TPK agonists and methods for treating neurodegenerative diseases using the same

Abstract

The present disclosure belongs to the field of biomedicine and specifically relates to a method for preventing or treating a neurodegenerative disease or alleviating a symptom of a neurodegenerative disease, which comprises administering to an individual in need thereof a prophylactically or therapeutically effective amount of a thiamine pyrophosphokinase (TPK) agonist.

Description

[Technical Field]

[0001] The present invention belongs to the field of biomedicine, and specifically relates to a method for preventing or treating a neurodegenerative disease or alleviating the symptoms of a neurodegenerative disease, which comprises administering to an individual in need thereof a prophylactically or therapeutically effective amount of a thiamine pyrophosphokinase (TPK) agonist. [Background technology]

[0002] Alzheimer's disease (AD) is the most common degenerative disease of the central nervous system. The large number of patients, prolonged disease course, prolonged survival time before patients lose the ability to live independently, and lack of effective preventive and therapeutic drugs place a huge economic and psychological burden on individuals, families, and society as a whole. According to reports, China spent US$167.74 billion on AD prevention and treatment in 2015, a figure projected to reach US$507.49 billion by 2030. In 2018, the world spent over US$10 trillion on dementia, primarily AD, accounting for more than 1% of global gross domestic product (GDP). Among the world's top 10 serious diseases, AD is the only one lacking effective preventive and therapeutic drugs. It has already become a serious disease that severely impacts the health systems and sustainable economic development of major economies, including China.

[0003] AD is a multi-pathophysiological disease characterized by neuronal loss, glial cell activation, and characteristic extracellular beta-amyloid (Aβ) deposition resulting in senile plaques, as well as neurofibrillary tangles resulting from the hyperphosphorylation of intracellular tau protein. Synaptic loss, impaired cerebral glucose metabolism, and oxidative stress are also constant pathological changes in the AD brain, and the decline in cerebral glucose metabolism in patients is closely related to cognitive impairment. Because the pathogenetic mechanism is unclear, there is still a lack of effective treatments for AD. Summary of the Invention

[0004] The present inventors have discovered that impaired glucose metabolism may be one of the early preclinical features of AD. The intracellular glucose metabolism in AD patients manifests as a significant decrease in the activity of three key enzymes (pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and transketolase) that primarily depend on thiamine diphosphate (TDP) as a coenzyme. Multicenter clinical studies have demonstrated that decreased TDP levels in AD patients are a unique and common phenomenon with good diagnostic value, while patients with vascular dementia and frontotemporal dementia do not exhibit thiamine metabolic disorders. Combined clinical and experimental studies have further demonstrated that decreased TDP is the cause of impaired cerebral glucose metabolism. The present inventors have discovered through their research that of four known thiamine metabolism-related genes, only the expression of thiamine pyrophosphokinase (TPK), a key enzyme responsible for converting thiamine to biologically active TDP, is significantly inhibited, and that the inhibition of TPK expression is specific to AD. Therefore, TPK agonists can be used to prevent or treat neurodegenerative diseases (particularly Alzheimer's disease).

[0005] In one aspect, the present invention provides a method for preventing or treating a neurodegenerative disease or alleviating a symptom of a neurodegenerative disease, comprising administering to an individual in need thereof a prophylactically or therapeutically effective amount of a thiamine pyrophosphokinase (TPK) agonist.

[0006] In another aspect, the present invention provides the use of a TPK agonist in the manufacture of a medicament for preventing or treating a neurodegenerative disease or alleviating the symptoms of a neurodegenerative disease.

[0007] In another aspect, the present invention provides a TPK agonist for preventing or treating a neurodegenerative disease or alleviating a symptom of a neurodegenerative disease.

[0008] The neurodegenerative disease is preferably Alzheimer's disease, and more preferably, the Alzheimer's disease is Alzheimer's disease in which the individual's TPK enzyme activity is reduced, TPK expression levels are reduced, and / or TDP levels are reduced.

[0009] In another aspect, the present invention relates to TPK agonists having novel structures. DETAILED DESCRIPTION OF THE INVENTION

[0010] definition Unless otherwise defined below, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. References to technology used herein are intended to mean technology as commonly understood in the art, including modifications of the technology or substitution of equivalent technology that would be apparent to those skilled in the art. Although the following terms are believed to be well understood by those skilled in the art, the following definitions are provided to better interpret the present invention.

[0011] The terms "comprise," "including," "having," "containing," or "relating to," and other variations thereof herein, are inclusive or open-ended and do not exclude other elements or method steps not listed.

[0012] As used herein, when describing a divalent group linking two other groups, it can be understood that the divalent group can be linked to the two groups in any direction. For example, if the other two groups linked by the divalent group -C(=O)NR- are (group 1) and (group 2), respectively, both (group 1)-C(=O)NR-(group 2) and (group 2)-C(=O)NR-(group 1) are included.

[0013] As used herein, the term "alkylene group" refers to a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, such as a methylene group, ethylene group, propylene group, or butylene group.

[0014] As used herein, the term "alkyl group" is defined as a straight or branched chain saturated aliphatic hydrocarbon. In some embodiments, an alkyl group has 1 to 12, e.g., 1 to 6, carbon atoms. For example, as used herein, the term "C 1-6 An "alkyl group" is a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl), which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents, such as halogen (the group is then referred to as a "haloalkyl group") (e.g., CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). The term "C 1-4 An "alkyl group" is a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0015] As used herein, the term "alkenyl group" refers to a linear or branched monovalent hydrocarbon group that contains one or more double bonds and has 2 to 6 carbon atoms ("C 2-6 The alkenyl group includes, for example, -CH=CH2, -CH2CH=CH2, -C(CH3)=CH2, -CH2-CH=CH-CH3, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compounds of the present invention contain an alkenyl group, the compound may exist in the pure E (entgegen) form, the pure Z (zusammen) form, or any mixture thereof. The term "alkenylene group" refers to the corresponding divalent radical, for example, "C 2-6 alkenylene group," "C 2-4Specific examples thereof include, but are not limited to, -CH=CH-, -CHCH=CH-, -C(CH)=CH-, a butenylene group, a pentenylene group, a hexenylene group, a cyclopentenylene group, a cyclohexenylene group, and the like.

[0016] As used herein, the term "alkynyl group" refers to a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5, or 6 carbon atoms, such as ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. The alkynyl group is optionally substituted with one or more (e.g., 1 to 3) of the same or different substituents. The term "alkynylene group" refers to the corresponding divalent group, such as "C 2-8 alkynylene group," "C 2-6 alkynylene group," "C 2-4 Examples of such groups include: [ka] The alkynylene groups include, but are not limited to, the following: optionally substituted with one or more (eg, 1 to 3) of the same or different substituents.

[0017] As used herein, the term "parallel ring" or "fused ring" refers to a ring system formed by two or more ring structures sharing two adjacent atoms with each other.

[0018] As used herein, the term "spirocycle" is a ring system formed by two or more ring structures sharing one ring atom with each other.

[0019] As used herein, the term "bridged ring" refers to a ring system formed by two or more ring structures sharing two atoms that are not directly connected to each other.

[0020] As used herein, the terms "cycloalkylene group," "cyclic hydrocarbon group," and "hydrocarbon ring" refer to saturated (i.e., "cycloalkylene group" and "cycloalkyl group") or unsaturated (i.e., having one or more double and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings (including spirocyclic, parallel (fused) or bridged ring systems) having, for example, 3 to 10 ring carbon atoms (suitably 3 to 8, more suitably 3 to 6) including, but not limited to, (ylidene)cyclopropyl (ring), (ylidene)cyclobutyl (ring), (ylidene)cyclopentyl (ring), (ylidene)cyclohexyl (ring), (ylidene)cycloheptyl (ring), (ylidene)cyclooctyl (ring), (ylidene)cyclononyl (ring), (ylidene)cyclohexenyl (ring), and the like.

[0021] As used herein, the term "cycloalkyl group" refers to a saturated monocyclic or polycyclic (e.g., bicyclic or tricyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused, or bridged systems (e.g., bicyclic [1.1.1] pentyl, bicyclic [2.2.1] heptyl, bicyclic [3.2.1] octyl, or bicyclic [5.2.0] nonyl, decahydronaphthalenyl, etc.), which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-10 A "cycloalkyl group" is a saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring of 3 to 10 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), which is optionally substituted by one or more (e.g., 1 to 3) suitable substituents, for example, a cyclopropyl group substituted with a methyl group.

[0022] As used herein, the term "heterocyclyl group" refers to a saturated or unsaturated monovalent monocyclic or polycyclic (e.g., bicyclic or tricyclic) group that contains 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms in the ring and O, S, N, S(=O), S(=O), S(=O)(=NR Z ), NR Z or P(=O)(R Z ), wherein R Z Each occurrence of represents independently a hydrogen atom or C 1-6 Alkyl group or halo-C 1-6 The heterocycloalkyl group may be linked to the remainder of the molecule via one of the carbon atoms or a nitrogen atom (if present). In particular, the 3- to 14-membered heterocyclyl group is a group having 3 to 14 carbon atoms and heteroatoms in the ring, such as, but not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.

[0023] As used herein, the term "heterocyclyl group" includes parallel ring structures, and the connection point between the parallel ring structure and another group may be at any one of the rings in the parallel ring structure. Thus, heterocyclyl groups of the present invention include heterocyclyl-fused heterocyclyl groups, heterocyclyl-fused cycloalkyl groups, monoheterocyclyl-fused monoheterocyclyl groups, and monoheterocyclyl-fused monocycloalkyl groups, such as 3- to 7-membered (mono)heterocyclyl-fused 3- to 7-membered (mono)heterocyclyl groups, 3- to 7-membered (mono)heterocyclyl-fused (mono)cycloalkyl groups, and 3- to 7-membered (mono)heterocyclyl-fused C 4-6Further included are (mono)cycloalkyl groups, examples of which include, but are not limited to, pyrrolealkyl-fused cyclopropyl groups, cyclopentyl-fused aziridinyl groups, pyrrolidinyl-fused cyclobutyl groups, pyrrolidinyl-fused pyrrolidinyl groups, pyrrolidinyl-fused piperidinyl groups, pyrrolidinyl-fused piperazinyl groups, piperidinyl-fused morpholinyl groups, [ka] Including, but not limited to:

[0024] As used herein, the term "heterocyclyl group" includes bridged heterocyclyl groups and spiro heterocyclyl groups.

[0025] As used herein, the term "bridged heterocycle" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, nitrogen, and / or sulfur atoms) formed by two saturated rings sharing two ring atoms that are not directly connected, such as a 7- to 10-membered bridged heterocycle, an 8- to 10-membered bridged heterocycle, a 7- to 10-membered nitrogen-containing bridged heterocycle, a 7- to 10-membered oxygen-containing bridged heterocycle, or a 7- to 10-membered sulfur-containing bridged heterocycle. [ka] The "nitrogen-containing bridged heterocycle", "oxygen-containing bridged heterocycle", and "sulfur-containing bridged heterocycle" optionally further contain one or more other heteroatoms selected from oxygen, nitrogen, and sulfur.

[0026] As used herein, the term "spiroheterocycle" refers to a cyclic structure containing one or more (e.g., one, two, three, or four) heteroatoms (e.g., oxygen, nitrogen, sulfur atoms) formed by two or more saturated rings sharing one ring atom, such as a 5- to 10-membered spiroheterocycle, a 6- to 10-membered spiroheterocycle, a 6- to 10-membered nitrogen-containing spiroheterocycle, a 6- to 10-membered oxygen-containing spiroheterocycle, or a 6- to 10-membered sulfur-containing spiroheterocycle. [ka] The "nitrogen-containing spiro heterocycle", "oxygen-containing spiro heterocycle", and "sulfur-containing spiro heterocycle" optionally further contain one or more other heteroatoms selected from oxygen, nitrogen, and sulfur. The term "6- to 10-membered nitrogen-containing spiro heterocyclyl group" refers to a spiro heterocyclyl group containing a total of 6 to 10 ring atoms, at least one of which is a nitrogen atom.

[0027] As used herein, the terms "(ylidene)aryl group" and "aromatic ring" refer to a monocyclic or fused-ring polycyclic aromatic group having a conjugated π-electron system. For example, as used herein, the term "C 6-10 (Ylidene)aryl group" and "C 6-10 "Aromatic ring" means an aromatic group containing 6 to 10 carbon atoms, such as an (ylidene)phenyl group (benzene ring) or an (ylidene)naphthyl group (naphthalene ring). The (ylidene)aryl group and the aromatic ring may optionally contain one or more (e.g., 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO, C 1-6 When the (ylidene)aryl group and the aromatic ring are fused together, the fused ring may be a hydrocarbon ring, a heterocyclic ring, or a heteroaromatic ring, and the connection point between the fused ring structure and another group may be on any one of the rings in the fused ring structure.

[0028] The term "aralkyl group" preferably refers to an alkyl group substituted with an aryl group, where the aryl group and the alkyl group are as defined herein. Typically, the aryl group may have 6 to 14 carbon atoms, and the alkyl group may have 1 to 6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl groups.

[0029] As used herein, the terms "(ylidene)heteroaryl group" and "heteroaromatic ring" refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom, which may be the same or different, such as oxygen, nitrogen or sulfur. In particular, "(ylidene)heteroaryl group" or "heteroaromatic ring" includes (ylidene)thienyl group (ring), (ylidene)furyl group (ring), (ylidene)pyrrolyl group (ring), (ylidene)oxazolyl group (ring), (ylidene)thiazolyl group (ring), (ylidene)imidazolyl group (ring), (ylidene)pyrazolyl group (ring), (ylidene)isoxazolyl group (ring), (ylidene)isothiazolyl ... The heteroaryl group is selected from a zolyl group (ring), (ylidene)oxadiazolyl group (ring), (ylidene)triazolyl group (ring), (ylidene)thiadiazolyl group (ring), etc., and benzo derivatives thereof, or a (ylidene)pyridyl group (ring), (ylidene)pyridazinyl group (ring), (ylidene)pyrimidinyl group (ring), (ylidene)pyrazinyl group (ring), (ylidene)triazinyl group (ring), etc. When the (ylidene)heteroaryl group and the heteroaromatic ring are fused rings, the fused ring may be a hydrocarbon ring, a heterocyclic ring, an aromatic ring, or a heteroaromatic ring, and the connection point between the fused ring structure and another group may be on any one of the rings in the fused ring structure.

[0030] As used herein, the term "halogenated" or "halogen" group is defined to include F, Cl, Br, or I.

[0031] As used herein, the term "alkylthio group" means an alkyl group, as defined above, connected to the parent molecular moiety through a sulfur atom. 1-6 Representative examples of alkylthio groups include, but are not limited to, methylthio, ethylthio, tert-butylthio, and hexylthio groups.

[0032] As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and at least one nitrogen atom in the ring, which may optionally contain one or more (e.g., one, two, three, or four) ring members selected from N, O, C=O, S, S=O, and S(=O)2, and the nitrogen-containing heterocycle is linked to the remainder of the molecule via a nitrogen atom. The nitrogen-containing heterocycle is preferably a saturated nitrogen-containing monocyclic ring. In particular, the 3- to 14-membered nitrogen-containing heterocycle is a group having 3 to 14 carbon atoms and heteroatoms (wherein at least one is a nitrogen atom) in the ring, including, but not limited to, a 3-membered nitrogen-containing heterocycle (e.g., an aziridinyl group), a 4-membered nitrogen-containing heterocycle (e.g., an azetidinyl group), a 5-membered nitrogen-containing heterocycle (e.g., a pyrrolyl group, a pyrrolidinyl group (pyrrolidine ring), a pyrrolinyl group, a pyrrolidonyl group, an imidazolyl group, an imidazolidinyl group, an imidazolinyl group, a pyrazolyl group, a pyrazolinyl group), a 6-membered nitrogen-containing heterocycle (e.g., a piperidinyl group (piperidine ring), a morpholinyl group, a thiomorpholinyl group, a piperazinyl group), a 7-membered nitrogen-containing heterocycle, etc.

[0033] The term "substituted" refers to the replacement of one or more (e.g., one, two, three, or four) hydrogens on the designated atom with the selected indicated group, provided that the valences do not exceed the normal valence of the designated atom in its current context and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0034] When a substituent is described as being "optionally substituted," the substituent may be (1) unsubstituted or (2) substituted. When a carbon of a substituent is described as being optionally substituted with one or more in a list of substituents, one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be replaced singly and / or together with independently selected optional substituents. When a nitrogen of a substituent is described as being optionally substituted with one or more in a list of substituents, one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may be replaced with each independently selected optional substituent.

[0035] When substituents are described as "independently selected" groups, each substituent is selected independently from the other groups, and therefore each substituent can be the same or different from another (other) substituent.

[0036] As used herein, the term "one or more" means one or more than one, where reasonable, for example, two, three, four, five or ten.

[0037] Unless otherwise specified, as used herein, the point of attachment of a substituent may be from any suitable position on the substituent.

[0038] When a bond of a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any one ring-forming atom in the substitutable ring.

[0039] The present invention further includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Examples of isotopes suitable for inclusion in compounds of the present invention include isotopes of hydrogen (e.g., deuterium (D), 2 H), tritium (T, 3 H), isotopes of carbon (e.g. 11 C. 13C and 14 C), isotopes of chlorine (e.g. 36 Cl), isotopes of fluorine (e.g. 18 F), isotopes of iodine (e.g. 123 I and 125 I), nitrogen isotopes (e.g. 13 N 15 N), isotopes of oxygen (e.g. 15 O. 17 O and 18 O), isotopes of phosphorus (e.g. 32 P), and sulfur isotopes (e.g. 35 Certain isotopically labeled compounds of the invention (e.g., those incorporating a radioactive isotope) can be used in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) can be particularly used for this purpose because of its ease of incorporation and detection. 11 C. 18 F, 15 O and 13 Substitution with N) can be used to verify substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the present invention can be prepared by the accompanying routes and / or analogous methods described in the Examples and Preparations, by substituting appropriate isotopically labeled reagents for previously employed unlabeled reagents. Pharmaceutically acceptable solvates of the present invention include those in which the solvent of crystallization may be isotopically substituted, e.g., DO, acetone-d6, or DMSO-d6.

[0040] It should be further understood that some compounds of the present invention may be present in free form for treatment, or may be present in their pharmaceutically acceptable derivative form, when appropriate. In the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, a pharmaceutically acceptable salt, ester, solvate, metabolite, or prodrug, which, upon administration to a patient in need thereof, can directly or indirectly provide the compound of the present invention or a metabolite or residue thereof. Therefore, when referring to a "compound of the present invention" herein, it is also intended to include the various derivative forms of the compound.

[0041] Pharmaceutically acceptable salts of the compounds of the present invention include the acid addition and base salts thereof.

[0042] Suitable acid addition salts are formed with acids that form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate / carbonate, hydrogensulfate / sulfate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrobromide / bromide, hydroiodide / iodide, maleate, malonate, methylsulfate, naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate, and other similar salts.

[0043] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, diethylamine salts, lysine salts, magnesium salts, meglumine salts, potassium salts and other similar salts.

[0044] For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use," Wiley-VCH, 2002. Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

[0045] As used herein, the term "ester" refers to an ester derived from a compound of each general formula in this application, including physiologically hydrolyzable esters (compounds of the invention that can be hydrolyzed under physiological conditions to release the free acid or alcohol form). The compounds of the invention themselves may be esters.

[0046] The compounds of the present invention may exist in the form of solvates, preferably hydrates, in which the compounds of the present invention contain a polar solvent, in particular water, methanol or ethanol, as a structural element of the crystal lattice of said compounds. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0047] Further included within the scope of this invention are metabolites of the compounds of this invention, i.e., substances formed in the body upon administration of a compound of this invention. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic hydrolysis, etc. of the administered compound. Thus, the present invention includes metabolites of the compounds of this invention, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0048] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are derivatives of the compounds of the present invention that themselves have little or no pharmacological activity and can be converted, for example, by hydrolytic cleavage, into compounds of the present invention having the desired activity when administered to or on the body. Generally, such prodrugs are functional derivatives of the compounds that are readily converted in vivo into the desired therapeutically active compound. For further information regarding the use of prodrugs, see "Prodrugs as Novel Delivery Systems," Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E.B. Roche, ed., American Pharmaceutical Association). Prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain "pro-moieties" known to those skilled in the art (e.g., as described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985)).

[0049] The present invention further includes compounds of the present invention that contain protecting groups. During any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a form of chemical protection for the compounds of the present invention. This can be achieved using common protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973, and T.W. Greene & P. ​​G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. The protecting groups can be removed at a suitable subsequent stage using methods known in the art.

[0050] As used herein, the term "about" refers to within ±10% of the numerical value, preferably within ±5%, and more preferably within ±2%.

[0051] As used herein, an "effective amount" is that amount of a compound which, after administration, relieves to some extent one or more of the symptoms of the condition being treated.

[0052] The term "prevention" as used herein refers to the administration of a drug in advance to avoid or prevent the occurrence of one or more symptoms of a disease or condition. Those of ordinary skill in the medical field will recognize that the term "prevention" is not an absolute term. In the medical field, it should be understood that a drug is administered prophylactically to substantially reduce the likelihood or severity of a disease or the symptoms of a disease, and this is the meaning intended in this disclosure. Prevention is divided into primary prevention (to prevent the progression of a disease) and secondary prevention (whereby a disease has already progressed and the patient is protected to prevent the process from worsening).

[0053] Unless otherwise specified, as used herein, the term "treating" means reversing, alleviating, or inhibiting the progression of the disease or condition to which such term applies, or one or more symptoms of such disease or condition.

[0054] As used herein, an "individual" includes a human or a non-human animal. Exemplary human individuals include human individuals (referred to as patients) suffering from a disease (e.g., a disease described herein) or normal individuals. "Non-human animals" in the present invention include all vertebrates, including non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, and livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0055] As used herein, the term "reduced TPK enzyme activity" refers to TPK enzyme activity in a treated individual being lower than the enzyme activity in a normal individual.

[0056] As used herein, the term "reduced TPK expression level" refers to a TPK mRNA / DNA or protein expression level in a treated individual that is lower than that in a normal individual.

[0057] As used herein, the term "reduced TDP levels" refers to TDP levels in a treated individual that are lower than levels in a normal individual.

[0058] In some embodiments, the present invention provides a method of preventing or treating a neurodegenerative disease or alleviating a symptom of a neurodegenerative disease, comprising administering to an individual in need thereof a prophylactically or therapeutically effective amount of a thiamine pyrophosphokinase (TPK) agonist.

[0059] In a preferred embodiment, the neurodegenerative disease is Alzheimer's disease.

[0060] In a more preferred embodiment, the Alzheimer's disease is Alzheimer's disease in which the individual has reduced TPK enzyme activity, reduced TPK expression levels, and / or reduced TDP levels.

