TPK agonists and methods of treating neurodegenerative diseases using same

Abstract

The present disclosure belongs to the field of biomedicine and specifically relates to a method of preventing or treating or reducing symptoms of a neurodegenerative disease comprising administering to an individual in need thereof a prophylactically or therapeutically effective amount of a thiamine pyrophosphate kinase (TPK) agonist.

Description

TPK agonists and methods of using the same to treat neurodegenerative diseases Field of the Invention

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

[0002] Background of the Invention

[0003] Alzheimer's disease (AD) is the most common degenerative disease of the central nervous system. Due to its large patient population, prolonged course, long lifespan with loss of self-care ability, and lack of effective preventive and therapeutic medications, AD imposes a tremendous economic and emotional burden on individuals, families, and society as a whole. According to reports, China spent $167.74 billion on AD prevention, treatment, and care in 2015, and this expenditure is projected to reach $507.49 billion by 2030. In 2018, global spending on dementia, primarily AD, exceeded one trillion US dollars, accounting for over 1% of global gross domestic product (GDP). AD is the only one of the top ten major diseases globally lacking effective preventive and therapeutic medications, and has become a major disease that severely impacts the healthcare systems and sustainable economic development of major economies, including China.

[0004] AD is a disease characterized by multiple pathophysiological changes, including neuronal loss, glial cell activation, characteristic extracellular amyloid-β (Aβ) deposition forming senile plaques, and intracellular Tau protein hyperphosphorylation causing neurofibrillary tangles. Furthermore, synaptic loss, impaired brain glucose metabolism, and oxidative stress are also common pathological changes in the AD brain. Furthermore, decreased brain glucose metabolism is closely associated with cognitive impairment. Due to the unclear pathogenesis, effective treatments for AD remain lacking.

[0005] SUMMARY OF THE INVENTION

[0006] The inventors of this application have discovered that impaired glucose metabolism may be an early preclinical feature of AD. The intracellular glucose metabolism process in AD patients is primarily manifested by a significant decrease in the activity of three key enzymes (pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and transketolase) that rely on thiamine diphosphate (TDP) as a coenzyme. Multicenter clinical studies have demonstrated that decreased TDP levels in AD patients are a specific and common phenomenon with good diagnostic value, while patients with vascular dementia and frontotemporal dementia do not exhibit abnormal thiamine metabolism. Clinical and experimental studies have further demonstrated that decreased TDP is the cause of impaired brain glucose metabolism. The inventors of this application have found that, among the four known genes involved in thiamine metabolism, only thiamine pyrophosphokinase (TPK), the key enzyme that converts thiamine to bioactive TDP, shows significant suppression of expression, and this suppression of TPK expression is specific to AD. Therefore, TPK agonists may be useful for the prevention or treatment of neurodegenerative diseases, particularly Alzheimer's disease.

[0007] 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 a subject in need thereof a prophylactically or therapeutically effective amount of a thiamine pyrophosphokinase (TPK) agonist.

[0008] In another aspect, the present invention provides use of a TPK agonist in the preparation of a medicament for preventing or treating a neurodegenerative disease or alleviating a symptom of a neurodegenerative disease.

[0009] In another aspect, the present invention provides a TPK agonist for use in preventing or treating a neurodegenerative disease or alleviating a symptom of a neurodegenerative disease.

[0010] The neurodegenerative disease is preferably Alzheimer's disease; more preferably, the Alzheimer's disease is Alzheimer's disease characterized by decreased TPK enzyme activity, decreased TPK expression level and / or decreased TDP level in an individual.

[0011] In another aspect, the present invention relates to TPK agonists having novel structures.

[0012] Detailed Description of the Invention

[0013] definition

[0014] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0015] The terms "comprises," "comprising," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

[0016] As used herein, when describing a divalent group that connects two other groups, it is understood that the divalent group can be connected to the two groups in any direction. For example, if the other two groups connected by the divalent group -C(=O)NR- are (group 1) and (group 2), then (group 1)-C(=O)NR-(group 2) and (group 2)-C(=O)NR-(group 1) are both included.

[0017] As used herein, the term "alkylene" 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 methylene, ethylene, propylene or butylene.

[0018] As used herein, the term "alkyl" is defined as a straight or branched chain saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, such as 1 to 6, carbon atoms. For example, as used herein, the term "C 1-6 "Alkyl" refers to 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 (in which case the group is referred to as "haloalkyl") (e.g., CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl or -CH2CH2CF3, etc.). The term "C 1-4 "Alkyl" refers to 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).

[0019] As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having 2 to 6 carbon atoms ("C 2-6The alkenyl group is, 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 compound of the present invention contains an alkenyl group, the compound may be in the pure E (entgegen) form, the pure Z (zusammen) form or any mixture thereof. The term "alkenylene" is a corresponding divalent group, including, for example, "C 2-6 Alkenylene", "C 2-4 Specific examples include, but are not limited to, -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, butenylene, pentenylene, hexenylene, cyclopentenylene, cyclohexenylene, etc.

[0020] As used herein, the term "alkynyl" refers to a monovalent hydrocarbon radical 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, etc. The alkynyl group is optionally substituted with one or more (such as 1 to 3) identical or different substituents. The term "alkynylene" is a corresponding divalent radical, including, for example, "C 2-8 Alkynylidene", "C 2-6 Alkynylidene", "C 2-4 Examples include, but are not limited to, The alkynylene group is optionally substituted with one or more (such as 1 to 3) substituents which may be the same or different.

[0021] As used herein, the term "paracyclic" or "fused ring" refers to a ring system formed by two or more cyclic structures that share two adjacent atoms.

[0022] As used herein, the term "spirocycle" refers to a ring system formed by two or more cyclic structures that share one ring atom with each other.

[0023] As used herein, the term "bridged ring" refers to a ring system formed by two or more cyclic structures sharing two atoms that are not directly connected to each other.

[0024] As used herein, the terms "cycloalkylene", "cycloalkyl" and "hydrocarbon ring" refer to saturated (i.e., "cycloalkylene" and "cycloalkyl") or unsaturated (i.e., having one or more double bonds and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings (including spiro, fused or bridged ring systems) having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbon atoms, including but not limited to (cyclo)propyl, (cyclo)butyl, (cyclo)pentyl, (cyclo)hexyl, (cyclo)heptyl, (cyclo)octyl, (cyclo)nonyl, (cyclo)hexenyl and the like.

[0025] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic or tricyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic, including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.), which is optionally substituted with one or more (such as one to three) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-10 "Cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 10 ring carbon atoms (for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents, for example methyl substituted cyclopropyl.

[0026] As used herein, the term "heterocyclyl" refers to a saturated or unsaturated monovalent monocyclic or polycyclic (such as bicyclic or tricyclic) group having 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms and one or more (e.g., one, two, three or four) selected from O, S, N, S(=O), S(=O)2, S(=O)(=NR Z ),NR Z or P(=O)(R Z ) containing a heteroatom, wherein R Z Each occurrence independently represents a hydrogen atom or a C 1-6 Alkyl or halo-C 1-6alkyl; the heterocycloalkyl group may be attached to the rest of the molecule via any of the carbon atoms or the nitrogen atom (if present). In particular, a 3-14 membered heterocyclyl group is a group having 3-14 carbon atoms and heteroatoms in the ring, such as, but not limited to, an oxirane, an aziridine, an azetidinyl, an oxetanyl, an tetrahydrofuranyl, a dioxolyl, a pyrrolidinyl, a pyrrolidonyl, an imidazolidinyl, a pyrazolidinyl, a pyrrolinyl, a tetrahydropyranyl, a piperidinyl, a morpholinyl, a dithianyl, a thiomorpholinyl, a piperazinyl or a trithianyl.

[0027] As used herein, the term "heterocyclyl" encompasses a cyclic structure, and the connection point of the cyclic structure to the other groups can be on any ring in the cyclic structure. Therefore, the heterocyclyl of the present invention also includes but is not limited to heterocyclyl and heterocyclyl, heterocyclyl and cycloalkyl, monoheterocyclyl and monoheterocyclyl, monoheterocyclyl and monocycloalkyl, such as 3-7 membered (mono) heterocyclyl and 3-7 membered (mono) heterocyclyl, 3-7 membered (mono) heterocyclyl and (mono) cycloalkyl, 3-7 membered (mono) heterocyclyl and C 4-6 (Mono)cycloalkyl, examples of which are not limited to pyrrolidinyl and cyclopropyl, cyclopentyl and aziridine, pyrrolidinyl and cyclobutyl, pyrrolidinyl and pyrrolidinyl, pyrrolidinyl and piperidinyl, pyrrolidinyl and piperazinyl, piperidinyl and morpholinyl,

[0028] As used herein, the term "heterocyclyl" encompasses bridged heterocyclyls and spiro heterocyclyls.

[0029] 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 atoms, nitrogen atoms, and / or sulfur atoms) formed by two saturated rings sharing two ring atoms that are not directly connected, including but not limited to 7-10 membered bridged heterocycles, 8-10 membered bridged heterocycles, 7-10 membered nitrogen-containing bridged heterocycles, 7-10 membered oxygen-containing bridged heterocycles, 7-10 membered sulfur-containing bridged heterocycles, etc., for example 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.

[0030] As used herein, the term "spiroheterocycle" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen atoms, nitrogen atoms, sulfur atoms) formed by two or more saturated rings sharing a ring atom, including but not limited to 5-10 membered spiroheterocycles, 6-10 membered spiroheterocycles, 6-10 membered nitrogen-containing spiroheterocycles, 6-10 membered oxygen-containing spiroheterocycles, 6-10 membered sulfur-containing spiroheterocycles, etc., for example The "nitrogen-containing spiroheterocycle", "oxygen-containing spiroheterocycle" and "sulfur-containing spiroheterocycle" optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur. The term "6-10 membered nitrogen-containing spiroheterocyclyl" refers to a spiroheterocyclyl containing 6-10 ring atoms, at least one of which is a nitrogen atom.

[0031] As used herein, the terms "(ene)aryl" 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 (E)aryl" and "C 6-10 The term "aromatic ring" means an aromatic group containing 6 to 10 carbon atoms, such as (ene)phenyl (phenyl ring) or (ene)naphthyl (naphthalene ring). The (ene)aryl group and the aromatic ring are optionally substituted by one or more (such as one to three) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C 1-6 When the (ene)aryl group and the aromatic ring are a fused ring, 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 the other group may be on any ring in the fused ring structure.

[0032] The term "aralkyl" preferably refers to an alkyl group substituted with an aryl group, wherein 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.

[0033] As used herein, the terms "heteroaryl(ene)" 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 identical or different (the heteroatom being for example oxygen, nitrogen or sulfur). In particular, "(ene)heteroaryl" or "heteroaromatic ring" is selected from (ene)thienyl (ring), (ene)furanyl (ring), (ene)pyrrolyl (ring), (ene)oxazolyl (ring), (ene)thiazolyl (ring), (ene)imidazolyl (ring), (ene)pyrazolyl (ring), (ene)isoxazolyl (ring), (ene)isothiazolyl (ring), (ene)oxadiazolyl (ring), (ene)triazolyl (ring), (ene)thiadiazolyl (ring), etc., and benzo derivatives thereof; or (ene)pyridinyl (ring), (ene)pyridazinyl (ring), (ene)pyrimidinyl (ring), (ene)pyrazinyl (ring), (ene)triazinyl (ring), etc. When the (ene)heteroaryl and heteroaromatic ring are fused rings, the fused rings may be hydrocarbon rings, heterocycles, aromatic rings or heteroaromatic rings, and the connection point between the fused ring structure and the other group may be on any ring in the fused ring structure.

[0034] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0035] The term "alkylthio" as used herein, means an alkyl group, as defined above, appended to the parent molecular moiety through a sulfur atom. 1-6 Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, and hexylthio.

[0036] 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 further 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); the nitrogen-containing heterocycle is linked to the rest of the molecule via the 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 3-14 carbon atoms and heteroatoms (at least one of which is a nitrogen atom) in the ring, including but not limited to a three-membered nitrogen-containing heterocycle (such as aziridine), a four-membered nitrogen-containing heterocycle (such as azetidinyl), a five-membered nitrogen-containing heterocycle (such as pyrrolyl, pyrrolidinyl (pyrrolidine ring), pyrrolinyl, pyrrolidonyl, imidazolyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl), a six-membered nitrogen-containing heterocycle (such as piperidinyl (piperidine ring), morpholinyl, thiomorpholinyl, piperazinyl), a seven-membered nitrogen-containing heterocycle, etc.

[0037] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valence is not exceeded in the 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.

[0038] If a substituent is described as being "optionally substituted," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, with independently selected optional substituents. If a nitrogen of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.

[0039] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0040] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.

[0041] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0042] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0043] The present invention also 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 an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (D, 2 H), tritium (T, 3 H)); carbon isotopes (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically labeled compounds of the invention (e.g., those incorporating radioactive isotopes) are useful 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) are particularly useful for this purpose because they are easy to incorporate and easy to detect. 11 C. 18 F. 15 O and 13 N) substitution can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the present invention can be prepared by methods analogous to those described in the accompanying schemes and / or examples and preparations by using appropriate isotopically labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent is isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6.

[0044] It should also be understood that certain compounds of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0045] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

[0046] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate / carbonate, bisulfate / sulfate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydrobromide / bromide, hydroiodide / iodide, maleate, malonate, methylsulfate, naphthoate (naphthylate), nicotinate, nitrate, orotate, oxalate, palmitate and other similar salts.

[0047] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, choline, diethylamine, lysine, magnesium, meglumine, potassium and other similar salts.

[0048] 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.

[0049] As used herein, the term "ester" refers to esters derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in the form of free acid or alcohol). The compounds of the present invention themselves may also be esters.

[0050] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0051] Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, and the like of the administered compound. Thus, the present invention includes metabolites of the compounds of the present invention, including compounds produced by contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0052] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Volume 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 moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985)).

[0053] The present invention also encompasses 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 chemically protected form of the compounds of the present invention. This can be achieved using conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & PGM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0054] As used herein, the term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0055] As used herein, the term "effective amount" refers to that amount of a compound which, when administered, relieves to some extent one or more of the symptoms of the condition being treated.

