Compound with proteasome agonistic activity as well as preparation method and application thereof

Abstract

The invention discloses a compound with proteasome agonist activity and a preparation method and application thereof.The structural general formula of the compound is shown in the specification, and the compound is a 20S proteasome agonist. According to the preparation method, phthalic acid and derivatives thereof serve as starting raw materials, and the compound with the proteasome agonist activity is obtained through an efficient synthesis route. A series of compounds with proteasome agonistic activity are prepared. Experiments prove that the target compound provided by the invention shows remarkable 20S proteasome agonistic activity. Therefore, the compound has a wide application prospect in the aspect of treating diseases related to insufficient 20S proteasome activity and dysstable protein homeostasis.

Description

Technical Field

[0001] This invention belongs to the field of drug development technology and relates to compounds with proteasome agonist activity, their preparation methods and applications. The compounds can be applied in the development of therapeutic drugs for diseases requiring enhanced 20S proteasome degradation activity. Background Technology

[0002] Protein homeostasis is central to maintaining normal cellular life activities. This homeostasis relies on a sophisticated signaling network comprised of protein synthesis, folding, modification, and degradation systems, which is precisely regulated to sustain cellular life activities. As a core component of this network, the proteasome is responsible for approximately 80% of intracellular protein degradation. Therefore, maintaining stable proteasome function is crucial for overall health.

[0003] Under pathological conditions such as stress and aging, cells exhibit a significant decline in their protein degradation capacity, leading to the inability to promptly clear misfolded or damaged proteins within the cell, which then form cytotoxic aggregates. The clearance of these abnormal proteins primarily relies on the 20S proteasome degradation pathway. Their massive accumulation not only constitutes the core pathological basis of many diseases but also further feedback-inhibits the hydrolytic activity of the proteasome, creating a vicious cycle. Based on this mechanism, developing specific activators targeting the 20S proteasome has become a highly promising direction in drug development. These drugs enhance the cell's inherent protein clearance capacity, reducing the accumulation of toxic proteins at the source, thereby delaying or blocking disease progression. Their potential applications extend beyond neurodegenerative diseases characterized by abnormal aggregation of specific proteins (such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis), also encompassing cardiovascular diseases such as ischemic cardiomyopathy, metabolic disorders, and various age-related pathological processes, demonstrating broad therapeutic potential.

[0004] In recent years, research on proteasome agonists has gradually attracted attention, and several compounds with proteasome agonistic activity have been reported. However, the development of this field still faces serious challenges. Currently known agonists generally suffer from weak activity, unclear structure-activity relationships, and poor selectivity, and related pharmacodynamic evaluations are mostly at the molecular level, lacking systematic and in-depth mechanistic studies. Therefore, developing novel proteasome agonists with higher agonistic activity, good selectivity, and excellent pharmacokinetic properties is not only of great significance for elucidating the mechanisms of protein homeostasis regulation, but also shows broad clinical application prospects in the treatment of diseases related to protein homeostasis dysregulation. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the technical problem to be solved by this invention is to provide compounds with proteasome agonist activity, their preparation methods, and applications. These compounds are a class of novel small-molecule 20S proteasome agonists with novel skeletons. Through evaluation of the 20S proteasome agonist activity of these compounds, it has been found that they have good 20S proteasome agonist activity, and it is expected that they can be applied to the development of drugs for diseases related to proteasome insufficiency.

[0006] Terminology definition: As used in this invention, the term "aryl" refers to a monocyclic or fused polycyclic group with 5-12 carbon atoms, possessing a fully conjugated π-electron system. Non-limiting examples of aromatic rings include benzene and naphthalene rings. Aromatic rings can be substituted or unsubstituted. Substituents in aromatic rings can be selected from halogens, nitro groups, cyano groups, hydroxyl groups, amino groups, and C6 groups. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamine group.

[0007] As used in this invention, the term "heterocyclic aryl" refers to an unsaturated carbon ring with 5-6 ring atoms, wherein one or more carbon atoms are replaced by heteroatoms such as oxygen, nitrogen, sulfur, etc. Specific heterocyclic aryl groups can be: pyridinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and isoxazolyl, etc.

[0008] As used in this invention, the term "heterocyclic group" refers to a cyclic structure composed of carbon atoms and non-carbon atoms, where the non-carbon atoms are called heteroatoms. Common heteroatoms include nitrogen, oxygen, and sulfur. Heterocyclic groups can be monocyclic groups, having 4-6 ring atoms, of which at least one or two ring atoms are selected from nitrogen, oxygen, or sulfur heteroatoms, and the remaining ring atoms are carbon atoms. Specific heterocyclic groups can be piperidinyl, piperazine, pyrrolidinyl, tetrahydropyranyl, oxoheterobutyl, etc.

[0009] The term "alkoxy group" as used in this invention refers to an -O-alkyl group. Specific alkoxy groups can be methoxy, ethoxy, tert-butoxy, etc.

[0010] As used in this invention, the term "heteroatom" refers to an atom composed of elements other than carbon. Specific heteroatoms can be nitrogen (N), sulfur (S), oxygen (O), etc.

[0011] As used in this invention, "fused-ring aromatic hydrocarbons" refers to compounds formed by the fusion of two or more benzene rings sharing two adjacent carbon atoms, such as naphthalene, anthracene, and phenanthrene. The concept of fused rings can also be extended to include benzene-fused heterocyclic compounds and fused heterocyclic compounds. The former are organic compounds formed by the fusion of benzene rings with heterocyclic compounds, such as indole and quinoline; the latter are organic compounds formed by the fusion of several heterocyclic rings, such as purines.

[0012] The purpose of this invention is to provide a compound having the general formula (I):

[0013] in: Ar1 is selected from hydrogen, aryl, heterocyclic aryl, aralkyl, or halogenated, C 1-4 Alkyl, C 3-8 cycloalkyl, C 1-4 Alkoxy, C 1-4 Aryl or heterocyclic aryl groups with arbitrary substitution of alkylamine group; Ar2 is selected from aryl, heterocyclic aryl, fused-ring aryl, fused-ring heterocyclic aryl, or omitted; Linker1 and Linker2 are independently selected from amino groups and C groups, respectively. 1-4 Alkyl, C 1-4 alkylamine group, C 1-4 Alkoxy, C 3-8 cycloalkyl, C 3-8 One or more combinations or deletions of heterocyclic alkyl groups and amino acids; R is selected from aryl, heterocyclic aryl, aralkyl, heteroalkyl, cycloalkyl, heteroalkyl, fused-ring aryl, fused-ring heteroalkyl, fused-ring aralkyl, fused-ring heteroalkyl, or the formyl group of the above groups, or halogenated, C 1-4 Alkyl, C 1-8 Alkoxy, C 1-8 alkylamine group, C 3-8 aryl or heterocyclic aryl groups that are substituted with cycloalkyl, heterocyclic alkyl, or halogen in any way, or which are omitted; X1 and X2 are independently selected from hydrogen and halogen, respectively; Y is selected from O and NH.

[0014] Furthermore, in the above technical solution, the compound contains: Ar1 is selected from hydrogen, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, N,N-dimethyl-4-aminophenyl, and pyrroleyl. Ar2 is selected from benzo[d]oxazol-5-yl, benzo[ d ]Oxazol-6-yl, benzo[ d Imidazol-5-yl, imidazo[1,2-] a ]Pyridin-6-yl, benzoylamino, phenoxy, 1-methyl-1 H -Indole-5-yl or missing; Linker1 and Linker2 are selected from one or more combinations or deletions of amino, piperazine, piperidinyl, pyrrolyl, alanine, valine, ethylenediamine, and phenyl. R is selected from substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, thiazolyl, naphthyl, quinolinyl, benzothiazolyl, benzoxazolyl, indolyl, fluorenyl, dibenzocycloalkenyl, benzocycloheptylpyridyl, phenothiazinyl, phenothiazinyl; substituted or unsubstituted diarylmethyl, diarylamino, aralkyl, heteroarylalkyl; substituted or unsubstituted cycloalkyl, monocyclic heterocyclic alkyl, fused-ring heterocyclic alkyl, spirocyclic heterocyclic alkyl; or formyl or methylamino corresponding to any of the aforementioned groups; or omitted. X1 and X2 are selected from H and Cl; Y is selected from O and NH.

[0015] Furthermore, R can be selected from: 3-bromo-4-methoxyphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-bromophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methylphenyl, 4-cyanophenyl, 4-(N,N-dimethyl)phenyl, 4-methyl carboxylate phenyl, 4-tert-butylphenyl, 3-tert-butylphenyl, 2-tert-butylphenyl, 4-isopropylphenyl, 2-isopropylphenyl, 4-cyclobutylphenyl, 4-cyclopropylphenyl, 3-cyclopropylphenyl, 3-(N-piperazinyl)phenyl, phenyl.

[0016] Alternatively, R may be selected from: pyridinyl, pyrimidinyl, thiazolyl, naphthyl, quinolinyl, benzo[d]thiazolyl, benzo[d]oxazolyl, indolyl, 9H-fluorene-9-yl, 5H-dibenzo[a,d][7]cycloen-5-yl, 8-chloro-11H-benzo[5,6]cycloheptane[1,2-b]pyridin-11-yl, 10H-phenoxazine-10-carboxylic acid, 10H-phenthiazine-10-yl, 2-imidazolyl, 4-methylpiperazine-1-yl, cyclopentyl, morpholinyl, isoindolin-2-yl, 1,2,4,5-tetrahydro-3H-benzo[d]azacycloheptane-3-yl, 3,4-dihydroisoquinoline-2(1H)-yl, spiro[ind-1,4'-piperidine]-1'-yl.

[0017] Alternatively, R may be selected from: diphenylmethyl, di(4-chlorophenyl)methyl, di(4-fluorophenyl)methyl, diphenylamino, 2-(2-ethoxyethoxy)ethanol-1-yl, methyl(phenethyl)amino, 2-(4-chlorophenyl)ethyl, 2-(4-chlorophenyl)butyl, 2-(4-chlorophenyl)-3-methylbutyl, 2-(4-chlorophenyl)-2-benzyl, 2-(4-fluorophenyl)-2-benzyl, 2-(4-methoxyphenyl)-2-benzyl, 2-(4-chlorophenyl)-2-(pyridin-2-yl)methyl, 2-phenyl-2-(pyrimidin-2-yl)methyl, 2-(pyridin-2-yl)-2-(pyridin-4-yl)methyl, 2 -(4-chlorophenyl)-2-(quinoline-2-yl)methyl, (R)-2-(3-acrylamidophenyl)ethyl, 2-(3-acrylamidophenyl)ethyl, (R)-2-(4-acrylamidophenyl)ethyl, benzoyl, pyrazin-2-carboxyl, pyridine-2-carboxyl, pyrimidin-2-carboxyl, 1-phenylethyl-2-acyl, di(4-chlorophenyl)carboxyl, dibenzoyl, (S)-N-(1-phenylethyl)methylaminoyl, (R)-N-(1-phenylethyl)methylaminoyl, quinoline-3-carboxyl, quinoline-2-carboxyl, quinazolinoline-2-carboxyl, 2,3-dihydrobenzo[b][1,4]dioxin-6-carboxyl.

[0018] Furthermore, the compound is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0019] Furthermore, the preparation method of the compound represented by general formula (Ⅰ) includes the following: The synthetic route of one of the key segments, namely the acid intermediates, is shown below. A-1 is formed by the Friedel-Crafts acylation reaction of phthalic anhydride and substituted benzene to form the corresponding acid, which is then cyclized with diethyl bromomalonate to generate the corresponding lactone-containing organic acid A-2. A-3 is derived from the amination of A-2.

[0020]

[0021] The synthetic route for substituted benzisoxazole and its analogues is as follows: 2-amino-4-nitrophenol (and its analogues) and substituted benzoic acid undergo dehydration cyclization via PPA, and the nitro group is reduced with iron powder to obtain the aromatic amine intermediate A-5; 2-amino-5-nitropyridine and β -Bromo-4-methoxyacetophenone reacts to produce imidazo[1,2-] a The pyridine ring is then reduced to A-7 by nitro group; 3-bromo-4-methoxyphenol reacts with p-fluoronitrobenzene by substitution to form an ether, which is then reduced to A-9.

[0022]

[0023] The synthesis of A-11 is shown below. It is prepared by acylation of 3-bromo-4-methoxybenzoic acid to obtain an acyl chloride, which is then reacted with the corresponding amine and deBoc protected by TFA.

[0024]

[0025] The synthetic route for the benzisoxazole-linked heterocyclic intermediate is shown below. 2-Amino-4-nitrophenol is cyclized via CS2 to generate a thiol, which is then reduced to A-14 after reacting with morpholine. The thiol is chlorinated to generate A-16, which can be reduced to A-18 after reacting with a substituted phenylpiperazine (piperazine can be replaced by other five-, six-, or seven-membered NH-containing heterocycles, and phenyl can be replaced by other aromatic heterocycles or substituted benzyl groups, etc.). The piperazine ring A-15 can be derived from the cyclization of an amine and bis(2-chloroethyl)amine hydrochloride.