[0061] In some embodiments, the TPK agonist is a compound of Formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof: [ka] where: A and B are independent of each other, C 3-10 Hydrocarbon ring, 3-14 membered heterocycle, C 6-10 an aromatic ring or a 5- to 14-membered heteroaromatic ring, L is -Q 1-, -W-, -Q 1 -W-, -WQ 1 -, -Q 1 -Q 2 -, -W-W'-, -WQ 1 -Q 2 -, -WQ 1 -W'-, -Q 1 -WQ 2 -, -Q 1 -WQ 2 -W'-, -WQ 1 -W'-Q 2 -, -Q 1 -Q 2 -W-W'- and -WQ 1 -Q 2 -W'-, Q 1 and Q 2 are each independently -C 1-6 Alkylene-, -C 2-6 Alkenylene-, -C 2-6 Alkynylene-, -C 3-10 Cycloalkylene-, -(3- to 14-membered heterocyclylene)-, -C 6-10 arylene- and -(5- to 14-membered heteroarylene)-, wherein the alkylene group, alkenylene group, and alkynylene group each optionally include -C 3-10 Cycloalkylene-, -(3- to 14-membered heterocyclylene)-, -C 6-10 interrupted by one group selected from arylene-, -(5- to 14-membered heteroarylene)-, -O-, -C(=O)-, -C(=O)O-, -NR-, -C(=O)NR-, -NR-C(=O)-NR'-, -NR-C(=O)O-, -(S=O)NR-, -S(=O)NR-, -S-, -S(=O)- and -S(=O)-, W and W' in each occurrence are independently selected from -O-, -C(=O)-, -C(=O)O-, -NR-, -C(=O)NR-, -NR-C(=O)-NR'-, -NR-C(=O)O-, -(S=O)NR-, -S(=O)NR-, -S-, -S(=O)- and -S(=O)-; R and R' are independently H and C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 Cyclic hydrocarbon groups, 3- to 14-membered heterocyclyl groups, C 6-10 Aryl groups, 5- to 14-membered heteroaryl groups, and C 6-12 aralkyl groups, The above alkyl group, alkylene group, alkenyl group, alkenylene group, alkynyl group, alkynylene group, cyclic hydrocarbon group, cycloalkylene group, hydrocarbon ring, heterocyclyl group, heterocyclylene group, heterocycle, aryl group, arylene group, aromatic ring, heteroaryl group, heteroarylene group, heteroaromatic ring, and aralkyl group each occurring optionally and independently include halogen, —OH, ═O, —NH, —CN, —NO, —C, 1-6 Alkyl group, halo C 1-6 Alkyl group, C 3-10 Cyclic hydrocarbon groups, 3- to 14-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 14-membered heteroaryl group, C 6-12 Aralkyl group, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O)2-R b , -NR a -C(=O)-NR a R b , -C 1-6 Alkylene-OR a , -C 1-6 Alkylene-NRa R b and -OC 1-6 Alkylene-NR a R b The alkyl, alkylene, cyclic hydrocarbon, heterocyclyl, aryl, heteroaryl, and aralkyl groups may further optionally be independently substituted with one or more substituents selected from halogen, —OH, ═O, —C(═O)O-tert-butyl, —NH, —CN, —NO, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-10 Cyclic hydrocarbon groups, 3- to 14-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 14-membered heteroaryl group, C 6-12 Aralkyl group, -OC 1-6 Alkyl groups and -C 1-6 Alkylene-OC 1-6 substituted with one or more substituents selected from alkyl groups, and R a and R b are independently H, C each time they occur. 1-6 Alkyl group, C 3-10 Cyclic hydrocarbon groups, 3- to 14-membered heterocyclyl groups, C 6-10 Aryl groups, 5- to 14-membered heteroaryl groups, and C 6-12 and aralkyl groups, wherein the alkyl groups, cyclic hydrocarbon groups, heterocyclyl groups, aryl groups, heteroaryl groups, and aralkyl groups are further optionally independently selected from halogen, —OH, ═O, —C(═O)O-tert-butyl groups, —NH, —CN, —NO, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-10 Cyclic hydrocarbon groups, 3- to 14-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 14-membered heteroaryl group, C 6-12 Aralkyl groups and -C 1-6 Alkylene-OC 1-6 It is substituted with one or more substituents selected from alkyl groups.

[0062] In some embodiments, A is [ka] is.

[0063] In some embodiments, L is -Q 1 -W-, -WQ 1 -, -Q 1 -Q 2 -, -WQ 1 -Q 2 -, -WQ 1 -W'-, -Q 1 -WQ 2 -, -Q 1 -WQ 2 -W'-, -WQ 1 -W'-Q 2 -, -Q 1 -Q 2 -W-W'- and -WQ 1 -Q 2 -W'-.

[0064] In some embodiments, L is [ka] [ka] [ka] is.

[0065] In some embodiments, B is [ka] is.

[0066] In some embodiments, the TPK agonist is a compound of formula (II), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof: AWQ 1 -Q 2 -B (II) where: A is a benzene ring optionally joined to a 5- or 6-membered heterocyclic ring or a 5- or 6-membered heteroaromatic ring, and the benzene ring is optionally independently selected from halogen, —OH, —NH, C 1-6 Alkyl group, -OC 1-6 Alkyl group, -NH(C 1-6 alkyl) and -N(C 1-6 and preferably the benzene ring is optionally substituted with one or more substituents independently selected from -Cl, -OH, -NH, -NH(CH), -N(CH), methyl, ethyl and methoxy; most preferably A is [ka] and B is C 3-10 Hydrocarbon ring, 3-14 membered heterocycle, C 6-10 The aromatic ring or the 5- to 14-membered heteroaromatic ring is preferably a benzene ring, and the benzene ring may optionally independently contain halogen, C 1-6 Alkyl group, halo C 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl group, -C(=O)-(3-14 membered heterocyclyl), -S(=O)2-N(C 1-6 and -S(=O)-(3- to 14-membered heterocyclyl), and preferably the benzene ring is optionally substituted with one or more substituents independently selected from -F, -Cl, methyl, isopropyl, trifluoromethyl, -NHC(=O)CH, -C(=O)-piperidinyl, -S(=O)-N(CH), -S(=O)-N(CHCH), -S(=O)-piperidinyl, and -S(=O)-azepanyl; Q 1 -C 1-6 Alkylene-, -C 2-6 Alkenylene- and -C 2-6 alkynylene-, Q 2 -C3-10 Cycloalkylene-, -(3- to 14-membered heterocyclylene)-, -C 6-10 selected from arylene- and -(5- to 14-membered heteroarylene)-, preferably -(3- to 14-membered heterocyclylene)-, more preferably a piperidinylene group or a piperazinylene group; W at each occurrence is independently selected from —O—, —C(═O)—, —C(═O)O—, —NR—, —C(═O)NR—, —NR—C(═O)—NR′—, —NR—C(═O)O—, —(S═O)NR—, —S(═O)NR—, —S—, —S(═O)— and —S(═O)—, preferably —O—, —NH— or —NH—C(═O)—; The remaining groups are as defined above.

[0067] In some embodiments, the TPK agonist is

[0068] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] is selected from.

[0069] In a preferred embodiment, the TPK agonist is administered in an amount of about 0.005 mg / day to about 5000 mg / day, for example, about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 mg / day.

[0070] In a preferred embodiment, the TPK agonist is administered in an amount of about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg of body weight daily, for example, about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, or about 180 μg / kg daily. g, approximately 200μg / kg, approximately 225μg / kg, approximately 250μg / kg, approximately 275μg / kg, approximately 300μg / kg, approximately 325μg / kg, approximately 350μg / kg, approximately 375μg / kg, approximately 400μ g / kg, approximately 425μg / kg, approximately 450μg / kg, approximately 475μg / kg, approximately 500μg / kg, approximately 525μg / kg, approximately 550μg / kg, approximately 575μg / kg, approximately 600μg / kg, approximately 62 5μg / kg, about 650μg / kg, about 675μg / kg, about 700μg / kg, about 725μg / kg, about 750μg / kg, about 775μg / kg, about 800μg / kg, about 825μg / kg, Approximately 850μg / kg, approximately 875μg / kg, approximately 900μg / kg, approximately 925μg / kg, approximately 950μg / kg, approximately 975μg / kg, approximately 1mg / kg, approximately 5mg / kg, approximately 10mg / kg, approximately 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg or about 300 mg / kg body weight.

[0071] In preferred embodiments, the daily dose of the TPK agonist is administered in one dose, or in two, three, or four divided doses.

[0072] In preferred embodiments, the TPK agonist is administered continuously for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days or at least 50 days.

[0073] In a preferred embodiment, the TPK agonist is administered over one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) treatment courses, wherein each treatment course lasts at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days, and the interval between each two treatment courses is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, 2 weeks, 3 weeks, or 4 weeks.

[0074] In preferred embodiments, the TPK agonist is administered by injection (e.g., intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including drip infusion), or transdermally, or in the form of oral, buccal, nasal, transmucosal, topical, ophthalmic formulations, or by inhalation.

[0075] In preferred embodiments, the TPK agonist is administered in a dosage form selected from a tablet, capsule, troche, hard candy, powder, spray, cream, ointment, suppository, gel, paste, lotion, ointment, aqueous suspension, injectable solution, elixir, and syrup.

[0076] In a preferred embodiment, the method improves the pathophysiological symptoms of cognitive and behavioral abnormalities, neurodegenerative changes (e.g., progressive synapse / neuron loss and brain atrophy), β-amyloid deposition, Tau abnormal phosphorylation and resulting neurofibrillary tangles, glial cell activation and inflammation, and / or impaired cerebral glucose metabolism in an individual.

[0077] In a preferred embodiment, the present disclosure further comprises administering one or more other therapeutic agents.

[0078] In some embodiments, the disclosure provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein said compound is

[0079] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] is selected from. Example

[0080] The present invention will now be further described in conjunction with the following examples, which are not intended to limit the scope of the invention.

[0081] The abbreviations used in the present invention have the following meanings:

[0082] [Table 3] Example 1: Synthesis of 7-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)but-1-yn-1-yl)oxy)-3,4-dihydroquinolin-2(1H)-one (Compound 1) [ka]

[0083] Step 1: 1a (5 g, 30.64 mmol) and K2CO3 (8.47 g, 61.28 mmol) were added to DMF (50 mL), and 3,4-dihydro-7-hydroxy-2(1H)-quinolinone (1b) (6.85 g, 45.96 mmol) was added. The reaction mixture was stirred at 100 °C for 24 h, diluted with water, extracted with ethyl acetate, the organic phase dried, filtered, and spun to give the crude product, which was purified by normal phase column chromatography (eluent: (dichloromethane:methanol = 20:1)) to give the desired product as a yellow liquid 1A (6.2 g, yield: 79.9%).

[0084] Step 2: 1A (5.2 g, 22.49 mmol) and triethylamine (6.84 g, 67.47 mmol) were added to DCM (60 mL), and MsCl (3.87 g, 33.7 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 h, and the reaction mixture was purified by normal phase column chromatography (eluent: (dichloromethane:ethyl acetate=10:1)) to obtain the desired product as a yellow solid 1B (6.1 g, yield: 91.2%).

[0085] Step 3: 1B (6.1 g, 19.72 mmol) and K2CO3 (8.18 g, 59.16 mmol) were added to DMF (70 mL), and 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c) (5.8 g, 21.69 mmol) was added. The reaction mixture was stirred at 50 °C for 16 h, diluted with water, extracted with ethyl acetate, the organic phase dried, filtered, and spun to give the crude product, which was purified by normal-phase column chromatography (eluent: (dichloromethane:methanol = 93:7)) and then purified again by C-18 reverse-phase column chromatography (eluent: (MeOH:HO (0.1% HCOOH) = 85:15)). The desired fraction was collected and lyophilized to give the title compound 1 (yellow solid) (12 mg, yield: 0.14%).

[0086] LCMS: 444 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ9.98(s,1H),7.30-7.29(m,2H),7.16-7.15(m,1H),7.05(d,1H),6.53(d,1H),6.46(s,1H), 4.10-4.01(m,2H),3.92-3.89(m,1H),3.39-3.38(m,1H),3.07-2.94(m,4H),2.79-2.64(m,6H),2.42-2.38(m,2H). Example 2: Synthesis of 7-((6-(4-(2,3-dichlorophenyl)piperazin-1-yl)hexyl)oxy)-3,4-dihydroquinolin-2(1H)-one (Compound 3) [ka]

[0087] A reaction flask was charged with 3a (0.32 g, 1.0 mmol, 1.0 eq.), 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c) (0.27 g, 1.1 mmol, 1.1 eq.), K2CO3 (0.55 g, 4.0 mmol, 4.0 eq.), potassium iodide (0.33 g, 2.0 mmol, 2.0 eq.), and acetonitrile (15 mL), and the mixture was refluxed for 4 h. After filtration, the filter cake was washed with DMSO, and the organic phase was concentrated to give a crude product. The crude product was separated and purified using a C18 reverse-phase column (eluent: methanol:0.5% formic acid aqueous solution = 85:15). The target component was collected, concentrated, and spin-dried to give the title compound 3 (135 mg, yield: 28.3%) as a white solid.

[0088] LCMS: 476 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 7.32-7.24 (m, 2H), 7.13 (dd, 1H), 7.02 (d, 1H), 6.47-6.41 (m, 2H), 3.87 (t, 2H), 2.96 (br, 4H), 2.76 (t, 2H), 2.41-2.32 (m, 4H), 1.72-1.63 (m, 2H), 1.46-1.32 (m, 6H). Note: Four hydrogen signal peaks were masked by the solvent signal peaks. Example 3: Synthesis of 7-((5-(4-(2,3-dichlorophenyl)piperazin-1-yl)pentyl)oxy)-3,4-dihydroquinolin-2(1H)-one (Compound 4) [ka]

[0089] The title compound 4 (white solid) was obtained by employing the same synthetic route as in Example 2, except that 3a in Example 2 was replaced with 4a.

[0090] LCMS: 462 [M+H] + 1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),7.32-7.28(m,2H),7.14(dd,1H),7.03(d,1H),6.48(d,1H),6.42(s,1H),3 .88(t,2H),2.97(br,4H),2.76(t,2H),2.51(br,2H),2.41-2.34(m,6H),1.75-1.66(m,2H),1.54-1.38(m,4H). Example 4: Synthesis of 7-(4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 6) [ka]

[0091] 7-(4-Bromobutoxy)-3,4-dihydro-2(1H)-quinolinone (6a) (100 mg, 0.34 mmol, 1.0 eq.) was dissolved in acetonitrile (2 mL), potassium iodide (185 mg, 1.34 mmol, 4.0 eq.) was added, and the mixture was heated to 85 °C and reacted for 1 h. 1-(3-Trifluoromethylphenyl)piperazine hydrochloride (6b) (134 mg, 0.50 mmol, 1.5 eq.) and anhydrous potassium carbonate (111 mg, 0.67 mmol, 2.0 eq.) were added, and the reaction was continued at 85 °C for 2 h. The mixture was filtered to remove inorganic salts, and the solid was washed with methanol (2 × 10 mL). The filtrate was concentrated under reduced pressure, and the residue was purified using a 18C reverse-phase column (eluent: methanol:0.1% formic acid aqueous solution = 70:30). The target component was collected and concentrated. The residue was dissolved in methanol (0.5 mL), purified water (1 mL) was added, and the mixture was concentrated under reduced pressure to remove the methanol. The mixture was then freeze-dried under reduced pressure to obtain the title compound 6 (pale yellow cotton-like solid, 80 mg, yield: 53%).

[0092] LCMS: 448 [M+H] + 1H NMR(400MHz,CD3OD)δ8.46(s,1H),7.42(t,1H),7.22(m,2H),7.14(d,1H),7.03(d,1H),6.54(d,1H),6.46(s,1H), 4.66(t,2H),4.15(br,4H),3.98(br,4H),3.81(t,2H),3.49(t,2H),3.17(t,2H),1.95(br,2H),1.85-1.82(m,2H). Example 5: Synthesis of 7-((5-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)pentyl)oxy)-3,4-dihydroquinolin-2(1H)-one (Compound 7) [ka]

[0093] The title compound 7 (pale yellow solid) was obtained by employing the same synthetic route as in Example 4, except that 6a in Example 4 was replaced with 4a.

[0094] LCMS: 462 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 7.40 (t, 1H), 7.20 (d, 1H), 7.13 (s, 1H), 7.03 (t, 2H), 6.47 (dd, 1H), 6.41 (d, 1H), 3.88 (t, 2H), 3.21-3.18 (m, 4H), 2.76 (t, 2H), 2.43-2.36 (t, 2H), 2.33 (t, 2H), 1.74-1.66 (m, 2H), 1.49 (m, 2H), 1.45-1.35 (m, 2H). Note: Four hydrogen signal peaks were obscured by solvent signal peaks. Example 7: Synthesis of 7-((5-(4-(2,3-dichlorophenyl)piperazin-1-yl)pentyl)oxy)quinolin-2(1H)-one (Compound 9) [ka]

[0095] 9a (100 mg, 0.32 mmol, 1.0 eq.) was dissolved in acetonitrile (5 mL), and 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c) (129 mg, 0.48 mmol, 1.5 eq.), anhydrous potassium carbonate (178 mg, 1.29 mmol, 4.0 eq.), and potassium iodide (107 mg, 0.64 mmol, 2.0 eq.) were added. The mixture was heated to 85 °C and reacted overnight. After filtration, the solid was washed with methanol (2 × 10 mL), and the filtrate was concentrated under reduced pressure. The residue was purified using a 18C reverse-phase column (eluent: methanol:0.1% formic acid aqueous solution = 70:30). The target component was collected, concentrated, and the residue was purified with methanol (5 mL) to give the title compound 9 (white solid) (12 g, yield: 8%).

[0096] LCMS: 460 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 7.78 (d, 1H), 7.54 (d, 1H), 7.31-7.26 (m, 2H), 7.12 (dd, 1H), 6.78-6.77 (m, 2H), 6.28 (d, 1H), 4.00 (t, 2H), 2.96 (br, 4H), 2.35 (t, 2H), 1.80-1.72 (m, 2H), 1.56-1.38 (m, 4H). Note: Four hydrogen signal peaks were masked by solvent signal peaks. Example 8: Synthesis of 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2(1H)-one (Compound 10) [ka]

[0097] The title compound 10 (white solid) was obtained by employing the same synthetic route as in Example 7, except that 9a in Example 7 was replaced with 10a.

[0098] LCMS: 446 [M+H] + 1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),7.80(d,1H),7.55(d,1H),7.30(s,2H),7.14(s,1H),6.78 (s,2H),6.29(d,1H),4.04(t,2H),3.02(br,4H),2.71(br,4H),2.58(br,2H),1.78-1.66(m,4H). Example 15: Synthesis of 7-(3-(1-(2,3-dichlorophenyl)piperidin-4-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 17) [ka]

[0099] Step 1: A reaction flask was charged with 17a (500 mg, 3.49 mmol, 1.0 eq.) and DCM (80 mL), and thionyl chloride (630 mg, 5.25 mmol, 1.5 eq.) was added dropwise under an ice-water bath. The reaction mixture was reacted at room temperature for 4 hours under nitrogen gas protection. The reaction mixture was monitored by LCMS for completion, and concentrated to give crude 17A (550 mg, 99% yield).

[0100] Step 2: A reaction flask was charged with 17A (550 mg, 3.49 mmol, 1.0 eq.), dioxane (10 mL), and triethylamine (1.05 mL, 10.5 mmol, 3.0 eq.). Boc-anhydride (900 mg, 4.2 mmol, 1.2 eq.) was added dropwise to the reaction mixture under ice-water bath conditions. After the addition was complete, the reaction mixture was allowed to react at room temperature for 4 hours. After the reaction of the raw materials was confirmed to be substantially complete by LCMS, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give 17B (650 mg, 80% yield).

[0101] Step 3: A reaction flask was charged with 17B (500 mg, 1.88 mmol, 1.0 eq.) and acetonitrile (20 mL), followed by potassium carbonate (380 mg, 2.74 mmol, 1.5 eq.) and 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (1b) (360 mg, 2.32 mmol, 1.2 eq.). The reaction mixture was heated at 85 °C for 4 h. Completion of the reaction mixture was monitored by LCMS. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give 17C (600 mg, 80% yield).

[0102] Step 4: A reaction flask was charged with 17C (600 mg, 1.32 mmol, 1.0 eq.) and ethyl acetate (10 mL), and then a solution of 4 M dioxane hydrochloric acid (10 mL) was added dropwise. The reaction mixture was allowed to react at room temperature for 4 hours. After the reaction of the raw materials was monitored by LCMS to be essentially complete, the mixture was concentrated under reduced pressure, and the residue was purified with ethyl acetate, filtered, and the filter cake was dried to give 17D (500 mg, yield: 90%).

[0103] Step 5: A reaction flask was charged with 17D (350 mg, 1.32 mmol, 1.0 eq.) and toluene (10 mL), followed by BINAP (150 mg, 0.27 mmol, 0.2 eq.), potassium tert-butoxide (290 mg, 2.64 mmol, 2.0 eq.), and 1-bromo-2,3-dichlorobenzene (17b) (240 mg, 1.59 mmol, 1.2 eq.). Tris(dibenzylideneacetone)dipalladium (150 mg, 0.2 mmol, 0.15 eq.) was added to the reaction mixture under nitrogen gas protection, and the reaction mixture was heated at 100 °C for 6 h. The reaction mixture was monitored for completion by LCMS, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by C18 reverse phase preparative chromatography (eluent: methanol: 0.1% formic acid aqueous solution = 70:30) to give a crude product, which was further separated by a silica gel column to give the title compound 17 (30 mg, yield: 10%).

[0104] LCMS: 433 [M+H]+ 1 H NMR(400MHz,DMSO-d6)δ9.96(s,1H),7.32-7.19(m,2H),7.11(d,1H),7.02(d,1H),6.46(d,1H),6.41(s,1H), 3.87(t,2H),3.26-3.23(m,2H),2.76(t,2H),2.61(t,2H),2.39(t,2H),1.79-1.73(m,4H),1.39-1.32(m,5H). Example 16: Synthesis of 7-(4-(1-(2,3-dichlorophenyl)piperidin-4-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 18) [ka]

[0105] The title compound 18 was obtained by employing the same synthetic route as in Example 15, except that 17a in Example 15 was replaced with 18a.

[0106] LCMS: 447 [M+H] + 1 H NMR(400MHz,CDCl3)δ7.67(s,1H),7.16(s,2H),7.06(d,1H),6.54(d,1H),6.31(s,1H),3.94(t,2H),3. 38(d,2H),2.90(t,2H),2.62(t,2H),1.80(dd,4H),1.52(s,2H),1.46-1.33(m,3H),1.33-1.17(m,4H). Example 17: Synthesis of 7-(4-(4-phenylpiperidin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 20) [ka]

[0107] A reaction flask was charged with 20a (500 mg, 1.65 mmol, 1.0 eq.), 7-(4-bromobutoxy)-3,4-dihydroquinolin-2(1H)-one (6a) (730 mg, 2.48 mmol, 1.5 eq.), potassium carbonate (700 mg, 4.95 mmol, 3.0 eq.), and MeCN (20 mL). The reaction mixture was purged with nitrogen gas three times and reacted at 85 °C for 12 h. After monitoring the completion of the reaction by TLC and LCMS, the crude product was filtered and purified using a C18 reverse-phase column. The target component was collected and concentrated to give the title compound 20 (white solid) (500 mg, yield: 70%).

