TPK agonist and method for treating neurodegenerative diseases using the same

Abstract

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

Description

[Technical Field]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0021] As used herein, the term "cycloalkyl group" refers to a saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused, or bridged systems (e.g., bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, or bicyclic [5.2.0]nonyl, decahydronaphthalenyl, etc.), which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-6 A "cycloalkyl group" is a saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring of 3 to 6 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), which is optionally substituted by one or more (e.g., 1 to 3) suitable substituents, for example, a cyclopropyl group substituted with a methyl group.

[0022] As used herein, the term "heterocyclyl group" refers to a saturated or unsaturated monovalent monocyclic or bicyclic group that contains 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms in the ring and O, S, N, S(=O), S(=O)2, S(=O)(=NR Z ), NR Z or P(=O)(R Z ), wherein R Z Each occurrence of represents independently a hydrogen atom or C 1-6 Alkyl group or halo-C 1-6 The heterocycloalkyl group may be linked to the remainder of the molecule via one of the carbon atoms or a nitrogen atom (if present). In particular, the 3- to 10-membered heterocyclyl group is a group having 3 to 10 carbon atoms and heteroatoms in the ring, including, but not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuran, dioxolinyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidine, morpholinyl, dithianyl, thiomorpholinyl, piperazine, or trithianyl.

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

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

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

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

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

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

[0029] As used herein, the terms "(ylidene)heteroaryl group" and "heteroaromatic ring" refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contain at least one heteroatom, which may be the same or different, such as oxygen, nitrogen or sulfur, and which may further be benzo-fused in each case. In particular, "(ylidene)heteroaryl group" or "heteroaromatic ring" includes (ylidene)thienyl group (ring), (ylidene)furyl group (ring), (ylidene)pyrrolyl group (ring), (ylidene)oxazolyl group (ring), (ylidene)thiazolyl group (ring), (ylidene)imidazolyl group (ring), (ylidene)pyrazolyl group (ring), (ylidene)isoxazolyl group (ring), (ylidene)isothiazolyl group (ring), , (ylidene)oxadiazolyl group (ring), (ylidene)triazolyl group (ring), (ylidene)thiadiazolyl group (ring), etc., and benzo derivatives thereof, or (ylidene)pyridine group (ring), (ylidene)pyridazinyl group (ring), (ylidene)pyrimidinyl group (ring), (ylidene)pyrazinyl group (ring), (ylidene)triazinyl group (ring), etc., and benzo derivatives thereof.

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

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

[0032] As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and at least one nitrogen atom in the ring, which may optionally contain one or more (e.g., 1, 2, 3, or 4) ring members selected from N, O, C=O, S, S=O, and S(=O)2, and the nitrogen-containing heterocycle is linked to the remainder of the molecule via a nitrogen atom. The nitrogen-containing heterocycle is preferably a saturated nitrogen-containing monocyclic ring. In particular, the 3- to 14-membered nitrogen-containing heterocycle is a group having 3 to 14 carbon atoms and heteroatoms (wherein at least one is a nitrogen atom) in the ring, including, but not limited to, a 3-membered nitrogen-containing heterocycle (e.g., aziridinyl), a 4-membered nitrogen-containing heterocycle (e.g., azetidinyl), a 5-membered nitrogen-containing heterocycle (e.g., pyrrolyl group, pyrrolidinyl group (pyrrolidine ring), pyrrolinyl group, pyrroloalkanone group, midazolyl group, imidazolidinyl group, imidazolinyl group, pyrazolyl group, pyrazolinyl), a 6-membered nitrogen-containing heterocycle (e.g., piperidine group (piperidine ring), morpholinyl group, thiomorpholinyl group, piperazine group), a 7-membered nitrogen-containing heterocycle, etc.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0061] In some embodiments, the TPK agonist is a compound of Formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof: [ka] Preferably, the TPK agonist is a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof: [ka] where: A and B are independent CR 3 or N, Ring C and ring D are each independently C 3-10 Hydrocarbon rings (e.g., C 3-6 hydrocarbon ring), 3-10 membered heterocyclic ring, C 6-10 an aromatic ring or a 5- to 14-membered heteroaromatic ring, and preferably, ring C is a 5- or 6-membered heteroaromatic ring; L 1 , L 2 and L 3 are not present independently, or -O-, -C(=O)-, -C(=O)O-, -NR-, -C(=O)NR-, -(S=O)NR-, -S(=O)2NR-, -S-, -S(=O)-, -S(=O)2-, -C 1-6 Alkylene-, -C 2-6 Alkenylene-, -C 2-6 Alkynylene-, -C 3-6 Cycloalkylene-, -(3- to 10-membered heterocyclylene)-, -C 6-10 Arylene-, -(5-14 membered heteroarylene)-, -WC 1-6 Alkylene-, -C 1-6Alkylene-W- and -WC 1-6 alkylene-W′-, wherein said alkylene group is optionally further interrupted by one or more W, provided that L 1 , L 2 and L 3 At least one of W and W' in each occurrence are independently selected from -O-, -C(=O)-, -C(=O)O-, -NR-, -C(=O)NR-, -(S=O)NR-, -S(=O)NR-, -S-, -S(=O)- and -S(=O)-; R 1 Each occurrence independently represents a halogen, -OH, -NH2, -CN, -NO2, C 1-6 Alkyl group, halo C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3- to 10-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 14-membered heteroaryl group, C 6-12 Aralkyl group, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O)2-R b , -NR a -C(=O)-NR a R b , -C 1-6 Alkylene-OR a , -C 1-6 Alkylene-NR a Rb and -OC 1-6 Alkylene-NR a R b is selected from R 2 and R 3 Each occurrence independently represents H, halogen, -OH, -NH2, -CN, -NO2, or C. 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3- to 10-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 14-membered heteroaryl group, C 6-12 Aralkyl group, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O)2-R b , -NR a -C(=O)-NR a R b , -C 1-6 Alkylene-OR a , -C 1-6 Alkylene-NR a R b and -OC 1-6 Alkylene-NR a R b is selected from R, R a and R b are independently H, C each time they occur. 1-6 Alkyl group, C 3-10 Cyclic hydrocarbon groups, 3- to 10-membered heterocyclyl groups, C 6-10Aryl groups, 5- to 14-membered heteroaryl groups and C 6-12 aralkyl groups, n is 0, 1, 2, 3 or 4, preferably n is 0, 1 or 2; The above alkyl group, alkylene group, alkenyl group, alkenylene group, alkynyl group, alkynylene group, cyclic hydrocarbon group, cycloalkylene group, hydrocarbon ring, heterocyclyl group, heterocyclylene group, heterocycle, aryl group, arylene group, aromatic ring, heteroaryl group, heteroarylene group, heteroaromatic ring and aralkyl group each and every occurrence optionally and independently include halogen, —OH, ═O, —NH, —CN, —NO, —C, 1-6 Alkyl group, halo C 1-6 Alkyl group, C 3-6 Cyclic hydrocarbon groups, 3- to 10-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 14-membered heteroaryl group, C 6-12 Aralkyl group, -C(=O)R c , -OC(=O)R c , -C(=O)OR c , -OR c , -SR c , -S(=O)R c , -S(=O)2R c , -S(=O)2NR c R d , -NR c R d , -C(=O)NR c R d , -NR c -C(=O)R d , -NR c -C(=O)OR d , -NR c -S(=O)2-R d , -NR c -C(=O)-NR c R d , -C 1-6 Alkylene-OR c , -C 1-6 Alkylene-NR c R d and -OC 1-6 Alkylene-NR c R dThe alkyl, alkylene, cyclic hydrocarbon, heterocyclyl, aryl, heteroaryl and aralkyl groups may further optionally independently be substituted with one or more substituents selected from halogen, —OH, ═O, —C(═O)O-tert-butyl, —NH, —CN, —NO, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-6 Cyclic hydrocarbon groups, 3- to 10-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 14-membered heteroaryl group, C 6-12 Aralkyl group, -OC 1-6 Alkyl groups and -C 1-6 Alkylene-OC 1-6 substituted with one or more substituents selected from alkyl groups, and R c and R d are independently H, C each time they occur. 1-6 Alkyl group, C 3-10 Cyclic hydrocarbon groups, 3- to 10-membered heterocyclyl groups, C 6-10 Aryl groups, 5- to 14-membered heteroaryl groups and C 6-12 and aralkyl groups, wherein the alkyl groups, cyclic hydrocarbon groups, heterocyclyl groups, aryl groups, heteroaryl groups, and aralkyl groups are further optionally independently selected from halogen, —OH, ═O, —C(═O)O-tert-butyl groups, —NH, —CN, —NO, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-6 Cyclic hydrocarbon groups, 3- to 10-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 14-membered heteroaryl group, C 6-12 Aralkyl groups and -C 1-6 Alkylene-OC 1-6 It is substituted with one or more substituents selected from alkyl groups.

[0062] In some embodiments, ring C is C 3-6 Hydrocarbon ring, 3-10 membered heterocycle, C 6-10 It is an aromatic ring or a 5- to 14-membered heteroaromatic ring.

[0063] In a preferred embodiment, 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: [ka] where: X is -C(R)2-, -NR-, -O- or -S-, preferably X is -NR-, -O- or -S-, more preferably X is -NH-, -N(CH3)-, -O- or -S-, and The remaining groups are as defined above.

[0064] In a preferred embodiment, [ka] teeth, [ka] is.

[0065] In a preferred embodiment, [ka] teeth, [ka] is.

[0066] In a preferred embodiment, [ka] teeth, [ka] is.

[0067] In a preferred embodiment, R 3 is independently H or C each time it occurs. 1-6an alkyl group (preferably a methyl group), Preferably, A and B are each independently CH, CCH or N; and More preferably, A is N and B is CH.

[0068] In a preferred embodiment, L 1 and L 3 are each independently absent, or -C(=O)-, -N(CH3)-, -C 1-6 Alkylene-, -WC 1-6 Alkylene- or -C 1-6 alkylene-W-, wherein the alkylene group is optionally further interrupted by one or more W; and W is -O-, -C(=O)-, -C(=O)O-, -NH-, -N(CH3)-, -C(=O)NH- or -C(=O)N(CH3)-.

[0069] In a preferred embodiment, L 1 and L 3 are each independently absent, or -C(=O)-, -N(CH3)-, -C 1-6 Alkylene- or -C 1-6 alkylene-W-, wherein the alkylene group is optionally further interrupted by one or more W; and W is -O-, -C(=O)-, -C(=O)O-, -NH-, -N(CH3)-, -C(=O)NH- or -C(=O)N(CH3)-.

[0070] In a preferred embodiment, L 2 is absent or is -(3- to 10-membered heterocyclylene)-; Preferably, L 2 is absent or is a piperazinylene group or a piperidinylene group.

[0071] In a preferred embodiment, [ka] teeth, [ka] is.

[0072] In a preferred embodiment, [ka] teeth, [ka] is.

[0073] In a preferred embodiment, R 1 Each occurrence independently represents a halogen, -CN, or C 1-6 Alkyl group, halo C 1-6 Alkyl groups and C 1-6 alkoxy groups, Preferably, R 1 is independently selected from -F, -Cl, -Br, -CN, -CH3, -CF3 and -OCH3 at each occurrence.

[0074] In a preferred embodiment, R 2 Independently H, C 1-6 Alkyl group, C 6-10 aryl groups and 5- to 14-membered heteroaryl groups, said groups optionally independently selected from halogen, —OH, —NH, —CN, —NO, C 1-6 Alkyl group, halo C 1-6 Alkyl group, -N(C 1-6 Alkyl)2, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, -C(=O)-C 1-6 Alkyl groups, -C(=O)OH, -C(=O)OC 1-6 Alkyl group, -SC 1-6 Alkyl group, -S(=O)2-C 1-6 substituted with one or more substituents selected from alkyl groups, -S(=O)2- (3- to 10-membered heterocyclyl groups), -S(=O)2NH2 and -C(=O)NH2; Preferably, R 2independently an isopropyl group, [ka] is selected from.

[0075] In a preferred embodiment, the TPK agonist is a compound of formula (III) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof: [ka] Here, each group is as defined above.

[0076] In some embodiments, the TPK agonist is a compound of formula (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof: [ka] where: Ring D is absent or C 3-6 Hydrocarbon ring, 3-10 membered heterocycle, C 6-10 an aromatic ring or a 5- to 14-membered heteroaromatic ring, L 4 -O-, -C(=O)-, -C(=O)O-, -NR'-, -C(=O)NR'-, -(S=O)NR'-, -S(=O)2NR'-, -S-, -S(=O)-, -S(=O)2-, -C 1-6 Alkylene-, -C 2-6 Alkenylene-, -C 2-6 Alkynylene-, -C 3-6 Cycloalkylene-, -(3- to 10-membered heterocyclylene)-, -C 6-10 Arylene-, -(5-14 membered heteroarylene)-, -UC 1-6 Alkylene-, -C 1-6 Alkylene-U-, -UC 1-6 Alkylene -U'- and -C 1-6 Alkylene-UC 1-6alkylene-, wherein said alkylene group is optionally further interrupted by one or more U; U and U' at each occurrence are independently selected from -O-, -C(=O)-, -C(=O)O-, -NR'-, -C(=O)NR'-, -(S=O)NR'-, -S(=O)NR'-, -S-, -S(=O)- and -S(=O)-; R 4 , R 4’ , R 5 , R 5’ , R 6 and R 7 Each occurrence independently represents H, halogen, -OH, -NH2, -CN, -NO2, or C. 1-6 Alkyl group, halo C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3- to 10-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 14-membered heteroaryl group, C 6-12 Aralkyl group, -C(=O)R e , -OC(=O)R e , -C(=O)OR e , -OR e , -SR e , -S(=O)R e , -S(=O)2R e , -S(=O)2NR e R f , -NR e R f , -C(=O)NR e R f , -NR e -C(=O)R f , -NR e -C(=O)OR f , -NR e -S(=O)2-R f , -NR e -C(=O)-NR e R f , -C 1-6 Alkylene-OR e , -C 1-6 Alkylene-NR e R f , -OC1-6 Alkylene-NR e R f and -C 1-6 Alkylene-OC(=O)-C 1-6 Alkylene-C(=O)OR e or R 4 and R 4’ or R 5 and R 5’ together form =O, or R 4 , R 4’ , R 5 , R 5’ together with the groups to which they are attached form C 3-6 Hydrocarbon ring, 3-10 membered heterocycle, C 6-10 constitutes an aromatic ring or a 5- to 14-membered heteroaromatic ring, R', R e and R f are independently H, C each time they occur. 1-6 Alkyl group, C 3-10 Cyclic hydrocarbon groups, 3- to 10-membered heterocyclyl groups, C 6-10 Aryl groups, 5- to 14-membered heteroaryl groups and C 6-12 aralkyl groups, p and q are each independently 1, 2, 3, or 4, preferably p and q are each independently 1 or 2, with the proviso that if ring D is absent, then q is 1; The above alkyl group, alkylene group, alkenyl group, alkenylene group, alkynyl group, alkynylene group, cyclic hydrocarbon group, cycloalkylene group, hydrocarbon ring, heterocyclyl group, heterocyclylene group, heterocycle, aryl group, arylene group, aromatic ring, heteroaryl group, heteroarylene group, heteroaromatic ring and aralkyl group each and every occurrence optionally and independently include halogen, —OH, ═O, —NH, —CN, —NO, —C, 1-6 Alkyl group, halo C 1-6 Alkyl group, C 3-6 Cyclic hydrocarbon groups, 3- to 10-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 14-membered heteroaryl group, C 6-12 Aralkyl group, -C(=O)R g , -OC(=O)R g, -C(=O)OR g , -OR g , -SR g , -S(=O)R g , -S(=O)2R g , -S(=O)2NR g R h , -NR g R h , -C(=O)NR g R h , -NR g -C(=O)R h , -NR g -C(=O)OR h , -NR g -S(=O)2-R h , -NR g -C(=O)-NR g R h , -C 1-6 Alkylene-OR g , -C 1-6 Alkylene-NR g R h and -OC 1-6 Alkylene-NR g R h The alkyl, alkylene, cyclic hydrocarbon, heterocyclyl, aryl, heteroaryl and aralkyl groups may further optionally independently be substituted with one or more substituents selected from halogen, —OH, ═O, —C(═O)O-tert-butyl, —NH, —CN, —NO, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-6 Cyclic hydrocarbon groups, 3- to 10-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 14-membered heteroaryl group, C 6-12 Aralkyl group, -OC 1-6 Alkyl groups and -C 1-6 Alkylene-OC 1-6 substituted with one or more substituents selected from alkyl groups, and R g and R h are independently H, C each time they occur. 1-6 Alkyl group, C 3-10 Cyclic hydrocarbon groups, 3- to 10-membered heterocyclyl groups, C 6-10Aryl groups, 5- to 14-membered heteroaryl groups and C 6-12 and aralkyl groups, wherein the alkyl groups, cyclic hydrocarbon groups, heterocyclyl groups, aryl groups, heteroaryl groups, and aralkyl groups are further optionally independently selected from halogen, —OH, ═O, —C(═O)O-tert-butyl groups, —NH, —CN, —NO, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 3-6 Cyclic hydrocarbon groups, 3- to 10-membered heterocyclyl groups, C 6-10 Aryl group, 5- to 14-membered heteroaryl group, C 6-12 Aralkyl groups and -C 1-6 Alkylene-OC 1-6 It is substituted with one or more substituents selected from alkyl groups.

[0077] In a preferred embodiment, the TPK agonist is a compound of formula (V) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof: [ka] Here, each group is as defined above.

[0078] In a preferred embodiment, the L 4 is selected from —(CH2)2—, —(CH2)3—, —(CH2)6—, —(CH2)3-NH—, —(CH2)3-O—, —(CH2)4-O—, —(CH2)5-O—, —(CH2)6-O—, —C(═O)—CH2—, —C(═O)—(CH2)2—, —(CH2)2-C(═O)NH—(CH2)2— and —CH2-CH(OH)—CH2-NH—.

[0079] In a preferred embodiment, [ka] are -CN, -NH2, [ka] is. In some embodiments, the TPK agonist is selected from the following:

[0080] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10]

[0081] In a preferred embodiment, the TPK agonist is administered in an amount of about 0.005 mg / day to about 5000 mg / day, for example, about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 mg / day.

[0082] In a preferred embodiment, the TPK agonist is administered in an amount of about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg of body weight daily, for example, about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, or about 180 μg / kg daily. g, approximately 200μg / kg, approximately 225μg / kg, approximately 250μg / kg, approximately 275μg / kg, approximately 300μg / kg, approximately 325μg / kg, approximately 350μg / kg, approximately 375μg / kg, approximately 400μ g / kg, approximately 425μg / kg, approximately 450μg / kg, approximately 475μg / kg, approximately 500μg / kg, approximately 525μg / kg, approximately 550μg / kg, approximately 575μg / kg, approximately 600μg / kg, approximately 62 5μg / kg, about 650μg / kg, about 675μg / kg, about 700μg / kg, about 725μg / kg, about 750μg / kg, about 775μg / kg, about 800μg / kg, about 825μg / kg, Approximately 850μg / kg, approximately 875μg / kg, approximately 900μg / kg, approximately 925μg / kg, approximately 950μg / kg, approximately 975μg / kg, approximately 1mg / kg, approximately 5mg / kg, approximately 10mg / kg, approximately 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg or about 300 mg / kg body weight.

[0083] In preferred embodiments, the daily dose of the TPK agonist is administered in one dose, or in two, three, or four divided doses.

[0084] In preferred embodiments, the TPK agonist is administered continuously for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days or at least 50 days.

[0085] In a preferred embodiment, the TPK agonist is administered over one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) treatment courses, wherein each treatment course lasts at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days, and the interval between each two treatment courses is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, 2 weeks, 3 weeks, or 4 weeks.

[0086] In preferred embodiments, the TPK agonist is administered by injection (e.g., intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including drip infusion), or transdermally, or in the form of oral, buccal, nasal, transmucosal, topical, ophthalmic formulations, or by inhalation.

[0087] In a preferred embodiment, the TPK agonist is administered in a dosage form selected from a tablet, capsule, lozenge, hard candy, powder, spray, cream, ointment, suppository, gel, paste, lotion, ointment, aqueous suspension, injectable solution, elixir, and syrup.

[0088] In a preferred embodiment, the method ameliorates the following pathophysiological symptoms in an individual: cognitive and behavioral abnormalities, neurodegenerative changes (e.g., progressive synapse / neuron loss and brain atrophy), β-amyloid deposition, Tau abnormal phosphorylation and resulting neurofibrillary tangles, glial cell activation and inflammation, and / or impaired cerebral glucose metabolism.

[0089] In a preferred embodiment, the present disclosure further comprises administering one or more other therapeutic agents.

[0090] In some embodiments, the disclosure provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound has a structure of Formula (III): [ka] wherein each group is as defined above, The condition is -L 3 -R 2 is not H and a methyl group.

[0091] The present invention further includes any combination of the above embodiments.

[0092] In some embodiments, the disclosure provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound is selected from the following:

[0093] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7]

[0094] Example The present invention will now be further described in conjunction with the following examples, which are not intended to limit the scope of the invention.

[0095] The abbreviations used in the present invention have the following meanings:

[0096] [Table 3]

[0097] Example 1: Synthesis of 3-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-oxopropyl)-8-methyl-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 1) [ka]

[0098] A reaction flask was charged with 1a (100 mg, 0.37 mmol, 1.0 eq.), 1-(2,3-dichlorophenyl)piperazine hydrochloride (1b) (118 mg, 0.44 mmol, 1.2 eq.), HATU (280 mg, 0.74 mmol, 2.0 eq.), and dichloromethane (3 mL). DIPEA (0.2 mL, 1.11 mmol, 3.0 eq.) was added and the mixture was allowed to react overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was purified using a 18C reverse-phase column (eluent: 0.1% formic acid in water: MeOH = 10% to 70%). The target component was collected and concentrated to give the title compound 1 (white solid). LCMS:484 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.99 (s,1H),8.32 (s,1H),7.76 (s,1H),7.41 (d,1H),7.26 (m,3H),7.00 (d,1H),4.30 (t,2H),3.64-3.54 (m,4H),2.95-2.83 (m,6H),2.44 (s,3H).

[0099] Example 2: Synthesis of 3-(3-(4-(2,5-dichlorophenyl)piperazin-1-yl)-3-oxopropyl)-8-methyl-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 2) [ka]

[0100] The title compound 2 (pseudo-white solid) was obtained by employing the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 1-(2,5-dichlorophenyl)piperazine hydrochloride (2b) and the reaction solvent was replaced with DMF. LCMS:484 [M+1] + 1H NMR (400MHz,DMSO-d6): δ 11.97 (s,1H),8.33 (s,1H),7.77 (s,1H),7.45-7.41 (m,2H),7.29 (d,1H),7.12-7.10 (m,2H),4.32 (t,2H),3.61-3.58 (m,4H),2.94-2.92 (m,6H),2.45 (s,3H).

[0101] Example 3: Synthesis of 3-(3-(4-(2,4-dichlorophenyl)piperazin-1-yl)-3-oxopropyl)-7-methyl-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 3) [ka]

[0102] Step 1: 3a (10 g, 75.8 mmol, 1.0 eq), triethylamine (15.3 g, 151.6 mmol, 2.0 eq), and DCM (100 mL) were added to a 500 mL three-neck flask, cooled in an ice bath, and acetyl chloride (7.1 g, 90.96 mmol, 1.2 eq) was added dropwise. The mixture was stirred at room temperature for 3 h, concentrated, and purified by column chromatography to give a yellow solid intermediate product 3A (8.0 g, yield: 60.6%).

[0103] Step 2: 3A (9.0 g, 51.7 mmol, 1.0 eq) and THF (100 mL) were added to a 250 mL three-neck flask and cooled in an ice bath. NaH (3.1 g, 77.6 mmol, 1.5 eq) and ethyl bromoacetate (12.9 g, 0.405 mmol, 1.2 eq) were added and stirred at room temperature for 2 hours. The mixture was quenched with water and extracted with EA. The organic phase was dried, concentrated, and purified by column chromatography to give white solid intermediate product 3B (8.4 g, yield: 62.4%).

[0104] Step 3: 3B (8.4 g, 32.3 mmol, 1.0 eq) and THF (100 mL) were added to a 250 mL three-neck flask, cooled in an ice bath, potassium tert-butoxide (3.84 g, 32.3 mmol, 1.0 eq) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to quench the reaction, followed by extraction with EA. The organic phase was dried, concentrated, and purified by column chromatography to give the white solid intermediate product 3C (4.4 g, yield: 62.4%).

[0105] Step 4: 3C (2 g, 9.17 mmol, 1.0 eq), DMF (20 mL), and DMF-DMA (4.36 g, 36.68 mmol, 4.0 eq) were added to a 100 mL one-neck flask, heated to 70 °C, and reacted for 7 h. The mixture was concentrated to give crude yellow solid 3D, which was directly used in the next step.

[0106] Step 5: 3D (crude, 9.17 mmol, 1.0 eq), ethanol (20 mL), and β-alanine ethyl ester hydrochloride (2.8 g, 18.34 mmol, 2.0 eq) were added to a 250 mL one-neck flask, heated to 70 °C, and reacted for 7 h. The mixture was cooled and crystallized, and filtered to give white solid intermediate product 3E (1.8 g, yield: 65.6%).

[0107] Step 6: 3E (1.8 g, 6.02 mmol, 1.0 eq), methanol (20 mL), and LiOH (0.433 g, 18.06 mmol, 3.0 eq) were added to a 100 mL one-neck flask and stirred at room temperature for 3 h. The mixture was concentrated to remove methanol, adjusted to pH = 4 with dilute hydrochloric acid, and filtered to give white solid intermediate product 3F (0.9 g, yield: 55.3%).

[0108] Step 7: 3F (150 mg, 0.55 mmol, 1.0 eq.) was added to N,N-dimethylformamide (7 mL), and HATU (252 mg, 0.66 mmol, 1.2 eq.) was added. The mixture was allowed to react at room temperature for 1 h. 1-(2,4-Dichlorophenyl)piperazine hydrochloride 3b (178 mg, 0.66 mmol, 1.2 eq.) and DIPEA (264 mg, 2.05 mmol, 3.7 eq.) were added, and the mixture was allowed to react at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was triturated with methanol to give the title compound 3 (pale yellow solid) (140 mg, yield: 52%). LCMS:484 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.98 (s,1H),8.35 (s,1H),7.89 (d,1H),7.56 (d,1H),7.34 (s,1H),7.31 (dd,1H),7.09 (d,1H),7.04 (d,1H),4.34 (t,2H),3.65-3.57 (m,4H),2.94 (t,2H),2.91-2.86 (m,4H),2.49 (s,3H).

[0109] Example 4 Synthesis of 8-methyl-3-(3-oxo-3-(4-(2-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 4) [ka]

[0110] The title compound 4 (white solid) was obtained by employing the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 1-(2-trifluoromethylphenyl)piperazine. LCMS: 484 [M+1]; 1H NMR (400MHz,DMSO-d6) δ 11.99 (s,1H),8.31 (s,1H),7.78 (s,1H),7.64 (d,1H),7.52 (s,1H),7.41 (d,1H),7.31 (m,3H),4.31 (s,2H),3.52 (s,4H),2.91 (s,2H),2.72 (d,4H),2.45 (s,3H).

[0111] Example 5 Synthesis of 3-(3-oxo-3-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 5) [ka]

[0112] Step 1: 5a (5 g, 28.54 mmol) was added to DCM (100 mL), and a mixture of 65% HNO3 (2.77 g, 28.54 mmol) and AcOH (17.14 g, 285.41 mmol) was added dropwise. The reaction mixture was stirred at 40 °C for 2 h. The reaction mixture was then slowly poured into saturated aqueous sodium bicarbonate solution to quench the reaction mixture and adjust the pH to 8-9. The mixture was extracted with dichloromethane, and the organic phase was dried, filtered, and spin-dried. The desired product was then purified by normal-phase column chromatography (eluent: petroleum ether:(ethyl acetate / dichloromethane (1:1))=5%-25%) to obtain a yellow solid intermediate product 5A (2.2 g, yield: 35.0%).

[0113] Step 2: 5A (2.2 g, 9.99 mmol) was added to methanol (30 mL), and 10% wt. Pd / C (220 mg) was added. The reaction mixture was stirred at room temperature under the protection of a hydrogen balloon for 3 hours, filtered, and the mother liquor was spin-dried to give brown solid intermediate product 5B (1.7 g, yield: 89.5%).

[0114] Step 3: 5B (1.7 g, 8.94 mmol) was added to DMF (20 mL), and DMF-DMA (4.26 g, 35.75 mmol) was added, and the reaction mixture was stirred at 80° C. for 3 hours, diluted with water, extracted with ethyl acetate, and the organic phase was dried, filtered, and spun to give brown solid intermediate product 5C (2 g, yield: 91.2%).