[0026]

[0027] The obtained acid intermediate (one of A-2 and A-3) was condensed with an amine intermediate containing benzisoxazole or its analogues (one of A-5, A-7, A-9, A-11, A14, and A18) under HATU and DIPEA conditions to obtain the target compounds Y-1 to Y-111.

[0028] Another object of the present invention is to provide a pharmaceutical composition comprising at least one compound in any of the forms described above, wherein a stereoisomer of the compound or a pharmaceutically acceptable salt thereof is an active component, and comprising one or more pharmaceutically acceptable carriers or excipients.

[0029] The pharmaceutical composition described in this invention can be formulated into various pharmaceutical dosage forms, such as oral, injection, inhalation, and implantation. Injection and oral administration are preferred, for example, injections, lyophilized powder injections, tablets, capsules, or granules.

[0030] The pharmaceutical compositions of the present invention and various formulations thereof can be prepared using conventional pharmaceutical carriers.

[0031] Another object of the present invention is to provide the pharmaceutical use of compounds of general formula (I) and pharmaceutical compositions containing said compounds. Specifically, the present invention provides the use of compounds of general formula (I) and pharmaceutical compositions containing said compounds in the preparation of remedies for diseases related to protein homeostasis disorders and insufficient proteasome activity, including neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, etc.), cardiovascular diseases such as ischemic cardiomyopathy, or metabolic disorders.

[0032] Experiments have demonstrated that the series of compounds of this invention possess excellent proteasome agonist activity. The raw materials required for the synthesis of these compounds are readily available, the route design is reasonable, the reaction conditions are mild, the yields at each step are high, the operation is simple, and they are suitable for industrial production. Detailed Implementation

[0033] The present invention will be further described in conjunction with the embodiments. The following embodiments are only illustrative of the present invention and are not intended to limit the present invention in any way.

[0034] Example Y-1 N -(2-(3-bromo-4-methoxyphenyl)benzo[ d [Oxazol-5-yl)-1-oxo-4-phenyl-1 H Preparation of isochrome-3-formamide

[0035] 2-Benzoylbenzoic acid (500 mg, 1.0 eq), diethyl bromide malonate (366.4 μL, 1.1 eq), and K₂CO₃ (539.1 mg, 2.0 eq) were dissolved in DMF and reacted overnight at room temperature. After the reaction was complete as determined by TLC, the mixture was diluted with ethyl acetate, extracted with water, and the organic layer was evaporated to dryness. Acetic acid (2 mL) and concentrated HCl (1.6 mL) were added to the residue, and the mixture was refluxed for 6 h. After the reaction was complete as determined by TLC, the reaction system was added dropwise to ice water, and a white solid precipitated. The solid was filtered to give 498.9 mg of white solid 1. Yield: 86.3%; 1 H NMR (400 MHz, DMSO- d 6 ) δ 13.57 (s, 1H), 8.30 (dd, J = 7.6, 1.2 Hz, 1H),7.87 – 7.82 (m, 1H), 7.77 – 7.72 (m, 1H), 7.53 – 7.46 (m, 3H), 7.34 – 7.30(m, 2H), 7.01 (d, J = 7.6 Hz, 1H). 2-Amino-4-nitrophenol (333.5 mg, 1.0 eq) and 3-bromo-4-methoxybenzoic acid (500.0 mg, 1.0 eq) were added to PPA (10 g) and reacted at 150 °C for 4 h. TLC analysis showed that after the reaction was complete, the reaction system was neutralized with concentrated KOH, resulting in the formation of a dark brown precipitate, which was filtered. The solid was dissolved in ethyl acetate, washed twice with water, and once with saturated NH4Cl. The organic layer was evaporated to dryness and passed through a column chromatography to give 310.0 mg of a yellow solid. Yield: 41.2%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.60 (s, 1H),8.32 (m, 2H), 8.20 (s, 1H), 8.00 (d, J = 7.2 Hz, 1H), 7.36 (d, J = 6.4 Hz, 1H), 3.98 (s, 3H). 2 (310.0 mg, 1.0 eq), iron powder (249.4 mg, 5.0 eq), and NH4Cl (142.9 mg, 3.0 eq) were mixed in a mixture of ethanol (9 mL) and water (3 mL). The mixture was reacted at 85 °C for 2 h. After the reaction was confirmed to be complete by TLC, the mixture was filtered, the filtrate was evaporated to dryness, dissolved in ethyl acetate, extracted with water, and the organic layer was evaporated to dryness to obtain a yellow solid 3, which was used directly in the next step.

[0036] In a single-necked flask, add 1 (124.1 mg, 1.0 eq), 3 (130.0 mg, 1.0 eq), HATU (222.6 mg, 1.5 eq), DIPEA (135.7 μL, 2.0 eq), and DMF (5 mL). Stir overnight at room temperature. After the reaction is complete as determined by TLC, if solid precipitates, filter directly and wash with DCM and CH3OH sequentially to obtain 154.8 mg of white solid Y-1. If no solid precipitates, dilute the reaction system with EA, extract with water, evaporate the organic layer to dryness, and pass through a column. Yield: 70.1%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.70 (s, 1H), 8.36 (d, J = 7.8 Hz, 1H), 8.29(d, J = 1.6 Hz, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.90 (dd, J = 14.4, 6.8 Hz, 2H), 7.76 (t, J = 7.6 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.49 (t, J = 8.0 Hz, 3H), 7.42(d, J = 7.6 Hz, 2H), 7.34 (d, J = 8.8 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 3.96 (s,3H). HRMS (ESI) calcd . for [C 30 H 20 BrN2O5] + ([M+H)) + ): m / z 567.0550, found:567.0559. Example Y-2

[0037] This example uses a similar procedure to Example Y-1, except that 2-(4-chlorobenzoyl)benzoic acid is used instead of 2-benzoylbenzoic acid.

[0038] 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.76 (s, 1H), 8.36 (d, J = 5.6 Hz, 1H), 8.30(s, 1H), 8.17 (d, J = 7.2 Hz, 1H), 7.97 (s, 1H), 7.89 (s, 1H), 7.77 (s, 1H),7.71 (d, J = 7.6 Hz, 1H), 7.56 (s, 3H), 7.43 (s, 2H), 7.34 (d,J = 6.8 Hz, 1H), 7.16 (d, J = 6.4 Hz, 1H), 3.97 (s, 3H). HRMS (ESI) calcd . for [C 30 H 19 BrClN2O5] + ([M+H)) + ): m / z 601.0160, found: 601.0158. Example Y-3

[0039] This example uses a similar procedure to Example Y-1, except that 2-(3-chlorobenzoyl)benzoic acid is used instead of 2-benzoylbenzoic acid.

[0040] HRMS (ESI) calcd . for [C 30 H 19 BrClN2O5] + ([M+H)) + ): m / z 601.0160, found:601.0155. Example Y-4

[0041] This example uses a similar procedure to Example Y-1, except that 2-(2-chlorobenzoyl)benzoic acid is used instead of 2-benzoylbenzoic acid.

[0042] HRMS (ESI) calcd . for [C 30 H 19 BrClN2O5] + ([M+H)) + ): m / z 601.0160, found:601.0159. Example Y-5

[0043] This example uses a similar procedure to Example Y-1, except that 2-(4-fluorobenzoyl)benzoic acid is used instead of 2-benzoylbenzoic acid.

[0044] 1 H NMR (400 MHz, CF3COOD) δ 8.62 (d, J= 8.0 Hz, 1H), 8.58 (d, J = 8.4 Hz, 2H), 8.43 (d, J = 8.0 Hz, 1H), 7.95 (m, 3H), 7.91 – 7.86 (m, 1H), 7.39 (m, 3H),7.32 (m, 3H), 4.16 (m, 3H). HRMS (ESI) calcd . for [C 30 H 19 BrFN2O5] + ([M+H)) + ): m / z585.0456, found: 585.0463. Example Y-6

[0045] This example uses a similar procedure to Example Y-1, except that 2-(4-oxymethylbenzoyl)benzoic acid is used instead of 2-benzoylbenzoic acid.

[0046] 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.68 (s, 1H), 8.34 (d, J = 7.6 Hz, 1H), 8.29(d, J = 2.0 Hz, 1H), 8.16 (dd, J = 8.8, 2.0 Hz, 1H), 7.95 (d, J = 1.6 Hz, 1H), 7.89(t, J = 7.2 Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.48 (dd, J = 8.8, 1.6 Hz, 1H), 7.34 (d, J = 8.4 Hz, 3H), 7.23 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 8.4 Hz, 2H), 3.97 (s, 3H), 3.79 (s, 3H). HRMS (ESI) calcd . for [C31 H 22 BrN2O6] + ([M+H)) + ): m / z 597.0656, found: 597.0645. Example Y-7

[0047] This example uses a similar procedure to Example Y-1, except that 2-(4-dimethylaminobenzoyl)benzoic acid is used instead of 2-benzoylbenzoic acid.

[0048] 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.68 (s, 1H), 8.35 – 8.30 (m, 2H), 8.17 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 5.2 Hz, 2H), 7.90 (t, J = 7.2 Hz, 1H), 7.75 (d, J =7.2 Hz, 1H), 7.71 (d, J = 9.2 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.33 (dd, J =14.4, 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 3.97 (s,3H), 2.93 (s, 6H). HRMS (ESI) calcd . for [C 32 H 25 BrN3O5] + ([M+H)) + ): m / z 610.0972, found: 610.0961. Example Y-8

[0049] This example uses a similar procedure to Example Y-1, except that 2-(1H-pyrrole-2-carbonyl)benzoic acid is used instead of 2-benzoylbenzoic acid.

[0050] HRMS (ESI) calcd . for [C 28 H 19 BrN3O5] + ([M+H)) + ): m / z 556.0503, found:556.0505. Example Y-9

[0051] This example uses a similar procedure to Example Y-1, except that 2-benzoyl-3-chlorobenzoic acid is used instead of 2-benzoylbenzoic acid.

[0052] HRMS (ESI) calcd . for [C 30 H 19 BrClN2O5] + ([M+H)) + ): m / z 601.0160, found:601.0162. Example Y-10

[0053] This example uses a similar procedure to Example Y-1, except that 2-benzoyl-4,5-dichlorobenzoic acid is used instead of 2-benzoylbenzoic acid.

[0054] HRMS (ESI) calcd . for [C 30 H 18 BrCl2N2O5] + ([M+H)) + ): m / z 643.9771, found:643.9773. Example Y-11

[0055] This example uses a similar operation to Example Y-1, except that 2-formylbenzoic acid is used instead of 2-benzoylbenzoic acid.

[0056] 1 H NMR (400 MHz, CF3COOD) δ 9.22 (s, 1H), 8.92 (m, 2H), 8.79 (m, 1H), 8.53 (s, 1H), 8.43 – 8.18 (m, 6H), 7.66 (m, 1H), 4.50 (s, 3H). HRMS (ESI) calcd . for [C 24 H 16 BrN2O5] + ([M+H)) + ): m / z 491.0237, found: 491.0240. Example Y-12

[0057] Dissolve 4 (100.0 mg, 1.0 eq) in 7N ammonia-methanol solution (5 mL) and reflux for 23 h. After the reaction was confirmed to be complete by TLC, the solution was evaporated to dryness to obtain a white solid 5, which was used directly in the next step. Yield: 98.2%; 1 H NMR (500 MHz, DMSO) δ 11.92 (s,1H), 11.11 (s, 1H), 8.33 (d, J = 7.2 Hz, 1H), 7.73 – 7.69 (m, 1H), 7.64 (t, J =7.2 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.0Hz, 1H). The other steps were performed similarly to those in Example Y-1, except that 5 was used instead of 1, yielding a gray solid Y-12. Yield: 52.7%; 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.02 (s, 1H), 10.63 (s, 1H), 8.35(d, J = 8.0 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.16 (dd, J = 8.8, 2.0 Hz, 1H), 7.89(d, J = 2.0 Hz, 1H), 7.75 – 7.70 (m, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.61 (t, J =7.6 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.43 (d,J = 8.4 Hz, 2H), 7.35 (dd, J =12.8, 5.6 Hz, 2H), 7.24 (d, J = 8.0 Hz, 1H), 3.97 (s, 3H). HRMS (ESI) calcd . for[C 30 H 20 BrClN3O4] + ([M+H)) + ): m / z 600.0320, found: 600.0319. Example Y-13

[0058] This example uses a similar procedure to Example Y-12, except that 2-(3-chlorobenzoyl)benzoic acid is used instead of 2-(4-chlorobenzoyl)benzoic acid. HRMS (ESI) calcd . for [C 30 H 20 BrClN3O4] + ([M+H)) + ): m / z600.0320, found: 600.0317. Example Y-14

[0059] This example uses a similar procedure to Example Y-1, except that p-bromobenzoic acid is used instead of 3-bromo-4-methoxybenzoic acid, and 2-(4-chlorobenzoyl)benzoic acid is used instead of 2-benzoylbenzoic acid.