[0056] As used herein, the term "prevention" refers to the preemptive administration of a drug to avoid or prevent the occurrence of one or more symptoms of a disease or condition. One of ordinary skill in the medical field recognizes that the term "prevention" is not an absolute term. In the medical field, it is understood that the prophylactic administration of a drug is to substantially reduce the likelihood or severity of a condition or the symptoms of a condition, which is the intended meaning of this disclosure. Prevention is divided into primary prevention (to prevent the development of a disease) and secondary prevention (whereby a disease has already developed and the patient is protected from worsening of the process).

[0057] As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, inhibiting the progression of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0058] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0059] As used herein, the term "reduction of TPK enzyme activity" means that the TPK enzyme activity in the treated individual is lower than the enzyme activity in a normal individual.

[0060] As used herein, the term "reduction in the expression level of TPK" means that the level of TPK mRNA / DNA or protein expression in a treated individual is lower than that in a normal individual.

[0061] As used herein, the term "reduction of TDP levels" means that the TDP level in a treated individual is lower than that in a normal individual.

[0062] In some embodiments, the present invention provides a method for preventing or treating a neurodegenerative disease or alleviating a symptom of a neurodegenerative disease, comprising administering to a subject in need thereof a prophylactically or therapeutically effective amount of a thiamine pyrophosphokinase (TPK) agonist.

[0063] In a preferred embodiment, the neurodegenerative disease is Alzheimer's disease.

[0064] 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 level and / or reduced TDP level.

[0065] 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: A—L—B (I)

[0066] in:

[0067] A and B are each independently C 3-10 Hydrocarbon ring, 3-14 membered heterocycle, C 6-10 Aromatic ring or 5-14 membered heteroaromatic ring;

[0068] L is selected from -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'-;

[0069] Q 1 and Q 2 Each independently selected from -C 1-6 Alkylene-, -C 2-6 Alkenylene-, -C 2-6 Alkynylidene-, -C 3-10 Cycloalkylene-、-(3-14 membered heterocyclylene)-、-C 6-10 Arylene- and -(5-14 membered heteroarylene)-, wherein the alkylene, alkenylene and alkynylene groups are each optionally interrupted by one group or by multiple adjacent or non-adjacent groups independently selected from: -C 3-10 Cycloalkylene-、-(3-14 membered heterocyclylene)-、-C 6-10 Arylene-, -(5-14 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)2NR-, -S-, -S(=O)-, and -S(=O)2-;

[0070] W and W' are each independently selected at each occurrence from -O-, -C(=O)-, -C(=O)O-, -NR-, -C(=O)NR-, -NR-C(=O)-NR'-, -NR-C(=O)O-, -(S=O)NR-, -S(=O)2NR-, -S-, -S(=O)-, and -S(=O)2-;

[0071] R and R' are each independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl;

[0072] The above alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, hydrocarbon ring, heterocyclyl, heterocyclylene, heterocycle, aryl, arylene, aromatic ring, heteroaryl, heteroarylene, heteroaromatic ring and aralkyl are each optionally substituted at each occurrence with one or more substituents independently selected from the group consisting of halogen, -OH, =O, -NH2, -CN, -NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -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 1-6Alkylene-OR a 、-C 1-6 Alkylene-NR a R b and-OC 1-6 Alkylene-NR a R b The alkyl, alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are further optionally substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -C(=O)O-tert-butyl, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -OC 1-6 Alkyl and -C 1-6 Alkylene-OC 1-6 alkyl; and

[0073] R a and R b Each occurrence is independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl, said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl further optionally substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -C(=O)O-tert-butyl, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl and -C 1-6 Alkylene-OC 1-6 alkyl.

[0074] In some embodiments, A is

[0075] In some embodiments, L is selected from -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'-.

[0076] In some embodiments, L is

[0077] In some embodiments, B is

[0078] 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)

[0079] in:

[0080] A is a benzene ring optionally fused to a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring, wherein the benzene ring is optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -NH(C 1-6 alkyl) and -N(C 1-6 alkyl) 2; preferably, the phenyl ring is optionally substituted by one or more substituents independently selected from the following: -Cl, -OH, -NH2, -NH(CH3), -N(CH3)2, methyl, ethyl and methoxy; most preferably, A is

[0081] B is C 3-10 Hydrocarbon ring, 3-14 membered heterocycle, C 6-10 aromatic ring or 5-14 membered heteroaromatic ring; preferably a benzene ring, the benzene ring is optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -NH-C(=O)-C 1-6Alkyl, -C(=O)-(3-14 membered heterocyclic group), -S(=O)2-N(C 1-6 Preferably, the phenyl ring is optionally substituted by one or more substituents independently selected from the group consisting of -F, -Cl, methyl, isopropyl, trifluoromethyl, -NHC(=O)CH3, -C(=O)-piperidinyl, -S(=O)2-N(CH3)2, -S(=O)2-N(CH2CH3)2, -S(=O)2-piperidinyl and -S(=O)2-azepanyl;

[0082] Q 1 Selected from -C 1-6 Alkylene-, -C 2-6 Alkenylene- and -C 2-6 Alkynylidene-;

[0083] Q 2 Selected from -C 3-10 Cycloalkylene-、-(3-14 membered heterocyclylene)-、-C 6-10 Arylene- and -(5-14 membered heteroarylene)-; preferably -(3-14 membered heterocyclylene)-; more preferably piperidinylene or piperazinylene;

[0084] W is independently selected at each occurrence from -O-, -C(=O)-, -C(=O)O-, -NR-, -C(=O)NR-, -NR-C(=O)-NR'-, -NR-C(=O)O-, -(S=O)NR-, -S(=O)2NR-, -S-, -S(=O)- and -S(=O)2-; preferably -O-, -NH- or -NH-C(=O)-;

[0085] The remaining groups are as defined above.

[0086] In some embodiments, the TPK agonist is selected from:

[0087] In preferred embodiments, 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.

[0088] In preferred embodiments, 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 per day, 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 225 μg / kg, about 250 μg / kg, about 275 μg / kg, about 300 μg / kg, about 325 μg / kg, about 350 μg / kg, about 375 μg / kg, about 400 μg / kg, about 425 μg / 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 / kg, 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 The present invention relates to an agent that is administered in an amount of about 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 of body weight.

[0089] In preferred embodiments, the daily dose of the TPK agonist is administered once or divided into two, three, or four doses.

[0090] 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 day, 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.

[0091] In preferred embodiments, the TPK agonist is administered for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) courses of treatment, wherein each course of treatment 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 day, 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 there is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, two weeks, three weeks, or four weeks between each course of treatment.

[0092] In a preferred embodiment, the TPK agonist is administered by injection (e.g., intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including infusion) or transdermal administration; or by oral, buccally, nasally, transmucosally, topically, in the form of an ophthalmic preparation or by inhalation.

[0093] In a preferred embodiment, the TPK agonist is administered in a dosage form selected from the group consisting of tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, and syrups.

[0094] In preferred embodiments, the method improves the following pathophysiological manifestations in an individual: cognitive behavioral abnormalities, neurodegenerative changes (e.g., progressive synaptic / neuronal loss and brain atrophy), β-amyloid deposition, abnormal Tau phosphorylation and the resulting neurofibrillary tangles, glial cell activation and inflammation, and / or brain glucose metabolism disorders.

[0095] In preferred embodiments, the present disclosure further comprises the administration of one or more additional therapeutic agents.

[0096] In some embodiments, the present disclosure provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound is selected from: Example

[0097] The present invention is further described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

[0098] The abbreviations used in this invention have the following meanings:

[0099] 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)

[0100] Step 1: 1a (5 g, 30.64 mmol) and K2CO3 (8.47 g, 61.28 mmol) were added to DMF (50 mL), followed by the addition of 3,4-dihydro-7-hydroxy-2(1H)-quinolinone (1b) (6.85 g, 45.96 mmol). The reaction mixture was stirred at 100°C for 24 h; diluted with water, extracted with ethyl acetate, and the organic phase was dried, filtered, and spin-dried to obtain the crude product, which was then purified by normal phase column chromatography (eluent: (dichloromethane:methanol = 20:1)); the target product was collected to obtain 1A (6.2 g, yield: 79.9%) as a yellow liquid.

[0101] 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 solution was stirred at room temperature for 1 hour. The reaction solution was purified by normal phase column chromatography (eluent: (dichloromethane:ethyl acetate = 10:1)); the desired product was collected to give 1B (6.1 g, yield: 91.2%) as a yellow solid.

[0102] Step 3: 1B (6.1 g, 19.72 mmol) and K2CO3 (8.18 g, 59.16 mmol) were added to DMF (70 mL), and then 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c) (5.8 g, 21.69 mmol) was added. The reaction solution was stirred at 50°C for 16 hours; diluted with water, extracted with ethyl acetate, and the organic phase was dried, filtered, and spin-dried to obtain the crude product. The product 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:H2O(0.1%HCOOH)=85:15). The target fractions were collected and lyophilized to obtain the title compound 1 (yellow solid) (12 mg, yield: 0.14%).

[0103] LCMS: 444[M+H] +

[0104] 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).

[0105] Example 2: Synthesis of 7-((6-(4-(2,3-dichlorophenyl)piperazin-1-yl)hexyl)oxy)-3,4-dihydroquinolin-2(1H)-one (Compound 3)

[0106] To a reaction flask were added 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). The mixture was heated under reflux for 4 hours. The mixture was filtered, the filter cake was washed with DMSO, and the organic phase was concentrated to obtain a crude product. This crude product was separated and purified by C18 reverse-phase column chromatography (eluent: methanol:0.5% aqueous formic acid = 85:15). The target fraction was collected, concentrated, and dried to give the title compound 3 as a white solid (135 mg, yield: 28.3%).

[0107] LCMS: 476 [M+H] +

[0108] 1 H NMR (400 MHz, DMSO-d6) δ9.97 (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 are covered by the solvent signal peak.

[0109] Example 3: Synthesis of 7-((5-(4-(2,3-dichlorophenyl)piperazin-1-yl)pentyl)oxy)-3,4-dihydroquinolin-2(1H)-one (Compound 4)

[0110] The title compound 4 (white solid) was prepared by the same synthetic route as in Example 2, except that 3a in Example 2 was replaced by 4a.

[0111] LCMS: 462 [M+H] +

[0112] 1 H 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).

[0113] Example 4: Synthesis of 7-(4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 6)

[0114] 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 for 1 hour. 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 then added, and the reaction was continued at 85°C for 2 hours. Inorganic salts were removed by filtration, and the solid was washed with methanol (2 × 10 mL). The filtrate was concentrated under reduced pressure, and the residue was purified using an 18C reverse-phase column (eluent: methanol: 0.1% formic acid aqueous solution = 70:30). The target fraction was collected and concentrated. The residue was dissolved in methanol (0.5 mL), and purified water (1 mL) was added. The mixture was concentrated under reduced pressure to remove methanol and then freeze-dried under reduced pressure to obtain the title compound 6 (light yellow flocculent solid, 80 mg, yield: 53%).

[0115] LCMS: 448 [M+H] +

[0116] 1 H 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).

[0117] Example 5: Synthesis of 7-((5-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)pentyl)oxy)-3,4-dihydroquinolin-2(1H)-one (Compound 7)

[0118] The title compound 7 (light yellow solid) was prepared by adopting the same synthetic route as Example 4, except that 6a in Example 4 was replaced by 4a.

[0119] LCMS: 462 [M+H] +

[0120] 1H NMR (400 MHz, DMSO-d6) δ9.96 (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: The four hydrogen signal peaks are covered by the solvent signal peak.

[0121] Example 7: Synthesis of 7-((5-(4-(2,3-dichlorophenyl)piperazin-1-yl)pentyl)oxy)quinolin-2(1H)-one (Compound 9)

[0122] Dissolve 9a (100 mg, 0.32 mmol, 1.0 eq.) in acetonitrile (5 mL), add 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.), and allow to react overnight at 85°C. Filter, wash the solid with methanol (2 × 10 mL), and concentrate the filtrate under reduced pressure. The residue is purified using an 18C reverse-phase column (eluent: methanol: 0.1% aqueous formic acid = 70:30). The desired fraction is collected and concentrated, and the residue is purified with methanol (5 mL) to afford the title compound 9 as a white solid (12 g, yield: 8%).

[0123] LCMS: 460 [M+H] +

[0124] 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: The four hydrogen signal peaks are covered by the solvent signal peak.

[0125] Example 8: Synthesis of 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2(1H)-one (Compound 10)

[0126] The title compound 10 (white solid) was prepared by the same synthetic route as in Example 7, except that 9a in Example 7 was replaced by 10a.

[0127] LCMS: 446 [M+H] +

[0128] 1 H 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).

[0129] Example 15: Synthesis of 7-(3-(1-(2,3-dichlorophenyl)piperidin-4-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 17)

[0130] Step 1: To a reaction flask, 17a (500 mg, 3.49 mmol, 1.0 eq.) and DCM (80 mL) were added dropwise. Thionyl chloride (630 mg, 5.25 mmol, 1.5 eq.) was added under an ice-water bath. The reaction mixture was incubated at room temperature under nitrogen for 4 hours. LCMS confirmed the reaction was complete, and the product was concentrated to afford crude 17A (550 mg, 99% yield).

[0131] Step 2: To a reaction flask, 17A (550 mg, 3.49 mmol, 1.0 eq.), dioxane (10 mL), and triethylamine (1.05 mL, 10.5 mmol, 3.0 eq.) were added dropwise to the reaction mixture under an ice-water bath. Boc-anhydride (900 mg, 4.2 mmol, 1.2 eq.) was added dropwise. After complete addition, the reaction mixture was incubated at room temperature for 4 hours. LCMS monitoring indicated that the starting material had substantially reacted. The mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to afford 17B (650 mg, 80% yield).

[0132] Step 3: To a reaction flask, 17B (500 mg, 1.88 mmol, 1.0 eq.) and acetonitrile (20 mL) were added, 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 incubated at 85°C for 4 hours. LCMS confirmed the complete reaction of the starting material. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to afford 17C (600 mg, 80% yield).