[0108] LCMS: 379 [M+H] + 1 H NMR(400MHz,CD3OD)δ8.46(s,1H),7.34-7.21(m,5H),7.07(d,1H),6.56(d,1H),6.47(s,1H),4.02(t,2H),3.69 -3.66(m,2H),3.23(t,2H),3.10(t,2H),2.88-2.86(m,3H),2.53(t,2H),2.11-1.94(m,6H),1.90-1.85(m,2H). Example 18: Synthesis of N-(4-(2,3-dichlorophenyl)cyclohexyl)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)acetamide (Compound 21) [ka]

[0109] 21a (550 mg, 2.25 mmol), 21b (748 mg, 3.38 mmol), and DIPEA (874 mg, 6.76 mmol) were added to DMF (6 mL), and HATU (1.28 g, 3.38 mmol) was added. The reaction mixture was stirred overnight at room temperature, diluted with water, extracted with ethyl acetate, the organic phase dried, filtered, and spun dry. The mixture was then purified on a reversed-phase C18 column (eluent: methanol:0.1% formic acid aqueous solution = 70:30). The desired product was collected and lyophilized to give the title compound 21 (white solid) (0.065 g, yield: 6.5%). LCMS: 447 [M+H] +; 1 H NMR(400MHz,DMSO-d6)δ10.1(s,1H),7.95(d,1H),7.47(d,1H),7.39(d,1H),7.35-7.31(m,1H),7.05(d,1H),6.49-6.47(m,2H), 4.37(s,2H),3.77-3.69(m,1H),2.98-2.91(m,1H),2.80-2.76(m,2H),2.42-2.39(m,2H),1.89-1.78(m,4H),1.56-1.43(m,4H). Example 19: Synthesis of 7-((5-(4-(2,3-dichlorophenyl)piperazin-1-yl)pentyl)oxy)-3,4-dihydroisoquinolin-1(2H)-one (Compound 23) [ka]

[0110] Step 1: 7-Hydroxy-3,4-dihydroisoquinolin-1(2H)-one (23a) (0.326 g, 2.0 mmol, 1.0 eq.), 1,5-dibromopentane (0.92 g, 4.0 mmol, 2.0 eq.), potassium carbonate (0.55 g, 2.0 mmol, 2.0 eq.), and DMF (8 mL) were added to a reaction flask and stirred at 85° C. for 7 hours. After filtration, the filter cake was washed with methanol, and the filtrate was concentrated to obtain a crude product. The crude product was purified using a C18 reverse-phase column (eluent: methanol:0.5% formic acid aqueous solution = 80:20). The target component was collected and concentrated to give a pale yellow solid 23A (540 mg, purity 60%, yield: 58.3%).

[0111] Step 2: The same synthetic route as in Example 2 was employed, except that 3a in Example 2 was replaced with 23A, to give the title compound 23 (pseudo-white solid).

[0112] LCMS: 462 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ7.92(s,1H),7.33(s,1H),7.31-7.28(m,2H),7.19(d,1H),7.16(dd,1H),7.05(dd,1H),3.98(t,2H),3.3 3-3.31(m,2H),2.99(br,4H),2.80(t,2H),2.63(br,4H),2.44(t,2H),1.77-1.67(m,2H),1.55-1.51(m,2H),1.46-1.42(m,2H). Example 20: Synthesis of 6-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)indolin-2-one (Compound 24) [ka]

[0113] A reaction flask was charged with 24a (100 mg, 0.37 mmol, 1.0 eq.) dissolved in acetonitrile (6 mL), and 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c) (130 mg, 0.45 mmol, 1.2 eq.), potassium carbonate (150 mg, 1.11 mmol, 3.0 eq.), and potassium iodide (10 mg, 0.0037 mmol, 0.1 eq.) were added, and the reaction mixture was reacted at 70 °C for 4 h. After LCMS monitoring showed that the reaction of the raw materials was essentially complete, the reaction mixture was filtered, spun dry, and purified by C18 reverse-phase column chromatography to give the title compound 24 (pseudo-white solid, 20 mg, 12% yield).

[0114] LCMS: 434 [M+H] + 1 H NMR(400MHz,CDCl3)δ7.79(s,1H),7.24-7.13(m,2H),7.14-7.06(m,1H),6.97(d,1H),6.53(d,1H) ,6.46(s,1H),3.98(t,2H),3.47(s,2H),3.15(s,4H),2.76(s,3H),2.61(d,2H),1.97-1.64(m,5H). Example 21: Synthesis of 6-(4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)butoxy)indolin-2-one (Compound 25) [ka]

[0115] To a reaction flask, 24a (100 mg, 0.37 mmol, 1.0 eq.) was added and dissolved in acetonitrile (6 mL). m-Trifluoromethylphenylpiperazine hydrochloride 6b (130 mg, 0.45 mmol, 1.2 eq.), potassium carbonate (150 mg, 1.11 mmol, 3.0 eq.), and potassium iodide (10 mg, 0.0037 mmol, 0.1 eq.) were added, and the reaction mixture was reacted at 70 °C for 4 h. After LCMS monitoring showed that the reaction of the raw materials was essentially complete, the reaction mixture was filtered, and the filtrate was spin-dried and purified by normal phase column chromatography (eluent DCM:MeOH = 10:1) to give the title compound 25 (pseudo-white solid, 80 mg, yield: 50%).

[0116] LCMS: 434 [M+H] + 1 H NMR(400MHz,CDCl3)δ8.10(s,1H),7.34(t,1H),7.12-7.06(m,4H),6.54(d,1H),6.47(s,1H),3.98 (t,2H),3.48(s,2H),3.28(s,4H),2.67(s,4H),2.52(s,2H),1.96-1.80(m,2H),1.79-1.65(m,2H). Example 22: Synthesis of 6-((5-(4-(2,3-dichlorophenyl)piperazin-1-yl)pentyl)oxy)-2H-benzo[b][1,4]oxazin-3(4H)-one (Compound 27) [ka]

[0117] Step 1: A reaction flask was charged with 27a (0.33 g, 2.0 mmol, 1.0 eq.), 1,4-dibromobutane (0.69 g, 3.0 mmol, 1.5 eq.), potassium carbonate (0.55 g, 2.0 mmol, 2.0 eq.), DMF (10 mL), and HO (2 mL), and the mixture was stirred at 40° C. for 5 h. The reaction mixture was filtered, and the filter cake was washed with DMSO. The filtrate was concentrated to give a crude product, which was purified using a C18 reverse-phase column (eluent: methanol:0.5% formic acid aqueous solution = 80:20). The target component was collected and concentrated to give 27A (120 mg, yield: 19%) as a white solid.

[0118] Step 2: The title compound 27 (white solid) was obtained by employing the same synthetic route as in Example 2, except that 3a in Example 2 was replaced with 27A.

[0119] LCMS: 464 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ10.62(s,1H),7.31(d,2H),7.16(t,1H),6.84(d,1H),6.48-6.46(m,2H),4.47(s,2H),3 .87(t,2H),3.07(br,4H),2.85(br,4H),2.67(br,2H),1.72-1.67(m,2H),1.59-1.57(m,2H),1.45-1.40(m,2H). Example 23: Synthesis of 6-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propoxy)benzo[d]thiazole (Compound 28) [ka]

[0120] Step 1: A reaction flask was charged with 28a (200 mg, 1.32 mmol, 1.0 eq.) and N,N-dimethylformamide (4 mL) in water (0.4 mL), followed by potassium carbonate (365 mg, 2.64 mmol, 2.0 eq.) and 1,3-dibromopropane (800 mg, 3.96 mmol, 3.0 eq.). The reaction mixture was reacted at 45 °C for 3 h. After LCMS monitoring showed that the reaction of the raw materials was essentially complete, water (10 mL) was added, and the mixture was extracted with ethyl acetate, dried, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give 28A (250 mg, 80% yield).

[0121] Step 2: A reaction flask was charged with 28A (350 mg, 1.32 mmol, 1.0 eq.) and N,N-dimethylformamide (10 mL), followed by potassium carbonate (710 mg, 5.28 mmol, 4.0 eq.), potassium iodide (200 mg, 1.32 mmol, 1.0 eq.), and 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c) (420 mg, 1.59 mmol, 1.2 eq.). The reaction mixture was reacted at 85 °C for 4 h. After LCMS monitoring showed substantial completion of the reaction of the starting material, the mixture was filtered, and the mother liquor was concentrated and spin-dried to give the crude product. The crude product was purified by C18 reverse-phase preparative chromatography (eluent: methanol:0.1% formic acid in water = 70:30) to give the title compound 28 (150 mg, yield: 40%).

[0122] LCMS: 422 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ9.17(s,1H),7.95(d,1H),7.72(d,1H),7.29-7.28(m,2H),7 .13-7.11(m,2H),4.10(t,2H),2.99(br,4H),2.62-2.49(m,6H),1.97-1.94(m,2H). Example 24: Synthesis of 6-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)benzo[d]thiazole (Compound 29) [ka]

[0123] The title compound 29 was obtained by the same synthetic route as in Example 23, except that 1,3-dibromopropane in Step 1 of Example 23 was replaced with 1,4-dibromobutane and the amount of potassium iodide in Step 2 was changed from 1.0 eq to 0.1 eq.

[0124] LCMS: 436 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 7.94 (d, 1H), 7.71 (d, 1H), 7.29-7.28 (m, 2H), 7.14-7.10 (m, 2H), 4.07 (t, 2H), 2.98 (br, 4H), 2.61 (br, 4H), 1.82-1.75 (m, 2H), 1.67-1.62 (m, 2H). Note: Two hydrogen signal peaks were obscured by the solvent signal peaks. Example 25: Synthesis of 4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-4-oxo-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)but-2-enamide (Compound 30) [ka]

[0125] Step 1: 30a (500 mg, 2.46 mmol, 1.0 eq) was added to toluene (5 mL), and 30b (242 mg, 2.46 mmol, 1.0 eq) was added. The mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered, and the filter cake was dried to give a yellow solid 30A (560 mg, yield: 75.5%).

[0126] Step 2: The same synthetic route as in Example 18 was employed, except that 21a in Example 18 was replaced with 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c) and 21b was replaced with 30A, to give the title compound 30 (white solid).

[0127] LCMS: 514 [M+H] + H NMR(400MHz,DMSO-d6)δ10.1(s,1H),7.47-7.40(m,2H),7.30-7.22(m,3H),7.10-7.08(m,1H),6.52(d,1H) ),6.23(d,1H),3.69-3.62(m,2H),3.51-3.44(m,2H),2.99-2.94(m,4H),1.66-1.55(m,4H),1.19(s,12H). Example 26: Synthesis of 4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-4-oxo-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)butanamide (Compound 31) [ka]

[0128] Step 1: 30a (500 mg, 2.46 mmol, 1.0 eq.) and triethylamine (636 mg, 4.92 mmol, 2.0 eq.) were added to DCM (10 mL), and 31a (271 mg, 2.71 mmol, 1.1 eq.) was added. The mixture was stirred at 25 °C for 16 h, and the reaction mixture was spun dry to give a yellow solid 31A (740 mg, 99.1% yield).

[0129] Step 2: The same synthetic route as in Example 18 was employed, except that 21a in Example 18 was replaced with 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c) and 21b was replaced with 31A, to give the title compound 31 (white solid).

[0130] LCMS: 518 [M+H] + H NMR(400MHz,DMSO-d6)δ9.81(s,1H),7.56-7.54(m,1H),7.39-7.33(m,3H),7.25-7.15(m,2H),3.68-3 .64(m,4H),3.03-2.96(m,4H),2.72-2.68(m,2H),2.60-2.57(m,2H),1.68-1.62(m,4H),1.24(s,12H). Example 27: Synthesis of 1-(4-(2,3-dichlorophenyl)piperazin-1-yl)-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)butan-1-one (Compound 32) [ka]

[0131] Step 1: 30a (1 g, 4.92 mmol, 1.0 eq.) and sodium carbonate (1.56 g, 14.75 mmol, 3.0 eq.) were added to acetonitrile (20 mL), and 32a (1.25 g, 6.39 mmol, 1.3 eq.) was added and stirred at 85 °C for 16 h. The reaction mixture was spun dry to give the crude product, which was purified by normal phase column chromatography (eluent: (petroleum ether:ethyl acetate=9:1)) to obtain the desired product as a yellow oil 32A (350 mg, yield: 22.4%).

[0132] Step 2: 32A (350 mg, 1.10 mmol, 1.0 eq) was dissolved in THF / MeOH / HO (6 mL / 2 mL / 2 mL). LiOH (66 mg, 2.76 mmol, 2.5 eq) was added and stirred at 25 °C for 2 h. The reaction mixture was diluted with water and then adjusted to pH 5-6 with 1 M aqueous hydrochloric acid. Extraction with ethyl acetate was performed. The organic phase was dried, and the reaction mixture was filtered and spin-dried to give a yellow solid 32B (300 mg, 94.0% yield).

[0133] Step 3: 32B (300 mg, 1.04 mmol, 1.0 eq), 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c) (416 mg, 1.55 mmol, 1.5 eq), and DIPEA (402 mg, 3.11 mmol, 3.0 eq) were added to DMF (5 mL), and HATU (590 mg, 1.55 mmol, 1.5 eq) was added. The mixture was stirred at 25 °C for 16 h. The reaction mixture was purified by C-18 reverse-phase column chromatography (eluent: methanol:0.1% formic acid aqueous solution = 85:15). The target fraction was collected and lyophilized to give the title compound 32 (white solid, 94 mg, yield: 18.0%).

[0134] LCMS: 502 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ7.31-7.27(m,2H),7.10-7.09(m,1H),6.98-6.96(m,1H),6.45(s,1H),6.36-6.34(m,1H),5.28-5.22(m,1H),3.6 0-3.57(m,4H),3.00-2.97(m,2H),2.95-2.84(m,4H),2.45-2.41(m,2H),1.78-1.72(m,2H),1.57-1.52(m,4H),1.17(s,6H),1.13(s,6H). Example 28: Synthesis of 4-(4-(2,3-dichlorophenyl)piperazine-1-carbonyl)-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzamide (Compound 33) [ka]

[0135] Step 1: Compound 33A (yellow solid) was obtained by employing the same synthetic route as in Example 18, except that 21a in Example 18 was replaced with 30a and 21b was replaced with 33a.

[0136] Step 2: Compound 33B was obtained by employing the same synthetic route as in Step 2 of Example 27, except that 32A in Step 2 of Example 27 was replaced with 33A.

[0137] Step 3: The same synthetic route as in Example 18 was employed, except that 21a in Example 18 was replaced with 1c and 21b with 33B, to give the title compound 33 (white solid).

[0138] LCMS: 564 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ10.16(s,1H),8.02-7.80(m,2H),7.70-7.65(m,1H),7.59-7.57(m,3H),7.33-7.26(m,3H),7.1 8-7.15(m,1H),3.90-3.72(m,2H),3.55-3.41(m,2H),3.06-2.97(m,4H),1.68-1.58(m,4H),1.23(s,6H),1.22(s,6H). Example 29: Synthesis of 7-(2-(4-(benzo[d]thiazol-2-yl)piperazin-1-yl)ethoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 34) [ka]

[0139] The title compound 34 was obtained by employing the same synthetic route as in Step 2 of Example 23, except that 28A was replaced with 34b and 1c was replaced with 34a.

[0140] LCMS: 408 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ9.99(s,1H),7.75(d,1H),7.44(d,1H),7.26(t,1H),7.06-7.03(m,2H),6.50(d ,1H),6.44(s,1H),4.03(t,2H),3.56-3.53(m,4H),2.81-2.73(m,4H),2.62-2.58(m,4H),2.40(t,2H). Example 30: Synthesis of 7-(2-(4-(benzothiazol-2-yl)piperazin-1-yl)ethoxy)quinolin-2(1H)-one (Compound 35) [ka]

[0141] The title compound 35 was obtained by employing the same synthetic route as in Step 2 of Example 23, except that 28A was replaced with 35a and 1c was replaced with 34a.

[0142] LCMS: 407 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ11.59(s,1H),7.81-7.74(m,2H),7.55(d,1H),7.44(d,1H),7.26(t,1H),7.06( t,1H),6.82-6.80(m,2H),6.30(d,1H),4.15(t,2H),3.57-3.55(m,4H),2.80(d,2H),2.65-2.63(m,4H). Example 31: Synthesis of 7-(4-(4-(benzo[d]thiazol-2-yl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 36) [ka]

[0143] A reaction flask was charged with 34a (100 mg, 0.39 mmol, 1.0 eq.), acetonitrile (4 mL), potassium carbonate (165.6 mg, 1.2 mmol, 3.0 eq.), potassium iodide (10 mg, 0.039 mmol, 0.1 eq.), and 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone (6a) (175 mg, 0.59 mmol, 1.5 eq.). The reaction mixture was purged with nitrogen gas three times and reacted at 85 °C for 4 h. After monitoring the completion of the reaction by TLC, the reaction mixture was filtered and spun dry. The resulting crude product was purified using a C18 reverse-phase column. The target component was collected and concentrated to give the title compound 36 (20 mg, 10% yield) as a white solid.

[0144] LCMS: 437 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 7.75 (d, 1H), 7.44 (d, 1H), 7.26 (t, 1H), 7.06-7.02 (m, 2H), 6.47 (d, 1H), 6.42 (s, 1H), 3.91 (t, 2H), 3.54 (br, 4H), 2.76 (t, 2H), 2.46-2.34 (m, 4H), 1.79-1.65 (m, 2H), 1.64-1.52 (m, 2H). Note: Four hydrogen signal peaks were masked by the solvent signal peaks. Example 32: Synthesis of 7-(4-(4-(benzo[d]thiazol-2-yl)piperazin-1-yl)butoxy)quinolin-2(1H)-one (Compound 37) [ka]

[0145] The title compound 37 (white solid) was obtained by employing the same synthetic route as in Example 31, except that 6a in Example 31 was replaced with 10a.

[0146] LCMS: 435 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 7.80 (d, 1H), 7.76 (d, 1H), 7.54 (d, 1H), 7.44 (d, 1H), 7.26 (t, 1H), 7.06 (t, 1H), 6.79-6.78 (m, 2H), 6.28 (d, 1H), 4.03 (t, 2H), 3.55 (t, 4H), 2.39 (t, 2H), 1.79-1.74 (m, 2H), 1.65-1.58 (m, 2H). Note: Four hydrogen signal peaks were masked by the solvent signal peaks. Example 33: Synthesis of 7-(3-(4-(benzo[d]thiazol-2-yl)piperazin-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 38) [ka]

[0147] A reaction flask was charged with 38a (0.14 g, 0.5 mmol, 1.0 eq.), 34a (0.15 g, 0.6 mmol, 1.2 eq.), potassium carbonate (0.13 g, 1.0 mmol, 2.0 eq.), and acetonitrile (15 mL), and the mixture was stirred at 85° C. for 6 h. The mixture was separated and purified on a silica gel column (eluent: dichloromethane:methanol=85:15), and the target component was collected and concentrated to give the title compound 38 (white solid) (50 mg, yield: 23.7%).

[0148] LCMS: 423 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ9.96(s,1H),7.75(d,1H),7.45(d,1H),7.27(t,1H),7.08-7.03(m,2H),6.48(d,1H) ),6.44(s,1H),3.95(t,2H),3.55(br,4H),2.76(t,2H),2.53-2.45(m,6H),2.41(t,2H),1.93-1.84(m,2H). Example 34: Synthesis of 7-(3-(4-(benzo[d]thiazol-2-yl)piperazin-1-yl)propoxy)quinolin-2(1H)-one (Compound 39) [ka]

[0149] The title compound 39 (white solid) was obtained by employing the same synthetic route as in Example 33, except that 38a in Example 33 was replaced with 39a.

[0150] LCMS: 421 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ11.83(s,1H),7.88-7.82(m,2H),7.58(t,2H),7.36(t,1H),7.17(t,1H),6.89-6.80(m,2H), 6.33(d,1H),4.24-4.20(m,2H),4.14(t,2H),3.79(t,2H),3.68-3.65(m,2H),3.38-3.16(m,4H),2.36-2.26(m,2H). Example 35: Synthesis of 7-(3-(4-(2-methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepin-4-yl)piperazin-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 40) [ka]

[0151] The same synthetic route as in Example 20 was employed, except that 24a in Example 20 was replaced with 38a and 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c) was replaced with 40a, to obtain the title compound 40 (pseudo-white solid).

[0152] LCMS: 502 [M+H] + 1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),7.62(s,1H),7.03(d,1H),6.92-6.74(m,3H),6.68(d,1H),6.47(d,1H),6.4 5(d,1H),6.35(s,1H),3.94(t,2H),3.41-3.16(m,4H),2.77(t,2H),2.48-2.32(m,8H),2.26(s,3H),1.89(s,2H). Example 36: Synthesis of 7-(4-(4-(2-methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepin-4-yl)piperazin-1-yl)-4-oxobutoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 41) [ka]

[0153] A reaction flask was charged with 41a (200 mg, 0.80 mmol, 1.0 eq.) and N,N-dimethylformamide (6 mL), followed by HATU (380 mg, 0.96 mmol, 1.2 eq.). The reaction was stirred at room temperature for 30 min. 40a (240 mg, 0.80 mmol, 1.0 eq.) and N,N-diisopropylethylamine (309 mg, 2.4 mmol, 3.0 eq.) were added, and the reaction was allowed to react at room temperature for 4 h. After monitoring the completion of the reaction by LCMS, the crude product was filtered, spun dry, and purified using a C18 reverse-phase column, which further purified using a normal-phase column to give the title compound 41 (100 mg, 24% yield) as a pseudo-white solid.

[0154] LCMS: 530 [M+H] + 1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),7.63(s,1H),7.03(d,1H),6.89-6.73(m,3H),6.68(d,1H),6.48(d,1H),6.42(s,1H),6.38(s,1H), 3.92(t,2H),3.52(s,4H),3.32(s,2H),3.29-3.20(m,2H),2.76(t,2H),2.49-2.44(m,2H),2.39(t,2H),2.27(s,3H),2.00-1.84(m,2H). Example 37: Synthesis of 7-(4-(4-(2-methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepin-4-yl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 42) [ka]

[0155] The same synthetic route as in Example 7 was employed, except that 9a in Example 7 was replaced with 6a and 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c) was replaced with 40a, to give the title compound 42 (pseudo-white solid).

[0156] LCMS: 516 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ9.96(s,1H),7.58(s,1H),7.04(d,1H),6.88-6.72(m,3H),6.68(d,1H),6.48(d,1H),6.42(s,1H),6.3 2(s,1H),3.90(t,2H),3.31-3.27(m,4H),2.76(t,2H),2.41-2.33(m,8H),2.26(s,3H),1.76-1.66(m,2H),1.62-1.52(m,2H). Example 38: Synthesis of 7-(2-(4-(1-propionylindolin-5-yl)piperazin-1-yl)ethoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 43) [ka]

[0157] A reaction flask was charged with 43a (506 mg, 2.0 mmol, 1.0 eq.), dioxane (10 mL), 43b (684 mg, 2.2 mmol, 1.1 eq.), and sodium tert-butoxide (576 mg, 6.0 mmol, 3.0 eq.), sequentially. The reaction mixture was purged with nitrogen gas three times, and then tris(dibenzylideneacetone)dipalladium (115 mg, 0.2 mmol, 0.1 eq.) was added. The mixture was then reacted at 100 °C under nitrogen gas protection for 12 h. After LCMS monitoring showed the reaction was complete, the mixture was filtered, spun dry, and purified using a C18 reverse-phase column. The mixture was then further purified using a normal-phase column (DCM:MeOH = 10:1) to give the title compound 43 (179 mg, 20% yield).

[0158] LCMS: 449 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ8.02(d,1H),7.51(s,1H),7.04(d,1H),6.84(s,1H),6.78(d,1H),6.55(d,1H),6.44(s,1H), 4.14(t,2H),4.05(t,2H),3.23-3.11(m,6H),2.93(t,2H),2.88-2.78(m,6H),2.54(t,2H),2.47(q,2H),1.18(t,3H). Example 39: Synthesis of 6-(4-(4-(benzo[d]thiazol-2-yl)piperazin-1-yl)butoxy)indolin-2-one (Compound 44) [ka]

[0159] 24a (100 mg, 0.37 mmol, 1.0 eq.) was added to a reaction flask and dissolved in acetonitrile (6 mL). 34a (130 mg, 0.45 mmol, 1.2 eq.), potassium carbonate (150 mg, 1.11 mmol, 3.0 eq.), and potassium iodide (10 mg, 0.0037 mmol, 0.1 eq.) were added, and the reaction mixture was reacted at 60° C. for 4 h. After monitoring the completion of the reaction by LCMS, the reaction mixture was filtered, and the filtrate was spin-dried and purified using a normal phase column (eluent: DCM:MeOH=10:1) to give the title compound 44 (pseudo-white solid, 80 mg, yield: 51%).