[0060] 1 H NMR (400 MHz, CF3COOD) δ 8.62 – 8.57 (m, 2H), 8.12 (t, J = 7.6 Hz, 1H), 8.05 (t, J = 7.6 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 11.6 Hz, 2H), 3.47 (m, 2H), 2.53 (s, 3H), 1.91 (dd, J = 14.4, 7.2Hz, 2H), 1.09 (t,J = 7.2 Hz, 3H). HRMS (ESI) calcd. for [C 24 H 22 N3O2] + ([M+H)) + ): m / z 384.1707, found: 384.1719. Example Y-15

[0061] This example uses a similar procedure to Example Y-1, except that p-methoxybenzoic acid is used instead of 3-bromo-4-methoxybenzoic acid, and 2-(4-chlorobenzoyl)benzoic acid is used instead of 2-benzoylbenzoic acid.

[0062] 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.73 (s, 1H), 8.36 (d, J = 7.6 Hz, 1H), 8.12(d, J = 8.4 Hz, 2H), 7.95 (s, 1H), 7.89 (t, J = 7.6 Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.4 Hz, 3H), 3.87 (s, 3H). HRMS (ESI) calcd . for [C 30 H 20 ClN2O5] + ([M+H)) + ): m / z 523.1055, found: 523.1047. Example Y-16

[0063] This example uses a similar procedure to Example Y-1, except that 3-bromo-4-methoxybenzoic acid is replaced with 4-(4-methylpiperazine)benzoic acid and 2-(4-chlorobenzoyl)benzoic acid is replaced with 2-benzoylbenzoic acid.

[0064] 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.79 (s, 1H), 8.35 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 8.8 Hz, 2H), 7.91 (d, J = 1.6 Hz, 1H), 7.90 – 7.87 (m, 1H), 7.77 (t, J =7.6 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4Hz, 1H), 7.48 (dd, J = 8.8, 2.0 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.16 (s, 1H), 7.14 (d, J = 3.2 Hz, 1H), 3.53 (m, 4H), 2.93 (m, 4H), 2.55 (s, 3H). HRMS (ESI) calcd . for [C 34 H 28 ClN4O4] + ([M+H)) + ): m / z 591.1794, found: 591.1798. Example Y-17

[0065] This example employs a similar procedure to Example Y-1, except that 3-bromo-4-methoxybenzoic acid is replaced with 4-(4-(2-(2-hydroxyethyl)ethoxy)ethyl)piperazin-1-ylbenzoic acid, and 2-(4-chlorobenzoyl)benzoic acid is replaced with 2-benzoylbenzoic acid. HRMS (ESI) calcd . for [C 39 H 38 ClN4O7]+ ([M+H)) + ): m / z 709.2424, found: 709.2425 Example Y-18

[0066] This example uses a similar operation to Example Y-1, except that 2-amino-5-nitrophenol is used instead of 2-amino-4-nitrophenol, and 2-(4-chlorobenzoyl)benzoic acid is used instead of 2-benzoylbenzoic acid.

[0067] 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.87 (s, 1H), 8.36 (d, J = 8.0 Hz, 1H), 8.28(s, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.10 (s, 1H), 7.90 (t, J = 7.6 Hz, 1H), 7.78(t, J = 7.6 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.51 (d, J =8.4 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.8 Hz, 1H), 7.16 (d, J = 8.0Hz, 1H), 3.97 (s, 3H). HRMS (ESI) calcd . for [C 30 H 19 BrClN2O5] + ([M+H)) + ): m / z601.0160, found: 601.0162. Example Y-19

[0068] This example uses a similar operation to Example Y-1, except that 2-amino-4-nitrophenol is replaced with 4-nitro-o-phenylenediamine and 2-(4-chlorobenzoyl)benzoic acid is replaced with 2-benzoylbenzoic acid.

[0069] 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.80 (s, 1H), 10.61 (s, 1H), 8.37 (d, J = 8.0Hz, 2H), 8.14 (d, J = 6.4 Hz, 1H), 7.97 (s, 1H), 7.90 (m, 2H), 7.78 (d, J = 7.2Hz, 1H), 7.58 (d, J = 7.2 Hz, 2H), 7.45 (d, J = 6.8 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 7.6 Hz, 1H), 3.95 (s, 3H). HRMS (ESI) calcd . for[C 30 H 20 BrClN3O4] + ([M+H)) + ): m / z 600.0320, found: 600.0328. Example Y-20

[0070] This example employs a similar procedure to Example Y-1, except that 2-amino-4-nitro-6-methoxyphenol is used instead of 2-amino-4-nitrophenol, and 2-(4-chlorobenzoyl)benzoic acid is used instead of 2-benzoylbenzoic acid. HRMS(ESI) calcd . for [C 31 H 21 BrClN2O6] + ([M+H)) + ): m / z 631.0266, found: 631.0268. Example Y-21

[0071] 2-Amino-5-nitropyridine (200.0 mg, 1.0 eq) was added to... β The mixture was refluxed overnight in an ethanol solution of 329.0 mg (1.0 eq) of 4-bromo-4-methoxyacetophenone. After the reaction was confirmed to be complete by TLC, the reaction system was cooled to room temperature, and a solid precipitated out. The solid was filtered to give 237.9 mg of a yellow solid, 6. Yield: 61.5%. 1 H NMR (400 MHz, DMSO) δ 9.92 (d, J =1.6 Hz, 1H), 8.62 (s, 1H), 8.14 (dd, J = 10.0, 2.0 Hz, 1H), 7.95 (d, J = 8.8 Hz, 2H), 7.84 (d, J = 10.0 Hz, 1H), 7.12 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H). The other steps were performed similarly to those in Example Y-1, except that 7 was used instead of 3, and 2-(4-chlorobenzoyl)benzoic acid was used instead of 2-benzoylbenzoic acid, yielding a yellow solid Y-21. Yield: 72.6%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.76 (s, 1H), 9.11 (s, 1H), 8.35 (m, 2H), 7.84 (m, 4H), 7.56 (d, J =14.8 Hz, 3H), 7.44 (s, 2H), 7.33 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 6.8 Hz, 1H), 7.01 (d, J = 7.2 Hz, 2H), 3.81 (s, 3H). HRMS (ESI) calcd . for [C 30 H 21 ClN3O4] + ([M+H)) + ): m / z 522.1215, found: 522.1219. Example Y-22

[0072] This example employs a similar procedure to Example Y-1, the only difference being the use of 5-nitrobenzo[ d Oxazole is used instead of 2, and 2-(4-chlorobenzoyl)benzoic acid is used instead of 2-benzoylbenzoic acid.

[0073] 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.75 (s, 1H), 8.73 (m, 1H), 8.35 (m, 1H), 8.02 (s, 1H), 7.89 (s, 1H), 7.75 (d, J = 14.4 Hz, 2H), 7.55 (m, 3H), 7.42 (m,2H), 7.15 (m, 1H). HRMS (ESI) calcd . for [C 23 H 14 ClN2O4] + ([M+H)) + ): m / z 417.0637, found: 417.0633. Example Y-23

[0074] This example employs a similar procedure to Example Y-1, the only difference being the use of 1-methyl-5-nitro-1- H -Indole replaces 2, and 2-(4-chlorobenzoyl)benzoic acid replaces 2-benzoylbenzoic acid.

[0075] 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.39 (s, 1H), 8.35 (d, J = 7.2 Hz, 1H), 7.91– 7.85 (m, 1H), 7.79 (d, J = 1.6 Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H), 7.56 (d, J =8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.8 Hz, 1H), 7.30 (d, J= 3.2Hz, 1H), 7.20 (dd, J = 8.8, 1.6 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.36 (d, J = 2.8Hz, 1H), 3.76 (s, 3H). HRMS (ESI) calcd . for [C 25 H 18 ClN2O3] + ([M+H)) + ): m / z429.1000, found: 429.1003. Example Y-24

[0076] This example employs a similar procedure to Example Y-1, the only difference being the use of 1-methyl-5-nitro-1- H -Indole replaces 2, and 2-(4-trifluoromethylbenzoyl)benzoic acid replaces 2-benzoylbenzoic acid.

[0077] HRMS (ESI) calcd . for [C 26 H 18 F3N2O3] + ([M+H)) + ): m / z 463.1264, found:463.1265. Example Y-25

[0078] 3-Bromo-4-methoxybenzoic acid (500.0 mg, 1.5 eq) was refluxed in SOCl2 for 2 h. After the reaction was complete, the solution was evaporated to dryness. The residue was dissolved in DCM, and N-Boc-m-phenylenediamine (300.5 mg, 1.0 eq) and Et3N (601.6 μL, 3.0 eq) were added. The mixture was refluxed overnight. After the reaction was confirmed to be complete by TLC, the solution was evaporated to dryness and passed through a column to give 784.5 mg of a yellow solid 8. Yield: 86.3%; 1 H NMR (400 MHz, DMSO-) d 6 ) δ 10.16 (s, 1H), 9.38 (s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.02(dd, J= 8.8, 2.2 Hz, 1H), 7.99 (m, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.8Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 3.94 (s, 3H), 1.48 (s, 9H). Dissolve 8 (100.0 mg, 1.0 eq) in DCM (3 mL), add TFA (1.5 mL), and react at room temperature for 1 h. After the reaction is complete as detected by TLC, the reaction system is evaporated to dryness to obtain oil 9, which is used directly in the next step.

[0079] The other steps were performed similarly to those in Example Y-1, except that 9 was used instead of 3, and 2-(4-chlorobenzoyl)benzoic acid was used instead of 2-benzoylbenzoic acid, yielding a yellow solid Y-25. Yield: 69.8%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.62 (s, 1H), 10.23 (s, 1H), 8.59 (d, J = 3.6 Hz, 1H), 8.38 (d, J =18.0 Hz, 1H), 8.23 ​​(d, J = 2.0 Hz, 1H), 8.11 (s, 1H), 8.01 (dd, J = 8.8, 2.0 Hz, 1H), 7.88 (t, J = 7.2 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.26 (m, 3H), 7.14 (d, J = 8.0 Hz, 1H), 3.94 (s, 3H).HRMS (ESI) calcd . for [C 30 H 21 BrClN2O5] + ([M+H)) +): m / z 603.0317, found: 603.0322. Example Y-26

[0080] 3-Bromo-4-methoxyphenol (500.0 mg, 1.0 eq), p-fluoronitrobenzene (267.3 μL, 1.0 eq), and K₂CO₃ (1.1 g, 3.0 eq) were mixed in DMF and reacted overnight at 70 °C under nitrogen protection. After the reaction was confirmed to be complete by TLC, the reaction mixture was diluted with EA, extracted with water, and the organic layer was evaporated to dryness and column chromatography to give 637.9 mg of white solid 10. Yield: 80.2%; 1 HNMR (400 MHz, DMSO- d 6 ) δ 8.31 – 8.28 (m, 2H), 7.57 (d, J = 2.0 Hz, 1H), 7.29 (d, J = 3.6 Hz, 2H), 7.16 (d, J = 9.2 Hz, 2H), 3.94 (s, 3H). The other steps were performed similarly to those in Example Y-1, except that 11 was used instead of 3, and 2-(4-chlorobenzoyl)benzoic acid was used instead of 2-benzoylbenzoic acid, yielding a yellow solid Y-26. Yield: 65.5%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.60 (s, 1H), 8.36 (d, J = 7.6 Hz, 1H), 7.90 (t, J = 7.6 Hz, 1H), 7.77(t, J = 7.6 Hz, 1H), 7.59 – 7.53 (m, 4H), 7.41 (d, J = 8.0 Hz, 2H), 7.27 (d, J =2.4 Hz, 1H), 7.15 (dd, J = 8.4, 4.0 Hz, 2H), 7.04 (dd, J = 8.8, 2.4 Hz, 1H), 6.95(d, J = 8.8 Hz, 2H), 3.84 (s, 3H). HRMS (ESI) calcd . for [C 29 H 20 BrClNO5] + ([M+H)) + ):m / z 576.0208, found: 576.0204. Example Y-27

[0081] This example uses a similar procedure to Example Y-25, except that L-alanine and 3 are used instead of N-Boc-m-phenylenediamine and 3-bromo-4-methoxybenzoic acid.

[0082] 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.23 (s, 1H), 8.80 (d, J = 7.2 Hz, 1H), 8.34– 8.30 (m, 2H), 8.17 (dd, J = 8.8, 2.0 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.89 –7.83 (m, 1H), 7.76 – 7.69 (m, 2H), 7.51 (dd, J = 8.8, 2.0 Hz, 3H), 7.37 (s,1H), 7.34 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.0 Hz, 1H), 4.43 (p, J = 7.2 Hz, 1H), 3.97 (s, 3H), 1.31 (d, J = 7.2 Hz, 3H). HRMS (ESI) calcd . for [C 33 H 24 BrClN3O6] + ([M+H)) + ): m / z 672.0532, found: 672.0541. Example Y-28

[0083] This example uses a similar procedure to Example Y-25, except that L-valine and 3 are used instead of N-Boc-m-phenylenediamine and 3-bromo-4-methoxybenzoic acid.