[0115] Step 4: 5C (1.8 g, 7.34 mmol) was added to MeOH (25 mL), and β-alanine ethyl ester hydrochloride (2.2 g, 14.68 mmol) was added, and the reaction was stirred at 70° C. for 3 hours. The reaction was cooled to room temperature, and a large amount of solid precipitated, which was filtered, and the filter cake was spin-dried to obtain brown solid intermediate product 5D (1.3 g, yield: 62.1%).

[0116] Step 5: 5D (500 mg, 1.75 mmol) was added to a mixed solvent of THF / MeOH / HO (6 mL / 2 mL / 2 mL), and LiOH (126 mg, 5.26 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, diluted with water, and adjusted to pH 5-6 with 1 M aqueous hydrochloric acid until a large amount of solid precipitated. The mixture was filtered, and the filter cake was spin-dried to give a yellow solid intermediate product 5E (430 mg, yield: 95.4%).

[0117] Step 6: The same synthetic route as in Example 1 was employed, except that 1b in Example 1 was replaced with 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (5b) and 1a was replaced with 5E, to obtain the title compound 5 (white solid). LCMS: 470 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 12.11 (s,1H),8.36 (s,1H),7.98 (d,1H),7.51 (d,1H),7.46 - 7.37 (m,2H),7.23 - 7.16 (m,3H),7.06 (d,1H),4.32 (t,2H),3.59-3.57 (m,4H),3.20-3.18 (m,4H),2.92 (t,2H).

[0118] Example 6: Synthesis of 3-(3-oxo-3-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)-8-(trifluoromethyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 6) [ka]

[0119] Step 1: Compound 6a (2.0 g, 7.35 mmol, 1.0 eq.) was dissolved in anhydrous tetrahydrofuran (30 mL). Potassium tert-butoxide (824 mg, 7.35 mmol, 1.0 eq.) was added portionwise under ice bath conditions. The mixture was allowed to react overnight at room temperature. Water (30 mL) was added for dilution and the mixture was extracted with ethyl acetate (2 × 30 mL). The combined organic phases were washed with saturated brine (20 mL), dried, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column separation (eluent: petroleum ether:ethyl acetate = 10:1 to 5:1). The target component was collected and concentrated to give a white solid 6A (1.0 g, yield: 50%).

[0120] Steps 2 to 4: Compound 6D was obtained using the same synthetic route as in Steps 4 to 6 in Example 3, except that 3C in Example 3 was replaced with 6A.

[0121] Step 5: The same synthetic route as in Example 1 was employed, except that 1a in Example 1 was replaced with 6D and 1b was replaced with 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (5b), to give the title compound 6 (yellow solid). LCMS:538 [M+H] + 1H NMR (400MHz,DMSO-d6) δ 12.61 (s,1H),8.44 (s,1H),8.29 (s,1H),7.75-7.69 (m,2H),7.39 (t,1H),7.18 (d,1H),7.15 (s,1H),7.06 (d,1H),4.33 (t,2H),3.60-3.56 (m,4H),3.21-3.17 (m,4H),2.93 (t,2H).

[0122] Example 7: Synthesis of 3-(3-(4-(2,4-dichlorophenyl)piperazin-1-yl)-3-oxopropyl)-8-methyl-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 7) [ka]

[0123] The title compound 7 (yellow solid) was obtained by employing the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 1-(2,4-dichlorophenyl)piperazine hydrochloride. LCMS:484 [M+1] + 1 H NMR (400MHz,DMSO-d6): δ 11.99 (s,1H),8.33 (s,1H),7.77 (s,1H),7.55-7.54 (m,1H),7.43 (d,1H),7.30-7.27 (m,2H),7.02 (d,1H),4.32 (t,2H),3.61-3.57 (m,4H),2.94 (t,2H),2.86 (br,4H),2.45 (s,3H).

[0124] Example 8: Synthesis of 3-(3-(4-(2,6-dichlorophenyl)piperazin-1-yl)-3-oxopropyl)-8-methyl-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 8) [ka]

[0125] The title compound 8 (white solid) was obtained by employing the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 1-(2,6-dichlorophenyl)piperazine hydrochloride. LCMS:484 [M+1] + 1 H NMR (400MHz,DMSO-d6): δ 11.97 (s,1H),8.33 (s,1H),7.78 (s,1H),7.44-7.10 (m,3H),7.30 (d,1H),7.18 (t,1H),4.33 (t,2H),3.60 (br,2H),3.54 (br,2H),3.05 (br,4H),2.94 (t,2H),2.45 (s,3H).

[0126] Example 9: Synthesis of 3-(3-(4-(3,4-dichlorophenyl)piperazin-1-yl)-3-oxopropyl)-8-methyl-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 9) [ka]

[0127] The title compound 9 (pseudo-white solid) was obtained by employing the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 1-(3,4-dichlorophenyl)piperazine hydrochloride. LCMS:484 [M+1] + 1 H NMR (400MHz,DMSO-d6): δ 11.96 (s,1H),8.32 (s,1H),7.76 (s,1H),7.43 (d,1H),7.39 (d,1H),7.29 (d,1H),7.11 (s,1H),6.91-6.88 (m,1H),4.31 (t,2H),3.57-3.55 (m,4H),3.18-3.13 (m,4H),2.94 (t,2H),2.45 (s,3H).

[0128] Example 10: Synthesis of 8-methyl-3-(3-oxo-3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 10) [ka]

[0129] The title compound 10 (white solid) was obtained by employing the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 10b. LCMS: 484 [M+1]; 1 H NMR (400MHz,DMSO-d6) δ 11.97 (s,1H),8.32 (s,1H),7.75 (s,1H),7.48 (d,2H),7.41 (d,1H),7.27 (d,1H),7.01 (d,2H),4.30 (t,2H),3.58 (br,4H),3.25 (d,4H),2.92 (t,2H),2.43 (s,3H).

[0130] Example 11: Synthesis of 9-methyl-3-(3-oxo-3-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 11) [ka]

[0131] Step 1: 11a (1.0 g, 5.29 mmol, 1.0 eq), acetic acid (3.17 g, 52.9 mmol, 10.0 eq), and DCM (20 mL) were added to a 100 mL one-neck flask and cooled in an ice bath. 65% nitric acid (0.513 g, 5.29 mmol, 1.0 eq) was added and stirred at room temperature for 12 h. Saturated sodium bicarbonate solution was added, and the layers were separated. The organic phase was dried, concentrated, and purified by silica gel column separation (eluent: DCM:MeOH = 30:1 to 10:1) to give a pale yellow solid 11a.

[0132] Steps 2 to 5: Compound 11E was obtained by employing the same synthetic route as in Steps 2 to 5 of Example 5, except that 5A in Example 5 was replaced with 11A.

[0133] Step 6: The same synthetic route as in Example 1 was employed, except that 1b in Example 1 was replaced with 5b and 1a with 11E, to give the title compound 11 (white solid). LCMS: 484 [M+1]; 1 H NMR (400MHz,DMSO-d6) δ 12.04 (s,1H),8.34 (s,1H),7.39 (t,1H),7.31 (d,2H),7.21-7.13 (m,2H),7.07 (d,1H),6.95 (d,1H),4.31 (t,2H),3.65-3.52 (br,4H),3.20 (s,4H),2.92 (t,2H),2.81 (s,3H).

[0134] Example 12: Synthesis of 8-bromo-3-(3-oxo-3-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 12) [ka]

[0135] The title compound 12 (white solid) was obtained by employing the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (5b) and 1a was replaced with 12a.

[0136] LCMS [M+H] + :548,550 1H NMR (400MHz,CD3OD) δ 8.38 (s,1H),8.18 (s,1H),7.57 (dd,1H),7.48 (d,1H),7.34 (t,1H),7.14-7.03 (m,3H),4.46 (t,2H),3.76-3.62 (m,4H),3.18-3.11 (m,4H),3.05 (t,2H).

[0137] Example 13: Synthesis of 3-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-oxopropyl)-7-methyl-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 13) [ka]

[0138] The title compound 13 (pale yellow solid) was obtained by employing the same synthetic route as in Example 1, except that 1a in Example 1 was replaced with 3F. LCMS:484 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.99 (s,1H),8.35 (s,1H),7.89 (d,1H),7.36-7.32 (m,2H),7.28 (t,1H),7.09 (d,1H),7.04 (d,1H),4.35 (t,2H),3.67-3.59 (m,4H),2.97-2.89 (m,6H),2.50 (s,3H).

[0139] Example 14: Synthesis of 3-(3-(4-(2,5-dichlorophenyl)piperazin-1-yl)-3-oxopropyl)-7-methyl-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 14) [ka]

[0140] The title compound 14 (pale yellow solid) was obtained by employing the same synthetic route as in Example 1, except that 1a in Example 1 was replaced with 3F and 1b was replaced with 1-(2,5-dichlorophenyl)piperazine hydrochloride. LCMS:484 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.99 (s,1H),8.37 (s,1H),7.90 (d,1H),7.47 (d,1H),7.35 (s,1H),7.16-7.12 (m,2H),7.09 (d,1H),4.35 (t,2H),3.66-3.59 (m,4H),2.99-2.93 (m,6H),2.49 (s,3H).

[0141] Example 15: Synthesis of 3-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-4-oxobutyl)-8-methyl-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 15) [ka]

[0142] Step 1: Compound 15A was obtained by the same synthetic method as in Step 1 of Example 11, except that 11a in Step 1 of Example 11 was replaced with 15a.

[0143] Steps 2 to 5: Compound 15E was obtained by the same synthetic method as in Steps 2 to 5 of Example 5, except that 5A in Step 2 of Example 5 was replaced with 15A and β-alanine ethyl ester hydrochloride in Step 4 was replaced with 15C-1.

[0144] Step 6: The same synthetic route as in Example 1 was employed, except that 1a in Example 1 was replaced with 15E, to give the title compound 15 (white solid). LCMS: 498 [M+H] + 1H NMR (400MHz,DMSO-d6) δ 11.99 (s,1H),8.28 (s,1H),7.80 (s,1H),7.46-7.44 (m,1H),7.36-7.31 (m,3H),7.14-7.13 (m,1H),4.18-4.15 (m,2H),3.67-3.56 (m,4H),2.99-2.91 (m,4H),2.48-2.46 (m,5H),2.08-2.01 (m,2H).

[0145] Example 16: Synthesis of 3-(3-(4-(3,5-bis(trifluoromethyl)phenyl)piperazin-1-yl)-3-oxopropyl)-8-methyl-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 16) [ka]

[0146] The title compound 16 (white solid) was obtained by employing the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 1-(3,5-bis(trifluoromethyl)phenyl)piperazine. LCMS: 552 [M+1]; 1 H NMR (400MHz,DMSO-d6) δ 11.97 (s,1H),8.31 (s,1H),7.74 (s,1H),7.44 (s,2H),7.40 (d,1H),7.33-7.22 (m,2H),4.30 (t,2H),3.58 (s,4H),3.33 (s,4H),2.93 (d,2H),2.43 (s,3H).

[0147] Example 17: Synthesis of 8-methyl-3-(4-oxo-4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)butyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 17) [ka]

[0148] The title compound 17 (white solid) was obtained by employing the same synthetic route as in Example 1, except that 1a in Example 1 was replaced with 15E and 1b was replaced with 5b. LCMS: 498 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.98 (s,1H),8.28 (s,1H),7.79 (s,1H),7.47-7.43 (m,2H),7.31-7.29 (m,1H),7.24-7.20 (m,2H),7.13-7.11 (m,1H),4.16 (t,2H),3.60-3.59 (m,4H),3.27-3.20 (m,4H),2.50-2.47 (m,5H),2.06-2.02 (m,2H).

[0149] Example 18: Synthesis of 3-(3-(4-(3-bromophenyl)piperazin-1-yl)-3-oxopropyl)-8-methyl-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 18) [ka]

[0150] The title compound 18 (white solid) was obtained by the same synthetic method as in Example 1, except that 1b in Example 1 was replaced with 1-(3-bromophenyl)piperazine. LCMS:494,496 [M+1] + 1 H NMR (400MHz,DMSO-d6) δ 11.96 (s,1H),8.31 (s,1H),7.75 (s,1H),7.41 (d,1H),7.27 (d,1H),7.13 (t,1H),7.06 (s,1H),6.97-6.84 (m,2H),4.29 (t,2H),3.59-3.50 (m,4H),3.13 (br,4H),2.90 (t,2H),2.44 (s,3H).

[0151] Example 19: Synthesis of 3-(3-(4-(3,4-dichlorophenyl)piperazin-1-yl)-3-oxopropyl)-7-methyl-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 19) [ka]

[0152] The same synthetic route as in Example 3 was employed, except that 1-(2,4-dichlorophenyl)piperazine hydrochloride in Step 7 of Example 3 was replaced with 1-(3,4-dichlorophenyl)piperazine hydrochloride, to give the title compound 19 (pale yellow solid). LCMS:484 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.97 (s,1H),8.35 (s,1H),7.88 (d,1H),7.41 (d,1H),7.34 (s,1H),7.14 (d,1H),7.09 (d,1H),6.93 (dd,1H),4.34 (t,2H),3.62-3.56 (m,4H),3.21-3.15 (m,4H),2.95 (t,2H),2.49 (s,3H).

[0153] Example 20: Synthesis of 3-(3-(4-(2,6-dichlorophenyl)piperazin-1-yl)-3-oxopropyl)-7-methyl-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 20) [ka]

[0154] The same synthetic route as in Example 3 was employed, except that 1-(2,4-dichlorophenyl)piperazine hydrochloride in Step 7 of Example 3 was replaced with 1-(2,6-dichlorophenyl)piperazine hydrochloride, to give the title compound 20 (a pale yellow solid). LCMS:484 [M+H] + 1H NMR (400MHz,DMSO-d6) δ 11.98 (s,1H),8.35 (s,1H),7.90 (d,1H),7.46-7.42 (m,2H),7.34 (s,1H),7.19 (t,1H),7.09 (d,1H),4.35 (t,2H),3.65-3.55 (m,4H),3.11-3.06 (m,4H),2.96 (t,2H),2.50 (s,3H).

[0155] Example 21: Synthesis of 7-methyl-3-(3-oxo-3-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 22) [ka]

[0156] The same synthetic route as in Example 3 was employed, except that 1-(2,4-dichlorophenyl)piperazine hydrochloride in Step 7 of Example 3 was replaced with 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride, to give the title compound 22 (white solid). LCMS:484 [M+1] + 1 H NMR (400MHz,DMSO-d6) δ 11.97 (s,1H),8.33 (s,1H),7.85 (d,1H),7.40 (t,1H),7.29 (s,1H),7.23-7.13 (m,2H),7.11-6.98 (m,2H),4.30 (s,2H),3.59 (d,4H),3.20 (d,4H),2.92 (s,2H),2.45 (s,3H).

[0157] Example 22: Synthesis of 6-methyl-3-(3-oxo-3-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 23) [ka]

[0158] The same synthetic route as in Example 3 was employed, except that 3a in Step 1 of Example 3 was replaced with 23a, and 1-(2,4-dichlorophenyl)piperazine hydrochloride in Step 7 was replaced with 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride, to give the title compound 23 (white solid). LCMS:484 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 12.00 (s,1H),8.38 (s,1H),7.84 (d,1H),7.44 (t,1H),7.28 (d,1H),7.26-7.08 (m,4H),4.36 (t,2H),3.66-3.58 (m,4H),3.29-3.20 (m,4H),2.97 (t,2H),2.59 (s,3H).

[0159] Example 23: Synthesis of 8-methoxy-3-(3-oxo-3-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 24) [ka]

[0160] The same synthetic route as in Example 3 was employed, except that 3a in Step 1 of Example 3 was replaced with 24a and 1-(2,4-dichlorophenyl)piperazine hydrochloride in Step 7 was replaced with 5b, to give the title compound 24 (white solid). LCMS: 500 [M+H] + 1H NMR (400MHz,DMSO-d6) δ 11.96 (s,1H),8.34 (s,1H),7.49-7.41 (m,3H),7.25-7.18 (m,2H),7.16-7.08 (m,2H),4.34 (t,2H),3.86 (s,3H),3.66-3.57 (m,4H),3.28-3.19 (m,4H),2.96 (t,2H).

[0161] Example 24: Synthesis of 3-(3-(4-(3-hydroxyphenyl)piperazin-1-yl)-3-oxopropyl)-8-methyl-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 25) [ka]

[0162] The title compound 25 (white solid) was obtained by employing the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 1-(3-hydroxyphenyl)piperazine. LCMS: 432 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.97 (s,1H),9.15 (s,1H),8.32 (s,1H),7.76 (s,1H),7.41 (d,1H),7.27 (d,1H),6.98-6.94 (m,1H),6.34 (d,1H),6.28 (s,1H),6.21 (d,1H),4.31-4.27 (m,2H),3.59-3.50 (m,4H),3.05-3.00 (m,4H),2.92-2.88 (m,2H),2.44 (s,3H).

[0163] Example 25: Synthesis of 3-(3-(4-(3-aminophenyl)piperazin-1-yl)-3-oxopropyl)-8-methyl-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 26) [ka]

[0164] Step 1: The same synthetic route as in Example 1 was employed, except that 1b in Example 1 was replaced with 1-(3-nitrophenyl)piperazine, to give intermediate product 26A (white solid).

[0165] Step 2: 26A (0.09 g, 0.2 mmol, 1.0 eq), Pd / C (0.1 g), and methanol (5 mL) were added to a 100 mL one-neck flask, and the mixture was stirred at room temperature for 12 hours after replacing the air with hydrogen gas. The mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (eluent: DCM:MeOH = 30:1 to 10:1) to give the title compound 26 (white solid). LCMS: 431 [M+1]; 1 H NMR (400MHz,CD3OD) δ 8.33 (s,1H),7.85 (s,1H),7.45 (d,1H),7.33 (d,1H),6.91 (t,1H),6.26 (dd,3H),4.45 (t,2H),3.72-3.66 (m,2H),3.63-3.59 (m,2H),3.05-2.97 (m,6H),2.48 (s,3H).

[0166] Example 26: Synthesis of 3-(4-(3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)propionyl)piperazin-1-yl)benzoic acid (Compound 27) [ka]

[0167] Step 1: The same synthetic route as in Example 1 was employed, except that 1b in Example 1 was replaced with 3-(piperazin-1-yl)benzoic acid ethyl ester to give intermediate product 27A (white solid).

[0168] Step 2: 27A (100 mg, 0.206 mmol, 1.0 eq), LiOH (7.4 mg, 0.309 mmol, 1.5 eq), and MeOH (20 mL) were added to a 100 mL one-neck flask and stirred at room temperature for 2 h, concentrated, adjusted to pH = 4 with dilute hydrochloric acid, filtered, and the filter cake was dried to give the title compound 27 (white solid). LCMS: 460 [M+1]; 1 H NMR (400MHz,DMSO-d6) δ 12.83 (s,1H),11.97 (s,1H),8.32 (s,1H),7.75 (s,1H),7.52-7.35 (m,3H),7.29 (dd,2H),7.17 (d,1H),4.30 (t,2H),3.68-3.50 (m,4H),3.14 (s,4H),2.91 (t,2H),2.43 (s,3H).

[0169] Example 27: Synthesis of 3-(4-(3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)propionyl)piperazin-1-yl)benzamide (Compound 28) [ka]

[0170] Step 1: 28a (200 mg, 1.07 mmol) was added to 90% H2SO4 (9 mL) and reacted at room temperature for 2 days. The reaction mixture was quenched by pouring it into ice water, adjusting the pH to 9-10 with aqueous ammonia, spin-drying it, triturating it with methanol, and filtering it to obtain white solid intermediate product 28A (0.1 g, yield: 45.6%).

[0171] Step 2: The title compound 28 (white solid) was obtained by employing the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 28A. LCMS: 459 [M+H] + 1H NMR (400MHz,DMSO-d6) δ 11.97 (s,1H),8.32 (s,1H),7.89 (s,1H),7.75 (s,1H),7.41- 7.39 (m,2H),7.30-7.23 (m,4H),7.07-7.04 (m,1H),4.32-4.28 (m,2H),3.61-3.56 (m,4H),3.20 -3.11 (m,4H),2.94-2.90 (m,2H),2.44 (s,3H).

[0172] Example 28: Synthesis of 3-(4-(3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)propionyl)piperazin-1-yl)benzenesulfonamide (Compound 29) [ka]

[0173] The title compound 29 (white solid) was obtained by employing the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 29a. LCMS: 495 [M+1]; 1 H NMR (400MHz,DMSO-d6) δ 11.95 (s,1H),8.31 (s,1H),7.74 (s,1H),7.44-7.30 (m,3H),7.30-7.14 (m,4H),7.11 (d,1H),4.29 (s,2H),3.58 (s,4H),3.21-3.13 (m,4H),2.91 (t,2H),2.42 (s,3H).

[0174] Example 29: Synthesis of 8-methyl-3-(4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)butyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 48) formate [ka]

[0175] Step 1: A reaction flask was charged with 15C (see Example 15 for the synthetic route) (550 mg, 2.06 mmol, 1.0 eq.), 4-aminobutanol (550 mg, 6.18 mmol, 3.0 eq.), and EtOH (8 mL). The reaction mixture was purged under nitrogen gas three times and 85 o C for 12 hours. After TLC monitoring showed the reaction of the starting material was complete, the mixture was spun dry and recrystallized with EtOAc (20 mL) to give a white solid 48A.

[0176] Step 2: A reaction flask was charged with 48A (270 mg, 1.0 mmol, 1.0 eq.) and toluene (5 mL), and sulfoxide dichloride (285 mg, 2.5 mmol, 2.5 eq.) was added dropwise to the reaction mixture. The reaction mixture was allowed to react at 45 °C for 3 h. After LCMS monitoring showed that the reaction of the raw materials was essentially complete, the mixture was concentrated to give crude 48B, which was directly used in the next step (280 mg, yield: 90%).

[0177] Step 3: A reaction flask was charged with 48B (280 mg, 0.9 mmol, 1.0 eq.), N,N-dimethylformamide (8 mL), potassium carbonate (478 mg, 3.6 mmol, 4.0 eq.), potassium iodide (20 mg, 0.09 mmol, 0.1 eq.), and 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (266 mg, 0.99 mmol, 1.1 eq.). The reaction mixture was purged under nitrogen gas three times and incubated at 85 °C for 4 h. After TLC monitoring showed the reaction was complete, the mixture was filtered and spun dry. The crude product was purified by C18 reverse-phase column chromatography (eluent: 0.1% formic acid in water: MeOH = 10% to 70%). The target component was collected and concentrated to give the formate salt of the title compound 48 (white solid). LCMS:484 [M+H] + 1H NMR (400MHz,DMSO-d6) δ 11.97 (s,1H),8.28 (s,1H),8.14 (s,1H),7.76 (s,1H),7.43-7.35 (m,2H),7.27(d,1H),7.18 (d,1H),7.13 (s,1H),7.04 (d,1H),4.10 (t,2H),3.23-3.14 (m,4H),2.55-2.50 (m,4H),2.43 (s,3H),2.39 (t,2H),1.83-1.64 (m,2H),1.59-1.42 (m,2H).

[0178] Example 30: Synthesis of 8-methyl-3-(3-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 49) [ka]

[0179] The same synthetic route as in Example 29 was employed, except that 4-aminobutanol in Step 1 of Example 29 was replaced with 3-amino-1-propanol, to give the title compound 49 (yellow solid). LCMS: 470 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.94 (s,1H),8.28 (s,1H),7.75 (s,1H),7.41-7.36 (m,2H),7.27 (d,1H),7.17 (d,1H),7.11 (s,1H),7.04 (d,1H),4.13 (t,2H),3.32 (br,2H),3.16 (br,4H),2.43-2.39 (m,7H),1.96-1.92 (m,2H).

[0180] Example 31: Synthesis of 3-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-8-methyl-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 50) [ka]

[0181] Step 1: 48A (270 mg, 1.0 mmol, 1.0 eq.) and DCM (5 mL) were added to a reaction flask, and Dess-Martin oxidant (510 mg, 1.2 mmol, 1.2 eq.) was added portionwise. The reaction mixture was allowed to react at room temperature for 1 hour. After LCMS monitoring showed that the reaction of the starting materials was essentially complete, the mixture was filtered, washed with saturated aqueous sodium bicarbonate, extracted with DCM, and the organic phase was dried and concentrated to give the crude product, which was further separated by normal phase chromatography (eluent PE:EA = 10:1 to 1:1) to give the pale yellow liquid intermediate product 50A (250 mg, yield: 90%).

[0182] Step 2: 50A (250 mg, 0.9 mmol, 1.0 eq.) was added to a reaction flask, which was dissolved in MeOH (8 mL), and 1-(2,3-dichlorophenyl)piperazine hydrochloride (359 mg, 1.35 mmol, 1.5 eq.) was added to the reaction mixture. The mixture was stirred at room temperature under nitrogen gas for 1 hour, and then sodium triacetoxyborohydride (780 mg, 2.70 mmol, 3.0 eq.) was added in small portions to the reaction mixture. The mixture was stirred at room temperature under nitrogen gas for 12 hours, and the reaction was completed. The mixture was spin-dried to obtain a crude product. The crude product was purified by C18 reverse phase column, and the target component was collected and concentrated to obtain the title compound 50 (white solid). LCMS:484 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.97 (s,1H),8.29 (s,1H),7.76 (s,1H),7.41 (d,1H),7.31-7.25 (m,3H),7.10 (t,1H),4.10 (t,2H),2.94 (br,4H),2.50 (br,4H),2.44 (s,3H),2.37 (t,2H),1.77-1.74 (m,2H),1.54-1.38 (m,2H).

[0183] Example 32: Synthesis of 8-(trifluoromethyl)-3-(3-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 51) [ka]

[0184] The same synthetic route as in Example 29 was employed, except that 4-aminobutanol in Step 1 of Example 29 was replaced with 3-amino-1-propanol and 15C was replaced with 6B, to give the title compound 51 (pale yellow solid). LCMS: 524 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 12.60 (s,1H),8.43 (s,1H),8.31 (s,1H),7.77-7.70 (m,2H),7.39 (t,1H),7.17 (dd,1H),7.09 (s,1H),7.05 (d,1H),4.20 (t,2H),3.18-3.08 (m,4H),2.51-2.46 (m,4H),2.42 (t,2H),2.03-1.92 (m,2H).

[0185] Example 33: Synthesis of 3-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)-8-methyl-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 52) diformate [ka]

[0186] The same synthetic route as in Example 29 was employed, except that 4-aminobutanol in step 1 of Example 29 was replaced with 3-amino-1-propanol and 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride in step 3 was replaced with 1-(2,3-dichlorophenyl)piperazine hydrochloride, to afford the diformate salt of title compound 52 (white solid). LCMS: 470,472 [M+H] + 1 H NMR (400MHz,CD3OD) δ 8.32 (s,1H),8.26 (br,2H),7.88 (s,1H),7.47 (d,1H),7.36 (d,1H),7.25-7.15 (m,2H),6.93 (d,1H),4.30 (t,2H),3.08-2.97 (m,8H),2.90 (t,2H),2.50 (s,3H),2.24-2.15 (m,2H).

[0187] Example 34: Synthesis of 3-(3-oxo-3-(4-(3-(trifluoromethyl)benzyl)piperazin-1-yl)propyl)-8-(trifluoromethyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 53) [ka]

[0188] The title compound 53 (pale yellow solid) was obtained by employing the same synthetic route as in Example 1, except that 1a in Example 1 was replaced with 6D and 1b was replaced with 53b. LCMS:552 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 12.59 (br,1H),8.44 (s,1H),8.35 (s,1H),7.81-7.73 (m,2H),7.66-7.55 (m,4H),4.34 (t,2H),3.54 (s,2H),3.51-3.42 (m,4H),2.90 (t,2H),2.35-2.28 (m,4H).

[0189] Example 35: Synthesis of 3-(3-oxo-3-(4-(3,4,5-trifluorobenzyl)piperazin-1-yl)propyl)-8-(trifluoromethyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 54) [ka]

[0190] The title compound 54 (pale yellow solid) was obtained by employing the same synthetic route as in Example 6, except that 1-(2,4-dichlorophenyl)piperazine hydrochloride in Example 6 was replaced with 1-(3,4,5-trifluorobenzyl)piperazine hydrochloride. LCMS:538 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 12.59 (br,1H),8.44 (s,1H),8.34 (s,1H),7.82-7.71 (m,2H),7.28-7.17 (m,2H),4.33 (t,2H),3.54-3.40 (m,6H),2.90 (t,2H),2.38-2.25 (m,4H).

[0191] Example 36: Synthesis of 8-methyl-3-(3-oxo-3-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)benzofuro[3,2-d]pyrimidin-4(3H)-one (Compound 57) [ka]

[0192] 57a (3 g, 22.6 mmol, 1.0 eq), methyl bromoacetate (4.14 g, 27 mmol, 1.2 eq), potassium carbonate (6.24 g, 45.2 mmol, 2.0 eq), and DMF (20 mL) were heated to 70 °C and reacted for 5 h, cooled, concentrated, extracted with EA, and the layers were separated. The organic phase was dried and concentrated to give white solid intermediate product 57A (2.5 g, yield: 54%).