[0133] Step 4: To a reaction flask, 17C (600 mg, 1.32 mmol, 1.0 eq.) and ethyl acetate (10 mL) were added dropwise, followed by the addition of a 4 M dioxane hydrochloride solution (10 mL). The reaction mixture was allowed to react at room temperature for 4 hours. LCMS confirmed the near-complete reaction of the starting material. The product was concentrated under reduced pressure, purified with ethyl acetate, filtered, and the filter cake dried to afford 17D (500 mg, 90% yield).

[0134] Step 5: To a reaction flask, 17D (350 mg, 1.32 mmol, 1.0 eq.) and toluene (10 mL) were added, 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, and the reaction mixture was incubated at 100°C for 6 hours. The reaction was complete as monitored by LCMS, and the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by C18 reverse-phase preparative chromatography (eluent: methanol: 0.1% aqueous formic acid = 70:30) to afford the crude product, which was then separated on a silica gel column to afford the title compound 17 (30 mg, 10% yield).

[0135] LCMS: 433 [M+H] +

[0136] 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).

[0137] Example 16: Synthesis of 7-(4-(1-(2,3-dichlorophenyl)piperidin-4-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 18)

[0138] The title compound 18 was prepared by adopting the same synthetic route as Example 15, except that 17a in Example 15 was replaced by 18a.

[0139] LCMS: 447 [M+H] +

[0140] 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).

[0141] Example 17: Synthesis of 7-(4-(4-phenylpiperidin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 20)

[0142] To a reaction flask were added 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 three times and allowed to react at 85°C for 12 hours. After the reaction was complete as monitored by TLC and LCMS, the crude product was filtered and purified using a C18 reverse-phase column. The desired fractions were collected and concentrated to afford the title compound 20 as a white solid (500 mg, 70% yield).

[0143] LCMS: 379 [M+H] +

[0144] 1H 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).

[0145] Example 18: Synthesis of N-(4-(2,3-dichlorophenyl)cyclohexyl)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)acetamide (Compound 21)

[0146] 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), followed by the addition of HATU (1.28 g, 3.38 mmol). The reaction mixture was stirred at room temperature overnight; diluted with water, extracted with ethyl acetate, and the organic phase was dried, filtered, and spin-dried. The organic phase was then purified by reverse phase chromatography on a C18 column (eluent: methanol:0.1% aqueous formic acid = 70:30). The desired product was collected and lyophilized to afford the title compound 21 (white solid) (0.065 g, yield: 6.5%).

[0147] LCMS: 447 [M+H] +；

[0148] 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).

[0149] Example 19: Synthesis of 7-((5-(4-(2,3-dichlorophenyl)piperazin-1-yl)pentyl)oxy)-3,4-dihydroisoquinolin-1(2H)-one (Compound 23)

[0150] Step 1: To a reaction flask were added 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). The mixture was stirred at 85°C for 7 hours. The mixture was filtered, the filter cake was washed with methanol, and the filtrate was concentrated to obtain the crude product. This crude product was purified using a C18 reverse-phase column (eluent: methanol: 0.5% aqueous formic acid = 80:20). The desired fractions were collected and concentrated to afford 23A as a pale yellow solid (540 mg, 60% purity, yield: 58.3%).

[0151] Step 2: The title compound 23 (off-white solid) was prepared by the same synthetic route as in Example 2, except that 3a in Example 2 was replaced by 23A.

[0152] LCMS: 462 [M+H] +

[0153] 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).

[0154] Example 20: Synthesis of 6-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)indolin-2-one (Compound 24)

[0155] To a reaction flask, 24a (100 mg, 0.37 mmol, 1.0 eq.) dissolved in acetonitrile (6 mL) was added, followed by 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.). The reaction mixture was incubated at 70°C for 4 hours. After LCMS monitoring indicated that the starting materials had substantially reacted, the reaction mixture was filtered, dried, and purified by C18 reverse-phase column chromatography to afford the title compound 24 (off-white solid, 20 mg, yield: 12%).

[0156] LCMS: 434 [M+H] +

[0157] 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).

[0158] Example 21: Synthesis of 6-(4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)butoxy)indolin-2-one (Compound 25)

[0159] To a reaction flask, 24a (100 mg, 0.37 mmol, 1.0 eq.) dissolved in acetonitrile (6 mL) was added, followed by 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.). The reaction mixture was incubated at 70°C for 4 hours. After LCMS monitoring indicated that the starting material had substantially reacted, the reaction mixture was filtered, the filtrate was dried, and purified by normal phase column chromatography (eluent: DCM:MeOH = 10:1) to afford the title compound 25 (an off-white solid, 80 mg, 50% yield).

[0160] LCMS: 434 [M+H] +

[0161] 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).

[0162] 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)

[0163] Step 1: To a reaction flask were added 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 H2O (2 mL). The mixture was stirred at 40°C for 5 hours. The reaction mixture was filtered, the filter cake was washed with DMSO, and the filtrate was concentrated to obtain the crude product, which was purified using a C18 reverse-phase column (eluent: methanol:0.5% aqueous formic acid = 80:20). The desired fractions were collected and concentrated to afford 27A (120 mg, 19% yield) as a white solid.

[0164] Step 2: The title compound 27 (white solid) was prepared by the same synthetic route as in Example 2, except that 3a in Example 2 was replaced by 27A.

[0165] LCMS: 464 [M+H] +

[0166] 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).

[0167] Example 23: Synthesis of 6-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propoxy)benzo[d]thiazole (Compound 28)

[0168] Step 1: To a reaction flask, 28a (200 mg, 1.32 mmol, 1.0 eq.) and N,N-dimethylformamide (4 mL) / water (0.4 mL) were added, 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 incubated at 45°C for 3 hours. After LCMS monitoring indicated substantial reaction, water (10 mL) was added, 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 afford 28A (250 mg, 80% yield).

[0169] Step 2: To a reaction flask, 28A (350 mg, 1.32 mmol, 1.0 eq.) and N,N-dimethylformamide (10 mL) were added, 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 incubated at 85°C for 4 hours. After LCMS monitoring indicated that the starting material had substantially reacted, the mixture was filtered, and the mother liquor was concentrated and dried to obtain the crude product. This crude product was purified by C18 reverse-phase preparative chromatography (eluent: methanol: 0.1% aqueous formic acid = 70:30) to afford the title compound 28 (150 mg, 40% yield).

[0170] LCMS: 422 [M+H] +

[0171] 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).

[0172] Example 24: Synthesis of 6-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)benzo[d]thiazole (Compound 29)

[0173] The title compound 29 was prepared by the same synthetic route as in Example 23, except that 1,3-dibromopropane in step 1 of Example 23 was replaced by 1,4-dibromobutane and the potassium iodide equivalent in step 2 was changed from 1.0 eq to 0.1 eq.

[0174] LCMS: 436 [M+H] +

[0175] 1 H NMR (400 MHz, DMSO-d6) δ9.17 (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: The two hydrogen signal peaks are covered by the solvent signal peak.

[0176] Example 25: Synthesis of 4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-4-oxo-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl)but-2-enamide (Compound 30)

[0177] Step 1: 30a (500 mg, 2.46 mmol, 1.0 eq) was added to toluene (5 mL), followed by 30b (242 mg, 2.46 mmol, 1.0 eq). The mixture was stirred at 25°C for 16 h. The reaction mixture was filtered and the filter cake was dried to give 30A (560 mg, 75.5% yield) as a yellow solid.

[0178] Step 2: The title compound 30 (white solid) was prepared by the same synthetic route as in Example 18, except that 21a was replaced by 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c) and 21b was replaced by 30A.

[0179] LCMS: 514[M+H] +

[0180] 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).

[0181] Example 26: Synthesis of 4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-4-oxo-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl)butanamide (Compound 31)

[0182] 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), followed by the addition of 31a (271 mg, 2.71 mmol, 1.1 eq.). The mixture was stirred at 25°C for 16 h. The reaction mixture was evaporated to dryness to afford 31A (740 mg, 99.1% yield) as a yellow solid.

[0183] Step 2: The title compound 31 (white solid) was prepared by the same synthetic route as in Example 18, except that 21a was replaced by 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c) and 21b was replaced by 31A.

[0184] LCMS: 518 [M+H] +

[0185] 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).

[0186] 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)

[0187] 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), followed by 32a (1.25 g, 6.39 mmol, 1.3 eq.). The mixture was stirred at 85°C for 16 hours. The reaction mixture was spin-dried to obtain the crude product, which was then purified using a normal phase column chromatography (eluent: petroleum ether:ethyl acetate = 9:1). The desired product was collected to afford 32A as a yellow oil (350 mg, yield: 22.4%).

[0188] Step 2: 32A (350 mg, 1.10 mmol, 1.0 eq) was dissolved in THF / MeOH / H2O (6 mL / 2 mL / 2 mL). LiOH (66 mg, 2.76 mmol, 2.5 eq) was then added and stirred at 25°C for 2 h. The reaction mixture was diluted with water and adjusted to pH 5-6 with 1 M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate and the organic phase was dried. The reaction mixture was filtered and dried to afford 32B (300 mg, 94.0% yield) as a yellow solid.

[0189] 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), followed by the addition of HATU (590 mg, 1.55 mmol, 1.5 eq). The mixture was stirred at 25°C for 16 h, and the reaction solution was purified by C-18 reverse-phase column chromatography (eluent: methanol: 0.1% formic acid aqueous solution = 85:15). The target fractions were collected and lyophilized to give the title compound 32 (white solid, 94 mg, yield: 18.0%).

[0190] LCMS: 502[M+H] +

[0191] 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).

[0192] 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)

[0193] Step 1: Compound 33A (yellow solid) was prepared by the same synthetic route as in Example 18, except that 21a was replaced by 30a and 21b was replaced by 33a.

[0194] Step 2: Compound 33B was prepared by the same synthetic route as in Step 2 of Example 27, except that 32A in Step 2 of Example 27 was replaced by 33A.

[0195] Step 3: The same synthetic route as in Example 18 was used, except that 21a in Example 18 was replaced by 1c, and 21b was replaced by 33B, to give the title compound 33 (white solid).

[0196] LCMS: 564[M+H] +

[0197] 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).

[0198] Example 29: Synthesis of 7-(2-(4-(Benzo[d]thiazol-2-yl)piperazin-1-yl)ethoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 34)

[0199] The title compound 34 was prepared by adopting the same synthetic route as in step 2 of Example 23, except that 28A was replaced by 34b and 1c was replaced by 34a.

[0200] LCMS: 408 [M+H] +

[0201] 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).

[0202] Example 30: Synthesis of 7-(2-(4-(Benzothiazol-2-yl)piperazin-1-yl)ethoxy)quinolin-2(1H)-one (Compound 35)

[0203] The title compound 35 was prepared by adopting the same synthetic route as in Step 2 of Example 23, except that 28A was replaced by 35a and 1c was replaced by 34a.

[0204] LCMS: 407 [M+H] +

[0205] 1H 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).

[0206] Example 31: Synthesis of 7-(4-(4-(Benzo[d]thiazol-2-yl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 36)

[0207] To a reaction flask were added 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 three times and allowed to react at 85°C for 4 hours. After complete reaction, as monitored by TLC, the reaction mixture was filtered and dried. The crude product was purified using a C18 reverse-phase column. The target fractions were collected and concentrated to afford the title compound 36 as a white solid (20 mg, 10% yield).

[0208] LCMS: 437 [M+H] +

[0209] 1 H NMR (400 MHz, DMSO-d6) δ9.97 (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 are covered by the solvent signal peak.

[0210] Example 32: Synthesis of 7-(4-(4-(Benzo[d]thiazol-2-yl)piperazin-1-yl)butoxy)quinolin-2(1H)-one (Compound 37)

[0211] The title compound 37 (white solid) was prepared by the same synthetic route as in Example 31, except that 6a in Example 31 was replaced by 10a.

[0212] LCMS: 435 [M+H] +

[0213] 1 H 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 are covered by the solvent signal peak.

[0214] Example 33: Synthesis of 7-(3-(4-(benzo[d]thiazol-2-yl)piperazin-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 38)

[0215] To a reaction flask, 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) were added and stirred at 85°C for 6 hours. The product was separated and purified by silica gel column chromatography (eluent: dichloromethane:methanol = 85:15). The desired fraction was collected and concentrated to afford the title compound 38 as a white solid (50 mg, yield: 23.7%).

[0216] LCMS: 423 [M+H] +

[0217] 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).

[0218] Example 34: Synthesis of 7-(3-(4-(Benzo[d]thiazol-2-yl)piperazin-1-yl)propoxy)quinolin-2(1H)-one (Compound 39)

[0219] The title compound 39 (white solid) was prepared by the same synthetic route as in Example 33, except that 38a in Example 33 was replaced by 39a.

[0220] LCMS: 421 [M+H] +

[0221] 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).

[0222] Example 35: 7-(3-(4-(2-methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepine Synthesis of 2-(4-yl)piperazin-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 40)

[0223] The title compound 40 (off-white solid) was prepared by the same synthetic route as in Example 20, except that 24a was replaced by 38a and 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c) was replaced by 40a.

[0224] LCMS: 502 [M+H] +

[0225] 1 H 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).

[0226] Example 36: 7-(4-(4-(2-methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepine Synthesis of 4-oxobutoxy-3,4-dihydroquinolin-2(1H)-one (Compound 41)

[0227] To a reaction flask, 41a (200 mg, 0.80 mmol, 1.0 eq.) and N,N-dimethylformamide (6 mL) were added, followed by HATU (380 mg, 0.96 mmol, 1.2 eq.). The reaction was stirred at room temperature for 30 minutes. 40a (240 mg, 0.80 mmol, 1.0 eq.) and N,N-diisopropylethylamine (309 mg, 2.4 mmol, 3.0 eq.) were then added, and the reaction was allowed to react at room temperature for 4 hours. After the reaction was complete as monitored by LCMS, the starting material was filtered, dried, and purified using a C18 reverse-phase column to afford the crude product, which was then purified using a normal-phase column to afford the title compound 41 as an off-white solid (100 mg, 24% yield).

[0228] LCMS: 530 [M+H] +

[0229] 1 H 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).

