072 mL, 0.763 mmol) and TEA (0.266 mL, 1.907 mmol) were added thereto. The mixture was stirred at 0° C. for 1 hour, and saturated sodium bicarbonate was added thereto, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the desired compound (0.115 g, 99.1%) as a white solid.

Step 2: Synthesis of compound 82

Methyl 4-(((3R, 5S)-4-acetyl-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-3, 0.052 g, 0.171 mmol) was dissolved in methanol (0.5 mL), and hydroxylamine (0.209 mL, 3.417 mmol, 50.00% aqueous solution) and potassium hydroxide (0.096 g, 1.708 mmol) were added thereto. The mixture was stirred at room temperature for 20 minutes and then concentrated under reduced pressure. Saturated sodium bicarbonate was added to the concentrate, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The concentrate was purified by PTLC (100% ethyl acetate) to give the desired compound 82 (0.016 g, 30.7%) as a white solid.

¹ H NMR (400MHz, CD ₃ OD) δ7.73 (d, 2H, J=8.3Hz), 7.50 (d, 2H, J=8.3Hz), 4.51-4.50 (m, 1H), 4.11-4.10 (m, 1H), 3.57 ( s, 2H), 2.71 (d, 2H, J=11.5Hz), 2.21-2.20 (m, 2H), 2.11 (s, 3H), 1.40-1.38 (m, 6H); LRMS (ES) m/z 306.2(M ⁺ +1).

Example 4: Synthesis of Compound 83 (4-(((3R,5S)-4-benzoyl-3,5-dimethylpiperazin-1-yl)methyl (4-Hydroxybenzamide)

Step 1: Synthesis of methyl 4-(((3R,5S)-4-benzoyl-3,5-dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-2, 0.100g, 0.381mmol) was dissolved in dichloromethane (3mL), and benzoyl chloride (0.049mL, 0.420mmol) and TEA (0.106mL, 0.763mmol) were then added thereto. The mixture was stirred at 0°C for 1 hour, and saturated sodium bicarbonate was added to the reaction mixture, followed by dichloromethane. The organic layer was separated and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica; ethyl acetate/hexane=30%) to give the desired compound (0.124g, 88.7%) as a light yellow oil.

Step 2: Synthesis of compound 83

Methyl 4-(((3R, 5S)-4-benzoyl-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-3, 0.060 g, 0.164 mmol) was dissolved in methanol (1 mL), and hydroxylamine (0.2 mL, 3.275 mmol, 50.00% aqueous solution) and potassium hydroxide (0.091 g, 1.637 mmol) were then added thereto. The mixture was stirred at room temperature for 20 minutes, and saturated sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure to give compound 83 (0.045 g, 74.8%) as a white solid.

¹ H NMR (400MHz, CD ₃ OD) δ7.72 (d, 2H, J = 8.3Hz), 7.49 (d, 2H, J = 8.2Hz), 7.46-7.44 (m, 3H), 7.36-7.34 (m, 2H), 3.59 (s, 2H), 2.71 (d, 2H, J=10.7Hz), 2.26 (dd, 2H, J=10.2, 3.6Hz), 1.39 (d, 6H, J=6.7Hz).

Example 5: Synthesis of Compound 84 (4-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)-N- Hydroxybenzamide)

Step 1: Synthesis of methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate

(2S,6R)-2,6-dimethylpiperazine (50.000 g, 437.867 mmol) and _Cs2CO3 (171.199 g, 525.440 mmol) were dissolved in acetonitrile (200 mL) at 0° _C , and methyl 4-(bromomethyl)benzoate (Formula 1-1, 80.242 g, 350.293 mmol) was added to the solution, followed by stirring at room temperature for 5 hours. The reaction mixture was filtered through a glass filter to remove solids, and the filtrate was concentrated under reduced pressure to remove the solvent. Water was added to the concentrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Hexane (100 mL) was added to the concentrate and stirred, and the precipitated solid was filtered, washed with hexane, and dried to obtain the desired compound (85.200 g, 74.2%) as a white solid.

Step 2: Synthesis of methyl 4-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 30.000 g, 114.351 mmol), benzyl bromide (14.961 mL, 125.786 mmol), and K ₂ CO ₃ (23.707 g, 171.527 mmol) were dissolved in acetonitrile (150 mL) at room temperature, and the solution was stirred at the same temperature for 17 hours. The reaction mixture was filtered through a glass filter to remove solids, and the filtrate was concentrated under reduced pressure to remove the solvent. Water was added to the concentrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; 120 g cartridge; ethyl acetate/hexane = from 0% to 30%) and concentrated to obtain the desired compound (22.400 g, 55.6%) as a white solid.

Step 3: Synthesis of compound 84

Methyl 4-(((3R, 5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-3, 15.000 g, 42.557 mmol), hydroxylamine (52.061 mL, 851.136 mmol, 50.00% aqueous solution) and potassium hydroxide (23.879 g, 425.568 mmol) were dissolved in methanol (300 mL) at 0°C, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; 120 g cartridge; methanol / dichloromethane = from 0% to 20%) and concentrated, and the obtained material was then crystallized from diethyl ether (200 mL) and dichloromethane (50 mL) at 25° C. and filtered. The resulting solid was washed with diethyl ether and dried to give compound 84 (12.580 g, 83.6%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.18 (brs, 1H), 9.03 (brs, 1H), 7.70 (d, 2H, J=8.2Hz), 7.36-7.33 (m, 4H), 7.28 (dd, 2H, J=7.5, 7.5Hz), 7.18 (dd, 1H, J=7.2, 7.2Hz ), 3.73 (s, 2H), 3.44 (s, 2H), 2.64 (d, 2H, J = 10.6Hz), 2.61-2.53 (m, 2H), 1.81 (t, 2H, J = 10.5Hz), 0.90 (d, 6H, J = 6.1Hz); LRMS (ES) m/z 354.2(M ⁺ +1).

Example 6: Synthesis of Compound 98 ((2S,6R)-4-(4-(hydroxycarbamoyl)benzyl)-N-isopropyl-2,6- dimethylpiperazine-1-carboxamide)

Step 1: Synthesis of 4-(((3R,5S)-4-isopropylcarbamoyl-3,5-dimethylpiperazin-1-yl)methyl)benzene Methyl formate

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol) was dissolved in dichloromethane (3 mL), and 2-isocyanatopropane (2-isocyanatopropane) (0.041 mL, 0.419 mmol) and TEA (0.080 mL, 0.572 mmol) were then added thereto. The mixture was stirred at 0° C. for 2 hours, and water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was concentrated under reduced pressure to give the desired compound (0.120 g, 90.6%) as a yellow solid.

Step 2: Synthesis of Compound 98

Methyl 4-(((3R, 5S)-4-isopropylcarbamoyl-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-3, 0.060 g, 0.173 mmol) was dissolved in methanol (1 mL), and hydroxylamine (0.211 mL, 3.454 mmol, 50.00% aqueous solution) and potassium hydroxide (0.097 g, 1.727 mmol) were added thereto. The mixture was stirred at room temperature for 1 hour, and saturated sodium bicarbonate was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Compound 98 (0.040 g, 66.5%) was obtained as a white solid.

¹ H NMR (400MHz, CD ₃ OD) δ7.72 (d, 2H, J=8.3Hz), 7.46 (d, 2H, J=8.2Hz), 4.06-4.03 (m, 2H), 3.96-3.93 (m, 1H), 3.54 (s, 2H), 2.68 (d, 2H, J = 11.1Hz), 2.15 (dd, 2H, J = 10.2, 3.6Hz), 1.29 (d, 6H, J = 6.8Hz), 1.14 (d, 6H, J = 6.6Hz); LRMS (ES) m/z 349.1(M ⁺ +1).

Example 7: Synthesis of Compound 99 ((2S,6R)-N-(3-chlorophenyl)-4-(4-(hydroxycarbamoyl)benzyl)- 2,6-dimethylpiperazine-1-carboxamide)

Step 1: Synthesis of 4-((4-(3-chlorophenylcarbamoyl-3,5-dimethylpiperazin-1-yl)methyl)benzoic acid ester

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol) was dissolved in dichloromethane (3 mL), and 3-chlorophenyl isocyanate (0.051 mL, 0.419 mmol) and TEA (0.080 mL, 0.572 mmol) were then added thereto. The mixture was stirred at 0 ° C for 2 hours, and water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was concentrated under reduced pressure to give the desired compound (0.018 g, 68.1%) as a white solid.

Step 2: Synthesis of Compound 99

Methyl 4-((4-(3-chlorophenylcarbamoyl-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-3, 0.050 g, 0.120 mmol) was dissolved in methanol (1 mL), and hydroxylamine (0.147 mL, 2.404 mmol, 50.00% aqueous solution) and potassium hydroxide (0.067 g, 1.202 mmol) were added thereto. The mixture was stirred at room temperature for 1 hour, and the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate was added to the concentrate, followed by stirring. The precipitated solid was filtered and dried to obtain compound 99 (0.040 g, 66.5%) as a white solid.

¹ H NMR (400MHz, CD ₃ OD) δ7.74 (d, 2H, J=8.0Hz), 7.53-7.52 (m, 1H), 7.45 (d, 2H, J=8.1Hz), 7.29-7.28 (m, 1H), 7.24-7.22 (m, 1H), 7.01 (d, 1H, J=7.8Hz), 4.21-4.20 (m, 2H), 3.56 (s, 2H), 2.74 (d, 2H, J=11.4Hz), 2.22 (dd, 2H, J=10.2, 3.6Hz), 1.25 (d, 6H, J=6.5Hz).

Example 8: Synthesis of Compound 100 (4-(((3R,5S)-3,5-dimethyl-4-(phenylsulfonyl)piperazin-1-yl) Methyl-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethylpiperazin-4-(phenylsulfonyl-1-yl)methyl)benzoic acid ester

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-2, 0.100g, 0.381mmol) was dissolved in dichloromethane (3mL), and benzenesulfonyl chloride (0.054mL, 0.419mmol) and TEA (0.080mL, 0.572mmol) were then added thereto. The mixture was stirred at 0°C for 2 hours and then at room temperature for 3 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane=25%) and concentrated to give the desired compound (0.048g, 31.3%) as a light yellow solid.

Step 2: Synthesis of Compound 100

Methyl 4-(((3R,5S)-3,5-dimethylpiperazine-4-(phenylsulfonyl-1-yl)methyl)benzoate (Formula 1-3, 0.048 g, 0.119 mmol) was dissolved in methanol (1 mL), and hydroxylamine (0.146 mL, 2.385 mmol, 50.00% aqueous solution) and potassium hydroxide (0.067 g, 1.193 mmol) were added thereto. The mixture was stirred at room temperature for 1 hour, and saturated sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give Compound 100 (0.034 g, 70.7%) as a white solid.

¹ H NMR (400MHz, CD ₃ OD) δ7.84 (d, 2H, J=8.1Hz), 7.68 (d, 2H, J=8.3Hz), 7.63-7.61 (m, 1H), 7.58-7.54 (m, 2H), 7.41 (d, 2H, J=8.3Hz), 4.06-4.03 (m, 2H), 3.41 (s, 2H), 2.53 (d, 2H, J=11.3Hz), 1.85-1.81 (m, 2H), 1.43 (d, 6H, J=6.9Hz); LRMS (ES) m/z 404.1(M ⁺ +1).

Example 9: Synthesis of Compound 103 ((3R,5S)-4-(4-(hydroxycarbamoyl)benzyl)-N-isopropyl-3, 5-dimethylpiperazine-1-carboxamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(isopropylcarbamoyl)-2,6-dimethylpiperazin-1-yl)methyl) Methyl benzoate

Methyl 4-(((2S, 6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.100 g, 0.381 mmol) was dissolved in dichloromethane (3 mL), and 2-isocyanatopropane (0.041 mL, 0.419 mmol) and TEA (0.079 mL, 0.572 mmol) were then added thereto. The mixture was stirred for 2 hours while the temperature was raised from 0° C. to room temperature, and then water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the desired compound (0.094 g, 70.1%).

Step 2: Synthesis of compound 103

4-(((2S, 6R)-4-(isopropylcarbamoyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.045g, 0.130mmol) was dissolved in methanol (0.5mL), and hydroxylamine (0.158mL, 2.590mmol, 50.00% aqueous solution) and potassium hydroxide (0.073g, 1.295mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and saturated sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Compound 103 (0.020g, 44.3%) was obtained as a white solid.

¹ H NMR (400MHz, CD ₃ OD) δ7.69 (d, 2H, J = 8.2Hz), 7.50 (d, 2H, J = 8.2Hz), 3.91-3.82 (m, 5H), 2.67-2.61 (m , 2H), 2.55-2.50 (m, 2H), 1.13 (d, 6H, J=6.6Hz), 1.03 (d, 6H, J=6.0Hz); LRMS (ES) m/z 349.2(M ⁺ +1).

Example 10: Synthesis of Compound 104 ((3R, 5S)-N-(3-chlorophenyl)-4-(4-(hydroxycarbamoyl)benzyl) 1-Methyl-3,5-dimethylpiperazine-1-carboxamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(3-chlorophenylcarbamoyl)-2,6-dimethylpiperazin-1-yl)methane methyl)benzoate

Methyl 4-(((2S, 6R)-2,6-dimethylpiperazine-1-yl)methyl)benzoate (Formula 13-2, 0.100 g, 0.381 mmol) was dissolved in dichloromethane (3 mL), and 3-chlorophenyl isocyanate (0.051 mL, 0.419 mmol) and TEA (0.079 mL, 0.572 mmol) were then added thereto. The mixture was stirred for 2 hours while the temperature was raised from 0° C. to room temperature, and then water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the desired compound (0.094 g, 70.1%).

Step 2: Synthesis of compound 104

4-(((2S, 6R)-4-(3-chlorophenylcarbamoyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.065g, 0.156mmol) is dissolved in methanol (0.5mL), and hydroxylamine (0.191mL, 3.126mmol, 50.00% aqueous solution) and potassium hydroxide (0.088g, 1.563mmol) are then added thereto. The mixture is stirred at room temperature for 1 hour, and the reaction mixture is concentrated under reduced pressure. Saturated sodium bicarbonate is added to the concentrate, which is then stirred. The precipitated solid is filtered and dried to give compound 104 (0.035g, 53.7%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.67 (s, 1H), 7.67 (d, 2H, J=8.2Hz), 7.63-7.62 (m, 1H), 7.41-7.38 (m, 3H), 7.24 (dd, 1H, J=10.2, 3.6Hz), 7.46 (dd, 1 H, J=10.2, 3.6Hz), 3.95 (d, 2H, J=12.8Hz), 3.77 (s, 2H), 2.68-2.65 (m, 2H), 2.53-2.52 (m, 2H), 0.97 (d, 6H, J=6.1Hz).

Example 11: Synthesis of Compound 105 (4-(((2S,6R)-2,6-dimethyl-4-(phenylsulfonyl)piperazine-1-yl) (4-(2-Methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-2,6-dimethyl-4-(phenylsulfonyl)piperazin-1-yl)methyl)benzoic acid Methyl ester

Methyl 4-(((2S, 6R)-2,6-dimethylpiperazine-1-yl)methyl)benzoate (Formula 13-2, 0.100g, 0.381mmol) was dissolved in dichloromethane (3mL), and benzenesulfonyl chloride (0.065g, 0.306mmol) and TEA (0.116mL, 0.835mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica; ethyl acetate/hexane=25%) to give the desired compound (0.108g, 88.8%) as a colorless oil.

Step 2: Synthesis of compound 105

4-(((2S, 6R)-2,6-dimethyl-4-(phenylsulfonyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.045g, 0.115mmol) was dissolved in methanol (0.5mL), and hydroxylamine (0.137mL, 2.236mmol, 50.00% aqueous solution) and potassium hydroxide (0.063g, 1.118mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate was added to the concentrate, followed by stirring. The precipitated solid was filtered and dried to give compound 105 (0.027g, 59.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.76-7.74(m, 3H), 7.69-7.68(m, 2H), 7.61(d, 2H, J=8.3Hz), 7.28(d, 2H, J=8.1Hz), 3.71(s, 2H), 3 .44 (d, 2H, J = 10.5Hz), 2.65-2.64 (m, 2H), 2.02 (t, 2H, J = 10.8Hz), 0.91 (d, 6H, J = 6.2Hz); LRMS (ES) m/z 404.1(M ⁺ +1).

Example 12: Synthesis of Compound 106 (4-(((2S,6R)-4-(4-chlorobenzoyl)-2,6-dimethylpiperazine-1- (4-(2-Methyl)-N-hydroxybenzamide)

Step 1: Synthesis of methyl 4-((4-(4-chlorobenzoyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((2S, 6R)-2,6-dimethylpiperazine-1-yl)methyl)benzoate (Formula 13-2, 0.100g, 0.381mmol) was dissolved in dichloromethane (3mL), and 4-chlorobenzoyl chloride (0.054mL, 0.419mmol) and TEA (0.159mL, 1.144mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica; ethyl acetate/hexane=30%) to give the desired compound (0.142g, 92.9%) as a brown oil.

Step 2: Synthesis of compound 106

4-((4-(4-chlorobenzoyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.070g, 0.175mmol) was dissolved in methanol (1mL), and hydroxylamine (0.214mL, 3.492mmol, 50.00% aqueous solution) and potassium hydroxide (0.098g, 1.746mmol) were then added thereto. The mixture was stirred at room temperature for 30 minutes, and saturated sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain compound 106 (0.028g, 39.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.69 (d, 2H, J = 8.3Hz), 7.51 (d, 2H, J = 8.4Hz), 7.48 (d, 2H, J = 8.3Hz), 7.41 (d, 2H, J = 8.4Hz), 4.38-4.37 (m, 1H), 3.88 (s, 2H), 3. 51-3.50 (m, 1H), 3.06-3.05 (m, 1H), 2.82-2.80 (m, 1H), 2.67-2.58 (m, 2H), 1.10 (s, 3H), 0.92-0.88 (m, 3H); LRMS (ES) m/z402.1 (M ⁺ +1).

Example 13: Synthesis of Compound 107 (4-(((2S,6R)-4-(3-chlorobenzoyl)-2,6-dimethylpiperazine-1- (4-(2-Methyl)-N-hydroxybenzamide)

Step 1: Synthesis of methyl 4-((4-(3-chlorobenzoyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((2S, 6R)-2,6-dimethylpiperazine-1-yl)methyl)benzoate (Formula 13-2, 0.100g, 0.278mmol) was dissolved in dichloromethane (3mL), and 3-chlorobenzoyl chloride (0.039mL, 0.306mmol) and TEA (0.116mL, 0.835mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica; ethyl acetate/hexane=30%) to give the desired compound (0.100g, 89.6%) as a yellow oil.

Step 2: Synthesis of compound 107

4-((4-(3-chlorobenzoyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.050g, 0.125mmol) is dissolved in methanol (1mL), and hydroxylamine (0.153mL, 2.494mmol, 50.00% aqueous solution) and potassium hydroxide (0.070g, 1.247mmol) are then added thereto. The mixture is stirred at room temperature for 30 minutes, and saturated sodium bicarbonate is then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer is concentrated under reduced pressure to obtain compound 107 (0.025g, 49.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.68 (d, 2H, J=8.2Hz), 7.54 (d, 1H, J=7.9Hz), 7.52-7.46 (m, 2H), 7.42 (d, 2H, J=8.0Hz), 7.36 (d, 1H, J=7.5Hz), 4.25 (d, 1H, J=9.4Hz), 3.78 (s, 2H), 2.98-2.96 (m, 2H), 2.71-2.68 (m, 3H), 1.02 (s, 3H), 0.84 (s, 3H); LRMS (ES) m/z402.1 (M ⁺ +1).

Example 14: Synthesis of Compound 108 (4-(((2S,6R)-4-(2-chlorobenzoyl)-2,6-dimethylpiperazine-1- (4-(2-Methyl)-N-hydroxybenzamide)

Step 1: Synthesis of methyl 4-((4-(2-chlorobenzoyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate

4-(((2S, 6R)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-2, 0.100g, 0.278mmol) is dissolved in dichloromethane (3mL), and 2-chlorobenzoyl chloride (0.039mL, 0.306mmol) and TEA (0.116mL, 0.835mmol) are then added thereto. The mixture is stirred at room temperature for 1 hour, and then water is added to the reaction mixture, followed by extraction with dichloromethane. The organic layer is concentrated under reduced pressure to obtain the desired compound (0.110g, 98.6%) as a yellow oil.

Step 2: Synthesis of compound 108

4-((4-(2-chlorobenzoyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.055g, 0.137mmol) was dissolved in methanol (1mL), and hydroxylamine (0.168mL, 2.744mmol, 50.00% aqueous solution) and potassium hydroxide (0.077g, 1.372mmol) were then added thereto. The mixture was stirred at room temperature for 30 minutes, and saturated sodium bicarbonate was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain compound 108 (0.025g, 45.3%) as a white solid.

¹ H NMR (400MHz, CD ₃ OD) δ11.13 (s, 1H), 8.97 (s, 1H), 7.68 (d, 2H, J=8.0Hz), 7.53 (d, 1H, J=7.2Hz), 7.44-7.35 (m, 5H), 4.28 (d, 2H, J=11.9Hz), 3.78 (s, 2H), 3.06 (d, 1H, J=12.8Hz), 2.92-2.89 (m, 1H), 2.74-2.61 (m, 3H), 1.02 (d, 3H, J=5.9Hz), 0.81-0.78 (m, 3H); LRMS (ES) m/z 402.1 (M ⁺ +1).

Example 15: Synthesis of Compound 109 (4-(((2S,6R)-4-((4-chlorophenyl)sulfonyl)-2,6-dimethylpiperidin ((1-oxazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S-6R)-4-((4-chlorophenyl)sulfonyl)-2,6-dimethylpiperazin-1-yl)methyl) Methyl benzoate

4-(((2S, 6R)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-2, 0.100g, 0.381mmol) was dissolved in dichloromethane (3mL), and 4-chlorobenzene-1-sulfonyl chloride (0.065g, 0.306mmol) and TEA (0.116mL, 0.835mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and then water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane=30%) and concentrated to give the desired compound (0.108g, 88.8%) as a colorless oil.

Step 2: Synthesis of compound 109

Methyl 4-(((2S, 6R)-4-((4-chlorophenyl)sulfonyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoate (Formula 13-3, 0.05g, 0.114mmol) was dissolved in methanol (1mL), and hydroxylamine (0.140mL, 2.289mmol, 50.00% aqueous solution) and potassium hydroxide (0.064g, 1.144mmol) were then added thereto. The mixture was stirred at room temperature for 30 minutes, and saturated sodium bicarbonate was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give compound 109 (0.035g, 69.8%) as a white solid.

¹ H NMR (400MHz, CD ₃ OD) δ7.78 (d, 2H, J=8.4Hz), 7.66 (d, 4H, J=7.2Hz), 7.43 (d, 2H, J=7.9Hz), 3.83 (s, 2H), 3.52 (d, 2H, J=11.3Hz), 2.21-2.20 (m, 2H), 3.52 (d, 2H, J=11.3Hz), 1.01 (d, 6H, J=6.1Hz); LRMS (ES) m/z 438.0(M ⁺ +1).

Example 16: Synthesis of Compound 110 (4-(((2S,6R)-4-((2-chlorophenyl)sulfonyl)-2,6-dimethylpiperidin ((1-oxazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-((2-chlorophenyl)sulfonyl)-2,6-dimethylpiperazin-1-yl)methyl) Methyl benzoate

Methyl 4-(((2S, 6R)-2,6-dimethylpiperazine-1-yl)methyl)benzoate (Formula 13-2, 0.100g, 0.381mmol) was dissolved in dichloromethane (3mL), and 2-chlorobenzene-1-sulfonyl chloride (0.042mL, 0.306mmol) and TEA (0.116mL, 0.835mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and then water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica; ethyl acetate/hexane=30%) to give the desired compound (0.105g, 68.3%) as a colorless oil.

Step 2: Synthesis of compound 110

4-(((2S, 6R)-4-((2-chlorophenyl)sulfonyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.060g, 0.137mmol) was dissolved in methanol (1mL), and hydroxylamine (0.168mL, 2.746mmol, 50.00% aqueous solution) and potassium hydroxide (0.077g, 1.373mmol) were then added thereto. The mixture was stirred at room temperature for 30 minutes, and saturated sodium bicarbonate was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Compound 110 (0.037g, 61.5%) was obtained as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.10(s, 1H), 9.00(s, 1H), 7.98(d, 1H, J=7.3Hz), 7.71-7.64(m, 4H), 7.60-7.52(m, 1H), 7.37(d, 2H, J=8.1Hz), 3.75 (s, 2H), 3.52 (d, 2H, J=11.3Hz), 2.60-2.56 (m, 4H), 0.93 (d, 6H, J=5.8Hz); LRMS (ES) m/z 438.1(M ⁺ +1).

Example 17: Synthesis of Compound 111 (4-(((2S,6R)-2,6-dimethyl-4-pyridinylpiperazin-1-yl) methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-2,6-dimethyl-4-pyridinylpiperazin-1-yl)methyl)benzoic acid ester

Methyl 4-(((2S, 6R)-2,6-dimethylpiperazine-1-yl)methyl)benzoate (Formula 13-2, 0.100g, 0.381mmol) was dissolved in dichloromethane (3mL), and picolinyl chloride (0.075g, 0.419mmol) and TEA (0.159mL, 1.144mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and then water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate = 100%) and concentrated to give the desired compound (0.046g, 32.8%) as a yellow oil.

Step 2: Synthesis of compound 111

4-(((2S, 6R)-2,6-dimethyl-4-pyridinylpiperazine-1-yl)methyl)methyl benzoate (Formula 13-3, 0.02g, 0.054mmol) is dissolved in methanol (1mL), and hydroxylamine (0.067mL, 1.089mmol, 50.00% aqueous solution) and potassium hydroxide (0.03g, 0.544mmol) are then added thereto. The mixture is stirred at room temperature for 30 minutes, and saturated sodium bicarbonate is then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer is concentrated under reduced pressure to obtain compound 111 (0.001g, 5.0%) as a colorless oil.

¹ H NMR (400 MHz, DMSO-d ₆ )δ8.65 (dd, 1H, J=10.2, 3.6Hz), 8.62 (d, 1H, J=3.0Hz), 7.90 (dd, 1H, J=10.2, 3.6Hz), 7.70 (d, 2H, J=8.4Hz), 7.55-7.51 (m, 3H), 4.42 (d, 1H, J=12. 3Hz), 3.89 (s, 2H), 3.49 (d, 1H, J=12.7Hz), 3.12-3.11 (m, 1H), 2.85-2.84 (m, 1H), 2.72-2.63 (m, 2H), 1.12 (d, 3H, J=3.6Hz), 0.92 (d, 3H, J=5.2Hz).

Example 18: Synthesis of Compound 112 (4-(((2S,6R)-2,6-dimethyl-4-nicotinoylpiperazin-1-yl)methyl 1-Hydroxybenzamide)

Step 1: Synthesis of methyl (((2S,6R)-2,6-dimethyl-4-nicotinoylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((2S, 6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.100 g, 0.381 mmol) was dissolved in dichloromethane (3 mL), and nicotinoyl chloride (0.075 g, 0.419 mmol) and TEA (0.159 mL, 1.144 mmol) were added thereto. The mixture was stirred at room temperature for 1 hour, and then water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; methanol/dichloromethane = 5%) and concentrated to give the desired compound (0.119 g, 85.0%) as a yellow oil.

Step 2: Synthesis of compound 112

Methyl (((2S, 6R)-2,6-dimethyl-4-nicotinoylpiperazine-1-yl)methyl)benzoate (Formula 13-3, 0.060 g, 0.163 mmol) was dissolved in methanol (1 mL), and hydroxylamine (0.200 mL, 3.266 mmol, 50.00% aqueous solution) and potassium hydroxide (0.092 g, 1.633 mmol) were added thereto. The mixture was stirred at room temperature for 30 minutes, and then saturated sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure and extracted with ethyl acetate and water. The organic layer was concentrated under reduced pressure to obtain compound 112 (0.001 g, 1.7%) as a colorless oil.

¹ H NMR (400 MHz, DMSO-d ₆ )δ8.65 (dd, 1H, J=10.2, 3.6Hz), 8.62 (d, 1H, J=3.0Hz), 7.90 (dd, 1H, J=10.2 , 3.6Hz), 7.70 (d, 2H, J = 8.4Hz), 7.55-7.51 (m, 3H), 4.42 (d, 1H, J = 12.3Hz), 3 .89(s, 2H), 3.49(d, 1H, J=12.7Hz), 3.12-3.11(m, 1H), 2.85-2.84(m, 1H), 2 .72-2.63 (m, 2H), 1.12 (d, 3H, J = 3.6Hz), 0.92 (d, 3H, J = 5.2Hz); LRMS (ES) m/z 369.2(M ⁺⁺ 1).

Example 19: Synthesis of Compound 113 (4-(((2S,6R)-2,6-dimethyl-4-(pyridin-3-ylsulfonyl)piperidin ((1-oxazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-2,6-dimethyl-4-(pyridin-3-ylsulfonyl)piperazin-1-yl)methyl)benzene Methyl formate

Methyl 4-(((2S, 6R)-2,6-dimethylpiperazine-1-yl)methyl)benzoate (Formula 13-2, 0.100g, 0.381mmol) was dissolved in dichloromethane (3mL), and pyridine-3-sulfonyl chloride (0.090g, 0.419mmol) and TEA (0.159mL, 1.144mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and then water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; methanol/dichloromethane=5%) and concentrated to give the desired compound (0.105g, 68.3%) as a white solid.

Step 2: Synthesis of compound 113

4-(((2S, 6R)-2,6-dimethyl-4-(pyridin-3-ylsulfonyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.600g, 0.149mmol) was dissolved in methanol (1mL), and hydroxylamine (0.182mL, 2.974mmol, 50.00% aqueous solution) and potassium hydroxide (0.830g, 1.487mmol) were then added thereto. The mixture was stirred at room temperature for 30 minutes, and saturated sodium bicarbonate was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Compound 113 (0.033g, 54.9%) was obtained as a white solid.

¹ H NMR (400MHz, CD ₃ OD) δ 8.93 (d, 1H, J = 2.3Hz), 8.84 (dd, 1H, J = 10.2, 3.6Hz), 8.22-8.20 (m, 1H), 7.66-7.65 (m, 1H), 7.65 (d, 2H, J = 8.3Hz), 7.42 (d, 2 H, J=8.2Hz), 3.83 (s, 2H), 3.58 (d, 2H, J=11.5Hz), 2.74-2.72 (m, 2H), 2.24 (t, 2H, J=10.8Hz), 1.01 (d, 6H, J=6.2Hz); LRMS (ES) m/z 405.1(M ⁺ +1).

Example 20: Synthesis of Compound 114 (4-(((2S,6R)-2,6-dimethyl-4-(thiophene-2-carbonyl)piperazine-1- (4-(2-Methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-2,6-dimethyl-4-(thiophene-2-carbonyl)piperazin-1-yl)methyl)benzoic acid Methyl ester

Methyl 4-(((2S, 6R)-2,6-dimethylpiperazine-1-yl)methyl)benzoate (Formula 13-2, 0.100g, 0.381mmol) was dissolved in dichloromethane (3mL), and thiophene-2-carbonyl chloride (0.046mL, 0.419mmol) and TEA (0.159mL, 1.144mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and then water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane=30%) and concentrated to give the desired compound (0.127g, 89.5%) as a yellow oil.

Step 2: Synthesis of compound 114

4-(((2S, 6R)-2,6-dimethyl-4-(thiophene-2-carbonyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.070g, 0.188mmol) was dissolved in methanol (1mL), and hydroxylamine (0.230mL, 3.759mmol, 50.00% aqueous solution) and potassium hydroxide (0.105g, 1.879mmol) were then added thereto. The mixture was stirred at room temperature for 30 minutes, and saturated sodium bicarbonate was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain compound 114 (0.013g, 18.5%) as a white solid.

¹ H NMR (400MHz, CD ₃ OD) δ7.70 (d, 2H, J=8.4Hz), 7.65 (dd, 1H, J=10.2, 3.6Hz), 7.52 (d, 2H, J=8.4Hz), 7.40 (dd, 1H, J=10.2, 3.6Hz), 7.12 (dd, 1H, J=10.2, 3.6Hz), 4.20-4.19 (m, 2H), 3.89 (s, 2H), 3.03-2.97 (m, 2H), 2.70-2.62 (m, 2H), 1.05 (d, 6H, J=5.6Hz); LRMS (ES) m/z 374.1(M ⁺ +1).

Example 21: Synthesis of Compound 115 (4-(((2S,6R)-4-(furan-2-carbonyl)-2,6-dimethylpiperazine-1- (4-(2-Methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(furan-2-carbonyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoic acid Methyl ester

Methyl 4-(((2S, 6R)-2,6-dimethylpiperazine-1-yl)methyl)benzoate (Formula 13-2, 0.100g, 0.381mmol) was dissolved in dichloromethane (3mL), and furan-2-carbonyl chloride (0.040mL, 0.419mmol) and TEA (0.159mL, 1.144mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and then water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane=30%) and concentrated to give the desired compound (0.115g, 84.7%) as a light yellow oil.

Step 2: Synthesis of compound 115

4-(((2S, 6R)-4-(furan-2-carbonyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.060g, 0.168mmol) was dissolved in methanol (1mL), and hydroxylamine (0.206mL, 3.367mmol, 50.00% aqueous solution) and potassium hydroxide (0.095g, 1.683mmol) were then added thereto. The mixture was stirred at room temperature for 30 minutes, and saturated sodium bicarbonate was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain compound 115 (0.007g, 11.6%) as a light yellow solid.

¹ H NMR (400MHz, CD ₃ OD) δ7.71-7.69 (m, 3H), 7.53 (d, 2H, J=8.4Hz), 7.04 (dd, 1H, J=10.2, 3.6Hz), 6.59 (dd, 1H, J=10.2, 3.6Hz), 4. 31 (d, 2H, J = 13.1Hz), 3.90 (s, 2H), 2.85-2.82 (m, 2H), 2.69-2.65 (m, 2H), 1.08 (d, 6H, J = 5.4Hz); LRMS (ES) m/z 358.1(M ⁺ +1).

Example 22: Synthesis of Compound 118 (4-(((2S,6R)-4-(2-chlorobenzyl)-2,6-dimethylpiperazin-1-yl) methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(2-chlorobenzyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoic acid ester

Methyl 4-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.100 g, 0.278 mmol) was dissolved in acetonitrile (2 mL), and ₂ -chlorobenzyl bromide (0.038 mL, 0.292 mmol) and _K₂CO₃ (0.096 g, 0.696 mmol) were added. The mixture was stirred at room temperature for 2 hours, and the reaction mixture was then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = 25%) and concentrated to give the desired compound (0.080 g, 74.3%) as a light yellow oil.

Step 2: Synthesis of compound 118

4-(((2S, 6R)-4-(2-chlorobenzyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.040g, 0.103mmol) is dissolved in methanol (1mL), and hydroxylamine (0.126mL, 2.068mmol, 50.00% aqueous solution) and potassium hydroxide (0.058g, 1.034mmol) are then added thereto. The mixture is stirred at room temperature for 30 minutes, and the reaction mixture is then concentrated under reduced pressure. Saturated sodium bicarbonate is added to the concentrate, followed by stirring. The precipitated solid is filtered and dried to give compound 118 (0.018g, 43.3%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.65(d, 2H, J=8.2Hz), 7.37-7.33(m, 4H), 7.33-7.31(m, 2H), 3.74(s, 2H), 3.41(s, 2H), 2 .65-2.62(m, 2H), 2.55-2.51(m, 2H), 1.83-1.82(m, 2H), 0.88(d, 6H, J=6.1Hz); LRMS(ES)m/z 388.1(M ⁺ +1).

Example 23: Synthesis of Compound 119 (4-(((2S,6R)-4-(4-fluorophenyl)-2,6-dimethylpiperazin-1-yl) methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(4-fluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoic acid ester

Pd(OAc) ₂ (0.006 g, 0.028 mmol) and xantphos (0.003 g, 0.006 mmol) were dissolved in toluene, and then 1-bromo-4-fluorobenzene (0.049 g, 0.278 mmol), methyl 4-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.100 g, 0.278 mmol), and Cs ₂ CO ₃ (0.227 g, 0.696 mmol) were added thereto. The mixture was heated and stirred at 100° C. for 17 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = 15%) and concentrated to obtain the desired compound (0.007 g, 7.1%) as a white solid.

Step 2: Synthesis of compound 119

4-(((2S, 6R)4-(4-fluorophenyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 19-1, 0.007g, 0.020mmol) is dissolved in methanol (1mL), and hydroxylamine (0.024mL, 0.393mmol, 50.00% aqueous solution) and potassium hydroxide (0.011g, 0.196mmol) are then added thereto. The mixture is stirred at room temperature for 30 minutes, and the reaction mixture is then concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate is added to the concentrate, followed by extraction with ethyl acetate. The organic layer is concentrated under reduced pressure to obtain compound 119 (0.003g, 58.0%) as a light brown solid.

¹ H NMR (400MHz, CD ₃ OD) δ7.71 (d, 2H, J=8.2Hz), 7.53 (d, 2H, J=8.2Hz), 6.98-6.95 (m, 4H), 4.12 (s, 2H), 3.41 (d, 2 H, J=11.4Hz), 2.81-2.78 (m, 2H), 2.51 (t, 2H, J=11.1Hz), 1.12 (d, 6H, J=6.1Hz); LRMS (ES) m/z 358.1(M ⁺ +1).

Example 24: Synthesis of Compound 120 (4-(((3R,5S)-4-(2-chlorobenzoyl)-3,5-dimethylpiperazine-1- (4-(2-Methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(2-chlorobenzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzyl Methyl ester

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-2, 0.100g, 0.381mmol) was dissolved in dichloromethane (1mL), and 2-chlorobenzoyl chloride (0.058mL, 0.801mmol) and TEA (0.106mL, 0.762mmol) were then added thereto. The mixture was stirred at room temperature for 2 hours, and then water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was separated and concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; methanol/dichloromethane=5%) and concentrated to give the desired compound (0.076g, 49.7%) as a yellow oil.

Step 2: Synthesis of Compound 120

Methyl 4-(((3R, 5S)-4-(2-chlorobenzoyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-3, 0.070 g, 0.175 mmol) was dissolved in methanol (1 mL) and hydroxylamine (0.214 mL, 3.492 mmol, 50.00% aqueous solution) and potassium hydroxide (0.098 g, 1.746 mmol) were added thereto. The mixture was stirred at room temperature for 1 hour, and saturated sodium bicarbonate was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure to give compound 120 (0.029 g, 41.3%) as a light yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.69 (d, 2H, J=8.1Hz), 7.41-7.40 (m, 3H), 7.33 (d, 2H, J=8.0Hz), 3.51 (s, 2H), 2.79-2.61 (m, 4H), 2.14-2.13 (m, 2H), 1.36 (d, 3H, J=6.8Hz), 1.24-1.18 (m, 3H).

Example 25: Synthesis of Compound 121 (4-(((3R,5S)-4-(3-chlorobenzoyl)-3,5-dimethylpiperazine-1- (4-(2-Methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-chlorobenzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzyl Methyl ester

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-2, 0.100g, 0.381mmol) was dissolved in dichloromethane (1mL), and 3-chlorobenzoyl chloride (0.080g, 0.457mmol) and TEA (0.106mL, 0.762mmol) were then added thereto. The mixture was stirred at room temperature for 2 hours, and then water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was separated and concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; methanol/dichloromethane=5%) and concentrated to give the desired compound (0.062g, 40.6%) as a light yellow oil.

Step 2: Synthesis of compound 121

Methyl 4-(((3R, 5S)-4-(3-chlorobenzoyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-3, 0.050 g, 0.125 mmol) was dissolved in methanol (1 mL) and hydroxylamine (0.153 mL, 2.494 mmol, 50.00% aqueous solution) and potassium hydroxide (0.070 g, 1.247 mmol) were added thereto. The mixture was stirred at room temperature for 1 hour, and saturated sodium bicarbonate was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure to give compound 121 (0.021 g, 41.9%) as a light yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.68 (d, 2H, J=8.0Hz), 7.47-7.41 (m, 3H), 7.32 (d, 2H, J=8.0Hz), 7.29 (s, 1 H), 3.49 (s, 2H), 2.61-2.50 (m, 4H), 2.16-2.12 (m, 2H), 1.28 (d, 6H, J=5.6Hz).

Example 26: Synthesis of Compound 122 (4-(((3R,5S)-4-(4-chlorobenzoyl)-3,5-dimethylpiperazine-1- (4-(2-Methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(4-chlorobenzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzyl Methyl ester

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-2, 0.100g, 0.381mmol) was dissolved in dichloromethane (1mL), and 4-chlorobenzoyl chloride (0.080g, 0.457mmol) and TEA (0.106mL, 0.762mmol) were then added thereto. The mixture was stirred at room temperature for 2 hours, and then water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was separated and concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; methanol/dichloromethane=5%) and concentrated to give the desired compound (0.059g, 38.6%) as a light yellow oil.

Step 2: Synthesis of compound 122

Methyl 4-(((3R, 5S)-4-(4-chlorobenzoyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-3, 0.050 g, 0.125 mmol) was dissolved in methanol (1 mL) and hydroxylamine (0.153 mL, 2.494 mmol, 50.00% aqueous solution) and potassium hydroxide (0.070 g, 1.247 mmol) were added thereto. The mixture was stirred at room temperature for 1 hour, and saturated sodium bicarbonate was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure to give compound 122 (0.014 g, 27.9%) as a light yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.10 (brs, 1H), 9.05 (brs, 1H), 7.72 (d, 2H, J=8.1Hz), 7.50 (d, 2H, J=8.3Hz), 7.43 (d, 2H, J=8.1Hz), 7.38 (d, 2H, J=8.4H z), 4.10 (brs, 2H), 3.54 (s, 2H), 2.63 (d, 2H, J = 11.1Hz), 2.15 (dd, 2H, J = 11.3, 4.1Hz), 1.29 (d, 6H, J = 6.1Hz); LRMS (ES) m/z 402.8(M ⁺ +1).

Example 27: Synthesis of Compound 123 (4-(((3R,5S)-3,5-dimethyl-4-pyridinylpiperazin-1-yl) methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-pyridinylpiperazin-1-yl)methyl)benzoic acid ester

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-2, 0.100g, 0.381mmol) was dissolved in dichloromethane (1mL), and picolinyl chloride (0.065g, 0.457mmol) and TEA (0.106mL, 0.762mmol) were then added thereto. The mixture was stirred at room temperature for 2 hours, and then water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was separated and concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; methanol/dichloromethane=5%) and concentrated to give the desired compound (0.042g, 30.0%) as a white solid.

Step 2: Synthesis of compound 123

Methyl 4-(((3R, 5S)-3,5-dimethyl-4-pyridinylpiperazine-1-yl)methyl)benzoate (Formula 1-3, 0.035g, 0.095mmol) was dissolved in methanol (1mL), and hydroxylamine (0.117mL, 1.905mmol, 50.00% aqueous solution) and potassium hydroxide (0.053g, 0.953mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and saturated sodium bicarbonate was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure to give compound 123 (0.011g, 31.3%) as a light yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.56-8.55 (m, 1H), 7.82 (d, 2H, J=8.0Hz), 3.71 (s, 2H), 2.96 (brs, 2H), 2.56 (brs, 2H), 1.02 (brs, 3H), 0.88 (brs, 3H); LRMS (ES) m/z 369.4 (M ⁺ +1).

Example 28: Synthesis of Compound 125 (4-(((3R,5S)-4-(furan-2-carbonyl)-3,5-dimethylpiperazine-1- (4-(2-Methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(furan-2-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoic acid Methyl ester

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 6.000 g, 22.870 mmol) and TEA (4.781 mL, 34.305 mmol) were dissolved in dichloromethane (120 mL) at 0°C, and furan-2-carbonyl chloride (2.488 mL, 25.157 mmol) was added to the solution, which was then stirred at the same temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica; 80 g cartridge; ethyl acetate/hexane = from 0% to 30%) to give the desired compound (7.440 g, 91.3%) as a white solid.

Step 2: Synthesis of compound 125

Methyl 4-(((3R,5S)-4-(furan-2-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-3, 7.440 g, 20.874 mmol), hydroxylamine (25.536 mL, 417.485 mmol, 50.00% aqueous solution) and potassium hydroxide (11.713 g, 208.742 mmol) were dissolved in methanol (150 mL) at 0°C, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to give compound 125 (5.330 g, 71.4%) as an apricot-yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.23 (brs, 1H), 9.06 (brs, 1H), 7.81 (s, 1H), 7.74 (d, 2H, J=7.6Hz), 7.42 (d, 2H, J=5.8Hz), 6.95 (d, 1H, J=3.3Hz), 6.61-6 .60 (m, 1H), 4.49 (brs, 2H), 3.54 (s, 2H), 2.68 (d, 2H, J = 11.0Hz), 2.14 (d, 2H, J = 8.2Hz), 1.25 (d, 6H, J = 5.6Hz); LRMS (ES) m/z 358.2(M ⁺ +1).

Example 29: Synthesis of Compound 126 (4-(((3R,5S)-3,5-dimethyl-4-(thiophene-2-carbonyl)piperazine-1- (4-(2-Methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(thiophene-2-carbonyl)piperazin-1-yl)methyl)benzoic acid Methyl ester

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-2, 0.100g, 0.381mmol) was dissolved in dichloromethane (1mL), and thiophene-2-carbonyl chloride (0.067g, 0.457mmol) and TEA (0.106mL, 0.762mmol) were then added thereto. The mixture was stirred at room temperature for 2 hours, and then water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was separated and concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; methanol/dichloromethane=5%) and concentrated to give the desired compound (0.061g, 43.0%) as a light yellow oil.

Step 2: Synthesis of compound 126

Methyl 4-(((3R, 5S)-3,5-dimethyl-4-(thiophene-2-carbonyl)piperazine-1-yl)methyl)benzoate (Formula 1-3, 0.050 g, 0.134 mmol) was dissolved in methanol (1 mL) and hydroxylamine (0.164 mL, 2.685 mmol, 50.00% aqueous solution) and potassium hydroxide (0.075 g, 1.342 mmol) were added thereto. The mixture was stirred at room temperature for 1 hour, and saturated sodium bicarbonate was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure to give compound 126 (0.019 g, 37.9%) as a light yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.72-7.71(m, 3H), 7.41-7.36(m, 3H), 7.10(brs, 1H), 4.43(brs, 2H), 3 .52 (s, 2H), 2.67-2.64 (m, 2H), 2.14-2.12 (m, 2H), 1.36 (d, 6H, J=5.5Hz).

Example 30: Synthesis of Compound 127 (4-(((3R,5S)-4-(2-chlorobenzyl)-3,5-dimethylpiperazin-1-yl) methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(2-chlorobenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoic acid ester

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol) was dissolved in acetonitrile (2 mL), followed by the addition _of 1-(bromomethyl)-2-chlorobenzene (0.094 g, 0.457 mmol) and _K₂CO₃ (0.105 g, 0.762 mmol). The mixture was stirred at room temperature for 16 hours, after which water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; methanol/dichloromethane = 5%) and concentrated to yield the desired compound (0.035 g, 23.7%) as a white oil.

Step 2: Synthesis of compound 127

Methyl 4-(((3R, 5S)-4-(2-chlorobenzyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-3, 0.030g, 0.078mmol) was dissolved in methanol (0.5mL), and hydroxylamine (0.095mL, 1.551mmol, 50.00% aqueous solution) and potassium hydroxide (0.044g, 0.775mmol) were added thereto. The mixture was stirred at room temperature for 1 hour, and then water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Compound 127 (0.011g, 36.6%) was obtained as a light yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.78-7.68 (m, 3H), 7.32-7.19 (m, 6H), 3.68 (s, 2H), 3.44 (s, 2H), 2.69-2.66 (m, 4H), 1.86-1.83 (m, 2H), 0.78 (brs, 6H).

Example 31: Synthesis of Compound 128 (4-(((3R,5S)-4-(3-chlorobenzyl)-3,5-dimethylpiperazin-1-yl) methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-chlorobenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoic acid ester

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol) was dissolved in acetonitrile (2 mL), followed by the addition of 1-(bromomethyl)-3-chlorobenzene (0.094 g, 0.457 mmol) and _K₂CO₃ (0.105 g, 0.762 mmol). The mixture was stirred at room temperature for 16 hours, after which water was added _to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; methanol/dichloromethane = 5%) and concentrated to yield the desired compound (0.041 g, 27.8%) as a white oil.

Step 2: Synthesis of Compound 128

Methyl 4-(((3R, 5S)-4-(3-chlorobenzyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-3, 0.035 g, 0.090 mmol) was dissolved in methanol (0.5 mL), and hydroxylamine (0.111 mL, 1.809 mmol, 50.00% aqueous solution) and potassium hydroxide (0.051 g, 0.905 mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and then water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Compound 128 (0.015 g, 42.7%) was obtained as a light yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.68 (d, 2H, J=9.6Hz), 7.38 (s, 1H), 7.30 (d, 2H, J=4.0Hz), 7.27-7.20 (m, 3H), 3.6 9 (s, 2H), 3.40 (s, 2H), 2.64-2.54 (m, 4H), 1.82-1.75 (m, 2H), 0.84 (d, 6H, J=8.0Hz).

Example 32: Synthesis of Compound 145 (4-(((3R,5S)-4-(furan-2-ylmethyl)-3,5-dimethylpiperazine- (1-amino)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(furan-2-ylmethyl)-3,5-dimethylpiperazin-1-yl)methyl)benzene Methyl ester

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.300 g, 1.144 mmol) and 2-furfural (0.104 mL, 1.258 mmol) were dissolved in dichloromethane (5 mL), and acetic acid (0.069 mL, 1.144 mmol) was added thereto at 40°C, followed by stirring for 1 hour. Na(CN) _BH3 (0.072 g, 1.144 mmol) was added to the reaction mixture, followed by stirring at the same temperature for 3 days. Then, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = 25%) and concentrated to obtain the desired compound (0.028 g, 7.2%) as a light yellow oil.

Step 2: Synthesis of compound 145

Methyl 4-(((3R, 5S)-4-(furan-2-ylmethyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-3, 0.028g, 0.082mmol) was dissolved in methanol (1mL), and hydroxylamine (0.100mL, 1.635mmol, 50.00% aqueous solution) and potassium hydroxide (0.046g, 0.818mmol) were then added thereto. The mixture was stirred at room temperature for 30 minutes, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate aqueous solution was added to the concentrate, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Compound 145 (0.013g, 46.3%) was obtained as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.10 (brs, 1H), 9.00 (brs, 1H), 7.67 (d, 2H, J=8.1Hz), 7.59 (d, 1H, J=2.4Hz), 7.30 (d, 2H, J=8.1Hz), 6.41-6.40 (m, 1H), 6.28- 6.27 (m, 1H), 3.86 (s, 2H), 3.38 (s, 2H), 2.60 (d, 2H, J=10.0Hz), 2.44-2.40 (m, 2H), 1.74 (t, 2H, J=10.6Hz), 0.87 (d, 6H, J=6.4Hz).

Example 33: Synthesis of Compound 146 (4-(((3R,5S)-3,5-dimethyl-4-(2-phenylacetyl)piperazine-1- (4-(2-Methyl)-N-hydroxybenzamide)

Step 1: Synthesis of methyl 4-(((3R , 5S)-3,5-dimethyl-4-(2-phenylacetyl)piperazin-1-yl) methyl ) benzoate

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-2, 0.100g, 0.381mmol) was dissolved in dichloromethane (1mL), and 2-phenylacetyl chloride (0.065g, 0.419mmol) and TEA (0.106mL, 0.762mmol) were then added thereto. The mixture was stirred at room temperature for 15 hours, and then water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was separated and concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; methanol/dichloromethane=5%) and concentrated to give the desired compound (0.042g, 29.0%) as a white solid.

Step 2: Synthesis of compound 146

Methyl 4-(((3R, 5S)-3,5-dimethyl-4-(2-phenylacetyl)piperazine-1-yl)methyl)benzoate (Formula 1-3, 0.030 g, 0.079 mmol) was dissolved in methanol (0.5 mL) and hydroxylamine (0.096 mL, 1.577 mmol, 50.00% aqueous solution) and potassium hydroxide (0.044 g, 0.788 mmol) were added thereto. The mixture was stirred at room temperature for 1 hour, and saturated sodium bicarbonate was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure to give compound 146 (0.014 g, 46.5%) as a light yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.69 (d, 2H, J=8.0Hz), 7.34 (d, 2H, J=8.0Hz), 7.31-7.27 (m, 2H), 7.22-7.20 (m, 3H), 4.41 (brs, 1H), 4.12(brs, 1H), 3.47-3.33(m, 2H), 3.31(s, 2H), 2.62-2.59(m, 2H), 2.02-2.01(m, 2H), 1.22(brs, 6H).

Example 34: Synthesis of Compound 147 (4-(((3R,5S)-4-ethyl-3,5-dimethylpiperazin-1-yl)methyl)- N-hydroxybenzamide)

Step 1: Synthesis of methyl 4-(((3R,5S)-4-ethyl-3,5-dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol), iodoethane (0.037 mL, 0.457 mmol), and _{K₂CO₃ (} 0.105 g, 0.762 mmol) were dissolved in acetonitrile (1 mL) and stirred at room temperature for 7 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; methanol/dichloromethane = 5%) and concentrated to obtain the desired compound (0.059 g, 53.3%) as a light yellow solid.

Step 2: Synthesis of compound 147

4-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 1-3, 0.040g, 0.174mmol) was dissolved in methanol (0.5mL), and hydroxylamine (0.213mL, 3.487mmol, 50.00% aqueous solution) and potassium hydroxide (0.098g, 1.744mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate aqueous solution was added to the concentrate, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Compound 147 (0.010g, 19.7%) was obtained as a brown solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.65 (d, 2H, J=7.8Hz), 7.20 (d, 2H, J=7.9Hz), 2.73 (q, 2H, J=7.6Hz), 2.61- 2.55 (m, 4H), 1.70-1.66 (m, 2H), 0.90 (d, 6H, J=5.9Hz), 0.81 (t, 3H, J=7.0Hz).

Compound 35: Synthesis of Compound 148 (4-(((3R,5S)-3,5-dimethyl-4-propylpiperazin-1-yl)methyl)- N-hydroxybenzamide)

Step 1: Synthesis of methyl 4-(((3R,5S)-3,5-dimethyl-4-propylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol), iodopropane (0.045 mL, 0.457 mmol), and _{K₂CO₃ (} 0.105 g, 0.762 mmol) were dissolved in acetonitrile (1 mL) and stirred at room temperature for 7 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; methanol/dichloromethane = 5%) and concentrated to obtain the desired compound (0.054 g, 46.5%) as a white solid.

Step 2: Synthesis of Compound 148

4-(((3R, 5S)-3,5-dimethyl-4-propylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 1-3, 0.040g, 0.131mmol) was dissolved in methanol (0.5mL), and hydroxylamine (0.161mL, 3.487mmol, 50.00% aqueous solution) and potassium hydroxide (0.074g, 1.314mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate aqueous solution was added to the concentrate, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Compound 148 (0.017g, 42.4%) was obtained as a brown solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.66 (d, 2H, J=8.0Hz), 7.21 (d, 2H, J=8.0Hz), 3.35 (s, 2H), 2.60-2.52 (m, 6H), 1.6 8 (t, 2H, J=10.4Hz), 1.32-1.30 (m, 2H), 0.90 (d, 6H, J=6.0Hz), 0.76 (t, 3H, J=7.4Hz).

Example 36: Synthesis of Compound 149 (4-(((3R,5S)-3,5-dimethyl-4-(2,2,2-trifluoroethyl)piperazine- (1-amino)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of methyl 4-(((3R,5S)-3,5-dimethyl-4-(2,2,2 - trifluoroethyl)piperazin-1-yl) methyl ) benzoate

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.066 mL, 0.457 mmol), and _K₂CO₃ (0.105 g, 0.762 mmol) were dissolved in _acetonitrile (1 mL) and stirred at room temperature for 12 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; methanol/dichloromethane = 5%) and concentrated to obtain the desired compound (0.062 g, 47.2%) as a white oil.

Step 2: Synthesis of Compound 149

Methyl 4-(((3R, 5S)-3,5-dimethyl-4-(2,2,2-trifluoroethyl)piperazine-1-yl)methyl)benzoate (Formula 1-3, 0.030 g, 0.087 mmol) was dissolved in methanol (0.5 mL), and hydroxylamine (0.107 mL, 1.742 mmol, 50.00% aqueous solution) and potassium hydroxide (0.049 g, 1.744 mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate aqueous solution was added to the concentrate, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Compound 149 (0.011 g, 36.6%) was obtained as a brown solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.68 (d, 2H, J=7.9Hz), 7.31 (d, 2H, J=8.0Hz), 3.41 (s, 2H), 3.28 (s, 2H), 2.70 -2.63 (m, 2H), 2.60-2.49 (m, 2H), 1.73 (t, 2H, J=10.5Hz), 0.96 (d, 6H, J=6.2Hz).

Example 37: Synthesis of Compound 154 (6-((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)-N-hydroxy Hexamethylene)

Step 1: Synthesis of ethyl 6-((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)hexanoate

(2S,6R)-1-benzyl-2,6-dimethylpiperazine (Formula 8-3, 0.100 g, 0.489 mmol) was dissolved in acetonitrile (1 mL), and ethyl 6-bromohexanoate (Formula 8-4, 0.131 g, 0.587 mmol) and _Cs2CO3 (0.319 _g , 0.979 mmol) were then added. The mixture was stirred at room temperature for 20 hours, after which water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = 20%) and concentrated to yield the desired compound (0.090 g, 53.1%) as a white oil.

Step 2: Synthesis of compound 154

6-((3R, 5S)-4-benzyl-3,5-dimethylpiperazine-1-yl)ethyl hexanoate (Formula 8-5, 0.040 g, 0.115 mmol) was dissolved in methanol (0.5 mL), and hydroxylamine (0.141 mL, 2.309 mmol, 50.00% aqueous solution) and potassium hydroxide (0.065 g, 1.154 mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate was added to the concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain compound 154 (0.021 g, 54.6%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.33-7.24(m, 4H), 7.17-7.15(m, 1H), 3.69(s, 2H), 2.68-2.53(m, 4H), 2.13(t, 2H, J=7.2Hz), 1.86( t, 2H, J=7.4Hz), 1.66 (t, 2H, J=10.6Hz), 1.45-1.34 (m, 4H), 1.20-1.18 (m, 2H), 0.84 (d, 6H, J=8.0Hz).

Example 38: Synthesis of Compound 159 ((2S,6R)-4-(4-(hydroxycarbamoyl)benzyl)-2,6-dimethyl- N-phenylpiperazine-1-carboxamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(phenylcarbamoyl)piperazin-1-yl)methyl)benzene Methyl formate

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Compound 1-2, 0.150 g, 0.572 mmol) was dissolved in dichloromethane (2 mL), and phenyl isocyanate (0.069 mL, 0.629 mmol) and TEA (0.119 mL, 0.858 mmol) were added thereto. The mixture was stirred at 0 ° C for 2 hours and then at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate / hexane = 30%) and concentrated to give the desired compound (0.171 g, 78.4%) as a white solid.

Step 2: Synthesis of compound 159

Methyl 4-(((3R, 5S)-3,5-dimethyl-4-(phenylcarbamoyl)piperazine-1-yl)methyl)benzoate (Formula 1-3, 0.100 g, 0.262 mmol) was dissolved in methanol (2 mL), and hydroxylamine (0.321 mL, 5.243 mmol, 50.00% aqueous solution) and potassium hydroxide (0.147 g, 2.621 mmol) were then added thereto. The mixture was stirred at room temperature for 30 minutes, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate was added to the concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give compound 159 (0.030 g, 29.9%) as a white solid.

¹ H NMR (400MHz, CD ₃ OD) δ8.22 (s, 1H), 7.69 (d, 2H, J=8.1Hz), 7.44 (d, 2H, J=7.4Hz), 7.34-7.32 (m, 2H), 6.92-6.89 (m, 1H), 4.20 -4.17 (m, 2H), 7.50 (s, 2H), 2.64 (d, 2H, J = 11.1Hz), 2.12-2.08 (m, 2H), 1.26 (d, 6H, J = 6.7Hz); LRMS (ES) m/z 383.2(M ⁺ +1).

Example 39: Synthesis of Compound 160 ((2S,6R)-4-(4-(hydroxycarbamoyl)benzyl)-2,6-dimethyl- N-o-Tolylpiperazine-1-carboxamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(o-tolylcarbamoyl)piperazin-1-yl)methyl methyl)benzoate

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-2, 0.200g, 0.762mmol) was dissolved in dichloromethane (3mL), and o-tolyl isocyanate (0.103mL, 0.839mmol) and TEA (0.159mL, 1.144mmol) were then added thereto. The mixture was stirred at 0°C for 2 hours and then at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica; methanol/dichloromethane = 5%) to give the desired compound (0.030g, 10.0%) as a white solid.

Step 2: Synthesis of compound 160

Methyl 4-(((3R, 5S)-3,5-dimethyl-4-(o-tolylcarbamoyl)piperazine-1-yl)methyl)benzoate (Formula 1-3, 0.030 g, 0.076 mmol) was dissolved in methanol (2 mL), and hydroxylamine (0.093 mL, 1.517 mmol, 50.00% aqueous solution) and potassium hydroxide (0.043 g, 0.759 mmol) were then added thereto. The mixture was stirred at room temperature for 30 minutes, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate was added to the concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give compound 160 (0.010 g, 33.3%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.10 (s, 1H), 9.00 (s, 1H), 7.85 (s, 1H), 7.72 (d, 2H, J=8.2Hz), 7.43 (d, 2H, J=8.0Hz), 7.17-7.10 (m, 3H), 7.03 (dd, 1H, J=10.2, 3.6Hz), 3.54 (s, 2H), 2.65 (d, 2H, J=11.2Hz), 2.16 (s, 3H), 2.12-2.13 (m, 1H). 1.30 (d, 6H, J=6.6Hz); LRMS (ES) m/z 397.2 (M ⁺ +1).

Example 40: Synthesis of Compound 161 ((2S,6R)-N-benzyl-4-(4-(hydroxycarbamoyl)benzyl)-2,6- dimethylpiperazine-1-carboxamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(benzylcarbamoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzene Methyl formate

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-2, 0.150 g, 0.572 mmol) was dissolved in dichloromethane (2 mL), and benzyl isocyanate (0.078 mL, 0.629 mmol) and TEA (0.119 mL, 0.858 mmol) were then added thereto at 0°C. The mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica; ethyl acetate/hexane=30%) to give the desired compound (0.517 g, 69.4%) as a white solid.

Step 2: Synthesis of compound 161

Methyl 4-(((3R, 5S)-4-(benzylcarbamoyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-3, 0.100 g, 0.253 mmol) was dissolved in methanol (2 mL), and hydroxylamine (0.309 mL, 5.057 mmol, 50.00% aqueous solution) and potassium hydroxide (0.114 g, 2.529 mmol) were then added thereto. The mixture was stirred at room temperature for 30 minutes, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate was added to the concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give compound 161 (0.062 g, 61.8%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.10(s, 1H), 9.10(s, 1H), 7.71(d, 2H, J=8.0Hz), 7.41(d, 2H, J=7.9Hz), 7.31-7.27(m, 2H), 7.24-7.18(m, 3H), 6.91-6.90(m , 1H), 4.25 (d, 2H, J=5.5Hz), 4.04-4.03 (m, 2H), 3.51 (s, 2H), 2.60 (d, 2H, J=11.0Hz), 2.08-2.05 (m, 2H), 1.22 (d, 6H, J=6.6Hz).

Example 41: Synthesis of Compound 162 ((3R,5S)-4-(4-(hydroxycarbamoyl)benzyl)-3,5-dimethyl- N-phenylpiperazine-1-carboxamide)

Step 1: Synthesis of 4-(((2S,6R)-2,6-dimethyl-4-(phenylcarbamoyl)piperazin-1-yl)methyl)benzene Methyl formate

4-(((2S, 6R)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-2, 0.150g, 0.572mmol) was dissolved in dichloromethane (4mL), and phenyl isocyanate (0.069mL, 0.629mmol) and TEA (0.119mL, 0.858mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and then water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica; ethyl acetate/hexane=25%) to give the desired compound (0.217g, 99.5%) as a light yellow oil.

Step 2: Synthesis of compound 162

4-(((2S, 6R)-2,6-dimethyl-4-(phenylcarbonyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.107g, 0.280mmol) is dissolved in methanol (3mL), and hydroxylamine (0.343mL, 5.610mmol, 50.00% aqueous solution) and potassium hydroxide (0.157g, 2.805mmol) are then added thereto. The mixture is stirred at room temperature for 30 minutes, and the reaction mixture is then concentrated under reduced pressure. Saturated sodium bicarbonate is added to the concentrate, followed by stirring. The precipitated solid is filtered and dried to give compound 162 (0.041g, 38.2%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.20 (s, 1H), 9.00 (s, 1H), 8.48 (s, 1H), 7.68 (d, 2H, J=8.0Hz), 7.45-7.42 (m, 4H), 7.22 (dd, 2H, J=10.2, 3.6Hz ), 6.93-6.91 (m, 1H), 3.97 (d, 2H, J = 13.3Hz), 3.78 (s, 2H), 2.63-2.60 (m, 1H), 0.97 (d, 6H, J = 6.0Hz); LRMS (ES) m/z 383.2(M ⁺ +1).