[0084] HRMS (ESI) calcd . for [C 33 H 24 BrClN3O6] + ([M+H)) + ): m / z 700.0845, found:700.0846. Example Y-29

[0085] A mixture of 3 (176.6 mg, 1.0 eq), bis(2-chloroethyl)amine hydrochloride (100.0 mg, 1.0 eq), and diethylene glycol methyl ether (3 mL) was heated at 150 °C for 12 h. After the reaction was complete as determined by TLC, the mixture was cooled to room temperature, dissolved in methanol (4 mL), and ether (15 mL) was added. A solid precipitated, which was filtered and washed with ether to give a yellowish-brown solid 12, which was used directly in the next step. HRMS (ESI) calcd . for [C 18 H 19 BrN3O2] + ([M+H)) + ): m / z388.0655, found: 388.0658. The other steps were performed similarly to those in Example Y-1, except that 12 was used instead of 3, and 2-(4-chlorobenzoyl)benzoic acid was used instead of 2-benzoylbenzoic acid, yielding a yellow solid Y-29. Yield: 74.4%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.30 (d, J = 7.6 Hz, 1H), 8.27 (s, 1H), 8.14(d, J = 8.8 Hz, 1H), 7.87 (t, J = 7.2 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.61 (dd, J = 8.4, 3.6 Hz, 3H), 7.45 (d, J= 8.4 Hz, 2H), 7.33 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.8 Hz, 1H), 3.96 (s, 3H), 3.57 (m, 4H), 2.99 (m,2H), 2.86 (m, 2H). HRMS (ESI) calcd . for [C 34 H 26 BrClN3O5] + ([M+H)) + ): m / z 670.0739, found: 670.0745. Example Y-30

[0086] This example uses a similar procedure to Example Y-29, except that 12 is replaced with 2-(4-chlorophenyl)-5-(piperazin-1-yl)benzo[d]oxazole.

[0087] HRMS (ESI) calcd . for [C 33 H 24 BrClN3O6] + ([M+H)) + ): m / z 596.1138, found:596.1140. Example Y-31

[0088] This example uses a similar procedure to Example Y-25, except that N-Boc-m-phenylenediamine is replaced with 4-(3-aminophenyl)piperazine-1-carboxylic acid tert-butyl ester.

[0089] 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.05 (s, 1H), 8.30 (d, J = 7.2 Hz, 1H), 8.22(d, J = 2.0 Hz, 1H), 8.00 (dd, J = 8.8, 2.0 Hz, 1H), 7.90 – 7.84 (m, 1H), 7.73(t, J= 7.2 Hz, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.35 (s,1H), 7.29 (d, J = 8.0 Hz, 1H), 7.24 (t, J = 8.4 Hz, 2H), 7.18 (t, J = 8.0 Hz, 1H), 6.66 (dd, J = 8.0, 1.6 Hz, 1H), 3.94 (s, 3H), 3.60 – 3.52 (m, 4H), 2.97 (m,2H), 2.85 (m, 2H). HRMS (ESI) calcd . for [C 34 H 28 BrClN3O5] + ([M+H)) + ): m / z 672.0895, found: 672.0901. Example Y-32

[0090] This example uses a similar procedure to Example Y-25, except that 4-(3-aminophenyl)piperazine-1-carboxylic acid tert-butyl ester is used instead of N-Boc-m-phenylenediamine, and 1H-imidazol-5-carboxylic acid is used instead of 3-bromo-4-methoxybenzoic acid.

[0091] HRMS (ESI) calcd . for [C 34 H 28 BrClN3O5] + ([M+H)) + ): m / z 554.1590, found:554.1588. Example Y-33

[0092] This example uses a similar operation to Example Y-1, except that diphenylmethylpiperazine is used instead of 3.

[0093] 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.32 (d, J= 7.6 Hz, 1H), 7.90 (t, J = 7.6 Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.44 (t, J = 6.4 Hz, 6H), 7.35 (t, J = 7.2 Hz, 4H), 7.25 (d, J = 7.2 Hz, 3H), 4.25 (s, 1H), 3.46 (m, 4H), 2.18 (m, 2H), 2.01 (m, 2H). HRMS (ESI) calcd . for [C 33 H 28 ClN2O3] + ([M+H)) + ): m / z535.1783, found: 535.1794. Example Y-34

[0094] This example uses a similar operation to Example Y-1, except that bis(4-chlorophenyl)methylpiperazine is used instead of 3.

[0095] 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.25 (d, J = 7.8 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.57 (d, J = 8.1 Hz, 2H), 7.41 – 7.30 (m, 10H), 7.17 (d, J = 8.0 Hz, 1H), 3.39 (s, 4H), 2.10 (s, 2H), 1.96 (s, 2H).HRMS (ESI) calcd . for [C 33 H 26 Cl3N2O3] + ([M+H)) + ): m / z 603.1004, found: 603.1006. Example Y-35

[0096] This example uses a similar operation to Example Y-1, except that bis(4-fluorophenyl)methylpiperazine is used instead of 3.

[0097] 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.25 (d, J = 7.6 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.37 (dd, J = 11.2, 8.00Hz, 6H), 7.22 – 7.07 (m, 5H), 3.39 (s, 4H), 2.10 (s, 2H), 1.96 (s, 2H).HRMS(ESI) calcd . for [C 33 H 26 ClF2N2O3] + ([M+H)) + ): m / z 571.1595, found: 571.1598. Example Y-36

[0098] In a single-necked flask, 4 (300.1 mg, 1.0 eq), N-Boc-piperazine (220.0 mg, 1.1 eq), HATU (570.0 mg, 1.5 eq), DIPEA (348.6 μL, 2.0 eq), and DMF (10 mL) were added. The mixture was stirred overnight at room temperature. After the reaction was complete as detected by TLC, the reaction mixture was diluted with EA, extracted with water, and the organic phase was concentrated under reduced pressure and column chromatography. Then, 10 mL of 30% TFA / DCM solution was added to the obtained intermediate. After reacting for 3 h, the reaction mixture was concentrated under reduced pressure to give 299.10 mg of compound 13, with a yield of 78.3% HRMS (ESI). calcd . for [C 21 H 20 ClN2O 33 ] + ([M+H)) +): m / z 383.1157, found:383.1152. 13 (382.0 mg, 1.0 eq), diphenylcarbamoyl chloride (231.1 mg, 1.0 eq), and triethylamine (112 mg, 1.1 eq) were added to DMF and refluxed for 12 h. After the reaction was complete as detected by TLC, the reaction system was diluted with EA, extracted with water, and the organic phase was concentrated under reduced pressure and then passed through a column to give 461.0 mg of white solid Y-36. Yield: 79.9%; 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.27 (d, J = 7.6 Hz, 1H), 7.84 (t, J = 7.6 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.56 (d, J = 5.6 Hz, 2H), 7.35 (dd, J = 15.2, 7.6Hz, 7H), 7.22 – 7.15 (m, 3H), 7.13 (d, J = 8.0 Hz, 3H), 4.06 (d, J = 12.4 Hz, 1H), 3.80 (d, J = 13.2 Hz, 1H), 2.98 (t, J = 12.0 Hz, 1H), 2.67 (t, J = 12.0 Hz, 1H), 1.70 (t, J = 12.8 Hz, 2H), 1.22 (d, J = 12.8 Hz, 2H). HRMS (ESI) calcd . for[C 34 H 29 ClN3O4] + ([M+H)) + ): m / z 578.1841, found: 578.1844. Example Y-37

[0099] This example uses a similar procedure to Example Y-36, except that 10H-phenthiazine-10-carbonyl chloride is used instead of diphenylcarbamoyl chloride.

[0100] 1 H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 7.6 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.63 (t, J = 7.2 Hz, 1H), 7.56 (d, J = 7.6 Hz, 2H), 7.46 (dd, J = 12.0, 8.4Hz, 4H), 7.40 – 7.29 (m, 5H), 7.26 (t, J = 8.0 Hz, 3H), 4.86 (d, J = 7.2 Hz, 1H), 4.33 (d, J = 13.2 Hz, 1H), 3.88 (s, 1H), 3.67 (d, J = 13.6 Hz, 1H), 3.03 (t, J =13.2 Hz, 1H), 2.74 (t, J = 12.0 Hz, 1H), 1.97 (d, J = 10.4 Hz, 2H). HRMS (ESI) calcd . for [C 40 H 30 Cl3N4O4] + ([M+H)) + ): m / z 608.1405, found: 608.1403. Example Y-38

[0101] In a single-necked flask, 4-benzylpiperazine-1-carbonyl chloride (314.1 mg, 1.0 eq), resorcinol (252.0 mg, 1.0 eq), Et3N (111 mg, 1.1 eq), and DMF (10 mL) were added. The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with EA, extracted with water, and distilled under reduced pressure and column-secreted to give compound 14, for a total yield of 262.5 mg. The yield was 68%. HRMS (ESI) calcd . for [C 24 H 27 N4O1] + ([M+H)) + ): m / z 387.2179, found: 387.2177. 14 (386.2 mg, 1.0 eq), 4 (202.1 mg, 1.0 eq), HATU (570.0 mg, 1.5 eq), and DIPEA (348.6 μL, 2.0 eq) were added to 10 mL of DMF and refluxed for 12 h. After the reaction was confirmed to be complete by TLC, the reaction mixture was diluted with EA, extracted with water, and distilled under reduced pressure and passed through a column to obtain 349.2 mg of white solid Y-38. Yield: 52.3%; 1 H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H) ,8.67 (m, 1H), 8.46 (dd, J = 7.6Hz, J = 4.8 Hz, 1H), 7.88 (dd, J = 6.4, 3.2Hz, 2H), 7.48-7.45 (m, 4H), 7.43 – 7.37(m, 4H), 7.35 – 7.28 (m, 3H), 7.16 (d, J = 8.0 Hz, 2H), 7.05 (t, J = 8.0 Hz, 4H), 5.18 (s, H), 3.29 (s, 2H), 2.47 (s, 2H). HRMS (ESI) calcd . for [C 24 H 27 N4O1] + ([M+H)) + ): m / z 669.2263, found: 669.2262. Example Y-39

[0102] 2-Amino-4-nitrophenol (1.0 g, 1.0 eq) and KOH (364.0 mg, 1.0 eq) were dissolved in ethanol (15 mL) and water (5 mL), and CS2 (615.0 μL, 2.0 eq) was added. The mixture was refluxed at 60 °C for 3 h. After the reaction was confirmed to be complete by TLC, the pH was adjusted to 4-5 with 2N HCl solution. A solid was formed, which was filtered to give 1.1 g of a pale yellow solid. Yield: 87.7%; 1 H NMR (400MHz, DMSO- d 6 ) δ 13.48 (s, 1H), 8.18 (dd, J= 8.8, 2.4 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H). Dissolve 16 (500.0 mg, 1.0 eq) in toluene, and slowly add PCl5 (637.3 mg, 1.5 eq) at 0 °C. React at 120 °C for 3 h. After the reaction is complete as determined by TCL, the reaction mixture is evaporated to dryness and purified by column chromatography to give 184.5 mg of white solid 17. Yield: 36.9%. 1 H NMR (400 MHz, DMSO) δ 8.53 (d, J = 2.4 Hz, 1H), 8.27 (dd, J = 8.8, 2.4Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H). Dissolve 17 (198.0 mg, 1.0 eq) in acetonitrile, add 15 (405.5 mg, 1.5 eq), and react overnight at 80 °C. After the reaction is complete as detected by TLC, quench the reaction mixture in ice water, extract with EA, evaporate the organic layer to dryness, and pass it through a column. 254.4 mg of yellow solid 18 was obtained. Yield: 58.9%; 1 H NMR (400 MHz, DMSO) δ 8.09 (d, J = 2.4 Hz, 1H), 8.00 (dd, J =8.8, 2.4 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.03 (m,2H), 3.80 (m, 4H), 3.78 (s, 3H), 3.23 – 3.19 (m, 4H). The other steps were performed similarly to those in Example Y-1, except that 19 was used instead of 3, and 2-(4-chlorobenzoyl)benzoic acid was used instead of 2-benzoylbenzoic acid, yielding a yellow solid Y-39. Yield: 64.7%. 1 H NMR (400 MHz, DMSO) δ 10.56 (s, 1H), 8.36 (d, J = 7.6 Hz, 1H), 7.90 (t, J = 7.6 Hz, 1H), 7.77 (t,J = 7.6 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 1.6 Hz, 1H), 7.43 (d, J =8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 1.6 Hz, 1H), 7.21 – 7.15 (m,2H), 7.03 (m, 2H), 3.79 (s, 3H), 3.75 – 3.71 (m, 4H), 3.21 – 3.16 (m, 4H).HRMS (ESI) calcd . for [C 32 H 25 ClN5O4] + ([M+H)) + ): m / z 578.1590, found: 578.1588. Example Y-40

[0103] This example uses a similar operation to Example Y-39, except that methylpiperazine is used instead of 15.