[0160] LCMS: 423 [M+H] + 1 H NMR(400MHz,CDCl3)δ7.79(s,1H),7.61(d,1H),7.56(d,1H),7.30(t,1H),7.10-7.08(m,2H),6.52(d,J=8.2Hz ,1H),6.44(s,1H),3.97(t,2H),3.72(s,3H),3.46(s,2H),2.80-2.45(m,5H),1.91-1.69(m,4H),1.61(s,2H). Example 40: Synthesis of 2-((2-(4-(3,5-bis(trifluoromethyl)phenyl)piperazin-1-yl)-2-oxoethyl)thio)-N-(m-methylphenyl)acetamide (Compound 45) [ka]

[0161] Step 1: A reaction flask was charged with 2,2'-thiodiacetic acid (45a) (1.00 g, 6.667 mmol, 1.0 eq.), DCM (10 mL), and DMF (49 mg, 0.67 mmol, 0.1 eq.), and oxalyl chloride (847 mg, 6.67 mmol, 1.0 eq.) was added under ice bath. After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. The mixture was then directly concentrated under reduced pressure to give 1.1 g of crude 45a.

[0162] Step 2: A reaction flask was charged with 45A (1.10 g, 6.55 mmol, 1.0 eq.), DCM (5 mL), TEA (2.54 g, 19.65 mmol, 3 eq.), and m-benzylamine (45b) (701 mg, 6.55 mmol, 1 eq.). The mixture was stirred at room temperature for 2 h. The reaction mixture was purified by column chromatography (eluent: dichloromethane:methanol = 9:1). The target product was collected and concentrated under reduced pressure to give 45B (1.0 g, 63% yield) as a white solid.

[0163] Step 3: A reaction flask was charged with 45B (100 mg, 0.42 mmol, 1.0 eq.), DCM (5 mL), and HATU (191 mg, 0.50 mmol, 1.2 eq.). After stirring at room temperature for 30 min, DIPEA (162 mg, 1.25 mmol, 3 eq.) and 1-(3,5-bis(trifluoromethyl)phenyl)piperazine (45c) (126 mg, 0.42 mmol, 1.0 eq.) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the mixture was purified by column chromatography (eluent: methanol:0.1% formic acid aqueous solution = 65:35). The target component was collected and concentrated under reduced pressure to give the title compound 45 (114 mg, yield: 52%) as a white solid.

[0164] LCMS: 520 [M+H] + 1 H NMR(400MHz,DMSO-d)δ9.97(s,1H),7.43(s,2H),7.38(s,1H),7.33-7.32(m,2H),7.15(t ,1H),6.85(d,1H),3.67-3.57(m,6H),3.44-3.38(m,4H),3.37-3.33(m,2H),2.24(s,3H). Example 41: Synthesis of 2-((2-(4-(2,3-dichlorophenyl)piperazin-1-yl)-2-oxoethyl)thio)-N-(m-methylphenyl)acetamide (Compound 46) [ka]

[0165] The same synthetic route as in Step 3 of Example 40 was employed, except that 1-(3,5-bis(trifluoromethyl)phenyl)piperazine (45c) in Step 3 of Example 40 was replaced with 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c) to give the title compound 46 (white solid).

[0166] LCMS: 452 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ10.03(s,1H),7.42(s,1H),7.36-7.28(m,3H),7.17(t,1H),7.10(d d,1H),6.86(d,1H),3.65-3.62(m,6H),3.40(s,2H),2.99(t,2H),2.92(t,2H),2.26(s,3H). Example 42: Synthesis of N-(3-amino-4-methoxyphenyl)-2-(4-(2,3-dichlorophenyl)piperazin-1-yl)acetamide (Compound 47) [ka]

[0167] Step 1: A 250 mL three-neck flask was charged with 47a (1.5 g, 0.0052 mol, 1 eq.), 4-methoxy-3-nitroaniline (47b) (0.7 g, 0.0052 mol, 1 eq.), HATU (3.8 g, 0.01 mol, 2 eq.), and dichloromethane (30 mL) and stirred at room temperature for 4 h. After the reaction was completed, the product was separated by silica gel column chromatography (dichloromethane:methanol = 10:1) and concentrated under reduced pressure to give 47A (1.6 g, yield: 70.2%) as a white solid.

[0168] Step 2: A 250 mL single-neck flask was charged with 47A (1.6 g, 0.0037 mol, 1 eq.), Pd / C (0.5 g), and methanol (50 mL). The mixture was purged with a hydrogen gas balloon three times and stirred at room temperature for 16 h. The reaction mixture was then purified by silica gel column chromatography (dichloromethane:methanol = 10:1) and concentrated under reduced pressure to give the crude product, which was then purified by preparative chromatography and lyophilized to give the title compound 47 (0.15 g, 9.9% yield) as a white solid.

[0169] LCMS:409[M+1] + 1 H NMR (400MHz, DMSO): δ9.34(s,1H),7.31(m,2H),7.17(m,1H),6.99(d,1H),6.74(m,2H),3.71(s,3H),3.14(s,2H),3.04(m,4H),2.69(m,4H). Example 43: Synthesis of 2-(4-(2,3-dichlorophenyl)piperazin-1-yl)-N-(3-(dimethylamino)-4-methoxyphenyl)acetamide (Compound 48) [ka]

[0170] A reaction flask was charged with 47 (80 mg, 0.20 mmol, 1.0 eq.) and methanol (6 mL), followed by the addition of paraformaldehyde (6.6 mg, 0.22 mmol, 1.1 eq.). The reaction was stirred at room temperature under nitrogen gas for 4 hours, after which sodium cyanoborohydride (63 mg, 1.0 mmol, 5.0 eq.) was added and the reaction was stirred at room temperature overnight. The reaction was then completed, filtered, spun dry, and separated by C18 reverse phase column chromatography to give the title compound 48 (white solid) (42 mg, yield: 50%).

[0171] LCMS: 437 [M+H] + 1H NMR(400MHz,DMSO-d6)δ9.54(s,1H),7.43-7.26(m,2H),7.27-7.13(m,3H),6.88(d,1H) ),3.78(s,3H),3.24-3.14(m,2H),3.13-3.04(m,4H),2.78-2.73(m,4H),2.71(s,6H). Example 44: Synthesis of N-(3-amino-4-methoxyphenyl)-3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propionamide (Compound 49) [ka]

[0172] Step 1: A reaction flask was charged with 49a (135 mg, 0.47 mmol, 1.0 eq.) and N,N-dimethylformamide (6 mL), and then HATU (214 mg, 0.56 mmol, 1.2 eq.) was added. The reaction was stirred at room temperature under nitrogen gas for 1 h. 4-Methoxy-3-nitroaniline (47b) (94 mg, 0.56 mmol, 1.0 eq.) and N,N-diisopropylethylamine (182 mg, 1.41 mmol, 3.0 eq.) were then added. The reaction was stirred at room temperature under nitrogen gas for 6 h. After that, the reaction was complete. The reaction solution was directly separated by C18 column chromatography to give white solid 49A (103 mg, yield: 50%).

[0173] Step 2: A reaction flask was charged with 49A (103 mg, 0.235 mmol, 1.0 eq.) and acetic acid (6 mL), and then iron powder (658 mg, 1.17 mmol, 5.0 eq.) was added. The reaction was stirred at 60°C under nitrogen gas for 4 hours, after which the reaction was completed. The reaction solution was filtered, spun dry, and separated by column chromatography (dichloromethane:methanol=10:1) to give the title compound 49 (gray solid) (80 mg, yield: 85%).

[0174] LCMS: 423 [M+H] + 1H NMR(400MHz,DMSO-d6)δ9.64(s,1H),7.36-7.23(m,2H),7.20-7.09(m,1H),6.94(d,1H),6.77-6.61 (m,2H),4.70(s,1H),3.70(s,3H),3.07-2.93(m,4H),2.67(t,2H),2.63-2.54(m,4H),2.43(t,2H). Example 45: Synthesis of 3-(4-(2,3-dichlorophenyl)piperazin-1-yl)-N-(4-methoxy-3-(methylamino)phenyl)propionamide (Compound 50) [ka]

[0175] The same synthetic route as in Example 43 was used, except that compound 47 in Example 43 was replaced with compound 49. During workup, the reaction solution was filtered and spin-dried, separated using a C18 reverse-phase through-column, and purified by normal-phase column chromatography to obtain the title compound 50 (white solid).

[0176] LCMS: 437 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ9.72(s,1H),7.33-7.23(m,2H),7.13(s,1H),6.79(d,1H),6.72(s,1H),6.66(d ,1H),5.00(s,1H),3.70(s,3H),3.06-2.88(m,4H),2.69-2.66(s,3H),2.62-2.52(m,4H),2.44(t,2H). Example 46:N 4 Synthesis of -(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)pyrimidine-2,4-diamine (Compound 51) [ka]

[0177] A 100 mL single-neck flask was charged with 51a (0.9 g, 0.0029 mol, 1 eq.), 4-bromo-2-aminopyrimidine (51b) (0.56 g, 0.0032 mol, 1.1 eq.), cesium carbonate (8.5 g, 0.0261 mol, 9 eq.), Pd2(dba)3 (0.53 g, 0.00058 mol, 0.2 eq.), Xphos (0.41 g, 0.00087 mol, 0.3 eq.), and 1,4-dioxane (30 mL). The atmosphere was flushed with nitrogen three times. The mixture was heated to 100 °C under nitrogen gas protection and reacted for 3 h. After completion of the reaction, the mixture was filtered, and the solvent was evaporated to dryness. The crude product was purified with methanol and filtered to give a yellow solid. The yellow solid was initially purified by column chromatography (eluent: DCM:MeOH = 100:1 to 10:1), and the initially purified product was further purified by column chromatography (eluent: methanol: 0.5% aqueous formic acid = 80:20) to give the title compound 51 (yellow oil) (0.01 g, yield: 9.4%).

[0178] LCMS:367[M+1] + 1 H NMR(400MHz,CD3OD):δ7.55-7.54(d,1H),7.25-7.23(m,2H),7.10-7.09(d, 1H),6.10-6.08(d,1H),3.70(s,2H),3.12-3.09(m,4H),2.88-2.69(m,6H). Example 47: Synthesis of 4-(((2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)amino)methyl)benzene-1,2-diol (Compound 52) [ka]

[0179] Step 1: Compound 52A (pseudo-white solid) was obtained by employing the same synthetic route as in Step 2 of Example 1, except that 1A in Step 2 of Example 1 was replaced with 52a.

[0180] Step 2: 52A (540 mg, 1.53 mmol, 1.0 eq.) was dissolved in dichloromethane (5 mL), and triethylamine (1.1 mL, 7.64 mmol, 5.0 eq.) and 3,4-dihydroxybenzylamine hydrochloride (52b) (673 mg, 3.06 mmol, 2.0 eq.) were added. The mixture was allowed to react overnight at room temperature. The crude product was concentrated under reduced pressure and purified by reverse-phase column chromatography (eluent: methanol:0.1% formic acid in water = 80:20). The target component was collected, concentrated, and spin-dried to give the title compound 52 (92 mg, 15% yield) as a yellow oil.

[0181] LCMS: 396 [M+H] + 1 H NMR(400MHz,CD3OD)δ7.26-7.17(m,2H),7.09(dd,1H),6.99(s,1H),6.88-6.8 1(m,2H),4.12(s,2H),3.17(t,2H),3.05(br,4H),2.76(t,2H),2.68(br,4H). Example 48: Synthesis of N-(4-(4-(3,5-bis(trifluoromethyl)phenyl)piperazin-1-yl)butyl)-4-chlorobenzamide (Compound 53) [ka]

[0182] Compound 53a (145 mg, 0.50 mmol, 1.0 eq.) was added to a reaction flask and dissolved in acetonitrile (10 mL). Potassium carbonate (207 mg, 1.50 mmol, 3.0 eq.), 1-(3,5-bistrifluoromethylphenyl)piperazine hydrochloride 45c (180 mg, 0.6 mmol, 1.2 eq.), and potassium iodide (10 mg, 0.05 mmol, 0.1 eq.) were added to the reaction flask, and the reaction mixture was reacted at 85° C. for 8 h. After monitoring the completion of the reaction by LCMS, the reaction mixture was filtered, spin-dried, and purified by C18 reverse-phase column separation to give the title compound 53 (pseudo-white solid, 127 mg, 50% yield).

[0183] LCMS: 508 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ8.53(t,1H),7.85(d,2H),7.52(d,2H),7.43(s,2H),7.28(s,1H),3.34-3.23(m,10H),2.35(t,2H),1.61-1.44(m,4H). Example 49: Synthesis of (E)-1-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-(3,4,5-trihydroxyphenyl)propan-2-en-1-one (Compound 55) [ka]

[0184] A reaction flask was charged with 57 (0.4 g, 0.88 mmol, 1.0 eq.) and dichloromethane (30 mL). Boron tribromide (17% dichloromethane solution, 4.0 mL, 3.0 mmol, 3.5 eq.) was added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred overnight at room temperature. The reaction was quenched by the addition of saturated sodium carbonate solution, and 50 mL of dichloromethane was added for extraction. The solid precipitated. The solid was dissolved in methanol and purified on a C18 reverse-phase column (eluent: methanol:0.5% formic acid aqueous solution = 65:35). The target component was collected and concentrated to give the title compound 55 (117 mg, 32.5% yield) as a white solid.

[0185] LCMS: 409 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ7.33-7.31(m,2H),7.28(d,1H),7.17-7.14(m,1H),6.89(d,1H),6.62(s,2H),3.81-3.72(m,4H),2.98(br,4H). Example 50: Synthesis of (E)-1-(4-(2,3-dichlorophenyl)piperazin-1-yl)-4-(3,4-dimethoxyphenyl)but-3-en-1-one (Compound 59) [ka]

[0186] The same synthetic route as in Step 3 of Example 40 was employed, except that 1-(3,5-bis(trifluoromethyl)phenyl)piperazine (45c) in Step 3 of Example 40 was replaced with 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c) and 45B was replaced with 59a, to give the title compound 59 (pseudo-white solid).

[0187] LCMS: 435 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ7.32-7.29(m,2H),7.14(dd,1H),7.02(s,1H),6.88(s,2H),6.39(d,1H) ),6.26-6.16(m,1H),3.76(s,3H),3.73(s,3H),3.64(br,4H),3.33(d,2H),2.98-2.94(m,4H). Example 51: Synthesis of (E)-1-(2,3-dichlorophenyl)-4-(3-(3,4-dimethoxyphenyl)allyl)piperazine (Compound 60) [ka]

[0188] A reaction flask was charged with 58 (1.1 g, 2.6 mmol, 1.0 eq.) and THF (30 mL). LiAlH (2.5 mol / L THF solution, 1.5 mL, 3.9 mmol, 1.5 eq.) was added dropwise under ice bath. After the addition was completed, the mixture was stirred at room temperature for 0.5 h. Saturated sodium sulfate solution was added dropwise, filtered, and the filter cake was washed with DMSO. The mother liquor was concentrated to give the crude product. The crude product was separated and purified on a C18 reverse-phase column (eluent: methanol:0.5% formic acid aqueous solution = 80:20). The target component was collected and concentrated to give the title compound 60 (0.54 g, 51% yield) as an oily liquid.

[0189] LCMS: 407 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ7.32-7.22(m,2H),7.14(dd,1H),7.08(s,1H),6.94-6.86(m,2H),6.48 (d,1H),6.25-6.16(m,1H),3.77(s,3H),3.73(s,3H),3.17(d,2H),3.00(br,4H),2.61(br,4H). Example 52: Synthesis of (E)-4-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propan-1-en-1-yl)benzene-1,2-diol (Compound 61) [ka]

[0190] The same synthetic route as in Example 51 was employed, except that 58 in Example 51 was replaced with 56, to give the title compound 61 (pseudo-white solid).

[0191] LCMS:379[M+1] + 1 H NMR (400MHz, DMSO): δ7.30(m,2H),7.14(m,1H),6.82(s,1H),6.68(m,2H),6.38(d,1H),5.99(m,1H),3.14(d,2H),2.99(s,4H),2.58(s,4H). Example 53: Synthesis of (E)-5-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propan-1-en-1-yl)-2-(2-hydroxypropoxy)phenol (Compound 62) [ka]

[0192] Step 1: Compound 62A (yellow oil) was obtained by employing the same synthetic route as in Step 1 of Example 1, except that 1a in Example 1 was replaced with 1-bromo-2-propanol and 1b was replaced with 61a.

[0193] Step 2: 62A (1.5 g, 5.06 mmol) was added to a mixed solvent of THF / HO (40 mL, 3:1), and sodium hydroxide (405 mg, 10.1 mmol) was added. The reaction was stirred at room temperature for 20 h, adjusted to pH 5-6 with 1 M aqueous HCl, extracted with ethyl acetate, and the organic phase was dried, filtered, and spun to give black solid 62B (700 mg, 58.0% yield).

[0194] Step 3: Compound 62C (brown solid) was obtained by employing the same synthetic route as in Example 18, except that 21b in Example 18 was replaced with 62B and 21a was replaced with 1c.

[0195] Step 4: 62C (420 mg, 0.93 mmol) was added to THF (5 mL) and LiAlH (1.1 mL, 2.5 M in THF) was slowly added dropwise at 0 °C. The reaction was stirred at 0 °C for 2 h, quenched with water, filtered, and the mother liquor was spun dry to give the crude product, which was purified by C-18 reverse-phase column (eluent: (HO (0.1% NHHCO):MeOH) = 20:80). The desired fraction was collected and lyophilized to give the title compound 62 (white solid, 76 mg, 16.9% yield).

[0196] LCMS: 437 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ8.69(s,1H),7.30-7.29(m,2H),7.15-7.13(m,1H),6.90(s,1H),6.84-6.78(m,2H),6.44-6.40(m,1H),6.11-6.05(m,1H) ),4.95(s,1H),3.99-3.91(m,1H),3.86-3.82(m,1H),3.70-3.64(m,1H) ,3.17(d,2H),3.05-2.94(m,4H),2.69-2.57(m,4H),1.14-1.11(m,3H). Example 54: Synthesis of 4-(2,3-dichlorophenyl)-N-(3,4-dihydroxyphenethyl)piperazine-1-carboxamide (Compound 63) [ka]

[0197] The title compound 63 (white solid) was obtained by employing the same synthetic route as in Example 49, except that 57 in Example 49 was replaced with 64.

[0198] LCMS: 410 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ8.72(s,1H),8.59(s,1H),7.31(d,2H),7.14(t,1H),6.65-6.59( m,2H),6.57(s,1H),6.42(d,1H),3.43(br,4H),3.15(q,2H),2.90(br,4H),2.52(t,2H). Example 55: Synthesis of 4-(2,3-dichlorophenyl)-N-(3,4-dimethoxyphenethyl)piperazine-1-carboxamide (Compound 64) [ka]

[0199] Triphosgene (89 mg, 0.30 mmol, 0.4 eq.) was dissolved in dichloromethane (2 mL), and a solution of 3,4-dimethoxyphenethylamine (64a) (163 mg, 0.90 mmol, 1.2 eq.) and triethylamine (0.3 mL, 2.24 mmol, 3.0 eq.) in dichloromethane (2 mL) was added dropwise and reacted at room temperature for 1 hour. 1-(2,3-Dichlorophenyl)piperazine hydrochloride (1c) (200 mg, 0.75 mmol, 1.0 eq.) was added and reacted at room temperature overnight. The crude product was concentrated under reduced pressure and purified on a 18C reverse-phase column (eluent: methanol:0.1% formic acid aqueous solution = 70:30). The target component was collected, concentrated, and spin-dried to give the title compound 64 (yellow solid) (80 mg, yield: 24%).

[0200] LCMS: 438 [M+H] + 1H NMR(400MHz,CD3OD)δ7.19-7.18(m,2H),6.98(t,1H),6.82-6.81(m,2H),6.74(d,1H), 3.79(s,3H),3.75(s,3H),3.50(br,4H),3.37(t,2H),2.94-2.87(m,4H),2.74(t,2H). Example 56: Synthesis of 4-(2,3-dichlorophenyl)-N-(2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)piperazine-1-carboxamide (Compound 65) [ka]

[0201] A reaction flask was charged with 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c) (0.5 g, 1.86 mmol, 1.0 eq.), pyridine (0.32 g, 4.1 mmol, 2.2 eq.), triphosgene (0.2 g, 0.69 mmol, 0.37 eq.), and dichloromethane (20 mL) and stirred at room temperature for 3 h. 65a (0.5 g, 2.04 mmol, 1.1 eq.) was dissolved in 10 mL of dichloromethane and DIPEA (1.4 g, 11.2 mmol, 6.0 eq.) was added dropwise in an ice bath. After the addition was complete, the mixture was stirred for 15 min. The above reaction mixture was added dropwise and, after the addition was complete, the mixture was stirred at room temperature overnight. The mixture was washed with 20 mL of water, extracted with 50 mL of dichloromethane, and separated. The organic phase was collected, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: dichloromethane:methanol = 85:15). The target component was collected, concentrated, and spin-dried to give the title compound 65 (white solid) (0.55 g, yield: 63.8%).

[0202] LCMS: 467 [M+H] + 1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),7.32-7.31(m,3H),7.16(t,1H),7.07(d,1H),6.96( t,1H),6.87(d,1H),3.77(d,2H),3.73(s,3H),3.71(s,3H),3.50(br,4H),2.95(br,4H). Example 57: Synthesis of 4-(2,3-dichlorophenyl)-N-(2-((3,4-dihydroxyphenyl)amino)-2-oxoethyl)piperazine-1-carboxamide (Compound 66) [ka]

[0203] The same synthetic route as in Example 49 was employed, except that 57 in Example 49 was replaced with 65, to give the title compound 66 (pseudo-white solid).

[0204] LCMS: 439 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ9.48(s,1H),8.90(s,1H),8.55(s,1H),7.31(d,2H),7.15(t,1H),7.11 (d,1H),6.93(t,1H),6.79(dd,1H),6.61(d,1H),3.73(d,2H),3.49(br,4H),2.95-2.93(m,4H). Example 58: Synthesis of 4-(2,3-dichlorophenyl)-N-(2-((3-hydroxyphenyl)amino)-2-oxoethyl)piperazine-1-carboxamide (Compound 67) [ka]

[0205] The same synthetic route as in Example 49 was employed, except that 57 in Example 49 was replaced with 68, to give the title compound 67 (pseudo-white solid).

[0206] LCMS: 423 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ9.74(s,1H),9.35(s,1H),7.31(d,2H),7.17-7.15(m,2H),7.05 (t,1H),7.00-6.94(m,2H),6.42(d,1H),3.77(d,2H),3.49(br,4H),3.00-2.89(m,4H). Example 59: Synthesis of 4-(2,3-dichlorophenyl)-N-(2-((3-methoxyphenyl)amino)-2-oxoethyl)piperazine-1-carboxamide (Compound 68) [ka]

[0207] The title compound 68 (white solid) was obtained by employing the same synthetic route as in Example 56, except that 65a in Example 56 was replaced with 68a.