Example 42: Synthesis of Compound 163 ((3R,5S)-4-(4-(hydroxycarbamoyl)benzyl)-N-(2-methoxy phenyl)-3,5-dimethylpiperazine-1-carboxamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(2-methoxyphenylcarbamoyl)-2,6-dimethylpiperazin-1-yl) Methyl)benzoate

4-(((2S, 6R)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-2, 0.150g, 0.572mmol) was dissolved in dichloromethane (4mL), and 2-methoxyphenyl isocyanate (0.094g, 0.629mmol) and TEA (0.119mL, 0.858mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and then water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica; ethyl acetate/hexane=25%) to give the desired compound (0.169g, 71.8%) as a light yellow oil.

Step 2: Synthesis of compound 163

4-(((2S, 6R)-4-(2-methoxyphenylcarbamoyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.100g, 0.243mmol) was dissolved in methanol (3mL), and hydroxylamine (0.297mL, 4.860mmol, 50.00% aqueous solution) and potassium hydroxide (0.136g, 2.430mmol) were then added thereto. The mixture was stirred at room temperature for 30 minutes, and saturated sodium bicarbonate was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Compound 163 (0.060g, 59.9%) was obtained as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.68-7.65 (m, 3H), 7.56 (d, 1H, J=8.0Hz), 7.39 (d, 2H, J=8.2Hz), 7.00-6.98 (m, 2H), 6.87-6.85 (m, 1H), 3.88 (d, 2 H, J=11.6Hz), 3.78 (s, 3H), 3.76 (s, 2H), 2.69-2.63 (m, 2H), 2.55-2.52 (m, 2H), 0.96 (d, 6H, J=6.0Hz); LRMS (ES) m/z 413.2(M ⁺ +1).

Example 43: Synthesis of Compound 164 ((3R,5S)-4-(4-(hydroxycarbamoyl)benzyl)-N-(3-methoxy phenyl)-3,5-dimethylpiperazine-1-carboxamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(3-methoxyphenylcarbamoyl)-2,6-dimethylpiperazin-1-yl) Methyl)benzoate

Methyl 4-(((2S, 6R)-2,6-dimethylpiperazine-1-yl)methyl)benzoate (Formula 13-2, 0.150 g, 0.572 mmol) was dissolved in dichloromethane (4 mL), and 3-methoxyphenyl isocyanate (0.094 g, 0.629 mmol) and TEA (0.119 mL, 0.858 mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and then water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica; ethyl acetate/hexane=25%) to give the desired compound (0.210 g, 89.3%) as a light yellow oil.

Step 2: Synthesis of compound 164

4-(((2S, 6R)-4-(3-methoxyphenylcarbamoyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.100g, 0.243mmol) was dissolved in methanol (3mL), and hydroxylamine (0.297mL, 4.860mmol, 50.00% aqueous solution) and potassium hydroxide (0.136g, 2.430mmol) were then added thereto. The mixture was stirred at room temperature for 30 minutes, and saturated sodium bicarbonate was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Compound 164 (0.025g, 24.9%) was obtained as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.10 (s, 1H), 9.00 (s, 1H), 8.46 (s, 1H), 7.67 (d, 2H, J=8.2Hz), 7.43 (d, 2H, J=8.2Hz), 7.14-7.11 (m, 1H), 7.09-7.02 (m, 1H), 6.57 (dd, 1H, J=10.2, 3.6Hz), 3.95 (d, 2H, J=12.8Hz), 3.77 (s, 2H), 3.69 (s, 3H), 2.35-2.54 (m, 2H), 2.50-2.48 (m, 2H), 0.96 (d, 6H, J=6.0Hz); LRMS (ES) m/z 413.2(M ⁺⁺ 1).

Example 44: Synthesis of Compound 165 ((3R,5S)-4-(4-(hydroxycarbamoyl)benzyl)-N-(4-methoxy phenyl)-3,5-dimethylpiperazine-1-carboxamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(4-methoxyphenylcarbamoyl)-2,6-dimethylpiperazin-1-yl) Methyl)benzoate

Methyl 4-(((2S, 6R)-2,6-dimethylpiperazine-1-yl)methyl)benzoate (Formula 13-2, 0.150g, 0.572mmol) was dissolved in dichloromethane (4mL), and 4-methoxyphenyl isocyanate (0.094g, 0.629mmol) and TEA (0.119mL, 0.858mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and then water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica; ethyl acetate/hexane=30%) to give the desired compound (0.022g, 9.4%) as a light yellow oil.

Step 2: Synthesis of compound 165

4-(((2S, 6R)-4-(4-methoxyphenylcarbamoyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.022g, 0.053mmol) is dissolved in methanol (3mL), and hydroxylamine (0.065mL, 1.069mmol, 50.00% aqueous solution) and potassium hydroxide (0.03g, 0.535mmol) are then added thereto. The mixture is stirred at room temperature for 30 minutes, and the reaction mixture is then concentrated under reduced pressure. Saturated sodium bicarbonate is added to the concentrate, followed by stirring. The precipitated solid is filtered and dried to give compound 165 (0.008g, 36.3%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.31 (s, 1H), 7.67 (d, 2H, J = 8.2Hz), 7.40 (d, 2H, J = 8.2Hz), 7.31 (d, 2H, J = 9.1Hz), 6.80 (d, 2H, J = 9.1Hz), 6.80 (d, 2H , J=9.1Hz), 3.94 (d, 2H, J=12.3Hz), 3.76 (s, 2H), 3.69 (s, 3H), 2.66-2.25 (m, 4H), 0.96 (d, 6H, J=6.0Hz); LRMS (ES) m/z 413.2(M ⁺ +1).

Example 45: Synthesis of Compound 166 ((3R,5S)-4-(4-(hydroxycarbamoyl)benzyl)-3,5-dimethyl- N-o-Tolylpiperazine-1-carboxamide)

Step 1: Synthesis of 4-(((2S,6R)-2,6-dimethyl-4-(o-tolylcarbamoyl)piperazin-1-yl)methyl methyl)benzoate

Methyl 4-(((2S, 6R)-2,6-dimethylpiperazine-1-yl)methyl)benzoate (Formula 13-2, 0.150 g, 0.572 mmol) was dissolved in dichloromethane (4 mL), and o-tolyl isocyanate (0.078 mL, 0.629 mmol) and TEA (0.119 mL, 0.858 mmol) were then added thereto at 0°C. The mixture was stirred at room temperature for 1 hour, and then water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica; ethyl acetate/hexane=30%) to give the desired compound (0.182 g, 80.5%) as a white solid.

Step 2: Synthesis of compound 166

4-(((2S, 6R)-2,6-dimethyl-4-(o-tolylcarbamoyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.082g, 0.207mmol) is dissolved in methanol (3mL), and hydroxylamine (0.254mL, 4.147mmol, 50.00% aqueous solution) and potassium hydroxide (0.116g, 2.073mmol) are then added thereto. The mixture is stirred at room temperature for 30 minutes, and the reaction mixture is then concentrated under reduced pressure. Saturated sodium bicarbonate is added to the concentrate, followed by stirring. The precipitated solid is filtered and dried to give compound 166 (0.010g, 12.2%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.04 (s, 1H), 7.66 (d, 2H, J=8.1Hz), 7.34 (d, 2H, J=8.1Hz), 7.16-7.10 (m, 3H), 7.04-7.02 (m, 1H), 3.90 (d, 2H, J=13.6Hz), 3.76 (s, 2H), 2.69-2.63 (m, 2H), 2.54-2.50 (m, 2H), 2.12 (s, 3H), 0.97 (d, 6H, J=6.0Hz); LRMS (ES) m/z 397.2(M ⁺ +1).

Example 46: Synthesis of Compound 167 ((3R,5S)-4-(4-(hydroxycarbamoyl)benzyl)-3,5-dimethyl- N-m-Tolylpiperazine-1-carboxamide)

Step 1: Synthesis of 4-(((2S,6R)-2,6-dimethyl-4-(m-tolylcarbamoyl)piperazin-1-yl)methyl methyl)benzoate

Methyl 4-(((2S, 6R)-2,6-dimethylpiperazine-1-yl)methyl)benzoate (Formula 13-2, 0.150 g, 0.572 mmol) was dissolved in dichloromethane (4 mL), and then m-tolyl isocyanate (0.084 mL, 0.629 mmol) and TEA (0.119 mL, 0.858 mmol) were added thereto at 0 ° C. The mixture was stirred at room temperature for 1 hour, and then water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane=30%) and concentrated to give the desired compound (0.170 g, 75.2%) as a white solid.

Step 2: Synthesis of Compound 167

4-(((2S, 6R)-2,6-dimethyl-4-(m-tolylcarbamoyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.070g, 0.177mmol) is dissolved in methanol (3mL), and hydroxylamine (0.217mL, 3.540mmol, 50.00% aqueous solution) and potassium hydroxide (0.099g, 1.770mmol) are then added thereto. The mixture is stirred at room temperature for 30 minutes, and the reaction mixture is then concentrated under reduced pressure. Saturated sodium bicarbonate is added to the concentrate, followed by stirring. The precipitated solid is filtered and dried to give compound 167 (0.008g, 36.3%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.40 (s, 1H), 7.68 (d, 2H, J=8.2Hz), 7.41 (d, 2H, J=8.2Hz), 7.26-7.24 (m, 2H), 7.11 (dd, 1H, J=10.2, 3.6Hz), 6.74 (d, 2H, J=7.2Hz), 3.96 (d, 2H, J=13.0Hz), 3.77 (s, 2H), 2.65-2.59 (m, 4H), 2.24 (s, 3H), 0.96 (d, 6H, J=6.0Hz); LRMS (ES) m/z 397.2(M ⁺ +1).

Example 47: Synthesis of Compound 168 ((3R,5S)-N-benzyl-4-(4-(hydroxycarbamoyl)benzyl)-3,5- dimethylpiperazine-1-carboxamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(benzylcarbamoyl)-2,6-dimethylpiperazin-1-yl)methyl)benzene Methyl formate

4-(((2S, 6R)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-2, 0.150g, 0.572mmol) was dissolved in dichloromethane (4mL), and benzyl isocyanate (0.078mL, 0.629mmol) and TEA (0.119mL, 0.858mmol) were added thereto at 0°C. The mixture was stirred at room temperature for 1 hour, and then water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica; ethyl acetate/hexane=30%) to give the desired compound (0.115g, 50.9%) as a light yellow solid.

Step 2: Synthesis of Compound 168

4-(((2S, 6R)-4-(benzylcarbamoyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.060g, 0.152mmol) is dissolved in methanol (3mL), and hydroxylamine (0.186mL, 3.034mmol, 50.00% aqueous solution) and potassium hydroxide (0.085g, 1.517mmol) are then added thereto. The mixture is stirred at room temperature for 30 minutes, and the reaction mixture is then concentrated under reduced pressure. Saturated sodium bicarbonate is added to the concentrate, followed by stirring. The precipitated solid is filtered and dried to give compound 168 (0.045g, 74.8%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.05 (s, 1H), 9.00 (s, 1H), 7.67 (d, 2H, J=8.2Hz), 7.42 (d, 2H, J=8.2Hz), 7.30-7.19 (m, 5H), 7.04-7.06 (m, 1H), 4.22 (d, 2H, J= 5.8Hz), 3.83 (d, 2H, J=12.1Hz), 3.75 (s, 2H), 2.56-2.54 (m, 2H), 2.45-2.43 (m, 2H), 0.92 (d, 6H, J=6.0Hz); LRMS (ES) m/z397.2 (M ⁺ +1).

Example 48: Synthesis of Compound 171 (4-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)- 2-Fluoro-N-hydroxybenzamide)

Step 1: Synthesis of methyl 4-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)-2-fluorobenzoate

(2S,6R)-1-benzyl-2,6-dimethylpiperazine (Formula 8-3, 0.200 g, 0.979 mmol) and methyl 4-formyl-2-fluorobenzoate (Formula 8-4, 0.178 g, 0.979 mmol) were dissolved in tetrahydrofuran (5 mL), and acetic acid (0.028 mL, 0.979 mmol) was added thereto at room temperature, followed by stirring for 1 hour. Next, Na(CN)BH ₃ (0.062 g, 0.979 mmol) was added to the reaction mixture, followed by stirring at the same temperature for 2 hours. Water was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = 25%) and concentrated to obtain the desired compound (0.028 g, 7.2%) as a light yellow oil.

Step 2: Synthesis of compound 171

4-(((3R, 5S)-4-benzyl-3,5-dimethylpiperazine-1-yl)methyl)-2-fluorobenzoic acid methyl ester (Formula 8-5, 0.100g, 0.264mmol) was dissolved in methanol (3mL), and hydroxylamine (0.323mL, 5.284mmol, 50.00% aqueous solution) and potassium hydroxide (0.148g, 2.642mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour and 40 minutes, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate aqueous solution was added to the concentrate, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Compound 171 (0.034g, 33.9%) was obtained as a light orange solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.00 (brs, 1H), 9.10 (brs, 1H), 7.47 (dd, 1H, J=7.5, 7.5Hz), 7.32 (d, 2H, J=7.6Hz), 7.26 (dd, 2H, J=7.5, 7.5Hz), 7.17 -7.13 (m, 2H), 3.71 (s, 2H), 3.42 (s, 2H), 2.63-2.53 (m, 4H), 1.81 (t, 2H, J=10.4Hz), 0.88 (d, 6H, J=6.0Hz); LRMS (ES) m/z 372.2(M ⁺ +1).

Example 49: Synthesis of Compound 172 ((E)-3-(4-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl) (methyl)phenyl)-N-hydroxyacrylamide)

Step 1: Synthesis of methyl (E)-3-(4-(dimethoxymethyl)phenyl)acrylate

(E)-3-(4-Formylphenyl)acrylic acid (1.000 g, 5.676 mmol) was dissolved in methanol (10 mL), and _SOCl₂ (0.824 mL, 11.353 mmol) was added at 0°C, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. Water was added to the concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the desired compound (0.870 g, 64.9%) as a light yellow solid.

Step 2: Synthesis of methyl (E)-3-(4-formylphenyl)acrylate

(E)-3-(4-(dimethoxymethyl)phenyl)acrylate (0.870 g, 3.682 mmol) was dissolved in methanol (15 mL) at room temperature, and HCl (15 mL, 1 N methanol solution) was added thereto at the same temperature, followed by stirring for 2 hours and 30 minutes. The reaction mixture was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the concentrate. The precipitated solid was filtered and dried to give the desired compound (0.695 g, 99.2%) as a light yellow solid.

Step 3: Synthesis of (E)-3-(4-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)phenyl)propane Methyl enoate

(2S,6R)-1-benzyl-2,6-dimethylpiperazine (Formula 8-3, 0.050 g, 0.245 mmol) and (E)-methyl 3-(4-formylphenyl)acrylate (0.047 g, 0.245 mmol) were dissolved in tetrahydrofuran (1 mL), and acetic acid (0.007 mL, 0.245 mmol) was added at room temperature, followed by stirring for 1 hour. Na(CN) _BH₃ (0.015 g, 0.245 mmol) was added to the reaction mixture, followed by stirring at the same temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = 25%) and concentrated to obtain the desired compound (0.012 g, 13.0%) as a white solid.

Step 4: Synthesis of Compound 172

(E)-3-(4-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)phenyl)acrylate (Formula 8-5, 0.050 g, 0.135 mmol) was dissolved in methanol (3 mL), and hydroxylamine (0.165 mL, 2.699 mmol, 50.00% aqueous solution) and potassium hydroxide (0.076 g, 1.350 mmol) were added thereto. The mixture was stirred at room temperature for 1 hour, and the reaction mixture was concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate was added to the concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give compound 172 (0.024 g, 47.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.60 (brs, 1H), 7.44 (d, 2H, J=8.0Hz), 7.32-7.24 (m, 7H), 7.15 (dd, 1H, J=7.1, 7.1Hz), 6.39 (d, 1H, J=15.8Hz), 3.70 (s, 2H), 3.37 (s, 2H), 2.62 (d, 2H, J=10.7Hz), 2.56-2.52 (m, 2H), 1.77 (t, 2H, J=10.5Hz), 0.87 (d, 6H, J=6.1Hz); LRMS (ES) m/z 380.5(M ⁺ +1).

Example 50: Synthesis of Compound 173 (2-(4-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl (4-(4-amino)phenyl)-N-hydroxyacetamide)

Step 1: Synthesis of methyl 2-(4-(bromomethyl)phenyl)acetate

2-(4-(Bromomethyl)phenyl)acetic acid (3.000 g, 13.096 mmol) was dissolved in methanol (30 mL), and _SOCl₂ (1.900 mL, 26.193 mmol) was added thereto at 0°C, followed by stirring at the same temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to remove the solvent. A saturated aqueous sodium bicarbonate solution was added to the concentrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the desired compound (3.140 g, 98.6%) as a colorless oil.

Step 2: Synthesis of 2-(4-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)phenyl)acetic acid ester

(2S,6R)-1-benzyl-2,6-dimethylpiperazine (Formula 8-3, 0.200 g, 0.979 mmol), methyl 2-(4-(bromomethyl)phenyl)acetate (Formula 8-4, 0.238 g, 0.979 mmol), and _Cs2CO3 (0.478 g, 1.468 _mmol ) were dissolved in acetonitrile (5 mL) at room temperature. The reaction solution was stirred at the same temperature for 2 hours, and then the reaction mixture was concentrated under reduced pressure to remove the solvent. Water was added to the concentrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = 25%) and concentrated to obtain the desired compound (0.273 g, 76.1%) as a light yellow oil.

Step 3: Synthesis of compound 173

2-(4-(((3R, 5S)-4-benzyl-3,5-dimethylpiperazine-1-yl)methyl)phenyl)acetic acid methyl ester (Formula 8-5, 0.173g, 0.472mmol) was dissolved in methanol (3mL), and hydroxylamine (0.577mL, 9.441mmol, 50.00% aqueous solution) and potassium hydroxide (0.265g, 4.720mmol) were added thereto. The mixture was stirred at room temperature for 1 hour, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate (20mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered and dried to give compound 173 (0.140g, 80.7%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ10.60(brs, 1H), 8.80(brs, 1H), 7.31(d, 2H, J=7.3Hz), 7.27-7.24(m, 2H), 7.17-7.15(m, 5H), 3.69(s, 2H), 3.33(s, 2 H), 3.22 (s, 2H), 2.61 (d, 2H, J=10.1Hz), 2.53-2.49 (m, 2H), 1.75 (t, 2H, J=10, 5Hz), 0.87 (d, 6H, J=6.1Hz); LRMS (ES) m/z 368.4(M ⁺ +1).

Example 51: Synthesis of Compound 174 (4-(((2S,6R)-4-benzyl-2,6-dimethylpiperazin-1-yl)methyl)- 2-Fluoro-N-hydroxybenzamide)

Step 1: Synthesis of methyl 4-(((2S,6R)-4-benzyl-2,6-dimethylpiperazin-1-yl)methyl)-2-fluorobenzoate

(3R,5S)-1-benzyl-3,5-dimethylpiperazine (Formula 16-1, 0.200 g, 0.979 mmol) was dissolved in acetonitrile (3 mL), and _methyl 4-(bromomethyl)-2-fluorobenzoate (Formula 8-4, 0.254 g, 1.028 mmol) and _Cs2CO3 (0.478 g, 1.468 mmol) were then added. The mixture was stirred at 80°C for 2 hours, and then water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = 15%) and concentrated to obtain the desired compound (0.211 g, 58.2%) as a light yellow oil.

Step 2: Synthesis of compound 174

4-(((2S, 6R)-4-benzyl-2,6-dimethylpiperazine-1-yl)methyl)-2-fluorobenzoic acid methyl ester (Formula 16-2, 0.100g, 0.270mmol) was dissolved in methanol (3mL), and hydroxylamine (0.330mL, 5.339mmol, 50.00% aqueous solution) and potassium hydroxide (0.151g, 2.699mmol) were then added thereto. The mixture was stirred at room temperature for 30 minutes, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate was added to the concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give compound 174 (0.058g, 57.8%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.46-7.44(m, 1H), 7.31-7.23(m, 5H), 7.20-7.16(m, 2H), 3.72(s, 2H), 3.40(s, 2H), 2.65( d, 2H, J = 10.4Hz), 2.56-2.54 (m, 2H), 1.82-1.80 (m, 2H), 0.85 (d, 6H, J = 6.1Hz); LRMS (ES) m/z 372.4(M ⁺ +1).

Example 52: Synthesis of Compound 175 ((E)-3-(4-(((2S,6R)-4-benzyl-2,6-dimethylpiperazin-1-yl) (methyl)phenyl)-N-hydroxyacrylamide)

Step 1: Synthesis of (3R,5S)-1-benzyl-3,5-dimethylpiperazine

(2S,6R)-2,6-Dimethylpiperazine (1.000 g, 8.757 mmol) and _K₂CO₃ (1.724 g, 13.136 mmol) were dissolved in acetonitrile (50 mL), and benzyl bromide (1.092 mL, 9.195 mmol) was added thereto at 0 _° C, and the mixture was stirred at the same temperature for 1 hour and 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; methanol/dichloromethane = 5%) and concentrated to obtain the desired compound (1.170 g, 65.4%) as a yellow oil.

Step 2: Synthesis of methyl (E)-3-(4-(hydroxymethyl)phenyl)acrylate

(E)-3-(4-(Hydroxymethyl)phenyl)acrylic acid (0.300 g, 1.577 mmol) was dissolved in methanol (5 mL), and _NaBH₄ (0.063 g, 1.656 mmol) was added at room temperature, followed by stirring at the same temperature for 50 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the desired compound (0.284 g, 93.7%) as a white solid.

Step 3: Synthesis of methyl (E)-3-(4-(bromomethyl)phenyl)acrylate

Methyl (E)-3-(4-(hydroxymethyl)phenyl)acrylate (0.284 g, 1.478 mmol) was dissolved in toluene (10 mL), and PBr ₃ (0.042 mL, 0.443 mmol) was added thereto at 0°C, followed by stirring at room temperature for 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the desired compound (0.260 g, 69.0%) as a white solid.

Step 4: Synthesis of (E)-3-(4-(((2S,6R)-4-benzyl-2,6-dimethylpiperazin-1-yl)methyl)phenyl)propane Methyl enoate

(3R,5S)-1-benzyl-3,5-dimethylpiperazine (Formula 16-1, 0.200 g, 0.979 mmol), (E)-methyl 3-(4-(bromomethyl)phenyl)acrylate (Formula 8-4, 0.250 g, 0.979 mmol), and _{Cs2CO3 (} 0.478 g, 1.468 mmol) were dissolved in acetonitrile (5 mL) at 80°C, and the reaction solution was stirred at the same temperature for 1 hour and 40 minutes. Water was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = 15%) and concentrated to obtain the desired compound (0.078 g, 21.1%) as a yellow oil.

Step 5: Synthesis of Compound 175

(E)-3-(4-(((2S,6R)-4-benzyl-2,6-dimethylpiperazin-1-yl)methyl)phenyl)acrylate (Formula 16-2, 0.078 g, 0.206 mmol) was dissolved in methanol (1.5 mL), and hydroxylamine (0.252 mL, 4.121 mmol, 50.00% aqueous solution) and potassium hydroxide (0.116 g, 2.061 mmol) were added thereto. The mixture was stirred at room temperature for 1 hour, and the reaction mixture was concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate was added to the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give compound 175 (0.040 g, 51.1%) as an orange solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ10.00 (s, 2H), 7.45 (d, 2H, J=8.0Hz), 7.36-7.21 (m, 8H), 6.40 (d, 1H, J=15.7Hz), 3.71 (s, 2H), 3.39 (s , 2H), 2.64 (d, 2H, J=10.6Hz), 2.59-2.54 (m, 2H), 1.81-1.76 (m, 2H), 0.87 (d, 6H, J=6.0Hz); LRMS (ES) m/z 380.4(M ⁺ +1).

Example 53: Synthesis of Compound 176 (2-(4-(((2S,6R)-4-benzyl-2,6-dimethylpiperazin-1-yl)methyl (4-(4-amino)phenyl)-N-hydroxyacetamide)

Step 1: Synthesis of 2-(4-(((2S,6R)-4-benzyl-2,6-dimethylpiperazin-1-yl)methyl)phenyl)acetic acid ester

(3R,5S)-1-benzyl-3,5-dimethylpiperazine (Formula 16-1, 0.200 g, 0.979 mmol), methyl 2-(4-(bromomethyl)phenyl)acetate (Formula 8-4, 0.238 g, 0.979 mmol), and _Cs2CO3 (0.478 g, 1.468 mmol) were dissolved in _acetonitrile (5 mL) at room temperature. The reaction solution was stirred at the same temperature for 5 hours, and then the reaction mixture was concentrated under reduced pressure to remove the solvent. Water was added to the resulting concentrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = 30%) and concentrated to obtain the desired compound (0.274 g, 76.4%) as a light yellow oil.

Step 2: Synthesis of compound 176

2-(4-(((2S, 6R)-4-benzyl-2,6-dimethylpiperazine-1-yl)methyl)phenyl)acetic acid methyl ester (Formula 16-2, 0.143g, 0.390mmol) was dissolved in methanol (3mL), and hydroxylamine (0.477mL, 7.804mmol, 50.00% aqueous solution) and potassium hydroxide (0.219g, 3.9902mmol) were added thereto. The mixture was stirred at room temperature for 1 hour, and the reaction mixture was then concentrated under reduced pressure. Saturated sodium bicarbonate (5mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered and dried to give compound 176 (0.105g, 73.2%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ10.50(s, 1H), 9.00(s, 1H), 7.32-7.21(m, 1H), 7.16(d, 2H, J=7.9Hz), 3.69(s, 2H), 3.37(s, 2H), 3.22( s, 2H), 2.62 (d, 2H, J=10.8Hz), 2.56-2.52 (m, 1H), 1.80-1.75 (m, 1H), 0.88 (d, 6H, J=6.0Hz); LRMS (ES) m/z 368.5(M ⁺ +1).

Example 54: Synthesis of Compound 177 ((2S,6R)-4-(4-(hydroxycarbamoyl)benzyl)-2,6-dimethyl Piperazine-1-carboxylic acid phenyl ester)

Step 1: Synthesis of (2S,6R)-4-(4-(methoxycarbonyl)benzyl)-2,6-dimethylpiperazine-1-carboxylic acid phenyl ester

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-2, 0.200g, 0.762mmol) was dissolved in dichloromethane (5mL), and phenyl chloroformate (0.105mL, 0.839mmol) and TEA (0.211mL, 1.525mmol) were then added thereto. The mixture was stirred at 0°C for 2 hours, and then water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica; ethyl acetate/hexane=25%) to give the desired compound (0.066g, 22.6%) as a colorless oil.

Step 2: Synthesis of Compound 177

(2S, 6R) -4- (4- (methoxycarbonyl) benzyl) -2,6- dimethylpiperazine -1- phenyl carboxylate (Formula 1-3, 0.066 g, 0.173 mmol) was dissolved in methanol (3 mL), and hydroxylamine (0.211 mL, 3.451 mmol, 50.00% aqueous solution) and potassium hydroxide (0.097 g, 1.726 mmol) were then added thereto. The mixture was stirred at room temperature for 10 minutes, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate was added to the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 177 (0.062 g, 61.8%) as a light orange solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.00 (s, 1H), 9.00 (s, 1H), 7.72 (d, 2H, J=8.0Hz), 7.43 (d, 2H, J=8.0Hz), 7.39-7.36 (m, 1H), 7.22 (dd, 1H, J=10.2, 3.6Hz), 7.10 (d, 2H, J=7.6Hz), 4.15-4.13 (m, 1H), 3.56 (s, 2H), 2.66 (d, 2H, J=11.4Hz), 2.21-2.17 (m, 1H), 1.35 (d, 6H, J=6.7Hz); LRMS (ES) m/z 384.2(M ⁺ +1).

Example 55: Synthesis of Compound 183 (4-(((2S,6R)-2,6-dimethyl-4-phenylethylpiperazin-1-yl)methyl (4-Hydroxybenzamide)

Step 1: Synthesis of methyl 4-(((2S,6R)-2,6-dimethyl-4-phenylethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.100 g, 0.381 mmol) and phenylacetaldehyde (0.049 mL, 0.419 mmol) were dissolved in tetrahydrofuran (2 mL), and acetic acid (0.021 mL, 0.381 mmol) was added thereto at room temperature, followed by stirring for 1 hour. Na(CN)BH ₃ (0.024 g, 0.381 mmol) was added to the reaction mixture, followed by stirring at the same temperature for 17 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; 4 g cartridge, ethyl acetate/hexane = 30%) and concentrated to obtain the desired compound (0.040 g, 28.6%) as a light yellow oil.

Step 2: Synthesis of compound 183

4-(((2S, 6R)-2,6-dimethyl-4-phenethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.045g, 0.123mmol) was dissolved in methanol (3mL), and hydroxylamine (0.150mL, 2.456mmol, 50.00% aqueous solution) and potassium hydroxide (0.069g, 1.228mmol) were then added thereto. The mixture was stirred at room temperature for 30 minutes, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate was added to the resulting concentrate, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give compound 183 (0.040g, 88.7%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.66 (d, 2H, J=8.0Hz), 7.38 (d, 2H, J=8.0Hz), 7.26-7.17 (m, 5H), 3.73 (s, 2H), 2.80 (d, 2H, J=10.1Hz), 2 .71 (t, 2H, J=7.8Hz), 2.55-2.53 (m, 2H), 2.42 (t, 2H, J=7.8Hz), 1.83-1.80 (m, 2H), 0.91 (d, 6H, J=6.1Hz).

Example 56: Synthesis of Compound 184 (4-(((3R,5S)-3,5-dimethyl-4-phenylethylpiperazin-1-yl)methyl (4-Hydroxybenzamide)

Step 1: Synthesis of methyl 4-(((3R,5S)-3,5-dimethyl-4-phenethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol) and phenylacetaldehyde (0.049 mL, 0.419 mmol) were dissolved in tetrahydrofuran (2 mL), and acetic acid (0.021 mL, 0.381 mmol) was added thereto at room temperature, followed by stirring for 1 hour. Na(CN) _BH₃ (0.024 g, 0.381 mmol) was added to the mixture, which was then stirred at the same temperature for 17 hours. The reaction mixture was washed with aqueous sodium chloride solution and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = 30%) and concentrated to obtain the desired compound (0.010 g, 7.2%) as a colorless oil.

Step 2: Synthesis of compound 184

Methyl 4-(((3R, 5S)-3,5-dimethyl-4-phenethylpiperazine-1-yl)methyl)benzoate (Formula 1-3, 0.010g, 0.027mmol) was dissolved in methanol (1mL), and hydroxylamine (0.033mL, 0.546mmol, 50.00% aqueous solution) and potassium hydroxide (0.015g, 0.273mmol) were then added thereto. The mixture was stirred at room temperature for 30 minutes, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate was added to the resulting concentrate, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give compound 184 (0.007g, 69.8%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.50 (s, 1H), 9.00 (s, 1H), 7.70 (d, 2H, J = 8.2Hz), 7.35 (d, 2H, J = 8.0Hz), 7.28 (d, 2H, J = 8.0Hz), 7.18 (d, 2H, J=8.2Hz), 3.43 (s, 1H), 2.83-2.79 (m, 2H), 2.72-2.59 (m, 6H), 1.77-1.72 (m, 2H), 1.00 (d, 6H, J=6.1Hz).

Example 57: Synthesis of Compound 185 ((3R,5S)-4-(4-(hydroxycarbamoyl)benzyl)-3,5-dimethyl- N-(1-methyl-1H-indol-5-yl)piperazine-1-carboxamide)

Step 1: Synthesis of 4-(((2S,6R)-2,6-dimethyl-4-(1-methyl-1H-indol-5-ylcarbamoyl)piperidin (methyl)benzoate

Methyl 4-(((2S, 6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.100 g, 0.381 mmol), 5-isocyanato-1-methyl-1H-indole (0.079 g, 0.457 mmol) and TEA (0.106 mL, 0.762 mmol) were dissolved in dichloromethane (1 mL) and stirred at room temperature for 3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; methanol/dichloromethane = 5%) and concentrated to give the desired compound (0.061 g, 36.8%) as a white solid.

Step 2: Synthesis of compound 185

4-(((2S, 6R)-2,6-dimethyl-4-(1-methyl-1H-indol-5-ylcarbamoyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.040g, 0.092mmol) was dissolved in methanol (0.5mL), and hydroxylamine (0.113mL, 1.841mmol, 50.00% aqueous solution) and potassium hydroxide (0.052g, 0.921mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate was added to the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give compound 185 (0.018g, 44.9%) as a light yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.30 (s, 1H), 7.67 (d, 2H, J = 8.2Hz), 7.57 (d, 1H, J = 1.7Hz), 7.38 (d, 2H, J = 8.2Hz), 7.27 (d, 1H, J = 8.8Hz), 7.23-7.22 (m, 1H), 7.17 (dd, 1 H, J=10.2, 3.6Hz), 6.29 (dd, 1H, J=10.2, 3.6Hz), 3.99-3.96 (m, 2H), 3.77 (s, 2H), 3.73 (s, 3H), 2.62-2.52 (m, 4H), 0.97 (d, 6H, J=6.0Hz).

Example 58: Synthesis of Compound 186 ((3R, 5S)-N-(3-(1H-pyrrol-1-yl)phenyl)-4-(4-(hydroxyamino)phenyl)- (methylformyl)benzyl)-3,5-dimethylpiperazine-1-carboxamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(3-(1H-pyrrol-1-yl)phenylcarbamoyl)-2,6-dimethylpiperidin (methyl)benzoate

Methyl 4-(((2S, 6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.100 g, 0.381 mmol), 1-(3-isocyanatophenyl)-1H-pyrrole (0.084 g, 0.457 mmol) and TEA (0.106 mL, 0.762 mmol) were dissolved in dichloromethane (1 mL) and stirred at room temperature for 3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; methanol/dichloromethane = 5%) and concentrated to give the desired compound (0.059 g, 34.7%) as a white solid.

Step 2: Synthesis of compound 186

4-(((2S, 6R)-4-(3-(1H-pyrrole-1-yl)phenylcarbamoyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.040g, 0.090mmol) was dissolved in methanol (0.5mL), and hydroxylamine (0.110mL, 1.792mmol, 50.00% aqueous solution) and potassium hydroxide (0.050g, 0.896mmol) were added thereto. The mixture was stirred at room temperature for 1 hour, and the reaction mixture was concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate was added to the concentrate, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain compound 186 (0.013g, 32.4%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.67(brs, 1H), 7.78-7.76(m, 3H), 7.36-7.22(m, 6H), 7.09(d, 2H, J=8.0Hz), 6.23( s, 2H), 3.97 (d, 2H, J=12.0Hz), 3.75 (s, 2H), 2.67-2.61 (m, 4H), 0.84 (d, 6H, J=4.8Hz).

Example 59: Synthesis of Compound 187 ((3R,5S)-N-(2,3-dihydrobenzofuran-5-yl)-4-(4-(hydroxyamino)- (methylformyl)benzyl)-3,5-dimethylpiperazine-1-carboxamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(2,3-dihydrobenzofuran-5-ylcarbamoyl)-2,6-dimethyl Methyl piperazin-1-yl)methyl)benzoate

Methyl 4-(((2S, 6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.100 g, 0.381 mmol), 5-isocyanato-2,3-dihydrobenzofuran (0.074 g, 0.457 mmol) and TEA (0.106 mL, 0.762 mmol) were dissolved in dichloromethane (1 mL) and stirred at room temperature for 3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; methanol/dichloromethane = 5%) and concentrated to give the desired compound (0.070 g, 43.4%) as a white solid.

Step 2: Synthesis of compound 187

4-(((2S, 6R)-4-(2,3-dihydrobenzofuran-5-ylcarbamoyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.040g, 0.094mmol) was dissolved in methanol (0.5mL), and hydroxylamine (0.116mL, 1.889mmol, 50.00% aqueous solution) and potassium hydroxide (0.053g, 0.945mmol) were added thereto. The mixture was stirred at room temperature for 1 hour, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate was added to the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give compound 187 (0.020g, 49.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.27 (s, 1H), 7.66 (d, 2H, J = 8.1Hz), 7.37 (d, 2H, J = 20.0Hz), 7.29 (d, 1H, J = 1.2Hz), 7.04-7.02 (m, 1H), 6.60 (d, 1H, J = 8.0Hz) , 4.45 (t, 2H, J=8.7Hz), 3.92 (d, 2H, J=12.0Hz), 3.74 (s, 2H), 3.11 (t, 2H, J=8.6Hz), 2.61-2.56 (m, 4H), 0.96 (d, 6H, J=6.0Hz).

Example 60: Synthesis of Compound 188 (4-(((3R,5S)-3,5-dimethyl-4-(3-phenylpropionyl)piperazine-1-yl)- (4-(2-Methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(3-phenylpropionyl)piperazin-1-yl)methyl)benzene Methyl ester

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-2, 0.070g, 0.267mmol) was dissolved in dichloromethane (1mL), and 3-phenylpropionyl chloride (0.054g, 0.320mmol) and TEA (0.074mL, 0.534mmol) were then added thereto. The mixture was stirred at room temperature for 3 hours, and then water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was separated and concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; methanol/dichloromethane=5%) and concentrated to give the desired compound (0.097g, 92.2%) as a white oil.

Step 2: Synthesis of Compound 188

Methyl 4-(((3R, 5S)-3,5-dimethyl-4-(3-phenylpropionyl)piperazin-1-yl)methyl)benzoate (Formula 1-3, 0.040 g, 0.101 mmol) was dissolved in methanol (0.5 mL) and hydroxylamine (0.124 mL, 2.028 mmol, 50.00% aqueous solution) and potassium hydroxide (0.057 g, 1.014 mmol) were added thereto. The mixture was stirred at room temperature for 1 hour, and then saturated sodium bicarbonate was added to the concentrate, followed by extraction with dichloromethane. The organic layer was concentrated under reduced pressure to obtain compound 188 (0.019 g, 47.4%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.70 (d, 2H, J=8.4Hz), 7.38 (d, 2H, J=8.0Hz), 7.27-7.14 (m, 5H), 4.39 (brs, 1H), 4.00 (brs, 1H), 3.4 8(s, 2H), 2.80-2.78(m, 2H), 2.69-2.66(m, 2H), 2.58-2.57(m, 2H), 2.01-1.98(m, 2H), 1.19(brs, 6H).

Example 61: Synthesis of Compound 189 (4-(((2S,6R)-2,6-dimethyl-4-(m-tolylcarbamothioyl) (4-(2-methyl-1-piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-2,6-dimethyl-4-(m-tolylcarbamothioyl)piperazin-1-yl) Methyl)benzoate

Methyl 4-(((2S, 6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (compound 13-2, 0.070 g, 0.267 mmol), 1-isothiocyanate-3-methylbenzene (0.048 g, 0.320 mmol) and TEA (0.106 mL, 0.762 mmol) were dissolved in dichloromethane (1 mL) and stirred at room temperature for 6 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; methanol/dichloromethane = 5%) and concentrated to give the desired compound (0.092 g, 83.8%) as a yellow solid.

Step 2: Synthesis of compound 189

4-(((2S, 6R)-2,6-dimethyl-4-(m-tolylaminothiocarbonyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.040g, 0.097mmol) was dissolved in methanol (0.5mL), and hydroxylamine (0.119mL, 1.944mmol, 50.00% aqueous solution) and potassium hydroxide (0.055g, 0.972mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate was added to the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give compound 189 (0.021g, 52.4%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.65 (d, 2H, J=8.0Hz), 7.30 (d, 2H, J=8.0Hz), 7.14 (t, 1H, J=8.0Hz), 7.05-7.04 (m, 1H), 6.88 (d, 1H, J=8.0Hz) , 4.55 (d, 2H, J=12.0Hz), 3.75 (s, 2H), 2.91-2.85 (m, 2H), 2.55-2.51 (m, 2H), 2.48 (s, 3H), 0.98 (d, 6H, J=6.1Hz).

Example 62: Synthesis of Compound 193 (4-(((2S,6R)-4-(2-fluoro-2-methylpropyl)-2,6-dimethylpiperidin ((1-oxazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(2-hydroxy-2-methylpropyl)-2,6-dimethylpiperazin-1-yl)methyl) Methyl benzoate

Methyl 4-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.100 g, 0.381 mmol) was dissolved in acetonitrile (2 mL), and 2,2 _- dimethyloxirane (0.041 g, 0.572 mmol) and _K₂CO₃ (0.105 g, 0.762 mmol) were added. The mixture was stirred at 80°C for 48 hours, after which water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = 50%) and concentrated to give the desired compound (0.040 g, 31.4%) as a brown oil.

Step 2: Synthesis of 4-(((2S,6R)-4-(2-fluoro-2-methylpropyl)-2,6-dimethylpiperazin-1-yl)methyl)benzene Methyl formate

Methyl 4-(((2S, 6R)-4-(2-hydroxy-2-methylpropyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 19-2, 0.080 g, 0.239 mmol) was dissolved in dichloromethane (4 mL) and DAST (0.042 g, 0.263 mmol) was added thereto at 0° C., followed by stirring at room temperature for 40 minutes. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica; ethyl acetate/hexane=50%) to give the desired compound (0.065 g, 80.8%) as a yellow oil.

Step 3: Synthesis of compound 193

Methyl 4-(((2S,6R)-4-(2-fluoro-2-methylpropyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (0.065 g, 0.193 mmol) was dissolved in methanol (2 mL) and hydroxylamine (0.236 mL, 3.864 mmol, 50.00% aqueous solution) and potassium hydroxide (0.108 g, 1.932 mmol) were added thereto. The mixture was stirred at room temperature for 30 minutes, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate was added to the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give compound 193 (0.030 g, 46.0%) as a light orange solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.65 (d, 2H, J=8.2Hz), 7.35 (d, 2H, J=8.2Hz), 3.72 (s, 2H), 2.74 (d, 2H, J=10.0Hz), 2.57-2.53 (m, 2H) , 2.35 (d, 2H, J = 22.1Hz), 1.95-1.93 (m, 2H), 1.29 (d, 6H, J = 22.1Hz), 0.89 (d, 6H, J = 6.1Hz); LRMS (ES) m/z 338.2(M ⁺ +1).

Example 63: Synthesis of Compound 194 (6-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)- N-hydroxynicotinamide)

Step 1: Synthesis of methyl 6-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)nicotinate

(2S,6R)-1-benzyl-2,6-dimethylpiperazine (Formula 8-3, 0.200 g, 0.831 mmol) was dissolved in acetonitrile (4 mL), and methyl 6-(bromomethyl)nicotinate (Formula 8-4, 0.191 g, 0.831 mmol) and _Cs2CO3 (0.541 _g , 1.661 mmol) were then added. The mixture was stirred at room temperature for 17 hours, after which water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = 25%) and concentrated to yield the desired compound (0.183 g, 62.3%) as a light yellow solid.

Step 2: Synthesis of compound 194

6-(((3R, 5S)-4-benzyl-3,5-dimethylpiperazine-1-yl)methyl)nicotinate (Formula 8-5, 0.100g, 0.283mmol) was dissolved in methanol (2mL), and hydroxylamine (0.346mL, 5.658mmol, 50.00% aqueous solution) and potassium hydroxide (0.159g, 2.829mmol) were then added thereto. The mixture was stirred at room temperature for 30 minutes, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate aqueous solution was added to the resulting concentrate, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Compound 194 (0.032g, 31.9%) was obtained as a light orange solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.75 (d, 1H, J=1.4Hz), 7.94 (dd, 1H, J=10.2, 3.6Hz), 7.35-7.33 (m, 2H), 7.30-7.24 (m, 3H), 7.17-7.15 (m, 1H), 3.73 (s, 2 H), 3.48 (s, 2H), 2.67 (d, 2H, J=9.9Hz), 2.58-2.54 (m, 2H), 1.88-1.83 (m, 2H), 0.90 (d, 6H, J=6.1Hz); LRMS (ES) m/z355.2 (M ⁺ +1).

Example 64: Synthesis of Compound 195 (6-(((2S,6R)-4-benzyl-2,6-dimethylpiperazin-1-yl)methyl)- N-hydroxynicotinamide)

Step 1: Synthesis of methyl 6-(((2S,6R)-4-benzyl-2,6-dimethylpiperazin-1-yl)methyl)nicotinate

(3R,5S)-1-benzyl-3,5-dimethylpiperazine (Formula 16-1, 0.150 g, 0.734 mmol) was dissolved in acetonitrile (4 mL), and methyl 4-(bromomethyl)nicotinate (Formula 8-4, 0.169 g, 0.734 mmol) and _Cs2CO3 (0.718 g, 2.203 mmol) were then _added . The mixture was stirred at room temperature for 17 hours, after which water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = 25%) and concentrated to yield the desired compound (0.108 g, 41.6%) as a yellow solid.

Step 2: Synthesis of compound 195

6-(((2S, 6R)-4-benzyl-2,6-dimethylpiperazine-1-yl)methyl)nicotinate (Formula 16-2, 0.050g, 0.141mmol) was dissolved in methanol (2mL), and hydroxylamine (0.173mL, 2.829mmol, 50.00% aqueous solution) and potassium hydroxide (0.079g, 1.415mmol) were then added thereto. The mixture was stirred at room temperature for 20 minutes, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate was added to the concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give compound 195 (0.022g, 43.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.75 (s, 1H), 7.99 (d, 1H, J=8.2Hz), 7.50 (d, 1H, J=8.2Hz), 7.35-7.21 (m, 5H), 3.82 (s, 2H) , 3.44 (s, 2H), 2.73-2.60 (m, 4H), 1.78 (t, 2H, J=9.9Hz), 0.88 (d, 6H, J=6.1Hz); LRMS (ES) m/z 355.2(M ⁺ +1).

Example 65: Synthesis of Compound 196 ((3R,5S)-4-(4-(hydroxycarbamoyl)benzyl)-N,3,5-trimethyl 1-Phenylpiperazine-1-carboxamide)

Step 1: Synthesis of 4-nitrophenyl methyl(phenyl)carbamate

N-Methylaniline (0.300 g, 2.800 mmol) and TEA (0.776 mL, 5.600 mmol) were dissolved in dichloromethane (5 mL), and 4-nitrophenyl chloroformate (0.621 g, 3.080 mmol) was added thereto at 0°C, followed by stirring for 2 hours at the same temperature. Water was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give the desired compound (0.709 g, 93.0%) as a yellow oil.

Step 2: Synthesis of 4-(((2S,6R)-2,6-dimethyl-4-(methyl(phenyl)carbamoyl)piperazin-1-yl)methane methyl)benzoate

4-Nitrophenyl methyl(phenyl)carbamate (0.500 g, 1.836 mmol), methyl 4-(((2S, 6R)-2,6-dimethylpiperazine-1-yl)methyl)benzoate (Formula 13-2, 0.549 g, 1.836 mmol) and TEA (0.382 mL, 2.755 mmol) were dissolved in N,N-dimethylformamide (20 mL). The reaction solution was stirred at 100 ° C for 17 hours, and then water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane=50%) and concentrated to give the desired compound (0.373 g, 51.4%) as a brown oil.

Step 3: Synthesis of Compound 196

Methyl 4-(((2S, 6R)-2,6-dimethyl-4-(methyl(phenyl)carbamoyl)piperazine-1-yl)methyl)benzoate (Formula 13-3, 0.110 g, 0.278 mmol) was dissolved in methanol (2 mL) and hydroxylamine (0.340 mL, 5.563 mmol, 50.00% aqueous solution) and potassium hydroxide (0.156 g, 2.781 mmol) were added thereto. The mixture was stirred at room temperature for 1 hour, and then saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain compound 196 (0.092 g, 83.4%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ10.90(s, 1H), 9.10(s, 1H), 7.64(d, 2H, J=8.3Hz), 7.35-7.30(m, 4H), 7.12-7.08(m, 3H), 3.65(s, 2H), 3.47( d, 2H, J=12.8Hz), 3.07 (s, 3H), 2.41 (t, 1H, J=11.5Hz), 2.33-2.28 (m, 2H), 0.86 (d, 6H, J=6.4Hz); LRMS (ES) m/z 397.2(M ⁺ +1).

Example 66: Synthesis of Compound 197 (N-hydroxy-4-(((2S,6R)-4-(dihydroindole-1-carbonyl)-2,6-dihydro- (methylpiperazin-1-yl)methyl)benzamide)

Step 1: Synthesis of 4-nitrophenyl indoline-1-carboxylate

Indoline (0.300 g, 2.518 mmol) and TEA (0.698 mL, 5.035 mmol) were dissolved in dichloromethane (5 mL), and 4-nitrophenyl chloroformate (0.558 g, 2.769 mmol) was added thereto at 0°C, followed by stirring at the same temperature for 30 minutes. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane=25%) and concentrated to give the desired compound (0.668 g, 93.3%) as a light brown solid.

Step 2: Synthesis of 4-(((2S,6R)-4-(dihydroindole-1-carbonyl)-2,6-dimethylpiperazin-1-yl)methyl)benzene Methyl formate

4-Nitrophenyl dihydroindole-1-carboxylate (0.300 g, 1.055 mmol), methyl 4-(((2S, 6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.315 g, 1.055 mmol) and TEA (0.439 mL, 3.166 mmol) were dissolved in N, N-dimethylformamide (6 mL) at 100 ° C., and then stirred at the same temperature for 17 hours. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate / hexane = 50%) and concentrated to give the desired compound (0.282 g, 65.6%) as a brown solid.

Step 3: Synthesis of Compound 197

Methyl 4-(((2S, 6R)-4-(dihydroindole-1-carbonyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoate (Formula 13-3, 0.100 g, 0.245 mmol) was dissolved in methanol (2 mL), and hydroxylamine (0.300 mL, 4.908 mmol, 50.00% aqueous solution) and potassium hydroxide (0.138 g, 2.454 mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and then saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain compound 197 (0.068 g, 67.8%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.67 (d, 2H, J=8.3Hz), 7.41 (d, 2H, J=8.1Hz), 7.18 (d, 1H, J=7.3Hz), 7.10-7.08 (m, 1H), 7.00 (d, 1H, J=7.8Hz), 6.87-6.85 (m, 1H), 3.83- 3.78 (m, 4H), 3.54 (d, 2H, J = 12.6Hz), 2.98 (t, 2H, J = 8.2Hz), 2.73 (t, 2H, J = 11.7Hz), 2.61-2.59 (m, 2H), 0.92 (d, 6H, J = 6.0Hz); LRMS (ES) m/z 409.2(M ⁺ +1).

Example 67: Synthesis of Compound 198 ((3R,5S)-N-butyl-4-(4-(hydroxycarbamoyl)benzyl)-3,5- dimethyl-N-phenylpiperazine-1-carboxamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(butylphenylcarbamoyl)-3,5-dimethylpiperazin-1-yl)methane methyl)benzoate

4-(((2S, 6R)-2,6-dimethyl-4-(phenylcarbamoyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.500g, 1.311mmol) and NaH (0.033g, 1.376mmol) were dissolved in N,N-dimethylformamide (10mL) and stirred at room temperature for 1 hour. Then, 1-iodobutane (0.164mL, 1.442mmol) was added to the reaction mixture, followed by stirring at the same temperature for 3 hours. Next, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica; ethyl acetate/hexane=50%) to obtain the desired compound (0.115g, 20.1%) as a light yellow oil.

Step 2: Synthesis of Compound 198

Methyl 4-(((3R,5S)-4-(butylphenylcarbamoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 20-1, 0.060 g, 0.137 mmol) was dissolved in methanol (2 mL) and hydroxylamine (0.168 mL, 2.742 mmol, 50.00% aqueous solution) and potassium hydroxide (0.077 g, 1.371 mmol) were added thereto. The mixture was stirred at room temperature for 20 minutes, and saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure to give compound 198 (0.038 g, 63.2%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.95 (s, 1H), 7.62 (d, 2H, J=8.2Hz), 7.35-7.30 (m, 4H), 7.12-7.06 (m, 3H), 3.63 (s, 2H), 3.52-3.48 (m, 2H), 3.43 (d, 2H, J=13.1Hz ), 2.39-2.37(m, 2H), 2.33-2.26(m, 2H), 1.43-1.37(m, 2H), 1.28-1.20(m, 2H), 0.92-0.90(m, 3H), 0.89-0.87(m, 6H); LRMS(ES)m/z 439.3(M ⁺ +1).

Example 68: Synthesis of Compound 204 (4-(((3R,5S)-3,5-dimethyl-4-(4,4,4-trifluorobutyl)piperazine- (1-amino)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(4,4,4-trifluorobutyl)piperazin-1-yl)methyl)benzene Methyl formate

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.300 g, 1.004 mmol) was dissolved in acetonitrile (5 mL), and 1,1,1-trifluoro-4-iodobutane (0.129 mL, 1.004 mmol) and _{Cs2CO3 (} 0.318 g, 2.510 mmol) were then added. The mixture was heated under reflux for 17 hours and then cooled to room temperature. The reaction mixture was filtered through a glass filter to remove solids, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = 50%) and concentrated to obtain the desired compound (0.115 g, 30.8%) as a light yellow oil.

Step 2: Synthesis of compound 204

Methyl 4-(((3R, 5S)-3,5-dimethyl-4-(4,4,4-trifluorobutyl)piperazine-1-yl)methyl)benzoate (Formula 1-3, 0.065g, 0.175mmol) was dissolved in methanol (2mL), and hydroxylamine (0.214mL, 3.491mmol, 50.00% aqueous solution) and potassium hydroxide (0.098g, 1.745mmol) were then added thereto. The mixture was stirred at room temperature for 40 minutes, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and aqueous layer, and the organic layer was concentrated under reduced pressure. Compound 204 (0.023g, 35.3%) was obtained as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.20(s, 1H), 9.00(s, 1H), 7.70(d, 2H, J=7.2Hz), 7.34(d, 2H, J=7.6Hz), 3.42(s, 2H), 2.62-2.59( m, 6H), 2.34-2.33 (m, 2H), 2.72-1.66 (m, 2H), 1.25-1.24 (m, 2H), 0.94 (d, 6H, J=5.1Hz); LRMS (ES) m/z 374.2(M ⁺ +1).

Example 69: Synthesis of Compound 211 (4-(((3R,5S)-4-(2-fluorobenzyl)-3,5-dimethylpiperazin-1-yl) methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(2-fluorobenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoic acid ester

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol), 1-(bromomethyl)-2-fluorobenzene (0.055 mL, 0.457 mmol), and _K₂CO₃ (0.105 _g , 0.762 mmol) were dissolved in acetonitrile (1 mL) and stirred at room temperature for 7 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; methanol/dichloromethane = 5%) and concentrated to obtain the desired compound (0.067 g, 47.4%) as a white oil.

Step 2: Synthesis of compound 211

Methyl 4-(((3R, 5S)-4-(2-fluorobenzyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-3, 0.050g, 0.135mmol) was dissolved in methanol (1mL), and hydroxylamine (0.165mL, 2.699mmol, 50.00% aqueous solution) and potassium hydroxide (0.076g, 1.350mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate aqueous solution was added to the concentrate, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Compound 211 (0.031g, 61.8%) was obtained as a yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.69 (d, 2H, J=7.3Hz), 7.63-7.60 (m, 1H), 7.30 (d, 2H, J=7.8Hz), 3.79 (s, 2H) , 3.43 (s, 2H), 2.68-2.56 (m, 4H), 1.81 (t, 2H, J=10.4Hz), 0.87 (d, 6H, J=6.0Hz).

Example 70: Synthesis of Compound 212 (4-(((3R,5S)-4-(2,5-difluorobenzyl)-3,5-dimethylpiperazine-1- (4-(2-Methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(2,5-difluorobenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzyl Methyl ester

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol), 2-(bromomethyl)-1,4-difluorobenzene (0.059 mL, 0.457 mmol), and _K₂CO₃ (0.105 _g , 0.762 mmol) were dissolved in acetonitrile (1 mL) and stirred at room temperature for 7 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; methanol/dichloromethane = 5%) and concentrated to obtain the desired compound (0.057 g, 38.5%) as a white solid.

Step 2: Synthesis of compound 212

Methyl 4-(((3R, 5S)-4-(2,5-difluorobenzyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-3, 0.050g, 0.129mmol) was dissolved in methanol (1mL), and hydroxylamine (0.157mL, 2.574mmol, 50.00% aqueous solution) and potassium hydroxide (0.072g, 1.287mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate aqueous solution was added to the concentrate, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Compound 212 (0.025g, 49.9%) was obtained as a light yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.69 (d, 2H, J=7.8Hz), 7.39-7.35 (m, 1H), 7.30 (d, 2H, J=7.9Hz), 7.18-7.15 (m, 1H), 3. 70 (s, 2H), 3.44 (s, 2H), 2.69-2.60 (m, 4H), 1.83 (t, 2H, J=10.4Hz), 0.84 (d, 6H, J=6.0Hz).

Example 71: Synthesis of Compound 213 (4-(((3R,5S)-3,5-dimethyl-4-(2,4,5-trifluorobenzyl)piperazine- (1-amino)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(2,4,5-trifluorobenzyl)piperazin-1-yl)methyl)benzene Methyl formate

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol), 1-(bromomethyl)-2,4,5-trifluorobenzene (0.103 g, 0.457 mmol), and _K₂CO₃ (0.105 _g , 0.762 mmol) were dissolved in acetonitrile (1 mL) and stirred at room temperature for 7 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; methanol/dichloromethane = 5%) and concentrated to obtain the desired compound (0.071 g, 45.8%) as a white solid.

Step 2: Synthesis of compound 213

Methyl 4-(((3R, 5S)-3,5-dimethyl-4-(2,4,5-trifluorobenzyl)piperazine-1-yl)methyl)benzoate (Formula 1-3, 0.050 g, 0.123 mmol) was dissolved in methanol (1 mL), and hydroxylamine (0.150 mL, 2.460 mmol, 50.00% aqueous solution) and potassium hydroxide (0.069 g, 1.230 mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Compound 213 (0.024 g, 47.9%) was obtained as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.64 (d, 2H, J=8.0Hz), 7.60-7.58 (m, 1H), 7.48-7.46 (m, 1H), 7.11 (d, 2H, J=8.0Hz), 3. 37 (s, 2H), 3.22 (s, 2H), 2.69-2.55 (m, 4H), 1.79 (t, 2H, J=10.2Hz), 0.84 (d, 6H, J=6.1Hz).

Example 72: Synthesis of Compound 214 (4-(((3R,5S)-4-(3,5-bis(trifluoromethyl)benzyl)-3,5-dimethyl (1-piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3,5-bis(trifluoromethyl)benzyl)-3,5-dimethylpiperazin-1-yl)methane methyl)benzoate

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol), 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene (0.084 mL, 0.457 mmol), and _K₂CO₃ (0.105 g, 0.762 mmol ₎ were dissolved in acetonitrile (1 mL) and stirred at room temperature for 7 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; methanol/dichloromethane = 5%) and concentrated to obtain the desired compound (0.075 g, 40.3%) as a white oil.

Step 2: Synthesis of compound 214

Methyl 4-(((3R, 5S)-4-(3,5-bis(trifluoromethyl)benzyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-3, 0.050g, 0.102mmol) was dissolved in methanol (1mL), and hydroxylamine (0.125mL, 2.047mmol, 50.00% aqueous solution) and potassium hydroxide (0.057g, 1.024mmol) were then added thereto. The mixture was stirred at room temperature for 1 hour, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate aqueous solution was added to the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Compound 214 (0.021g, 41.9%) was obtained as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.06(s, 2H), 7.91(s, 2H), 7.67(d, 2H, J=6.7Hz), 7.22(d, 2H, J=7.3Hz), 3.89(s, 2H), 3.41 (s, 2H), 2.70-2.55 (m, 4H), 1.83 (t, 2H, J=10.1Hz), 0.82 (d, 6H, J=5.9Hz).

Example 73: Synthesis of Compound 215 (4-(((2S,6R)-2,6-dimethyl-4-(2,4,5-trifluorobenzyl)piperazine- (1-amino)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-2,6-dimethyl-4-(2,4,5-trifluorobenzyl)piperazin-1-yl)methyl)benzene Methyl formate

Methyl 4-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.100 g, 0.381 mmol), 1-(bromomethyl)-2,4,5-trifluorobenzene (0.103 g, 0.457 mmol), and K ₂ CO ₃ (0.105 g, 0.762 mmol) were dissolved in acetonitrile (1 ml) at 25° C., and the reaction solution was stirred at the same temperature for 7 hours. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; 4 g cartridge; methanol/dichloromethane = 0% to 5%) and concentrated to obtain the desired compound (0.071 g, 45.8%) as a white solid.

Step 2: Synthesis of compound 215

4-(((2S, 6R)-2,6-dimethyl-4-(2,4,5-trifluorobenzyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.050g, 0.123mmol), hydroxylamine (0.150mL, 2.460mmol, 50.00% aqueous solution) and potassium hydroxide (0.069g, 1.230mmol) were dissolved in methanol (1ml) at 25°C, and the reaction solution was stirred at the same temperature for 1 hour. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain compound 215 (0.024g, 47.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.64 (d, 2H, J=8.04Hz), 7.60-7.46 (m, 3H), 7.11 (d, 2H, J=8.04Hz), 3.67 (s, 2H), 3.17 ( s, 2H), 2.69-2.61 (m, 2H), 2.60-2.57 (m, 2H), 1.82-1.76 (m, 2H), 0.83 (d, 6H, J=6.12Hz).

Example 74: Synthesis of Compound 218 (4-(2-((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)ethyl) 1-Hydroxybenzamide)

Step 1: Synthesis of methyl 4-(2-((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)ethyl)benzoate

(2S, 6R) -1-benzyl -2,6- dimethylpiperazine (Formula 8-3, 0.200 g, 0.831 mmol) and DIPEA (0.363 mL, 2.077 mmol) were dissolved in acetonitrile (5 mL) and methyl 4- (2-bromoethyl) benzoate (Formula 8-4, 0.404 g, 1.661 mmol) was added thereto at room temperature. The mixture was stirred at 60 ° C for 17 hours, and then water was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate / hexane = 25%) and concentrated to obtain the desired compound (0.075 g, 24.6%) as a light yellow oil.

Step 2: Synthesis of compound 218

4-(2-((3R, 5S)-4-benzyl-3,5-dimethylpiperazine-1-yl)ethyl)benzoic acid methyl ester (Formula 8-5, 0.075g, 0.205mmol) was dissolved in methanol (3mL), and hydroxylamine (0.125mL, 0.2046mmol, 50.00% aqueous solution) and potassium hydroxide (0.266g, 4.093mmol) were then added thereto. The mixture was stirred at room temperature for 30 minutes, and the reaction mixture was then concentrated under reduced pressure. Saturated sodium bicarbonate was added to the concentrate, followed by stirring. The precipitated solid was filtered and dried to give compound 218 (0.058g, 77.1%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.64 (d, 2H, J=8.2Hz), 7.35 (d, 2H, J=7.4Hz), 7.31-7.27 (m, 2H), 7.17-7.16 (m, 1H), 3.72 (s, 2H), 2. 80 (d, 2H, J=10.0Hz), 2.74-2.71 (m, 2H), 2.46-2.42 (m, 2H), 1.82-1.80 (m, 2H), 0.93 (d, 6H, J=6.1Hz).

Example 75: Synthesis of Compound 219 (4-(1-((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)ethyl) 1-Hydroxybenzamide)

Step 1: Synthesis of methyl 4-(1-bromoethyl)benzoate

Methyl 4-(1-hydroxyethyl)benzoate (0.500 g, 2.775 mmol) was dissolved in toluene (10 mL) and PBr ₃ (0.079 mL, 0.832 mmol) was added thereto at 0° C. The mixture was stirred at the same temperature for 1 hour and 20 minutes and the reaction mixture was concentrated under reduced pressure to give the desired compound (0.410 g, 60.8%) as a purple oil.

Step 2: Synthesis of methyl 4-(1-((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)ethyl)benzoate

(3R,5S)-1-benzyl-3,5-dimethylpiperazine (Formula 8-3, 0.200 g, 0.831 mmol), methyl 4-(1-bromoethyl)benzoate (Formula 8-4, 0.222 g, 0.914 mmol), and _Cs2CO3 (0.812 g, 2.492 mmol) were dissolved in N,N-dimethylformamide (4 mL) at room temperature, and _the reaction solution was stirred at 50°C for 17 hours. The reaction mixture was filtered through a glass filter to remove solids, and water was added to the filtrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = 25%) and concentrated to obtain the desired compound (0.168 g, 55.2%) as a light yellow oil.

Step 3: Synthesis of Compound 219

Methyl 4-(1-((3R, 5S)-4-benzyl-3,5-dimethylpiperazine-1-yl)ethyl)benzoate (Formula 8-5, 0.080 g, 0.218 mmol) was dissolved in methanol (3 mL), and hydroxylamine (0.134 mL, 2.183 mmol, 50.00% aqueous solution) and potassium hydroxide (0.284 g, 4.366 mmol) were then added thereto. The mixture was stirred at room temperature for 30 minutes, and the reaction mixture was concentrated under reduced pressure to remove the solvent. Saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and aqueous layer, and the organic layer was concentrated under reduced pressure to obtain compound 219 (0.051 g, 63.6%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.10 (s, 1H), 9.10 (s, 1H), 7.67 (d, 2H, J = 6.9Hz), 7.31-7.23 (m, 6H), 7.16-7.14 (m, 1H), 3.68 (s, 2H), 2.82 (d, 2H, J = 11.0Hz), 2.53-2.82 (m , 3H), 1.74 (t, 1H, J=10.2Hz), 1.64 (t, 1H, J=10.5Hz), 1.24 (d, 3H, J=6.7Hz), 0.90 (d, 3H, J=6.0Hz), 0.86-0.84 (m, 1H), 0.81 (d, 3H, J=6.7Hz).