[0193] The title compound 57 (white solid) was obtained by employing the same synthetic route as in Steps 4-7 in Example 3, except that 3C in Step 4 of Example 3 was replaced with 57A and 1-(2,4-dichlorophenyl)piperazine hydrochloride in Step 7 was replaced with 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride. LCMS: 485 [M+1]; 1 H NMR (400MHz,DMSO-d6) δ 8.59 (s,1H),7.80 (s,1H),7.70 (d,1H),7.47 (d,1H),7.39 (d,1H),7.22-7.13 (m,2H),7.06 (d,1H),4.30 (d,2H),3.66-3.49 (m,4H),3.19 (d,4H),2.92 (d,2H),2.47 (s,3H).

[0194] Example 37: Synthesis of 6-methyl-2-(3-oxo-3-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one (Compound 59) [ka]

[0195] Step 1: 59a (5 g, 28.54 mmol), triethylamine (8.66 g, 85.62 mmol) were added to DMF (50 mL), and HATU (16.3 g, 42.78 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then aminoacetaldehyde dimethyl acetal (3.6 g, 34.25 mmol) was added. The reaction mixture was allowed to react at room temperature for 2 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phase was dried, filtered, and spin-dried. The desired product was then purified by normal phase column chromatography (eluent: (petroleum ether:ethyl acetate = 5% to 50%)) to obtain a white solid intermediate product 59A (5 g, yield: 66.8%).

[0196] Step 2: 59A (4 g, 14.2 mmol) was added to polyphosphoric acid (40 mL), and the reaction mixture was stirred at 110 °C for 1 h. The mixture was diluted with water, adjusted to pH 8-9 with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, and the organic phase was dried, filtered, and spun dry. The desired product was then purified by normal phase column chromatography (eluent: dichloromethane:methanol=20:1) to give a yellow solid intermediate product 59B (1.3 g, yield: 34.4%).

[0197] Step 3: 59B (1.3 g, 6.56 mmol) and potassium carbonate (1.81 g, 13.12 mmol) were added to DMF (20 mL), and methyl 3-bromopropionate (1.2 g, 7.21 mmol) was added. The reaction was stirred at room temperature overnight, diluted with water, extracted with ethyl acetate, the organic phase was dried, filtered, and spun to give the crude product, which was purified by normal phase column chromatography (eluent: dichloromethane:methanol=25:1) and the desired product was collected to give yellow solid intermediate product 59C (1.2 g, yield: 64.4%).

[0198] Step 4-5: The title compound 59 (white solid) was obtained by employing the same synthetic route as in Steps 6-7 in Example 3, except that 3E in Step 6 in Example 3 was replaced with 59C and 1-(2,4-dichlorophenyl)piperazine hydrochloride in Step 7 was replaced with 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride. LCMS: 483 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.83 (s,1H),7.76 (s,1H),7.41 - 7.35 (m,3H),7.21 (d,1H),7.14 - 7.11 (m,2H),7.06 (d,1H),6.96 (d,1H),4.28 (t,2H),3.60 - 3.55 (m,4H),3.17 - 3.16 (m,4H),2.86 (t,2H),2.41 (s,3H).

[0199] Example 38: Synthesis of 5-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)-N-(3-(trifluoromethyl)benzyl)valeramide (Compound 65) [ka]

[0200] The same synthetic route as in Example 15 was employed, except that 15C-1 in Step 4 of Example 15 was replaced with 5-aminopentanoic acid ethyl ester hydrochloride, and 1b in Step 6 was replaced with m-trifluoromethylbenzylamine, to give the title compound 65 (pale yellow solid). LCMS:457 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.96 (s,1H),8.44 (t,1H),8.26 (s,1H),7.76 (s,1H),7.62-7.48 (m,4H),7.41 (d,1H),7.27 (d,1H),4.33 (d,2H),4.07 (t,2H),2.44 (s,3H),2.21 (t,2H),1.73-1.68 (m,2H),1.60-1.54 (m,2H).

[0201] Example 39: Synthesis of N-(3,5-bis(trifluoromethyl)benzyl)-3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)propionamide (Compound 66) [ka]

[0202] The title compound 66 (pseudo-white solid) was obtained by employing the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 3,5-bis(trifluoromethyl)benzylamine. LCMS: 497 [M+H] + 1H NMR (400MHz,DMSO-d6) δ 11.96 (s,1H),8.64 (t,1H),8.15 (s,1H),7.94 (s,1H),7.90 (s,2H),7.74 (s,1H),7.40 (d,1H),7.28 (d,1H),4.42 (d,2H),4.29 (t,2H),2.73 (t,2H),2.44 (s,3H).

[0203] Example 40: Synthesis of 3-(6-methyl-1-oxo-1,9-dihydro-2H-pyrido[3,4-b]indol-2-yl)-N-(3-(trifluoromethyl)benzyl)propionamide (Compound 67) [ka]

[0204] The same synthetic route as in Example 37 was employed, except that 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride in Step 5 of Example 37 was replaced with m-trifluoromethylbenzylamine to give the title compound 67 (yellow solid). LCMS: 428 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.82 (s,1H),8.55 (t,1H),7.77 (s,1H),7.58-7.53 (m,2H),7.47-7.43 (m,2H),7.39 (d,1H),7.26-7.21 (m,2H),6.91 (d,1H),4.33 (d,2H),4.27 (t,2H),2.66 (t,2H),2.43 (s,3H).

[0205] Example 41: Synthesis of 4-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)-N-(3-(trifluoromethyl)benzyl)butanamide (Compound 68) [ka]

[0206] The title compound 68 (yellow solid) was obtained by employing the same synthetic route as in Example 15, except that 1-(2,3-dichlorophenyl)piperazine hydrochloride in Example 15 was replaced with m-trifluoromethylbenzylamine. LCMS: 443 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.98 (s,1H),8.47 (t,1H),8.24 (s,1H),7.76 (s,1H),7.61-7.50 (m,4H),7.41 (d,1H),7.28 (d,1H),4.32 (d,2H),4.10 (t,2H),2.44 (s,3H),2.23 (t,2H),2.04-1.94 (m,2H).

[0207] Example 42: Synthesis of 3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)-N-(3-(3-(trifluoromethyl)phenyl)propyl)propionamide (Compound 69) [ka]

[0208] The title compound 69 (pseudo-white solid) was obtained by employing the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 3-(3-(trifluoromethyl)phenyl)propan-1-amine. LCMS:457 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.97 (s,1H),8.15 (s,1H),8.00 (t,1H),7.71 (s,1H),7.49 (s,2H),7.43-7.36 (m,3H),7.26 (d,1H),4.27 (t,2H),3.02 (q,2H),2.61 (t,2H),2.53 (t,2H),2.42 (s,3H),1.66-1.56 (m,2H).

[0209] Example 43: Synthesis of 3-(4-oxo-8-(trifluoromethyl)-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)-N-(3-(trifluoromethyl)benzyl)propionamide (Compound 71) [ka]

[0210] The same synthetic route as in Example 6 was employed, except that 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (5b) in Step 5 of Example 6 was replaced with m-trifluoromethylbenzylamine, to give the title compound 71 (white solid). LCMS: 483 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 12.62 (s,1H),8.58 (t,1H),8.30 (s,1H),8.28 (s,1H),7.77-7.70 (m,2H),7.51 (s,2H),7.42-7.40 (m,2H),4.34-4.31 (m,4H),2.73 (t,2H).

[0211] Example 44: Synthesis of N-(2-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)ethyl)-2-(3-(trifluoromethyl)phenyl)acetamide (Compound 72) [ka]

[0212] Step 1: The same synthetic method as in Step 1 of Example 29 was employed, except that 4-aminobutanol in Step 1 of Example 29 was replaced with mono-Boc-ethylenediamine to give intermediate product 72A (white solid).

[0213] Step 2: To a reaction flask was added 72A (410 mg, 1.20 mmol, 1.0 eq.), EtOAc (4 mL), and 2M EtOAc / HCl solution (4 mL). The reaction mixture was allowed to react at room temperature for 4 hours. After monitoring by LCMS, the reaction mixture was complete and spin-dried to give the white solid intermediate product 72B (400 mg, 90% yield).

[0214] Step 3: The title compound 72 (white solid) was obtained by employing the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with m-trifluoromethylphenylacetic acid and 1a was replaced with 72B. LCMS:429 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.98 (s,1H),8.29 (t,1H),8.03 (s,1H),7.76 (s,1H),7.55 (s,2H),7.47 (s,2H),7.41 (d,1H),7.28 (d,1H),4.12 (t,2H),3.51-3.43 (m,4H),2.45 (s,3H).

[0215] Example 45: Synthesis of 3-(6-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)-N-(3-(trifluoromethyl)benzyl)propionamide (Compound 73) [ka]

[0216] The same synthetic route as in Example 22 was employed, except that 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride in the last step of Example 22 was replaced with 3-(trifluoromethyl)benzylamine, to give the title compound 73 (white solid). LCMS:429 [M+H] + 1H NMR (400MHz,DMSO-d6) δ 12.02 (s,1H),8.59 (t,1H),8.24 (s,1H),7.85 (d,1H),7.61-7.53 (m,2H),7.47-7.43 (m,2H),7.29 (d,1H),7.17 (t,1H),4.43-4.32 (m,4H),2.76 (t,2H),2.60 (s,3H).

[0217] Example 46: Synthesis of 3-(7-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)-N-(3-(trifluoromethyl)benzyl)propionamide (Compound 74) [ka]

[0218] The title compound 74 (white solid) was obtained by employing the same synthetic route as in Example 3, except that 1-(2,4-dichlorophenyl)piperazine hydrochloride in Example 3 was replaced with 3-(trifluoromethyl)benzylamine. LCMS: 429 [M+1]; 1 H NMR (400MHz,DMSO-d6) δ 11.97 (s,1H),8.57 (t,1H),8.17 (s,1H),7.86 (d,1H),7.53 (d,2H),7.40 (d,2H),7.30 (s,1H),7.06 (d,1H),4.42-4.19 (m,4H),2.71 (t,2H),2.45 (s,3H).

[0219] Example 47: Synthesis of N-(3-bromobenzyl)-3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)propionamide (Compound 75) [ka]

[0220] The title compound 75 (white solid) was obtained by employing the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 3-bromobenzylamine. LCMS: 439,441 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.97 (s,1H),8.50 (t,1H),8.17 (s,1H),7.76 (s,1H),7.41 (d,1H),7.37-7.34 (m,2H),7.28 (d,1H),7.19-7.03 (m,2H),4.29 (t,2H),4.22 (d,2H),2.71 (t,2H),2.44 (s,3H).

[0221] Example 48: Synthesis of 3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)-N-(3-(trifluoromethyl)phenylethyl)propionamide (Compound 76) [ka]

[0222] The title compound 76 (white solid) was obtained by employing the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 76b. LCMS: 443 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.98 (s,1H),8.14 (s,1H),8.05 (t,1H),7.76 (s,1H),7.51 (s,1H),7.47-7.39 (m,2H),7.36-7.25 (m,3H),4.24 (t,2H),3.26 (q,2H),2.73 (t,2H),2.58 (t,2H),2.44 (s,3H).

[0223] Example 49: Synthesis of 3-(9-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)-N-(3-(trifluoromethyl)benzyl)propionamide (Compound 77) [ka]

[0224] The same synthetic route as in Example 11 was employed, except that 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride in the last step of Example 11 was replaced with 3-(trifluoromethyl)benzylamine, to give the title compound 77 (white solid). LCMS: 429 [M+1]; 1 H NMR (400MHz,DMSO-d6) δ 12.07 (s,1H),8.60 (t,1H),8.19 (s,1H),7.53 (d,2H),7.39 (s,2H),7.32 (d,2H),6.96 (s,1H),4.31 (t,4H),2.82 (s,3H),2.73 (t,2H).

[0225] Example 50: Synthesis of 3-(8-bromo-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)-N-(3-(trifluoromethyl)benzyl)propionamide (Compound 79) [ka]

[0226] The title compound 79 (white solid) was obtained by employing the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with m-trifluoromethylbenzylamine and 1a was replaced with 12a.

[0227] LCMS [M+H] + :493,495 1 H NMR (400MHz,DMSO-d6) δ 12.35 (s,1H),8.57 (t,1H),8.11 (s,1H),7.58 (d,1H),7.53 (br,2H),7.49 (d,1H),7.42-7.41 (m,2H),4.33-4.28 (m,4H),2.72 (t,2H).

[0228] Example 51: Synthesis of 3-(8-methoxy-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)-N-(3-(trifluoromethyl)benzyl)propionamide (Compound 80) [ka]

[0229] The title compound 80 (pale yellow solid) was obtained by employing the same synthetic route as in Example 23, except that compound 5b in Example 23 was replaced with m-trifluoromethylbenzylamine. LCMS: 445 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.98 (s,1H),8.59 (t,1H),8.20 (s,1H),7.60-7.54 (m,2H),7.48-7.42 (m,4H),7.14 (dd,1H),4.39-4.29 (m,4H),3.87 (s,3H),2.75 (t,2H).

[0230] Example 52: Synthesis of N-(3-hydroxybenzyl)-3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)propionamide (Compound 82) [ka]

[0231] 81 (200 mg, 0.52 mmol, 1.0 eq.) was dissolved in dichloromethane (2 mL), and a solution of boron tribromide in dichloromethane (2.3 g, 1.54 mmol, 3.0 eq., 17%) was added dropwise under ice bath conditions. The mixture was allowed to react overnight at room temperature. After filtration, the filter cake was washed with dichloromethane (2 × 10 mL). The filter cake was dissolved in ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 × 20 mL). The combined organic phases were washed with saturated brine (20 mL), dried, filtered, and concentrated under reduced pressure to give the title compound 82 (white solid). LCMS:377 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 12.00 (s,1H),9.41 (s,1H),8.49 (t,1H),8.21 (s,1H),7.76 (s,1H),7.42 (d,1H),7.28 (d,1H),6.95 (t,1H),6.62 (s,1H),6.58 (d,1H),6.52 (d,1H),4.29 (t,2H),4.13 (d,2H),2.68 (t,2H),2.44 (s,3H).

[0232] Example 53: Synthesis of 3-((3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)propionamido)methyl)benzoic acid methyl ester (Compound 83) [ka]

[0233] The title compound 83 (white solid) was obtained by employing the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 3-(aminomethyl)benzoic acid methyl ester. LCMS: 419 [M+H] + 1H NMR (400MHz,DMSO-d6) δ 11.97 (s,1H),8.56 (t,1H),8.16 (s,1H),7.82-7.74 (m,3H),7.43-7.26 (m,4H),4.33-4.26 (m,4H),3.79 (s,3H),2.70 (t,2H),2.44 (s,3H).

[0234] Example 54: Synthesis of 3-((3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)propionamido)methyl)benzamide (Compound 84) [ka]

[0235] Step 1: Compound 85 (380 mg, 0.94 mmol, 1.0 eq.) and dichloromethane (5 mL) were added to a reaction flask and transferred to an ice bath. (COCl)2 (240 mg, 1.88 mmol, 2.0 eq.) was dissolved in 5 mL of dichloromethane (2 mL) and added dropwise to the reaction mixture. After the addition was complete, the mixture was stirred at room temperature for 2 hours. After evaporating the solvent to dryness, an orange-yellow solid was obtained, which was directly used in the next step (396 mg, 100% yield).

[0236] Step 2: A reaction flask was charged with 84A (396 mg, 0.94 mmol, 1.0 eq.) and tetrahydrofuran (5 mL), and the flask was transferred to an ice bath. Aqueous ammonia (5 mL, 40%) was added dropwise to the reaction mixture. After the addition was completed, the mixture was stirred at room temperature for half an hour. The organic phase was concentrated to give a crude product, which was purified using a C18 reverse-phase column (eluent: 0.5% formic acid in water: MeOH = 10% to 80%). The target component was collected and concentrated to give the title compound 84 (white solid). LCMS:404 [M+H] + 1H NMR (400MHz,DMSO-d6) δ 11.97 (s,1H),8.50 (t,1H),8.19 (s,1H),7.92 (s,1H),7.77-7.67 (m,3H),7.41 (d,1H),7.33-7.22 (m,4H),4.32-4.23 (m,4H),2.70 (t,2H),2.44 (s,3H).

[0237] Example 55: Synthesis of 3-((3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)propionamido)methyl)benzoic acid (Compound 85) [ka]

[0238] Compound 83 (150 mg, 0.358 mmol, 1.0 eq.), LiOH (34 mg, 1.43 mmol, 4.0 eq.), ethanol (10 mL), and water (2 mL) were added to a reaction flask and stirred overnight at room temperature. 1.0 mol / L hydrochloric acid was added to adjust the pH to 5-6, followed by filtration. The filter cake was washed with water until neutral and dried to give the title compound 85 (white solid). LCMS: 405 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.99 (s,1H),8.55 (t,1H),8.19 (s,1H),7.81-7.74 (m,3H),7.41 (d,1H),7.36-7.27 (m,3H),4.31-4.28 (m,4H),2.70 (t,2H),2.44 (s,3H).

[0239] Example 56: Synthesis of N-(3-aminobenzyl)-3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)propionamide (Compound 86) hydrochloride [ka]

[0240] The same synthetic route as in Example 1 was employed, except that 1b in Example 1 was replaced with m-Boc-aminobenzylamine, to give intermediate product 86A (yellow solid).

[0241] Intermediate 86A (200 mg, 0.42 mmol, 1.0 eq.) was dissolved in 1,4-dioxane (10 mL), and a solution of hydrogen chloride in dioxane (2 mL, 8 mmol, 20.0 eq., 4.0 M) was added. The mixture was allowed to react at room temperature for 2 hours. After filtration, the filter cake was washed with ethyl acetate (2 × 10 mL) and dried at 45 °C to give compound 86 hydrochloride (yellow solid). LCMS:376 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 12.04 (s,1H),8.63 (t,1H),8.29 (s,1H),7.79 (s,1H),7.42 (d,1H),7.30 (m,2H),7.21-7.13 (m,3H),4.32 (t,2H),4.26 (d,2H),2.71 (t,2H),2.45 (s,3H).

[0242] Example 57: Synthesis of 3-(8-methyl-4-oxobenzofuro[3,2-d]pyrimidin-3(4H)-yl)-N-(3-(trifluoromethyl)benzyl)propionamide (Compound 87) [ka]

[0243] The same synthetic route as in Example 36 was employed, except that 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride in the last step of Example 36 was replaced with 3-(trifluoromethyl)benzylamine to give the title compound 87 (white solid). LCMS: 430 [M+1]; 1H NMR (400MHz,DMSO-d6) δ 8.58 (t,1H),8.44 (s,1H),7.82 (s,1H),7.71 (d,1H),7.49 (d,3H),7.42 (s,2H),4.31 (d,4H),3.33 (s,3H),2.74 (d,2H).

[0244] Example 58: Synthesis of 3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)-N-(3-sulfonamidobenzyl)propionamide (Compound 88) [ka]

[0245] The title compound 88 (white solid) was obtained by employing the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 3-aminomethylbenzenesulfonamide. LCMS:440 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 12.00 (s,1H),8.61 (t,1H),8.18 (s,1H),7.77 (s,1H),7.70-7.60 (m,2H),7.42-7.21 (m,6H),4.43-4.19 (m,4H),2.71 (t,2H),2.44 (s,3H).

[0246] Example 59: Synthesis of 3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)-N-(2-((3-(trifluoromethyl)phenyl)amino)ethyl)propionamide (Compound 89) [ka]

[0247] The title compound 89 (white solid) was obtained by employing the same synthetic route as in Example 1, except that compound 1b in Example 1 was replaced with 89b. LCMS:458 [M+H]+ 1 H NMR (400MHz,DMSO-d6) δ 11.99 (s,1H),8.18 (s,1H),8.10 (t,1H),7.75 (s,1H),7.40 (d,1H),7.30-7.18 (m,2H),6.79-6.74 (m,3H),6.09 (t,1H),4.28 (t,2H),3.17 (q,2H),3.04 (q,2H),2.62 (t,2H),2.43 (s,3H).

[0248] Example 60: Synthesis of 3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)-N-(2-(3-(trifluoromethyl)phenoxy)ethyl)propionamide (Compound 90) [ka]

[0249] The title compound 90 (white solid) was obtained by employing the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 90b. LCMS:459 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.96 (s,1H),8.23 (t,1H),8.16 (s,1H),7.72 (s,1H),7.45-7.36 (m,2H),7.29-7.21 (m,2H),7.17 (s,1H),7.13 (d,1H),4.27 (t,2H),3.99 (t,2H),3.42-3-38 (m,2H),2.64 (t,2H),2.43 (s,3H).

[0250] Example 61: Synthesis of N-methyl-3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)-N-(2-((3-(trifluoromethyl)phenyl)amino)ethyl)propionamide (Compound 91) [ka]

[0251] Step 1: A reaction flask was charged with m-trifluoromethylbenzene bromide (1.125 g, 5.0 mmol, 1.0 eq.), compound 91a-1 (1.3 g, 7.5 mmol, 1.5 eq.), Pd(dba) (0.915 g, 1.0 mmol, 0.2 eq.), X-phos (0.475 g, 1.0 mmol, 0.2 eq.), potassium phosphate (3.18 g, 15 mmol, 3.0 eq.), and 1,4-dioxane (30 mL). The mixture was purged with nitrogen gas three times and stirred at 100 °C for 12 h. The filter cake was filtered, washed with ethyl acetate, concentrated, and purified on a silica gel column (eluent: PE:EtOAc = 100:1 to 90:10). The target component was collected and concentrated to give intermediate product 91A (1.0 g, yield: 62.9%) as a wine-red oily liquid.

[0252] Step 2: A reaction flask was charged with 91A (1.0 g, 3.1 mmol, 1.0 eq.), a solution of hydrochloric acid (2.0 mol / L) in ethyl acetate (12.4 mL, 12.4 mmol, 4.0 eq.), and ethyl acetate (10 mL), and the mixture was stirred at room temperature for 3 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate and dried to give the white-orange intermediate product 91B (0.8 g, 100% yield).

[0253] Step 3: The title compound 91 (white solid) was obtained by employing the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 91B. LCMS:472 [M+H] +

[0254] 1H NMR (400 MHz, DMSO-d6) δ 11.97-11.94 (m, 1H), 8.31-8.22 (m, 1H), 7.76 (s, 1H), 7.42-7.39 (m, 1H), 7.30-7.16 (m, 2H), 6.86-6.72 (m, 3H), 6.16-6.13 (m, 1H), 4.30-4.21 (m, 2H), 3.43-3.39 (m, 2H), 3.27-3.13 (m, 2H), 2.95 (s, 2H), 2.85-2.79 (m, 3H), 2.44 (s, 3H). Note: Due to the influence of the chiral nitrogen, most hydrogens appear as two pairs of peaks.

[0255] Example 62: Synthesis of N-methyl-N-(2-(methyl(3-(trifluoromethyl)phenyl)amino)ethyl)-3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)propionamide (Compound 92) [ka]

[0256] Step 1: Compound 92A was obtained by the same synthetic method as in Step 1 of Example 61, except that 91a-1 in Example 61 was replaced with N,N'-dimethylethylenediamine.

[0257] Step 2: The title compound 92 (white solid) was obtained by employing the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 92A. LCMS: 486 [M+H] +

[0258] 1H NMR (400 MHz, DMSO-d6) δ 11.96-11.93 (m, 1H), 8.30-8.19 (m, 1H), 7.76 (s, 1H), 7.43-7.39 (m, 1H), 7.30-7.20 (m, 2H), 6.98-6.76 (m, 3H), 4.26-4.21 (m, 2H), 3.56-3.34 (m, 4H), 2.93-2.87 (m, 5H), 2.84-2.69 (m, 3H), 2.44 (s, 3H). Note: Most hydrogens exhibit two pairs of peaks due to the chiral nitrogen.

[0259] Example 63: Synthesis of N-(2-(methyl(3-(trifluoromethyl)phenyl)amino)ethyl)-3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)propionamide (Compound 93) [ka]

[0260] The title compound 93 (white solid) was obtained by employing the same synthetic route as in Example 61, except that 91a-1 in Example 61 was replaced with 2-(methylamino)ethylcarbamic acid tert-butyl ester. LCMS:472 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.98 (s,1H),8.16 (s,1H),8.10 (t,1H),7.75 (s,1H),7.40 (d,1H),7.31-7.26 (m,2H),6.92 (d,1H),6.88-6.82 (m,2H),4.24 (t,2H),3.36 (t,2H),3.17 (q,2H),2.84 (s,3H),2.56 (t,2H),2.43 (s,3H).

[0261] Example 64: Synthesis of 8-methyl-3-(3-((3-(trifluoromethyl)benzyl)amino)propyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (Compound 94) [ka]

[0262] Step 1: The same synthetic route as in Example 29 was employed, except that 4-aminobutanol in Step 1 of Example 29 was replaced with 3-amino-1-propanol to give intermediate product 94A (yellow solid).

[0263] Step 2: The same synthetic route as in Example 31 was employed, except that 1-(2,3-dichlorophenyl)piperazine hydrochloride in Example 31 was replaced with 3-(trifluoromethyl)benzylamine, to give the title compound 94 (white solid). LCMS: 415 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.97 (s,1H),8.26 (s,1H),8.18 (s,1H),7.76 (d,2H),7.66 (d,1H),7.60 (d,1H),7.54 (t,1H),7.41 (d,1H),7.28 (d,1H),4.15 (t,2H),3.85 (s,2H),2.62 (t,2H),2.44 (s,3H),2.01-1.83 (m,2H).

[0264] Example 65: Synthesis of 3-(trifluoromethyl)benzyl 3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)propionate (Compound 95) [ka]

[0265] The title compound 95 (pseudo-white solid) was obtained by employing the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with m-trifluoromethylbenzyl alcohol. LCMS: 430 [M+H] + 1H NMR (400MHz,DMSO-d6) δ 11.98 (s,1H),8.26 (s,1H),7.75 (s,1H),7.72 (s,1H),7.64 (t,2H),7.53 (t,1H),7.41 (d,1H),7.28 (d,1H),5.17 (s,2H),4.33 (t,2H),2.95 (t,2H),2.44 (s,3H).

[0266] Example 66: Synthesis of 3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)-N-(2-((5,6,7,8-tetralin-1-yl)amino)ethyl)propionamide (Compound 129) [ka]

[0267] Step 1: A 100 mL single-neck flask was charged with 5,6,7,8-tetrahydro-1-naphthylamine (129a) (2 g, 0.0136 mol, 1.0 eq.), 2-(BOC-amino)bromoethane (3.35 g, 0.0149 mol, 1.1 eq.), cesium carbonate (8.9 g, 0.0272 mol, 2.0 eq.), and anhydrous DMF (50 mL). The mixture was heated to 70 °C under nitrogen gas protection for 1 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with a large amount of water, extracted twice with DCM, and the DCM layer was washed three times with saturated brine, separated, and dried over anhydrous sodium sulfate. The solvent was removed from the organic phase, and the crude product was purified by column chromatography (eluent: DCM:MeOH=100:1 to 10:1) to give a pale yellow oily intermediate product 129A (0.45 g, yield: 11.4%).

[0268] Step 2: 129A (0.15 g, 0.000517 mol, 1.0 eq.) and a solution of hydrogen chloride in 1,4-dioxane (2 mL) were added to a 50 mL one-neck flask and reacted at room temperature for 1 h. The solvent was removed by spin-drying to give crude 129B, which was used directly in the next step.

[0269] Step 3: The same synthetic route as in Example 1 was employed, except that 1b in Example 1 was replaced with 129B, to give the title compound 129 (white solid). LCMS:444 [M+1] + 1 H NMR (400MHz,DMSO-d6): δ 12.00 (s,1H),8.23-8.13 (m,2H),7.76 (s,1H),7.42 (d,1H),7.29 (d,1H),6.85 (t,1H),6.31 (dd,2H),4.69 (s,1H),4.30 (t,2H),3.23 (q,2H),3.05 (q,2H),2.65 (t,2H),2.58 (t,2H),2.45 (s,3H),2.23 (t,2H),1.75-1.65 (m,2H),1.63-1.53 (m,2H).

[0270] Example 67: Synthesis of N-(2-(methyl(5,6,7,8-tetralin-1-yl)amino)ethyl)-3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)propionamide (Compound 130) [ka]

[0271] The same synthetic route as in Example 66 was employed, with the following step added between Step 1 and Step 2 of the synthetic route in Example 66, to give the title compound 130 (white solid).