[0208] LCMS: 437 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ9.86(s,1H),7.32-7.31(m,3H),7.22-7.15(m,2H),7.11(d, 1H),6.99(t,1H),6.62(dd,1H),3.79(d,2H),3.71(s,3H),3.50(t,4H),2.96(t,4H). Example 60: Synthesis of 1-(2,3-dichlorophenyl)-4-(3-(5-methoxypyridin-3-yl)propan-2-en-1-yl)piperazine (Compound 69) [ka]

[0209] Step 1: A reaction flask was charged with 1-(2,3-dichlorophenyl)piperazine hydrochloride 1C (1.08 g, 4.69 mmol, 1.0 eq.), bromopropyne (830 mg, 7.04 mmol, 1.5 eq.), potassium carbonate (2.9 g, 14.1 mmol, 3.0 eq.), and MeCN (20 mL). The reaction mixture was purged with nitrogen gas three times and allowed to react at room temperature for 12 hours. After monitoring the completion of the reaction by TLC and LCMS, the crude product was filtered, spin-dried, and further purified by normal phase column chromatography to give compound 69A (colorless liquid, 1 g, 70% yield).

[0210] Step 2: A reaction flask was charged with 69A (500 mg, 1.86 mmol, 1.0 eq.), anhydrous acetonitrile (10 mL), CsCO (606 mg, 1.86 mmol, 1.0 eq.), 3-bromo-5-methoxypyridine (69b) (490.2 mg, 2.79 mmol, 1.5 eq.), and triethylenediamine (208.7 mg, 1.86 mmol, 1.0 eq.). The reaction mixture was purged with nitrogen gas three times, and tris(dibenzylideneacetone)dipalladium (110 mg, 0.19 mmol, 0.1 eq.) was added. The mixture was stirred at 50 °C for 16 h. After monitoring the completion of the reaction by TLC, the crude was filtered, spun dry, and further purified by C18 reverse-phase preparative chromatography, and the target component was collected and concentrated to give the title compound 69 (white solid) (220 mg, yield: 30%).

[0211] LCMS: 376 [M+H] + 1 H NMR(400MHz,CDCl3)δ8.30(s,1H),8.25(d,1H),7.24(s,1H),7.20-7.09(m,2H),6.98(dd,1H),3.85(s,3H),3.62(s,2H),3.15(br,4H),2.86(br,4H). Example 61: Synthesis of 5-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propan-1-yn-1-yl)pyridin-3-ol (Compound 70) [ka]

[0212] The same synthetic route as in Step 2 of Example 60 was employed, except that 3-bromo-5-methoxypyridine (69b) in Step 2 of Example 60 was replaced with 3-hydroxy-5-bromopyridine (70a) to give the title compound 70 (gray solid).

[0213] LCMS: 362 [M+H] + 1 H NMR(400MHz,CD3OD)δ8.34(s,1H),8.07(d,2H),7.26-7.22(m,3H),7.11(dd,1H),3.65(s,2H),3.13(br,4H),2.87(br,4H). Example 62: Synthesis of 1-(2,3-dichlorophenyl)-4-(4-(5-methoxypyridin-3-yl)but-3-yn-1-yl)piperazine (Compound 71) [ka]

[0214] Step 1: The same synthetic route as in Example 7 was employed, except that 9a in Example 7 was replaced with 71a, to give a yellow solid 71A.

[0215] Step 2: 71A (200 mg, 0.71 mmol, 1.0 eq.) was dissolved in acetonitrile (3 mL) and 3-bromo-5-methoxypyridine (186 mg, 0.99 mmol, 1.4 eq.), cesium carbonate (690 mg, 2.12 mmol, 3.0 eq.), triethylenediamine (8 mg, 0.07 mmol, 0.1 eq.), and Pd(dba) (32 mg, 0.04 mmol, 0.05 eq.) were added. The mixture was heated to 50 °C under nitrogen gas protection and reacted overnight. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine (50 mL), dried, and concentrated. The residue was purified by silica gel column separation (eluent: petroleum ether:ethyl acetate = 2:1). The target components were collected and concentrated under reduced pressure to give the crude product. The crude was purified by preparative TLC (dichloromethane:methanol=20:1) to give the title compound 71 (yellow solid) (15 mg, yield: 5%).

[0216] LCMS: 390 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ8.23(d,1H),8.17(s,1H),7.38(s,1H),7.30-7.28(m,2H),7.14(dd,1H),3.81(s,3H),2.98(br,4H),2.66-2.63(m,8H). Example 63: Synthesis of 1-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-(5-methoxypyridin-3-yl)propan-2-yn-1-one (Compound 72) [ka]

[0217] Step 1: Propiolic acid 72a (100 mg, 1.43 mmol, 1.0 eq.) was dissolved in dichloromethane (3 mL). 1-(2,3-dichlorophenyl)piperazine hydrochloride 1c (458 mg, 1.71 mmol, 1.2 eq.), HATU (1.1 g, 2.86 mmol, 2.0 eq.), and DIPEA (0.7 mL, 4.28 mmol, 3.0 eq.) were added and the mixture was allowed to react overnight at room temperature. The crude product was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1). The target component was collected and concentrated to give white solid 72A (380 mg, yield: 94%).

[0218] Step 2: 3-Bromo-5-methoxypyridine (69b) (280 mg, 1.49 mmol, 1.0 eq.) was dissolved in N,N-dimethylformamide (5 mL). Cuprous iodide (57 mg, 0.30 mmol, 0.2 eq.), 72A (590 mg, 2.08 mmol, 1.4 eq.), cesium carbonate (485 mg, 1.49 mmol, 1.0 eq.), and PdCl(PPh) (52 mg, 0.07 mmol, 0.05 eq.) were added, and the mixture was heated to 70 °C under nitrogen gas protection and reacted overnight. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried, and concentrated. The residue was separated and purified by silica gel column (eluent: petroleum ether: ethyl acetate = 2:1). The target component was collected and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative TLC (petroleum ether: ethyl acetate = 1:1) to obtain the title compound 72 (brown oily liquid) (20 mg, yield: 3%).

[0219] LCMS: 390 [M+H] + 1 H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 8.33 (s, 1H), 7.35 (s, 1H), 7.21-7.14 (m, 2H), 6.93 (d, 1H), 4.00 (t, 2H), 3.11 (t, 2H), 3.06 (t, 2H). Note: Five hydrogen signal peaks were obscured by the solvent signal peak. Example 64: Synthesis of (E)-2-(4-(3-(3,4-dimethoxyphenyl)allyl)piperazin-1-yl)benzo[d]thiazole (Compound 73) [ka]

[0220] A reaction flask was charged with 74 (200 mg, 0.49 mmol, 1.0 eq.) and tetrahydrofuran (5 mL), and a solution of lithium aluminum hydride in tetrahydrofuran (0.3 mL, 0.74 mmol, 1.5 eq.) was added in an ice-water bath under nitrogen gas protection. The reaction was warmed to room temperature and stirred under nitrogen gas for 0.5 h. The reaction was then quenched with saturated aqueous sodium sulfate, filtered, concentrated, and further separated on a C18 column to obtain the crude product, which was further purified with methanol to give the title compound 73 (white solid) (26 mg, yield: 13%).

[0221] LCMS: 396 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ7.75(d,1H),7.44(d,1H),7.25(t,1H),7.07-7.03(m,2H),6.93(dd,2H),6 .43(d,1H),6.23-6.16(m,1H),3.76(s,3H),3.72(s,3H),3.55(br,4H),3.13(d,2H),2.53(br,4H). Example 65: Synthesis of (E)-1-(4-(benzo[d]thiazol-2-yl)piperazin-1-yl)-3-(3,4-dimethoxyphenyl)propan-2-en-1-one (Compound 74) [ka]

[0222] A reaction flask was charged with 3,4-dimethoxycinnamic acid (74a) (1.0 g, 4.81 mmol, 1.0 eq.) and DCM (30 mL), and then HATU (2.74 g, 7.21 mmol, 1.5 eq.) was added. The reaction was stirred at room temperature under nitrogen gas for 1 hour, after which 34a (1.3 g, 5.04 mmol, 1.05 eq.) and DIPEA (1.86 g, 14.23 mmol, 3.0 eq.) were added. The reaction was stirred at room temperature under nitrogen gas for 6 hours, after which the reaction was complete. The crude product was filtered and further purified with methanol to give the title compound 74 (white solid) (1.2 g, yield: 61%).

[0223] LCMS: 410 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ7.78(d,1H),7.51-7.47(m,2H),7.38(s,1H),7.28(t,1H),7.24(d,1H),7. 19(d,1H),7.08(t,1H),6.98(d,1H),3.89(br,2H),3.82(s,3H),3.78-3.75(m,5H),3.63(br,4H). Example 66: Synthesis of 4-(5-(4-(2,3-dichlorophenyl)piperazin-1-yl)pentyl)-6-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (Compound 75) [ka]

[0224] Step 1: A reaction flask was charged with 75a (0.3 g, 2.0 mmol, 1.0 eq.), 1,5-dibromopentane (0.68 g, 3.0 mmol, 1.5 eq.), and DMF (10 mL). NaH (0.16 g, 4.0 mmol, 2.0 eq.) was added portionwise under ice bath. After completion, the mixture was stirred at room temperature for 2 h. The reaction was quenched by dropwise addition of water under ice bath. The target compound was isolated and purified by silica gel column chromatography (eluent: dichloromethane:methanol = 95:5). The collected product was concentrated to give 75A (0.24 g, yield: 80.2%) as a pale yellow oil.

[0225] Step 2: The same synthetic route as in Example 2 was used, except that 3a in Example 2 was replaced with 75A, to give the title compound 75 (colorless oily liquid) (127 mg, yield: 35.3%).

[0226] LCMS: 449 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ7.30-7.29(m,2H),7.12(t,1H),6.76(d,1H),6.26(d,1H),4.10(t,2H),3.52(t,2H) ,3.40(t,2H),2.98(br,4H),2.61(br,4H),2.43(t,2H),2.20(s,3H),1.59-1.46(m,4H),1.35-1.20(m,2H). Example 67: Synthesis of N-(2-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)ethyl)-3-(6-methyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)propionamide (Compound 76) [ka]

[0227] Steps 1-2: A reaction flask was charged with 75a (0.3 g, 2.0 mmol, 1.0 eq.), methyl bromopropionate (0.4 g, 2.4 mmol, 1.2 eq.), and DMF (10 mL). NaH (0.2 g, 5.0 mmol, 2.5 eq., 60%) was added portionwise under ice bath. After completion of the reaction, the mixture was heated to 25 °C and reacted for 4 h. Water was added dropwise to quench the reaction. The product was separated and purified on a silica gel column (eluent: DCM:MeOH = 60:40). The target product was collected and concentrated to give a white solid 76B (0.35 g, yield: 78.7%).

[0228] Step 3: A reaction flask was charged with 76B (175 mg, 0.78 mmol, 1.0 eq.), HATU (358 mg, 0.94 mmol, 1.2 eq.), and DMF (8 mL) and stirred at 25° C. for 30 min. 76a (274 mg, 0.94 mmol, 1.2 eq.) and DIPEA (252 mg, 1.95 mmol, 2.5 eq.) were then added and stirred at 25° C. for 2 h. After concentration, the crude product was obtained and purified by C18 reverse-phase column (eluent: 0.5% formic acid aqueous solution:acetonitrile=40:60). The target component was collected and concentrated to give the title compound 76 (pseudo-white solid) (45 mg, yield: 12.6%).

[0229] LCMS: 458 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ9.41(s,1H),7.34-722(m,2H),7.10-7.07(m,2H),6.61(s,1H),4.22(t,2H) ,3.88(t,2H),3.74-3.58(m,10H),3.47(q,2H),2.94(t,2H),2.61(t,2H),2.41(s,3H),2.24(s,3H). Example 68: Synthesis of 4-(5-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)pentyl)-6-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (Compound 77) [ka]

[0230] The title compound 77 (colorless oily liquid) was obtained by employing the same synthetic route as in Example 2, except that 3a in Example 2 was replaced with 75A and 1c was replaced with 77a.

[0231] LCMS: 429 [M+H] + 1H NMR(400MHz,CDCl3)δ7.09(d,1H),6.99-6.97(d,2H),6.79(d,1H),6.29(d,1H),4.17(t,2H),3.62(t,2H),3.43(t,2H),3.07 (s,4H),2.94(br,4H),2.76-2.68(m,2H),2.32(s,3H),2.24(s,3H),1.80-1.71(m,2H),1.68-1.62(m,2H),1.43-1.38(m,2H). Example 69: Synthesis of 5,6-dimethoxy-1-(4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)butyl)indol-2-one (Compound 78) [ka]

[0232] Step 1: A reaction flask was charged with 78a (1.0 g, 5.0 mmol, 1.0 eq.) and acetonitrile (30 mL), and then potassium carbonate (1.38 g, 10.0 mmol, 2.0 eq.) and 1,4-dibromobutane (3.34 g, 15.0 mmol, 3.0 eq.) were added, and the reaction mixture was reacted at 95 °C for 8 h. After monitoring the completion of the reaction by LCMS, the raw material was filtered, spin-dried, and separated on a silica gel column to give a white solid 78A (500 mg, 31% yield).

[0233] Step 2: The same synthetic route as in Example 20 was employed, except that 24a in Example 20 was replaced with 78A and 1c was replaced with 6b, to give the title compound 78 (pseudo-white solid).

[0234] LCMS: 478 [M+H] + 1H NMR(400MHz,DMSO-d6)δ7.39(t,1H),7.19(d,1H),7.12(s,1H),7.04(d,1H),6.96(s,1H),6.74(s,1H),3.77(s,3H),3.68( s,3H),3.65(t,2H),3.44(s,2H),3.24-3.14(m,4H),2.53-2.43(m,4H),2.34(t,2H),1.66-1.53(m,2H),1.49-1.38(m,2H). Example 70: Synthesis of 1-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-5,6-dimethoxyindolin-2-one (Compound 79) [ka]

[0235] The title compound 79 (pseudo-white solid) was obtained by employing the same synthetic route as in Example 20, except that 24a in Example 20 was replaced with 78A.

[0236] LCMS: 478 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ7.30-7.24(m,2H),7.12(dd,1H),6.96(s,1H),6.74(s,1H),3.78(s,3H),3.68(s,3H),3. 65(t,2H),3.44(s,2H),2.99-2.90(m,4H),2.54-2.50(m,4H),2.37(t,2H),1.64-1.55(m,2H),1.51-1.41(m,2H). Example 71: Synthesis of ethyl 2-((4-(4-(benzo[d]thiazol-2-yl)piperazin-1-yl)butanamido)methyl)-5-methylthiazole-4-carboxylate (Compound 80) [ka]

[0237] The same synthetic route as in Step 3 of Example 67 was employed, except that 76a was replaced with 80b and 76B was replaced with 80a in Step 3 of Example 67, to give the title compound 80 (white solid).

[0238] LCMS: 488 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ8.78(t,1H),7.77(d,1H),7.46(d,1H),7.28(t,1H),7.08(t,1H),4.44(d,2H),4.25( q,2H),3.62(br,4H),3.34(br,2H),2.77(br,4H),2.64(s,3H),2.22(t,2H),1.83-1.72(m,2H),1.27(t,3H). Example 72: Synthesis of 4-(4-(benzo[d]thiazol-2-yl)piperazin-1-yl)-N-((4-(hydroxymethyl)-5-methylthiazol-2-yl)methyl)butanamide (Compound 81) [ka]

[0239] Compound 80 (0.276 g, 0.566 mmol, 1.0 eq.) and THF (10 mL) were added to a reaction flask, and LiAlH (0.9 mL, 2.264 mmol, 4.0 eq., 2.5 mol / L in THF) was added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred for 1 h. The reaction was quenched by the dropwise addition of saturated NaSO solution. The solvent was evaporated to dryness, and the residue was dissolved in 4 mL of DMSO. The mixture was purified on a C18 reverse-phase column (eluent: 0.5% formic acid in water: MeOH = 25:75). The target component was collected and concentrated to give the title compound 81 (white solid, 90 mg, yield: 35.7%).

[0240] LCMS: 446 [M+H] + 1H NMR(400MHz,DMSO-d6)δ8.65(t,1H),7.75(d,1H),7.44(d,1H),7.27(t,1H),7.06(t,1H),4.41- 4.39(m,4H),3.54(t,4H),2.53-2.50(m,4H),2.40-2.30(m,5H),2.18(t,2H),1.76-1.67(m,2H). Example 73: Synthesis of ethyl 2-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butanamido)methyl)-5-methylthiazole-4-formate (Compound 82) [ka]

[0241] The same synthetic route as in Step 3 of Example 67 was employed, except that 76a was replaced with 80b and 76B was replaced with 82a in Step 3 of Example 67, to give the title compound 82 (white solid).

[0242] LCMS: 499 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ8.83(t,1H),7.38-7.29(m,2H),7.20(dd1H),4.46(d,2H),4.26(q,2H),3. 32(br,4H),3.14(br,4H),2.92(br,2H),2.65(s,3H),2.25(t,2H),1.90-1.82(m,2H),1.28(t,3H). Example 74: Synthesis of 4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-N-((4-(hydroxymethyl)-5-methylthiazol-2-yl)methyl)butanamide (Compound 83) [ka]

[0243] The title compound 83 (pale yellow oily liquid) was obtained by employing the same synthetic route as in Example 51, except that 58 in Example 51 was replaced with 82.

[0244] LCMS: 457 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (t, 1H), 7.33-7.28 (m, 2H), 7.15 (dd, 1H), 4.42-4.41 (m, 4H), 2.99 (br, 4H), 2.55 (br, 2H), 2.40-2.35 (m, 5H), 2.19 (t, 2H), 1.76-1.71 (m, 2H). Note: Two H signal peaks were obscured by the solvent signal peak. Example 75: Synthesis of N-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetamide (Compound 85) [ka]

[0245] The same synthetic route as in Step 3 of Example 67 was employed, except that 76a was replaced with 51a and 76B was replaced with 85b in Step 3 of Example 67, to give the title compound 85 (white solid).

[0246] LCMS: 463 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ10.71(s,1H),7.96(t,1H),7.35-7.30(m,2H),7.16(dd,1H),6.96-6.90 (m,4H),4.93(dd,1H),3.26(q,2H),3.01(br,4H),2.77-2.66(m,2H),2.61(br,4H),2.47(t,2H). Example 76: (S)-N 6 Synthesis of -(3-(4-(benzo[d]thiazol-2-yl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (Compound 86) [ka]

[0247] Step 1: 2-(Piperazin-1-yl)benzo[d]thiazole hydrochloride (34a) (200 mg, 0.78 mmol, 1.0 eq.) was dissolved in acetone (3 mL). A solution of sodium hydroxide (66 mg, 1.64 mmol, 2.1 eq.) and water (0.3 mL) was added and the mixture was reacted at room temperature for 1 h. 1-Bromo-3-chloropropane (123 mg, 0.78 mmol, 1.0 eq.) was added and the mixture was reacted at room temperature overnight. The mixture was concentrated under reduced pressure to remove acetone, and the residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 1:4) to give 86A (60 mg, yield: 26%) as a white solid.

[0248] Step 2: 86A (60 mg, 0.20 mmol, 1.0 eq.) was dissolved in acetonitrile (1 mL), and (S)-2,6-diamino-4,5,6,7-tetrahydrobenzo[d]thiazole (86a) (41 mg, 0.24 mmol, 1.2 eq.), N,N-diisopropylethylamine (105 mg, 0.81 mmol, 4.0 eq.), and potassium iodide (34 mg, 0.20 mmol, 1.0 eq.) were added. The mixture was heated to 85° C. and reacted overnight. After concentration under reduced pressure, the residue was separated and purified by C18 reverse phase (eluent: methanol: 0.1% aqueous ammonia = 90:10) to give a white solid (40 mg), which was again separated and purified by C18 reverse phase (eluent: methanol: 0.1% aqueous formic acid = 70:30) to give the title compound 86 (pale yellow viscous solid) (18 mg, yield: 19%).

[0249] LCMS: 215 [M / 2+H] + 1 H NMR(400MHz,CD3OD)δ7.65(d,1H),7.48(d,1H),7.30(t,1H),7.10(t,1H),3.65-3.50(m,5H),3.27(t,2H) ,3.08(dd,1H),2.79(dd,1H),2.71-2.56(m,8H),2.27-2.19(m,1H),2.13-2.04(m,1H),2.02-2.91(m,2H). Example 77: Synthesis of (S)—N-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-3-(4-(benzo[d]thiazol-2-yl)piperazin-1-yl)propionamide (Compound 87) [ka]

[0250] The same synthetic route as in Step 3 of Example 40 was employed, except that 45B in Step 3 of Example 40 was replaced with 87a and 1-(3,5-bis(trifluoromethyl)phenyl)piperazine (45c) was replaced with 86a, to give the title compound 87 (white solid).

[0251] LCMS: 443 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ8.09(d,1H),7.75(d,1H),7.44(d,1H),7.26(t,1H),7.06(t,1H),6.63(s,2H),4.06-3.96(m,1H),3.54-3.46(m, 4H),2.73(dd,1H),2.58(t,2H),2.53-2.49(m,4H),2.47-2.39(m,2H),2.35(dd,1H),2.27(t,2H),1.84-1.76(m,1H),1.74-1.63(m,1H). Example 78: (S)-N 6 Synthesis of -(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (Compound 88) [ka]

[0252] The same synthetic route as in Step 2 of Example 76 was employed, except that 86A in Step 2 of Example 76 was replaced with 88a, to give the title compound 88 (white solid).

[0253] LCMS: 221 [M / 2+H]+ 1 H NMR(400MHz,DMSO-d6)δ7.33-7.24(m,2H),7.13(dd,1H),6.57(s,2H),2.94(br,4H),2.83-2.76(m,1H),2.74-2.6 8(m,1H),2.60(t,2H),2.50(br,4H),2.47-2.29(m,5H),2.24-2.18(m,1H),1.90-1.83(m,1H),1.60-1.45(m,3H). Example 79: Synthesis of (S)—N-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propionamide (Compound 89) [ka]

[0254] The same synthetic route as in Step 3 of Example 40 was employed, except that 45B in Step 3 of Example 40 was replaced with 49a and 1-(3,5-bis(trifluoromethyl)phenyl)piperazine (45c) was replaced with 86a to give the title compound 89 (pale yellow solid).

[0255] LCMS: 454 [M+H] + 1 H NMR(400MHz,CDCl3)δ9.04(br,1H),7.19-7.14(m,2H),7.04-7.00(m,1H),4.72-4.50(m,3H) ,2.97-2.90(m,2H),2.73-2.47(m,10H),2.44(t,2H),2.08-1.98(m,1H),1.92-1.82(m,1H). Example 80: Synthesis of 3-((3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propoxy)methyl)-2-methylimidazo[5,1-b]thiazole (Compound 90) [ka]

[0256] A reaction flask was charged with 90a (200 mg, 1.19 mmol, 1.0 eq) and DMF (2 mL) and cooled to 0 °C under nitrogen gas protection. 1-(3-chloropropyl)-4-(2,3-dichlorophenyl)piperazine (88a) (364 mg, 1.19 mmol, 1.0 eq) and potassium iodide (10 mg) were added in an ice bath. The mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by dropwise addition of water and further extracted with 20 mL of EA. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (eluent: DCM: 1% aqueous ammonia in methanol = 80:20) to give the title compound 90 (pale yellow solid) (98 mg, yield: 19%).