[0104] 1 H NMR (400 MHz, DMSO) δ 10.53 (s, 1H), 8.35 (d, J = 7.6 Hz, 1H), 7.89(t, J = 7.6 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.47 (d, J =1.2 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.8 Hz, 1H), 7.17 (dd, J =10.8, 4.4 Hz, 2H), 3.64 – 3.59 (m, 4H), 2.50 (m, 4H), 2.28 (s, 3H). HRMS(ESI) calcd . for [C28 H 24 ClN4O4] + ([M+H)) + ): m / z 515.1481, found: 515.1477. Example Y-41

[0105] This example uses a similar procedure to Example Y-39, except that 15 is replaced with 1-cyclohexylpiperazine.

[0106] 1 H NMR (400 MHz, DMSO) δ 10.52 (s, 1H), 8.35 (d, J = 7.6 Hz, 1H), 7.89(t, J = 7.6 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.45 (d, J =1.2 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 8.4Hz, 2H), 3.58 (m, 4H), 2.68 (m, 4H), 2.41 – 2.29 (m, 1H), 1.76 (d, J = 9.6 Hz,4H), 1.58 (m, 1H), 1.20 (m, 4H), 1.09 (m, 1H). HRMS (ESI) calcd . for[C 33 H 32 ClN4O4] + ([M+H)) + ): m / z 583.2107, found: 583.2110. Example Y-42

[0107] This example uses a similar procedure to Example Y-39, except that morphine is used instead of 15.

[0108] 1H NMR (400 MHz, DMSO- d 6 ) δ 10.53 (s, 1H), 8.34 (dd, J = 8.0, 0.8 Hz, 1H),7.92 – 7.85 (m, 1H), 7.79 – 7.73 (m, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.48 (d, J =2.0 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 1H), 7.21 – 7.13 (m,2H), 3.73 – 3.68 (m, 4H), 3.60 – 3.54 (m, 4H). HRMS (ESI) calcd . for[C 27 H 21 ClN3O5] + ([M+H)) + ): m / z 502.1164, found: 502.1160. Example Y-43

[0109] This example employs a similar operation to that of Example Y-39, the only difference being that (...) S )-3-phenylpyrrolidine replaces 15.

[0110] 1 H NMR (400 MHz, DMSO) δ 10.52 (s, 1H), 8.36 (d, J = 7.6 Hz, 1H), 7.90(t, J = 7.6 Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.46 (s,1H), 7.43 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 3.6 Hz, 4H), 7.34 (d, J= 8.4 Hz, 1H),7.30 – 7.25 (m, 1H), 7.16 (m, 2H), 4.05 (t, J = 7.2 Hz, 1H), 3.81 (t, J = 8.0 Hz,1H), 3.65 (m, 1H), 3.54 (m, 2H), 2.39 (m, 1H), 2.19 – 2.07 (m, 1H). HRMS(ESI) calcd . for [C 33 H 25 ClN3O4] + ([M+H)) + ): m / z 562.1528, found: 562.1530. Example Y-44

[0111] This example uses a similar operation to Example Y-39, except that phenylpiperidine is used instead of 15.

[0112] 1 H NMR (400 MHz, DMSO) δ 10.57 (s, 1H), 8.40 (d, J = 7.6 Hz, 1H), 7.93(t, J = 7.6 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.51 (d, J =1.6 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.8 Hz, 2H), 7.34 – 7.31 (m,3H), 7.26 (d, J = 6.8 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 4.31 (d, J = 13.2 Hz, 2H), 3.26 (t, J = 11.6 Hz, 2H), 2.86 (t, J = 12.0 Hz, 1H), 1.92 (d, J= 12.0 Hz, 2H), 1.76 (qd, J = 12.4, 3.6 Hz, 2H). HRMS (ESI) calcd . for [C 34 H 27 ClN3O4] + ([M+H)) + ): m / z576.1685, found: 576.1692. Example Y-45

[0113] This example uses a similar operation to Example Y-39, except that isoindoline is used instead of 15.

[0114] 1 H NMR (400 MHz, CF3COOD) δ 8.93 (d, J = 7.6 Hz, 1H), 8.53 (s, 1H), 8.28(t, J = 7.6 Hz, 1H), 8.20 (t, J = 7.6 Hz, 1H), 7.97 (t, J = 7.6 Hz, 2H), 7.92 (d, J =8.0 Hz, 2H), 7.81 (m, 2H), 7.77 (m, 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.68 (d, J =8.0 Hz, 2H), 5.65 (s, 2H), 5.56 (s, 2H). HRMS (ESI) calcd . for [C 31 H 31 ClN3O4] + ([M+H)) + ): m / z 534.1215, found: 534.1209. Example Y-46

[0115] This example uses a similar operation to Example Y-39, except that 15 is replaced with 1,2,3,4-tetrahydroisoquinoline.

[0116] 1 H NMR (400 MHz, DMSO) δ 10.56 (s, 1H), 8.36 (m, 1H), 7.90 (m, 1H),7.78 (m, 1H), 7.58 (m, 2H), 7.51 – 7.37 (m, 4H), 7.23 (m, 6H), 4.80 (s, 2H),3.88 (m, 2H), 2.97 (m, 2H). HRMS (ESI) calcd . for [C 32 H 23 ClN3O4] + ([M+H)) + ): m / z548.1372, found: 548.1369. Example Y-47

[0117] This example uses a similar procedure to Example Y-39, except that 15 is replaced with 2,3,4,5-tetrahydro-1H-benzo[D]azapyrrolidone.

[0118] 1 H NMR (400 MHz, DMSO) δ 10.53 (s, 1H), 8.35 (d, J = 6.4 Hz, 1H), 7.88 (d, J = 5.6 Hz, 1H), 7.80 – 7.73 (m, 1H), 7.56 (d, J = 6.8 Hz, 2H), 7.47 (s, 1H),7.43 (m, 2H), 7.35 (d, J = 7.2 Hz, 1H), 7.16 (m, 6H), 3.79 (m, 4H), 3.02 (m,4H). HRMS (ESI) calcd . for [C 33 H 25 ClN3O4] + ([M+H)) + ): m / z 562.1528, found:562.1521. Example Y-48

[0119] This example uses a similar operation to Example Y-39, except that 15 is replaced with spiro[indene-1,4'-piperidine].

[0120] 1 H NMR (400 MHz, DMSO) δ 10.54 (s, 1H), 8.35 (d, J = 7.6 Hz, 1H), 7.89(t, J = 7.2 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.49 –7.46 (m, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.35 (t, J = 8.4 Hz, 2H), 7.24 (t, J = 7.2Hz, 1H), 7.17 (dd, J = 10.4, 4.8 Hz, 4H), 6.87 (d, J = 5.6 Hz, 1H), 4.24 (d, J =13.2 Hz, 2H), 3.55 (t, J = 11.6 Hz, 2H), 2.16 (td, J = 12.8, 4.0 Hz, 2H), 1.30(d, J = 13.2 Hz, 2H). HRMS (ESI) calcd . for [C 36 H 27 ClN3O4] + ([M+H)) + ): m / z 600.1685, found: 600.1690. Example Y-49

[0121] This example uses a similar operation to Example Y-39, except that n-methylphenylethylamine is used instead of 15.

[0122] 1 H NMR (400 MHz, DMSO) δ 10.53 (s, 1H), 8.36 (d, J = 7.6 Hz, 1H), 7.90(t, J = 7.6 Hz, 1H), 7.77 (t, J= 7.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.43 (d, J =7.6 Hz, 3H), 7.28 (d, J = 5.6 Hz, 5H), 7.21 (d, J = 5.2 Hz, 1H), 7.17 (d, J = 8.0Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 3.73 (t, J = 7.2 Hz, 2H), 3.08 (s, 3H), 2.94(t, J = 7.2 Hz, 2H). HRMS (ESI) calcd . for [C 33 H 25 ClN3O4] + ([M+H)) + ): m / z 562.1528, found: 562.1540. Example Y-50

[0123] This example uses a similar operation to Example Y-39, except that phenylpiperazine is used instead of 15.

[0124] 1 H NMR (400 MHz, DMSO) δ 10.54 (s, 1H), 8.35 (d, J = 7.2 Hz, 1H), 7.91 –7.86 (m, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.57 (s, 1H), 7.55 (s, 1H), 7.49 (d, J =2.0 Hz, 1H), 7.42 (s, 1H), 7.40 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.28 – 7.22(m, 2H), 7.18 (dd, J = 8.8, 2.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 8.0Hz, 2H), 6.83 (t,J = 7.2 Hz, 1H), 3.77 – 3.71 (m, 4H), 3.30 – 3.24 (m, 4H).HRMS (ESI) calcd . for [C 33 H 26 ClN4O4] + ([M+H)) + ): m / z 577.1637, found: 577.1624. Example Y-51

[0125] This example uses a similar procedure to Example Y-39, except that 1-(4-methoxyphenyl)piperazine is used instead of 15.

[0126] 1 H NMR (400 MHz, DMSO) δ 10.54 (s, 1H), 8.36 (d, J = 5.2 Hz, 1H), 7.89 (d, J = 4.4 Hz, 1H), 7.77 (d, J = 4.4 Hz, 1H), 7.56 (m, 2H), 7.49 (s, 1H), 7.43(m, 2H), 7.35 (d, J = 6.4 Hz, 1H), 7.18 (d, J = 7.2 Hz, 2H), 6.96 (m, 2H), 6.87(m, 2H), 3.74 (m, 4H), 3.70 (s, 3H), 3.14 (m, 4H). HRMS (ESI) calcd . for[C 34 H 28 ClN4O5] + ([M+H)) + ): m / z 607.1743, found: 607.1741. Example Y-52

[0127] This example uses a similar procedure to Example Y-39, except that 1-(3-methoxyphenyl)piperazine is used instead of 15.

[0128] 1 H NMR (400 MHz, DMSO) δ 10.55 (s, 1H), 8.36 (d, J = 7.6 Hz, 1H), 7.89(d, J = 7.6 Hz, 1H), 7.77 (t, J = 7.2 Hz, 1H), 7.57 (d, J = 7.6 Hz, 2H), 7.50 (s,1H), 7.43 (d, J = 7.6 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.21 – 7.14 (m, 3H), 6.60 (d, J = 7.6 Hz, 1H), 6.54 (s, 1H), 6.43 (d, J = 7.2 Hz, 1H), 3.74 (m, 8H), 3.29 (s, 3H). HRMS (ESI) calcd . for [C 34 H 28 ClN4O5] + ([M+H)) + ): m / z 607.1743, found:607.1748. Example Y-53

[0129] This example employs a similar procedure to Example Y-39, except that 15 is replaced with 1-(2-methoxyphenyl)piperazine. HRMS (ESI) calcd . for [C 34 H 28 ClN4O5] + ([M+H)) + ): m / z 607.1743, found:607.1748. Example Y-54

[0130] This example uses a similar procedure to Example Y-39, except that 15 is replaced with 1-(4-fluorophenyl)piperazine.

[0131] 1 H NMR (400 MHz, DMSO) δ 10.55 (s, 1H), 8.37 (d, J= 8.0 Hz, 1H), 7.91(t, J = 7.6 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.51 (s,1H), 7.44 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.4 Hz, 1H), 7.23 – 7.16 (m, 2H), 7.11 (t, J = 8.8 Hz, 2H), 7.07 – 7.02 (m, 2H), 3.76 (m, 4H), 3.23 (m, 4H). HRMS(ESI) calcd . for [C 33 H 25 ClFN4O4] + ([M+H)) + ): m / z 595.1543, found: 595.1547. Example Y-55

[0132] This example uses a similar procedure to Example Y-39, except that 1-(4-methylphenyl)piperazine is used instead of 15.

[0133] 1 H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 8.25 (m, 1H), 7.77 (m, 1H),7.66 (m, 1H), 7.45 (m, 2H), 7.38 (s, 1H), 7.28 (m, 3H), 7.06 (m, 2H), 6.96(m, 2H), 6.80 (m, 2H), 3.62 (m, 4H), 3.09 (m, 4H), 2.10 (s, 3H). HRMS (ESI) calcd . for [C 34 H 28 ClN4O4] + ([M+H)) + ): m / z 591.1794, found: 591.1794. Example Y-56

[0134] This example uses a similar operation to Example Y-39, except that 15 is replaced with 4-piperazinylbenzonitrile.

[0135] 1 H NMR (400 MHz, DMSO) δ 10.57 (s, 1H), 8.38 (d, J = 7.2 Hz, 1H), 7.92(t, J = 7.2 Hz, 1H), 7.80 (t, J = 6.8 Hz, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.60 (d, J =7.2 Hz, 2H), 7.52 (s, 1H), 7.45 (d, J = 7.2 Hz, 2H), 7.39 (d, J = 8.8 Hz, 1H), 7.20 (t, J = 8.8 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 3.77 (m, 4H), 3.57 (m, 4H).HRMS (ESI) calcd . for [C 34 H 25 ClN5O4] + ([M+H)) + ): m / z 602.1590, found: 602.1597. Example Y-57

[0136] This example uses a similar procedure to Example Y-39, except that 15 is replaced with 4-amino-N,N-dimethylphenylpiperazine.