[0272] A 100 mL three-neck flask was charged with 130A (0.15 g, 0.000517 mol, 1.0 eq.) and anhydrous DMF (3 mL). The mixture was cooled in an ice bath under nitrogen gas protection. After cooling to 0-5 °C, NaH (0.025 g, 0.00062 mol, 1.2 eq., 60%) was added. The mixture was incubated for 1 h, and then a solution of methyl iodide (0.088 g, 0.00062 mol, 1.2 eq.) in anhydrous DMF (1 mL) was added. The mixture was then incubated at room temperature for 1 h. After the reaction was complete, the mixture was diluted with a large amount of water and extracted with EA. The EA layer was washed three times with saturated brine, separated, and dried over anhydrous sodium sulfate. The solvent was removed from the organic phase, and the crude product was purified by column chromatography (eluent: DCM:MeOH=100:1 to 10:1) to give a pale yellow oily intermediate product 130B (0.13 g, yield: 82.8%). LCMS:458 [M+1] + 1 H NMR (400MHz,DMSO-d6): δ 11.98 (s,1H),8.37 (d,2H),7.77 (s,1H),7.43 (d,1H),7.30 (d,1H),6.89-6.83 (m,1H),6.45-6.30 (m,2H),4.32-4.24 (m,2H),3.53-3.44 (m,2H),3.23-3.18 (m,2H),2.96 (s,2H),2.86-2.81 (m,3H),2.60-2.58 (m,2H),2.45 (s,3H),2.28-2.27 (m,2H),1.73-1.72 (m,2H),1.59-1.58 (m,2H).

[0273] Example 68: Synthesis of 3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)-N-(2-((5,6,7,8-tetralin-2-yl)amino)ethyl)propionamide (Compound 131) [ka]

[0274] The same synthetic route as in Example 66 was employed, except that 129a in Example 66 was replaced with 131a, to give the title compound 131 (white solid). LCMS:444 [M+1] + 1 H NMR (400MHz,DMSO-d6): δ 12.00 (s,1H),8.19 (s,1H),8.08 (s,1H),7.77 (s,1H),7.43 (d,1H),7.30 (d,1H),6.70 (d,1H),6.29 (d,1H),6.18 (s,1H),5.14 (s,1H),4.30 (t,2H),3.17-3.15 (m,2H),2.96 (s,2H),2.64 (t,2H),2.54 (s,4H),2.45 (s,3H),1.65 (s,4H).

[0275] Example 69: Synthesis of 3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)-N-(2-(naphth-2-ylamino)ethyl)propionamide (Compound 132) [ka]

[0276] The same synthetic route as in Example 66 was employed, except that 129a in Example 66 was replaced with 132a, to give the title compound 132 (white solid). LCMS:440 [M+1] + 1 H NMR (400MHz,DMSO-d6): δ 12.00 (s,1H),8.22 (s,1H),8.17 (t,1H),7.78 (s,1H),7.61 (d,1H),7.54 (dd,2H),7.43 (d,1H),7.33-7.24 (m,2H),7.10 (t,1H),6.90 (d,1H),6.71 (s,1H),5.86 (t,1H),4.31 (t,2H),3.28 (q,2H),3.12 (q,2H),2.66 (t,2H),2.44 (s,3H).

[0277] Example 70: Synthesis of N-(2-(6-chloro-1H-pyrrolo[3,2-c]pyridin-1-yl)ethyl)-3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)propionamide (Compound 133) [ka]

[0278] The title compound 133 (white solid) was obtained by employing the same synthetic route as in Example 66, except that 129a in Example 66 was replaced with 133a. LCMS: 449 [M+1]; 1 H NMR (400MHz,DMSO-d6) δ 11.99 (s,1H),8.52 (s,1H),8.14 (s,1H),8.08 (s,1H),7.76 (s,1H),7.61 (s,1H),7.41 (d,1H),7.27 (t,2H),6.37 (d,1H),4.19 (d,4H),3.34 (d,4H),2.44 (s,3H).

[0279] Example 71: Synthesis of N-(imidazol[1,2-a]pyridin-2-ylmethyl)-3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)propionamide (Compound 134) [ka]

[0280] The title compound 134 (pseudo-white solid) was obtained by employing the same synthetic route as in Example 1, except that 1b in Example 1 was replaced with 134a. LCMS: 401 [M+1]; 1H NMR (400MHz,DMSO-d6) δ 12.00 (s,1H),8.49 (s,1H),8.30 (d,1H),8.20 (s,1H),7.75 (s,1H),7.57 (s,1H),7.47-7.36 (m,2H),7.28 (d,1H),7.20-7.12 (m,1H),6.79 (t,1H),4.39-4.26 (m,4H),2.69 (t,2H),2.44 (s,3H).

[0281] Example 72: Synthesis of N-(2-(6-chloro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethyl)-3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)propionamide (Compound 135) [ka]

[0282] The same synthetic route as in Example 66 was employed, except that 129a in Example 66 was replaced with 135a, to give the title compound 135 (white solid). LCMS: 449 [M+1]; 1 H NMR (400MHz,DMSO-d6) δ 12.00 (s,1H),8.27 (s,1H),8.16 (s,1H),8.07 (s,2H),7.76 (s,1H),7.42 (d,2H),7.28 (d,1H),6.32 (s,1H),4.21 (d,4H),3.33 (s,4H),2.43 (s,3H).

[0283] Example 73: Synthesis of 8-methyl-3-(3-oxo-3-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)pyrimido[5,4-b]quinolin-4(3H)-one (Compound 138) [ka]

[0284] Step 1: 2-Amino-5-methylbenzyl alcohol (5 g, 0.0365 mol, 1 eq.) (138a), manganese dioxide (3.2 g, 0.0365 mol, 1.0 eq.), and dichloromethane (100 mL) were added to a 250 mL three-neck flask, heated to 50 °C under nitrogen gas protection, and stirred for 3 hours. After the reaction was completed, the product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) and concentrated under reduced pressure to give yellow solid intermediate product 138A (4.5 g, yield: 91.3%).

[0285] Step 2: To a 250 mL three-neck flask, add methyl bromopyruvate (0.8 g, 0.0044 mol, 1 eq.) and ethanol (20 mL), then add pyridine (0.35 g, 0.0044 mol, 1 eq.), reflux, stir for 1 hour, cool to 20 °C, add pyridine (1.6 g, 0.02 mol, 4.6 eq.) and 138A (0.6 g, 0.0044 mol, 1 eq.), continue refluxing for 4 hours, add tetrahydropyrrole (0.94 g, 0.0132 mol, 3.0 eq.), heat to 90 °C, reflux for 1 hour, cool to 20 °C, and purify by silica gel column chromatography (ethyl acetate:petroleum ether = 1:5) and concentrate under reduced pressure to obtain yellow liquid intermediate product 138B (0.86 g, yield: 85%).

[0286] Step 3: A 250 mL three-neck flask was charged with 138B (0.9 g, 0.0039 mol, 1 eq.) in DMF-DMA (1.8 mL) and DMF (10 mL), heated to 90 °C, and stirred for 2 hours. 3-Aminopropionic acid ethyl ester (1.3 g, 0.008 mol, 2 eq.) and ethanol (10 mL) were then added, and the mixture was refluxed for 3 hours. The reaction was completed, and the mixture was purified by silica gel column chromatography (dichloromethane:methanol = 20:1), concentrated under reduced pressure, and dried to give yellow solid intermediate product 138C (0.95 g, yield: 76.9%).

[0287] Step 4-6: The same synthetic route as in Example 3 was employed, except that 3E in Example 3 was replaced with 138D and 1-(2,4-dichlorophenyl)piperazine hydrochloride was replaced with 1-(3-(trifluoromethyl)phenyl)piperazine, to give the title compound 138 (pseudo-white solid). LCMS:496 [M+1] + 1 H NMR (400MHz,DMSO-d6): δ 8.59 (s,1H),δ 8.44 (s,1H),δ 8.09 (d,1H),δ 7.90 (s,1H),7.71 (d,1H),δ 7.38 (s,1H),7.18-7.13 (m,2H),7.05 (s,1H),4.23 (t,2H),3.57 (br,4H),3.21-3.16 (m,4H),2.93 (t,2H),2.53(s,3H).

[0288] Example 74: Synthesis of methyl (2-(4-(3-(2-(trifluoromethyl)-10H-phenothiazin-10-yl)propyl)piperazin-1-yl)ethyl)succinate (Compound 184) [ka]

[0289] A reaction flask was charged with 184a (100 mg, 0.23 mmol, 1.0 eq.) and dichloromethane (4 mL), and then triethylamine (70 mg, 0.69 mmol, 3.0 eq.) was added. Succinic acid monomethyl ester chloride (52 mg, 0.34 mmol, 1.5 eq.) was added dropwise in an ice-water bath. The reaction mixture was warmed to room temperature and reacted for 4 h. After LCMS monitoring showed the reaction of the raw materials was complete, the reaction mixture was filtered, concentrated, and separated using a C18 reverse-phase column to give the title compound 184 (white solid) (84 mg, yield: 66%). LCMS:552 [M+H] + 1H NMR (400MHz,DMSO-d6) δ 7.24-7.14 (m,4H),7.04 (s,1H),7.00 (t,1H),6.93 (d,1H),4.13 (t,2H),4.01 (t,2H),3.68 (s,3H),3.15-3.12 (m,2H),2.76 (t,2H),2.61 (br,4H),2.21-2.15 (m,4H),1.74-1.71 (m,2H),1.59-1.57 (m,2H),1.47 (br,2H).

[0290] Example 75: Synthesis of formate salt of 1-(3-(10H-phenothiazin-10-yl)propyl)piperidine-2-carboxamide (Compound 185) [ka]

[0291] 185a (100 mg, 0.31 mmol, 1.0 eq.) and N,N-dimethylformamide (4 mL) were added to a reaction flask, followed by potassium carbonate (130 mg, 0.93 mmol, 3.0 eq.), 2-piperidineformamide (185b) (54 mg, 0.37 mmol, 1.2 eq.) and potassium iodide (10 mg, 0.038 mmol, 0.1 eq.). The reaction mixture was diluted to 95°C. o The reaction was continued at C for 4 hours. After LCMS monitoring showed that the reaction of the raw materials was complete, the reaction mixture was filtered and separated and purified using a C18 reverse phase column to give the formate salt of the title compound 185 (60 mg, yield: 52%). LCMS:368 [M+H] + 1H NMR (400MHz,DMSO-d6) δ 8.16 (s,1H),7.20-7.11 (m,4H),7.03-6.90 (m,4H),3.96-3.92 (m,1H),3.79-3.75 (m,1H),3.00-2.97 (m,1H),2.69-2.52 (m,2H),2.31-2.29 (m,1H),2.02-1.97 (m,1H),1.86-1.82 (m,2H),1.68-1.43 (m,5H),1.24-1.19 (m,1H).

[0292] Example 76: Synthesis of 1-(3-(10H-phenothiazin-10-yl)propyl)piperidin-2-one (Compound 186) [ka]

[0293] A reaction flask was charged with 185a (100 mg, 0.31 mmol, 1.0 eq.) and N,N-dimethylformamide (4 mL). Sodium hydride (20 mg, 0.48 mmol, 1.5 eq.) and piperidone 118b (50 mg, 0.48 mmol, 1.5 eq.) were then added, and the reaction mixture was allowed to react at room temperature for 4 h. After LCMS monitoring showed the reaction of the raw materials was complete, the reaction was quenched by adding ice water. The mixture was extracted with ethyl acetate, dried, concentrated, and purified by silica gel column chromatography (DCM:MeOH=20:1) to give the title compound 186 (gray liquid) (100 mg, yield: 94%). LCMS: 339 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 7.23-7.11 (m,4H),7.00 (d,2H),6.93 (t,2H),3.84 (t,2H),3.35 (s,1H),3.31 (s,1H),3.19-3.09 (m,2H),2.19-2.08 (m,2H),1.94-1.81 (m,2H),1.66-1.54 (m,4H).

[0294] Example 77: Synthesis of 1-(6-(2-(trifluoromethyl)-10H-phenothiazin-10-yl)hexyl)piperidin-2-one (Compound 187) [ka]

[0295] 2-Piperidone (186b) (86 g, 0.87 mmol, 1.25 eq.) was dissolved in N,N-dimethylformamide (3 mL). Sodium hydride (45 mg, 1.12 mmol, 1.6 eq.) was slowly added in an ice bath and the reaction mixture was allowed to react for 0.5 h. A solution of 187a (300 mg, 0.70 mmol, 1.0 eq.) in N,N-dimethylformamide was added dropwise and the reaction mixture was allowed to react for 4 h at room temperature. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine (20 mL), dried, and concentrated to give the crude product. The crude product was purified by reverse-phase column chromatography (eluent: 0.1% formic acid aqueous solution: MeOH = 9:1 to 2:8). The target component was collected and concentrated to give the title compound 187 (200 mg, 64% yield) as a brown oil. LCMS:448 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 7.33 (d,1H),7.26-7.13 (m,4H),7.03 (d,1H),6.97 (t,1H),3.90 (t,2H),3.18-3.09 (m,4H),2.11 (t,2H),1.68-1.57 (m,6H),1.41-1.30 (m,4H),1.22-1.16 (m,2H).

[0296] Example 78: Synthesis of N-(3-(10H-phenothiazin-10-yl)propyl)imidazole[1,2-a]pyridin-3-amine (Compound 188) formate [ka]

[0297] A reaction flask was charged with 185a (383 mg, 1.2 mmol, 1.2 eq.) and acetonitrile (6 mL). Potassium carbonate (415 mg, 3.0 mmol, 3.0 eq.), imidazole[1,2-a]pyridin-3-amine (188b) (133 mg, 1.0 mmol, 1.0 eq.), and potassium iodide (20 mg, 0.12 mmol, 0.1 eq.) were then added, and the reaction mixture was heated at 60 °C for 4 h. After LCMS monitoring showed the reaction of the starting materials was complete, the reaction mixture was filtered, spun dry, and purified by C18 reverse phase column separation to give the formate salt of the title compound 188 (160 mg, 36% yield) as a white solid. LCMS:373 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 8.48 (d,1H),8.39 (s,1H),7.83 (d,1H),7.63-7.47 (m,1H),7.33 (t,1H),7.27 (s,1H),7.16 (t,4H),7.04-6.88 (m,4H),6.06 (s,1H),4.43 (s,2H),3.92 (t,2H),2.29-2.15 (m,2H).

[0298] Example 79: Synthesis of 2-(3-(10H-phenothiazin-10-yl)propyl)isoindolin-1-one (Compound 189) [ka]

[0299] The title compound 189 (white solid) was obtained by employing the same synthetic route as in Example 76, except that 186b in Example 76 was replaced with 189b. LCMS:373 [M+H] + 1H NMR (400MHz,DMSO-d6) δ 7.63 (d,1H),7.60-7.48 (m,2H),7.44 (t,1H),7.21-7.10 (m,4H),7.01 (d,2H),6.93 (t,2H),4.41 (s,2H),3.93 (t,2H),3.62 (t,2H),2.15-1.96 (m,2H).

[0300] Example 80: Synthesis of 6-(3-(10H-phenothiazin-10-yl)propoxy)indolin-2-one (Compound 190) [ka]

[0301] The title compound 190 (white solid) was obtained by employing the same synthetic route as in Example 78, except that 188b in Example 78 was replaced with 190b. LCMS:389 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 10.27 (s,1H),7.23-7.10 (m,4H),7.07 (d,2H),7.01 (d,1H),6.93 (t,2H),6.41 (d,1H),6.33 (s,1H),4.02 (d,4H),3.32 (d,2H),2.15-1.97 (m,2H).

[0302] Example 81: Synthesis of methyl 1-(3-(10H-phenothiazin-10-yl)propyl)piperidine-2-carboxylate (Compound 191) formate [ka]

[0303] The formate salt of the title compound 191 (white solid) was obtained by employing the same synthetic route as in Example 75, except that 185b in Example 75 was replaced with 191b. LCMS:383 [M+H] + 1H NMR (400MHz,DMSO-d6) δ 8.13 (s,1H),7.18 (t,2H),7.12 (d,2H),7.02 (d,2H),6.92 (t,2H),3.96-3.81 (m,2H),3.54 (s,3H),3.14 (s,1H),2.92-2.78 (m,1H),2.61-2.50 (m,1H),2.42-2.36 (m,1H),2.24-2.20 (m,1H),1.79-1.72 (m,2H),1.62-1.54 (m,2H),1.44-1.32 (m,4H).

[0304] Example 82: Synthesis of 1-(3-(10H-phenothiazin-10-yl)propyl)piperidine-2-carboxylic acid (Compound 192) [ka]

[0305] 191 (100 mg, 0.26 mmol, 1.0 eq.) and methanol (3 mL) / water (1 mL) were added to a reaction flask, and lithium hydroxide (60 mg, 1.3 mmol, 5.0 eq.) was added. The reaction mixture was cooled to 45°C. o The reaction was continued at C for 12 hours. After LCMS monitoring showed that the reaction of the raw materials was complete, the reaction solution was spin-dried, and the concentrated solution was adjusted to pH 3-5, spin-dried, and further purified by C18 reverse phase column separation to give the title compound 192 (gray solid) (40 mg, yield: 42%). LCMS:369 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 8.30 (s,1H),7.19 (t,2H),7.14 (d,2H),7.04 (d,2H),6.93 (t,2H),3.95-3.82 (m,4H),3.11-3.05 (m,2H),2.97-2.94 (m,1H),2.73-2.70 (m,1H),1.93-1.90 (m,2H),1.79-1.74 (m,1H),1.64-1.62 (m,1H),1.51 (br,2H),1.34 (br,1H).

[0306] Example 83: Synthesis of 1-(6-(6-(trifluoromethyl)-2,3-dihydro-4H-benzo[b][1,4]thiazol-4-yl)hexyl)piperidin-2-one (Compound 193) [ka]

[0307] Step 1: A reaction flask was charged with 193a (600 mg, 2.73 mmol, 1.0 eq.), DMF (10 mL), K2CO3 (1.13 g, 8.19 mmol, 3.0 eq.), and 1,6-dibromohexane (660 mg, 2.73 mmol, 1.0 eq.). o The mixture was stirred overnight at C. The reaction mixture was filtered and then purified by column chromatography (eluent: 0.1% formic acid aqueous solution:MeOH=4:6) to collect the target component, which was then concentrated under reduced pressure to give a white solid 193A (200 mg, yield: 19%).

[0308] Step 2: Add 193A (200 mg, 0.53 mmol, 1.0 eq.) and DMF (2 mL) to a reaction flask. o The temperature was lowered to 20°C and the atmosphere was replaced with nitrogen gas. Sodium hydride (38 mg, 1.59 mmol, 3.0 eq.) was added, and the mixture was stirred at room temperature for 30 min. After that, piperidin-2-one (186b) (79 mg, 0.80 mmol, 1.5 eq.) was added. The mixture was stirred at room temperature for 2 h. Water was added dropwise to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was concentrated and purified by column chromatography (eluent: 0.1% formic acid aqueous solution:MeOH = 55:45). The target component was collected and concentrated under reduced pressure to give the title compound 193 (white solid) (64 mg, yield: 30%). LCMS:401 [M+H] + 1H NMR (400MHz,DMSO-d6) δ 7.15 (d,1H),6.85-6.78 (m,2H),3.65-3.61 (m,2H),3.27-3.22 (m,4H),3.13-3.06 (m,2H),2.20 (t,2H),1.75-1.65 (m,4H),1.62-1.42 (m,5H),1.40-1.24 (m,5H).

[0309] Example 84: Synthesis of 1-(3-(6-(trifluoromethyl)-2,3-dihydro-4H-benzo[b][1,4]thiazin-4-yl)propyl)piperidin-2-one (Compound 194) [ka]

[0310] Step 1: Compound 194A (white solid) was obtained by employing the same synthetic route as in Step 1 of Example 83, except that 1,6-dibromohexane in Step 1 of Example 83 was replaced with 3-bromopropan-1-ol.

[0311] Step 2: 194A (200 mg, 0.72 mmol, 1.0 eq.) and 40% aqueous hydrobromic acid were added to a reaction flask, refluxed at 100° C., and stirred overnight. The reaction mixture was concentrated under reduced pressure to give a white solid 194B (150 mg, yield: 62%).

[0312] Step 3: The same synthetic route as in Step 2 of Example 83 was employed, except that 193A in Step 2 of Example 83 was replaced with 194B to give the title compound 194 (white solid). LCMS:359 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 7.16 (d,1H),6.85-6.81 (m,2H),3.64-3.61 (m,2H),3.37-3.32 (m,6H),3.13-3.10 (m,2H),2.23 (t,2H),1.80-1.70 (m,6H).

[0313] Example 85: Synthesis of 4-(6-(2-oxopiperidin-1-yl)hexyl)-6-(trifluoromethyl)-2H-benzo[b][1,4]thiazin-3(4H)-one (Compound 195) [ka]

[0314] Compound 195 (white solid) was obtained by employing the same synthetic route as in Example 83, except that 193a in Example 83 was replaced with 195a. LCMS: 415 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 7.69 (d,1H),7.59 (s,1H),7.42 (d,1H),4.09 (t,2H),3.60 (s,2H),3.26-3.19 (m,4H),2.19 (t,2H),1.72-1.68 (m,4H),1.51-1.47 (m,2H),1.42-1.38 (m,2H),1.28-1.21 (m,4H).

[0315] Example 86: Synthesis of 4-(3-(2-oxopiperidin-1-yl)propyl)-6-(trifluoromethyl)-2H-benzo[b][1,4]thiazin-3(4H)-one (Compound 196) [ka]

[0316] Step 1: Compound 196A was obtained by employing the same synthetic route as in Step 1 of Example 83, except that 1,6-dibromohexane in Step 1 of Example 83 was replaced with 3-bromopropan-1-ol and 193a was replaced with 195a.

[0317] Step 2: Compound 196B was obtained by employing the same synthetic route as in Step 2 of Example 84, except that 194A in Step 2 of Example 84 was replaced with 196A.

[0318] Step 3: The same synthetic route as in Step 2 of Example 83 was employed, except that 193A in Step 2 of Example 83 was replaced with 196B to give the title compound 196 (white solid). LCMS:373 [M+H] + 1 H NMR (400MHz,CD3OD) δ 7.64 (d,1H),7.55 (s,1H),7.39 (d,1H),4.13 (t,2H),3.53 (s,2H),3.45 (t,2H),3.41-3.32 (m,2H),2.39 (t,2H),1.93-1.83 (m,6H).

[0319] Example 87: Synthesis of 2-(3-(6-(trifluoromethyl)-2,3-dihydro-4H-benzo[b][1,4]thiazin-4-yl)propyl)isoindolin-1-one (Compound 197) [ka]

[0320] The same synthetic route as in Step 2 of Example 83 was employed, except that 193A was replaced with 194B and 186b was replaced with 197a in Step 2 of Example 83, to give the title compound 197 (white solid). LCMS:393 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 7.71 (d,1H),7.63-7.62 (m,2H),7.52 (dd,1H),7.16 (d,1H),6.83-7.81 (m,2H),4.54 (s,2H),3.67-3.61 (m,4H),3.45-3.39 (t,2H),3.14-3.10 (m,2H),1.98-1.85 (m,2H).

[0321] Example 88: Synthesis of 7-(4-(2-(trifluoromethyl)-10H-phenothiazin-10-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 205) [ka]

[0322] A reaction flask was charged with 205a (200 mg, 0.75 mmol, 1.0 eq.) and N,N-dimethylformamide (4 mL). Sodium bicarbonate (60 mg, 1.50 mmol, 2.0 eq.) was added, and the reaction mixture was allowed to react at room temperature for 30 min. After this, 205b (268 mg, 0.90 mmol, 1.2 eq.) was added. The reaction mixture was allowed to react at room temperature for 4 h. After monitoring the reaction of the raw materials for essentially complete reaction by LCMS, the reaction was quenched by adding ice water, extracted with ethyl acetate, dried, and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH=20:1), and the target component was collected. It was then concentrated under reduced pressure to give the title compound (250 mg, 69% yield) as a pseudo-white solid. LCMS: 485 [M+H] + 1 H NMR (400MHz,CDCl3) δ 7.93 (s,1H),7.21-7.12 (m,4H),7.03-6.94 (m,3H),6.91 (d,1H),6.44 (dd,1H),6.21 (d,1H),3.99-3.92 (m,4H),2.89 (t,2H),2.60 (t,2H),2.0-1.88 (m,4H).

[0323] Example 89: Synthesis of 7-((5-(2-(trifluoromethyl)-10H-phenothiazin-10-yl)pentyl)oxy)-3,4-dihydroquinolin-2(1H)-one (Compound 206) [ka]

[0324] A reaction flask was charged with 205a (0.294 g, 1.1 mmol, 1.1 eq.) and DMF (10 mL), and NaH (52 mg, 1.3 mmol, 1.3 eq.) was added portionwise under ice bath. After the addition was complete, the mixture was stirred for 15 min, and then 206b (0.312 g, 1.0 mmol, 1.0 eq.) was added and stirred for 3 h. The reaction was quenched with water under ice bath and concentrated to give the crude product. The crude product was purified by silica gel column separation (eluent: PE: EtOAc = 1:1). The target component was collected, concentrated, and spin-dried to give the title compound 206 (white solid) (85 mg, yield: 57.8%). LCMS: 499 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 9.93 (s,1H),7.33 (d,1H),7.24-7.19 (m,3H),7.15 (d,1H),7.04 (d,1H),6.99-6.95 (m,2H),6.41-6.37 (m,2H),3.94 (t,2H),3.80 (t,2H),2.76 (t,2H),2.37 (t,2H),1.75-1.63 (m,4H),1.55-1.44 (m,2H).

[0325] Example 90: Synthesis of 7-((6-(2-(trifluoromethyl)-10H-phenothiazin-10-yl)hexyl)oxy)-3,4-dihydroquinolin-2(1H)-one (Compound 207) [ka]

[0326] Compound 187a (100 mg, 0.23 mmol, 1.0 eq.) was dissolved in N,N-dimethylformamide (1 mL) and water (0.1 mL). Anhydrous potassium carbonate (42 mg, 0.30 mmol, 1.3 eq.) and 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (207b) (46 mg, 0.28 mmol, 1.2 eq.) were added, and the mixture was heated to 35 °C and reacted overnight. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic phases were washed with saturated brine (20 mL), dried, and concentrated to give the crude product. The crude product was purified by C18 reverse-phase column chromatography (eluent: 0.1% formic acid in water:MeOH = 1:9 to 9:1). The target component was collected and concentrated to give the title compound (60 mg, yield: 50%) as a white solid. LCMS:513 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 9.94 (s,1H),7.32 (d,1H),7.25-7.17 (m,3H),7.15 (d,1H),7.04 (d,1H),6.97 (m,2H),6.41-6.34 (m,2H),3.92 (t,2H),3.80 (t,2H),2.74 (t,2H),2.38 (t,2H),1.72-1.56 (m,4H),1.37 (m,4H).

[0327] Example 91: Synthesis of 3-(3-oxo-3-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)benzo[4,5]thieno[3,2-d]pyrimidin-4(3H)-one [ka]

[0328] Step 1: 144a (5 g, 24.13 mmol, 1.0 eq) was added to DMF (50 mL), and DMF-DMA (11.5 g, 96.50 mmol, 4.0 eq) was added, stirred at 80 °C for 3 h, diluted with water, extracted with ethyl acetate, the organic phase was dried, filtered and spun to give brown oil 144A (6 g, yield: 94.8%).

[0329] Step 2: 144A (6 g, 22.87 mmol, 1.0 eq) was added to MeOH (100 mL), and then methyl 3-aminopropionate hydrochloride (6.39 g, 45.74 mmol, 2.0 eq) was added, and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was cooled to room temperature, and a large amount of solid precipitated. The solid was filtered, and the filter cake was dried to give brown solid 144B (4.1 g, yield: 62.17%).

[0330] Step 3: 144B (2 g, 6.94 mmol, 1.0 eq) was added to THF / MeOH / HO (60 mL / 20 mL / 20 mL) and LiOH (498 mg, 20.81 mmol, 3.0 eq) was added and stirred at 25 °C for 3 h. The reaction mixture was diluted with water and adjusted to pH 6-7 with 1 M aqueous hydrochloric acid until a large amount of solid precipitated. The mixture was filtered and the filter cake was dried to give yellow solid 144C (1.2 g, yield: 63.0%).

[0331] Step 4: 144C (150 mg, 0.547 mmol, 1.0 eq), 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (144b) (175 mg, 0.656 mmol, 1.2 eq), and DIPEA (353 mg, 2.73 mmol, 5.0 eq) were added to DMF (3 mL), and HATU (312 mg, 0.821 mmol, 1.5 eq) was added. The mixture was stirred at 25 °C for 2 h. The reaction mixture was purified by C18 reverse-phase chromatography (eluent: 0.1% formic acid aqueous solution:MeOH = 1:20 to 9:1). The target fraction was collected, freeze-dried, and dried to give 144 (37 mg, 13.9% yield) as a white solid. LCMS: 487 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 8.72 (s,1H),8.28 (d,1H),8.18 (d,1H),7.73-7.69 (m,1H),7.66-7.62 (m,1H),7.46-7.42 (m,1H),7.24-7.20 (m,2H),7.12-7.10 (m,1H),4.35 (t,2H),3.64-3.60 (m,4H),3.36-3.21 (m,4H),2.99 (t,2H).