[0257] LCMS: 439 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.30-7.25(m,2H),7.11(d,1H),6.99(s,1H),4.64(s,2 H),3.50(t,2H),3.00-2.86(m,4H),2.47-2.42(m,4H),2.37-2.31(m,5H),1.73-1.65(m,2H). Example 84: Synthesis of 7-(4-((1,2,3,4-tetrahydroacridin-9-yl)amino)butoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 95) [ka]

[0258] A reaction flask was charged with 95a (600 mg, 3.0 mmol, 1.0 eq.) and N,N-dimethylformamide (10 mL). Sodium hydride (144 mg, 3.6 mmol, 1.2 eq.) was added and the reaction was allowed to react at 0 °C for 30 min. 7-(4-Bromobutoxy)-3,4-dihydroquinolin-2(1H)-one (6a) (900 mg, 3.0 mmol, 1.0 eq.) was added and the reaction was allowed to react at room temperature for an additional 1 h. After monitoring by LC-MS, 40% of the starting material remained. The mixture was quenched with ice water, extracted with dichloromethane, dried, concentrated, and spun dry. The product was purified by normal phase column chromatography (eluent: dichloromethane:methanol = 10:1) to give the title compound 95 (40 mg, 10% yield) as a gray solid.

[0259] LCMS: 416 [M+H] + 1 H NMR(400MHz,CD3OD)δ8.39(d,1H),7.83(d,1H),7.74(d,1H),7.52(d,1H),7.01(d,1H),6.43(d,1H),6.35(s,1H),4. 07(t,2H),4.02(t,2H),2.97(br,2H),2.87(t,2H),2.67(br,2H),2.54(t,2H),2.07-2.00(m,2H),1.96-1.88(m,6H). Example 85: Synthesis of N-(2-((2,3-dichlorobenzyl)amino)ethyl)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)acetamide (Compound 96) [ka]

[0260] Step 1: The same synthetic route as in Example 18 was employed, except that 21a in Example 18 was replaced with 96b, to give white solid 96A (510 mg, yield: 62.0%).

[0261] Step 2: 96A (500 mg, 1.38 mmol) was added to 4 M HCl / 1,4-dioxane (5 mL) and stirred at room temperature for 1 h. The reaction mixture was then spun dry to give a white solid, 96B (400 mg, 97.0% yield).

[0262] Step 3: 96B (300 mg, 1.00 mmol), 96c (176 mg, 1.00 mmol), and triethylamine (102 mg, 1.00 mmol) were added to MeOH (5 mL) and stirred at room temperature for 0.5 h. NaBHCN (189 mg, 3.00 mmol) was added, and the reaction mixture was stirred at 0 °C for 16 h. The mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was dried, and the reaction mixture was filtered and spun to give the crude product, which was purified by C18 reverse-phase column chromatography (eluent: methanol:0.1% formic acid aqueous solution = 75:25). The desired fraction was collected and lyophilized to give the title compound 96 (86 mg, yield: 20.3%) as a white solid.

[0263] LCMS: 422 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ10.06(s,1H),8.17(s,1H),8.06-8.03(m,1H),7.54-7.47(m,2H),7.36-7.32(m,1H),7.0 4(d,1H),6.49-6.48(m,2H),4.39(s,2H),3.8(s,2H),3.28-3.24(m,2H),2.77(t,2H),2.44(t,2H),2.40(t,2H). Example 86: Synthesis of 7-(2-((2-((2,3-dichlorobenzyl)(methyl)amino)ethyl)amino)ethoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 97) [ka]

[0264] A 250 mL three-neck flask was charged with 34b (2.7 g, 0.01 mol, 1 eq.), 97a (2.33 g, 0.01 mol, 1 eq.), potassium carbonate (2.76 g, 0.02 mol, 2 eq.), and acetonitrile (50 mL), heated to 90 °C, and refluxed with stirring for 5 h. After the reaction was completed, the crude product was separated by silica gel column chromatography (dichloromethane:methanol = 10:1) and concentrated under reduced pressure. The crude product was then separated by preparative chromatography and lyophilized to give compound 97 (0.05 g, yield: 1.2%) as a white solid.

[0265] LCMS:422[M+1] + 1 H NMR(400MHz,CD3OD):δ8.46(s,1H),7.47(m,2H),7.28(t,1H),7.06(d,1H),6.59(dd,1H),6.52(d ,1H),4.26(t,2H),3.74(s,2H),3.47(t,2H),3.32(t,2H),2.88(m,4H),2.50(t,2H),2.28(s,3H). Example 87: Synthesis of 7-(2-((2-((2,3-dichlorobenzyl)oxy)ethyl)(methyl)amino)ethoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 98) [ka]

[0266] The title compound 98 (white solid) was obtained by employing the same synthetic route as in Example 86, except that 97a in Example 86 was replaced with 98a.

[0267] LCMS:423[M+1] + 1H NMR(400MHz,CD3OD):δ8.47(s,1H),7.48(t,2H),7.29(t,1H),7.08(d,1H),6.60(dd,1H),6.49(d ,1H),4.67(s,2H),4.28(t,2H),3.90(t,2H),3.47(t,2H),3.37(m,2H),2.87(m,5H),2.54(t,2H). Example 88: Synthesis of 1-(3,4-dichlorophenethyl)-3-(2-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)ethyl)uronium (Compound 99) [ka]

[0268] A reaction flask was charged with 3,4-dichlorophenethylamine (99b) (0.19 g, 1.0 mmol, 1.0 eq.), triphosgene (0.11 g, 0.37 mmol, 0.37 eq.), and dichloromethane (10 mL). Pyridine (0.173 g, 2.2 mmol, 2.2 eq.) was added dropwise in an ice bath. After the addition was complete, the mixture was warmed to room temperature and stirred for 2 h. 99a (0.24 g, 1.0 mmol, 1.0 eq.) was dissolved in 5 mL of dichloromethane. DIPEA (0.775 g, 6.0 mmol, 6.0 eq.) was added in an ice bath. The above solution was then added dropwise to the reaction mixture. After the addition was complete, the mixture was stirred at room temperature for 2 h. Filtration, purification of the filter cake with dichloromethane, filtration, and drying of the filter cake gave the title compound 99 (white solid) (0.16 g, yield: 37.9%).

[0269] LCMS: 422 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ9.99(s,1H),7.51-7.45(m,2H),7.17(d,1H),7.03(d,1H),6.48(d,1H),6.42(d,1H) ),6.08(t,1H),5.96(t,1H),3.83(t,2H),3.30(t,2H),3.22(q,2H),2.77(t,2H),2.67(t,2H),2.40(t,2H). Example 89: Synthesis of 7-(2-((4-(trifluoromethyl)benzyl)amino)ethoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 100) [ka]

[0270] The title compound 100 (pale yellow solid) was obtained by employing the same synthetic route as in Example 7, except that 9a in Example 7 was replaced with 34b and 1c was replaced with 100a.

[0271] LCMS: 365 [M+H] + 1 H NMR(400MHz,CD3OD)δ7.68-7.62(m,4H),7.08(d,1H),6.59(d,1H),6.51(s,1H),4.14(t,2H),4.08(s,2H),3.13(t,2H),2.87(t,2H),2.53(t,2H). Example 90: Synthesis of 7-(2-(((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)ethoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 101) [ka]

[0272] The title compound 101 (pseudo-white solid) was obtained by employing the same synthetic route as in Example 7, except that 9a in Example 7 was replaced with 34b and 1c was replaced with 101a.

[0273] LCMS: 366 [M+H] + 1 H NMR(400MHz,CD3OD)δ8.83(s,1H),8.18(d,1H),7.88(d,1H),7.10(d,1H),6.62(d, 1H),6.52(s,1H),4.32(s,2H),4.22(t,2H),3.37(t,2H),2.88(t,2H),2.54(t,2H). Example 91: Synthesis of 7-(2-((2-(2-(2,3-dichlorophenyl)cyclopropyl)ethyl)amino)ethoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 102) [ka]

[0274] Step 1: A 250 mL three-neck flask was charged with diiodomethane (2.68 g, 0.01 mol, 1.1 eq.) and dichloromethane (100 mL). The mixture was cooled to -20 °C. Diethylzinc (10 mL, 0.01 mol, 1.1 eq.) was added and stirred for 30 min. The mixture was cooled to 0 °C. Trifluoroacetic acid (2.2 g, 0.02 mol, 2.2 eq.) was slowly added dropwise. The mixture was kept warm and stirred at 0-10 °C for 1 h. 102a (2.0 g, 0.009 mol, 1 eq.) was added and stirred at room temperature for 15 h. After the reaction was completed, water (100 mL) was added to quench the reaction. The mixture was extracted with dichloromethane. The organic phase was separated by column chromatography (dichloromethane:methanol = 20:1), concentrated under reduced pressure, and dried to give 102A (1.3 g, 62.5% yield) as a white solid.

[0275] Step 2: A 250 mL three-neck flask was charged with 102A (1.3 g, 0.0056 mol, 1 eq.) and dichloromethane (50 mL), cooled to 0 °C, and Dess-Martin (3.6 g, 0.0084 mol, 1.5 eq.) was added. The mixture was kept warm and stirred at 0-10 °C for 2 h. Upon completion of the reaction, water (100 mL) was added to quench the reaction. The mixture was extracted with dichloromethane, and the organic phase was separated by column chromatography (ethyl acetate:petroleum ether = 1:5). The product was eluted, concentrated under reduced pressure, and dried to give 102B (1.1 g, 84.6% yield) as a white solid.

[0276] Step 3: A 250 mL three-neck flask was charged with 102B (0.46 g, 0.002 mol, 1 eq.), 99a (0.41 g, 0.002 mol, 1 eq.), sodium borohydride acetate (2.1 g, 0.01 mol, 5 eq.), and dichloromethane (50 mL). The mixture was cooled to 0 °C and reacted for 3 h. Upon completion of the reaction, the mixture was quenched with saturated sodium bicarbonate solution and extracted twice with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by preparative liquid chromatography to give the title compound 102 (pseudo-white solid) (0.04 g, yield: 4.8%).

[0277] LCMS:419[M+1] + 1 H NMR(400MHz,CD3OD):δ7.33(dd,1H),7.18(t,1H),7.07(d,1H),6.96(dd,1H),6.57(dd,1H),6.48(d,1H),4.12( t,2H),3.14(t,2H),2.97(m,2H),2.88(t,2H),2.55(t,2H),2.05(m,1H),1.84(m,2H),1.05(m,2H),0.92(d,1H). Example 92: Synthesis of 7-(2-(5-chloroindolin-1-yl)ethoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 103) [ka]

[0278] The same synthetic route as in Example 86 was employed, except that 97a in Example 86 was replaced with 103a, to give the title compound 101 (pseudo-white solid).

[0279] LCMS:343[M+1] + 1H NMR(400MHz,DMSO-d6):δ9.99(s,1H),7.06-7.01(m,2H),6.99(d,1H),6.56-6.4 2(m,3H),4.08(t,2H),3.47-3.40(m,4H),2.92(t,2H),2.77(t,2H),2.42(t,2H). Example 93: Synthesis of N-(4-fluorobenzo[d]thiazol-2-yl)-4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)butanamide (Compound 104) [ka]

[0280] The same synthetic route as in Step 3 of Example 40 was employed, except that 1-(3,5-bis(trifluoromethyl)phenyl)piperazine (45c) in Step 3 of Example 40 was replaced with 104a and 45B was replaced with 41a, to give the title compound 104 (white solid).

[0281] LCMS: 400 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ12.61(s,1H),9.96(s,1H),7.79(d,1H),7.32-7.22(m,2H),7.01(d,1H),6 .45(dd,1H),6.41(d,1H),3.93(t,2H),2.75(t,2H),2.65(t,2H),2.38(t,2H),2.07-1.99(m,2H). Example 94: Synthesis of 7-(4-((4-fluorobenzo[d]thiazol-2-yl)amino)butoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 105) [ka]

[0282] The title compound 105 (white solid) was obtained by employing the same synthetic route as in Example 7, except that 9a in Example 7 was replaced with 6a and 1c was replaced with 104a.

[0283] LCMS: 386 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ9.97(s,1H),8.25(t,1H),7.49(d,1H),7.10-6.97(m,3H),6.48(dd,1 H),6.43(d,1H),3.92(t,2H),3.46-3.39(m,2H),2.77(t,2H),2.40(t,2H),1.81-1.69(m,4H). Example 95: Synthesis of 7-(2-((8-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino)ethoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 107) [ka]

[0284] Step 1: 99a (1.1 g, 2.27 mmol, 1.0 eq), 107a (1.04 g, 5.89 mmol, 1.3 eq), and TEA (459 mg, 4.53 mmol, 1.0 eq) were added to DCM (50 mL), and NaBH(OAc) (4.8 g, 22.66 mmol, 5.0 eq) was added. The reaction was stirred at room temperature for 16 h, diluted with water, and adjusted to pH 7-8 with saturated aqueous sodium bicarbonate. The DCM was spun off, the aqueous phase was extracted with ethyl acetate, the organic phase was dried, the reaction mixture was filtered, and the spun off to give the crude product, which was purified by normal phase column chromatography (eluent: dichloromethane:methanol = 10:1). The desired fraction was collected and lyophilized to give 107A (1.2 g, 72.3% yield) as a yellow solid.

[0285] Step 2: 107A (1.2 g, 3.46 mmol, 1.0 eq) was added to DCM (50 mL) and 2 M boron tribromide in dichloromethane (10 mL, 20.79 mmol, 10.0 eq) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 4 h under nitrogen gas protection. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, quenched, and adjusted to pH 7-8. The dichloromethane was evaporated to dryness. The aqueous phase was extracted with ethyl acetate, the organic phase was dried, the reaction mixture was filtered, and the crude product was spin-dried to obtain the product. The crude product was purified by normal phase column chromatography (eluent: (dichloromethane:methanol=10:1)). The desired fraction was collected and lyophilized to obtain the title compound 107 (yellow solid) (152 mg, yield: 13.2%).

[0286] LCMS: 353 [M+H] + 1H NMR(400MHz,DMSO-d6)δ10.0(s,1H),9.19(s,1H),7.03(d,1H),6.88-6.84(m,1H),6.57-6.45(m,4H),3.99- 3.97(m,2H),3.01-2.62(m,9H),2.42-2.38(m,2H),2.22-2.16(m,1H),1.98-1.95(m,1H),1.49-1.39(m,1H). Example 96: Synthesis of 7-(2-((7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino)ethoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 108) [ka]

[0287] The same synthetic route as in Step 1 of Example 95 was employed, except that 107a in Step 1 of Example 95 was replaced with 108a, to give the title compound 108 (white solid).

[0288] LCMS: 353 [M+H] + H NMR(400MHz,DMSO-d6)δ10.03(s,1H),8.30(s,1H),7.04(d,1H),6.84(d,1H),6.52-6.46(m,5H),4.07-4.05(m,2H) ,3.17-3.14(m,3H),2.79-2.75(m,1H),2.62-2.49(m,5H),2.42-2.38(m,2H),2.09-2.06(m,1H),1.59-1.54(m,1H). Example 97: Synthesis of 7-(3-(imidazo[1,2-a]pyridin-3-ylamino)propoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 109) [ka]

[0289] The title compound 109 (yellow oily liquid) was obtained by employing the same synthetic route as in Example 7, except that 9a in Example 7 was replaced with 38a and 1c was replaced with 109a.

[0290] LCMS: 337 [M+H] + 1 H NMR(400MHz,CD3OD)δ8.50(d,2H),7.95(d,1H),7.76(d,1H),7.40(t,1H),7.34(s,1H),7.00(d,1H) ,6.40(d,1H),6.31(s,1H),4.60(t,2H),3.96(t,2H),2.82(t,2H),2.50(t,2H),2.43-2.32(m,2H). Example 98: Synthesis of 7-(4-(imidazo[1,2-a]pyridin-3-ylamino)butoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 110) [ka]

[0291] The title compound 110 (white solid) was obtained by employing the same synthetic route as in Example 7, except that 9a in Example 7 was replaced with 6a and 1c was replaced with 109a.

[0292] LCMS: 351 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ10.04(s,1H),8.57(d,1H),8.13(d,1H),7.83(t,1H),7.45-7.30(m,2H),7.02(d,1H),6. 52-6.34(m,2H),4.42(t,2H),3.90(t,2H),2.76(t,2H),2.44-2.33(m,2H),2.03-1.84(m,2H),1.76-1.58(m,2H). Example 99: Synthesis of 7-((5-(imidazo[1,2-a]pyridin-3-ylamino)pentyl)oxy)-3,4-dihydroquinolin-2(1H)-one (Compound 111) [ka]

[0293] The title compound 111 (pale yellow oily liquid) was obtained by employing the same synthetic route as in Example 2, except that 3a was replaced with 4a and 1c was replaced with 109a.

[0294] LCMS: 365 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ10.13(s,1H),8.64(d,1H),8.12(d,1H),7.78(t,1H),7.46-7.36(m,2H),7.00(d,1H),6.42-6.41(m,2H) ),6.33(br,1H),4.37(t,2H),3.84(t,2H),2.75(t,2H),2.38(t,2H),1.90-1.79(m,2H),1.77-1.63(m,2H),1.41-1.32(m,2H).

[0295] Example 100: Synthesis of 6-((2-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)ethyl)amino)benzo[d]oxazol-2(3H)-one (Compound 112) [ka]

[0296] A 250 mL three-neck flask was charged with 34b (0.54 g, 0.002 mol, 1 eq.), 6-amino-2-benzoxazolone (112a) (0.3 g, 0.002 mol, 1 eq.), potassium carbonate (0.52 g, 0.04 mol, 2.0 eq.), and DMF (15 mL), and the mixture was heated to 90 °C and reacted for 4 h. After the reaction was completed, the potassium carbonate was removed by filtration, and the filtrate was separated by column chromatography (dichloromethane:methanol = 10:1) and concentrated under reduced pressure to obtain the crude product, which was then purified by preparative liquid chromatography to give the title compound 112 (pseudo-white solid) (0.074 g, yield: 10.9%).

[0297] LCMS:340[M+1] + 1 H NMR (400MHz, DMSO-d6): δ9.95(s,1H),7.03(d,1H),6.97(d,1H),6.62(d,1H),4.47(dd,1H), 6.38(d,1H),6.29(dd,1H),5.06(s,2H),4.17(t,2H),4.08(t,2H),2.77(t,2H),2.40(t,2H). Example 101: Synthesis of N-(4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)butyl)-4H-thieno[3,2-b]pyrrole-5-carboxamide (Compound 113) [ka]

[0298] The title compound 113 (pale yellow solid) was obtained by employing the same synthetic route as in Example 36, except that 41a in Example 36 was replaced with 113a and 40a was replaced with 113b.

[0299] LCMS: 384 [M+H] + 1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),9.96(s,1H),8.22(t,1H),7.34(d,1H),7.04(s,1H),7.01(d,1H),6.93(d,1H), 6.46(dd,1H),6.41(d,1H),3.91(t,2H),3.30(q,2H),2.75(t,2H),2.38(t,2H),1.74-1.69(m,2H),1.66-1.60(m,2H).

[0300] Example 102: Synthesis of N-((4-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)methyl)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetamide (Compound 114) [ka]

[0301] Step 1: A 250 mL single-neck flask was charged with 114a (0.4 g, 0.02 mol, 1.0 eq.), palladium on carbon (0.4 g, 1.0 eq.), and ethyl acetate (50 mL). The mixture was purged with a hydrogen gas balloon three times and then incubated and stirred at 10-20°C for 16 hours. After the reaction was completed, the palladium on carbon was removed by filtration, and the mixture was concentrated under reduced pressure and dried to give a white solid 114A (0.38 g, 100% yield).

[0302] Step 2: A 250 mL three-neck flask was charged with 114A (0.44 g, 0.002 mol, 1 eq.), 114b (0.38 g, 0.002 mol, 1 eq.), HATU (0.76 g, 0.002 mol, 1 eq.), DIPEA (0.52 g, 0.004 mol, 2 eq.), and DMF (10 mL). The mixture was cooled to 0 °C and reacted for 3 h. After the reaction was completed, the mixture was washed with 100 mL of water and extracted twice with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by preparative liquid chromatography to give the title compound 114 (pseudo-white solid) (0.035 g, yield: 4.4%).

[0303] LCMS:395[M+1] + 1 H NMR (400MHz, DMSO-d6): δ9.92(s,1H),9.17(s,1H),7.63(t,1H),7.13(m,2H),6.85(m,2H),6.74(m ,3H),6.64(dd,1H),4.36(s,2H),3.46(m,1H),3.34(m,1H),2.82(t,2H),2.40(t,2H),2.37(s,3H). Example 103: Synthesis of 6-chloro-4-(3-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)propyl)-3,4-dihydroquinoxalin-2(1H)-one (Compound 115) [ka]

[0304] 115a (300 mg, 1.64 mmol), K2CO3 (681 mg, 4.92 mmol) were added to DMF (5 mL), and 115b (1.03 g, 3.6 mmol) was added. The mixture was stirred at 50 °C for 16 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, the organic phase was dried, the reaction mixture was filtered, and the crude product was spin-dried to give the product. The crude product was purified by normal phase column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) and then by C-18 reverse phase column chromatography (eluent: methanol: 0.1% formic acid aqueous solution = 80:20). The target fraction was collected and lyophilized to give the title compound 115 (white solid) (127 mg, yield: 20%).

[0305] LCMS: 386 [M+H] + H NMR(400MHz,DMSO-d6)δ9.91(s,1H),7.00(d,1H),6.75-6.67(m,5H),6.32(s,1H),3.9 9-3.97(m,4H),3.79(s,2H),2.82-2.79(m,2H),2.40-2.36(m,2H),1.96-1.85(m,2H). Example 104: Synthesis of N-(2-((8-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino)ethyl)-2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetamide (Compound 130) [ka]

[0306] Step 1: 85b (1 g, 4.83 mmol), 96b (1.16 g, 7.24 mmol), and DIEA (1.47 g, 14.5 mmol) were added to DCM (20 mL), and HATU (2.7 g, 7.25 mmol) was added. The mixture was stirred at room temperature for 3 h. The reaction mixture was filtered, and the filter cake was spin-dried to give a white solid 130A (770 mg, yield: 45.7%).

[0307] Step 2: 130A (770 g, 2.20 mmol) was added to 4 M HCl / 1,4-dioxane (10 mL) and stirred at room temperature for 1 h. The reaction filter cake was spun dry to give a gray solid 130B (600 mg, 95.3% yield).

[0308] Step 3-4: The title compound 130 (white solid) was obtained by employing the same synthetic route as in Example 95, except that 99a in Example 95 was replaced with 130B.

[0309] LCMS: 396 [M+H] + H NMR(400MHz,DMSO-d6)δ10.7(s,1H),8.38-8.32(m,2H),6.94-6.87(m,5H),6.59(d,1H),6.51(d,1H),4.91-4.88(m,1H),3.38-3.23(m,2) H),3.10-3.00(m,2H),2.94-2.84(m,2H),2.78-2.61(m,4H),2.49-2.45(m,1H),2.35-2.28(m,1H),2.06-2.03(m,1H),1.56-1.52(m,1H). Example 105: Synthesis of N-(2-((7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino)ethyl)-2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetamide (Compound 131) [ka]

[0310] The same synthetic route as in Example 95 was employed, except that 99a in Example 95 was replaced with 130B and 107a was replaced with 108a, to give the title compound 131 (white solid).