Example 76: Synthesis of Compound 220 (4-(((2S,6R)-2,6-dimethyl-4-(1-phenylethyl)piperazine-1- (4-(2-Methyl)-N-hydroxybenzamide)

Step 1: Synthesis of (1-bromoethyl)benzene

(1-Hydroxyethyl)benzene (1.000 g, 8.186 mmol) and PBr ₃ (0.233 mL, 2.456 mmol) were dissolved in toluene (10 mL) at 0°C, and the reaction solution was stirred at the same temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure to obtain the desired compound (0.900 g, 59.4%) as a light brown oil.

Step 2: Synthesis of 4-(((2S,6R)-2,6-dimethyl-4-(1-phenylethyl)piperazin-1-yl)methyl)benzoic acid Methyl ester

Methyl 4-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.200 g, 0.669 mmol), (1-bromoethyl)benzene (0.136 g, 0.736 mmol), and _Cs2CO3 (0.654 _g , 2.008 mmol) were dissolved in N,N-dimethylformamide (4 mL) at room temperature, and the reaction solution was stirred at 50°C for 17 hours. Water was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = 25%) and concentrated to obtain the desired compound (0.22 g, 89.7%) as a colorless oil.

Step 3: Synthesis of Compound 220

Methyl 4-(((2S, 6R)-2,6-dimethyl-4-(1-phenylethyl)piperazine-1-yl)methyl)benzoate (Formula 13-3, 0.110 g, 0.300 mmol) was dissolved in methanol (3 mL), and hydroxylamine (0.184 mL, 3.001 mmol, 50.00% aqueous solution) and potassium hydroxide (0.391 g, 6.003 mmol) were then added thereto. The mixture was stirred at room temperature for 20 minutes, and the reaction mixture was then concentrated under reduced pressure to remove the solvent. Saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and aqueous layer, and the organic layer was concentrated under reduced pressure to give compound 220 (0.063 g, 57.1%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.63(d, 2H, J=8.3Hz), 7.35-7.33(m, 2H), 7.30-7.26(m, 4H), 7.24-7.21(m, 1H), 3.69(s, 2H), 2.85-2.83(m, 1H), 2.55-2.50(m, 3H), 1.75-1.74 (m, 1H), 1.63-1.62 (m, 1H), 1.25 (d, 3H, J=6.8Hz), 0.91-0.90 (m, 1H), 0.88 (d, 3H, J=4.9Hz), 0.78 (d, 3H, J=6.1Hz).

Example 77: Synthesis of Compound 222 (4-(((3R,5S)-4-(2-(3-fluorophenyl)acetyl)-3,5-dimethyl (piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(2-(3-fluorophenyl)acetyl)-3,5-dimethylpiperazin-1-yl)methane methyl)benzoate

At 25 ° C, 4- (((3R, 5S) -3,5- dimethylpiperazine -1- base) methyl) benzoic acid methyl ester (Formula 1-2, 0.100 g, 0.381 mmol), 2- (3- fluorophenyl) acetic acid (0.088 g, 0.572 mmol), HOBt (0.077 g, 0.572 mmol), EDCI (0.110 g, 0.572 mmol) and DIPEA (0.133 mL, 0.762 mmol) were dissolved in dichloromethane (2 ml), and the reaction solution was stirred at the same temperature for 20 hours. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; 4 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to give the desired compound (0.047 g, 30.9%) as a light yellow solid.

Step 2: Synthesis of compound 222

Methyl 4-(((3R, 5S)-4-(2-(3-fluorophenyl)acetyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-3, 0.040 g, 0.100 mmol), hydroxylamine (0.123 mL, 2.008 mmol, 50.00% aqueous solution) and potassium hydroxide (0.056 g, 1.004 mmol) were dissolved in methanol (1 ml) at 25 ° C, and the reaction solution was stirred at the same temperature for 1 hour. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain compound 222 (0.019 g, 47.4%) as an orange solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.64 (d, 2H, J=8.0Hz), 7.32-7.27 (m, 1H), 7.24 (d, 2H, J=8.0Hz), 7.04-7.01 (m, 3H), 4.35 (brs, 1H), 4.0 7 (brs, 1H), 3.75-3.62 (m, 2H), 3.46 (s, 2H), 2.63-2.52 (m, 2H), 1.99-1.73 (m, 2H), 1.20 (d, 6H, J=17.2Hz).

Example 78: Synthesis of Compound 223 (4-(((3R,5S)-3,5-dimethyl-4-(2-(3-(trifluoromethyl)phenyl) (acetyl)piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(2-(3-(trifluoromethyl)phenyl)acetyl)piperazine- 1-aminobenzoic acid methyl ester

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol), 2-(3-(trifluoromethyl)phenyl)acetic acid (0.117 g, 0.572 mmol), HOBt (0.077 g, 0.572 mmol), EDCI (0.110 g, 0.572 mmol) and DIPEA (0.133 mL, 0.762 mmol) were dissolved in dichloromethane (2 ml) at 25 ° C., and the reaction solution was stirred at the same temperature for 20 hours. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; 12 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to give the desired compound (0.037 g, 21.6%) as a colorless oil.

Step 2: Synthesis of compound 223

4-(((3R, 5S)-3,5-dimethyl-4-(2-(3-(trifluoromethyl)phenyl)acetyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 1-3, 0.030g, 0.067mmol), hydroxylamine (0.082mL, 1.338mmol, 50.00% aqueous solution) and potassium hydroxide (0.038g, 0.669mmol) were dissolved in methanol (1ml) at 25°C, and the reaction solution was stirred at the same temperature for 1 hour. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain compound 223 (0.013g, 43.2%) as a light yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.64 (d, 2H, J=8.0Hz), 7.56-7.48 (m, 4H), 7.20 (d, 2H, J=8-4Hz), 4.36 (brs, 1H), 4.12 (brs, 1H), 3 .92-3.67 (brs, 1H), 3.48 (s, 2H), 2.61 (d, 2H, J=11.2Hz), 2.05-2.00 (m, 2H), 1.23 (d, 6H, J=31.6Hz).

Example 79: Synthesis of Compound 224 (4-(((3R,5S)-4-(2-(3-chlorophenyl)acetyl)-3,5-dimethyl (piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(2-(3-chlorophenyl)acetyl)-3,5-dimethylpiperazin-1-yl)methane methyl)benzoate

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol), 2-(3-chlorophenyl)acetic acid (0.098 g, 0.572 mmol), HOBt (0.077 g, 0.572 mmol), EDCI (0.110 g, 0.572 mmol) and DIPEA (0.133 mL, 0.762 mmol) were dissolved in dichloromethane (2 ml) at 25 ° C., and the reaction solution was stirred at the same temperature for 20 hours. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; 4 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to give the desired compound (0.042 g, 26.6%) as a colorless oil.

Step 2: Synthesis of compound 224

Methyl 4-(((3R, 5S)-4-(2-(3-chlorophenyl)acetyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-3, 0.035g, 0.084mmol), hydroxylamine (0.103mL, 1.687mmol, 50.00% aqueous solution) and potassium hydroxide (0.047g, 0.844mmol) were dissolved in methanol (1ml) at 25°C, and the reaction solution was stirred at the same temperature for 1 hour. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain compound 224 (0.020g, 57.0%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.62 (d, 2H, J=7.6Hz), 7.31-7.23 (m, 4H), 7.15 (d, 2H, J=6.4Hz), 4.35 (brs, 1H), 4.07 (brs, 1H) , 3.76-3.47 (m, 2H), 3.30 (s, 2H), 2.62 (d, 2H, J=10.8Hz), 1.98 (brs, 2H), 1.23 (d, 6H, J=25.2Hz).

Example 80: Synthesis of Compound 225 (4-(((3R,5S)-4-(3-fluorobenzyl)-3,5-dimethylpiperazin-1-yl) methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-fluorobenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoic acid ester

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Compound 1-2, 0.150 g, 0.572 mmol), 3-fluorobenzyl bromide (0.077 mL, 0.629 mmol), and K ₂ CO ₃ (0.119 g, 0.858 mmol) were dissolved in acetonitrile (4 mL) at room temperature, and the reaction solution was stirred at the same temperature for 17 hours. Water was then added to the reaction mixture, followed by extraction with ethyl acetate. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; 4 g cartridge; ethyl acetate/hexane = 0% to 40%) and concentrated to give the desired compound (0.110 g, 51.9%) as a white solid.

Step 2: Synthesis of compound 225

Methyl 4-(((3R,5S)-4-(3-fluorobenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Compound 1-3, 0.060 g, 0.162 mmol), hydroxylamine (0.099 mL, 1.620 mmol, 50.00% aqueous solution) and potassium hydroxide (0.211 g, 3.239 mmol) were dissolved in methanol (3 mL) at room temperature, and the reaction solution was stirred at the same temperature for 1 hour and then concentrated under reduced pressure to remove the solvent. Saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure to give Compound 225 (0.044 g, 73.1%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.65 (d, 2H, J=8.0Hz), 7.31-7.27 (m, 1H), 7.22 (d, 2H, J=8.0Hz), 7.17-7.13 (m, 2H), 6.97-6.96 (m, 1H), 3.70 (s, 2H), 3. 43 (s, 2H), 2.64 (d, 2H, J = 11.2Hz), 2.57-2.56 (m, 2H), 1.78 (t, 2H, J = 10.6Hz), 0.84 (d, 6H, J = 6.0Hz); LRMS (ES) m/z 372.2 (M ⁺ +1).

Example 81: Synthesis of Compound 230 ((3R,5S)-4-(4-(hydroxycarbamoyl)benzyl)-N-(3-methoxy benzyl)-3,5-dimethylpiperazine-1-carboxamide (trifluoroacetate)

Step 1: Synthesis of 4-nitrophenyl 3-methoxybenzylcarbamate

3-Methoxybenzylamine (0.100 g, 0.729 mmol) and TEA (0.152 mL, 1.093 mmol) were dissolved in dichloromethane (2 mL) and 4-nitrophenyl chloroformate (0.162 g, 0.802 mmol) was added thereto at 0°C and stirred for 2 hours at the same temperature. Water was then added to the reaction mixture, which was then extracted with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and aqueous layer, and the organic layer was concentrated under reduced pressure. The product obtained was used without additional purification (0.200 g, 90.8%, yellow oil).

Step 2: Synthesis of 4-(((2S,6R)-4-((3-methoxybenzyl)carbamoyl)-2,6-dimethylpiperazine-1-yl methyl)benzoate

4-Nitrophenyl 3-methoxybenzylcarbamate (0.130 g, 0.430 mmol), 4-(((2S, 6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.129 g, 0.430 mmol) and TEA (0.179 mL, 1.290 mmol) were dissolved in N, N-dimethylformamide (4 mL) at room temperature, and the reaction solution was stirred at 100 ° C for 3 hours. Then, the reaction mixture was concentrated under reduced pressure. The obtained product was used without additional purification (0.180 g, 98.4%, brown oil).

Step 3: Synthesis of Compound 230

Methyl 4-(((2S,6R)-4-((3-methoxybenzyl)carbamoyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-3, 0.180 g, 0.423 mmol), hydroxylamine (0.517 mL, 8.460 mmol, 50.00% aqueous solution) and potassium hydroxide (0.237 g, 4.230 mmol) were dissolved in methanol (2 mL) at room temperature, and the reaction solution was stirred at the same temperature for 17 hours. The concentrate was purified by column chromatography (Waters, _C18 , 19*100 mm column, 0.1% trifluoroacetic acid/acetonitrile = from 5% to 80%) and concentrated to give Compound 230 (0.033 g, 18.3%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ )δ11.11(brs, 1H), 8.95(brs, 1H), 7.64(d, 2H, J=8.4Hz), 7.39(d, 2H, J=8.0H z), 7.17 (dd, 1H, J=7.0, 7.0Hz), 7.03 (dd, 1H, J=6.0, 6.0Hz), 6.75-6.72 (m, 2H ), 4.16 (d, 2H, J = 5.6Hz), 3.80 (d, 2H, J = 12.4Hz), 3.72 (s, 2H), 3.68 (s, 3H), 2 .53 (d, 2H, J = 10.4Hz), 2.42-2.38 (m, 2H), 0.89 (d, 6H, J = 6.0Hz); LRMS (ES) m/z 427.3(M ⁺⁺ 1).

Example 82: Synthesis of Compound 231 ((3R,5S)-N-(3-fluorobenzyl)-4-(4-(hydroxycarbamoyl)benzyl) 1-Methyl-3,5-dimethylpiperazine-1-carboxamide)

Step 1: Synthesis of 4-nitrophenyl 3-fluorobenzylcarbamate

(3-Fluorophenyl)methylamine (0.200 g, 1.598 mmol) and TEA (0.243 g, 2.397 mmol) were dissolved in dichloromethane (2 mL) and 4-nitrophenyl chloroformate (0.354 g, 1.758 mmol) was added thereto at 0° C. and stirred at the same temperature for 1 hour. Water was then added to the reaction mixture, which was then extracted with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and aqueous layer, and the organic layer was concentrated under reduced pressure. The product obtained was used without additional purification (0.410 g, 88.4%, yellow solid).

Step 2: Synthesis of 4-(((2S,6R)-4-((3-fluorobenzyl)carbamoyl)-2,6-dimethylpiperazin-1-yl)carbamoyl methyl)benzoate

4-Nitrophenyl 3-fluorobenzylcarbamate (0.200 g, 0.689 mmol), 4-(((2S, 6R)-2,6-dimethylpiperazine-1-yl)methyl)benzoate (Formula 13-2, 0.216 g, 0.724 mmol) and TEA (0.287 mL, 2.067 mmol) were dissolved in N,N-dimethylformamide (3 mL) at room temperature, and the reaction solution was stirred at 100 ° C for 2 hours and 30 minutes. The reaction mixture was then concentrated under reduced pressure using V10. The concentrate was purified and concentrated by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 50%) to give the desired compound (0.178 g, 62.5%) as a light brown oil.

Step 3: Synthesis of Compound 231

4-(((2S, 6R)-4-((3-fluorobenzyl)carbamoyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.100g, 0.242mmol), hydroxylamine (0.296mL, 4.837mmol, 50.00% aqueous solution) and potassium hydroxide (0.136g, 2.418mmol) were dissolved in methanol (3mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution (10mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered and dried to give compound 231 (0.055g, 54.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.64 (d, 2H, J=8.0Hz), 7.38 (d, 2H, J=8.0Hz), 7.33-7.27 (m, 1H), 7.10 (t, 1H, J=5.8Hz), 7.06-6.98 (m, 3H), 4.20 (d, 2H, J=5.6H z), 3.79 (d, 2H, J = 12.8Hz), 3.72 (s, 2H), 2.52 (t, 2H, J = 11.6Hz), 2.42-2.38 (m, 2H), 0.89 (d, 6H, J = 6.0Hz); LRMS (ES) m/z 415.2 (M ⁺ +1).

Example 83: Synthesis of Compound 232 ((2S,6R)-N-(3-fluorobenzyl)-4-(4-(hydroxycarbamoyl)benzyl) 2,6-dimethylpiperazine-1-carboxamide)

Step 1: Synthesis of 4-(((3R,5S)-4-((3-fluorobenzyl)carbamoyl)-3,5-dimethylpiperazin-1-yl)carbamoyl methyl)benzoate

4-Nitrophenyl 3-fluorobenzylcarbamate (0.220 g, 0.758 mmol), methyl 4-(((3R, 5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.209 g, 0.796 mmol) and TEA (0.315 mL, 2.274 mmol) were dissolved in N,N-dimethylformamide (3 mL) at room temperature, and the reaction solution was stirred at 100 ° C for 2 hours and 30 minutes. Then, the reaction mixture was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 50%) and concentrated to give the desired compound (0.185 g, 59.0%) as a colorless oil.

Step 2: Synthesis of compound 232

Methyl 4-(((3R, 5S)-4-((3-fluorobenzyl)carbamoyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-3, 0.100 g, 0.242 mmol), hydroxylamine (0.296 mL, 4.837 mmol, 50.00% aqueous solution) and potassium hydroxide (0.136 g, 2.418 mmol) were dissolved in methanol (3 mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to remove the solvent. Saturated aqueous sodium bicarbonate solution was added to the concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure to obtain compound 232 (0.026 g, 25.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.70 (d, 2H, J = 8.0Hz), 7.48 (d, 2H, J = 8.4Hz), 7.31-7.25 (m, 1H), 7.06 (d, 1H, J = 7.6Hz), 6.98 (d, 1H, J = 10.0Hz), 6.93-6.88 (m , 1H), 4.35 (s, 2H), 4.07-4.04 (m, 2H), 3.54 (s, 2H), 2.67 (d, 2H, J=11.2Hz), 2.17 (dd, 2H, J=10.2, 3.6Hz), 1.31 (d, 6H, J=6.8Hz).

Example 84: Synthesis of Compound 233 (4-(((2S,6R)-4-(2-(3-chlorophenyl)acetyl)-2,6-dimethyl (piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(2-(3-chlorophenyl)acetyl)-2,6-dimethylpiperazin-1-yl)methane methyl)benzoate

2-(3-chlorophenyl)acetic acid (0.200 g, 0.669 mmol), 4-(((2S, 6R)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-2, 0.126 g, 0.736 mmol), EDCI (0.257 g, 1.339 mmol), HOBt (0.205 g, 1.339 mmol) and DIPEA (0.584 mL, 3.347 mmol) were dissolved in dichloromethane (5 mL) at room temperature, and the reaction solution was stirred at the same temperature for 17 hours. Then, saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove solid residues and the aqueous solution, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 10% to 70%) and concentrated to give the desired compound (0.187 g, 67.3%) as a colorless oil.

Step 2: Synthesis of compound 233

4-(((2S, 6R)-4-(2-(3-chlorophenyl) acetyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.100g, 0.241mmol), hydroxylamine (50.00% aqueous solution, 0.295mL, 4.820mmol) and potassium hydroxide (0.135g, 2.410mmol) were dissolved in methanol (3mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. Then, saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove solid residue and the aqueous solution, and the organic layer was concentrated under reduced pressure. Diethyl ether (3mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered and dried to obtain compound 233 (0.053g, 52.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.63 (d, 2H, J=8.4Hz), 7.33 (d, 2H, J=8.4Hz), 7.27-7.24 (m, 3H), 7.16-7.14 (m, 1H), 4.10 (d, 1H, J=12.4Hz), 3.81 (d, 1H, J=1 3.2Hz), 3.76-3.65 (m, 4H), 2.86-2.52 (m, 1H), 2.43 (d, 1H, J=12.4Hz), 2.38-2.28 (m, 2H), 0.90 (t, 6H, J=5.4Hz); LRMS (ES) m/z 416.1(M ⁺ +1).

Example 85: Synthesis of Compound 234 (4-(((3R,5S)-4-(2-([1,1′-biphenyl]-3-yl)acetyl)-3, 5-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(2-([1,1′-biphenyl]-3-yl)acetyl)-3,5-dimethylpiperazine- 1-amino)methyl)benzoate

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol), 2-([1,1′-biphenyl]-3-yl)acetic acid (0.097 g, 0.457 mmol), HOBt (0.077 g, 0.572 mmol), EDCI (0.110 g, 0.572 mmol) and DIPEA (0.099 g, 0.762 mmol) were dissolved in dichloromethane (2 ml) at 25° C., and the reaction solution was stirred at the same temperature for 7 hours. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 12 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to give the desired compound (0.114 g, 65.5%) as a yellow solid.

Step 2: Synthesis of compound 234

Methyl 4-(((3R,5S)-4-(2-([1,1′-biphenyl]-3-yl)acetyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 4-2, 0.050 g, 0.110 mmol), hydroxylamine (0.134 mL, 2.190 mmol, 50.00% aqueous solution) and potassium hydroxide (0.061 g, 1.095 mmol) were dissolved in methanol (1 ml) at 25° C., and the reaction solution was stirred at the same temperature for 1 hour. Saturated sodium bicarbonate was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give compound 234 (0.027 g, 53.9%) as a light yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.70(d, 2H, J=7.6Hz), 7.68(d, 2H, J=8.0Hz), 7.58-7.30(m, 8H), 7.21(m, 1H), 4.39(brs, 1H), 4.14( brs, 1H) 3.83-3.64 (m, 2H), 3.48 (s, 2H), 2.62 (d, 2H, J=10.8Hz), 2.29 (brs, 2H), 1.22 (d, 6H, J=20Hz).

Example 86: Synthesis of Compound 242 (4-(((3R,5S)-4-(3-(furan-2-yl)benzoyl)-3,5-dimethyl (1-piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 3-iodobenzoyl chloride

3-Iodobenzoic acid (0.200 g, 0.806 mmol) was dissolved in _SOCl2 (1.170 mL, 16.128 mmol) and stirred at 100°C for 2 hours, and the reaction mixture was concentrated under reduced pressure. The obtained product was used without additional purification (0.215 g, 100.0%, brown oil).

Step 2: Methyl 4-(((3R,5S)-4-(3-iodobenzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate ester

4-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 1-2, 0.215g, 0.807mmol), 3-iodobenzoyl chloride (0.233mL, 0.887mmol) and TEA (0.224mL, 1.613mmol) were dissolved in dichloromethane (5mL) at 0°C, and the reaction solution was stirred at the same temperature for 2 hours. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica; ethyl acetate/hexane=from 30% to 50%) to obtain the desired compound (0.365g, 91.8%) as a colorless oil.

Step 3: 4-(((3R,5S)-4-(3-(furan-2-yl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl) Methyl benzoate

1,2-Dimethoxyethane/water (v/v = 3/1) (1 mL) was added to a mixture of methyl 4-(((3R,5S)-4-(3-iodobenzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 4-1, 0.346 g, 0.703 mmol), furan-2-ylboronic acid (0.118 g, 1.054 mmol), Pd(dppf) _Cl₂ (0.029 g, 0.035 mmol), and _{Na₂CO₃ (} 0.223 g, 2.108 mmol), and heated at 120°C for 30 minutes by microwave irradiation, followed by cooling to room temperature. A 1N aqueous solution of hydrochloric acid was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 10% to 25%) and concentrated to give the desired compound (0.301 g, 99.0%) as a brown oil.

Step 4: Synthesis of Compound 242

4-(((3R, 5S)-4-(3-(furan-2-yl)benzoyl)-3,5-dimethylpiperazine-1-yl)methyl)methyl benzoate (Formula 4-2, 0.050g, 0.116mmol), hydroxylamine (0.141mL, 2.312mmol, 50.00% aqueous solution) and potassium hydroxide (0.065g, 1.156mmol) were dissolved in methanol (2mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the precipitated solid was filtered and dried to obtain compound 242 (0.034g, 67.6%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.79 (s, 1H), 7.78-7.70 (m, 3H), 7.64 (s, 1H), 7.48 (t, 1H, J=7.7Hz), 7.37 (d, 2H, J=8.0Hz), 7.24 (d, 1H, J=7. 6Hz), 7.08 (d, 1H, J = 3.4Hz), 6.63-6.61 (m, 1H), 3.53 (s, 2H), 2.63 (brs, 2H), 2.18-2.14 (m, 2H), 1.31 (brs, 6H).

Example 87: Synthesis of Compound 243 (4-(((3R,5S)-4-(3-(furan-3-yl)benzoyl)-3,5-dimethyl (1-piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-(furan-3-yl)benzoyl)-3,5-dimethylpiperazin-1-yl) Methyl)benzoate

1,2-Dimethoxyethane/water (v/v = 3/1) (1 mL) was added to a mixture of methyl 4-(((3R,5S)-4-(3-iodobenzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 4-1, 0.120 g, 0.244 mmol), furan-3-ylboronic acid (0.041 g, 0.366 mmol), Pd(dbpf) _Cl₂ (0.008 g, 0.012 mmol), and _{Na₂CO₃ (} 0.077 g, 0.731 mmol), and heated at 120°C for 30 minutes by microwave irradiation, followed by cooling to room temperature. A 1N aqueous solution of hydrochloric acid was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 10% to 30%) and concentrated to give the desired compound (0.050 g, 47.0%) as a brown solid.

Step 2: Synthesis of compound 243

4-(((3R, 5S)-4-(3-(furan-3-yl)benzoyl)-3,5-dimethylpiperazine-1-yl)methyl)methyl benzoate (Formula 4-2, 0.050g, 0.114mmol), hydroxylamine (0.140mL, 2.289mmol, 50.00% aqueous solution) and potassium hydroxide (0.064g, 1.144mmol) were dissolved in methanol (2mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the precipitated solid was filtered and dried to give compound 243 (0.029g, 57.4%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.29 (s, 1H), 7.76-7.70 (m, 3H), 7.66 (d, 1H, J=8.0Hz), 7.46-7.38 (m, 3H), 7.20 (d, 1H, J=7 .6Hz), 7.05-7.04(m, 1H), 3.54(s, 2H), 2.68-2.64(m, 2H), 2.19-2.15(m, 2H), 1.32(brs, 6H).

Example 88: Synthesis of Compound 244 (4-(((3R,5S)-4-(3-(3,6-dihydro-2H-pyran-4-yl)benzoyl) 1-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-(3,6-dihydro-2H-pyran-4-yl)benzoyl)-3,5-dimethyl methyl)benzoate

1,2-Dimethoxyethane/water (v/v=3/1) (1 mL) was added to a mixture of methyl 4-(((3R,5S)-4-(3-iodobenzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 4-1, 0.120 g, 0.244 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.077 g, 0.366 mmol), Pd(dbpf)Cl ₂ (0.008 g, 0.012 mmol) and Na ₂ CO ₃ (0.077 g, 0.731 mmol), and heated at 120° C. for 30 minutes by microwave irradiation, followed by cooling to room temperature. A 1N aqueous solution of hydrochloric acid was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 10% to 50%) and concentrated to give the desired compound (0.049 g, 44.8%) as a brown oil.

Step 2: Synthesis of compound 244

4-(((3R, 5S)-4-(3-(3,6-dihydro-2H-pyrans-4-yl)benzoyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 4-2, 0.049g, 0.113mmol), hydroxylamine (0.139mL, 2.266mmol, 50.00% aqueous solution) and potassium hydroxide (0.064g, 1.133mmol) were dissolved in methanol (2mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the precipitated solid was filtered and dried to obtain compound 244 (0.013g, 24.7%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.72 (d, 2H, J=8.0Hz), 7.50 (d, 1H, J=7.7Hz), 7.45-7.37 (m, 4H), 7.22 (d, 1H, J=7.4Hz), 6.33 (s, 1H), 4. 23-4.22 (m, 2H), 3.82 (t, 2H, J=5.3Hz), 3.53 (s, 2H), 2.68-2.63 (m, 2H), 2.18-2.14 (m, 2H), 1.30 (brs, 6H).

Example 89: Synthesis of Compound 245 (4-(((3R,5S)-3,5-dimethyl-4-(3-(pyridin-4-yl)benzoyl) (4-(2-Methyl)piperazin-1-yl)methyl)-N-hydroxybenzamide (trifluoroacetate))

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(3-(pyridin-4-yl)benzoyl)piperazin-1-yl) Methyl)benzoate

1,2-Dimethoxyethane/water (v/v = 3/1) (1 mL) was added to a mixture of methyl 4-(((3R,5S)-4-(3-iodobenzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 4-1, 0.200 g, 0.406 mmol), pyridine-4-boronic acid hydrate (0.086 g, 0.609 mmol), Pd(dbpf) _Cl₂ (0.013 g, 0.020 mmol), and _{Na₂CO₃ (} 0.129 g, 1.219 mmol). The mixture was heated at 120°C for 20 minutes under microwave irradiation, followed by cooling to room temperature. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; methanol/dichloromethane = from 0% to 5%) and concentrated to give the desired compound (0.167 g, 92.8%) as a brown oil.

Step 2: Synthesis of Compound 245

Methyl 4-(((3R, 5S)-3,5-dimethyl-4-(3-(pyridin-4-yl)benzoyl)piperazine-1-yl)methyl)benzoate (Formula 4-2, 0.105 g, 0.236 mmol), hydroxylamine (0.288 mL, 4.712 mmol, 50.00% aqueous solution) and potassium hydroxide (0.132 g, 2.356 mmol) were dissolved in methanol (2 mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. Then, a saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Then, the concentrate was purified by column chromatography (Waters, C ₁₈ , 19*100 mm column, 0.1% trifluoroacetic acid aqueous solution/acetonitrile = from 5% to 80%) and concentrated to give compound 245 (0.072 g, 54.6%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.91 (d, 2H, J = 6.6Hz), 8.24 (d, 2H, J = 6.0Hz), 8.05 (d, 1H, J = 7.9Hz), 7.98 (s, 1H), 7.81 (d, 2H, J = 7.9Hz), 7. 68 (t, 1H, J=7.7Hz), 7.61-7.56 (m, 3H), 4.78 (brs, 1H), 4.24-4.00 (m, 3H), 3.23-3.10 (m, 2H), 1.36 (brs, 6H).

Example 90: Synthesis of Compound 246 (4-(((3R,5S)-3,5-dimethyl-4-(3-pyridin-3-yl)benzoyl) (4-(2-methyl-1-piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(3-(pyridin-3-yl)benzoyl)piperazin-1-yl) methyl)benzoate

1,2-Dimethoxyethane/water (v/v = 3/1) (1.2 mL) was added to a mixture of methyl 4-(((3R,5S)-4-(3-iodobenzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 4-1, 0.100 g, 0.203 mmol), pyridin-3-ylboronic acid (0.050 g, 0.406 mmol), _Na₂CO₃ (0.065 _g , 0.609 mmol), and Pd(dbpf) _Cl₂ (0.007 g, 0.010 mmol), and heated at 120°C for 20 minutes by microwave irradiation, followed by cooling to room temperature. Water was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 80%) and concentrated to give the desired compound (0.080 g, 88.8%) as a yellow solid.

Step 2: Synthesis of Compound 246

Methyl 4-(((3R,5S)-3,5-dimethyl-4-(3-(pyridin-3-yl)benzoyl)piperazin-1-yl)methyl)benzoate (Formula 4-2, 0.065 g, 0.147 mmol), hydroxylamine (0.090 mL, 1.465 mmol, 50.00% aqueous solution) and potassium hydroxide (0.191 g, 2.931 mmol) were dissolved in methanol (3 mL) at room temperature, and the reaction solution was stirred at the same temperature for 2 hours and then concentrated. The concentrate was washed with saturated sodium bicarbonate aqueous solution and distilled water to obtain compound 246 (0.035 g, 53.7%) as a yellow solid.

¹ H NMR (400MHz, CDCl ₃ ): 8.93 (d, 1H, J = 2.3Hz), 8.60 (m, 1H), 7.06 (dd, 1H, J = 8.0, 1.6Hz), 7.82-7.77 (m, 1H), 7.72-7.69 (m, 3H), 7.5 8-7.48 (m, 2H), 7.39-7.35 (m, 3H), 3.37-3.28 (m, 2H), 2.63 (m, 2H), 2.19 (dd, 2H, J=11.4, 4.0Hz), 1.32 (s, 6H).

Example 91: Synthesis of Compound 247 ((4-(((3R,5S)-4-(4′,4′-dimethyl-2′,3′,4′,5′-tetrahydro- [1,1′-biphenyl]-3-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-(4,4-dimethylcyclohex-1-enyl)benzoyl)-3,5-dimethyl methyl)benzoate

1,2-Dimethoxyethane (0.9 mL) / water (0.3 mL) was added to a mixture of methyl 4-(((3R,5S)-4-(3-iodobenzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 4-1, 0.100 g, 0.203 mmol), 2-(4,4-dimethylcyclohex-1-enyl)-4,4,5,5-tetramethyl-1,3,2- _{dioxaborolane} (0.096 g, 0.406 mmol), _Na₂CO₃ (0.065 g, 0.609 mmol), and Pd(dbpf) _Cl₂ (0.007 g, 0.010 mmol). The mixture was heated at 120°C for 20 minutes by microwave irradiation, followed by cooling to room temperature. Water was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 40%) and concentrated to give the desired compound (0.030 g, 31.1%) as a yellow solid.

Step 2: Synthesis of Compound 247

Methyl 4-(((3R,5S)-4-(3-(4,4-dimethylcyclohex-1-enyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 4-2, 0.030 g, 0.063 mmol), hydroxylamine (0.039 mL, 0.632 mmol, 50.00% aqueous solution) and potassium hydroxide (0.082 g, 1.264 mmol) were dissolved in methanol (3 mL) at room temperature, and the reaction solution was stirred at the same temperature for 2 hours. Then, the reaction mixture was concentrated. The concentrate was washed with saturated sodium bicarbonate aqueous solution and distilled water to obtain the desired compound 247 (0.021 g, 69.9%) as a yellow solid.

¹ H NMR (400MHz, CDCl ₃ ): 7.71 (d, 1H, J = 8.0Hz), 7.47-7.45 (m, 1H), 7.38-7.32 (m, 4H), 7.18 (d, 1H, J = 7.6Hz), 6.16 (s, 1H), 3.51 ( m, 2H), 2.62 (m, 2H), 2.38 (m, 2H), 2.15 (m, 2H), 1.98 (m, 2H), 1.50-1.46 (m, 2H), 2.29 (m, 6H), 0.94 (s, 6H).

Example 92: Synthesis of Compound 248 (4-(((3R,5R)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)- N-hydroxybenzamide)

Step 1: Synthesis of methyl 4-(((3R,5R)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((3R,5R)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 21-1, 0.050 g, 0.191 mmol), benzyl bromide (0.023 mL, 0.191 mmol), and _{K₂CO₃ (} 0.040 g, 0.286 mmol) were dissolved in acetonitrile (2 mL) at room temperature, and the reaction solution was stirred at the same temperature for 17 hours. The reaction mixture was then filtered through a plastic filter to remove solids, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = 0% to 30%) and concentrated to give the desired compound (0.038 g, 56.6%) as a colorless oil.

Step 2: Synthesis of Compound 248

4-(((3R, 5R)-4-benzyl-3,5-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 21-2, 0.038g, 0.108mmol), hydroxylamine (0.132mL, 2.156mmol, 50.00% aqueous solution) and potassium hydroxide (0.060g, 1.078mmol) were dissolved in methanol (2mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate aqueous solution was added to the obtained concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove solid residue and water layer, and the organic layer was concentrated under reduced pressure to obtain compound 248 (0.018g, 47.2%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.71 (d, 2H, J=8.2Hz), 7.44 (d, 2H, J=8.2Hz), 7.38 (d, 2H, J=7.3Hz), 7.29 (dd, 1H, J=7.4, 7.4Hz), 7.23-7.22 (m, 1H), 4.02 (d, 1H, J=13.4H z), 3.58 (d, 1H, J = 13.5Hz), 3.43-3.42 (m, 2H), 2.92-2.88 (m, 2H), 2.49-2.47 (m, 2H), 2.25-2.25 (m, 2H), 1.09 (d, 6H, J = 6.4Hz); LRMS (ES) m/z 354.2(M ⁺⁺ 1).

Example 93: Synthesis of Compound 249 (4-(((3R,5R)-4-(furan-2-carbonyl)-3,5-dimethylpiperazine-1- (4-(2-Methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5R)-4-(furan-2-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoic acid Methyl ester

Methyl 4-(((3R, 5R)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 21-1, 0.050 g, 0.191 mmol) and TEA (0.053 mL, 0.381 mmol) were dissolved in dichloromethane (2 mL), and 2-furoyl chloride (0.019 mL, 0.191 mmol) was added thereto at 0° C., followed by stirring at the same temperature for 3 hours. Saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane=from 0% to 40%) to give the desired compound (0.033 g, 48.6%) as a yellow oil.

Step 2: Synthesis of Compound 249

4-(((3R, 5R)-4-(furan-2-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 21-3, 0.033g, 0.093mmol), hydroxylamine (0.113mL, 1.852mmol, 50.00% aqueous solution) and potassium hydroxide (0.052g, 0.926mmol) were dissolved in methanol (2mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate aqueous solution was added to the concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove solid residue and water layer, and the organic layer was concentrated under reduced pressure to obtain compound 249 (0.019g, 57.4%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.73 (d, 2H, J=7.9Hz), 7.66 (s, 1H), 7.48 (d, 2H, J=7.9Hz), 7.01 (d, 1H, J=3.3Hz), 6.58 (s, 1H), 4.17-4.13 (m, 2H), 3. 67 (d, 1H, J = 13.5Hz), 3.53 (d, 1H, J = 13.8Hz), 2.68-2.65 (m, 2H), 2.42-2.38 (m, 2H), 1.35 (d, 6H, J = 6.4Hz); LRMS (ES) m/z 358.1(M ⁺ +1).

Example 94: Synthesis of Compound 250 (4-(((2S,6R)-4-(2-([1,1′-biphenyl]-3-yl)acetyl)-2, 6-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide (trifluoroacetate)

Step 1: Synthesis of 4-(((2S,6R)-4-(2-(3-bromophenyl)acetyl)-2,6-dimethylpiperazin-1-yl)methane methyl)benzoate

Methyl 4-(((2S, 6R)-2,6-dimethylpiperazine-1-yl)methyl)benzoate (Formula 13-2, 2.000 g, 6.693 mmol), 2-(3-bromophenyl)acetic acid (1.583 g, 7.363 mmol), EDCI (2.566 g, 13.386 mmol), HOBt (2.050 g, 13.386 mmol) and DIPEA (5.845 mL, 33.466 mmol) were dissolved in dichloromethane (5 mL) at room temperature, and the reaction solution was stirred at the same temperature for 17 hours. Then, saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 12 g cartridge; ethyl acetate/hexane = from 40% to 70%) and concentrated to give the desired compound (2.230 g, 72.5%) as a colorless oil.

Step 2: Synthesis of 4-(((2S,6R)-4-(2-(3-bromophenyl)acetyl)-2,6-dimethylpiperazin-1-yl)methane methyl)benzoate

1,2-Dimethoxyethane (2 mL) was added to a mixture of methyl 4-(((2S,6R)-4-(2-(3-bromophenyl)acetyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 15-1, 0.100 g, 0.218 mmol), phenylboronic acid (0.029 g, 0.239 mmol), Pd(PPh ₃ ) ₄ (0.013 g, 0.011 mmol), and Na ₂ CO ₃ (0.069 g, 0.653 mmol) at room temperature, and the reaction solution was stirred at 100° C. for 17 hours. Then, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 40%) and concentrated to give the desired compound (0.043 g, 43.3%) as a colorless oil.

Step 3: Synthesis of Compound 250

Methyl 4-(((2S,6R)-4-(2-([1,1′-biphenyl]-3-yl)acetyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 15-2, 0.043 g, 0.094 mmol), hydroxylamine (0.115 mL, 1.884 mmol, 50.00% aqueous solution) and potassium hydroxide (0.053 g, 0.942 mmol) were dissolved in methanol (2 mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove solid residues and the aqueous solution, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (Waters, C ₁₈ , 19*100 mm column, 0.1% trifluoroacetic acid/acetonitrile = from 5% to 80%) and concentrated to give compound 250 (0.015 g, 34.8%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.55-7.37(m, 9H), 7.30(d, 2H, J=7.7Hz), 7.22(dd, 1H, J=7.2, 7.2Hz), 7.12( d, 2H, J=7.0Hz), 4.55-4.48 (m, 2H), 4.38 (d, 1H, J=14.7Hz), 4.15 (d, 1H, J=15.0 Hz), 3.91 (d, 1H, J = 15.0Hz), 3.68 (d, 1H, J = 6.5Hz), 3.67 (d, 1H, J = 14.5Hz), 3.3 5-3.27 (m, 1H), 2.97-2.91 (m, 3H), 1.54 (d, 3H, J=5.7Hz), 1.31 (d, 3H, J=6.4Hz).

Example 95: Synthesis of Compound 251 (4-(((2S,6R)-2,6-dimethyl-4-(2-(3-pyridin-4-yl)benzene (methyl)-N-hydroxybenzamide (trifluoroacetate)

Step 1: Synthesis of 4-(((2S,6R)-2,6-dimethyl-4-(2-(3-(pyridin-4-yl)phenyl)acetyl)piperazine- 1-aminobenzoic acid methyl ester

1,2-Dimethoxyethane (4 mL) / water (1 mL) was added to a mixture of methyl 4-(((2S,6R)-4-(2-(3-bromophenyl)acetyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 15-1, 0.200 g, 0.435 mmol), pyridin-4-ylboronic acid (borinic acid) (0.059 g, 0.479 mmol), Pd(PPh ₃ ) ₄ (0.025 g, 0.022 mmol) and Na ₂ CO ₃ (0.138 g, 1.306 mmol) at room temperature, and the reaction mixture was heated under reflux for 17 hours and then cooled to room temperature. Then, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to give the desired compound (0.123 g, 61.7%) as a yellow oil.

Step 2: Synthesis of compound 251

4-(((2S,6R)-2,6-dimethyl-4-(2-(3-(pyridin-4-yl)phenyl)acetyl)piperazin-1-yl)methyl)benzoic acid methyl ester (Formula 15-2, 0.100 g, 0.219 mmol), hydroxylamine (0.267 mL, 4.371 mmol, 50.00% aqueous solution) and potassium hydroxide (0.123 g, 2.186 mmol) were dissolved in methanol (2 mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated sodium bicarbonate aqueous solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove solid residues and the aqueous solution, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (Waters, C ₁₈ , 19*100 mm column, 0.1% trifluoroacetic acid/acetonitrile = from 5% to 80%) and concentrated to give compound 251 (0.006 g, 6.0%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.65 (d, 2H, J=5.9Hz), 7.69-7.64 (m, 5H), 7.45 (dd, 1H, J=7.7, 7.7Hz), 7.34 (d, 3H, J=8.3Hz), 4.16 (d, 1H, J=12.8Hz), 3.91 (d, 1H, J=13.1Hz), 3.82 (d, 2H, J=8.0Hz), 3.71 (s, 2H), 2.90 (dd, 1H, J=10.4, 13.3Hz), 2.41-2.32 (m, 2H), 0.96-0.85 (m, 6H).

Example 96: Synthesis of Compound 252 (4-(((2S,6R)-4-(2-(3-(3,6-dihydro-2H-pyran-4-yl)benzene (2,6-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(2-(3-(3,6-dihydro-2H-pyran-4-yl)phenyl)acetyl)-2, Methyl 6-dimethylpiperazin-1-yl)methyl)benzoate

1,2-Dimethoxyethane (4 mL) / water (1 mL) was added to a mixture of methyl 4-(((2S,6R)-4-(2-(3-bromophenyl)acetyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 15-1, 0.200 g, 0.435 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.101 g, 0.479 mmol), Pd(PPh ₃ ) ₄ (0.025 g, 0.022 mmol) and Na ₂ CO ₃ (0.138 g, 1.306 mmol) at room temperature, and the reaction mixture was heated under reflux for 17 hours and then cooled to room temperature. Then, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 30% to 100%) and concentrated to give the desired compound (0.084 g, 41.7%) as a white solid.

Step 2: Synthesis of compound 252

4-(((2S,6R)-4-(2-(3-(3,6-dihydro-2H-pyran-4-yl)phenyl)acetyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 15-2, 0.050g, 0.108mmol), hydroxylamine (0.132mL, 2.162mmol, 50.00% aqueous solution) and potassium hydroxide (0.061g, 1.081mmol) were dissolved in methanol (2mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove solid residues and the aqueous solution, and the organic layer was concentrated under reduced pressure to obtain compound 252 (0.016g, 31.9%) as a white solid.

¹ H NMR (400MHz, CH ₃ OD) δ7.70-7.69 (m, 2H), 7.43 (d, 2H, J=8.3Hz), 7.34 (d, 2H, J=5.8Hz), 7.30-7.28 (m, 1H), 7.16-7.16(m, 1H), 6.20-6.19(m, 1H), 4.32-4.30(m, 3H), 3.94(t, 2H, J=5.5Hz) , 3.86-3.77(m, 5H), 2.85(dd, 1H, J=11.3, 11.3Hz), 2.59-2.56(m, 1H), 2.52-2.50(m , 3H), 2.19-2.18 (m, 1H), 1.06 (d, 3H, J=6.1Hz), 0.95 (d, 3H, J=6.2Hz); LRMS (ES) m/z 464.2(M ⁺ +1).

Example 97: Synthesis of Compound 253 (4-(((2S,6R)-4-(2-(4′,4′-dimethyl-2′,3′,4′,5′-tetramethyl O-[1,1′-biphenyl]-3-yl)acetyl)-2,6-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide (trifluoroacetic acid Salt))

Step 1: Synthesis of 4-(((2S,6R)-4-(2-(4′,4′-dimethyl-2′,3′,4′,5′-tetrahydro-[1,1′- phenyl]-3-yl)acetyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoic acid methyl ester

1,2-Dimethoxyethane (4 mL) / water (1 mL) was added to a mixture of methyl 4-(((2S,6R)-4-(2-(3-bromophenyl)acetyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 15-1, 0.150 g, 0.327 mmol), 2-(4,4-dimethylcyclo-1-hexenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.085 g, 0.359 mmol), Pd(PPh ₃ ) ₄ (0.019 g, 0.016 mmol) and Na ₂ CO ₃ (0.104 g, 0.980 mmol) at room temperature, and the reaction mixture was heated under reflux for 17 hours and then cooled to room temperature. Then, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 20%) and concentrated to give the desired compound (0.089 g, 55.8%) as a light yellow oil.

Step 2: Synthesis of compound 253

Methyl 4-(((2S,6R)-4-(2-(4′,4′-dimethyl-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-3-yl)acetyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 15-2, 0.050 g, 0.102 mmol), hydroxylamine (0.125 mL, 2.046 mmol, 50.00% aqueous solution) and potassium hydroxide (0.057 g, 1.023 mmol) were dissolved in methanol (2 mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove solid residues and the aqueous solution, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (Waters, C ₁₈ , 19*100 mm column, 0.1% trifluoroacetic acid/acetonitrile = from 5% to 80%) and concentrated to give compound 253 (0.015 g, 29.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.65 (d, 2H, J=8.2Hz), 7.33-7.26 (m, 4H), 7.23 (dd, 1H, J=7.6, 7.6Hz), 7.07 (d, 1H , J=6.9Hz), 6.07 (s, 1H), 4.15 (d, 1H, J=11.0Hz), 3.85 (d, 1H, J=13.2Hz), 3.76-3.65 ( m, 4H), 2.85 (dd, 1H, J=11.3, 11.3Hz), 2.47-2.44 (m, 1H), 2.37 (s, 3H), 2.25 (s, 1H), 1.98 (s, 1H), 1.49 (t, 2H, J=6.3Hz), 0.94 (s, 9H), 0.89 (d, 3H, J=5.8Hz); LRMS (ES) m/z 490.3(M ⁺ +1).

Example 98: Synthesis of Compound 255 (4-(((3R,5S)-4-(3-(1H-pyrrol-1-yl)benzyl)-3,5-dimethoxy (1-piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-(1H-pyrrol-1-yl)benzyl)-3,5-dimethylpiperazin-1-yl)methane methyl)benzoate

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.200 g, 0.762 mmol), 1-(3-(bromomethyl)phenyl)-1H-pyrrole (0.198 g, 0.839 mmol), and K ₂ CO ₃ (0.211 g, 1.525 mmol) were dissolved in acetonitrile (2 ml) at 25°C, and the reaction solution was stirred at the same temperature for 8 hours. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 12 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to obtain the desired compound (0.164 g, 51.5%) as a colorless oil.

Step 2: Synthesis of compound 255

Methyl 4-(((3R,5S)-4-(3-(1H-pyrrol-1-yl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-3, 0.050 g, 0.120 mmol), hydroxylamine (0.146 mL, 2.395 mmol, 50.00% aqueous solution) and potassium hydroxide (0.067 g, 1.197 mmol) were dissolved in methanol (1 ml) at 25 ° C, and the solution was stirred at the same temperature for 1 hour. Then, saturated sodium bicarbonate was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain compound 255 (0.024 g, 47.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.61 (d, 2H, J=8.4Hz), 7.45-7.42 (m, 1H), 7.32 (d, 2H, J=5.2Hz), 7.26 (d, 2H, J=2.4Hz), 7.22-7.21 (m, 1H), 7.13-7. 11 (m, 2H) 6.22-6.21 (m, 2H), 3.80 (s, 2H), 3.33 (s, 2H), 2.63-2.57 (m, 4H), 1.79-1.72 (m, 2H), 0.85 (d, 6H, J=16.8Hz).

Example 99: Synthesis of Compound 256 (4-(((2S,6R)-4-(3-(1H-pyrrol-1-yl)benzyl)-2,6-dimethyl (1-piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(3-(1H-pyrrol-1-yl)benzyl)-2,6-dimethylpiperazin-1-yl)methane methyl)benzoate

Methyl 4-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.200 g, 0.762 mmol), 1-(3-(bromomethyl)phenyl)-1H-pyrrole (0.198 g, 0.839 mmol), and K ₂ CO ₃ (0.211 g, 1.525 mmol) were dissolved in acetonitrile (2 ml) at 25° C., and the reaction solution was stirred at the same temperature for 8 hours. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 12 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to obtain the desired compound (0.177 g, 55.6%) as a white solid.

Step 2: Synthesis of compound 256

Methyl 4-(((2S,6R)-4-(3-(1H-pyrrole-1-yl)benzyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoate (Formula 13-3, 0.050 g, 0.120 mmol), hydroxylamine (0.146 mL, 2.395 mmol, 50.00% aqueous solution) and potassium hydroxide (0.067 g, 1.197 mmol) were dissolved in methanol (1 ml) at 25 ° C, and the reaction solution was stirred at the same temperature for 1 hour. Then, saturated sodium bicarbonate was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain compound 256 (0.031 g, 61.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.61 (d, 2H, J=8.4Hz), 7.41-7.30 (m, 7H), 7.14 (d, 2H, J=7.2Hz), 6.22-6.21 (m, 2H, J=2.4Hz), 3.70 (s , 2H), 3.42 (s, 2H), 2.66 (d, 2H, J=10Hz), 2.57-2.52 (m, 2H), 1.83-1.77 (m, 2H), 0.85 (d, 6H, J=10.4Hz).

Example 100: Synthesis of Compound 257 (4-(((2S,6R)-4-(3-(furan-2-yl)benzoyl)-2,6-diol (methylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(3-iodobenzoyl)-2,6-dimethylpiperazin-1-yl)methyl)benzyl Methyl ester

At room temperature, 4-(((2S, 6R)-2,6-dimethylpiperazine-1-yl)methyl)methylbenzoate (Formula 13-2,7.000g, 28.224mmol), 3-iodobenzoic acid (8.145g, 31.046mmol), EDCI (10.821g, 56.447mmol), HOBt (7.628g, 56.447mmol) and N, N-diisopropylethylamine (18.238g, 141.118mmol) were dissolved in dichloromethane (150mL), and the reaction solution was stirred at the same temperature overnight. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 30% to 50%) and concentrated to give the desired compound (10.737 g, 77.3%) as a white solid.

Step 2: Synthesis of 4-(((2S,6R)-4-(3-(furan-2-yl)benzoyl)-2,6-dimethylpiperazin-1-yl) Methyl)benzoate

1,2-Dimethoxyethane/water (v/v = 3/1) (3 mL) was added to a mixture of methyl 4-(((2S,6R)-4-(3-iodobenzoyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 15-1, 0.400 g, 0.812 mmol), furan-2-ylboronic acid (0.136 g, 1.219 mmol), Pd(dbpf) _Cl₂ (0.026 g, 0.041 mmol), and _Na₂CO₃ (0.258 g, 2.437 mmol), and heated at 120°C for 30 minutes by microwave irradiation, followed by cooling to room temperature. A 1N aqueous solution _of hydrochloric acid was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 10% to 50%) and concentrated to give the desired compound (0.030 g, 8.5%) as a yellow oil.

Step 3: Synthesis of compound 257

At room temperature by 4- (((2S, 6R) -4- (3- (furans -2- bases) benzoyl) -2,6- dimethylpiperazine -1- bases) methyl) methyl benzoate (formula 15-2, 0.030g, 0.069mmol), hydroxylamine (0.084mL, 1.378mmol, 50% aqueous solution) and potassium hydroxide (0.039g, 0.689mmol) are dissolved in methanol (1mL), and the reaction solution is stirred at the same temperature for 30 minutes. Then, the reaction mixture is concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution is added to the concentrate, and the precipitated solid is filtered and dried to obtain compound 257 (0.012g, 41.2%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.79-7.79 (m, 2H), 7.77-7.68 (m, 3H), 7.50 (t, 1H, J=7.7Hz), 7.41 (d, 2H, J=7.9Hz), 7.29 (d, 1H, J=7.6Hz), 7.07 (d, 1H, J=3.3Hz), 6 .63-6.62 (m, 1H), 4.30-4.27 (m, 1H), 3.78 (s, 2H), 3.01-2.99 (m, 1H), 2.73-2.71 (m, 1H), 2.56-2.51 (m, 3H), 1.03 (s, 3H), 0.82 (s, 3H).

Example 101: Synthesis of Compound 258 (4-(((2S,6R)-4-(3-(furan-3-yl)benzoyl)-2,6-diol (methylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(3-(furan-3-yl)benzoyl)-2,6-dimethylpiperazin-1-yl) Methyl)benzoate

1,2-Dimethoxyethane/water (v/v = 3/1) (3 mL) was added to a mixture of methyl 4-(((2S,6R)-4-(3-iodobenzoyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 15-1, 0.400 g, 0.812 mmol), furan-3-ylboronic acid (0.136 g, 1.219 mmol), Pd(dbpf) _Cl₂ (0.026 g, 0.041 mmol), and _Na₂CO₃ (0.258 g, 2.437 mmol), and heated at 120°C for 30 minutes by microwave irradiation, followed by cooling to room temperature. A 1N aqueous solution _of hydrochloric acid was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 10% to 50%) and concentrated to give the desired compound (0.061 g, 17.4%) as a yellow oil.

Step 2: Synthesis of compound 258

At room temperature by 4- (((2S, 6R) -4- (3- (furans -3- bases) benzoyl) -2,6- dimethylpiperazine -1- bases) methyl) methyl benzoate (formula 15-2, 0.061g, 0.141mmol), hydroxylamine (0.173mL, 2.830mmol, 50% aqueous solution) and potassium hydroxide (0.079g, 1.415mmol) are dissolved in methanol (2mL), and the reaction solution is stirred at the same temperature for 30 minutes. Then, the reaction mixture is concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution is added to the concentrate, and the precipitated solid is filtered and dried to obtain compound 258 (0.016g, 25.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.29 (s, 1H), 7.77 (s, 1H), 7.72-7.68 (m, 3H), 7.64 (s, 1H), 7.47-7.41 (m, 3H), 7.25 (d, 1H, J=7.6Hz), 7.03 (s, 1H), 4.31-4.28 (m, 1H), 3.79 (s, 2H), 3.00-2.98 (m, 1H), 2.71-2.68 (m, 1H), 2.56-2.51 (m, 3H), 1.03 (s, 3H), 0.82 (s, 3H).

Example 102: Synthesis of Compound 259 (4-(((2S,6R)-4-(3-(3,6-dihydro-2H-pyran-4-yl)benzene (acyl)-2,6-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(3-(3,6-dihydro-2H-pyran-4-yl)benzoyl)-2,6-dimethyl methylpiperazin-1-yl (1-methyl)benzoate

1,2-Dimethoxyethane/water (v/v=3/1) (3 mL) was added to a mixture of methyl 4-(((2S,6R)-4-(3-iodobenzoyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 15-1, 0.400 g, 0.812 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.256 g, 1.219 mmol), Pd(dbpf)Cl ₂ (0.026 g, 0.041 mmol) and Na ₂ CO ₃ (0.258 g, 2.437 mmol), and heated at 120° C. for 30 minutes under microwave irradiation, followed by cooling to room temperature. Saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure.The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 20% to 65%) and concentrated to give the desired compound (0.290 g, 79.6%) as a brown solid.

Step 2: Synthesis of compound 259

At room temperature 4-(((2S, 6R)-4-(3-(3,6-dihydro-2H-pyrans-4-yl)benzoyl)-2,6-dimethylpiperazine-1-yl)methyl)methyl benzoate (Formula 15-2, 0.060g, 0.134mmol), hydroxylamine (0.164mL, 2.675mmol, 50.00% aqueous solution) and potassium hydroxide (0.075g, 1.338mmol) were dissolved in methanol (2mL), and the reaction solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the precipitated solid was filtered and dried to obtain compound 259 (0.010g, 16.6%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.69 (d, 2H, J=8.0Hz), 7.54 (d, 1H, J=7.9Hz), 7.44-7.41 (m, 4H), 7.28 (d, 1H, J=7.7Hz), 6.33 (s, 1H), 4.24-4.23 (m, 3H), 3.83 (t, 2H, J=5.4Hz), 3.78 (s, 2H), 2.98-2.96 (m, 1H), 2.70-2.68 (m, 1H), 2.55-2.51 (m, 3H), 2.46 (s, 2H), 1.02 (s, 3H), 0.82 (s, 3H).

Example 103: Synthesis of Compound 260 (4-(((2S,6R)-2,6-dimethyl-4-(3-pyridin-4-yl)benzoyl) (4-(2-methyl-1-piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-2,6-dimethyl-4-(3-(pyridin-4-yl)benzoyl)piperazin-1-yl) Methyl)benzoate

1,2-Dimethoxyethane/water (v/v = 3/1) (3 mL) was added to a mixture of methyl 4-(((2S,6R)-4-(3-iodobenzoyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 15-1, 0.400 g, 0.812 mmol), pyridine-4-boronic acid hydrate (0.172 g, 1.219 mmol), Pd(dbpf) _Cl₂ (0.026 g, 0.041 mmol), and _{Na₂CO₃ (} 0.258 g, 2.437 mmol). The mixture was heated at 120°C for 30 minutes under microwave irradiation, followed by cooling to room temperature. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 50% to 65%) and concentrated to give the desired compound (0.354 g, 98.3%) as a brown oil.

Step 2: Synthesis of Compound 260

4-(((2S, 6R)-2,6-dimethyl-4-(3-(pyridin-4-yl)benzoyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 15-2,0.060g, 0.135mmol), hydroxylamine (0.165mL, 2.706mmol, 50.00% aqueous solution) and potassium hydroxide (0.076g, 1.353mmol) were dissolved in methanol (2mL) at room temperature, and the reaction solution was stirred at the same temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the precipitated solid was filtered and dried to obtain compound 260 (0.003g, 5.5%) as a light brown solid.

¹ H NMR (400 MHz, DMSO-d ₆ )δ8.67-8.66 (m, 2H), 7.91 (d, 1H, J=7.9Hz), 7.81 (s, 1H), 7.77-7.75 (m, 2H), 7.68 (d, 2H, J=8.2Hz), 7.61 (t, 1H, J=7.7Hz), 7.49 (d, 1H, J=7.6 Hz), 7.43-7.41(m, 2H), 4.31-4.29(m, 1H), 3.79(s, 2H), 3.02-3.02(m , 1H), 2.73-2.68(m, 1H), 2.67-2.55(m, 3H), 1.04(s, 3H), 0.86(s, 3H).

Example 104: Synthesis of Compound 261 (4-(((2S,6R)-2,6-dimethyl-4-(3-(pyridin-3-yl)benzoyl) (4-(2-methyl-1-piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-2,6-dimethyl-4-(3-(pyridin-3-yl)benzoyl)piperazin-1-yl) Methyl)benzoate

1,2-Dimethoxyethane/water (v/v = 3/1) (3 mL) was added to a mixture of methyl 4-(((2S,6R)-4-(3-iodobenzoyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 15-1, 0.328 g, 0.665 mmol), pyridin-3-ylboronic acid (0.090 g, 0.732 mmol), Pd(dbpf) _Cl₂ (0.022 g, 0.033 mmol), and _{Na₂CO₃ (} 0.155 g, 1.464 mmol). The mixture was heated at 120°C for 30 minutes under microwave irradiation, followed by cooling to room temperature. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 50% to 65%) and concentrated to give the desired compound (0.244 g, 82.8%) as a brown solid.

Step 2: Synthesis of compound 261

4-(((2S, 6R)-2,6-dimethyl-4-(3-(pyridin-3-yl)benzoyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 15-2,0.060g, 0.135mmol), hydroxylamine (0.165mL, 2.706mmol, 50.00% aqueous solution) and potassium hydroxide (0.076g, 1.353mmol) were dissolved in methanol (2mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the precipitated solid was filtered and dried to obtain compound 261 (0.014g, 23.3%) as a light brown solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.91-8.90(m, 1H), 8.59-8.58(m, 1H), 8.12-8.09(m, 1H), 7.81(d, 1H, J=7.8 Hz), 7.72 (s, 1H), 7.67 (d, 2H, J=8.1Hz), 7.56 (t, 1H, J=7.7Hz), 7.51-7.47 (m, 1H), 7.43-7.39(m, 3H), 4.29-4.26(m, 1H), 3.77(s, 2H), 3.44-3.42(m, 1H), 3. 01-2.99 (m, 1H), 2.71-2.66 (m, 1H), 2.58 (brs, 2H), 1.01 (s, 3H), 0.81 (s, 3H).

Example 105: Synthesis of Compound 262 (4-(((2S,6R)-4-(3-(2-fluoropyridin-4-yl)benzoyl)-2, 6-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(3-(2-fluoropyridin-4-yl)benzoyl)-2,6-dimethylpiperazine-1-yl)- methyl)benzoate

1,2-Dimethoxyethane/water (v/v = 3/1) (3 mL) was added to a mixture of methyl 4-(((2S,6R)-4-(3-iodobenzoyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 15-1, 0.400 g, 0.812 mmol), (2-fluoropyridin-4-yl)boronic acid (0.172 g, 1.219 mmol), Pd(dbpf) _Cl₂ (0.026 g, 0.041 mmol), and _Na₂CO₃ (0.258 g, 2.437 mmol ₎ . The mixture was heated at 120°C for 30 minutes under microwave irradiation, followed by cooling to room temperature. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 10% to 50%) and concentrated to give the desired compound (0.366 g, 97.5%) as a brown oil.

Step 2: Synthesis of compound 262

At room temperature 4-(((2S, 6R)-4-(3-(2-fluoropyridin-4-yl)benzoyl)-2,6-dimethylpiperazine-1-yl)methyl)methyl benzoate (Formula 15-2,0.060g, 0.130mmol), hydroxylamine (0.159mL, 2.600mmol, 50.00% aqueous solution) and potassium hydroxide (0.073g, 1.300mmol) were dissolved in methanol (2mL), and the solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the precipitated solid was filtered and dried to give compound 262 (0.009g, 14.1%) as a light brown solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.77 (d, 1H, J=8.0Hz), 7.67-7.65 (m, 3H), 7.54 (t, 1H, J=7.7Hz), 7.47-7.44 (m, 2H), 7.38 (d, 2H, J=8.1Hz), 6.60-6.59 (m, 1H), 6.51 (dd , 1H, J=6.8, 1.6Hz), 4.26-4.24 (m, 1H), 3.77 (s, 2H), 2.99-2.97 (m, 1H), 2.72-2.70 (m, 1H), 2.66-2.54 (m, 3H), 1.01 (s, 3H), 0.81 (s, 3H).

Example 106: Synthesis of Compound 263 (4-(((2S,6R)-4-(4′,4′-dimethyl-2′,3′,4′,5′-tetrahydro- [1,1′-biphenyl]-3-carbonyl)-2,6-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(4′,4′-dimethyl-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-3- methyl)benzoate

1,2-Dimethoxyethane/water (v/v=3/1) (3 mL) was added to a mixture of methyl 4-(((2S,6R)-4-(3-iodobenzoyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 15-1, 0.400 g, 0.812 mmol), 2-(4,4-dimethylcyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.288 g, 1.219 mmol), Pd(dbpf)Cl ₂ (0.026 g, 0.041 mmol) and Na ₂ CO ₃ (0.258 g, 2.437 mmol), and heated at 120° C. for 30 minutes under microwave irradiation, followed by cooling to room temperature. Saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure.The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 10% to 20%) and concentrated to give the desired compound (0.065 g, 16.8%) as a brown oil.

Step 2: Synthesis of compound 263

4-(((2S, 6R)-4-(4′, 4′-dimethyl-2′, 3′, 4′, 5′-tetrahydro-[1,1′-biphenyl]-3-carbonyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 15-2, 0.065g, 0.137mmol), hydroxylamine (0.167mL, 2.735mmol, 50.00% aqueous solution) and potassium hydroxide (0.077g, 1.367mmol) were dissolved in methanol (2mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the precipitated solid was filtered and dried to give compound 263 (0.044g, 68.3%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.66 (d, 2H, J=8.1Hz), 7.49 (d, 1H, J=8.0Hz), 7.38-7.34 (m, 4H), 7.21 (d, 1H, J=7.6Hz), 6.15-6.13 (m, 1H), 4.24-4.22 (m, 1H), 3.76 ( s, 2H), 2.95-2.93 (m, 1H), 2.67-2.50 (m, 4H), 2.37 (s, 2H), 1.96 (s, 2H), 1.47 (t, 2H, J=6.3Hz), 1.05 (s, 3H), 0.92 (s, 6H), 0.80 (s, 3H).

Example 107: Synthesis of Compound 265 (4-(((3R,5S)-3,5-dimethyl-4-(naphthalen-2-ylmethyl)piperazine-1-yl) (4-(2-Methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(naphthalen-2-ylmethyl)piperazin-1-yl)methyl)benzoic acid Methyl ester

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.150 g, 0.572 mmol), Cs ₂ CO ₃ (0.279 g, 0.858 mmol), and 2-(bromomethyl)naphthalene (0.126 g, 0.572 mmol) were dissolved in acetonitrile (3 mL) at room temperature, and the reaction solution was stirred at the same temperature for 48 hours. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The obtained product was used without additional purification (0.230 g, 99.9%).