[0332] Example 92: Synthesis of 3-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-oxopropyl)benzo[4,5]thieno[3,2-d]pyrimidin-4(3H)-one [ka]

[0333] The same synthetic route as in Example 91 was employed, except that 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (144b) in Step 4 of Example 91 was replaced with 1-(2,3-dichlorophenyl)piperazine hydrochloride (145b), to give the title compound 145 (pseudo-white solid). LCMS: 487 [M+H]+ 1 H NMR (400MHz,DMSO-d6) δ 8.72 (s,1H),8.29 (d,1H),8.20 (d,1H),7.73-7.70 (m,1H),7.66-7.63 (m,1H),7.35-7.27 (m,2H),7.09-7.06 (m,1H),4.35 (t,2H),3.64-3.62 (m,4H),3.00-2.92 (m,6H).

[0334] Example 93: Synthesis of 3-(3-(4-(4-fluorobenzyl)piperidin-1-yl)-3-oxopropyl)benzo[4,5]thieno[3,2-d]pyrimidin-4(3H)-one [ka]

[0335] The same synthetic route as in Example 91 was employed, except that 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (144b) in Step 4 of Example 91 was replaced with 4-(4-fluorobenzyl)piperidine (146b), to give the title compound 146 (pseudo-white solid). LCMS: 450 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 8.67 (s,1H),8.28 (d,1H),8.20 (d,1H),7.73-7.69 (m,1H),7.66-7.62 (m,1H),7.14-7.06 (m,4H),4.38-4.28 (m,3H),3.82-3.78 (m,1H),2.96-2.81 (m,3H),2.49-2.35 (m,3H),1.76-1.64 (m,1H),1.55-1.50 (m,2H),0.98-0.87 (m,2H).

[0336] Example 94: Synthesis of 3-(3-(4-hydroxy-4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-3-oxopropyl)benzo[4,5]thieno[3,2-d]pyrimidin-4(3H)-one [ka]

[0337] The same synthetic route as in Example 91 was employed, except that 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (144b) in Step 4 of Example 91 was replaced with 4-(3-(trifluoromethyl)phenyl)piperidin-4-ol (147b), to give the title compound 147 (pseudo-white solid). LCMS: 502 [M+H]+ 1H NMR (400MHz,DMSO-d6) δ 8.72 (s,1H),8.29 (d,1H),8.19 (d,1H),7.86 (s,1H),7.73-7.58 (m,4H),7.50 (t,1H),5.41 (s,1H),4.41-4.34 (m,3H),3.81-3.78 (m,1H),3.45-3.41 (m,1H),3.05-2.90 (m,3H),1.99-1.91 (m,1H),1.82-1.75 (m,1H),1.63-1.59 (m,2H).

[0338] Example 95: Synthesis of 8-fluoro-3-(3-oxo-3-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)benzofuro[3,2-d]pyrimidin-4(3H)-one [ka]

[0339] Step 1: A 100 mL single-neck flask was charged with 148a (2 g, 0.0146 mol, 1.0 eq.), methyl bromoacetate (2.68 g, 0.0175 mol, 1.2 eq.), potassium carbonate (4 g, 0.0292 mol, 2.0 eq.), and DMF (20 mL) and reacted at 60 °C for 16 h. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate. A large amount of water was added to the filtrate, which was extracted twice with ethyl acetate. The ethyl acetate phase was washed three times with saturated brine, dried, and the solvent was removed to give 148A as a brown oil. The crude product was used directly in the next step.

[0340] Step 2: 148A (crude, 0.0146 mol, 1.0 eq.), DMF-DMA (5.22 g, 0.0438 mol, 3.0 eq.), and DMF (40 mL) were added to a 100 mL single-neck flask and reacted at 60 °C for 3 h. After the reaction was completed and cooled to room temperature, a large amount of water was added to the reaction mixture, which was extracted twice with ethyl acetate. The ethyl acetate phase was washed three times with saturated brine, dried, and the solvent was removed to give brown oil 148B, which was used directly in the next step.

[0341] Step 3: A 100 mL single-neck flask was charged with 148B (crude, 0.0146 mol, 1.0 eq.), methyl 3-aminopropionate hydrochloride (4.08 g, 0.0292 mol, 2.0 eq.), and acetonitrile (40 mL). The mixture was refluxed for 16 h. The mixture was stirred and cooled to room temperature, then placed in an ice bath and cooled. The mixture was filtered. The filter cake was washed with methanol and dried to give 148C (1.43 g, 33.7% yield) as a white solid.

[0342] Step 4: A 100 mL single-neck flask was charged with 148C (1.43 g, 0.00493 mol, 1.0 eq.), THF (12 mL), and water (3 mL). The mixture was cooled to 0-5 °C in an ice bath. LiOH (0.236 g, 0.00986 mol, 2.0 eq.) was added and the mixture was incubated in an ice bath for 1 h. After the reaction was complete, the pH was adjusted to 3-4 with dilute hydrochloric acid in an ice bath. A large amount of solid precipitated, filtered, and the filter cake was washed with water and dried to obtain a white solid, 148D (1.12 g, 82.2% yield).

[0343] Step 5: A 100 mL single-neck flask was charged with 148D (0.15 g, 0.000543 mol, 1.0 eq.), 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (144b) (0.22 g, 0.000815 mol, 1.5 eq.), HATU (0.31 g, 0.00815 mol, 1.5 eq.), anhydrous DMF (5 mL), and DIPEA (0.35 g, 0.00272 mol, 5.0 eq.) and allowed to react at room temperature for 1 h. The reaction mixture was purified by reverse-phase column chromatography (eluent: 0.5% formic acid / methanol = 100:0 to 10:90). The product was then evaporated to dryness and freeze-dried to give 148 (0.16 g, 21.4% yield) as a pale yellow solid. LCMS:489 [M+1] + 1H NMR (400MHz,DMSO-d6): δ 8.63 (s,1H),7.92 (dd,1H),7.86 (dd,1H),7.58-7.52 (m,1H),7.43 (t,1H),7.22-7.20 (m,1H),7.16 (m,1H),7.09 (d,1H),4.35 (t,2H),3.61-3.56 (m,4H),3.25-3.18 (m,4H),2.96 (t,2H).

[0344] Example 96: Synthesis of 3-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-oxopropyl)-8-fluorobenzofuro[3,2-d]pyrimidin-4(3H)-one [ka]

[0345] The same synthetic route as in Example 95 was employed, except that 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (144b) in step 5 of Example 95 was replaced with 1-(2,3-dichlorophenyl)piperazine hydrochloride (145b) to give title compound 149 (white solid). LCMS:489 [M+1] + 1 H NMR (400MHz,DMSO-d6): δ 8.64 (s,1H),7.93 (dd,1H),7.88-7.85 (m,1H),7.58-7.53 (m,1H),7.33-7.27 (m,2H),7.09-7.07 (m,1H),4.35 (t,2H),3.61-3.57 (m,4H),2.96-2.90 (m,6H).

[0346] Example 97: Synthesis of 8-fluoro-3-(3-(4-(4-fluorobenzyl)piperidin-1-yl)-3-oxopropyl)benzofuro[3,2-d]pyrimidin-4(3H)-one [ka]

[0347] The same synthetic route as in Example 95 was employed, except that 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (144b) in step 5 of Example 95 was replaced with 4-(4-fluorobenzyl)piperidine (146b) to give title compound 150 (white solid). LCMS:452 [M+1] + 1 H NMR (400MHz,DMSO-d6): δ 8.60 (s,1H),7.93 (dd,1H),7.88 (dd,1H),7.58-7.53 (m,1H),7.15-7.11 (m,2H),7.09-7.04 (m,2H),4.36-4.32 (m,1H),4.31 (t,2H),3.79-3.75 (m,1H),2.91-2.77 (m,3H),2.50-2.33 (m,3H),1.74-1.65 (m,1H),1.55-1.50 (m,2H),1.02-0.86 (m,2H).

[0348] Example 98: Synthesis of 8-fluoro-3-(3-(4-hydroxy-4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-3-oxopropyl)benzofuro[3,2-d]pyrimidin-4(3H)-one [ka]

[0349] The same synthetic route as in Example 95 was employed, except that 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (144b) in Example 95 was replaced with 4-(3-(trifluoromethyl)phenyl)piperidin-4-ol (147b), to give title compound 151 (white solid). LCMS:504 [M+1] + 1H NMR (400MHz,DMSO-d6): δ 8.64 (s,1H),7.92 (dd,1H),7.88 (dd,1H),7.82 (br,1H),7.73 (d,1H),7.59-7.50 (m,3H),5.38 (s,1H),4.38-4.32 (m,3H),3.77-3.74 (m,1H),3.43-3.36 (m,1H),3.01-2.86 (m,3H),1.97-1.90 (m,1H),1.81-1.74 (m,1H),1.61-1.58 (m,2H).

[0350] Example 99: Synthesis of 3-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one formate [ka]

[0351] Step 1: 152a (5 g, 24.1 mmol, 1.0 eq) was dissolved in DCM (30 mL). A mixture of 65% HNO3 and acetic acid (2.34 g 65% HNO3 / 15 g acetic acid) was slowly added dropwise. After the addition was complete, the mixture was stirred at 40 °C for 16 h. After the reaction was complete, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution at 0 °C. The mixture was then extracted with water (100 mL) and dichloromethane (50 mL). The organic phase was spin-dried and purified by flash column chromatography (PE:EA = 1:1) to give a yellow solid 152A (3 g, 49.3% yield).

[0352] Step 2: 152A (3 g) was dissolved in MeOH (50 mL), and Pd / C (300 mg, 0.1 w / w) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. After the reaction was complete, the mixture was filtered, and the filtrate was spun dry and purified by flash column chromatography (PE:EA = 1:1) to give yellow solid 152B (2.23 g, 84.3% yield).

[0353] Step 3: 152B (2.23 g, 10.0 mmol, 1.0 eq) was dissolved in DMF (30 mL), and DMF-DMA (5.96 g, 50.0 mmol, 5.0 eq) was added, and the mixture was stirred at 80 °C for 16 h. After the reaction was complete, it was extracted with water (100 mL) and dichloromethane (50 mL * 2), and the organic phase was spun to dryness to give 152C (3 g) as a red oil.

[0354] Step 4: 152C (3 g, 10.83 mmol, 1.0 eq) was dissolved in methanol (30 mL), and methyl 3-aminopropionate (1.6 g, 16.24 mmol, 1.5 eq) was added. The mixture was stirred at 70 °C for 16 h. After the reaction was complete, filtration gave a white solid 152D (1 g, yield: 31.9%).

[0355] Step 5: 152D (1 g) was added to THF / HO (10 mL / 3 mL) and 10% sodium hydroxide (3 mL) was added. The mixture was stirred at room temperature for 16 h. After the reaction was complete, the mixture was spin-dried, the pH was adjusted to 5-6, and the mixture was filtered to give 152E (0.7 g, 73.0% yield) as a white solid.

[0356] Step 6: 152E (200 mg, 0.72 mmol, 1.0 eq), 145b (290 mg, 1.08 mmol, 1.5 eq), HATU (550 mg, 1.45 mmol, 2.0 eq), and DIPEA (233 mg, 1.81 mmol, 2.5 eq) were added to DCM (5 mL), and the mixture was stirred at room temperature for 16 h. After the reaction was complete, the mixture was extracted with water (20 mL) and dichloromethane (10 mL). The organic phase was spin-dried and purified using a reverse-phase column (0.1% FA / HO:MeOH = 30:70). The resulting fraction was freeze-dried to give the formate salt of compound 152 (40 mg, 11.3% yield) as a yellow solid. LCMS: 488 [M+H] + 1H NMR (400MHz,DMSO-d6) δ 12.19 (s,1H),8.35 (s,1H),7.71 (dd,1H),7.56-7.52 (m,1H),7.41 (t,1H),7.36-7.30 (m,1H),7.21 (d,1H),7.16 (s,1H),7.08 (d,1H),4.32 (t,2H),3.62-3.57 (m,4H),3.23-3.17 (m,4H),2.93 (t,2H).

[0357] Example 100: Synthesis of 8-fluoro-3-(3-oxo-3-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one [ka]

[0358] The same synthetic route as in Example 99 was employed, except that 145b in step 6 of Example 99 was replaced with 1-(3-(trifluoromethyl)phenyl)piperazine (144b) to give the title compound 153 (white solid). LCMS: 488 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 12.20 (s,1H),8.36 (s,1H),7.70 (dd,1H),7.56-7.52 (m,1H),7.41 (t,1H),7.36-7.31 (m,1H),7.21-7.16 (m,2H),7.08 (d,1H),4.32 (t,2H),3.62-3.57(m,4H),3.23-3.17 (m,4H),2.93 (t,2H).

[0359] Example 101: Synthesis of 8-fluoro-3-(3-(4-(4-fluorobenzyl)piperidin-1-yl)-3-oxopropyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one [ka]

[0360] The same synthetic route as in Example 99 was employed, except that 145b in step 6 of Example 99 was replaced with 146b, to give the title compound 154 (white solid). LCMS: 451[M+H] + 1 H NMR (400MHz,DMSO-d6) δ 12.22 (s,1H),8.30 (s,1H),7.72 (dd,1H),7.57-7.54 (m,1H),7.37-7.31 (m,1H),7.10-7.02 (m,4H),4.34 (d,1H),4.29-4.26 (t,2H),3.77(d,1H),2.94-2.83 (m,2H),2.81-2.73 (m,1H),2.45-2.38 (m,2H),2.34-2.29 (m,1H),1.72-1.61 (m,1H),1.53-1.44 (m,2H),0.92-0.83 (m,2H).

[0361] Example 102: Synthesis of 3-(4-fluorobenzyl)piperidin-1-yl)-3-oxopropyl-8-methyl-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one [ka]

[0362] A reaction flask was charged with 165a (100 mg, 0.37 mmol, 1.0 eq.), DMF (2 mL), and HATU (169 mg, 0.44 mmol, 1.2 eq.) and stirred at room temperature for 30 min. 4-(4-fluorobenzyl)piperidine (146b) (79 mg, 0.41 mmol, 1.1 eq.) and DIPEA (143 mg, 1.11 mmol, 3.0 eq.) were then added. The mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography (eluent: 0.1% formic acid in water: MeOH = 44%). The target component was collected and concentrated under reduced pressure to give 164 (49 mg, yield: 29.70%) as a white solid. LCMS:447 [M+H]+ 1 H NMR (400MHz,DMSO-d6) δ 11.98 (s,1H),8.29 (s,1H),7.81 (s,1H),7.46 (d,1H),7.34-7.29 (dd,1H),7.10-7.06 (m,4H),4.37 (d,1H),4.34-4.27 (m,2H),3.80 (d,1H),2.98-2.87 (m,2H),2.87-2.55 (m,2H),2.48 (s,3H),2.43-2.31 (m,2H),1.69 (s,1H),1.57-1.44 (m,2H),0.95-0.84 (m,2H).

[0363] Example 103: Synthesis of 3-(3-(4-hydroxy-4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-3-oxopropyl)-8-methyl-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one [ka]

[0364] The same synthetic route as in Example 102 was employed, except that 4-(4-fluorobenzyl)piperidine (146b) in Example 102 was replaced with 4-(3-(trifluoromethyl)phenyl)piperidin-4-ol (147b), to give title compound 165 (white solid). LCMS: 499 [M+H] 1H NMR (400MHz,DMSO-d6) δ 11.98 (s,1H),8.34 (s,1H),7.83 (d,2H),7.61 (dd,2H),7.46 (t,2H),7.32 (dd,1H),5.38 (s,1H),4.45-4.30 (m,3H),3.79 (d,1H),3.41 (t,1H),3.05-2.85 (m,3H),2.49 (s,3H),1.95-1.71 (m,2H),1.60 (t,2H).

[0365] Example 104: Synthesis of 3-(3-(4-((2,3-dichlorophenyl)(methyl)amino)piperidin-1-yl)-3-oxopropyl)-8-methyl-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one [ka]

[0366] The same synthetic route as in Example 102 was employed, except that 4-(4-fluorobenzyl)piperidine (146b) in Example 102 was replaced with N-(2,3-dichlorophenyl)-N-methylpiperidin-4-amine (166b), to give the title compound 166 (white solid). LCMS:513 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.99 (s,1H),8.32 (s,1H),7.80 (s,1H),7.45 (d,1H),7.33-7.27 (m,3H),7.19-7.14 (m,1H),4.41 (d,1H),4.31 (t,2H),3.87 (d,1H),3.31-3.24 (m,1H),3.02-2.91 (m,2H),2.88-2.80 (m,1H),2.60-2.55 (m,1H),2.53-2.51 (m,3H),2.48 (s,3H),1.65-1.61 (m,2H),1.50-1.47 (m,2H).

[0367] Example 105: Synthesis of 8-methyl-3-(3-oxo-3-(4-(pyridin-3-yl)piperazin-1-yl)propyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one formate [ka]

[0368] The same synthetic route as in Example 102 was employed, except that 4-(4-fluorobenzyl)piperidine (146b) in Example 102 was replaced with 1-(pyridin-3-yl)piperazine (167b), to give the formate salt of compound 167 (white solid). LCMS: 417 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.97 (s,1H),8.34 (s,1H),8.31 (s,1H),8.17 (s,1H),8.05-8.00 (m,1H),7.78 (s,1H),7.44 (d,1H),7.34-7.29 (m,2H),7.24-7.19 (m,1H),4.33 (t,2H),3.64-3.59 (m,4H),3.21-3.16 (m,4H),2.95 (t,2H),2.47 (s,3H).

[0369] Example 106: Synthesis of 8-methyl-3-(3-(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)-3-oxopropyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one [ka]

[0370] The same synthetic route as in Example 102 was employed, except that 4-(4-fluorobenzyl)piperidine (146b) in Example 102 was replaced with 1-(4-(methylsulfonyl)phenyl)piperazine (168b), to give the title compound 168 (white solid). LCMS:494 [M+H] + 1H NMR (400MHz,DMSO-d6) δ 11.96 (s,1H),8.35 (s,1H),7.79 (s,1H),7.70 (d,2H),7.44 (d,1H),7.33-7.29 (dd,1H),7.07 (d,2H),4.34 (t,2H),3.66-3.58 (m,4H),3.41-3.37 (m,4H),3.10 (s,3H),2.95 (t,2H),2.47 (s,3H).

[0371] Example 107: Synthesis of 8-methyl-3-(3-oxo-3-(4-(4-(piperidin-1-ylsulfonyl)phenyl)piperazin-1-yl)propyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one [ka]

[0372] The same synthetic route as in Example 102 was employed, except that 4-(4-fluorobenzyl)piperidine (146b) in Example 102 was replaced with 1-(4-(piperidin-1-ylsulfonyl)phenyl)piperazine (169b), to give the title compound 169 (white solid). LCMS: 563 [M+H]+ 1 H NMR (400MHz,DMSO-d6) δ 11.97 (s,1H),8.35 (s,1H),7.79 (s,1H),7.52 (d,2H),7.45 (d,1H),7.33-7.29(m,1H),7.06 (d,2H),4.34 (t,2H),3.65-3.60 (m,4H),3.39-3.35 (m,4H),2.95 (t,2H),2.83 (t,4H),2.47 (s,3H),1.57-1.52 (m,4H),1.38-1.34 (m,2H).

[0373] Example 108: Synthesis of 8-methyl-3-(3-oxo-3-(4-(3-(piperidin-1-ylsulfonyl)phenyl)piperazin-1-yl)propyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one [ka]

[0374] The same synthetic route as in Example 102 was employed, except that 4-(4-fluorobenzyl)piperidine (146b) in Example 102 was replaced with 1-(3-(piperidin-1-ylsulfonyl)phenyl)piperazine hydrochloride (170b), to give title compound 170 (white solid). LCMS:563 [M+1] + 1 H NMR (400MHz,DMSO-d6) δ 11.97 (s,1H),8.35 (s,1H),7.79 (s,1H),7.49-7.43 (m,2H),7.32-7.26 (m,2H),7.14-7.11 (m,2H),4.34 (t,2H),3.63 (m,4H),3.24 (m,4H),2.97-2.88 (m,6H),2.47 (s,3H),1.58-1.52 (m,4H),1.40-1.36 (m,2H).

[0375] Example 109: Synthesis of 3-(4-(3-(8-methyl-4-oxo-4,5-dihydro-3H-pyrimido[5,4-b]indol-3-yl)propionyl)piperazin-1-yl)benzonitrile [ka]

[0376] The same synthetic route as in Example 102 was employed, except that 4-(4-fluorobenzyl)piperidine (146b) in Example 102 was replaced with 3-cyanophenylpiperazine hydrochloride (171b), to give the title compound 171 (white solid). LCMS:441 [M+1] + 1H NMR (400MHz,DMSO-d6) δ 11.97 (s,1H),8.34 (s,1H),7.78 (s,1H),7.45-7.37 (m,2H),7.33-7.25 (m,3H),7.19 (d,1H),4.33 (t,2H),3.62-3.57 (m,4H),3.25-3.20 (m,4H),2.95 (t,2H),2.53-2.52 (m,3H).

[0377] Example 110: Synthesis of 8-methyl-3-(3-(4-(3-nitrophenyl)piperazin-1-yl)-3-oxopropyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one [ka]

[0378] The same synthetic route as in Example 102 was employed, except that 4-(4-fluorobenzyl)piperidine (146b) in Example 102 was replaced with 3-nitrophenylpiperazine (172b), to give the title compound 172 (yellow solid). LCMS:461 [M+1] + 1 H NMR (400MHz,DMSO-d6) δ 11.96 (s,1H),8.34 (s,1H),7.77 (s,1H),7.64-7.60 (m,2H),7.50-7.38 (m,3H),7.31 (d,1H),4.34 (t,2H),3.63 (m,4H),3.33-3.27 (m,4H),2.96 (t,2H),2.46 (s,3H).

[0379] Example 111: Synthesis of 3-(3-(4-(3-chlorobenzoyl)piperazin-1-yl)-3-oxopropyl)-8-methyl-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one [ka]

[0380] The same synthetic route as in Example 102 was employed, except that 4-(4-fluorobenzyl)piperidine (146b) in Example 102 was replaced with (3-chlorophenyl)(piperazin-1-yl)methanone hydrochloride (173b), to give the title compound 173 (white solid). LCMS:478 [M+1] + 1 H NMR (400MHz,DMSO-d6) δ 11.97 (s,1H),8.34 (s,1H),7.79 (s,1H),7.56-7.54 (m,1H),7.52-7.50 (m,2H),7.48-7.44 (m,1H),7.39-7.37 (m,1H),7.32-7.30 (m,1H),4.32 (t,2H),3.54 (m,8H),2.92 (s,2H),2.48 (s,3H).

[0381] Example 112: Synthesis of 3-(3-(4-isobutylpiperazin-1-yl)-3-oxopropyl)-8-methyl-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one [ka]

[0382] The same synthetic route as in Example 102 was employed, except that 4-(4-fluorobenzyl)piperidine (146b) in Example 102 was replaced with 1-isobutylpiperazine (174b), to give the title compound 174 (white solid). LCMS: 396 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.94 (s,1H),8.29 (s,1H),7.77 (s,1H),7.42 (d,1H),7.28 (dd,1H),4.28 (t,2H),3.44-3.41 (m,4H),2.85 (t,2H),2.45(s,3H),2.22 (t,4H),1.99-1.95 (m,2H),1.74-1.67 (m,1H),0.83 (s,3H),0.81 (s,3H).

[0383] Example 113: Synthesis of 3-(3-(4-isobutyrylpiperazin-1-yl)-3-oxopropyl)-8-methyl-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one [ka]

[0384] The same synthetic route as in Example 102 was employed, except that 4-(4-fluorobenzyl)piperidine (146b) in Example 102 was replaced with 2-methyl-1-(piperazin-1-yl)propan-1-one (175b), to give the title compound 175 (white solid). LCMS: 410 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 11.94 (s,1H),8.31 (s,1H),7.77 (s,1H),7.42 (d,1H),7.30-7.27 (m,1H),4.29 (t,2H),3.51-3.32 (m,8H),2.91-2.81 (m,3H),2.45 (s,3H),0.98 (s,3H),0.97 (s,3H).

[0385] Example 114: Synthesis of 8-chloro-3-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-oxopropyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one [ka]

[0386] Step 1: 176a (5.0 g, 32.14 mmol, 1.0 eq.) was dissolved in acetonitrile (50 mL), DIPEA (20.8 g, 160.71 mmol, 5.0 eq.) and glycine ethyl ester hydrochloride (6.7 g, 48.21 mmol, 1.5 eq.) were added, and the mixture was heated to 85 °C for 3 days (the reaction was not yet complete, so it was processed directly). The reaction mixture was filtered, and the solid was washed with acetonitrile (2 × 20 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by normal phase silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 67:33) to give 176A (2.1 g, 27.37% yield) as a yellow solid.

[0387] Step 2: 176A (1.6 g, 6.70 mmol, 1.0 eq.) was dissolved in acetonitrile (20 mL), potassium carbonate (5.6 g, 40.22 mmol, 6.0 eq.) was added, and the mixture was heated to 85° C. and reacted for 9 days. The reaction mixture was filtered, the solid was washed with ethyl acetate (2×20 mL), and the filtrate was concentrated under reduced pressure to dryness to give 176B (1.2 g, 75.00% yield) as a brown solid.

[0388] Step 3: 176B (1.1 g, 4.61 mmol, 1.0 eq.) was dissolved in N,N-dimethylformamide (5 mL), and N,N-dimethylformamide dimethyl acetal (5.5 g, 46.09 mmol, 10.0 eq.) was added. The mixture was heated to 60 °C and reacted overnight. The mixture was concentrated to dryness under reduced pressure to give a brown solid 176C (1.3 g, 96.02% yield).

[0389] Step 4: 176C (1.3 g, 4.43 mmol, 1.0 eq.) was dissolved in methanol (20 mL), and methyl 3-aminopropionate hydrochloride (2.5 g, 17.70 mmol, 4.0 eq.) was added. The mixture was heated to 70 °C and reacted overnight. After concentration under reduced pressure, the residue was purified by normal phase silica gel column chromatography (eluent: dichloromethane:methanol = 90:10) to give pale yellow solid 176D (670 mg, yield: 47.69%).

[0390] Step 5: 176D (670 mg, 2.19 mmol, 1.0 eq.) was dissolved in methanol (10 mL), and lithium hydroxide (210 mg, 8.77 mmol, 4.0 eq.) and water (2 mL) were added. The mixture was allowed to react overnight at room temperature. The solvent was removed by concentration under reduced pressure, and the residue was dissolved in water (10 mL). The pH was adjusted to 5 with dilute hydrochloric acid, filtered, and the filter cake was washed with water (2 × 10 mL) and dried to give 176E (580 mg, 90.73% yield) as a pale yellow solid.

[0391] Step 6: A reaction flask was charged with 176E (100 mg, 0.34 mmol, 1.0 eq.), HATU (156 mg, 0.41 mmol, 1.2 eq.), and N,N-dimethylformamide (3 mL). The mixture was allowed to react at room temperature for 0.5 h. 1-(2,3-Dichlorophenyl)piperazine hydrochloride (145b) (110 mg, 0.41 mmol, 1.2 eq.) and DIPEA (164 mg, 1.27 mmol, 3.7 eq.) were added and the mixture was allowed to react at room temperature overnight. The reaction mixture was filtered, and the filter cake was washed with dichloromethane (2 × 10 mL) and dried to give 176 (60 mg, 34.67% yield) as a white solid. LCMS:504 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 12.37 (s,1H),8.40 (s,1H),8.01 (d,1H),7.57 (d,1H),7.49 (dd,1H),7.37-7.24 (m,2H),7.05 (d,1H),4.35 (t,2H),3.69-3.54 (m,4H),2.97-2.88 (m,6H).

[0392] Example 115: Synthesis of 8-chloro-3-(3-oxo-3-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one [ka]

[0393] The same synthetic route as in Example 114 was employed, except that 145b in step 6 of Example 114 was replaced with 1-(3-trifluoromethylphenyl)piperazine hydrochloride (144b), to afford the title compound 177 (white solid). LCMS:504 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 12.37 (s,1H),8.42 (s,1H),8.01 (d,1H),7.58 (d,1H),7.50 (dd,1H),7.45 (t,1H),7.24 (d,1H),7.20 (s,1H),7.12 (d,1H),4.35 (t,2H),3.68-3.57 (m,4H),3.28-3.20 (m,4H),2.97 (t,2H).

[0394] Example 116: Synthesis of 8-chloro-3-(3-(4-hydroxy-4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-3-oxopropyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one [ka]

[0395] The same synthetic route as in Example 114 was employed, except that 145b in step 6 of Example 114 was replaced with 4-(3-trifluoromethyl)phenyl-4-piperidinol (147b), to give the title compound 178 (yellow solid). LCMS: 519 [M+H]+ 1H NMR (400MHz,DMSO-d6) δ 12.35 (s,1H),8.39 (s,1H),8.00 (d,1H),7.83 (s,1H),7.65 (d,1H),7.60-7.53 (m,2H),7.51-7.44 (m,2H),5.39 (s,1H),4.44-4.28 (m,3H),3.82-3.70 (m,1H),3.44-3.37 (m,1H),3.02-2.84 (m,3H),1.93-1.65 (m,2H),1.57 (t,2H).