[0230] Example 37: 7-(4-(4-(2-methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepine Synthesis of 2-(4-yl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 42)

[0231] The title compound 42 (off-white solid) was prepared by the same synthetic route as in Example 7, except that 9a was replaced by 6a and 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c) was replaced by 40a.

[0232] LCMS: 516 [M+H] +

[0233] 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).

[0234] Example 38: Synthesis of 7-(2-(4-(1-propionylindolin-5-yl)piperazin-1-yl)ethoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 43)

[0235] To a reaction flask were added 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.) in sequence. The reaction mixture was purged with nitrogen three times, and tris(dibenzylideneacetone)dipalladium (115 mg, 0.2 mmol, 0.1 eq.) was added. The mixture was reacted at 100°C under nitrogen for 12 hours. LCMS monitoring indicated that the reaction mixture had reacted completely. The reaction mixture was then filtered and dried, purified by C18 reverse-phase column separation, and then purified by normal-phase column separation (DCM:MeOH = 10:1) to afford the title compound 43 (179 mg, 20% yield).

[0236] LCMS: 449 [M+H] +

[0237] 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).

[0238] Example 39: Synthesis of 6-(4-(4-(Benzo[d]thiazol-2-yl)piperazin-1-yl)butoxy)indolin-2-one (Compound 44)

[0239] To a reaction flask, 24a (100 mg, 0.37 mmol, 1.0 eq.) dissolved in acetonitrile (6 mL) was added, followed by 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.). The reaction mixture was incubated at 60°C for 4 hours. After the reaction was complete, as monitored by LCMS, the reaction mixture was filtered, the filtrate was dried, and purified using a forward column chromatography (eluent: DCM:MeOH = 10:1) to afford the title compound 44 as an off-white solid, 80 mg, yield: 51%.

[0240] LCMS: 423 [M+H] +

[0241] 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).

[0242] Example 40: Synthesis of 2-((2-(4-(3,5-bis(trifluoromethyl)phenyl)piperazin-1-yl)-2-oxoethyl)thio)-N-(m-methylphenyl)acetamide (Compound 45)

[0243] Step 1: To a reaction flask, add 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.). Add oxalyl chloride (847 mg, 6.67 mmol, 1.0 eq.) dropwise under ice. Stir the reaction mixture at room temperature for 2 hours. Concentrate under reduced pressure to obtain 1.1 g of crude product 45a.

[0244] Step 2: To a reaction flask, 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.) were added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by column chromatography (eluent: dichloromethane:methanol = 9:1) to collect the desired fraction, which was then concentrated under reduced pressure to afford 45B (1.0 g, 63% yield) as a white solid.

[0245] Step 3: To a reaction flask, 45B (100 mg, 0.42 mmol, 1.0 eq.), DCM (5 mL), and HATU (191 mg, 0.50 mmol, 1.2 eq.) were added. After stirring at room temperature for 30 minutes, 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 purified by column chromatography (eluent: methanol:0.1% aqueous formic acid = 65:35). The desired fraction was collected and concentrated under reduced pressure to afford the title compound 45 as a white solid (114 mg, yield: 52%).

[0246] LCMS: 520 [M+H] +

[0247] 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).

[0248] Example 41: Synthesis of 2-((2-(4-(2,3-dichlorophenyl)piperazin-1-yl)-2-oxoethyl)thio)-N-(m-methylphenyl)acetamide (Compound 46)

[0249] The title compound 46 (white solid) was prepared by the same synthetic route as in Step 3 of Example 40, except that 1-(3,5-bis(trifluoromethyl)phenyl)piperazine (45c) was replaced by 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c).

[0250] LCMS: 452 [M+H] +

[0251] 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).

[0252] Example 42: Synthesis of N-(3-amino-4-methoxyphenyl)-2-(4-(2,3-dichlorophenyl)piperazin-1-yl)acetamide (Compound 47)

[0253] Step 1: To a 250 mL three-necked flask was added 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). The mixture was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was separated by silica gel column chromatography (dichloromethane:methanol = 10:1) and concentrated under reduced pressure to afford 47A (1.6 g, 70.2% yield) as an off-white solid.

[0254] Step 2: To a 250 mL single-necked flask, add 47A (1.6 g, 0.0037 mol, 1 eq.), Pd / C (0.5 g), and methanol (50 mL). The mixture was replaced with a hydrogen balloon three times and stirred at room temperature for 16 hours. After completion of the reaction, the mixture was separated 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 afford the title compound 47 as an off-white solid (0.15 g, yield: 9.9%).

[0255] LCMS: 409[M+1] +

[0256] 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).

[0257] Example 43: Synthesis of 2-(4-(2,3-dichlorophenyl)piperazin-1-yl)-N-(3-(dimethylamino)-4-methoxyphenyl)acetamide (Compound 48)

[0258] To a reaction flask were added 47 (80 mg, 0.20 mmol, 1.0 eq.) and methanol (6 mL), followed by paraformaldehyde (6.6 mg, 0.22 mmol, 1.1 eq.). The reaction was stirred at room temperature under nitrogen for 4 hours, and then sodium cyanoborohydride (63 mg, 1.0 mmol, 5.0 eq.) was added. The reaction mixture was stirred at room temperature overnight and the reaction was completed. The reaction mixture was filtered and dried, and the title compound 48 was isolated by C18 reverse phase column chromatography as a white solid (42 mg, yield: 50%).

[0259] LCMS: 437 [M+H] +

[0260] 1 H 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).

[0261] Example 44: Synthesis of N-(3-amino-4-methoxyphenyl)-3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propionamide (Compound 49)

[0262] Step 1: To a reaction flask were added 49a (135 mg, 0.47 mmol, 1.0 eq.) and N,N-dimethylformamide (6 mL), followed by the addition of HATU (214 mg, 0.56 mmol, 1.2 eq.). The reaction was stirred at room temperature under nitrogen for 1 hour. 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 for 6 hours. The reaction was completed and the reaction solution was directly separated by C18 column chromatography to obtain 49A (103 mg, yield: 50%) as a white solid.

[0263] Step 2: To a reaction flask were added 49A (103 mg, 0.235 mmol, 1.0 eq.) and acetic acid (6 mL), followed by iron powder (658 mg, 1.17 mmol, 5.0 eq.). The reaction was stirred at 60°C under nitrogen for 4 hours. The reaction mixture was filtered and dried, and separated by column chromatography (dichloromethane:methanol = 10:1) to give the title compound 49 as a gray solid (80 mg, yield: 85%).

[0264] LCMS: 423 [M+H] +

[0265] 1 H 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).

[0266] Example 45: Synthesis of 3-(4-(2,3-dichlorophenyl)piperazin-1-yl)-N-(4-methoxy-3-(methylamino)phenyl)propionamide (Compound 50)

[0267] The same synthetic route as in Example 43 was adopted except that compound 47 in Example 43 was replaced by compound 49. During post-treatment, the reaction solution was filtered and dried, and separated by C18 reverse phase column and normal phase column chromatography to obtain the title compound 50 (white solid).

[0268] LCMS: 437 [M+H] +

[0269] 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).

[0270] Example 46: N 4 Synthesis of -(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)pyrimidine-2,4-diamine (Compound 51)

[0271] To a 100 mL single-necked flask, 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) were added. The atmosphere was purged with nitrogen three times. The mixture was heated to 100°C under nitrogen for 3 hours. After the reaction was complete, the mixture was filtered and the filtrate was evaporated to dryness. The crude product was purified with methanol and filtered to yield 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% formic acid aqueous solution = 80:20) to give the title compound 51 (yellow oil) (0.01 g, yield: 9.4%).

[0272] LCMS: 367[M+1] +

[0273] 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).

[0274] Example 47: Synthesis of 4-(((2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)amino)methyl)benzene-1,2-diol (Compound 52)

[0275] Step 1: Compound 52A (off-white solid) was prepared by the same synthetic route as in Step 2 of Example 1, except that 1A in Step 2 of Example 1 was replaced by 52a.

[0276] 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 reaction was allowed to react at room temperature overnight. The mixture was concentrated under reduced pressure to afford the crude product, which was then purified by reverse-phase column chromatography (eluent: methanol:0.1% formic acid aqueous solution = 80:20). The target fraction was collected and concentrated to dryness to afford the title compound 52 (92 mg, 15% yield) as a yellow oil.

[0277] LCMS: 396 [M+H] +

[0278] 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).

[0279] Example 48: Synthesis of N-(4-(4-(3,5-bis(trifluoromethyl)phenyl)piperazin-1-yl)butyl)-4-chlorobenzamide (Compound 53)

[0280] Compound 53a (145 mg, 0.50 mmol, 1.0 eq.) dissolved in acetonitrile (10 mL) was added to a reaction flask. Potassium carbonate (207 mg, 1.50 mmol, 3.0 eq), 1-(3,5-ditrifluoromethylphenyl)piperazine hydrochloride 45c (180 mg, 0.6 mmol, 1.2 eq), and potassium iodide (10 mg, 0.05 mmol, 0.1 eq) were then added to the flask. The reaction mixture was incubated at 85°C for 8 hours. After the reaction was complete, the mixture was filtered, dried, and purified using a C18 reverse-phase column to obtain the title compound 53 (an off-white solid, 127 mg, 50% yield).

[0281] LCMS: 508 [M+H] +

[0282] 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).

[0283] Example 49: Synthesis of (E)-1-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-(3,4,5-trihydroxyphenyl)prop-2-en-1-one (Compound 55)

[0284] To a reaction flask, 57 (0.4 g, 0.88 mmol, 1.0 eq.) and dichloromethane (30 mL) were added dropwise. Boron tribromide (17% solution in dichloromethane, 4.0 mL, 3.0 mmol, 3.5 eq.) was added dropwise under an ice bath. The mixture was stirred overnight at room temperature. The reaction was quenched by the addition of saturated sodium carbonate solution and extracted with 50 mL of dichloromethane. A solid precipitated, which was dissolved in methanol and purified using a C18 reverse-phase column (eluent: methanol:0.5% aqueous formic acid = 65:35). The desired fraction was collected and concentrated to afford the title compound 55 as a white solid (117 mg, yield: 32.5%).

[0285] LCMS: 409 [M+H] +

[0286] 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).

[0287] Example 50: Synthesis of (E)-1-(4-(2,3-dichlorophenyl)piperazin-1-yl)-4-(3,4-dimethoxyphenyl)but-3-en-1-one (Compound 59)

[0288] The title compound 59 (off-white solid) was prepared by the same synthetic route as in Step 3 of Example 40, except that 1-(3,5-bis(trifluoromethyl)phenyl)piperazine (45c) was replaced by 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c) and 45B was replaced by 59a.

[0289] LCMS: 435 [M+H] +

[0290] 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).

[0291] Example 51: Synthesis of (E)-1-(2,3-dichlorophenyl)-4-(3-(3,4-dimethoxyphenyl)allyl)piperazine (Compound 60)

[0292] To a reaction flask, 58 (1.1 g, 2.6 mmol, 1.0 eq.) and THF (30 mL) were added dropwise. LiAlH₄ (2.5 mol / L THF solution, 1.5 mL, 3.9 mmol, 1.5 eq.) was added dropwise under an ice bath. The mixture was stirred at room temperature for half an hour. Saturated sodium sulfate solution was added dropwise, the mixture was filtered, and the filter cake was washed with DMSO. The mother liquor was concentrated to obtain the crude product, which was separated and purified using a C18 reverse-phase column (eluent: methanol:0.5% aqueous formic acid = 80:20). The desired fractions were collected and concentrated to give the title compound 60 (0.54 g, 51% yield) as an oily liquid.

[0293] LCMS: 407 [M+H] +

[0294] 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).

[0295] Example 52: Synthesis of (E)-4-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)prop-1-en-1-yl)benzene-1,2-diol (Compound 61)

[0296] The title compound 61 (off-white solid) was prepared by the same synthetic route as in Example 51, except that 58 in Example 51 was replaced by 56.

[0297] LCMS: 379[M+1] +

[0298] 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).

[0299] Example 53: Synthesis of (E)-5-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)prop-1-en-1-yl)-2-(2-hydroxypropoxy)phenol (Compound 62)

[0300] Step 1: Compound 62A (yellow oil) was prepared by the same synthetic route as in Step 1 of Example 1, except that 1a in Example 1 was replaced by 1-bromo-2-propanol and 1b was replaced by 61a.

[0301] Step 2: 62A (1.5 g, 5.06 mmol) was added to a mixed solvent of THF / H2O (40 mL, 3:1), followed by the addition of sodium hydroxide (405 mg, 10.1 mmol); the reaction mixture was stirred at room temperature for 20 h; the pH was adjusted to 5-6 with 1 M aqueous HCl, and the mixture was extracted with ethyl acetate. The organic phase was dried, filtered, and dried to afford 62B (700 mg, 58.0% yield) as a black solid.

[0302] Step 3: Compound 62C (brown solid) was prepared by the same synthetic route as in Example 18, except that 21b was replaced by 62B and 21a was replaced by 1c.

[0303] Step 4: 62C (420 mg, 0.93 mmol) was added to THF (5 mL), and then LiAlH4 (1.1 mL, 2.5 M in THF) was slowly added dropwise at 0°C. The reaction solution was stirred at 0°C for 2 h; water was added to quench the reaction, and the mixture was filtered. The mother liquor was spin-dried to give the crude product, which was purified using a C-18 reverse-phase column (eluent: (H2O (0.1% NH4HCO3):MeOH) = 20:80). The target fractions were collected and lyophilized to give the title compound 62 (white solid, 76 mg, yield 16.9%).

[0304] LCMS: 437 [M+H] +

[0305] 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).

[0306] Example 54: Synthesis of 4-(2,3-dichlorophenyl)-N-(3,4-dihydroxyphenylethyl)piperazine-1-carboxamide (Compound 63)

[0307] The title compound 63 (white solid) was prepared by the same synthetic route as in Example 49, except that 57 in Example 49 was replaced by 64.

[0308] LCMS: 410 [M+H] +

[0309] 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).