Step 2: Synthesis of compound 265

4-(((3R, 5S)-3,5-dimethyl-4-(naphthalene-2-ylmethyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 1-3, 0.230 g, 0.571 mmol), hydroxylamine (0.699 mL, 11.428 mmol, 50.00% aqueous solution) and potassium hydroxide (0.321 g, 5.714 mmol) were dissolved in methanol (3 mL)/tetrahydrofuran (1 mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was crystallized from methanol (5 mL) to obtain compound 265 (0.042 g, 18.2%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.87-7.82 (m, 4H), 7.66 (d, 2H, J=8.0Hz), 7.50 (d, 1H, J=9.0Hz), 7.47-7.44 (m, 2H), 7.23 (d, 2H, J=8.0Hz ), 3.88 (s, 2H), 3.41 (s, 2H), 2.67-2.61 (m, 4H), 1.84 (t, 2H, J=10.1Hz), 0.93 (d, 6H, J=6.0Hz); LRMS (ES) m/z 404.2(M ⁺ +1).

Example 108: Synthesis of Compound 266 (4-(((3R,5S)-3,5-dimethyl-4-(pyridin-4-ylmethyl)piperazine- 1-amino)methyl)-N-hydroxybenzamide (trifluoroacetate)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(pyridin-4-ylmethyl)piperazin-1-yl)methyl)benzene Methyl ester

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.150 g, 0.572 mmol), Cs ₂ CO ₃ (0.279 g, 0.858 mmol), and 4-(bromomethyl)pyridine (0.098 g, 0.572 mmol) were dissolved in acetonitrile (3 mL) at room temperature, and the reaction solution was stirred at the same temperature for 17 hours. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The product was used without additional purification (0.200 g, 99.0%).

Step 2: Synthesis of compound 266

Methyl 4-(((3R, 5S)-3,5-dimethyl-4-(pyridin-4-ylmethyl)piperazine-1-yl)methyl)benzoate (Formula 1-3, 0.200 g, 0.566 mmol), hydroxylamine (0.692 mL, 11.317 mmol, 50.00% aqueous solution) and potassium hydroxide (0.317 g, 5.658 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (Waters, C ₁₈ , 19*100 mm column, 0.1% trifluoroacetic acid/acetonitrile = from 5% to 80%) and concentrated to give the desired compound 266 (0.019 g, 9.5%) as a white solid.

¹ H NMR (400MHz, CH ₃ OD) δ 8.77 (d, 2H, J = 6.7Hz), 8.17 (d, 2H, J = 6.7Hz), 7.90 (d, 2H, J = 8.3Hz), 7.67 (d, 2H, J = 8.3Hz) ), 4.45 (s, 2H), 4.18 (s, 2H), 3.41 (d, 2H, J=11.4Hz), 3.03-3.00 (m, 4H), 1.04 (d, 6H, J=6.0Hz).

Example 109: Synthesis of Compound 267 (4-(((3R,5S)-4-(3-chloro-2-(trifluoromethyl)benzyl)-3,5-difluoromethane (methylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-chloro-2-(trifluoromethyl)benzyl)-3,5-dimethylpiperazin-1-yl) Methyl)benzoate

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.150 g, 0.572 mmol), Cs ₂ CO ₃ (0.279 g, 0.858 mmol), and 1-(bromomethyl)-3-chloro-2-(trifluoromethyl)benzene (0.156 g, 0.572 mmol) were dissolved in acetonitrile (3 mL) at room temperature, and the reaction solution was stirred at the same temperature for 17 hours. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = 0% to 30%) and concentrated to obtain the desired compound (0.203 g, 78.0%).

Step 2: Synthesis of compound 267

Methyl 4-(((3R,5S)-4-(3-chloro-2-(trifluoromethyl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-3, 0.100 g, 0.220 mmol), hydroxylamine (0.269 mL, 4.396 mmol, 50.00% aqueous solution) and potassium hydroxide (0.123 g, 2.198 mmol) were dissolved in methanol (3 mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure to give compound 267 (0.044 g, 43.9%) as a white solid.

¹ H NMR (400MHz, CDCl ₃ )δ9.80 (brs, 2H), 7.82 (s, 1H), 7.71-7.65 (m, 4H), 7.33 (d, 2H, J=3.9Hz), 4.58 (s, 2H), 3.44-3.3 5 (m, 3H), 2.67 (d, 2H, J=10.3Hz), 2.60 (s, 2H), 1.82 (t, 2H, J=9.4Hz), 0.83 (s, 6H); LRMS (ES) m/z 456.1(M ⁺ +1).

Example 110: Synthesis of Compound 268 (4-(((2S,6R)-2,6-dimethyl-4-(naphthalen-2-ylmethyl)piperazine-1-yl) (4-(2-Methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-2,6-dimethyl-4-(naphthalen-2-ylmethyl)piperazin-1-yl)methyl)benzoic acid Methyl ester

Methyl 4-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.150 g, 0.502 mmol), Cs ₂ CO ₃ (0.245 g, 0.753 mmol), and 2-(bromomethyl)naphthalene (0.111 g, 0.502 mmol) were dissolved in acetonitrile (3 mL) at room temperature, and the reaction solution was stirred at the same temperature for 17 hours. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The product was used without additional purification (0.200 g, 99.0%).

Step 2: Synthesis of Compound 268

4-(((2S, 6R)-2,6-dimethyl-4-(naphthalene-2-ylmethyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.200g, 0.497mmol), hydroxylamine (0.608mL, 9.937mmol) and potassium hydroxide (0.279g, 4.969mmol) were dissolved in methanol (3mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution (3mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered and dried, and the resulting product was purified by ketone column chromatography (silica, 4g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to give compound 268 (0.075g, 37.4%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.13 (s, 1H), 8.99 (s, 1H), 7.90-7.86 (m, 3H), 7.78 (s, 1H), 7.67 (d, 2H, J=7.2Hz), 7.50-7.47 (m, 3H), 7.42 (d, 2H, J=7.8Hz), 3 .76 (s, 2H), 3.57 (s, 2H), 2.71 (d, 2H, J=10.6Hz), 2.60-2.56 (m, 2H), 1.86 (t, 2H, J=10.5Hz), 0.88 (d, 6H, J=6.0Hz); LRMS (ES) m/z 404.2(M ⁺ +1).

Example 111: Synthesis of Compound 270 (N-hydroxy-4-(((3R,5S)-4-isopentyl-3,5-dimethylpiperazine-1- (4-(2-Methyl)benzamide (trifluoroacetate))

Step 1: Synthesis of methyl 4-(((3R,5S)-4-isopentyl-3,5-dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.150 g, 0.572 mmol), Cs ₂ CO ₃ (0.279 g, 0.858 mmol), and 1-bromo-3-methylbutane (0.086 mL, 0.720 mmol) were dissolved in N,N-dimethylformamide (100 ml) at room temperature, and the reaction solution was stirred at the same temperature for 17 hours. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The product was used without additional purification (0.190 g, 99.9%).

Step 2: Synthesis of Compound 270

Methyl 4-(((3R, 5S)-4-isopentyl-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-3, 0.190 g, 0.571 mmol), hydroxylamine (0.699 mL, 11.429 mmol, 50.00% aqueous solution) and potassium hydroxide (0.321 g, 5.715 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (Waters, C ₁₈ , 19*100 mm column, 0.1% trifluoroacetic acid/acetonitrile = from 5% to 80%) and concentrated to give compound 270 (0.025 g, 13.1%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.23(brs, 1H), 9.10(brs, 1H), 7.75(d, 2H, J=8.2Hz), 7.42(d, 2H, J=8.1Hz), 3.71(s, 2H), 3.45-3.45(m, 2H), 3.18-3.18(m, 2H), 3.01( d, 2H, J=11.3Hz), 2.28 (t, 2H, J=11.3Hz), 1.67-1.60 (m, 1H), 1.52-1.48 (m, 2H), 1.22 (d, 6H, J=6.3Hz), 0.93 (d, 6H, J=6.6Hz); LRMS (ES) m/z 334.2(M ⁺ +1).

Example 112: Synthesis of Compound 271 (N-hydroxy-4-(((2S,6R)-4-isopentyl-2,6-dimethylpiperazine-1- (4-(2-Methyl)benzamide (trifluoroacetate))

Step 1: Synthesis of methyl 4-(((2S,6R)-4-isopentyl-2,6-dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.150 g, 0.502 mmol), Cs ₂ CO ₃ (0.245 g, 0.753 mmol), and 1-bromo-3-methylbutane (0.060 mL, 0.502 mmol) were dissolved in acetonitrile (3 mL) at room temperature, and the reaction solution was stirred at the same temperature for 17 hours. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The product was used without additional purification (0.170 g, 101.9%).

Step 2: Synthesis of compound 271

Methyl 4-(((2S,6R)-4-isopentyl-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-3, 0.170 g, 0.511 mmol), hydroxylamine (0.626 mL, 10.226 mmol, 50.00% aqueous solution) and potassium hydroxide (0.287 g, 5.113 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The concentrate was then purified by column chromatography (Waters, C ₁₈ , 19*100 mm column, 0.1% trifluoroacetic acid/acetonitrile = from 5% to 80%) and concentrated to give Compound 271 (0.097 g, 56.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.18 (brs, 1H), 9.00 (brs, 1H), 7.67 (d, 2H, J=8.3Hz), 7.41 (d, 2H, J=8.2Hz), 3.74 (s, 2H), 2.70 (d, 2H, J=10.8Hz), 2.56-2.53 (m, 2H), 2.1 9 (t, 2H, J = 7.6Hz), 1.70 (t, 2H, J = 10.6Hz), 1.57-1.54 (m, 1H), 1.32-1.26 (m, 2H), 0.89 (d, 6H, J = 6.2Hz), 0.86 (d, 6H, J = 6.6Hz); LRMS (ES) m/z 334.2(M ⁺⁺ 1).

Example 113: Synthesis of Compound 272 (4-(((3R,5S)-3,5-dimethyl-4-(3-methylbut-2-en-1-yl) (piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(3-methylbut-2-en-1-yl)piperazin-1-yl)methane methyl)benzoate

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.150 g, 0.572 mmol), Cs ₂ CO ₃ (0.279 g, 0.858 mmol), and 1-bromo-3-methyl-2-butene (0.067 mL, 0.572 mmol) were dissolved in N,N-dimethylformamide (3 mL) at room temperature, and the reaction solution was stirred at 100° C. for 17 hours. Then, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove solid residues and the aqueous solution, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to obtain the desired compound (0.123 g, 65.1%) as a crude product.

Step 2: Synthesis of compound 272

4-(((3R, 5S)-3,5-dimethyl-4-(3-methylbut-2-ene-1-yl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 1-3, 0.070 g, 0.212 mmol), hydroxylamine (0.259 mL, 4.237 mmol, 50.00% aqueous solution) and potassium hydroxide (0.119 g, 2.118 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure to give compound 272 (0.030 g, 42.7%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.10(brs, 1H), 9.00(brs, 1H), 7.69(d, 2H, J=8.0Hz), 7.33(d, 2H, J=8.0Hz), 5.30(s, 1H), 3.40(s, 2H), 3.35(s, 2H), 3 .29 (d, 2H, J=6.1Hz), 2.62-2.60 (m, 4H), 1.74-1.72 (m, 2H), 1.69 (s, 3H), 1.60 (s, 3H), 0.92 (d, 6H, J=7.0Hz); LRMS (ES) m/z 332.2(M ⁺ +1).

Example 114: Synthesis of Compound 273 (N-hydroxy-4-(((2S,6R)-4-isopropyl-2,6-dimethylpiperazine-1-yl) (4-(2-Methyl)benzamide (trifluoroacetate))

Step 1: Synthesis of methyl 4-(((2S,6R)-4-isopropyl-2,6-dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.150 g, 0.502 mmol), Cs ₂ CO ₃ (0.245 g, 0.753 mmol), and 2-iodopropane (0.050 mL, 0.502 mmol) were dissolved in acetonitrile (3 mL) at room temperature, and the reaction solution was stirred at the same temperature for 17 hours. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove solid residues and the aqueous solution, and the organic layer was concentrated under reduced pressure. The product was used without additional purification (0.150 g, 98.2%).

Step 2: Synthesis of compound 273

Methyl 4-(((2S,6R)-4-isopropyl-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-3, 0.150 g, 0.493 mmol), hydroxylamine (0.603 mL, 10.226 mmol, 50.00% aqueous solution) and potassium hydroxide (0.276 g, 4.927 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The concentrate was then purified by column chromatography (Waters, _C18 , 19*100 mm column, 0.1% trifluoroacetic acid/acetonitrile = from 5% to 80%) and concentrated to give Compound 273 (0.097 g, 64.5%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.20(s, 1H), 9.36(s, 1H), 7.72(d, 2H, J=8.2Hz), 7.46(d, 2H, J=8.2Hz), 3.93(s, 2H), 3.44-3.41(m, 1H), 3.35( d, 2H, J = 11.6Hz), 2.92-2.90 (m, 2H), 2.77-2.74 (m, 2H), 1.25 (d, 6H, J = 6.6Hz), 1.08 (d, 6H, J = 4.8Hz); LRMS (ES) m/z 306.2(M ⁺ +1).

Example 115: Synthesis of Compound 274 (4-(((2S,6R)-4-butyl-2,6-dimethylpiperazin-1-yl)methyl)- N-Hydroxybenzamide (trifluoroacetate)

Step 1: Synthesis of methyl 4-(((2S,6R)-4-butyl-2,6-dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.150 g, 0.502 mmol), Cs ₂ CO ₃ (0.245 g, 0.753 mmol), and 1-iodobutane (0.057 mL, 0.502 mmol) were dissolved in acetonitrile (3 mL) at room temperature, and the reaction solution was stirred at the same temperature for 17 hours. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove solid residues and the aqueous solution, and the organic layer was concentrated under reduced pressure. The product was used without additional purification (0.160 g, 100.1%).

Step 2: Synthesis of compound 274

Methyl 4-(((2S,6R)-4-butyl-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-3, 0.160 g, 0.502 mmol), hydroxylamine (0.615 mL, 10.049 mmol, 50.00% aqueous solution) and potassium hydroxide (0.282 g, 5.024 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The concentrate was then purified by column chromatography (Waters, _C18 , 19*100 mm column, 0.1% trifluoroacetic acid/acetonitrile = from 5% to 80%) and concentrated to give Compound 274 (0.087 g, 54.2%) as a white solid.

¹ H NMR (400MHz, D ₂ O) δ7.66 (d, 2H, J=8.3Hz), 7.51 (d, 2H, J=8.4Hz), 4.40 (s, 2H), 3.58 (d, 2H, J=12.4Hz), 3.37-3.36 (m, 2H), 3.07 -2.97 (m, 4H), 1.57-1.54 (m, 2H), 1.39 (d, 6H, J=6.3Hz), 1.26-1.20 (m, 2H), 0.79 (t, 3H, J=7.4Hz); LRMS (ES) m/z 320.2(M ⁺ +1).

Example 116: Synthesis of Compound 275 (4-(((3R,5S)-4-butyl-3,5-dimethylpiperazin-1-yl)methyl)- N-Hydroxybenzamide (trifluoroacetate)

Step 1: Synthesis of methyl 4-(((3R,5S)-4-butyl-3,5-dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.150 g, 0.502 mmol), Cs ₂ CO ₃ (0.245 g, 0.753 mmol), and 1-iodobutane (0.057 mL, 0.502 mmol) were dissolved in acetonitrile (3 mL), and the reaction mixture was heated under reflux for 17 hours and then cooled to room temperature. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove solid residues and the aqueous solution, and the organic layer was concentrated under reduced pressure. The product was used without additional purification (0.120 g, 98.9%).

Step 2: Synthesis of compound 275

Methyl 4-(((3R, 5S)-4-butyl-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-3, 0.120 g, 0.377 mmol), hydroxylamine (0.461 mL, 7.537 mmol, 50.00% aqueous solution) and potassium hydroxide (0.211 g, 3.768 mmol) were dissolved in methanol (3 mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (Waters, C ₁₈ , 19*100 mm column, 0.1% trifluoroacetic acid/acetonitrile = from 5% to 80%) and concentrated to give the desired compound 275 (0.088 g, 73.1%) as a white solid.

¹ H NMR (400MHz, D ₂ O) δ7.66 (d, 2H, J=8.3Hz), 7.47 (d, 2H, J=8.2Hz), 4.15-4.15 (m, 2H), 3.57-3.56 (m, 2H), 3.44 (d, 2H, J=13.2Hz), 3.2 2 (t, 2H, J = 8.5Hz), 2.91-2.90 (m, 2H), 1.58-1.54 (m, 2H), 1.28 (d, 6H, J = 6.4Hz), 0.82 (t, 3H, J = 7.4Hz); LRMS (ES) m/z 320.2(M ⁺ +1).

Example 117: Synthesis of Compound 276 (4-(((2S,6R)-4-(2-(furan-2-yl)benzoyl)-2,6-diol (methylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(2-iodobenzoyl)-2,6-dimethylpiperazin-1-yl)methyl)benzyl Methyl ester

At room temperature, 4-(((2S, 6R)-2,6-dimethylpiperazine-1-yl)methyl)methylbenzoate (Formula 13-2, 4.000g, 16.128mmol), 2-iodobenzoic acid (4.654g, 17.741mmol), EDCI (6.183g, 32.255mmol), HOBt (4.359g, 32.255mmol) and N, N-diisopropylethylamine (10.422g, 80.639mmol) were dissolved in dichloromethane (100mL), and the solution was stirred at the same temperature overnight. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 30% to 50%) and concentrated to give the desired compound (7.630 g, 96.1%) as a white solid.

Step 2: Synthesis of 4-(((2S,6R)-4-(2-(furan-2-yl)benzoyl)-2,6-dimethylpiperazin-1-yl) Methyl)benzoate

1,2-Dimethoxyethane/water (v/v = 3/1) (3 mL) was added to a mixture of methyl 4-(((2S,6R)-4-(2-iodobenzoyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 15-1, 0.400 g, 0.812 mmol), furan-2-ylboronic acid (0.136 g, 1.219 mmol), Pd(dbpf) _Cl₂ (0.026 g, 0.041 mmol), and _{Na₂CO₃ (} 0.258 g, 2.437 mmol). The mixture was heated at 120°C for 30 minutes under microwave irradiation, followed by cooling to room temperature. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 10% to 30%) and concentrated to give the desired compound (0.211 g, 60.1%) as a white solid.

Step 3: Synthesis of Compound 276

At room temperature by 4-(((2S, 6R)-4-(2-(furan-2-yl)benzoyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (formula 15-2,0.060g, 0.139mmol), hydroxylamine (0.170mL, 2.775mmol, 50.00% aqueous solution) and potassium hydroxide (0.078g, 1.387mmol) are dissolved in methanol (1mL), and the reaction solution is stirred at the same temperature for 30 minutes.Then, the reaction mixture is concentrated under reduced pressure.Saturated sodium bicarbonate aqueous solution is added to the concentrate, and the precipitated solid is filtered and dried to obtain compound 276 (0.017g, 27.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.80-7.65(m, 4H), 7.50-7.47(m, 1H), 7.40-7.30(m, 3H), 7.26(t, 1H, J=6.8Hz), 6.69(dd, 1H, J=27.4, 9.3Hz), 6.61-6.51(m, 1H), 4.36-4.33 (m, 1H), 3.76-3.61 (m, 2H), 3.09-2.99 (m, 1H), 2.83-2.77 (m, 1H), 2.69-2.55 (m, 3H), 1.03 (d, 3H, J=5.9Hz), 0.70 (m, 3H).

Example 118: Synthesis of Compound 277 (4-(((2S,6R)-4-(2-(furan-3-yl)benzoyl)-2,6-diol (methylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(2-(furan-3-yl)benzoyl)-2,6-dimethylpiperazin-1-yl) Methyl)benzoate

1,2-Dimethoxyethane/water (v/v = 3/1) (3 mL) was added to a mixture of methyl 4-(((2S,6R)-4-(2-iodobenzoyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 15-1, 0.400 g, 0.812 mmol), furan-3-ylboronic acid (0.136 g, 1.219 mmol), Pd(dbpf) _Cl₂ (0.026 g, 0.041 mmol), and _{Na₂CO₃ (} 0.258 g, 2.437 mmol). The mixture was heated at 120°C for 30 minutes under microwave irradiation, followed by cooling to room temperature. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 10% to 30%) and concentrated to give the desired compound (0.186 g, 52.8%) as a brown solid.

Step 2: Synthesis of compound 277

At room temperature, 4-(((2S, 6R)-4-(2-(furan-3-yl)benzoyl)-2,6-dimethylpiperazine-1-yl)methyl)methylbenzoate (Formula 15-2, 0.060g, 0.139mmol), hydroxylamine (0.170mL, 2.775mmol, 50.00% aqueous solution) and potassium hydroxide (0.078g, 1.387mmol) were dissolved in methanol (1mL), and the solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the precipitated solid was filtered and dried to give compound 277 (0.023g, 37.6%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ )δ7.82 (s, 1H), 7.77-7.64 (m, 3H), 7.58-7.52 (m, 1H), 7.46 (t, 1H, J=7.5Hz), 7.36 (q, 2H, J=8.1Hz), 7.29-7.25 (m, 2H), 6.67-6.66 (m, 1H), 4.3 1(d, 1H, J=10.5Hz), 3.74(s, 1H), 3.62(q, 2H, J=18.9Hz), 2.90(m, 1H), 2.76-2.68(m, 1H), 2.62-2.56(m, 2H), 1.00-0.98(m, 3H), 0.66(m, 3H).

Example 119: Synthesis of Compound 278 (4-(((2S,6R)-4-(2-(3,6-dihydro-2H-pyran-4-yl)benzene (acyl)-2,6-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(2-(3,6-dihydro-2H-pyran-4-yl)benzoyl)-2,6-dimethyl methyl)benzoate

Methyl 4-(((2S,6R)-4-(2-iodobenzoyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 15-1, 0.400 g, 0.812 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.256 g, 1.219 mmol), Pd(dbpf) _Cl₂ (0.026 g, 0.041 mmol), and _Na₂CO₃ (0.258 g, 2.437 mmol) were dissolved in 1,2-dimethoxyethane/water (v/v = 3/1) (3 mL) at room temperature, and the reaction solution was stirred at 100 _° C. overnight. Then, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure.The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 10% to 50%) and concentrated to give the desired compound (0.272 g, 74.6%) as a brown solid.

Step 2: Synthesis of Compound 278

By 4-(((2S, 6R)-4-(2-(3,6-dihydro-2H-pyrans-4-yl)benzoyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (formula 15-2,0.060g, 0.134mmol), hydroxylamine (0.164mL, 2.675mmol, 50.00% aqueous solution) and potassium hydroxide (0.075g, 1.338mmol) at room temperature in methanol (1mL), and the solution was stirred at the same temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the precipitated solid was filtered and dried to obtain compound 278 (0.049g, 81.8%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ )δ7.68 (d, 2H, J=8.0Hz), 7.45-7.39 (m, 3H), 7.31 (t, 2H, J=7.5Hz), 7.23 -7.18(m, 1H), 5.83-5.76(m, 1H), 4.32-4.29(m, 1H), 4.15-4.10(m, 2H), 3.78-3.73 (m, 4H), 3.06 (d, 1H, J=12.6Hz), 2.78 (q, 1H, J=10.9Hz), 2.67 -2.56 (m, 2H), 2.24-2.10 (m, 1H), 1.03-1.02 (m, 3H), 0.80-0.78 (m, 3H).

Example 120: Synthesis of Compound 279 (4-(((2S,6R)-2,6-dimethyl-4-(2-(pyridin-3-yl)benzoyl) (4-(2-methyl-1-piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-2,6-dimethyl-4-(2-(pyridin-3-yl)benzoyl)piperazin-1-yl) Methyl)benzoate

Methyl 4-(((2S,6R)-4-(2-iodobenzoyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 15-1, 0.400 g, 0.812 mmol), pyridin-3-ylboronic acid (boronioc acid) (0.150 g, 1.219 mmol), Pd(dbpf) _Cl₂ (0.026 g, 0.041 mmol), and _Na₂CO₃ (0.258 g, 2.437 _mmol ) were dissolved in 1,2-dimethoxyethane/water (v/v = 3/1) (3 mL) at room temperature, and the reaction solution was stirred at 100°C overnight. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 50% to 60%) and concentrated to give the desired compound (0.348 g, 96.7%) as a brown oil.

Step 2: Synthesis of Compound 279

4-(((2S, 6R)-2,6-dimethyl-4-(2-(pyridin-3-yl)benzoyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 15-2, 0.070g, 0.158mmol), hydroxylamine (0.193mL, 3.156mmol, 50.00% aqueous solution) and potassium hydroxide (0.089g, 1.578mmol) were dissolved in methanol (1mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the precipitated solid was filtered and dried to obtain compound 279 (0.062g, 88.4%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ )δ8.62-8.53(m, 2H), 7.82-7.76(m, 1H), 7.67(d, 2H, J=8.0Hz), 7.60-7.43( m, 4H), 7.34 (dd, 3H, J=36.4, 7.5Hz), 4.20 (d, 1H, J=12.5Hz), 3.72-3.60 (m, 1H), 3.55-3.41(m, 1H), 3.06-2.86(m, 1H), 2.66-2.63(m, 1H), 2.28-2.22(m , 1H), 1.99 (brs, 1H), 1.06 (brs, 1H), 0.92-0.91 (m, 3H), 0.68-0.62 (m, 3H).

Example 121: Synthesis of Compound 280 (4-(((2S,6R)-4-(4′,4′-dimethyl-2′,3′,4′,5′-tetrahydro- [1,1′-biphenyl]-2-carbonyl)-2,6-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(4′,4′-dimethyl-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-2- methyl)benzoate

Methyl 4-(((2S,6R)-4-(2-iodobenzoyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 15-1, 0.400 g, 0.812 mmol), 2-(4,4-dimethylcyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.288 g, 1.219 mmol), Pd(dbpf) _Cl₂ (0.026 g, 0.041 mmol), and _Na₂CO₃ (0.258 g, 2.437 mmol) were dissolved in 1,2-dimethoxyethane/water (v/v = 3/1) (3 mL) at room temperature, and the reaction solution was stirred overnight at 100 _° C. Then, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure.The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 10% to 20%) and concentrated to give the desired compound (0.274 g, 71.1%) as a brown solid.

Step 2: Synthesis of Compound 280

4-(((2S, 6R)-4-(4′, 4′-dimethyl-2′, 3′, 4′, 5′-tetrahydro-[1,1′-biphenyl]-2-carbonyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 15-2, 0.060g, 0.135mmol), hydroxylamine (0.165mL, 2.706mmol, 50.00% aqueous solution) and potassium hydroxide (0.076g, 1.353mmol) were dissolved in methanol (1mL) at room temperature, and the reaction solution was stirred at the same temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the precipitated solid was filtered and dried to obtain compound 280 (0.049g, 75.7%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.69-7.67(m, 2H), 7.38-7.34(m, 3H), 7.31-7.24(m, 2H), 7.16(t, 1H, J=8.7H z), 5.56 (s, 1H), 4.29 (dd, 1H, J=31.1, 13.2Hz), 3.81-3.71 (m, 2H), 3.09 (t, 1H, J =14.5Hz), 2.84-2.62(m, 2H), 2.46-2.33(m, 3H), 2.10(brs, 1H), 1.88-1.73(m, 2 H), 1.44-1.38 (m, 2H), 1.05-1.00 (m, 3H), 0.95-0.89 (m, 6H), 0.81-0.67 (m, 3H).

Example 122: Synthesis of Compound 283 (4-(((3R,5S)-4-(2-(furan-2-yl)benzoyl)-3,5-diol (methylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 2-iodobenzoyl chloride

2-Iodobenzoic acid (4.000 g, 16.128 mmol) and SOCl ₂ (23.399 mL, 322.555 mmol) were stirred at 100° C. overnight, and the reaction mixture was concentrated under reduced pressure. The product was used without additional purification (4.295 g, 99.9%, brown oil).

Step 2: Synthesis of 4-(((3R,5S)-4-(2-iodobenzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzyl Methyl ester

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-2, 4.295g, 16.119mmol), 2-iodobenzoyl chloride (4.652g, 17.731mmol) and TEA (4.469mL, 32.237mmol) were dissolved in dichloromethane (70mL) at room temperature, and the reaction solution was stirred at the same temperature for 1 hour. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica; ethyl acetate/hexane=from 30% to 50%) to obtain the desired compound (7.120g, 89.7%) as a white solid.

Step 3: Synthesis of 4-(((3R,5S)-4-(2-(furan-2-yl)benzoyl)-3,5-dimethylpiperazin-1-yl) Methyl)benzoate

1,2-Dimethoxyethane/water (v/v = 3/1) (3 mL) was added to a mixture of methyl 4-(((3R,5S)-4-(2-iodobenzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 4-1, 0.400 g, 0.812 mmol), furan-2-ylboronic acid (0.136 g, 1.219 mmol), Pd(dbpf) _Cl₂ (0.026 g, 0.041 mmol), and _{Na₂CO₃ (} 0.258 g, 2.437 mmol). The mixture was heated at 120°C for 30 minutes under microwave irradiation, followed by cooling to room temperature. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 0% to 15%) and concentrated to give the desired compound (0.040 g, 11.4%) as a colorless oil.

Step 4: Synthesis of compound 283

At room temperature, 4-(((3R, 5S)-4-(2-(furan-2-yl)benzoyl)-3,5-dimethylpiperazine-1-yl)methyl)methylbenzoate (Formula 4-2, 0.040g, 0.092mmol), hydroxylamine (0.113mL, 1.850mmol, 50.00% aqueous solution) and potassium hydroxide (0.052g, 0.925mmol) were dissolved in methanol (2mL), and the reaction solution was stirred at the same temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the precipitated solid was filtered and dried to give compound 283 (0.016g, 39.4%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ )δ7.78-7.68(m, 4H), 7.46(t, 1H, J=7.6Hz), 7.41-7.21(m, 4H), 6.73(dd, 1H, J=33.6, 3.4Hz), 6.61-6.59 (m, 1H), 4.70-4.65 (m, 1H), 3.56-3.41 (m, 3 H), 2.72-2.66(m, 1H), 2.41-2.33(m, 1H), 2.18-2.03(m, 1H), 1.63-1.60(m , 1H), 1.33 (t, 3H, J=9.8Hz), 1.16 (d, 2H, J=6.8Hz), 0.86 (d, 1H, J=6.8Hz).

Example 123: Synthesis of Compound 284 (4-(((3R,5S)-4-(2-(furan-3-yl)benzoyl)-3,5-diol (methylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(2-(furan-3-yl)benzoyl)-3,5-dimethylpiperazin-1-yl) Methyl)benzoate

1,2-Dimethoxyethane/water (v/v = 3/1) (3 mL) was added to a mixture of methyl 4-(((3R,5S)-4-(2-iodobenzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 4-1, 0.400 g, 0.812 mmol), furan-3-ylboronic acid (0.136 g, 1.219 mmol), Pd(dbpf) _Cl₂ (0.026 g, 0.041 mmol), and _{Na₂CO₃ (} 0.258 g, 2.437 mmol). The mixture was heated at 120°C for 30 minutes under microwave irradiation, followed by cooling to room temperature. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 0% to 10%) and concentrated to give the desired compound (0.128 g, 36.5%) as a colorless oil.

Step 2: Synthesis of compound 284

4-(((3R, 5S)-4-(2-(furan-3-yl)benzoyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 4-2, 0.128g, 0.296mmol), hydroxylamine (0.362mL, 5.919mmol, 50.00% aqueous solution) and potassium hydroxide (0.166g, 2.959mmol) were dissolved in methanol (3mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the precipitated solid was filtered and dried to obtain compound 284 (0.038g, 29.5%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.85-7.75(m, 2H), 7.68(d, 2H, J=8.2Hz), 7.60-7.51(m, 1H), 7.46-7.35(m, 2 H), 7.33-7.21(m, 3H), 6.82-6.66(m, 1H), 4.69-4.54(m, 1H), 3.52-3.49(m, 1H), 3.27-3.25(m, 1H), 2.70-2.56(m, 1H), 2.37-2.34(m, 1H), 2.16-2.04(m, 1H), 1.8 6-1.82 (m, 1H), 1.39-1.21 (m, 4H), 1.12 (d, 2H, J=6.8Hz), 0.82 (d, 1H, J=6.8Hz).

Example 124: Synthesis of Compound 285 (4-(((3R,5S)-3,5-dimethyl-4-(2-(pyridin-4-yl)benzoyl )piperazin-1-yl)methyl ) -N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(2-(pyridin-4-yl)benzoyl)piperazin-1-yl) Methyl)benzoate

1,2-Dimethoxyethane/water (v/v = 3/1) (3 mL) was added to a mixture of methyl 4-(((3R,5S)-4-(2-iodobenzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 4-1, 0.400 g, 0.812 mmol), pyridine-4-boronic acid hydrate (0.172 g, 1.219 mmol), Pd(dbpf) _Cl₂ (0.026 g, 0.041 mmol), and _{Na₂CO₃ (} 0.258 g, 2.437 mmol). The mixture was heated at 120°C for 30 minutes under microwave irradiation, followed by cooling to room temperature. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 50% to 60%) and concentrated to give the desired compound (0.129 g, 35.9%) as a pale yellow solid.

Step 2: Synthesis of compound 285

4-(((3R, 5S)-3,5-dimethyl-4-(2-(pyridin-4-yl)benzoyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 4-2, 0.060g, 0.135mmol), hydroxylamine (0.165mL, 2.706mmol, 50.00% aqueous solution) and potassium hydroxide (0.076g, 1.353mmol) were dissolved in methanol (3mL) at room temperature, and the reaction solution was stirred at the same temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the precipitated solid was filtered and dried to obtain compound 285 (0.016g, 26.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.64 (d, 2H, J=5.8Hz), 7.67 (d, 2H, J=8.0Hz), 7.61-7.41 (m, 6H), 7.30 (d, 1H, J=8.0Hz), 4.34 (brs, 1H), 3 .24-3.17 (m, 3H), 2.24 (d, 1H, J=11.0Hz), 1.44-1.40 (m, 1H), 1.29 (d, 3H, J=6.7Hz), 1.07 (d, 3H, J=6.6Hz).

Example 125: Synthesis of Compound 286 (4-(((3R,5S)-3,5-dimethyl-4-(2-(pyridin-3-yl)benzoyl) (4-(2-methyl-1-piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of ((3R,5S)-3,5-dimethyl-4-(2-(pyridin-3-yl)benzoyl)piperazin-1-yl)methane methyl)benzoate

1,2-Dimethoxyethane/water (v/v = 3/1) (3 mL) was added to a mixture of methyl 4-(((3R,5S)-4-(2-iodobenzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 4-1, 0.400 g, 0.812 mmol), pyridin-3-ylboronic acid (0.150 g, 1.219 mmol), Pd(dbpf) _Cl₂ (0.026 g, 0.041 mmol), and _{Na₂CO₃ (} 0.258 g, 2.437 mmol). The mixture was heated at 120°C for 30 minutes under microwave irradiation, followed by cooling to room temperature. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = 50%) and concentrated to give the desired compound (0.292 g, 81.1%) as a yellow solid.

Step 2: Synthesis of compound 286

At room temperature, ((3R, 5S) -3,5- dimethyl -4- (2- (pyridin-3-yl) benzoyl) piperazine -1- base) methyl) methyl benzoate (formula 4-2, 0.060g, 0.135mmol), hydroxylamine (0.165mL, 2.706mmol, 50.00% aqueous solution) and potassium hydroxide (0.076g, 1.353mmol) were dissolved in methanol (3mL), and the reaction solution was stirred at the same temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the precipitated solid was filtered and dried to obtain compound 286 (0.050g, 83.8%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.58-8.57 (m, 2H), 7.78 (d, 1H, J=7.9Hz), 7.68 (d, 2H, J=8.1Hz), 7.57-7.43 (m, 5H), 7.30 (d, 2H, J=7.9Hz), 4.31-4. 29 (m, 1H), 3.26-3.18 (m, 3H), 2.23 (d, 1H, J=11.2Hz), 1.37-1.35 (m, 1H), 1.28 (d, 3H, J=6.7Hz), 1.07 (d, 3H, J=6.7Hz).

Example 126: Synthesis of Compound 288 (4-(((3R,5S)-4-(4′,4′-dimethyl-2′,3′,4′,5′-tetrahydro- [1,1′-biphenyl]-2-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(4′,4′-dimethyl-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-2- (carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoic acid methyl ester

1,2-Dimethoxyethane/water (v/v=3/1) (3 mL) was added to a mixture of methyl 4-(((3R,5S)-4-(2-iodobenzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 4-1, 0.400 g, 0.812 mmol), 2-(4,4-dimethylcyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.288 g, 1.219 mmol), Pd(dbpf) _Cl₂ (0.026 g, 0.041 mmol) and _Na₂CO₃ (0.258 g, 2.437 mmol), and heated at 120°C for 30 minutes under microwave irradiation, followed by cooling to room temperature. Saturated aqueous _sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure.The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 0% to 10%) and concentrated to give the desired compound (0.143 g, 37.0%) as a brown solid.

Step 2: Synthesis of Compound 288

4-(((3R, 5S)-4-(4′, 4′-dimethyl-2′, 3′, 4′, 5′-tetrahydro-[1,1′-biphenyl]-2-carbonyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 4-3, 0.060g, 0.126mmol), hydroxylamine (0.155mL, 2.528mmol, 50.00% aqueous solution) and potassium hydroxide (0.071g, 1.264mmol) were dissolved in methanol (3mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the precipitated solid was filtered and dried to obtain compound 288 (0.047g, 78.0%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.71 (d, 2H, J=8.0Hz), 7.36-7.26 (m, 4H), 7.21-7.19 (m, 2H), 5.55 (s, 1H), 4.48 (brs, 1H), 3.50-3.47 (m, 2H), 2.69 (d, 1H, J=11.0Hz), 2. 40-2.37 (m, 1H), 2.12-1.98 (m, 3H), 1.86-1.81 (m, 2H), 1.41-1.38 (m, 2H), 1.34 (d, 3H, J=6.6Hz), 1.17 (d, 3H, J=6.6Hz), 0.93-0.91 (m, 6H).

Example 127: Synthesis of Compound 290 (4-(((3R,5S)-3,5-dimethyl-4-(4-methylbenzoyl)piperidin ((1-oxazin-1-yl)methyl)-N-hydroxybenzamide (trifluoroacetate))

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(4-methylbenzoyl)piperazin-1-yl)methyl)benzene Methyl formate

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol), 4-methylbenzoyl chloride (0.060 mL, 0.457 mmol) and TEA (0.077 g, 0.762 mmol) were dissolved in dichloromethane (1 ml) at 25 ° C, and the reaction solution was stirred at the same temperature for 3 hours. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the desired compound (0.078 g, 53.8%) as a light yellow solid.

Step 2: Synthesis of Compound 290

Methyl 4-(((3R,5S)-3,5-dimethyl-4-(4-methylbenzoyl)piperazin-1-yl)methyl)benzoate (Formula 1-3, 0.050 g, 0.131 mmol), hydroxylamine (0.161 mL, 2.628 mmol, 50.00% aqueous solution) and potassium hydroxide (0.074 g, 1.314 mmol) were dissolved in methanol (0.5 ml) at 25° C., and the reaction solution was stirred at the same temperature for 1 hour. Then, a saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (Waters, C ₁₈ , acetonitrile/0.1% trifluoroacetic acid aqueous solution = from 5% to 70%) to obtain compound 290 (0.019 g, 37.9%) as a white solid.

¹ H NMR (400MHz, D ₂ O) δ7.67 (d, 2H, J = 8.4Hz), 7.53 (d, 2H, J = 8.3Hz), 7.21 (d, 2H, J = 7.8Hz), 7. 17 (d, 2H, J=8.2Hz), 4.38 (s, 2H), 3.20 (m, 4H), 2.24 (s, 3H), 1.29 (brs, 6H).

Example 128: Synthesis of Compound 291 (N-hydroxy-4-(((3R,5S)-4-(4-methoxybenzoyl)-3,5- dimethylpiperazin-1-yl)methyl)benzamide (trifluoroacetate)

Step 1: Synthesis of 4-(((3R,5S)-4-(4-methoxybenzoyl)-3,5-dimethylpiperazin-1-yl)methyl) Methyl benzoate

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol), 4-methoxybenzoyl chloride (0.062 mL, 0.457 mmol) and TEA (0.077 g, 0.762 mmol) were dissolved in dichloromethane (1 ml) at 25 ° C, and the reaction solution was stirred at the same temperature for 3 hours. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the desired compound (0.088 g, 58.2%) as a light yellow solid.

Step 2: Synthesis of compound 291

Methyl 4-(((3R,5S)-4-(4-methoxybenzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-3, 0.050 g, 0.126 mmol), hydroxylamine (0.154 mL, 2.522 mmol, 50.00% aqueous solution) and potassium hydroxide (0.071 g, 1.261 mmol) were dissolved in methanol (0.5 ml) at 25° C., and the reaction solution was stirred at the same temperature for 1 hour. Then, a saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (Waters, C ₁₈ , acetonitrile/0.1% trifluoroacetic acid aqueous solution = from 5% to 70%) to obtain compound 291 (0.023 g, 45.9%) as a white solid.

¹ H NMR (400MHz, D ₂ O) δ7.67 (d, 2H, J = 8.4Hz), 7.52 (d, 2H, J = 8.3Hz), 7.24 (d, 2H, J = 8.8Hz), 6.93 ( d, 2H, J=8.8Hz), 4.38 (s, 2H), 3.73 (s, 3H), 3.36-3.20 (m, 4H), 1.29 (brs, 6H).

Example 129: Synthesis of Compound 292 (4-(((3R,5S)-3,5-dimethyl-4-pivaloylpiperazin-1-yl)methyl 1-Hydroxybenzamide (trifluoroacetate)

Step 1: Synthesis of methyl 4-(((3R,5S)-3,5-dimethyl-4-pivaloylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol), pivaloyl chloride (0.055 g, 0.457 mmol) and TEA (0.077 g, 0.762 mmol) were dissolved in dichloromethane (1 ml) at 25 ° C, and the reaction solution was stirred at the same temperature for 3 hours. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the desired compound (0.105 g, 79.5%) as a yellow oil.

Step 2: Synthesis of compound 292

Methyl 4-(((3R,5S)-3,5-dimethyl-4-pivaloylpiperazin-1-yl)methyl)benzoate (Formula 1-3, 0.050 g, 0.144 mmol), hydroxylamine (0.177 mL, 2.886 mmol) and potassium hydroxide (0.081 g, 1.443 mmol) were dissolved in methanol (0.5 ml) at 25° C., and the reaction solution was stirred at the same temperature for 1 hour. Then, a saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (Waters, C ₁₈ , acetonitrile/0.1% trifluoroacetic acid aqueous solution = from 5% to 70%) and concentrated to obtain the desired compound 292 (0.018 g, 35.9%) as a white solid.

¹ H NMR (400MHz, D ₂ O) δ7.66 (d, 2H, J=8.3Hz), 7.52 (d, 2H, J=8.2Hz), 4.75-4.73 (m, 2H), 4.35 (s, 2H), 3.34 (m, 2H), 3.13 (m, 2H), 1.31 (brs, 6H), 1.12 (s, 9H).

Example 130: Synthesis of Compound 293, (4-(((3R,5S)-3,5-dimethyl-4-propionylpiperazin-1-yl)methyl 1-Hydroxybenzamide (trifluoroacetate)

Step 1: Synthesis of methyl 4-(((3R,5S)-3,5-dimethyl-4-propionylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol), propionyl chloride (0.042 g, 0.457 mmol) and TEA (0.077 g, 0.762 mmol) were dissolved in dichloromethane (1 ml) at 25 ° C, and the reaction solution was stirred at the same temperature for 3 hours. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the desired compound (0.113 g, 93.1%) as a yellow oil.

Step 2: Synthesis of compound 293

Methyl 4-(((3R,5S)-3,5-dimethyl-4-propionylpiperazin-1-yl)methyl)benzoate (Formula 1-3, 0.050 g, 0.157 mmol), hydroxylamine (0.192 mL, 3.141 mmol, 50.00% aqueous solution) and potassium hydroxide (0.088 g, 1.570 mmol) were dissolved in methanol (0.5 ml) at 25 ° C., and the reaction solution was stirred at the same temperature for 1 hour. Then, a saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (Waters, C ₁₈ , acetonitrile/0.1% trifluoroacetic acid aqueous solution = from 5% to 70%) to obtain compound 293 (0.027 g, 53.8%) as a white solid.

¹ H NMR (400MHz, D ₂ O) δ7.66 (d, 2H, J=7.9Hz), 7.52 (d, 2H, J=8.0Hz), 4.75-4.73 (m, 2H), 4.37 (s, 2H), 3.40-3 .37 (m, 2H), 3.12-3.08 (m, 2H), 2.42-2.27 (m, 2H), 1.31 (brs, 6H), 0.95 (t, 3H, J=11.6Hz).

Example 131: Synthesis of Compound 294 (4-(((3R,5S)-4-butanoyl-3,5-dimethylpiperazin-1-yl)methyl 1-Hydroxybenzamide (trifluoroacetate)

Step 1: Synthesis of methyl 4-(((3R,5S)-4-butyryl-3,5-dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol), butyryl chloride (0.049 g, 0.457 mmol) and TEA (0.077 g, 0.762 mmol) were dissolved in dichloromethane (1 ml) at 25 ° C, and the reaction solution was stirred at the same temperature for 3 hours. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the desired compound (0.077 g, 60.8%) as a light yellow oil.

Step 2: Synthesis of compound 294

Methyl 4-(((3R,5S)-4-butyryl-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-3, 0.050 g, 0.150 mmol), hydroxylamine (0.184 mL, 3.008 mmol) and potassium hydroxide (0.084 g, 1.504 mmol) were dissolved in methanol (0.5 ml) at 25° C., and the reaction solution was stirred at the same temperature for 1 hour. Then, a saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (Waters, C ₁₈ , acetonitrile/0.1% trifluoroacetic acid aqueous solution = from 5% to 70%) to obtain compound 294 (0.024 g, 47.9%) as a white solid.

¹ H NMR (400MHz, D ₂ O) δ7.67 (d, 2H, J=6.5Hz), 7.52 (d, 2H, J=6.1Hz), 4.73-4.71 (m, 2H), 4.35 (s, 2H), 3.40-3.37 (m, 2H), 3.11-3.0 9 (m, 2H), 2.35-2.23 (m, 2H), 1.44 (q, 6H, J=14.8, 7.4Hz), 1.33 (brs, 3H), 1.22 (brs, 3H), 0.77 (t, 3H, J=7.4Hz).

Example 132: Synthesis of Compound 295 (4-(((3R,5S)-4-(cyclopropanecarbonyl)-3,5-dimethylpiperazine-1- (4-(2-Methyl)-N-Hydroxybenzamide (Trifluoroacetate))

Step 1: Synthesis of 4-(((3R,5S)-4-(cyclopropanecarbonyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoic acid Methyl ester

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol), cyclopropanecarbonyl chloride (0.042 mL, 0.457 mmol) and TEA (0.077 g, 0.762 mmol) were dissolved in dichloromethane (1 ml) at 25 ° C, and the reaction solution was stirred at the same temperature for 3 hours. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the desired compound (0.105 g, 83.4%) as a yellow oil.

Step 2: Synthesis of compound 295

Methyl 4-(((3R,5S)-4-(cyclopropanecarbonyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-3, 0.050 g, 0.151 mmol), hydroxylamine (0.185 mL, 3.026 mmol, 50.00% aqueous solution) and potassium hydroxide (0.085 g, 1.513 mmol) were dissolved in methanol (0.5 ml) at 25° C., and the reaction solution was stirred at the same temperature for 1 hour. Then, a saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (Waters, C ₁₈ , acetonitrile/0.1% trifluoroacetic acid aqueous solution = from 5% to 70%) to obtain compound 295 (0.021 g, 41.9%) as a white solid.

¹ H NMR (400MHz, D ₂ O) δ7.66 (d, 2H, J=8.2Hz), 7.53 (d, 2H, J=8.2Hz), 4.73-4.71 (m, 2H), 4.38 (s, 2H), 3.43 -3.40 (m, 2H), 3.14-3.12 (m, 2H), 1.83-1.25 (m, 1H), 1.28 (brs, 6H), 0.79-0.75 (m, 4H).

Example 133: Synthesis of Compound 296 (N-hydroxy-4-(((3R,5S)-4-isobutyryl-3,5-dimethylpiperazine- 1-amino)methyl)benzamide (trifluoroacetate)

Step 1: Synthesis of methyl 4-(((3R,5S)-4-isobutyryl-3,5-dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol), isobutyryl chloride (0.048 mL, 0.457 mmol) and TEA (0.077 g, 0.762 mmol) were dissolved in dichloromethane (1 ml) at 25 ° C, and the reaction solution was stirred at the same temperature for 3 hours. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the desired compound (0.097 g, 76.5%) as a yellow oil.

Step 2: Synthesis of Compound 296

Methyl 4-(((3R,5S)-4-isobutyryl-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-3, 0.050 g, 0.150 mmol), hydroxylamine (0.184 mL, 3.008 mmol, 50.00% aqueous solution) and potassium hydroxide (0.084 g, 1.504 mmol) were dissolved in methanol (0.5 ml) at 25 ° C., and the reaction solution was stirred at the same temperature for 1 hour. Then, saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (Waters, C ₁₈ , acetonitrile/0.1% trifluoroacetic acid aqueous solution = from 5% to 70%) and concentrated to obtain compound 296 (0.025 g, 49.9%) as a white solid.

¹ H NMR (400MHz, D ₂ O) δ7.67 (d, 2H, J=8.2Hz), 7.52 (d, 2H, J=8.2Hz), 4.73 (m, 1H), 4.49 (m, 1H), 4.37 (s, 2H), 3.41-3.3 8(m, 2H), 3.13-3.09(m, 2H), 2.83-2.79(m, 1H), 1.33(brs, 3H), 1.22(brs, 3H), 0.95-0.93(m, 6H).

Example 134: Synthesis of Compound 297 (4-(((3R,5S)-3,5-dimethyl-4-(3-methylbutanoyl)piperazin- 1-yl)methyl ) -N-hydroxybenzamide (trifluoroacetate))

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(3-methylbutanoyl)piperazin-1-yl)methyl)benzene Methyl ester

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol), 3-methylbutyryl chloride (55 mg, 0.457 mmol) and TEA (0.077 g, 0.762 mmol) were dissolved in dichloromethane (1 ml) at 25 ° C, and the reaction solution was stirred at the same temperature for 3 hours. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the desired compound (0.078 g, 59.1%) as a yellow oil.

Step 2: Synthesis of Compound 297

Methyl 4-(((3R,5S)-3,5-dimethyl-4-(3-methylbutanoyl)piperazin-1-yl)methyl)benzoate (Formula 1-3, 0.050 g, 0.144 mmol), hydroxylamine (0.177 mL, 2.886 mmol, 50.00% aqueous solution) and potassium hydroxide (0.081 g, 1.443 mmol) were dissolved in methanol (0.5 ml) at 25° C., and the reaction solution was stirred at the same temperature for 1 hour. Then, a saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (Waters, C ₁₈ , acetonitrile/0.1% trifluoroacetic acid aqueous solution = from 5% to 70%) and concentrated to obtain the desired compound 297 (0.021 g, 41.9%) as a white solid.

¹ H NMR (400MHz, D ₂ O) δ7.66 (d, 2H, J=8.3Hz), 7.52 (d, 2H, J=8.3Hz), 4.78-4.75 (m, 1H), 4.44-4.43 (m, 1H), 4.37 (s, 2H), 3.40-3.38 (m , 2H), 3.10-3.09(m, 2H), 2.32-2.08(m, 2H), 1.91-1.84(m, 1H), 1.32(brs, 3H), 1.25(brs, 1H), 0.82-0.72(m, 6H).

Example 135: Synthesis of Compound 298 (4-(((2S,6R)-2,6-dimethyl-4-(3-(trifluoromethyl)benzyl)piperidin ((1-oxazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-2,6-dimethyl-4-(,3-(trifluoromethyl)benzyl)piperazin-1-yl)methyl) Methyl benzoate

Methyl 4-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.200 g, 0.762 mmol), 3-(trifluoromethyl)benzaldehyde (0.133 g, 0.762 mmol) and acetic acid (0.022 mL, 0.762 mmol) were dissolved in 1,2-dichloroethane (4 mL) and stirred at room temperature for 2 hours. Na(CN)BH ₃ (0.048 g, 0.762 mmol) was then added, followed by stirring at the same temperature for 17 hours. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 20%) and concentrated to give the desired compound (0.246 g, 76.7%) as a colorless oil.

Step 2: Synthesis of Compound 298

4-(((2S, 6R)-2,6-dimethyl-4-(3-(trifluoromethyl)benzyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.100g, 0.238mmol), hydroxylamine (0.291mL, 4.757mmol, 50.00% aqueous solution) and potassium hydroxide (0.133g, 2.378mmol) were dissolved in methanol (3mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated sodium bicarbonate aqueous solution was added to the obtained concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure to obtain compound 298 (0.061g, 60.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.67-7.56(m, 6H), 7.28(d, 2H, J=8.2Hz), 3.73(s, 2H), 3.50(s, 2H), 2.6 5-2.26 (m, 4H), 1.85 (t, 2H, J = 10.4Hz), 0.91 (d, 6H, J = 6.1Hz); LRMS (ES) m/z 422.1(M ⁺ +1).

Example 136: Synthesis of Compound 299 (4-(((2S,6R)-4-(4-(dimethylamino)benzyl)-2,6-dimethyl (piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(4-(dimethylamino)benzyl)-2,6-dimethylpiperazin-1-yl)methane methyl)benzoate

Methyl 4-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.100 g, 0.381 mmol), 4-(dimethylamino)benzaldehyde (0.057 g, 0.381 mmol) and acetic acid (0.011 mL, 0.381 mmol) were dissolved in 1,2-dichloroethane (4 mL) and stirred at room temperature for 2 hours. Na(CN)BH ₃ (0.024 g, 0.381 mmol) was then added, followed by stirring at the same temperature for 17 hours. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 20%) and concentrated to give the desired compound (0.062 g, 41.1%) as a colorless oil.

Step 2: Synthesis of Compound 299

At room temperature, 4-(((2S, 6R)-4-(4-(dimethylamino)benzyl)-2,6-dimethylpiperazine-1-yl)methyl)methyl benzoate (Formula 13-3, 0.062g, 0.157mmol), hydroxylamine (0.192mL, 3.135mmol, 50.00% aqueous solution) and potassium hydroxide (0.088g, 1.567mmol) were dissolved in methanol (3mL), and the reaction solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution (5mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered and dried to give compound 299 (0.041g, 66.0%) as a white solid.

¹ H NNR (400MHz, DMSO-d ₆ ) δ7.65 (d, 2H, J = 8.2Hz), 7.36 (d, 2H, J = 8.1Hz), 7.07 (d, 2H, J = 8.6Hz), 6.67 (d, 2H, J = 8.6Hz), 3.72 (s, 2H), 3.27 (s, 2H), 2.63 (d, 2H, J=10.5Hz), 2.55-2.51 (m, 2H), 1.73 (t, 2H, J=10.6Hz), 0.87 (d, 6H, J=6.1Hz); LRMS (ES) m/z 397.2(M ⁺ +1).

Example 137: Synthesis of Compound 300 (4-(((2S,6R)-2,6-dimethyl-4-(4-(methylsulfonyl)benzyl) (piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-2,6-dimethyl-4-(4-(methylsulfonyl)benzyl)piperazin-1-yl)methane methyl)benzoate

Methyl 4-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.100 g, 0.381 mmol), 4-(methylsulfonyl)benzaldehyde (0.070 g, 0.381 mmol) and acetic acid (0.011 mL, 0.381 mmol) were dissolved in 1,2-dichloroethane (4 mL) and stirred at room temperature for 2 hours. Na(CN)BH ₃ (0.024 g, 0.381 mmol) was then added, followed by stirring at the same temperature for 17 hours. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 10% to 70%) and concentrated to give the desired compound (0.058 g, 35.3%) as a yellow oil.

Step 2: Synthesis of compound 300

4-(((2S, 6R)-2,6-dimethyl-4-(4-(methylsulfonyl)benzyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.058g, 0.135mmol), hydroxylamine (0.165mL, 2.694mmol, 50.00% aqueous solution) and potassium hydroxide (0.076g, 1.347mmol) were dissolved in methanol (3mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution was added to the concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and aqueous layer, and the organic layer was concentrated under reduced pressure to obtain compound 300 (0.015g, 25.8%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.87 (d, 2H, J=8.2Hz), 7.65 (d, 2H, J=8.1Hz), 7.57 (d, 2H, J=8.1Hz), 7.30 (d, 2H, J=8.0Hz), 3.74 (s, 2H), 3.52 (s, 2H ), 3.21 (s, 3H), 2.65 (d, 2H, J = 11.8Hz), 2.60-2.56 (m, 2H), 1.85 (t, 2H, J = 10.4Hz), 0.93 (d, 6H, J = 6.8Hz); LRMS (ES) m/z 432.2(M ⁺ +1).

Example 138: Synthesis of Compound 301 (4-(((2S,6R)-4-(4-(1H-imidazol-1-yl)benzyl)-2,6-dimethyl (1-piperazin-1-yl)methyl-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(4-(1H-imidazol-1-yl)benzyl)-2,6-dimethylpiperazin-1-yl)methane methyl)benzoate

Methyl 4-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.100 g, 0.381 mmol), 4-(1H-imidazol-1-yl)benzaldehyde (0.066 g, 0.381 mmol) and acetic acid (0.011 mL, 0.381 mmol) were dissolved in 1,2-dichloroethane (4 mL) and stirred at room temperature for 2 hours. Na(CN)BH ₃ (0.024 g, 0.381 mmol) was then added, followed by stirring at the same temperature for 17 hours. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to give the desired compound (0.065 g, 40.7%) as a light yellow oil.

Step 2: Synthesis of compound 301

4-(((2S,6R)-4-(4-(1H-imidazole-1-yl)benzyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.065g, 0.155mmol), hydroxylamine (0.190mL, 3.106mmol, 50.00% aqueous solution) and potassium hydroxide (0.087g, 1.553mmol) were dissolved in methanol (3mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution was added to the concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure to obtain compound 301 (0.037g, 56.8%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.18 (brs, 1H), 9.00 (brs, 1H), 8.24 (s, 1H), 7.74 (s, 1H), 7.67 (d, 2H, J=8.0Hz), 7.60 (d, 2H, J=8.3Hz), 7.42 (d, 4H, J=8.0Hz), 7.10 ( s, 1H), 3.86 (s, 2H), 3.46 (s, 2H), 2.68 (d, 2H, J=10.6Hz), 2.60-2.58 (m, 2H), 1.83 (t, 2H, J=10.6Hz), 0.89 (d, 6H, J=6.0Hz); LRMS (ES) m/z 420.2(M ⁺ +1).

Example 139: Synthesis of Compound 302 (4-(((2S,6R)-2,6-dimethyl-4-(4-(thiophen-2-yl)benzyl) (piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-2,6-dimethyl-4-(4-(thiophen-2-yl)benzyl)piperazin-1-yl)methyl) Methyl benzoate

Methyl 4-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.100 g, 0.381 mmol), 4-(thiophen-2-yl)benzaldehyde (0.072 g, 0.381 mmol) and acetic acid (0.011 mL, 0.381 mmol) were dissolved in 1,2-dichloroethane (4 mL) and stirred at room temperature for 2 hours. Na(CN)BH ₃ (0.024 g, 0.381 mmol) was then added, followed by stirring at the same temperature for 17 hours. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 20%) and concentrated to give the desired compound (0.022 g, 13.3%) as a light yellow oil.

Step 2: Synthesis of compound 302

4-(((2S, 6R)-2,6-dimethyl-4-(4-(thiophene-2-yl)benzyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.022g, 0.051mmol), hydroxylamine (0.062mL, 1.012mmol, 50.00% aqueous solution) and potassium hydroxide (0.028g, 0.506mmol) were dissolved in methanol (3mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution was added to the concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure to obtain compound 302 (0.019g, 86.2%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.65 (d, 2H, J=8.1Hz), 7.61 (d, 2H, J=8.0Hz), 7.53 (d, 1H, J=5.0Hz), 7.49 (d, 1H, J=3.2Hz), 7.33-7.31 (m, 4H), 7.13 (dd, 1H, J=4.4, 4 .4Hz), 3.74 (s, 2H), 3.41 (s, 2H), 2.67 (d, 2H, J=9.5Hz), 2.56-2.51 (m, 2H), 1.82 (t, 2H, J=10.6Hz), 0.90 (d, 6H, J=6.1Hz); LRMS (ES) m/z 436.2(M ⁺ +1).

Example 140: Synthesis of Compound 303 (4-(((2S,6R)-4-(4-(furan-2-yl)benzyl)-2,6-dimethyl (piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(4-(furan-2-yl)benzyl)-2,6-dimethylpiperazin-1-yl)methyl) Methyl benzoate

Methyl 4-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.100 g, 0.381 mmol), 4-(furan-2-yl)benzaldehyde (0.066 g, 0.381 mmol) and acetic acid (0.011 mL, 0.381 mmol) were dissolved in 1,2-dichloroethane (4 mL) and stirred at room temperature for 2 hours. Na(CN)BH ₃ (0.024 g, 0.381 mmol) was then added, followed by stirring at the same temperature for 17 hours. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 20%) and concentrated to give the desired compound (0.053 g, 33.2%) as a light yellow oil.

Step 2: Synthesis of compound 303

4-(((2S, 6R)-4-(4-(furan-2-yl)benzyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.053g, 0.127mmol), hydroxylamine (0.155mL, 2.533mmol, 50.00% aqueous solution) and potassium hydroxide (0.071g, 1.266mmol) were dissolved in methanol (3mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution (5mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered and dried to give compound 303 (0.045g, 84.7%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.74 (s, 1H), 7.73-7.63 (m, 4H), 7.33 (d, 2H, J=8.2Hz), 7.26 (d, 2H, J=8.1Hz), 6.91 (d, 1H, J=3.1Hz), 6.59 (dd, 1H, J=3.4, 1.8H z), 3.72 (s, 2H), 3.41 (s, 2H), 2.65 (d, 2H, J = 10.8Hz), 2.56-2.55 (m, 2H), 1.81-1.79 (m, 2H), 0.91 (d, 6H, J = 6.1Hz); LRMS (ES) m/z 420.2(M ⁺ +1).

Example 141: Synthesis of Compound 304 (4-(((2S,6R)-4-(4-(4H-1,2,4-triazol-4-yl)benzyl)-2, 6-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(4-(4H-1,2,4-triazol-4-yl)benzyl)-2,6-dimethylpiperazine- 1-amino)methyl)benzoate

Methyl 4-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.100 g, 0.381 mmol), 4-(4H-1,2,4-triazol-4-yl)benzaldehyde (0.066 g, 0.381 mmol) and acetic acid (0.011 mL, 0.381 mmol) were dissolved in 1,2-dichloroethane (4 mL) and stirred at room temperature for 2 hours. Na(CN)BH ₃ (0.024 g, 0.381 mmol) was then added, followed by stirring at the same temperature for 17 hours. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to give the desired compound (0.064 g, 40.0%) as a light yellow oil.

Step 2: Synthesis of compound 304

4-(((2S,6R)-4-(4-(4H-1,2,4-triazol-4-yl)benzyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.064g, 0.153mmol), hydroxylamine (0.187mL, 3.051mmol, 50.00% aqueous solution) and potassium hydroxide (0.086g, 1.526mmol) were dissolved in methanol (3mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated sodium bicarbonate aqueous solution was added to the concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure to obtain compound 304 (0.016g, 24.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.18 (brs, 1H), 9.28 (s, 1H), 9.00 (brs, 1H), 8.23 (s, 1H), 7.81 (d, 2H, J=8.5Hz), 7.67 (d, 2H, J=8.2Hz), 7.47 (d, 2H, J=8.5Hz), 7.41 (d, 2H , J=8.4Hz), 3.75 (s, 2H), 3.47 (s, 2H), 2.68 (d, 2H, J=10.2Hz), 2.61-2.26 (m, 2H), 1.84 (t, 2H, J=10.6Hz), 0.89 (d, 6H, J=6.1Hz); LRMS (ES) m/z 421.2(M ⁺⁺ 1).

Example 142: Synthesis of Compound 305 (4-(((2S,6R)-2,6-dimethyl-4-(2-(2-methyl-1H-imidazole- (1-yl)benzyl)piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-2,6-dimethyl-4-(2-(2-methyl-1H-imidazol-1-yl)benzyl)piperazine- 1-amino)methyl)benzoate

Methyl 4-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 13-2, 0.100 g, 0.381 mmol), 2-(2-methyl-1H-imidazol-1-yl)benzaldehyde (0.071 g, 0.381 mmol) and acetic acid (0.011 mL, 0.381 mmol) were dissolved in 1,2-dichloroethane (4 mL) and stirred at room temperature for 2 hours. Na(CN)BH ₃ (0.024 g, 0.381 mmol) was then added, followed by stirring at the same temperature for 17 hours. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to give the desired compound (0.066 g, 40.0%) as a light yellow oil.