[0396] Example 117: Synthesis of 8-chloro-3-(3-(4-(4-fluorobenzyl)piperidin-1-yl)-3-oxopropyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one [ka]

[0397] The same synthetic route as in Example 114 was employed, except that 145b in step 6 of Example 114 was replaced with 4-(4'-fluorobenzyl)piperidine (146b) to give the title compound 179 (yellow solid). LCMS: 467 [M+H]+ 1 H NMR (400MHz,DMSO-d6) δ 12.37 (s,1H),8.35 (s,1H),8.01 (d,1H),7.58 (d,1H),7.49 (dd,1H),7.12-7.05 (m,4H),4.37 (d,1H),4.30 (t,2H),3.79 (d,1H),2.96-2.75 (m,3H),2.50-2.30 (m,3H),1.74-1.60 (m,1H),1.56-1.43 (m,2H),0.95-0.83 (m,2H).

[0398] Example 118: Synthesis of 9-methyl-3-(3-oxo-3-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)-3,5-dihydro-2H-chromeno[4,3-d]pyrimidin-2-one [ka]

[0399] Step 1: 208a (500 mg, 2.33 mmol, 1.0 eq) and potassium carbonate (968 g, 7.00 mmol, 3.0 eq) were added to DMF (5 mL), and tert-butyl bromopropionate (976 mg, 4.67 mmol, 2.0 eq) was added. The mixture was reacted at 40 °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 crude product was purified by normal phase column chromatography (petroleum ether:ethyl acetate = 5% to 60%). The target fraction was collected, frozen, and dried to obtain white solid 208A (700 mg, yield: 87.5%).

[0400] Step 2: 208A (700 mg, 2.04 mmol, 1.0 eq) was added to 4 M HCl / 1,4-dioxane (10 mL) and stirred at 25 °C for 3 h. The reaction was then spun to dryness to give yellow solid 208B (550 mg, yield: 93.9%).

[0401] Step 3: 208B (200 mg, 0.699 mmol, 1.0 eq), 144b (279 mg, 1.05 mmol, 1.5 eq), and DIPEA (451 mg, 3.49 mmol, 5.0 eq) were added to DMF (3 mL), and HATU (399 mg, 1.05 mmol, 1.5 eq) was added. The mixture was stirred at 25 °C for 16 h. The reaction mixture was purified on a C18 reverse-phase column (eluent: 0.1% formic acid aqueous solution:MeOH = 1:20 to 9:1). The target fraction was collected, freeze-dried, and dried to give 208 (77 mg, 22.1% yield) as a white solid. LCMS: 499 [M+H] + 1H NMR (400MHz,DMSO-d6) δ 8.22 (s,1H),7.83 (d,1H),7.43 (t,1H),7.33 (dd,1H),7.24-7.19 (m,2H),7.10 (d,1H),6.94 (d,1H),5.02 (s,2H),4.08 (t,2H),3.63-3.58 (m,4H),3.26-3.19 (m,4H),2.91 (t,2H),2.32 (s,3H).

[0402] Example 119: Synthesis of 3-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)-9-methyl-5,6-dihydrobenzo[h]quinazolin-4(3H)-one [ka]

[0403] Step 1: 209a (3.2 g, 20.0 mmol, 1.0 eq) was added to anhydrous THF (30 ml), and 60% NaH (2.0 g, 50.0 mmol, 2.5 eq) was added. The mixture was stirred at 0°C for 0.5 hours under nitrogen gas protection. DMC (20 ml) was added via syringe and the mixture was stirred at 70°C for 16 hours. After the reaction was completed, methanol was added to quench the reaction. The mixture was spin-dried and then purified by normal phase column chromatography (eluent: petroleum ether: ethyl acetate = 1% to 10%). The resulting organic phase was spin-dried to give 209A (3.0 g, yield: 68.8%) as a colorless oil.

[0404] Step 2: 209A (2.0 g, 9.16 mmol, 1.0 eq) and ammonium acetate (3.5 g, 45.82 mmol, 5.0 eq) were added to methanol (20 mL), and the mixture was stirred at 30 °C for 16 h. The reaction mixture was spin-dried, followed by extraction with saturated sodium bicarbonate solution (50 mL) and ethyl acetate (20 mL). The organic phase was spin-dried to give 209B (1.8 g, 89.6% yield) as a white oil.

[0405] Step 3: 209B (1.8 g, 8.29 mmol, 1.0 eq) and DMF-DMA (4.9 g, 41.47 mmol, 5.0 eq) were added to DMF (20 mL) and stirred at 80 °C for 24 h. Water (100 mL) and ethyl acetate (30 mL*2) were added, and the organic phase was spin-dried to give 209C (2 g, yield: 88.6%) as a blue oil.

[0406] Step 4: 209C (2 g, 7.34 mmol, 1.0 eq) was added to formamide (20 mL) and stirred at 200 °C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, and water (100 ml) was added to precipitate a solid. The solid was filtered to give brown solid 209D (0.9 g, yield: 57.7%).

[0407] Step 5: 209D (500 mg, 2.36 mmol, 1.0 eq), 209b (724 mg, 2.36 mmol, 1.0 eq), and potassium carbonate (651 mg, 4.72 mmol, 2.0 eq) were added to acetonitrile (5 mL), and the mixture was stirred at 70 °C for 4 h. The reaction mixture was spin-dried, and then water (30 mL) was added to precipitate a solid. The solid was filtered to give 200 mg of a white solid. The white solid was purified by reverse-phase preparative chromatography (0.1% FA). The resulting solution was concentrated, freeze-dried, and gave 209 (20 mg, 1.75% yield). LCMS: 483[M+H] + 1 H NMR (400MHz,CDCl3) δ 8.23 (s,1H),7.98 (s,1H),7.22-7.15 (m,4H),6.97-6.94 (m,1H),4.12 (t,2H),3.11 (s,4H),2.91 (s,4H),2.70 (s,4H),2.55 (s,2H),2.43 (s,3H),2.10 (t,2H).

[0408] Example 120: Synthesis of 8-methoxy-3-(3-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)-3,5-dihydro-4H-pyrrolo[2,3-c]quinolin-4-one [ka]

[0409] Step 1: A 250 mL single-neck flask was charged with bis(pinacolato)diboron (2.5 g, 0.01 mol, 2.0 eq.), 201a (1.4 g, 0.005 mol, 1.0 eq.), DMSO (30 mL), sodium carbonate (1.1 g, 0.01 mol, 2.0 eq.), and tetrakistriphenylphosphorus palladium (0.3 g, 0.00026 mol, 2.6%). The mixture was heated to 80 °C under nitrogen gas protection and reacted for 6 h. The reaction mixture was concentrated and purified by silica gel column chromatography. The product was eluted with ethyl acetate:petroleum ether (1:2) and concentrated to give 210A (1.8 g, 64.5% yield) as a pale white liquid.

[0410] Step 2: A 250 mL single-neck flask was charged with methyl 3-bromopyrrole-2-formate (1.62 g, 0.0064 mol, 1.0 eq.), 210A (1.8 g, 0.0064 mol, 1.0 eq.), potassium carbonate (4.2 g, 0.03 mol, 5.0 eq.), Pd(dppf)Cl (0.6 g, 0.00074 mol, 11.6%), dioxane (60 mL), and water (10 mL). The mixture was heated to 100 °C under nitrogen gas protection and reacted for 3 h. After completion of the reaction, the product was purified by silica gel column chromatography. The product was eluted with petroleum ether:ethyl acetate = 2:1 and concentrated to give a yellow solid 210B (2.1 g, yield: 100%).

[0411] Step 3: A 250 mL single-neck flask was charged with 210B (2.1 g, 0.0064 mol, 1.0 eq.), Pd / C (0.5 g, 25% wt.), and methanol (50 mL). The mixture was protected with hydrogen gas and reacted at room temperature for 6 h. After completion of the reaction, the mixture was filtered and the organic phase was purified by silica gel column chromatography. The product was eluted with dichloromethane:methanol = 10:1 and concentrated to give a pale white liquid, 210C (0.21 g, yield: 15.3%).

[0412] Step 4: In a 250 mL one-neck flask, add 210C (0.21 g, 0.001 mol, 1.0 eq.), acetonitrile (50 mL), and potassium carbonate (0.42 g, 0.003 mol, 3 eq.). Under nitrogen gas protection, add 1-chloro-3-bromopropane (0.45 g, 0.003 mol, 3.0 eq.) and react at 60 °C for 3 h. After the reaction was completed, the product was purified by silica gel column chromatography. The product was eluted with dichloromethane:methanol = 10:1 and concentrated to give a white solid 210D (0.2 g, yield: 68.8%).

[0413] Step 5: A 250 mL single-neck flask was charged with 210D (0.2 g, 0.0007 mol, 1.0 eq.), acetonitrile (10 mL), potassium carbonate (0.28 g, 0.002 mol, 3 eq.), and 3-trifluorophenylpiperazine (144b) (0.46 g, 0.002 mol, 3 eq.) and reacted under nitrogen gas protection at 80 °C for 16 h. After the reaction was completed, the product was purified by silica gel column chromatography. The product was eluted with dichloromethane:methanol = 10:1 and concentrated to give the crude product. The eluate was purified by chromatography and concentrated to give a white solid 210 (0.02 g, 6% yield). LCMS:485 [M+1] + 1 H NMR (400MHz,CD3OD): δ 7.54-7.49 (m,3H),7.38-7.32(m,3H),7.26 (d,1H),7.09 (dd,1H),7.01 (d,1H),4.81-4.77 (t,2H),3.96-3.93 (m,5H),3.75 (b,2H),3.29-3.25 (m,6H),2.49-2.42 (m,2H).

[0414] Example 121: Synthesis of 3-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)-9-methylpyrimido[5,4-c]quinolin-4(3H)-one formate [ka]

[0415] Step 1: 211a (10 g, 93.32 mmol, 1.0 eq) was added to AcOH (20 mL), and methyl 3-bromopropionate (8.03 g, 93.32 mmol, 1.0 eq) was added. The mixture was stirred at 70 °C for 4 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was dried, filtered, and spin-dried to obtain the crude product. The crude product was purified by normal phase column chromatography (petroleum ether:ethyl acetate = 5% to 10%). The target fraction was collected and spin-dried to obtain yellow solid 211A (15.3 g, yield: 84.8%).

[0416] Step 2: 211A (15.3 g, 79.18 mmol, 1.0 eq) was added to MeOH / HO (150 mL / 50 mL) and NaOH (4.75 g, 118.7 mmol, 1.5 eq) was added, stirred at 25 °C for 2 h, diluted with water, washed with ethyl acetate, the aqueous phase was adjusted to pH 5-6 with saturated aqueous citric acid, extracted with ethyl acetate, the organic phase was dried, filtered, and spun to give yellow oil 211B (14.1 g, yield: 99.3%).

[0417] Step 3: 211B (14.1 g, 78.68 mmol, 1.0 eq) was added to PPA (50 mL) and stirred at 130 °C for 3 hours. The reaction mixture was poured into saturated aqueous sodium carbonate solution, adjusted to pH 7-8, extracted with ethyl acetate, and the organic phase was dried, filtered, and spin-dried to obtain the crude product. The crude product was purified by normal phase column chromatography (petroleum ether:ethyl acetate = 5%-50%). The target fraction was collected and spin-dried to obtain yellow solid 211C (4.2 g, yield: 33.1%).

[0418] Step 4: 211C (4.2 g, 26.05 mmol, 1.0 eq) and DMAP (4.77 g, 39.08 mmol, 1.5 eq) were added to DCM (50 mL), and BocO (11.37 g, 52.11 mmol, 2.0 eq) was added. The mixture was stirred at 25 °C for 16 h. The reaction mixture was spin-dried to give the crude product, which was purified by normal phase column chromatography (petroleum ether:ethyl acetate = 1% to 20%). The target fraction was collected and spin-dried to give white solid 211D (6 g, yield: 88.1%).

[0419] Step 5: 211D (6 g, 22.96 mmol, 1.0 eq) was added to THF (60 mL) and 60% wt. NaH (2.3 g, 57.40 mmol, 2.5 eq in mineral oil) was added portionwise at 0 °C. The mixture was stirred at 25 °C for 0.5 hours, followed by the addition of dimethyl carbonate (3.1 g, 34.4 mmol, 1.5 eq). The mixture was stirred at 70 °C for 2 hours under nitrogen gas protection. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried, filtered, and spin-dried to obtain the crude product, which was purified by normal phase column chromatography (petroleum ether:ethyl acetate = 1% to 10%). The target fraction was collected and spin-dried to obtain yellow solid 211E (6 g, yield: 81.8%).

[0420] Step 6: 211E (2.5 g, 7.83 mmol, 1.0 eq) was added to MeOH (30 mL), and NHOAc (3.02 g, 39.14 mmol, 5.0 eq) was added, and the mixture was stirred at 80 °C for 16 hours. The reaction mixture was spin-dried to give the crude product, which was purified by normal phase column chromatography (petroleum ether:ethyl acetate = 1% to 15%). The target fraction was collected and spin-dried to give white solid 211F (2 g, yield: 80.2%).

[0421] Step 7: 211F (2 g, 6.28 mmol, 1.0 eq) was added to DMF (20 mL), and DMF-DMA (3.74 g, 31.41 mmol, 5.0 eq) was added, stirred at 80 °C for 16 h, diluted with water, extracted with ethyl acetate, the organic phase was dried, filtered, and spun to give black solid 211G (2.1 g, yield: 89.5%).

[0422] Step 8: 211G (700 mg, 1.88 mmol, 1.0 eq) was added to MeOH (10 mL), and NHOAc (1.44 g, 18.8 mmol, 10.0 eq) was added, and the mixture was stirred at 80 °C for 16 hours. The reaction mixture was spin-dried to give the crude product, which was purified by normal phase column chromatography (dichloromethane:methanol = 1% to 10%). The target fraction was collected and spin-dried to give white solid 211H (580 mg, yield: 98.7%).

[0423] Step 9: 211H (300 mg, 0.957 mmol, 1.0 eq) and potassium carbonate (265 mg, 1.91 mmol, 2.0 eq) were added to ACN (5 mL), and 209b (442 mg, 1.44 mmol, 1.5 eq) was added. The mixture was stirred at 50 °C for 16 h. The reaction mixture was spin-dried to give the crude product, which was purified by normal phase column chromatography (petroleum ether:ethyl acetate = 5% to 100%). The target fraction was collected and spin-dried to give white solid 211I (440 mg, yield: 78.6%).

[0424] Step 10: 211I (440 mg, 0.75 mmol, 1.0 eq) was added to DCM (6 mL), and TFA (3 mL) was added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was spin-dried to obtain a crude product, which was purified by C18 reverse-phase column (eluent: 0.1% formic acid aqueous solution:MeOH = 1:20 to 9:1). The target fraction was collected, freeze-dried, and the formate salt of compound 211 was obtained as a white solid (85 mg, yield: 23.4%). LCMS: 482 [M+H]+ 1H NMR (400MHz,DMSO-d6) δ 9.40 (s,1H),8.86 (s,1H),8.59 (s,1H),8.20 (s,1H),8.03 (d,1H),7.82-7.80 (m,1H),7.28-7.26 (m,1H),7.18 (t,1H),6.79-6.77 (m,1H),4.18 (t,2H),2.84-2.72 (m,4H),2.61 (s,3H),2.50-2.47 (m,6H),2.02-1.95 (m,2H).

[0425] Example 122: Synthesis of 9-methyl-3-(3-oxo-3-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)pyrimido[5,4-c]quinolin-4(3H)-one [ka]

[0426] Step 1: 211G (500 mg, 1.34 mmol, 1.0 eq) was added to MeOH (10 mL), and methyl 3-aminopropionate hydrochloride (374 mg, 2.68 mmol, 2.0 eq) was added. The mixture was stirred at 70 °C for 16 hours, and the reaction mixture was spin-dried to obtain a crude product. The crude product was purified by normal phase column chromatography (petroleum ether:ethyl acetate = 5% to 50%), and the target fraction was collected and spin-dried to obtain a yellow solid 212A (200 mg, yield: 37.4%).

[0427] Step 2: 212A (200 mg, 0.5 mmol, 1.0 eq) was added to THF / HO (8 mL / 2 mL) and LiOH (30 mg, 1.25 mmol, 2.5 eq) was added and stirred at 0 °C for 2 h. The reaction mixture was diluted with water and adjusted to pH 5-6 with 1 M aqueous hydrochloric acid, extracted with ethyl acetate, and the organic phase was dried, filtered, and spun to give white solid 212B (190 mg, 98.4% yield).

[0428] Step 3: 212B (190 mg, 0.493 mmol, 1.0 eq), 144b (197 mg, 0.739 mmol, 1.5 eq), and DIPEA (319 mg, 2.46 mmol, 5.0 eq) were added to DMF (2 mL), and HATU (281 mg, 0.739 mmol, 1.5 eq) was added. The mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried, filtered, and spin-dried to give the crude product, which was purified by normal phase column chromatography (dichloromethane:methanol = 1% to 5%). The desired fraction was collected and spin-dried to give yellow solid 212D (200 mg, yield: 67.8%).

[0429] Step 4: 212D (200 mg, 0.335 mmol, 1.0 eq) was added to 4 M HCl / 1,4-dioxane (3 mL) and stirred at 25 °C for 2 h. The reaction mixture was spin-dried to give the crude product, which was then purified on a C18 reverse-phase column (eluent: 0.1% formic acid in water:MeOH = 1:20 to 9:1). The desired fraction was collected, freeze-dried, and gave a white solid 212 (28 mg, yield: 16.8%). LCMS: 496 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 9.40 (s,1H),8.90 (s,1H),8.59 (s,1H),8.05 (s,1H),7.84-7.81 (m,1H),7.44 (t,1H),7.24-7.19 (m,2H),7.10 (d,1H),4.33 (t,2H),3.64-3.59 (m,4H),3.28-3.21 (m,4H),3.00 (t,2H),2.62 (s,3H).

[0430] Example 123: Synthesis of 3-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)-9-methyl-3,5-dihydro-2H-chromeno[4,3-d]pyrimidin-2-one [ka]

[0431] Step 1: 213a (4.5 g, 27.72 mmol, 1.0 eq), urea (1.84 g, 30.51 mmol, 1.1 eq), and triethyl orthoformate (4.11 g, 27.72 mmol, 1.0 eq) were added to MeOH (5 mL), and methanesulfonic acid (15 drops) was added. The mixture was stirred at 130 °C for 6 h. The reaction mixture was diluted with methanol, filtered, and the filter cake was spin-dried to give yellow solid 213A (3.3 g, yield: 55.5%).

[0432] Step 2: 213A (500 mg, 2.33 mmol, 1.0 eq) and potassium carbonate (968 mg, 7.00 mmol, 3.0 eq) were added to DMF (5 mL), and 209b (862 mg, 2.80 mmol, 1.2 eq) was added. The mixture was stirred at 50 °C for 24 h, diluted with water, extracted with ethyl acetate, and the organic phase was dried, filtered, and spin-dried to give the crude product, which was purified by normal-phase column chromatography (dichloromethane:methanol = 1% to 10%) and C18 reverse-phase column chromatography (eluent: 0.1% formic acid aqueous solution:MeOH = 1:20 to 9:1). The target fraction was collected, frozen, and dried to give white solid 213 (155 mg, yield: 13.6%). LCMS: 485 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 8.20 (s,1H),7.87-7.86 (m,1H),7.36-7.01 (m,3H),7.0 (d,1H),6.96 (d,1H),5.04 (s,2H),3.94 (t,2H),3.00-2.86 (m,4H),2.54-2.53 (m,4H),2.44 (t,2H),2.34 (s,3H),1.95-1.88 (m,2H).

[0433] Example 125: Synthesis of 9-methyl-3-(3-oxo-3-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)-5,6-dihydrobenzo[h]quinazolin-4(3H)-one [ka]

[0434] Step 1: 209D (0.50 g, 2.36 mmol, 1.0 eq) was added to anhydrous DMF (30 mL), and potassium carbonate (0.73 g, 4.7 mmol, 2.0 eq) and methyl 3-bromopropionate (1 g, 5.62 mmol, 2.4 eq) were added. The mixture was stirred at 80° C. for 4 h. After the reaction was completed, the mixture was cooled to room temperature, and water (100 mL) was added until the system became cloudy. The mixture was filtered to obtain a white filter cake, which was dried to give 215A (0.48 g, yield: 68.2%).

[0435] Step 2: 215A (0.48 g, 1.60 mmol, 1.0 eq) was dissolved in THF (3 mL). Water (1 mL) and LiOH (116 mg, 4.80 mmol, 3.0 eq) were added to the mixture and stirred at 30 °C for 16 h. After the reaction was completed, the mixture was spin-dried. Water (10 mL) was added and the mixture was adjusted to pH 5-6. Extraction was performed with DCM (5 mL * 2). The organic phase was spin-dried to give white solid 215B (0.45 g, yield: 98.9%).

[0436] Step 3: 215B (0.40 g, 1.40 mmol, 1.0 eq), DIPEA (0.45 g, 3.5 mmol, 2.5 eq), HATU (1.1 g, 2.80 mmol), and 144b (0.39 g, 1.70 mmol, 1.2 eq) were added to DMF (5 mL) and stirred at 30 °C for 16 h. After the reaction was completed, water (20 mL) and ethyl acetate (10 mL) were added for extraction. The organic phase was spun dry, purified by reverse-phase preparative chromatography (0.1% FA), and then concentrated, freeze-dried to give white solid 215 (0.05 g, yield: 7.19%). LCMS: 497 [M+H] + 1H NMR (400MHz,DMSO-d6) δ 8.52 (s,1H),7.89 (s,1H),7.44 (t,1H),7.25-7.20 (m,4H),7.11 (d,1H),4.17 (t,2H),3.64-3.58 (m,4H),3.27-3.20 (m,4H),2.91 (t,2H),2.81 (t,2H),2.70 (t,2H),2.35 (s,3H).

[0437] Example 126: Synthesis of 3-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)-8-methoxy-3,5-dihydro-4H-imidazole[4,5-c]quinolin-4-one formate [ka]

[0438] Step 1: 216a (0.8 g, 0.0039 mol, 1.5 eq.), 209b (0.8 g, 0.0026 mol, 1.0 eq.), cesium carbonate (1.7 g, 0.0052 mol, 2.0 eq.), and DMF (10 mL) were added to a 100 mL three-neck flask and stirred at 80 °C overnight. After the reaction was completed, the product was purified by silica gel column chromatography. The product was eluted with 10% MeOH:DCM. After concentration, yellow oil 216A (1.2 g, 79.56% yield) was obtained.

[0439] Step 2: A 250 mL three-neck flask was charged with 216A (1.14 g, 0.0024 mol, 1.0 eq.), 210A (1.0 g, 0.0036 mol, 1.5 eq.), Pd-118 (0.15 g, 0.00024 mol, 0.1 eq.), potassium carbonate (0.66 g, 0.0048 mol, 2.0 eq.), 1,4-dioxane (20 mL), and HO (5 mL) and stirred overnight at 100 °C under nitrogen gas protection. After completion of the reaction, the product was purified by column chromatography eluting with MeOH:DCM=7%. After concentration under reduced pressure, brown oil 216B (1.14 g, yield: 86.83%) was obtained.

[0440] Step 3: A 100 mL three-neck flask was charged with 216B (0.5 g, 0.0009 mol, 1.0 eq.), zinc powder (0.6 g, 0.009 mol, 10.0 eq.), saturated aqueous NH4Cl (0.5 mL), and EtOH (5 mL) and stirred at 80 °C overnight. After the reaction was complete, the product was purified by reverse-phase column chromatography and eluted with methanol / water. After lyophilization, the formate salt of compound 216 (0.052 g, 5.91% yield) was obtained as a yellow solid. LCMS:486 [M+1]+ 1 H NMR (400MHz,DMSO-d6) δ 11.55 (s,1H),8.29 (s,1H),8.21 (s,1H),7.54 (d,1H),7.39 (d,1H),7.32-7.30 (m,2H),7.11-7.05 (m,2H),4.54 (t,2H),3.86 (s,3H),3.42 (m,3H),3.02-2.95 (m,5H),2.37 (t,2H),2.16-2.01 (m,2H).

[0441] Example 127: Synthesis of 3-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-4-oxobutyl)-9-methylpyrimido[5,4-c]quinolin-4(3H)-one [ka]

[0442] Step 1: 211H (180 mg, 0.574 mmol, 1.0 eq) was added to ACN (2 mL), and potassium carbonate (238 mg, 1.72 mmol, 3.0 eq) and tert-butyl 4-bromobutyrate (192 mg, 0.862 mmol, 1.5 eq) were added. The mixture was stirred at 40° C. for 16 hours. The reaction mixture was then spun dry to give the crude product, which was purified by normal phase column chromatography (eluent: petroleum ether:ethyl acetate=5% to 40%). The target fraction was collected and spun dry to give yellow oil 217A (220 mg, yield: 84.0%).

[0443] Step 2: 217A (220 mg, 0.483 mmol, 1.0 eq) was added to 4 M HCl / 1,4-dioxane (5 mL) and stirred at 25 °C for 1 h. The reaction mixture was then spun to dryness to give yellow solid 217B (140 mg, 97.5% yield).

[0444] Step 3: 217B (70 mg, 0.236 mmol, 1.0 eq), 145b (82 mg, 0.305 mmol, 1.3 eq), and DIPEA (152 mg, 1.18 mmol, 5.0 eq) were added to DMF (2 mL), and HATU (135 mg, 0.354 mmol, 1.5 eq) was added. The mixture was stirred at 25 °C for 2 h. The reaction mixture was purified on a C18 reverse-phase column (eluent: 0.1% formic acid in water:MeOH = 1:20 to 9:1). The desired fraction was collected, freeze-dried, and dried to give 217 (14 mg, 11.6% yield) as a white solid. LCMS: 510 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 9.38 (s,1H),8.80 (s,1H),8.56 (s,1H),8.02 (d,1H),7.81-7.78 (m,1H),7.33-7.29 (m,2H),7.11-7.09 (m,1H),4.12 (t,2H),3.58-3.54 (m,4H),3.00-2.92 (m,2H),2.87-2.85 (m,2H),2.58 (s,3H),2.50-2.47 (m,2H),2.08-2.01 (m,2H).

[0445] Example 128: Synthesis of 3-(4-(4-(4-fluorobenzyl)piperidin-1-yl)-4-oxobutyl)-9-methylpyrimido[5,4-c]quinolin-4(3H)-one [ka]

[0446] The same synthetic route as in Example 127 was employed, except that 145b in Step 3 of Example 127 was replaced with 4-(4-fluorobenzyl)piperidine (146b), to afford the title compound 218 (pseudo-white solid). LCMS: 473 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 9.44 (s,1H),8.82 (s,1H),8.63 (s,1H),8.09 (d,1H),7.87-7.84 (m,1H),7.23-7.19 (m,2H),7.15-7.10 (m,2H),4.31-4.28 (m,1H),4.15 (t,2H),3.86-3.83 (m,1H),2.95-2.89 (m,1H),2.65 (s,3H),2.51-2.38 (m,5H),2.11-2.01 (m,2H),1.79-1.68 (m,1H),1.60-1.47 (m,2H),1.14-1.04 (m,1H),0.93-0.82 (m,1H).

[0447] Example 129: Synthesis of 3-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-4-oxobutyl)-9-methyl-3,5-dihydro-2H-chromeno[4,3-d]pyrimidin-2-one [ka]

[0448] Step 1: 213A (600 mg, 2.80 mmol, 1.0 eq) was added to DMF (10 mL), and potassium carbonate (1.16 g, 8.40 mmol, 3.0 eq) and tert-butyl 4-bromobutyrate (937 mg, 4.20 mmol, 1.5 eq) were added. The mixture was stirred at 40°C for 16 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phase was spin-dried to obtain a crude product. The crude product was purified by normal phase column chromatography (eluent: petroleum ether:ethyl acetate = 5% to 80%). The target fraction was collected and spin-dried to obtain a yellow solid 219A (690 mg, yield: 69.1%).

[0449] Step 2: 219A (690 mg, 1.94 mmol, 1.0 eq) was added to 4 M HCl / 1,4-dioxane (10 mL) and stirred at 25 °C for 2 h. The reaction was then spun to dryness to give yellow solid 219B (550 mg, 94.6% yield).

[0450] Step 3: 219B (150 mg, 0.499 mmol, 1.0 eq), 145b (160 mg, 0.599 mmol, 1.2 eq), and DIPEA (323 mg, 2.50 mmol, 5.0 eq) were added to DMF (3 mL), and HATU (285 mg, 0.749 mmol, 1.5 eq) was added. The mixture was stirred at 25 °C for 2 h. The reaction mixture was purified on a C18 reverse-phase column (eluent: 0.1% formic acid aqueous solution:MeOH = 1:20 to 9:1). The desired fraction was collected, freeze-dried, and dried to give 219 (169 mg, 65.9% yield) as a pseudo-white solid. LCMS: 513 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 8.17 (s,1H),7.88-7.87 (m,1H),7.38-7.34 (m,3H),7.18-7.16 (m,1H),6.97 (d,1H),5.06 (s,2H),3.94 (t,2H),3.69-3.60 (m,4H),3.02-2.96 (m,4H),2.48 (m,2H),2.35 (s,3H),2.04-1.97 (m,2H).