[0311] LCMS: 396 [M+H] + H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.28(s,2H),6.95-6.83(m,5H),6.51-6.49(m,1H),6.45(s,1 H),4.91-4.88(m,1H),3.33-3.22(m,2H),3.04-2.54(m,10H),2.04-2.01(m,1H),1.57-1.46(m,1H). Example 106: Synthesis of 5-(5,6-dimethoxy-2-oxoindolin-3-yl)-N-(4-isopropylbenzyl)valeramide (Compound 132) [ka]

[0312] The same synthetic route as in Example 7 was employed, except that 9a in Example 7 was replaced with 132a and 1c was replaced with 78a, to give the title compound 132 (pseudo-white solid).

[0313] LCMS: 425 [M+H] + 1H NMR(400MHz,DMSO-d6)δ10.57(t,1H),10.11(s,1H),7.25(s,4H),6.80(s,1H),6.52(s,1H),4.61(d,2H),4.48(t,1H),3 .72(s,3H),3.71(s,3H),3.47-3.40(m,2H),2.89-2.86(m,1H),2.80-2.70(m,2H),1.64-1.60(m,4H),1.18-1.23(d,6H). Example 107: Synthesis of (R)-7-(4-(3-((2,3-dichlorophenyl)(methyl)amino)pyrrolidin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 133) [ka]

[0314] 133a (0.38 g, 0.0013 mol, 1 eq.) was dissolved in DMF (5 mL), and anhydrous potassium carbonate (0.54 g, 0.0039 mol, 3 eq.) was added under stirring, followed by heating to 60 °C. 7-(4-Bromobutoxy)-3,4-dihydroquinolin-2(1H)-one (6a) (0.39 g, 0.0013 mol, 1 eq.) was added at 60 °C, and the mixture was allowed to react for 3 h. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filter cake was washed with DMF, and the filtrate was collected. A large amount of water was added to the filtrate, which was then extracted with ethyl acetate. The ethyl acetate phase was concentrated, and the crude product was initially purified by column chromatography (eluent: dichloromethane:methanol = 1:1). After purification, the crude product was purified by reverse phase column (eluent: methanol: 0.5% formic acid aqueous solution = 80:20), and the obtained component was lyophilized to give the title compound 133 (pseudo-white solid) (0.04 g, yield: 6.7%).

[0315] LCMS:462[M+1] + 1H NMR(400MHz,CD3OD):δ8.43(s,1H),7.33-7.24(m,3H),7.07-7.05(d,1H),6.55 -6.53(dd,1H),6.45-6.44(d,1H),4.19-4.13(m,1H),4.00-3.97(t,2H),3.58-3 .53(m,1H),3.51-3.38(m,3H),3.28-3.24(t,2H),2.88-2.84(t,2H),2.72(s,3 H),2.55-2.51(t,2H),2.27-2.19(m,1H),2.13-2.04(m,1H),1.90-1.84(m,4H). Example 108: Synthesis of 7-(2-(1-(4-(4-methoxybenzyl)-4H-thieno[3,2-b]pyrrole-5-carbonyl)piperidin-4-yl)ethoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 134) [ka]

[0316] Step 1: 3,4-Dihydro-7-hydroxy-2(1H)-quinolinone (1b) (100 mg, 0.61 mmol, 1.0 eq.) was dissolved in anhydrous tetrahydrofuran (3 mL). 4-Piperidineethanol (134a) (158 mg, 1.23 mmol, 2.0 eq.), diethyl azodicarboxylate (213 mg, 1.23 mmol, 2.0 eq.), and triphenylphosphine (321 mg, 1.23 mmol, 2.0 eq.) were added. The mixture was heated to 75 °C under nitrogen gas protection and reacted overnight. After concentration under reduced pressure, the residue was purified by reverse-phase column chromatography (eluent: methanol:0.1% formic acid aqueous solution = 70:30) to give 134A (130 mg, yield: 77%) as a pale yellow oil.

[0317] Step 2: 134A (124 mg, 0.45 mmol, 1.0 eq.) was dissolved in dichloromethane (2 mL), triethylamine (137 mg, 1.35 mmol, 3.0 eq.) was added, and the mixture was allowed to react at room temperature for 5 min. A solution of 134b (138 mg, 0.45 mmol, 1.0 eq.) in dichloromethane (2 mL) was added dropwise, and the mixture was allowed to react at room temperature overnight. After concentration under reduced pressure, the residue was purified by reverse-phase column chromatography (eluent: methanol:0.1% formic acid aqueous solution = 80:20) to give the title compound 134 (white solid) (14 mg, yield: 6%).

[0318] LCMS: 544 [M+H] + 1 H NMR(400MHz,CDCl3)δ8.25(s,1H),7.17(d,1H),7.09(d,2H),7.05(d,1H),6.91(d,1H),6.79(d,2H),6.54-6.46(m,2H),6.33(s,1H), 5.40(s,2H),4.40(br,2H),3.94(t,2H),3.75(s,3H),2.90(t,2H),2.87-2.73(m,2H),2.62(t,2H),1.80-1.55(m,5H),0.90(br,2H). Example 109: Synthesis of 7-(((3R,5R)-1-((R)-3-amino-3-(2,3-dichlorophenyl)propyl)-5-methylpiperidin-3-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 135) [ka]

[0319] Step 1: A 100 mL three-neck flask was charged with zinc powder (0.65 g, 0.01 mol, 1.0 eq.) and anhydrous THF (30 mL). The system was flushed with nitrogen three times. Ethyl bromoacetate (135b) (1.67 g, 0.01 mol, 1.0 eq.) was added via syringe. After the addition was complete, a solution of one grain of iodine in THF (3 mL) was added via syringe and the system was heated to reflux. Under reflux, a solution of 135a (1.78 g, 0.006 mol, 0.6 eq.) in anhydrous THF (15 mL) was added via syringe. After the addition was complete, the reaction was maintained at reflux for 6 hours. Upon completion of the reaction, water was added to quench the reaction. The crude product was purified by column chromatography (eluent: dichloromethane:methanol=70:30), and the target product was collected. The solvent was removed by spin evaporation to give a pale yellow gel-like solid 135A (1.26 g, yield: 34.3%).

[0320] Step 2: A 100 mL three-neck flask was charged with 135A (0.93 g, 0.00253 mol, 1.0 eq.) and anhydrous THF (10 mL). The flask was protected with nitrogen gas and cooled in an ice-salt bath. When the temperature was lowered below 0°C, a THF solution of lithium aluminum hydride (6.3 mL, 0.00253 mol, 1.0 eq.) was added dropwise via syringe. Obvious heat was released and a large amount of bubbles were generated. The temperature of the system was controlled by adjusting the rate of addition. After the addition was complete, the reaction was allowed to proceed for 1 hour. The reaction was then filtered to remove the solids, and the filtrate was concentrated to give 135B (0.7 g, 85.4% yield) as an oil.

[0321] Step 3: A 100 mL single-neck flask was charged with 135B (0.7 g, 0.00216 mol, 1.0 eq.) and dichloromethane (10 mL) and stirred to dissolve. Dess-Martin reagent (0.92 g, 0.00216 mol, 1.0 eq.) was added under stirring and the reaction was allowed to proceed at room temperature for 1 hour. The reaction was completed and washed twice with saturated sodium bicarbonate solution. The layers were separated, and the DCM layer was dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with DCM. The solvent was removed from the filtrate to give yellow oil 135C, which was used directly in the next step.

[0322] Step 4: A 100 mL three-neck flask was charged with 135c (1.6 g, 0.007 mol, 1.0 eq.), triethylamine (2.08 g, 0.021 mol, 3 eq.), and DCM (10 mL), protected with nitrogen gas, and placed in an ice bath. When the system temperature had cooled to 0 °C, a solution of methanesulfonyl chloride (0.96 g, 0.0084 mol, 1.2 eq.) in DCM (2 mL) was added dropwise via syringe. After the addition was complete, the mixture was stirred overnight. The reaction was then completed, filtered to remove solids, and concentrated to give 135D, which was used crude in the next step.

[0323] Step 5: The crude 135D obtained in the previous step was dissolved in DMF (20 mL). 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (1b) (1.14 g, 0.007 mol, 1.0 eq.) and anhydrous potassium carbonate (2.9 g, 0.021 mol, 3 eq.) were added to the mixture, and the mixture was reacted at 100 °C for 2 h. After the reaction was completed, the mixture was cooled to room temperature, a large amount of water was added, and the product was extracted with EA. The extract was concentrated and initially purified by column chromatography (eluent: dichloromethane:methanol = 80:20). The desired product components were collected and concentrated to give crude 135E (2.9 g, 100% yield) as a yellow solid.

[0324] Step 6: A 100 mL single-neck flask was charged with 135E (2.9 g, 0.00774 mol, 1.0 eq.) and a solution of hydrogen chloride in dioxane (15 mL, 4 mol / L) and the mixture was reacted at room temperature for 1 h. After filtration, the filter cake was washed with DCM and dried to give a white solid 135F (0.93 g, 38.8% yield).

[0325] Step 7: A 100 mL single-neck flask was charged with 135F (0.38 g, 0.00124 mol, 0.5 eq.), DCM (10 mL), and triethylamine (0.125 g, 0.00125 mol, 0.5 eq.) and stirred to dissolve. After dissolution, 135C (0.8 g, 0.00248 mol, 1.0 eq.) and acetic acid (0.177 g, 0.00496 mol, 2.0 eq.) were added and stirred for 1 hour. Sodium triacetylborohydride (1.05 g, 0.00496 mol, 2.0 eq.) was added and the mixture was allowed to react at room temperature for 4 hours. The reaction was completed, filtered, the filter cake was washed with DCM, the filtrate was washed with saturated sodium bicarbonate solution and water, and the layers were separated, the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the crude product was initially purified by column chromatography (eluent: dichloromethane:methanol=1:1) to collect the target product components, which were then concentrated to obtain a pseudo-white solid 135G (0.57 g, yield: 91.9%).

[0326] Step 8: A 100 mL one-neck flask was charged with 135G (0.26 g, 0.000448 mol, 1.0 eq.) and EA (5 mL), stirred to dissolve, and a solution of hydrogen chloride in dioxane (0.6 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 30 min, filtered, and the filter cake was washed with EA. The filter cake was separated (eluent: methanol:0.5% formic acid aqueous solution = 80:20) to give the title compound 135 (white solid) (0.02 g, yield: 9.5%).

[0327] LCMS:476[M+1] + 1H NMR(400MHz,CD3OD):δ7.63-7.54(m,2H),7.51-7.39(m,1H),7.08-7.06(m,1H ),6.60-6.54(m,1H),6.49-6.45(m,1H),4.02-3.78(m,2H),3.50(d,1H),3.34 (s,1H),3.05(m,1H),2.88-2.84(t,3H),2.80-2.73(m,1H),2.55-2.51(t,2H) ,2.44-2.14(m,4H),2.03-1.75(m,3H),1.44-1.28(m,1H),1.04-0.99(m,3H). Example 110: Synthesis of 6-((4-(2,3-dichlorophenyl)piperazin-1-yl)sulfonyl)-3,4-dihydroquinolin-2(1H)-one (Compound 158) [ka]

[0328] 1-(2,3-Dichlorophenyl)piperazine hydrochloride (1c) (200 mg, 0.75 mmol, 1.0 eq.) was dissolved in dichloromethane (5 mL), triethylamine (227 mg, 2.24 mmol, 3.0 eq.) was added, and 158a (220 mg, 0.90 mmol, 1.2 eq.) was slowly added and reacted at room temperature for 3 h. The mixture was concentrated under reduced pressure, and methanol (5 mL) was added to the residue. The mixture was stirred uniformly and filtered. The filter cake was washed with methanol (2 × 4 mL) and dried to give the title compound 158 (white solid) (215 mg, yield: 65.32%).

[0329] LCMS: 440 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ10.56(s,1H),7.65-7.57(m,2H),7.36-7.30(m,2H),7.22-7.16(m,1H),7.10(d,1H),3.13-3.00(m,10H),2.56(t,2H). Example 111: Synthesis of 6-((4-hydroxy-4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)sulfonyl)-3,4-dihydroquinolin-2(1H)-one (Compound 159) [ka]

[0330] The title compound 159 (white solid) was obtained by employing the same synthetic route as in Example 110, except that 1c in Example 110 was replaced with 159b.

[0331] LCMS: 455 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ10.53(s,1H),7.81-7.75(m,2H),7.66-7.55(m,4H),7.09(d,1H),5.23(s,1H) ),3.62-3.53(m,2H),3.04(t,2H),2.65(t,2H),2.58-2.54(m,2H),2.06(td,2H),1.72-1.64(m,2H). Example 112: Synthesis of 6-((4-(4-fluorobenzyl)piperidin-1-yl)sulfonyl)-3,4-dihydroquinolin-2(1H)-one (Compound 160) [ka]

[0332] The title compound 160 (white solid) was obtained by employing the same synthetic route as in Example 110, except that 1c in Example 110 was replaced with 160b.

[0333] LCMS: 403 [M+H] + 1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),7.55-7.47(m,2H),7.19-7.14(m,2H),7.11-7.05(m,2H),7.03(d,1H),3.63-3.55(m,2 H),2.98(t,2H),2.54-2.52(m,2H),2.50-2.47(m,2H),2.15(t,2H),1.65-1.55(m,2H),1.54-1.39(m,1H),1.26-1.13(m,2H). Example 113: Synthesis of 2-oxo-N-(2-oxo-2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1,2,3,4-tetrahydroquinoline-6-sulfonamide (Compound 161) [ka]

[0334] 161a (100 mg, 0.35 mmol, 1.0 eq.) was dissolved in N,N-dimethylformamide (3 mL), and HATU (161 mg, 0.42 mmol, 1.2 eq.) was added. The mixture was allowed to react at room temperature for 0.5 h. 1-(3-Trifluoromethylphenyl)piperazine hydrochloride (6b) (113 mg, 0.42 mmol, 1.2 eq.) and DIPEA (168 mg, 1.30 mmol, 3.7 eq.) were added, and the mixture was allowed to react at room temperature overnight. After concentration under reduced pressure, the residue was purified by reversed-phase C18 column (eluent: 0.1% formic acid aqueous solution:methanol = 30:70) to give the title compound 161 (100 mg, yield: 57.26%) as a white solid.

[0335] LCMS: 497 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ10.44(s,1H),7.65(s,1H),7.62(dd,1H),7.57(br,1H),7.45(t,1H),7.24(dd,1H),7.19 (s,1H),7.11(d,1H),6.98(d,1H),3.78(s,2H),3.56-3.50(m,4H),3.27-3.15(m,4H),2.95(t,2H),2.49(t,2H). Example 114: Synthesis of N-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)-2-oxoethyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide (Compound 162) [ka]

[0336] The same synthetic route as in Example 113 was employed, except that 6b in Example 113 was replaced with 1c, to give the title compound 162 (white solid).

[0337] LCMS: 497 [M+H]+ 1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),7.66(s,1H),7.62(dd,1H),7.55(t,1H),7.37-7.33(m,2 H),7.13(dd,1H),6.99(d,1H),3.77(d,2H),3.57-3.50(m,4H),2.99-2.88(m,6H),2.49(t,2H). Example 115: Synthesis of N-(2-(4-hydroxy-4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-2-oxoethyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide (Compound 163) [ka]

[0338] The same synthetic route as in Example 113 was employed, except that 6b in Example 113 was replaced with 159b, to give the title compound 163 (white solid).

[0339] LCMS: 512 [M+H] + 1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),7.84(s,1H),7.75(d,1H),7.67(d,1H),7.65-7.56(m,3H),7.46(s,1H),6.99(d,1H),5.42(s,1H),4. 25(d,1H),3.83-3.61(m,3H),3.34-3.30(m,1H),2.99-2.88(m,3H),2 .48(t,2H),2.04-1.94(m,1H),1.81-1.69(m,1H),1.64-1.54(m,2H). Example 116: Synthesis of N-(2-(4-(4-fluorobenzyl)piperidin-1-yl)-2-oxoethyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide (Compound 164) [ka]

[0340] The same synthetic route as in Example 114 was employed, except that 6b in Example 114 was replaced with 160b, to give the title compound 164 (white solid).

[0341] LCMS: 460 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ10.49(s,1H),7.67-7.58(m,2H),7.45(s,1H),7.25-7.19(m,2H),7.16-7.09(m,2H),6.99(d,1H),4.23( d,1H),3.77-3.59(m,3H),2.97(t,2H),2.87(t,1H),2.52-2.40(m,5H),1.79-1.64(m,1H),1.58-1.48(m,2H),1.09-0.81(m,2H). Example 117: Synthesis of 1-(6-(4-(3-(trifluoromethyl)phenyl)piperazine-1-carbonyl)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (Compound 165) [ka]

[0342] Step 1: A reaction flask was charged with 165a (0.10 g, 0.56 mmol, 1.0 eq.), 6b (0.17 g, 0.62 mmol, 1.1 eq.), HATU (0.26 g, 0.68 mmol, 1.2 eq.), DIPEA (0.27 g, 2.09 mmol, 3.7 eq.) and solvent DMF (3 mL). The mixture was stirred at room temperature for 1 h and concentrated to give a crude product. The crude product was purified by C18 reverse-phase column (eluent: 0.5% formic acid aqueous solution: MeOH = 25:75). The target component was collected and concentrated to give a pseudo-white solid 165A (150 mg, yield: 68.8%).

[0343] Step 2: A reaction flask was charged with 165A (0.16 g, 0.41 mmol, 1.0 eq.), TEA (0.08 g, 0.82 mmol, 2.0 eq.), and DCM (6 mL). The mixture was cooled to 0 °C, and acetyl chloride (0.04 g, 0.45 mmol, 1.1 eq.) was added dropwise. The mixture was allowed to react for 1 h. The mixture was purified by silica gel column chromatography (eluent: DCM:MeOH=90:10) to give the title compound 165 (pseudo-white solid) (166 mg, yield: 93.8%).

[0344] LCMS: 432 [M+H] + 1 H NMR (400MHz, CDCl3) δ7.52-7.31(m,7H),4.11-3.95(m,4H),3.83(t,2H),3.37(s,4H),2.82(t,2H),2.31(s,3H),2.07-2.00(m,2H). Example 118: Synthesis of 1-(6-(4-(2,3-dichlorophenyl)piperazine-1-carbonyl)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (Compound 166) [ka]

[0345] The same synthetic route as in Example 117 was employed, except that 6b in Example 117 was replaced with 1c, to give the title compound 166 (pseudo-white solid).

[0346] LCMS: 432 [M+H] + 1 H NMR(500MHz,DMSO-d6)δ7.59(s,1H),7.35-7.30(m,2H),7.29-7.22(m,2H),7.20-7. 14(m,1H),3.73(m,6H),3.00(br,4H),2.75(t,2H),2.20(s,3H),1.91-1.85(m,2H). Example 119: Synthesis of 1-(6-(4-hydroxy-4-(3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (Compound 167) [ka]

[0347] The same synthetic route as in Example 117 was employed, except that 6b in Example 117 was replaced with 159b, to give the title compound 167 (pseudo-white solid).

[0348] LCMS: 447 [M+H] + 1 H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.85(d,1H),7.64-7.50(m,3H),7.30-7.26(m,2H),4.45(s,1H),3.70(t,2H),3 .64-3.44(m,2H),3.24-3.04(m,2H),2.75(t,2H),2.20(s,3H),2.00(td,2H),1.92-1.85(m,2H),1.68-1.58(m,2H). Example 120: Synthesis of 1-(6-(4-(4-fluorobenzyl)piperidine-1-carbonyl)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (Compound 168) [ka]

[0349] The same synthetic route as in Example 118 was employed, except that 6b in Example 118 was replaced with 168b, to give the title compound 168 (pseudo-white solid).

[0350] LCMS: 395 [M+H] + 1 H NMR(500MHz,CDCl3)δ7.30-7.27(m,1H),7.25-7.17(m,2H),7.13-7.05(m,2H),7.03-6.95(m,2H),4. 69(s,1H),3.94-3.75(m,3H),2.92-2.49(m,6H),2.26(s,3H),2.18-1.92(m,3H),1.85-1.65(m,4H). Example 121: Synthesis of N-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-oxopropyl)-3,4-dimethoxybenzamide (Compound 169) [ka]

[0351] The same synthetic route as in Step 3 of Example 40 was employed, except that 1-(3,5-bis(trifluoromethyl)phenyl)piperazine (45c) in Step 3 of Example 40 was replaced with 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c) and 45B was replaced with 169a, to give the title compound 169 (colorless oily liquid).

[0352] LCMS: 466 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ8.43(t,1H),7.48-7.41(m,2H),7.34-7.26(m,2H),7.05(d,1H),7.00 (d,1H),3.79(s,3H),3.78(s,3H),3.64-3.58(m,4H),3.49(q,2H),2.92(br,4H),2.63(t,2H). Example 122: Synthesis of N-(4-(2,3-dichlorophenyl)piperazin-1-yl)-4-oxobutyl)-3,4-dimethoxybenzamide (Compound 170) [ka]

[0353] The same synthetic route as in Step 3 of Example 40 was employed, except that 1-(3,5-bis(trifluoromethyl)phenyl)piperazine (45c) in Step 3 of Example 40 was replaced with 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c) and 45B was replaced with 170a, to give the title compound 170 (colorless oily liquid).

[0354] LCMS: 480 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ8.34(t,1H),7.47-7.42(m,2H),7.35-7.26(m,2H),7.13(dd,1H),6.99(d ,1H),3.78(s,6H),3.60(br,4H),3.30(q,2H),2.96-2.90(m,4H),2.41(t,2H),1.81-1.74(m,2H). Example 123: Synthesis of N-(5-(4-(2,3-dichlorophenyl)piperazin-1-yl)-5-oxopentyl)-3,4-dimethoxybenzamide (Compound 171) [ka]

[0355] The same synthetic route as in Step 3 of Example 40 was employed, except that 1-(3,5-bis(trifluoromethyl)phenyl)piperazine (45c) in Step 3 of Example 40 was replaced with 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c), 45B was replaced with 171a, and the reagent DCM was replaced with DMF, to give the title compound 171 (white solid).

[0356] LCMS: 494 [M+H]+ 1 H NMR(400MHz,DMSO-d6)δ8.32(t,1H),7.48-7.39(m,2H),7.33-7.27(m,2H),7.12(dd,1H),6.98( d,1H),3.78(s,6H),3.59(br,4H),3.26(q,2H),2.95-2.86(m,4H),2.38(br,2H),1.55(br,4H). Example 124: Synthesis of 3,4-dimethoxy-N-(5-oxo-5-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)pentyl)benzamide (Compound 172) [ka]

[0357] The same synthetic route as in Step 3 of Example 40 was employed, except that 1-(3,5-bis(trifluoromethyl)phenyl)piperazine (45c) in Step 3 of Example 40 was replaced with 6b, 45B was replaced with 171a, and the reagent DCM was replaced with DMF to give the title compound 172 (white solid).

[0358] LCMS: 494 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ8.32(t,1H),7.46-7.40(m,3H),7.22-7.15(m,2H),7.08(d,1H),6. 98(d,1H),3.78(s,6H),3.61-3.55(m,4H),3.26-3.18(m,6H),2.38(br,2H),1.54(br,4H). Example 125: Synthesis of methyl 2-(4-(2,3-dichlorophenyl)piperazine-1-carbonyl)-4,5-dimethoxybenzoate (Compound 173) [ka]

[0359] Step 1: 173a (200 mg, 0.96 mmol, 1.0 eq.) was dissolved in toluene (5 mL), and 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c) (308 mg, 1.15 mmol, 1.2 eq.) was added. The mixture was heated to 100 °C and reacted overnight. After concentration under reduced pressure, the residue was separated and purified using a C18 reverse-phase column (0.1% formic acid aqueous solution:methanol = 70:30) to give a yellow solid 173A (400 mg, yield: 95%).