Step 2: Synthesis of compound 305

4-(((2S, 6R)-2,6-dimethyl-4-(2-(2-methyl-1H-imidazole-1-yl)benzyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 13-3, 0.066g, 0.153mmol), hydroxylamine (0.187mL, 3.052mmol, 50.00% aqueous solution) and potassium hydroxide (0.086g, 1.526mmol) were dissolved in methanol (3mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution (5mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered and dried to give compound 305 (0.036g, 54.4%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.66 (d, 2H, J=8.2Hz), 7.56 (dd, 1H, J=7.6, 1.5Hz), 7.49 (ddd, 1H, J=7.5, 7.5, 1.4H z), 7.43 (dt, 1H, J=7.5, 7.5, 1.7Hz), 7.37 (d, 2H, J=8.2Hz), 7.31 (dd, 1H, J=7.7, 1.2Hz ), 7.15 (d, 1H, J = 1.3Hz), 6.91 (d, 1H, J = 1.2Hz), 3.75 (s, 2H), 3.12-3.04 (m, 2H), 2.48- 2.46 (m, 4H), 2.05 (s, 3H), 1.68 (t, 2H, J=10.7Hz), 0.85 (d, 6H, J=7.0Hz); LRMS (ES) m/z 434.2(M ⁺ +1).

Example 143: Synthesis of Compound 309 (4-(((3R,5S)-4-(4-(furan-3-yl)benzyl)-3,5-dimethyl (piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(4-(furan-3-yl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl) Methyl benzoate

1,2-Dimethoxyethane (1 ml) / water (0.5 ml) was added to a mixture of methyl 4-(((3R,5S)-4-(4-iodobenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 2-1, 0.100 g, 0.209 mmol ₎ , furan-3-ylboronic acid (0.028 g, 0.251 mmol), Pd(dbpf) _Cl2 (0.007 g, 0.010 mmol) and _Na2CO3 (0.066 g, 0.627 mmol) at room temperature and heated by microwave at 120°C for 20 minutes. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 12 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to give the desired compound (0.052 g, 59.4%) as a light brown solid.

Step 2: Synthesis of compound 309

4-(((3R, 5S)-4-(4-(furan-3-yl)benzyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 2-2, 0.030g, 0.072mmol), hydroxylamine (0.088mL, 1.434mmol, 50.00% aqueous solution) and potassium hydroxide (0.040g, 0.717mmol) were dissolved in methanol (0.5mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain compound 309 (0.021g, 69.8%) as a light orange solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.15(s, 1H), 7.73(s, 1H), 7.65(d, 2H, J=8.1Hz), 7.55(d, 2H, J=8.1Hz), 7.31-7.27(m, 4H), 3.72(s, 1H), 3.39(s, 2H), 2.67-2.64(m, 2H), 2.58-2.56(m, 2H), 1.83-1.73(m, 2H), 0.90(s, 3H), 0.88(s, 3H).

Example 144: Synthesis of Compound 321 ((2S,6R)-N-(3-(1H-pyrrol-1-yl)phenyl)-4-(4-((E)-3- (hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)-2,6-dimethylpiperazine-1-carboxamide)

Step 1: Synthesis of methyl (E)-3-(4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)acrylate

(2S,6R)-2,6-dimethylpiperazine (0.500 g, 4.379 mmol), (E)-methyl 3-(4-(bromomethyl)phenyl)acrylate (Formula 8-4, 1.173 g, 4.598 mmol), and _Cs2CO3 (2.140 g, 6.568 mmol) were dissolved in acetonitrile (10 mL) at room temperature, and _the reaction solution was stirred at the same temperature for 5 hours. The reaction mixture was then filtered through a glass filter to remove solids, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 12 g cartridge; methanol/dichloromethane = 0% to 15%) and concentrated to obtain the desired compound (1.090 g, 86.3%) as an orange solid.

Step 2: Synthesis of (E)-3-(4-(((3R,5S)-4-((3-(1H-pyrrol-1-yl)phenyl)carbamoyl)-3, Methyl 5-dimethylpiperazin-1-yl)methyl)phenyl)acrylate

(E) -3- (4- (( (3R, 5S) -3,5- dimethylpiperazin-1-yl) methyl) phenyl) acrylate (Formula 9-1, 0.050 g, 0.173 mmol) and TEA (0.036 mL, 0.260 mmol) were dissolved in dichloromethane (2 mL), and 1- (3-isocyanatophenyl) -1H- pyrrole (0.034 g, 0.182 mmol) was added thereto at 0 ° C., followed by stirring at the same temperature for 1 hour and 40 minutes. Then, the reaction mixture was filtered through a celite pad to remove the solid, and water was added to the filtrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 40%) and concentrated to give the desired compound (0.050 g, 61.0%) as a white solid.

Step 3: Synthesis of compound 321

(E)-3-(4-(((3R,5S)-4-((3-(1H-pyrrol-1-yl)phenyl)carbamoyl)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)acrylate (Formula 9-2, 0.050 g, 0.106 mmol), hydroxylamine (0.129 mL, 2.116 mmol, 50.00% aqueous solution) and potassium hydroxide (0.059 g, 1.058 mmol) were dissolved in methanol (3 mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure to obtain compound 321 (0.048 g, 95.8%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.90 (brs, 1H), 8.41 (s, 1H), 7.73-7.72 (m, 1H), 7.52 (d, 1H, J=7.7Hz), 7.42-7 .28 (m, 6H), 7.24 (dd, 2H, J=2.1, 2.1Hz), 7.12 (dd, 1H, J=7.9, 1.3Hz), 6.45 (d, 1H , J=15.9Hz), 6.26 (dd, 1H, J=2.1, 2.1Hz), 4.24 (t, 2H, J=5.0Hz), 3.53 (s, 2H), 2. 69 (d, 2H, J = 11.1Hz), 2.14 (d, 2H, J = 7.4Hz), 1.31 (d, 6H, J = 6.6Hz); LRMS (ES) m/z 474.2(M ⁺ +1).

Example 145: Synthesis of Compound 322 ((E)-3-(4-(((3R,5S)-4-(furan-2-carbonyl)-3,5-dimethyl (piperazin-1-yl)methyl)phenyl)-N-hydroxyacrylamide)

Step 1: Synthesis of (E)-3-(4-(((3R,5S)-4-(furan-2-carbonyl)-3,5-dimethylpiperazin-1-yl)methane methyl)phenyl)acrylate

(E)-3-(4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)acrylate (Formula 9-1, 0.050 g, 0.173 mmol) and TEA (0.036 mL, 0.260 mmol) were dissolved in dichloromethane (2 mL), and then furan-2-carbonyl chloride (0.018 mL, 0.182 mmol) was added thereto at 0°C, followed by stirring at the same temperature for 1 hour and 30 minutes. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 20%) and concentrated to give the desired compound (0.053 g, 79.9%) as a colorless oil.

Step 2: Synthesis of compound 322

(E)-3-(4-(((3R,5S)-4-(furan-2-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)acrylate (Formula 9-2, 0.053 g, 0.139 mmol), hydroxylamine (0.170 mL, 2.772 mmol, 50.00% aqueous solution) and potassium hydroxide (0.078 g, 1.386 mmol) were dissolved in methanol (3 mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure to obtain compound 322 (0.027 g, 50.8%) as a light yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.50 (brs, 1H), 7.82 (s, 1H), 7.46 (d, 2H, J=7.8Hz), 7.34 (d, 2H, J=7.8Hz), 7.10 (d, 1H, J=15.7Hz), 6.95 (s, 1H), 6.61 (d, 1H, J=1.5Hz), 6 .39 (d, 1H, J = 15.8Hz), 4.49-4.48 (m, 2H), 3.50 (s, 2H), 2.70 (d, 2H, J = 11.0Hz), 2.12 (d, 2H, J = 7.2Hz), 1.37 (d, 6H, J = 6.2Hz); LRMS (ES) m/z 384.1(M ⁺ +1).

Example 146: Synthesis of Compound 323 ((E)-3-(4-(((3R,5S)-3,5-dimethyl-4-(2-phenylacetyl)- (4-(4-(4-methyl)piperazin-1-yl)methyl)phenyl)-N-hydroxyacrylamide)

Step 1: Synthesis of ((E)-3-(4-(((3R,5S)-3,5-dimethyl-4-(2-phenylacetyl)piperazin-1-yl)methane methyl)phenyl)acrylate

Methyl (E)-3-(4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)acrylate (Formula 9-1, 0.050 g, 0.173 mmol) and TEA (0.036 mL, 0.260 mmol) were dissolved in dichloromethane (2 mL), and 2-phenylacetyl chloride (0.024 mL, 0.182 mmol) was added thereto at 0° C., followed by stirring at the same temperature for 2 hours. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 30%) and concentrated to give the desired compound (0.037 g, 52.5%) as a colorless oil.

Step 2: Synthesis of compound 323

(E)-3-(4-(((3R,5S)-3,5-dimethyl-4-(2-phenylacetyl)piperazin-1-yl)methyl)phenyl)acrylate (Formula 9-2, 0.037 g, 0.091 mmol), hydroxylamine (0.111 mL, 1.820 mmol, 50.00% aqueous solution) and potassium hydroxide (0.051 g, 0.910 mmol) were dissolved in methanol (3 mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure to obtain compound 323 (0.021 g, 56.6%) as a light yellow solid.

¹ H NMR (400MHz, D ₂ O) δ9.90 (brs, 1H), 7.48 (d, 2H, J = 8.0Hz), 7.35 (d, 2H, J = 8.1Hz), 7.32-7.28 (m, 2H), 7.23-7.17 (m, 4H), 6.41 (d, 1H, J = 15.8Hz), 4.42 (s, 1H), 4.1 1 (s, 1H), 3.77 (d, 1H, J = 13.8Hz), 3.62 (d, 1H, J = 15.9Hz), 3.48 (s, 2H), 2.68-2.62 (m, 2H), 2.01 (d, 2H, J = 8.0Hz), 0.88-0.85 (m, 6H); LRMS (ES) m/z 408.2(M ⁺⁺ 1).

Example 147: Synthesis of Compound 326 (4-(((3R,5S)-4-(2-(3,6-dihydro-2H-pyran-4-yl)benzene (acyl)-3,5-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(2-(3,6-dihydro-2H-pyran-4-yl)benzoyl)-3,5-dimethyl methyl)benzoate

1,2-Dimethoxyethane/water (v/v=3/1) (3 mL) was added to a mixture of methyl 4-(((3R,5S)-4-(2-iodobenzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 4-1, 0.400 g, 0.812 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.256 g, 1.219 mmol), Pd(dbpf) _Cl₂ (0.026 g, 0.041 mmol) and _Na₂CO₃ (0.258 g, 2.437 mmol), and heated at 120°C for 30 minutes under microwave irradiation, followed by cooling to room temperature. Saturated aqueous _sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure.The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 0% to 20%) and concentrated to give the desired compound (0.098 g, 26.8%) as a brown oil.

Step 2: Synthesis of compound 326

4-(((3R, 5S)-4-(2-(3,6-dihydro-2H-pyrans-4-yl)benzoyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 4-2, 0.098g, 0.218mmol), hydroxylamine (0.267mL, 4.370mmol, 50.00% aqueous solution) and potassium hydroxide (0.123g, 2.185mmol) were dissolved in methanol (3mL) at room temperature, and the reaction solution was stirred at the same temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the precipitated solid was filtered and dried to obtain compound 326 (0.010g, 9.7%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.69 (d, 2H, J=8.1Hz), 7.41-7.23 (m, 6H), 5.81 (s, 1H), 4.49 (br, 1H), 4.15-4.14 (m, 2H), 3.78 (t, 2H, J= 5.4Hz), 3.49 (s, 2H), 2.71-2.68 (m, 2H), 2.15-2.02 (m, 3H), 1.34 (d, 3H, J=6.7Hz), 1.13 (d, 3H, J=6.7Hz).

Example 148: Synthesis of Compound 327 (4-(((3R,5S)-4-(2-(furan-2-yl)benzyl)-3,5-dimethyl (piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(2-(furan-2-yl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl) Methyl benzoate

1,2-Dimethoxyethane/water (v/v = 3/1) (2 mL) was added to a mixture of methyl 4-(((3R,5S)-4-(2-iodobenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 2-1, 0.250 g, 0.523 mmol), furan-2-ylboronic acid (0.088 g, 0.784 mmol), Pd(dbpf) _Cl₂ (0.017 g, 0.026 mmol), and _{Na₂CO₃ (} 0.166 g, 1.568 mmol), and heated at 120°C for 30 minutes by microwave irradiation, followed by cooling to room temperature. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 0% to 10%) and concentrated to give the desired compound (0.066 g, 30.0%) as a brown oil.

Step 2: Synthesis of compound 327

4-(((3R, 5S)-4-(2-(furan-2-yl)benzyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 2-2, 0.066g, 0.157mmol), hydroxylamine (0.192mL, 3.140mmol, 50.00% aqueous solution) and potassium hydroxide (0.088g, 1.570mmol) were dissolved in methanol (2mL) at room temperature, and the reaction solution was stirred at the same temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the precipitated solid was filtered and dried to obtain compound 327 (0.044g, 66.5%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.95 (d, 1H, J=7.7Hz), 7.80 (s, 1H), 7.70 (d, 2H, J=8.1Hz), 7.56-7.54 (m, 1H), 7.33-7.23 (m, 4H), 6.71 (d, 1H , J=3.3Hz), 6.64-6.62 (m, 1H), 3.79 (s, 2H), 2.69-2.60 (m, 4H), 1.85 (t, 2H, J=10.4Hz), 0.76 (d, 6H, J=6.0Hz).

Example 149: Synthesis of Compound 328 (4-(((3R,5S)-4-(2-(furan-3-yl)benzyl)-3,5-dimethyl (piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(2-(furan-3-yl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl) Methyl benzoate

1,2-Dimethoxyethane/water (v/v = 3/1) (2 mL) was added to a mixture of methyl 4-(((3R,5S)-4-(2-iodobenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 2-1, 0.250 g, 0.523 mmol), furan-3-ylboronic acid (0.088 g, 0.784 mmol), Pd(dbpf) _Cl₂ (0.017 g, 0.026 mmol), and _{Na₂CO₃ (} 0.166 g, 1.568 mmol), and heated at 120°C for 30 minutes by microwave irradiation, followed by cooling to room temperature. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 0% to 5%) and concentrated to give the desired compound (0.020 g, 9.3%) as a brown oil.

Step 2: Synthesis of compound 328

At room temperature, 4-(((3R, 5S)-4-(2-(furan-3-yl)benzyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 2-2, 0.020g, 0.049mmol), hydroxylamine (0.060mL, 0.975mmol, 50.00% aqueous solution) and potassium hydroxide (0.027g, 0.487mmol) were dissolved in methanol (1mL), and the reaction solution was stirred at the same temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the precipitated solid was filtered and dried to obtain compound 328 (0.010g, 50.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.85-7.84 (m, 2H), 7.76-7.76 (m, 1H), 7.69 (d, 2H, J=8.1Hz), 7.28 (t, 4H, J=8.0Hz), 7.19 (t, 1H, J=7.5Hz), 6.76- 6.75 (m, 1H), 3.69 (s, 2H), 2.65 (d, 2H, J=10.3Hz), 2.58-2.55 (m, 2H), 1.84 (t, 2H, J=10.5Hz), 0.76 (d, 1H, J=6.1Hz).

Example 150: Synthesis of Compound 329 (4-(((3R,5S)-3,5-dimethyl-4-(2-(pyridin-4-yl)benzyl) (piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(2-(pyridin-4-yl)benzyl)piperazin-1-yl)methyl) Methyl benzoate

1,2-Dimethoxyethane/water (v/v = 3/1) (2 mL) was added to a mixture of methyl 4-(((3R,5S)-4-(2-iodobenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 2-1, 0.250 g, 0.523 mmol), pyridine-4-boronic acid hydrate (0.110 g, 0.784 mmol), Pd(dbpf) _Cl₂ (0.017 g, 0.026 mmol), and _{Na₂CO₃ (} 0.166 g, 1.568 mmol) at room temperature, and the reaction solution was stirred at 100°C overnight. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 20% to 60%) and concentrated to give the desired compound (0.139 g, 62.1%) as a white solid.

Step 2: Synthesis of compound 329

4-(((3R, 5S)-3,5-dimethyl-4-(2-(pyridin-4-yl)benzyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 2-2, 0.088g, 0.204mmol), hydroxylamine (0.250mL, 4.083mmol, 50.00% aqueous solution) and potassium hydroxide (0.115g, 2.042mmol) were dissolved in methanol (3mL) at room temperature, and the reaction solution was stirred at the same temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the precipitated solid was filtered and dried to obtain compound 329 (0.076g, 86.1%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.65-8.63 (m, 2H), 7.85 (d, 1H, J=7.7Hz), 7.69 (d, 2H, J=8.2Hz), 7.43-7.38 (m, 3H), 7.32-7.27 (m, 3H), 7.18-7. 16 (m, 1H), 3.58 (s, 2H), 2.58 (d, 2H, J=10.2Hz), 2.44-2.43 (m, 2H), 1.82 (t, 2H, J=10.4Hz), 0.75 (d, 6H, J=6.2Hz).

Example 151: Synthesis of Compound 330 (4-(((3R,5S)-3,5-dimethyl-4-(2-(pyridin-3-yl)benzyl) (piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(2-(pyridin-3-yl)benzyl)piperazin-1-yl)methyl) Methyl benzoate

1,2-Dimethoxyethane/water (v/v = 3/1) (2 mL) was added to methyl 4-(((3R,5S)-4-(2-iodobenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 2-1, 0.250 g, 0.523 mmol), pyridin-3-ylboronic acid (0.096 g, 0.784 mmol), Pd(dbpf) _Cl₂ (0.017 g, 0.026 mmol), and _{Na₂CO₃ (} 0.166 g, 1.568 mmol) at room temperature, and the reaction solution was stirred at 100°C overnight. A saturated aqueous sodium bicarbonate solution was then added to the reaction solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 20% to 60%) and concentrated to give the desired compound (0.083 g, 36.8%) as a yellow oil.

Step 2: Synthesis of compound 330

4-(((3R, 5S)-3,5-dimethyl-4-(2-(pyridin-3-yl)benzyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 2-2, 0.083g, 0.192mmol), hydroxylamine (0.235mL, 3.841mmol, 50.00% aqueous solution) and potassium hydroxide (0.108g, 1.921mmol) were dissolved in methanol (3mL) at room temperature, and the reaction solution was stirred at the same temperature for 1 hour. Then, the reaction solution was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the precipitated solid was filtered and dried. The obtained material was purified by column chromatography (Waters, _C18 , C19*100 column, 0.1% aqueous trifluoroacetic acid/acetonitrile = from 5% to 80%), after which the compound was passed through a cartridge (PL- _HCO3 MP resin, methanol) and then concentrated to give compound 330 (0.012 g, 14.5%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.61-8.59 (m, 1H), 8.55 (d, 1H, J=2.1Hz), 7.82 (dd, 2H, J=13.4, 4.8Hz), 7.68 (d, 2H, J=8.1Hz), 7.50-7.47 (m, 1H), 7.40 (t, 1H, J=7.0Hz), 7 .38-7.26 (m, 3H), 7.18-7.16 (m, 1H), 3.56 (s, 2H), 2.58 (d, 2H, J=10.0Hz), 2.46-2.43 (m, 2H), 1.82 (t, 2H, J=10.4Hz), 0.75 (d, 6H, J=6.2Hz).

Example 152: Synthesis of Compound 331 (4-(((3R,5S)-4-((4′,4′-dimethyl-2′,3′,4′,5′-tetramethyl (1,1′-biphenyl-2-yl)methyl)-3,5-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-((4′,4′-dimethyl-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]- 2-(2-methyl)methyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoic acid methyl ester

1,2-Dimethoxyethane/water (v/v = 3/1) (2 mL) was added to a mixture of methyl 4-(((3R,5S)-4-(2-iodobenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 2-1, 0.250 g, 0.523 mmol), 2-(4,4-dimethylcyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.185 g, 0.784 mmol), Pd(dbpf) _Cl₂ (0.017 g, 0.026 mmol), and _Na₂CO₃ (0.166 g, 1.568 mmol) at room temperature, and the reaction solution was heated at 120°C for 30 minutes by microwave irradiation, followed by cooling to room temperature. A saturated aqueous _sodium bicarbonate solution was then added to the reaction solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure.The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 0% to 5%) and concentrated to give the desired compound (0.044 g, 18.4%) as a white solid.

Step 2: Synthesis of compound 331

4-(((3R, 5S)-4-((4′, 4′-dimethyl-2′, 3′, 4′, 5′-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 2-2, 0.044g, 0.096mmol), hydroxylamine (0.118mL, 1.928mmol, 50.00% aqueous solution) and potassium hydroxide (0.054g, 0.964mmol) were dissolved in methanol (2mL) at room temperature, and the reaction solution was stirred at the same temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the precipitated solid was filtered and dried to give compound 331 (0.038g, 85.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.67 (d, 3H, J=8.1Hz), 7.22-7.20 (m, 3H), 7.10 (t, 1H, J=7.2Hz), 5.40 (s, 1H), 3.60 (s, 2H), 2.64 (d, 2H, J=10.4 Hz), 2.16 (s, 2H), 1.94 (s, 2H), 1.82 (t, 2H, J=10.5Hz), 1.47 (t, 2H, J=6.2Hz), 1.00 (s, 6H), 0.78 (d, 6H, J=6.1Hz).

Example 153: Synthesis of Compound 332 (4-(((3R,5S)-4-(2-(3,6-dihydro-2H-pyran-4-yl)benzyl) 1-dimethylpiperazin-1-yl)methyl-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(2-(3,6-dihydro-2H-pyran-4-yl)benzyl)-3,5-dimethylpiperidin (methyl)benzoate

1,2-Dimethoxyethane/water (v/v=3/1) (2 mL) was added to a mixture of methyl 4-(((3R,5S)-4-(2-iodobenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 2-1, 0.250 g, 0.523 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.165 g, 0.784 mmol), Pd(dbpf) _Cl₂ (0.017 g, 0.026 mmol) and _Na₂CO₃ (0.166 g, 1.568 mmol) at room temperature, and the reaction solution was stirred overnight at 100° C. Then, a saturated aqueous _sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure.The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 0% to 20%) and concentrated to give the desired compound (0.108 g, 47.6%) as a light brown solid.

Step 2: Synthesis of compound 332

4-(((3R, 5S)-4-(2-(3,6-dihydro-2H-pyran-4-yl)benzyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 2-2, 0.108g, 0.249mmol), hydroxylamine (0.304mL, 4.970mmol, 50.00% aqueous solution) and potassium hydroxide (0.139g, 2.485mmol) were dissolved in methanol (2mL) at room temperature, and the reaction solution was stirred at the same temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the precipitated solid was filtered and dried. The obtained material was purified by column chromatography (Waters, _C18 , C19*100 column, 0.1% trifluoroacetic acid aqueous solution/acetonitrile = from 5% to 80%), after which the compound was passed through a cartridge (PL- _HCO3 MP resin, methanol) and then concentrated to give compound 332 (0.017 g, 15.3%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.73-7.68(m, 3H), 7.29-7.20(m, 3H), 7.14(t, 1H, J=6.9Hz), 7.04-7.02(m, 1H), 5.60(s, 1H), 4.19-4.19(m, 2H ), 3.82 (t, 2H, J=5.3Hz), 3.64 (s, 2H), 2.66-2.57 (m, 4H), 2.26 (s, 2H), 1.84 (t, 2H, J=10.3Hz), 0.79-0.78 (m, 6H).

Example 154: Synthesis of Compound 340 (4-(((3R,5S)-4-(4-(furan-2-yl)benzoyl)-3,5-diol (methylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(4-bromobenzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzyl Methyl ester

4-Bromobenzoyl chloride (1.000 g, 4.557 mmol), 4-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 1-2, 1.315 g, 5.012 mmol) and TEA (1.263 mL, 9.113 mmol) were dissolved in dichloromethane (20 mL) at room temperature, and the reaction solution was stirred at the same temperature for 2 hours. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 30% to 50%) and concentrated to give the desired compound (2.007 g, 98.9%) as a white solid.

Step 2: Synthesis of 4-(((3R,5S)-4-(4-(furan-2-yl)benzoyl)-3,5-dimethylpiperazin-1-yl) Methyl)benzoate

1,2-Dimethoxyethane/water (v/v = 3/1) (4 mL) was added to a mixture of methyl 4-(((3R,5S)-4-(4-bromobenzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 4-1, 0.500 g, 1.123 mmol), furan-2-ylboronic acid (0.138 g, 1.235 mmol), Pd(dbpf) _Cl₂ (0.037 g, 0.056 mmol), and _Na₂CO₃ (0.262 g, 2.470 mmol), and heated at 120°C for 30 minutes by microwave irradiation, followed by cooling to room temperature. A saturated _aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; ethyl acetate/hexane = from 0% to 20%) and concentrated to give the desired compound (0.163 g, 33.5%) as a white solid.

Step 3: Synthesis of Compound 340

4-(((3R, 5S)-4-(4-(furan-2-yl)benzoyl)-3,5-dimethylpiperazine-1-yl)methyl)methyl benzoate (Formula 4-2, 0.100g, 0.231mmol), hydroxylamine (0.283mL, 4.624mmol, 50.00% aqueous solution) and potassium hydroxide (0.130g, 2.312mmol) were dissolved in methanol (4mL) at room temperature, and the reaction solution was stirred at the same temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the concentrate, and the precipitated solid was filtered and dried to obtain compound 340 (0.049g, 48.7%) as a light yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.85 (d, 1H, J=7.7Hz), 7.76-7.71 (m, 4H), 7.40-7.36 (m, 3H), 7.24 (d, 1H, J=7.9Hz), 7.01 (d, 1H, J= 3.0Hz), 6.60-6.59(m, 1H), 3.51-3.47(m, 2H), 2.62-2.60(m, 2H), 2.15-2.09(m, 2H), 1.27(brs, 6H).

Example 155: Synthesis of Compound 342 (4-(((3R,5S)-4-(3-(furan-2-yl)benzyl)-3,5-dimethyl (piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-(furan-2-yl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl) Methyl benzoate

1,2-Dimethoxyethane (4 mL) / water (1 mL) was added to a mixture of methyl 4-(((3R,5S)-4-(3-iodobenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 2-1, 0.100 g, 0.209 mmol), furan-2-ylboronic acid (0.047 g, 0.418 mmol), Pd(dbpf) _2Cl2 (0.007 _g , 0.010 mmol), and _{Na2CO3 (} 0.044 g, 0.418 mmol), and heated at 120°C for 20 minutes by microwave irradiation, followed by cooling to room temperature. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (Waters, _C18 , 19*100 mm column, 0.1% trifluoroacetic acid/acetonitrile = from 5% to 80%) and concentrated. The resulting material was dissolved in a solvent and the compound was passed through a cartridge (PL- _HCO3 MP resin, methanol only) and concentrated to give the desired compound (0.064 g, 73.2%) as a brown oil.

Step 2: Synthesis of compound 342

Methyl 4-(((3R,5S)-4-(3-(furan-2-yl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (compound 2-2, 0.064 g, 0.153 mmol), hydroxylamine (0.094 mL, 1.529 mmol, 50.00% aqueous solution) and potassium hydroxide (0.172 g, 3.058 mmol) were dissolved in methanol (2 mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure to give compound 342 (0.031 g, 48.3%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.10 (brs, 1H), 9.00 (brs, 1H), 7.75 (d, 1H, J=1.3Hz), 7.69 (d, 2H, J=7.8Hz ), 7.66 (s, 1H), 7.52 (d, 1H, J = 7.5Hz), 7.35-7.31 (m, 3H), 7.28 (d, 1H, J = 7.5Hz) , 6.90 (d, 1H, J = 3.0Hz), 6.58 (dd, 1H, J = 3.4, 1.8Hz), 3.75 (s, 2H), 3.44 (s, 2H), 2.66-2.57 (m, 4H), 1.83 (t, 2H, J=10.5Hz), 0.91 (d, 6H, J=6.1Hz); LRMS (ES) m/z 420.2(M ⁺ +1).

Example 156: Synthesis of Compound 343 (4-(((3R,5S)-4-(3-(furan-3-yl)benzyl)-3,5-dimethyl (piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-(furan-2-yl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl) Methyl benzoate

1,2-Dimethoxyethane (4 mL) / water (1 mL) was added to a mixture of methyl 4-(((3R,5S)-4-(3-iodobenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 2-1, 0.100 g, 0.209 mmol), furan-3-ylboronic acid (0.047 g, 0.418 mmol), Pd(dbpf) _2Cl2 (0.007 _g , 0.010 mmol), and _{Na2CO3 (} 0.044 g, 0.418 mmol), and heated at 120°C for 20 minutes by microwave irradiation, followed by cooling to room temperature. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (Waters, _C18 , 19*100 mm column, 0.1% trifluoroacetic acid/acetonitrile = from 5% to 80%) and concentrated. The resulting material was dissolved in a solvent and the compound was passed through a cartridge (PL- _HCO3 MP resin, methanol only) and then concentrated to give the desired compound (0.061 g, 69.7%) as a brown oil.

Step 2: Synthesis of compound 343

Methyl 4-(((3R, 5S)-4-(3-(furan-3-yl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 2-2, 0.061 g, 0.146 mmol), hydroxylamine (0.089 mL, 1.457 mmol, 50.00% aqueous solution) and potassium hydroxide (0.164 g, 2.915 mmol) were dissolved in methanol (2 mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 100%) and concentrated to give compound 343 (0.008 g, 13.1%) as a white solid.

¹ H NMR (400MHz, CH ₃ OD) δ7.89-7.89 (m, 1H), 7.72 (d, 2H, J=8.2Hz), 7.57 (dd, 1H, J=1.6, 1.6Hz), 7.54 (s, 1H), 7.44 (d, 3H, J=7.9Hz), 7.33-7.30 (m, 2 H), 6.80-6.79 (m, 1H), 3.95 (s, 2H), 3.54 (s, 2H), 2.77-2.17 (m, 4H), 1.97 (t, 2H, J=10.8Hz), 1.13 (d, 6H, J=6.0Hz); LRMS (ES) m/z 420.2(M ⁺ +1).

Example 157: Synthesis of Compound 344 (4-(((3R,5S)-3,5-dimethyl-4-(3-(pyridin-3-yl)benzyl) (piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(3-(pyridin-3-yl)benzyl)piperazin-1-yl)methyl) Methyl benzoate

1,2-Dimethoxyethane (4 mL)/water (1 mL) was added to a mixture of methyl 4-(((3R,5S)-4-(3-iodobenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 2-1, 0.100 g, 0.209 mmol), pyridin-3-ylboronic acid (0.051 g, 0.418 mmol), Pd(dbpf) _2Cl2 (0.007 g, 0.010 mmol), and _{Na2CO3 (} 0.044 g, 0.418 mmol). The mixture was heated at 120°C for 20 minutes under microwave irradiation, followed by cooling to room temperature. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (Waters, _C18 , 19*100 mm column, 0.1% trifluoroacetic acid/acetonitrile = from 5% to 80%) and concentrated. The resulting material was dissolved in a solvent and the compound was passed through a cartridge (PL- _HCO3 MP resin, methanol only) and concentrated to give the desired compound (0.085 g, 94.7%) as a colorless oil.

Step 2: Synthesis of compound 344

4-(((3R, 5S)-3,5-dimethyl-4-(3-(pyridin-3-yl)benzyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 2-2, 0.085 g, 0.198 mmol), hydroxylamine (0.121 mL, 1.979 mmol, 50.00% aqueous solution) and potassium hydroxide (0.222 g, 3.958 mmol) were dissolved in methanol (3 mL) at room temperature, and the reaction solution was stirred at the same temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the concentrate, followed by extraction with dichloromethane. The extract was filtered through a plastic filter equipped with an anhydrous sodium sulfate cartridge to remove the solid residue and the aqueous layer, and the filtrate was concentrated under reduced pressure to give compound 344 (0.055 g, 64.6%) as a white solid.

¹ H NMR (400MHz, CDCl ₃ ) δ 8.86 (d, 1H, J = 1.9Hz), 8.58 (d, 1H, J = 3.4Hz), 8.04 (d, 1H, J = 7.8Hz), 7.68 (d, 3H, J = 8.1Hz), 7.54-7.48 (m, 2H), 7.43 (d, 2H, J = 4.8Hz), 7.26 (d, 2H, J=8.0Hz), 3.81 (s, 2H), 3.41 (s, 2H), 2.66 (d, 2H, J=11.0Hz), 2.63-2.59 (m, 2H), 1.82 (t, 2H, J=10.2Hz), 0.93 (d, 6H, J=6.0Hz); LRMS (ES) m/z 431.2(M ⁺⁺ 1).

Example 158: Synthesis of Compound 345 (4-(((3R,5S)-3,5-dimethyl-4-(3-(pyridin-4-yl)benzyl) (piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(3-(pyridin-4-yl)benzyl)piperazin-1-yl)methyl) Methyl benzoate

1,2-Dimethoxyethane (4 mL) / water (1 mL) was added to a mixture of methyl 4-(((3R,5S)-4-(3-iodobenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 2-1, 0.100 g, 0.209 mmol), pyridin-4-ylboronic acid (0.051 g, 0.418 mmol), Pd(dbpf) _2Cl2 (0.007 _g , 0.010 mmol), and _{Na2CO3 (} 0.044 g, 0.418 mmol). The mixture was heated at 120°C for 20 minutes under microwave irradiation, followed by cooling to room temperature. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (Waters, _C18 , 19*100 mm column, 0.1% trifluoroacetic acid/acetonitrile = from 5% to 80%) and concentrated. The resulting material was dissolved in a solvent and the compound was passed through a cartridge (PL- _HCO3 MP resin, methanol only) and then concentrated to give the desired compound (0.088 g, 98.0%) as a colorless oil.

Step 2: Synthesis of compound 345

A mixture of methyl 4-(((3R, 5S)-3,5-dimethyl-4-(3-(pyridin-4-yl)benzyl)piperazin-1-yl)methyl)benzoate (Formula 4-2, 0.040 g, 0.093 mmol), hydroxylamine (0.031 g, 0.931 mmol) and potassium hydroxide (0.105 g, 1.862 mmol) was added to methanol (3 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Then, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to give compound 345 (0.005 g, 12.5%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.64 (d, 2H, J=5.2Hz), 7.74 (s, 1H), 7.62-7.61 (m, 5H), 7.47-7.45 (m, 2H), 7.25 (d, 2H, J=7.8Hz), 3. 82 (s, 2H), 3.41 (s, 2H), 2.68-2.61 (m, 4H), 1.83 (t, 2H, J=9.9Hz), 0.92 (d, 6H, J=5.8Hz); LRMS (ES) m/z 431.2(M ⁺ +1).

Example 159: Synthesis of Compound 346 (4-(((3R,5S)-4-(3-(3,6-dihydro-2H-pyran-4-yl)benzyl) 1-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-(3,6-dihydro-2H-pyran-4-yl)benzyl)-3,5-dimethylpiperidin (methyl)benzoate

1,2-Dimethoxyethane (4 mL) / water (1 mL) was added to a mixture of methyl 4-(((3R,5S)-4-(3-iodobenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 2-1, 0.100 g, 0.209 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.088 g, 0.418 mmol), Pd(dbpf) _{2Cl2 (} 0.007 g, 0.010 mmol) and _Na2CO3 (0.044 _g , 0.418 mmol), and the mixture was heated at 120°C for 20 minutes under microwave irradiation, followed by cooling to room temperature. Saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (Waters, _C18 , 19*100 mm column, 0.1% trifluoroacetic acid/acetonitrile = from 5% to 80%) and concentrated. The resulting material was dissolved in a solvent and the compound was passed through a cartridge (PL- _HCO3 MP resin, methanol only) and then concentrated to give the desired compound (0.068 g, 74.9%) as a light brown oil.

Step 2: Synthesis of compound 346

Methyl 4-(((3R,5S)-4-(3-(3,6-dihydro-2H-pyran-4-yl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 2-2, 0.068 g, 0.156 mmol), hydroxylamine (0.096 mL, 1.565 mmol, 50.00% aqueous solution) and potassium hydroxide (0.176 g, 3.130 mmol) were mixed in methanol (3 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Then, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (Waters, C ₁₈ , 19*100 mm column, 0.1% trifluoroacetic acid/acetonitrile = from 5% to 80%) and concentrated. The resulting material was dissolved in solvent and the compound was passed through a cartridge (PL- _HCO3 MP resin, 100% methanol) and then concentrated to afford compound 346 (0.005 g, 7.3%) as an apricot solid.

¹ H NMR (400MHz, CH ₃ OD) δ7.72 (d, 2H, J=8.2Hz), 7.42 (d, 3H, J=8.4Hz), 7.31-7.28 (m, 3H), 6.17 (t, 1H, J=1.5Hz), 4.32-4.30 (m, 2H), 3.95-3.9 2(m, 4H), 3.52(s, 2H), 2.75-2.69(m, 4H), 2.39-2.52(m, 2H), 1.94(t, 2H, J=11.2Hz), 1.11(d, 6H, J=6.1Hz); LRMS(ES)m/z 436.2(M ⁺ +1).

Example 160: Synthesis of Compound 347 (4-(((3R,5S)-4-((4′,4′-dimethyl-2′,3′,4′,5′-tetramethyl (H-[1,1′-biphenyl]-3-yl)methyl)-3,5-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-((4′,4′-dimethyl-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]- 3-(2-methyl-3-piperazin-1-yl)methyl)benzoic acid methyl ester

1,2-Dimethoxyethane (4 mL) / water (1 mL) was added to a mixture of methyl 4-(((3R,5S)-4-(3-iodobenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 2-1, 0.100 g, 0.209 mmol), 2-(4,4-dimethylcyclo-1-hexenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.099 g, 0.418 mmol), Pd(dbpf) _{2Cl2 (} 0.007 g, 0.010 mmol) and _Na2CO3 (0.044 g, 0.418 _mmol ), and heated at 120°C for 20 minutes by microwave irradiation, followed by cooling to room temperature. Then, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and the organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (Waters, _C18 , 19*100 mm column, 0.1% trifluoroacetic acid/acetonitrile = from 5% to 80%) and concentrated. The resulting material was dissolved in a solvent and the compound was passed through a cartridge (PL- _HCO3 MP resin, methanol only) and then concentrated to give the desired compound (0.064 g, 66.5%) as a brown oil.

Step 2: Synthesis of compound 347

Methyl 4-(((3R, 5S)-4-((4′, 4′-dimethyl-2′, 3′, 4′, 5′-tetrahydro-[1,1′-biphenyl]-3-yl)methyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 2-2, 0.064 g, 0.139 mmol), hydroxylamine (0.085 mL, 1.389 mmol, 50.00% aqueous solution) and potassium hydroxide (0.156 g, 2.779 mmol) were mixed in methanol (3 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 347 (0.020 g, 31.2%) as an orange solid.

¹ H NMR (400MHz, CH ₃ OD) δ7.72 (d, 2H, J=8.1Hz), 7.43 (d, 2H, J=8.0Hz), 7.40 (s, 1H), 7.28-7.23 (m, 3H), 6.06 (s, 1H), 3.93 (s, 2H), 3.52 (s, 2H), 2.76-2.69 (m, 4 LRMS(ES)m/z 462.3(M ⁺ +1).

Example 161: Synthesis of Compound 348 (4-(((2S,6R)-4-(2-(furan-3-yl)benzyl)-2,6-dimethyl (piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(2-(furan-3-yl)benzyl)-2,6-dimethylpiperazin-1-yl)methyl) Methyl benzoate

1,2-Dimethoxyethane (4 mL) / water (1 mL) was added to a mixture of methyl 4-(((2S,6R)-4-(2-iodobenzyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 14-1, 0.100 g, 0.209 mmol), furan-3-ylboronic acid (0.047 g, 0.418 mmol), Pd(dbpf) ₂ Cl ₂ (0.007 g, 0.010 mmol), and Na ₂ CO ₃ (0.044 g, 0.418 mmol), and heated at 120° C. for 20 minutes by microwave irradiation, followed by cooling to room temperature. Then, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The product was used without additional purification (0.090 g, 102.9%, crude product).

Step 2: Synthesis of compound 348

A mixture of methyl 4-(((2S,6R)-4-(2-(furan-3-yl)benzyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 14-2, 0.090 g, 0.215 mmol), hydroxylamine (0.132 mL, 2.150 mmol, 50.00% aqueous solution) and potassium hydroxide (0.241 g, 4.301 mmol) was added to methanol (3 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Then, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 15%) and concentrated to give compound 348 (0.023 g, 25.5%) as a light orange solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.13 (s, 1H), 8.98 (s, 1H), 8.99 (d, 1H, J=1.6Hz), 7.98-7.98 (m, 1H), 7.76 (dd, 1H, J=1.7, 1.7Hz), 7.67 (d, 2H, J=8.6Hz), 7.44-7.39 (m, 4H) , 7.33-7.29 (m, 2H), 6.84 (dd, 1H, J=1.8, 0.7Hz), 3.75 (s, 2H), 3.37 (s, 2H), 2.68 (d, 2H, J=10.7Hz), 1.85-1.84 (m, 2H), 0.89 (d, 6H, J=6.1Hz).

Example 162: Synthesis of Compound 349 (4-(((2S,6R)-2,6-dimethyl-4-(2-(pyridin-3-yl)benzyl) (piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-2,6-dimethyl-4-(2-(pyridin-3-yl)benzyl)piperazin-1-yl)methyl) Methyl benzoate

1,2-Dimethoxyethane (4 mL)/water (1 mL) was added to a mixture of methyl 4-(((2S,6R)-4-(2-iodobenzyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 14-1, 0.100 g, 0.209 mmol), pyridin-3-ylboronic acid (0.051 g, 0.418 mmol), Pd(dbpf) _2Cl2 (0.007 _g , 0.010 mmol), and _Na2CO3 (0.044 g, 0.418 mmol), and heated at 120°C for 20 minutes by microwave irradiation, followed by cooling to room temperature. Saturated aqueous _sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The product was used without additional purification (0.090 g, 100.2%).

Step 2: Synthesis of compound 349

At room temperature by 4- (((2S, 6R) -2,6- dimethyl -4- (2- (pyridin-3-yl) benzyl) piperazine -1- yl) methyl) methyl benzoate (Formula 14-2, 0.090g, 0.210mmol), hydroxylamine (0.128mL, 2.095mmol, 50.00% aqueous solution) and potassium hydroxide (0.235g, 4.190mmol) mixture in methanol (3mL), and the mixture was stirred at the same temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution (20mL) was added to the concentrate, and the precipitated solid was filtered and dried to give compound 349 (0.041g, 45.5%) as an apricot yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.60-8.56 (m, 2H), 7.86 (d, 1H, J=7.6Hz), 7.65 (d, 2H, J=7.6Hz), 7.49-7.38 (m, 4H), 7.35 (d, 2H, J=7.9Hz), 7.28 (d, 1 H, J=6.5Hz), 3.70 (s, 2H), 3.30 (s, 2H), 2.50-2.48 (m, 4H), 1.72 (t, 2H, J=10.2Hz), 0.83 (d, 6H, J=5.9Hz); LRMS (ES) m/z 431.2(M ⁺ +1).

Example 163: Synthesis of Compound 350 (4-(((2S,6R)-2,6-dimethyl-4-(2-(pyridin-4-yl)benzyl) (piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-2,6-dimethyl-4-(2-(pyridin-4-yl)benzyl)piperazin-1-yl)methyl) Methyl benzoate

1,2-Dimethoxyethane (3 mL) / water (1 mL) was added to a mixture of methyl 4-(((2S,6R)-4-(2-iodobenzyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 14-1, 0.100 g, 0.209 mmol), pyridin-4-ylboronic acid (0.051 g, 0.418 mmol), Pd(dbpf) ₂ Cl ₂ (0.007 g, 0.010 mmol), and Na ₂ CO ₃ (0.044 g, 0.418 mmol), and heated at 120° C. for 20 minutes by microwave irradiation, followed by cooling to room temperature. Saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The product was used without additional purification (0.090 g, 100.2%).

Step 2: Synthesis of compound 350

Methyl 4-(((2S,6R)-2,6-dimethyl-4-(2-(pyridin-4-yl)benzyl)piperazin-1-yl)methyl)benzoate (Formula 14-2, 0.090 g, 0.210 mmol), hydroxylamine (0.128 mL, 2.095 mmol, 50.00% aqueous solution) and potassium hydroxide (0.235 g, 4.190 mmol) were mixed in methanol (3 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 15%) to give compound 350 (0.026 g, 28.8%) as a light orange solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.52 (d, 2H, J = 6.1Hz), 7.70 (d, 2H, J = 8.2Hz), 7.49 (d, 2H, J = 6.4Hz), 7.50-7.47 (m, 5H), 7.42-7.40 (m, 2H), 7.29-7.27 (m , 1H), 3.85 (s, 2H), 3.42 (s, 2H), 2.56 (d, 2H, J=10.6Hz), 2.47-2.46 (m, 2H), 1.79 (t, 2H, J=10.7Hz), 0.97 (d, 6H, J=6.2Hz).

Example 164: Synthesis of Compound 351 (4-(((2S,6R)-4-(2-(3,6-dihydro-2H-pyran-4-yl)benzyl) 1-(2,6-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(2-(3,6-dihydro-2H-pyran-4-yl)benzyl)-2,6-dimethylpiperidin (methyl)benzoate

1,2-Dimethoxyethane (3 mL) / water (1 mL) was added to a mixture of methyl 4-(((2S,6R)-4-(2-iodobenzyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 14-1, 0.100 g, 0.209 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.088 g, 0.418 mmol), Pd(dbpf) ₂ Cl ₂ (0.007 g, 0.010 mmol) and Na ₂ CO ₃ (0.044 g, 0.418 mmol), and heated at 120° C. for 20 minutes under microwave irradiation, followed by cooling to room temperature. Saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 60%) and concentrated to give the desired compound (0.017 g, 18.7%) as a light yellow oil.

Step 2: Synthesis of compound 351

A mixture of 4-(((2S,6R)-4-(2-(3,6-dihydro-2H-pyran-4-yl)benzyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 14-2, 0.017 g, 0.039 mmol), hydroxylamine (0.024 mL, 0.391 mmol, 50.00% aqueous solution) and potassium hydroxide (0.044 g, 0.782 mmol) was added to methanol (1 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Then, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The extract was filtered through a plastic filter equipped with an anhydrous sodium sulfate cartridge to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to obtain compound 351 (0.012 g, 70.4%) as a white solid.

¹ H-NMR (400 MHz, CD ₃ OD) δ7.71 (d, 2H, J=8.3Hz), 7.49 (d, 2H, J=8.3Hz), 7.38-7.37 (m, 1H), 7.2 4-7.22(m, 2H), 7.12-7.11(m, 1H), 5.61(s, 1H), 4.26-4.24(m, 2H), 3.90-3 .87(m, 4H), 3.48(s, 2H), 2.70(d, 2H, J=11.0Hz), 2.69-2.64(m, 2H), 2.36 -2.35 (m, 2H), 1.90 (t, 2H, J = 10.9Hz), 1.03 (d, 6H, J = 6.1Hz); LRMS (ES) m/z 436.2(M ⁺ +1).

Example 165: Synthesis of Compound 352 (4-(((2S,6R)-4-((4′,4′-dimethyl-2′3′,4′,5′-tetrahydro- [1,1′-biphenyl]-2-yl)methyl)-2,6-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-((4′,4′-dimethyl-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]- methyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate

1,2-Dimethoxyethane (3 mL) / water (1 mL) was added to a mixture of methyl 4-(((2S,6R)-4-(2-iodobenzyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 14-1, 0.100 g, 0.209 mmol), 2-(4,4-dimethylcyclo-1-hexenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.099 g, 0.418 mmol), Pd(dbpf) _{2Cl2 (} 0.007 g, 0.010 mmol) and _Na2CO3 (0.044 g, 0.418 _mmol ), and heated at 120°C for 20 minutes by microwave irradiation, followed by cooling to room temperature. Saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 10%) and concentrated to give the desired compound (0.013 g, 13.5%) as a light yellow oil.

Step 2: Synthesis of compound 352

Methyl 4-(((2S,6R)-4-((4′,4′-dimethyl-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 14-2, 0.013 g, 0.028 mmol), hydroxylamine (50.00% aqueous solution, 0.017 mL, 0.282 mmol) and potassium hydroxide (0.032 g, 0.564 mmol) were mixed in methanol (1 mL) at room temperature and the mixture was stirred at the same temperature for 30 minutes. Then, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by PTLC (silica; 100% ethyl acetate) and concentrated to give compound 352 (0.007 g, 53.7%) as an orange solid.

¹ H-NMR (400MHz, CD ₃ OD) δ7.71 (d, 2H, J=7.1Hz), 7.49 (d, 2H, J=6.9Hz), 7.37-7.36 (m, 1H), 7.20-7.18 (m, 2H), 7.07-7.04 (m, 1H), 5.43 (s, 1H), 3.91 (s, 2H), 3.4 8 (s, 2H), 2.72-2.66 (m, 4H), 2.24 (s, 2H), 1.96 (s, 2H), 1.88 (t, 2H, J=10.4Hz), 1.50 (t, 2H, J=6.2Hz), 1.03 (d, 12H, J=3.9Hz); LRMS (ES) m/z 462.2(M ⁺ +1).

Example 166: Synthesis of Compound 354 (4-(((3R,5S)-3,5-dimethyl-4-(oxazol-4-ylmethyl)piperazine- (1-amino)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of oxazol-4-yl methanesulfonate

Oxazol-4-ylmethanol (0.300 g, 3.028 mmol) and TEA (0.633 mL, 4.541 mmol) were mixed in dichloromethane (5 mL) at 0 ° C, and MsCl (0.258 mL, 3.330 mmol) was added to the mixture, followed by stirring at the same temperature. Water was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane=from 0% to 50%) and concentrated to give the desired compound (0.119 g, 22.2%) as an orange oil.

Step 2: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(oxazol-4-ylmethyl)piperazin-1-yl)methyl)benzene Methyl ester

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.150 g, 0.572 mmol), oxazol-4-ylmethyl(emthyl)methanesulfonate (0.111 g, 0.629 mmol), and Cs ₂ CO ₃ (0.279 g, 0.858 mmol) were added to N,N-dimethylformamide (3 mL) at 80° C., and the mixture was stirred at the same temperature for 17 hours. The reaction mixture was then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 15%) and concentrated to give the desired compound (0.054 g, 27.5%) as a light yellow oil.

Step 3: Synthesis of compound 354

At room temperature, a mixture of 4-(((3R, 5S)-3,5-dimethyl-4-(oxazol-4-ylmethyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 1-3, 0.054 g, 0.157 mmol), hydroxylamine (0.096 mL, 1.572 mmol, 50.00% aqueous solution) and potassium hydroxide (0.176 g, 3.145 mmol) was added to methanol (1 mL) and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was filtered through a plastic filter equipped with an anhydrous sodium sulfate cartridge to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 354 (0.003 g, 5.5%) as a yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.16(s, 1H), 7.92(s, 1H), 7.72(d, 2H, J=8.1Hz), 7.41(d, 2H, J=8.0Hz), 3.98(s, 2H), 3.51(s, 2H), 2 .73 (d, 2H, J = 11.8Hz), 2.70-2.66 (m, 2H), 1.93 (t, 2H, J = 10.8Hz), 1.19 (d, 6H, J = 6.1Hz); LRMS (ES) m/z 345.2(M ⁺ +1).

Example 167: Synthesis of Compound 355 (4-(((3R,5S)-3,5-dimethyl-4-(pyrimidin-5-ylmethyl)piperazine- (1-amino)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(pyrimidin-5-ylmethyl)piperazin-1-yl)methyl)benzene Methyl ester

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.200 g, 0.762 mmol), 5-(chloromethyl)pyrimidine (0.108 g, 0.839 mmol), and Cs ₂ CO ₃ (0.373 g, 1.144 mmol) were added to N,N-dimethylformamide (3 mL) at room temperature, and the mixture was stirred at 120° C. for 48 hours. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and water was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 15%) and concentrated to obtain the desired compound (0.027 g, 10.0%) as a yellow solid.

Step 2: Synthesis of compound 355

Methyl 4-(((3R,5S)-3,5-dimethyl-4-(pyrimidin-5-ylmethyl)piperazine-1-yl)methyl)benzoate (Formula 1-3, 0.027 g, 0.076 mmol), hydroxylamine (0.047 mL, 0.762 mmol, 50.00% aqueous solution) and potassium hydroxide (0.085 g, 1.523 mmol) were mixed in methanol (1 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was filtered through a plastic filter equipped with an anhydrous sodium sulfate cartridge to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 355 (0.003 g, 11.1%) as a light yellow solid.

¹ H NMR (400MHz, CH ₃ OD) δ9.03 (s, 1H), 8.83 (s, 1H), 7.74 (d, 2H, J=8.3Hz), 7.46 (d, 2H, J=8.3Hz), 3.92 (s, 2H), 3.56 (s, 2H), 2.78 (d, 2H, J = 10.7Hz), 2.72-2.68 (m, 2H), 1.97 (t, 2H, J = 10.8Hz), 0.93 (d, 6H, J = 6.6Hz); LRMS (ES) m/z 356.1(M ⁺ +1).

Example 168: Synthesis of Compound 356 (4-(((3R,5S)-3,5-dimethyl-4-(3-(morpholinomethyl)benzyl) (piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzyl Methyl ester

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.500 g, 1.906 mmol), 3-(bromomethyl)benzaldehyde (0.417 g, 2.096 mmol), and Cs ₂ CO ₃ (0.931 g, 2.859 mmol) were mixed in acetonitrile (20 mL) at room temperature, and the mixture was stirred at the same temperature for 17 hours. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and water was added to the resulting concentrate, followed by extraction with ethyl acetate. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; 12 g cartridge; ethyl acetate/hexane = from 0% to 60%) and concentrated to obtain the desired compound (0.530 g, 73.1%) as a light brown oil.

Step 2: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(3-(morpholinomethyl)benzyl)piperazin-1-yl)methane methyl)benzoate

Methyl 4-(((3R,5S)-4-(3-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.200 g, 0.526 mmol), morpholine (0.050 mL, 0.578 mmol), and acetic acid (0.015 mL, 0.526 mmol) were added and mixed in tetrahydrofuran (5 mL) at room temperature, and the mixture was stirred. Na(CN)BH ₃ (0.033 g, 0.526 mmol) was then added to the mixture, followed by stirring at the same temperature for 17 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; 4 g cartridge; ethyl acetate/hexane = from 20% to 100%) and concentrated to give the desired compound (0.109 g, 45.9%) as a colorless oil.

Step 3: Synthesis of compound 356

Methyl 4-(((3R, 5S)-3,5-dimethyl-4-(3-(morpholinomethyl)benzyl)piperazin-1-yl)methyl)benzoate (Formula 5-2, 0.050 g, 0.111 mmol), hydroxylamine (0.135 mL, 2.214 mmol, 50.00% aqueous solution) and potassium hydroxide (0.072 g, 1.107 mmol) were mixed in methanol (2 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was filtered through a plastic filter equipped with an anhydrous sodium sulfate cartridge to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 356 (0.034 g, 67.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.66 (d, 2H, J=8.0Hz), 7.27-7.22 (m, 5H), 7.10 (s, 1H), 3.71 (s, 2H), 3.55 (s, 4H), 3.44 (s, 2H), 3.39 (s, 2H), 2. 63 (d, 2H, J = 10.5Hz), 2.57-2.55 (m, 2H), 2.32 (s, 4H), 1.78 (t, 2H, J = 10.5Hz), 0.89 (d, 6H, J = 6.0Hz); LRMS (ES) m/z 453.2(M ⁺ +1).

Example 169: Synthesis of Compound 376 (4-(((3R,5S)-3,5-dimethyl-4-(4-(morpholinomethyl)benzyl) (piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(4-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzyl Methyl ester

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.200 g, 0.762 mmol), 4-(bromomethyl)benzaldehyde (0.167 g, 0.839 mmol), and Cs ₂ CO ₃ (0.373 g, 1.144 mmol) were mixed in acetonitrile (5 mL) at room temperature, and the mixture was stirred at the same temperature for 17 hours. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 5% to 70%) and concentrated to obtain the desired compound (0.131 g, 45.2%) as a light yellow oil.

Step 2: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(4-(morpholinomethyl)benzyl)piperazin-1-yl)methane methyl)benzoate

Methyl 4-(((3R,5S)-4-(4-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.131 g, 0.344 mmol) and morpholine (0.033 g, 0.379 mmol) were mixed in dichloromethane (4 mL) at room temperature, and the mixture was stirred for 30 minutes. Na(OAc) ₃ BH (0.109 g, 0.516 mmol) was then added, followed by stirring at the same temperature for 17 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = 0% to 10%) and concentrated to obtain the desired compound (0.134 g, 86.2%) as a light yellow oil.

Step 3: Synthesis of Compound 376

Methyl 4-(((3R, 5S)-3,5-dimethyl-4-(4-(morpholinomethyl)benzyl)piperazine-1-yl)methyl)benzoate (Formula 5-2, 0.134 g, 0.297 mmol), hydroxylamine (0.181 mL, 2.967 mmol, 50.00% aqueous solution) and potassium hydroxide (0.386 g, 5.934 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 376 (0.030 g, 22.3%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ )δ11.18(brs, 1H), 9.04(brs, 1H), 7.70(d, 2H, J=8.2Hz), 7.35(d, 2H, J=8.1 Hz), 7.28 (d, 2H, J=8.0Hz), 7.21 (d, 2H, J=8.0Hz), 3.71 (s, 2H), 3.56 (t, 4H, J =4.4Hz), 3.43 (s, 2H), 3.41 (s, 2H), 2.63 (d, 2H, J = 10.4Hz), 2.58-2.53 (m, 2 H), 2.32 (s, 4H), 1.80 (t, 2H, J = 10.4Hz), 0.90 (d, 6H, J = 6.1Hz); LRMS (ES) m/z 453.2(M ⁺⁺ 1).

Example 170: Synthesis of Compound 380 (4-(((3R,5S)-4-(3-((1-(2-fluoro-2-methylpropyl)piperidin-4- (4-(2-(4-(2-methyl-1-piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of tert-butyl 4-((3-(hydroxymethyl)phenoxy)methyl)piperidine-1-carboxylate

3-(Hydroxymethyl)phenol (0.500 g, 4.028 mmol), tert-butyl 4-((methylsulfonyloxy)methyl)piperidine-1-carboxylate (Formula 12-1, 1.300 g, 4.430 mmol), Cs ₂ CO ₃ (1.968 g, 6.042 mmol), and NaI (0.030 g, 0.201 mmol) were mixed in acetonitrile (50 mL) at room temperature and heated under reflux for 5 hours, then cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 12 g cartridge; ethyl acetate/hexane = 10% to 60%) and concentrated to obtain the desired compound (0.790 g, 61.0%) as a colorless oil.

Step 2: Synthesis of tert-butyl 4-((3-(hydroxymethyl)phenoxy)methyl)piperidine-1-carboxylate

tert-Butyl 4-((3-(hydroxymethyl)phenoxy)methyl)piperidine-1-carboxylate (Formula 12-2, 0.500 g, 1.556 mmol) and TEA (0.434 mL, 3.111 mmol) were mixed in dichloromethane (50 mL) at 0°C, and MsCl (0.132 mL, 1.711 mmol) was added to the mixture. Next, the mixture was stirred at the same temperature for 1 hour, and then at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 40%) to give the desired compound (0.204 g, 38.6%) as a colorless oil.

Step 3: Synthesis of 4-((3-(((2S,6R)-4-(4-(methoxycarbonyl)benzyl)-2,6-dimethylpiperazin-1-yl) tert-Butyl (methyl)phenoxy)methyl)piperidine-1-carboxylate

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.150 g, 0.572 mmol), tert-butyl 4-((3-(chloromethyl)phenoxy)methyl)piperidine-1-carboxylate (Formula 12-3, 0.194 g, 0.572 mmol), and Cs ₂ CO ₃ (0.279 g, 0.858 mmol) were mixed in acetonitrile (10 mL) at room temperature, and the mixture was heated under reflux for 5 hours and then cooled to room temperature. Water was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 10% to 70%) and concentrated to obtain the desired compound (0.181 g, 56.0%) as a light yellow oil.

Step 4: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(3-(piperidin-4-ylmethoxy)benzyl)piperazine-1-yl)- methyl)benzoate

Tert-butyl 4-((3-(((2S,6R)-4-(4-(methoxycarbonyl)benzyl)-2,6-dimethylpiperazin-1-yl)methyl)phenoxy)methyl)piperidine-1-carboxylate (Formula 12-4, 0.180 g, 0.318 mmol) was added to 1,4-dioxane (5 mL) at room temperature, and HCl (4.00 M 1,4-dioxane solution, 0.795 mL, 3.182 mmol) was added to the mixture, which was then stirred at the same temperature for 17 hours. Saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The product was used without additional purification (0.141 g, 95.2%, light yellow oil).

Step 5: Synthesis of 4-(((3R,5S)-4-(3-((1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)methoxy)benzyl ethyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate

Ethanol (4 mL) was added to a mixture of methyl 4-(((3R,5S)-3,5-dimethyl-4-(3-(piperidin-4-ylmethoxy)benzyl)piperazin-1-yl)methyl)benzoate (Formula 12-5, 0.150 g, 0.322 mmol), 2,2-dimethyloxirane (0.044 mL, 0.483 mmol), and K ₂ CO ₃ (0.089 g, 0.644 mmol), and the mixture was heated at 110° C. for 20 minutes under microwave irradiation, followed by cooling to room temperature. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to give the desired compound (0.091 g, 52.5%) as a colorless oil.

Step 6: Synthesis of 4-(((3R,5S)-4-(3-((1-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)benzyl ethyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate

Ethyl 4-(((3R,5S)-4-(3-((1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)methoxy)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 12-6, 0.090 g, 0.163 mmol) was dissolved in dichloromethane (5 mL), and DAST (0.029 g, 0.179 mmol) was added thereto at 0°C. The mixture was stirred at the same temperature for 30 minutes and then at room temperature for 1 hour. Then, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 8 g cartridge; ethyl acetate/hexane = from 0% to 50%) and concentrated to give the desired compound (0.088 g, 97.4%) as a light brown oil.

Step 7: Synthesis of Compound 380

4-(((3R,5S)-4-(3-((1-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoic acid ethyl ester (Formula 12-7, 0.088 g, 0.159 mmol), hydroxylamine (0.097 mL, 1.589 mmol, 50.00% aqueous solution) and potassium hydroxide (0.207 g, 3.178 mmol) were dissolved in methanol (10 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 380 (0.027 g, 31.4%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.70 (d, 2H, J=8.1Hz), 7.34 (d, 2H, J=8.1Hz), 7.18 (dd, 1H, J=8.0, 8.0Hz), 6.91-6.89 (m, 2H), 6.7 3 (d, 1H, J = 8.5Hz), 3.78 (d, 2H, J = 5.4Hz), 3.68 (s, 2H), 3.51 (s, 2H), 2.91 (d, 2H, J = 11.3Hz), 2.64 (d , 2H, J=10.8Hz), 2.58-2.56 (m, 2H), 2.41 (d, 2H, J=22.9Hz), 2.07 (t, 2H, J=10.8Hz), 1.81 (t, 2H, J=1 0.6Hz), 1.71 (d, 3H, J=11.5Hz), 1.33 (s, 3H), 1.28-1.24 (m, 5H), 0.89 (d, 6H, J=6.0Hz); LRMS (ES) m/z 541.3(M ⁺ +1).

Example 171: Synthesis of Compound 382 (4-(((3R,5S)-3,5-dimethyl-4-(3-(piperidin-1-ylmethyl)benzyl) (4-(2-methyl-1-piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(3-(piperidin-1-ylmethyl)benzyl)piperazin-1-yl) Methyl)benzoate

Methyl 4-(((3R,5S)-4-(3-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.150 g, 0.394 mmol) and piperidine (0.038 mL, 0.434 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 30 minutes. Na(OAc) _3BH (0.125 g, 0.591 mmol) was added to the reaction solution, followed by stirring at the same temperature for 17 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = 0% to 10%) and concentrated to obtain the desired compound (0.095 g, 53.6%) as a light yellow oil.

Step 2: Synthesis of compound 382

4-(((3R, 5S)-3,5-dimethyl-4-(3-(piperidin-1-ylmethyl)benzyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 5-2, 0.044g, 0.098mmol), hydroxylamine (0.060mL, 0.979mmol, 50.00% aqueous solution) and potassium hydroxide (0.127g, 1.957mmol) were dissolved in methanol (3mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution was added to the concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to obtain compound 382 (0.037g, 83.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.68 (d, 2H, J=8.2Hz), 7.30-7.28 (m, 3H), 7.22-7.20 (m, 2H), 7.08 (d, 1H, J=6.2Hz), 3.72 (s, 2H), 3.41 (s, 2H), 3.40 (s, 2H), 2.65-2.62 ( m, 2H), 2.58-2.53 (m, 2H), 2.29 (s, 4H), 1.80 (t, 2H, J=10.7Hz), 1.49-1.46 (m, 4H), 1.40-1.38 (m, 2H), 0.90 (d, 6H, J=6.1Hz); LRMS (ES) m/z 451.2(M ⁺⁺ 1).