[0137] 1 H NMR (400 MHz, DMSO) δ 10.54 (s, 1H), 8.35 (d, J = 7.6 Hz, 1H), 7.89(t, J = 7.6 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.48 (d, J=2.0 Hz, 1H), 7.43 (s, 1H), 7.40 (d, J = 2.8 Hz, 2H), 7.39 (m, 2H), 7.36 (d, J =6.4 Hz, 1H), 7.34 (d, J = 6.4 Hz, 1H), 7.16 (t, J = 7.6 Hz, 2H), 3.73 (m, 4H), 3.08 (m, 4H), 2.80 (s, 6H). HRMS (ESI) calcd . for [C 35 H 31 ClN5O4] + ([M+H)) + ): m / z620.2059, found: 620.2065. Example Y-58

[0138] This example uses a similar procedure to Example Y-39, except that methyl 4-piperazine-1-ylbenzoate is used instead of 15.

[0139] 1 H NMR (400 MHz, DMSO) δ 10.55 (s, 1H), 8.36 (d, J = 7.6 Hz, 1H), 7.90(t, J = 7.6 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.77 (t, J = 7.6 Hz, 1H), 7.57 (d, J =8.4 Hz, 2H), 7.51 (d, J = 1.6 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.8Hz, 1H), 7.22 – 7.15 (m, 2H), 7.06 (d, J = 8.8 Hz, 2H), 3.80 (s, 3H), 3.77 –3.73 (m, 4H), 3.54 – 3.50 (m, 4H). HRMS (ESI) calcd . for [C 35H 28 ClN4O6] + ([M+H)) + ):m / z 635.1692, found: 635.1688. Example Y-59

[0140] This example uses a similar operation to Example Y-39, except that 15 is replaced with 4-tert-butylphenylpiperazine.

[0141] 1 H NMR (400 MHz, DMSO) δ 10.56 (s, 1H), 8.37 (d, J = 7.6 Hz, 1H), 7.90(t, J = 7.2 Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.51 (s,1H), 7.43 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H),7.22 – 7.15 (m, 2H), 6.95 (d, J = 8.4 Hz, 2H), 3.75 (m, 4H), 3.23 (m, 4H), 1.26(s, 9H). HRMS (ESI) calcd . for [C 37 H 34 ClN4O4] + ([M+H)) + ): m / z 633.2263, found:633.2260. Example Y-60

[0142] This example uses a similar operation to Example Y-39, except that 15 is replaced with 3-tert-butylphenylpiperazine.

[0143] HRMS (ESI) calcd . for [C 37 H 34 ClN4O4] + ([M+H))+ ): m / z 633.2263, found:633.2261. Example Y-61

[0144] This example uses a similar operation to Example Y-39, except that 15 is replaced with 2-tert-butylphenylpiperazine.

[0145] HRMS (ESI) calcd . for [C 37 H 34 ClN4O4] + ([M+H)) + ): m / z 633.2263, found:633.2263. Example Y-62

[0146] This example uses a similar operation to Example Y-39, except that 15 is replaced with 4-isopropylphenylpiperazine.

[0147] HRMS (ESI) calcd . for [C 36 H 32 ClN4O4] + ([M+H)) + ): m / z 619.2107, found:619.2108. Example Y-63

[0148] This example uses a similar operation to Example Y-39, except that 15 is replaced with 2-isopropylphenylpiperazine.

[0149] HRMS (ESI) calcd . for [C 36 H 32 ClN4O4] + ([M+H)) + ): m / z 619.2107, found:619.2105. Example Y-64

[0150] This example uses a similar operation to Example Y-39, except that 15 is replaced with 4-cyclobutylphenylpiperazine.

[0151] HRMS (ESI) calcd . for [C 37 H 32 ClN4O4] + ([M+H)) + ): m / z 631.2107, found:631.2103. Example Y-65

[0152] This example uses a similar operation to Example Y-39, except that 15 is replaced with 4-cyclopropylphenylpiperazine.

[0153] HRMS (ESI) calcd . for [C 36 H 30 ClN4O4] + ([M+H)) + ): m / z 617.1950, found:617.1955. Example Y-66

[0154] This example uses a similar operation to Example Y-39, except that 15 is replaced with 3-cyclopropylphenylpiperazine.

[0155] HRMS (ESI) calcd . for [C 36 H 30 ClN4O4] + ([M+H)) + ): m / z 617.1950, found:617.1951. Example Y-67

[0156] This example uses a similar procedure to Example Y-39, except that N-(3-piperidine)phenylpiperazine is used instead of 15.

[0157] HRMS (ESI) calcd . for [C 38 H 35 ClN5O4] + ([M+H)) + ): m / z 660.2372, found:660.2370. Example Y-68

[0158] This example uses a similar procedure to Example Y-39, except that 15 is replaced with 1-(3-pyridyl)piperazine.

[0159] 1 H NMR (400 MHz, DMSO) δ 10.54 (s, 1H), 8.35 (d, J = 7.6 Hz, 1H), 8.15(d, J = 3.6 Hz, 1H), 7.88 (t, J = 7.6 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.57 (t, J =8.4 Hz, 3H), 7.49 (s, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.8 Hz, 1H), 7.18 (dd, J = 8.8, 1.6 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.71 – 6.66 (m, 1H), 3.68 (m, 8H). HRMS (ESI) calcd . for [C 32 H 25 ClN5O4] + ([M+H)) + ):m / z 578.1590, found: 578.1588. Example Y-69

[0160] This example uses a similar procedure to Example Y-39, except that 15 is replaced with 1-(2-pyrimidinyl)piperazine.

[0161] 1 H NMR (400 MHz, DMSO) δ 10.52 (s, 1H), 8.42 (d, J = 4.4 Hz, 2H), 8.36(d, J = 7.6 Hz, 1H), 7.89 (t, J = 7.6 Hz, 1H), 7.77 (t, J= 7.6 Hz, 1H), 7.57 (d, J =8.0 Hz, 2H), 7.49 (s, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.4 Hz, 1H),7.22 – 7.14 (m, 2H), 6.70 (t, J = 4.4 Hz, 1H), 3.91 (m, 4H), 3.69 (m, 4H). HRMS(ESI) calcd . for [C 31 H 24 ClN6O4] + ([M+H)) + ): m / z 579.1542, found: 579.1539. Example Y-70

[0162] This example uses a similar procedure to Example Y-39, except that 15 is replaced with 1-(thiazo-2-yl)piperazine.

[0163] 1 H NMR (400 MHz, DMSO) δ 10.56 (s, 1H), 8.36 (d, J = 7.2 Hz, 1H), 7.90(t, J = 6.8 Hz, 1H), 7.77 (t, J = 6.8 Hz, 1H), 7.57 (d, J = 7.2 Hz, 2H),50 (s, 1H),7.43 (d, J = 7.2 Hz, 2H), 7.37 (d, J = 8.4 Hz, 1H), 7.18 (m, 3H), 6.93 (s, 1H), 3.75 (m, 4H), 3.58 (m, 4H). HRMS (ESI) calcd . for [C 30 H 23 ClN5O4S] + ([M+H)) + ): m / z584.1154, found: 584.1150. Example Y-71

[0164] This example uses a similar procedure to Example Y-39, except that 15 is replaced with 2-naphthylaminepiperazine.

[0165] 1 H NMR (400 MHz, DMSO) δ 10.55 (s, 1H), 8.36 (d, J = 7.6 Hz, 1H), 7.89(t, J = 7.6 Hz, 1H), 7.78 (m, 4H), 7.57 (d, J = 8.0 Hz, 2H), 7.51 (s, 1H), 7.42(d, J = 7.2 Hz, 4H), 7.37 (d, J = 8.4 Hz, 1H), 7.32 – 7.27 (m, 1H), 7.26 (s, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 3.80 (m, 4H), 3.41 (m, 4H).HRMS (ESI) calcd . for [C 37 H 28 ClN4O4] + ([M+H)) + ): m / z 627.1794, found: 627.1802. Example Y-72

[0166] This example uses a similar procedure to Example Y-39, except that quinoperazine is used instead of 15.

[0167] 1 H NMR (400 MHz, DMSO) δ 10.56 (s, 1H), 8.36 (d, J = 6.8 Hz, 1H), 8.12(d, J = 8.4 Hz, 1H), 7.90 (s, 1H), 7.80 – 7.73 (m, 2H), 7.62 (s, 1H), 7.58 (d, J= 6.8 Hz, 3H), 7.51 (s, 1H), 7.43 (d, J = 7.2 Hz, 2H), 7.35 (dd, J = 16.4, 8.8Hz, 2H), 7.27 (s, 1H), 7.23 – 7.15 (m, 2H), 3.89 (m, 4H), 3.76 (m, 4H). HRMS(ESI) calcd . for [C 36 H 27 ClN5O4] + ([M+H)) + ): m / z 628.1746, found: 628.1744. Example Y-73

[0168] This example uses a similar procedure to Example Y-39, except that 15 is replaced with 1-piperazine-1-isoquinoline.

[0169] 1 H NMR (400 MHz, DMSO) δ 10.57 (s, 1H), 8.36 (d, J = 7.6 Hz, 1H), 8.19(d, J = 8.4 Hz, 1H), 8.15 (d, J = 5.6 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.89 (d, J =8.0 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.68 – 7.64 (m,1H), 7.58 (d, J = 8.0 Hz, 2H), 7.51 (s, 1H), 7.46 (d, J = 5.6 Hz, 1H), 7.43 (d, J =8.0 Hz, 2H), 7.37 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.16 (d, J= 8.0Hz, 1H), 3.90 (m, 4H), 3.45 (m, 4H). HRMS (ESI) calcd . for [C 36 H 27 ClN5O4] + ([M+H)) + ): m / z 628.1746, found: 628.1749. Example Y-74

[0170] This example employs a similar procedure to Example Y-39, except that 15 is replaced with 6-(piperazin-1-yl)benzo[d]thiazole. HRMS (ESI) calcd . for [C 34 H 25 ClN5O4S] + ([M+H)) + ): m / z 634.1310, found:634.1311. Example Y-75

[0171] This example employs a similar procedure to Example Y-39, except that 15 is replaced with 6-(piperazin-1-yl)benzo[d]oxazole. HRMS (ESI) calcd . for [C 34 H 25 Cl1N5O5] + ([M+H)) + ): m / z 618.1539, found:618.1540. Example Y-76

[0172] This example uses a similar operation to Example Y-39, except that 15 is replaced with 2-(piperazin-1-yl)-1H-indole.

[0173] HRMS (ESI) calcd . for [C 35 H 27 Cl1N5O4] + ([M+H)) + ): m / z 616.1746, found:616.1747. Example Y-77

[0174] 9-Bromofluorene (300.0 mg, 1.0 eq), anhydrous piperazine (738.0 mg, 7.0 eq), and Et3N (25.5 μL, 0.15 eq) were added to dry THF (5 mL) and refluxed for 6 h. After TLC detection of complete reaction, the reaction system was evaporated to dryness and passed through a column to obtain 237.6 mg of white solid 22. Yield: 77.6%; 1 H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.6 Hz, 2H), 7.69 (d, J = 7.6 Hz, 2H), 7.40 (t, J = 7.2 Hz, 2H), 7.34 – 7.30 (m, 2H), 4.84 (s,1H), 2.91 – 2.87 (m, 4H), 2.68 – 2.63 (m, 4H), 1.33 (m, 1H). The remaining steps were performed similarly to those in Example Y-39, except that 15 was replaced with 22, yielding the yellow solid Y-77. Yield: 58.2%. 1 H NMR (400 MHz, DMSO) δ 10.53 (s, 1H), 8.35 (d, J = 7.6 Hz, 1H), 7.90(d, J = 7.6 Hz, 1H), 7.86 (d, J = 7.6 Hz, 2H), 7.76 (t, J = 7.6 Hz, 1H), 7.65 (d, J =7.2 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.45 (s, 1H), 7.41 (dd, J = 7.6, 3.2 Hz,4H), 7.32 (m, 3H), 7.18 – 7.14 (m, 2H), 5.03 (s, 1H), 3.57 (m, 4H), 2.65 (m,4H). HRMS (ESI) calcd . for [C 40 H 30 ClN4O4] + ([M+H)) +): m / z 665.1950, found:665.1957. Example Y-78

[0175] This example employs a similar procedure to Example Y-77, except that 9-bromofluorene is replaced with 5-chloro-5H-dibenzo[a,d][7]annulene. HRMS (ESI) calcd . for [C 37 H 34 ClN4O4] + ([M+H)) + ): m / z 633.2263, found: 633.2263. Example Y-79

[0176] This example employs a similar procedure to Example Y-77, except that 9-bromofluorene is replaced with 8,11-dichloro-11H-benzo[5,6]cycloheptane[1,2-b]pyridine. HRMS (ESI) calcd . for [C 41 H 30 Cl2N5O4] + ([M+H)) + ): m / z726.1669, found: 726.1670. Example Y-80

[0177] This example employs a similar procedure to Example Y-77, except that 15 is replaced with 10-(piperidin-4-yl)-10H-phenthiazide. HRMS (ESI) calcd . for [C 40 H 30 ClN4O4S] + ([M+H)) + ): m / z 697.1671, found:697.1674. Example Y-81

[0178] This example employs a similar procedure to Example Y-77, except that 15 is replaced with 10-(piperidin-4-yl)-10H-phenoxazine. HRMS (ESI) calcd . for [C 40 H 30 ClN4O5]+ ([M+H)) + ): m / z 681.1899, found:681.1900. Example Y-82

[0179] This example uses a similar operation to Example Y-39, except that 15 is replaced with diphenylmethylpiperazine.