[0360] Step 2: 173A (400 mg, 0.91 mmol, 1.0 eq.) was dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (315 mg, 2.28 mmol, 2.5 eq.) was added, and the mixture was allowed to react at room temperature for 0.5 h. Iodomethane (194 mg, 1.37 mmol, 1.5 eq.) was added, and the mixture was allowed to react at room temperature overnight. The reaction mixture was separated and purified using a reverse-phase C18 column (0.1% formic acid:methanol = 30:70) and further purified by prep-TLC (eluent: petroleum ether:ethyl acetate = 1:1) to give the title compound 173 (pale yellow solid) (144 mg, yield: 35%).

[0361] LCMS: 453 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ7.46(s,1H),7.36(d,2H),7.19(t,1H),6.95(s,1H),3.89 (s,3H),3.87(s,3H),3.85-3.77(m,5H),3.27(br,2H),3.10(t,2H),2.93(t,2H). Example 126: Synthesis of (R)-7-(2-hydroxy-3-((2-(2-methoxyphenoxy)ethyl)amino)propoxy)quinolin-2(1H)-one (Compound 174) [ka]

[0362] A reaction flask was charged with 174a (868 mg, 4.0 mmol, 1.0 eq.) and ethanol (20 mL), and then 2-(2-methoxyphenoxy)ethylamine (668 mg, 4.0 mmol, 1.0 eq.) was added. The reaction was completed after stirring at 90 °C for 12 h under sealed tube conditions. The reaction solution was spun dry and directly purified by C18 reverse phase column to give the title compound 174 (768 mg, 50% yield).

[0363] LCMS: 385 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ11.58(s,1H),7.79(d,1H),7.54(d,1H),6.95-6.73(m,6H),6.29(d,1H), 4.06(t,2H),4.00-3.94(m,3H),3.73(s,3H),3.01(t,2H),2.90-2.88(m,1H),2.81-2.72(m,1H). Example 127: Synthesis of (S)-7-(3-((2-(3,4-dimethoxyphenoxy)ethyl)amino)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 175) [ka]

[0364] The title compound 175 was obtained by employing the same synthetic route as in Example 126, except that 174a in Example 126 was replaced with 175a and 174b was replaced with 175b.

[0365] LCMS: 417 [M+H] + 1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),7.03(d,1H),6.83(d,1H),6.56(s,1H),6.48-6.41(m,3H),4.02(t,2H),3.99-3.9 1(m,1H),3.90-3.77(m,2H),3.71(s,3H),3.67(s,3H),3.01(t,2H),2.92-2.83(m,1H),2.81-2.68(m,3H),2.40(t,2H). Example 128: Synthesis of N-(2-(7-hydroxynaphthalen-1-yl)ethyl)-3-((1-(pyridin-2-yl)piperidin-4-yl)amino)propionamide (Compound 176) [ka]

[0366] Step 1: A 250 mL three-neck flask was charged with 176a (0.25 g, 0.001 mol, 1 eq.), 2-(7-methoxynaphthalen-1-yl)ethan-1-amine (176b) (0.23 g, 0.001 mol, 1 eq.), HATU (0.76 g, 0.002 mol, 2 eq.), DIPEA (0.26 g, 0.002 mol, 2 eq.), and dichloromethane (50 mL). The mixture was cooled to 0 °C and reacted for 2 h. Upon completion of the reaction, the mixture was quenched with saturated sodium bicarbonate solution and extracted twice with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The product was eluted by silica gel column chromatography (dichloromethane:methanol = 7:1), concentrated under reduced pressure, and dried to give 176A (0.43 g, 100% yield) as a white solid.

[0367] Step 2: 176A (0.6 g, 0.0015 mol, 1 eq.), dichloromethane (30 mL), and boron tribromide (7.5 mL, 0.015 mol, 10 eq.) were added to a 250 mL three-neck flask, and the mixture was incubated at 20 °C for 5 hours. After completion of the reaction, the mixture was quenched with saturated sodium bicarbonate solution, extracted twice with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by preparative separation to give the title compound 176 (pseudo-white solid) (0.08 g, yield: 12.7%).

[0368] LCMS:419[M+1] + 1 H NMR(400MHz,CD3OD):δ8.02-7.94(m,2H),7.71(d,1H),7.62(d,1H),7.38-7.32(m,2H),7.27(d,1H),7.20(t,1H),7.09(d, 1H),6.99(t,1H),4.29(d,2H),3.54(t,3H),3.35-3.27(m,4H),3.19(t,2H),2.64(t,2H),2.30(d,2H),1.83-1.75(m,2H). Example 129: Synthesis of 1-(4-(4-(((6-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)methyl)phenoxy)butyl)-5-(2-(trifluoromethyl)phenyl)-1H-indazole-6-carbonitrile (Compound 177) [ka]

[0369] Step 1: A 100 mL single-neck flask was charged with 177a (0.5 g, 0.00174 mol, 1.0 eq.), 1,4-dibromobutane (177b) (0.75 g, 0.00348 mol, 2.0 eq.), potassium carbonate (0.72 g, 0.00522 mol, 3.0 eq.), and anhydrous acetonitrile (15 mL). The mixture was heated to reflux and reacted for 20 min. The solvent was removed from the reaction mixture, and the crude product was purified by column chromatography (eluent: DCM:MeOH = 100:0 to 70:30). The collected product was evaporated to dryness to give 177A (0.2 g, 27.4% yield) as a yellow oil.

[0370] Step 2: A 50 mL single-neck flask was charged with 177A (0.2 g, 0.00048 mol, 1.0 eq.), 177c (0.19 g, 0.000707 mol, 1.5 eq.), potassium carbonate (0.17 g, 0.0012 mol, 2.5 eq.), anhydrous DMF (5 mL), and water (1 mL) and reacted overnight at room temperature. The mixture was filtered, the filter cake was washed with water, and the filtrate was purified by reverse-phase column chromatography (eluent: 0.5% formic acid aqueous solution: MeOH = 100:0 to 10:90). The collected product was lyophilized and further purified by preparative liquid chromatography (eluent: 0.5% formic acid aqueous solution: MeOH = 100:0 to 25:75). Lyophilization afforded the title compound 177 (0.03 g, 10.3% yield) as a pale yellow solid.

[0371] LCMS:611[M+1] + 1 H NMR(400MHz,DMSO-d6):δ10.06(s,1H),10.01(s,1H),8.60(s,1H),8.28(d,1 H),7.93(d,1H),7.87(s,1H),7.82(t,1H),7.75(t,1H),7.54(d,1H),7.24(d, 2H),6.85(d,2H),6.59(s,1H),6.03(s,1H),5.09(br,1H),4.66-4.54(m,2H), 4.22(s,2H),3.97(t,2H),2.12(s,3H),2.07-1.99(m,2H),1.75-1.68(m,2H). Example 130: Synthesis of N-(2-(7-hydroxynaphthalen-1-yl)ethyl)-3-((6-(piperidin-1-yl)pyridin-3-yl)methoxy)propionamide (Compound 178) [ka]

[0372] Step 1: 178a (1.0 g, 5.34 mmol, 1.0 eq), imidazole (0.726 g, 10.68 mmol, 2.0 eq), and DMF (10 mL) were added to a 100 mL one-neck flask, and TBDMSCl (1.2 g, 8.02 mmol, 1.5 eq) was added and stirred at room temperature for 12 h. The reaction mixture was added with water, extracted with EA, concentrated, and purified with MTBE to give 178A (0.3 g, 18.7% yield) as a white solid.

[0373] Step 2: 178b (2.5 g, 13 mmol, 1.0 eq), cesium carbonate (8.5 g, 26 mmol, 2.0 eq), ethyl acrylate (5.5 g, 65 mmol, 5.0 eq), and toluene (20 mL) were added to a 100 mL one-neck flask, heated to 50 °C, and reacted for 12 h. The mixture was cooled, filtered, and the filtrate was concentrated to give the crude product, which was purified by silica gel column chromatography (eluent: DCM:MeOH = 30:1 to 10:1) to give 178B (0.8 g, yield: 21%) as a pale yellow oil.

[0374] Step 3: 178B (800 mg, 2.74 mmol, 1.0 eq), methanol (10 mL), and water (2 mL) were added to a 100 mL one-neck flask, and LiOH (197 mg, 8.22 mmol, 3.0 eq) was added. The mixture was stirred at room temperature for 5 hours, concentrated to remove methanol, adjusted to pH = 4 with dilute hydrochloric acid, filtered, and the filter cake was dried to give a white solid 178C (0.5 g, yield: 69%).

[0375] Step 4: 178C (200 mg, 0.76 mmol, 1.0 eq), 178A (274 mg, 0.9 mmol, 1.2 eq), HATU (578 mg, 1.52 mmol, 2 eq), DIEA (588 mg, 4.56 mmol, 6.0 eq) and DMF (10 mL) were added to a 100 mL one-neck flask, stirred at room temperature for 2 h, and purified by reverse-phase column chromatography to give the title compound 178 (white solid) (0.052 g, yield: 12.5%).

[0376] LCMS:434[M+1] + 1 H NMR(400MHz,DMSO-d6)δ9.71(s,1H),8.00(s,2H),7.74(d,1H),7.62(d,1H),7.41(d,1H),7.30(s,1H),7.21(d,1H),7.17-7.11(m ,1H),7.07(d,1H),6.74(d,1H),4.28(s,2H),3.57(t,2H),3.47(s,4H),3.35(s,2H),3.03(t,2H),2.32(t,2H),1.65-1.40(m,6H). Experimental Example 1: Pharmacodynamics experiment (TPK enzyme activity test) 1.1 Experimental Objective

[0377] The purpose of this example was to test the promoting effect of compounds on TPK enzyme activity and to evaluate the EC 50 and E max The objective of this study is to evaluate the in vitro activity of compounds based on the above method. 1.2 Experimental method 1.2.1 Experimental materials

[0378] [Table 4] 1.2.2 Experimental steps

[0379] 1.1) Preheat the thermostatic water bath shaker half an hour in advance to a preheat temperature of 37°C. 1.2) The stock solution of the compound to be tested was taken and left at room temperature to dissolve, and then diluted to the desired concentration. 1.3) The desired reagent was placed on ice and allowed to dissolve.

[0380] 2.1) Each reaction system required the addition of TPK enzyme solution, Tris-HCl buffer solution, and ATP solution. The ATP used ranged from 1 to 500 mM, and the above three solutions were mixed to form a homogeneous mixture. 2.2) The above three mixtures were dispensed into centrifuge tubes, and the desired concentrations of compounds were added to each tube. Finally, thiamine solution (1-100 μM) was added to each tube. After the above additions were completed, the centrifuge tubes were tightly capped, inserted into a floating plate, and placed in a 37°C water bath shaker for 0.5-2.0 hours of incubation. 2.3) After incubation, perchloric acid stop solution was added and mixed well, and the sample was collected in a 1.5 mL centrifuge tube and stored at -20°C.

[0381] 3.1) The sample stored at -20°C was taken out and dissolved at room temperature, and then derivatized. The sample was placed in a centrifuge tube, and potassium ferricyanide derivatization reagent was added to it. Finally, phosphoric acid stop solution was added to stop the reaction. 3.2) The derivatized sample was placed in a liquid chromatography analysis sample bottle and the TDP / thiamine content was detected by high performance liquid chromatography. TKP enzyme activity = TDP (nM) / mg protein / min. 1.3 Experimental results

[0382] According to the above procedure, the effect of the compound of the present invention on TPK enzyme activity at different concentrations was measured, and the obtained E max( The effect of DMSO on TPK enzyme activity was calculated as 100% (EC 50 The data is shown in Table 2 below.

[0383] [Table 5-1] [Table 5-2] [Table 5-3]

[0384] [Table 6-1] [Table 6-2]

[0385] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) is hereby incorporated by reference in its entirety.

Claims

1. 1. A method for preventing or treating a neurodegenerative disease or alleviating a symptom of a neurodegenerative disease, comprising administering to an individual in need thereof a prophylactically or therapeutically effective amount of a thiamine pyrophosphokinase (TPK) agonist; wherein the TPK agonist is a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof; 【Chemistry 1】 where: A and B are each independently ３－１０ Hydrocarbon ring, 3- to 14-membered heterocycle, C ６－１０ an aromatic ring or a 5- to 14-membered heteroaromatic ring; L is -Q １ -, -W-, -Q １ -W-, -W-Q １ -, -Q １ -Q ２ -, -W-W'-, -W-Q １ -Q ２ -, -W-Q １ -W'-, -Q １ -W-Q ２ -, -Q １ -W-Q ２ -W'-, -W-Q １ -W'-Q ２ -, -Q １ -Q ２ -W-W'- and -W-Q １ -Q ２ -W'-; Q １ and Q ２ are each independently -C １－６ Alkylene-, -C ２－６ Alkenylene-, -C ２－６ Alkynylene-, -C ３－１０ Cycloalkylene-, -(3- to 14-membered heterocyclylene)-, -C ６－１０ arylene- and -(5- to 14-membered heteroarylene)-, wherein the alkylene, alkenylene, and alkynylene groups are each optionally selected from -C ３－１０ Cycloalkylene-, -(3- to 14-membered heterocyclylene)-, -C ６－１０ Arylene, -(5- to 14-membered heteroarylene), -O-, -C(=O)-, -C(=O)O-, -NR-, -C(=O)NR-, -NR-C(=O)-NR'-, -NR-C(=O)O-, -(S=O)NR-, -S(=O) ２ NR-, -S-, -S(=O)- and -S(=O) ２ - or is interrupted by adjacent or non-adjacent groups independently selected from the above, W and W' each independently represent -O-, -C(=O)-, -C(=O)O-, -NR-, -C(=O)NR-, -NR-C(=O)-NR'-, -NR-C(=O)O-, -(S=O)NR-, or -S(=O) ２ NR-, -S-, -S(=O)- and -S(=O) ２ - is selected from, R and R' are independently H, C, or １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１０ Cyclic hydrocarbon group, 3- to 14-membered heterocyclyl group, C ６－１０ aryl groups, 5- to 14-membered heteroaryl groups, and C ６－１２ aralkyl groups, The alkyl group, alkylene group, alkenyl group, alkenylene group, alkynyl group, alkynylene group, cyclic hydrocarbon group, cycloalkylene group, hydrocarbon ring, heterocyclyl group, heterocyclylene group, heterocycle, aryl group, arylene group, aromatic ring, heteroaryl group, heteroarylene group, heteroaromatic ring, and aralkyl group each appearing optionally and independently represent halogen, —OH, ═O, —NH ２ , -CN, -NO ２ , C １－６ Alkyl group, halo C １－６ Alkyl group, C ３－１０ Cyclic hydrocarbon group, 3- to 14-membered heterocyclyl group, C ６－１０ aryl group, 5- to 14-membered heteroaryl group, C ６－１２ Aralkyl group, —C(═O)R ａ , —OC(═O)R ａ , -C(=O)OR ａ , -OR ａ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ａ R ｂ , -NR ａ R ｂ , —C(═O)NR ａ R ｂ , -NR ａ -C(=O)R ｂ , -NR ａ -C(=O)OR ｂ , -NR ａ -S(=O) ２ -R ｂ , -NR ａ —C(═O)—NR ａ R ｂ , -C １－６ Alkylene-OR ａ , -C １－６ Alkylene -NR ａ R ｂ and -O-C １－６ Alkylene -NR ａ R ｂ and the alkyl group, alkylene group, cyclic hydrocarbon group, heterocyclyl group, aryl group, heteroaryl group, and aralkyl group are further optionally substituted independently with one or more substituents selected from halogen, —OH, ═O, —C(═O)O-tert-butyl group, —NH ２ , -CN, -NO ２ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－１０ Cyclic hydrocarbon group, 3- to 14-membered heterocyclyl group, C ６－１０ aryl group, 5- to 14-membered heteroaryl group, C ６－１２ aralkyl group, —O—C １－６ Alkyl group and -C １－６ Alkylene -O-C １－６ substituted with one or more substituents selected from alkyl groups, and R ａ and R ｂ are independently H, C each time they appear. １－６ Alkyl group, C ３－１０ Cyclic hydrocarbon group, 3- to 14-membered heterocyclyl group, C ６－１０ aryl groups, 5- to 14-membered heteroaryl groups, and C ６－１２ and aralkyl groups, wherein the alkyl groups, cyclic hydrocarbon groups, heterocyclyl groups, aryl groups, heteroaryl groups, and aralkyl groups are further optionally independently selected from halogen, —OH, ═O, —C(═O)O-tert-butyl groups, —NH ２ , -CN, -NO ２ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－１０ Cyclic hydrocarbon group, 3- to 14-membered heterocyclyl group, C ６－１０ aryl group, 5- to 14-membered heteroaryl group, C ６－１２ Aralkyl groups and —C １－６ Alkylene -O-C １－６ substituted with one or more substituents selected from alkyl groups; Preferably, the neurodegenerative disease is Alzheimer's disease; More preferably, the Alzheimer's disease is Alzheimer's disease in which the individual has reduced TPK enzyme activity, reduced TPK expression levels, and / or reduced TDP levels.

2. A is, 【Chemistry 2】 The method of claim 1, wherein

3. L is -Q １ -W-, -W-Q １ -, -Q １ -Q ２ -, -W-Q １ -Q ２ -, -W-Q １ -W'-, -Q １ -W-Q ２ -, -Q １ -W-Q ２ -W'-, -W-Q １ -W'-Q ２ -, -Q １ -Q ２ -W-W'- and -W-Q １ -Q ２ -W'-; Preferably, L is 【Transformation 3】 【Chemistry 4】 【Transformation 5】 The method according to claim 1 or 2, wherein

4. B is, 【Transformation 6】 The method according to any one of claims 1 to 3, wherein

5. the TPK agonist is a compound of formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof; A-W-Q １ -Q ２ -B (II) where: A is a benzene ring optionally fused to a 5- or 6-membered heterocyclic ring or a 5- or 6-membered heteroaromatic ring, and the benzene ring is optionally independently selected from the group consisting of halogen, —OH, —NH ２ , C １－６ Alkyl group, —O—C １－６ Alkyl group, —NH(C １－６ alkyl) and -N(C １－６ alkyl) ２ and preferably, the benzene ring is optionally substituted with one or more substituents selected independently from -Cl, -OH, -NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , methyl, ethyl and methoxy groups, and most preferably A is 【Transformation 7】 and B is C ３－１０ Hydrocarbon ring, 3- to 14-membered heterocycle, C ６－１０ The aromatic ring or the 5- to 14-membered heteroaromatic ring is preferably a benzene ring, and the benzene ring may optionally independently contain halogen, C １－６ Alkyl group, halo C １－６ Alkyl group, —NH—C(═O)—C １－６ Alkyl group, —C(═O)-(3- to 14-membered heterocyclyl), —S(═O) ２ -N(C １－６ alkyl) ２ and -S(=O) ２ -(3- to 14-membered heterocyclyl), and preferably the benzene ring is optionally and independently substituted with one or more substituents selected from -F, -Cl, a methyl group, an isopropyl group, a trifluoromethyl group, -NHC(=O)CH ３ , —C(═O)-piperidinyl group, —S(═O) ２ -N(CH ３ ) ２ , -S(=O) ２ -N(CH ２ CH ３ ) ２ , -S(=O) ２ -piperidinyl group and -S(=O) ２ -azepanyl groups, Q １ is -C １－６ Alkylene-, -C ２－６ Alkenylene- and -C ２－６ alkynylene-, Q ２ is -C ３－１０ Cycloalkylene-, -(3- to 14-membered heterocyclylene)-, -C ６－１０ selected from arylene- and -(5- to 14-membered heteroarylene)-, preferably -(3- to 14-membered heterocyclylene)-, more preferably a piperidinylene group or a piperazinylene group; W, at each occurrence, independently represents -O-, -C(=O)-, -C(=O)O-, -NR-, -C(=O)NR-, -NR-C(=O)-NR'-, -NR-C(=O)O-, -(S=O)NR-, or -S(=O) ２ NR-, -S-, -S(=O)- and -S(=O) ２ -, preferably -O-, -NH- or -NH-C(=O)-; 5. The method of any one of claims 1 to 4, wherein each remaining group is as defined in any one of claims 1 to 4.

6. 1. A method for preventing or treating a neurodegenerative disease or alleviating a symptom of a neurodegenerative disease, comprising administering to an individual in need thereof a prophylactically or therapeutically effective amount of a thiamine pyrophosphokinase (TPK) agonist; Preferably, the neurodegenerative disease is Alzheimer's disease; More preferably, the Alzheimer's disease is Alzheimer's disease in which the individual has reduced TPK enzyme activity, reduced TPK expression levels, and / or reduced TDP levels; wherein the TPK agonist is Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 is selected from.

7. 7. The method of any one of claims 1 to 6, wherein the TPK agonist is administered in an amount of about 0.005 mg / day to about 5000 mg / day, e.g., about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 mg / day.

8. The TPK agonist is administered in an amount of about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg of body weight daily, for example, about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, about 200 μg / kg, about 22 μg / kg, or about 30 μg / kg daily. 5μg / kg, about 250μg / kg, about 275μg / kg, about 300μg / kg, about 325μg / kg, about 350μg / kg, about 375μg / kg, about 400μg / kg, about 425μg / kg, about 450 μg / kg, about 475 μg / kg, about 500 μg / kg, about 525 μg / kg, about 550 μg / kg, about 575 μg / kg, about 600 μg / kg, about 625 μg / kg, about 650 μg / kg, About 675 μg / kg, about 700 μg / kg, about 725 μg / kg, about 750 μg / kg, about 775 μg / kg, about 800 μg / kg, about 825 μg / kg, about 850 μg / kg, about 875 μg / k g, about 900 μg / kg, about 925 μg / kg, about 950 μg / kg, about 975 μg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 m 8. The method of claim 1, wherein the compound is administered in an amount of about 100 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg or about 300 mg / kg of body weight.

9. 9. The method of any one of claims 1 to 8, wherein the daily dose of the TPK agonist is administered in one dose, or in two, three, or four divided doses.

10. 10. The method of any one of claims 1 to 9, wherein the TPK agonist is administered continuously for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days.

11. 11. The method of claim 1, wherein the TPK agonist is administered over one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) treatment courses, wherein each treatment course lasts at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days, and the interval between each two treatment courses is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, 2 weeks, 3 weeks, or 4 weeks.

12. 12. The method of any one of claims 1 to 11, wherein the TPK agonist is administered by injection (e.g., intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including drip infusion), or transdermally, or in the form of an oral, buccal, nasal, transmucosal, topical, ophthalmic formulation, or by inhalation.

13. 13. The method of any one of claims 1 to 12, wherein the TPK agonist is administered in a dosage form selected from a tablet, capsule, troche, hard candy, powder, spray, cream, ointment, suppository, gel, paste, lotion, salve, aqueous suspension, injectable solution, elixir, and syrup.

14. 14. The method of any one of claims 1 to 13, wherein the method improves the pathophysiological symptoms of cognitive and behavioral abnormalities, neurodegenerative changes (e.g., progressive synapse / neuron loss and brain atrophy), β-amyloid deposition, Tau abnormal phosphorylation and resulting neurofibrillary tangles, glial cell activation and inflammation, and / or impaired cerebral glucose metabolism in the individual.

15. 15. The method of any one of claims 1 to 14, further comprising administering one or more other therapeutic agents.

16. or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein said compound is Table 2-1 Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6 is selected from.

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