Example 172: Synthesis of Compound 383 (4-(((3R,5S)-4-(3-(((R)-3-fluoropyrrolidin-1-yl)methyl) (Benzyl)-3,5-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-(((R)-3-fluoropyrrolidin-1-yl)methyl)benzyl)-3,5-dimethyl methyl)benzoate

Methyl 4-(((3R,5S)-4-(3-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.150 g, 0.394 mmol) and (R)-3-fluoropyrrolidine hydrochloride (0.054 g, 0.434 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 30 minutes. Na(OAc) _3BH (0.125 g, 0.591 mmol) was added to the reaction solution, which was then stirred at the same temperature for 17 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to give the desired compound (0.120 g, 67.1%) as a light yellow oil.

Step 2: Synthesis of compound 383

Methyl 4-(((3R,5S)-4-(3-(((R)-3-fluoropyrrolidin-1-yl)methyl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-2, 0.060 g, 0.132 mmol), hydroxylamine (0.081 mL, 1.323 mmol, 50.00% aqueous solution) and potassium hydroxide (0.172 g, 2.646 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 383 (0.048 g, 79.8%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.58 (brs, 1H), 7.67 (d, 2H, J=8.0Hz), 7.28-7.17 (m, 5H), 7.11 (s, 1H), 5.18 (d, 1H, J=55.7Hz), 3.72 (s, 2H), 3.39 (s, 2H), 2.80-2.71 ( m, 2H), 2.64 (d, 2H, J=10.5Hz), 2.60-2.55 (m, 2H), 2.31-2.27 (m, 1H), 2.17-1.89 (m, 2H), 1.79 (t, 2H, J=10.4Hz), 0.89 (d, 6H, J=5.9Hz).

Example 173: Synthesis of Compound 384 (4-(((3R,5S)-4-(3-((3,3-difluoroazetidin-1-yl)methane 1-(4-(4-(4-(4-methyl)piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-((3,3-difluoroazetidin-1-yl)methyl)benzyl)-3,5- Methyl dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((3R,5S)-4-(3-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.150 g, 0.394 mmol) and 3,3-difluoroazetidine hydrochloride (0.056 g, 0.434 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 30 minutes. Na(OAc) _3BH (0.125 g, 0.591 mmol) was added to the reaction solution, which was then stirred at the same temperature for 17 hours. Saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to give the desired compound (0.131 g, 72.6%) as a light yellow oil.

Step 2: Synthesis of compound 384

4-(((3R,5S)-4-(3-((3,3-difluoroazetidine-1-yl)methyl)benzyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 5-2, 0.058g, 0.127mmol), hydroxylamine (0.078mL, 1.268mmol, 50.00% aqueous solution) and potassium hydroxide (0.165g, 2.535mmol) were dissolved in methanol (3mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution was added to the obtained concentrate, followed by extraction with ethyl acetate. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 384 (0.037g, 63.7%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.69 (d, 2H, J=8.2Hz), 7.32 (d, 2H, J=8.2Hz), 7.27-7.24 (m, 3H), 7.11-7.10 (m, 1H), 3.72 (s, 2H), 3.70 (s, 2H), 3.58 (t, 4H, J=1 2.5Hz), 3.43 (s, 2H), 2.65-2.63 (m, 2H), 2.59-2.53 (m, 2H), 1.81 (t, 2H, J=10.6Hz), 0.89 (d, 6H, J=6.1Hz); LRMS (ES) m/z459.2 (M ⁺ +1).

Example 174: Synthesis of Compound 385 (4-(((3R,5S)-4-(3-((4-benzylpiperazin-1-yl)methyl) ... 1-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-((4-benzylpiperazin-1-yl)methyl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzyl)-3,5-dimethylpiperazin-1-yl (methyl)benzoate

Methyl 4-(((3R,5S)-4-(3-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.150 g, 0.394 mmol) and 1-benzylpiperazine (0.076 g, 0.434 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 30 minutes. Na(OAc) _3BH (0.125 g, 0.591 mmol) was added to the reaction solution, which was then stirred at the same temperature for 17 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to obtain the desired compound (0.158 g, 74.1%) as a light yellow oil.

Step 2: Synthesis of compound 385

Methyl 4-(((3R,5S)-4-(3-((4-benzylpiperazine-1-yl)methyl)benzyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 5-2, 0.095 g, 0.176 mmol), hydroxylamine (0.107 mL, 1.757 mmol, 50.00% aqueous solution) and potassium hydroxide (0.229 g, 3.514 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 385 (0.084 g, 88.3%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.67(d, 2H, J=8.2Hz), 7.33-7.22(m, 10H), 7.09-7.07(m, 1H), 3.71(s, 2H), 3.45(s, 2H), 3.44(s, 2H), 3.40(s, 2H), 2.6 5-2.62 (m, 2H), 2.56-2.52 (m, 2H), 2.37-2.34 (m, 8H), 1.79 (t, 2H, J=10.5Hz), 0.89 (d, 6H, J=5.9Hz); LRMS (ES) m/z542.3 (M ⁺ +1).

Example 175: Synthesis of Compound 386 (N-hydroxy-4-(((3R,5S)-4-(3-((4-(2-hydroxy-2-methylpropane) 1-yl)piperazin-1-yl)methyl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzamide)

Step 1: Synthesis of 4-(3-(((2S,6R)-4-(4-(methoxycarbonyl)benzyl)-2,6-dimethylpiperazin-1-yl) tert-Butyl)methyl)benzyl)piperazine-1-carboxylate

Methyl 4-(((3R,5S)-4-(3-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.500 g, 1.314 mmol) and tert-butyl piperazine-1-carboxylate (0.269 g, 1.446 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 30 minutes. Na(OAc) _3BH (0.418 g, 1.971 mmol) was added to the reaction solution, which was then stirred at the same temperature for 17 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to give the desired compound (0.303 g, 41.9%) as a yellow oil.

Step 2: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(3-(piperazin-1-ylmethyl)benzyl)piperazin-1-yl) Methyl)benzoate

Tert-butyl 4-(3-(((2S,6R)-4-(4-(methoxycarbonyl)benzyl)-2,6-dimethylpiperazin-1-yl)methyl)benzyl)piperazine-1-carboxylate (Formula 7-1, 0.303 g, 0.550 mmol) was dissolved in 1,4-dioxane (5 mL) at room temperature, and HCl (4.00 M 1,4-dioxane solution, 1.375 mL, 5.502 mmol) was added to the solution, which was then stirred at the same temperature for 17 hours. Saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The product was used without additional purification (0.235 g, 94.8%, yellow oil).

Step 3: Synthesis of 4-(((3R,5S)-4-(3-((4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)methyl)benzyl ethyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((3R,5S)-3,5-dimethyl-4-(3-(piperazin-1-ylmethyl)benzyl)piperazin-1-yl)methyl)benzoate (Formula 7-2, 0.190 g, 0.422 mmol), methylpropylene oxide (0.380 mL, 4.216 mmol), and K ₂ CO ₃ (0.583 g, 4.216 mmol) were added to ethanol (5 mL) and heated at 110° C. for 20 minutes under microwave irradiation, followed by cooling to room temperature to terminate the reaction. Saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The product was used without additional purification (0.196 g, 84.2%, yellow oil).

Step 4: Synthesis of Compound 386

4-(((3R,5S)-4-(3-((4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)methyl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoic acid ethyl ester (Formula 7-3, 0.050 g, 0.093 mmol), hydroxylamine (0.057 mL, 0.932 mmol, 50.00% aqueous solution) and potassium hydroxide (0.121 g, 1.863 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 386 (0.032 g, 65.6%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.17 (brs, 1H) 9.01 (brs, 1H) 7.70 (d, 2H, J = 8.0Hz), 7.34 (d, 2H, J = 7.8Hz), 7.27 (s, 1H), 7.23-7.21 (m, 1H), 7. 09 (d, 1H, J = 6.6Hz), 4.06 (brs, 1H) 3.72 (s, 2H), 3.43 (s, 2H), 3.42 (s, 2H), 2.65-2.62 (m, 2H), 2.55-2.54 (m, 2H).

Example 176: Synthesis of Compound 387 (4-(((3R,5S)-4-(3-((4-(2-fluoro-2-methylpropyl)piperazine-1- (4-(2-(4-(2-methyl-1-piperazin-1-yl)methyl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-((4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)methyl)benzyl ethyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate

Ethyl 4-(((3R,5S)-4-(3-((4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)methyl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 7-3, 0.150 g, 0.287 mmol) was dissolved in dichloromethane (5 mL), and DAST (0.042 mL, 0.316 mmol) was added thereto at 0°C. The mixture was stirred at the same temperature for 30 minutes and then at room temperature for 1 hour. Then, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 12 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to give the desired compound (0.098 g, 63.4%) as a yellow oil.

Step 2: Synthesis of compound 387

Ethyl 4-(((3R,5S)-4-(3-((4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)methyl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 7-4, 0.098 g, 0.177 mmol), hydroxylamine (0.108 mL, 1.770 mmol, 50.00% aqueous solution) and potassium hydroxide (0.230 g, 3.540 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was filtered through a plastic filter equipped with an anhydrous sodium sulfate cartridge to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 387 (0.089 g, 93.0%) as an apricot yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.68 (d, 2H, J=7.9Hz), 7.29 (d, 3H, J=7.7Hz), 7.23-7.21 (m, 2H), 7.09-7.08 (m, 1H), 3.72 (s, 2H), 3.43 (s, 2H), 3.41 (s, 2H), 2.65-2.62 (m, 2H), 2.56-2.54 (m, 2H), 2.47-2.43 (m, 4H), 2.40 (d, 2H, J=23.3Hz), 2.35-2.33 (m, 4H), 1.80 (t , 2H, J=10.4Hz), 1.32 (s, 3H), 1.26 (s, 3H), 0.90 (d, 6H, J=6.0Hz); LRMS (ES) m/z 526.3(M ⁺ +1).

Example 177: Synthesis of Compound 388 (4-(((3R,5S)-4-(4-((1-(2-fluoro-2-methylpropyl)piperidin-4- (methyl)-N-hydroxybenzamide

Step 1: Synthesis of tert-butyl 4-((4-(hydroxymethyl)phenoxy)methyl)piperidine-1-carboxylate

4-(Hydroxymethyl)phenol (0.500 g, 4.028 mmol), tert-butyl 4-((methylsulfonyloxy)methyl)piperidine-1-carboxylate (Formula 12-1, 1.300 g, 4.430 mmol), Cs ₂ CO ₃ (1.968 g, 6.042 mmol), and NaI (0.030 g, 0.201 mmol) were mixed in acetonitrile (20 mL) at room temperature, and the mixture was heated under reflux for 17 hours. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 50%) and concentrated to obtain the desired compound (0.552 g, 42.6%) as a colorless oil.

Step 2: Synthesis of tert-butyl 4-((4-(chloromethyl)phenoxy)methyl)piperidine-1-carboxylate

tert-Butyl 4-((4-(hydroxymethyl)phenoxy)methyl)piperidine-1-carboxylate (Formula 12-2, 0.500 g, 1.556 mmol) and TEA (0.434 mL, 3.111 mmol) were dissolved in dichloromethane (30 mL) at 0°C, and methanesulfonyl chloride (0.132 mL, 1.711 mmol) was added to the solution, followed by stirring at the same temperature for 2 hours. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 40%) and concentrated to give the desired compound (0.136 g, 25.7%) as a white solid.

Step 3: Synthesis of 4-((4-(((2S,6R)-4-(4-(methoxycarbonyl)benzyl)-2,6-dimethylpiperazin-1-yl) tert-Butyl (methyl)phenoxy)methyl)piperidine-1-carboxylate

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol), tert-butyl 4-((4-(chloromethyl)phenoxy)methyl)piperidine-1-carboxylate (Formula 12-3, 0.130 g, 0.381 mmol), Cs ₂ CO ₃ (0.186 g, 0.572 mmol), and NaI (0.003 g, 0.019 mmol) were mixed in acetonitrile (5 mL) at room temperature, and the mixture was heated under reflux for 3 hours and then cooled to room temperature. Water was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 10% to 60%) and concentrated to give the desired compound (0.130 g, 60.3%) as a yellow oil.

Step 4: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(4-(piperidin-4-ylmethoxy)benzyl)piperazine-1-yl)- Methyl)benzoate (hydrochloride)

Tert-butyl 4-((4-(((2S,6R)-4-(4-(methoxycarbonyl)benzyl)-2,6-dimethylpiperazin-1-yl)methyl)phenoxy)methyl)piperidine-1-carboxylate (Formula 12-4, 0.150 g, 0.265 mmol) was dissolved in 1,4-dioxane (5 mL) at room temperature, and HCl (4.00 M solution in 1,4-dioxane, 1.326 mL, 5.303 mmol) was added to the solution, followed by stirring at the same temperature for 17 hours. The precipitated solid was washed with diethyl ether and dried to give the desired compound (0.126 g, 94.6%) as a white solid.

Step 5: Synthesis of 4-(((3R,5S)-4-(4-((1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)methoxy)benzyl ethyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((3R,5S)-3,5-dimethyl-4-(4-(piperidin-4-ylmethoxy)benzyl)piperazin-1-yl)methyl)benzoate hydrochloride (Formula 12-5, 0.102 g, 0.203 mmol), 1,1-dimethyloxirane (0.073 g, 1.016 mmol), and K ₂ CO ₃ (0.281 g, 2.032 mmol) were added to ethanol (3 mL) and heated at 110° C. for 20 minutes under microwave irradiation, followed by cooling to room temperature. Saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The product was used without additional purification (0.102 g, 93.4%, pale yellow oil).

Step 6: Synthesis of 4-(((3R,5S)-4-(4-((1-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)benzyl ethyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate

4-(((3R, 5S)-4-(4-((1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)methoxy)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoic acid ethyl ester (Formula 12-6, 0.102 g, 0.185 mmol) was dissolved in dichloromethane (5 mL) and DAST (0.027 mL, 0.203 mmol) was added thereto at 0°C. The mixture was stirred at the same temperature for 30 minutes and then at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The product was used without additional purification (0.083 g, 81.1%, light brown oil).

Step 7: Synthesis of Compound 388

4-(((3R,5S)-4-(4-((1-(2-fluoro-2-methylpropyl)piperidin-4-yl)methoxy)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoic acid ethyl ester (Formula 12-7, 0.083 g, 0.150 mmol), hydroxylamine (0.092 mL, 1.499 mmol, 50.00% aqueous solution) and potassium hydroxide (0.195 g, 2.998 mmol) were dissolved in methanol (5 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 388 (0.073 g, 90.1%) as an apricot yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.68 (d, 2H, J = 8.2Hz), 7.29 (d, 2H, J = 8.1Hz), 7.21 (d, 2H, J = 8.6Hz), 6.84 (d, 2H, J =8.6Hz), 3.77 (d, 2H, J = 5.9Hz), 3.68 (s, 2H), 3.40 (s, 2H), 2.91 (d, 2H, J = 11.5Hz), 2. 62 (d, 2H, J = 9.8Hz), 2.55-2.53 (m, 2H), 2.41 (d, 2H, J = 22.9Hz), 2.08 (t, 2H, J = 10.8H z), 1.81-1.69 (m, 6H), 1.33 (s, 3H), 1.29 (s, 4H), 0.92 (d, 6H, J=6.1Hz); LRMS (ES) m/z 541.3(M ⁺ +1).

Example 178: Synthesis of Compound 396 (4-(((2S,6R)-4-(3-(furan-3-yl)benzyl)-2,6-dimethyl (piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(3-(furan-3-yl)benzyl)-2,6-dimethylpiperazin-1-yl)methyl) Methyl benzoate

1,2-Dimethoxyethane (1 ml) / water (0.5 ml) was added to a mixture of methyl 4-(((2S,6R)-4-(3-iodobenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 14-1, 0.100 g, 0.209 mmol), furan-3-ylboronic acid (0.028 g, 0.251 mmol), Pd(dbpf)Cl ₂ (0.007 g, 0.010 mmol) and Na ₂ CO ₃ (0.066 g, 0.627 mmol), and the solution was heated at 120° C. for 20 minutes by microwave, then filtered through celite and concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 12 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to give the desired compound (0.051 g, 58.3%) as a white solid.

Step 2: Synthesis of compound 396

At room temperature, 4-(((2S, 6R)-4-(3-(furan-3-yl)benzyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 14-2, 0.030g, 0.072mmol), hydroxylamine (0.088mL, 1.434mmol, 50.00% aqueous solution) and potassium hydroxide (0.040g, 0.717mmol) mixture was added to methanol (0.5mL), and the mixture was stirred at the same temperature for 1 hour. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain compound 396 (0.020g, 66.5%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.18 (s, 1H), 7.73 (s, 1H), 7.64 (d, 2H, J = 8.0Hz), 7.49-7.47 (m, 2H), 7.34-7.18 (m, 4H), 6.94 (d, 1H, J = 0.96Hz) ), 3.72 (s, 2H), 3.41 (s, 2H), 2.68-2.65 (m, 2H), 2.55-2.51 (m, 2H), 1.84-1.79 (m, 2H), 0.91 (s, 3H), 0.89 (s, 3H).

Example 179: Synthesis of Compound 400 (4-(((2S,6R)-4-((4′,4′-dimethyl-2′,3′,4′,5′-tetramethyl (H-[1,1′-biphenyl]-4-yl)methyl)-2,6-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-((4′,4′-dimethyl-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]- methyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate

1,2-Dimethoxyethane (1 ml) / water (0.5 ml) was added to a mixture of methyl 4-(((2S,6R)-4-(4-iodobenzyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 14-1, 0.100 g, 0.209 mmol), (4,4-dimethylcyclohex-1-en-1-yl)boronic acid (0.038 g, 0.251 mmol), Pd(dbpf)Cl ₂ (0.007 g, 0.010 mmol) and Na ₂ CO ₃ (0.066 g, 0.627 mmol), and the solution was heated at 120° C. for 20 minutes by microwave, after which it was filtered through celite and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 12 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to give the desired compound (0.05 g, 51.9%) as a light brown solid.

Step 2: Synthesis of Compound 400

At room temperature, a mixture of 4-(((2S, 6R)-4-((4′, 4′-dimethyl-2′, 3′, 4′, 5′-tetrahydro-[1,1′-biphenyl]-4-yl)methyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 14-3, 0.030 g, 0.065 mmol), hydroxylamine (0.080 mL, 1.303 mmol, 50.00% aqueous solution) and potassium hydroxide (0.037 g, 0.651 mmol) was added to methanol (0.5 mL) and the mixture was stirred at the same temperature for 1 hour. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give compound 400 (0.023 g, 76.5%) as a light yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.64 (d, 2H, J=7.9Hz), 7.36 (d, 2H, J=8.1Hz), 7.24-7.20 (m, 4H), 6.09 (brs, 1H), 3.71 (s, 2H), 2.64- 2.51 (m, 4H), 2.37 (brs, 2H), 1.97 (brs, 2H), 1.80-1.75 (m, 2H), 1.49-1.46 (m, 2H), 0.93-0.89 (m, 12H).

Example 180: Synthesis of Compound 401 (4-(((2S,6R)-4-(4-(3,6-dihydro-2H-pyran-4-yl)benzyl) 1-(2,6-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((2S,6R)-4-(4-(3,6-dihydro-2H-pyran-4-yl)benzyl)-2,6-dimethylpiperidin (methyl)benzoate

1,2-Dimethoxyethane (1 ml) / water (0.5 ml) was added to a mixture of methyl 4-(((2S,6R)-4-(4-iodobenzyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 14-1, 0.100 g, 0.209 mmol), (3,6-dihydro-2H-pyran-4-yl)boronic acid (0.032 g, 0.251 mmol), Pd(dbpf) _Cl2 (0.007 g, 0.010 mmol) and _{Na2CO3 (} 0.066 g, 0.627 mmol), followed by heating at 120°C for 20 minutes by microwave. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 12 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to give the desired compound (0.029 g, 31.9%) as a light brown solid.

Step 2: Synthesis of Compound 401

At room temperature, a mixture of 4-(((2S, 6R)-4-(4-(3,6-dihydro-2H-pyran-4-yl)benzyl)-2,6-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 14-2, 0.025 g, 0.058 mmol), hydroxylamine (0.070 mL, 1.151 mmol, 50.00% aqueous solution) and potassium hydroxide (0.032 g, 0.575 mmol) was added to methanol (0.5 mL) and the mixture was stirred at the same temperature for 1 hour. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium bicarbonate aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give compound 401 (0.011 g, 43.9%) as a light yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.66 (d, 2H, J=8.12Hz), 7.40-7.36 (m, 4H), 7.25 (d, 2H, J=8.12Hz), 6.23 (brs, 1H), 4.21 (s, 2H), 3.81 (t, 2H, J=5. 3Hz), 3.73(s, 2H), 3.39(s, 2H), 2.66-2.54(m, 4H), 2.47-2.43(m, 2H), 1.82-1.76(m, 2H), 0.88(s, 3H), 0.87(s, 3H).

Example 181: Synthesis of Compound 402 (4-(((3R,5S)-3,5-dimethyl-4-(tetrahydrofuran-2-carbonyl)piperidin ((1-oxazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of tert-butyl (3R,5S)-4-(furan-2-carbonyl)-3,5-dimethylpiperazine-1-carboxylate

(3R, 5S)-tert-butyl 3,5-dimethylpiperazine-1-carboxylic acid (Formula 8-1, 0.500 g, 2.333 mmol), furan-2-carbonyl chloride (0.276 mL, 2.800 mmol) and TEA (0.976 mL, 7.000 mmol) were dissolved in dichloromethane (10 mL) at 0°C, and the solution was stirred at the same temperature for 1 hour. Then, water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 12 g cartridge; ethyl acetate/hexane = from 0% to 30%) and concentrated to obtain the desired compound (0.620 g, 86.2%) as a colorless oil.

Step 2: Synthesis of tert-butyl (3R..5S)-3,5-dimethyl-4-(tetrahydrofuran-2-carbonyl)piperazine-1-carboxylate

At room temperature, (3R, 5S) -4- (furan-2-carbonyl) -3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (Formula 11-1, 0.100 g, 0.324 mmol) was dissolved in ethanol / water (8: 1) (2 mL), and Pd / C (0.010 g) was slowly added thereto. Then, a hydrogen balloon was placed above the solution, followed by stirring at the same temperature for 2 hours. The reaction mixture was filtered through a celite pad to remove solids, and the filtrate was concentrated under reduced pressure to remove the solvent. The product was used without additional purification (0.100 g, 98.7%, colorless oil).

Step 3: Synthesis of ((2S,6R)-2,6-dimethylpiperazin-1-yl)(tetrahydrofuran-2-yl)methanone (hydrochloride)

At room temperature, (3R, 5S) -3,5-dimethyl-4- (tetrahydrofuran-2-carbonyl) piperazine-1-carboxylic acid tert-butyl ester (Formula 11-2, 0.540 g, 1.729 mmol) and HCl (4.00M 1,4-dioxane solution, 8.643 mL, 34.571 mmol) were dissolved in 1,4-dioxane (20 mL), and the solution was stirred at the same temperature for 17 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the product was used without additional purification (0.400 g, 109.0%, colorless oil).

Step 4: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)methyl)benzene Methyl formate

((2S,6R)-2,6-Dimethylpiperazin-1-yl)(tetrahydrofuran-2-yl)methanone hydrochloride (Formula 11-3, 0.400 g, 1.608 mmol), _methyl 4-(bromomethyl)benzoate (Formula 1-1, 0.368 g, 1.608 mmol), and _Cs2CO3 (1.572 g, 4.824 mmol) were dissolved in acetonitrile (15 mL) at room temperature, and the solution was stirred at the same temperature for 17 hours. The reaction mixture was filtered through a glass filter to remove solids, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 12 g cartridge; ethyl acetate/hexane = 0% to 40%) and concentrated to obtain the desired compound (0.196 g, 33.8%) as a colorless oil.

Step 5: Synthesis of Compound 402

Methyl 4-(((3R,5S)-3,5-dimethyl-4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)methyl)benzoate (0.140 g, 0.388 mmol), hydroxylamine (0.238 mL, 3.884 mmol, 50.00% aqueous solution) and potassium hydroxide (0.436 g, 7.768 mmol) were dissolved in methanol (4 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, then concentrated under reduced pressure to afford compound 402 (0.067 g, 47.7%) as an apricot-yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.10 (brs, 1H) 9.00 (brs, 1H) 7.73 (d, 2H, J = 8.1Hz), 7.43 (d, 2H, J = 8.0Hz), 4.63-4.56 (m, 1H), 4.37-4.35 (m, 2H), 3.75-3.72 ( m, 2H), 3.35 (s, 2H), 2.65-2.62 (m, 2H), 2.11-2.09 (m, 3H), 1.88-1.80 (m, 3H), 1.35-1.21 (m, 6H), 1.35-1.21 (m, 6H); LRMS (ES) m/z 362.1(M ⁺ +1).

Example 182: Synthesis of Compound 403 (4-(((3R,5S)-3,5-dimethyl-4-(1H-pyrazole-3-carbonyl)piperidin ((1-oxazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(1H-pyrazole-3-carbonyl)piperazin-1-yl)methyl)benzene Methyl formate

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol), 1H-pyrazole-3-carboxylic acid (0.047 g, 0.419 mmol), HATU (0.290 g, 0.762 mmol) and DIPEA (0.333 mL, 1.906 mmol) were dissolved in N,N-dimethylformamide (3 mL) at room temperature, and the solution was stirred at the same temperature for 17 hours. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The product was used without additional purification (0.150 g, 110.4%, yellow oil).

Step 2: Synthesis of compound 403

At room temperature, 4-(((3R, 5S)-3,5-dimethyl-4-(1H-pyrazole-3-carbonyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 1-3, 0.150g, 0.421mmol), hydroxylamine (0.257mL, 4.209mmol, 50.00% aqueous solution) and potassium hydroxide (0.472g, 8.417mmol) were dissolved in methanol (4mL), and the solution was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution (20mL) and dichloromethane (10mL) were added to the concentrate, followed by stirring. The precipitated solid was filtered, washed with water, and dried to give compound 403 (0.046g, 30.6%) as a white solid.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ13.12 (brs, 1H), 11.19 (brs, 1H), 3.02 (brs 1H), 7.79 (s, 1H), 7.73 (d, 2H, J=8.2Hz), 7.45 (d, 2H, J=8.3Hz), 6.54 (d, 1H, J=2.0Hz), 4.69 (br s, 1H), 3.55 (s, 2H), 2.68-2.65 (m, 2H), 2.16-2.12 (m, 2H), 1.35 (d, 6H, J=6.7Hz); LRMS (ES) m/z 358.2(M ⁺ +1).

Example 183: Synthesis of Compound 404 (4-(((3R,5S)-3,5-dimethyl-4-(pyrazine-2-carbonyl)piperazine-1- (4-(2-Methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(pyrazine-2-carbonyl)piperazin-1-yl)methyl)benzoic acid Methyl ester

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol), pyrazine-2-carboxylic acid (0.052 g, 0.419 mmol), HATU (0.290 g, 0.762 mmol) and DIPEA (0.333 mL, 1.906 mmol) were dissolved in N,N-dimethylformamide (3 mL) at room temperature, and the solution was stirred at the same temperature for 17 hours. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The product was used without additional purification (0.150 g, 106.8%, brown oil).

Step 2: Synthesis of compound 404

Methyl 4-(((3R, 5S)-3,5-dimethyl-4-(pyrazine-2-carbonyl)piperazine-1-yl)methyl)benzoate (Formula 1-3, 0.150 g, 0.408 mmol), hydroxylamine (0.250 mL, 4.082 mmol, 50.00% aqueous solution) and potassium hydroxide (0.458 g, 8.165 mmol) were dissolved in methanol (4 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (Waters, _C18 ; 0.1% aqueous trifluoroacetic acid/acetonitrile = from 5% to 80%), after which it was passed through an SPE cartridge (PL- _HCO3 MP SPE) and concentrated to give compound 404 (0.043 g, 28.6%) as a white solid.

¹ H-NMR (400MHz, CD ₃ OD) δ 8.85 (d, 1H, J = 1.5Hz), 8.75 (d, 1H, J = 2.5Hz), 8.65 (dd, 1H, J = 2.6, 1.6Hz), 7.82 (d, 2H, J = 8.2Hz), 7 .60 (d, 2H, J = 8.2Hz), 4.10 (brs, 2H), 3.18 (brs, 2H), 2.85 (brs, 2H), 1.52 (d, 6H, J = 7.1Hz); LRMS (ES) m/z 370.1(M ⁺ +1).

Example 184: Synthesis of Compound 405 (N-hydroxy-4-(((3R,5S)-4-isonicotinoyl-3,5-dimethylpiperazine- 1-amino)methyl)benzamide)

Step 1: Synthesis of methyl 4-(((3R,5S)-4-isonicotinoyl-3,5-dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 1-2, 0.100 g, 0.381 mmol) and TEA (0.159 mL, 1.144 mmol) were dissolved in dichloromethane (4 mL) at room temperature, and isonicotinoyl chloride (0.081 g, 0.572 mmol) was added to the solution, followed by stirring at the same temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The product was used without additional purification (0.150 g, 107.1%, light yellow oil).

Step 2: Synthesis of compound 405

Methyl 4-(((3R,5S)-4-isonicotinoyl-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-3, 0.150 g, 0.408 mmol), hydroxylamine (0.250 mL, 4.082 mmol, 50.00% aqueous solution), and potassium hydroxide (0.458 g, 8.165 mmol) were dissolved in methanol (4 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (Waters, _C18 ; 0.1% aqueous trifluoroacetic acid/acetonitrile = from 5% to 80%), after which it was passed through an SPE cartridge (PL- _HCO3 MP SPE) and concentrated to give compound 405 (0.043 g, 28.6%) as a white solid.

¹ H NMR (400MHz, CD ₃ OD) δ8.73 (d, 2H, J = 6.2Hz), 7.79 (d, 2H, J = 8.2Hz), 7.60-7.55 (m, 4H), 3.89 (brs, 2H), 2.96 (brs, 2H), 2.61 (brs, 2H), 1.45 (d, 6H, J=6.0Hz); LRMS (ES) m/z369.1 (M ⁺ +1).

Example 185: Synthesis of Compound 411 (4-(((3R,5S)-4-(4-(((R)-3-fluoropyrrolidin-1-yl)methyl) (Benzyl)-3,5-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(4-(((R)-3-fluoropyrrolidin-1-yl)methyl)benzyl)-3,5-dimethyl methyl)benzoate

Methyl 4-(((3R,5S)-4-(4-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.100 g, 0.263 mmol) was dissolved in dichloromethane (1 mL) at room temperature, and (R)-3-fluoropyrrolidine (0.036 g, 0.289 mmol) was added to the mixture, followed by stirring for 30 minutes. Na(OAc) _3BH (0.061 g, 0.289 mmol) was added to the mixture, which was then stirred at the same temperature overnight. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to obtain the desired compound (0.059 g, 49.7%) as a light brown solid.

Step 2: Synthesis of compound 411

By 4-(((3R, 5S)-4-(4-(((R)-3-fluoropyrrolidin-1-yl)methyl)benzyl)-3,5-dimethylpiperazine-1-yl)methyl)methylbenzoate (formula 5-2,0.059g, 0.130mmol), hydroxylamine (0.159mL, 2.601mmol, 50.00% aqueous solution) and potassium hydroxide (0.073g, 1.301mmol) are dissolved in methanol (1mL) at room temperature, and the solution is stirred at the same temperature for 2 hours.Then, the reaction mixture is concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution (10mL) is added to the enriched material, then stirred.The precipitated solid is filtered, washed with water, and dried to obtain compound 411 (0.011g, 17.8%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.67(d, 1H, J=11.2Hz), 7.43-7.20(m, 6H), 5.25-5.11(m, 1H), 3.72(s, 2H), 3.55(s, 2H) , 3.43 (s, 2H), 2.81-2.53 (m, 7H), 2.35-2.08 (m, 2H), 1.90-1.78 (m, 3H), 0.91-0.89 (m, 6H).

Example 186: Synthesis of Compound 412 (4-(((3R,5S)-4-(4-((3,3-difluoroazetidin-1-yl)methane 1-(4-(4-(4-(4-methyl)piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(4-((3,3-difluoroazetidin-1-yl)methyl)benzyl)-3,5- Methyl dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((3R,5S)-4-(4-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.100 g, 0.263 mmol) was dissolved in dichloromethane (1 mL) at room temperature, and 3,3-difluoroazetidine (0.037 g, 0.289 mmol) was added to the mixture, followed by stirring for 30 minutes. Na(OAc) _3BH (0.061 g, 0.289 mmol) was added to the reaction mixture, which was stirred at the same temperature overnight. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to give the desired compound (0.073 g, 60.6%) as a white solid.

Step 2: Synthesis of compound 412

By 4-(((3R, 5S)-4-(4-((3,3-difluoroazetidine-1-yl)methyl)benzyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (formula 5-2,0.073g, 0.160mmol), hydroxylamine (0.195mL, 3.191mmol, 50.00% aqueous solution) and potassium hydroxide (0.090g, 1.595mmol) are dissolved in methanol (1mL) at room temperature, and the solution is stirred at the same temperature for 2 hours.Then, the reaction mixture is concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution (10mL) is added to the concentrate, then stirred.The precipitated solid is filtered, washed with water, and dried to obtain compound 412 (0.014g, 18.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.69(d, 2H, J=8.2Hz), 7.30-7.19(m, 6H), 3.71-3.67(m, 4H), 3.59-3.52(m, 5 H), 3.41 (m, 1H), 2.64-2.62 (m, 4H), 1.80 (t, 2H, J=10.4Hz), 0.90-0.88 (m, 6H).

Example 187: Synthesis of Compound 413 (4-(((3R,5S)-4-(4-((4-benzylpiperazin-1-yl)methyl) ... 1-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(4-((4-benzylpiperazin-1-yl)methyl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzyl)-3,5-dimethylpiperazin-1-yl (methyl)benzoate

Methyl 4-(((3R,5S)-4-(4-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.100 g, 0.263 mmol) was dissolved in dichloromethane (1 mL), and 1-benzylpiperazine (0.049 mL, 0.289 mmol) was added to the mixture, followed by stirring for 30 minutes. Na(OAc) _3BH (0.061 g, 0.289 mmol) was added to the reaction mixture, which was then stirred at the same temperature overnight. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to obtain the desired compound (0.074 g, 51.8%) as a white solid.

Step 2: Synthesis of compound 413

By 4-(((3R, 5S)-4-(4-((4-benzylpiperazine-1-yl)methyl)benzyl)-3,5-dimethylpiperazine-1-yl)methyl)methylbenzoate (formula 5-2,0.074g, 0.137mmol), hydroxylamine (0.168mL, 2.742mmol, 50.00% aqueous solution) and potassium hydroxide (0.077g, 1.371mmol) are dissolved in methanol (1mL) at room temperature, and the solution is stirred at the same temperature for 2 hours.Then, the reaction mixture is concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution (10mL) is added to the enriched material, then stirred.The precipitated solid is filtered, washed with water, and dried to obtain compound 413 (0.053g, 71.1%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.67(d, 2H, J=8.0Hz), 7.32-7.14(m, 11H), 3.70(s, 2H), 3.44(m, 6H), 3.22(m, 2H), 2.68-2.64(m, 4H), 2.35(m, 6H), 1.78(t, 2H, J=10.4Hz), 0.90-0.88(m, 6H).

Example 188: Synthesis of Compound 423 (4-(((3R,5S)-3,5-dimethyl-4-(3-pyrrolidin-1-ylmethyl) (benzoyl)piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 3-(chloromethyl)benzoyl chloride

3-(Bromomethyl)benzoic acid (4.301 g, 20.000 mmol) and SOCl ₂ (43.793 mL, 600.000 mmol) were mixed at 50° C. and stirred at the same temperature overnight, then cooled to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the product was used without additional purification (3.778 g, 99.9%, brown liquid).

Step 2: Synthesis of 4-(((3R,5S)-4-(3-(chloromethyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methane methyl)benzoate

Methyl 4-(((3R, 5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 2.622 g, 9.993 mmol), 3-(chloromethyl)benzoyl chloride (Formula 6-1, 3.778 g, 19.986 mmol) and TEA (2.770 mL, 19.986 mmol) were dissolved in dichloromethane (40 mL) at room temperature, and the solution was stirred at the same temperature for 3 hours. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica, 12 g cartridge; 100% dichloromethane) to give the desired compound (2.047 g, 49.4%) as a brown liquid.

Step 3: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(3-(pyrrolidin-1-ylmethyl)benzoyl)piperazine- 1-amino)methyl)benzoate

Methyl 4-(((3R,5S)-4-(3-(chloromethyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 6-2, 0.178 g, 0.388 mmol), pyrrolidine (0.032 mL, 0.388 mmol) and TEA (0.108 mL, 0.777 mmol) were dissolved in dichloromethane (2 mL) at room temperature, and the solution was stirred at the same temperature overnight. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 5%) to give the desired compound (0.155 g, 88.8%) as a light yellow liquid.

Step 4: Synthesis of Compound 423

Methyl 4-(((3R,5S)-3,5-dimethyl-4-(3-(pyrrolidin-1-ylmethyl)benzoyl)piperazin-1-yl)methyl)benzoate (Formula 6-3, 0.155 g, 0.345 mmol), hydroxylamine (0.422 mL, 6.895 mmol, 50.00% aqueous solution) and potassium hydroxide (0.193 g, 3.448 mmol) were dissolved in methanol (1.5 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. Then, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to give compound 423 (0.070 g, 44.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.2(brs, 1H), 9.03(brs, 1H), 7.72(d, 2H, J=8.6Hz), 7.43(d, 2H, J=8.2Hz), 7.38-7.32(m, 2H), 7.24(s, 1H), 7.20-7.17(m, 2 H), 4.06 (brs, 2H), 3.58-3.54 (m, 4H), 2.68-2.61 (m, 2H), 2.40 (s, 4H), 2.16-2.12 (m, 2H), 1.69-1.67 (m, 4H), 1.21-1.28 (m, 6H).

Example 189: Synthesis of Compound 424 (4-(((3R,5S)-3,5-dimethyl-4-(3-(piperidin-1-ylmethyl)benzene (formyl)piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(3-(piperidin-1-ylmethyl)benzoyl)piperazine-1-yl) methyl)benzoate

Methyl 4-(((3R,5S)-4-(3-(chloromethyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 6-2, 0.165 g, 0.359 mmol), piperidine (0.036 mL, 0.359 mmol), and Cs ₂ CO ₃ (0.142 g, 0.431 mmol) were dissolved in acetonitrile (1.5 mL) at room temperature, and the solution was stirred overnight at the same temperature. Water was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to obtain the desired compound (0.127 g, 76.0%) as a colorless liquid.

Step 2: Synthesis of compound 424

4-(((3R, 5S)-3,5-dimethyl-4-(3-(piperidin-1-ylmethyl)benzoyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 6-3, 0.127g, 0.273mmol), hydroxylamine (0.334mL, 5.461mmol, 50.00% aqueous solution) and potassium hydroxide (0.153g, 2.731mmol) were dissolved in methanol (1.5mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain compound 424 (0.101g, 79.4%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.72 (d, 2H, J=8.2Hz), 7.43 (d, 2H, J=8.1Hz), 7.38-7.30 (m, 2H), 7.23 (s, 1H), 7.20-7.18 (m, 1H), 3.54 (s, 2H), 3 .44(s, 2H), 2.63-2.61(m, 2H), 2.30(m, 4H), 2.16-2.12(m, 2H), 1.49-1.46(m, 4H), 1.38-1.37(m, 2H), 1.29(s, 6H).

Example 190: Synthesis of Compound 425 (4-(((3R,5S)-4-(3-((diethylamino)methyl)benzoyl)- 3,5-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-((diethylamino)methyl)benzoyl)-3,5-dimethylpiperidin (methyl)benzoate

Methyl 4-(((3R,5S)-4-(3-(chloromethyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 6-2, 0.165 g, 0.359 mmol), diethylamine hydrochloride (0.039 g, 0.359 mmol), and Cs ₂ CO ₃ (0.142 g, 0.431 mmol) were dissolved in acetonitrile (1.5 mL) at room temperature, and the solution was stirred overnight at the same temperature. Water was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to obtain the desired compound (0.115 g, 71.1%) as a colorless liquid.

Step 2: Synthesis of compound 425

Methyl 4-(((3R,5S)-4-(3-((diethylamino)methyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 6-3, 0.115 g, 0.255 mmol), hydroxylamine (0.312 mL, 5.106 mmol, 50.00% aqueous solution) and potassium hydroxide (0.143 g, 2.553 mmol) were dissolved in methanol (1.5 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. Then, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 5%) to give compound 425 (0.061 g, 53.1%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.2 (brs, 1H), 9.03 (brs, 1H), 7.72 (d, 2H, J=8.2Hz), 7.43 (d, 2H, J=8.2Hz), 7.36-7.34 (m, 2H), 7.25 (s, 1H), 7.18 -7.16 (m, 1H), 3.54 (s, 4H), 2.63-2.61 (m, 2H), 2.46-2.41 (m, 4H), 2.16-2.12 (m, 2H), 1.29 (m, 6H), 0.98-0.94 (m, 6H).

Example 191: Synthesis of Compound 426 (4-(((3R,5S)-4-(3-((diethylamino)methyl)benzyl)-3,5- dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-((diethylamino)methyl)benzyl)-3,5-dimethylpiperazine-1-yl)- methyl)benzoate

Methyl 4-(((3R,5S)-4-(3-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.200 g, 0.526 mmol) and diethylamine hydrochloride (0.086 g, 0.788 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 1 hour. Na(OAc) _3BH (0.223 g, 1.051 mmol) was added to the solution, followed by stirring at the same temperature for 17 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to obtain the desired compound (0.026 g, 11.3%) as a light yellow oil.

Step 2: Synthesis of compound 426

4-(((3R, 5S)-4-(3-((diethylamino)methyl)benzyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 5-2, 0.026g, 0.059mmol), hydroxylamine (0.073mL, 1.188mmol, 50.00% aqueous solution) and potassium hydroxide (0.033g, 0.594mmol) were dissolved in methanol (4mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. Then, the reaction solution was concentrated under reduced pressure to remove the solvent, and a saturated sodium bicarbonate aqueous solution was added to the obtained concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to obtain compound 426 (0.019g, 72.9%) as a white solid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ1.10 (brs, 1H), 9.00 (brs, 1H), 7.69 (d, 2H, J=8.3Hz), 7.33 (d, 2H, J=8. 1Hz), 7.29 (s, 1H), 7.24-7.18 (m, 2H), 7.12-7.10 (m, 1H), 3.72 (s, 2H), 3.5 0(s, 2H), 3.43(s, 2H), 2.68-2.54(m, 4H), 2.43(q, 4H, J=7.1Hz), 1.80(t, 2H, J=10.5Hz), 0.96 (t, 6H, J=7.1Hz), 0.90 (d, 6H, J=6.0Hz); LRMS (ES) m/z 439.3(M ⁺ +1).

Example 192: Synthesis of Compound 427 (4-(((3R,5S)-3,5-dimethyl-4-(3-pyrrolidin-1-ylmethyl) (Benzyl)piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(3-(pyrrolidin-1-ylmethyl)benzyl)piperazine-1-yl) methyl)benzoate

Methyl 4-(((3R,5S)-4-(3-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.200 g, 0.526 mmol) and pyrrolidine (0.066 mL, 0.788 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 1 hour. Na(OAc) _3BH (0.223 g, 1.051 mmol) was added to the solution, followed by stirring at the same temperature for 17 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = 0% to 10%) and concentrated to obtain the desired compound (0.161 g, 70.3%) as a colorless oil.

Step 2: Synthesis of compound 427

Methyl 4-(((3R,5S)-3,5-dimethyl-4-(3-(pyrrolidin-1-ylmethyl)benzyl)piperazine-1-yl)methyl)benzoate (Formula 5-2, 0.086 g, 0.197 mmol), hydroxylamine (0.242 mL, 3.949 mmol, 50.00% aqueous solution) and potassium hydroxide (0.111 g, 1.974 mmol) were dissolved in methanol (4 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 427 (0.033 g, 38.3%) as a white solid.

¹ H-NMR (400MHz, DMSO-d ₆ )δ11.10(brs, 1H), 9.00(brs, 1H), 7.70(d, 2H, J=8.2Hz), 7.35(d, 2H, J=8.1Hz), 7.26(s, 1H), 7.22-7.21(m, 2H), 7.11-7.09(m, 1H), 3.72( s, 2H), 3.54 (s, 2H), 3.44 (s, 2H), 2.65-2.55 (m, 4H), 2.40 (s, 4H), 1.81 (t, 2H, J=10.5Hz), 1.69 (s, 4H), 0.90 (d, 6H, J=6.1Hz); LRMS (ES) m/z 437.3(M ⁺⁺ 1).

Example 193: Synthesis of Compound 428 (4-(((3R,5S)-3,5-dimethyl-4-(3-((4-methylpiperazine-1- (4-(4-(4-(4-methyl)piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(3-((4-methylpiperazin-1-yl)methyl)benzyl)piperidin (methyl)benzoate

Methyl 4-(((3R,5S)-4-(3-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.200 g, 0.526 mmol) and 1-methylpiperazine (0.088 mL, 0.788 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 1 hour. Na(OAc) _3BH (0.223 g, 1.051 mmol) was added to the solution, followed by stirring at the same temperature for 17 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to obtain the desired compound (0.152 g, 62.2%) as a light yellow oil.

Step 2: Synthesis of Compound 428

Methyl 4-(((3R, 5S)-3,5-dimethyl-4-(3-((4-methylpiperazine-1-yl)methyl)benzyl)piperazine-1-yl)methyl)benzoate (Formula 5-2, 0.075 g, 0.161 mmol), hydroxylamine (0.197 mL, 3.228 mmol, 50.00% aqueous solution) and potassium hydroxide (0.091 g, 1.614 mmol) were dissolved in methanol (4 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 428 (0.031 g, 41.2%) as a white solid.

¹ H-NMR (400MHz, DMSO-d ₆ )δ7.69 (d, 2H, J=8.2Hz), 7.30 (d, 2H, J=8.1Hz), 7.27 (s, 1H), 7.23-7.21 (m, 2H), 7.09-7.08 (m, 1H), 3.72 (s, 2H), 3.43 (s, 2H) ), 3.42 (s, 2H), 2.63 (d, 2H, J=10.2Hz), 2.58-2.51 (m, 2H), 2.36-2.33 (m, 8H), 1.80 (t, 2H, J=10.5Hz), 0.90 (d, 6H, J=6.1Hz).

Example 194: Synthesis of Compound 429 (4-(((3R,5S)-4-(3-((4-ethylpiperazin-1-yl)methyl)benzyl) 1-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-((4-ethylpiperazin-1-yl)methyl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzyl (methyl)benzoate

Methyl 4-(((3R,5S)-4-(3-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.200 g, 0.526 mmol) and 1-ethylpiperazine (0.100 mL, 0.788 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 1 hour. Na(OAc) _3BH (0.223 g, 1.051 mmol) was added to the solution, followed by stirring at the same temperature for 17 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = 0% to 10%) and concentrated to obtain the desired compound (0.099 g, 39.3%) as a light yellow oil.

Step 2: Synthesis of Compound 429

Methyl 4-(((3R,5S)-4-(3-((4-ethylpiperazine-1-yl)methyl)benzyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 5-2, 0.055 g, 0.115 mmol), hydroxylamine (0.141 mL, 2.298 mmol, 50.00% aqueous solution) and potassium hydroxide (0.064 g, 1.149 mmol) were dissolved in methanol (4 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 429 (0.031 g, 56.2%) as a white solid.

¹ H-NMR (400MHz, DMSO-d ₆ )δ11.10(brs, 1H), 9.00(brs, 1H), 7.70(d, 2H, J=8.3Hz), 7.34(d, 2H, J=8.2Hz ), 7.27(s, 1H), 7.23-7.21(m, 2H), 7.09-7.08(m, 1H), 3.72(s, 2H), 3.43(s, 4H ), 2.63 (d, 2H, J = 10.2Hz), 2.59-2.51 (m, 2H), 2.36-2.33 (m, 8H), 2.28 (q, 2H, J =7.2Hz), 1.81 (t, 2H, J = 10.5Hz), 0.97 (t, 3H, J = 7.2Hz), 0.90 (d, 6H, J = 6.1Hz).

Example 195: Synthesis of Compound 430 (N-hydroxy-4-(((3R,5S)-4-(3-((4-isopropylpiperazin-1-yl) methyl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-((4-isopropylpiperazin-1-yl)methyl)benzyl)-3,5-dimethyl Methyl piperazin-1-yl)methyl)benzoate

Methyl 4-(((3R,5S)-4-(3-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.200 g, 0.526 mmol) and 1-isopropylpiperazine (0.113 mL, 0.788 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 1 hour. Na(OAc) _3BH (0.223 g, 1.051 mmol) was added to the solution, followed by stirring at the same temperature for 17 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = 0% to 10%) and concentrated to obtain the desired compound (0.225 g, 86.9%) as a light brown oil.

Step 2: Synthesis of Compound 430

Methyl 4-(((3R,5S)-4-(3-((4-isopropylpiperazin-1-yl)methyl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-2, 0.100 g, 0.203 mmol), hydroxylamine (0.248 mL, 4.059 mmol, 50.00% aqueous solution) and potassium chloride (0.114 g, 2.030 mmol) were dissolved in methanol (4 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 430 (0.055 g, 54.9%) as a white solid.

¹ H-NMR (400MHz, DMSO-d ₆ )δ11.10 (brs, 1H), 9.00 (brs, 1H), 7.70 (d, 2H, J=8.0Hz), 7.35 (d, 2H, J=8.0Hz), 7.09-7.08 (m, 2H), 3.72 (s, 2H), 3.43 (s, 2H), 3.42 (s , 2H), 2.65-2.62 (m, 2H), 2.59-2.51 (m, 3H), 2.41-2.34 (m, 8H), 1.81 (t, 2H, J=10.3Hz), 0.94 (d, 6H, J=6.5Hz), 0.90 (d, 6H, J=6.0Hz).

Example 196: Synthesis of Compound 431 (4-(((3R,5S)-4-(3-((4-acetylpiperazin-1-yl) methyl )benzyl )-3,5-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-((4-acetylpiperazin-1-yl)methyl)benzyl)-3,5-dimethyl Methyl piperazin-1-yl)methyl)benzoate

Methyl 4-(((3R,5S)-4-(3-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.200 g, 0.526 mmol) and 1-acetylpiperazine (0.101 g, 0.788 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 1 hour. Na(OAc) _3BH (0.223 g, 1.051 mmol) was added to the reaction solution, followed by stirring at the same temperature for 17 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = 0% to 10%) and concentrated to obtain the desired compound (0.253 g, 97.7%) as a light brown oil.

Step 2: Synthesis of compound 431

Methyl 4-(((3R,5S)-4-(3-((4-acetylpiperazin-1-yl)methyl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-2, 0.070 g, 0.142 mmol), hydroxylamine (0.174 mL, 2.842 mmol, 50.00% aqueous solution) and potassium hydroxide (0.080 g, 1.421 mmol) were dissolved in methanol (4 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 431 (0.067 g, 95.5%) as a white solid.

¹ H-NMR (400MHz, DMSO-d ₆ )δ7.69 (d, 2H, J=8.1Hz), 7.32 (d, 2H, J=8.1Hz), 7.28 (s, 1H), 7.25-7.23 (m, 2H), 7.12-7.11 (m, 1H), 3.73 (s, 2H), 3.43-3. 39 (m, 6H), 2.64 (d, 2H, J=10.1Hz), 2.59-2.53 (m, 2H), 2.34 (t, 2H, J=4.8Hz), 2.28 (t, 2H, J=5.0Hz), 0.90 (d, 6H, J=6.1Hz).

Example 197: Synthesis of Compound 432 (4-(((3R,5S)-3,5-dimethyl-4-(3-((4-methylpiperazine-1- (4-(2-Yl)-1-Methyl)-2-Methyl-3-Methyl-4-Methyl-5-Methyl-6-Methyl-7-Methyl-8-Methyl-9-Methyl-10-Methyl-11-Methyl-2-Methyl-12-Methyl-13-Methyl-24-Methyl-13-Methyl-14 ...13-Methyl-

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(3-((4-methylpiperazin-1-yl)methyl)benzoyl) methyl)piperazin-1-yl)methyl)benzoate

Methyl 4-(((3R,5S)-4-(3-(chloromethyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 6-2, 0.200 g, 0.482 mmol), 1-methylpiperazine (0.059 mL, 0.530 mmol), and Cs ₂ CO ₃ (0.188 g, 0.578 mmol) were dissolved in acetonitrile (2 mL) at room temperature, and the solution was stirred at the same temperature overnight. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to obtain the desired compound (0.163 g, 70.5%) as a light yellow liquid.

Step 2: Synthesis of compound 432

4-(((3R, 5S)-3,5-dimethyl-4-(3-((4-methylpiperazine-1-yl)methyl)benzoyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 6-3, 0.163 g, 0.340 mmol), hydroxylamine (0.416 mL, 6.794 mmol, 50.00% aqueous solution) and potassium hydroxide (0.191 g, 3.397 mmol) were dissolved in methanol (1.5 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. Then, saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain compound 432 (0.095 g, 58.1%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.72 (d, 2H, J=8.2Hz), 7.43 (d, 2H, J=8.2Hz), 7.38-7.30 (m, 2H), 7.23-7.18 (m, 2H), 3 .54-3.47(m, 6H), 2.67-2.61(m, 2H), 2.33(m, 8H), 2.16-2.13(m, 5H), 1.28-1.23(m, 6H).

Example 198: Synthesis of Compound 433 (4-(((3R,5S)-4-(3-((4-ethylpiperazin-1-yl)methyl)benzyl) (acyl)-3,5-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-((4-ethylpiperazin-1-yl)methyl)benzoyl)-3,5-dimethylpiperidin methyl)benzoate

Methyl 4-(((3R,5S)-4-(3-(chloromethyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 6-2, 0.200 g, 0.482 mmol), 1-ethylpiperazine (0.067 mL, 0.530 mmol), and Cs ₂ CO ₃ (0.188 g, 0.578 mmol) were dissolved in acetonitrile (2 mL) at room temperature, and the solution was stirred at the same temperature overnight. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to obtain the desired compound (0.165 g, 69.4%) as a light yellow liquid.

Step 2: Synthesis of compound 433

4-(((3R, 5S)-4-(3-((4-ethylpiperazine-1-yl)methyl)benzoyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 6-3, 0.165g, 0.334mmol), hydroxylamine (50.00% aqueous solution, 0.409mL, 6.686mmol) and potassium hydroxide (0.188g, 3.343mmol) were dissolved in methanol (1.5mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. Then, saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain compound 433 (0.116g, 70.0%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.2(brs, 1H), 9.03(brs, 1H), 7.89(d, 2H, J=7.8Hz), 7.72(d, 2H, J=8.2Hz), 7.44-7.30(m, 2H), 7.23(s, 1H), 7.20-7.19(m , 1H), 4.51 (s, 4H), 2.67-2.61 (m, 2H), 2.34-2.25 (m, 8H), 2.14 (dd, 2H, J=11.3, 4.1Hz), 1.28-1.23 (m, 6H), 0.98-0.85 (m, 3H).

Example 199: Synthesis of Compound 434 (N-hydroxy-4-(((3R,5S)-4-(3-((4-isopropylpiperazin-1-yl) methyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-((4-isopropylpiperazin-1-yl)methyl)benzoyl)-3,5-diol Methyl benzoate

Methyl 4-(((3R,5S)-4-(3-(chloromethyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 6-2, 0.200 g, 0.482 mmol), 1-isopropylpiperazine (0.076 mL, 0.530 mmol), and Cs ₂ CO ₃ (0.188 g, 0.578 mmol) were dissolved in acetonitrile (2 mL) at room temperature, and the solution was stirred at the same temperature overnight. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to obtain the desired compound (0.170 g, 69.5%) as a light yellow liquid.

Step 2: Synthesis of compound 434

Methyl 4-(((3R,5S)-4-(3-((4-isopropylpiperazin-1-yl)methyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 6-3, 0.170 g, 0.335 mmol), hydroxylamine (0.410 mL, 6.699 mmol, 50.00% aqueous solution) and potassium hydroxide (0.188 g, 3.349 mmol) were dissolved in methanol (1.5 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. Then, saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain compound 434 (0.128 g, 75.5%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.2(brs, 1H), 9.02(brs, 1H), 7.72(d, 2H, J=8.2Hz), 7.43(d, 2H, J=8.2Hz), 7.39-7.30(m, 2H), 7.23-7.19(s, 2H), 3.54(s , 2H), 3.47(s, 2H), 2.67-2.60(m, 3H), 2.43-2.33(m, 9H), 2.15(dd, 1H, J=11.3, 4.0Hz), 1.29-1.18(m, 6H), 0.96-0.94(m, 6H).

Example 200: Synthesis of Compound 435 (4-(((3R,5S)-4-(3-((4-acetylpiperazin-1-yl)methyl)benzene (formyl)-3,5-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-((4-acetylpiperazin-1-yl)methyl)benzoyl)-3,5-diol Methyl benzoate

Methyl 4-(((3R,5S)-4-(3-(chloromethyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 6-2, 0.200 g, 0.482 mmol), 1-acetylpiperazine (0.068 g, 0.530 mmol), and Cs ₂ CO ₃ (0.188 g, 0.578 mmol) were dissolved in acetonitrile (2 mL), and the solution was stirred overnight at the same temperature. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to obtain the desired compound (0.186 g, 76.2%) as a light yellow liquid.

Step 2: Synthesis of compound 435

Methyl 4-(((3R,5S)-4-(3-((4-acetylpiperazine-1-yl)methyl)benzoyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 6-3, 0.186 g, 0.367 mmol), hydroxylamine (0.449 mL, 7.346 mmol, 50.00% aqueous solution) and potassium hydroxide (0.206 g, 3.673 mmol) were dissolved in methanol (1.5 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. Then, saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain compound 435 (0.121 g, 64.7%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.2(brs, 1H), 9.04(brs, 1H), 7.72(d, 2H, J=8.1Hz), 7.42-7.33(m, 4H), 7.25-7.20(s, 2H), 4.52(brs, 2H), 3.53-3.52(m, 4 H), 3.41-3.40(m, 4H), 2.67-2.62(m, 2H), 2.36-2.34(m, 2H), 2.29-2.27(m, 2H), 2.16-2.13(m, 2H), 1.97(s, 3H), 1.29(s, 6H).

Example 201: Synthesis of Compound 439 (4-(((3R,5S)-3,5-dimethyl-4-(3-(morpholinomethyl)benzyl) (acyl)piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(3-(morpholinomethyl)benzoyl)piperazin-1-yl) Methyl)benzoate

Methyl 4-(((3R,5S)-4-(3-(chloromethyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 6-2, 0.200 g, 0.482 mmol), morpholine (0.069 g, 0.530 mmol), and Cs ₂ CO ₃ (0.188 g, 0.578 mmol) were dissolved in acetonitrile (2 mL) at room temperature, and the solution was stirred at the same temperature overnight. Water was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 10%) and concentrated to obtain the desired compound (0.163 g, 66.6%) as a light yellow liquid.

Step 2: Synthesis of compound 439

Methyl 4-(((3R, 5S)-3,5-dimethyl-4-(3-(morpholinomethyl)benzoyl)piperazin-1-yl)methyl)benzoate (Formula 6-3, 0.163 g, 0.321 mmol), hydroxylamine (0.392 mL, 6.416 mmol, 50.00% aqueous solution) and potassium hydroxide (0.180 g, 3.208 mmol) were dissolved in methanol (1.5 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. Then, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to obtain compound 439 (0.105 g, 64.3%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.71(d,2H,J=8.2Hz),7.39-7.33(m,4H),7.22(s,1H),7.22-7.20(m,1H),4.41(brs,1H)3.57- 3.55(m, 4H), 3.48(s, 4H), 2.65-2.61(m, 2H), 2.34(s, 4H), 2.15-2.11(m, 2H), 1.29-1.23(m, 6H).

Example 202: Synthesis of Compound 440 (4-(((3R,5S)-4-(3-(((1-(diethylamino)propan-2-yl)amino (4-(2-(4-(2-methyl-1-piperazin-1-yl)methyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-(((1-(diethylamino)propan-2-yl)amino)methyl)benzoyl methyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((3R,5S)-4-(3-(chlorophenyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 6-2, 0.200 g, 0.482 mmol), _N1 , _N1 -diethylpropane-1,2-diamine (0.069 g, 0.530 mmol), and _Cs2CO3 (0.188 g, 0.578 mmol) were dissolved in _acetonitrile (2 mL) at room temperature, and the solution was stirred at the same temperature overnight. Water was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 10%) and concentrated to obtain the desired compound (0.163 g, 66.6%) as a light yellow liquid.

Step 2: Synthesis of Compound 440

Methyl 4-(((3R,5S)-4-(3-(((1-(diethylamino)propan-2-yl)amino)methyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 6-3, 0.163 g, 0.321 mmol), hydroxylamine (0.392 mL, 6.416 mmol, 50.00% aqueous solution) and potassium hydroxide (0.180 g, 3.208 mmol) were dissolved in methanol (1.5 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. Then, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to obtain compound 440 (0.105 g, 64.3%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.71(d, 2H, J=8.2Hz), 7.38-7.32(m, 4H), 7.25(s, 1H), 7.18-7.16(m, 1H), 4.37(brs, 2H), 3.83-3.80(m, 1H), 3.67-3.64(m, 1H), 3.52(s, 2H), 2.67-2.57(m, 3H), 2.45-2.37(m, 2H), 2.35-2.26(m, 2H), 2.25-2.11(m, 5H), 1.29(s, 6H), 0.93-0.86(m, 9H).

Example 203: Synthesis of Compound 441 (4-(((3R,5S)-4-(3-(((1-(Benzyl(methyl)amino)propane-2- (4-(2-(4-(2-methyl-1-piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-(((1-(benzyl(methyl)amino)propan-2-yl)amino)methyl)benzene (formyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoic acid methyl ester

Methyl 4-(((3R,5S)-4-(3-(chloromethyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 6-2, 0.200 g, 0.482 mmol), N1-benzyl- _N1 -methylpropane-1,2-diamine (0.095 g, 0.530 mmol), and _Cs2CO3 (0.188 g, 0.578 _mmol ) were dissolved in acetonitrile (2 mL) at room temperature, and the solution was stirred at the same temperature overnight. Water was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 5%) and concentrated to obtain the desired compound (0.167 g, 62.2%) as a light yellow liquid.

Step 2: Synthesis of compound 441

Methyl 4-(((3R,5S)-4-(3-(((1-(benzyl(methyl)amino)propyl-2-yl)amino)methyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 6-3, 0.167 g, 0.300 mmol), hydroxylamine (0.367 mL, 5.999 mmol, 50.00% aqueous solution) and potassium hydroxide (0.168 g, 3.000 mmol) were dissolved in methanol (1.5 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. Then, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to obtain compound 441 (0.134 g, 80.3%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ )δ7.71 (d, 2H, J=8.2Hz), 7.37-7.30 (m, 4H), 7.28-7.19 (m, 6H), 7.18-7.16 (m, 1H), 4.42 (brs, 2H), 3.83-3.79 (m, 1H), 3.67-3.64 (m, 1H), 3.50 (s, 2H) , 3.46-3.43(m, 1H), 3.31(s, 1H), 2.74-2.69(m, 1H), 2.60(m, 1H), 2.33-2. 28(m, 2H), 2.13-2.08(m, 3H), 1.27(s, 6H), 0.93-0.91(m, 3H); LRMS(ES)m/z 558.4(M ⁺⁺ 1).

Example 204: Synthesis of Compound 442 (N-hydroxy-4-(((3R,5S)-4-(3-((4-isopentylpiperazin-1-yl) methyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-((4-isopentylpiperazin-1-yl)methyl)benzoyl)-3,5-diol Methyl benzoate

Methyl 4-(((3R,5S)-4-(3-(chloromethyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 6-2, 0.200 g, 0.482 mmol), 1-isobutylpiperazine trifluoroacetate (0.136 g, 0.530 mmol), and Cs ₂ CO ₃ (0.188 g, 0.578 mmol) were dissolved in acetonitrile (2 mL) at room temperature, and the solution was stirred at the same temperature overnight. Water was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to obtain the desired compound (0.162 g, 64.6%) as a light yellow liquid.

Step 2: Synthesis of compound 442

Methyl 4-(((3R,5S)-4-(3-((4-isopentylpiperazine-1-yl)methyl)benzoyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoate (Formula 6-3, 0.162 g, 0.311 mmol), hydroxylamine (0.381 mL, 6.226 mmol, 50.00% aqueous solution) and potassium hydroxide were dissolved in methanol (1.5 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. Then, saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain compound 442 (0.121 g, 74.6%) as a yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.2 (brs, 1H), 9.03 (brs, 1H), 7.72 (d, 2H, J = 8.2Hz), 7.43 (d, 2H, J = 8.1Hz), 7.38-7.30 (m, 2H), 7.23-7.19 (m, 2H), 4.50 (brs, 2H), 3.5 4-3.47(m, 4H), 2.62(m, 2H), 2.34(m, 6H), 2.26-2.22(m, 3H), 2.16-2.12(m, 3H), 1.56-1.53(m, 1H), 1.31-1.25(m, 8H), 0.86-0.84(m, 6H).

Example 205: Synthesis of Compound 443 (4-(((3R,5S)-3,5-dimethyl-4-(3-((4-(2,2,2-trifluoroethyl) 1-Yl)piperazin-1-yl)methyl)benzoyl)piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(3-((4-(2,2,2-trifluoroethyl)piperazin-1-yl) methyl)benzoyl)piperazin-1-yl)methyl)benzoic acid methyl ester

Methyl 4-(((3R,5S)-4-(3-(chloromethyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 6-2, 0.200 g, 0.482 mmol), 1-(2,2,2-trifluoroethyl)piperazine trifluoroacetate (0.141 g, 0.530 mmol), and Cs ₂ CO ₃ (0.188 g, 0.578 mmol) were dissolved in acetonitrile (2 mL) at room temperature, and the solution was stirred at the same temperature overnight. Water was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to obtain the desired compound (0.164 g, 62.3%) as a light yellow liquid.