[0310] Example 55: Synthesis of 4-(2,3-dichlorophenyl)-N-(3,4-dimethoxyphenethyl)piperazine-1-carboxamide (Compound 64)

[0311] 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. The mixture was allowed to react at room temperature for 1 hour. 1-(2,3-Dichlorophenyl)piperazine hydrochloride (1c) (200 mg, 0.75 mmol, 1.0 eq.) was then added and allowed to react at room temperature overnight. The mixture was concentrated under reduced pressure to obtain a crude product, which was then purified using an 18C reverse-phase column (eluent: methanol:0.1% formic acid aqueous solution = 70:30). The target fraction was collected, concentrated, and dried to give the title compound 64 as a yellow solid (80 mg, yield: 24%).

[0312] LCMS: 438 [M+H] +

[0313] 1 H 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).

[0314] Example 56: Synthesis of 4-(2,3-dichlorophenyl)-N-(2-((3,4-dimethoxyphenyl)amino)-2-oxoethyl)piperazine-1-carboxamide (Compound 65)

[0315] To a reaction flask, 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) were added and stirred at room temperature for 3 hours. 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 under ice-cooling. The mixture was stirred for 15 minutes, and the above reaction solution was added dropwise. The mixture was stirred at room temperature overnight. The reaction mixture was washed with 20 mL of water and extracted with 50 mL of dichloromethane. The organic phase was separated and dried over anhydrous sodium sulfate. The mixture was separated and purified by silica gel column chromatography (eluent: dichloromethane:methanol = 85:15). The target fraction was collected, concentrated and dried to give the title compound 65 (white solid) (0.55 g, yield: 63.8%).

[0316] LCMS: 467 [M+H] +

[0317] 1 H 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).

[0318] Example 57: Synthesis of 4-(2,3-dichlorophenyl)-N-(2-((3,4-dihydroxyphenyl)amino)-2-oxoethyl)piperazine-1-carboxamide (Compound 66)

[0319] The title compound 66 (off-white solid) was prepared by the same synthetic route as in Example 49, except that 57 in Example 49 was replaced by 65.

[0320] LCMS: 439 [M+H] +

[0321] 1H 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).

[0322] Example 58: Synthesis of 4-(2,3-dichlorophenyl)-N-(2-((3-hydroxyphenyl)amino)-2-oxoethyl)piperazine-1-carboxamide (Compound 67)

[0323] The title compound 67 (off-white solid) was prepared by the same synthetic route as in Example 49, except that 57 in Example 49 was replaced by 68.

[0324] LCMS: 423 [M+H] +

[0325] 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).

[0326] Example 59: Synthesis of 4-(2,3-dichlorophenyl)-N-(2-((3-methoxyphenyl)amino)-2-oxoethyl)piperazine-1-carboxamide (Compound 68)

[0327] The title compound 68 (white solid) was prepared by the same synthetic route as in Example 56, except that 65a in Example 56 was replaced by 68a.

[0328] LCMS: 437 [M+H] +

[0329] 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).

[0330] Example 60: Synthesis of 1-(2,3-dichlorophenyl)-4-(3-(5-methoxypyridin-3-yl)prop-2-en-1-yl)piperazine (Compound 69)

[0331] Step 1: To a reaction flask, add 1-(2,3-dichlorophenyl)piperazine hydrochloride 1C (1.08 g, 4.69 mmol, 1.0 eq.), propargyl bromide (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 three times and allowed to react at room temperature for 12 hours. After reaction, as monitored by TLC and LCMS, the crude product was filtered, dried, and purified by normal-phase column chromatography to yield Compound 69A (colorless liquid, 1 g, 70% yield).

[0332] Step 2: To a reaction flask were added 69A (500 mg, 1.86 mmol, 1.0 eq.), anhydrous acetonitrile (10 mL), Cs2CO3 (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 three times under nitrogen atmosphere, and tris(dibenzylideneacetone)dipalladium (110 mg, 0.19 mmol, 0.1 eq.) was added. The reaction was stirred at 50°C for 16 hours. After complete reaction, the starting material was filtered, the crude product was dried, and purified by C18 reverse-phase preparative chromatography. The desired fractions were collected and concentrated to afford the title compound 69 as a white solid (220 mg, 30% yield).

[0333] LCMS: 376 [M+H] +

[0334] 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).

[0335] Example 61: Synthesis of 5-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)prop-1-yn-1-yl)pyridin-3-ol (Compound 70)

[0336] The title compound 70 (gray solid) was prepared by the same synthetic route as in Step 2 of Example 60, except that 3-bromo-5-methoxypyridine (69b) was replaced by 3-hydroxy-5-bromopyridine (70a).

[0337] LCMS: 362 [M+H] +

[0338] 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).

[0339] Example 62: Synthesis of 1-(2,3-dichlorophenyl)-4-(4-(5-methoxypyridin-3-yl)but-3-yn-1-yl)piperazine (Compound 71)

[0340] Step 1: Except replacing 9a in Example 7 with 71a, the same synthetic route as Example 7 was adopted to prepare yellow solid 71A.

[0341] 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 Pd2(dba)3 (32 mg, 0.04 mmol, 0.05 eq.) were added. The mixture was heated to 50°C under nitrogen and allowed to react 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 purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 2:1) to collect the desired fraction, which was then concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (dichloromethane:methanol=20:1) to obtain the title compound 71 (yellow solid) (15 mg, yield: 5%).

[0342] LCMS: 390 [M+H] +

[0343] 1H 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).

[0344] Example 63: Synthesis of 1-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-(5-methoxypyridin-3-yl)prop-2-yn-1-one (Compound 72)

[0345] Step 1: Propiolic acid (72a) (100 mg, 1.43 mmol, 1.0 eq.) was dissolved in dichloromethane (3 mL), and 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. The mixture was allowed to react overnight at room temperature. The mixture was concentrated under reduced pressure to afford a crude product, which was then purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1). The desired fractions were collected and concentrated to afford 72A (380 mg, 94% yield) as a white solid.

[0346] Step 2: 3-Bromo-5-methoxypyridine (69b) (280 mg, 1.49 mmol, 1.0 eq.) was dissolved in N,N-dimethylformamide (5 mL), and 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 PdCl2(PPh3)2 (52 mg, 0.07 mmol, 0.05 eq.) were added. The temperature was raised to 70°C under nitrogen protection and the reaction was carried out overnight. The mixture was diluted with water (50 mL), extracted with ethyl acetate (3×50 mL), and the combined organic phases were washed with saturated brine (50 mL), dried, and concentrated. The residue was separated and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 2:1). The target fractions were collected and concentrated under reduced pressure to give a crude product, which was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1) to give the title compound 72 (brown oily liquid) (20 mg, yield: 3%).

[0347] LCMS: 390 [M+H] +

[0348] 1H NMR (400 MHz, CDCl3) δ8.37 (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: The five hydrogen signal peaks are covered by the solvent signal peak.

[0349] Example 64: Synthesis of (E)-2-(4-(3-(3,4-dimethoxyphenyl)allyl)piperazin-1-yl)benzo[d]thiazole (Compound 73)

[0350] To the reaction flask were added 74 (200 mg, 0.49 mmol, 1.0 eq.) and tetrahydrofuran (5 mL), and then a solution of lithium aluminum tetrahydride in tetrahydrofuran (0.3 mL, 0.74 mmol, 1.5 eq.) was added under nitrogen in an ice-water bath. The reaction was allowed to warm to room temperature and stirred under nitrogen for 0.5 h. The mixture was then quenched by the addition of saturated aqueous sodium sulfate solution, filtered, and concentrated. The crude product was separated on a C18 column and purified with methanol to give the title compound 73 (white solid) (26 mg, yield: 13%).

[0351] LCMS: 396 [M+H] +

[0352] 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).

[0353] Example 65: Synthesis of (E)-1-(4-(Benzo[d]thiazol-2-yl)piperazin-1-yl)-3-(3,4-dimethoxyphenyl)prop-2-en-1-one (Compound 74)

[0354] To a reaction flask were added 3,4-dimethoxycinnamic acid (74a) (1.0 g, 4.81 mmol, 1.0 eq.) and DCM (30 mL), followed by the addition of HATU (2.74 g, 7.21 mmol, 1.5 eq.). The reaction was stirred at room temperature under nitrogen for 1 hour, and then 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 for 6 hours before the reaction was completed. The crude product was filtered and purified with methanol to give the title compound 74 (white solid) (1.2 g, yield: 61%).

[0355] LCMS: 410 [M+H] +

[0356] 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).

[0357] 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)

[0358] Step 1: To a reaction flask, add 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). Add NaH (0.16 g, 4.0 mmol, 2.0 eq.) portionwise under ice-cooling. Stir at room temperature for 2 hours. Quench the reaction dropwise with water under ice-cooling. Purify the product by silica gel column chromatography (eluent: dichloromethane:methanol = 95:5) to collect the desired fraction. Concentrate to afford 75A as a pale yellow oil (0.24 g, yield: 80.2%).

[0359] Step 2: The title compound 75 (colorless oily liquid) (127 mg, yield: 35.3%) was prepared by the same synthetic route as in Example 2, except that 3a in Example 2 was replaced by 75A.

[0360] LCMS: 449 [M+H] +

[0361] 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).

[0362] 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)propanamide (Compound 76)

[0363] Step 1-2: To a reaction flask, 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) were added. NaH (0.2 g, 5.0 mmol, 2.5 eq., 60%) was added portionwise under an ice bath. The temperature was raised to 25°C and the reaction was incubated for 4 hours. The reaction was quenched by dropwise addition of water. The product was purified by silica gel column chromatography (eluent: DCM:MeOH = 60:40). The desired fraction was collected and concentrated to afford 76B (0.35 g, 78.7%) as an off-white solid.

[0364] Step 3: To a reaction flask were added 76B (175 mg, 0.78 mmol, 1.0 eq.), HATU (358 mg, 0.94 mmol, 1.2 eq.), and DMF (8 mL). The mixture was 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. The crude product was concentrated to afford the crude product, which was purified using a C18 reverse-phase column (eluent: 0.5% aqueous formic acid:acetonitrile = 40:60). The desired fractions were collected and concentrated to afford the title compound 76 as an off-white solid (45 mg, yield: 12.6%).

[0365] LCMS: 458 [M+H] +

[0366] 1H 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).

[0367] 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)

[0368] The title compound 77 (colorless oily liquid) was prepared by the same synthetic route as in Example 2, except that 3a was replaced by 75A and 1c was replaced by 77a.

[0369] LCMS: 429 [M+H] +

[0370] 1 H 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).

[0371] Example 69: Synthesis of 5,6-dimethoxy-1-(4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)butyl)indole-2-one (Compound 78)

[0372] Step 1: To a reaction flask, 78a (1.0 g, 5.0 mmol, 1.0 eq.) and acetonitrile (30 mL) were added. 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 then added. The reaction mixture was incubated at 95°C for 8 hours. After completion of the reaction as monitored by LCMS, the product was filtered, dried, and isolated on a silica gel column to afford 78A (500 mg, 31% yield) as an off-white solid.

[0373] Step 2: The title compound 78 (off-white solid) was prepared by the same synthetic route as in Example 20, except that 24a was replaced by 78A and 1c was replaced by 6b.

[0374] LCMS: 478 [M+H] +

[0375] 1 H 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).

[0376] Example 70: Synthesis of 1-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-5,6-dimethoxyindolin-2-one (Compound 79)

[0377] The title compound 79 (off-white solid) was prepared by the same synthetic route as in Example 20, except that 24a in Example 20 was replaced by 78A.

[0378] LCMS: 478 [M+H] +

[0379] 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).

[0380] Example 71: Synthesis of ethyl 2-((4-(4-(benzo[d]thiazol-2-yl)piperazin-1-yl)butanamido)methyl)-5-methylthiazole-4-carboxylate (Compound 80)

[0381] The title compound 80 (white solid) was prepared by following the same synthetic route as in Step 3 of Example 67, except that 76a was replaced by 80b and 76B was replaced by 80a.

[0382] LCMS: 488 [M+H] +

[0383] 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).

[0384] 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)

[0385] Compound 80 (0.276 g, 0.566 mmol, 1.0 eq.) and THF (10 mL) were added dropwise to a reaction flask under an ice bath. LiAlH₄ (0.9 mL, 2.264 mmol, 4.0 eq., 2.5 mol / L in THF) was added dropwise and stirred for 1 hour. The reaction was quenched by the dropwise addition of saturated Na₂SO₄ solution. The solvent was evaporated to dryness, and 4 mL of DMSO was added to dissolve the residue. The residue was purified using a C₁8 reverse-phase column (eluent: 0.5% aqueous formic acid:MeOH = 25:75). The target fractions were collected and concentrated to obtain the title compound 81 (white solid, 90 mg, yield: 35.7%).

[0386] LCMS: 446 [M+H] +

[0387] 1 H 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).

[0388] Example 73: Synthesis of ethyl 2-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butanamido)methyl)-5-methylthiazole-4-carboxylate (Compound 82)

[0389] The title compound 82 (white solid) was prepared by the same synthetic route as in Step 3 of Example 67, except that 76a was replaced by 80b and 76B was replaced by 82a.

[0390] LCMS: 499 [M+H] +

[0391] 1 H NMR(400MHz,DMSO-d6)δ8.83(t,1H),7.38-7.29(m,2H),7.20(dd 1H),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).

[0392] Example 74: Synthesis of 4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-N-((4-(hydroxymethyl)-5-methylthiazol-2-yl)methyl)butanamide (Compound 83)

[0393] The title compound 83 (light yellow oily liquid) was prepared by the same synthetic route as in Example 51, except that 58 in Example 51 was replaced by 82.

[0394] LCMS: 457 [M+H] +

[0395] 1 H NMR (400 MHz, DMSO-d6) δ8.68 (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 are covered by the solvent signal peak.

[0396] 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)

[0397] The title compound 85 (white solid) was prepared by the same synthetic route as in Step 3 of Example 67, except that 76a was replaced by 51a and 76B was replaced by 85b.

[0398] LCMS: 463 [M+H] +

[0399] 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).