[0451] Example 130: Synthesis of 3-(4-(4-(4-fluorobenzyl)piperidin-1-yl)-4-oxobutyl)-9-methyl-3,5-dihydro-2H-chromeno[4,3-d]pyrimidin-2-one [ka]

[0452] The same synthetic route as in Example 129 was employed, except that 145b in Step 3 of Example 129 was replaced with 4-(4-fluorobenzyl)piperidine (146b), to afford the title compound 220 (pseudo-white solid). LCMS: 476 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 8.12 (s,1H),7.86-7.85 (m,1H),7.36-7.34 (m,1H),7.22-7.18 (m,2H),7.13-7.09 (m,2H),6.95 (d,1H),5.03 (s,2H),4.37-4.34 (m,1H),3.90-3.79 (m,3H),2.94-2.88 (m,1H),2.49-2.33 (m,8H),1.96-1.89 (m,2H),1.77-1.67 (m,1H),1.58-1.52 (m,2H),1.13-0.94 (m,2H).

[0453] Example 131: Synthesis of 3-(3-oxo-3-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)-3,5,6,7-tetrahydro-4H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-one [ka]

[0454] Step 1: 220D (200 mg, 0.94 mmol, 1.0 eq), methyl 3-bromopropionate (224 mg, 1.13 mmol, 1.2 eq), and potassium carbonate (325 mg, 2.36 mmol, 2.5 eq) were dissolved in ACN (10 mL), and the mixture was stirred at 70 °C for 16 h. After completion of the reaction, the reaction solution was spun down and purified by flash column chromatography (PE:EA = 1:1) to give 221A (250 mg, 89.1% yield) as a white oil.

[0455] Step 2: 221A (250 mg) was dissolved in THF / HO (5 mL / 2 mL), and LiOH (50 mg, 0.2 w / w) was added. The mixture was stirred at room temperature for 16 h. After the reaction was complete, the mixture was filtered, and the filtrate was spun dry and purified by flash column chromatography (PE:EA = 1:1) to give 221B (150 mg, 62.9% yield) as a white solid.

[0456] Step 3: 221B (150 mg, 0.52 mmol, 1.0 eq), 144b (181 mg, 0.79 mmol, 1.5 eq), HATU (400 mg, 1.05 mmol, 2.0 eq), and DIPEA (169 mg, 1.31 mmol, 2.5 eq) were dissolved in DCM (5 mL). The mixture was stirred at room temperature for 16 h. After the reaction was complete, the mixture was extracted with water (20 mL) and dichloromethane (5 mL). The organic phase was spin-dried and purified using a reverse-phase column (0.1% FA / HO:MeOH = 30:70). The resulting fraction was freeze-dried to give 221 (100 mg, 38.7% yield) as a white solid. LCMS: 497 [M+H] + 1H NMR (400MHz,DMSO-d6) δ 8.50 (s,1H),7.59-7.56 (m,1H),7.43 (t,1H),7.39-7.35 (m,2H),7.34-7.30 (m,1H),7.24 (dd,1H),7.18 (s,1H),7.19 (dd,1H),4.16 (t,2H),3.64-3.56(m,4H),3.25-3.19 (m,4H),2.91(t,2H),2.48-2.46 (m,2H),2.33-2.30(m,2H),2.17-2.12 (m,2H).

[0457] Example 132: Synthesis of 3-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)-3,5,6,7-tetrahydro-4H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-one formate [ka]

[0458] Step 1: 222a (10 g, 62.4 mmol, 1.0 eq) was dissolved in THF (100 mL). The mixture was cooled to 0 °C, and 60% NaHCO₂ was added. The mixture was stirred at room temperature for 30 min under nitrogen gas protection. Finally, DMC (30 mL) was added and the mixture was stirred at room temperature for 16 h. After the reaction was complete, it was quenched with MeOH (100 mL). The mixture was spun to dryness and purified by flash column chromatography (PE:EA = 1:1) to give 222A (13 g, yield: 95.4%) as a yellow oil.

[0459] Step 2: 222A (3 g, 13.74 mmol, 1.0 eq) and ammonium acetate (4.2 g, 54.98 mmol) were dissolved in MeOH (50 mL), and the mixture was stirred at room temperature for 16 h. After the reaction was complete, the mixture was spin-dried, extracted with water (50 mL) and dichloromethane (20 mL), and the organic phase was spin-dried to give 222B (3 g, yield: 99.6%) as a white oil.

[0460] Step 3: 222B (3 g, 13.8 mmol, 1.0 eq) was dissolved in DMF (30 mL), and DMF-DMA (6.58 g, 55.256 mmol, 4.0 eq) was added, and the mixture was stirred at 80 °C for 16 h. After the reaction was completed, it was extracted with water (100 mL) and dichloromethane (50 mL * 2), and the organic phase was spun dry to give red oil 222C (3.76 g, crude yield: 99.2%).

[0461] Step 4: 222C (3.76 g) was dissolved in formamide (20 mL) and the mixture was stirred at 200 °C for 1 h. After the reaction was complete, it was extracted with water (50 mL) and dichloromethane (20 mL * 2). The organic phase was spun dry and purified by flash column chromatography (DCM:MeOH = 20:1) to give yellow solid 222D (1.2 g, yield: 41.2%).

[0462] Step 5: 222D (200 mg, 0.94 mmol, 1.0 eq), 209b (347 mg, 1.13 mmol, 1.2 eq), and potassium carbonate (325 mg, 2.36 mmol, 2.5 eq) were added to acetonitrile (5 mL), and the mixture was stirred at 70 °C for 16 h. After the reaction was complete, the mixture was spun down, extracted with water (20 mL) and dichloromethane (10 mL). The organic phase was spun down, purified by reverse-phase column chromatography (0.05% FA / HO:MeOH = 30:70), and lyophilized to give the formate salt of compound 222 (90 mg, 19.8% yield) as a white solid. LCMS: 483 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 8.47 (s,1H),8.21 (s,1H),7.62-7.60 (m,1H),7.39-7.36 (m,2H),7.34-7.31 (m,1H),7.30-7.27 (m,2H),7.10-7.06 (m,1H),4.01 (t,2H),2.95(s,5H),2.56-2.53 (m,5H),2.44 (t,2H),2.33 (t,2H),2.18-2.13 (m,2H),1.95-1.90 (m,2H).

[0463] Example 133: Synthesis of 3-(4-(3-(4-fluorobenzyl)piperidin-1-yl)-4-oxobutyl)-9-methyl-5,6-dihydrobenzo[h]quinazolin-4(3H)-one [ka]

[0464] Step 1: 215B (500 mg, 2.35 mmol, 1.0 eq), methyl 4-bromobutyrate (639 mg, 3.53 mmol, 1.5 eq), and potassium carbonate (813 mg, 5.89 mmol, 2.5 eq) were dissolved in ACN (10 mL), and the mixture was stirred at 70 °C for 16 h. After completion of the reaction, the reaction solution was spun dry and purified by flash column chromatography (PE:EA = 1:1) to give 223A (600 mg, 81.7% yield) as a yellow oil.

[0465] Step 2: 223A (600 mg) was dissolved in THF / HO (10 mL / 3 mL), and LiOH (120 mg, 0.2 w / w) was added. The mixture was stirred at room temperature for 16 h. After the reaction was complete, the mixture was filtered, and the filtrate was spun dry and purified by flash column chromatography (PE:EA = 1:1) to give white solid 223B (500 mg, 87.2% yield).

[0466] Step 3: 223B (200 mg, 0.67 mmol, 1.0 eq), 146b (194 mg, 1.00 mmol, 1.5 eq), HATU (510 mg, 1.34 mmol, 2.0 eq), and DIPEA (216 mg, 1.67 mmol, 2.5 eq) were dissolved in DCM (5 mL). The mixture was stirred at room temperature for 16 h. After the reaction was complete, the mixture was extracted with water (20 mL) and dichloromethane (5 mL). The organic phase was spin-dried and purified using a reverse-phase column (0.1% FA / HO:MeOH = 30:70). The resulting fraction was freeze-dried to give 223 (50 mg, 15.7% yield) as a yellow solid. LCMS: 474 [M+H] + 1H NMR (400MHz,DMSO-d6) δ 8.39 (s,1H),7.88 (s,1H),7.20-7.15 (m,4H),7.11-7.06 (m,2H),4.33 (dd,1H),3.93 (t,2H),3.79 (d,1H),2.90 (t,1H),2.83-2.79 (m,2H),2.70-2.66 (m,2H),2.47-2.41 (m,3H),2.36-2.32 (m,5H),1.94-1.89 (m,2H),1.72-1.68 (m,1H),1.53(t ,2H),1.13-0.88 (m,2H).

[0467] Example 134: Synthesis of 3-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-oxopropyl)-8-methoxy-3,5-dihydro-4H-imidazol[4,5-c]quinolin-4-one [ka]

[0468] Step 1: A 250 mL three-neck flask was charged with 224a (1.11 g, 0.0054 mol, 1.0 eq.), tert-butyl 4-bromopropionate (1.7 g, 0.0108 mol, 2.0 eq.), cesium carbonate (3.53 g, 0.0108 mol, 2.0 eq.), DIPEA (1 mL), and DMF (20 mL) and stirred at 80 °C overnight. After the reaction was completed, the product was purified by column chromatography eluting with 20:80 EtOAc:PE. After concentration under reduced pressure, yellow oil 224A (1.1 g, yield: 61.45%) was obtained.

[0469] Step 2: A 250 mL three-neck flask was charged with 224A (1.1 g, 0.0033 mol, 1.0 eq.), 210A (1.38 g, 0.0049 mol, 1.5 eq.), Pd-118 (0.2 g, 0.00033 mol, 0.1 eq.), potassium carbonate (0.91 g, 0.0066 mol, 2.0 eq.), dioxane (20 mL), and water (5 mL) and stirred overnight at 100 °C under nitrogen gas protection. The reaction was then purified by silica gel column chromatography. The product was eluted with 20:80 EtOAc:PE. After concentration, 224B (1.24 g, 93.23% yield) was obtained as a yellow oil.

[0470] Step 3: 224B (1.24 g, 0.003 mol, 1.0 eq.), zinc powder (1.95 g, 0.03 mol, 10.0 eq.), saturated aqueous NH4Cl (1.2 mL), and EtOH (10 mL) were added to a 100 mL three-neck flask and stirred overnight at 85 °C. After the reaction was completed, the mixture was filtered, and the filtrate was spin-dried to give crude 224C (0.5 g).

[0471] Step 4: 224C (0.5 g) and HCl / 1,4-dioxane solution (1 M, 10 mL) were added to a 50 mL three-neck flask and stirred overnight at room temperature. After the reaction was complete, the product was purified by reverse-phase column chromatography. The desired fraction was collected and spin-dried to give 224D (0.1 g, 27.03% yield) as a white solid.

[0472] Step 5: A 100 mL three-neck flask was charged with 224D (0.1 g, 0.35 mmol, 1.0 eq.), 2,3-dichlorophenylpiperazine hydrochloride (145b) (0.096 g, 0.42 mmol, 1.2 eq.), HATU (0.16 g, 0.42 mmol, 1.2 eq.), DIPEA (0.3 mL), and DCM (5 mL) and stirred overnight at room temperature. After the reaction was complete, the product was purified by reverse-phase column chromatography (RPC) eluting with MeOH / HO. The desired fraction was collected and lyophilized to give 224 (0.014 g, 8.05% yield) as a white solid. LCMS:500 [M+1]+ 1 H NMR (400MHz,DMSO-d6) δ 11.58 (s,1H),8.29 (s,1H),7.52 (d,1H),7.40-7.28 (m,3H),7.11-7.05 (m,2H),4.71 (t,2H),3.86 (s,3H),3.64-3.61 (m,4H),3.07 (t,2H),2.92-2.91 (m,4H).

[0473] Example 135: Synthesis of 3-(3-(4-(4-fluorobenzyl)piperidin-1-yl)-3-oxopropyl)-9-methyl-5,6-dihydrobenzo[h]quinazolin-4(3H)-one [ka]

[0474] The same synthetic route as in Example 125 was employed, except that 144b in Step 3 of Example 125 was replaced with 146b, to give the title compound 225 (white solid). LCMS: 460 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 8.45 (s,1H),7.88 (s,1H),7.19-7.17 (m,2H),7.14-7.04 (m,4H),4.34 (d,1H),4.10 (t,2H),3.77 (d,1H),2.92-2.87 (m,1H),2.82-2.72 (m,4H),2.68-2.65 (m,2H),2.47-2.40 (m,3H),2.34(s,3H),1.74-1.64 (m,1H),1.52 (d,2H),1.01-0.85 (m,2H).

[0475] Example 136: Synthesis of 3-(8-methyl-4-oxopyrimido[5,4-b]quinolin-3(4H)-yl)-N-(3-(trifluoromethyl)benzyl)propionamide [ka]

[0476] A 250 mL three-neck flask was charged with 226a (0.28 g, 0.001 mol, 1 eq.), 3-(trifluoromethyl)benzylamine (226b) (0.17 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 and concentrated. The fraction was purified by chromatography. The product was eluted with methanol / water, concentrated under reduced pressure, and lyophilized to give 226 (0.06 g, 13.6% yield) as a white solid. LCMS:441 [M+1]+ 1 H NMR (400MHz,DMSO-d6): δ 8.59 (t,2H),δ 8.30 (s,1H),δ 8.12 (d,1H),δ 7.92 (s,1H),7.72 (d,1H),δ 7.50 (s,2H),7.43-7.38 (m,2H),4.41 (d,2H),4.26(t,2H),2.75(t,2H),2.54 (s,3H).

[0477] Example 137: Synthesis of 3-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-4-oxobutyl)-8-methoxy-3,5-dihydro-4H-imidazol[4,5-c]quinolin-4-one [ka]

[0478] A 100 mL single-neck flask was charged with 227a (0.23 g, 0.681 mmol, 1.0 eq.), 1-(2,3-dichlorophenyl)piperazine hydrochloride (145b) (0.27 g, 1.02 mmol, 1.5 eq.), HATU (0.39 g, 1.02 mmol, 1.5 eq.), anhydrous DMF (5 mL), and DIPEA (0.44 g, 3.41 mmol, 5.0 eq.) and reacted at room temperature for 1 h. The reaction mixture was subjected to reverse-phase column chromatography (eluent: 0.5% formic acid / methanol = 10:90). The product was collected by evaporation of methanol to dryness, and the solid was precipitated. The filter cake was washed with water and dried under reduced pressure to give 227 (0.21 g, 59.9% yield) as a whitish-brown solid. LCMS:514 [M+1] + 1 H NMR (400MHz,DMSO-d6): 11.57 (s,1H),8.18 (s,1H),7.51 (d,1H),7.37-7.29 (m,3H),7.10-7.05 (m,2H),4.50 (t,2H),3.83 (s,3H),3.58-3.53 (m,4H),2.92-2.87 (m,4H),2.38 (t,2H),2.16-2.09 (m,2H).

[0479] Example 138: Synthesis of 3-(4-oxo-4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)butyl)-3,5,6,7-tetrahydro-4H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-one [ka]

[0480] Step 1: 222D (200 mg, 0.94 mmol, 1.0 eq), methyl 4-bromobutyrate (240 mg, 1.13 mmol, 1.2 eq), and potassium carbonate (325 mg, 2.36 mmol, 2.5 eq) were dissolved in ACN (10 mL), and the mixture was stirred at 70 °C for 16 h. After completion of the reaction, the reaction solution was spun down and purified by flash column chromatography (PE:EA = 1:1) to afford 228A (150 mg, 51.1% yield) as a white oil.

[0481] Step 2: 228A (150 mg) was dissolved in THF / HO (5 mL / 2 mL), and LiOH (50 mg, 0.2 w / w) was added. The mixture was stirred at room temperature for 16 h. After the reaction was complete, the mixture was filtered, and the filtrate was spun dry. Purification by flash column chromatography (PE:EA = 1:1) afforded white solid 228B (120 mg, 83.3% yield).

[0482] Step 3: 228B (120 mg, 0.40 mmol, 1.0 eq), 1-(3-(trifluoromethyl)phenyl)piperazine (144b) (138 mg, 0.60 mmol, 1.5 eq), HATU (305 mg, 0.80 mmol, 2.0 eq), and DIPEA (129 mg, 1.00 mmol, 2.5 eq) were dissolved in DCM (5 mL). The mixture was stirred at room temperature for 16 h. After the reaction was complete, the mixture was extracted with water (20 mL) and dichloromethane (5 mL). The organic phase was spin-dried and purified using a reverse-phase column (0.1% FA / HO:MeOH = 30:70). The resulting fraction was freeze-dried to give 228 (40 mg, 19.6% yield) as a white solid. LCMS: 511 [M+H] + 1H NMR (400MHz,DMSO-d6) δ 8.43 (s,1H),7.61-7.59 (m,1H),7.45-7.41 (m,1H) ,7.39-7.36 (m,2H),7.33-7.31 (m,1H),7.24 (d,1H),7.18 (s,1H),7.09 (d,1H),3.98 (t,2H),3.61-3.58(m,4H),3.28-3.25 (m,2H),3.21-3.19 (m,2H),2.55-2.53 (m,2H),2.46(t,2H),2.31(t,2H),2.17-2.09 (m,2H),2.01-1.94 (m,2H).

[0483] Example 139: Synthesis of 8-methoxy-2-(4-oxo-4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)butyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,4-c]quinolin-4-one [ka]

[0484] Step 1: A 100 mL single-neck flask was charged with 229a (0.2 g, 0.791 mmol, 1.0 eq.), tert-butyl 4-bromobutyrate (0.26 g, 1.19 mmol, 1.5 eq.), triethylamine (0.4 g, 3.96 mmol, 5.0 eq.), and acetonitrile (15 mL), and the mixture was reacted at 60 °C for 24 h. After the reaction was completed, the crude product was purified by column chromatography (eluent: DCM:MeOH = 96:4). The product components were collected and concentrated to give a whitish-brown solid 229A (0.4 g, crude product was initially purified and used directly in the next step).

[0485] Step 2: 229A (0.4 g, 0.791 mmol, 1.0 eq.) and HCl in 1,4-dioxane (5 mL, 4 mol / L) were added to a 100 mL one-neck flask and reacted at room temperature for 1 h. After the reaction was complete, the mixture was filtered and the filter cake was washed with 1,4-dioxane to give a white solid 229B (0.18 g, 67.1% yield).

[0486] Step 3: In a 100 mL single-neck flask, add 229B (0.18 g, 0.571 mmol, 1.0 eq.), 1-(3-trifluoromethylphenyl)piperazine hydrochloride (144b) (0.21 g, 0.797 mmol, 1.5 eq.), HATU (0.3 g, 0.797 mmol, 1.5 eq.), anhydrous DMF (5 mL), and DIPEA (0.34 g, 2.66 mmol, 5.0 eq.) and react at room temperature for 1 h. The reaction mixture was initially purified by reverse-phase column chromatography (eluent: 0.5‰ formic acid in water:methanol = 51:49), and the resulting crude product was purified by preparative chromatography (eluent: 0.5‰ formic acid in water:methanol = 44:56). The product components were collected, evaporated to dryness, and freeze-dried to give a white solid 229 (0.08 g, yield: 27.1%). LCMS:515 [M+1] + 1 H NMR (400MHz,CDCl3): 11.79 (s,1H),7.38-7.34 (m,2H),7.15-7.10 (m,3H),7.07-7.05 (m,1H),6.77 (d,1H),4.41 (s,2H),4.23 (s,2H),3.85 (s,3H),3.82-3.80 (m,2H),3.69-3.67 (m,2H),3.24-3.21 (m,4H),3.04 (t,2H),2.57 (t,2H),2.10-2.04 (m,2H).

[0487] Example 140: Synthesis of 2-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-oxopropyl)-8-methoxy-1,2,3,5-tetrahydro-4H-pyrrolo[3,4-c]quinolin-4-one [ka]

[0488] Step 1: A 100 mL single-neck flask was charged with 229a (crude, 0.665 mmol, 1.0 eq.), tert-butyl 3-bromopropionate (0.21 g, 0.998 mmol, 1.5 eq.), triethylamine (0.27 g, 2.66 mmol, 4.0 eq.), and acetonitrile (15 mL), and the mixture was reacted at 60 °C for 24 h. After the reaction was completed, the crude product was purified by column chromatography (eluent: DCM:MeOH = 95:5). The collected product was concentrated to give a whitish-brown solid 230A (0.33 g, crude product was initially purified and used directly in the next step).

[0489] Step 2: 230A (0.33 g, 0.665 mmol, 1.0 eq.) and HCl in 1,4-dioxane (5 mL, 4 mol / L) were added to a 100 mL one-neck flask and reacted at room temperature for 1 h. After completion of the reaction, the crude product 230B was obtained as a pale yellow solid, which was used directly in the next step.

[0490] Step 3: A 100 mL single-neck flask was charged with 230B (crude, 0.831 mmol, 1.0 eq.), 1-(2,3-dichlorophenyl)piperazine hydrochloride (145b) (0.33 g, 1.25 mmol, 1.5 eq.), HATU (0.48 g, 1.25 mmol, 1.5 eq.), anhydrous DMF (5 mL), and DIPEA (0.54 g, 4.16 mmol, 5.0 eq.) and allowed to react at room temperature for 1 h. The reaction mixture was initially purified by reverse-phase column chromatography (eluent: 0.5% aqueous formic acid:methanol = 55:45). The crude product was then purified by preparative chromatography (eluent: 1% aqueous formic acid:methanol = 43:57). The product was collected, evaporated to dryness, and lyophilized to give 230 (0.05 g, 11.9% yield) as a pale yellow solid. LCMS:501 [M+1] + 1H NMR (400MHz,DMSO-d6): 11.62 (s,1H),7.35-7.30 (m,3H),7.16-7.13 (m,2H),6.96 (d,1H),4.21-4.20 (m,2H),3.88-3.86 (m,2H),3.79 (s,3H),3.70-3.63 (m,4H),3.01-2.93 (m,6H),2.68-2.64 (m,2H).

[0491] Example 141: Synthesis of 3-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-4-oxobutyl)-8-methoxy-3,5-dihydro-4H-imidazol[4,5-c]quinolin-4-one [ka]

[0492] Step 1: A 250 mL three-neck flask was charged with 216a (1.11 g, 0.0054 mol, 1.0 eq.), tert-butyl 4-bromobutyrate (1.7 g, 0.0108 mol, 2.0 eq.), cesium carbonate (3.53 g, 0.0108 mol, 2.0 eq.), DIPEA (1 mL), and DMF (20 mL) and stirred at 80 °C overnight. After the reaction was completed, the product was purified by column chromatography eluting with 20:80 EtOAc:PE. After concentration under reduced pressure, yellow oil 231A (1.1 g, yield: 61.45%) was obtained.

[0493] Step 2: A 250 mL three-neck flask was charged with 231A (1.1 g, 0.0033 mol, 1.0 eq.), 201A (1.38 g, 0.0049 mol, 1.5 eq.), Pd-118 (0.2 g, 0.00033 mol, 0.1 eq.), potassium carbonate (0.91 g, 0.0066 mol, 2.0 eq.), dioxane (20 mL), and water (5 mL) and stirred overnight at 100 °C under nitrogen gas protection. The reaction was then purified by silica gel column chromatography. The product was eluted with 20:80 EtOAc:PE. After concentration, 231B (1.24 g, 93.23% yield) was obtained as a yellow oil.

[0494] Step 3: 231B (1.24 g, 0.003 mol, 1.0 eq.), zinc powder (1.95 g, 0.03 mol, 10.0 eq.), saturated aqueous NH4Cl (1.2 mL), and EtOH (10 mL) were added to a 100 mL three-neck flask and stirred overnight at 85 °C. After the reaction was completed, the mixture was filtered, and the filtrate was spin-dried to give crude 231C (0.5 g).

[0495] Step 4: 231C (0.5 g) and HCl / 1,4-dioxane solution (1 M, 10 mL) were added to a 50 mL three-neck flask and stirred overnight at room temperature. After the reaction was complete, the product was purified by reverse-phase column chromatography. The desired fraction was collected and spin-dried to give 231D (0.1 g, 27.03% yield) as a white solid.

[0496] Step 5: A 100 mL three-neck flask was charged with 231D (0.1 g, 0.35 mmol, 1.0 eq.), 2,3-dichlorophenylpiperazine hydrochloride (145b) (0.096 g, 0.42 mmol, 1.2 eq.), HATU (0.16 g, 0.42 mmol, 1.2 eq.), DIPEA (0.3 mL), and DCM (5 mL) and stirred overnight at room temperature. After the reaction was complete, the product was purified by reverse-phase column chromatography (RPC) eluting with MeOH / HO. The desired fraction was collected and lyophilized to give 231 (0.008 g, 4.44% yield) as a white solid. LCMS:514 [M+1]+ 1 H NMR (500MHz,DMSO-d6) δ 11.57 (s,1H),8.27 (s,1H),7.50 (d,1H),7.36-7.29 (m,3H),7.10-7.05 (m,2H),4.50 (t,2H),3.83 (s,3H),3.57-3.54 (m,4H),2.92-2.88 (m,4H),2.38 (t,2H),2.15-2.09 (m,2H).

[0497] Example 142: Synthesis of 2-methyl-N-(3-(4-(3-trifluoromethylphenyl)piperazin-1-yl)propyl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazine-7-carboxamide formate [ka]

[0498] A reaction flask was charged with 232a (50 mg, 0.20 mmol, 1.0 eq.), DMF (2 mL), and HATU (93 mg, 0.24 mmol, 1.2 eq.) and stirred at room temperature for 30 min. 3-(4-(3-trifluoromethylphenyl)piperazin-1-ylpropylamine (232b) (72 mg, 0.22 mmol, 1.1 eq.) and DIPEA (78 mg, 0.61 mmol, 3.0 eq.) were then added. The mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography (eluent: 0.1% formic acid in MeOH = 46%). The target product was collected and concentrated under reduced pressure to give 232 (40 mg, 38.31% yield) as a white solid. LCMS: 517 [M+H]+ 1 H NMR (400MHz,DMSO-d6) δ 8.16 (s,1H),8.03 (t,0.73 H),7.77 (t,0.23 H),7.41 (t,1H),7.26-7.11 (m,2H),7.06 (d,1H),6.81 (s,0.25 H),6.71 (s,0.76 H),6.56 (t,1H),6.47 (d,0.25 H),6.38 (d,0.77 H),4.06-3.99 (m,1H),3.92-3.78 (m,2H),3.35-2.94 (m,8H),2.63-2.54 (m,4H),2.47 (t,1H),2.40-2.31 (m,2H),2.17 (s,3H),1.87-1.79 (m,1H),1.71-1.57 (m,4H),1.54-1.43 (m,1H).

[0499] Example 143: Synthesis of N-(2-4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-2-methyl-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazine-7-carboxamide [ka]

[0500] Step 1: A reaction flask was charged with 233a (4.50 g, 29.41 mmol, 1.0 eq.), MeCN (100 mL), 4-bromobut-2-enoic acid methyl ester (11.35 g, 58.82 mmol, 2.0 eq.), potassium carbonate (12.18 g, 88.24 mmol, 3.0 eq.), and potassium iodide (976 mg, 5.88 mmol, 0.2 eq.). The mixture was stirred at 85 °C overnight. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was added to silica gel, concentrated, and purified by column chromatography (eluent: ethyl acetate:petroleum ether = 45%). The target component was collected and concentrated under reduced pressure to give 233A (7.3 g, yield: 93.66%) as a white solid.

[0501] Step 2: A reaction flask was charged with 233A (7.30 g, 27.55 mmol, 1.0 eq.), acetic acid (100 mL), iron powder (9.26 g, 165.28 mmol, 6.0 eq.), potassium carbonate (12.18 g, 88.24 mmol, 3.0 eq.), and potassium iodide (976 mg, 5.88 mmol, 0.2 eq.). The mixture was stirred at 120 °C for 30 min. After cooling, the reaction mixture was extracted three times with ethyl acetate. The organic phase was washed with aqueous sodium bicarbonate and concentrated to give crude 233B (10.0 g) as a black oil.

[0502] Step 3: A reaction flask was charged with 233B (1.26 g, 5.36 mmol, 1.0 eq.), DMF (10 mL), DIPEA (2.07 g, 16.09 mmol, 3.0 eq.), and 1-bromo-3-chloropropane (1.68 g, 10.72 mmol, 2.0 eq.). The mixture was stirred at 80 °C overnight. After cooling, the reaction mixture was added with water and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. After addition of silica gel, the mixture was concentrated and purified by column chromatography (eluent: ethyl acetate:petroleum ether = 12%). The target component was collected and concentrated under reduced pressure to give 233C (635 mg, yield: 39.87%) as a white solid.