[0180] 1 H NMR (400 MHz, DMSO) δ 10.53 (s, 1H), 8.35 (d, J = 7.6 Hz, 1H), 7.88(t, J = 7.6 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.47 (d, J =7.6 Hz, 5H), 7.42 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 7.6 Hz, 3H), 7.31 (s, 2H),7.24 – 7.18 (m, 3H), 7.15 (d, J = 8.4 Hz, 1H), 4.37 (s, 1H), 3.62 (m, 4H), 2.44(m, 4H). HRMS (ESI) calcd . for [C 40 H 32 ClN4O4] + ([M+H)) + ): m / z 667.2107, found:667.2102. Example Y-83

[0181] This example uses a similar operation to Example Y-39, except that 15 is replaced with bis(4-chlorophenyl)methylpiperazine.

[0182] 1 H NMR (400 MHz, DMSO) δ 10.55 (s, 1H), 8.35 (t, J = 7.2 Hz, 1H), 7.87(t,J = 6.4 Hz, 1H), 7.76 (d, J = 6.4 Hz, 1H), 7.54 (d, J = 6.8 Hz, 2H), 7.46 (d, J =7.6 Hz, 5H), 7.40 (m, 6H), 7.31 (d, J = 8.0 Hz, 1H), 7.17 (dd, J = 18.4, 7.6 Hz,2H), 4.45 (s, 1H), 3.61 (m, 4H), 2.41 (m, 4H). HRMS (ESI) calcd . for[C 40 H 30 Cl3N4O4] + ([M+H)) + ): m / z 735.1327, found: 735.1331. Example Y-84

[0183] This example employs a similar operation to that of Example Y-39, the only difference being the use of N. 1 -(bis(4-chlorophenyl)methyl)ethane-1,2-diamine replaced by 15. HRMS (ESI) calcd . for [C 38 H 28 Cl3N4O4] + ([M+H)) + ): m / z 709.1171, found: 709.1172. Example Y-85

[0184] This example uses a similar operation to Example Y-39, except that 15 is replaced with bis(4-fluorophenyl)methylpiperazine.

[0185] 1 H NMR (400 MHz, DMSO) δ 10.53 (s, 1H), 8.35 (d, J = 7.6 Hz, 1H), 7.88(t, J = 7.6 Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H), 7.55 (d, J= 8.0 Hz, 2H), 7.50 –7.44 (m, 5H), 7.41 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.4 Hz, 1H), 7.16 (t, J = 8.4Hz, 6H), 4.46 (s, 1H), 3.61 (m, 4H), 2.41 (m, 4H). HRMS (ESI) calcd . for[C 40 H 30 ClF2N4O4] + ([M+H)) + ): m / z 703.1918, found: 703.1925. Example Y-86

[0186] This example employs a similar procedure to Example Y-77, except that 9-bromofluorene is replaced with 1-chloro-4-(1-chloroethyl)benzene. HRMS (ESI) calcd . for [C 35 H 29 Cl2N4O4] + ([M+H)) + ): m / z 639.1560, found:639.1562. Example Y-87

[0187] This example employs a similar procedure to Example Y-77, the only difference being the substitution of 9-bromofluorene with 1-chloro-4-(1-chloropropyl)benzene. HRMS (ESI) calcd . for [C 36 H 31 Cl2N4O4] + ([M+H)) + ): m / z 653.1717, found:653.1719. Example Y-88

[0188] This example employs a similar procedure to Example Y-77, the only difference being the substitution of 9-bromofluorene with 1-chloro-4-(1-chloro-2-methylpropyl)benzylphenazine. HRMS (ESI) calcd . for [C 37 H 33ClN4O4] + ([M+H)) + ): m / z 667.1873, found: 667.1870. Example Y-89

[0189] This example employs a similar procedure to Example Y-77, except that 9-bromofluorene is replaced with 1-chloro-4-(chloro(phenyl)methyl)benzene. HRMS (ESI) calcd . for [C 40 H 31 Cl2N4O4] + ([M+H)) + ): m / z 701.1717, found:701.1715. Example Y-90

[0190] This example employs a similar procedure to Example Y-77, except that 9-bromofluorene is replaced with 1-fluoro-4-(chloro(phenyl)methyl)benzene. HRMS (ESI) calcd . for [C 40 H 31 ClFN4O4] + ([M+H)) + ): m / z 685.2012, found:685.2016. Example Y-91

[0191] This example employs a similar procedure to Example Y-77, except that 9-bromofluorene is replaced with 1-methoxy-4-(chloro(phenyl)methyl)benzene. HRMS (ESI) calcd . for [C 41 H 34 ClN4O5] + ([M+H)) + ): m / z 697.2212, found: 697.2215. Example Y-92

[0192] This example employs a similar procedure to Example Y-77, except that 9-bromofluorene is replaced with 2-(chloro(4-chlorophenyl)methyl)pyridine. HRMS (ESI) calcd . for [C 39 H30 Cl2N5O4] + ([M+H)) + ): m / z 685.2012, found: 685.2016. Example Y-93

[0193] This example employs a similar procedure to Example Y-77, the only difference being the substitution of 9-bromofluorene with 2-(chloro(phenyl)methyl)pyrimidine. HRMS (ESI) calcd . for [C 38 H 30 ClN6O4] + ([M+H)) + ): m / z 669.2012, found:669.2015. Example Y-94

[0194] This example employs a similar procedure to Example Y-77, except that 2-(chloro(pyridin-4-yl)methyl)pyridine is used instead of 9-bromofluorene. HRMS (ESI) calcd . for [C 38 H 30 ClN6O4] + ([M+H)) + ): m / z 669.2012, found: 669.2010. Example Y-95

[0195] This example employs a similar procedure to Example Y-77, except that 2-(chloro(4-chlorophenyl)methyl)quinoline is used instead of 9-bromofluorene. HRMS (ESI) calcd . for [C 43 H 32 Cl2N5O4] + ([M+H)) + ): m / z 752.1826, found: 752.1825. Example Y-96

[0196] This example uses a similar procedure to Example Y-77, except that (R)-N-(3-(1-bromoethyl)phenyl)acrylamide is used instead of 9-bromofluorene.

[0197] 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.32 (m, 1H) , 8.21 (dd, J = 5.6, 2.4 Hz, 1H), 7.86 (dd, J = 17.4, 8.4 Hz, 1H), 7.79 (s, 1H), 7.73 (dd, J = 16.0, 8.4 Hz, 1H),7.60 – 7.51 (m, 3H), 7.48 – 7.29 (m, 3H), 7.16 (t, J = 8.4 Hz, 1H),7.03(m, 1H),6.25(dd, J = 5.6, 3.6 Hz, 2H), 5.19 (dd, J = 5.6, 2.4 Hz, 1H), 3.58 (s, 4H), 3.47 (s, 4H), 1.88 (s, 3H). HRMS (ESI) calcd . for [C 38 H 33 ClN5O5] + ([M+H)) + ): m / z674.2165, found: 674.2160. Example Y-97

[0198] This example uses a similar procedure to Example Y-77, except that N-(3-(1-bromoethyl)phenyl)acrylamide is used instead of 9-bromofluorene.

[0199] 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.43 (m, 1H) , 8.26 (dt, J = 13.2, 7.6 Hz, 1H), 7.93 (dd, J , 8.3 Hz, 1H), 7.88(m, 4H), 7.63 (dd, J = 16.2, 8.4 Hz, 2H),7.50- 7.29 (m, 5H), 7.18 (t, J = 4.0 Hz, 1H) ,7.10 (m, 1H) ,6.35 (dd,J = 6.4, 3.6 Hz, 2H), 5.25 (dd, J = 4.5, 2.3 Hz, 1H), 3.62(m, 4H), 3.56(m, 4H), 2.01(s,3H). HRMS (ESI) calcd . for [C 38 H 33 ClN5O5] + ([M+H)) + ): m / z 674.2165, found:674.2166. Example Y-98

[0200] This example uses a similar procedure to Example Y-77, except that (R)-N-(4-(1-bromoethyl)phenyl)acrylamide is used instead of 9-bromofluorene.

[0201] 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.43 (m, 1H) , 8.26 (dt, J = 13.2, 7.6 Hz, 1H), 7.93 (dd, J , 8.3 Hz, 1H), 7.88(m, 4H), 7.63 (dd, J = 16.2, 8.4 Hz, 2H),7.50- 7.29 (m, 5H), 7.18 (t, J = 4.0 Hz, 1H) ,7.10 (m, 1H) ,6.35 (dd, J = 6.4, 3.6 Hz, 2H), 5.25 (dd, J = 4.5, 2.3 Hz, 1H), 3.62(m, 4H), 3.56(m, 4H), 2.01(s,3H). HRMS (ESI) calcd . for [C 38 H 33 ClN5O5] + ([M+H)) + ): m / z 674.2165, found:674.2166. Example Y-99

[0202] The preceding steps were performed similarly to those in Example Y-39, except that Boc-piperazine was used instead of morpholine, yielding a yellow solid 28. Yield: 66.4%; HRMS (ESI) calcd . for [C 27 H 22 ClN4O4] + ([M+H)) + ): m / z 501.1324, found:501.1326. In a single-necked flask, 28 (500.0 mg, 1.0 eq), 2,2-diphenylacetic acid (212.1 mg, 1.0 eq), HATU (570.0 mg, 1.5 eq), DIPEA (348.6 μL, 2.0 eq), and DMF (10 mL) were added. The mixture was stirred overnight at room temperature. After the reaction was confirmed to be complete by TLC, the reaction mixture was diluted with EA, extracted with water, and the organic phase was distilled under reduced pressure and column filtered to give 118.9 mg of a white solid, Y-99. Yield: 35.8%; HRMS (ESI) calcd . for [C 19 H 29 N2O3] + ([M+H)) + ): m / z 333.2173, found: 333.2170. 1 H NMR (400 MHz, DMSO) δ 10.55 (s, 1H), 8.35 (t, J = 5.6 Hz, 1H), 7.90(t, J = 7.2 Hz, 1H), 7.77 (d, J = 6.0 Hz, 1H), 7.56 (d, J = 6.0 Hz, 2H), 7.47 (s,1H), 7.42 (d, J = 6.4 Hz, 2H), 7.34 – 7.28 (m, 10H), 7.21 – 7.14 (m, 3H), 5.63(s, 1H), 3.72 – 3.56 (m, 8H). HRMS (ESI) calcd . for [C 41 H 32 ClN4O5] + ([M+H)) + ): m / z695.2056, found: 695.2065. Example Y-100

[0203] This example uses a similar procedure to Example Y-98, except that 2,2-bis(4-chlorophenyl)acetic acid is used instead of 2,2-diphenylacetic acid.

[0204] HRMS (ESI) calcd . for [C 41 H 30 Cl3N4O5] + ([M+H)) + ): m / z 763.1276, found: 735.763.1273. Example Y-101

[0205] This example employs a similar procedure to Example Y-98, the only difference being the use of piperazine benzoate instead of 2,2-diphenylacetic acid. HRMS (ESI) calcd . for [C 34 H 26 ClN4O5] + ([M+H)) + ): m / z 605.1586, found:605.1588. Example Y-102

[0206] This example employs a similar procedure to Example Y-98, the only difference being the use of pyrazine-2-carboxylic acid instead of 2,2-diphenylacetic acid. HRMS (ESI) calcd . for [C 32 H 24 ClN6O5] + ([M+H)) + ): m / z 607.1491, found:607.1492. Example Y-103

[0207] This example uses a similar procedure to Example Y-98, except that pyridinecarboxylic acid is used instead of 2,2-diphenylacetic acid.