Step 2: Synthesis of compound 443

Methyl 4-(((3R,5S)-3,5-dimethyl-4-(3-((4-(2,2,2-trifluoroethyl)piperazin-1-yl)methyl)benzoyl)piperazin-1-yl)methyl)benzoate (0.148 g, 0.270 mmol), hydroxylamine (0.331 mL, 5.408 mmol, 50.00% aqueous solution) and potassium hydroxide (0.152 g, 2.704 mmol) were dissolved in methanol (1.5 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. Then, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to give compound 443 (0.119 g, 80.5%) as a light yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.2(brs, 1H), 9.08(brs, 1H), 7.72(d, 2H, J=8.2Hz), 7.39-7.19(m, 6H), 4.47(brs, 2H), 3. 52-3.44(m, 4H), 3.17-3.10(m, 2H), 2.61(s, 6H), 2.36(s, 4H), 2.14-2.12(m, 2H), 1.29(m, 6H).

Example 206: Synthesis of Compound 444 (4-(((3R,5S)-3,5-dimethyl-4-(3-((4-(methylsulfonyl) (piperazin-1-yl)methyl)benzoyl)piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(3-((4-(methylsulfonyl)piperazin-1-yl)methyl) benzoyl)piperazin-1-yl)methyl)benzoic acid methyl ester

Methyl 4-(((3R,5S)-4-(3-(chloromethyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 6-2, 0.200 g, 0.482 mmol), 1-(methylsulfonyl)piperazine (0.087 g, 0.530 mmol), and Cs ₂ CO ₃ (0.188 g, 0.578 mmol) were dissolved in acetonitrile (2 mL) at room temperature, and the solution was stirred at the same temperature overnight. Water was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to obtain the desired compound (0.164 g, 62.8%) as a white solid.

Step 2: Synthesis of compound 444

4-(((3R, 5S)-3,5-dimethyl-4-(3-((4-(methylsulfonyl)piperazine-1-yl)methyl)benzoyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 6-3, 0.059 g, 0.109 mmol), hydroxylamine (0.133 mL, 2.178 mmol, 50.00% aqueous solution) and potassium hydroxide (0.061 g, 1.089 mmol) were dissolved in methanol (1.5 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. Then, saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain compound 444 (0.042 g, 71.6%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.2(brs, 1H), 9.01(brs, 1H), 7.72(d, 2H, J=8.2Hz), 7.42-7.33(m, 4H), 7.25-7.21(m, 2H), 4.47(brs, 2H), 3.55-3.53(m, 4H), 3.10(m, 4H), 2.87(m, 3H), 2.69-2.56(m, 2H), 2.45(s, 4H), 2.16-2.12(m, 2H), 1.29(m, 6H).

Example 207: Synthesis of Compound 446 (4-(((3R,5S)-3,5-dimethyl-4-(3-(morpholine-4-carbonyl)benzyl) (4-(2-methyl-1-piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 3-(chloromethyl)benzoyl chloride

A mixture of 3-(bromomethyl)benzoic acid (1.000 g, 4.650 mmol) and SOCl ₂ (10.120 mL, 139.509 mmol) was stirred at room temperature and at 70° C. for 16 hours, then cooled to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure, and the product was used without additional purification (0.879 g, 100.0%, brown oil).

Step 2: Synthesis of (3-(chloromethyl)phenyl)(morpholino)methanone

3-(Chloromethyl)benzoyl chloride (Formula 6-1, 0.879 g, 4.650 mmol), morpholine (0.409 mL, 4.650 mmol) and TEA (1.289 mL, 9.300 mmol) were dissolved in dichloromethane (10 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica, 12 g cartridge; ethyl acetate/hexane = from 15% to 40%) to obtain the desired compound (0.415 g, 37.2%) as a colorless oil.

Step 3: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(3-(morpholine-4-carbonyl)benzyl)piperazin-1-yl)methane methyl)benzoate

(3-(Chloromethyl)phenyl)(morpholino)methanone (Formula 6-4, 0.415 g, 1.730 mmol), methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.454 g, 1.730 mmol), and Cs ₂ CO ₃ (1.127 g, 3.459 mmol) were dissolved in acetonitrile (2 mL) and stirred at room temperature for 16 hours, then at 100° C. for 6 hours, and then cooled to room temperature to terminate the reaction. Water was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 12 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to obtain the desired compound (0.381 g, 47.3%) as a yellow oil.

Step 4: Synthesis of Compound 446

Methyl 4-(((3R,5S)-3,5-dimethyl-4-(3-(morpholine-4-carbonyl)benzyl)piperazin-1-yl)methyl)benzoate (0.095 g, 0.204 mmol), hydroxylamine (0.250 mL, 4.085 mmol, 50.00% aqueous solution) and potassium hydroxide (0.115 g, 2.043 mmol) were dissolved in methanol (2 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. Compound 446 was used without additional purification (0.064 g, 67.4%, white solid).

¹ H-NMR (400MHz, CDCl ₃ )δ11.2 (brs, 1H), 9.01 (brs, 1H), 7.69 (d, 2H, J=8.0Hz), 7.48-7.34 (m, 5H), 7.21 (d, 1H, J=7.1Hz), 3.75 (s, 2H), 3.61 (brs, 7H), 3.44 (s, 3H), 2.66-2.63 (m, 4H), 1.84-1.78 (m, 2H), 0.87 (d, 6H, J=6.0Hz); LRMS (ES) m/z 467.2(M ⁺ +1).

Example 208: Synthesis of Compound 452 (4-(((3R,5S)-3,5-dimethyl-4-(3-((4-(methylsulfonyl) (piperazin-1-yl)methyl)benzyl)piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 1-benzyl-4-(methylsulfonyl)piperazine

1-Benzylpiperazine (2.000 g, 11.347 mmol), MsCl (0.922 mL, 11.914 mmol) and TEA (2.372 mL, 17.020 mmol) were dissolved in dichloromethane (100 mL), and the solution was stirred for 3 hours at the same temperature. Water was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove solid residue and water layer, then concentrated under reduced pressure. The concentrate was crystallized and filtered from diethyl ether (20 mL) and hexane (5 mL) at room temperature, and the gained solid was washed with hexane and dried to obtain the required compound (0.857 g, 29.7%) as a white solid.

Step 2: Synthesis of 1-(methylsulfonyl)piperazine

1-Benzyl-4-(methylsulfonyl)piperazine (0.700 g, 2.752 mmol) was dissolved in methanol (30 mL) at room temperature, and Pd/C (0.075 g) was slowly added to the solution. A hydrogen balloon was then placed over the solution, followed by stirring for 3 hours at the same temperature. The reaction mixture was filtered through a celite pad to remove solids, and the filtrate was concentrated under reduced pressure to remove the solvent. The product was used without additional purification (0.335 g, 74.1%) as a white solid.

Step 3: 4-(((3R,5S)-3,5-dimethyl-4-(3-((4-(methylsulfonyl)piperazin-1-yl)methyl)benzyl methyl)piperazin-1-yl)methyl)benzoate

Methyl 4-(((3R,5S)-4-(3-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.200 g, 0.526 mmol) and 1-(methylsulfonyl)piperazine (0.129 g, 0.788 mmol) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 1 hour. Na(OAc) _3BH (0.223 g, 1.051 mmol) was added to the reaction solution, which was then further stirred at the same temperature for 17 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to give the desired compound (0.254 g, 91.4%) as a light yellow oil.

Step 4: Synthesis of Compound 452

Methyl 4-(((3R,5S)-3,5-dimethyl-4-(3-((4-(methylsulfonyl)piperazin-1-yl)methyl)benzyl)piperazin-1-yl)methyl)benzoate (Formula 5-2, 0.254 g, 0.480 mmol), hydroxylamine (0.588 mL, 9.608 mmol, 50.00% aqueous solution) and potassium hydroxide (0.270 g, 4.804 mmol) were dissolved in methanol (7 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove solids, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was filtered through a plastic filter equipped with an anhydrous sodium sulfate cartridge to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 452 (0.115 g, 45.2%) as a white solid.

¹ H-NMR (400MHz, DMSO-d ₆ )δ7.69 (d, 2H, J=7.7Hz), 7.31 (d, 2H, J=7.8Hz), 7.26-7.24 (m, 3H), 7.12 (s, 1H), 3.72 (s, 2H), 3.51 (s, 2H), 3.42 (s, 2H), 3.10 (s, 4H), 2.87 (s, 3H), 2.64 (d, 2H, J=10.7Hz), 2.57-2.55 (m, 2H), 2.44 (s, 4H), 1.81 (t, 2H, J=10.3Hz), 0.90 (d, 6H, J=5.8Hz).

Example 209: Synthesis of Compound 453 (4-(((3R,5S)-3,5-dimethyl-4-(3-((4-(2,2,2-trifluoroethyl) (4-(2-methyl-1-piperazin-1-yl)methyl)benzyl)piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of tert-butyl 4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate

Tert-butyl piperazine-1-carboxylate (2.000 g, 10.738 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.625 mL, 11.275 mmol), and Cs ₂ CO ₃ (4.198 g, 12.886 mmol) were dissolved in acetonitrile (100 mL) at room temperature, and the solution was stirred at the same temperature for 17 hours. The reaction mixture was filtered through a glass filter to remove solids, and the filtrate was concentrated under reduced pressure to remove the solvent. The concentrate was purified by column chromatography (silica, 12 g cartridge; ethyl acetate/hexane = from 0% to 20%) and concentrated to give the desired compound (2.150 g, 74.7%) as a colorless oil.

Step 2: Synthesis of 1-(2,2,2-trifluoroethyl)piperazine

Tert-butyl 4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate (2.000 g, 7.455 mmol) was dissolved in dichloromethane (10 mL)/trifluoroacetic acid (5 mL) at room temperature, and the solution was stirred at the same temperature for 17 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the concentrate was crystallized from ethyl acetate (20 mL) at room temperature and filtered, and the resulting solid was washed with ethyl acetate and dried to give the desired compound (0.457 g, 23.1%) as a white solid.

Step 3: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(3-((4-(2,2,2-trifluoroethyl)piperazin-1-yl) methyl)benzyl)piperazin-1-yl)methyl)benzoate

Methyl 4-(((3R,5S)-4-(3-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.200 g, 0.526 mmol) and 1-(2,2,2-trifluoroethyl)piperazine (0.209 g, 0.788 mmol) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 1 hour. Na(OAc) _3BH (0.223 g, 1.051 mmol) was added to the reaction solution, which was then further stirred at the same temperature for 17 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to give the desired compound (0.115 g, 41.1%) as a light yellow oil.

Step 4: Synthesis of compound 453

Methyl 4-(((3R,5S)-3,5-dimethyl-4-(3-((4-(2,2,2-trifluoroethyl)piperazin-1-yl)methyl)benzyl)piperazin-1-yl)methyl)benzoate (Formula 5-2, 0.115 g, 0.216 mmol), hydroxylamine (0.264 mL, 4.318 mmol, 50.00% aqueous solution) and potassium hydroxide (0.121 g, 2.159 mmol) were dissolved in methanol (5 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was filtered through a plastic filter equipped with an anhydrous sodium sulfate cartridge to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (Waters, _C18 ; 0.1% aqueous trifluoroacetic acid/acetonitrile = from 0% to 30%), followed by SPE cartridge (PL- _HCO3 MPSPE) and concentration to give compound 453 (0.012 g, 10.4%) as a white solid.

¹ H-NMR (400 MHz, DMSO-d ₆ )δ11.17(brs, 1H), 9.01(brs, 1H), 7.70(d, 2H, J=8.3Hz), 7.35(d, 2H, J=8.2Hz), 7.27(s, 1H), 7.23-7.22(m, 2H), 7.10-7.09(m, 1H), 3.72(s, 2H ), 3.44(s, 4H), 3.14(q, 2H, J=10.4Hz), 2.68-2.65(m, 2H), 2.61-2.53(m , 6H), 2.37-2.33 (m, 4H), 1.81 (t, 2H, J=10.3Hz), 0.90 (d, 6H, J=6.0Hz).

Example 210: Synthesis of Compound 454 (N-hydroxy-4-(((3R,5S)-4-(3-((4-isopentylpiperazin-1-yl) methyl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzamide)

Step 1: Synthesis of tert-butyl 4-isopentylpiperazine-1-carboxylate

Tert-butyl piperazine-1-carboxylate (2.000 g, 10.738 mmol), 1-bromo-3-methylbutane (1.352 mL, 11.275 mmol), and _Cs2CO3 (4.198 g, 12.886 mmol) were dissolved in acetonitrile (150 mL) at room temperature and the solution was stirred at the same temperature _for 17 hours. The reaction mixture was filtered through a glass filter to remove solids, and the filtrate was concentrated under reduced pressure to remove the solvent. The concentrate was purified by column chromatography (silica, 12 g cartridge; ethyl acetate/hexane = from 0% to 10%) and concentrated to give the desired compound (1.220 g, 44.3%) as a colorless oil.

Step 2: Synthesis of 1-isoamylpiperazine trifluoroacetate

Tert-butyl 4-isopentylpiperazine-1-carboxylate (1.000 g, 3.900 mmol) was dissolved in dichloromethane (10 mL)/trifluoroacetic acid (5 mL), and the solution was stirred at the same temperature for 17 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the concentrate was crystallized from ethyl acetate (20 mL) at room temperature and filtered, and the resulting solid was washed with ethyl acetate and dried to give the desired compound (0.929 g, 94.0%) as a white solid.

Step 3: Synthesis of 4-(((3R,5S)-4-(3-((4-isopentylpiperazin-1-yl)methyl)benzyl)-3,5-dimethyl Methyl piperazin-1-yl)methyl)benzoate

Methyl 4-(((3R,5S)-4-(3-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.220 g, 0.578 mmol) and 1-isoamylpiperazine trifluoroacetate (0.220 g, 0.867 mmol) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 1 hour. Na(OAc) _3BH (0.245 g, 1.156 mmol) was added to the reaction solution, which was then further stirred at the same temperature for 17 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to give the desired compound (0.232 g, 77.0%) as a light yellow oil.

Step 4: Synthesis of Compound 454

Methyl 4-(((3R,5S)-4-(3-((4-isopentylpiperazin-1-yl)methyl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-2, 0.232 g, 0.446 mmol), hydroxylamine (0.545 mL, 8.910 mmol, 50.00% aqueous solution) and potassium hydroxide (0.250 g, 4.455 mmol) were dissolved in methanol (5 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 454 (0.067 g, 29.6%) as a white solid.

¹ H-NMR (400MHz, DMSO-d ₆ )δ7.69 (d, 2H, J=8.2Hz), 7.30 (d, 2H, J=8.1Hz), 7.27 (s, 1H), 7.23-7.21 (m, 2H), 7. 09-7.08 (m, 1H), 3.72 (s, 2H), 3.42 (s, 2H), 3.41 (s, 2H), 2.63 (d, 2H, J=10.2Hz), 2. 58-2.53(m, 2H), 2.34-2.27(m, 8H), 2.24(t, 2H, J=7.6Hz), 1.80(t, 2H, J=10.5Hz), 1.57-1.53 (m, 1H), 1-31-1.25 (m, 2H), 0.89 (d, 6H, J=6.1Hz), 0.85 (d, 6H, J=6.6Hz).

Example 211: Synthesis of Compound 455 (4-(((3R,5S)-4-(3-(((1-(diethylamino)propan-2-yl)amino (4-(2-(4-(2-methyl-1-piperazin-1-yl)methyl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-(((1-(diethylamino)propan-2-yl)amino)methyl)benzyl)- Methyl 3,5-dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((3R,5S)-4-(3-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.200 g, 0.526 mmol) and N ₁ ,N ₁ -diethylpropane-1,2-diamine (0.103 g, 0.788 mmol) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 1 hour. Na(OAc) ₃ BH (0.223 g, 1.051 mmol) was added to the reaction solution, which was then further stirred at the same temperature for 17 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to give the desired compound (0.149 g, 57.3%) as a light yellow oil.

Step 2: Synthesis of compound 455

Methyl 4-(((3R,5S)-4-(3-(((1-(diethylamino)propan-2-yl)amino)methyl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-2, 0.149 g, 0.301 mmol), hydroxylamine (0.368 mL, 6.024 mmol, 50.00% aqueous solution) and potassium hydroxide (0.169 g, 3.012 mmol) were dissolved in methanol (5 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 455 (0.064 g, 42.9%) as a white solid.

¹ H-NMR (400MHz, DMSO-d ₆ )δ7.70 (d, 2H, J=8.2Hz), 7.34 (d, 2H, J=8.0Hz), 7.26 (s, 1H), 7.24-7.18 (m, 2H), 3.79-3.55 (m, 4H), 3.43 (s, 2H), 2.63 (d, 2H, J=1 0.1Hz), 2.59-2.54(m, 2H), 2.46-2.37(m, 2H), 2.34-2.25(m, 2H), 2.23-2.15(m, 2H), 1.81(t, 2H, J=10.4Hz), 0.92-0.86(m, 15H).

Example 212: Synthesis of Compound 456 (4-(((3R,5S)-4-(3-(((1-(Benzyl(methyl)amino)propane-2- (4-(4-(4-(4-methyl-2-piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(3-(((1-(benzyl(methyl)amino)propan-2-yl)amino)methyl)benzyl methyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((3R,5S)-4-(3-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.200 g, 0.526 mmol) and N ₁ -benzyl-N ₁ -methylpropane-1,2-diamine (0.141 g, 0.788 mmol) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 1 hour. Na(OAc) ₃ BH (0.223 g, 1.051 mmol) was added to the reaction solution, which was then further stirred at the same temperature for 17 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to give the desired compound (0.252 g, 88.3%) as a light yellow oil.

Step 2: Synthesis of compound 456

Methyl 4-(((3R,5S)-4-(3-(((1-(benzyl(methyl)amino)propyl-2-yl)amino)methyl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-2, 0.252 g, 0.464 mmol), hydroxylamine (0.568 mL, 9.286 mmol, 50.00% aqueous solution) and potassium hydroxide (0.261 g, 4.643 mmol) were dissolved in methanol (5 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 456 (0.196 g, 77.6%) as a white solid.

¹ H-NMR (400 MHz, DMSO-d ₆ )δ7.69(d, 2H, J=8.2Hz), 7.33(d, 2H, J=8.2Hz), 7.31-7.20(m, 8H), 7.12( d, 1H, J=6.5Hz), 3.80-3.57 (m, 4H), 3.39 (s, 2H), 2.70-2.69 (m, 1H), 2.61 (d, 2H, J = 10.8Hz), 2.55-2.53 (m, 2H), 2.34-2.29 (m, 1H), 2.12-2.09 (m, 1 H), 1.79 (t, 2H, J=10.4Hz), 0.92 (d, 3H, J=6.1Hz), 0.88 (d, 6H, J=6.0Hz).

Example 213: Synthesis of Compound 457 (4-(((3R,5S)-3,5-dimethyl-4-(2-(morpholinomethyl)benzyl) (piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 2-(bromomethyl)benzaldehyde

2-(Bromomethyl)benzonitrile (2.500 g, 12.752 mmol) was dissolved in dichloromethane (30 mL) at 0°C, and DIBAL-H (1.00 M solution, 13.390 mL, 13.390 mmol) was added to the solution, followed by stirring at the same temperature for 2 hours. Then, aqueous hydrochloric acid was added to the reaction mixture at 0°C, followed by stirring for 30 minutes. After the reaction was complete, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 40 g cartridge; ethyl acetate/hexane = from 0% to 30%) and concentrated to give the desired compound (0.400 g, 15.8%) as a brown oil.

Step 2: Synthesis of 4-(((3R,5S)-4-(2-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzyl Methyl ester

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 0.500 g, 1.906 mmol), 2-(bromomethyl)benzaldehyde (0.379 g, 1.906 mmol), and _Cs2CO3 (0.931 g, 2.859 mmol) were dissolved in _acetonitrile (10 mL), and the solution was stirred at the same temperature for 17 hours. Water was added to the reaction mixture, which was then extracted with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 12 g cartridge; ethyl acetate/hexane = from 0% to 40%) and concentrated to obtain the desired compound (0.116 g, 16.0%) as a light brown oil.

Step 3: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(2-(morpholinomethyl)benzyl)piperazin-1-yl)methane methyl)benzoate

Methyl 4-(((3R,5S)-4-(2-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.116 g, 0.305 mmol) and morpholine (0.040 mL, 0.457 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 30 minutes. Na(OAc) _3BH (0.129 g, 0.610 mmol) was added to the reaction solution, which was then further stirred at the same temperature for 17 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 30%) and concentrated to obtain the desired compound (0.076 g, 55.2%) as a light yellow oil.

Step 4: Synthesis of Compound 457

Methyl 4-(((3R,5S)-3,5-dimethyl-4-(2-(morpholinomethyl)benzyl)piperazin-1-yl)methyl)benzoate (Formula 5-2, 0.076 g, 0.168 mmol), hydroxylamine (0.018 mL, 3.366 mmol, 50.00% aqueous solution) and potassium hydroxide (0.094 g, 1.683 mmol) were dissolved in methanol (5 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was filtered through a plastic filter equipped with an anhydrous sodium sulfate cartridge to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 457 (0.060 g, 78.8%) as a light yellow solid.

¹ H-NMR (400MHz, DMSO-d ₆ )δ7.77 (d, 1H, J=7.8Hz), 7.71 (d, 2H, J=8.1Hz), 7.33 (d, 2H, J=8.1Hz), 7.22-7.21 (m, 1H), 7.11-7.08 (m, 2H), 3.86 (s, 2H), 3.52 (s, 4H), 3.4 6 (s, 2H), 3.43 (s, 2H), 2.68 (d, 2H, J = 10.8Hz), 2.65-2.61 (m, 2H), 2.33 (s, 4H), 1.87 (t, 2H, J = 10.3Hz), 0.80 (d, 6H, J = 6.0Hz); LRMS (ES) m/z 453.2(M ⁺⁺ 1).

Example 214: Synthesis of Compound 458 (4-(((3R,5S)-3,5-dimethyl-4-(4-(morpholinomethyl)benzyl) (acyl)piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(chloromethyl)benzoyl chloride

A mixture of 4-(bromomethyl)benzoic acid (5.000 g, 23.251 mmol) and SOCl ₂ (8.444 mL, 116.257 mmol) was stirred at room temperature and at 50° C. for 17 hours, then cooled to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the product was used without additional purification (4.400 g, 100.1%, light purple solid).

Step 2: Synthesis of 4-(((3R,5S)-4-(4-(chloromethyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methane methyl)benzoate

4-(((3R, 5S)-3,5-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 1-2, 4.400g, 23.275mmol), 4-(chloromethyl)benzoyl chloride (Formula 6-1, 3.053g, 11.638mmol) and TEA (6.488mL, 46.551mmol) were dissolved in dichloromethane (150mL) at 0°C and stirred at room temperature for 3 hours. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 40 g cartridge; ethyl acetate/hexane = from 5% to 70%) and concentrated, and the resulting material was then purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 5% to 20%) and concentrated to give the desired compound (1.720 g, 17.8%) as an orange solid.

Step 3: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(4-(morpholinomethyl)benzoyl)piperazin-1-yl) Methyl)benzoate

Methyl 4-(((3R,5S)-4-(4-(chloromethyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 6-2, 0.100 g, 0.241 mmol), morpholine (0.031 mL, 0.362 mmol), and Cs ₂ CO ₃ (0.157 g, 0.482 mmol) were dissolved in acetonitrile (4 mL) at room temperature, and the solution was stirred in the same for 17 hours. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and water was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to obtain the desired compound (0.107 g, 95.4%) as a colorless oil.

Step 4: Synthesis of Compound 458

Methyl 4-(((3R,5S)-3,5-dimethyl-4-(4-(morpholinomethyl)benzoyl)piperazin-1-yl)methyl)benzoate (Formula 6-3, 0.107 g, 0.230 mmol), hydroxylamine (0.281 mL, 4.596 mmol, 50.00% aqueous solution) and potassium hydroxide (0.129 g, 2.298 mmol) were dissolved in methanol (5 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was filtered through a plastic filter equipped with an anhydrous sodium sulfate cartridge to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 458 (0.034 g, 31.6%) as a light orange solid.

¹ H-NMR (400MHz, DMSO-d ₆ )δ7.70 (d, 2H, J=8.0Hz), 7.36-7.34 (m, 4H), 7.28 (d, 2H, J=8.0Hz), 4.12 (brs, 2H), 3.57 (t, 4H, J=4.4Hz), 3.52 (s , 2H), 3.48 (s, 2H), 2.62-2.61 (m, 2H), 2.35 (s, 4H), 2.13 (dd, 2H, J=11.2, 4.2Hz), 1.28-1.25 (m, 6H); LRMS (ES) m/z 467.2(M ⁺ +1).

Example 215: Synthesis of Compound 459 (4-(((3R,5S)-3,5-dimethyl-4-(4-(piperidin-1-ylmethyl)benzene (formyl)piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(4-piperidin-1-ylmethyl)benzoyl)piperazine-1-yl methyl)benzoate

Methyl 4-(((3R,5S)-4-(4-(chloromethyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 6-2, 0.100 g, 0.241 mmol), piperidine (0.031 mL, 0.362 mmol), and Cs ₂ CO ₃ (0.157 g, 0.482 mmol) were dissolved in acetonitrile (4 mL) at room temperature, and the solution was stirred at the same temperature for 17 hours. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and water was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to obtain the desired compound (0.101 g, 90.4%) as a colorless oil.

Step 2: Synthesis of compound 459

Methyl 4-(((3R,5S)-3,5-dimethyl-4-(4-piperidin-1-ylmethyl)benzoyl)piperazin-1-yl)methyl)benzoate (Formula 6-3, 0.101 g, 0.218 mmol), hydroxylamine (0.267 mL, 4.357 mmol, 50.00% aqueous solution) and potassium hydroxide (0.122 g, 2.179 mmol) were dissolved in methanol (5 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica, 12 g cartridge; ethyl acetate/hexane = from 0% to 30%) to give compound 459 (0.073 g, 72.1%) as a white solid.

¹ H-NMR (400MHz, DMSO-d ₆ )δ7.72 (d, 2H, J=8.2Hz), 7.42 (d, 2H, J=8.2Hz), 7.33 (d, 2H, J=8.1Hz), 7.27 (d, 2H, J=8.1Hz), 4.12 (brs, 1H), 3.54 (s, 2H), 3.43 (s, 2H), 2.64-2.62 (m, 2H), 2.31 (s, 4H), 2.15 (dd, 2H, J=11.4, 4.2Hz), 1.52-1.46 (m, 4H), 1.39-1.38 (m, 2H), 1.29 (d, 6H, J=6.1Hz); LRMS (ES) m/z 465.2(M ⁺ +1).

Example 216: Synthesis of Compound 460 (4-(((3R,5S)-4-(4-(((R)-3-fluoropyrrolidin-1-yl)methyl) (benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(4-(((R)-3-fluoropyrrolidin-1-yl)methyl)benzoyl)-3,5- Methyl dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((3R,5S)-4-(4-(chloromethyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 6-2, 0.100 g, 0.241 mmol), (R)-3-fluoropyrrolidine (0.045 g, 0.362 mmol), and Cs ₂ CO ₃ (0.157 g, 0.482 mmol) were dissolved in acetonitrile (4 mL) at room temperature, and the solution was stirred at the same temperature for 17 hours. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and water was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to obtain the desired compound (0.103 g, 91.4%) as a light yellow oil.

Step 2: Synthesis of Compound 460

Methyl 4-(((3R, 5S)-4-(4-(((R)-3-fluoropyrrolidin-1-yl)methyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 6-3, 0.103 g, 0.220 mmol), hydroxylamine (0.269 mL, 4.406 mmol, 50.00% aqueous solution) and potassium hydroxide (0.124 g, 2.203 mmol) were dissolved in methanol (5 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 12 g cartridge; ethyl acetate/hexane = from 0% to 30%) and concentrated to give compound 460 (0.082 g, 79.4%) as a white solid.

¹ H-NMR (400MHz, DMSO-d ₆ )δ11.19 (brs, 1H), 9.04 (brs, 1H), 7.72 (d, 2H, J = 8.2Hz), 7.43 (d, 2H, J = 8.1Hz) , 7.36 (d, 2H, J = 8.1Hz), 7.29 (d, 2H, J = 8.1Hz), 5.20 (dt, 1H, J = 55.5, 5.8Hz), 4. 15(brs, 2H), 3.62(s, 2H), 3.55(s, 2H), 2.82-2.73(m, 2H), 2.68-2.61(m, 3H), 2 .33-2.28 (m, 1H), 2.17-2.13 (m, 3H), 1.94-1.89 (m, 1H), 1.29 (d, 6H, J=5.3Hz).

Example 217: Synthesis of Compound 461 (4-(((3R,5S)-3,5-dimethyl-4-(4-pyrrolidin-1-ylmethyl) (benzoyl)piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(4-(pyrrolidin-1-ylmethyl)benzoyl)piperazine- 1-amino)methyl)benzoate

Methyl 4-(((3R,5S)-4-(4-(chloromethyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 6-2, 0.100 g, 0.241 mmol), pyrrolidine (0.030 mL, 0.362 mmol), and Cs ₂ CO ₃ (0.157 g, 0.482 mmol) were dissolved in acetonitrile (4 mL) at room temperature, and the solution was stirred at the same temperature for 17 hours. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and water was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to obtain the desired compound (0.102 g, 94.1%) as a light yellow oil.

Step 2: Synthesis of Compound 461

Methyl 4-(((3R, 5S)-3,5-dimethyl-4-(4-(pyrrolidin-1-ylmethyl)benzoyl)piperazin-1-yl)methyl)benzoate (Formula 6-3, 0.102 g, 0.227 mmol), hydroxylamine (0.278 mL, 4.537 mmol, 50.00% aqueous solution) and potassium hydroxide (0.127 g, 2.269 mmol) were dissolved in methanol (5 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 12 g cartridge; ethyl acetate/hexane = from 0% to 30%) and concentrated to give compound 461 (0.071 g, 69.5%) as a light yellow solid.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ11.18 (brs, 1H), 9.04 (brs, 1H), 7.72 (d, 2H, J = 8.2Hz), 7.43 (d, 2H, J = 8.1Hz), 7.35 (d, 2H, J = 8.0Hz), 7.27 (d, 2H, J = 8.0Hz), 4.19 (brs, 2 H), 3.58 (s, 2H), 3.55 (s, 2H), 2.63 (d, 2H, J=10.0Hz), 2.41 (s, 4H), 2.15 (dd, 2H, J=11.4, 4.2Hz), 1.70-1.68 (m, 4H), 1.29 (d, 6H, J=6.1Hz).

Example 218: Synthesis of Compound 462 (4-(((3R,5S)-3,5-dimethyl-4-(4-((4-methylpiperazine-1- (4-(2-Yl)-1-Methyl)-2-Methyl-3-Methyl-4-Methyl-5-Methyl-6-Methyl-7-Methyl-8-Methyl-9-Methyl-10-Methyl-11-Methyl-2-Methyl-12-Methyl-13-Methyl-24-Methyl-13-Methyl-14 ...13-Methyl-

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(4-((4-methylpiperazin-1-yl)methyl)benzoyl methyl)piperazin-1-yl)methyl)benzoate

Methyl 4-(((3R,5S)-4-(4-(chloromethyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 6-2, 0.100 g, 0.241 mmol), 1-methylpiperazine (0.040 mL, 0.362 mmol), and Cs ₂ CO ₃ (0.157 g, 0.482 mmol) were dissolved in acetonitrile (4 mL) at room temperature, and the solution was stirred at the same temperature for 17 hours. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and water was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to obtain the desired compound (0.102 g, 88.4%) as a colorless oil.

Step 2: Synthesis of compound 462

At room temperature 4-(((3R, 5S)-3,5-dimethyl-4-(4-((4-methylpiperazine-1-yl)methyl)benzoyl)piperazine-1-yl)methyl)methylbenzoate (Formula 6-3, 0.102g, 0.213mmol), hydroxylamine (0.261mL, 4.262mmol, 50.00% aqueous solution) and potassium hydroxide (0.120g, 2.131mmol) were dissolved in methanol (5mL), and the solution was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution (20mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered, washed with water, and dried to give compound 462 (0.057g, 55.8%) as a white solid.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ11.20 (brs, 1H), 9.04 (brs, 1H), 7.72 (d, 2H, J = 8.2Hz), 7.43 (d, 2H, J = 8.1Hz), 7.33 (d, 2H, J = 8.1Hz), 7.27 (d, 2H, J = 7.8Hz), 4. 21 (brs, 2H), 3.54 (s, 2H), 3.47 (s, 2H), 2.63 (d, 2H, J=11.4Hz), 2.33-2.32 (m, 8H), 2.17-2.14 (m, 5H), 1.30 (s, 6H); LRMS (ES) m/z 480.2(M ⁺ +1).

Example 219: Synthesis of Compound 463 (4-(((3R,5S)-3,5-dimethyl-4-(4-((4-(methylsulfonyl) (piperazin-1-yl)methyl)benzoyl)piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(4-((4-(methylsulfonyl)piperazin-1-yl)methyl) benzoyl)piperazin-1-yl)methyl)benzoic acid methyl ester

Methyl 4-(((3R,5S)-4-(4-(chloromethyl)benzoyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 6-2, 0.100 g, 0.241 mmol), 1-(methylsulfonyl)piperazine (0.059 g, 0.362 mmol), and Cs ₂ CO ₃ (0.157 g, 0.482 mmol) were dissolved in acetonitrile (4 mL) at room temperature, and the solution was stirred at the same temperature for 17 hours. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and water was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to obtain the desired compound (0.126 g, 96.3%) as a colorless oil.

Step 2: Synthesis of compound 463

Methyl 4-(((3R, 5S)-3,5-dimethyl-4-(4-((4-(methylsulfonyl)piperazin-1-yl)methyl)benzoyl)piperazin-1-yl)methyl)benzoate (Formula 6-3, 0.126 g, 0.297 mmol), hydroxylamine (0.364 mL, 5.950 mmol, 50.00% aqueous solution) and potassium hydroxide (0.167 g, 2.975 mmol) were dissolved in methanol (5 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 12 g cartridge; ethyl acetate/hexane = from 0% to 30%) and concentrated to give compound 463 (0.065 g, 53.2%) as a white solid.

¹ H-NMR (400MHz, DMSO-d ₆ )δ7.72 (d, 2H, J = 8.3Hz), 7.42 (d, 2H, J = 8.1Hz), 7.36 (d, 2H, J = 8.1Hz), 7.30 (d, 2H, J = 8.2Hz), 4.25 (brs, 2H), 3.55 (s, 4H), 3.11 (t, 4H, J=4.5Hz), 2.87 (s, 3H), 2.63 (d, 2H, J=10.3Hz), 2.47 (s, 4H), 2.15 (dd, 2H, J=11.4, 4.1Hz), 1.29-1.28 (m, 6H).

Example 220: Synthesis of Compound 466 (4-(((3R,5S)-3,5-dimethyl-4-(4-pyrrolidin-1-ylmethyl) (Benzyl)piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(4-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzyl Methyl ester

Methyl 4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 1-2, 1.000 g, 3.812 mmol), 4-(bromomethyl)benzaldehyde (0.759 g, 3.812 mmol), and _Cs2CO3 (2.484 g, 7.623 mmol) were dissolved in _acetonitrile (25 mL) at room temperature, and the solution was stirred at the same temperature for 16 hours. The reaction mixture was filtered through a filter paper filter to remove solids, and the filtrate was concentrated under reduced pressure to remove the solvent. The concentrate was purified by column chromatography (silica, 40 g cartridge; ethyl acetate/hexane = 0% to 25%) and concentrated to obtain the desired compound (0.934 g, 64.4%) as a white solid.

Step 2: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(4-(pyrrolidin-1-ylmethyl)benzyl)piperazine-1-yl)- methyl)benzoate

Methyl 4-(((3R,5S)-4-(4-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.180 g, 0.473 mmol) and pyrrolidine (0.044 mL, 0.520 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 1 hour. Na(OAc) _3BH (0.150 g, 0.710 mmol) was added to the reaction solution, which was then further stirred at the same temperature for 16 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 30% to 100%) and concentrated to obtain the desired compound (0.098 g, 47.5%) as a yellow solid.

Step 3: Synthesis of Compound 466

4-(((3R, 5S)-3,5-dimethyl-4-(4-(pyrrolidin-1-ylmethyl)benzyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 5-2, 0.098g, 0.225mmol) and hydroxylamine (0.275mL, 4.490mmol, 50.00% aqueous solution) are dissolved in methanol (3mL) at room temperature, and potassium hydroxide (0.126g, 2.245mmol) is added to the solution, which is then stirred at the same temperature for 1 hour. Then, the reaction mixture is concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution is added to the gained concentrate, followed by extraction with dichloromethane. The organic layer is washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain compound 466 (0.055g, 56.0%) as a white solid.

¹ H-NMR (400 MHz, DMSO-d ₆ )δ10.9 (brs, 1H), 9.07 (brs, 1H), 7.69 (d, 2H, J=7.9Hz), 7.34 (d, 2H, J=7.8Hz), 7.26 (d, 2H, J=7.8Hz), 7.20 (d, 2H, J=7.8Hz), 3.70 (s, 2H), 3.51 ( s, 2H), 3.42 (s, 2H), 2.66-2.64 (m, 2H), 2.60-2.55 (m, 2H), 2.39 (s, 4H), 1.79 (t, 2H, J=10.4Hz), 1.66 (s, 4H), 0.90 (d, 6H, J=6.0Hz); LRMS (ES) m/z 437.3(M ⁺ +1).

Example 221: Synthesis of Compound 467 (4-(((3R,5S)-3,5-dimethyl-4-(4-(piperidin-1-ylmethyl)benzyl) (4-(2-methyl-1-piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(4-(piperidin-1-ylmethyl)benzyl)piperazin-1-yl) Methyl)benzoate

Methyl 4-(((3R,5S)-4-(4-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.180 g, 0.473 mmol) and piperidine (0.052 mL, 0.520 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 1 hour. Na(OAc) _3BH (0.150 g, 0.710 mmol) was added to the reaction solution, which was then further stirred at the same temperature for 16 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 30% to 100%) and concentrated to obtain the desired compound (0.149 g, 70.1%) as a white solid.

Step 2: Synthesis of Compound 467

4-(((3R, 5S)-3,5-dimethyl-4-(4-(piperidin-1-ylmethyl)benzyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 5-2, 0.149g, 0.332mmol) and hydroxylamine (0.406mL, 6.637mmol, 50.00% aqueous solution) were dissolved in methanol (3mL) at room temperature, and potassium hydroxide (0.186g, 3.318mmol) was added to the solution, which was then stirred at the same temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to give compound 467 (0.118g, 78.8%) as a white solid.

¹ H-NMR (400 MHz, DMSO-d ₆ )δ11.2(brs, 1H), 9.04(brs, 1H), 7.69(d, 2H, J=7.7Hz), 7.33(d, 2H, J=7.7 Hz), 7.26 (d, 2H, J=7.7Hz), 7.18 (d, 2H, J=7.8Hz), 3.70 (s, 2H), 3.42 (s, 2H) , 2.62 (d, 2H, J = 10.4Hz), 2.55 (m, 2H), 2.27 (s, 4H), 1.79 (t, 2H, J = 10.4Hz) , 1.48-1.45 (m, 4H), 1.37-1.36 (m, 2H), 0.90 (d, 6H, J=5.9Hz); LRMS (ES) m/z 451.2(M ⁺⁺ 1).

Example 222: Synthesis of Compound 468 (4-(((3R,5S)-3,5-dimethyl-4-(4-((4-methylpiperazine-1- (4-(4-(4-(4-methyl)piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(4-((4-methylpiperazin-1-yl)methyl)benzyl)piperidin (methyl)benzoate

Methyl 4-(((3R,5S)-4-(4-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.180 g, 0.473 mmol) and 1-methylpiperazine (0.058 mL, 0.520 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 1 hour. Na(OAc) _3BH (0.150 g, 0.710 mmol) was added to the reaction solution, which was then further stirred at the same temperature for 16 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 30% to 100%) and concentrated to obtain the desired compound (0.193 g, 87.7%) as a white solid.

Step 2: Synthesis of Compound 468

4-(((3R, 5S)-3,5-dimethyl-4-(4-((4-methylpiperazine-1-yl)methyl)benzyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 5-2, 0.192g, 0.413mmol) and hydroxylamine (0.506mL, 8.264mmol, 50.00% aqueous solution) were dissolved in methanol (3mL) at room temperature, and potassium hydroxide (0.232g, 4.132mmol) was added to the solution, which was then stirred at the same temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to give compound 468 (0.041g, 21.5%) as a white solid.

¹ H-NMR (400 MHz, DMSO-d ₆ )δ11.1 (brs, 1H), 9.06 (brs, 1H), 7.68 (d, 2H, J=8.1Hz), 7.31 (d, 2H, J=7. 9Hz), 7.27 (d, 2H, J=8.0Hz), 7.18 (d, 2H, J=7.9Hz), 3.70 (s, 2H), 3.42 (s, 2 H), 3.39(s, 2H), 2.67-2.61(m, 2H), 2.59-2.54(m, 2H), 2.43-2.17(m, 8H) , 2.13 (s, 3H), 1.79 (t, 2H, J = 11.1Hz), 0.89 (d, 6H, J = 6.0Hz); LRMS (ES) m/z 466.3(M ⁺ +1).

Example 223: Synthesis of Compound 472 ((E)-3-(4-(((3R,5S)-3,5-dimethyl-4-(3-(morpholinomethyl) (4-(4-(4-methyl)phenyl)piperazin-1-yl)methyl)phenyl)-N-hydroxyacrylamide)

Step 1: Synthesis of (E)-3-(4-(((3R,5S)-4-(3-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl methyl)phenyl)acrylate

Methyl (E)-3-(4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)acrylate (Formula 9-1, 0.300 g, 1.040 mmol), 3-(bromomethyl)benzaldehyde (0.207 g, 1.040 mmol), and _Cs2CO3 (0.678 g, 2.081 mmol) were dissolved in acetonitrile (3 mL) at room temperature, and the solution was stirred at the same temperature _for 16 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane, and the extract was passed through a plastic filter to remove the solid residue and the aqueous layer, then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 12 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to give the desired compound (0.250 g, 59.2%) as a yellow oil.

Step 2: Synthesis of (E)-3-(4-(((3R,5S)-3,5-dimethyl-4-(3-(morpholinomethyl)benzyl)piperazine-1-yl)- methyl)phenyl)acrylate

Methyl (E)-3-(4-(((3R,5S)-4-(3-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)acrylate (Formula 10-1, 0.250 g, 0.616 mmol) and morpholine (0.060 mL, 0.677 mmol) were dissolved in dichloromethane (3 mL) and stirred at room temperature for 1 hour. Na(OAc) _3BH (0.196 g, 0.924 mmol) was added to the reaction solution, which was then further stirred at the same temperature for 16 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 30% to 100%) and concentrated to give the desired compound (0.186 g, 63.1%) as a yellow oil.

Step 3: Synthesis of Compound 472

(E) -3- (4- (( (3R, 5S) -3, 5- dimethyl -4- (3- (morpholinomethyl) benzyl) piperazin-1-yl) methyl) phenyl) acrylate (Formula 10-2, 0.186 g, 0.389 mmol) and hydroxylamine (0.476 mL, 7.788 mmol, 50.00% aqueous solution) were dissolved in methanol (4 mL) at room temperature, and potassium hydroxide (0.219 g, 3.894 mmol) was added to the solution, which was then stirred at the same temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (Waters, _C18 ; acetonitrile/0.1% trifluoroacetic acid = from 5% to 70%), followed by SPE cartridge (PL- _HCO3 MP SPE) and concentrated to give the desired compound 472 (0.142 g, 63.4%) as a white solid.

¹ H-NMR (400MHz, DMSO-d ₆ )δ10.8(brs, 1H), 9.06(brs, 1H), 7.51-7.49(m, 2H), 7.45-7.41(m, 1H), 7.38-7.19(m, 4H), 7.17-7.11(m, 2H), 6.44-6.41(m, 1H), 3. 71 (s, 2H), 3.56 (s, 4H), 3.43-3.41 (m, 4H), 2.65-2.62 (m, 4H), 2.33 (brs, 4H), 1.82-1.72 (m, 2H), 0.89 (d, 6H, J=6.0Hz); LRMS (ES) m/z 479.3(M ⁺ +1).

Example 224: Synthesis of Compound 475 ((E)-3-(4-(((2S,6R)-2,6-dimethyl-4-(3-(pyrrolidine-1- (methyl)benzyl)piperazin-1-yl)methyl)phenyl)-N-hydroxyacrylamide)

Step 1: Synthesis of tert-butyl (3R,5S)-3,5-dimethylpiperazine-1-carboxylate

(2S,6R)-2,6-dimethylpiperazine (10.000 g, 87.573 mmol) and TEA (24.278 mL, 175.147 mmol) were dissolved in dichloromethane (150 mL) at room temperature, and _Boc2O (20.119 mL, 87.573 mmol) was added to the solution, which was then stirred at the same temperature for 16 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 80 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to give the desired compound (15.393 g, 82.0%) as a yellow solid.

Step 2: Synthesis of (3R,5S)-4-(4-((E)-3-methoxy-3-oxoprop-1-en-1-yl)benzyl)-3,5-diol tert-Butyl methylpiperazine-1-carboxylate

Tert-butyl (3R,5S)-3,5-dimethylpiperazine-1-carboxylate (Formula 8-1, 5.000 g, 23.332 mmol), methyl 3-(4-bromomethyl)cinnamate (Formula 8-4, 5.952 g, 23.332 mmol), and _Cs2CO3 (15.204 _g , 46.664 mmol) were mixed in acetonitrile (150 mL) at room temperature and heated under reflux, then cooled to room temperature. The reaction mixture was filtered through a filter paper filter to remove solids, and the filtrate was concentrated under reduced pressure to remove the solvent. The concentrate was purified by column chromatography (silica, 80 g cartridge; ethyl acetate/hexane = from 0% to 20%) and concentrated to obtain the desired compound (6.800 g, 75.0%) as a yellow oil.

Step 3: Synthesis of methyl (E)-3-(4-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)phenyl)acrylate

Tert-butyl (3R,5S)-4-(4-((E)-3-methoxy-3-oxoprop-1-en-1-yl)benzyl)-3,5-dimethylpiperazine-1-carboxylate (6.800 g, 17.503 mmol) and HCl (4.00 M in dioxane, 21.879 mL, 87.516 mmol) were dissolved in 1,4-dioxane (100 mL) at room temperature, and the solution was stirred at the same temperature for 16 hours. Then, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The precipitated solid was filtered, washed with hexane, and dried to give the desired compound (2.970 g, 58.8%) as a brown solid.

Step 4: Synthesis of (E)-3-(4-(((2S,6R)-4-(3-formylbenzyl)-2,6-dimethylpiperazin-1-yl)methyl methyl)phenyl)acrylate

Methyl (E)-3-(4-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)phenyl)acrylate (Formula 17-1, 0.300 g, 1.040 mmol), 3-(bromomethyl)benzaldehyde (0.207 g, 1.040 mmol), and _Cs2CO3 (0.678 g, 2.081 mmol) were dissolved in acetonitrile (3 mL) at room temperature, and the solution was stirred at the same temperature _for 16 hours. The reaction mixture was filtered through a filter paper filter to remove solids, and the filtrate was concentrated under reduced pressure to remove the solvent. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to give the desired compound (0.293 g, 69.3%) as a white solid.

Step 5: Synthesis of (E)-3-(4-(((2S,6R)-2,6-dimethyl-4-(3-(pyrrolidin-1-ylmethyl)benzyl)piperidin (methyl)phenyl)acrylate

Methyl (E)-3-(4-(((2S,6R)-4-(3-formylbenzyl)-2,6-dimethylpiperazin-1-yl)methyl)phenyl)acrylate (Formula 17-2, 0.130 g, 0.320 mmol) and pyrrolidine (0.029 mL, 0.352 mmol) were dissolved in dichloromethane (3 mL) and stirred at room temperature for 1 hour. Na(OAc) _3BH (0.102 g, 0.480 mmol) was added to the reaction solution, which was then further stirred at the same temperature for 16 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to give the desired compound (0.062 g, 42.0%) as a yellow oil.

Step 6: Synthesis of Compound 475

(E) -3- (4- (( (2S, 6R) -2,6- dimethyl -4- (3- (pyrrolidin-1-ylmethyl) benzyl) piperazine-1-yl) methyl) phenyl) acrylate (Formula 17-3, 0.062 g, 0.133 mmol) and hydroxylamine (0.163 mL, 2.664 mmol, 50.00% aqueous solution) were dissolved in methanol (2 mL) at room temperature, and potassium hydroxide (0.075 g, 1.332 mmol) was added to the solution, which was then stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution (10 mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered, washed with hexane, and dried to give compound 475 (0.039 g, 63.8%) as a white solid.

¹ H-NMR (400MHz, DMSO-d ₆ )δ9.58(brs, 1H), 7.45-7.40(m, 2H), 7.33-7.31(m, 2H), 7.27-7.21(m, 3H), 7.18-7.12(m, 2H), 6.39-6.35(m, 1H), 3.71(s, 2H), 3.53(s, 2H), 2.65-2.63 (m, 3H), 2.55-2.50 (m, 3H), 2.39-2.33 (m, 4H), 1.78 (t, 2H, J=10.4Hz), 1.67 (s, 4H), 0.89 (d, 6H, J=6.0Hz); LRMS (ES) m/z 463.2(M ⁺⁺ 1).

Example 225: Synthesis of Compound 476 ((E)-3-(4-(((2S,6R)-4-(3-((diethylamino)methyl)benzyl) (2,6-dimethylpiperazin-1-yl)methyl)phenyl)-N-hydroxyacrylamide)

Step 1: Synthesis of (E)-3-(4-(((2S,6R)-4-(3-((diethylamino)methyl)benzyl)-2,6-dimethyl Methyl piperazin-1-yl)methyl)phenyl)acrylate

Methyl (E)-3-(4-(((2S,6R)-4-(3-formylbenzyl)-2,6-dimethylpiperazin-1-yl)methyl)phenyl)acrylate (Formula 17-2, 0.130 g, 0.320 mmol) and diethylamine (0.039 g, 0.352 mmol) were dissolved in dichloromethane (3 mL) and stirred at room temperature for 1 hour. Na(OAc) _3BH (0.102 g, 0.480 mmol) was added to the reaction solution, which was then further stirred at the same temperature for 16 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to give the desired compound (0.061 g, 41.1%) as a yellow oil.

Step 2: Synthesis of Compound 476

(E)-3-(4-(((2S,6R)-4-(3-((diethylamino)methyl)benzyl)-2,6-dimethylpiperazin-1-yl)methyl)phenyl)acrylate (Formula 17-3, 0.061 g, 0.134 mmol) and hydroxylamine (0.164 mL, 2.683 mmol, 50.00% aqueous solution) were dissolved in methanol (2 mL) at room temperature, and potassium hydroxide (0.075 g, 1.342 mmol) was added to the solution, which was then stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to give compound 476 (0.026 g, 41.2%) as a white solid.

¹ H-NMR (400MHz, DMSO-d ₆ )δ10.7(brs, 1H), 9.04(brs, 1H), 7.47-7.45(m, 3H), 7.37-7.36(m, 2H), 7.25- 7.21(m, 2H), 7.16-7.11(m, 2H), 6.42-6.38(m, 1H), 3.72(s, 2H), 3.50(s, 2H), 3.37(s, 2H), 2.65-2.63(m, 2H), 2.62-2.50(m, 2H), 2.42(q, 4H, J=7.1Hz), 1.7 8 (t, 2H, J = 10.4Hz), 0.95 (t, 6H, J = 7.1Hz), 0.87 (d, 6H, J = 6.0Hz); LRMS (ES) m/z 465.3(M ⁺ +1).

Example 226: Synthesis of Compound 477 ((E)-3-(4-(((2S,6R)-4-(4-(furan-2-yl)benzyl)-2,6- dimethylpiperazin-1-yl)methyl)phenyl)-N-hydroxyacrylamide)

Step 1: Synthesis of (E)-3-(4-(((2S,6R)-4-(4-bromobenzyl)-2,6-dimethylpiperazin-1-yl)methyl)benzene Methyl acrylate

Methyl (E)-3-(4-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)phenyl)acrylate (Formula 17-1, 0.200 g, 0.694 mmol), 1-(bromomethyl)-4 _- bromobenzene (0.173 g, 0.694 mmol), and _Cs2Co3 (0.452 g, 1.387 mmol) were dissolved in acetonitrile (3 mL) at room temperature, and the solution was stirred at the same temperature for 16 hours. The reaction mixture was filtered through a filter paper filter to remove solids, and the filtrate was concentrated under reduced pressure to remove the solvent. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to give the desired compound (0.209 g, 65.9%) as a white solid.

Step 2: Synthesis of (E)-3-(4-(((2S,6R)-4-(4-(furan-2-yl)benzyl)-2,6-dimethylpiperazine-1-yl)- methyl)phenyl)acrylate

1,2-Dimethoxyethane (0.9 mL)/water (0.1 mL) was added to a mixture of (E)-methyl 3-(4-(((2S,6R)-4-(4-bromobenzyl)-2,6-dimethylpiperazin-1-yl)methyl)phenyl)acrylate (Formula 18-1, 0.100 g, 0.219 mmol), furan-2-boronic acid (0.027 g, 0.240 mmol), Pd(dbpf) _Cl₂ (0.007 g, 0.011 mmol), and _{Na₂CO₃ (} 0.070 g, 0.656 mmol) at room temperature, and the solution was stirred at 50°C for 16 hours, then cooled to room temperature to terminate the reaction. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; 4 g cartridge; methanol/dichloromethane = from 0% to 3%) and concentrated to give the desired compound (0.080 g, 82.4%) as a white solid.

Step 3: Synthesis of Compound 477

(E) -3- (4- (( (2S, 6R) -4- (4- (furan -2- base) benzyl) -2,6- dimethylpiperazine -1- base) methyl) phenyl) methyl acrylate (Formula 18-2, 0.077 g, 0.174 mmol), hydroxylamine (0.213 mL, 3.478 mmol, 50.00% aqueous solution) and potassium hydroxide (0.098 g, 1.739 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution (20 mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered, washed with hexane, and dried to give compound 477 (0.075 g, 96.8%) as a brown solid.

¹ H-NMR (400MHz, DMSO-d ₆ )δ9.23(brs, 1H), 7.73-7.72(m, 1H), 7.65-7.63(m, 1H), 7.50-7.48(m, 1H), 7. 38-7.36(m, 2H), 7.33-7.27(m, 3H), 7.25-7.23(m, 1H), 7.06-7.02(m, 1H), 6.90 (d, 1H, J=3.3Hz), 6.59-6.57(m, 1H), 6.37-6.32(m, 1H), 3.70(s, 2H), 3.39(s, 2H), 2.66-2.53 (m, 4H), 1.82-1.76 (m, 2H), 0.90 (d, 6H, J=5.9Hz); LRMS (ES) m/z 446.2(M ⁺ +1).

Example 227: Synthesis of Compound 478 (4-(((2S,6R)-4-(3-((diethylamino)methyl)benzyl)-2,6- dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide (hydrochloride)

Step 1: Synthesis of 4-(((2S,6R)-4-(3-((diethylamino)methyl)benzyl)-2,6-dimethylpiperazine-1-yl)- methyl)benzoate

Methyl 4-(((2S,6R)-4-(3-formylbenzyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 17-2, 0.150 g, 0.394 mmol) and diethylamine hydrochloride (0.065 g, 0.591 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 1 hour. Na(OAc) _3BH (0.167 g, 0.788 mmol) was added to the reaction solution, which was then further stirred at the same temperature for 17 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 5% to 10%) and concentrated to give the desired compound (0.054 g, 31.3%) as an orange oil.

Step 2: Synthesis of Compound 478

4-(((2S,6R)-4-(3-((diethylamino)methyl)benzyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoic acid methyl ester (Formula 17-3, 0.054g, 0.123mmol), hydroxylamine (0.151mL, 2.468mmol, 50.00% aqueous solution) and potassium hydroxide (0.069g, 1.234mmol) were dissolved in methanol (3mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the obtained concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The product was used without additional purification (0.045g, 83.1%, light brown oil).

Step 3: Synthesis of the hydrochloride salt of compound 478

4-(((2S,6R)-4-(3-((diethylamino)methyl)benzyl)-2,6-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide (0.048 g, 0.110 mmol) and HCl (4.00 M solution in dioxane, 0.137 mL, 0.548 mmol) were dissolved in 1,4-dioxane (3 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and ethyl acetate (20 mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered, washed with ethyl acetate, and dried to give compound 478 (0.039 g, 75.0%) as a white solid.

¹ H-NMR (400MHz, D ₂ O) δ7.65 (d, 2H, J=7.6Hz), 7.51 (d, 2H, J=8.4Hz), 7.46-7.42 (m, 4H), 4.52 (s, 2H), 2.22 (s, 2H), 2 .20 (s, 2H), 3.47-3.44 (m, 4H), 3.08-3.05 (m, 6H), 1.42 (d, 6H, J=5.7Hz), 1.17 (t, 6H, J=7.0Hz).

Example 228: Synthesis of Compound 479 (4-(((2S,6R)-2,6-dimethyl-4-(3-pyrrolidin-1-ylmethyl) (Benzyl)piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of methyl 4-(((2S,6R)-2,6-dimethyl-4-(3-(pyrrolidin-1-ylmethyl)benzyl)piperazin- 1- yl)methyl)benzoate

Methyl 4-(((2S,6R)-4-(3-formylbenzyl)-2,6-dimethylpiperazin-1-yl)methyl)benzoate (Formula 17-2, 0.150 g, 0.394 mmol) and pyrrolidine (0.049 mL, 0.591 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 1 hour. Na(OAc) _3BH (0.167 g, 0.788 mmol) was added to the reaction solution, which was then further stirred at the same temperature for 17 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 5% to 10%) and concentrated to give the desired compound (0.122 g, 71.0%) as an orange oil.

Step 2: Synthesis of Compound 479

4-(((2S,6R)-2,6-dimethyl-4-(3-(pyrrolidin-1-ylmethyl)benzyl)piperazine-1-yl)methyl)benzoic acid methyl ester (Formula 17-3, 0.122g, 0.280mmol), hydroxylamine (0.343mL, 5.601mmol, 50.00% aqueous solution) and potassium hydroxide (0.157g, 2.801mmol) were dissolved in methanol (5mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution was added to the obtained concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to obtain compound 479 (0.069g, 56.4%) as a white solid.

¹ H-NMR (400MHz, DMSO-d ₆ )δ11.11 (brs, 1H), 9.05 (brs, 1H), 7.66 (d, 2H, J=8.1Hz), 7.41 (d, 2H, J=8.1Hz), 7.26-7.22 (m, 2H), 7.15 (dd, 2H, J=7.3, 7.3Hz), 3.74 (s, 2H), 3.54(s, 2H), 3.39(s, 2H), 2.65(d, 2H, J=10.8Hz), 2.56-2.55(m, 2H), 2 .40(s, 4H), 1.79(t, 2H, J=10.6Hz), 1.67(s, 4H), 0.87(d, 6H, J=6.1Hz).

Example 229: Synthesis of Compound 480 ((E)-3-(4-(((2S,6R)-2,6-dimethyl-4-(3-(pyrrolidine-1- (methyl)benzoyl)piperazin-1-yl)methyl)phenyl)-N-hydroxyacrylamide)

Step 1: Synthesis of (E)-3-(4-(((2S,6R)-4-(3-formylbenzoyl)-2,6-dimethylpiperazine-1-yl)- methyl)phenyl)acrylate

Methyl (E)-3-(4-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)phenyl)acrylate (Formula 17-1, 0.300 g, 1.040 mmol), 3-formylbenzoic acid (0.172 g, 1.144 mmol), EDCI (0.399 g, 2.081 mmol), HOBt (0.319 g, 2.081 mmol) and DIPEA (0.921 mL, 5.201 mmol) were dissolved in dichloromethane (3 mL) at room temperature, and the solution was stirred at the same temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 30% to 40%) and concentrated to give the desired compound (0.386 g, 88.2%) as a white solid.

Step 2: Synthesis of (E)-3-(4-(((2S,6R)-2,6-dimethyl-4-(3-(pyrrolidin-1-ylmethyl)benzoyl) methyl)piperazin-1-yl)methyl)phenyl)acrylate

Methyl (E)-3-(4-(((2S,6R)-4-(3-formylbenzoyl)-2,6-dimethylpiperazin-1-yl)methyl)phenyl)acrylate (Formula 17-2, 0.190 g, 0.452 mmol) and pyrrolidine (0.035 g, 0.497 mmol) were dissolved in dichloromethane (3 mL) and stirred at room temperature for 1 hour. Na(OAc) _3BH (0.144 g, 0.678 mmol) was added to the reaction solution, which was then further stirred at the same temperature for 12 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to give the desired compound (0.105 g, 49.0%) as a white solid.

Step 3: Synthesis of Compound 480

(E)-3-(4-(((2S,6R)-2,6-dimethyl-4-(3-(pyrrolidin-1-ylmethyl)benzoyl)piperazin-1-yl)methyl)phenyl)acrylate (Formula 17-3, 0.100 g, 0.210 mmol) and hydroxylamine (0.257 mL, 4.205 mmol, 50.00% aqueous solution) were dissolved in methanol (3 mL) at room temperature, and potassium hydroxide (0.118 g, 2.103 mmol) was added to the solution, which was then stirred at the same temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to give compound 480 (0.049 g, 48.8%) as a white solid.

¹ H-NMR (400MHz, CD ₃ OD)δ7.45-7.30(m,9H),6.51-6.46(m,1H),4.41-4.38(m,1H),3.85(s,2H),3.67(s,2H),3.54-3.48(m,1H),3.04-3.00(m,1H) , 2.79-2.76(m, 1H), 2.70-3.67(m, 1H), 2.54(s, 6H), 1.80(s, 4H), 1.14-1.08(m, 3H), 0.93-0.92(m, 3H); LRMS(ES) m/z477.2(M ⁺ +1).

Example 230: Synthesis of Compound 481 (4-(((3R.5S)-3,5-dimethyl-4-(2-(1-(methylsulfonyl)- (1,2,3,6-tetrahydropyridin-4-yl)benzyl)piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(2-(((2S,6R)-4-(4-(methoxycarbonyl)benzyl)-2,6-dimethylpiperazin-1-yl) tert-Butyl (methyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate

1,2-Dimethoxyethane (15 mL) / water (5 mL) was added to a mixture of methyl 4-(((3R,5S)-4-(2-iodobenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 2-1, 1.600 g, 3.345 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.068 g, 6.689 mmol), Pd(dbpf)2Cl2 (0.109 _g , 0.167 _mmol ) and _Na2CO3 (0.709 g, 6.689 mmol) at room temperature, and the solution was stirred at 50°C for 17 hours, then cooled to room temperature to terminate the reaction. Saturated aqueous _sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 12 g cartridge; ethyl acetate/hexane = from 5% to 50%) and concentrated to give the desired compound (1.090 g, 61.1%) as a brown oil.

Step 2: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(2-(1,2,3,6-tetrahydropyridin-4-yl)benzyl)piperidin (methyl)benzoate

4-(2-(((2S,6R)-4-(4-(methoxycarbonyl)benzyl)-2,6-dimethylpiperazin-1-yl)methyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (Formula 3-1, 1.080 g, 2.024 mmol) was dissolved in 1,4-dioxane (15 mL) at room temperature, and HCl (4.00 M 1,4-dioxane solution, 5.059 mL, 20.236 mmol) was added to the solution, which was then stirred at the same temperature for 17 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and ethyl acetate (200 mL) and methanol (10 mL) were added to the concentrate, followed by stirring. The precipitated solid was filtered, washed with ethyl acetate, and dried to give the desired compound (0.851 g, 89.5%) as a light yellow solid.

Step 3: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(2-(1-methylsulfonyl)-1,2,3,6-tetrahydropyridine (4-pyridin-4-yl)benzyl)piperazin-1-yl)methyl)benzoic acid methyl ester

Methyl 4-(((3R,5S)-3,5-dimethyl-4-(2-(1,2,3,6-tetrahydropyridin-4-yl)benzyl)piperazin-1-yl)methyl)benzoate hydrochloride (Formula 3-2, 0.060 g, 0.128 mmol) and TEA (0.053 mL, 0.383 mmol) were dissolved in dichloromethane (4 mL) at room temperature, and MsCl (0.015 mL, 0.191 mmol) was added to the solution, followed by stirring at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to give the desired compound (0.055 g, 84.2%) as a light yellow oil.

Step 4: Synthesis of Compound 481

Methyl 4-(((3R,5S)-3,5-dimethyl-4-(2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)benzyl)piperazine-1-yl)methyl)benzoate (Formula 3-3, 0.055 g, 0.107 mmol), hydroxylamine (0.131 mL, 2.150 mmol, 50.00% aqueous solution) and potassium hydroxide (0.060 g, 1.075 mmol) were dissolved in methanol (2 mL)/tetrahydrofuran (1 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 481 (0.048 g, 87.1%) as a white solid.