[0400] 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)

[0401] 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 allowed to react at room temperature for 1 hour. 1-Bromo-3-chloropropane (123 mg, 0.78 mmol, 1.0 eq.) was then added and the mixture was allowed to react at room temperature overnight. The acetone was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 1:4) to afford 86A (60 mg, yield: 26%) as a white solid.

[0402] 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. The mixture was concentrated under reduced pressure, and the residue was purified by C18 reverse phase separation (eluent: methanol:0.1% aqueous ammonia solution = 90:10) to give an off-white solid (40 mg). The title compound 86 was further purified by C18 reverse phase separation (eluent: methanol:0.1% aqueous formic acid solution = 70:30) to give the title compound 86 as a pale yellow viscous solid (18 mg, yield: 19%).

[0403] LCMS: 215 [M / 2+H] +

[0404] 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).

[0405] 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)propanamide (Compound 87)

[0406] The title compound 87 (white solid) was prepared by the same synthetic route as in Step 3 of Example 40, except that 45B in Step 3 of Example 40 was replaced by 87a and 1-(3,5-bis(trifluoromethyl)phenyl)piperazine (45c) was replaced by 86a.

[0407] LCMS: 443 [M+H] +

[0408] 1H 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).

[0409] 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)

[0410] The title compound 88 (white solid) was prepared by the same synthetic route as in Step 2 of Example 76, except that 86A was replaced by 88a.

[0411] LCMS: 221 [M / 2+H] +

[0412] 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).

[0413] 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)propanamide (Compound 89)

[0414] The title compound 89 (pale yellow solid) was prepared by the same synthetic route as in Step 3 of Example 40, except that 45B in Step 3 of Example 40 was replaced by 49a and 1-(3,5-bis(trifluoromethyl)phenyl)piperazine (45c) was replaced by 86a.

[0415] LCMS: 454 [M+H]+

[0416] 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).

[0417] Example 80: Synthesis of 3-((3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propoxy)methyl)-2-methylimidazo[5,1-b]thiazole (Compound 90)

[0418] To a reaction flask, 90a (200 mg, 1.19 mmol, 1.0 eq) and DMF (2 mL) were added and cooled to 0°C under nitrogen. 1-(3-chloropropyl)-4-(2,3-dichlorophenyl)piperazine (88a) (364 mg, 1.19 mmol, 1.0 eq) and potassium iodide (10 mg) were added while in an ice bath. The mixture was stirred at room temperature for 2 hours. Water was added dropwise to the reaction solution to quench the mixture, followed by extraction with 20 mL of EA. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (eluent: DCM: 1% ammonia in methanol = 80:20) to afford the title compound 90 as a pale yellow solid (98 mg, yield: 19%).

[0419] LCMS: 439 [M+H] +

[0420] 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).

[0421] Example 84: Synthesis of 7-(4-((1,2,3,4-tetrahydroacridin-9-yl)amino)butoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 95)

[0422] To a reaction flask, 95a (600 mg, 3.0 mmol, 1.0 eq.) and N,N-dimethylformamide (10 mL) were added, followed by sodium hydride (144 mg, 3.6 mmol, 1.2 eq.). The reaction mixture was allowed to react at 0°C for 30 minutes. 7-(4-bromobutoxy)-3,4-dihydroquinolin-2(1H)-one (6a) (900 mg, 3.0 mmol, 1.0 eq.) was then added to the reaction mixture, and the reaction was allowed to continue at room temperature for 1 hour. LC-MS monitoring revealed that 40% of the starting material remained. The product was quenched with ice water, extracted with dichloromethane, dried, concentrated, and purified by spin-drying. The product was then separated and purified by normal phase column chromatography (eluent: dichloromethane:methanol = 10:1) to afford the title compound 95 as a gray solid (40 mg, yield: 10%).

[0423] LCMS: 416 [M+H] +

[0424] 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).

[0425] 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)

[0426] Step 1: 96A (510 mg, yield: 62.0%) as a white solid was prepared by the same synthetic route as in Example 18, except that 21a in Example 18 was replaced by 96b.

[0427] Step 2: 96A (500 mg, 1.38 mmol) was added to 4M HCl / 1,4-dioxane (5 mL) and stirred at room temperature for 1 hour. The reaction solution was spin-dried to give 96B (400 mg, yield: 97.0%) as a white solid.

[0428] 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). After stirring at room temperature for half an hour, NaBH3CN (189 mg, 3.00 mmol) was added and the reaction solution was stirred at 0°C for 16 hours. The reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried and the reaction solution was filtered and spin-dried to give the crude product. The crude product was purified by C18 reverse phase column chromatography (eluent: methanol: 0.1% formic acid aqueous solution = 75:25). The target fractions were collected and lyophilized to give the title compound 96 (white solid) (86 mg, yield: 20.3%).

[0429] LCMS: 422[M+H] +

[0430] 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).

[0431] Example 86: Synthesis of 7-(2-((2-((2,3-dichlorobenzyl)(methyl)amino)ethyl)amino)ethoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 97)

[0432] To a 250 mL three-necked flask were added 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). The mixture was heated to 90°C and refluxed with stirring for 5 hours. After completion of the reaction, the mixture was separated by silica gel column chromatography (dichloromethane:methanol = 10:1) and concentrated under reduced pressure to afford the crude product. The crude product was then separated by preparative chromatography and lyophilized to afford compound 97 (0.05 g, 1.2% yield) as a white solid.

[0433] LCMS: 422[M+1] +

[0434] 1H 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).

[0435] Example 87: Synthesis of 7-(2-((2-((2,3-dichlorobenzyl)oxy)ethyl)(methyl)amino)ethoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 98)

[0436] The title compound 98 (white solid) was prepared by the same synthetic route as in Example 86, except that 97a was replaced by 98a.

[0437] LCMS: 423[M+1] +

[0438] 1 H 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).

[0439] Example 88: Synthesis of 1-(3,4-dichlorophenethyl)-3-(2-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)ethyl)urea (Compound 99)

[0440] To a reaction flask, 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) were added dropwise. Pyridine (0.173 g, 2.2 mmol, 2.2 eq.) was added dropwise under an ice bath. The mixture was warmed to room temperature and stirred for 2 hours. 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 dropwise under an ice bath. The mixture was stirred for 2 hours at room temperature. The mixture was filtered, and the filter cake was purified with dichloromethane, filtered, and dried to obtain the title compound 99 as a white solid (0.16 g, yield: 37.9%).

[0441] LCMS: 422 [M+H] +

[0442] 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).

[0443] Example 89: Synthesis of 7-(2-((4-(trifluoromethyl)benzyl)amino)ethoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 100)

[0444] The title compound 100 (pale yellow solid) was prepared by the same synthetic route as in Example 7, except that 9a was replaced by 34b and 1c was replaced by 100a.

[0445] LCMS: 365 [M+H] +

[0446] 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).

[0447] Example 90: Synthesis of 7-(2-(((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)ethoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 101)

[0448] The title compound 101 (off-white solid) was prepared by the same synthetic route as in Example 7, except that 9a was replaced by 34b and 1c was replaced by 101a.

[0449] LCMS: 366 [M+H] +

[0450] 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).

[0451] Example 91: Synthesis of 7-(2-((2-(2-(2,3-dichlorophenyl)cyclopropyl)ethyl)amino)ethoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 102)

[0452] Step 1: To a 250 mL three-necked flask, add diiodomethane (2.68 g, 0.01 mol, 1.1 eq.) and dichloromethane (100 mL). Cool the mixture to -20°C, then add diethylzinc (10 mL, 0.01 mol, 1.1 eq.). Stir for 30 minutes, cool the mixture to 0°C, and then slowly add trifluoroacetic acid (2.2 g, 0.02 mol, 2.2 eq.) dropwise. Stir at 0-10°C for 1 hour. Then, add 102a (2.0 g, 0.009 mol, 1 eq.), and stir at room temperature for 15 hours. After the reaction is complete, quench the reaction with water (100 mL), extract with dichloromethane, and separate the organic phase by column chromatography (dichloromethane:methanol = 20:1). Concentrate under reduced pressure to dryness to afford 102A (1.3 g, 62.5% yield) as a white solid.

[0453] Step 2: To a 250 mL three-necked flask, 102A (1.3 g, 0.0056 mol, 1 eq.) and dichloromethane (50 mL) were added. The temperature was cooled to 0°C, followed by the addition of Dess-Martin (3.6 g, 0.0084 mol, 1.5 eq.) and the mixture was stirred at 0-10°C for 2 hours. After the reaction was completed, water (100 mL) was added to quench the reaction, followed by extraction with dichloromethane. The organic phase was separated by column chromatography (ethyl acetate:petroleum ether = 1:5) to elute the product, which was then concentrated under reduced pressure to dryness to afford 102B (1.1 g, 84.6% yield) as a white solid.

[0454] Step 3: To a 250 mL three-necked flask were added 102B (0.46 g, 0.002 mol, 1 eq.), 99a (0.41 g, 0.002 mol, 1 eq.), sodium acetate borohydride (2.1 g, 0.01 mol, 5 eq.), and dichloromethane (50 mL). The temperature was lowered to 0°C and the reaction was allowed to react for 3 hours. After completion of the reaction, the reaction 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 afford the title compound 102 as an off-white solid (0.04 g, yield: 4.8%).

[0455] LCMS: 419[M+1] +

[0456] 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).

[0457] Example 92: Synthesis of 7-(2-(5-chloroindolin-1-yl)ethoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 103)

[0458] The title compound 101 (off-white solid) was prepared by the same synthetic route as in Example 86, except that 97a was replaced by 103a.

[0459] LCMS: 343[M+1] +

[0460] 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).

[0461] 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)

[0462] The title compound 104 (white solid) was prepared by the same synthetic route as in Step 3 of Example 40, except that 1-(3,5-bis(trifluoromethyl)phenyl)piperazine (45c) was replaced by 104a and 45B was replaced by 41a.

[0463] LCMS: 400 [M+H] +

[0464] 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).

[0465] Example 94: Synthesis of 7-(4-((4-fluorobenzo[d]thiazol-2-yl)amino)butoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 105)

[0466] The title compound 105 (white solid) was prepared by the same synthetic route as in Example 7, except that 9a was replaced by 6a and 1c was replaced by 104a.

[0467] LCMS: 386 [M+H] +

[0468] 1H 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).

[0469] 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)

[0470] 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), followed by the addition of NaBH(OAc)3 (4.8 g, 22.66 mmol, 5.0 eq). The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with water and the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution. The DCM was dried and the aqueous phase was extracted with ethyl acetate. The organic phase was dried and the reaction mixture was filtered and dried to give the crude product. The product was purified by normal phase column chromatography (eluent: (dichloromethane:methanol=10:1). The target fractions were collected and lyophilized to give 107A (1.2 g, yield: 72.3%) as a yellow solid.

[0471] Step 2: 107A (1.2 g, 3.46 mmol, 1.0 eq) was added to DCM (50 mL), and then a 2 M solution of boron tribromide in dichloromethane (10 mL, 20.79 mmol, 10.0 eq) was added dropwise at 0°C. The reaction solution was stirred at 0°C under nitrogen for 4 hours. The reaction solution was poured into saturated aqueous sodium bicarbonate solution to quench and the pH was adjusted to 7-8. The dichloromethane was evaporated to dryness, the aqueous phase was extracted with ethyl acetate, and the organic phase was dried. The reaction solution was filtered and dried to give the crude product, which was purified using a normal phase column (eluent: (dichloromethane:methanol = 10:1). The target fractions were collected and lyophilized to give the title compound 107 as a yellow solid (152 mg, yield: 13.2%).

[0472] LCMS: 353 [M+H] +

[0473] 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).

[0474] 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)

[0475] The title compound 108 (white solid) was prepared by the same synthetic route as in Step 1 of Example 95, except that 107a was replaced by 108a.

[0476] LCMS: 353 [M+H] +

[0477] 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).

[0478] Example 97: Synthesis of 7-(3-(imidazo[1,2-a]pyridin-3-ylamino)propoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 109)

[0479] The title compound 109 (yellow oily liquid) was prepared by the same synthetic route as in Example 7, except that 9a was replaced by 38a and 1c was replaced by 109a.

[0480] LCMS: 337 [M+H] +

[0481] 1H 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).

[0482] Example 98: Synthesis of 7-(4-(imidazo[1,2-a]pyridin-3-ylamino)butoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 110)

[0483] The title compound 110 (white solid) was prepared by the same synthetic route as in Example 7, except that 9a was replaced by 6a and 1c was replaced by 109a.

[0484] LCMS: 351 [M+H] +

[0485] 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).

[0486] Example 99: Synthesis of 7-((5-(imidazo[1,2-a]pyridin-3-ylamino)pentyl)oxy)-3,4-dihydroquinolin-2(1H)-one (Compound 111)

[0487] The title compound 111 (light yellow oily liquid) was prepared by the same synthetic route as in Example 2, except that 3a was replaced by 4a and 1c was replaced by 109a.

[0488] LCMS: 365 [M+H] +

[0489] 1H 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).

[0490] 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)

[0491] To a 250 mL three-necked flask were added 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). The temperature was raised to 90°C and the reaction was allowed to proceed for 4 hours. After the reaction was complete, 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 a crude product, which was then purified by preparative liquid chromatography to afford the title compound 112 as an off-white solid (0.074 g, yield: 10.9%).

[0492] LCMS: 340[M+1] +

[0493] 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).

[0494] 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)

[0495] The title compound 113 (pale yellow solid) was prepared by the same synthetic route as in Example 36, except that 41a was replaced by 113a and 40a was replaced by 113b.

[0496] LCMS: 384 [M+H] +

[0497] 1 H 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).

[0498] 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)

[0499] Step 1: To a 250 mL single-necked flask was added 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 replaced with a hydrogen balloon three times and stirred at 10-20°C for 16 hours. After the reaction, the palladium on carbon was removed by filtration, and the mixture was concentrated under reduced pressure to dryness to afford 114A (0.38 g, 100% yield) as a white solid.

[0500] Step 2: To a 250 mL three-necked flask were added 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 temperature was lowered to 0°C and the reaction was allowed to proceed for 3 hours. After the reaction, 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 afford the title compound 114 as an off-white solid (0.035 g, yield: 4.4%).

[0501] LCMS: 395[M+1] +

[0502] 1H 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).