[0208] HRMS (ESI) calcd . for [C 33 H 25 ClN5O5] + ([M+H)) +): m / z 606.1539, found:606.1540. Example Y-104

[0209] This example employs a similar procedure to Example Y-98, the only difference being the use of pyrimidine-2-carboxylic acid instead of 2,2-diphenylacetic acid. HRMS (ESI) calcd . for [C 32 H 24 ClN6O5] + ([M+H)) + ): m / z 607.1491, found:607.1493. Example Y-105

[0210] This example uses a similar procedure to Example Y-98, except that 2-phenylacetic acid is used instead of 2,2-diphenylacetic acid. HRMS (ESI) calcd . for [C 35 H 28 ClN4O5] + ([M+H)) + ): m / z 619.1743, found:619.1745. Example Y-106

[0211] This example employs a similar procedure to Example Y-98, the only difference being the use of quinoline-3-carboxylic acid instead of 2,2-diphenylacetic acid. HRMS (ESI) calcd . for [C 37 H 27 ClN5O5] + ([M+H)) + ): m / z 656.1695, found:656.1696. Example Y-107

[0212] This example employs a similar procedure to Example Y-98, the only difference being the substitution of 2,2-diphenylacetic acid with quinoline-2-carboxylic acid n. HRMS (ESI) calcd . for [C 37 H 27 ClN5O5] + ([M+H)) +): m / z 656.1695, found:656.1697. Example Y-108

[0213] This example follows a similar procedure to Example Y-98, except that quinazoline-2-carboxylic acid is used instead of 2,2-diphenylacetic acid. HRMS (ESI) calcd . for [C 36 H 26 ClN6O5] + ([M+H)) + ): m / z 657.1648, found:657.1645. Example Y-109

[0214] This example employs a similar procedure to Example Y-98, except that 2,2-diphenylacetic acid is replaced with 2,3-dihydrobenzo[b][1,4]dioxin-6-carboxylic acid. HRMS (ESI) calcd . for [C 36 H 28 ClN4O7] + ([M+H)) + ): m / z663.1641, found: 663.1640. Example Y-110

[0215] In a single-necked flask, 1-(tert-butyloxycarbonyl)piperidine-4-carboxylic acid (229.1 mg, 1.0 eq) and (S)-1-phenylethanol-1-amine (121.1 mg, 1.0 eq), HATU (570.0 mg, 1.5 eq), DIPEA (348.6 μL, 2.0 eq), and DMF (10 mL) were added. The mixture was stirred overnight at room temperature. After the reaction was confirmed to be complete by TLC, the reaction mixture was diluted with EA, extracted with water, and the organic phase was distilled under reduced pressure and column filtered to give 118.9 mg of a white solid. Yield: 35.8%; HRMS (ESI) calcd . for [C 19 H 29 N2O3] + ([M+H)) + ): m / z 333.2173, found: 333.2170. In a single-necked flask, 29 g (333.2 mg, 1.0 eq) and 30% TFA / DCM (5 mL) were added. The mixture was stirred overnight at room temperature. After the reaction was confirmed to be complete by TLC, the organic phase was distilled under reduced pressure and then column-secreted to give 232.2 mg of a white solid (30 g), yield 100%; HRMS (ESI). calcd . for [C 14 H 21 N2O] + ([M+H)) + ): m / z 233.1648, found: 233.1644. 30 (232.2 mg, 1.0 eq) and 2-(methylthio)-5-nitrobenzoxazole (210.0 mg, 1.0 eq) were added to 5 mL of CH3CN and refluxed for 12 h. After the reaction was complete as detected by TLC, the reaction mixture was diluted with EA, extracted with water, and the organic phase was distilled under reduced pressure and passed through a column to give 300.0 mg of yellow solid 31. Yield 76.1%; HRMS (ESI) calcd . for [C 21 H 23 N4O4] + ([M+H)) + ): m / z 395.1714, found: 395.1715. 31 (394.2 mg, 1.0 eq) and Pd / C (300 mg, 10% wt) were added to MeOH and reacted under a hydrogen atmosphere for 12 h. After the reaction was complete as detected by TLC, the reaction system was diluted with EA, extracted with water, and the organic phase was distilled under reduced pressure and passed through a column to give 364.2 mg of yellow solid 32. Yield 100%; HRMS (ESI) calcd . for [C 21 H2N4O2] + ([M+H)) + ): m / z365.1972, found: 365.1970. In a single-necked flask, 32 (364.2 mg, 1.0 eq), 4 (300.0 mg, 1.0 eq), HATU (570.0 mg, 1.5 eq), DIPEA (348.6 μL, 2.0 eq), and DMF (10 mL) were added. The mixture was stirred overnight at room temperature. After the reaction was confirmed to be complete by TLC, the reaction mixture was diluted with EA, extracted with water, and the organic phase was distilled under reduced pressure and column filtered to give 253.8 mg of a white solid, Y-110. Yield: 35.8%. 1 H NMR (400 MHz, DMSO- d6 ) δ 10.44 (s, 1H), 8.34 (d, J = 7.2 Hz, 1H), 8.29 (d, J = 7.6 Hz, 1H), 7.88 (s, 1H), 7.75 (s, 1H), 7.55 (d, J = 7.2 Hz, 2H),7.43 – 7.38 (m, 3H), 7.29 (s, 5H), 7.14 (d, J = 7.2 Hz, 2H), 4.85 (d, J = s, 1H),4.12 (s, 2H), 3.12 (s, 3H), 1.80 (s, 2H), 1.59 (dd, J = 21.6, 11.6 Hz, 2H), 1.34 (d, J = 6.0 Hz, 3H). HRMS (ESI) calcd . for [C 37 H 32 ClN4O5] + ([M+H)) + ): m / z647.2056, found: 647.2055. Example Y-111

[0216] This example uses a similar procedure to Example Y-110, except that (R)-1-phenylethanol-1-amine is used instead of (S)-1-phenylethanol-1-amine.

[0217] 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.48 (s, 1H), 8.34 (d, J = 6.4 Hz, 1H), 8.29 (d, J = 6.4 Hz, 1H), 7.88 (s, 1H), 7.75 (s, 1H), 7.55 (d, J = 6.4 Hz, 2H),7.47 – 7.40 (m, 3H), 7.30 (s, 4H), 7.21 (s, 1H), 7.15 (d, J= 6.8 Hz, 2H), 4.91(s, 1H), 4.13 (s, 2H), 3.13 (s, 3H), 1.81 (s, 2H), 1.60 (d, J = 11.2 Hz, 2H), 1.34 (d, J = 5.2 Hz, 3H), 1.24 (s, 1H); HRMS (ESI) calcd . for [C 37 H 32 ClN4O5] + ([M+H)) + ): m / z 647.2056, found: 647.2053. Experimental Example 1: Test of the proteasome agonist activity of the compounds of the present invention Experimental Methods: The activity of different compounds on the enzyme was detected using the fluorescent substrate Suc-Leu-Leu-Val-Tyr-AMC to preliminarily evaluate their agonistic effects. The Tyr-AMC sequence in the substrate was hydrolyzed by a proteasome-like protease, releasing AMC. The fluorescence absorption of the hydrolyzed product AMC could be detected under excitation conditions of 355 nm and emission conditions of 460 nm. The agonistic effect of the compounds on the 20S proteasome activity was observed, and the results are shown in Table 1. It can be seen that the compounds of this invention exhibit good agonistic activity against the 20S proteasome CT-L.

[0218] Table 1. Agonistaltic activity of compounds against 20S proteasome CT-L

[0219]

[0220]

[0221]

[0222] The embodiments described above are merely some preferred embodiments of the present invention, and are not intended to limit the invention. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Therefore, all technical solutions obtained by equivalent substitution or equivalent transformation fall within the protection scope of the present invention.

Claims

1. A compound having the general formula (Ⅰ): ， in: Ar1 is selected from hydrogen, aryl, heterocyclic aryl, aralkyl, or halogenated, C 1-4 Alkyl, C 3-8 cycloalkyl, C 1-4 Alkoxy, C 1-4 Aryl or heterocyclic aryl groups with arbitrary substitution of alkylamine group; Ar2 is selected from aryl, heterocyclic aryl, fused-ring aryl, fused-ring heterocyclic aryl, or omitted; Linker1 and Linker2 are independently selected from amino groups and C groups, respectively. 1-4 Alkyl, C 1-4 alkylamine group, C 1-4 Alkoxy, C 3-8 cycloalkyl, C 3-8 One or more combinations or deletions of heterocyclic alkyl groups and amino acids; R is selected from aryl, heterocyclic aryl, aralkyl, heteroalkyl, cycloalkyl, heteroalkyl, fused-ring aryl, fused-ring heteroalkyl, fused-ring aralkyl, fused-ring heteroalkyl, or the formyl group of the above groups, or halogenated, C 1-4 Alkyl, C 1-8 Alkoxy, C 1-8 alkylamine group, C 3-8 aryl or heterocyclic aryl groups that are substituted with cycloalkyl, heterocyclic alkyl, or halogen in any way, or which are omitted; X1 and X2 are independently selected from hydrogen and halogen, respectively; Y is selected from O and NH.

2. The compound according to claim 1, characterized in that, In the compound: Ar1 is selected from hydrogen, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, N,N-dimethyl-4-aminophenyl, and pyrroleyl. Ar2 is selected from benzo[d]oxazol-5-yl, benzo[ d ]Oxazol-6-yl, benzo[ d Imidazol-5-yl, imidazo[1,2-] a ]Pyridin-6-yl, benzoylamino, phenoxy, 1-methyl-1 H -Indole-5-yl or missing; Linker1 and Linker2 are selected from one or more combinations or deletions of amino, piperazine, piperidinyl, pyrrolyl, alanine, valine, ethylenediamine, and phenyl. R is selected from substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, thiazolyl, naphthyl, quinolinyl, benzothiazolyl, benzoxazolyl, indolyl, fluorenyl, dibenzocycloalkenyl, benzocycloheptylpyridyl, phenothiazinyl, phenothiazinyl; substituted or unsubstituted diarylmethyl, diarylamino, aralkyl, heteroarylalkyl; substituted or unsubstituted cycloalkyl, monocyclic heterocyclic alkyl, fused-ring heterocyclic alkyl, spirocyclic heterocyclic alkyl; or formyl or methylamino corresponding to any of the aforementioned groups; or omitted. X1 and X2 are selected from H and Cl; Y is selected from O and NH.

3. The compound according to claim 2, characterized in that, The R is selected from: 3-bromo-4-methoxyphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-bromophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methylphenyl, 4-cyanophenyl, 4-(N,N-dimethyl)phenyl, 4-methyl carboxylate phenyl, 4-tert-butylphenyl, 3-tert-butylphenyl, 2-tert-butylphenyl, 4-isopropylphenyl, 2-isopropylphenyl, 4-cyclobutylphenyl, 4-cyclopropylphenyl, 3-cyclopropylphenyl, 3-(N-piperazinyl)phenyl, phenyl.

4. The compound according to claim 2, characterized in that, The R is selected from: pyridinyl, pyrimidinyl, thiazolyl, naphthyl, quinolinyl, benzo[d]thiazolyl, benzo[d]oxazolyl, indolyl, 9H-fluorene-9-yl, 5H-dibenzo[a,d][7]cycloen-5-yl, 8-chloro-11H-benzo[5,6]cycloheptane[1,2-b]pyridin-11-yl, 10H-phenoxazine-10-carboxylic acid, 10H-phenthiazine-10-yl, 2-imidazolyl, 4-methylpiperazine-1-yl, cyclopentyl, morpholinyl, isoindolin-2-yl, 1,2,4,5-tetrahydro-3H-benzo[d]azacycloheptane-3-yl, 3,4-dihydroisoquinolin-2(1H)-yl, spiro[ind-1,4'-piperidine]-1'-yl.

5. The compound according to claim 2, characterized in that, The R is selected from: diphenylmethyl, di(4-chlorophenyl)methyl, di(4-fluorophenyl)methyl, diphenylamino, 2-(2-ethoxyethoxy)ethanol-1-yl, methyl(phenethyl)amino, 2-(4-chlorophenyl)ethyl, 2-(4-chlorophenyl)butyl, 2-(4-chlorophenyl)-3-methylbutyl, 2-(4-chlorophenyl)-2-benzyl, 2-(4-fluorophenyl)-2-benzyl, 2-(4-methoxyphenyl)-2-benzyl, 2-(4-chlorophenyl)-2-(pyridin-2-yl)methyl, 2-phenyl-2-(pyrimidin-2-yl)methyl, 2-(pyridin-2-yl)-2-(pyridin-4-yl)methyl, 2-( (4-Chlorophenyl)-2-(quinoline-2-yl)methyl, (R)-2-(3-acrylamidophenyl)ethyl, 2-(3-acrylamidophenyl)ethyl, (R)-2-(4-acrylamidophenyl)ethyl, benzoyl, pyrazin-2-carboxyl, pyridine-2-carboxyl, pyrimidin-2-carboxyl, 1-phenylethyl-2-acyl, di(4-chlorophenyl)carboxyl, dibenzoyl, (S)-N-(1-phenylethyl)methylaminoyl, (R)-N-(1-phenylethyl)methylaminoyl, quinoline-3-carboxyl, quinoline-2-carboxyl, quinazolinoline-2-carboxyl, 2,3-dihydrobenzo[b][1,4]dioxin-6-carboxyl.

6. The compound according to claim 1, characterized in that, The compound is selected from: ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， 。 7. A pharmaceutical composition comprising at least one compound as claimed in any one of claims 1-6, wherein a stereoisomer or pharmaceutically acceptable salt of the compound is an active component, and comprising one or more pharmaceutically acceptable carriers or excipients.

8. The pharmaceutical composition according to claim 7, characterized in that: The administration route of the pharmaceutical composition is selected from oral, injection, inhalation, and implantation.

9. The pharmaceutical composition according to claim 7, characterized in that: The dosage form of the pharmaceutical composition is injection, lyophilized powder for injection, tablet, capsule or granule.

10. The use of any compound of claims 1-6, a pharmaceutically acceptable salt thereof, a solvate thereof, or the pharmaceutical composition of claim 7 in the preparation of a treatment for diseases related to protein homeostasis disorder and insufficient 20S proteasome activity.

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