¹ H-NMR (400MHz, DMSO-d ₆ )δ7.72 (d, 1H, J = 8.2Hz), 7.70 (d, 2H, J = 8.2Hz), 7.32 (d, 2H, J = 8.1Hz), 7.24 (dd, 1H, J=7.5, 7.5Hz), 7.15 (dd, 1H, J=7.4, 7.4Hz), 7.04 (d, 1H, J=7.4Hz), 5.59 (s, 1H), 3.8 3(d, 2H, J=2.1Hz), 3.62 (s, 2H), 3.45 (s, 2H), 3.40-3.38 (m, 2H), 2.65 (d, 2H, J=10.7 Hz), 2.61-2.57 (m, 2H), 2.40 (s, 2H), 1.85 (t, 2H, J=10.3Hz), 0.78 (d, 6H, J=6.0Hz).

Example 231: Synthesis of Compound 482 (4-(((3R,5S)-4-(2-(1-acetyl-1,2,3,6-tetrahydropyridine- 4-yl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(2-(1-acetyl-1,2,3,6-tetraoxypyridin-4-yl)benzyl)-3,5- Methyl dimethylpiperazin-1-yl)methyl)benzoate

Methyl 4-(((3R,5S)-3,5-dimethyl-4-(2-(1,2,3,6-tetrahydropyridin-4-yl)benzyl)piperazin-1-yl)methyl)benzoate hydrochloride (Formula 3-2, 0.060 g, 0.128 mmol) and TEA (0.053 mL, 0.383 mmol) were dissolved in dichloromethane (4 mL) at room temperature, and acetic anhydride (0.020 g, 0.191 mmol) was added to the solution, followed by stirring at the same temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 5%) and concentrated to give the desired compound (0.046 g, 75.8%) as a light yellow oil.

Step 2: Synthesis of compound 482

Methyl 4-(((3R,5S)-4-(2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 3-3, 0.046 g, 0.097 mmol), hydroxylamine (0.118 mL, 1.934 mmol, 50.00% aqueous solution) and potassium hydroxide (0.054 g, 0.967 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 482 (0.036 g, 78.1%) as a white solid.

¹ H-NMR (400MHz, DMSO-d ₆ )δ11.05(brs, 1H), 9.12(brs, 1H), 7.71(d, 3H, J=7.9Hz), 7.36(d, 2H, J=7.9Hz), 7.23( dd, 1H, J=7.7, 7.7Hz), 7.14 (dd, 1H, J=7.4, 7.4Hz), 7.03 (d, 1H, J=7.5Hz), 5.55 (s, 1H) , 4.08 (d, 2H, J = 21.4Hz), 3.68-3.62 (m, 4H), 3.46 (s, 2H), 2.68-2.57 (m, 4H), 2.35 (s, 1 H), 2.25 (s, 1H), 2.07 (d, 3H, J=8.5Hz), 1.85 (t, 2H, J=10.0Hz), 0.78 (d, 6H, J=5.9Hz).

Example 232: Synthesis of Compound 483 (4-(((3R,5S)-3,5-dimethyl-4-(2-(1-(2,2,2-trifluoroethyl) 4-(2-(2-(2-(2-(2-(2-methyl-1-thiazolyl)piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(2-(1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrafluoroethyl)- (4-Hydroxypyridin-4-yl)benzyl)piperazin-1-yl)methyl)benzoic acid methyl ester

Methyl 4-(((3R,5S)-3,5-dimethyl-4-(2-(1,2,3,6-tetrahydropyridin-4-yl)benzyl)piperazin-1-yl)methyl)benzoate (0.050 g, 0.115 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (Formula 3-2, 0.025 mL, 0.173 mmol), and _K₂CO₃ (0.032 g, 0.231 mmol) were dissolved in _acetonitrile (4 mL) at room temperature, and the solution was stirred at the same temperature for 4 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 12 g cartridge; ethyl acetate/hexane = from 0% to 30%) and concentrated to obtain the desired compound (0.032 g, 53.9%) as a yellow oil.

Step 2: Synthesis of compound 483

Methyl 4-(((3R,5S)-3,5-dimethyl-4-(2-(1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridin-4-yl)benzyl)piperazin-1-yl)methyl)benzoate (Formula 3-3, 0.032 g, 0.062 mmol), hydroxylamine (0.076 mL, 1.241 mmol, 50.00% aqueous solution) and potassium hydroxide (0.035 g, 0.621 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (Waters, _C18 ; acetonitrile/0.1% aqueous trifluoroacetic acid solution = from 5% to 70%), followed by SPE cartridge (PL- _HCO3 MPS PE) and concentration to give compound 483 (0.007 g, 21.8%) as a white solid.

¹ H-NMR (400 MHz, DMSO-d ₆ )δ9.03 (s, 1H), 7.71-7.69 (m, 3H), 7.39-7.38 (m, 2H), 7.22 (dd, 1H, J=7.3 , 7.3Hz), 7.13 (dd, 1H, J=7.2, 7.2Hz), 7.03 (d, 1H, J=7.4Hz), 5.49 (s, 1H), 3.62(s, 2H), 3.47(s, 2H), 3.31-3.28(m, 4H), 2.88(t, 2H, J=5.0Hz), 2.68- 2.61 (m, 4H), 2.33-2.30 (m, 2H), 1.85-1.84 (m, 2H), 0.79 (d, 6H, J=5.7Hz).

Example 233: Synthesis of Compound 484 (N-hydroxy-4-(((3R,5S)-4-(2-(1-isopropyl-1,2,3,6-tetramethyl-1- (4-(2-(2-(2-(2-piperidin-4-yl)-2-hydrogen)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(2-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)benzyl)-3,5- Methyl dimethylpiperazin-1-yl)methyl)benzoate

4-(((3R, 5S)-3,5-dimethyl-4-(2-(1,2,3,6-tetrahydropyridin-4-yl)benzyl)piperazine-1-yl)methyl)benzoic acid methyl ester hydrochloride (Formula 3-2, 0.150 g, 0.319 mmol) and TEA (0.222 mL, 1.596 mmol) were dissolved in dichloromethane (10 mL) at room temperature, and 2-iodopropane (0.075 g, 0.479 mmol) was added to the solution, which was then heated under reflux for 5 hours and then cooled to room temperature to terminate the reaction. Water was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexanes = from 0% to 20%) and concentrated, and the resulting material was then purified by chromatography (Waters, _C18 ; acetonitrile/0.1% aqueous trifluoroacetic acid = from 5% to 70%), followed by purification by SPE cartridge (PL- _HCO3 MP SPE) and concentration to give the desired compound (0.032 g, 21.1%) as a light yellow oil.

Step 2: Synthesis of Compound 484

At room temperature, 4-(((3R, 5S)-4-(2-(1-isopropyl-1,2,3,6-tetrahydropyridine-4-yl)benzyl)-3,5-dimethylpiperazine-1-yl)methyl)methyl benzoate (Formula 3-3, 0.032g, 0.067mmol), hydroxylamine (0.082mL, 1.345mmol, 50.00% aqueous solution) and potassium hydroxide (0.038g, 0.673mmol) were dissolved in methanol (3mL), and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution (20mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered, washed with water, and dried to give compound 484 (0.006g, 18.7%) as a white solid.

¹ H-NMR (400MHz, CD ₃ OD) δ7.78 (d, 1H, J=6.7Hz), 7.74 (d, 2H, J=8.3Hz), 7.47 (d, 2H, J=8.1Hz), 7.20 (dd , 1H, J=6.5, 6.5Hz), 7.13 (dd, 1H, J=7.2, 7.2Hz), 7.03 (d, 1H, J=7.4Hz), 5.55 (s, 1 H), 3.75(s, 2H), 3.57(s, 2H), 3.30(s, 2H), 2.87-2.81(m, 3H), 2.76-2.69(m, 4H), 2.42 (s, 2H), 1.97 (t, 2H, J=10.4Hz), 1.19 (d, 6H, J=6.5Hz), 0.87 (d, 6H, J=6.0Hz).

Example 234: Synthesis of Compound 485 (4-(((3R,5S)-4-(2-(1-ethyl-1,2,3,6-tetraoxypyridine-4- 1-(4-(4-(4-(4-methyl)piperazin-1-yl)methyl)-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-(2-(1-ethyl-1,2,3,6-tetraoxypyridin-4-yl)benzyl)-3,5-diol Methyl benzoate

Methyl 4-(((3R,5S)-3,5-dimethyl-4-(2-(1,2,3,6-tetrahydropyridin-4-yl)benzyl)piperazin-1-yl)methyl)benzoate hydrochloride (Formula 3-2, 0.150 g, 0.319 mmol) and TEA (0.222 mL, 1.596 mmol) were dissolved in dichloromethane (4 mL) at room temperature, and 2-iodopropane (0.048 mL, 0.479 mmol) was added to the solution, which was then stirred at the same temperature for 3 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 20%) and concentrated to give the desired compound (0.048 g, 32.6%) as a yellow liquid.

Step 2: Synthesis of compound 485

Methyl 4-(((3R,5S)-4-(2-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)benzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 3-3, 0.048 g, 0.104 mmol), hydroxylamine (0.127 mL, 2.080 mmol, 50.00% aqueous solution) and potassium hydroxide (0.058 g, 1.040 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure to give compound 485 (0.033 g, 68.6%) as a white solid.

¹ H-NMR (400MHz, DMSO-d ₆ )δ7.70 (d, 3H, J=8.2Hz), 7.35 (d, 2H, J=8.1Hz), 7.20 (dd, 1H, J=7.5, 7.5Hz), 7 .12 (dd, 1H, J=7.5, 7.5Hz), 7.00 (dd, 1H, J=7.5, 1.3Hz), 5.49 (s, 1H), 3.62 (s, 2 H), 3.46 (s, 2H), 3.03 (s, 2H), 2.66-2.56 (m, 6H), 2.45 (q, 2H, J=7.2Hz), 2.28 ( brs, 2H), 1.84 (t, 2H, J=10.4Hz), 1.07 (t, 3H, J=7.2Hz), 0.78 (d, 6H, J=6.1Hz).

Example 235: Synthesis of Compound 486 (4-(((3R,5S)-4-(4-((4-acetylpiperazin-1-yl)methyl)benzyl) (3,5-dimethylpiperazin-1-yl)methyl)-N-hydroxybenzamide (hydrochloride)

Step 1: Synthesis of 4-(((3R,5S)-4-(4-((4-acetylpiperazin-1-yl)methyl)benzyl)-3,5-dimethyl Methyl piperazin-1-yl)methyl)benzoate

Methyl 4-(((3R,5S)-4-(4-formylbenzyl)-3,5-dimethylpiperazin-1-yl)methyl)benzoate (Formula 5-1, 0.180 g, 0.473 mmol) and 1-(piperazin-1-yl)ethanone (0.067 g, 0.520 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 1 hour. Na(OAc) _3BH (0.150 g, 0.710 mmol) was added to the reaction solution, which was then further stirred at the same temperature for 16 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The extract was passed through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica; 4 g cartridge; ethyl acetate/hexane = from 30% to 100%) and concentrated to give the desired compound (0.112 g, 48.2%) as a white solid.

Step 2: Synthesis of Compound 486

4-(((3R, 5S)-4-(4-((4-acetylpiperazine-1-yl)methyl)benzyl)-3,5-dimethylpiperazine-1-yl)methyl)benzoic acid methyl ester (Formula 5-2, 0.112g, 0.228mmol) and hydroxylamine (0.279mL, 4.563mmol, 50.00% aqueous solution) were dissolved in methanol (3mL) at room temperature, and potassium hydroxide (0.128g, 2.282mmol) was added to the solution, which was then stirred at the same temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (Waters, _C18 ; acetonitrile/0.1% aqueous trifluoroacetic acid solution = from 5% to 70%), followed by SPE cartridge (PL- _HCO3 MP SPE) and concentration to give compound 486 (0.049 g, 43.5%) as a white solid.

Step 3: Synthesis of the hydrochloride salt of compound 486

Compound 486 (0.049 g, 0.099 mmol) and HCl (4.00 M solution in dioxane, 0.124 mL, 0.496 mmol) were dissolved in 1,4-dioxane (1 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The precipitated solid was filtered, washed with ethyl acetate, and dried to give the desired compound (0.034 g, 63.9%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.72 (d, 2H, J=8.2Hz), 7.61-7.55 (m, 4H), 7.52 (d, 2H, J=8.0Hz), 4.59 (s, 2H), 4.39 (s, 2H), 4.23 (s, 2H), 3.71-3.69(m, 8H), 3.56-3.46(m, 6H), 3.06(m, 3H), 2.11(s, 3H), 1.51-1.50(m, 6H); LRMS(ES)m/z 494.2(M ⁺ +1).

Example 236: Synthesis of Compound 487 ((E)-3-(4-(((2S,6R)-4-(3-((diethylamino)methyl)benzene (formyl)-2,6-dimethylpiperazin-1-yl)methyl)phenyl)-N-hydroxyacrylamide)

Step 1: Synthesis of (E)-3-(4-(((2S,6R)-4-(3-((diethylamino)methyl)benzoyl)-2,6-diol methylpiperazin-1-yl)methyl)phenyl)acrylate

Methyl (E)-3-(4-(((2S,6R)-4-(3-formylbenzoyl)-2,6-dimethylpiperazin-1-yl)methyl)phenyl)acrylate (Formula 17-2, 0.190 g, 0.452 mmol) and diethylamine (0.054 g, 0.497 mmol) were dissolved in dichloromethane (3 mL) and stirred at room temperature for 1 hour. Na(OAc) _3BH (0.144 g, 0.678 mmol) was added to the reaction solution, which was then further stirred at the same temperature for 12 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to give the desired compound (0.060 g, 27.8%) as a white solid.

Step 2: Synthesis of Compound 487

(E)-3-(4-(((2S,6R)-4-(3-((diethylamino)methyl)benzoyl)-2,6-dimethylpiperazin-1-yl)methyl)phenyl)acrylate (Formula 17-3, 0.060 g, 0.126 mmol) and hydroxylamine (0.154 mL, 2.512 mmol, 50.00% aqueous solution) were dissolved in methanol (2 mL) at room temperature, and potassium hydroxide (0.070 g, 1.256 mmol) was added to the solution, which was then stirred at the same temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to give compound 487 (0.006 g, 9.3%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ )δ7.57-7.53(m, 1H), 7.51-7.46(m, 3H), 7.45-7.39(m, 4H), 7.36-7.34(m , 1H), 6.45 (d, 1H, J=15.9Hz), 4.42-4.39 (m, 1H), 3.87-3.82 (m, 2H), 3.53- 3.50 (m, 1H), 3.07-3.01 (m, 1H), 2.83-2.77 (m, 2H), 2.73-2.68 (m, 4H), 2.5 7(s, 1H), 1.29(m, 2H), 1.15-1.11(m, 9H), 0.93-0.88(m, 3H); LRMS(ES)m/z 479.2(M ⁺⁺ 1).

Example 237: Synthesis of Compound 520 (3-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)- N-hydroxy-1H-indole-6-carboxamide)

Step 1: Synthesis of 3-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)-1H-indole-6-carboxylic acid Methyl ester

3-Formyl-1H-indole-6-carboxylate (Formula 8-4, 0.500 g, 2.461 mmol), (2S,6R)-1-benzyl-2,6-dimethylpiperazine (0.553 g, 2.707 mmol) and STAB (0.782 g, 3.691 mmol) were dissolved in dichloromethane (20 mL) at room temperature, and the solution was stirred at the same temperature for 5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 12 g cartridge; ethyl acetate/hexane = from 0% to 30%) and concentrated to obtain the desired compound (0.551 g, 57.2%) as a creamy white solid.

Step 2: Synthesis of Compound 520

3-(((3R, 5S)-4-benzyl-3,5-dimethylpiperazine-1-yl)methyl)-1H-indole-6-carboxylate (Formula 8-5, 0.150g, 0.383mmol), hydroxylamine (50.00% aqueous solution, 0.234mL, 3.831mmol) and potassium hydroxide (0.215g, 3.831mmol) were dissolved in dichloromethane (10mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution (20mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered and dried to give compound 520 (0.149g, 99.4%) as a white solid.

¹ H-NMR (400MHz, CD ₃ OD) δ7.80 (s, 1H), 7.56 (d, 2H, J=8.3Hz), 7.42 (d, 1H, J=8.3Hz), 7.34-7.25 (m, 5H), 7.16 (t, 1H, J=7.2Hz), 3.70 (s, 2H), 3.55 (s, 2H), 2.72 (d, 2H, J=10.0Hz), 2.55-2.53 (m, 2H), 1.78 (t, 2H, J=10.6Hz), 0.89 (s, 3H), 0.87 (s, 3H); LRMS (ES) m/z 393.0(M ⁺ +1).

Example 238: Synthesis of Compound 569 (5-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)- N-hydroxy-1H-indole-2-carboxamide)

Step 1: Synthesis of 5-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)-1H-indole-1,2-dimethylpiperazin-1-yl)methyl 1-(tert-Butyl) 2-ethyl formate

1-(tert-Butyl)-2-ethyl 5-(bromomethyl)-1H-indole-1,2-dicarboxylate (Formula 22-1, 2.000 g, 5.232 mmol), DIPEA (2.779 mL, 15.697 mmol) and (2S,6R)-1-benzyl-2,6-dimethylpiperazine (1.069 g, 5.232 mmol) were dissolved in dichloromethane (10 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The precipitated solid was filtered, washed with acetonitrile, and dried to give the desired compound (1.100 g, 41.6%) as a white solid.

Step 2: Synthesis of 5-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)-1H-indole-2-carboxylic acid Ethyl ester

5-(((3R, 5S)-4-benzyl-3,5-dimethylpiperazine-1-yl)methyl)-1H-indole-1,2-dicarboxylic acid 1-tert-butyl 2-ethyl ester (Formula 22-2, 1.100g, 2.175mmol) and hydrochloric acid (4.00M1,4-dioxane solution, 2.719mL, 10.877mmol) are mixed in 1,4-dioxane (2mL) at room temperature, and the mixture is stirred at the same temperature for 16 hours.Then, the reaction mixture is concentrated under reduced pressure to remove the solvent, and diethyl ether (20mL) is added to the concentrate, followed by stirring.The precipitated solid is filtered, washed with diethyl ether, and dried to obtain the desired compound (0.832g, 94.3%) as a light pink solid.

Step 3: Synthesis of Compound 569

At room temperature by 5-(((3R, 5S)-4-benzyl-3,5-dimethylpiperazine-1-yl) methyl)-1H-indole-2-ethyl formate (formula 22-3, 0.100g, 0.247mmol), hydroxylamine (50.00% aqueous solution, 0.151mL, 2.466mmol) and potassium hydroxide (0.138g, 2.466mmol) are dissolved in methanol (1mL)/tetrahydrofuran (1mL), and the solution is stirred at the same temperature for 1 hour.Then, the reaction mixture is concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution (20mL) is added to the concentrate, then stirred.The precipitated solid is filtered and dried to obtain compound 569 (0.079g, 81.6%), which is a white solid.

¹ H-NMR (400MHz, CD ₃ OD) δ7.46 (s, 1H), 7.38-7.28 (m, 5H), 7.24-7.20 (m, 1H), 7.11 (dd, 1H, J=8.4, 1.3Hz), 6.79 (s, 1H), 3.91 (s, 2H), 3.5 3 (s, 2H), 2.79 (d, 2H, J = 11.0Hz), 2.72-2.68 (m, 2H), 1.93 (t, 2H, J = 11.1Hz), 1.11 (s, 3H), 1.10 (s, 3H); LRMS (ES) m/z 393.0(M ⁺ +1).

Example 239: Synthesis of Compound 571 (5-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)- N-hydroxybenzofuran-2-carboxamide)

Step 1: Synthesis of 5-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)benzofuran-2-carboxylic acid Methyl ester

Methyl 5-(bromomethyl)benzofuran-2-carboxylate (Formula 8-4, 0.500 g, 1.858 mmol), DIPEA (0.720 g, 5.574 mmol) and (2S, 6R)-1-benzyl-2,6-dimethylpiperazine (0.380 g, 1.858 mmol) were dissolved in acetonitrile (10 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the precipitated solid was filtered, washed with acetonitrile, and dried to give the desired compound (0.200 g, 27.4%) as a white solid.

Step 2: Synthesis of compound 571

5-(((3R, 5S)-4-benzyl-3,5-dimethylpiperazine-1-yl)methyl)benzofuran-2-methylformate (Formula 8-5, 0.050g, 0.127mmol), hydroxylamine (50.00% aqueous solution, 0.078mL, 1.274mmol) and potassium hydroxide (0.071g, 1.274mmol) were dissolved in methanol (1mL)/tetrahydrofuran (1mL) at room temperature, and the solution was stirred for 1 hour at the same temperature. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution (20mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered and dried to obtain compound 571 (0.010g, 19.4%) as a light pink solid.

¹ H-NMR (400MHz, CD ₃ OD) δ7.60 (s, 1H), 7.49 (d, 1H, J=8.4Hz), 7.38-7.34 (m, 3H), 7.31 (t, 1H, J=7.5Hz), 7.25-7.21 (m, 2H), 3.92 (s, 2H), 3. 56 (s, 2H), 2.77 (d, 2H, J=10.8Hz), 2.73-2.66 (m, 2H), 1.94 (t, 2H, J=10.9Hz), 1.12 (s, 3H), 1.10 (s, 3H); LRMS (ES) m/z 392.2(M ⁺ -1).

Example 240: Synthesis of Compound 573 (6-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)- N-hydroxy-1H-indole-2-carboxamide)

Step 1: Synthesis of 6-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)-1H-indole-1,2-dimethylpiperazin-1-yl)methyl 1-tert-Butyl 2-methyl formate

1-tert-Butyl 2-methyl 6-(bromomethyl)-1H-indole-1,2-dicarboxylate (Formula 22-1, 0.410 g, 1.113 mmol), DIPEA (0.432 g, 3.340 mmol), and (2S,6R)-1-benzyl-2,6-dimethylpiperazine (0.227 g, 1.113 mmol) were dissolved in acetonitrile (10 mL) at room temperature, and the solution was stirred at the same temperature for 16 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 40 g cartridge; ethyl acetate/hexane = from 0% to 20%) and concentrated to obtain the desired compound (0.224 g, 40.9%) as a yellow liquid.

Step 2: Synthesis of 6-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)-1H-indole-2-carboxylic acid Methyl ester (hydrochloride)

6-(((3R, 5S)-4-benzyl-3,5-dimethylpiperazine-1-yl)methyl)-1H-indole-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (Formula 22-2, 0.224 g, 0.456 mmol) and hydrochloric acid (4.00 M 1,4-dioxane solution, 0.570 mL, 2.278 mmol) were dissolved in 1,4-dioxane (2 mL) at room temperature, and the solution was stirred at the same temperature for 16 hours. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and diethyl ether (20 mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered, washed with diethyl ether, and dried to give the desired compound (0.167 g, 85.6%) as an ochre solid.

Step 3: Synthesis of Compound 573

At room temperature by 6-(((3R, 5S)-4-benzyl-3,5-dimethylpiperazine-1-yl) methyl)-1H-indole-2-methylformate (formula 22-3, 0.050g, 0.117mmol), hydroxylamine (50.00% aqueous solution, 0.071mL, 1.168mmol) and potassium hydroxide (0.066g, 1.168mmol) are dissolved in methanol (1mL)/tetrahydrofuran (1mL), and the solution is stirred at the same temperature for 1 hour.Then, the reaction mixture is concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution (20mL) is added to the enriched material, then stirred.The precipitated solid is filtered and dried to obtain compound 573 (0.025g, 53.4%), which is a yellow solid.

¹ H-NMR (400MHz, CD ₃ OD) δ7.49 (d, 1H, J=8.3Hz), 7.37 (d, 2H, J=7.4Hz), 7.31 (t, 3H, J=7.5Hz), 7.23 (t, 1H, J=7.4Hz), 7.00 (d, 1H, J=8.2Hz), 6.81 (s, 1H), 3.91 (s, 2H), 3.55 (s, 2H), 2.79 (d, 2H, J=10.9Hz), 2.71-2.68 (m, 2H), 1.93 (t, 2H, J=10.7Hz), 1.11 (s, 3H), 1.10 (s, 3H); LRMS (ES) m/z 391.2(M ⁺ -1)

Example 241: Synthesis of Compound 574 (2-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)- N-hydroxybenzofuran-5-carboxamide)

Step 1: Synthesis of 2-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)benzofuran-5-carboxylic acid Methyl ester

Methyl 2-(bromomethyl)benzofuran-5-carboxylate (Formula 8-4, 0.691 g, 2.568 mmol), DIPEA (1.364 mL, 7.704 mmol) and (2S, 6R)-1-benzyl-2,6-dimethylpiperazine (0.525 g, 2.568 mmol) were dissolved in acetonitrile (10 mL) at room temperature, and the solution was stirred at the same temperature for 16 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 40 g cartridge; ethyl acetate/hexane = from 0% to 20%) and concentrated to give the desired compound (0.460 g, 45.6%) as a milky white solid.

Step 2: Synthesis of compound 574

At room temperature, 2-(((3R, 5S)-4-benzyl-3,5-dimethylpiperazine-1-yl)methyl)benzofuran-5-methylformate (Formula 8-5, 0.100g, 0.254mmol), hydroxylamine (50.00% aqueous solution, 0.155mL, 2.541mmol) and potassium hydroxide (0.143g, 2.541mmol) were dissolved in methanol (1mL)/tetrahydrofuran (1mL), and the solution was stirred at the same temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution (20mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered and dried to obtain compound 574 (0.013g, 13.0%), which was a light pink solid.

¹ H-NMR (400MHz, CD ₃ OD) δ8.00 (d, 1H, J=1.4Hz), 7.72 (dd, 1H, J=8.6, 1.8Hz), 7.50 (d, 1H, J=8.7Hz), 7.38-7.20 (m, 5H), 6.80 (s, 1H), 3.90 (s, 2H ), 3.70 (s, 2H), 2.85 (d, 1H, J = 10.7Hz), 2.76-2.71 (m, 2H), 2.07 (t, 2H, J = 11.0Hz), 1.12 (s, 3H), 1.10 (s, 3H); LRMS (ES) m/z 394.0(M ⁺ +1).

Example 242: Synthesis of Compound 609 (5-(((3R,5S)-3,5-dimethyl-4-(3-(morpholinomethyl)benzyl) (piperazin-1-yl)methyl)-N-hydroxypicolinamide)

Step 1: Synthesis of tert-butyl (3R,5S)-4-(3-formylbenzyl)-3,5-dimethylpiperazine-1-carboxylate

Tert-butyl (3R,5S)-3,5-dimethylpiperazine-1-carboxylate (Formula 8-1, 2.730 g, 12.739 mmol), 3-(bromomethyl)benzaldehyde (2.789 g, 14.013 mmol) and _Cs2CO3 (8.301 g, 25.478 mmol) were _mixed in acetonitrile (50 mL) at room temperature and the mixture was stirred at the same temperature for 18 hours. The reaction mixture was filtered through a filter paper filter to remove solids, and the filtrate was purified by column chromatography (silica, 120 g cartridge; ethyl acetate/hexane = from 5% to 30%) and concentrated to give the desired compound (2.730 g, 64.5%) as a yellow oil.

Step 2: Synthesis of tert-butyl (3R,5S)-3,5-dimethyl-4-(3-(morpholinomethyl)benzyl)piperazine-1-carboxylate

(3R,5S)-tert-butyl 4-(3-formylbenzyl)-3,5-dimethylpiperazine-1-carboxylate (Formula 23-1, 1.246 g, 3.749 mmol), morpholine (0.656 mL, 7.497 mmol), and acetic acid (0.429 mL, 7.497 mmol) were mixed in dichloromethane (15 mL), and the mixture was stirred at room temperature for 1 hour. Na(CN)BH ₃ (0.942 g, 14.995 mmol) was added to the reaction mixture, which was then further stirred at the same temperature for 4 hours. A saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 24 g cartridge; methanol/dichloromethane = from 0% to 10%) and concentrated to give the desired compound (1.272 g, 84.0%) as a yellow oil.

Step 3: Synthesis of 4-(3-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)benzyl)morpholine (hydrochloride)

(3R, 5S) -3,5- dimethyl -4- (3- (morpholinomethyl) benzyl) piperazine -1- carboxylic acid tert-butyl ester (Formula 23-2, 1.270g, 3.147mmol) and HCl (4.00M1, 4- dioxane solution, 3.934mL, 15.735mmol) were dissolved in dichloromethane (15mL) at room temperature, and the solution was stirred at the same temperature for 18 hours. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous sodium bicarbonate solution was added to the resulting concentrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The product was used without additional purification (0.855g, 89.5%, yellow oil).

Step 4: Synthesis of 5-(((3R,5S)-3,5-dimethyl-4-(3-(morpholinomethyl)benzyl)piperazin-1-yl)methane methyl picolinate

Methyl 5-formylpicolinate (0.200 g, 1.211 mmol), 4-(3-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)benzyl)morpholine (0.735 g, 2.422 mmol) and acetic acid (0.139 mL, 2.422 mmol) were mixed in dichloromethane (8 mL), and the mixture was stirred at room temperature for 1 hour. Na(CN)BH ₃ (0.304 g, 4.844 mmol) was added to the reaction mixture, which was then further stirred at the same temperature for 15 hours. Saturated aqueous sodium bicarbonate solution was then added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 12 g cartridge; ethyl acetate/hexane = from 60% to 100%) and concentrated to give the desired compound (0.317 g, 57.8%) as a yellow oil.

Step 5: Synthesis of Compound 609

A mixture of methyl 5-(((3R,5S)-3,5-dimethyl-4-(3-(morpholinomethyl)benzyl)piperazin-1-yl)methyl)picolinate (Formula 23-4, 0.059 g, 0.130 mmol) and hydroxylamine (0.333 mL, 2.594 mmol, 50.00% aqueous solution) was added to methanol (1 mL), and potassium hydroxide (0.130 mL, 1.297 mmol, 10.00 M aqueous solution) was added thereto at 0° C. The mixture was then stirred at the same temperature for 5 minutes and then at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was purified by column chromatography (Waters, C18; 0.1% aqueous formic acid/acetonitrile = from 5% to 30%), followed by purification by SPE cartridge (PL-HCO ₃ MP SPE) and concentration to give compound 609 (0.006 g, 10.2%) as a brown oil.

¹ H NMR (400MHz, CD ₃ OD) δ8.52 (s, 1H), 7.99-7.87 (m, 2H), 7.36 (s, 1H), 7.28-7.27 (m, 2H), 7.21-7.20 (m, 1H), 3.90 (s, 2H), 3.69-3.67 (m, 4H), 3.54-3.52 (m, 4H), 2.73-2.65 (m, 4H), 2.45 (s, 4H), 1.96 (t, 2H, J=10.6Hz), 1.09 (d, 6H, J=6.0Hz); LRMS (ES) m/z 454.5(M ⁺ +1).

Example 243: Synthesis of Compound 652 (4-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)- N,2-dihydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)-2-hydroxybenzoic acid ester

Methyl 4-(bromomethyl)-2-hydroxybenzoate (Formula 8-4, 1.144 g, 4.668 mmol), TEA (0.776 mL, 5.602 mmol) and (2S, 6R)-1-benzyl-2,6-dimethylpiperazine (0.954 g, 4.668 mmol) were dissolved in acetonitrile (10 mL) at room temperature, and the solution was stirred at the same temperature for 16 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica, 40 g cartridge; ethyl acetate/hexane = from 0% to 20%) to obtain the desired compound (0.583 g, 33.9%) as a yellow liquid.

Step 2: Synthesis of compound 652

At room temperature by 4-(((3R, 5S)-4-benzyl-3,5-dimethylpiperazine-1-yl) methyl)-2-hydroxybenzoic acid methyl ester (formula 8-5, 0.050g, 0.136mmol), hydroxylamine (50.00% aqueous solution, 0.083mL, 1.357mmol) and potassium hydroxide (0.076g, 1.357mmol) are dissolved in methanol (1mL)/tetrahydrofuran (1mL), and the solution is stirred at the same temperature for 1 hour.Then, the reaction mixture is concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution (20mL) is added to enriched material, then stirred.The precipitated solid is filtered and dried to obtain compound 652 (0.035g, 70.0%), which is a pink solid.

¹ H-NMR (400MHz, CD ₃ OD) δ7.61 (d, 1H, J=8.1Hz), 7.39 (d, 2H, J=7.1Hz), 7.33 (t, 2H, J=7.5Hz), 7.25 (t, 1H, J=7.2Hz), 6.90 (s, 1H), 6.86 (d, 1H, J =8.1Hz), 3.96 (s, 2H), 3.45 (s, 2H), 2.78-2.72 (m, 4H), 1.99-1.94 (m, 4H), 1.15 (s, 3H), 1.32 (s, 3H); LRMS (ES) m/z370.2 (M ⁺ +1).

Example 244: Synthesis of Compound 653 (4-(((3R,5S)-3,5-dimethyl-4-(3-(morpholinomethyl)benzyl) (piperazin-1-yl)methyl)-N,2-dihydroxybenzamide)

Step 1: Synthesis of tert-butyl (3R,5S)-3,5-dimethyl-4-(3-(morpholinomethyl)benzyl)piperazine-1-carboxylate

Tert-butyl (3R,5S)-4-(3-formylbenzyl)-3,5-dimethylpiperazine-1-carboxylate (Formula 23-1, 10.439 g, 31.401 mmol) was dissolved in dichloromethane (150 mL) at room temperature, and morpholine (2.747 mL, 31.401 mmol) was added to the solution, followed by stirring at the same temperature for 1 hour. STAB (13.310 g, 62.802 mmol) was added to the reaction mixture, which was then further stirred at the same temperature for 16 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 80 g cartridge; ethyl acetate/hexane = from 0% to 80%) and concentrated to obtain the desired compound (11.080 g, 87.4%) as a colorless liquid.

Step 2: Synthesis of 4-(3-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)benzyl)morpholine (hydrochloride)

At room temperature by (3R, 5S) -3,5- dimethyl -4- (3- (morpholinomethyl) benzyl) piperazine -1- tert-butyl formate (formula 23-2, 11.080g, 27.456mmol) and hydrochloric acid (4.00M1, 4- dioxane solution, 34.320mL, 137.278mmol) be dissolved in 1,4- dioxane (2mL), and the solution is stirred at the same temperature for 16 hours. Then, the reaction mixture is concentrated under reduced pressure to remove the solvent, and diethyl ether (150mL) is added to the enriched material, followed by stirring. The precipitated solid is filtered and dried to obtain the desired compound (7.800g, 83.6%) as a white solid.

Step 3: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(3-(morpholinomethyl)benzyl)piperazin-1-yl)methane methyl)-2-hydroxybenzoate

4-(3-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)benzyl)morpholine hydrochloride (Formula 23-3, 0.832 g, 2.448 mmol) and methyl 4-(bromomethyl)-2-hydroxybenzoate (0.600 g, 2.448 mmol) and TEA (0.407 mL, 2.938 mmol) were dissolved in acetonitrile (10 mL) at room temperature, and the solution was stirred at the same temperature for 16 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 40 g cartridge; ethyl acetate/hexane = from 0% to 50%) and concentrated to give the desired compound (0.441 g, 38.5%) as a yellow liquid.

Step 4: Synthesis of compound 653

At room temperature by 4-(((3R, 5S)-3,5-dimethyl-4-(3-(morpholinomethyl)benzyl)piperazine-1-yl)methyl)-2-hydroxybenzoic acid methyl ester (formula 23-4, 0.050g, 0.107mmol), hydroxylamine (50.00% aqueous solution, 0.065mL, 1.069mmol) and potassium hydroxide (0.060g, 1.069mmol) are dissolved in methanol (1mL)/tetrahydrofuran (1mL), and the solution is stirred at the same temperature for 1 hour.Then, the reaction mixture is concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution (20mL) is added to enriched material, then stirred.The precipitated solid is filtered and dried to obtain compound 653 (0.033g, 83.7%), which is a reddish-brown solid.

¹ H-NMR (400MHz, CD ₃ OD) δ7.65 (d, 1H, J=8.0Hz), 7.38 (s, 1H), 7.30 (d, 2H, J=5.2Hz), 7.23-7.22 (m, 1H), 6.81 (s, 1H), 6.74 (d, 2H, J=7.8Hz), 3.92 (s, 2H), 3. 71-3.69(m, 4H), 3.54(s, 2H), 3.41(s, 2H), 2.77-2.67(m, 4H), 2.47(m, 4H), 1.93-1.90(m, 2H), 1.11(s, 3H), 1.10(s, 3H); LRMS(ES)m/z 469.3(M ⁺ +1).

Example 245: Synthesis of Compound 696 (4-(((3R,5S)-3,5-dimethyl-4-(3-(morpholinomethyl)benzyl) (piperazin-1-yl)methyl)-3-fluoro-N-hydroxybenzamide)

Step 1: Synthesis of 4-(((3R,5S)-3,5-dimethyl-4-(3-(morpholinomethyl)benzyl)piperazin-1-yl)methane methyl)-3-fluorobenzoate

4-(3-(((2S,6R)-2,6-dimethylpiperazin-1-yl)methyl)benzyl)morpholine (Formula 23-3, 1.376 g, 4.048 mmol), TEA (0.673 mL, 4.857 mmol) and methyl 4-(bromomethyl)-3-fluorobenzoate (1.000 g, 4.048 mmol) were dissolved in acetonitrile (150 mL) at room temperature, and the solution was stirred at the same temperature for 16 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 80 g cartridge; ethyl acetate/hexane = from 0% to 20%) and concentrated to give the desired compound (0.438 g, 35.5%) as a yellow liquid.

Step 2: Synthesis of compound 696

At room temperature by 4-(((3R, 5S)-3,5-dimethyl-4-(3-(morpholinomethyl) benzyl) piperazine-1-yl) methyl)-3-fluorobenzoic acid methyl ester (formula 23-4, 0.100g, 0.213mmol), hydroxylamine (0.070g, 2.130mmol) and potassium hydroxide (0.119g, 2.130mmol) are dissolved in methanol (2mL), and the solution is stirred at the same temperature for 3 hours.Then, the reaction mixture is concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution (20mL) is added to enriched material, then stirred.The precipitated solid is filtered and dried to obtain compound 696 (0.025g, 25.0%), which is a yellow solid.

¹ H-NMR (400MHz, CD ₃ OD) δ7.58-7.20 (m, 7H), 3.90 (s, 2H), 3.71-3.68 (m, 4H), 3.57 (s, 2H), 3.53 (s, 2H), 2.77 (d, 2H, J=10.2Hz ), 2.71-2.67 (m, 2H), 2.46-2.45 (m, 4H), 1.99 (t, 2H, J=10.8Hz), 1.10 (s, 3H), 1.09 (s, 3H); LRMS (ES) m/z 471.2(M ⁺ +1).

Example 246: Synthesis of Compound 812 (5-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)- N-hydroxypicolinamide)

Step 1: Synthesis of methyl 5-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)picolinate

Methyl 5-formylpicolinate (Formula 8-4, 0.200 g, 0.831 mmol), (2S,6R)-1-benzyl-2,6-dimethylpiperazine (0.151 g, 0.914 mmol) and STAB (0.264 g, 1.246 mmol) were dissolved in dichloromethane (5 mL) at room temperature, and the solution was stirred at the same temperature for 16 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 12 g cartridge; ethyl acetate/hexane = from 0% to 20%) and concentrated to give the desired compound (0.116 g, 39.5%) as a yellow liquid.

Step 2: Synthesis of compound 812

At room temperature by 5-(((3R, 5S)-4-benzyl-3,5-dimethylpiperazine-1-yl)methyl)picolinic acid methyl ester (formula 8-5, 0.116g, 0.328mmol), hydroxylamine (50.00% aqueous solution, 0.100mL, 1.641mmol) and potassium hydroxide (0.092g, 1.641mmol) are dissolved in methanol (1mL)/tetrahydrofuran (1mL), and the solution is stirred at the same temperature for 1 hour.Then, the reaction mixture is concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution (20mL) is added to the enriched material, then stirred.The precipitated solid is filtered and dried to obtain compound 812 (0.088g, 75.7%) as a white solid.

¹ H-NMR (400MHz, CDCl ₃ )δ8.47 (s, 1H), 8.07 (d, 1H, J=7.9Hz), 7.83 (d, 1H, J=7.9Hz), 7.38-7.24 (m, 5H), 3.91 (s, 2H) , 3.53 (s, 2H), 2.75-2.68 (m, 4H), 2.09-2.03 (m, 2H), 1.11 (s, 3H), 1.10 (s, 3H); LRMS (ES) m/z 353.1(M ⁺ +1).

Example 247: Synthesis of Compound 813 (4-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)- 3-Fluoro-N-hydroxybenzamide)

Step 1: Synthesis of methyl 4-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)-3-fluorobenzoate

Methyl 4-(bromomethyl)-3-fluorobenzoate (Formula 8-4, 0.200 g, 0.831 mmol), (2S, 6R)-1-benzyl-2,6-dimethylpiperazine (0.226 g, 0.914 mmol) and sodium carbonate (0.230 g, 1.661 mmol) were dissolved in acetonitrile (5 mL) at room temperature, and the solution was stirred at the same temperature for 16 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 12 g cartridge; ethyl acetate/hexane = from 0% to 20%) and concentrated to give the desired compound (0.135 g, 43.9%) as a milky white solid.

Step 2: Synthesis of compound 813

At room temperature by 4-(((3R, 5S)-4-benzyl-3,5-dimethylpiperazine-1-yl) methyl)-3-fluorobenzoic acid methyl ester (formula 8-5, 0.135g, 0.364mmol), hydroxylamine (50.00% aqueous solution, 0.111mL, 1.822mmol) and potassium hydroxide (0.102g, 1.822mmol) are dissolved in methanol (1mL)/tetrahydrofuran (1mL), and solution is stirred 1 hour at the same temperature.Then, reaction mixture is concentrated under reduced pressure to remove solvent, and saturated sodium bicarbonate aqueous solution (20mL) is added to enriched material, then stir.Precipitated solid is filtered and dried to obtain compound 813 (0.087g, 64.3%), which is a milky white solid.

¹ H-NMR (400MHz, CDCl ₃ )δ8.47 (s, 1H), 8.07 (d, 1H, J=7.9Hz), 7.83 (d, 2H, J=8.2Hz), 7.38-7.24 (m, 5H), 3.91 (s, 2H) , 3.53(s, 2H), 2.75-2.68(m, 4H), 2.10-2.04(m, 2H), 1.11(s, 3H), 1.10(s, 3H); LRMS(ES)m/z 372.1(M ⁺ +1).

Example 248: Synthesis of Compound 814 (4-((3R,5S)-4-benzyl-3,5-dimethylpiperazine-1-carbonyl)-N-hydroxy Benzamide)

Step 1: Synthesis of methyl 4-((3R,5S)-4-benzyl-3,5-dimethylpiperazine-1-carbonyl)benzoate

Methyl 4-(chlorocarbonyl)benzoate (Formula 8-4, 0.200 g, 0.831 mmol), (2S, 6R)-1-benzyl-2,6-dimethylpiperazine (0.181 g, 0.914 mmol) and TEA (0.232 mL, 1.661 mmol) were dissolved in dichloromethane (5 mL) at room temperature, and the solution was stirred at the same temperature for 16 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica, 12 g cartridge; ethyl acetate/hexane = from 0% to 20%) to give the desired compound (0.152 g, 49.9%) as a white solid.

Step 2: Synthesis of Compound 814

At room temperature by 4-((3R, 5S)-4-benzyl-3,5-dimethylpiperazine-1-carbonyl) methyl benzoate (formula 8-4, 0.152g, 0.415mmol), hydroxylamine (50.00% aqueous solution, 0.127mL, 2.074mmol) and potassium hydroxide (0.116g, 2.074mmol) are dissolved in methanol (1mL)/tetrahydrofuran (1mL), and the solution is stirred at the same temperature for 1 hour.Then, the reaction mixture is concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution (20mL) is added to enriched material, then stirred.The precipitated solid is filtered and dried to obtain compound 814 (0.118g, 77.4%), which is a white solid.

¹ H-NMR (400MHz, CDCl ₃ )δ7.66(d, 2H, J=6.7Hz), 7.20-6.99(m, 7H), 3.61(s, 2H), 2.74-2.68(m, 2H), 2 .49(m, 2H), 2.37-2.33(m, 2H), 0.92(s, 3H), 0.71(s, 3H); LRMS(ES)m/z368.1(M ⁺ +1)

Example 249: Synthesis of Compound 818 (4-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)sulfonyl 1-Hydroxybenzamide)

Step 1: Synthesis of methyl 4-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)sulfonyl)benzoate

Methyl 4-(chlorosulfonyl)benzoate (Formula 8-4, 0.200 g, 0.852 mmol), (2S, 6R)-1-benzyl-2,6-dimethylpiperazine (0.186 g, 0.938 mmol) and TEA (0.236 mL, 1.705 mmol) were dissolved in dichloromethane (10 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 50%) to obtain the desired compound (0.181 g, 52.8%) as a white solid.

Step 2: Synthesis of Compound 818

At room temperature by 4-(((3R, 5S)-4-benzyl-3,5-dimethylpiperazine-1-yl) sulfonyl) methyl benzoate (formula 8-5, 0.100g, 0.248mmol), hydroxylamine (50.00% aqueous solution, 0.076mL, 1.242mmol) and potassium hydroxide (0.070g, 1.242mmol) are dissolved in methanol (1mL)/tetrahydrofuran (1mL), and solution is stirred 1 hour at the same temperature.Then, reaction mixture is concentrated under reduced pressure to remove solvent, and saturated sodium bicarbonate aqueous solution (20mL) is added to enriched material, then stir.Precipitated solid is filtered and dried to obtain compound 818 (0.042g, 41.9%), which is a creamy white solid.

¹ H-NMR (400MHz, CD ₃ OD)) δ8.00 (d, 2H, J=8.3Hz), 7.81 (d, 2H, J=8.4Hz), 7.32-7.25 (m, 4H), 7.19 (t, 1H, J=7.0Hz), 3.82 (s, 2H), 3.52 (d, 2H, J=11.2Hz), 2.73-2.68 (m, 2H), 2.19 (t, 2H, J=10.6Hz), 1.07 (s, 3H), 1.05 (s, 3H); LRMS (ES) m/z 404.1(M ⁺ +1).

Example 250: Synthesis of Compound 820 (2-(4-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)sulfone (acyl)phenyl)-N-hydroxyacetamide)

Step 1: Synthesis of 2-(4-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)sulfonyl)phenyl)acetic acid Methyl ester

Methyl 2-(4-(chlorosulfonyl)phenyl)acetate (Formula 8-4, 0.200 g, 0.804 mmol), (2S,6R)-1-benzyl-2,6-dimethylpiperazine (0.176 g, 0.885 mmol) and TEA (0.223 mL, 1.608 mmol) were dissolved in dichloromethane (10 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 20%) and concentrated to give the desired compound (0.198 g, 59.2%) as a colorless liquid.

Step 2: Synthesis of Compound 820

2-(4-(((3R, 5S)-4-benzyl-3,5-dimethylpiperazine-1-yl)sulfonyl)phenyl)acetic acid methyl ester (Formula 8-5, 0.198 g, 0.475 mmol), hydroxylamine (50.00% aqueous solution, 0.145 mL, 2.377 mmol) and potassium hydroxide (0.133 g, 2.377 mmol) were dissolved in methanol (1 mL)/tetrahydrofuran (1 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution (20 mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered and dried to give compound 820 (0.124 g, 62.5%) as a white solid.

¹ H-NMR (400MHz, CDCl ₃ )δ7.67 (d, 2H, J=7.6Hz), 7.37-7.15 (m, 7H), 3.74 (s, 2H), 3.49 (d, 2H, J=7.8Hz), 3. 21(s, 2H), 2.74(m, 2H), 2.23-2.18(m, 2H), 0.99(s, 3H), 0.98(s, 3H); LRMS(ES)m/z 418.1(M ⁺ +1).

Example 251: Synthesis of Compound 822

(4-(((3R,5S)-4-Benzyl-3,5-dimethylpiperazin-1-yl)methyl)-N-hydroxycyclohexane-1-carboxamide)

Step 1: Synthesis of 4-(((3R,5S)-4-benzyl-3,5-dimethylpiperazin-1-yl)methyl)cyclohexane-1-carboxylic acid ester

Methyl 4-formylcyclohexane-1-carboxylate (Formula 8-4, 0.150 g, 0.881 mmol), (2S,6R)-1-benzyl-2,6-dimethylpiperazine (0.212 g, 0.881 mmol), and STAB (0.280 g, 1.322 mmol) were dissolved in dichloromethane (10 mL) at room temperature, and the solution was stirred at the same temperature for 16 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 50%) and concentrated to obtain the desired compound (0.175 g, 55.4%) as a colorless liquid.

Step 2: Synthesis of Compound 822

At room temperature by 4-(((3R, 5S)-4-benzyl-3,5-dimethylpiperazine-1-yl) methyl) cyclohexane-1-methyl formate (formula 8-5, 0.175g, 0.488mmol), hydroxylamine (50.00% aqueous solution, 0.149mL, 2.441mmol) and potassium hydroxide (0.137g, 2.441mmol) are dissolved in methanol (1mL)/tetrahydrofuran (1mL), and the solution is stirred at the same temperature for 1 hour.Then, the reaction mixture is concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution (20mL) is added to the enriched material, then stirred.The precipitated solid is filtered and dried to obtain compound 822 (0.050g, 28.5%) as a white solid.

¹ H-NMR (400MHz, CDCl ₃ )δ7.38 (d, 2H, J=7.4Hz), 7.32-7.28 (m, 2H), 7.21 (t, 1H, J=7.3Hz), 3.82 (s, 2H), 2.72-2.67 (m, 4H), 2.19-1.96 (m, 3H), 1.83-1.67 (m, 6H), 1.48-1.45 (m, 5H), 1.03 (s, 6H); LRMS (ES) m/z 360.2(M ⁺ +1).

Example 252: Synthesis of Compound 823

(2-(4-((3R,5S)-4-Benzyl-3,5-dimethylpiperazine-1-carbonyl)phenyl)-N-hydroxyacetamide)

Step 1: Synthesis of methyl 2-(4-((3R,5S)-4-benzyl-3,5-dimethylpiperazine-1-carbonyl)phenyl)acetate

4-(2-Methoxy-2-oxoethyl)benzoic acid (Formula 8-4, 0.150 g, 0.772 mmol), (2S,6R)-1-benzyl-2,6-dimethylpiperazine (0.186 g, 0.772 mmol), EDC (0.296 g, 1.545 mmol), HOBt (0.237 g, 1.545 mmol), and DIPEA (0.684 mL, 3.862 mmol) were dissolved in dichloromethane (10 mL) at room temperature, and the solution was stirred at the same temperature for 16 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 50%) and concentrated to obtain the desired compound (0.133 g, 45.3%) as a colorless liquid.

Step 2: Synthesis of Compound 823

At room temperature, 2-(4-((3R, 5S)-4-benzyl-3,5-dimethylpiperazine-1-carbonyl)phenyl)methyl acetate (Formula 8-5, 0.133 g, 0.350 mmol), hydroxylamine (50.00% aqueous solution, 0.107 mL, 1.748 mmol) and potassium hydroxide (0.098 g, 1.748 mmol) were dissolved in methanol (1 mL)/tetrahydrofuran (1 mL), and the solution was stirred at the same temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution (20 mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered and dried to give compound 823 (0.015 g, 11.2%) as a white solid.

¹ H-NMR (400MHz, CDCl ₃ )δ7.36 (d, 2H, J=7.5Hz), 7.30 (t, 3H, J=7.5Hz), 7.25-7.21 (m, 5H), 4.44 (d, 1H, J=9.6Hz), 3.84-3.75 (m, 2H), 3.51 ( d, 1H, J=11.2Hz), 3.23 (m, 2H), 2.95-2.88 (m, 1H), 2.69 (m, 1H), 2.53 (m, 1H), 1.11 (s, 3H), 0.88 (s, 3H); LRMS (ES) m/z 382.2(M ⁺ +1).

Example 253: Synthesis of Compound 824

(3-(4-((3R,5S)-4-Benzyl-3,5-dimethylpiperazine-1-carbonyl)phenyl)-N-hydroxypropionamide)

Step 1: Synthesis of methyl 3-(4-((3R,5S)-4-benzyl-3,5-dimethylpiperazine-1-carbonyl)phenyl)propanoate

4-(3-Methoxy-3-oxopropyl)benzoic acid (Formula 8-4, 0.150 g, 0.724 mmol), (2S,6R)-1-benzyl-2,6-dimethylpiperazine (0.174 g, 0.724 mmol), EDC (0.278 g, 1.448 mmol), HOBt (0.222 g, 1.448 mmol), and DIPEA (0.641 mL, 3.620 mmol) were dissolved in dichloromethane (10 mL) at room temperature, and the solution was stirred at the same temperature for 16 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, 4 g cartridge; ethyl acetate/hexane = from 0% to 50%) and concentrated to obtain the desired compound (0.089 g, 31.2%) as a clear liquid.

Step 2: Synthesis of Compound 824

At room temperature by 3-(4-((3R, 5S)-4-benzyl-3,5-dimethylpiperazine-1-carbonyl) phenyl) methyl propionate (formula 8-5, 0.089g, 0.226mmol), hydroxylamine (50.00% aqueous solution, 0.069mL, 1.128mmol) and potassium hydroxide (0.063g, 1.128mmol) are dissolved in methanol (1mL)/tetrahydrofuran (1mL), and the solution is stirred at the same temperature for 1 hour.Then, the reaction mixture is concentrated under reduced pressure to remove the solvent, and saturated sodium bicarbonate aqueous solution (20mL) is added to the enriched material, then stirred.The precipitated solid is filtered and dried to obtain compound 824 (0.052g, 58.3%), which is a white solid.

¹ H-NMR (400MHz, CDCl ₃ )δ7.36 (d, 2H, J=7.4Hz), 7.30 (t, 2H, J=7.5Hz), 7.24 (t, 3H, J=8.6Hz), 7.26-7.22 (m, 3H), 7.18 (d, 2H, J=7.8Hz), 4.44 (d, 1H, J=8.0Hz), 3. 85-3.76 (m, 2H), 3.53 (d, 1H, J=9.0Hz), 2.92-2.87 (m, 3H), 2.69 (m, 2H), 2.53 (m, 1H), 2.30 (m, 2H), 1.11 (s, 3H), 0.90 (s, 3H); LRMS (ES) m/z 396.2(M ⁺ +1).

The structural formulas of compounds 080 to 824 prepared as described above are shown in Table 16 below.

[Table 16] Structural formula of dimethylpiperazine derivative compounds

Experimental Example 1: HDAC enzyme activity inhibition assay (in vitro)

In order to examine the HDAC6 selectivity of the compound of formula I of the present invention by HDAC1 and HDAC6 enzyme activity inhibition assay, experiments were performed using conventional substances as controls.

HDAC enzyme activity was measured using an HDAC Fluorimetric Drug Discovery Kit (BML-AK511, 516, Enzo Life Science). For the HDAC1 enzyme activity test, human recombinant HDAC1 (BML-SE456) was used as an enzyme source, and Fluor de-"SIRT1 (BNL-KI177) was used as a substrate. A 5-fold dilution of the compound was inoculated into a 96-well plate, and then 0.3 μg of the enzyme and 10 μM of the substrate were added to each well of the plate and allowed to react at 30°C for 60 minutes. Then, Fluor deDeveloper II (BML-KI176) was added thereto and allowed to react for 30 minutes, after which fluorescence values were measured using a multiplate reader (Flexstation 3, Molecular Device) (Ex 360, Em 460). According to the same protocol as the HDAC1 enzyme activity test method, human recombinant HDAC6 (382180) (Calbiochem) was used to test the HDAC6 enzyme. Based on the obtained values, each IC ₅₀ value was calculated using the GraphPad Prism 4.0 program.

[Table 17] Results of HDAC enzyme activity inhibition assay

As can be seen in Table 16 above, the dimethylpiperazinehydroxamic acid derivative compounds of the present invention exhibited about 2 to about 5500-fold more selective HDAC6 inhibitory activity in the HDAC1 and HDAC6 activity inhibition assays.

Industrial Applicability

The compound represented by formula I, its isomer or pharmaceutically acceptable salt thereof can be used for preventing or treating histone deacetylase 6 activity-related diseases.

Claims (10)

1. A compound represented by Formula I, its stereoisomer, or a pharmaceutical salt thereof: Formula I in _R1 is hydrogen or _-CH3 . _R2 is either hydrogen or _-CH3 , provided that _R1 is hydrogen and _R2 is _-CH3 , and _R1 is _-CH3 and _R2 is hydrogen. L represents -( _C4 - _C5 alkyl)-; -( _C1 - _C3 alkyl) _-L1- ; -C(=O) _-L1- or -S(=O) ₂ - _L1- . Wherein -( _C4 - _C5 alkyl)- and -( _C1 - _C3 alkyl)- can be unsubstituted or substituted with _-CH3 . _L1 is -( _C3 - _C6 )cycloalkyl-; _A1 and _A2 are each independently -N- or _-CR3- , provided that _A1 and _A2 cannot both be -N-. R ₃ is hydrogen; -F, -Cl, -Br, -I or -OH, and _A3 is -NH- or -O-. Q can be selected from the following groups: -( _C1 - _C6 )alkyl-; -( _C2 - _C6 )alkenyl-; -C(=O)-; -C(=S)- or Wherein -( _C1 - _C6 )alkyl- and -( _C2 - _C6 )alkenyl- can be unsubstituted or independently substituted by 1 to 3 _-CH3 groups or halogen atoms, _Q1 is hydrogen; -F, -Cl, -Br, or I, n is an integer of 0, 1, or 2, provided that n is 0 when Q is -F, -Cl, -Br, or I; n is 1 when Q is -C(=O)- or -C(=S)-; and n is 1 or 2 when Q is -( _C1 - _C6 )alkyl- or -( _C2 - _C6 )alkenyl-. X can be selected from the group consisting of: _-C1 - _C6 alkyl; -C3- _C6 cycloalkyl; _-C2 - _C6 alkenyl; _{-C3 - C6} cycloalkenyl; -( _C0 - _C2 alkyl)Ar; -OAr; -( _C0 - _C2 alkyl)Het; naphthyl; and the following groups: Where _R4 is H or a _-C1 - _C4 alkyl group, _{-C0- C2} alkyl, -C2 _{- C6} alkenyl, and _-C1 - _C6 alkyl can be unsubstituted or substituted with 1 to 2 _-CH3 groups; 1 to 3 -F groups, or combinations thereof. Ar is a _C6 monocyclic aromatic compound that may be unsubstituted or substituted with one or more of the following groups: halogen atom; -OH; _-NH₂ ; _-C₁ - _C₆ alkyl; -O( _C₁ - _C₆ )alkyl; _-C₃ - _C₆ cycloalkenyl; -NH( _C₁ - _C₆ alkyl); -N( _C₁ - _C₃ alkyl) _₂ ; _-CH₂N ( _C₁ - _C₃ alkyl) _₂ ; -S(=O) _₂- ( _C₁ - _C₃ alkyl) or phenyl group, wherein _-C₁ - _C₃ alkyl; _-C₁ - _C₆ alkyl and -C₃ _{- C₆} cycloalkenyl can each be independently substituted by 1 to 5 -F or _-CH₃ groups, and Het is a 4- to 6-membered heteroaromatic or nonaromatic ring compound containing 1 to 3 elements selected from the group consisting of N, O, and S, and may be unsubstituted or substituted by one or more of the following groups: halogen atom; _-C1 - _C6 alkyl; -C(=O)( _C1 - _C3 alkyl); -S(=O) ₂ ( _C1 - _C3 alkyl) or benzyl group, wherein _-C1 - _C3 alkyl and -C1 _{- C6} alkyl may each be independently substituted by the following groups: -OH; 1 to 5 -F or _-CH3 groups. 2. The compound represented by Formula I according to claim 1, its stereoisomers, or pharmaceutical salts thereof, wherein the compound represented by Formula I is a compound represented by Formula II or Formula III: Formula II Formula III in L represents -( _C5 alkyl)-; -( _C1 - _C2 alkyl) _-L1- ; -C(=O) _-L1- or -S(=O) ₂ - _L1- . Wherein -( _C5 alkyl)- and -( _C1 - _C2 alkyl)- are straight chains and may be unsubstituted or substituted with _-CH3 . _L1 is -( _C3 - _C6 )cycloalkyl-; _A1 and _A2 are each independently -N- or _-CR3- , provided that _A1 and _A2 cannot both be -N-. R ₃ is hydrogen; -F or -OH, and _A3 is -NH- or -O-. Q is selected from the following groups: -( _C1 - _C3 )alkyl-; -C(=O)-; -C(=S)- or Wherein the -( _C1 - _C3 )alkyl- can be unsubstituted or substituted with 1 to 3 _-CH3 groups or halogen atoms, _Q1 is hydrogen; -F or -Cl, n is an integer of 0 or 1, provided that n is 0 when Q is -C(=O)-, -C(=S)-, or -( _C1 - _C3 )alkyl-, and n is 1. X can be selected from the group consisting of: _-C1 - _C6 alkyl; -C3- _C6 cycloalkyl; _-C2 - _C6 alkenyl; _{-C3 - C6} cycloalkenyl; -( _C0 - _C2 alkyl)Ar; -OAr; -( _C0 - _C2 alkyl)Het; naphthyl; and the following groups: Where _R4 is H or a _-C1 - _C4 alkyl group, _-C0 - _C2 alkyl; _-C2 - _C6 alkenyl and _-C1 - _C6 alkyl may be unsubstituted or substituted with 1 or 2 _-CH3 groups or 1 to 3 F groups. Ar is a _C6 monocyclic aromatic compound that may be unsubstituted or substituted with one or more of the following groups: halogen atom; -OH; _-NH₂ ; _-C₁ - _C₆ alkyl; -O( _C₁ - _C₆ )alkyl; _-C₃ - _C₆ cycloalkenyl; -NH( _C₁ - _C₆ alkyl); -N( _C₁ - _C₃ alkyl) _₂ ; _-CH₂N ( _C₁ - _C₃ alkyl) _₂ ; -S(=O) _₂- ( _C₁ - _C₃ alkyl) or phenyl group, wherein _-C₁ - _C₃ alkyl; _-C₁ - _C₆ alkyl and -C₃ _{- C₆} cycloalkenyl can each be independently substituted by 1 to 5 -F or _-CH₃ groups, and Het is a 4- to 6-membered heteroaromatic or nonaromatic ring compound containing 1 to 3 elements selected from the group consisting of N, O, and S, and may be unsubstituted or substituted by one or more of the following groups: halogen atom; _-C1 - _C6 alkyl; -C(=O)( _C1 - _C3 alkyl); -S(=O) ₂ ( _C1 - _C3 alkyl) or benzyl group, wherein _-C1 - _C3 alkyl and _-C1 - _C6 alkyl may each be independently substituted by the following groups: -OH; or 1 to 5 -F or _-CH3 groups. 3. The compound represented by formula I according to claim 1, its stereoisomers or pharmaceutical salts thereof, wherein Het is selected from the following groups: _R5 is independently hydrogen; -F; -Cl; _-C1 - _C6 alkyl; -C(=O)( _C1 - _C3 alkyl); -S(=O) ₂ ( _C1 - _C3 alkyl) or benzyl, wherein _-C1 - _C3 alkyl and -C1 _{- C6} alkyl can be independently substituted by the following groups: -OH; 1 to 5 -F or _-CH3 groups, m is an integer of 0, 1, 2, or 3, and When m is 0, Het is unsubstituted, and when m is 1, 2 or 3, Het can be substituted by R ₅ independently. 4. The compound represented by formula I according to claim 1, its stereoisomers or pharmaceutical salts thereof, wherein L, _L1 , _A1 , _A2 , _A3 , _R3 , _R4 , Q and X are defined as follows: L is -CH ₂ -L ₁ -, in _L1 is _A1 and _A2 are each independently -N- or _-CR3- , provided that _A1 and _A2 cannot both be -N-. R ₃ is hydrogen; -F or -OH, and _A3 is -NH- or -O-. Q is _-CH2- or -C (=O), and X can be selected from the group consisting of: _-C1 - _C6 alkyl; -( _C0 - _C2 alkyl)Ar; -( _C0 - _C2 alkyl)Het; -OAr; or the following groups: Where _R4 is H or a _-C1 - _C4 alkyl group, _-C0 - _C2 alkyl and _-C1 - _C6 alkyl can be unsubstituted or substituted with one or two _-CH3 groups and/or one to three -F groups, and Ar and Het are each defined independently as in Equations I through III. 5. The compound represented by Formula I according to claim 1, its stereoisomers, or pharmaceutical salts thereof, wherein the compound represented by Formula I is any one of the compounds shown in the table below: 6. The compound represented by Formula I according to claim 5, its stereoisomers, or pharmaceutical salts thereof, wherein the compound represented by Formula I is any one of the compounds shown in the table below: 7. The compound represented by Formula I according to claim 6, its stereoisomers, or pharmaceutical salts thereof, wherein the compound represented by Formula I is any one of the compounds shown in the table below: 8. A pharmaceutical composition comprising a compound represented by Formula I according to any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutical salt thereof. 9. The pharmaceutical composition of claim 8, for the prevention or treatment of cancer, inflammatory diseases, autoimmune diseases, neurological diseases or neurodegenerative diseases. 10. Use of a composition comprising a compound of formula I according to any one of claims 1 to 7, its stereoisomers or pharmaceutical salts thereof as an active ingredient for the preparation of a medicament for the prevention or treatment of cancer, inflammatory diseases, autoimmune diseases, neurological diseases or neurodegenerative diseases.