[0503] 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)

[0504] 115a (300 mg, 1.64 mmol) and K2CO3 (681 mg, 4.92 mmol) were added to DMF (5 mL), followed by 115b (1.03 g, 3.6 mmol), and the mixture was stirred at 50°C for 16 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried and filtered to dryness to give the crude product, which was then purified using a normal phase column (eluent: (petroleum ether:ethyl acetate = 1:1)) and then purified using a C-18 reverse phase column (eluent: methanol:0.1% formic acid aqueous solution = 80:20). The target fractions were collected and lyophilized to give the title compound 115 as a white solid (127 mg, yield: 20%).

[0505] LCMS: 386[M+H] +

[0506] 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).

[0507] 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)

[0508] Step 1: Compound 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), followed by the addition of HATU (2.7 g, 7.25 mmol). The mixture was stirred at room temperature for 3 h. The reaction mixture was filtered and the filter cake was dried to afford 130A (770 mg, 45.7% yield) as a white solid.

[0509] Step 2: 130A (770 g, 2.20 mmol) was added to 4M HCl / 1,4-dioxane (10 mL) and stirred at room temperature for 1 hour. The reaction mixture was dried to give 130B (600 mg, yield: 95.3%) as a gray solid.

[0510] Step 3-4: The title compound 130 (white solid) was prepared by the same synthetic route as in Example 95, except that 99a in Example 95 was replaced by 130B.

[0511] LCMS: 396[M+H] +

[0512] 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).

[0513] 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)

[0514] The title compound 131 (white solid) was prepared by the same synthetic route as in Example 95, except that 99a was replaced by 130B and 107a was replaced by 108a.

[0515] LCMS: 396[M+H] +

[0516] 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).

[0517] Example 106: Synthesis of 5-(5,6-dimethoxy-2-oxoindolin-3-yl)-N-(4-isopropylbenzyl)pentanamide (Compound 132)

[0518] The title compound 132 (off-white solid) was prepared by the same synthetic route as in Example 7, except that 9a was replaced by 132a and 1c was replaced by 78a.

[0519] LCMS: 425 [M+H] +

[0520] 1 H 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).

[0521] 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)

[0522] 133a (0.38 g, 0.0013 mol, 1 eq.) was dissolved in DMF (5 mL). Anhydrous potassium carbonate (0.54 g, 0.0039 mol, 3 eq.) was added with stirring and heated 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 reaction was maintained for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filter cake was washed with DMF. The filtrate was collected. A large amount of water was added to the filtrate, and the mixture was 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 resulting fractions were lyophilized to give the title compound 133 (off-white solid) (0.04 g, yield: 6.7%).

[0523] LCMS: 462[M+1] +

[0524] 1 H 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).

[0525] 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)

[0526] 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 and reacted overnight. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (eluent: methanol:0.1% aqueous formic acid = 70:30) to afford 134A (130 mg, 77% yield) as a pale yellow oil.

[0527] Step 2: 134a (124 mg, 0.45 mmol, 1.0 eq.) was dissolved in dichloromethane (2 mL), and triethylamine (137 mg, 1.35 mmol, 3.0 eq.) was added. 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 allowed to react at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was purified by reverse phase column chromatography (eluent: methanol:0.1% aqueous formic acid = 80:20) to afford the title compound 134 as a white solid (14 mg, yield: 6%).

[0528] LCMS: 544 [M+H] +

[0529] 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).

[0530] 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)

[0531] Step 1: Zinc powder (0.65 g, 0.01 mol, 1.0 eq.) and anhydrous THF (30 mL) were added to a 100 mL three-necked flask and the atmosphere was purged with nitrogen three times. Ethyl bromoacetate (135b) (1.67 g, 0.01 mol, 1.0 eq.) was added dropwise to the system. A solution of one grain of iodine in THF (3 mL) was added dropwise to the system and 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 dropwise to the system. Reflux was maintained 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). The desired product fraction was collected and the solvent was removed by rotary evaporation to afford 135A (1.26 g, 34.3% yield) as a pale yellow gummy solid.

[0532] Step 2: To a 100 mL three-necked flask, add 135A (0.93 g, 0.00253 mol, 1.0 eq.) and anhydrous THF (10 mL). Cool the mixture under nitrogen in an ice-salt bath. When the temperature drops below 0°C, add a solution of lithium aluminum hydride in THF (6.3 mL, 0.00253 mol, 1.0 eq.) dropwise via syringe. A significant exotherm and abundant bubbling are generated. The addition rate is controlled to maintain the system temperature. After the addition is complete, the reaction is allowed to proceed for 1 hour. Upon completion of the reaction, the solid is removed by filtration, and the filtrate is concentrated to afford 135B as an oil (0.7 g, 85.4% yield).

[0533] Step 3: To a 100 mL single-necked flask, add 135B (0.7 g, 0.00216 mol, 1.0 eq.) and dichloromethane (10 mL) and stir to dissolve. Add Desmartine reagent (0.92 g, 0.00216 mol, 1.0 eq.) with stirring and allow to react at room temperature for 1 hour. After the reaction is complete, wash the mixture twice with saturated sodium bicarbonate solution. Separate the layers, dry the DCM layer over anhydrous sodium sulfate, filter, and wash the filter cake with DCM. Remove the solvent from the filtrate to afford 135C as a yellow oil, which is used directly in the next step.

[0534] Step 4: To a 100 mL three-necked flask, 135c (1.6 g, 0.007 mol, 1.0 eq.), triethylamine (2.08 g, 0.021 mol, 3 eq.), and DCM (10 mL) were added under nitrogen and placed in an ice bath. When the system temperature dropped 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 addition was complete, the mixture was stirred overnight. Upon completion of the reaction, the solid was removed by filtration and concentrated to yield 135D, which was used crude directly in the next step.

[0535] Step 5: The crude product 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 system and reacted at 100°C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, and a large amount of water was added. The product was extracted with EA and concentrated. The concentrate was initially purified by column chromatography (eluent: dichloromethane:methanol = 80:20) to collect the desired product fractions. The crude product 135E was then concentrated to give a yellow solid (2.9 g, yield: 100%).

[0536] Step 6: To a 100 mL single-necked vial, 135E (2.9 g, 0.00774 mol, 1.0 eq.) and a solution of hydrogen chloride in dioxane (15 mL, 4 mol / L) were added and reacted at room temperature for 1 hour. The mixture was filtered, the filter cake washed with DCM, and dried to afford 135F (0.93 g, 38.8% yield) as a white solid.

[0537] Step 7: To a 100 mL single-necked vial, add 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 stir to dissolve. Once dissolved, add 135C (0.8 g, 0.00248 mol, 1.0 eq.) and acetic acid (0.177 g, 0.00496 mol, 2.0 eq.) and stir for 1 hour. Then, add sodium triacetylborohydride (1.05 g, 0.00496 mol, 2.0 eq.) and react at room temperature for 4 hours. After the reaction was completed, the product was filtered and the filter cake was washed with DCM. The filtrate was washed with saturated sodium bicarbonate solution and water. The organic phase was separated and dried over anhydrous sodium sulfate. The solvent was removed and the crude product was initially purified by column chromatography (eluent: dichloromethane:methanol = 1:1). The target product fractions were collected and concentrated to give an off-white solid 135G (0.57 g, yield: 91.9%).

[0538] Step 8: To a 100 mL single-necked flask, add 135G (0.26 g, 0.000448 mol, 1.0 eq.) and EA (5 mL). Stir to dissolve. Add a solution of hydrogen chloride in dioxane (0.6 mL) dropwise. React at room temperature for 30 min, filter, and wash the filter cake with EA. Filter cake preparation (eluent: methanol: 0.5% aqueous formic acid = 80:20) afforded the title compound 135 as a white solid (0.02 g, yield: 9.5%).

[0539] LCMS: 476[M+1] +

[0540] 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).

[0541] Example 110: Synthesis of 6-((4-(2,3-dichlorophenyl)piperazin-1-yl)sulfonyl)-3,4-dihydroquinolin-2(1H)-one (Compound 158)

[0542] 1-(2,3-Dichlorophenyl)piperazine hydrochloride (1c) (200 mg, 0.75 mmol, 1.0 eq.) was dissolved in dichloromethane (5 mL), and triethylamine (227 mg, 2.24 mmol, 3.0 eq.) was added. 158a (220 mg, 0.90 mmol, 1.2 eq.) was then slowly added. The mixture was allowed to react 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 thoroughly and filtered. The filter cake was washed with methanol (2 × 4 mL) and dried to afford the title compound 158 as a white solid (215 mg, yield: 65.32%).

[0543] LCMS: 440 [M+H] +

[0544] 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).

[0545] Example 111: Synthesis of 6-((4-hydroxy-4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)sulfonyl)-3,4-dihydroquinolin-2(1H)-one (Compound 159)

[0546] The title compound 159 (white solid) was prepared by the same synthetic route as in Example 110, except that 1c was replaced by 159b.

[0547] LCMS: 455 [M+H] +

[0548] 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).

[0549] Example 112: Synthesis of 6-((4-(4-fluorobenzyl)piperidin-1-yl)sulfonyl)-3,4-dihydroquinolin-2(1H)-one (Compound 160)

[0550] The title compound 160 (white solid) was prepared by the same synthetic route as in Example 110, except that 1c in Example 110 was replaced by 160b.

[0551] LCMS: 403 [M+H] +

[0552] 1 H 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).

[0553] 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)

[0554] 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 reaction was allowed to proceed 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 then added and the reaction was allowed to proceed at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was purified by reverse phase separation on a C18 column (eluent: 0.1% aqueous formic acid:methanol = 30:70) to afford the title compound 161 (white solid) (100 mg, yield: 57.26%).

[0555] LCMS: 497 [M+H] +

[0556] 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).

[0557] 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)

[0558] The title compound 162 (white solid) was prepared by the same synthetic route as in Example 113, except that 6b in Example 113 was replaced by 1c.

[0559] LCMS: 497 [M+H]+

[0560] 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).

[0561] 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)

[0562] The title compound 163 (white solid) was prepared by the same synthetic route as in Example 113, except that 6b in Example 113 was replaced by 159b.

[0563] LCMS: 512 [M+H] +

[0564] 1 H 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).

[0565] 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)

[0566] The title compound 164 (white solid) was prepared by the same synthetic route as in Example 114, except that 6b in Example 114 was replaced by 160b.

[0567] LCMS: 460 [M+H] +

[0568] 1H 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).

[0569] Example 117: Synthesis of 1-(6-(4-(3-(trifluoromethyl)phenyl)piperazine-1-carbonyl)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (Compound 165)

[0570] Step 1: To a reaction flask were added 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 DMF (3 mL). The mixture was stirred at room temperature for 1 h and concentrated to give a crude product which was purified using a C18 reverse phase column (eluent: 0.5% aqueous formic acid:MeOH = 25:75). The target fractions were collected and concentrated to give 165A (150 mg, 68.8% yield) as an off-white solid.

[0571] Step 2: To a reaction flask were added 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 temperature was lowered to 0°C, and acetyl chloride (0.04 g, 0.45 mmol, 1.1 eq.) was added dropwise. The reaction mixture was allowed to react for 1 h. The mixture was purified by silica gel column chromatography (eluent: DCM:MeOH = 90:10) to afford the title compound 165 as an off-white solid (166 mg, yield: 93.8%).

[0572] LCMS: 432 [M+H] +

[0573] 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).

[0574] Example 118: Synthesis of 1-(6-(4-(2,3-dichlorophenyl)piperazine-1-carbonyl)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (Compound 166)

[0575] The title compound 166 (off-white solid) was prepared by the same synthetic route as in Example 117, except that 6b in Example 117 was replaced by 1c.

[0576] LCMS: 432 [M+H] +

[0577] 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).

[0578] 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)

[0579] The title compound 167 (off-white solid) was prepared by the same synthetic route as in Example 117, except that 6b in Example 117 was replaced by 159b.

[0580] LCMS: 447 [M+H] +

[0581] 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).

[0582] Example 120: Synthesis of 1-(6-(4-(4-fluorobenzyl)piperidine-1-carbonyl)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (Compound 168)

[0583] The title compound 168 (off-white solid) was prepared by the same synthetic route as in Example 118, except that 6b in Example 118 was replaced by 168b.

[0584] LCMS: 395 [M+H] +

[0585] 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).

[0586] Example 121: Synthesis of N-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-oxopropyl)-3,4-dimethoxybenzamide (Compound 169)

[0587] The title compound 169 (colorless oily liquid) was prepared by the same synthetic route as in Step 3 of Example 40, except that 1-(3,5-bis(trifluoromethyl)phenyl)piperazine (45c) was replaced by 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c) and 45B was replaced by 169a.

[0588] LCMS: 466 [M+H] +

[0589] 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).

[0590] Example 122: Synthesis of N-(4-(2,3-dichlorophenyl)piperazin-1-yl)-4-oxobutyl)-3,4-dimethoxybenzamide (Compound 170)

[0591] The title compound 170 (colorless oily liquid) was prepared by the same synthetic route as in Step 3 of Example 40, except that 1-(3,5-bis(trifluoromethyl)phenyl)piperazine (45c) was replaced by 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c) and 45B was replaced by 170a.

[0592] LCMS: 480 [M+H] +

[0593] 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).

[0594] Example 123: Synthesis of N-(5-(4-(2,3-dichlorophenyl)piperazin-1-yl)-5-oxopentyl)-3,4-dimethoxybenzamide (Compound 171)

[0595] The title compound 171 (white solid) was prepared by the same synthetic route as in Step 3 of Example 40, except that 1-(3,5-bis(trifluoromethyl)phenyl)piperazine (45c) was replaced by 1-(2,3-dichlorophenyl)piperazine hydrochloride (1c), 45B was replaced by 171a, and the reagent DCM was replaced by DMF.

[0596] LCMS: 494 [M+H] +

[0597] 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).

[0598] Example 124: Synthesis of 3,4-dimethoxy-N-(5-oxo-5-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)pentyl)benzamide (Compound 172)

[0599] The title compound 172 (white solid) was prepared by the same synthetic route as in Step 3 of Example 40, except that 1-(3,5-bis(trifluoromethyl)phenyl)piperazine (45c) was replaced by 6b, 45B was replaced by 171a, and the reagent DCM was replaced by DMF.