[0503] Step 4: A reaction flask was charged with 233C (635 mg, 2.042 mmol, 1.0 eq.) and anhydrous tetrahydrofuran (20 mL). The mixture was purged with nitrogen gas and cooled to -78 °C. LiHMDS (1 M) (13.2 mL, 6.5 eq.) was added and the mixture was allowed to warm to room temperature for 4 h. The reaction mixture was quenched by adding water dropwise and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, added to silica gel, concentrated, and purified by column chromatography (eluent: ethyl acetate:petroleum ether = 20%). The target component was collected and concentrated under reduced pressure to give 233D (300 mg, yield: 47.24%) as a white solid.

[0504] Step 5: A reaction flask was charged with 233D (300 mg, 1.09 mmol, 1.0 eq.), tetrahydrofuran (3 mL), water (1 mL), and lithium hydroxide (79 mg, 3.27 mmol, 3.0 eq.). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and then water (5 mL) was added. 2M HCl was added dropwise until no more white solid precipitated. The mixture was filtered and dried to give 232a (250 mg, 92.77% yield) as a white solid.

[0505] Step 6: A reaction flask was charged with 232a (50 mg, 0.20 mmol, 1.0 eq.), DMF (2 mL), and HATU (93 mg, 0.24 mmol, 1.2 eq.) and stirred at room temperature for 30 min. 2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethan-1-amine (233b) (123 mg, 0.44 mmol, 1.2 eq.) and DIPEA (78 mg, 0.61 mmol, 3.0 eq.) were then added. The mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography (eluent: 0.1% formic acid in water: MeOH = 46%). The target component was collected and concentrated under reduced pressure to give 233 (30 mg, yield: 29.58%) as a white solid. LCMS:503 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 7.97 (t,1H),7.37-7.25 (m,2H),7.14 (dd,1H),6.71 (s,1H),6.54 (d,1H),6.39 (d,1H),4.16(dd,1H),3.91-3.84 (m,2H),3.35-3.30 (m,2H),3.16-3.13 (m,2H),2.98 (br,4H),2.61-2.54 (m,4H),2.43 (t,2H),2.24-2.19 (m,1H),2.17 (s,3H),1.86-1.80 (m,1H),1.72-1.60 (m,2H),1.54-1.44 (m,1H).

[0506] Example 144: Synthesis of N-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)-2-methyl-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazine-7-carboxamide formate [ka]

[0507] The same synthetic route as in Example 143 was employed, except that 233b in Step 6 of Example 143 was replaced with 234b, to give the title compound 234 (white solid). LCMS: 517 [M+H]+ 1 H NMR (400MHz,DMSO-d6) δ 8.14 (s,1H),8.05 (t,1H),7.31 (d,2H),7.17-7.11 (m,1H),6.81 (s,0.23 H),6.72 (s,0.74 H),6.58 (d,1H),6.55 (d,0.24 H),6.39 (d,0.75 H),4.02 (dd,1H),3.91-3.82 (m,2H),3.22-3.08 (m,4H),3.06-2.96 (m,4H),2.67-2.57 (m,6H),2.48-2.43 (m,1H),2.17 (s,3H),1.87-1.76 (m,1H),1.72-1.57 (m,4H),1.55-1.46 (m,1H).

[0508] Example 145: Synthesis of 2-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)-8-methoxy-1,2,3,5-tetrahydro-4H-pyrrolo[3,4-c]quinolin-4-one [ka]

[0509] Step 1: A 250 mL single-neck flask was charged with 235a (2 g, 7.17 mmol, 1.0 eq.), 10% Pd / C (0.3 g, 15% w / w), and ethyl acetate (80 mL). The mixture was hydrogenated under atmospheric pressure and reacted at room temperature for 16 h. After completion of the reaction, the mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated to give 235A, which was used directly in the next step.

[0510] Step 2: A 250 mL single-neck flask was charged with 235A (crude, 7.71 mmol, 1.5 eq.), 235b (2 g, 5.14 mmol, 1.0 eq.), Pd(dppf)Cl-DCM (0.84 g, 1.03 mmol, 0.2 eq.), sodium carbonate (1.63 g, 15.4 mmol, 3.0 eq.), 1,4-dioxane (100 mL), and water (10 mL). The mixture was reacted at 100 °C for 16 h under nitrogen gas protection. After completion of the reaction, the mixture was filtered. The filter cake was washed with DCM. The filtrate was concentrated, and the crude product was purified by silica gel column chromatography (eluent: DCM:MeOH = 97:3). The solvent was evaporated to dryness to give 235B (0.7 g, yield: 43.0%) as a brown solid.

[0511] Step 3: A 100 mL single-neck flask was charged with 235B (0.7 g, 2.22 mmol, 1.0 eq.) and a 1,4-dioxane solution of HCl (7 mL, 4 mol / L) and the mixture was allowed to react at room temperature for 1 h. After the reaction was complete, the mixture was filtered. The filter cake was washed with 1,4-dioxane and dried to give a light brown solid, 235C (0.45 g, 80.2% yield).

[0512] Step 4: A 100 mL single-neck flask was charged with 235C (0.25 g, 0.989 mmol, 1.0 eq.), 1-(3-bromopropyl)-4-(2,3-dichlorophenyl)piperazine (235c) (0.7 g, 1.98 mmol, 2.0 eq.), triethylamine (0.5 g, 4.95 mmol, 5.0 eq.), and acetonitrile (15 mL). The reaction was allowed to proceed at 60 °C for 16 h. After completion of the reaction, the mixture was filtered, washed with acetonitrile, and then added to DMSO (10 mL). The mixture was stirred for 30 min and then filtered. The filter cake was washed with DMSO and methanol, and dried to give 235 (0.12 g, 24.9% yield) as a white solid. LCMS:487 [M+1] + 1H NMR (400MHz,CDCl3): 11.81 (s,1H),7.44 (d,1H),7.22-7.16 (m,3H),7.03 (dd,1H),6.83-6.82 (m,1H),4.30-4.28 (m,2H),4.16-4.14 (m,2H),3.90 (s,3H),3.17 (br,4H),2.93 (t,2H),2.77-2.64 (m,6H),1.97-1.92 (m,2H).

[0513] Experimental example Experimental Example 1. Pharmacodynamics experiment (TPK enzyme activity test) 1.1 Purpose of the experiment The purpose of this experiment was to test the promoting effect of compounds on TPK enzyme activity and to evaluate the EC 50 and E max The objective of this study is to evaluate the in vitro activity of compounds based on the above method.

[0514] 1.2 Experimental Method 1.2.1 Experimental materials

[0515] [Table 4]

[0516] 1.2.2 Experimental steps 1.1). Preheat the thermostatic water bath shaker half an hour in advance to a preheat temperature of 37°C.

[0517] 1.2). Take the stock solution of the compound to be tested, leave it at room temperature to dissolve, and dilute it to the desired concentration.

[0518] 1.3). Place the desired reagent on ice and allow to dissolve.

[0519] 2.1) Each reaction system required the addition of TPK enzyme solution, Tris-HCl buffer solution, and ATP solution. The ATP used ranged from 1 to 500 mM, and the above three solutions were mixed to form a homogeneous mixture.

[0520] 2.2) The above three mixtures were dispensed into centrifuge tubes, and the desired concentrations of compounds were added to each tube. Finally, thiamine solution (1-100 μM) was added to each tube. After the above additions were completed, the centrifuge tubes were tightly capped, inserted into a floating plate, and placed in a 37°C water bath shaker for 0.5-2.0 hours of incubation.

[0521] 2.3). After the incubation, perchloric acid stop solution was added and mixed well, and the sample was collected in a 1.5 mL centrifuge tube and stored at -20°C.

[0522] 3.1). The sample stored at -20°C was taken out and dissolved at room temperature, and then derivatized. The sample was placed in a centrifuge tube, and potassium ferricyanide derivatization reagent was added to it. Finally, phosphoric acid stop solution was added to stop the reaction.

[0523] 3.2). The derivatized sample was placed in a liquid chromatography analysis sample bottle and the TDP / thiamine content was detected by high performance liquid chromatography. TPK enzyme activity = TDP (nM) / mg protein / min.

[0524] 1.3 Experimental results According to the above procedure, the effect of the compound of the present invention on TPK enzyme activity at different concentrations was measured, and E max (Calculated assuming the effect of DMSO on TPK enzyme activity as 100%) and EC 50 The data is shown in the following table.

[0525] [Table 5-1] [Table 5-2] [Table 5-3]

[0526] [Table 6-1] [Table 6-2] [Table 6-3]

[0527] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) is hereby incorporated by reference in its entirety.

Claims

1. 1. A method for preventing or treating a neurodegenerative disease or alleviating a symptom of a neurodegenerative disease, comprising administering to an individual in need thereof a prophylactically or therapeutically effective amount of a thiamine pyrophosphokinase (TPK) agonist; Preferably, the neurodegenerative disease is Alzheimer's disease; More preferably, the Alzheimer's disease is Alzheimer's disease in which the individual has reduced TPK enzyme activity, reduced TPK expression levels, and / or reduced TDP levels; wherein the TPK agonist is a compound of Formula (I)-I, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof; 【Chemical 1】 Preferably, the TPK agonist is a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof: 【Chemistry 2】 where: A and B are independently CR ３ or N, Ring C and ring D are each independently C ３－１０ Hydrocarbon rings (e.g., C ３－６ hydrocarbon ring), 3- to 10-membered heterocyclic ring, C ６－１０ an aromatic ring or a 5- to 14-membered heteroaromatic ring, preferably, ring C is a 5- or 6-membered heteroaromatic ring; L １ , L ２ and L ３ are not present independently, or —O—, —C(═O)—, —C(═O)O—, —NR—, —C(═O)NR—, —(S═O)NR—, —S(═O) ２ NR-, -S-, -S(=O)-, -S(=O) ２ -, -C １－６ Alkylene-, -C ２－６ Alkenylene-, -C ２－６ Alkynylene-, -C ３－６ Cycloalkylene-, -(3- to 10-membered heterocyclylene)-, -C ６－１０ Arylene-, -(5- to 14-membered heteroarylene)-, -W-C １－６ Alkylene-, -C １－６ Alkylene -W- and -W-C １－６ alkylene-W′—, wherein said alkylene group is optionally further interrupted by one or more W, provided that L １ , L ２ and L ３ At least one of W and W' each independently represent -O-, -C(=O)-, -C(=O)O-, -NR-, -C(=O)NR-, -(S=O)NR-, or -S(=O) ２ NR-, -S-, -S(=O)- and -S(=O) ２ - is selected from, R １ each occurrence independently represents a halogen, —OH, or —NH ２ , -CN, -NO ２ , C １－６ Alkyl group, halo C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－６ Cyclic hydrocarbon group, 3- to 10-membered heterocyclyl group, C ６－１０ aryl group, 5- to 14-membered heteroaryl group, C ６－１２ Aralkyl group, —C(═O)R ａ , —OC(═O)R ａ , -C(=O)OR ａ , -OR ａ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ａ R ｂ , -NR ａ R ｂ , —C(═O)NR ａ R ｂ , -NR ａ -C(=O)R ｂ , -NR ａ -C(=O)OR ｂ , -NR ａ -S(=O) ２ -R ｂ , -NR ａ —C(═O)—NR ａ R ｂ , -C １－６ Alkylene-OR ａ , -C １－６ Alkylene -NR ａ R ｂ and-O-C １－６ Alkylene -NR ａ R ｂ is selected from R ２ and R ３ each occurrence independently represents H, a halogen, —OH, or —NH ２ , -CN, -NO ２ , C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－６ Cyclic hydrocarbon group, 3- to 10-membered heterocyclyl group, C ６－１０ aryl group, 5- to 14-membered heteroaryl group, C ６－１２ Aralkyl group, —C(═O)R ａ , —OC(═O)R ａ , -C(=O)OR ａ , -OR ａ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ａ R ｂ , -NR ａ R ｂ , —C(═O)NR ａ R ｂ , -NR ａ -C(=O)R ｂ , -NR ａ -C(=O)OR ｂ , -NR ａ -S(=O) ２ -R ｂ , -NR ａ —C(═O)—NR ａ R ｂ , -C １－６ Alkylene-OR ａ , -C １－６ Alkylene -NR ａ R ｂ and-O-C １－６ Alkylene -NR ａ R ｂ is selected from R, R ａ and R ｂ are independently H, C each time they appear. １－６ Alkyl group, C ３－１０ Cyclic hydrocarbon group, 3- to 10-membered heterocyclyl group, C ６－１０ Aryl groups, 5- to 14-membered heteroaryl groups and C ６－１２ aralkyl groups, n is 0, 1, 2, 3 or 4, preferably n is 0, 1 or 2; The alkyl group, alkylene group, alkenyl group, alkenylene group, alkynyl group, alkynylene group, cyclic hydrocarbon group, cycloalkylene group, hydrocarbon ring, heterocyclyl group, heterocyclylene group, heterocycle, aryl group, arylene group, aromatic ring, heteroaryl group, heteroarylene group, heteroaromatic ring and aralkyl group each appearing optionally and independently represent halogen, —OH, ═O, —NH ２ , -CN, -NO ２ , C １－６ Alkyl group, halo C １－６ Alkyl group, C ３－６ Cyclic hydrocarbon group, 3- to 10-membered heterocyclyl group, C ６－１０ aryl group, 5- to 14-membered heteroaryl group, C ６－１２ Aralkyl group, —C(═O)R ｃ , —OC(═O)R ｃ , -C(=O)OR ｃ , -OR ｃ , -SR ｃ , -S(=O)R ｃ , -S(=O) ２ R ｃ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , —C(═O)NR ｃ R ｄ , -NR ｃ -C(=O)R ｄ , -NR ｃ -C(=O)OR ｄ , -NR ｃ -S(=O) ２ -R ｄ , -NR ｃ —C(═O)—NR ｃ R ｄ , -C １－６ Alkylene-OR ｃ , -C １－６ Alkylene -NR ｃ R ｄ and-O-C １－６ Alkylene -NR ｃ R ｄ and wherein the alkyl group, alkylene group, cyclic hydrocarbon group, heterocyclyl group, aryl group, heteroaryl group and aralkyl group are further optionally independently substituted with one or more substituents selected from halogen, —OH, ═O, —C(═O)O-tert-butyl group, —NH ２ , -CN, -NO ２ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－６ Cyclic hydrocarbon group, 3- to 10-membered heterocyclyl group, C ６－１０ aryl group, 5- to 14-membered heteroaryl group, C ６－１２ aralkyl group, —O—C １－６ Alkyl group and -C １－６ Alkylene -O-C １－６ substituted with one or more substituents selected from alkyl groups, and R ｃ and R ｄ are independently H, C each time they appear. １－６ Alkyl group, C ３－１０ Cyclic hydrocarbon group, 3- to 10-membered heterocyclyl group, C ６－１０ Aryl groups, 5- to 14-membered heteroaryl groups and C ６－１２ and aralkyl groups, wherein the alkyl groups, cyclic hydrocarbon groups, heterocyclyl groups, aryl groups, heteroaryl groups and aralkyl groups may further optionally independently be selected from the group consisting of halogen, —OH, ═O, —C(═O)O-tert-butyl, —NH ２ , -CN, -NO ２ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－６ Cyclic hydrocarbon group, 3- to 10-membered heterocyclyl group, C ６－１０ aryl group, 5- to 14-membered heteroaryl group, C ６－１２ Aralkyl group and -C １－６ Alkylene -O-C １－６ substituted with one or more substituents selected from alkyl groups.

2. 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; 【Chemistry 3】 where: X is -C(R) ２ X is -, -NR-, -O- or -S-, preferably X is -NR-, -O- or -S-, more preferably X is -NH-, -N(CH ３ ) —, —O—, or —S—, and 2. The method of claim 1, wherein each remaining group is as defined in claim 1. 【Request 3】 【Chemical 4】 teeth, 【Chemistry 5】 The method of claim 1, wherein

4. R ３ is independently H or C each time it occurs. １－６ an alkyl group (preferably a methyl group), Preferably, A and B are each independently CH, CCH ３ or N, and More preferably, A is N and B is CH.

5. L １ and L ３ are each independently absent, or are each independently —C(═O)—, —N(CH ３ ) -, -C １－６ Alkylene-, -W-C １－６ Alkylene- or -C １－６ alkylene-W-, wherein the alkylene group is optionally further interrupted by one or more W; and W is -O-, -C(=O)-, -C(=O)O-, -NH-, -N(CH ３ )-, -C(=O)NH- or -C(=O)N(CH ３ 5. The method according to claim 1, wherein

6. L ２ is absent or is -(3- to 10-membered heterocyclylene)-; Preferably, L ２ The method of any one of claims 1 to 5, wherein is absent or is a piperazinylene group or a piperidinylene group. 【Request 7】 【Chemical 6】 teeth, 【Chemistry 7】 7. The method according to claim 1, wherein

8. R １ Each occurrence independently represents a halogen, —CN, C １－６ Alkyl group, halo C １－６ Alkyl group and C １－６ alkoxy groups, Preferably, R １ each occurrence independently represents —F, —Cl, —Br, —CN, or —CH ３ , -CF ３ and -OCH ３ The method according to any one of claims 1 to 7, wherein the compound is selected from the group consisting of:

9. R ２ are independently H, C １－６ Alkyl group, C ６－１０ aryl groups and 5- to 14-membered heteroaryl groups, said groups optionally independently selected from halogen, —OH, —NH ２ , -CN, -NO ２ , C １－６ Alkyl group, halo C １－６ alkyl group, —N(C １－６ alkyl) ２ , C １－６ Alkoxy group, halo C １－６ Alkoxy group, —C(═O)—C １－６ Alkyl group, —C(═O)OH, —C(═O)O—C １－６ Alkyl group, —S—C １－６ Alkyl group, —S(═O) ２ -C １－６ Alkyl group, —S(═O) ２ -(3- to 10-membered heterocyclyl group), -S(=O) ２ NH ２ and -C(=O)NH ２ and is substituted with one or more substituents selected from Preferably, R ２ are independently an isopropyl group, 【Chemistry 8】 9. The method of claim 1, wherein the compound is selected from the group consisting of:

10. the TPK agonist is a compound of formula (III) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof; 【Chemistry 9】 10. The method of any one of claims 1 to 9, wherein each group is as defined in any one of claims 1 to 9.

11. 1. A method for preventing or treating a neurodegenerative disease or alleviating a symptom of a neurodegenerative disease, comprising administering to an individual in need thereof a prophylactically or therapeutically effective amount of a thiamine pyrophosphokinase (TPK) agonist; Preferably, the neurodegenerative disease is Alzheimer's disease; More preferably, the Alzheimer's disease is Alzheimer's disease in which the individual has reduced TPK enzyme activity, reduced TPK expression levels, and / or reduced TDP levels; wherein the TPK agonist is a compound of formula (IV) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof; 【Chemistry 10】 where: Ring D is absent or C ３－６ Hydrocarbon ring, 3- to 10-membered heterocycle, C ６－１０ an aromatic ring or a 5- to 14-membered heteroaromatic ring; L ４ -O-, -C(=O)-, -C(=O)O-, -NR'-, -C(=O)NR'-, -(S=O)NR'-, -S(=O) ２ NR'-, -S-, -S(=O)-, -S(=O) ２ -, -C １－６ Alkylene-, -C ２－６ Alkenylene-, -C ２－６ Alkynylene-, -C ３－６ Cycloalkylene-, -(3- to 10-membered heterocyclylene)-, -C ６－１０ Arylene-, -(5- to 14-membered heteroarylene)-, -U-C １－６ Alkylene-, -C １－６ Alkylene-U-, -U-C １－６ Alkylene -U'- and -C １－６ Alkylene-U-C １－６ alkylene-, wherein said alkylene group is optionally further interrupted by one or more U; U and U' each independently represent -O-, -C(=O)-, -C(=O)O-, -NR'-, -C(=O)NR'-, -(S=O)NR'-, or -S(=O) ２ NR'-, -S-, -S(=O)- and -S(=O) ２ - is selected from, R ４ , R ４’ , R ５ , R ５’ , R ６ and R ７ each occurrence independently represents H, a halogen, —OH, or —NH ２ , -CN, -NO ２ , C １－６ Alkyl group, halo C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－６ Cyclic hydrocarbon group, 3- to 10-membered heterocyclyl group, C ６－１０ aryl group, 5- to 14-membered heteroaryl group, C ６－１２ Aralkyl group, —C(═O)R ｅ , -OC(=O)R ｅ , -C(=O)OR ｅ , -OR ｅ , -SR ｅ , -S(=O)R ｅ , -S(=O) ２ R ｅ , -S(=O) ２ NR ｅ R ｆ , -NR ｅ R ｆ , —C(═O)NR ｅ R ｆ , -NR ｅ -C(=O)R ｆ , -NR ｅ -C(=O)OR ｆ , -NR ｅ -S(=O) ２ -R ｆ , -NR ｅ —C(═O)—NR ｅ R ｆ , -C １－６ Alkylene-OR ｅ , -C １－６ Alkylene -NR ｅ R ｆ , —O—C １－６ Alkylene -NR ｅ R ｆ and -C １－６ Alkylene-OC(=O)-C １－６ Alkylene -C(=O)OR ｅ or R ４ and R ４’ or R ５ and R ５’ together form =O, or R ４ , R ４’ , R ５ , R ５’ together with the groups to which they are attached form C ３－６ Hydrocarbon ring, 3- to 10-membered heterocycle, C ６－１０ constitutes an aromatic ring or a 5- to 14-membered heteroaromatic ring, R', R ｅ and R ｆ are independently H, C each time they appear. １－６ Alkyl group, C ３－１０ Cyclic hydrocarbon group, 3- to 10-membered heterocyclyl group, C ６－１０ Aryl groups, 5- to 14-membered heteroaryl groups and C ６－１２ aralkyl groups, p and q are each independently 1, 2, 3, or 4, preferably p and q are each independently 1 or 2, with the proviso that if Ring D is absent, then q is 1; The alkyl group, alkylene group, alkenyl group, alkenylene group, alkynyl group, alkynylene group, cyclic hydrocarbon group, cycloalkylene group, hydrocarbon ring, heterocyclyl group, heterocyclylene group, heterocycle, aryl group, arylene group, aromatic ring, heteroaryl group, heteroarylene group, heteroaromatic ring and aralkyl group each appearing optionally and independently represent halogen, —OH, ═O, —NH ２ , -CN, -NO ２ , C １－６ Alkyl group, halo C １－６ Alkyl group, C ３－６ Cyclic hydrocarbon group, 3- to 10-membered heterocyclyl group, C ６－１０ aryl group, 5- to 14-membered heteroaryl group, C ６－１２ Aralkyl group, —C(═O)R ｇ , —OC(═O)R ｇ , -C(=O)OR ｇ , -OR ｇ , -SR ｇ , -S(=O)R ｇ , -S(=O) ２ R ｇ , -S(=O) ２ NR ｇ R ｈ , -NR ｇ R ｈ , —C(═O)NR ｇ R ｈ , -NR ｇ -C(=O)R ｈ , -NR ｇ -C(=O)OR ｈ , -NR ｇ -S(=O) ２ -R ｈ , -NR ｇ —C(═O)—NR ｇ R ｈ , -C １－６ Alkylene-OR ｇ , -C １－６ Alkylene -NR ｇ R ｈ and-O-C １－６ Alkylene -NR ｇ R ｈ and wherein the alkyl group, alkylene group, cyclic hydrocarbon group, heterocyclyl group, aryl group, heteroaryl group and aralkyl group are further optionally independently substituted with one or more substituents selected from halogen, —OH, ═O, —C(═O)O-tert-butyl group, —NH ２ , -CN, -NO ２ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－６ Cyclic hydrocarbon group, 3- to 10-membered heterocyclyl group, C ６－１０ aryl group, 5- to 14-membered heteroaryl group, C ６－１２ aralkyl group, —O—C １－６ Alkyl group and -C １－６ Alkylene -O-C １－６ substituted with one or more substituents selected from alkyl groups, and R ｇ and R ｈ are independently H, C each time they appear. １－６ Alkyl group, C ３－１０ Cyclic hydrocarbon group, 3- to 10-membered heterocyclyl group, C ６－１０ Aryl groups, 5- to 14-membered heteroaryl groups and C ６－１２ and aralkyl groups, wherein the alkyl groups, cyclic hydrocarbon groups, heterocyclyl groups, aryl groups, heteroaryl groups and aralkyl groups may further optionally independently be selected from the group consisting of halogen, —OH, ═O, —C(═O)O-tert-butyl, —NH ２ , -CN, -NO ２ , C １－６ Alkyl group, C １－６ Haloalkyl group, C ３－６ Cyclic hydrocarbon group, 3- to 10-membered heterocyclyl group, C ６－１０ aryl group, 5- to 14-membered heteroaryl group, C ６－１２ Aralkyl group and -C １－６ Alkylene -O-C １－６ substituted with one or more substituents selected from alkyl groups.

12. The TPK agonist is a compound of formula (V) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof: 【Chemistry 11】 12. The method of claim 11, wherein each group is as defined in claim 11.

13. L ４ is -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ６ -, -(CH ２ ) ３ -NH-, -(CH ２ ) ３ -O-, -(CH ２ ) ４ -O-, -(CH ２ ) ５ -O-, -(CH ２ ) ６ -O-, -C(=O)-CH ２ -, -C(=O)-(CH ２ ) ２ -, -(CH ２ ) ２ -C(=O)NH-(CH ２ ) ２ - and -CH ２ -CH(OH)-CH ２ The method according to claim 11 or 12, wherein the alkyl group is selected from -NH-.

14.

12. is -CN, -NH ２ , 【Chemistry 13】 14. The method according to any one of claims 11 to 13, wherein

15. 1. A method for preventing or treating a neurodegenerative disease or alleviating a symptom of a neurodegenerative disease, comprising administering to an individual in need thereof a prophylactically or therapeutically effective amount of a thiamine pyrophosphokinase (TPK) agonist; Preferably, the neurodegenerative disease is Alzheimer's disease; More preferably, the Alzheimer's disease is Alzheimer's disease in which the individual has reduced TPK enzyme activity, reduced TPK expression levels, and / or reduced TDP levels; wherein the TPK agonist is selected from the following compounds, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】

16. 16. The method of any one of claims 1 to 15, wherein the TPK agonist is administered in an amount of about 0.005 mg / day to about 5000 mg / day, e.g., about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 mg / day.

17. The TPK agonist is administered in an amount of about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg of body weight daily, for example, about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, about 200 μg / kg, about 22 μg / kg, or about 30 μg / kg daily. 5μg / kg, about 250μg / kg, about 275μg / kg, about 300μg / kg, about 325μg / kg, about 350μg / kg, about 375μg / kg, about 400μg / kg, about 425μg / kg, about 450 μg / kg, about 475 μg / kg, about 500 μg / kg, about 525 μg / kg, about 550 μg / kg, about 575 μg / kg, about 600 μg / kg, about 625 μg / kg, about 650 μg / kg, About 675 μg / kg, about 700 μg / kg, about 725 μg / kg, about 750 μg / kg, about 775 μg / kg, about 800 μg / kg, about 825 μg / kg, about 850 μg / kg, about 875 μg / k g, about 900 μg / kg, about 925 μg / kg, about 950 μg / kg, about 975 μg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 m 17. The method of any one of claims 1 to 16, wherein the compound is administered in an amount of about 100 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg or about 300 mg / kg of body weight.

18. 18. The method of any one of claims 1 to 17, wherein the daily dose of the TPK agonist is administered in one dose, or in two, three, or four divided doses.

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

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

21. 21. The method of any one of claims 1 to 20, wherein the TPK agonist is administered by injection (e.g., intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including drip infusion), or transdermally, or in the form of an oral, buccal, nasal, transmucosal, topical, ophthalmic formulation, or by inhalation.

22. 22. The method of any one of claims 1 to 21, wherein the TPK agonist is administered in a dosage form selected from a tablet, capsule, troche, hard candy, powder, spray, cream, ointment, suppository, gel, paste, lotion, ointment, aqueous suspension, injectable solution, elixir, and syrup.

23. 23. The method of any one of claims 1 to 22, wherein the method ameliorates the following pathophysiological symptoms in an individual: cognitive and behavioral abnormalities, neurodegenerative changes (e.g., progressive synaptic / neuron loss and brain atrophy), β-amyloid deposition, Tau abnormal phosphorylation and resulting neurofibrillary tangles, glial cell activation and inflammation, and / or impaired cerebral glucose metabolism.

24. 24. The method of any one of claims 1 to 23, further comprising administering one or more other therapeutic agents.

25. A compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein said compound has the structure of formula (III): 【Chemistry 14】 wherein each group is as defined in any one of claims 1 to 9; The condition is -L ３ -R ２ is not H and a methyl group, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof.

26. A compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein said compound is selected from the following: 【Table 2-1】 【Table 2-2】 【Table 2-3】 【Table 2-4】 【Table 2-5】 【Table 2-6】 【Table 2-7】

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