[0600] LCMS: 494 [M+H] +

[0601] 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).

[0602] Example 125: Synthesis of methyl 2-(4-(2,3-dichlorophenyl)piperazine-1-carbonyl)-4,5-dimethoxybenzoate (Compound 173)

[0603] 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 allowed to react overnight. The mixture was concentrated under reduced pressure, and the residue was purified by reverse phase separation on a C18 column (0.1% aqueous formic acid:methanol = 70:30) to afford 173A (400 mg, 95% yield) as a yellow solid.

[0604] Step 2: 173A (400 mg, 0.91 mmol, 1.0 eq.) was dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (315 mg, 2.28 mmol, 2.5 eq.) was added. The mixture was allowed to react at room temperature for 0.5 h. Methyl iodide (194 mg, 1.37 mmol, 1.5 eq.) was added, and the mixture was allowed to react at room temperature overnight. The reaction solution was purified by reverse phase separation on a C18 column (0.1% aqueous formic acid: methanol = 30:70), followed by prep-TLC (developing solvent: petroleum ether:ethyl acetate = 1:1) to afford the title compound 173 as a pale yellow solid (144 mg, yield: 35%).

[0605] LCMS: 453 [M+H] +

[0606] 1H 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).

[0607] Example 126: Synthesis of (R)-7-(2-hydroxy-3-((2-(2-methoxyphenoxy)ethyl)amino)propoxy)quinolin-2(1H)-one (Compound 174)

[0608] To a reaction flask, 174a (868 mg, 4.0 mmol, 1.0 eq.) and ethanol (20 mL) were added, followed by 2-(2-methoxyphenoxy)ethylamine (668 mg, 4.0 mmol, 1.0 eq.). The reaction was stirred at 90°C with a sealed tube for 12 hours, after which the reaction was complete. The reaction solution was then dried and directly purified using a C18 reverse-phase column to afford the title compound 174 (768 mg, 50% yield).

[0609] LCMS: 385 [M+H] +

[0610] 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).

[0611] Example 127: Synthesis of (S)-7-(3-((2-(3,4-dimethoxyphenoxy)ethyl)amino)-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 175)

[0612] The title compound 175 was prepared by the same synthetic route as in Example 126, except that 174a was replaced by 175a and 174b was replaced by 175b.

[0613] LCMS: 417 [M+H] +

[0614] 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).

[0615] Example 128: Synthesis of N-(2-(7-hydroxynaphthalen-1-yl)ethyl)-3-((1-(pyridin-2-yl)piperidin-4-yl)amino)propanamide (Compound 176)

[0616] Step 1: To a 250 mL three-necked flask were added 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. After 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 eluted by silica gel column chromatography (dichloromethane:methanol = 7:1). The product was then concentrated under reduced pressure to afford 176A (0.43 g, 100% yield) as an off-white solid.

[0617] Step 2: To a 250 mL three-necked flask was added 176A (0.6 g, 0.0015 mol, 1 eq.), dichloromethane (30 mL), and boron tribromide (7.5 mL, 0.015 mol, 10 eq.). The mixture was incubated at 20°C for 5 h. After 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 afford the title compound 176 as an off-white solid (0.08 g, 12.7% yield).

[0618] LCMS: 419[M+1] +

[0619] 1H 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).

[0620] 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)

[0621] Step 1: To a 100 mL single-necked flask were added 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 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 product fractions were collected and the solvent was evaporated to dryness to afford 177A (0.2 g, yield: 27.4%) as a yellow oil.

[0622] Step 2: To a 50 mL single-necked vial were added 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). The mixture was allowed to react at room temperature overnight. The mixture was filtered, the filter cake washed with water, and the filtrate was purified by reverse-phase column chromatography (eluent: 0.5‰ aqueous formic acid:MeOH = 100:0 to 10:90). The product fractions were collected, lyophilized, and further purified by preparative liquid chromatography (eluent: 0.5‰ aqueous formic acid:MeOH = 100:0 to 25:75) to afford the title compound 177 as a pale yellow solid (0.03 g, yield: 10.3%).

[0623] LCMS: 611[M+1] +

[0624] 1H 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).

[0625] Example 130: Synthesis of N-(2-(7-hydroxynaphthalen-1-yl)ethyl)-3-((6-(piperidin-1-yl)pyridin-3-yl)methoxy)propionamide (Compound 178)

[0626] 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 placed in a 100 mL single-necked flask. TBDMSCl (1.2 g, 8.02 mmol, 1.5 eq) was added and stirred at room temperature for 12 h. Water was added to the reaction mixture, which was extracted with EA. The mixture was concentrated and purified with MTBE to afford 178A (0.3 g, 18.7% yield) as a white solid.

[0627] 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 single-necked flask, heated to 50°C for 12 h, cooled, filtered, and the filtrate was concentrated to obtain the crude product, which was separated and purified by silica gel column chromatography (eluent: DCM:MeOH = 30:1 to 10:1) to obtain a light yellow oil 178B (0.8 g, yield: 21%).

[0628] Step 3: 178B (800 mg, 2.74 mmol, 1.0 eq), methanol (10 mL) and water (2 mL) were added to a 100 mL single-necked flask, and LiOH (197 mg, 8.22 mmol, 3.0 eq) was added. The mixture was stirred at room temperature for 5 h, concentrated to remove methanol, and the pH was adjusted to 4 with dilute hydrochloric acid. The mixture was filtered and the filter cake was dried to obtain 178C (0.5 g, yield: 69%) as a white solid.

[0629] Step 4: Add 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) into a 100 mL single-necked bottle, stir at room temperature for 2 hours, and obtain the title compound 178 (white solid) (0.052 g, yield: 12.5%) by reverse phase column chromatography.

[0630] LCMS: 434[M+1] +

[0631] 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).

[0632] Experimental Example 1. Pharmacodynamics Experiment (TPK Enzyme Activity Test)

[0633] 1.1 Experimental Purpose

[0634] The purpose of this example is to test the promoting effect of the compound on TPK enzyme activity. 50 and E max Evaluate the in vitro activity of the compounds.

[0635] 1.2 Experimental methods

[0636] 1.2.1 Experimental Materials

[0637] Table 1

[0638] 1.2.2 Experimental steps

[0639] 1.1). Preheat the constant temperature water bath shaker to 37℃ half an hour in advance.

[0640] 1.2) Take out the stock solution of the compound to be tested, thaw it at room temperature, and dilute it to the required concentration.

[0641] 1.3) Thaw the required reagents on ice.

[0642] 2.1) Each reaction system needs to add TPK enzyme solution, Tris-HCl buffer, and ATP solution. The ATP used is 1-500mM. The above three solutions are prepared into a uniform mixture.

[0643] 2.2) Aliquot the mixture of the three solutions into centrifuge tubes. Add the desired concentration of compound to each tube, and finally add thiamine solution (1-100 μM). After the addition of the above systems, tightly seal the centrifuge tube caps, insert the tubes into the float plate, and incubate in a shaker water bath preheated to 37°C for 0.5-2.0 hours.

[0644] 2.3) After incubation, add perchloric acid stop solution and mix thoroughly. Transfer the sample to a 1.5 mL centrifuge tube and store at -20°C.

[0645] 3.1) Remove the sample stored at -20°C, thaw it at room temperature, and then perform derivatization. Place the sample in a centrifuge tube, add potassium ferricyanide derivatization reagent, and finally add phosphoric acid stop solution to stop the reaction.

[0646] 3.2) Place the derivatized sample in a liquid chromatography sample vial and measure the TDP / thiamine content by high performance liquid chromatography. TKP enzyme activity = TDP (nM) / mg protein / min.

[0647] 1.3 Experimental Results

[0648] According to the above operation, the effect of the compound of the present invention on TPK enzyme activity at different concentrations was determined. max (The effect of DMSO on TPK enzyme activity was calculated as 100%) and EC 50 The data are shown in Table 2 below.

[0649] Table 2

[0650] Table 3

[0651] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. A method for preventing or treating a neurodegenerative disease or alleviating the symptoms of a neurodegenerative disease, comprising administering to a subject in need thereof a preventive or therapeutically effective amount of a thiamine pyrophosphokinase (TPK) agonist; The TPK agonist is a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof: A——L——B (I) in: A and B are each independently C 3-10 Hydrocarbon ring, 3-14 membered heterocycle, C 6-10 Aromatic ring or 5-14 membered heteroaromatic ring; L is selected from -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 Each independently selected from -C 1-6 Alkylene-, -C 2-6 Alkenylene-, -C 2-6 Alkynylidene-, -C 3-10 Cycloalkylene-、-(3-14 membered heterocyclylene)-、-C 6-10 Arylene- and -(5-14 membered heteroarylene)-, wherein the alkylene, alkenylene and alkynylene groups are each optionally interrupted by one group or by multiple adjacent or non-adjacent groups independently selected from: -C 3-10 Cycloalkylene-、-(3-14 membered heterocyclylene)-、-C 6-10 Arylene-, -(5-14 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)2NR-, -S-, -S(=O)-, and -S(=O)2-; W and W' are each independently selected at each occurrence from -O-, -C(=O)-, -C(=O)O-, -NR-, -C(=O)NR-, -NR-C(=O)-NR'-, -NR-C(=O)O-, -(S=O)NR-, -S(=O)2NR-, -S-, -S(=O)-, and -S(=O)2-; R and R' are each independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cyclic hydrocarbon group, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl; The above alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, hydrocarbon ring, heterocyclyl, heterocyclylene, heterocycle, aryl, arylene, aromatic ring, heteroaryl, heteroarylene, heteroaromatic ring and aralkyl are each optionally substituted at each occurrence with one or more substituents independently selected from the group consisting of halogen, -OH, =O, -NH2, -CN, -NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-10 Cyclic hydrocarbon group, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -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-NR a R b and-OC 1-6 Alkylene-NR a R b The alkyl, alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are further optionally substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -C(=O)O-tert-butyl, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cyclic hydrocarbon group, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -OC 1-6 Alkyl and -C 1-6 Alkylene-OC 1-6 alkyl; and R a and R b Each occurrence is independently selected from H, C 1-6 Alkyl, C 3-10 Cyclic hydrocarbon group, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl, said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl further optionally substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -C(=O)O-tert-butyl, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cyclic hydrocarbon group, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl and -C 1-6 Alkylene-OC 1-6 alkyl; Preferably, the neurodegenerative disease is Alzheimer's disease; More preferably, the Alzheimer's disease is Alzheimer's disease characterized by decreased TPK enzyme activity, decreased TPK expression level and / or decreased TDP level in an individual.

2. The method of claim 1, wherein A is 3. The method of claim 1 or 2, wherein L is selected from -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'-; Preferably, L is 4. The method of any one of claims 1 to 3, wherein B is 5. The method of any one of claims 1 to 4, wherein 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) in: A is a benzene ring optionally fused to a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring, wherein the benzene ring is optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -NH(C 1-6 Alkyl) and -N(C 1-6 alkyl) 2; preferably, the phenyl ring is optionally substituted by one or more substituents independently selected from the following: -Cl, -OH, -NH2, -NH(CH3), -N(CH3)2, methyl, ethyl and methoxy; most preferably, A is B is C 3-10 Hydrocarbon ring, 3-14 membered heterocycle, C 6-10 aromatic ring or 5-14 membered heteroaromatic ring; preferably a benzene ring, the benzene ring is optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -NH-C(=O)-C 1-6 Alkyl, -C(=O)-(3-14 membered heterocyclic group), -S(=O)2-N(C 1-6 Preferably, the phenyl ring is optionally substituted by one or more substituents independently selected from the group consisting of -F, -Cl, methyl, isopropyl, trifluoromethyl, -NHC(=O)CH3, -C(=O)-piperidinyl, -S(=O)2-N(CH3)2, -S(=O)2-N(CH2CH3)2, -S(=O)2-piperidinyl and -S(=O)2-azepanyl; Q 1 Selected from -C 1-6 Alkylene-, -C 2-6 Alkenylene- and -C 2-6 Alkynylidene-; Q 2 Selected from -C 3-10 Cycloalkylene-、-(3-14 membered heterocyclylene)-、-C 6-10 Arylene- and -(5-14 membered heteroarylene)-; preferably -(3-14 membered heterocyclylene)-; more preferably piperidinylene or piperazinylene; W is independently selected at each occurrence from -O-, -C(=O)-, -C(=O)O-, -NR-, -C(=O)NR-, -NR-C(=O)-NR'-, -NR-C(=O)O-, -(S=O)NR-, -S(=O)2NR-, -S-, -S(=O)- and -S(=O)2-; preferably -O-, -NH- or -NH-C(=O)-; The remaining groups are as defined in any one of claims 1 to 4.

6. A method for preventing or treating a neurodegenerative disease or alleviating the symptoms of a neurodegenerative disease, comprising administering to a subject in need thereof a preventively 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 characterized by decreased TPK enzyme activity, decreased TPK expression level and / or decreased TDP level in the individual; The TPK agonist is selected from the following compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs thereof:

7. The method of any one of claims 1-6, wherein 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.

8. The method of any one of claims 1 to 7, wherein 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 per day, 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 100 μg / kg per day. μg / kg, about 200 μg / kg, about 225 μg / kg, about 250 μg / kg, about 275 μg / kg, about 300 μg / kg, about 325 μg / kg, about 350 μg / kg, about 375 μg / kg, about 400 μg / kg, about 425 μg / 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 / kg, 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 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.

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

10. The method of any one of claims 1-9, 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 day, 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. The method of any one of claims 1-10, wherein the TPK agonist is administered for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) courses of treatment, wherein each course of treatment 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 day, 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 wherein each course of treatment is separated by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, two weeks, three weeks, or four weeks.

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 infusion) or transdermal administration; or by oral, buccally, nasally, transmucosally, topically, in the form of an ophthalmic preparation, or by inhalation.

13. The method of any one of claims 1-12, wherein the TPK agonist is administered in a dosage form selected from the group consisting of tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, and syrups.

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

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

16. A compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein the compound is selected from: